Clinical trial NCT04322539
Conditions: Metastatic Colorectal Cancer Metastatic Colon Cancer
Keywords: colon colorectal mcrc crc metastatic colon metastatic colorectal VEGF VEGFR
Sponsor: Hutchison Medipharma Limited
Start date: 2020-08-12; Completion date: 2024-04-24
Enrollment: 691 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a global, randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial to compare the efficacy and safety of fruquintinib plus best supportive care (BSC) versus placebo plus BSC in participants with refractory metastatic colorectal cancer (mCRC). 691 participants were randomized to one of the following treatment arms in a 2:1 ratio, fruquintinib plus BSC or placebo plus BSC.

Detailed description:
This is a global, randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial to compare the efficacy and safety of fruquintinib in combination with BSC versus placebo in combination with BSC in metastatic colorectal cancer participants who have progressed on, or were intolerant to, chemotherapy, anti-VEGF and anti-EGFR biologics, and TAS-102 or regorafenib. Participants with MSI-H/MMR deficient tumors must have also received an immune checkpoint inhibitor if approved and available and if deemed appropriate. Subjects with BRAF-mutant tumors must have been treated with a BRAF inhibitor if approved and available and if deemed appropriate.

Metastatic colorectal cancer cannot be cured by surgery. Therefore, treatment principals are primarily aimed at controlling disease progression and prolonging survival. Standard first- and second-line therapy includes cytotoxic drugs such as 5-fluorouracil, oxaliplatin, and irinotecan; anti-VEGF therapy; and, if RAS wild type, anti-EGFR therapy. After the first two lines of chemotherapy, standard third-line treatment is either TAS-102 or regorafenib. There are currently no effective treatments for patients who have progressed on standard, approved therapies, and treatment options include reuse of prior therapies, clinical trials or BSC. Consequently, there is an unmet medical need for additional safe and effective treatment.

Arms: arm 1: Participants will be orally administered Fruquintinib 5 mg in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break (with each cycle length of 28 days). arm 2: Participants will be orally administered Placebo 5 mg in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break (with each cycle length of 28 days).
Interventions: intervention 1: Fruquintinib intervention 2: Placebo
Intervention descriptions: intervention 1: Oral VEGFR inhibitor intervention 2: Placebo capsule

Protocol documents:
Prot_SAP_000.pdf: 




Clinical Study Protocol 2019-013-GLOB1 
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STATEMENT OF COMPLIANCE 
The study will be conducted in compliance with this clinical study protocol, Good Clinical 
Practices (GCP) as outlined by ICH E6(R2), and all applicable local and national regulatory 
requirements.  Enrollment at any clinical study site may not begin prior to that site receiving 
approval from the ethics committee of record for the protocol and all materials provided to 
potential participants. 
Any amendments to the protocol or changes to the consent document will be approved before 
implementation of that amendment.  Reconsent of previously enrolled participants may be 
necessary depending on the nature of the amendment. 
The Principal Investigator will ensure that changes to the study plan as defined by this protocol 
will not be made without prior agreement from the Sponsor and documented approval from the 
ethics committee of record, unless such a change is necessary to eliminate an immediate hazard to 
the study participants. 
All personnel involved in the conduct of this study have completed Human Patients Protection and 
GCP Training as outlined by their governing institution. 




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INVESTIGATOR’S AGREEMENT 
I have read the protocol, appendices, and accessory materials related to Study 2019-013-GLOB1 
and agree to the following: 
•
To conduct this study as described by the protocol and any accessory materials
•
To protect the rights, safety, and welfare of the participants under my care
•
To provide oversight of all personnel to whom study activities have been delegated
•
To control all investigational products provided by the sponsor and maintain records
of the disposition of those products
•
To conduct the study in accordance with all applicable local and national regulations,
the requirements of the ethics committee of record for my clinical site, and Good
Clinical Practices as outlined by ICH E6(R2).
•
To obtain approval for the protocol and all written materials provided to participants
prior to initiating the study at my site
•
To obtain informed consent – and updated consent in the event of new information or
amendments – from all participants enrolled at my study site prior to initiating any
study-specific procedures or administering investigational products to those
participants
•
To maintain records of each patient’s participation and all data required by the
protocol
Name [Last name, first name] 
Title [Title at institution] 
Institution [Address] 
Signature 
Date [DD Month YYYY] 


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TABLE OF CONTENTS 
A GLOBAL, MULTICENTER, RANDOMIZED, PLACEBO-CONTROLLED PHASE 3 
TRIAL TO COMPARE THE EFFICACY AND SAFETY OF FRUQUINTINIB 
PLUS BEST SUPPORTIVE CARE TO PLACEBO PLUS BEST SUPPORTIVE 
CARE IN PATIENTS WITH REFRACTORY METASTATIC COLON CANCER 
(FRESCO-2) ............................................................................................................... 1 
STATEMENT OF COMPLIANCE ............................................................................................... 2 
SPONSOR’S APPROVAL ............................................................................................................ 3 
INVESTIGATOR’S AGREEMENT ............................................................................................. 4 
TABLE OF CONTENTS ............................................................................................................... 5 
LIST OF TABLES ....................................................................................................................... 10 
LIST OF FIGURES ..................................................................................................................... 11 
LIST OF APPENDICES .............................................................................................................. 11 
LIST OF ABBREVIATIONS ...................................................................................................... 12 
1.
SYNOPSIS ............................................................................................................... 15 
Study Schematic ....................................................................................................... 20 
Schedule of Events ................................................................................................... 20 
Footnotes for Schedule of Events Table 1 ................................................................ 22 
Footnotes for the Schedule of Events Tables 2 and 3 ............................................... 26 
2.
INTRODUCTION .................................................................................................... 27
Background ............................................................................................................... 27 
Administration Regimen ........................................................................................... 28 
Justification for Dosing Strategy .............................................................................. 28 
Supportive Nonclinical Data ..................................................................................... 29 
Pharmacology ........................................................................................................... 29 
Metabolism and Pharmacokinetic Drug Interaction ................................................. 29 
Toxicology ................................................................................................................ 30 
Supportive Clinical Data ........................................................................................... 30 
Clinical Pharmacokinetics ........................................................................................ 30 
Clinical Safety .......................................................................................................... 31 
Benefit/Risk Assessment .......................................................................................... 33 
Risk Assessment ....................................................................................................... 33 
Benefit Assessment ................................................................................................... 33 
Overall Benefit/Risk Conclusion .............................................................................. 34 


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Study Rationale ......................................................................................................... 34 
3.
OBJECTIVES AND ENDPOINTS .......................................................................... 35 
Primary Objective ..................................................................................................... 35 
Secondary Objectives ............................................................................................... 35 
Exploratory Objectives ............................................................................................. 35 
4.
STUDY PLAN .......................................................................................................... 37 
Study Design ............................................................................................................. 37 
Enrollment in Study .................................................................................................. 37 
Rationale for the Electrocardiogram Collection and Pharmacokinetic Sampling 
Schedule .................................................................................................................... 38 
5.
POPULATION ......................................................................................................... 39
Recruitment ............................................................................................................... 39 
Definitions ................................................................................................................ 39 
Inclusion Criteria ...................................................................................................... 39 
Exclusion Criteria ..................................................................................................... 40 
6.
STUDY CONDUCT ................................................................................................. 43 
Study Procedures ...................................................................................................... 43 
Study Assessments .................................................................................................... 43 
Informed Consent ..................................................................................................... 43 
Medical History ........................................................................................................ 43 
Tumor Diagnosis and Treatment History ................................................................. 43 
Demographics ........................................................................................................... 43 
Concomitant Medication and Procedures ................................................................. 44 
Comprehensive Physical Examination ..................................................................... 44 
Limited Physical Examination .................................................................................. 44 
Eastern Cooperative Oncology Group (ECOG) Performance Status ....................... 44 
Vital Signs ................................................................................................................ 44 
Hematology ............................................................................................................... 44 
Blood Chemistry ....................................................................................................... 44 
Coagulation ............................................................................................................... 45 
Thyroid Function ...................................................................................................... 45 
Urinalysis .................................................................................................................. 45 
Pregnancy Test .......................................................................................................... 45 


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Electrocardiograms Monitoring ................................................................................ 45 
Echocardiogram ........................................................................................................ 46 
Tumor Evaluation/Imaging ....................................................................................... 46 
Tumor Markers ......................................................................................................... 47 
Circulating Tumor DNA ........................................................................................... 47 
Subject Randomization ............................................................................................. 47 
Quality of Life Assessment ...................................................................................... 47 
Pharmacokinetics Evaluations .................................................................................. 47 
Sample Collection and Handling .............................................................................. 47 
Analytical Procedures ............................................................................................... 48 
End of Treatment Visit ............................................................................................. 48 
Safety Follow-Up Visit ............................................................................................. 48 
Efficacy Follow-Up .................................................................................................. 48 
Survival Follow-Up .................................................................................................. 48 
Long-term Extension ................................................................................................ 48 
Discontinuation or Withdrawal ................................................................................. 48 
Permanent Discontinuation of Treatment ................................................................. 48 
Withdrawal from Study ............................................................................................ 49 
Replacement of Subjects ........................................................................................... 49 
Subjects Lost to Follow-up ....................................................................................... 49 
Study Termination .................................................................................................... 50 
End of Study ............................................................................................................. 50 
7.
STUDY DRUGS ...................................................................................................... 51 
Study Drug Administration ....................................................................................... 51 
Description of Products ............................................................................................ 51 
Formulation, Storage, Preparation and Handling ..................................................... 51 
Drug Accountability ................................................................................................. 51 
Assignment/Disposal (Study Site) ............................................................................ 51 
Drug Return (Subject) ............................................................................................... 52 
Treatment Assignment and Bias Minimization ........................................................ 52 
Treatment Allocation ................................................................................................ 52 
Extent and Maintenance of Blinding ........................................................................ 52 
Unblinding Procedures ............................................................................................. 53 


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Emergency Unblinding ............................................................................................. 53 
Assessment and Verification of Compliance ............................................................ 53 
Prior and Concomitant Therapies ............................................................................. 53 
Prohibited Therapies ................................................................................................. 53 
Permitted Therapies .................................................................................................. 53 
Drug-Drug Interactions ............................................................................................. 54 
Rescue Therapies ...................................................................................................... 54 
General Dose Adjustment Note ................................................................................ 55 
Dose Modification Guidance .................................................................................... 55 
Dose Modification Sequence by Starting Dose and for General Hematologic and 
Non-Hematologic Toxicity ....................................................................................... 55 
Dose Modification for Important Identified Risks ................................................... 56 
8.
SAFETY MONITORING ........................................................................................ 60 
Definitions ................................................................................................................ 60 
Adverse Event ........................................................................................................... 60 
Serious Adverse Event .............................................................................................. 60 
Adverse Event Reporting .......................................................................................... 60 
Adverse Event Reporting Period .............................................................................. 60 
Expedited Reporting ................................................................................................. 60 
Eliciting Adverse Events .......................................................................................... 61 
Assessment of Severity ............................................................................................. 61 
Causality assessment ................................................................................................ 62 
Documenting Adverse Events .................................................................................. 62 
Diagnosis versus Symptoms and Signs .................................................................... 63 
Adverse Event Occurring Secondary to Other Events ............................................. 63 
Persistent or Recurrent Adverse Events ................................................................... 63 
Abnormal Laboratory Values or Abnormal Vital Signs ........................................... 63 
Preexisting Medical Condition ................................................................................. 64 
Pregnancy ................................................................................................................. 64 
Worsening of Solid Tumor ....................................................................................... 64 
Death ......................................................................................................................... 65 
Duration of Follow-up for Adverse Events .............................................................. 65 
9.
STATISTICAL ANALYSIS .................................................................................... 66 


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Statistics and Analysis Method ................................................................................. 66 
Statistical Hypothesis ................................................................................................ 66 
Sample Size Rationale .............................................................................................. 66 
Analysis Sets ............................................................................................................. 67 
Primary and Secondary Endpoints ............................................................................ 67 
Primary Endpoint ...................................................................................................... 67 
Secondary Efficacy Endpoints .................................................................................. 67 
Progression-free Survival ......................................................................................... 67 
Objective Response Rate .......................................................................................... 67 
Disease Control Rate ................................................................................................ 68 
Duration of Response ............................................................................................... 68 
Secondary Safety Endpoints ..................................................................................... 68 
Other Endpoints ........................................................................................................ 68 
Patient Reported Outcomes ...................................................................................... 68 
Assessment of Resource Utilization ......................................................................... 68 
Statistical Methods .................................................................................................... 68 
Analysis of Efficacy Endpoints ................................................................................ 68 
Analysis of Safety Endpoints .................................................................................... 69 
Analysis of Other Endpoints ..................................................................................... 69 
Pharmacokinetic and Pharmacodynamic Analyses .................................................. 70 
Population PK and Exposure-Response Analyses .................................................... 70 
Pharmacodynamic (ECG) Analysis .......................................................................... 70 
QTc Intervals ............................................................................................................ 70 
Heart Rate, QRS, and PR intervals ........................................................................... 71 
T-wave and U-wave Morphology ............................................................................. 71 
QTc-PK Analysis ...................................................................................................... 71 
Interim Analysis ........................................................................................................ 72 
10.
ETHICAL CONSIDERATIONS .............................................................................. 73 
Quality Control and Quality Assurance .................................................................... 73 
Ethics Review ........................................................................................................... 73 
Ethical Conduct of the Study .................................................................................... 73 
Informed Consent ..................................................................................................... 73 
Data Privacy .............................................................................................................. 73 


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Disclosure ................................................................................................................. 74 
Biological Specimens and Data ................................................................................ 74 
11.
OVERSIGHT ............................................................................................................ 75
Independent Monitoring ........................................................................................... 75 
Independent Data Monitoring Committee ................................................................ 75 
Quality Control and Assurance ................................................................................. 75 
Monitoring ................................................................................................................ 75 
Audits ........................................................................................................................ 76 
Protocol Deviations .................................................................................................. 76 
Records ..................................................................................................................... 76 
Data Capture and Management ................................................................................ 76 
Source Documentation .............................................................................................. 77 
Study Files ................................................................................................................ 77 
Records Retention ..................................................................................................... 77 
Study Termination or Study Site Closure ................................................................. 78 
12.
PUBLICATION POLICY ........................................................................................ 79 
13.
FINANCING AND INSURANCE ........................................................................... 80 
14.
REFERENCES ......................................................................................................... 81 
15.
APPENDICES .......................................................................................................... 82
LIST OF TABLES 
Table 1 ............ Schedule of Events ............................................................................................... 21 
Table 2 ............ Schedule of Events for Pharmacokinetic and Electrocardiogram Evaluations for 
the First Approximately 120 Patients .................................................................. 25 
Table 3 ............ Schedule of Events for Pharmacokinetic and Electrocardiogram Evaluations for 
Patients Enrolled After the First Approximately 120 Patients ............................. 26 
Table 4 ............ Objectives and Corresponding Endpoints ............................................................ 35 
Table 5 ............ Information on Investigational Products .............................................................. 51 
Table 6 ............ Dose Modification Sequence by Starting Dose ................................................... 55 
Table 7 ............ Dose Modification Recommendations for Hematologic and Non-Hematologic 
Toxicity ................................................................................................................ 56 
Table 8 ............ Dose Modification for Palmar-Plantar Erythrodysethesia ................................... 56 
Table 9 ............ Dose Modification for Proteinuriaa ...................................................................... 57 


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Table 10 .......... Dose Modification for Hypertension ................................................................... 57 
Table 11 .......... Dose Adjustment for Decreased Platelet Count ................................................... 58 
Table 12 .......... Dose Adjustment for Hemorrhage at any Site ..................................................... 58 
Table 13 .......... Dose Adjustment for Abnormal Liver Function .................................................. 58 
Table 14 .......... Time Point Response: Patients with Target Lesions (with or without Non-Target 
Lesions) ................................................................................................................ 90 
Table 15 .......... Time Point Response: Patients with Non-Target Lesions Only .......................... 91 
Table 16 .......... Best Overall Response When Confirmation of Complete Response and Partial 
Response is Required ........................................................................................... 92 
Table 17 .......... Typical Strong Inhibitors of CYP3A4 ................................................................. 96 
Table 18 .......... Typical Strong Inducers of CYP3A4 ................................................................... 97 
Table 19 .......... Sensitive Substrates of P-gp or BCRP ................................................................. 98 
Table 20 .......... Summary of Clinical Trial Program of Fruquintinib in China and the US .......... 99 
LIST OF FIGURES 
Figure 1 ........... Study Design Schema .......................................................................................... 20 
Figure 2 ........... Severe or Serious Hemorrhagic Events Management Flow Chart .................... 108 
Figure 3 ........... Schema from American Heart Association/ American College of Cardiology for 
Controlling Hypertension in Adults ................................................................... 110 
LIST OF APPENDICES 
Appendix 1 ..... ECOG Performance Status .................................................................................. 83 
Appendix 2 ..... Response Evaluation Criteria in Solid Tumors (RECIST v1.1) .......................... 84 
Appendix 3 ..... Prohibited Medication .......................................................................................... 95 
Appendix 4 ..... Study Plan ............................................................................................................ 99 
Appendix 5 ..... Clinical Evaluation of Possible Drug-Induced Liver Injury (DILI) .................. 104 
Appendix 6 ..... Clinical Management of Severe or Serious Hemorrhagic Events ..................... 106 
Appendix 7 ..... Management of Hypertension in Patients Receiving Fruquintinib .................... 109 
Appendix 8 ..... Conversion Table for Urinalysis Results ........................................................... 113 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase/glutamic-pyruvic transaminase 
ANC 
Absolute neutrophil count 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase/glutamic-oxalacetic transaminase 
AUC 0-24 hr 
Area under the concentration-time curve from 0 to 24 hours after drug 
administration 
BCRP 
Breast cancer resistance protein 
BSC 
Best supportive care 
CDK 
Cyclin-dependent kinase 
CEA 
Carcino-embryonic antigen 
CHL 
Chinese Hamster Lung 
c-MET
Mesenchymal epithelial cells transforming factor 
CR 
Complete response 
CRC 
Colorectal cancer 
CRO 
Contract research organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Event 
DCR 
Disease control rate 
dMMR 
Deficient mismatch repair 
DoR 
Duration of response 
IDMC 
Independent Data Monitoring Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End of treatment 
EC 
Ethics Committee 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 


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Abbreviation 
Definition 
FDG-PET 
Fluorodeoxyglucose positron emission tomography 
IB 
Investigator’s brochure 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IDMC 
Independent data monitoring committee 
INR 
International normalized ratio 
ITT 
Intent-to-treat 
IWRS 
Interactive web response system 
LDH 
Lactic dehydrogenase 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MID 
Minimally important difference 
mL 
Milliliter 
MRI 
Magnetic resonance imaging 
MSI-H 
High levels of microsatellite instability 
MTD 
Maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE 
The National Cancer Institute Common Terminology Criteria for Adverse 
Event 
NE 
Not evaluable 
NOAEL 
No observed adverse effect level 
NSCLC 
Non-small-cell lung cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive disease 
PDGFR 
Platelet-derived growth factor receptor 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PO 
Per os (oral administration) 
PPE 
Palmar-plantar erythrodysesthesia 
PR 
Partial response 


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Abbreviation 
Definition 
PS  
Performance status 
PT 
Preferred term 
PTT 
Prothrombin time 
QD 
Quaque die (once daily) 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D 
Recommended phase 2 dose 
SAE  
Serious adverse event 
SD 
Stable disease 
SOC 
System organ class 
TSH 
Thyroid stimulating hormone 
TTD 
Time to deterioration 
TTP 
Time to progression 
ULN 
Upper limit of normal 
VEGF 
Vascular endothelial growth factor 
VEGFR 
Vascular endothelial growth factor receptor 
WHO  
World Health Organization 
 
 


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1.
SYNOPSIS
Title 
A Global, Multicenter, Randomized, Placebo-Controlled Phase 3 Trial to 
Compare the Efficacy and Safety of Fruquintinib Plus Best Supportive Care to 
Placebo Plus Best Supportive Care in Patients with Refractory Metastatic Colon 
Cancer (FRESCO-2) 
Short Title 
A global, randomized, placebo-controlled phase 3 study of fruquintinib in 
patients with refractory metastatic colorectal cancer 
Acronym 
FRESCO-2 
Phase 
3 
Study Design 
This is a global, randomized, double-blind, placebo-controlled, multicenter 
phase 3 clinical trial to compare the efficacy and safety of fruquintinib plus best 
supportive care (BSC) versus placebo plus BSC in subjects with refractory 
metastatic colorectal cancer (mCRC).  Approximately 522 subjects will be 
randomized in a 2:1 ratio to either the fruquintinib plus BSC treatment group or 
the placebo plus BSC treatment group. 
Randomization will be stratified by the following factors: 
•
Prior therapy with trifluridine/tipiracil (TAS-102) versus regorafenib
versus both trifluridine/tipiracil (TAS-102) and regorafenib
•
RAS status (wild type versus mutant)
•
Duration of metastatic disease (<18 months versus ≥18 months)
Subjects will receive study treatment with each 4-week cycle consisting of 
3 weeks of daily oral (PO) study medication and 1 week of study drug 
interruption (3 weeks on/1 week off).  Tumor evaluation will be performed by 
imaging (computed tomography [CT] or magnetic resonance imaging [MRI] 
scan) every 8 weeks until there is progression of disease (PD), death, new anti-
cancer treatment, or study completion, whichever comes first.  Safety parameters 
will include adverse events (AE), and results from laboratory tests, vital signs, 
ECG, and echocardiogram.  Post-discontinuation anti-tumor treatment and 
survival follow up after PD will also be recorded. 
Rationale 
Colorectal cancer (CRC) is the second most common malignancy in both men 
and women and the third most common cause of cancer-related death in the US, 
with an estimated 145,600 new cases and 51,020 deaths in 2019.  Similarly, CRC 
is a major global health issue, with an estimated 1.8 million new cases and 
880,000 deaths in 2018 worldwide (Bray 2018). 
There is no standard of care for patients who have progressed on approved 
standard-of-treatments, including chemotherapy, relevant biologics and TAS-
102 and/or regorafenib.  Patients who are well enough to receive additional 
therapy following all standard therapies either are considered for treatment on a 
clinical trial when available or are re-challenged with agents such as 5-FU or 
bevacizumab.  Consequently, there is an unmet medical need for new 
medications that are safe and effective in patients with refractory mCRC who 
have progressed on, or had intolerable toxicity from, available standard systemic 
therapies, and for whom no effective therapy or standard of care exists.   
Fruquintinib is a novel, potent, and highly selective small molecule tyrosine 
kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, 
and -3.  In the FRESCO trial conducted in China, fruquintinib improved the 
median overall survival in patients with mCRC in a third-line or later setting 
when compared to placebo (median overall survival 9.3 months versus 


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6.6 months; hazard ratio for death 0.65 (95% CI: 0.51-0.83; p < 0.001)(Li 2018). 
The results from this pivotal trial led to fruquintinib’s approval in China. 
The safety profile of fruquintinib from an ongoing phase 1/1b study in the US is 
consistent with that of clinical studies performed in China, as well as published 
data for other small molecule VEGF inhibitors.  The pharmacokinetic (PK) 
profile of fruquintinib in the US phase 1/1b study is also comparable to the PK 
profile in patients treated with fruquintinib in China at the same dose and dosing 
regimen (5 mg PO, QD, 3 weeks on, 1 week off, for each 4-week cycle).   
These data showing favorable efficacy and acceptable safety indicates 
fruquintinib is a promising candidate for development as a new treatment for 
patients with refractory mCRC and may address an unmet medical need globally. 
This global, multicenter, randomized, double-blind, placebo-controlled clinical 
trial will compare the efficacy and safety of fruquintinib in combination with 
BSC, to placebo in combination with BSC, in patients with refractory metastatic 
colorectal cancer who have progressed on, or were intolerant to, TAS-102 and/or 
regorafenib.  Patients must have also received prior standard therapies, including 
two lines of chemotherapy (fluoropyrimidine-, oxaliplatin-, and irinotecan-
based), a biological VEGF inhibitor, and, if RAS wild type, an EGFR inhibitor. 
Patients with MSI-H/MMR deficient tumors must have also received an immune 
checkpoint inhibitor if approved and available and if deemed appropriate. 
Target Population 
The study population will consist of subjects ≥18 years of age with histologically 
and/or cytologically documented metastatic colorectal adenocarcinoma who 
progressed on, or were intolerant to, all standard chemotherapies and relevant 
biologics and TAS-102 and/or regorafenib. 
Inclusion/Exclusion 
Criteria 
Inclusion Criteria 
Subjects may be enrolled in this study only if they satisfy all the following 
criteria: 
1.
Provide written informed consent;
2.
Age ≥18 years;
3.
Histologically and/or cytologically documented metastatic colorectal
adenocarcinoma;
4.
Subjects must have progressed on or been intolerant to treatment with
either trifluridine/tipiracil (TAS-102) or regorafenib if approved and
available in the subject’s country.  Subjects are considered intolerant to
TAS-102 or regorafenib if they have received at least one dose of either
agent and were discontinued from therapy for reasons other than disease
progression.  Subjects who have been treated with both TAS-102 and
regorafenib are permitted.  Subjects must also have been previously
treated 
with 
standard 
approved 
therapies: 
fluoropyrimidine-,
oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF
biological therapy, and, if RAS wild-type, an anti-EGFR therapy.
5.
Subjects with microsatellite-high (MSI-H) or mismatch repair deficient
(dMMR) tumors must have been treated with immune checkpoint
inhibitors if approved and available in the subject’s country and if
deemed appropriate;
6.
Subjects who received oxaliplatin in the adjuvant setting must have
progressed within 6 months of completing adjuvant therapy;
7.
Body weight ≥40kg;
8.
Eastern Cooperative Oncology Group (ECOG) performance status of 0
to 1;


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9.
Have measurable disease according to RECIST Version 1.1
(RECIST v1.1), assessed locally.  Tumors that were treated with
radiotherapy are not measurable per RECIST v1.1, unless there has been 
documented progression of those lesions.
10. Expected survival >12 weeks.
11. For female subjects of childbearing potential and male subjects 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, 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 criteria are applicable to male
subjects involved in this clinical trial if they have a partner of childbirth
potential, and male subjects must always use a condom.
Exclusion Criteria: 
Subjects are not eligible for enrollment into this study if they have any of the 
following criteria: 
1.
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;
2.
Serum total bilirubin >1.5 × the upper limit of normal (ULN).  Subjects
with Gilbert syndrome, bilirubin <2 X ULN, and normal aspartate
aminotransferase (AST)/alanine aminotransferase (ALT) are eligible;
3.
ALT or  AST >2.5 × ULN in subjects without hepatic metastases;
ALT or AST >5  × ULN in subjects with hepatic metastases;
4.
Serum electrolytes, potassium, calcium, or magnesium levels outside of
the normal laboratory reference range, and clinically significant in the
investigator’s judgment;
5.
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.
6.
Urine dipstick protein ≥2+ or 24-hour urine protein ≥1.0 g/24-h.
Subjects with greater than 1+ proteinuria on urinalysis must undergo a
24-hour urine collection.  For conversion between qualitative and
quantitative results, please see Appendix 8;
7.
Uncontrolled hypertension, defined as: systolic blood pressure
≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg despite
optimal medical management;
8.
International Normalized Ratio (INR) >1.5 x ULN or activated partial
thromboplastin time (aPTT) >1.5 × ULN, unless the subject is currently
receiving or intended to receive anticoagulants for prophylactic
purposes;
9.
History of, or 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, in the


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investigator’s judgment, result in gastrointestinal hemorrhage or 
perforation; within the 6 months prior to screening; 
10. History or presence of hemorrhage from any other site (eg, hemoptysis
or hematemesis) within 2 months prior to screening;
11. History of a thromboembolic event, including deep vein thrombosis
(DVT), pulmonary embolism (PE), or arterial embolism within
6 months prior to screening.
12. Stroke and/or transient ischemic attack within 12 months prior to
screening;
13. 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% by echocardiogram;
14. 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.
15. Concomitant medications with a known risk of causing QT prolongation 
and/or torsades de pointes (See list in Appendix 3 source list is
continuously updated online at www.crediblemeds.org).
16. Systemic anti-neoplastic therapies (except for those described in
Exclusion Criterion 18) or any investigational therapy within 4 weeks
prior to the first dose of study drug, including chemotherapy, radical
radiotherapy, hormonotherapy, biotherapy and immunotherapy;
17. 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;
18. Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior
to the initiation of study drug;
19. Brachytherapy (ie, implantation of radioactive seeds) within 60 days
prior to the first dose of study drug.
20. Use of strong inducers or inhibitors of CYP3A4 within 2 weeks before
the first dose of study drug; (see Appendix 3 for a list of applicable
drugs);
21. Surgery or invasive procedure (ie, a procedure that includes a biopsy;
central venous catheter placement is allowed) within 60 days prior to
the first dose of study drug or unhealed surgical incision;
22. Any unresolved toxicities from a previous antitumor treatment greater
than National Cancer Institute (NCI) Common Terminology Criteria for
Adverse Event (CTCAE) v5.0 grade 1 (except for alopecia or
neurotoxicity grade≤2).
23. Known human immunodeficiency virus (HIV) infection;
24. Known history of active viral hepatitis.  For subjects with evidence of
chronic hepatitis B virus (HBV) infection, the HBV viral load must be
undetectable on suppressive therapy, if indicated.  Subjects with HCV
infection who are currently on treatment are eligible if they have an
undetectable HCV viral load.
25. Clinically uncontrolled active infection requiring IV antibiotics;
26. Tumor invasion of a large vascular structure (eg, pulmonary artery,
superior or inferior vena cava);


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27. Women who are pregnant or lactating;  
28. 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; subjects requiring steroids within 4 weeks 
prior to start of study treatment are excluded; 
29. No other malignancy, except for non-melanoma skin cancer, in situ 
cervical ca or bladder ca (Tis and T1) that have been adequately treated 
during the 5 years prior to screening;  
30. 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;  
31. Other disease, metabolic disorder, physical examination anomaly, 
abnormal laboratory result, or any other condition (eg, current alcohol 
or drug abuse) that investigators suspect may prohibit use of the 
investigational product, affect interpretation of study results, or put the 
subject at undue risk of harm based on the investigator’s assessment;  
32. Known hypersensitivity to fruquintinib or any of its inactive ingredients. 
Number of Subjects 
Approximately 522 subjects will be randomized 2:1 (fruquintinib plus BSC: 
placebo plus BSC). 
Length of Participation 
Subjects may continue to receive treatment until they meet a criterion for 
discontinuation.   
Intervention 
Investigational Drug:  Fruquintinib (HMPL-013) capsule 5 mg will be 
administered PO, QD, 3 weeks on, 1 week off (4-week cycles).  Doses may be 
given either in the fasting state or after meals.  If dose adjustment is required, 
1 mg fruquintinib capsules will be used. 
Reference Drug:  Placebo capsules matching fruquintinib 5 mg will be 
administered PO, QD, 3 weeks on, 1 week off (4-week cycles).  Doses may be 
given either in the fasting state or after meals.  If dose adjustment is required, 
1 mg matching placebo capsules will be used. 
Primary Objective  
To evaluate the overall survival of fruquintinib plus BSC compared to placebo 
plus BSC in subjects with refractory mCRC. 
Secondary Objective(s)  
• 
To evaluate progression-free survival (PFS) of fruquintinib plus BSC 
compared to placebo plus BSC 
• 
To evaluate the objective response rate (ORR), disease control rate 
(DCR), and duration of response (DoR) 
• 
To assess the safety and tolerability of fruquintinib plus BSC compared 
to placebo plus BSC 
• 
To characterize the PK exposure of fruquintinib and metabolite M11 in 
subjects with refractory mCRC 
• 
To evaluate the effect of fruquintinib on cardiac repolarization, as 
detected by changes in electrocardiogram (ECG) QTc intervals, and the 
potential relationship with fruquintinib and M11 plasma concentrations 
• 
To evaluate the relationship between fruquintinib exposure and 
endpoints for efficacy and safety 
• 
To evaluate quality of life (QoL) as assessed by using QLQ-C30: 
cancer-specific; and EQ-5D-5L questionnaires 
• 
To assess resource utilization  


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Exploratory 
Objective(s)  
To assess potential predictive biomarkers of response to fruquintinib 
Number of Sites 
This study will be conducted at approximately 100 sites globally. 
Study Duration 
Recruitment period is estimated to take approximately 13 months.  Estimated 
duration for the entire study from time the study is open to enrollment until 
completion of data analyses is approximately 20 months.   
Independent Data 
Safety Monitoring 
Committee 
The IDMC will be comprised of at least 4 independent oncologists from 
representative geographies and at least 1 independent statistician. 
 
 
Study Schematic 
The study schematic is presented in Figure 1. 
Figure 1 
Study Design Schema 
 
 
 
Schedule of Events 
The schedules of events (SOE) are presented in Table 1, Table 2, and Table 3. 
 






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Procedural details for medical history are available in Section 6.1.1.2.  Tumor diagnosis, tumor treatment history, and 
evaluation of RAS status is described in Section 6.1.1.3. 
 
Procedural details for patient demographics, including baseline characteristics are available in Section 6.1.1.4. 
 
Procedural details for concomitant medications/treatments are available in Section 6.1.1.5. 
 
Procedural details for comprehensive physical examination are available in Section 6.1.1.6. 
 
Procedural details for limited physical examination are available in Section 6.1.1.7. 
 
Procedural details for ECOG performance status are available in Section 6.1.1.8. 
 
Procedural details for vital signs are available in Section 6.1.1.9. 
 
Procedural details for hematology are available in Section 6.1.1.10. 
 
Procedural details for blood chemistry are available in Section 6.1.1.11. 
 
Coagulation tests include prothrombin time (PTT), international normalized ratio (INR), and activated partial thromboplastin 
time (APTT).  Additional procedural details are available in Section 6.1.1.12. 
 
Thyroid function tests include serum free triiodothyronine (fT3), serum free thyroxine (fT4) and thyroid stimulating hormone 
(TSH).  Additional procedural details are available in Section 6.1.1.13. 
 
Twenty-four-hour urine for quantitative protein should be collected from all patients with ≥ 2+ proteinuria during screening.  
If urine protein ≥ 2+ during the period of study treatment, a 24-hour urine protein should be collected within 1 week.  
Additional procedural details for urinalysis are available in Section 6.1.1.14. 
 
All female patients of childbearing potential must complete a blood pregnancy test at screening and at the Safety Follow up 
Visit.  Serum pregnancy test should be repeated for patients with suspected pregnancy.  This is not applicable for 
postmenopausal female patients, but the date of menopause should be recorded instead.  Additional procedural details are 
available in Section 6.1.1.15. 
 
All female patients of childbearing potential must complete a urine pregnancy test at each day 1-visit starting at cycle 2. 
 
See Table 2 and Table 3 for specific ECG parameters and time points.  Electrocardiogram is to be performed before PK and 
echocardiogram assessments at each relevant visit.  Other procedural details for Holter Monitor and 12-lead ECG are available 
in Section 6.1.1.16. 


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An echocardiogram should be done at Screening, C2D1, and on the first day, every 3 cycles thereafter.  Additional procedural 
details for echocardiogram are available in Section 6.1.1.17.  MUGA scans are acceptable if an echocardiogram cannot be 
performed. 
 
Baseline tumor assessment should be completed within 28 days prior to enrollment.  Post-baseline tumor evaluations shall be 
performed on C3D1, C5D1, and day 1 of every other cycle thereafter until progression of disease (PD).  Each tumor 
assessment should document measurable lesions at the scheduled visit ± 7 days.  Additional procedural details are available in 
Section 6.1.1.18. 
 
Serum carcino-embryonic antigen (CEA) level is collected at screening and at day 1 of every cycle (±1 week) starting at cycle 
2 until disease progression.  Additional procedural details are available in Section 6.1.1.19. 
 
Collection of circulating tumor DNA (ctDNA).  Additional procedural details are available in Section 6.1.1.20. 
 
See Table 2 and Table 3 for specific PK time points.  Sampling for PK assessments is described in Section 6.1.2.1, and 
evaluation procedures are described in Section 6.1.2.2 
 
Patient randomization occurs on day -2 to day 1.  Additional procedural details on patient randomization are available in 
Section 6.1.1.21.  
 
For the method of drug dispensation and return, see Section 7.2.2. 
 
Study drug is taken daily on a 3 weeks on, 1 week off schedule for each 28-day cycle.  On days with PK collection, treatment 
should be administered at the site by a delegated study staff member. 
 
After informed consent, but prior to initiation of study drug, all SAEs regardless of attribution will be collected.  After 
initiation of study drug, all SAEs and AEs regardless of attribution will be collected until 30 days after 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. 
 
Survival follow-up (by telephone) should be performed every 12 weeks (±2 weeks) after the end of treatment (EOT) visit.  All 
subsequent anti-tumor therapy and information about study drug-related SAEs shall be collected.  For the patients that 
discontinue the study without PD, all available tumor assessment results during survival follow up shall be recorded in the eCRF 
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 follow up for survival will be performed. 
 


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Table 2 
Schedule of Events for Pharmacokinetic and Electrocardiogram Evaluations 
for the First Approximately 120 Patients 
Study day 
Time Relative 
to Dosing 
Study Drug 
Intake 1 
Pharmacokinetic 
Samples 2 
Triplicate ECG for 
QTc Evaluation 
(Holter Monitor) 
Safety ECG 
(Standard 
Equipment) 
C1D1 
Pre-dose 3 
 
X 
X 
- 
0 h 
X 
- 
- 
- 
1 h 
 
X 
X 
- 
2 h 
 
X 
X 
- 
3 h 
 
X 
X 
- 
4 h 
 
X 
X 
- 
C1D21 
Pre-dose 3 
 
X 
X 
- 
0 h 
X 
- 
- 
- 
1 h 
 
X 
X 
- 
2 h 
 
X 
X 
- 
3 h 
 
X 
X 
- 
4 h 
 
X 
X 
- 
C2D1 
Pre-dose 3 
 
X 
- 
- 
0 h 
X 
- 
- 
- 
C2D21 
Pre-dose 3 
 
X 
- 
- 
0 h 
X 
- 
- 
- 
2 h 
 
X 
- 
X 
C3D1 
Pre-dose 3 
 
X 
- 
- 
0 h 
X 
- 
- 
- 
C3D21 
Pre-dose 3 
 
X 
- 
- 
0 h 
X 
- 
- 
- 
2 h 
 
X 
- 
X 
C5D1 and every 
other cycle 
thereafter 
Pre-dose 3 
 
X 
- 
- 
0 h 
X 
- 
- 
- 
C1D1= cycle 1, day 1; C1D21 = cycle 1, day 21; C2D1 = cycle 2, day 1; C2D21 = cycle 2, day 21; C3D1 = cycle 3, day 1; C3D21 = cycle 3, 
day 21; C5D1 = cycle 1, day 1; ECG = Electrocardiogram 


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Table 3 
Schedule of Events for Pharmacokinetic and Electrocardiogram Evaluations 
for Patients Enrolled After the First Approximately 120 Patients 
Study day 
Time Relative to 
Dosing 
Study Drug Intake 1 
Pharmacokinetic 
Samples 2 
Safety ECG 
(Standard 
Equipment) 
C1D1 
Pre-dose 3 
 
X 
X 
0 h 
X 
- 
- 
2 h 
 
X 
X 
C1D21 
Pre-dose 3 
 
X 
- 
0 h 
X 
- 
- 
2 h 
 
X 
X 
C2D1 
Pre-dose 3 
 
X 
- 
0 h 
X 
- 
- 
C2D21 
Pre-dose 3 
 
X 
- 
0 h 
X 
- 
- 
2 h 
 
X 
X 
C3D1 
Pre-dose 3 
 
X 
- 
0 h 
X 
- 
- 
C3D21 
Pre-dose 3 
 
X 
- 
0 h 
X 
- 
- 
2 h 
 
X 
X 
C5D1 and every other 
cycle thereafter 
Pre-dose 3 
 
X 
- 
0 h 
X 
- 
- 
C1D1= cycle 1, day 1; C1D21 = cycle 1, day 21; C2D1 = cycle 2, day 1; C2D21 = cycle 2, day 21; C3D1 = cycle 3, day 1; C3D21 = cycle 3, 
day 21; C5D1 = cycle 1, day 1; ECG = Electrocardiogram 
 
Footnotes for the Schedule of Events Tables 2 and 3 
 On PK sampling day, study drug must be taken at the investigative site under the supervision 
of the investigator or designee and should not be taken at home on the morning of the visits.  
The date and time of the dose administered on the day of PK collection and one day before 
PK collection must be recorded in the eCRF. 
 The actual date and time of the PK samples must be recorded on the eCRF. 
 Pre-dose PK and ECG should be performed within 30 minutes BEFORE study drug 
administration. 


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2. 
INTRODUCTION 
During tumorigenesis, malignancies release growth factors to induce angiogenesis, which provides 
nutrients and oxygen for rapid tumor growth.  The immature arrangement of endothelial cells on 
the rapidly growing blood vessels can result in exudation of tumor cells into the circulatory system, 
through which the tumor cells may spread to other tissues, leading to tumor metastasis.  Vascular 
endothelial growth factor receptor (VEGF) is one of the key factors known to induce tumor 
angiogenesis, and agents that target VEGF and the VEGFR are important therapies for malignant 
solid tumors, including colorectal cancer (Duda 2016, Jayson 2016). 
Fruquintinib (HMPL-013) is a small molecule anti-tumor drug with a novel chemical structure that 
belongs to the quinazoline class and is a potent and highly selective tyrosine kinase inhibitor of 
vascular endothelial growth factor receptors (VEGFR).  In vitro studies demonstrated that 
fruquintinib is highly selective for VEGFR-1, -2, and -3, which are related to tumor angiogenesis, 
and possess weak or no measurable activity against other kinases (Sun 2014).  Fruquintinib was 
discovered by Hutchison MediPharma Limited (hereafter referred to as the sponsor) through in 
vitro and in vivo biological screening of a large number of synthetic compounds. 
Results from preclinical and clinical studies conducted in China and in the US have provided 
evidence that fruquintinib has anti-cancer activity in solid tumors.  The clinical development 
program in China has been ongoing since 2009.  In the phase 3 clinical trial, FRESCO,  that led to 
the drug’s approval in China, fruquintinib improved median overall survival in patients with 
metastatic colorectal cancer (mCRC) in a third-line or later setting when compared to placebo from 
6.6 to 9.3 months (hazard ratio for death 0.65; 95% confidence interval [CI] 0.51-0.83; P < 
0.001).(Li 2018)  The cumulative safety data from the clinical trial program has shown that 
fruquintinib has an acceptable level of toxicity that is consistent with other antiangiogenic drugs, 
particularly small molecule VEGFR inhibitors.  These data provide a strong justification for the 
investigation of fruquintinib in patients with refractory mCRC globally. 
 
Background 
Colorectal cancer (CRC) is a major global health issue, with an estimated 1.8 million new cases 
and 880,000 deaths in 2018 worldwide (Bray 2018).  The established initial and second-line 
systemic therapy for mCRC consists of fluoropyrimidine-, oxaliplatin, and irinotecan-based 
cytotoxic chemotherapy (eg, FOLFOX: [5-Fluorouracil, leucovorin, and oxaliplatin] and FOLFIRI 
[5-fluorouracil, leucovorin, and irinotecan]).  In addition, a biologic anti-VEGF therapy is typically 
given with chemotherapy (eg, bevacizumab), and if the tumor is RAS wild type, an anti-EGFR 
therapy (eg, cetuximab) is administered.  In the small proportion of patients that are deficient 
mismatch repair (dMMR)/ high levels of microsatellite instability (MSI-H) in the metastatic setting 
(Koopman 2009), immunotherapy with nivolumab or pembrolizumab may be used (NCCN 2019). 
When there is disease progression after the first two lines of chemotherapy, the established 
options are either:  
• Trifluridine/tipiracil (LONSURF®, TAS-102), an oral combination of trifluridine, a 
nucleoside metabolic inhibitor, and tipiracil, a thymidine phosphorylase inhibitor; 
(LONSURF® USPI) or 
• Regorafenib (STIVARGA®), a multikinase inhibitor with numerous in vitro targets that 
include VEGFR (STIVARGA® USPI). 


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There is an unmet medical need for new medications that are safe and effective in patients with 
refractory mCRC who have progressed on, or had intolerable toxicity from, available standard 
systemic therapies, and for whom no effective therapy or standard of care exists.  A recent 
estimation of the median overall survival (OS) for patients with mCRC, based on data from phase 
3 clinical trials, observation studies, and registries, is 30 months (Grothey 2013, Mayer 2015).  
During this time, patients may receive several lines of therapy, with one or more “breaks.”  Both 
TAS-102 and regorafenib are approved in the third-line or greater (3+ line) of therapy after 
progression on chemotherapy, and there are no approved treatments following progression on these 
agents.  In this setting, the current options for patients with good performance status are to enter a 
clinical trial or to be re-challenged with prior chemotherapy (eg, 5-FU).  Patients with poor 
performance status generally enter hospice care.   
The purpose of this global, phase 3 clinical trial is to evaluate the efficacy and safety of fruquintinib 
in patients with refractory mCRC who have progressed on standard approved therapies, including 
TAS-102 and/or regorafenib.  
 
Administration Regimen 
Fruquintinib (HMPL-013) capsule 5 mg will be administered orally (PO) once daily (QD), 3 weeks 
on, 1 week off (4-week cycles).  Doses may be given either in the fasting state or after meals.  If 
dose adjustment is required, 1 mg capsules will be used. 
 
Justification for Dosing Strategy 
The optimal fruquintinib dose and dosing regimen were determined in two Chinese phase 1 studies, 
2009-013-00CH1 and 2012-013-00CH3, as well as one US phase 1/1b study, 2015-013-00US1.  
During dose escalation, study 2009-013-00CH1 investigated continuous daily doses of 1 mg, 
2 mg, 4 mg, 5 mg, and 6 mg; in addition, 5 mg QD and 6 mg QD were studied on a regimen of 3 
weeks on, 1 week off (4-week) cycles.  The maximum-tolerated dose (MTD)/ recommended 
phase 2 dose (RP2D) was 4 mg QD (continuous) or 5 mg QD (3 weeks on, 1 week off). 
In study 2012-013-00CH3, the safety and tolerability of these two dosing regimens (4 mg QD 
continuously versus 5 mg QD, 3 weeks on, 1 week off) were compared in patients with mCRC.  
The safety profile was better in the 5 mg QD (3 weeks on, 1 week off) group than the 4 mg QD 
(continuous) group.  In addition, there was accumulation of drug over time in the 4 mg QD 
(continuous) group.  Thus, the 5 mg PO, QD, 3 weeks on, 1 week off, dose and regimen was 
selected as the RP2D and the dosing regimen to be used in subsequent clinical development in 
China.  
The RP2D and dosing regimen were tested in the phase 2 (2012-013-00CH1) and phase 3 (2013-
013-00CH1 [FRESCO]) studies, which confirmed that the dose and dosing regimen were safe and 
effective in patients with refractory mCRC.  The 5 mg PO, QD, 3 weeks on, 1 week off is the 
standard dose and dosing regimen in all other completed, ongoing, and planned studies in patients 
with advanced cancer. 
In the US phase 1/1b study (2015-013-00US1), there were 2 dose cohorts in the dose escalation 
phase, 3 mg PO, QD (n=7) and 5 mg PO, QD (n=7).  Fruquintinib was well tolerated in both dose 
cohorts.  Therefore, 5 mg PO, QD, 3 weeks on, 1 week off was confirmed as the RP2D for global 
studies, as well. 






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5 mg QD and 6 mg QD at the 3 week on/1 week off schedule, plasma fruquintinib concentrations 
declined during the off week, as expected.  Preliminary PK results from the US patient population 
(ongoing Study 2015-013-00US1) that received fruquintinib at 3 mg and 5 mg QD 3 weeks 
on/1 week off suggested that there were no meaningful differences in fruquintinib exposure 
between Chinese and US patients.  Following fruquintinib 5 mg QD 3 weeks on/1 week off, mean 
fruquintinib Cmax and AUCtau values on day 21 were 326 ng/mL and 5969 ng*h/mL in Chinese 
patients (Study 2012-013-00CH3), respectively, compared with 385 ng/L and 7530 ng*h/mL in 
US patients, respectively. 
The effect of a high fat high calorie meal on the PK of fruquintinib 4 mg (4 x 1 mg capsules) was 
studied in healthy Chinese males (Study 2012-013-00CH2).  Food delayed Tmax of fruquintinib by 
2.6 hours.  A slight decrease in fruquintinib Cmax by 17% was seen, though there was no observed 
effect on the AUC0-∞.  These results were sufficient to recommend dosing of fruquintinib without 
regard to food. 
The results from the mass balance study conducted in healthy Chinese subjects (Study 2015-013-
00CH2) indicated that 60.31% of total radioactivity was recovered in urine and 29.80% in feces.  
A total of 22 metabolites were identified in the plasma, urine, and feces samples.  The M11 (N-
desmethylation product) and M9 (carboxylic acid product) were the main metabolites, where M11 
accounted for 17.31% and M9 accounted for 4.46% of the plasma exposure of total radioactivity.  
Only a small amount of unchanged fruquintinib was detected in urine, which accounted for 0.50% 
of the dose administered.  The amount of fruquintinib in feces accounted for 5.34% of the dose 
administered. 
M11 is a pharmacologically active metabolite found to inhibit VEGFR2 kinase activity and VEGF-
induced VEGFR2 phosphorylation, with a potency approximately 2 to 10 times lower than that of 
fruquintinib.  After multiple doses of fruquintinib 5 mg QD to patients for 21 days (Study 2015-
013-00US1, preliminary data), M11 reached Tmax after 1 hour.  The mean (standard deviation) 
Cmax and AUC0-24 values were 144 (56.2) ng/mL and 3080 (1250) h*ng/mL, respectively.  M11 
accumulated by 31.5-fold after multiple dosing.  The mean (standard deviation) metabolite-to-
parent ratio of M11 was 0.409 (0.135) at steady state.  Overall, M11 is not expected to have 
clinically meaningful contribution to the total pharmacological activity of fruquintinib at 
therapeutic exposure. 
 
Clinical Safety 
As of the data cut-off date (03 Sep 2019), 7 clinical trials in patients with cancer were completed.  
In order to conduct a comprehensive and robust safety assessment across the fruquintinib clinical 
studies, a pooled dataset has been generated and analyzed, which consists of data from 739 patients 
in 4 completed double-blind studies (2012-013-00CH1, 2013-013-00CH1, 2014-013-00CH1, and 
2015-013-00CH1) (Table 20 ) who received fruquintinib monotherapy.  In addition, the safety data 
from 2 completed early phase open-label studies (phase 1 2009-013-00CH1, phase 1b 2012-013-
00CH3) and 1 completed phase 1b/2 study (2014-013-00CH3) has also been analyzed.  
As of the data cut-off date, 5 clinical studies in patients with cancer were ongoing.  The safety 
profile of fruquintinib from a US phase 1/1b open-label, multi-center study (2015-013-00US1), 
from a China phase 2 open-label study of fruquintinib in combination with gefitinib (2016-013-
00CH1), and from a China phase 1b/2 open-label study of fruquintinib in combination with 
sintilimab (2018-013-00CH3) are also presented in this section.  No formal analysis is available 


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for the safety profile of fruquintinib in the other 2 ongoing studies; the China randomized phase 3 
study of paclitaxel with or without fruquintinib in metastatic gastric cancer (2017-013-00CH1) 
remains blinded, and no patients have been enrolled into the China open label single arm study 
evaluating fruquintinib in elderly patients with NSCLC (2017-013-00CH2). 
Adverse Events in Completed Studies: 
A total of 739 patients received at least 1 dose of fruquintinib in the 4 completed double-blind, 
placebo-controlled, monotherapy studies, among whom 729 (98.6 %) patients reported treatment-
emergent adverse events (TEAEs).  The incidence of the most commonly reported TEAEs (≥10% 
of patients) are provided in the current investigator’s brochure (IB). 
In the pooled data of all-causality TEAEs reported, the most commonly reported TEAEs of grade 
≥3 (≥5% of patients) included Hypertension (19.9%) and Palmar-plantar erythrodysaesthesia 
syndrome (10.7%). 
Serious Adverse Events in Completed Studies: 
A total of 1 or more serious adverse events (SAEs) have been reported by 169 (22.9%) patients 
out of the 739 patients who received fruquintinib.  The most common SAEs (≥1.0%) by MedDRA 
preferred term (PT) included Infectious pneumonia in 24 (3.2%) patients, intestinal obstruction in 
17 (2.3%) patients, pleural effusion in 9 (1.2%) patients, death in 10 (1.4%) patients, hepatic 
function abnormal in 8 (1.1%) patients, and gastrointestinal haemorrhage in 8 (1.1%) patients.  The 
SAEs in more than 1 patient in the pooled data are summarized in the current IB. 
2.1.4.2.1. Clinical Efficacy 
Monotherapy Efficacy:  
As of the data cut-off date (03 September 2019), the available fruquintinib efficacy data from the 
completed open-label and double-blind studies showed strong antitumor activity, including 
improved overall survival (OS) and progression-free survival (PFS), durable partial response (PR) 
and durable stable disease (SD), and improved overall response rate (ORR) in heavily pre-treated 
patients with advanced cancer.  
Two (2) proof-of-concept studies have been conducted in patients with CRC who were previously 
treated with two or more lines of standard chemotherapeutic regimens (Study 2012-013-00CH1) 
and in patients with NSCLC who have failed two lines of standard chemotherapies (Study 2014-
013-00CH1).  The studies both met their primary efficacy endpoint of PFS and demonstrated a 
significant improvement in PFS in the fruquintinib arm compared to the placebo arm. 
In addition, the phase 3 pivotal trial (FRESCO) was completed in patients with CRC who were 
previously treated with 2 or more lines of standard chemotherapeutic regimens (Study 2013-013-
00CH1).  In this study, fruquintinib significantly prolonged the OS compared to placebo with a 
hazard ratio of 0.65 (95% CI: 0.51-0.83; 2-sided p <0.001).  Statistically significant benefits were 
also seen with fruquintinib in all secondary endpoints, including as PFS, ORR, and disease control 
rate (DCR).  
One phase 3 study of fruquintinib was completed in patients with NSCLC who had failed second-
line standard chemotherapy (2015-013-00CH1): there was no significant difference between the 
fruquintinib group and the placebo group in the primary efficacy endpoint (OS).  However, 
fruquintinib significantly prolonged the PFS comparing to placebo with a HR of 0.34 (95% CI: 


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0.279, 0.425) with p < 0.001 (stratified log-rank test).  Statistically significant benefits were also 
shown with fruquintinib in ORR and DCR. 
The efficacy data in the ongoing study of fruquintinib in patients with advanced solid tumors 
(2015-013-00US1) are not available as of the data cut-off date (03 Sep 2019). 
Combination Therapy Efficacy  
A phase 1b/2 study had been conducted to investigate the treatment of fruquintinib, in combination 
with paclitaxel, as second-line therapy in patients with gastric cancer (GC) (2014-013-00CH3).  
The results showed that the ORR and DCR were 27.3% (9/33) and 63.6% (21/33), respectively.  
The median PFS and median OS at the RP2D (fruquintinib 4 mg + paclitaxel) were 4.0 months 
and 8.5 months, respectively. 
The efficacy data in 1 ongoing study of fruquintinib in combination with gefitinib in patients with 
NSCLC (2016-013-00CH1) and in 1 ongoing study of fruquintinib in combination sintilimab 
patients with advanced solid tumor are not available as of the data cut-off date (03 Sep 2019). 
 
Benefit/Risk Assessment 
There are robust cumulative efficacy and safety data for fruquintinib from the entire clinical 
program in China, as well as the ongoing US phase 1/1b study.  As of the data cut-off date 
(03 September 2019) a total of 1600 patients and 87 healthy volunteers had received at least one 
dose of fruquintinib or placebo through development programs.  Among them, 955 patients and 
87 healthy volunteers had received at least one dose of fruquintinib, 284 patients had received at 
least one dose of blinded treatment (fruquintinib versus placebo), and 361 patients had received at 
least one dose of placebo. 
 
Risk Assessment 
A total of 739 patients received at least 1 dose of fruquintinib in the 4 completed double-blind 
studies, among whom 739 (98.6 %) patients reported TEAEs.  
In the pooled data of all-causality TEAEs reported in the 3 completed double-blind, monotherapy 
studies, the most commonly reported TEAEs of grade ≥3 (≥5% of patients) included hypertension 
(19.9 %) and palmar-plantar erythrodysaesthesia syndrome (10.7 %).  
The incidence of the most commonly reported TEAEs (≥10% of patients) is provided in the current 
IB.  
The safety analysis that resulted in the identified risks was performed on the pooled data set from 
4 completed double-blind studies (N= 739 fruquintinib; N= 361 placebo), in which the incidence 
of adverse events (AEs) in fruquintinib-treated patients was compared with those in the placebo-
treated control patients.  The identified risks presented by Standardized Medical Dictionary for 
Regulatory Activities (MedDRA) Query (SMQ) are presented in Table 54 of the current IB.  
 
Benefit Assessment 
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 the current IB).  The results of two phase 2 proof-
of-concept (POC) studies provided evidence of clinical efficacy in patients with metastatic CRC 


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(Study 2012-013-00CH1, third or later lines therapy) and NSCLC (Study 2014-013-00CH1, third-
line therapy) as compared with placebo.  The PFS results established POC in both studies by 
meeting their respective primary efficacy endpoints.  Clinical efficacy was also provided by the 
phase 3, double-blind, placebo-controlled trial, 2013-013-00CH1 (FRESCO). 
 
Overall Benefit/Risk Conclusion 
The safety profile of fruquintinib is consistent with those of other anti-angiogenic therapies, 
particularly the small molecule tyrosine kinase inhibitors (ie, sorafenib, regorafenib, axitinib, and 
sunitinib), as demonstrated by the identified risks for fruquintinib (Section 2.1.5.1).  In addition, 
safety data from the completed and ongoing studies showed that fruquintinib was well tolerated, 
with most of the AEs reported as grade 1 to 2 (see current IB).  There have been no new or 
unexpected safety findings from the ongoing clinical trials to date. 
 
Study Rationale 
Colorectal cancer (CRC) is a major global health issue, with an estimated 1.8 million new cases 
and 880,000 deaths in 2018 worldwide (Bray 2018).  There is an unmet medical need for new 
medications that are safe and effective in patients with refractory mCRC who have progressed 
after treatment with, or had intolerable toxicity from, available standard systemic therapies. 
There is no standard of care after patients progress on-chemotherapy, relevant biologics and TAS-
102 or regorafenib.  In clinical studies performed in China, fruquintinib has demonstrated robust 
anti-tumor activity and was well tolerated.  Fruquintinib is approved in China for the treatment of 
patients with refractory mCRC.  The safety profile of fruquintinib from an ongoing phase 1/1b 
study in the US is consistent with those from clinical studies performed in China.  This global 
phase 3 trial is being conducted to confirm the results of the FRESCO trial conducted in China in 
patients with refractory mCRC. 
This is a randomized, double-blind, placebo-controlled, clinical trial to compare the efficacy and 
safety of fruquintinib in combination with the best supportive care (BSC) versus placebo in 
combination with BSC in patients with refractory mCRC who have progressed on, or were 
intolerant to TAS-102 and/or regorafenib. 


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3. 
OBJECTIVES AND ENDPOINTS 
 
Primary Objective 
To evaluate the overall survival (OS) of fruquintinib plus BSC compared to placebo plus BSC in 
subjects with refractory mCRC 
 
Secondary Objectives 
• To PFS of fruquintinib plus BSC compared to placebo plus BSC 
• To evaluate the objective response rate (ORR), disease control rate (DCR), and duration 
of response (DoR) 
• To assess the safety and tolerability of fruquintinib plus BSC compared to placebo plus 
BSC 
• To characterize the PK exposure of fruquintinib and metabolite M11 in subjects with 
refractory mCRC 
• To evaluate the effect of fruquintinib on cardiac repolarization, as detected by changes in 
electrocardiogram (ECG) QTc intervals, and the potential relationship with fruquintinib 
and M11 plasma concentrations 
• To explore the relationship between fruquintinib exposure and endpoints for efficacy and 
safety 
• To evaluate quality of life (QoL) as assessed by using QLQ-C30: cancer-specific; and 
EQ-5D-5L questionnaires 
• To assess resource utilization (for example, hospitalizations, concomitant medications) 
 
Exploratory Objectives 
• To assess potential predictive biomarkers of response to fruquintinib 
The objectives and corresponding endpoints are summarized in Table 4. 
Table 4 
Objectives and Corresponding Endpoints 
Tier 
Objectives 
Endpoints 
Primary 
To evaluate the overall survival (OS) of 
fruquintinib plus BSC compared to placebo 
plus BSC in subjects with refractory mCRC 
OS 
Secondary 
 
To evaluate progression-free survival (PFS) 
of fruquintinib plus BSC compared to 
placebo plus BSC  
PFS 
To evaluate the objective response rate 
(ORR), disease control rate (DCR), and 
duration of response (DoR) 
• 
ORR 
• 
DCR 
• 
DoR 


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Table 4 
Objectives and Corresponding Endpoints 
Tier 
Objectives 
Endpoints 
To assess the safety and tolerability of 
fruquintinib plus BSC compared to placebo 
plus BSC 
Safety including TEAEs, SAEs, deaths, ECG’s, 
and clinical laboratory abnormalities 
To characterize the pharmacokinetic (PK) 
profile of fruquintinib in subjects with 
refractory mCRC 
Observed plasma concentrations, estimated 
population PK and exposure parameters of 
fruquintinib and M11 
To evaluate the effect of fruquintinib on 
cardiac repolarization, as detected by 
changes in electrocardiogram (ECG) QTc 
intervals, and the potential relationship with 
fruquintinib and M11 plasma concentrations 
QTc interval and plasma concentrations of 
fruquintinib and M11 at specified time points 
To evaluate the relationship between 
fruquintinib exposure and endpoints for 
efficacy and safety 
Parameters describing exposure-response with 
efficacy (eg, OS) and safety (eg, AEs) 
endpoints 
 
To evaluate quality of life (QoL) as 
assessed by using QLQ-C30: cancer-
specific; and EQ-5D-5L questionnaires 
Changes in health status (QLQ-C30: cancer-
specific; and EQ-5D-5L) 
 
To assess resource utilization (for example, 
hospitalizations, medications) 
Resource utilization including all concomitant 
medications, days in hospital 
Exploratory  
To assess potential predictive biomarkers of 
response to fruquintinib 
• 
Change from baseline in ctDNA 
• 
Change from baseline in tumor markers 
(CEA) 
• 
Pharmacogenomics 
 
 


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4. 
STUDY PLAN 
Detailed information on the fruquintinib clinical trial program in China and in the US can be found 
in Appendix 4 of this protocol and also in the fruquintinib IB. 
 
Study Design 
This is a global, randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial 
to compare the efficacy and safety of fruquintinib in combination with BSC versus placebo in 
combination with BSC in advanced colorectal cancer patients who have progressed on or were 
intolerant to chemotherapy, biologics and TAS-102 or regorafenib. 
Metastatic colorectal cancer cannot be cured by surgery.  Therefore, treatment principals are 
primarily aimed at controlling disease progression and prolonging survival.  Standard first- and 
second-line therapy includes cytotoxic drugs such as 5-fluorouracil, oxaliplatin, and irinotecan; 
anti-VEGF therapy; and, if RAS wild type, anti-EGFR therapy.  After the first two lines of 
chemotherapy, standard third-line treatment is either TAS-102 or regorafenib.  There are currently 
no effective treatments for patients who have progressed on standard, approved therapies, and 
treatment options include reuse of prior therapies, clinical trials, or BSC.  Consequently, there is 
an unmet medical need for additional safe and effective treatment. 
 
Enrollment in Study 
After checking the eligibility criteria, subjects will be randomized into either fruquintinib in 
combination with BSC group (treatment group) or placebo in combination with BSC group 
(control group) in a 2:1 ratio (Figure 1). 
• Treatment group: Fruquintinib 5 mg PO, QD, plus BSC, 3 weeks on/ 1 week off, every 4-
week cycle). 
• Control group: Matching placebo 5 mg PO, QD plus BSC, 3 weeks on/ 1 week off, every 
4-week cycle. 
A treatment cycle is 4 weeks.  Patients’ safety assessment and drug accountability will be 
performed at each treatment cycle.  Continuous drug safety monitoring and assessment will be 
performed through the whole study period (including a 30-day observation period after the end of 
treatment). 
As described in Section 2, in the phase 3 FRESCO trial that led to the drug’s approval in China, 
fruquintinib improved the median overall survival in patients with metastatic colorectal cancer 
(mCRC) in a third line or later setting when compared to placebo (median OS 9.3 versus 6.6 
months); hazard ratio for death was 0.65 (95% CI, 0.51-0.83; P < 0.001) (Li 2018).  The results of 
the FRESCO study indicate that fruquintinib is a candidate therapy for patients with refractory 
mCRC globally, and provides the strongest rationale for the current clinical trial. 
Since the current standard of care for patients with mCRC in the US, EU, and Japan is different 
than it was in China during the conduct of the FRESCO trial, the current study is necessary to 
evaluate fruquintinib in a patient population that is representative of global treatment practices.  In 
FRESCO, prior therapy included the standard first two lines of cytotoxic chemotherapy 
(fluoropyrimidine-, oxaliplatin- and irinotecan-based), but only about 30% of patients had received 


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prior therapy with a VEGF inhibitor (bevacizumab), and patients with prior exposure to VEGFR 
inhibitors such as regorafenib were excluded. 
 
Rationale for the Electrocardiogram Collection and Pharmacokinetic Sampling 
Schedule 
In accordance with ICH E14 guideline, QT evaluation is expected to be routine in oncology drug 
development, and a thorough QT (TQT) study should be conducted, if possible.  In the case of 
fruquintinib, in view of nonclinical (hERG and CV safety study) and clinical data suggesting no 
apparent relationship between fruquintinib and QT prolongation, an alternative design to the TQT 
study has been chosen. 
In this study, changes in QTc interval following drug administration will be evaluated relative to 
the baseline measurement.  Electrocardiogram time points have been selected to match the 
expected PK profile of fruquintinib and metabolite M11.  The ECG time points have also been 
selected to explore a potential relationship between exposure and effect on QTc. 
In order to assess the QTc interval prior to exposure to fruquintinib, baseline triplicate ECG 
assessments will be performed prior to first study drug administration on cycle 1 day 1 (within 
30 minutes before dosing).  A baseline PK sample will also be collected at pre-dose, immediately 
after the ECGs have been collected and prior to the first dose of fruquintinib or placebo.  
Subsequently, the purpose of all other ECGs is to assess for potential prolongation of the QTc 
interval and other ECG changes as a result of fruquintinib administration, with ECG collection 
coinciding with PK measurements to establish correlations between ECG changes and drug 
exposure.  Triplicate ECGs, followed by blood samples for PK assessment, will be collected at 
multiple time points post-dose around Tmax of fruquintinib and M11 after the first dose and at 
steady-state as described in Table 2. 


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5. 
POPULATION 
 
Recruitment 
To randomize 522 patients, approximately 100 sites will be opened globally for patient 
recruitment.  
 
Definitions 
Subjects officially enter the Screening Period after providing informed consent, either directly or 
via a legally authorized representative. 
Subjects who withdraw from the study after signing the ICF and before the randomization will be 
considered screen failures.  Subjects who failed the original screening may be screened again using 
their original subject number as assigned by interactive web response system (IWRS).  A subject 
may only be re-screened once. 
A randomized subject is one who has been deemed eligible and has been assigned to a treatment 
group by IRT/IWRS.  
 
Inclusion Criteria 
Subjects may be enrolled in this study only if they satisfy all the following criteria: 
1. 
Provide written informed consent;  
2. 
Age ≥18 years; 
3. 
Histologically and/or cytologically documented metastatic colorectal adenocarcinoma;  
4. 
Subjects must have progressed on or been intolerant treatment with either 
trifluridine/tipiracil (TAS-102) or regorafenib if approved and available in the subject’s 
country.  Subjects are considered intolerant to TAS-102 or regorafenib if they have 
received at least 1 dose of either agents and were discontinued from therapy for reasons 
other than disease progression.    Subjects who have been treated with both TAS-102 and 
regorafenib are permitted.  Subjects must also have been previously treated with standard 
approved therapies: fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, 
an anti-VEGF biological therapy, and, if RAS wild-type, an anti-EGFR therapy. 
5. 
Subjects with microsatellite-high (MSI-H) or mismatch repair deficient (dMMR) tumors 
must have been treated with immune checkpoint inhibitors if approved and available in the 
subject’s country and if deemed appropriate; 
6. 
Subjects who received oxaliplatin in the adjuvant setting must have progressed within 6 
months of completion of adjuvant therapy;  
7. 
Body weight ≥40kg; 
8. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1;   
9. 
Have measurable disease according to RECIST Version1.1 (RECIST v1.1), assessed 
locally.  Tumors that were treated with radiotherapy are not measurable per RECIST v1.1, 
unless there has been documented progression of those lesions. 
10. 
Expected survival >12 weeks. 


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11. 
For female subjects of childbearing potential and male subjects 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, 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 criteria are applicable to male subjects 
involved in this clinical trial if they have a partner of childbirth potential, and male subjects 
must always use a condom. 
 
Exclusion Criteria 
Subjects are not eligible for enrollment into this study if they have any of the following criteria: 
1. 
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; 
2. 
Serum total bilirubin >1.5 × the upper limit of normal (ULN).  Subjects with Gilbert 
syndrome, bilirubin <2 X ULN, and normal aspartate aminotransferase (AST)/ alanine 
aminotransferase (ALT) are eligible;  
3. 
ALT or AST >2.5 × ULN in subjects without hepatic metastases; ALT or AST >5  × ULN 
in subjects with hepatic metastases;  
4. 
Serum electrolytes, potassium, calcium, or magnesium levels outside of the normal 
laboratory reference range, and clinically significant in the investigator’s judgment;  
5. 
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. 
6. 
Urine dipstick protein ≥2+ or 24-hour urine protein ≥1.0 g/24-h.  Subjects with greater 
than 1+ proteinuria on urinalysis must undergo a 24-hour urine collection.  For conversions 
between quantitative and qualitative results, please see Appendix 8;  
7. 
Uncontrolled hypertension, defined as: systolic blood pressure ≥140 mmHg and/or 
diastolic blood pressure ≥90 mm Hg despite optimal medical management;  
8. 
International Normalized Ratio (INR) >1.5 x ULN or activated partial thromboplastin time 
(aPTT) >1.5 × ULN, unless the subject is currently receiving or intended to receive 
anticoagulants for prophylactic purposes; 
9. 
History of, or 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, in the investigator’s judgment, result in gastrointestinal hemorrhage or 
perforation; within the 6 months prior to screening; 


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10. 
History or presence of hemorrhage from any other site (eg, hemoptysis or hematemesis) 
within 2 months prior to screening;  
11. 
History of a thromboembolic event, including deep vein thrombosis (DVT), pulmonary 
embolism (PE), or arterial embolism within 6 months prior to screening.  
12. 
Stroke and/or transient ischemic attack within 12 months prior to screening;  
13. 
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% by echocardiogram;  
14. 
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.  
15. 
Concomitant medications with a known risk of causing QT prolongation and/or Torsades 
de Pointes (See list in Appendix 3; source list is continuously updated online at 
www.crediblemeds.org). 
16. 
Systemic anti-neoplastic therapies (except for those described in Exclusion Criterion 18) 
or any investigational therapy within 4 weeks prior to the first dose of study drug, including 
chemotherapy, radical radiotherapy, hormonotherapy, biotherapy and immunotherapy;  
17. 
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;  
18. 
Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the initiation of 
study drug;  
19. 
Brachytherapy (ie, implantation of radioactive seeds) within 60 days prior to the first dose 
of study drug. 
20. 
Use of strong inducers or inhibitors of CYP3A4 within 2 weeks before the first dose of 
study drug (see Appendix 3 for a list of applicable drugs); 
21. 
Surgery or invasive procedure (ie, a procedure that includes a biopsy; central venous 
catheter placement is allowed) within 60 days prior to the first dose of study drug or 
unhealed surgical incision; 
22. 
Any unresolved toxicities from a previous antitumor treatment greater than National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) v5.0 
grade 1 (except for alopecia or neurotoxicity grade≤2). 
23. 
Known human immunodeficiency virus (HIV) infection;  
24. 
Known history of active viral hepatitis.  For subjects with evidence of chronic hepatitis B 
virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if 
indicated.  Subjects with HCV infection who are currently on treatment are eligible if they 
have an undetectable HCV viral load. 


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25. 
Clinically uncontrolled active infection requiring IV antibiotics;   
26. 
Tumor invasion of a large vascular structure (eg, pulmonary artery, superior or inferior 
vena cava);   
27. 
Women who are pregnant or lactating;  
28. 
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; 
subjects requiring steroids within 4 weeks prior to start of study treatment are excluded; 
29. 
No other malignancy, except for non-melanoma skin cancer, in situ cervical ca or bladder 
ca (Tis and T1) that have been adequately treated during the 5 years prior to screening;  
30. 
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;  
31. 
Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory 
result, or any other condition (eg, current alcohol or drug abuse) that investigators suspect 
may prohibit use of the investigational product, affect interpretation of study results, or put 
the subject at undue risk of harm based on the investigator’s assessment;  
32. 
Known hypersensitivity to fruquintinib or any of its inactive ingredients. 
 


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6. 
STUDY CONDUCT 
 
Study Procedures 
 
Study Assessments 
The following procedures will be performed according to the schedule in Table 1.  All assessments 
must occur within ± 3 days (±1 day during cycle 1) from the scheduled date, unless otherwise 
noted.  
 
Informed Consent 
All subjects must sign the informed consent form (ICF) prior to any study-related examinations 
or protocol procedures.  Tumor assessments completed as standard of care prior to signing the 
informed consent, but within 28 days of first dose of study treatment, may be used as baseline 
scans. 
All subjects who sign ICF are to be entered into the IWRS system.  The system will generate a 
subject identification number, which will be assigned to the subject. 
 
Medical History 
A complete medical history, including the subject’s medical history, disease history and prior 
therapies for disease prior to signing of the ICF, should be recorded at screening.  Comorbidities 
that began prior to signing the ICF should be recorded and followed as medical history. 
 
Tumor Diagnosis and Treatment History 
Tumor diagnosis should include the date of primary diagnosis of CRC and its type, disease stage, 
the date of first metastasis, type of previous treatment, start and end date/s, best overall response, 
date of PD, adverse reaction with severity ≥ grade 3.  Prior use (yes/no) of trifluridine/tipiracil 
(Lonsurf®, TAS-102), regorafenib (Stivarga®), or both of these drugs, prior use of 
fluoropyrimidine-, oxaliplatin, and irinotecan-based chemotherapy.  Prior use of a biological anti-
VEGF therapy (yes versus no), prior RAS gene status (mutant versus wild type). 
If the RAS gene test was not performed previously, it should be performed during screening.  In 
subjects who are RAS wild type, anti-EGFR therapy must be offered unless medically 
contraindicated. 
The subject’s history of radiation therapy, including the start and end date/s and the site of radiation 
must be recorded.  Surgical history, including operations and less-invasive diagnostic or 
therapeutic procedures (such as GI endoscopy, biopsy, etc.), the start and end date/s, name of each 
procedure and operation site must also be recorded at screening and in the appropriate eCRF. 
 
Demographics 
Demographic characteristics, including date of birth, sex, ethnic group/race, and any relevant 
lifestyle habits should be recorded at screening and in the applicable eCRF (as permitted by local 
regulations). 


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Concomitant Medication and Procedures 
Concomitant therapy includes any prescription medications or over-the-counter preparations used 
by a subject.  All concomitant medications within 28 days before randomization must be recorded 
in the eCRF, including the generic name of the drug and daily dose, the reason/s for using the 
medication, as well as the start and stop date/s of the medication.  Concomitant medications should 
be reviewed during the study according to the schedule in Table 1. 
 
Comprehensive Physical Examination 
A comprehensive physical examination includes subject height, weight and general condition, as 
well as an examination of the head, heart, chest (including the lungs), abdomen, extremities, skin, 
lymph nodes, nervous system and additional areas/systems as clinically indicated. 
 
Limited Physical Examination 
Limited physical examination includes vital signs and any change from baseline, any new 
abnormalities, examination of weight, thorax, abdomen, and additional areas/systems as clinically 
indicated.  In order to assess changes from baseline and to evaluate for new abnormalities, the 
limited physical examination should assess for new or changed skin lesions, enlarged lymph nodes, 
palpable masses, and appropriate examination to address any subject-reported symptoms. 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
Subject performance status will be graded according to the Eastern Cooperative Oncology Group 
(ECOG) performance status scale at study visits as detailed in Table 1.  It is recommended that 
ECOG performance status scores be evaluated by the same investigator throughout the study.  
Details on the ECOG assessment and grading scale are available in Appendix 1. 
 
Vital Signs 
Vital signs include blood pressure, heart rate, respiration rate and temperature.  For subjects with 
a baseline history of hypertension or hypertension that develops on study, blood pressure should 
be monitored per institutional standard practice.  
 Hematology 
Hematology assessments include red blood cell count, hemoglobin, hematocrit, platelet count, 
white blood count with differential (absolute counts).   
Note: If neutrophil count ≤1.0×109/L or platelet count≤ 25 ×109/L, hematology assessments 
should be conducted per institutional standard practice.  
 Blood Chemistry 
The blood chemistry panel includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
creatinine, glucose, calcium, magnesium, phosphorus, total bilirubin, ALT, AST, ALP, lactate 
dehydrogenase, non-fasting total cholesterol, triglycerides, uric acid, total protein and albumin. 
Blood chemistry tests for subjects with ALT or AST increase by >3x ULN, or increase by >2x 
baseline value should performed per institutional standard practice. 


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Creatinine clearance (CrCl) rate (units, mL/min) should be calculated using the baseline serum 
creatinine (Scr) value according to the Cockroft-Gault formula: for males: Ccr = [(140 - age) × 
weight (kg)] / [72 × Scr (mg/dL) x ideal body weight (IBW)].  For females, the same formula 
should be calculated and multiplied by 0.85. 
 Coagulation 
Coagulation tests include prothrombin time (PTT), international normalized ratio (INR), and 
activated partial thromboplastin time (APTT). 
 Thyroid Function 
Thyroid function tests include serum free triiodothyronine (fT3), serum free thyroxine (fT4) and 
thyroid stimulating hormone (TSH). 
 Urinalysis 
Urinalysis parameters include urine pH, protein, glucose, and blood; microscopic for white blood 
cell and red blood cell count.  A 24-hour urine for quantitative protein must be collected from all 
subjects with ≥ 2+ proteinuria.  For conversions between quantitative and qualitative results, 
please see Appendix 8. 
 Pregnancy Test 
All female subjects of childbearing potential must complete a blood pregnancy test at screening 
and within 30 days at the Safety Follow Up Visit, and a urine pregnancy test on day 1 of every 
cycle starting at cycle 2.  Serum pregnancy test should be repeated for women with suspected 
pregnancy.  This is not applicable for postmenopausal female subjects (ie, no menses for 12 months 
without an alternative medical cause), and the date of menopause should be recorded instead.  
Pregnancy testing and contraception are not required for women with documented permanent 
sterilization (eg, hysterectomy, bilateral salpingectomy and bilateral oophorectomy, or tubal 
ligation). 
 Electrocardiograms Monitoring 
Single 12-lead electrocardiograms (ECG) will be collected in all subjects using standardized 
equipment, as described in Table 1, Table 2, and Table 3 during cycles 1 to 3.  ECGs from standard 
equipment will be evaluated for safety by the principal investigator.  In addition, continuous 12-
lead Holter monitor will be used for QTc evaluation during cycle 1 in a subset of subjects and will 
be sent for central reading (see below in Continuous 12-Lead Holter Monitor for QTc Evaluation 
for details).  From cycle 4 onward, ECG will only be performed as clinically indicated.  Vital signs 
will be measured, a symptom-directed physical exam will be conducted, and safety related blood 
samples will be collected as per the time points in Table 1.  These assessments should be completed 
before the start of any ECG recordings. 
Continuous 12-Lead Holter Monitor for QTc Evaluation 
Continuous ECG recordings using 12-lead Holter monitoring will be collected from the first 
approximately 120 patients (80 fruquintinib, 40 placebo) enrolled in the study to evaluate the 
effects of fruquintinib on ventricular repolarization.  The assessments will be conducted at pre-


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dose and post-dose on cycle 1 day 1 and cycle 1 day 21 at specific time points summarized in 
Table 2. 
Subjects should reside in a quiet setting without distractions (eg, television, cell phones and staff 
talking) at each scheduled time point for ECG measurements.  Subjects should rest in a supine 
position for at least 10 minutes before and 5 minutes after the scheduled time point and should 
refrain from talking or moving arms or legs.  Skin preparation should be optimal to obtain high 
quality ECGs; if deemed appropriate, the chest should be shaved and prepared with light abrasion. 
Continuous digital 12-lead Holter ECGs will be recorded as described in the ECG/Holter manual. 
Good quality 12-lead ECG selection and extraction will occur during a 10-minute timeframe 
starting 5 minutes before and ending 5 minutes after the scheduled ECG time point.  All Holter 
recorder devices (as supplied by the central ECG laboratory) will be of the same brand and model 
with the same software, and would have been recently serviced and calibrated.  Documentation 
describing the brand, type, software and service/calibration history of Holter recorders will be 
provided by the central ECG laboratory and archived at the site as well as in the sponsor’s study 
file.  Transfer of the Holter recordings and extraction of the ECG tracings will be performed as 
described in the ECG/Holter manual. 
Ten-second digital ECG tracings will be extracted from the Holter device in triplicate by the 
central ECG laboratory according to the following principles: 
• The actual time of dosing will be communicated to the central ECG laboratory on the 
Holter acquisition form completed by the site. 
• Using visual inspection or automated tools as appropriate, the central ECG laboratory 
will identify a period of stable HR on the continuous Holter tracing within ±5 minutes 
of the nominal ECG time point (determined relative to the actual dosing time for an 
individual subject).  Three 10-second ECGs will be extracted in close succession 
from this identified segment. 
• The scheduled time points for triplicate ECG extraction are summarized in Table 2. 
Unless warranted by a specific safety endpoint of the study, the Holter tracings will not be routinely 
analyzed for rhythm and conduction abnormalities.  These analyses will only be performed on 
individual subject’s Holter if warranted by TEAEs (eg, syncope). 
 Echocardiogram 
An echocardiogram should be done at Screening, cycle 2 day 1, and on day 1, every 3 cycles 
thereafter.  Assessment parameters include left ventricular ejection fraction and general assessment 
of cardiac function.  MUGAs are permitted if echocardiograms cannot be performed. 
 Tumor Evaluation/Imaging 
Tumor assessments will be performed at study visits specified in Table 1. 
All measurable and evaluable lesions should be assessed and documented using image-based 
evaluation.  All subjects are to be evaluated utilizing contrast-enhanced computed tomography 
(CT) scan of the chest, abdomen, and pelvis, or other acceptable cross-sectional imaging per 
RECIST v1.1.  Evaluations should include other areas of the body, as clinically indicated.  Disease 
status will be assessed by the investigator or designated site staff using RECIST v1.1.  The same 


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imaging procedure used to define measurable lesions at baseline must be used throughout the study 
for each subject, unless medically contra-indicated.  At the investigator’s discretion, other methods 
of assessment of measurable disease as per RECIST v1.1 may be used.   
Tumor assessments completed as standard of care prior to signing the informed consent, but within 
28 days of first dose of study treatment, may be used as baseline scans. 
Imaging for all subjects will also be collected for central storage.  Please refer to the study-specific 
central imaging manual for collection and shipping instructions. 
 Tumor Markers 
Assessment of serum carcino-embryonic antigen (CEA) levels will be performed according to the 
schedule in Table 1.  The dates of blood sampling must be recorded in the eCRF. 
 Circulating Tumor DNA 
Collection of circulating tumor DNA (ctDNA) will be collected according to the schedule in 
Table 1.  For collection and shipping instructions please refer to study specific laboratory manual. 
The dates of blood sampling must be recorded in the eCRF. 
 Subject Randomization 
On day -2 to day 1, after verifying the subject’s eligibility, the site will log into the IWRS and the 
subject will be randomized by the system.  The system will generate a serial number matching a 
bottle of investigational product in the site’s inventory.  The site will take investigational product 
with the serial number assigned by IWRS from inventory and dispense it to the subject.  The first 
dose should be administered on cycle 1 day 1. 
 Quality of Life Assessment 
A quality of life assessment, using QLQ-C30: cancer-specific; and EQ-5D-5L: general, must be 
performed during the screening visit as well as day 1 of each cycle until treatment is discontinued. 
 
Pharmacokinetics Evaluations 
 
Sample Collection and Handling 
Samples for PK analysis will be collected in all subjects according to the schedule in Table 2 and 
Table 3.  The actual dates and times of PK sampling should be recorded in appropriate eCRF.  In 
addition, the dates and times of the dose administered on the day of PK collection and one day 
before PK collection must be recorded in the eCRF. 
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided to the sites.  Collection, handling, storage, and shipment 
of samples must be under the specified, and where applicable, controlled temperature conditions 
as indicated in the laboratory manual. 


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Analytical Procedures 
Plasma samples will be analyzed to determine concentrations of fruquintinib and its active 
metabolite M11 using a validated, specific, and sensitive Liquid Chromatography-Tandem Mass 
Spectrometry (LC MS/MS) method. 
If required, then plasma samples may be analyzed to document the presence of circulating 
metabolites using a qualified research method. 
 
End of Treatment Visit  
Subjects who have completed the study or have discontinued study treatment will be asked to 
return to the investigational site to receive safety examinations and assessments within 7 (±3) days 
after the last dose of study drug. 
 
Safety Follow-Up Visit 
All subjects who have completed an End of Treatment Visit will have a Safety Follow-Up Visit.  
The Safety Follow-Up Visit will be conducted at 30 (±7) days from the EOT Visit. 
 
Efficacy Follow-Up 
Any subject who discontinues study treatment for any reason other than disease progression should 
be followed until progression is documented or until a new anti-cancer treatment is initiated for 
PFS assessment and until death for OS assessment. 
 
Survival Follow-Up 
Every 12 (±2) weeks after the End of Treatment Visit the investigator or their designee should 
call the subject to collect information related to survival status and their use of other anti-
cancer treatments, including drug name, dosage, treatment start and end dates, and efficacy.  
Information related to radiotherapy received after disease progression is also needed, including 
radiotherapy location, radiation dose, start date, and end date. 
 
Long-term Extension 
Subjects who are still on study treatment at the time of study completion may continue to receive 
study treatment if they are experiencing clinical benefit and no undue risks. 
Continued access will apply to this study only if at least 1subject is still on study treatment when 
study completion occurs.  The sponsor will notify investigators when the continued access period 
begins. 
 
Discontinuation or Withdrawal 
 
Permanent Discontinuation of Treatment 
The investigator has the right to discontinue a subject from the study for any medical condition 
that the investigator determines is in the best interest of the subject, reasons of non-compliance 
(eg, missed doses, visits), or pregnancy.  


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Any subject who discontinues treatment should be encouraged to return to the study site for an 
End of Treatment Visit and continue with the remaining study visits outlined in Table 1.  The 
primary reason for discontinuation must be recorded on the appropriate eCRF. 
Subjects may be discontinued from treatment for any of the following reasons: 
 Disease progression (according to RECIST 1.1), unless there is reasonable evidence of 
clinical benefit to justify continuation on the study treatment.  The continuation decision 
should be made by the investigators in consultation with the sponsor.  The disease 
progression date is the date when radiological disease progression is first reported according 
to RECIST 1.1 criteria. 
 
Withdrawal of consent;  
 
Intolerable toxicity;  
 
Poor subject compliance;  
 
Use of other antitumor treatment during the study;  
 
Pregnancy;  
 
Subject is lost to follow-up; 
 
The investigator or sponsor determines it is in the best interest of the subject; 
 
Study is terminated by the sponsor;  
 
Death; 
 
End of this study. 
 
Withdrawal from Study 
All study participants have the right to withdraw from the study at any time.  During the treatment 
period and follow-up period, a subject who withdraws consent to continue participation in the 
study will not be followed for any reason after consent has been withdrawn.  Every effort should 
be made to obtain information on subjects who discontinue study treatment but who do not 
withdraw consent to continue participation in the study.  If a participant withdraws consent for 
disclosure of future information, the sponsor may retain and continue to use any data collected 
before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
 
Replacement of Subjects 
Subjects will not be replaced in this study. 
 
Subjects Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
Before a participant is deemed lost to follow up, the investigator or designee must make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a 


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certified letter to the participant’s last known mailing address or local equivalent methods).  These 
contact attempts should be documented in the participant’s medical record. 
Should the participant continue to be unreachable, he/she will be considered to be withdrawn from 
the study.  
 
Study Termination 
The sponsor has the right to terminate the study prematurely.  Reasons may include efficacy, 
safety, or futility, among others.  Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
 
End of Study 
The end of the study defined as the last visit of the last subject in the study.  


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7. 
STUDY DRUGS 
 
Study Drug Administration 
Fruquintinib (at a dose of 5 mg) or matching placebo will be administered PO, QD, on a 3 weeks 
on, 1 week off schedule.  One treatment cycle is 4 weeks.  The administration time should be 
recorded accurately.  Study drug may be given either in the fasting state or after meals.  If dose 
adjustment is required, 1 mg fruquintinib or matching placebo capsules will be used. 
On days with PK collection, treatment should be administered at the site by a delegated study staff 
member. 
 
Description of Products 
Fruquintinib will be provided as 1 mg or 5 mg capsules for oral administration.  Matching placebo 
capsules for each strength will also be provided.   
 
Formulation, Storage, Preparation and Handling 
The investigational drugs are formulated as capsules, which are packaged in labeled bottles.  The 
drug information is provided in Table 5.  Additional information is available in the pharmacy 
manual. 
Table 5 
Information on Investigational Products 
Name 
Dosage 
Specification 
Administration Method 
Fruquintinib 
Capsule 
5 mg 
Oral 
Fruquintinib 
Capsule 
1 mg 
Oral 
Matching placebo* 
Capsule 
5 mg 
Oral 
Matching placebo * 
Capsule 
1 mg 
Oral 
* The appearance of the matching placebo is identical to that of the study drug. 
All the investigational drugs should be sealed and stored in a secure, limited access area under 
appropriate conditions.  The storage temperature should be between 10℃ to 30℃.  Investigational 
drugs should not be used beyond expiration date provided by the manufacturer. 
The temperature-monitoring log should be recorded and filed in the study binder. 
 
Drug Accountability 
 
Assignment/Disposal (Study Site) 
All study drug required for this study will be provided by Hutchison MediPharma Limited.  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. 


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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 Limited 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. 
 
Drug Return (Subject) 
On day -2 to day 1, only subject randomization and drug assignment will be performed.  The first 
dose of study drug should be administered on C1D1.  Subjects will be provided with a pill diary 
at randomization and be instructed on how to account for each day’s dose appropriately.  Subjects 
should return all unused study drug and containers from the previous cycle on day 1 (date of 
scheduled visits) of each subsequent cycle, and new study drug will be dispensed on the same day.  
Site study staff should review subjects pill diary and provide a new diary if necessary at the day 1 
visit of each cycle. 
If a dose adjustment is required (eg, decrease from 5 mg QD to 4 mg QD), the subject must return 
to the investigational site and return all unused study drug.  The site must log into the IWRS, adjust 
the dose, reassign the drug serial number, and dispense new study drug dose (in 1 mg capsules) to 
the subject.  If the dose is adjusted a second time, ie, from 4 mg QD to 3 mg QD, the site must log 
into the IWRS and record the second dose adjustment.  On this occasion, it is not necessary to 
reassign a new drug serial number.  If tumor evaluation shows PD during the previous cycle and 
new drug has been dispensed, the subject must return all unused study drug on the 30-day safety 
visit after EOT. 
 
Treatment Assignment and Bias Minimization 
 
Treatment Allocation 
Treatment will be allocated using IWRS randomization strategy and procedure (refer to the IWRS 
manual).  After screening, subjects who meet the eligibility criteria will be randomized into the 
fruquintinib or placebo group in a 2:1 ratio.  Randomization will be stratified by:  
• Prior therapy with trifluridine/tipiracil (TAS-102) versus regorafenib versus both 
trifluridine/tipiracil (TAS-102) and regorafenib;  
• RAS status (wild type versus mutant); and  
• Duration of metastatic disease (≤ 18 months versus > 18 months).  
 
Extent and Maintenance of Blinding 
The study subject, investigators, and study site personnel will remain blinded to all randomization 
assignments throughout the study except for the specific circumstances described in Section 7.3.3.  
The sponsor’s study director, study monitor, and any other sponsor and contract research 
organization (CRO) personnel who are in regular contact with the study site will remain blinded 
to all subject randomization assignments, except sponsor pharmacovigilance personnel for the 
purpose of IND safety reports. 


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Unblinding Procedures 
 
Emergency Unblinding 
Unblinding can occur in emergency cases.  If unblinding is required for treatment of a subject for 
an SAE, the investigator must first contact the sponsor’s medical monitor before unblinding, and 
then unblind the subject using the IWRS.  Once unblinded, the subject should discontinue the 
treatment but will continue to be followed for safety and efficacy.  The investigator should record 
the event in the source document. 
 
Assessment and Verification of Compliance 
The investigator is responsible for ensuring the subject’s treatment compliance.  The sponsor will 
provide supervision through on-site monitoring visits made by its representatives.  The 
investigators should maintain complete and accurate records of drug use.  The dosing regimen and 
subject’s actual dosing should be recorded in the original treatment records as well as eCRF.  At 
each treatment visit, the investigators or study staff should comprehensively assess the subject's 
treatment compliance according to the drug dispensing and return status at each visit and the actual 
dosing conditions, such as missed doses and overdosing reported by the subject.  The subjects must 
return all drug bottles and remaining capsules at the end of the study.  The investigational sites 
must return all remaining supplies and drugs to the sponsor or provide evidence of destruction at 
the conclusion of the study.  
 
Prior and Concomitant Therapies 
 
Prohibited Therapies 
Any therapy intended for the treatment of cancer (with the exceptions as noted in Section 7.5.2, 
whether currently marketed or experimental, is prohibited.  This includes, but is not limited to, the 
following: chemotherapy, hormonal therapy, biologic therapy, radiotherapy, or herbal therapy. 
Concomitant use of medications that have a known risk of causing QT prolongation and/or 
torsades de pointes (see “combined” list at http://www.crediblemeds.org, with attention to those 
drugs listed as KR (“known risk”).  
 
Permitted Therapies 
Concomitant therapy includes any prescription medications or over-the-counter preparations used 
by a subject.  All concomitant therapy within 28 days prior to randomization and the Safety Follow 
Up visit.  All concomitant medications should be reported to the investigator and recorded on the 
appropriate eCRF. 
Subjects who use oral contraceptives, hormone-replacement therapy, or other allowed 
maintenance therapy may continue their use if indicated. 
Prophylactic use of anticoagulation for the maintenance of patency of permanent indwelling 
central venous access devices or for subjects at high risk of venous thromboembolism is permitted 
during study treatment.  If subjects are receiving anti-coagulation, they should be very closely 
monitored for potential hemorrhage, and: 


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The investigator should closely monitor subjects 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 subjects that report grade ≥2 hemorrhagic events at any site, based on an individual 
assessment of the risk-benefit balance (See Appendix 6 for additional information on the clinical 
management of severe or serious hemorrhagic AEs). 
Subjects that develop arterial thromboembolic events should discontinue the study drug.  If a 
subject 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. 
Prophylactic antiemetic, granulocyte colony stimulating factors, granulocyte macrophage colony-
stimulating factors, platelet simulating factors or erythropoietin are permitted as clinically 
indicated. 
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. 
All supportive measures consistent with optimal subject care will be given throughout the study. 
 
Drug-Drug Interactions 
In vitro metabolism data indicate that CYP3A plays an important role in the metabolism of 
fruquintinib.  The potential effects of medications that can affect the PK of fruquintinib via the 
CYP3A pathway have not been tested in the clinic.  Therefore, medications that are strong inhibitor 
or strong inducer of CYP3A should not be administered concomitantly with fruquintinib.  
Examples of these medications to avoid are listed in Appendix 3.  
In vitro, fruquintinib is shown to have the potential to inhibit P-gp and BCRP (see Section 2.1.3.2).  
Avoid concomitant use with medications that are sensitive substrates of P-gp or BCRP where 
possible.  If used together, monitor subjects more frequently for adverse reactions, and consider 
dose reduction of the P-gp or BCRP substrate medication.  Examples of the medications that are 
sensitive substrates of P-gp and BCRP are listed in Appendix 3. 
Fruquintinib shows pH-dependent solubility (ie, solubility at pH 6.0–6.5 < solubility at pH 1–2) 
and is less well absorbed as gastrointestinal pH increases.  Subjects should avoid using proton 
pump inhibitors (eg, esomeprazole, lansoprazole, pantoprazole) during the study.  If concomitant 
use of an acid-reducing agent is unavoidable, H2-antagonist (eg famotidine, ranitidine, nizatidine) 
may be used but should be administered approximately 10 hours before or 2 hours after 
fruquintinib dosing.  Antacid may be used, but the antacid dose should be administered at least 2 
hours before or 2 hours after fruquintinib dosing. 
 
Rescue Therapies 
Not applicable. 


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General Dose Adjustment Note 
The severity of AEs will be graded according to the NCI CTCAE v5.0.  Reasons for dose 
modifications or delays, the supportive measures taken, and the outcome should be documented 
in the subject’s chart and recorded in the eCRF. 
• For any concomitant conditions already apparent at baseline, the dose modifications 
will apply according to the corresponding shift in toxicity grade, if the investigator feels 
it is appropriate.  For example, if a subject 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 can be continued at the same dose.  
• To recover from acute toxicity, unless otherwise indicated, the treatment can be delayed 
for up to 14 days.  If a treatment delay longer than 14 days is required, treatment should 
be discontinued.  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. 
 
Dose Modification Guidance 
 
Dose Modification Sequence by Starting Dose and for General Hematologic and 
Non-Hematologic Toxicity 
The dose reduction sequence by starting dose is shown in Table 6.  Subjects are allowed to have 
no more than 2 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 (see Table 6).  Once a dose has been 
reduced, it cannot be re-escalated. 
Table 6 
Dose Modification Sequence by Starting Dose  
Dose Level 0* 
(Original dose) 
5 mg QD 3 weeks on, 1 week off 
Fruquintinib of 5 mg, 1 capsule, or 
1 capsule of the matching placebo  
Dose Level -1* 
(the 1st dose reduction) 
4 mg QD 3 weeks on, 1 week off 
Fruquintinib of 1 mg, 4 capsules, or 
4 capsules of the matching placebo 
Dose Level -2* 
(the 2nd dose reduction) 
3 mg QD 3 weeks on, 1 week off 
Fruquintinib of 1 mg, 3 capsules, or 
3 capsules of the matching placebo 
* Doses are daily, on days 1-21 each 28-day cycle (3 weeks on, 1 week off) 
 
Dose reduction guidelines for haematologic and non-haematologic toxicities, other than Palmar-
plantar erythrodysesthesia (PPE), Proteinuria, Hypertension, Decreased platelet count, 
Hemorrhage, and liver function impairment, are shown in are shown in Table 7.  Treatment should 
be held until AE/toxicity resolves or improves to ≤ grade 1.  If a subject has a grade 3 toxicity that 


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is expected to be manageable and reversible with a dose reduction, treatment should be held until 
toxicity resolves to ≤grade 1.  Subjects with grade 3 non-haematologic toxicity not described 
below that does not resolve to ≤grade 1 within 14 days should permanently discontinue the study 
drug unless approval to continue is obtained in writing from the sponsor. 
Table 7 
Dose Modification Recommendations for Hematologic and Non-
Hematologic Toxicity 
NCI CTCAE v5.0 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. 
 
Dose Modification for Important Identified Risks 
The dose modification and treatment suggestions for specific identified risks are provided in 
Table 8(PPE), Table 9 (proteinuria), Table 10 (hypertension), Table 11 (decreased platelet 
count), Table 12 (hemorrhage at any site), and Table 13 (abnormal liver function). 
Table 8 
Dose Modification for Palmar-Plantar Erythrodysethesia 
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 
Hold treatment.  Resume at 
the same dose 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.   
Hold treatment.  Dose 
reduce and resume 
treatment at the next lowest 
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. 
 


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Table 9 
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) 
Hold treatment.  Dose reduce 
and resume treatment at the 
next lowest dose level 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 
Hold treatment.  Dose reduce 
and resume treatment at the 
next lowest dose level 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 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. 
 
Table 10 
Dose Modification for Hypertension 
AE Grading 
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 mm Hg 
(or <130/80 mm Hg in subjects 
with chronic renal disease and/or 
diabetes).  
 
Refer to Appendix 7.   
Grade 3: SBP ≥ 160 mmHg or 
DBP ≥100mmHg; or more than 
one drug or more intensive 
therapy are used 
If BP >160/100mmHg lasts for >7 days 
after initiation of anti-hypertensive 
treatment or modification of current anti-
hypertensive treatment, treatment should 
be held.  If hypertension resolves to 
grade 1 or baseline level within 14 days, 
treatment should be resumed at the next 
lowest dose level. 
Treatment objective: lower the 
blood pressure to <140/90 mmHg 
(or <130/80 mm Hg in subject 
with chronic renal disease and/or 
diabetes).  
 
Refer to Appendix 7. 
Grade 4: Life threatening (eg, 
malignant hypertension, 
temporary or permanent 
neurological deficits and 
hypertensive crisis) 
Permanently discontinue study 
treatment. 
Emergent medical treatment. 


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Table 11 
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 
Hold treatment.  Resume at the 
same dose if 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. 
Hold treatment.  Dose reduce and 
resume treatment at the next lowest 
dose level if 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  
Hold treatment.  Dose reduce and 
resume treatment at the next lowest 
dose level if the AE recovers 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 
Permanently discontinue study 
treatment. 
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 12 
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 
Permanently discontinue study treatment. 
Emergent medical 
interventionb 
a Refer to Appendix 6 for clinical management of severe or serious hemorrhage. 
b The investigator should closely monitor subjects 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 subjects that 
report grade ≥2 hemorrhagic events at any site, based on an individual assessment of the risk-benefit balance 
(See Section 7.5.2). 
 
Table 13 
Dose Adjustment for Abnormal Liver Function 
AE Gradinga 
Dose Adjustment 
Treatment Suggestions 
Grade 1 
None. 
Follow up per planned 
schedule. 


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Table 13 
Dose Adjustment for Abnormal Liver Function 
AE Gradinga 
Dose Adjustment 
Treatment Suggestions 
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 alkaline phosphatase 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 8.2.2 for special 
reporting requirements and Appendix 5 for additional information regarding Hy’s Law. 


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8. 
SAFETY MONITORING 
 
Definitions 
 
Adverse Event 
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 v5.0. 
 
Serious Adverse Event 
An AE is considered “serious” if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes:  
• Death 
• A life-threatening AE.  An event is considered “life-threatening” if, in the view of the 
investigator, its occurrence places the subject at immediate risk of death.  It does not 
include an AE or suspected adverse reaction (AR) that, had it occurred in a more severe 
form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject or patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
Adverse Event Reporting 
 
Adverse Event Reporting Period 
After informed consent, but prior to initiation of study drug, all serious adverse events (SAEs) 
regardless of attribution will be collected.  After initiation of study drug, all SAEs and AEs 
regardless of attribution will be collected until 30 days after 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. 
 
Expedited Reporting 
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 


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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: 
• SAEs (from informed consent to 30 days following the last dose of study drug or a new 
treatment of anti-tumor therapy), 
• Abnormal hepatic function is defined as serum AST or ALT ≥3 × ULN together with total 
bilirubin ≥2 × ULN, regardless of seriousness. 
o For management for hepatic function abnormal event, refer to Table 13 (Dose 
Adjustment for Abnormal Liver Function).  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 alkaline phosphatase (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 Appendix 5 (Clinical Evaluation of Possible Drug-
Induced Liver Injury (DILI) for additional information regarding Hy’s Law. 
• CTCAE grade ≥3 hemorrhagic event, 
o When there is a grade ≥3 hemorrhagic event per NCI CTCAE (Version 5.0).  The 
management of severe or serious hemorrhagic events will be conducted according 
to Appendix 6 (Clinical Management of Severe or Serious Hemorrhagic Events).   
• Pregnancy, 
 
Eliciting Adverse Events 
A consistent methodology of non-directive questioning for eliciting AEs at all subject 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?” 
 
Assessment of Severity 
Investigators will seek information on AEs and SAEs at each subject contact.  All AEs and 
SAEs, whether reported by the subject or noted by authorized study personnel, will be recorded 
in the subject’s medical record and on the appropriate AE/SAE form. 
For each AE and SAE recorded on the applicable eCRF, the investigator will make an assessment 
of severity through clinical description by referring to the five-grade determination standard in the 
NCI CTCAE v5.0.  Please use the guideline below for the assessment of severity when the 
observed or reported AE is not listed in the NCI CTCAE v5.0: 


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• 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. 
Note: 
*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. 
 
Causality assessment 
Investigators should use their knowledge of the subject, the circumstances surrounding the AE, 
and an evaluation of any potential alternative causes to determine whether or not an AE is 
considered to be related to the study drug.  To ensure consistency of causality assessments, 
investigators should apply the general guidelines in provided as below: 
 
• Related: There is a reasonable possibility that the event may have been caused by the 
product under investigation.  Factors that point toward this assessment include but are not 
limited to: a positive re-challenge, a reasonable temporal sequence between administration 
of the drug and the event, a known response pattern of the suspected drug, improvement 
following discontinuation or dose reduction, a biologically plausible relationship between 
the drug and the AE, or a lack of an alternative explanation for the AE. 
 
• Not Related: There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established. 
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. 
 
Documenting Adverse Events 
When an AE or SAE is recorded, the preferred medical terminology or concept should be used.  
Abbreviations and colloquialisms (eg, jargon or slang) should be avoided. 
All AEs (including SAEs) should be recorded on the AE eCRF, and the check box for “Serious” 
should be ticked for entries that fit the criteria for SAEs.  The investigator should also complete 
an SAE report and submit this to the sponsor or its designee within 24 hours of knowledge of the 
event.  


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Only one medical concept should be recorded in the event field on the eCRF. 
 
Diagnosis versus Symptoms and Signs 
If known, a diagnosis should be recorded on the eCRF rather than individual signs and symptoms 
(eg, hepatic failure should be recorded instead of jaundice, asterixis, and elevated transaminases).  
However, if a constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded as an AE 
or SAE on the eCRF.  If a diagnosis is subsequently established, it should be reported as follow-
up information. 
 
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 eCRF 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 eCRF.  For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the eCRF. 
 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution between subject evaluation 
time points.  Such events should only be recorded once in the eCRF.  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 and resolves between subject evaluation time points and 
subsequently recurs.  All recurrent AEs should be recorded on the eCRF respectively. 
 
Abnormal Laboratory Values or Abnormal Vital Signs 
Not every laboratory abnormality/abnormal vital sign qualifies as an AE.  A laboratory test 
result/abnormal vital sign must be reported as an AE if it is a change from baseline and meets any 
of the following criteria:  
• Accompanied by clinical symptoms,  
• Results in a change in study treatment (eg, dosage modification, treatment interruption, or 
treatment discontinuation),  
• Results in a medical intervention (eg, potassium supplementation for hypokalemia) or a 
change in concomitant therapy,  
• Clinically significant in the investigator’s judgment.  
Investigators are responsible for reviewing all laboratory findings and abnormal vital signs and 
determining whether or not each abnormality should be reported as an AE. 


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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 eCRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the eCRF.  If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE.  For example, an elevated serum potassium level of 7.0 mmol/L should be recorded as 
“hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the eCRF, unless their severity, seriousness, or 
etiology changes. 
 
Preexisting Medical Condition 
A preexisting medical condition is one that is present at screening.  Such conditions should be 
recorded on the eCRF 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 eCRF, it is important to convey the concept that the preexisting condition has changed by 
including applicable descriptors (eg, “more frequent headaches”). 
 
Pregnancy 
A female subject 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 of awareness to the sponsor (the reporting period for pregnancy 
continues up to 30 days after completion of the study drug).  The investigator should counsel the 
subject and discuss the risks of continuing with the pregnancy and the possible effects on the fetus.  
Monitoring of the subject should continue until outcome of the pregnancy.  Pregnancies occurring 
up to 30 days after the completion of the study drug must also be reported to the investigator. 
Male subjects 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. 
Pregnancy loss of any kind should always be classified as serious AE (as the sponsor considers 
these medically significant), recorded on the eCRF, and expeditiously reported to sponsor. 
Any congenital anomaly/birth defect in a child born to a female subject or female partner of a male 
subject exposed to the investigational product should be recorded and reported as an SAE. 
 
Worsening of Solid Tumor 
Worsening and/or progression of the subject’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. 


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Death 
All deaths that occur during the protocol-specified AE reporting period must have the underlying 
cause reported to the sponsor as an SAE with death listed as the outcome.  Deaths due solely to 
the progression of disease must also be reported to the sponsor as an SAE.  Death events that occur 
after 30 days following last dose of study drug must be reported to the sponsor as an SAE only if 
it is confirmed as related to study drug.  If the primary cause of death is unknown and cannot be 
ascertained at the time of reporting, please record “Unknown cause death” on the eCRF, and the 
“unexplained/unknown death” should be  reported expeditiously as an SAE.  The SAE should be 
reported before the specific cause of death has been determined. 
 
Duration of Follow-up for Adverse Events 
The investigator will follow all unresolved AEs and SAEs until the events are resolved or 
stabilized, the subject is lost to follow-up, subject death, or end of study.  Resolution of AEs and 
SAEs (with dates) should be documented on the appropriate eCRF and in the subject’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 eCRF. 
For some SAEs, additional case details deemed necessary to appropriately evaluate the SAE report 
(eg, hospital discharge summary, consultant report, or autopsy report) may be followed-up by 
telephone, fax, email, and/or a monitoring visit. 
All pregnancies that occur during the study should be followed until pregnancy outcome.  
 


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9. 
STATISTICAL ANALYSIS 
 
Statistics and Analysis Method 
A separate statistical analysis plan (SAP) will provide specific details on analytical methods.   
 
Statistical Hypothesis 
This study is designed to demonstrate superiority of fruquintinib plus BSC (treatment arm) over 
placebo plus BSC (placebo arm) in prolonging OS for subjects with refractory mCRC.  The study 
is designed to test the null hypothesis H0: λ=1.0 versus the alternative hypothesis Ha: λ < 1.0, 
where λ is the hazard ratio (treatment arm/placebo arm). 
 
Sample Size Rationale 
The total sample size and number of OS events required for efficacy assessment in the ITT 
population is calculated based on the following assumptions:  
• A one-sided significance level of 0.025;  
• Assuming an OS HR (treatment arm/placebo arm) of 0.73, this sample size yields 
approximately 80% statistical power to detect superiority of the fruquintinib arm over 
placebo arm.  If the true median OS for the placebo arm is 5 months, then the HR of 0.73 
corresponds to median OS of 6.8 months in the fruquintinib arm (median OS improvement 
of 1.8 months).   
• An enrollment rate of 30 subjects per month during the first 3 months and 50 subjects per 
month thereafter; 
• Yearly dropout rate of 10%; 
• Randomization ratio = 2:1; 
• Data maturity = 70%; 
• One interim futility analysis when 1/3 of the total number of OS events  (ie, 121 OS 
events) have occurred  
Under the premise of these assumptions, approximately 522 subjects will be randomized to this 
study over approximately 13 months in this study.  OS will be analyzed when 364 OS events are 
observed, which is expected to occur in approximately 7 months after the end of enrollment. 
In clinical practice, TAS-102 is used more commonly than regorafenib.  To ensure that the subject 
population is representative of clinical practice, post-regorafenib subjects will be capped at 
262 subjects if there is an unanticipated enrichment of that population.  This will ensure that at 
least 50% of the subjects will be post-TAS.  Subjects are considered in post-TAS-102 or post-
regorafenib populations if they have received at least one dose of either agent, respectively, prior 
to entering the study.  Based on the similar mechanisms of action between regorafenib and 
fruquintinib, it will be of clinical interest to evaluate the magnitude of benefit in each of the 
populations when compared to the ITT population. 
    


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Analysis Sets 
Intent-to-Treat (ITT) Population  
All randomized subjects will be included in the ITT population.  Subjects will be analyzed by 
treatment arm as randomized.  The ITT population will be the primary population for evaluating 
all efficacy endpoints and patient characteristics.   
Safety Analysis Population 
All randomized subjects who received at least one dose of study treatment will be included in the 
safety analysis population.  Subjects in this population will be analyzed according to the treatment 
they actually received.  This population will be used for all safety analyses. 
 
Primary and Secondary Endpoints 
 
Primary Endpoint 
The primary endpoint of the study is overall survival, defined as the time (months) from date of 
randomization to death from any cause.  Subjects without report of death at the time of analysis 
will be censored at the date last known alive. 
 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include PFS, ORR, DCR, and DoR.  
 
Progression-free Survival 
PFS is defined as the time (months) from randomization until the first radiographic documentation 
of objective progression as assessed by investigator using RECIST v1.1, or death from any cause.  
Subjects who did not die or progress will be censored at the date of last radiographic assessment.  
If no baseline or post-baseline radiologic assessment was available, the subject will be censored at 
the date of randomization.  The use of new anticancer therapy prior to progression will result in 
censoring at the date of last radiographic assessment prior to initiation of new therapy.  If death/PD 
occurred after two or more consecutive missed radiographic visits, subjects will be censored at the 
date of last radiographic assessment prior to missed visits.  
 
Objective Response Rate 
Objective response rate is defined as the proportion of subjects achieving a best overall response 
of confirmed complete response (CR) or partial response (PR), per RECIST v1.1, as determined 
by the investigator.  


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Disease Control Rate 
Disease control rate is defined as proportion of subjects achieving a best overall response of 
confirmed CR, PR, or SD, per RECIST v1.1, as determined by the investigator.  To be qualified 
for SD, the duration of SD should last for at least 6 weeks. 
 
Duration of Response 
Duration of response is defined as the time (months) from the first occurrence of PR or CR, 
whichever comes first, until the date of radiographic PD or death.  The duration of response will 
be determined for subjects with best overall response of confirmed CR or PR. 
 
Secondary Safety Endpoints 
Safety 
endpoints 
include 
AE, 
laboratory 
tests, 
vital 
signs 
and 
weight, 
ECG, 
echocardiogram/MUGA (especially LVEF) and ECOG PS.  
All AEs, whether related to the drug or not, will be recorded in the eCRF including the start/end 
date, measures taken, treatment affected (yes versus no) and the outcome.  For all the events, the 
causality with the treatment and the severity will be determined by the investigator. 
 
Other Endpoints 
 
Patient Reported Outcomes 
Quality of life will be assessed using EORTC QLQ-C30 and EQ-5D-5L questionnaires.  Quality 
of life score, change from baseline, subjects achieving minimally important difference (MID) 
cut-off, and time to deterioration (TTD) will be assessed. 
 
Assessment of Resource Utilization 
Health care resource utilization assessments such as physician visits, emergency room visits, 
hospital care (eg, inpatient and outpatient), drug prescriptions etc. will be assessed. 
 
Statistical Methods 
 
Analysis of Efficacy Endpoints 
Efficacy analyses will be based on ITT population.  All secondary endpoints based on radiological 
assessments of tumor burden will be derived from investigator assessment using RECIST v1.1.  
Additional sensitivity analyses may be performed and will be outlined in the SAP. 
9.2.5.1.1. Primary Endpoint - Overall Survival 
A 1-sided stratified log-rank test will be used for the comparison of OS of the fruquintinib with 
placebo group at a significance level of 0.025.  The same factors used for randomization will be 
used for stratification: prior therapy with TAS versus regorafenib versus both trifluridine/tipiracil 
(TAS-102) and regorafenib; RAS status (wild type versus mutant); and duration of metastatic 
disease (<18 months versus ≥18 months).  Kaplan-Meier methodology will be used to estimate the 
median OS and its 2-sided 95% Confidence Interval (CI) for each treatment arm.  Plots will be 
produced by treatment arm.  The Hazard Ratio (HR) will be estimated by stratified COX model 
including a 2-sided 95% Confidential Interval (CI).   


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9.2.5.1.2. Secondary Efficacy Endpoints (PFS, ORR, DCR, DoR)  
First secondary endpoint is to evaluate PFS in subjects with refractory mCRC treated with 
fruquintinib plus BSC versus placebo plus BSC.  The Fixed-Sequence Method will be used to 
adjust for multiple comparisons of OS between the fruquintinib plus BSC arm and the placebo 
plus BSC arm (primary endpoint) and PFS (first secondary endpoint).  If the primary endpoint 
analysis is significant at the 0.05 (two-sided) level, a superiority test of PFS in the first secondary 
endpoint will be done at the 0.05 (two-sided) significant level.  Kaplan-Meier methodology will 
be used to estimate the median PFS and its 2-sided 95% confidence interval (CI) for each treatment 
arm.  Plots will be produced by treatment arm. 
The hazard ratio (HR) will be estimated by stratified COX model including a 2-sided 95% CI.   
The estimates of DCR and ORR in each treatment group and their 2-sided 95% CIs will be 
presented.  Comparison of DCR and ORR between treatment groups will be performed using 
stratified Cochran-Mantel-Haenszel test.  The CI of difference in DCR and ORR between 
treatment groups will be calculated using the approximate normal distribution method of binomial 
distribution. 
Duration of response (DoR) will only be determined for subjects who responded (confirmed best 
overall response of CR or PR).  Statistical test will not be conducted, as subjects with response are 
not randomized.  Descriptive analysis will be adopted for DoR.  For each treatment group, results 
will be presented by Kaplan-Meier estimates and distribution curve. 
9.2.5.1.3. Subgroup Analyses 
Subset analyses may be conducted, for example, by age, performance status, prior lines of therapy, 
prior use of TAS-102, prior use of regorafenib, region, and others as deemed appropriate. 
 
Analysis of Safety Endpoints 
All safety parameters will be summarized and listed by using the safety population.  
TEAEs will be summarized by MedDRA system organ class (SOC) and PT.  The incidence and 
percentage of subjects with at least 1 occurrence of a preferred term will be included according to 
the most severe NCI-CTCAE version 5.0.  Relationship to study therapy (causality) will be 
summarized separately.  If more than one AE was recorded for a subject within a PT, the subject 
will be counted once in the most severe grade.   
Laboratory data will be summarized by visit.  All TEAEs and abnormal laboratory variables shall 
be evaluated by the NCI CTC AE Version 5.0 Classification System.  Other safety data including 
vital signs, ECG, ECOG PS will be summarized using descriptive statistics. 
 
Analysis of Other Endpoints 
9.2.5.3.1. Subject Reported Outcomes 
Subject reported outcomes will be assessed using EORTC QLQ-C30 and EQ-5D-5L 
questionnaires.  The number and percentage of subjects who completed the questionnaires will be 
summarized for each treatment arm by visit.  Reasons for non-completion will be presented.  
Quality of life scores and change from baseline scores will be compared between treatment arms 
using mixed model repeated measures approach adjusting for covariates.  For each scale, 


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appropriate minimally important difference (MID) cut-off will be determined and number and 
percent of subjects achieving the MID will be presented.  In addition, time to deterioration (TTD) 
will be summarized using Kaplan-Meier methodology.  
9.2.5.3.2. Resource Utilization 
Health care resource utilization data including number and percent of subjects hospitalized, 
reasons for hospitalizations, emergency room visits, drug prescriptions will be summarized. 
 
Pharmacokinetic and Pharmacodynamic Analyses 
 
Population PK and Exposure-Response Analyses 
Descriptive statistics (including but not limited to arithmetic mean, standard deviation, coefficient 
of variation, median, minimum, maximum and geometric mean) will be provided for the observed 
concentrations for fruquintinib and metabolite M11. 
Population PK analysis of plasma concentration-time data of fruquintinib and metabolite M11 will 
be performed using nonlinear mixed-effects modeling.  The population PK modeling will include 
all subjects with sufficient and interpretable PK assessments.  The data from the population PK 
samples may be combined together with the data from other studies for the population PK analysis.  
If relevant and sufficient data are available, the relationship of exposure to fruquintinib and M11 
to measures of efficacy and AEs may also be analyzed.  Details of the population PK and/or 
exposure-response analysis will be given in a population PK/pharmacodynamic analysis plan.  The 
results of the population PK/pharmacodynamic analysis will be presented in a separate report. 
 
Pharmacodynamic (ECG) Analysis 
Subjects who 1) receive at least 1 dose of study drug, and 2) have baseline and at least 1 post-dose 
ECG measurement will be evaluable for pharmacodynamic (ECG) evaluation.  Subjects who had 
reduced dosage, prolonged dose interruption of >2 days in cycle 1, or who had any dose 
interruption within 7 days before cycle 1 day 21, or were discontinued from the study prior to the 
completion of ECG data collection (cycle 1 day 21) will be excluded.  For each of the ECG 
parameters, the average values from the 3 readings of a triplicate ECG set will be used in the 
analysis. 
For all ECG parameters, the baseline will be defined as the mean values of the triplicate ECG 
measurements taken at pre-dose on cycle 1 day 1. 
 
QTc Intervals 
The terminology QTc is used in this section as a general notation for corrected QT intervals using 
any of the specified methods. 
The QT interval data will be corrected for heart rate using 2 correction methods (Fridericia – QTcF 
and Bazett – QTcB).  For each QTc correction method, the relationship between QTc and RR at 
baseline will be evaluated graphically by plotting the logarithm of baseline QTc values against the 
logarithm of corresponding RR intervals.  Fridericia will be used as the primary correction method 
for statistical analysis.  If the correlation between QTc and RR intervals remains significant using 
the Fridericia correction method, an alternative correction method may be considered for statistical 
analysis in addition to QTcF. 


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For the statistical analysis based on the primary correction method (QTcF), the mean changes from 
baseline (ΔQTc) at each time point will be summarized (mean, standard deviation, median and 
range, 2-sided 90% confidence interval).  The difference in ΔQTc between fruquintinib and 
placebo (ΔΔQTc) for each individual will also be calculated at each time point (individual ΔQTc 
for fruquintinib – mean ΔQTc for placebo at the same time point).  Mean values for the difference 
and 2-sided 90% CI for mean difference will be calculated at each time point. 
The primary analysis will focus on the maximum mean change from baseline in QTc (ΔQTc) on 
cycle 1 day 21, which will be estimated by the mean QTc change at around Tmax, the time when 
the maximum plasma concentration is reached (ie, steady state).  The same analysis will be 
performed for ΔQT data using other correction methods if data warrant.  The mean change from 
baseline in QTc (±standard deviation) over time will be plotted. 
In addition, QTc will be categorized based on ICH E14 guidelines.  Tables will present the number 
and percentage of subjects meeting or exceeding the following categories: 
• QTc interval prolongation: 
− Absolute values > 450 to ≤ 480 msec 
− Absolute values > 480 to ≤ 500 msec 
− Absolute values > 500 msec 
• QTc interval change from baseline: 
− Increase from baseline > 30 to ≤ 60 msec 
− Increase from baseline > 60 msec 
 
Heart Rate, QRS, and PR intervals 
For each treatment and time point of measurement, heart rate (HR), QRS interval and PR interval, 
as well as the change from baseline in HR, QRS and PR (∆HR, ∆QRS, ∆PR), will be summarized 
using descriptive statistics (mean, standard deviation, median, range, and 90% CI).  The number 
and percentage of subjects with HR >100 bpm will be tabulated for each time point.  The number 
and percentage of subjects with QRS >110 msec will be tabulated for each time point.  The number 
and percentage of subjects with PR >200 msec will be tabulated for each time point. 
 
T-wave and U-wave Morphology 
The number and percentage of subjects having T-wave morphology changes from baseline and/or 
the occurrence of abnormal U-waves that represent the appearance or worsening of the 
morphological abnormality will be summarized.  Subjects with abnormal ECG findings will be 
listed.  Additional analyses will be performed if deemed necessary. 
 
QTc-PK Analysis 
The potential relationship between QTc and PK will be evaluated using data from all subjects who 
have data from baseline and at least 1 post-dose ECG measurement following the first dose.  QTc 
change from baseline before and after correction for placebo (ΔQTc and ΔΔQTc) using the primary 
correction method (see Section 9.3.2.1) at each time point of measurement will be plotted against 


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the corresponding plasma concentrations of fruquintinib and M11 separately.  Additional plots will 
be produced, if deemed necessary. 
A linear mixed effects model will be fitted to the ∆QTc and ΔΔQTc data from cycle 1 day 1 and 
cycle 1 day 21 with either parent or metabolite concentration as a predictor and subject as a random 
effect; if the intercept term is not significant, the model will be re-fitted with a zero intercept term.  
Based upon these relationships, the predicted population average ΔQTc and ΔΔQTc as well as 
their corresponding upper 90% 2-sided confidence interval bound will be computed at the mean 
maximum plasma concentrations (ie, Cmax) of fruquintinib and M11, or other concentrations of 
interest. 
 
Interim Analysis 
An independent data monitoring committee (IDMC) will be convened to review accumulating 
safety data.  During the study, safety interim analyses will be performed approximately every 
6 months.  The frequency of safety interim analysis may be modified upon IDMC 
recommendation.   
One interim futility analysis will be performed when approximately 1/3 of the total number of OS 
events (ie, 121 OS events) had occurred.  This interim analysis is for futility only.  The IDMC will 
be instructed to recommend stopping the study for futility if the 1-sided p-value from a stratified 
log-rank test is at least 0.622 (corresponding to an observed HR of 1.062).  Otherwise, the study 
will continue with full enrollment.  There is a 37.8% chance of terminating the study for futility at 
the interim analysis if the true median OS in fruquintinib arm is 5 months, ie, fruquintinib is 
ineffective.  There is a 2.6% chance of stopping for futility, declaring fruquintinib ineffective at 
the interim if the true median OS in fruquintinib arm is 6.8 months, ie, fruquintinib is effective in 
our study population.   


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10. 
ETHICAL CONSIDERATIONS 
 
Quality Control and Quality Assurance 
The clinical study will be executed and reported following GCPs, all applicable regulatory 
requirements and applicable SOPs, including quality control of documents.  Deviations will be 
documented.  To ensure compliance, the sponsor may conduct one or several quality assurance 
audit(s).  
 
Ethics Review 
The Independent Ethics Committee (IEC) / Institutional Review Board (IRB) must review the 
protocol and amendments, investigator’s brochure, informed consent form, study-relevant 
materials (such as advertisements for subject recruitment) and any other essential documents.  
IEC/IRB approval is to be obtained prior to the study. 
All amendments are to be reviewed and approved by the IEC/IRB, applicable regulatory 
authorities (as required) and documented.  All unexpected SAEs should be reported to the sponsor, 
IEC/IRB and applicable regulatory authorities as required.  During the study, protocol deviations 
that may increase a subject’s risk should be reported to the IEC/IRB in a timely manner. 
 
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. 
 
Informed Consent 
Investigators or designees must obtain the signed informed consent form from subjects prior to 
conducting any study-related procedures.  The nature, objectives, and potential risks and benefits 
of participating in the study must be explained to subjects.  Subjects must be informed that they 
may withdraw consent to participate in the study without any limitations.  If the subject cannot 
sign the informed consent form, a legally acceptable representative of the subject must sign the 
informed consent form.  If the subject and the legally acceptable representative are not able to read 
and write, an impartial witness should be present throughout the whole process of providing 
informed consent.  Once the subject and the legally acceptable representative give their oral 
consent, the informed consent form should be signed by the impartial witness to confirm that the 
subject and the legally acceptable representative fully understand the study and their right to 
withdraw informed consent without any limitations.  Informed consent should be recorded in the 
CRF.  If the risk and benefit assessment changes after the safety analysis, the informed consent 
form needs to be reviewed and updated and all updated information should be provided to subjects 
(including subjects who have already received the study drug). 
 
Data Privacy 
All information about fruquintinib (such as patent application, formulation, manufacturing process 
and basic study information) is considered confidential as long as it is unpublished. 


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All information obtained in the study is considered confidential.  Hutchison MediPharma Limited 
will open the information to investigational personnel, the NMPA (National Medical Products 
Administration), and any other regulatory authority when necessary.  To ensure the completeness 
of the study analysis data, investigational personnel are accountable for providing all results and 
data to the sponsor. 
Investigators must guarantee the privacy of subjects by not disclosing subject-related information 
to third parties without authorization.  eCRFs and other documents submitted to the sponsor should 
not contain the subject’s name.  Subjects are identified only by Patient Code.  Investigators may 
retain the identification forms, which include subject numbers, names, and addresses.  Informed 
consent forms and other documents should be documented properly, and should not be given to 
the sponsor. 
 
Disclosure 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations. 
 
Biological Specimens and Data 
Subjects who agree to participate in a future biomedical research sub-study will be required to 
consent to this optional sub-study before samples are collected for long-term storage.  No 
additional samples will be collected for future biomedical research.  Samples will be single/double-
coded as defined by ICH guideline E15. 
The unused samples for study-related research, as well as unused PK samples, will be stored for 
up to 15 years after the final date of the database lock.  The unused samples may be utilized for 
future biomedical research.  After 15 years, any residual samples will be destroyed.  The results of 
these future biomedical research analyses will not be shared with subjects and will not be presented 
in the CSR. 
If there are specific site or country requirements involving the pharmacogenomic analyses that the 
sponsor is unable to comply with, samples will not be collected at those sites. 


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11. 
OVERSIGHT 
 
Independent Monitoring 
 
Independent Data Monitoring Committee 
An IDMC will be established in this study.  The IDMC will consist of at least 4 independent 
clinical oncology physicians and 1 independent statistician with no conflicts of interest with the 
sponsor.  The IDMC will evaluate the safety data regularly, and the patients’ safety will be 
determined by the evaluation of the risk/benefit at a regular review meeting.  The responsibilities 
of the IDMC will include: 
• 
Regular (approximately every 6 months) blinded review of the study data to provide 
suggestions such as “continue as planned, suspend, protocol amendment, terminate study” 
so as to prevent patients from being exposed to unsafe dose and treatment regimes. 
• 
Review of interim analysis data to provide suggestions such as “continue as planned, 
suspend, protocol amendment, terminate study.” 
Upon completion of the data review, the IDMC will provide suggestions on whether or not to 
continue the study, if modification of the protocol is recommended or if study termination is 
required.  The final decision shall be made by Hutchison MediPharma Limited.  The IDMC 
membership and governance is outlined in a separate IDMC charter. 
 
Quality Control and Assurance 
In accordance with ICH, the sponsor is responsible for quality assurance to ensure that the study 
is conducted, and the data are generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s).  The investigator is responsible for supervising 
any individual or party to whom the investigator delegates trial-related duties and functions 
conducted at the trial site.  The sponsor and investigator ensure that any individual or party who 
performs trial-related duties or functions on behalf of the sponsor/investigator is qualified to 
perform the trial-related duties or functions. 
The overall procedures for quality assurance of clinical study data are described in the sponsor or 
designee’s standard operational procedures.  The planned quality assurance and quality control 
procedures for the study are described in the following sections. 
 
Monitoring 
Monitors designated by the sponsor will contact and visit investigators at regular intervals to verify 
that data recorded in the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents, that the safety and rights of subjects are being protected, and that the study 
is being conducted in accordance with the current approved protocol version and any other study 
agreements, GCP, and all applicable regulatory requirements.  During regular visits, the monitors 
may verify CRFs for protocol compliance, data completeness, consistency, and accuracy.  
Monitors may also obtain laboratory test results and other records for verifying CRF accuracy.  
Investigators (or their designee) should cooperate with monitors to resolve questions raised during 
monitoring. 
The investigator must allow study-related monitoring. 


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Audits 
Authorized representatives of Hutchison MediPharma Limited, a regulatory/competent authority, 
and/or an IRB/IEC representative may visit the site to perform audits or inspections, including 
source data verification.  The purpose of an audit or inspection is to examine all study-related 
activities and documents systematically and independently to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines, and any applicable regulatory requirements.  The investigator should 
notify the sponsor (eg, CRA) listed within the protocol or other contacts provided immediately if 
contacted by a regulatory agency about an inspection. 
 
Protocol Deviations 
This protocol is monitored at several levels, as described elsewhere in this section.  The study 
principal investigator is responsible for monitoring the conduct and progress of the clinical trial, 
including the ongoing review of accrual, subject-specific clinical and laboratory data, and routine 
and SAEs; reporting of expedited AEs; and accumulation of reported AEs from other trials testing 
the same drug(s).  The sponsor and statistician have access to the data at all times. 
All study investigators at participating sites who register/enroll subjects on a given protocol are 
responsible for timely submission of data via the mechanism described elsewhere in this section.  
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
Records 
 Data Capture and Management 
The term case report form (CRF) or electronic case report form (eCRF) should be understood to 
refer to electronic data capture (EDC) system.  The EDC system is the database where pertinent 
study data are collected.  For all subjects, including screen failures, data will be collected on source 
documents first.  The principal investigator is responsible for assuring that the data entered into 
eCRFs is complete, accurate, and that entry and updates are performed in a timely manner.  Blood 
and tumor samples for PK and biomarkers assessments will be collected by study sites and sent to 
the designated central laboratory for processing.  Data from ECG will be collected at the study 
sites, and the data will be transmitted to a designated CRO for centralized analysis, as well as 
for further processing and data reconciliation.  Imaging data will be collected at the study sites, 
and a designated CRO will perform further processing, data reconciliation, and holding. 
At all times, the principal investigator has final responsibility for the accuracy and authenticity of 
all clinical and laboratory data entered in the EDC.  Subject source documents are the 
investigator's/physician's subject records maintained at the study site.  In cases where the source 
documents are the hospital or the physician's chart, the information collected in the EDC must 
match those charts.  All final data recorded in EDC system will be copied onto CDs and kept by 
the sponsor.  A copy of these CDs will also be kept at the clinical site.  All data recorded on source 
documents will be kept at the clinical site. 
The completed pages of the EDC system are the sole property of the sponsor and should not be 
made available in any form to third parties without written permission from the sponsor, except 
for authorized representatives of the sponsor or appropriate regulatory authorities. 


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 Source Documentation 
The investigator/institution should maintain adequate and accurate source documents and study 
records that include all pertinent observations on each of the site’s study subjects.  Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete.  Changes to 
source data should be traceable and not obscure the original entry.  Any changes should be 
explained if necessary (eg, via an audit trail). 
 Study Files 
For studies using eCRFs, Hutchison MediPharma Limited personnel (or designated CRO) will 
review the data entered by investigational staff for completeness and accuracy.  Electronic data 
queries stating the nature of the problem and requesting clarification will be created for 
discrepancies and missing values and sent to the investigational site via the EDC system.  
Designated investigator site staff is required to respond promptly to queries and to make any 
necessary changes to the data.  Concomitant treatments and prior medications entered into the 
database will be coded using the World Health Organization (WHO) Drug Reference List, which 
employs the Anatomical Therapeutic Chemical classification system.  Medical history/current 
medical conditions and AEs will be coded using the MedDRA terminology.  Samples collected 
for all third party data such as ECG, PK and biomarker will be processed centrally and the results 
will be sent electronically to HMP (or a designated CRO).  At the conclusion of the study, the 
occurrence of any protocol deviations will be determined.  After these actions have been completed 
and the data has been verified to be complete and accurate, the database will be declared locked. 
Authorization is required prior to making any database changes to locked data, by joint written 
agreement between the Head of Biostatistics and Data Management and the Head of Clinical 
Development.  For EDC studies, after database lock, the investigator will receive a CD-ROM or 
paper copies of the subject data for archiving at the investigational site. 
 Records Retention 
The study should be recorded accurately by investigators so that study data can be verified.  The 
study documents can be divided into two types:  investigator documents and subject source data.  
Investigator documents include protocol and amendments, the eCRF and data clarification forms, 
approvals and correspondence with the IEC and regulatory authorities, ICF, study drug records, 
study personnel curriculum vitae and authorization forms, and any other essential documents. 
Subject source data documents (recording primary efficacy/safety data) include clinic/hospital 
medical history, scheduled visit dates, original laboratory test results, ECG, electroencephalogram, 
radiological imaging, pathological and specific assessment reports, signed ICF, medical records, 
and subject screening forms.  The documents mentioned above should be properly stored by the 
investigator for 5 years after the study is completed.  If investigators need to transfer the documents 
to another party or place, the sponsor must be notified in advance. 
If the documents cannot be stored properly at the investigational site, the documents can be 
transferred by the investigator and sponsor to an approved storage facility.  The documents must 
be sealed for storage and easily found for review in the case of a regulatory authority audit.  If the 
documents are still in use, they can be copied and stored elsewhere. 


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Study Termination or Study Site Closure 
The sponsor and the investigator have the right to close out a site prematurely. 
Investigator’s Decision  
The investigator must notify the sponsor of a desire to close out a site in writing, providing at least 
30 days’ notice.  The final decision should be made through mutual agreement with the 
sponsor.  Both parties will arrange the close out procedures after review and consultation 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close out a study site in writing.  Reasons 
may include the following, among others:   
• The investigator has received all items and information necessary to perform the 
study, but has not enrolled any subject within a reasonable period of time  
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines   
• The total number of subjects required for the study are enrolled earlier than expected  
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CROs used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements.  The 
investigator shall promptly inform the subject and should assure appropriate subject therapy and/or 
follow-up.  
 


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12. 
PUBLICATION POLICY 
The study results may be published in scientific journals.  The names of investigators who make 
an important contribution to the study implementation and management, and personnel who make 
an important contribution to the study design, analysis, and interpretation (such as staff or 
consultants from Hutchison MediPharma Limited) will be listed in the publication.  Hutchison 
MediPharma Limited agrees to provide the article to investigators for review prior to publishing 
any study results.  Investigators must obtain approval from the sponsor before contributing to any 
related articles or abstracts. 
The property of confidential information belongs to Hutchison MediPharma Limited.  Without 
permission from Hutchison MediPharma Limited, the information cannot be used for any purpose 
other than this study. 


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


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14. 
REFERENCES 
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cancer/ colon-rectal-cancer/about/key-statistics.html; accessed February 12, 2019. 
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: 
GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.  
CA Cancer J Clin.  2018 Nov;68(6):394-424  
Duda DG, Batchelor TT, Willett CG, Jain RK.  VEGF-targeted cancer therapy strategies: current 
progress, hurdles and future prospects.  Trends Mol Med. 2007 Jun;13(6):223-30. 
Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, 
Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, GoldbergRM, Sargent DJ, 
Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group.  Regorafenib monotherapy 
for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, 
randomised, placebo-controlled, phase 3 trial.  Lancet 2013 Jan 26;381(9863):303-12. 
Izzedine H, Ederhy S, Goldwasser F, Soria JC, Milano G, Cohen A, Khayat D, Spano JP. 
Management of hypertension in angiogenesis inhibitor-treated patients.  Ann Oncol. 2009 
May;20(5):807-15. 
Jayson GC, Kerbel R, Ellis LM, Harris AL. Antiangiogenic therapy in oncology: current status 
and future directions.  Lancet.  2016 Jul 30;388 (10043):518-29. 
Koopman M, Kortman GA, Mekenkamp L, Ligtenberg MJ, Hoogerbrugge N, Antonini NF, Punt 
CJ, van Krieken JH.  Deficient mismatch repair system in patients with sporadic advanced 
colorectal cancer.  Br J Cancer.  2009 Jan 27;100(2):266-73. 
Li J, Qin S, Xu R, et al. Effect of fruquintinib vs placebo on overall survival in patients with 
previously treated metastatic colorectal cancer.  JAMA. 2018;319(24):2486-96. 
LONSURF® (trifluridine and tipiracil) Prescribing Information.  Taiho Pharmaceutical Co, Taiho 
Oncology, Inc. Princeton NJ, USA.  Revised Feb 2019 
Mayer R, Van Cutsem E, Falcone A, et al. Randomized Trial of TAS-102 for Refractory 
Metastatic Colorectal Cancer (RECOURSE). N Engl J Med 2015; 372: 1909-19. 
National Comprehensive Cancer Network (NCCN), Version 2019.  
STIVARGA® (regorafenib) Prescribing Information.  Bayer HealthCare Pharmaceuticals, Inc, 
Whippany NJ, USA.  Revised Apr 2017. 
Sun Q, Zhou J, Zhang Z, Guo M et al., Discovery of fruquintinib, a potent and highly selective 
small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy. Cancer Biol 
Ther. 2014;15 (12):1635-45. 


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15. 
APPENDICES 


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APPENDIX 1 
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 house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled, cannot carry on any self-care, totally confined to bed or 
chair 
5 
Death 
 
 


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APPENDIX 2 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST V1.1) 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, 
are presented below. 
1. Measurability of Tumor at Baseline 
1.1 Definitions 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
described below. 
1.1.1 Measurable Tumor Lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size as follows: 
• 10  mm by CT or magnetic resonance imaging (MRI) scan (CT/MRI scan slice 
thickness/interval no greater than 5 mm) 
• 10-mm caliper measurement by clinical examination (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 the short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and follow-up, only the 
short axis will be measured and followed.  
1.1.2 Non-Measurable Tumor Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or pathological 
lymph nodes with short axis ≥ 10 but < 15 mm) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, peritoneal 
spread, and abdominal mass/abdominal organomegaly identified by physical examination that is 
not measurable by reproducible imaging techniques. 
1.1.3 Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment, as outlined below. 
Bone Lesions: 
• Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques for measuring bone lesions.  However, these techniques can 
be used to confirm the presence or disappearance of bone lesions. 
• 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 as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 


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• Blastic bone lesions are non-measurable. 
Cystic Lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
• Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
Lesions with Prior Local Treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
1.2 Specifications by Methods of Measurements 
1.2.1 Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never more 
than 4 weeks before the beginning of the treatment. 
1.2.2 Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during the study.  Imaging-based evaluation should 
always be the preferred option. 
Clinical Lesions.  Clinical lesions will only be considered measurable when they are superficial 
and ≥ 10 mm in diameter as assessed using calipers (eg, skin nodules).  For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. 
Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung. 
CT, MRI.  CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 5 mm or less.  When CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  MRI is 
also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with intravenous 
(IV) contrast because of allergy or renal insufficiency, the decision as to whether a non-contrast 
CT or MRI (without IV contrast) will be used to evaluate the patient at baseline and during the 


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


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measurement.  All other pathological nodes (those with short axis ≥10 mm but <15 mm) should 
be considered non-target lesions.  Nodes that have a short axis of <10 mm are considered non-
pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum of diameters.  If lymph nodes are to be 
included in the sum, then, as noted above, only the short axis is added into the sum.  The baseline 
sum of diameters will be used as a reference to characterize further any objective tumor regression 
in the measurable dimension of the disease. 
All other lesions (or sites of disease), including pathological lymph nodes, should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required and 
these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal progression.” 
In addition, it is possible to record multiple non-target lesions involving the same organ as a single 
item on the Case Report Form (eCRF) (eg, “multiple enlarged pelvic lymph nodes” or “multiple 
liver metastases”). 
2.3 Response Criteria 
2.3.1 Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
• 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 (nadir), including baseline. In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 
The appearance of one or more new lesions is also considered progression. 
• Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum on study 
2.3.2 Special Notes on the Assessment of Target Lesions 
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even 
if the nodes regress to < 10 mm on study.  This means that when lymph nodes are included as 
target lesions, the sum of lesions may not be 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.  During the study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that the radiologist 


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may not feel comfortable assigning an exact measure and may report them as being too small to 
measure.  When this occurs, it is important that a value be recorded on the eCRF, as follows: 
• If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. If the lesion is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned and 
BML (below measurable limit) should be ticked. (BML is equivalent to a “less than” 
sign.) (Note: It is less likely that this rule will be used for lymph nodes since they usually 
have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm should be assigned in this circumstance 
as well and BML should also be ticked). 
To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm, and in that case BML should not be ticked. 
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly coalesced 
such that they are no longer separable, the vector of the longest diameter in this instance should be 
the maximum longest diameter for the coalesced lesion. 
2.3.3 Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions.  While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol. 
• Complete response (CR): Disappearance of all non-target lesions and (if applicable) 
normalization of tumor marker level.  All lymph nodes must be non-pathological in size 
(< 10 mm short axis). 
• Non-CR/Non-PD: Persistence of one or more non-target lesions and/or (if applicable) 
maintenance of tumor marker level above the normal limits 
• Progressive disease (PD): Unequivocal progression of existing non-target lesions. The 
appearance of one or more new lesions is also considered progression. 
2.3.4 Special Notes on Assessment of Progression of Non-Target Disease 
When the Patient Also Has Measurable Disease.  In this setting, to achieve unequivocal 
progression on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease in a magnitude that, even in the presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A 
modest increase in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 


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When the Patient Has Only Non-Measurable Disease.  This circumstance arises in some phase 3 
trials when it is not a criterion of study entry to have measurable disease.  The same general 
concepts apply here as noted above; however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden.  
Because worsening in non-target disease cannot be easily quantified (by definition: if all lesions 
are truly non-measurable), a useful test that can be applied when assessing patients for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in non-
measurable disease is comparable in magnitude to the increase that would be required to declare 
PD for measurable disease, that is, an increase in tumor burden representing an additional 73% 
increase in volume (which is equivalent to a 20% increase in diameter in a measurable lesion). 
Examples include an increase in a pleural effusion from “trace” to “large” or an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols as “sufficient 
to require a change in therapy.”  If unequivocal progression is seen, the patient should be 
considered to have had overall PD at that point.  While it would be ideal to have objective criteria 
to apply to non-measurable disease, the very nature of that disease makes it impossible to do so; 
therefore, the increase must be substantial. 
2.3.5 New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important.  There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal, that is, not 
attributable to differences in scanning technique, change in imaging modality, or findings thought 
to represent something other than tumor (for example, some “new” bone lesions may be simply 
healing or flare of preexisting lesions).  This is particularly important when the patient’s baseline 
lesions show partial or complete response.  For example, necrosis of a liver lesion may be reported 
on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease.  If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
(18) F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly, possible “new” disease).  New lesions on the basis of FDG-PET imaging 
can be identiﬁed according to the following algorithm: 
A negative FDG-PET scan at baseline with a positive FDG-PET scan during the study is a sign of 
PD based on a new lesion. 
In the case of no FDG-PET scan at baseline and a positive FDG-PET scan during the study: 
• If the positive FDG-PET scan during the study corresponds to a new site of disease 
conﬁrmed by CT, this will be considered PD. 


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• If the positive FDG-PET scan during the study is not conﬁrmed as a new site of disease on 
CT, additional follow-up CT scans are needed to determine whether there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan). 
• If the positive FDG-PET scan during the study corresponds to a preexisting site of disease 
on CT that is not progressing on the basis of the anatomic images, this will not be 
considered PD. 
2.4 Evaluation of Response 
2.4.1 Time Point Response (Overall Response) 
It is assumed that at each protocol-specified time point, a response assessment occurs.  Table 14 
provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 15 is to be used. 
Table 14 
Time Point Response: Patients with Target Lesions (with or without Non-
Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable 
disease. 
 


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Table 15 
Time Point Response: Patients with Non-Target Lesions Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease. 
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable disease is increasingly 
used as an endpoint for assessment of efficacy in some trials; thus, assigning “stable disease” when no lesions can 
be measured is not advised. 
 
2.4.2 Missing Assessments and Not-Evaluable Designation 
When no imaging/measurement is done at all at a particular time point, the patient is not evaluable 
at that time point.  If only a subset of lesion measurements are made at an assessment, usually the 
case is also considered not evaluable at that time point, unless a convincing argument can be made 
that the contribution of the individual missing lesion(s) would not change the assigned time point 
response.  This would be most likely to happen in the case of PD.  For example, if a patient had a 
baseline sum of 50 mm with 3 measured lesions and, during the study, only 2 lesions were 
assessed, but those gave a sum of 80 mm, the patient will have achieved PD status, regardless of 
the contribution of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done or the scan 
could not be assessed because of poor image quality or obstructed view, the response for target 
lesions should be “unable to assess” since the patient is not evaluable.  Similarly, if one or more 
non-target lesions are not assessed, the response for non-target lesions should be “unable to assess” 
except where there is clear progression.  Overall response would be “unable to assess” if either the 
target response or the non-target response is “unable to assess” except where this is clear evidence 
of progression, as this equates with the case being not evaluable at that time point. 
2.4.3 Best Overall Response: All Time Points 
The best overall response is determined once all the data for the patient is known.  Best response 
determination in trials where confirmation of complete or partial response IS NOT required: Best 
response in these trials is defined as the best response across all time points (for example, a patient 
who has SD at first assessment, PR at second assessment, and PD on last assessment has a best 
overall response of PR).  When SD is believed to be best response, it must also meet the protocol 
specified minimum time from baseline.  If the minimum time is not met when SD is otherwise the 
best time point response, the patient’s best response depends on the subsequent assessments.  For 
example, a patient who has SD at first assessment, PD at second and does not meet minimum 
duration for SD, will have a best response of PD.  The same patient lost to follow-up after the first 
SD assessment would be considered inevaluable. 


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Best response determination in trials where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as specified in the protocol (generally 4 weeks later).  In this circumstance, 
the best overall response can be interpreted as in Table 16. 
Table 16 
Best Overall Response When Confirmation of Complete Response and 
Partial Response is Required 
Overall response 
First time point 
Overall response 
Subsequent time point 
BEST overall response 
CR 
CR 
CR 
CR 
PR 
SD，PD or PRa 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
NE 
NE 
NE 
 
CR = complete response, PR = partial response, SD = stable disease, PD =progressive disease, and NE = inevaluable. 
a: If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the first 
time point. Under these circumstances, the original CR should be changed to PR and the best response is PR. 
 
Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 0 mm), they may still have a measurement reported on scans.  This measurement should be 
recorded even though the nodes are normal in order not to overstate progression should it be based 
on increase in size of the nodes.  As noted earlier, this means that patients with CR may not have 
a total sum of “zero” on the eCRF. 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 


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deterioration.”  Every effort should be made to document objective progression even after 
discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an objective 
response; it is a reason for stopping study therapy.  The objective response status of such patients 
is to be determined by evaluation of target and non-target disease as shown in Table 14 and 
Table 15. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the 
next scheduled assessment, progression is confirmed, the date of progression should be the earlier 
date when progression was suspected. 
In studies for which patients with advanced disease are eligible (ie, primary disease still or partially 
present), the primary tumor should also be captured as a target or non-target lesion, as appropriate. 
This is to avoid an incorrect assessment of complete response if the primary tumor is still present 
but not evaluated as a target or non-target lesion. 
2.5 Frequency of Tumor Re-evaluation 
Frequency of tumor re-evaluation while on treatment should be protocol specific and adapted to 
the type and schedule of treatment.  However, in the context of phase 2 studies where the beneficial 
effect of therapy is not known, follow-up every 6–8 weeks (timed to coincide with the end of a 
cycle) is reasonable.  Smaller or greater time intervals than these could be justified in specific 
regimens or circumstances.  The protocol should specify which organ sites are to be evaluated at 
baseline (usually those most likely to be involved with metastatic disease for the tumor type under 
study) and how often evaluations are repeated.  Normally, all target and non-target sites are 
evaluated at each assessment.  In selected circumstances certain non-target organs may be 
evaluated less frequently.  For example, bone scans may need to be repeated only when complete 
response is identified in target disease or when progression in bone is suspected. 
After the end of the treatment, the need for repetitive tumor evaluations depends on whether the 
trial has as a goal the response rate or the time to an event (progression/death).  If ‘time to an event’ 
(eg, time to progression, disease-free survival, progression-free survival) is the main endpoint of 
the study, then routine scheduled re-evaluation of protocol specified sites of disease is warranted.  
In randomized comparative trials in particular, the scheduled assessments should be performed as 
identified on a calendar schedule (for example: every 6–8 weeks on treatment or every 3–4 months 
after treatment) and should not be affected by delays in therapy, drug holidays or any other events 
that might lead to imbalance in a treatment arm in the timing of disease assessment. 
2.6 Confirmatory measurement/duration of response 
2.6.1. Confirmation 
In non-randomized 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 (see the paper by Bogaerts et al. in this Special 
Issue10).  However, in all other circumstances, for example in randomized trials (phase 2 or 3) or 
in 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 


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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. 
2.6.2. Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study). 
The duration of overall complete response is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented. 
2.6.3. Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and diseases.  If 
the proportion of patients achieving stable disease for a minimum period of time is an endpoint of 
importance in a particular trial, the protocol should specify the minimal time interval required 
between two measurements for determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation.  It is not in the scope of this 
guideline to define a standard follow-up frequency.  The frequency should take into account many 
parameters including disease types and stages, treatment periodicity and standard practice.  
However, these limitations of the precision of the measured endpoint should be taken into account 
if comparisons between trials are to be made. 
 


Clinical Study Protocol 2019-013-GLOB1 
Fruquintinib 
Version 1.0 / Original Protocol 
 
 
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Page 95 of 113 
 
CONFIDENTIAL 
 
 
APPENDIX 3 
PROHIBITED MEDICATION 
A series of strong inducers and strong inhibitors of CYP3A are listed in Table 17 and Table 18 
below.  Examples of sensitive substrates of P-gp and BCRP are listed in Table 19. 
Patients who received a CYP3A strong inducer or strong inhibitor within 2 weeks (3 weeks for 
hyperforin perforatum/St. John’s Wort treatment) prior to the first dose of the study drug will not 
be allowed to participate in the study.  During the study, co-administration of strong inducers and 
inhibitors of CYP3A with fruquintinib should be avoided unless investigators consider it 
necessary.  In this case, fruquintinib efficacy reduction or toxicity increases resulting from the 
interaction should be closely monitored. 
Not all the medications are listed in the following tables.  Other drugs known possibly to affect 
CYP3A activity and to be substrates of P-gp and BCRP should be used with caution.  When 
combining fruquintinib with other drugs the prescription information of all concomitant 
medications should be reviewed. 
 
 


Clinical Study Protocol 2019-013-GLOB1 
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Page 96 of 113 
 
CONFIDENTIAL 
 
 
Table 17 
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, Seville oranges, 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. 
 
 


Clinical Study Protocol 2019-013-GLOB1 
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Version 1.0 / Original Protocol 
 
 
Hutchison MediPharma 
 
Page 97 of 113 
 
CONFIDENTIAL 
 
 
Table 18 
Typical Strong Inducers of CYP3A4 
Strong Inducers of CYP3A4 
Apalutamide 
Avasimibe 
Carbamazepine 
Enzalutamide 
Mitotane 
Phenobarbital 
Phenytoin 
Rifabutin 
Rifampin (or rifampicin) 
St. John’s wort 
 
 


Clinical Study Protocol 2019-013-GLOB1 
Fruquintinib 
Version 1.0 / Original Protocol 
 
 
Hutchison MediPharma 
 
Page 98 of 113 
 
CONFIDENTIAL 
 
 
Table 19 
Sensitive Substrates of P-gp or 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 
 
 
 




Clinical Study Protocol 2019-013-GLOB1 
Fruquintinib 
Version 1.0 / Original Protocol 
 
 
Hutchison MediPharma 
 
Page 100 of 113 
 
CONFIDENTIAL 
 
 
Table 20 
Summary of Clinical Trial Program of Fruquintinib in China and the US 
Study 
Number 
(Name) 
NCT# and 
Indication 
Study Title 
Study 
Objectives and 
Phase  
Study Subjects 
 
Study Design 
Current* 
Status 
2012-013-
00CH3 
NCT01975077 
3rd or above 
line mCRC 
A Phase Ib, 
Randomized, Open-
Label Study for 
Comparing Two 
Different Dosing 
Regimens of 
Fruquintinib as Third-
Line or up Therapy for 
Advanced Colorectal 
Cancer in Patients Who 
Had Failed with 
Standard Therapy 
Compare two 
dosing regimens 
of fruquintinib. 
(Safety, 
tolerability, PK, 
preliminary 
efficacy) 
Phase 1b 
Fruquintinib  
N=62 
Randomized, 
two-stage, open-
label, multicenter 
study. 
Stage 1: two 
arms, two dose 
regimens, 
randomized 
Stage 2: selected 
dose regimen 
expansion 
Completed 
2012-013-
00CH1 
NCT02691299 
3rd line 
mCRC 
A Randomized, 
Double-blind, Placebo-
controlled, Multi-center 
Phase II Clinical Trial 
to Evaluate the 
Efficacy and Safety of 
Fruquintinib  Plus Best 
Supportive Care in 
advanced colorectal 
cancer patients who 
have progressed after 
second-line 
chemotherapy 
PFS 
(Fruquintinib 
versus PBO), 
OS, ORR, safety 
Phase 2 
Fruquintinib: 
N=47; Placebo: 
N=24 (Tot. 71) 
Randomized, 
double-blind, 
placebo-
controlled, 
multicenter study 
Completed 
2014-013-
00CH1  
NCT02590965 
3rd line 
NSCLC 
A Randomized, 
Double-blind, Placebo-
controlled, Multi-center 
Phase II Clinical Trial 
to Evaluate the 
Efficacy and Safety of 
Fruquintinib Plus Best 
Supportive Care in 
Patients With 
Advanced Non-
squamous Non-small 
Cell Lung Cancer 
(Fruquintinib 
versus PBO), 
OS, ORR, safety 
Phase 2 
Fruquintinib 
N=61. Placebo: 
N=30  
(Tot. 91) 
Randomized, 
double-blind, 
placebo-
controlled, 
multicenter study 
Completed 


Clinical Study Protocol 2019-013-GLOB1 
Fruquintinib 
Version 1.0 / Original Protocol 
 
 
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Page 101 of 113 
 
CONFIDENTIAL 
 
 
Table 20 
Summary of Clinical Trial Program of Fruquintinib in China and the US 
Study 
Number 
(Name) 
NCT# and 
Indication 
Study Title 
Study 
Objectives and 
Phase  
Study Subjects 
 
Study Design 
Current* 
Status 
2015-013-
00CH1 
NCT02691299 
(FALUCA) 
3rd line 
NSCLC 
A Randomized, 
Double-blind, Placebo-
controlled, Multi-center 
Phase III Clinical Trial 
in Patients With 
Advanced Non-
squamous Non-small 
Cell Lung Cancer 
Treated With 
Fruquintinib 
Confirmatory 
efficacy and 
safety NSCLC. 
Phase 3 
Fruquintinib 
N=352 
Placebo N= 171 
(Total N=523) 
Randomized, 
double-blind, 
placebo-
controlled, 
multicenter study 
Ongoing 
(Enrollment 
completed) 
2017-013-
00CH1 
NCT03223376 
2nd line 
gastric cancer 
A Phase III Study to 
Evaluate the Efficacy 
and Safety of 
Fruquintinib in 
Combination With 
Paclitaxel Versus 
Paclitaxel Alone in 
Second Line Gastric 
Cancer 
Phase 3 
Planned: 544 
Current: N=120 
Randomized, 
double-blind, 
placebo-
controlled, 
multicenter study 
Ongoing 
2014-013-
00CH3 
NCT02415023 
2nd line 
gastric cancer 
 
A Phase Ib/2 Clinical 
Study to Evaluate the 
Safety, 
Pharmacokinetic 
Characteristics and 
Preliminary Efficacy of 
Fruquintinib Combined 
With Paclitaxel in 
Patients With 
Advanced Gastric 
Cancer 
(Fruquintinib + 
paclitaxel 
combo), safety, 
tolerability, PK, 
preliminary 
efficacy Phase 
1b/2 
Fruquintinib 
N=34 
Two-stage, open-
label, multicenter 
study. Stage 1: 
dose escalation. 
Stage 2: selected 
dose regimen 
expansion 
(combo + 
paclitaxel) 
Completed 




Clinical Study Protocol 2019-013-GLOB1 
Fruquintinib 
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Page 103 of 113 
 
CONFIDENTIAL 
 
 
Table 20 
Summary of Clinical Trial Program of Fruquintinib in China and the US 
Study 
Number 
(Name) 
NCT# and 
Indication 
Study Title 
Study 
Objectives and 
Phase  
Study Subjects 
 
Study Design 
Current* 
Status 
2013-013-
00CH2 
A Single Center, Open-
label, Randomized, 
Two-period Crossover 
Study to Evaluate the 
Pharmacokinetics and 
Bioequivalence in 
Healthy Male Chinese 
Volunteers Following 
Single Doses of 
Fruquintinib Capsules 
Produced by Two 
Different 
Manufacturers 
Primary: to 
determine the 
bioequivalence 
of fruquintinib 
produced at two 
manufacturing 
sites. 
Secondary: to 
assess the safety 
and tolerability 
Phase 1 
Healthy males  
N=28 
Randomized, 
open-label, two-
period crossover, 
two-stage, single 
center study.  
Stage 1: 
Exploring 
preliminary 
study. Stage 2: 
Bioequivalence 
study 
Completed 
2014-013-
00CH5 
 
A Single Center, Open-
label, Randomized, 
Two-period Crossover 
Study to Evaluate the 
Pharmacokinetics and 
Bioequivalence in 
Healthy Male Chinese 
Volunteers Following 
Single Doses of 
Fruquintinib Capsules 
Produced by Two 
Different 
Manufacturers 
Primary: to 
assess the 
bioequivalence 
of fruquintinib 
produced at two 
manufacturers; 
Secondary: 
safety, explore 
metabolism and 
excretion 
Phase 1 
Healthy Males 
(N=24) 
Randomized, 
open-label, two-
period crossover, 
two-stage, single 
center study. 
 
Completed 
2015-013-
00CH2 
NCT02689752 
 
Absorption, 
Metabolism and 
Excretion of [14C] 
Fruquintinib in Healthy 
Male Volunteers after a 
Single Oral 
Administration of 
5mg/100 μCi/Subject 
of [14C] Fruquintinib 
Evaluate mass 
balance in 
healthy male 
volunteers 
following a 
single oral 
administration 
of 5 mg/100 
μCi/Subject of 
[14C] 
fruquintinib 
Phase 1 
Healthy Males 
(N=6) 
To investigate the 
absorption, drug 
biotransformation 
and mass balance 
and to evaluated 
the PK and safety 
of fruquintinib. 
To identify the 
compound's 
major 
metabolites  
Completed 
*Fruquintinib Investigator’s Brochure, v11.0 
 
 


Clinical Study Protocol 2019-013-GLOB1 
Fruquintinib 
Version 1.0 / Original Protocol 
 
 
Hutchison MediPharma 
 
Page 104 of 113 
 
CONFIDENTIAL 
 
 
APPENDIX 5 
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. This 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 
hepatoligist should be considered. 
If the biochemical criteria for Hy’s Law have been met, expedited reporting is required (see 
Section 8.1.1 ), 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 eCRFs 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 Hematology 
o Clinical biochemistry: ALT, AST, bilirubin (including total bilirubin and direct 
bilirubin), ALP, albumin, PTT 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). 
• 
Complete appropriate auxiliary examination: 


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Page 105 of 113 
 
CONFIDENTIAL 
 
 
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. 
 


Clinical Study Protocol 2019-013-GLOB1 
Fruquintinib 
Version 1.0 / Original Protocol 
 
 
Hutchison MediPharma 
 
Page 106 of 113 
 
CONFIDENTIAL 
 
 
APPENDIX 6 
CLINICAL MANAGEMENT OF SEVERE OR SERIOUS 
HEMORRHAGIC EVENTS 
If hemorrhagic events are evaluated as severe (CTCAE grade ≥3) or SAEs, fruquintinib treatment 
should be discontinued or interrupted immediately, and appropriate treatment measures initiated 
to control bleeding (eg 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 7.5.6.2).  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 SAE after taking fruquintinib, 
the investigator is required to report the event in an expedited fashion (within 24 hours of first 
awareness) to sponsor (see Section 8.2.2).  
See Figure 2 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 (eg warfarin) 
 NSAIDs (eg aspirin) 
 Anti-platelet drugs (eg, clopidogrel/glycoprotein GPIIb/IIIa 
inhibitors/dipyridamole) 
 Other anticoagulants (eg heparin/thrombolytics/SSRIs) 
 Food and herbal supplements with anticoagulant property 
 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 


Clinical Study Protocol 2019-013-GLOB1 
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Page 107 of 113 
 
CONFIDENTIAL 
 
 
o Clinical biochemistry: bleeding time, PTT, 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). 
 


Clinical Study Protocol 2019-013-GLOB1 
Fruquintinib 
Version 1.0 / Original Protocol 
 
 
Hutchison MediPharma 
 
Page 108 of 113 
 
CONFIDENTIAL 
 
 
Figure 2 
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 
report Grade ≥2 hemorrhagic 
events at any site 
•
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 Grade ≥ 2 
hemorrhagic events at any site 
Grade=2 
Grade=1 
Yes 
No 
•
Closely monitor 
•
Initiate appropriate measures to control 
bleeding if necessary 


Clinical Study Protocol 2019-013-GLOB1 
Fruquintinib 
Version 1.0 / Original Protocol 
 
 
Hutchison MediPharma 
 
Page 109 of 113 
 
CONFIDENTIAL 
 
 
APPENDIX 7 
MANAGEMENT OF HYPERTENSION IN PATIENTS RECEIVING 
FRUQUINTINIB 
Hypertension is a common AE that has been reported in patients taking angiogenesis inhibitors 
(Izzedine 2009), 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 (Figure 3), please see a summary of the most recent AHA/ACC hypertension 
treatment guidelines. 
 


Clinical Study Protocol 2019-013-GLOB1 
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Version 1.0 / Original Protocol 
 
 
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Page 110 of 113 
 
CONFIDENTIAL 
 
 
Figure 3 
Schema from American Heart Association/ American College of Cardiology 
for Controlling Hypertension in Adults 
 




Clinical Study Protocol 2019-013-GLOB1 
Fruquintinib 
Version 1.0 / Original Protocol 
 
 
Hutchison MediPharma 
 
Page 112 of 113 
 
CONFIDENTIAL 
 
 
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. 
 


Clinical Study Protocol 2019-013-GLOB1 
Fruquintinib 
Version 1.0 / Original Protocol 
 
 
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Page 113 of 113 
 
CONFIDENTIAL 
 
 
APPENDIX 8 
CONVERSION TABLE FOR URINALYSIS RESULTS 
Blood 
Leucocytes 
Negative 
0 
0 cells/μL 
Negative 
0 
<10 mg/dL 
Trace 
1+ 
1-24 cells/μL 
Trace 
1+ 
11-99 mg/dL 
Small 
2+ 
25-79 cells/μL 
Small 
2+ 
99-299 mg/dL 
Medium 
3+ 
80-199 cells/μL 
Medium 
3+ 
300-999 mg/dL 
Large 
4+ 
≥ 200 cells/μL 
large 
4+ 
>1000 mg/dL 
 


Clinical Study Protocol 2019-013-GLOB1 
Fruquintinib 
Amendment 4 
 
 
Hutchison MediPharma 
 
Page 1 
 
CONFIDENTIAL 
 
 
 
 
Clinical Study Protocol 
A GLOBAL, MULTICENTER, RANDOMIZED, PLACEBO-
CONTROLLED PHASE 3 TRIAL TO COMPARE THE EFFICACY AND 
SAFETY OF FRUQUINTINIB PLUS BEST SUPPORTIVE CARE TO 
PLACEBO PLUS BEST SUPPORTIVE CARE IN PATIENTS WITH 
REFRACTORY METASTATIC COLORECTAL CANCER (FRESCO-2) 
Short Title: 
A global, randomized, placebo-controlled phase 3 study of 
fruquintinib in patients with refractory metastatic 
colorectal cancer 
Acronym: 
FRESCO-2 
 
Investigational Product(s) 
Fruquintinib 
Protocol Number: 
2019-013-GLOB1 
Clinical Phase: 
3 
Date of Issue: 
24 June 2021 
Amendment: 
4 
Version Number: 
1 (for sponsor’s use only) 
Sponsor 
Hutchison MediPharma Limited 
Building 4, 720 Cailun Road,  
Zhangjiang Hi-Tech Park, Shanghai, China 
Post Code: 201203 
Regulatory Agency Identifier 
Number(s) 
IND: 131038 
EudraCT 2020-000158-88 
Confidentiality Statement 
The information contained in this protocol and all other information relevant to fruquintinib 
are the confidential and proprietary information of Hutchison MediPharma Limited, and 
except as may be required by federal, state, or local laws or regulation, may not be disclosed 
to others without prior written permission of Hutchison MediPharma Limited 
 


Clinical Study Protocol 2019-013-GLOB1 
Fruquintinib 
Amendment 4 
 
 
Hutchison MediPharma 
 
Page 2 
 
CONFIDENTIAL 
 
 
STATEMENT OF COMPLIANCE 
The study will be conducted in compliance with this clinical study protocol, Good Clinical 
Practices (GCP) as outlined by ICH E6(R2), and all applicable local and national regulatory 
requirements.  Enrollment at any clinical study site may not begin prior to that site receiving 
approval from the ethics committee of record for the protocol and all materials provided to 
potential participants. 
Any amendments to the protocol or changes to the consent document will be approved before 
implementation of that amendment.  Reconsent of previously enrolled participants may be 
necessary depending on the nature of the amendment. 
The Principal Investigator will ensure that changes to the study plan as defined by this protocol 
will not be made without prior agreement from the Sponsor and documented approval from the 
ethics committee of record, unless such a change is necessary to eliminate an immediate hazard to 
the study participants. 
All personnel involved in the conduct of this study have completed Human Patients Protection and 
GCP Training as outlined by their governing institution. 


Clinical Study Protocol 2019-013-GLOB1 
Fruquintinib 
Amendment 4 
 
 
Hutchison MediPharma 
 
Page 3 
 
CONFIDENTIAL 
 
 
SPONSOR’S APPROVAL 
Title 
A Global, Multicenter, Randomized, Placebo-Controlled Phase 3 Trial to Compare 
the Efficacy and Safety of Fruquintinib Plus Best Supportive Care to Placebo Plus 
Best Supportive Care in Patients with Refractory Metastatic Colorectal Cancer 
(FRESCO-2) 
Protocol Number 
2019-013-GLOB1 
Amendment 
4 
Version Number 
(for sponsor’s use only) 
1 
 
The design of this study as outlined by this protocol has been reviewed and approved by the 
sponsor’s responsible personnel as indicated in the signature table below. 
Name: [last name, first name] 
Title: 
 
Chief Medical Officer, Managing Director 
HUTCHMED International Corp 
Signature: 
See appended signature page 
Date: [DD Month YYYY] 
 
Name: [last name, first name] 
Title: 
 
Chief Scientific Officer 
Hutchison MediPharma Limited 
Signature: 
See appended signature page 
Date: [DD Month YYYY] 
 


Clinical Study Protocol 2019-013-GLOB1 
Fruquintinib 
Amendment 4 
 
 
Hutchison MediPharma 
 
Page 4 
 
CONFIDENTIAL 
 
 
INVESTIGATOR’S AGREEMENT 
I have read the protocol, appendices, and accessory materials related to Study 2019-013-GLOB1 
and agree to the following: 
• To conduct this study as described by the protocol and any accessory materials 
• To protect the rights, safety, and welfare of the participants under my care 
• To provide oversight of all personnel to whom study activities have been delegated 
• To control all investigational products provided by the sponsor and maintain records 
of the disposition of those products 
• To conduct the study in accordance with all applicable local and national regulations, 
the requirements of the ethics committee of record for my clinical site, and Good 
Clinical Practices as outlined by ICH E6(R2). 
• To obtain approval for the protocol and all written materials provided to participants 
prior to initiating the study at my site 
• To obtain informed consent – and updated consent in the event of new information or 
amendments – from all participants enrolled at my study site prior to initiating any 
study-specific procedures or administering investigational products to those 
participants 
• To maintain records of each patient’s participation and all data required by the 
protocol 
Name: 
Title:  
Institution:  
 
 
 
Signature:  
Date:   
 
 
 
 
 


Clinical Study Protocol 2019-013-GLOB1 
Fruquintinib 
Amendment 4 
 
 
Hutchison MediPharma 
 
Page 5 
 
CONFIDENTIAL 
 
 
DOCUMENT HISTORY 
All prior amendments of this study protocol are shown in the table below. 
Amendment 
Date 
Original Protocol 
25 Feb 2020 
Amendment 1 
08 Apr 2020 
Amendment 2 
30 Oct 2020 
Amendment 3 
16 Mar 2021 
Amendment 3.1 
25 Mar 2021 
 


Clinical Study Protocol 2019-013-GLOB1 
Fruquintinib 
Amendment 4 
 
 
Hutchison MediPharma 
 
Page 6 
 
CONFIDENTIAL 
 
 
AMENDMENT SUMMARY 
This 2019-013-GLOB1 Protocol Amendment 4 replaces 2019-013-GLOB1 Protocol 
Amendment 3.1.  This amendment is considered non-substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union. 
The primary purpose of Protocol Amendment 4 is to provide clarity for select inclusion/exclusion 
criteria and the schedule of events, to remove instructions for concomitant proton pump inhibitors 
and H2-receptor antagonists, and to discontinue collection of circulating tumor DNA (ctDNA)due 
to supply chain issues related to COVID-19.  
The major changes incorporated in Amendment 4 relative to Amendment 3.1 are summarized 
below.  Editorial and formatting changes are not included in this summary.  Summaries of prior 
amendments are available in Appendix 11. 
Section 
Summary of Change 
Rationale for Change 
Section 7.5.3 - Drug-Drug 
Interactions (Therapies to Avoid or 
Use with Special Caution) 
Removed instruction that subjects 
should avoid proton pump inhibitor 
drugs and H2 blockers 
Update made based on recent data 
indicating that concomitant use of 
proton pump inhibitors with 
fruquintinib had no effect on 
pharmacokinetic (PK) parameters 
Section 1 - Synopsis 
Section 5.1 - Recruitment 
Revised the planned estimated 
number of study sites from 140 to 
160 
Reflect potential increase in number 
of study sites 
Section 1 - Synopsis, Inclusion 
Criterion #4 
Section 5.3 - Inclusion Criteria, #4  
For the inclusion criterion requiring 
patients must have received 
treatment with prior therapy, 
including anti-VEGF or anti-EGFR, 
examples of these treatments were 
added 
Clarification 
Section 1 - Synopsis, Exclusion 
Criterion #5 
Section 5.4 - Exclusion Criteria, #5  
Changed the protein level for which 
a 24-hour urine assessment is 
required. 
Correction  
Section 1 - Synopsis, Exclusion 
Criterion #6 
Section 5.4 - Exclusion Criteria, #6  
Added in details for blood pressure 
assessment process. 
Clarification 
Section 1.2 – Schedule of Events 
Table 1 Schedule of Events 
Removed visit window day 21 of 
cycle 2 and cycle 3 
Clarification for these particular 
study visits that have study drug 
administration and PK sampling, 
which preclude the use of visit 
window 
Table 2 Schedule of Events for 
Dense Pharmacokinetic and 
Electrocardiogram Evaluations for 
the Subset of Approximately 120 
Patients with Evaluable ECGs 
Revised title 
Added the requirement for 120 
patients to have evaluable ECGs for 
PK/QTc evaluation. 


Clinical Study Protocol 2019-013-GLOB1 
Fruquintinib 
Amendment 4 
 
 
Hutchison MediPharma 
 
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CONFIDENTIAL 
 
 
Section 
Summary of Change 
Rationale for Change 
Table 3 Schedule of Events for 
Sparse Pharmacokinetic and 
Electrocardiogram Evaluations for 
Patients Not Included in the 
Approximately 120 Evaluable 
Patients in the Subset in Table 2 
Revised title 
Changed the title to harmonize with 
change of title of Table 2. 
Table 1 Schedule of Events 
Section 1.2.1 - Footnotes for 
Schedule of Events Table 1, #21 
(footnote removed) 
Section 6.1.1.21 - Circulating 
Tumor DNA 
Removed requirement for the 
collection of blood to evaluate 
ctDNA.  Further noted that analysis 
of ctDNA samples collected would 
be performed according to the 
statistical analysis plan 
Appropriate sample collection tubes 
are unable to be procured due to 
supply chain issues as a result of 
the COVID-19 pandemic. 
Section 6.1.1.17 - 
Electrocardiograms Monitoring 
Added that any subject with a 
pacemaker should undergo PK and 
safety ECG evaluations according 
to the schedule outlined in Table 3 
Clarification to ensure subjects with 
pacemakers undergo sparse 
sampling 
Section 6.1.1.18 - Echocardiogram 
Added that echocardiograms 
completed as standard of care prior 
to signing the informed consent, but 
within 28 days of first dose of study 
treatment, may be used as baseline 
assessment. 
Clarification 
Section 1.2.2 - Footnotes for the 
Schedule of Events Tables 2 and 3, 
#4 (footnote added) 
Added instruction to refer to the 
Holter Monitor instruction manual 
for appropriate timing of the start of 
the ECG recording. 
Clarification 
Appendix 9 
Conversion 
Tables for Urinalysis Results 
Added table to aid in conversion of 
proteins measured by urinalysis for 
assessment of proteinuria 
Correct an oversight 
 


Clinical Study Protocol 2019-013-GLOB1 
Fruquintinib 
Amendment 4 
 
 
Hutchison MediPharma 
 
Page 8 
 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
A GLOBAL, MULTICENTER, RANDOMIZED, PLACEBO-CONTROLLED PHASE 3 
TRIAL TO COMPARE THE EFFICACY AND SAFETY OF FRUQUINTINIB PLUS 
BEST SUPPORTIVE CARE TO PLACEBO PLUS BEST SUPPORTIVE CARE IN 
PATIENTS WITH REFRACTORY METASTATIC COLORECTAL CANCER 
(FRESCO-2) ...................................................................................................................... 1 
STATEMENT OF COMPLIANCE ............................................................................................... 2 
SPONSOR’S APPROVAL ............................................................................................................ 3 
INVESTIGATOR’S AGREEMENT ............................................................................................. 4 
DOCUMENT HISTORY............................................................................................................... 5 
AMENDMENT SUMMARY ........................................................................................................ 6 
TABLE OF CONTENTS ............................................................................................................... 8 
LIST OF TABLES ....................................................................................................................... 13 
LIST OF FIGURES ..................................................................................................................... 14 
LIST OF APPENDICES .............................................................................................................. 15 
LIST OF ABBREVIATIONS ...................................................................................................... 16 
1 
SYNOPSIS ....................................................................................................................... 20 
1.1 
Study Schematic............................................................................................................ 25 
1.2 
Schedule of Events ........................................................................................................ 26 
1.2.1 
Footnotes for Schedule of Events Table 1 ................................................................. 28 
1.2.2 
Footnotes for the Schedule of Events Tables 2 and 3 ................................................ 32 
2 
INTRODUCTION ........................................................................................................... 33 
2.1 
Study Rationale ............................................................................................................. 33 
2.2 
Background ................................................................................................................... 34 
2.2.1 
Justification for Dosing Strategy ............................................................................... 34 
2.2.2 
Supportive Nonclinical Data ...................................................................................... 35 
2.2.2.1 
Pharmacology ......................................................................................................... 35 
2.2.2.2 
Metabolism and Pharmacokinetic Drug Interaction ............................................... 35 
2.2.2.3 
Toxicology .............................................................................................................. 36 
2.2.3 
Supportive Clinical Data ............................................................................................ 36 
2.2.3.1 
Clinical Pharmacokinetics ...................................................................................... 36 
2.2.3.2 
Clinical Safety ......................................................................................................... 37 
2.2.3.3 
Clinical Efficacy ..................................................................................................... 38 


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2.2.4 
Benefit/Risk Assessment ........................................................................................... 39 
2.2.4.1 
Risk Assessment ..................................................................................................... 39 
2.2.4.2 
Benefit Assessment ................................................................................................. 40 
2.2.4.3 
Overall Benefit/Risk Conclusion ............................................................................ 40 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 41 
3.1 
Primary Objective ......................................................................................................... 41 
3.2 
Secondary Objectives.................................................................................................... 41 
3.3 
Exploratory Objectives ................................................................................................. 41 
4 
STUDY PLAN ................................................................................................................. 43 
4.1 
Study Design ................................................................................................................. 43 
4.1.1 
Enrollment in Study ................................................................................................... 43 
4.1.2 
Electrocardiogram Collection and Pharmacokinetic Sampling ................................. 44 
4.1.2.1 
Rationale for Electrocardiogram Collection and Pharmacokinetic Sampling 
Schedule .................................................................................................................. 44 
4.1.2.2 
Electrocardiogram Collection and Pharmacokinetic Sampling Schedule .............. 44 
4.1.2.3 
Temporary and Permanent Changes in Pharmacokinetic Sampling, Holter Monitor 
QTc Evaluations, and Circulating Tumor DNA Sample Collection ...................... 44 
5 
POPULATION ................................................................................................................ 46 
5.1 
Recruitment ................................................................................................................... 46 
5.2 
Definitions..................................................................................................................... 46 
5.3 
Inclusion Criteria .......................................................................................................... 46 
5.4 
Exclusion Criteria ......................................................................................................... 47 
6 
STUDY CONDUCT ........................................................................................................ 50 
6.1 
Study Procedures .......................................................................................................... 50 
6.1.1 
Study Assessments ..................................................................................................... 50 
6.1.1.1 
Informed Consent.................................................................................................... 50 
6.1.1.2 
Medical History ...................................................................................................... 50 
6.1.1.3 
Tumor Diagnosis and Treatment History ............................................................... 50 
6.1.1.4 
Demographics ......................................................................................................... 51 
6.1.1.5 
Concomitant Medication and Procedures ............................................................... 51 
6.1.1.6 
Comprehensive Physical Examination ................................................................... 51 
6.1.1.7 
Limited Physical Examination ................................................................................ 51 


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6.1.1.8 
Eastern Cooperative Oncology Group (ECOG) Performance Status ..................... 51 
6.1.1.9 
Vital Signs ............................................................................................................... 51 
6.1.1.10 
Hematology ............................................................................................................. 51 
6.1.1.11 
Blood Chemistry ..................................................................................................... 52 
6.1.1.12 
Blood Amylase and Lipase ..................................................................................... 52 
6.1.1.13 
Coagulation ............................................................................................................. 52 
6.1.1.14 
Thyroid Function .................................................................................................... 52 
6.1.1.15 
Urinalysis ................................................................................................................ 52 
6.1.1.16 
Pregnancy Test ........................................................................................................ 52 
6.1.1.17 
Electrocardiograms Monitoring .............................................................................. 52 
6.1.1.18 
Echocardiogram ...................................................................................................... 54 
6.1.1.19 
Tumor Evaluation/Imaging ..................................................................................... 54 
6.1.1.20 
Tumor Markers ....................................................................................................... 54 
6.1.1.21 
Circulating Tumor DNA ......................................................................................... 54 
6.1.1.22 
Subject Randomization ........................................................................................... 55 
6.1.1.23 
Quality of Life Assessment ..................................................................................... 55 
6.1.2 
Pharmacokinetics Evaluations ................................................................................... 55 
6.1.2.1 
Sample Collection and Handling ............................................................................ 55 
6.1.2.2 
Analytical Procedures ............................................................................................. 55 
6.1.3 
End of Treatment Visit............................................................................................... 55 
6.1.4 
Safety Follow-Up Visit .............................................................................................. 55 
6.1.5 
Efficacy Follow-Up ................................................................................................... 55 
6.1.6 
Survival Follow-Up ................................................................................................... 56 
6.1.7 
Long-term Extension ................................................................................................. 56 
6.2 
Discontinuation or Withdrawal ..................................................................................... 56 
6.2.1 
Permanent Discontinuation of Treatment .................................................................. 56 
6.2.2 
Withdrawal from Study.............................................................................................. 57 
6.2.3 
Replacement of Subjects ............................................................................................ 57 
6.2.4 
Subjects Lost to Follow-up ........................................................................................ 57 
6.3 
Study Termination ........................................................................................................ 57 
6.4 
End of Study ................................................................................................................. 57 
7 
STUDY DRUGS .............................................................................................................. 58 


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7.1 
Study Drug Administration ........................................................................................... 58 
7.2 
Description of Products................................................................................................. 58 
7.2.1 
Formulation, Storage, Preparation and Handling ...................................................... 58 
7.2.2 
Drug Accountability................................................................................................... 58 
7.2.2.1 
Assignment/Disposal (Study Site) .......................................................................... 58 
7.2.2.2 
Drug Return (Subject) ............................................................................................. 59 
7.3 
Treatment Assignment and Bias Minimization ............................................................ 59 
7.3.1 
Treatment Allocation ................................................................................................. 59 
7.3.2 
Extent and Maintenance of Blinding ......................................................................... 59 
7.3.3 
Unblinding Procedures............................................................................................... 60 
7.3.3.1 
Emergency Unblinding ........................................................................................... 60 
7.4 
Assessment and Verification of Compliance ................................................................ 60 
7.5 
Prior and Concomitant Therapies ................................................................................. 60 
7.5.1 
Prohibited Therapies .................................................................................................. 60 
7.5.2 
Permitted Therapies ................................................................................................... 60 
7.5.3 
Drug-Drug Interactions (Therapies to Avoid or Use with Special Caution) ............. 61 
7.5.4 
Rescue Therapies ....................................................................................................... 61 
7.5.5 
General Dose Adjustment Note ................................................................................. 61 
7.5.6 
Dose Modification Guidance ..................................................................................... 62 
7.5.6.1 
Dose Modification Sequence by Starting Dose and for General Hematologic and 
Non-Hematologic Toxicity ..................................................................................... 62 
7.5.6.2 
Dose Modifications for Important Identified Risks and Potential Risks ................ 63 
8 
SAFETY MONITORING ................................................................................................ 68 
8.1 
Definitions..................................................................................................................... 68 
8.1.1 
Adverse Event ............................................................................................................ 68 
8.1.2 
Serious Adverse Event ............................................................................................... 68 
8.2 
Adverse Event Reporting .............................................................................................. 68 
8.2.1 
Adverse Event Reporting Period ............................................................................... 68 
8.2.2 
Expedited Reporting .................................................................................................. 68 
8.3 
Eliciting Adverse Events............................................................................................... 69 
8.4 
Assessment of Severity ................................................................................................. 69 
8.5 
Causality assessment ..................................................................................................... 70 


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8.6 
Documenting Adverse Events....................................................................................... 70 
8.6.1 
Diagnosis versus Symptoms and Signs...................................................................... 71 
8.6.2 
Adverse Event Occurring Secondary to Other Events ............................................... 71 
8.6.3 
Persistent or Recurrent Adverse Events ..................................................................... 71 
8.6.4 
Abnormal Laboratory Values or Abnormal Vital Signs ............................................ 71 
8.6.5 
Preexisting Medical Condition .................................................................................. 72 
8.6.6 
Pregnancy ................................................................................................................... 72 
8.6.7 
Worsening of Solid Tumor ........................................................................................ 72 
8.6.8 
Death .......................................................................................................................... 73 
8.7 
Duration of Follow-up for Adverse Events .................................................................. 73 
9 
STATISTICAL ANALYSIS ........................................................................................... 74 
9.1 
Statistics and Analysis Method ..................................................................................... 74 
9.1.1 
Statistical Hypothesis ................................................................................................. 74 
9.1.2 
Sample Size Rationale ............................................................................................... 74 
9.1.3 
Analysis Sets .............................................................................................................. 75 
9.2 
Primary and Secondary Endpoints ................................................................................ 75 
9.2.1 
Primary Endpoint ....................................................................................................... 75 
9.2.2 
Secondary Efficacy Endpoints ................................................................................... 75 
9.2.2.1 
Key Secondary Endpoint: Progression-free Survival ............................................. 75 
9.2.2.2 
Objective Response Rate ........................................................................................ 75 
9.2.2.3 
Disease Control Rate............................................................................................... 76 
9.2.2.4 
Duration of Response .............................................................................................. 76 
9.2.3 
Secondary Safety Endpoints ...................................................................................... 76 
9.2.4 
Other Endpoints ......................................................................................................... 76 
9.2.4.1 
Patient Reported Outcomes..................................................................................... 76 
9.2.4.2 
Assessment of Resource Utilization ....................................................................... 76 
9.2.5 
Statistical Methods ..................................................................................................... 76 
9.2.5.1 
Analysis of Efficacy Endpoints .............................................................................. 76 
9.2.5.2 
Analysis of Safety Endpoints .................................................................................. 77 
9.2.5.3 
Analysis of Other Endpoints ................................................................................... 78 
9.3 
Pharmacokinetic and Pharmacodynamic Analyses ...................................................... 78 
9.3.1 
Population PK and Exposure-Response Analyses ..................................................... 78 


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9.3.2 
Pharmacodynamic (ECG) Analysis ........................................................................... 78 
9.3.2.1 
QTc Intervals .......................................................................................................... 79 
9.3.2.2 
Heart Rate, QRS, and PR intervals ......................................................................... 79 
9.3.2.3 
T-wave and U-wave Morphology ........................................................................... 80 
9.3.3 
QTc-PK Analysis ....................................................................................................... 80 
9.4 
Interim Analysis ............................................................................................................ 80 
10 
ETHICAL CONSIDERATIONS ..................................................................................... 81 
10.1 
Good Clinical Practice .................................................................................................. 81 
10.2 
Ethics Review ............................................................................................................... 81 
10.3 
Informed Consent.......................................................................................................... 81 
10.4 
Data Privacy .................................................................................................................. 82 
10.5 
Disclosure ..................................................................................................................... 83 
10.6 
Biological Specimens and Data .................................................................................... 83 
10.7 
Data Quality Assurance ................................................................................................ 83 
11 
OVERSIGHT ................................................................................................................... 84 
11.1 
Independent Monitoring................................................................................................ 84 
11.1.1 
Independent Data Monitoring Committee ................................................................. 84 
11.2 
Quality Control and Assurance ..................................................................................... 84 
11.2.1 
Monitoring ................................................................................................................. 84 
11.2.2 
Audits ......................................................................................................................... 85 
11.2.3 
Records ...................................................................................................................... 85 
11.2.3.1 
Data Capture and Management ............................................................................... 85 
11.2.3.2 
Source Documentation ............................................................................................ 86 
11.2.3.3 
Records Retention ................................................................................................... 86 
11.3 
Study Termination or Study Site Closure ..................................................................... 86 
12 
PUBLICATION POLICY ............................................................................................... 88 
13 
FINANCING AND INSURANCE .................................................................................. 89 
14 
REFERENCES ................................................................................................................ 90 
15 
APPENDICES ................................................................................................................. 91 
 
LIST OF TABLES 
Table 1 
Schedule of Events ............................................................................................... 27 


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Table 2 
Schedule of Events for Dense Pharmacokinetic and Electrocardiogram 
Evaluations for the Subset of Approximately 120 Patients with Evaluable ECGs31 
Table 3 
Schedule of Events for Sparse Pharmacokinetic and Electrocardiogram 
Evaluations for Patients Not Included in the Approximately 120 Evaluable 
Patients in the Subset in Table 2 .......................................................................... 32 
Table 4 
Objectives and Corresponding Endpoints ............................................................ 41 
Table 5 
Information on Investigational Products .............................................................. 58 
Table 6 
Dose Modification Sequence by Starting Dose ................................................... 62 
Table 7 
Dose Modifications for Hematologic and Non-Hematologic Toxicity ............... 63 
Table 8 
Dose Modification for Potential Risks ................................................................. 63 
Table 9 
Dose Modifications for Dermatological Toxicity ................................................ 64 
Table 10 
Dose Modifications for Proteinuriaa .................................................................... 64 
Table 11 
Dose Modifications for Hypertension .................................................................. 65 
Table 12 
Dose Modifications for Decreased Platelet Count ............................................... 65 
Table 13 
Dose Modifications for Hemorrhage at Any Site ................................................ 66 
Table 14 
Dose Modifications for Abnormal Liver Function .............................................. 66 
Table 15 
Time Point Response: Patients with Target Lesions (with or without Non-Target 
Lesions) .............................................................................................................. 101 
Table 16 
Time Point Response: Patients with Non-Target Lesions Only ........................ 102 
Table 17 
Best Overall Response When Confirmation of Complete Response and Partial 
Response is Required ......................................................................................... 103 
Table 18 
Typical Strong Inhibitors of CYP3A4 ............................................................... 107 
Table 19 
Typical Strong Inducers of CYP3A4 ................................................................. 108 
Table 20 
Sensitive Substrates of P-gp or BCRP ............................................................... 109 
Table 21 
Summary of Clinical Trial Program of Fruquintinib in China and the US* ...... 110 
 
LIST OF FIGURES 
Figure 1 
Study Design Schema .......................................................................................... 26 
Figure 2 
Severe or Serious Hemorrhagic Events Management Flow Chart .................... 118 
Figure 3 
Schema from American Heart Association/ American College of Cardiology for 
Controlling Hypertension in Adults ................................................................... 120 
 


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LIST OF APPENDICES 
Appendix 1 
COVID-19 Risk Assessment ............................................................................... 92 
Appendix 2 
ECOG Performance Status .................................................................................. 94 
Appendix 3 
Response Evaluation Criteria in Solid Tumors (RECIST v1.1) .......................... 95 
Appendix 4 
Prohibited Medication ........................................................................................ 106 
Appendix 5 
Study Plan .......................................................................................................... 110 
Appendix 6 
Clinical Evaluation of Possible Drug-Induced Liver Injury (DILI) .................. 114 
Appendix 7 
Clinical Management of Severe or Serious Hemorrhagic Events ..................... 116 
Appendix 8 
Management of Hypertension in Patients Receiving Fruquintinib .................... 119 
Appendix 9 
Conversion Tables for Urinalysis Results.......................................................... 124 
Appendix 10 Cockgroft Gault formula .................................................................................... 125 
Appendix 11 Amendment History ........................................................................................... 126 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADL 
Activities of daily living 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase/glutamic-pyruvic transaminase 
ANC  
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AR 
Adverse reaction 
AST 
Aspartate aminotransferase/glutamic-oxalacetic transaminase 
AUC 0-24 
Area under the concentration-time curve from 0 to 24 hours after drug 
administration 
BCRP 
Breast cancer resistance protein 
BRAF 
B-Raf proto-oncogene 
BSC 
Best supportive care 
CAM 
Chorioallantoic membrane 
CDK 
Cyclin-dependent kinase 
CEA 
Carcino-embryonic antigen 
CFR 
Code of Federal Regulations 
CHL 
Chinese Hamster Lung 
CI 
Confidence interval 
Cmax 
Maximum plasma concentration 
c-MET 
Mesenchymal epithelial cells transforming factor  
COVID-19 
Coronavirus Disease 2019 
CR 
Complete response 
CRC 
Colorectal cancer 
CrCl 
Creatinine clearance 
CRO 
Contract research organization 
CT 
Computed tomography 
ctDNA 
Circulating tumor DNA 
CTCAE  
Common Terminology Criteria for Adverse Event 
DCR 
Disease control rate 
dMMR 
Deficient mismatch repair 
DoR 
Duration of response 


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Abbreviation 
Definition 
DVT 
Deep vein thrombosis 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EGFR  
Epidermal growth factor receptor 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End of treatment 
EC 
Ethics Committee 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FD&C 
The United States Federal Food, Drug and Cosmetic Act 
FDG-PET 
Fluorodeoxyglucose positron emission tomography 
fT3 
Serum free triiodothyronine 
fT4 
Serum free thyroxine 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HA 
Health Authority 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
IB 
Investigator’s brochure 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IDMC 
Independent data monitoring committee 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IWRS 
Interactive web response system 
LDH 
Lactic dehydrogenase 


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Abbreviation 
Definition 
LVEF 
Left ventricular ejection fraction 
mCRC 
Metastatic colorectal cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MID 
Minimally important difference 
mL 
Milliliter 
MMR 
Mismatch repair 
MRI 
Magnetic resonance imaging 
MSI 
Microsatellite instability 
MSI-H 
High levels of microsatellite instability 
MTD 
Maximum tolerated dose 
MUGA 
Multigated acquisition scan 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE 
The National Cancer Institute Common Terminology Criteria for Adverse 
Event 
NE 
Not evaluable 
NOAEL 
No observed adverse effect level 
NSCLC 
Non-small-cell lung cancer 
ORR 
Objective response rate 
OS 
Overall survival 
PD  
Progressive disease 
PDGFR 
Platelet-derived growth factor receptor 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PO 
Per os (oral administration) 
PPE 
Palmar-plantar erythrodysesthesia 
PR 
Partial response 
PS  
Performance status 
PT 
Preferred term 
PTT 
Prothrombin time 
QD 
Quaque die (once daily) 
QoL 
Quality of life 
RECIST 
Response Evaluation Criteria In Solid Tumors 


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Abbreviation 
Definition 
RP2D 
Recommended phase 2 dose 
SAE  
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SMQ 
Standardized MedDRA Query 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time of observed maximum plasma concentration 
TQT 
Thorough QT 
TSH 
Thyroid stimulating hormone 
TTD 
Time to deterioration 
TTP 
Time to progression 
ULN 
Upper limit of normal 
US 
United States 
VEGF 
Vascular endothelial growth factor 
VEGFR 
Vascular endothelial growth factor receptor 
WHO  
World Health Organization 


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1 
SYNOPSIS 
Title 
A Global, Multicenter, Randomized, Placebo-Controlled Phase 3 Trial to 
Compare the Efficacy and Safety of Fruquintinib Plus Best Supportive Care to 
Placebo Plus Best Supportive Care in Patients with Refractory Metastatic 
Colorectal Cancer (FRESCO-2) 
Short Title 
A global, randomized, placebo-controlled phase 3 study of fruquintinib in 
patients with refractory metastatic colorectal cancer 
Acronym 
FRESCO-2 
Phase 
3 
Study Design 
This is a global, randomized, double-blind, placebo-controlled, multicenter 
phase 3 clinical trial to compare the efficacy and safety of fruquintinib plus best 
supportive care (BSC) versus placebo plus BSC in subjects with refractory 
metastatic colorectal cancer (mCRC).  Approximately 687 subjects will be 
randomized in a 2:1 ratio to either the fruquintinib plus BSC treatment group or 
the placebo plus BSC treatment group. 
Randomization will be stratified by the following factors: 
• 
Prior therapy with trifluridine/tipiracil (TAS-102) versus regorafenib 
versus both trifluridine/tipiracil (TAS-102) and regorafenib  
• 
RAS status (wild type versus mutant) 
• 
Duration of metastatic disease (≤ 18 months versus > 18 months) 
Subjects will receive study treatment with each 4-week cycle consisting of 
3 weeks of daily oral (PO) study medication and 1 week of study drug 
interruption (3 weeks on/1 week off).  Tumor evaluation will be performed by 
imaging (computed tomography [CT] or magnetic resonance imaging [MRI] 
scan) every 8 weeks until there is progression of disease (PD), death, new anti-
cancer treatment, or study completion, whichever comes first.  Safety parameters 
will include adverse events (AE), and results from laboratory tests, vital signs, 
ECG, and echocardiogram.  Post-discontinuation anti-tumor therapy and survival 
follow up after PD will also be recorded. 
Rationale 
Colorectal cancer (CRC) is the second most common malignancy in both men 
and women and the third most common cause of cancer-related death in the US, 
with an estimated 145,600 new cases and 51,020 deaths in 2019.  Similarly, CRC 
is a major global health issue, with an estimated 1.8 million new cases and 
880,000 deaths in 2018 worldwide (Bray 2018). 
There is no standard of care for patients who have progressed on approved 
standard-of-treatments, including chemotherapy, relevant biologics and TAS-
102 and/or regorafenib.  Patients who are well enough to receive additional 
therapy following all standard therapies either are considered for treatment on a 
clinical trial when available or are re-challenged with agents such as 5-FU or 
bevacizumab.  Consequently, there is an unmet medical need for new 
medications that are safe and effective in patients with refractory mCRC who 
have progressed on, or had intolerable toxicity from, available standard systemic 
therapies, and for whom no effective therapy or standard of care exists.   
Fruquintinib is a novel, potent, and highly selective small molecule tyrosine 
kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, 
and -3.  In the FRESCO trial conducted in China, fruquintinib improved the 
median overall survival in patients with mCRC in a third-line or later setting 
when compared to placebo (median overall survival 9.3 months versus 


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6.6 months; hazard ratio for death 0.65 (95% CI: 0.51-0.83; p < 0.001)(Li 2018).  
The results from this pivotal trial led to fruquintinib’s approval in China. 
The safety profile of fruquintinib from an ongoing phase 1/1b study in the US is 
consistent with that of clinical studies performed in China, as well as published 
data for other small molecule VEGF inhibitors.  The pharmacokinetic (PK) 
profile of fruquintinib in the US phase 1/1b study is also comparable to the PK 
profile in patients treated with fruquintinib in China at the same dose and dosing 
regimen (5 mg PO, QD, 3 weeks on, 1 week off, for each 4-week cycle).   
These data showing favorable efficacy and acceptable safety indicates 
fruquintinib is a promising candidate for development as a new treatment for 
patients with refractory mCRC and may address an unmet medical need globally. 
This global, multicenter, randomized, double-blind, placebo-controlled clinical 
trial will compare the efficacy and safety of fruquintinib in combination with 
BSC, to placebo in combination with BSC, in patients with refractory mCRC 
who have progressed on, or were intolerant to, TAS-102 and/or regorafenib.  
Patients must have also received prior standard therapies, including two lines of 
chemotherapy (fluoropyrimidine-, oxaliplatin-, and irinotecan-based), a 
biological VEGF inhibitor, and, if RAS wild type, an EGFR inhibitor.  Patients 
with high microsatellite instability (MSI-H)/mismatch repair deficient  (dMMR) 
tumors must have also received an immune checkpoint inhibitor if approved and 
available and if deemed appropriate. 
Target Population 
The study population will consist of subjects ≥18 years of age with histologically 
and/or cytologically documented metastatic colorectal adenocarcinoma who 
progressed on, or were intolerant to, all standard chemotherapies and relevant 
biologics and TAS-102 and/or regorafenib. 
Inclusion/Exclusion Criteria 
Inclusion Criteria 
Subjects may be enrolled in this study only if they satisfy all the following 
criteria: 
1. Provide written informed consent;  
2. Age ≥18 years;  
3. Histologically and/or cytologically documented metastatic colorectal 
adenocarcinoma.  RAS, BRAF, and microsatellite instability 
(MSI)/MMR status must be documented, according to country level 
guidelines; 
4. Subjects must have progressed on or been intolerant to treatment with 
either trifluridine/tipiracil (TAS-102) or regorafenib.  Subjects are 
considered intolerant to TAS-102 or regorafenib if they have received 
at least 1 dose of either agent and were discontinued from therapy for 
reasons other than disease progression.  Subjects who have been treated 
with both TAS-102 and regorafenib are permitted.   
Subjects must also have been previously treated with: 
• 
standard approved therapies: fluoropyrimidine-, oxaliplatin-, 
and irinotecan-based chemotherapy, 
• 
an 
anti-VEGF 
biological 
therapy 
(eg, 
bevacizumab, 
aflibercept, ramucirumab) [Please note that regorafenib is 
NOT an anti-VEGF biologic], and,  
• 
if RAS wild-type, an anti-EGFR therapy (eg, cetuximab, 
panitumumab); 
5. Subjects with microsatellite-high (MSI-H) or mismatch repair deficient 
(dMMR) tumors must have been treated with immune checkpoint 


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inhibitors if approved and available in the subject’s country unless the 
subject is ineligible for treatment with a checkpoint inhibitor;  
6. Subjects who received oxaliplatin in the adjuvant setting and 
developed metastatic disease during or within 6 months of completing 
adjuvant therapy are considered eligible without receiving oxaliplatin 
in the metastatic setting. Subjects who developed metastatic disease 
more than 6 months after completion of oxaliplatin-containing 
adjuvant treatment must be treated with oxaliplatin-based therapy in 
the metastatic setting to be eligible; 
7. Body weight ≥40kg; 
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 
to 1;   
9. Have measurable disease according to RECIST Version 1.1 
(RECIST v1.1), assessed locally.  Tumors that were treated with 
radiotherapy are not measurable per RECIST v1.1, unless there has been 
documented progression of those lesions; 
10. Expected survival >12 weeks; 
11. For female subjects of childbearing potential and male subjects 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, intrauterine 
device (IUD), intrauterine hormone-releasing system (IUS), bilateral 
tubal ligation, vasectomized partner, or true sexual abstinence in line 
with the preferred and usual lifestyle of the subject.   Highly effective 
contraception should always be combined with an additional barrier 
method (eg, diaphragm, with a spermicide).  The same criteria are 
applicable to male subjects involved in this clinical trial if they have a 
partner of childbirth potential, and male subjects must always use a 
condom; 
12. Subjects with BRAF-mutant tumors must have been treated with a 
BRAF inhibitor if approved and available in the subject’s country unless 
the subject is ineligible for treatment with a BRAF inhibitor. 
Exclusion Criteria: 
Subjects are not eligible for enrollment into this study if they have any of the 
following criteria: 
1. 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; 
2. Serum total bilirubin >1.5 × the upper limit of normal (ULN).  Subjects 
with previously documented Gilbert syndrome and bilirubin <2 X ULN 
are eligible;  
3. ALT or AST >2.5 × ULN in subjects without hepatic metastases; ALT 
or AST >5 × ULN in subjects with hepatic metastases;  
4. 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; 


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5. Urine dipstick or urinalysis with protein ≥2+ or 24-hour urine protein 
≥1.0 g/24-h.  Subjects with 1+ proteinuria must undergo a 24-hour urine 
collection to assess urine protein level.  For conversions between 
qualitative and quantitative results, please see Appendix 9; 
6. Uncontrolled hypertension, defined as: systolic blood pressure 
≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg despite 
optimal medical management.  The subject must have blood pressures 
below both limits.  Repeated assessments are permitted;  
7. International Normalized Ratio (INR) >1.5 x ULN or activated partial 
thromboplastin time (aPTT) >1.5 × ULN, unless the subject is currently 
receiving or intended to receive anticoagulants for prophylactic 
purposes;   
8. History of, or 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, in the 
investigator’s judgment, result in gastrointestinal hemorrhage or 
perforation; within the 6 months prior to screening; 
9. History or presence of hemorrhage from any other site (eg, hemoptysis 
or hematemesis) within 2 months prior to screening; 
10. History of a thromboembolic event, including deep vein thrombosis 
(DVT), pulmonary embolism (PE), or arterial embolism within 
6 months prior to screening;  
11. Stroke and/or transient ischemic attack within 12 months prior to 
screening;  
12. 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% by echocardiogram;  
13. 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.  
14. Concomitant medications with a known risk of causing QT prolongation 
and/or torsades de pointes (Source list is continuously updated online at 
www.crediblemeds.org); 
15. Systemic anti-neoplastic therapies (except for those described in 
Exclusion Criterion 18) or any investigational therapy within 4 weeks 
prior to the first dose of study drug, including chemotherapy, radical 
radiotherapy, hormonotherapy, biotherapy and immunotherapy;  
16. 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;  
17. Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior 
to the initiation of study drug;  
18. Brachytherapy (ie, implantation of radioactive seeds) within 60 days 
prior to the first dose of study drug; 
19. Use of strong inducers or inhibitors of CYP3A4 within 2 weeks (or 5 
half-lives, whichever is longer) before the first dose of study drug; (see 
Appendix 4 for a list of applicable drugs); 


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20. Surgery or invasive procedure (ie, a procedure that includes a biopsy; 
central venous catheter placement is allowed) within 60 days prior to 
the first dose of study drug or unhealed surgical incision; 
21. Any unresolved toxicities from a previous antitumor treatment greater 
than National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Event (CTCAE) v5.0 grade 1 (except for alopecia or 
neurotoxicity grade≤2); 
22. Known human immunodeficiency virus (HIV) infection;  
23. Known history of active viral hepatitis.  For subjects with evidence of 
chronic hepatitis B virus (HBV) infection, the HBV viral load must be 
undetectable on suppressive therapy, if indicated.  Subjects with HCV 
infection who are currently on treatment are eligible if they have an 
undetectable HCV viral load; 
24. Clinically uncontrolled active infection requiring IV antibiotics;   
25. Tumor invasion of a large vascular structure (eg, pulmonary artery, 
superior or inferior vena cava);   
26. Women who are pregnant or lactating;  
27. 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; subjects requiring steroids within 4 weeks 
prior to start of study treatment are excluded; 
28. Other malignancy, except for non-melanoma skin cancer, in situ 
cervical cancer or bladder cancer (Tis and T1) that have been adequately 
treated during the 5 years prior to screening;  
29. 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;  
30. Other disease, metabolic disorder, physical examination anomaly, 
abnormal laboratory result, or any other condition (eg, current alcohol 
or drug abuse) that investigators suspect may prohibit use of the 
investigational product, affect interpretation of study results, or put the 
subject at undue risk of harm based on the investigator’s assessment;  
31. Known hypersensitivity to fruquintinib or any of its (or placebo) 
inactive ingredients including the azo dyes Tartrazine - FD&C Yellow 
5 and Sunset yellow FCF - FD&C Yellow 6; 
32. Subjects who have received prior fruquintinib; 
33. Live vaccine ≤28 days before the first dose of study drug(s). 
Seasonal vaccines for influenza are generally inactivated vaccines and 
are allowed. Intranasal vaccines are live vaccines and are not allowed. 
Number of Subjects 
Approximately 687 subjects will be randomized 2:1 (fruquintinib plus BSC: 
placebo plus BSC). 
Length of Participation 
Subjects may continue to receive treatment until they meet a criterion for 
discontinuation.   
Intervention 
Investigational Drug:  Fruquintinib (HMPL-013) capsule 5 mg will be 
administered PO, QD, 3 weeks on, 1 week off (4-week cycles).  Doses may be 
given either in the fasting state or after meals, around the same time each day.  If 
dose adjustment is required, 1 mg fruquintinib capsules will be used. 
Reference Drug:  Placebo capsules matching fruquintinib 5 mg will be 
administered PO, QD, 3 weeks on, 1 week off (4-week cycles).  Doses may be 


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given either in the fasting state or after meals, around the same time each day.  If 
dose adjustment is required, 1 mg matching placebo capsules will be used. 
Primary Objective  
To evaluate the overall survival of fruquintinib plus BSC compared to placebo 
plus BSC in subjects with refractory mCRC. 
Secondary Objective(s)  
• 
To evaluate progression-free survival (PFS) of fruquintinib plus BSC 
compared to placebo plus BSC 
• 
To evaluate the objective response rate (ORR), disease control rate 
(DCR), and duration of response (DoR) 
• 
To assess the safety and tolerability of fruquintinib plus BSC compared 
to placebo plus BSC 
• 
To characterize the PK exposure of fruquintinib and metabolite M11 in 
subjects with refractory mCRC 
• 
To evaluate the effect of fruquintinib on cardiac repolarization, as 
detected by changes in electrocardiogram (ECG) QTc intervals, and the 
potential relationship with fruquintinib and M11 plasma concentrations 
• 
To evaluate the relationship between fruquintinib exposure and 
endpoints for efficacy and safety 
• 
To evaluate quality of life (QoL) as assessed by using QLQ-C30: 
cancer-specific; and EQ-5D-5L questionnaires 
• 
To assess resource utilization (for example, hospitalizations and 
concomitant medications) 
Exploratory Objective(s)  
To assess potential predictive biomarkers of response to fruquintinib 
Number of Sites 
This study will be conducted at approximately 160 sites globally. 
Study Duration 
Recruitment period is estimated to take approximately 15 months.  Estimated 
duration for the entire study from time the study is open to enrollment until 
completion of data analyses is approximately 22 months.   
Independent Data Safety 
Monitoring Committee 
The IDMC will be comprised of at least 4 independent oncologists from 
representative geographies and at least 1 independent statistician. 
 
1.1 
Study Schematic 
The study schematic is presented in Figure 1. 


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Figure 1 
Study Design Schema 
 
1.2 
Schedule of Events 
The schedules of events (SOEs) are presented in Table 1, Table 2, and Table 3. 
 






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2. Procedural details for medical history are available in Section 6.1.1.2.  Tumor diagnosis, tumor treatment history, and 
evaluation of RAS, microsatellite instability (MSI)/mismatch repair (MMR), and BRAF status is described in Section 6.1.1.3. 
3. Procedural details for patient demographics, including baseline characteristics are available in Section 6.1.1.4. 
4. Procedural details for concomitant medications/treatments are available in Section 6.1.1.5. 
5. Procedural details for comprehensive physical examination are available in Section 6.1.1.6. 
6. Procedural details for limited physical examination are available in Section 6.1.1.7. 
7. Procedural details for ECOG performance status are available in Section 6.1.1.8. 
8. Procedural details for vital signs are available in Section 6.1.1.9. 
9. Procedural details for hematology are available in Section 6.1.1.10. 
10. Procedural details for blood chemistry are available in Section 6.1.1.11. 
11. Procedural details for amylase and lipase are available in Section 6.1.1.12. 
12. Coagulation tests include prothrombin time (PTT), international normalized ratio (INR), and activated partial thromboplastin 
time (aPTT).  Additional procedural details are available in Section 6.1.1.13. 
13. Thyroid function tests include serum free triiodothyronine (fT3), serum free thyroxine (fT4) and thyroid stimulating hormone 
(TSH).  Additional procedural details are available in Section 6.1.1.14. 
14. Twenty-four-hour urine for quantitative protein should be collected from all patients with 1+ proteinuria during screening.  If 
urine protein ≥2+ during the period of study treatment, a 24-hour urine protein should be collected within 1 week.  Additional 
procedural details for urinalysis are available in Section 6.1.1.15. 
15. All female patients of childbearing potential must complete a blood pregnancy test at screening and at the Safety Follow up 
Visit.  Serum pregnancy test should be repeated for patients with suspected pregnancy or an equivocal urine pregnancy test.  
This is not applicable for postmenopausal female patients, but the date of menopause should be recorded instead.  Additional 
procedural details are available in Section 6.1.1.16. 
16. All female patients of childbearing potential must complete a urine pregnancy test at each day 1-visit starting at cycle 2. 
17. See Table 2 and Table 3 for specific ECG parameters and time points.  Electrocardiogram is to be performed before PK and 
echocardiogram assessments at each relevant visit.  Other procedural details for Holter Monitor and 12-lead ECG are available 
in Section 6.1.1.17. 


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18. An echocardiogram should be done at Screening, C2D1, and on the first day, every 3 cycles thereafter.  Additional procedural 
details for echocardiogram are available in Section 6.1.1.18.  MUGA scans are acceptable if an echocardiogram cannot be 
performed. 
19. Baseline tumor assessment should be completed within 28 days prior to enrollment.  Post-baseline tumor evaluations shall be 
performed on C3D1, C5D1, and day 1 of every other cycle thereafter until progression of disease (PD).  Each tumor 
assessment should document measurable lesions at the scheduled visit (every 8 weeks ± 1 week).  Additional procedural 
details are available in Section 6.1.1.19. 
20. Serum carcino-embryonic antigen (CEA) level is collected at screening and at day 1 of every cycle (±1 week) starting at cycle 
2 until disease progression.  Additional procedural details are available in Section 6.1.1.20. 
21. 6.1.1.21See Table 2 and Table 3 for specific PK time points.  Sampling for PK assessments is described in Section 6.1.2.1, and 
evaluation procedures are described in Section 6.1.2.2 
22. Patient randomization occurs on day -2 to day 1.  Additional procedural details on patient randomization are available in 
Section 6.1.1.22.  
23. For the method of drug dispensation and return, see Section 7.2.2. 
24. Study drug is taken daily on a 3 weeks on, 1 week off schedule for each 28-day cycle.  On days with PK collection, treatment 
should be administered at the site by a delegated study staff member. 
25. After informed consent, but prior to initiation of study drug, all SAEs regardless of attribution will be collected.  After 
initiation of study drug, all SAEs and AEs regardless of attribution will be collected until 30 days after 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 related to the study drug. 
26. Survival follow-up (by telephone) should be performed every 12 weeks (±2 weeks) after the end of treatment (EOT) visit.  All 
subsequent anti-tumor therapy and information about study drug-related SAEs shall be collected.  For the patients that 
discontinue the study without PD, all available tumor assessment results during survival follow up shall be recorded in the 
eCRF 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 follow up for survival will be performed. 
27. Events can be performed up to and including C1D1. 
 


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Table 2 
Schedule of Events for Dense Pharmacokinetic and Electrocardiogram 
Evaluations for the Subset of Approximately 120 Patients with Evaluable 
ECGs 
Study day 
Time Relative 
to Dosing 
(±10 minutes) 
Study Drug 
Intake 1 
Pharmacokinetic 
Samples 2 
Triplicate ECG for 
QTc Evaluation 
(Holter Monitor4) 
Safety ECG 
(Standard 
Equipment) 
C1D1 
Pre-dose 3 
 
X 
X 
- 
0 h 
X 
- 
- 
- 
1 h 
 
X 
X 
- 
2 h 
 
X 
X 
- 
3 h 
 
X 
X 
- 
4 h 
 
X 
X 
- 
C1D21 
Pre-dose 3 
 
X 
X 
- 
0 h 
X 
- 
- 
- 
1 h 
 
X 
X 
- 
2 h 
 
X 
X 
- 
3 h 
 
X 
X 
- 
4 h 
 
X 
X 
- 
C2D1 
Pre-dose 3 
 
X 
- 
- 
0 h 
X 
- 
- 
- 
C2D21 
Pre-dose 3 
 
X 
- 
- 
0 h 
X 
- 
- 
- 
2 h 
 
X 
- 
X 
C3D1 
Pre-dose 3 
 
X 
- 
- 
0 h 
X 
- 
- 
- 
C3D21 
Pre-dose 3 
 
X 
- 
- 
0 h 
X 
- 
- 
- 
2 h 
 
X 
- 
X 
C5D1 and every 
other cycle 
thereafter 
Pre-dose 3 
 
X 
- 
- 
0 h 
X 
- 
- 
- 
C1D1= cycle 1, day 1; C1D21 = cycle 1, day 21; C2D1 = cycle 2, day 1; C2D21 = cycle 2, day 21; C3D1 = cycle 3, day 1; C3D21 = cycle 3, 
day 21; C5D1 = cycle 1, day 1 ECG = Electrocardiogram 
 


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Table 3 
Schedule of Events for Sparse Pharmacokinetic and Electrocardiogram 
Evaluations for Patients Not Included in the Approximately 120 Evaluable 
Patients in the Subset in Table 2 
Study day 
Time Relative to 
Dosing 
(±10 minutes) 
Study Drug Intake 1 
Pharmacokinetic 
Samples 2 
Safety ECG 
(Standard 
Equipment) 
C1D1 
Pre-dose 3 
 
X 
X 
0 h 
X 
- 
- 
2 h 
 
X 
X 
C1D21 
Pre-dose 3 
 
X 
- 
0 h 
X 
- 
- 
2 h 
 
X 
X 
C2D1 
Pre-dose 3 
 
X 
- 
0 h 
X 
- 
- 
C2D21 
Pre-dose 3 
 
X 
- 
0 h 
X 
- 
- 
2 h 
 
X 
X 
C3D1 
Pre-dose 3 
 
X 
- 
0 h 
X 
- 
- 
C3D21 
Pre-dose 3 
 
X 
- 
0 h 
X 
- 
- 
2 h 
 
X 
X 
C5D1 and every other 
cycle thereafter 
Pre-dose 3 
 
X 
- 
0 h 
X 
- 
- 
C1D1= cycle 1, day 1; C1D21 = cycle 1, day 21; C2D1 = cycle 2, day 1; C2D21 = cycle 2, day 21; C3D1 = cycle 3, day 1; C3D21 = cycle 3, 
day 21; C5D1 = cycle 1, day 1; ECG = Electrocardiogram 
1.2.2 
Footnotes for the Schedule of Events Tables 2 and 3 
1. On PK sampling day, study drug must be taken at the investigative site under the supervision 
of the investigator or designee and should not be taken at home on the morning of the visits.  
The date and time of the dose administered on the day of PK collection and one day before 
PK collection must be recorded in the electronic case report form (eCRF). 
2. The actual date and time of the PK samples must be recorded on the eCRF.  There is a 
window of ± 10 minutes for the PK sampling procedure. 
3. Pre-dose PK and ECG should be performed within 30 minutes BEFORE study drug 
administration. 
4. Refer to the Holter Monitor instruction manual for appropriate timing of the start of the ECG 
recording.   


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2 
INTRODUCTION 
During tumorigenesis, malignancies release growth factors to induce angiogenesis, which provides 
nutrients and oxygen for rapid tumor growth.  The immature arrangement of endothelial cells on 
the rapidly growing blood vessels can result in exudation of tumor cells into the circulatory system, 
through which the tumor cells may spread to other tissues, leading to tumor metastasis.  Vascular 
endothelial growth factor receptor (VEGFR) is one of the key factors known to induce tumor 
angiogenesis, and agents that target VEGF and the VEGFR are important therapies for malignant 
solid tumors, including colorectal cancer (Duda 2007, Jayson 2016). 
Fruquintinib (HMPL-013) is a small molecule anti-tumor drug with a novel chemical structure that 
belongs to the quinazoline class and is a potent and highly selective tyrosine kinase inhibitor of 
VEGFRs.  In vitro studies demonstrated that fruquintinib is highly selective for VEGFRs-1, -2, 
and -3, which are related to tumor angiogenesis, and possess weak or no measurable activity 
against other kinases (Sun 2014).  Fruquintinib was discovered by Hutchison MediPharma Limited 
(hereafter referred to as the sponsor) through in vitro and in vivo biological screening of a large 
number of synthetic compounds. 
Results from preclinical and clinical studies have provided evidence that fruquintinib has anti-
cancer activity in solid tumors.  The clinical development program in China has been ongoing 
since 2009.  In the phase 3 clinical trial, FRESCO, that led to the drug’s approval in China, 
fruquintinib improved median overall survival in patients with metastatic colorectal cancer 
(mCRC) in a third-line or later setting when compared to placebo from 6.6 to 9.3 months (hazard 
ratio for death 0.65; 95% confidence interval [CI] 0.51-0.83; P < 0.001)(Li 2018).  The cumulative 
safety data from the clinical trial program has shown that fruquintinib has an acceptable level of 
toxicity that is consistent with other antiangiogenic drugs, particularly small molecule VEGFR 
inhibitors.  These data provide a strong justification for the investigation of fruquintinib in patients 
with refractory mCRC globally. 
2.1 
Study Rationale 
Colorectal cancer (CRC) is a major global health issue, with an estimated 1.8 million new cases 
and 880,000 deaths in 2018 worldwide (Bray 2018).  The established initial and second-line 
systemic therapy for mCRC consists of fluoropyrimidine-, oxaliplatin, and irinotecan-based 
cytotoxic chemotherapy (eg, FOLFOX: [5-Fluorouracil, leucovorin, and oxaliplatin] and FOLFIRI 
[5-fluorouracil, leucovorin, and irinotecan]).  In addition, a biologic anti-VEGF therapy is typically 
given with chemotherapy (eg, bevacizumab), and if the tumor is RAS wild type, an anti-EGFR 
therapy (eg, cetuximab) is administered.  In the small proportion of patients that are deficient 
mismatch repair (dMMR)/ high levels of microsatellite instability (MSI-H) in the metastatic setting 
(Koopman 2009), immunotherapy with nivolumab or pembrolizumab may be used (NCCN 2019). 
When there is disease progression after the first two lines of chemotherapy, the established options 
are either:  
• Trifluridine/tipiracil (LONSURF®, TAS-102), an oral combination of trifluridine, a 
nucleoside metabolic inhibitor, and tipiracil, a thymidine phosphorylase inhibitor; 
(LONSURF® USPI) or 
• Regorafenib (STIVARGA®), a multikinase inhibitor with numerous in vitro targets that 
include VEGFR (STIVARGA® USPI). 


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There is no standard of care for patients who have progressed on chemotherapy, relevant biologics, 
and TAS‑102 and/or regorafenib.  Accordingly, there is an unmet medical need for new 
medications that are safe and effective in patients with refractory mCRC who have progressed on, 
or had intolerable toxicity from, available standard systemic therapies, and for whom no effective 
therapy or standard of care exists.  A recent estimation of the median overall survival (OS) for 
patients with mCRC, based on data from phase 3 clinical trials, observation studies, and registries, 
is 30 months (Grothey 2013, Mayer 2015).  During this time, patients may receive several lines of 
therapy, with one or more “breaks.”  Both TAS-102 and regorafenib are approved in the third-line 
or greater (3+ line) of therapy after progression on chemotherapy, and there are no approved 
treatments following progression on these agents.  In this setting, the current options for patients 
with good performance status are to enter a clinical trial or to be re-challenged with prior 
chemotherapy (eg, 5-FU).  Patients with poor performance status generally enter hospice care.   
Fruquintinib is currently in clinical development for a number of different cancer indications, 
including advanced non-small-cell lung cancer (NSCLC), gastric cancer, and mCRC.  All clinical 
studies of fruquintinib that led to the first approval of fruquintinib (Elunate®) capsule, granted on 
04 September 2018 in China for the treatment of patients with mCRC, were conducted in China in 
primarily Asian study populations.  At the time this study was conceived, a phase 1/1b study of 
fruquintinib in the United States (US) was being conducted.  Preliminary data indicated that the 
safety profile of fruquintinib from this ongoing phase 1/1b study in the US was consistent with 
those from the clinical studies performed in China.   
This global phase 3 trial (FRESCO-2) is being conducted to confirm the results of the phase 3 
FRESCO trial conducted in China in patients with refractory mCRC.  This randomized, 
double-blind, placebo-controlled, clinical trial will compare the efficacy and safety of fruquintinib 
in combination with the best supportive care (BSC) versus placebo in combination with BSC in 
patients with refractory mCRC who have progressed on, or were intolerant to, TAS-102 and/or 
regorafenib.   
2.2 
Background 
2.2.1 
Justification for Dosing Strategy 
The optimal fruquintinib dose and dosing regimen were determined in two Chinese phase 1 studies, 
2009-013-00CH1 and 2012-013-00CH3, as well as one US phase 1/1b study, 2015-013-00US1.  
During dose escalation, study 2009-013-00CH1 investigated continuous daily doses of 1 mg, 
2 mg, 4 mg, 5 mg, and 6 mg; in addition, 5 mg QD and 6 mg QD were studied on a regimen of 3 
weeks on, 1 week off (4-week) cycles.  The maximum-tolerated dose (MTD)/ recommended 
phase 2 dose (RP2D) was 4 mg QD (continuous) or 5 mg QD (3 weeks on, 1 week off). 
In study 2012-013-00CH3, the safety and tolerability of these two dosing regimens (4 mg QD 
continuously versus 5 mg QD, 3 weeks on, 1 week off) were compared in patients with mCRC.  
The safety profile was better in the 5 mg QD (3 weeks on, 1 week off) group than the 4 mg QD 
(continuous) group.  In addition, there was accumulation of drug over time in the 4 mg QD 
(continuous) group.  Thus, the 5 mg PO, QD, 3 weeks on, 1 week off, dose and regimen was 
selected as the RP2D and the dosing regimen to be used in subsequent clinical development in 
China. 
The RP2D and dosing regimen were tested in the phase 2 (2012-013-00CH1) and phase 3 (2013-
013-00CH1 [FRESCO]) studies, which confirmed that the dose and dosing regimen were safe and 


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effective in patients with refractory mCRC.  The 5 mg PO, QD, 3 weeks on, 1 week off, on a 28 
day cycle, is the standard dose and dosing regimen in all other completed, ongoing, and planned 
studies in patients with advanced cancer. 
In the US phase 1/1b study (2015-013-00US1), there were 2 dose cohorts in the dose escalation 
phase, 3 mg PO, QD (n=7) and 5 mg PO, QD (n=7).  Fruquintinib was well tolerated in both dose 
cohorts.  Therefore, 5 mg PO, QD, 3 weeks on, 1 week off, on a 28 day cycle, was confirmed as 
the RP2D for global studies, as well. 
2.2.2 
Supportive Nonclinical Data 
2.2.2.1 
Pharmacology 
Fruquintinib is highly selective for VEGFRs -1, -2, and -3, with a 50% inhibitory concentration 
(IC50) of 33 nM, 35 nM and 0.5 nM, respectively.  Fruquintinib was found to have low activity on 
other kinases, with IC50 greater than 10 μM for cyclin-dependent kinases (CDKs 1, 2, and 5), 
platelet-derived growth factor receptor β (PDGFRβ), epidermal growth factor receptor (EGFR), 
and mesenchymal-epithelial transition factor (c-Met) in a panel of 264 kinases, which confirms 
the selectivity of fruquintinib.  
In cellular assays, fruquintinib inhibited VEGFR family kinases and suppressed VEGFR 
phosphorylation with IC50 at low (nanomolar) levels.  Consistently, in functional assays, 
fruquintinib blocked VEGF-dependent human umbilical vein endothelial cell (HUVEC) 
proliferation and tube formation and also exhibited this anti-angiogenic effect in the 
chorioallantoic membrane (CAM) model. 
In animal models, a pharmacokinetic (PK)/pharmacodynamic study revealed that fruquintinib 
suppressed VEGF-induced VEGFR2 phosphorylation (p-VEGFR2) in lung tissues of nude mouse 
in a drug exposure-dependent manner.  Fruquintinib also achieved near complete target inhibition 
(>80%), following a single oral dose of 2.5 mg/kg, which was maintained for >8 hours with a 
corresponding plasma drug concentration of 176 ng/mL at the 8-hour time point. 
In multiple human tumor xenograft models in Nu/Nu mice, fruquintinib demonstrated a dose 
dependent anti-tumor activity accompanied by strong anti-angiogenesis effect in tumor tissues.  In 
all tumor models tested, fruquintinib showed statistically significant tumor growth inhibition at 
doses as low as 2 mg/kg/day.  Complete target coverage for more than 8 hours, with plasma 
concentration over 176 ng/mL maintained for 8 hours, was shown to significantly suppress tumor 
growth. 
The combination of fruquintinib with cytotoxic chemotherapies (oxaliplatin or docetaxel), with 
molecular targeted therapies (EGFR or MET inhibitors) or with an immune checkpoint inhibitor 
(anti-PD-L1) demonstrated a synergistic or additive anti-tumor effect in multiple preclinical tumor 
models. 
2.2.2.2 
Metabolism and Pharmacokinetic Drug Interaction 
 
  
 
 
  
 
 


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In vitro, fruquintinib had no significant reversible or 
 on 
CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5 (IC50 >10 µM).  There was also no induction of 
CYP1A2, 
and CYP3A4 by fruquintinib at concentrations up to 10 µM. 
According to the investigations on drug transporters, fruquintinib was not a substrate of P-
glycoprotein (P-gp), breast cancer resistance protein (BCRP),
 
 
 
 
2.2.2.3 
Toxicology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
2.2.3 
Supportive Clinical Data 
2.2.3.1 
Clinical Pharmacokinetics 
Single-dose and multiple-dose PK of fruquintinib have been characterized in Chinese and US 
patient populations, and single-dose PK has been evaluated in healthy Chinese males. 


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In Chinese patients with cancer, plasma fruquintinib exposure increased proportionally over the 
single dose range tested from 1 mg to 6 mg.  Fruquintinib was rapidly absorbed with mean Tmax 
ranging from 1.5 to 4.7 hours.  Mean t1/2 ranging from 35.2 hours to 48.5 hours was observed for 
fruquintinib.  Following continuous dosing of fruquintinib 1, 2, 4, 5, or 6 mg QD, plasma 
fruquintinib concentration reached steady state by 14 days after dosing with exposure 
accumulating 3- to 4-fold at steady state compared to day 1.  Following dosing of fruquintinib at 
5 mg QD and 6 mg QD at the 3 week on/1 week off schedule, plasma fruquintinib concentrations 
declined during the off week, as expected.  Preliminary PK results from the US patient population 
(ongoing Study 2015-013-00US1) that received fruquintinib at 3 mg and 5 mg QD 3 weeks 
on/1 week off suggested that there were no meaningful differences in fruquintinib exposure 
between Chinese and US patients.  Following fruquintinib 5 mg QD 3 weeks on/1 week off, mean 
fruquintinib maximum plasma concentration (Cmax) and area under the plasma concentration-time 
curve over a dosing interval (AUCtau) values on day 21 were 326 ng/mL and 5969 ng*h/mL in 
Chinese patients (Study 2012-013-00CH3), respectively, compared with 385 ng/L and 
7530 ng*h/mL in US patients, respectively. 
The effect of a high fat high calorie meal on the PK of fruquintinib 4 mg (4 x 1 mg capsules) was 
studied in healthy Chinese males (Study 2012-013-00CH2).  Food delayed Tmax of fruquintinib by 
2.6 hours.  A slight decrease in fruquintinib Cmax by 17% was seen, though there was no observed 
effect on the AUC0-∞.  These results were sufficient to recommend dosing of fruquintinib without 
regard to food. 
The results from the mass balance study conducted in healthy Chinese subjects (Study 2015-013-
00CH2) indicated that 60.31% of total radioactivity was recovered in urine and 29.80% in feces.  
A total of 22 metabolites were identified in the plasma, urine, and feces samples.  The M11 (N-
demethylation product) and M9 (carboxylic acid product) were the main metabolites, where M11 
accounted for 17.31% and M9 accounted for 4.46% of the plasma exposure of total radioactivity.  
Only a small amount of unchanged fruquintinib was detected in urine, which accounted for 0.50% 
of the dose administered.  The amount of fruquintinib in feces accounted for 5.34% of the dose 
administered. 
M11 is a pharmacologically active metabolite found to inhibit VEGFR2 kinase activity and VEGF-
induced VEGFR2 phosphorylation, with a potency approximately 2 to 10 times lower than that of 
fruquintinib.  After multiple doses of fruquintinib 5 mg QD to patients for 21 days (Study 2015-
013-00US1, preliminary data), M11 reached Tmax after 1 hour.  The mean (standard deviation) 
Cmax and area under the concentration-time curve from 0 to 24 hours after drug administration 
(AUC0-24) values were 144 (56.2) ng/mL and 3080 (1250) h*ng/mL, respectively.  M11 
accumulated by 31.5-fold after multiple dosing.  The mean (standard deviation) metabolite-to-
parent ratio of M11 was 0.409 (0.135) at steady state.  Overall, M11 is not expected to have 
clinically meaningful contribution to the total pharmacological activity of fruquintinib at 
therapeutic exposure. 
2.2.3.2 
Clinical Safety 
As of the data cut-off date (03 Sep 2019), 7 clinical trials in patients with cancer were completed.  
In order to conduct a comprehensive and robust safety assessment across the fruquintinib clinical 
studies, a pooled dataset has been generated and analyzed, which consists of data from 739 patients 
in 4 completed double-blind studies (2012-013-00CH1, 2013-013-00CH1, 2014-013-00CH1, and 
2015-013-00CH1) (Table 21 ) who received fruquintinib monotherapy.  In addition, the safety data 


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from 2 completed early phase open-label studies (phase 1 2009-013-00CH1, phase 1b 2012-013-
00CH3) and 1 completed phase 1b/2 study (2014-013-00CH3) has also been analyzed.  
As of the data cut-off date, 5 clinical studies in patients with cancer were ongoing.  The safety 
profile of fruquintinib from a US phase 1/1b open-label, multi-center study (2015-013-00US1), 
from a China phase 2 open-label study of fruquintinib in combination with gefitinib (2016-013-
00CH1), and from a China phase 1b/2 open-label study of fruquintinib in combination with 
sintilimab (2018-013-00CH3) are also presented in this section.  No formal analysis is available 
for the safety profile of fruquintinib in the other 2 ongoing studies; the China randomized phase 3 
study of paclitaxel with or without fruquintinib in metastatic gastric cancer (2017-013-00CH1) 
remains blinded, and no patients have been enrolled into the China open label single arm study 
evaluating fruquintinib in elderly patients with NSCLC (2017-013-00CH2). 
Adverse Events in Completed Studies: 
A total of 739 patients received at least 1 dose of fruquintinib in the 4 completed double-blind, 
placebo-controlled, monotherapy studies, among whom 729 (98.6 %) patients reported treatment-
emergent adverse events (TEAEs).  The incidence of the most commonly reported TEAEs (≥10% 
of patients) are provided in the current investigator’s brochure (IB). 
In the pooled data of all-causality TEAEs reported, the most commonly reported TEAEs of grade 
≥3 (≥5% of patients) included Hypertension (19.9%) and Palmar-plantar erythrodysaesthesia 
syndrome (10.7%). 
Serious Adverse Events in Completed Studies: 
A total of 1 or more serious adverse events (SAEs) have been reported by 169 (22.9%) patients 
out of the 739 patients who received fruquintinib.  The most common SAEs (≥1.0%) by MedDRA 
preferred term (PT) included Infectious pneumonia in 24 (3.2%) patients, intestinal obstruction in 
17 (2.3%) patients, pleural effusion in 9 (1.2%) patients, death in 10 (1.4%) patients, hepatic 
function abnormal in 8 (1.1%) patients, and gastrointestinal haemorrhage in 8 (1.1%) patients.  The 
SAEs in more than 1 patient in the pooled data are summarized in the current IB. 
2.2.3.3 
Clinical Efficacy 
Monotherapy Efficacy:  
As of the data cut-off date (03 September 2019), the available fruquintinib efficacy data from the 
completed open-label and double-blind studies showed strong antitumor activity, including 
improved OS and progression-free survival (PFS), durable partial response (PR) and durable stable 
disease (SD), and improved overall response rate (ORR) in heavily pre-treated patients with 
advanced cancer.  
Two proof-of-concept studies have been conducted in patients with CRC who were previously 
treated with two or more lines of standard chemotherapeutic regimens (2012-013-00CH1) and in 
patients with NSCLC who have failed 2 lines of standard chemotherapies (2014-013-00CH1).  The 
studies both met their primary efficacy endpoint of PFS and demonstrated a significant 
improvement in PFS in the fruquintinib arm compared to the placebo arm. 
In addition, the phase 3 pivotal trial (FRESCO) was completed in patients with CRC who were 
previously treated with 2 or more lines of standard chemotherapeutic regimens (2013-013-
00CH1).  In this study, fruquintinib significantly prolonged the OS compared to placebo with a 


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hazard ratio (HR) of 0.65 (95% CI: 0.51-0.83; 2-sided p <0.001).  Statistically significant benefits 
were also seen with fruquintinib in all secondary endpoints, including as PFS, ORR, and disease 
control rate (DCR).  
One phase 3 study of fruquintinib was completed in patients with NSCLC who had failed second-
line standard chemotherapy (2015-013-00CH1): there was no significant difference between the 
fruquintinib group and the placebo group in the primary efficacy endpoint (OS).  However, 
fruquintinib significantly prolonged the PFS comparing to placebo with a HR of 0.34 (95% CI: 
0.279, 0.425) with p < 0.001 (stratified log-rank test).  Statistically significant benefits were also 
shown with fruquintinib in ORR and DCR. 
The efficacy data in the ongoing study of fruquintinib in patients with advanced solid tumors 
(2015-013-00US1) are not available as of the data cut-off date (03 September 2019). 
Combination Therapy Efficacy  
A phase 1b/2 study had been conducted to investigate the treatment of fruquintinib, in combination 
with paclitaxel, as second-line therapy in patients with gastric cancer (GC) (2014-013-00CH3).  
The results showed that the ORR and DCR were 27.3% (9/33) and 63.6% (21/33), respectively.  
The median PFS and median OS at the RP2D (fruquintinib 4 mg + paclitaxel) were 4.0 months 
and 8.5 months, respectively. 
The efficacy data in 1 ongoing study of fruquintinib in combination with gefitinib in patients with 
NSCLC (2016-013-00CH1) and in 1 ongoing study of fruquintinib in combination sintilimab 
patients with advanced solid tumors (2018-013-00CH3) are not available as of the data cut-off date 
(03 September 2019). 
2.2.4 
Benefit/Risk Assessment 
There are robust cumulative efficacy and safety data for fruquintinib from the entire clinical 
program in China, as well as the ongoing US phase 1/1b study.  As of the data cut-off date 
(03 September 2019) a total of 1600 patients and 87 healthy volunteers had received at least one 
dose of fruquintinib or placebo through development programs.  Among them, 955 patients and 
87 healthy volunteers had received at least one dose of fruquintinib, 284 patients had received at 
least one dose of blinded treatment (fruquintinib versus placebo), and 361 patients had received at 
least one dose of placebo.  
2.2.4.1 
Risk Assessment 
A total of 739 patients received at least 1 dose of fruquintinib in the 4 completed double-blind 
studies, among whom 739 (98.6 %) patients reported TEAEs.  
In the pooled data of all-causality TEAEs reported in the 3 completed double-blind, monotherapy 
studies, the most commonly reported TEAEs of grade ≥3 (≥5% of patients) included hypertension 
(19.9 %) and palmar-plantar erythrodysaesthesia syndrome (10.7 %).  
The incidence of the most commonly reported TEAEs (≥10% of patients) is provided in the current 
IB.  
The safety analysis that resulted in the identified risks was performed on the pooled data set from 
4 completed double-blind studies (N= 739 fruquintinib; N= 361 placebo), in which the incidence 
of adverse events (AEs) in fruquintinib-treated patients was compared with those in the placebo-


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treated control patients.  The identified risks presented by Standardized Medical Dictionary for 
Regulatory Activities (MedDRA) Query (SMQ) are presented in Table 54 of the current IB.  
2.2.4.2 
Benefit Assessment 
The efficacy data in the phase 1 study conducted in China (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 the current IB).  The results of two phase 2 proof-of-concept 
(POC) studies provided evidence of clinical efficacy in patients with metastatic CRC (2012-013-
00CH1, third or later lines therapy) and NSCLC (2014-013-00CH1, third-line therapy) as 
compared with placebo.  The PFS results established POC in both studies by meeting their 
respective primary efficacy endpoints.  Clinical efficacy was also provided by the phase 3, double-
blind, placebo-controlled trial, 2013-013-00CH1 (FRESCO). 
2.2.4.3 
Overall Benefit/Risk Conclusion 
The safety profile of fruquintinib is consistent with those of other anti-angiogenic therapies, 
particularly the small molecule tyrosine kinase inhibitors (ie, sorafenib, regorafenib, axitinib, and 
sunitinib), as demonstrated by the identified risks for fruquintinib (Section 2.2.4.1).  In addition, 
safety data from the completed and ongoing studies showed that fruquintinib was well tolerated, 
with most of the AEs reported as grade 1 to 2 (see current IB).  There have been no new or 
unexpected safety findings from the ongoing clinical trials to date. 


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3 
OBJECTIVES AND ENDPOINTS 
3.1 
Primary Objective 
To evaluate the overall survival (OS) of fruquintinib plus BSC compared to placebo plus BSC in 
subjects with refractory mCRC 
3.2 
Secondary Objectives 
• To evaluate PFS of fruquintinib plus BSC compared to placebo plus BSC 
• To evaluate the objective response rate (ORR), disease control rate (DCR), and duration 
of response (DoR) 
• To assess the safety and tolerability of fruquintinib plus BSC compared to placebo plus 
BSC 
• To characterize the PK exposure of fruquintinib and metabolite M11 in subjects with 
refractory mCRC 
• To evaluate the effect of fruquintinib on cardiac repolarization, as detected by changes in 
electrocardiogram (ECG) QTc intervals, and the potential relationship with fruquintinib 
and M11 plasma concentrations 
• To explore the relationship between fruquintinib exposure and endpoints for efficacy and 
safety 
• To evaluate quality of life (QoL) as assessed by using QLQ-C30: cancer-specific; and 
EQ-5D-5L questionnaires 
• To assess resource utilization (for example, hospitalizations and concomitant 
medications) 
3.3 
Exploratory Objectives 
• To assess potential predictive biomarkers of response to fruquintinib 
The objectives and corresponding endpoints are summarized in Table 4. 
Table 4 
Objectives and Corresponding Endpoints 
Tier 
Objectives 
Endpoints 
Primary 
To evaluate the overall survival (OS) of 
fruquintinib plus BSC compared to placebo 
plus BSC in subjects with refractory mCRC 
OS 
Secondary 
 
To evaluate progression-free survival (PFS) 
of fruquintinib plus BSC compared to 
placebo plus BSC  
PFS 
To evaluate the objective response rate 
(ORR), disease control rate (DCR), and 
duration of response (DoR) 
• 
ORR 
• 
DCR 
• 
DoR 


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Table 4 
Objectives and Corresponding Endpoints 
Tier 
Objectives 
Endpoints 
To assess the safety and tolerability of 
fruquintinib plus BSC compared to placebo 
plus BSC 
Safety including TEAEs, SAEs, deaths, ECG’s, 
and clinical laboratory abnormalities 
To characterize the pharmacokinetic (PK) 
profile of fruquintinib in subjects with 
refractory mCRC 
Observed plasma concentrations, estimated 
population PK and exposure parameters of 
fruquintinib and M11 
To evaluate the effect of fruquintinib on 
cardiac repolarization, as detected by 
changes in electrocardiogram (ECG) QTc 
intervals, and the potential relationship with 
fruquintinib and M11 plasma concentrations 
QTc interval and plasma concentrations of 
fruquintinib and M11 at specified time points 
To evaluate the relationship between 
fruquintinib exposure and endpoints for 
efficacy and safety 
Parameters describing exposure-response with 
efficacy (eg, OS) and safety (eg, AEs) 
endpoints 
 
To evaluate quality of life (QoL) as 
assessed by using QLQ-C30: cancer-
specific; and EQ-5D-5L questionnaires 
Changes in health status (QLQ-C30: cancer-
specific; and EQ-5D-5L) 
 
To assess resource utilization (for example, 
hospitalizations 
and 
concomitant  
medications) 
Resource utilization including all concomitant 
medications, days in hospital 
Exploratory  
To assess potential predictive biomarkers of 
response to fruquintinib 
• 
Change from baseline in ctDNA 
• 
Change from baseline in tumor markers 
(CEA) 
• 
Pharmacogenomics 
 
 


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4 
STUDY PLAN 
Detailed information on the fruquintinib clinical trial program in China and in the US can be 
found in Appendix 5 and in the fruquintinib IB. 
4.1 
Study Design 
This is a global, randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial 
to compare the efficacy and safety of fruquintinib in combination with BSC versus placebo in 
combination with BSC in advanced colorectal cancer patients who have progressed on or were 
intolerant to chemotherapy, biologics and TAS-102 or regorafenib. 
Metastatic colorectal cancer cannot be cured by surgery.  Therefore, treatment principals are 
primarily aimed at controlling disease progression and prolonging survival.  Standard first- and 
second-line therapy includes cytotoxic drugs such as 5-fluorouracil, oxaliplatin, and irinotecan; 
anti-VEGF therapy; and, if RAS wild type, anti-EGFR therapy.  After the first two lines of 
chemotherapy, standard third-line treatment is either TAS-102 or regorafenib.  There are currently 
no effective treatments for patients who have progressed on standard, approved therapies, and 
treatment options include reuse of prior therapies, clinical trials, or BSC.  Consequently, there is 
an unmet medical need for additional safe and effective treatment. 
4.1.1 
Enrollment in Study 
After checking the eligibility criteria, subjects will be randomized into either fruquintinib in 
combination with BSC group (fruquintinib group) or placebo in combination with BSC group 
(placebo group) in a 2:1 ratio (Figure 1).  
• Fruquintinib group: Fruquintinib 5 mg PO, QD, plus BSC, 3 weeks on/ 1 week off, every 
4-week cycle). 
• Control group: Matching placebo 5 mg PO, QD plus BSC, 3 weeks on/ 1 week off, every 
4-week cycle. 
A 2:1 randomization ratio is used in this study as it is expected that fruquintinib will produce better 
efficacy results and robust safety data compared to the placebo arm.  This is supported by robust 
efficacy and safety data from the fruquintinib clinical program, including from the pivotal phase 3 
FRESCO trial.  
A treatment cycle is 4 weeks.  Subjects’ safety assessment and drug accountability will be 
performed at each treatment cycle.  Continuous drug safety monitoring and assessment will be 
performed through the whole study period (including a 30-day observation period after the end of 
treatment). 
As described in Section 2.2.3.3, in the phase 3 FRESCO trial that led to the drug’s approval in 
China, fruquintinib improved the median OS in patients with mCRC in a third line or later setting 
when compared to placebo (median OS 9.3 versus 6.6 months); HR for death was 0.65 (95% CI, 
0.51-0.83; P < 0.001) (Li 2018).  The results of the FRESCO study indicate that fruquintinib is a 
candidate therapy for patients with refractory mCRC globally, and provides the strongest rationale 
for the current clinical trial. 
Since the current standard of care for patients with mCRC in the US, EU, and Japan is different 
than it was in China during the conduct of the FRESCO trial, the current study is necessary to 


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evaluate fruquintinib in a patient population that is representative of global treatment practices.  In 
FRESCO, prior therapy included the standard first two lines of cytotoxic chemotherapy 
(fluoropyrimidine-, oxaliplatin- and irinotecan-based), but only about 30% of patients had received 
prior therapy with a VEGF inhibitor (bevacizumab), and patients with prior exposure to VEGFR 
inhibitors such as regorafenib were excluded. 
4.1.2 
Electrocardiogram Collection and Pharmacokinetic Sampling  
4.1.2.1 
Rationale for Electrocardiogram Collection and Pharmacokinetic Sampling 
Schedule 
In accordance with International Conference on Harmonization (ICH) E14 guideline, QT 
evaluation is expected to be routine in oncology drug development, and a thorough QT (TQT) 
study should be conducted, if possible.  In the case of fruquintinib, in view of nonclinical (hERG 
and CV safety study) and clinical data suggesting no apparent relationship between fruquintinib 
and QT prolongation, an alternative design to the TQT study has been chosen. 
In this study, changes in QTc interval following drug administration will be evaluated relative to 
the baseline measurement.  Electrocardiogram time points have been selected to match the 
expected PK profile of fruquintinib and metabolite M11.  The ECG time points have also been 
selected to explore a potential relationship between exposure and effect on QTc. 
4.1.2.2 
Electrocardiogram Collection and Pharmacokinetic Sampling Schedule 
In order to assess the QTc interval prior to exposure to fruquintinib, baseline triplicate ECG 
assessments will be performed prior to first study drug administration on cycle 1 day 1 (within 
30 minutes before dosing).  A baseline PK sample will also be collected at pre-dose, immediately 
after the ECGs have been collected and prior to the first dose of fruquintinib or placebo.  
Subsequently, the purpose of all other ECGs is to assess for potential prolongation of the QTc 
interval and other ECG changes as a result of fruquintinib administration, with ECG collection 
coinciding with PK measurements to establish correlations between ECG changes and drug 
exposure.  Triplicate ECGs, followed by blood samples for PK assessment, will be collected at 
multiple time points post-dose around Tmax of fruquintinib and metabolite M11 after the first dose 
and at steady-state as described in Table 2. 
4.1.2.3 
Temporary and Permanent Changes in Pharmacokinetic Sampling, Holter 
Monitor QTc Evaluations, and Circulating Tumor DNA Sample Collection 
During the conduct of this 2019-013-GLOB1 study, the COVID-19 pandemic caused significant 
delays in laboratory kit production and delivery from the central vendor.  In order to mitigate the 
delays and allow study sites to screen and treat patients, temporary and permanent measures have 
been implemented as needed to permit changes in the collection of PK and ctDNA sampling and 
Holter monitor QTc evaluations until the supply issues that affected the laboratory kits have been 
resolved.  These temporary measures have been implemented in region-specific addenda to this 
2019-013-GLOB1 protocol.  The temporary pauses on blood sample collection and Holter 
monitoring were terminated once the issues that affected the laboratory kits had been resolved.  
The details of the country-level changes are detailed in separate country-level addenda. 
Due to a continued shortage of tubes for ct 


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DNA collection, an adequate supply to ensure continued collection of all samples for all patients 
cannot be maintained and ctDNA collections will be permanently discontinued in Protocol 
Amendment 4. 
Subjects who do not have PK and ctDNA sample collection and Holter monitor QTc evaluations 
and post-dose safety ECG evaluations performed during the time that an addendum for the region 
is effective are to have “Not Done” entered in the corresponding eCRFs.  Queries are to be issued 
for these pages, and site responses are to include “COVID-19 – supply chain” as the reason for 
missed assessment. 
Pharmacokinetic and ctDNA sample collection and Holter monitor QTc evaluations do not affect 
patient safety and are not required for subject-level treatment decisions on this study.  Additionally, 
with the resumption of PK and ctDNA sample collection and Holter monitor QTc evaluations, the 
integrity of trial data will be preserved and the eventual evaluation of the respective secondary 
objectives will not be compromised. 


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5 
POPULATION 
5.1 
Recruitment 
To randomize 687 patients, approximately 160 sites will be opened globally for patient 
recruitment.  
5.2 
Definitions 
Subjects officially enter the Screening Period after providing informed consent, either directly or 
via a legally authorized representative, where permissible. 
Subjects who withdraw from the study after signing the ICF and before the randomization will be 
considered screen failures.  Subjects who failed the original screening may be screened again using 
their original subject number as assigned by interactive web response system (IWRS).  A subject 
may only be re-screened once.  Randomization will occur centrally using IWRS.  Subjects will be 
assigned randomly in a 2:1 ratio to receive fruquintinib + BSC or placebo + BSC using centrally 
randomized blocks stratified according to stratification factors.  
A randomized subject is one who has been deemed eligible and has been assigned to a treatment 
group by Interactive Response Technology /IWRS.  
5.3 
Inclusion Criteria 
Subjects may be enrolled in this study only if they satisfy all the following criteria: 
1. Provide written informed consent;  
2. Age ≥18 years; 
3. Histologically and/or cytologically documented metastatic colorectal adenocarcinoma.  
RAS, BRAF, and microsatellite instability (MSI)/mismatch repair (MMR) status for each 
subject must be documented, according to country level guidelines; 
4. Subjects must have progressed on or been intolerant to treatment with either 
trifluridine/tipiracil (TAS-102) or regorafenib.  Subjects are considered intolerant to 
TAS-102 or regorafenib if they have received at least 1 dose of either agent and were 
discontinued from therapy for reasons other than disease progression.  Subjects who have 
been treated with both TAS-102 and regorafenib are permitted.  Subjects must also have 
been previously treated with: 
• standard approved therapies: fluoropyrimidine-, oxaliplatin-, and irinotecan-based 
chemotherapy,  
• an anti-VEGF biological therapy (eg, bevacizumab, aflibercept, ramucirumab). 
[Please note that regorafenib is NOT an anti-VEGF biologic], and,  
• if RAS wild-type, an anti-EGFR therapy (eg, cetuximab, panitumumab); 
•  
5. Subjects with microsatellite-high (MSI-H) or mismatch repair deficient (dMMR) tumors 
must have been treated with immune checkpoint inhibitors if approved and available in 
the subject’s country unless the subject is ineligible for treatment with a checkpoint 
inhibitor; 


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6. Subjects who received oxaliplatin in the adjuvant setting and developed metastatic 
disease during or within 6 months of completing adjuvant therapy are considered eligible 
without receiving oxaliplatin in the metastatic setting.  Subjects who developed 
metastatic disease more than 6 months after completion of oxaliplatin-containing 
adjuvant treatment must be treated with oxaliplatin-based therapy in the metastatic setting 
to be eligible; 
7. Body weight ≥40kg; 
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1;   
9. Have measurable disease according to RECIST Version1.1 (RECIST v1.1), assessed 
locally.  Tumors that were treated with radiotherapy are not measurable per RECIST 
v1.1, unless there has been documented progression of those lesions; 
10. Expected survival >12 weeks; 
11. For female subjects of childbearing potential and male subjects 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, intrauterine device (IUD), intrauterine hormone-releasing system 
(IUS), bilateral tubal ligation, vasectomized partner, or true sexual abstinence in line with 
the preferred and usual lifestyle of the subject.  Highly effective contraception should 
always be combined with an additional barrier method (eg, diaphragm, with a 
spermicide).  The same criteria are applicable to male subjects involved in this clinical 
trial if they have a partner of childbirth potential, and male subjects must always use a 
condom; 
12. Subjects with BRAF-mutant tumors must have been treated with a BRAF inhibitor if 
approved and available in the subject’s country unless the subject is ineligible for 
treatment with a BRAF inhibitor. 
5.4 
Exclusion Criteria 
Subjects are not eligible for enrollment into this study if they have any of the following criteria: 
1. 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; 
2. Serum total bilirubin >1.5 × the upper limit of normal (ULN).  Subjects with previously 
documented Gilbert syndrome and bilirubin <2 X ULNare eligible;  
3. ALT or AST >2.5 × ULN in subjects without hepatic metastases; ALT or AST >5 × ULN 
in subjects with hepatic metastases;  
4. 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 
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5. Urine dipstick or urinalysis with protein ≥2+ or 24-hour urine protein ≥1.0 g/24-h.  
Subjects with 1+ proteinuria must undergo a 24-hour urine collection to assess urine 
protein level.  For conversions between quantitative and qualitative results, please see 
Appendix 9;  
6. Uncontrolled hypertension, defined as: systolic blood pressure ≥140 mmHg and/or 
diastolic blood pressure ≥90 mm Hg despite optimal medical management.  The subject 
must have blood pressures below both limits.  Repeated assessments are permitted;  
7. International Normalized Ratio (INR) >1.5 x ULN or activated partial thromboplastin 
time (aPTT) >1.5 × ULN, unless the subject is currently receiving or intended to receive 
anticoagulants for prophylactic purposes; 
8. History of, or 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, in the investigator’s judgment, result in gastrointestinal hemorrhage or 
perforation; within the 6 months prior to screening; 
9. History or presence of hemorrhage from any other site (eg, hemoptysis or hematemesis) 
within 2 months prior to screening;  
10. History of a thromboembolic event, including deep vein thrombosis (DVT), pulmonary 
embolism (PE), or arterial embolism within 6 months prior to screening;  
11. Stroke and/or transient ischemic attack within 12 months prior to screening;  
12. 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% by echocardiogram;  
13. 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; 
14. Concomitant medications with a known risk of causing QT prolongation and/or torsades 
de pointes (Source list is continuously updated online at www.crediblemeds.org); 
15. Systemic anti-neoplastic therapies (except for those described in Exclusion Criterion 18) 
or any investigational therapy within 4 weeks prior to the first dose of study drug, 
including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy and 
immunotherapy;  
16. 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;  
17. Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the initiation of 
study drug;  
18. Brachytherapy (ie, implantation of radioactive seeds) within 60 days prior to the first 
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19. Use of strong inducers or inhibitors of CYP3A4 within 2 weeks (or 5 half-lives, 
whichever is longer) before the first dose of study drug (see Appendix 4 for a list of 
applicable drugs); 
20. Surgery or invasive procedure (ie, a procedure that includes a biopsy; central venous 
catheter placement is allowed) within 60 days prior to the first dose of study drug or 
unhealed surgical incision; 
21. Any unresolved toxicities from a previous antitumor treatment greater than National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) v5.0 
grade 1 (except for alopecia or neurotoxicity grade≤2); 
22. Known human immunodeficiency virus (HIV) infection;  
23. Known history of active viral hepatitis.  For subjects with evidence of chronic hepatitis B 
virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, 
if indicated.  Subjects with HCV infection who are currently on treatment are eligible if 
they have an undetectable HCV viral load; 
24. Clinically uncontrolled active infection requiring IV antibiotics;   
25. Tumor invasion of a large vascular structure (eg, pulmonary artery, superior or inferior 
vena cava);   
26. Women who are pregnant or lactating;  
27. 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; subjects requiring steroids within 4 weeks prior to start of study treatment are 
excluded; 
28. Other malignancy, except for non-melanoma skin cancer, in situ cervical ca or bladder ca 
(Tis and T1) that have been adequately treated during the 5 years prior to screening;  
29. 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;  
30. Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory 
result, or any other condition (eg, current alcohol or drug abuse) that investigators suspect 
may prohibit use of the investigational product, affect interpretation of study results, or 
put the subject at undue risk of harm based on the investigator’s assessment;  
31. Known hypersensitivity to fruquintinib or any of its (or placebo) inactive ingredients 
including the azo dyes Tartrazine - FD&C Yellow 5 and Sunset yellow FCF - FD&C 
Yellow 6; 
32. Subjects who have received prior fruquintinib; 
33. Live vaccine ≤28 days before the first dose of study drug(s).  
Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. 
Intranasal vaccines are live vaccines and are not allowed. 
 


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6 
STUDY CONDUCT 
6.1 
Study Procedures 
6.1.1 
Study Assessments 
The following procedures will be performed according to the schedule in Table 1.  All assessments 
must occur within ± 3 days (±1 day during cycle 1) from the scheduled date, unless otherwise 
noted.  
6.1.1.1 
Informed Consent 
All subjects must sign the informed consent form (ICF) prior to any study-related examinations or 
protocol procedures.  Tumor assessments completed as standard of care prior to signing the 
informed consent, but within 28 days of first dose of study treatment, may be used as baseline 
scans. 
All subjects who sign ICF are to be entered into the IWRS system.  The system will generate a 
subject identification number, which will be assigned to the subject. 
6.1.1.2 
Medical History 
A complete medical history, including the subject’s medical history, disease history and prior 
therapies for disease prior to signing of the ICF, should be recorded at screening.  Comorbidities 
that began prior to signing the ICF should be recorded and followed as medical history. 
6.1.1.3 
Tumor Diagnosis and Treatment History 
Tumor diagnosis should include the date of primary diagnosis of CRC and its type, disease stage, 
the date of first metastasis, type of previous treatment, start and end date/s, best overall response, 
date of PD, adverse reaction with severity ≥ grade 3.  Prior use (yes/no) of trifluridine/tipiracil 
(Lonsurf®, TAS-102), regorafenib (Stivarga®), or both of these drugs, prior use of 
fluoropyrimidine-, oxaliplatin, and irinotecan-based chemotherapy must be documented.  Prior use 
of a biological anti-VEGF therapy (yes versus no), prior RAS gene status (mutant versus wild 
type) and prior use of a biologic anti-EGFR therapy (yes versus no) must also be documented. 
RAS, BRAF, and MSI)/MMR status for each subject must be documented, if available.  If the 
RAS gene test was not performed previously, it should be performed during screening.  Unless 
medically contraindicated or not available in the subject’s country of residence, the following 
therapies should have been received based on tumor types in order to be considered eligible: 
• Subjects with a RAS wild type tumor must have received an anti-EGFR therapy. 
• Subjects with a BRAF-mutant tumor must have received a BRAF inhibitor. 
• Subjects with a MSI/MMR deficient tumor must have received an immune checkpoint 
inhibitor. 
The subject’s history of radiation therapy, including the start and end date/s and the site of radiation 
must be recorded.  Surgical history, including operations and less-invasive diagnostic or 
therapeutic procedures (such as GI endoscopy, biopsy, etc.), the start and end date/s, name of each 
procedure and operation site must also be recorded at screening and in the appropriate eCRF. 


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6.1.1.4 
Demographics 
Demographic characteristics, including year of birth, sex, ethnic group/race, and any relevant 
lifestyle habits should be recorded at screening and in the applicable eCRF (as permitted by local 
regulations). 
6.1.1.5 
Concomitant Medication and Procedures 
Concomitant therapy includes any prescription medications or over-the-counter preparations used 
by a subject.  All concomitant medications within 28 days before randomization must be recorded 
in the eCRF, including the generic name of the drug and daily dose, the reason/s for using the 
medication, as well as the start and stop date/s of the medication.  Concomitant medications should 
be reviewed during the study according to the schedule in Table 1. 
6.1.1.6 
Comprehensive Physical Examination 
A comprehensive physical examination includes subject height, weight and general condition, as 
well as an examination of the head, heart, chest (including the lungs), abdomen, extremities, skin, 
lymph nodes, nervous system and additional areas/systems as clinically indicated. 
6.1.1.7 
Limited Physical Examination 
Limited physical examination includes vital signs and any change from baseline, any new 
abnormalities, examination of the thorax, abdomen, and additional areas/systems as clinically 
indicated.  In order to assess changes from baseline and to evaluate for new abnormalities, the 
limited physical examination should assess for new or changed skin lesions, enlarged lymph nodes, 
palpable masses, and appropriate examination to address any subject-reported symptoms. 
6.1.1.8 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
Subject performance status will be graded according to the ECOG PS scale at study visits as 
detailed in Table 1.  It is recommended that ECOG PS scores be evaluated by the same investigator 
throughout the study.  Details on the ECOG assessment and grading scale are available in 
Appendix 2. 
6.1.1.9 
Vital Signs 
Vital signs include blood pressure, heart rate, respiration rate, temperature, and weight.  For 
subjects with a baseline history of hypertension or hypertension that develops on study, blood 
pressure should be monitored per institutional standard practice.  
6.1.1.10 
Hematology 
Hematology assessments include red blood cell count, hemoglobin, hematocrit, platelet count, 
white blood count with differential (absolute counts).   
Note: If neutrophil count ≤1.0×109/L or platelet count≤ 25 ×109/L, hematology assessments 
should be conducted per institutional standard practice.  


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6.1.1.11 
Blood Chemistry 
The blood chemistry panel includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
creatinine, glucose, calcium, magnesium, phosphorus, total bilirubin, ALT, AST, alkaline 
phosphatase (ALP), lactate dehydrogenase, non-fasting total cholesterol, triglycerides, uric acid, 
total protein, and albumin. 
Blood chemistry tests for subjects with ALT or AST increase by >3x ULN, or increase by >2x 
baseline value should performed per institutional standard practice. 
Creatinine clearance (CrCl) rate (units, mL/min) should be calculated using the baseline serum 
creatinine (Scr) value according to the Cockroft-Gault formula (Appendix 10). 
6.1.1.12 
Blood Amylase and Lipase  
Tests for blood amylase and lipase will be performed during the study according to the schedule 
of events in Table 1. 
6.1.1.13 
Coagulation 
Coagulation tests include prothrombin time (PTT), international normalized ratio (INR), and 
activated partial thromboplastin time (APTT). 
6.1.1.14 
Thyroid Function 
Thyroid function tests include serum free triiodothyronine (fT3), serum free thyroxine (fT4) and 
thyroid stimulating hormone (TSH). 
6.1.1.15 
Urinalysis 
Urinalysis parameters include urine pH, protein, glucose, and blood; microscopic for white blood 
cell and red blood cell count.  A 24-hour urine for quantitative protein must be collected from all 
subjects with  1+ proteinuria during screening.  If urine protein ≥2+ during the period of study 
treatment, a 24-hour urine protein should be collected within 1 week.  For conversions between 
quantitative and qualitative results, please see Appendix 9. 
6.1.1.16 
Pregnancy Test 
All female subjects of childbearing potential must complete a blood pregnancy test at screening 
and within 30 days at the Safety Follow Up Visit, and a urine pregnancy test on day 1 of every 
cycle starting at cycle 2.  Serum pregnancy test should be repeated for women with suspected 
pregnancy or an equivocal urine pregnancy test.  This is not applicable for postmenopausal female 
subjects (ie, no menses for 12 months without an alternative medical cause), and the date of 
menopause should be recorded instead.  Pregnancy testing and contraception are not required for 
women with documented permanent sterilization (eg, hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy, or tubal ligation). 
6.1.1.17 
Electrocardiograms Monitoring 
Single 12-lead ECG will be collected in all subjects using standardized equipment, as described in 
Table 1 and Table 3 during cycles 1 to 3.  Any ECGs from standard equipment will be evaluated 


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for safety by the principal investigator.  All ECGs for the purposes of screening will be performed 
using standard, local equipment. 
In addition, continuous 12-lead Holter monitor will be used for QTc evaluation during cycle 1 in 
a subset of subjects and will be sent for central reading (see below in Continuous 12-Lead Holter 
Monitor for QTc Evaluation for details).  From cycle 4 onward, ECG will only be performed as 
clinically indicated.  Vital signs will be measured, a symptom-directed physical exam will be 
conducted, and safety related blood samples will be collected as per the time points in Table 1.  
These assessments should be completed before the start of any ECG recordings. 
Continuous 12-Lead Holter Monitor for QTc Evaluation 
As described in Section 4.1.2.3, continuous ECG recordings using 12-lead Holter monitoring was 
planned to be collected from the first approximately 120 subjects (80 fruquintinib, 40 placebo) 
enrolled in the study to evaluate the effects of fruquintinib on ventricular repolarization.  However, 
the COVID-19 pandemic caused significant delays in laboratory kit production and delivery from 
the central vendor starting in October 2020.  In order to allow sites to screen and treat subjects 
without delay, a US and Europe Addendum to 2019-013-GLOB1, version 1, was issued on 13 
November 2020 to pause collection of blood for PK sampling and ctDNA and Holter monitoring 
for QTc evaluations.  Due to continued supply chain issues in January 2021, version 2 of the 
addendum was issued on 22 January 2021 to extend the hold on blood sample collection and Holter 
monitoring to 01 April 2021.  Blood sample collection for PK sampling and ctDNA and Holter 
monitor collection was resumed in 2019-013-GLOB1 Amendment 3.  Continuous ECG recordings 
using 12-lead Holter monitoring will be collected from approximately 120 evaluable subjects (80 
fruquintinib, 40 placebo) enrolled in the study to evaluate the effects of fruquintinib on ventricular 
repolarization.  The assessments will be conducted at pre-dose and post-dose on cycle 1 day 1 and 
cycle 1 day 21 at specific time points summarized in Table 2.   
Any subject with a pacemaker will not be a candidate for Holter monitor evaluation according to 
Table 2.  If a subject has a pacemaker, please contact the Sponsor for consideration of ECG and 
PK assessments according to the schedule in Table 3. 
Subjects should reside in a quiet setting without distractions (eg, television, cell phones, and staff 
talking) at each scheduled time point for ECG measurements.  Subjects should rest in a supine 
position for at least 10 minutes before and 5 minutes after the scheduled time point and should 
refrain from talking or moving arms or legs.  Skin preparation should be optimal to obtain high 
quality ECGs; if deemed appropriate, the chest should be shaved and prepared with light abrasion. 
Continuous digital 12-lead Holter ECGs will be recorded as described in the ECG/Holter manual.  
Good quality 12-lead ECG selection and extraction will occur during a 10-minute timeframe 
starting 5 minutes before and ending 5 minutes after the scheduled ECG time point.  All Holter 
recorder devices (as supplied by the central ECG laboratory) will be of the same brand and model 
with the same software, and would have been recently serviced and calibrated.  Documentation 
describing the brand, type, software, and service/calibration history of Holter recorders will be 
provided by the central ECG laboratory and archived at the site as well as in the sponsor’s study 
file.  Transfer of the Holter recordings and extraction of the ECG tracings will be performed as 
described in the ECG/Holter manual. 
Ten-second digital ECG tracings will be extracted from the Holter device in triplicate by the 
central ECG laboratory according to the following principles: 


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• The actual time of dosing will be communicated to the central ECG laboratory on the 
Holter acquisition form completed by the site. 
• Using visual inspection or automated tools as appropriate, the central ECG laboratory 
will identify a period of stable heart rate on the continuous Holter tracing within ±5 
minutes of the nominal ECG time point (determined relative to the actual dosing time 
for an individual subject).  Three 10-second ECGs will be extracted in close 
succession from this identified segment. 
• The scheduled time points for triplicate ECG extraction are summarized in Table 2. 
Unless warranted by a specific safety endpoint of the study, the Holter tracings will not be routinely 
analyzed for rhythm and conduction abnormalities.  These analyses will only be performed on 
individual subject’s Holter if warranted by TEAEs (eg, syncope).   
6.1.1.18 
Echocardiogram 
An echocardiogram should be done at Screening, cycle 2 day 1, and on day 1, every 3 cycles 
thereafter.  Assessment parameters include left ventricular ejection fraction and general assessment 
of cardiac function.  MUGAs are permitted if echocardiograms cannot be performed. 
Echocardiograms completed as standard of care prior to signing the informed consent, but within 
28 days of first dose of study treatment, may be used as baseline assessment. 
6.1.1.19 
Tumor Evaluation/Imaging 
Tumor assessments (local) will be performed at study visits specified in Table 1. 
All measurable and evaluable lesions should be assessed and documented using image-based 
evaluation.  All subjects are to be evaluated utilizing contrast-enhanced computed tomography 
(CT) scan of the chest, abdomen, and pelvis, or other acceptable cross-sectional imaging per 
RECIST v1.1.  Evaluations should include other areas of the body, as clinically indicated.  Disease 
status will be assessed by the investigator or designated site staff using RECIST v1.1.  The same 
imaging procedure used to define measurable lesions at baseline must be used throughout the study 
for each subject, unless medically contra-indicated.  At the investigator’s discretion, other methods 
of assessment of measurable disease as per RECIST v1.1 may be used.   
Tumor assessments completed as standard of care prior to signing the informed consent, but within 
28 days of first dose of study treatment, may be used as baseline scans. 
Imaging for all subjects will also be collected for central storage.  Please refer to the study-specific 
central imaging manual for collection and shipping instructions. 
6.1.1.20 
Tumor Markers 
Assessment of serum carcino-embryonic antigen (CEA) levels will be performed according to the 
schedule in Table 1.  The dates of blood sampling must be recorded in the eCRF. 
6.1.1.21 
Circulating Tumor DNA 
Blood samples for circulating Tumor DNA will no longer be collected as of Protocol 
Amendment 4 due to continued shortage of collection tubes.  All previously collected samples 
will be analyzed according to the statistical analysis plan (SAP).  


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6.1.1.22 
Subject Randomization 
On day -2 to day 1, after verifying the subject’s eligibility, the site will log into the IWRS and the 
subject will be randomized by the system.  The system will generate a serial number matching a 
bottle of investigational product in the site’s inventory.  The site will take investigational product 
with the serial number assigned by IWRS from inventory and dispense it to the subject.  The first 
dose should be administered on cycle 1 day 1. 
6.1.1.23 
Quality of Life Assessment 
A quality of life assessment, using QLQ-C30: cancer-specific; and EQ-5D-5L: general, must be 
performed during the screening visit as well as day 1 of each cycle until treatment is discontinued. 
6.1.2 
Pharmacokinetics Evaluations 
6.1.2.1 
Sample Collection and Handling 
Samples for PK analysis will be collected in all subjects according to the schedule in Table 2 and 
Table 3.  The actual dates and times of PK sampling should be recorded in appropriate eCRF.  In 
addition, the dates and times of the dose administered on the day of PK collection and one day 
before PK collection must be recorded in the eCRF. 
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided to the sites.  Collection, handling, storage, and shipment 
of samples must be under the specified, and where applicable, controlled temperature conditions 
as indicated in the laboratory manual. 
6.1.2.2 
Analytical Procedures 
Plasma samples will be analyzed to determine concentrations of fruquintinib and its active 
metabolite M11 using a validated, specific, and sensitive Liquid Chromatography-Tandem Mass 
Spectrometry (LC MS/MS) method. 
If required, then plasma samples may be analyzed to document the presence of circulating 
metabolites using a qualified research method. 
6.1.3 
End of Treatment Visit  
Subjects who have completed the study or have discontinued study treatment will be asked to 
return to the investigational site to receive safety examinations and assessments within 7 (±3) days 
after the last dose of study drug. 
6.1.4 
Safety Follow-Up Visit 
All subjects who have completed an End of Treatment Visit will have a Safety Follow-Up Visit.  
The Safety Follow-Up Visit will be conducted at 30 (±7) days from the EOT Visit. 
6.1.5 
Efficacy Follow-Up 
Any subject who discontinues study treatment for any reason other than disease progression should 
be followed until progression is documented or until a new anti-cancer treatment is initiated for 
PFS assessment and until death for OS assessment. 


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6.1.6 
Survival Follow-Up 
Every 12 weeks (±2 weeks) after the End of Treatment Visit the investigator or their designee 
should call the subject to collect information related to survival status and their use of other anti-
cancer treatments, including drug name, dosage, treatment start and end dates, and efficacy.  
Information related to radiotherapy received after disease progression is also needed, including 
radiotherapy location, radiation dose, start date, and end date. 
6.1.7 
Long-term Extension 
Subjects who are still on study treatment at the time of study completion may continue to receive 
study treatment if they are experiencing clinical benefit and no undue risks. 
Continued access will apply to this study only if at least 1subject is still on study treatment when 
study completion occurs.  The sponsor will notify investigators when the continued access period 
begins. 
6.2 
Discontinuation or Withdrawal 
6.2.1 
Permanent Discontinuation of Treatment 
The investigator has the right to discontinue a subject from the study for any medical condition 
that the investigator determines is in the best interest of the subject, reasons of non-compliance 
(eg, missed doses, visits), or pregnancy.  
Any subject who discontinues treatment should be encouraged to return to the study site for an 
End of Treatment Visit and continue with the remaining study visits outlined in Table 1.  The 
primary reason for discontinuation must be recorded on the appropriate eCRF. 
Subjects could be discontinued from treatment for any of the following reasons: 
1. Disease progression (according to RECIST v1.1).  If the subject is experiencing a 
treatment benefit, in the opinion of the investigator, the subject may continue study 
treatment beyond radiographic progression until clinical progression.  Determination of 
clinical progression is at the discretion of the investigator and may include both objective 
and subjective data.  The continuation decision should be made by the investigator in 
consultation with the sponsor; 
2. Withdrawal of consent;  
3. Intolerable toxicity or AEs that warrant withdrawal of study treatment as determined by 
the principal investigator; 
4. Poor subject compliance;  
5. Use of other antitumor treatment during the study;  
6. Pregnancy;  
7. Subject is lost to follow-up; 
8. The investigator or sponsor determines it is in the best interest of the subject; 
9. Study is terminated by the sponsor;  
10. Death; 
11. End of this study. 


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6.2.2 
Withdrawal from Study 
All study participants have the right to withdraw from the study at any time.  During the treatment 
period and follow-up period, a subject who withdraws consent to continue participation in the 
study will not be followed for any reason after consent has been withdrawn.  Every effort should 
be made to obtain information on subjects who discontinue study treatment but who do not 
withdraw consent to continue participation in the study.  If a participant withdraws consent for 
disclosure of future information, the sponsor may retain and continue to use any data collected 
before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
6.2.3 
Replacement of Subjects 
Subjects will not be replaced in this study. 
6.2.4 
Subjects Lost to Follow-up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
Before a participant is deemed lost to follow up, the investigator or designee must make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a 
certified letter to the participant’s last known mailing address or local equivalent methods).  These 
contact attempts should be documented in the participant’s medical record. 
Should the participant continue to be unreachable, he/she will be considered to be withdrawn from 
the study.  
6.3 
Study Termination 
The sponsor has the right to terminate the study prematurely.  Reasons may include efficacy, 
safety, or futility, among others.  Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
6.4 
End of Study 
The end of the study defined as the last visit of the last subject in the study.  


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7 
STUDY DRUGS 
7.1 
Study Drug Administration 
Fruquintinib (at a dose of 5 mg) or matching placebo will be administered PO, QD, on a 3 weeks 
on, 1 week off schedule.  One treatment cycle is 4 weeks.  The administration time should be 
recorded accurately.  Study drug may be given either in the fasting state or after meals, around the 
same time each day.  If dose adjustment is required, 1 mg fruquintinib or matching placebo 
capsules will be used. 
On days with PK collection, treatment should be administered at the site by a delegated study staff 
member. 
If vomiting occurs after dosing, study drug doses should not be replaced.  If a dose is missed, the 
missed dose can be taken within a 12-hour window of time the subject typically takes the dose.  A 
double dose should not be administered to make up for missed individual doses.   
7.2 
Description of Products 
Fruquintinib will be provided as 1 mg or 5 mg capsules for oral administration.  Matching placebo 
capsules for each strength will also be provided.   
7.2.1 
Formulation, Storage, Preparation and Handling 
The investigational drugs are formulated as capsules, which are packaged in labeled bottles.  The 
drug information is provided in Table 5.  Additional information is available in the pharmacy 
manual. 
Table 5 
Information on Investigational Products 
Name 
Dosage 
Form 
Specification 
Administration Method 
Fruquintinib 
Capsule 
5 mg 
Oral 
Fruquintinib 
Capsule 
1 mg 
Oral 
Matching placebo* 
Capsule 
5 mg 
Oral 
Matching placebo * 
Capsule 
1 mg 
Oral 
* The appearance of the matching placebo is identical to that of the study drug. 
All the investigational drugs should be sealed and stored in a secure, limited access area under 
appropriate conditions.  The storage temperature should be between 10℃ to 30℃.  Investigational 
drugs should not be used beyond expiration date provided by the manufacturer. 
The temperature-monitoring log should be recorded and filed in the study binder. 
7.2.2 
Drug Accountability 
7.2.2.1 
Assignment/Disposal (Study Site) 
All study drug required for this study will be provided by Hutchison MediPharma Limited.  The 
recipient will acknowledge receipt of the drug by returning the appropriate documentation form 
indicating shipment content and condition.  Damaged supplies will be replaced. 


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Accurate records of all study drug received at, dispensed from, returned to and disposed 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 Limited 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. 
7.2.2.2 
Drug Return (Subject) 
On day -2 to day 1, only subject randomization and drug assignment will be performed.   Subjects 
will be provided with a pill diary at randomization and be instructed on how to account for each 
day’s dose appropriately.  Subjects should return all unused study drug and containers from the 
previous cycle on day 1 (date of scheduled visits) of each subsequent cycle, and new study drug 
will be dispensed on the same day.  Site study staff should review subjects pill diary and provide 
a new diary if necessary at the day 1 visit of each cycle. 
If a dose adjustment is required (eg, decrease from 5 mg QD to 4 mg QD), the subject must return 
to the investigational site and return all unused study drug.  The site must log into the IWRS, adjust 
the dose, reassign the drug serial number, and dispense new study drug dose (in 1 mg capsules) to 
the subject.  If the dose is adjusted a second time, ie, from 4 mg QD to 3 mg QD, the site must log 
into the IWRS and record the second dose adjustment.  On this occasion, it is not necessary to 
reassign a new drug serial number.  If tumor evaluation shows PD during the previous cycle and 
new drug has been dispensed, the subject must return all unused study drug on the 30-day safety 
visit after EOT. 
7.3 
Treatment Assignment and Bias Minimization 
7.3.1 
Treatment Allocation 
Treatment will be allocated using IWRS randomization strategy and procedure (refer to the IWRS 
manual).  After screening, subjects who meet the eligibility criteria will be randomized into the 
fruquintinib or placebo group in a 2:1 ratio.  Randomization will be stratified by:  
• Prior therapy with trifluridine/tipiracil (TAS-102) versus regorafenib versus both 
trifluridine/tipiracil (TAS-102) and regorafenib;  
• RAS status (wild type versus mutant); and  
• Duration of metastatic disease (≤ 18 months versus > 18 months).  
7.3.2 
Extent and Maintenance of Blinding 
The study subject, investigators, and study site personnel will remain blinded to all randomization 
assignments throughout the study except for the specific circumstances described in Section 7.3.3.  
The sponsor’s study director, study monitor, and any other sponsor and contract research 
organization (CRO) personnel who are in regular contact with the study site will remain blinded 
to all subject randomization assignments, except sponsor pharmacovigilance personnel for the 
purpose of IND safety reports. 


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7.3.3 
Unblinding Procedures 
7.3.3.1 
Emergency Unblinding 
Unblinding of the study treatment can occur in emergency cases and should not occur unless it is 
needed to manage a subject’s medical condition. 
• In an emergency, when specific knowledge of the subject’s treatment assignment is 
needed to manage a subject’s medical condition, the Investigator can unblind the subject 
using the IWRS to obtain the subject’s treatment assignment. It is recommended that the 
Investigator then inform the Sponsor’s Medical Monitor of the case. 
• In a non-emergent situation, the Investigator is encouraged to contact the Sponsor’s 
Medical Monitor to discuss the case prior to unblinding. 
Once unblinded, the subject should discontinue the treatment but will continue to be followed for 
safety and efficacy.  The investigator should record the event in the source document. 
7.4 
Assessment and Verification of Compliance 
The investigator is responsible for ensuring the subject’s treatment compliance.  The sponsor will 
provide supervision through on-site monitoring visits made by its representatives.  The 
investigators should maintain complete and accurate records of drug use.  The dosing regimen and 
subject’s actual dosing should be recorded in the original treatment records as well as the eCRF.  
At each treatment visit, the investigators or study staff should comprehensively assess the subject's 
treatment compliance according to the drug dispensing and return status at each visit and the actual 
dosing conditions, such as missed doses and overdosing reported by the subject.  The subjects must 
return all drug bottles and remaining capsules at the end of the study.  The investigational sites 
must return all remaining supplies and drugs to the sponsor or provide evidence of destruction at 
the conclusion of the study.  
7.5 
Prior and Concomitant Therapies 
7.5.1 
Prohibited Therapies 
Any therapy intended for the treatment of cancer (with the exceptions as noted in Section 7.5.2), 
whether currently marketed or experimental, is prohibited.  This includes, but is not limited to, the 
following: chemotherapy, hormonal therapy, biologic therapy, radiotherapy, or herbal therapy. 
Concomitant use of medications that have a known risk of causing QT prolongation and/or 
torsades de pointes (see “combined” list at http://www.crediblemeds.org, with attention to those 
drugs listed as KR (“known risk”) are prohibited.  
Live vaccines are prohibited during the study and for 3 months after the last dose of study drug(s). 
Seasonal vaccines for influenza are generally inactivated vaccines and are allowed.  Intranasal 
vaccines are live vaccines and are not allowed. 
7.5.2 
Permitted Therapies 
Concomitant therapy includes any prescription medications or over-the-counter preparations used 
by a subject.  All concomitant therapy within 28 days prior to randomization and to the Safety 
Follow Up visitshould be reported to the investigator and recorded on the appropriate eCRF. 


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Subjects who use oral contraceptives, hormone-replacement therapy, or other allowed 
maintenance therapy may continue their use if indicated. 
Prophylactic use of anticoagulation for the maintenance of patency of permanent indwelling 
central venous access devices or for subjects at high risk of venous thromboembolism is permitted 
during study treatment.  If subjects are receiving anti-coagulation, they should be very closely 
monitored for potential hemorrhage. 
Please see Appendix 7 for additional information on the clinical management of severe or serious 
hemorrhagic AEs. 
Subjects that develop arterial thromboembolic events should discontinue the study drug.  If a 
subject 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. 
Prophylactic antiemetic, granulocyte colony stimulating factors, granulocyte macrophage colony-
stimulating factors, platelet simulating factors or erythropoietin are permitted as clinically 
indicated. 
Palliative radiation for symptom control is allowed provided it does not compromise tumor 
assessments of target lesions.  However, study 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. 
All supportive measures consistent with optimal subject care will be given throughout the study. 
7.5.3 
Drug-Drug Interactions (Therapies to Avoid or Use with Special Caution) 
In vitro metabolism data indicate that CYP3A plays an important role in the metabolism of 
fruquintinib.  The potential effects of medications that can affect the PK of fruquintinib via the 
CYP3A pathway have not been tested in the clinic.  Therefore, medications that are strong inhibitor 
or strong inducer of CYP3A should not be administered concomitantly with fruquintinib.  
Examples of these medications to avoid are listed in Appendix 4.  
In vitro, fruquintinib is shown to have the potential to inhibit P-gp and BCRP (see Section 2.2.2.2).  
Avoid concomitant use with medications that are sensitive substrates of P-gp or BCRP where 
possible.  If used together, monitor subjects more frequently for adverse reactions, and consider 
dose reduction of the P-gp or BCRP substrate medication.  Examples of the medications that are 
sensitive substrates of P-gp and BCRP are listed in Appendix 4. 
7.5.4 
Rescue Therapies 
Not applicable. 
7.5.5 
General Dose Adjustment Note 
The severity of AEs will be graded according to the NCI CTCAE v5.0.  Reasons for dose 
modifications or delays, the supportive measures taken, and the outcome should be documented 
in the subject’s chart and recorded in the eCRF. 


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• 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 subject 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 can be continued at the same dose.  
• To recover from acute toxicity, unless otherwise indicated, the treatment can be delayed 
for up to 14 days.  If a treatment delay longer than 14 days is required, treatment should 
be discontinued.  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. 
7.5.6 
Dose Modification Guidance 
7.5.6.1 
Dose Modification Sequence by Starting Dose and for General Hematologic and 
Non-Hematologic Toxicity 
The dose reduction sequence by starting dose is shown in Table 6.  Subjects are allowed to have 
no more than 2 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 (see Table 6).  Once a dose has been 
reduced, it cannot be re-escalated. 
Table 6 
Dose Modification Sequence by Starting Dose  
Dose Level 0* 
(Original dose) 
5 mg QD 3 weeks on, 1 week off 
Fruquintinib of 5 mg, 1 capsule, or 
1 capsule of the matching placebo  
Dose Level -1* 
(the 1st dose reduction) 
4 mg QD 3 weeks on, 1 week off 
Fruquintinib of 1 mg, 4 capsules, or 
4 capsules of the matching placebo 
Dose Level -2* 
(the 2nd dose reduction) 
3 mg QD 3 weeks on, 1 week off 
Fruquintinib of 1 mg, 3 capsules, or 
3 capsules of the matching placebo 
* Doses are daily, on days 1-21 each 28-day cycle (3 weeks on, 1 week off) 
QD = once daily 
 
Dose reduction guidelines for hematologic and non-hematologic toxicities, other than Palmar-
plantar erythrodysesthesia (PPE), Proteinuria, Hypertension, Decreased platelet count, 
Hemorrhage, and liver function impairment, are shown in are shown in Table 7.  Treatment should 
be held until AE/toxicity resolves or improves to ≤ grade 1.  If a subject has a grade 3 toxicity that 
is expected to be manageable and reversible with a dose reduction, treatment should be held until 
toxicity resolves to ≤grade 1.  Subjects with grade 3 non-hematologic toxicity not described below 
that does not resolve to ≤grade 1 within 14 days should permanently discontinue the study drug 
unless approval to continue is obtained in writing from the sponsor. 


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Table 7 
Dose Modifications for Hematologic and Non-Hematologic Toxicity 
NCI CTCAE v5.0 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 a lower dose level 
Grade 4 
Discontinue treatment permanently 
a. 
If amylase and/or lipase are elevated, and if clinically indicated, further evaluation for pancreatitis should be 
performed. 
b. Including grade 3 diarrhea and stomatitis, etc. that are ineffectively treated by drug therapies, but excluding 
grade 3 menstrual cycle extension.    
 
7.5.6.2 
Dose Modifications for Important Identified Risks and Potential Risks 
This section provides details of the recommended dose modifications for the currently identified 
and potential risks that have been determined in both clinical and nonclinical studies.  The dose 
modification and treatment suggestions for both potential risks and specific important identified 
risks are provided in Table 8 (potential risks) Table 9(dermatological toxicity), Table 10 
(proteinuria), Table 11 (hypertension), Table 12 (decreased platelet count), Table 13 (hemorrhage 
at any site), and Table 14 (abnormal liver function). 
Table 8 
Dose Modification for Potential Risks 
AE 
Dose Adjustment 
Gastrointestinal perforation 
Study drug should be discontinued. 
Arterial Thrombosisa 
Study drug should be discontinued. 
 
Reversible Posterior Leukoencephalopathy Syndrome 
(RPLS)b 
If suspected as RPLS, the study drug should be 
discontinued. 
Delayed Wound Healing 
The general guidance for dose 
interruptions/reductions/discontinuations in response to 
AEs should be followed. 
RPLS = Reversible Posterior Leukoencephalopathy Syndrome. 
a. 
The event term of arterial thrombosis encompasses the preferred terms (PT) of Aortic thrombosis, 
Cerebrovascular insufficiency, Embolism arterial, Peripheral embolism, Retinal artery occlusion, 
Subclavian artery thrombosis, and Transient ischemic attack. 
b. The signs and symptoms of RPLS include seizure, headache, altered mental status, visual impairment or 
cortical blindness with or without hypertension.  The diagnosis of RPLS must be verified using brain 
magnetic resonance imaging (MRI).  
 


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Table 9 
Dose Modifications for Dermatological Toxicity 
AE Grading Standard 
Dose Adjustment 
Treatment Suggestions 
Grade 1 
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 
• 
Hold treatment. 
• 
If the AE recovers to 
grade 1 or baseline 
level within 14 days, 
resume treatment at the 
same dose level. 
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 
• 
Hold treatment.  
• 
If the AE recovers to 
grade 1 or baseline 
level within 14 days, 
resume treatment with 
a dose reduction to the 
next lower dose level. 
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. 
Grade 4 
• 
Permanently 
discontinue study 
treatment. 
Emergent medical treatment. 
AE = adverse event 
 
Table 10 
Dose Modifications 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  
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) 
• 
Hold treatment.   
• 
If the AE recovers to 
grade 1 or baseline level 
within 14 days, resume 
treatment with a dose 
reduction to the next 
lower dose level. 
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 
• 
Hold treatment.   
• 
If the AE recovers to 
grade 1 or baseline level 
within 14 days, resume 
treatment with a dose 
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. 


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Table 10 
Dose Modifications for Proteinuriaa 
AE Grading Standard 
Dose Adjustment 
Treatment Suggestions 
reduction to the next 
lower dose level. 
AE = adverse event. 
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. 
 
Table 11 
Dose Modifications for Hypertension 
AE Grading 
Dose adjustment 
Treatment Suggestions 
Grade 1 
None. 
Follow up as planned schedule 
Grade 2:  
None. 
Treatment objective: lower the 
blood pressure to <140/90 mm Hg 
(or <130/80 mm Hg in subjects 
with chronic renal disease and/or 
diabetes).  
 
Refer to Appendix 8.   
Grade 3:  
• 
If BP >160/100mmHg lasts for >7 
days after initiation of anti-
hypertensive treatment or 
modification of current anti-
hypertensive treatment, treatment 
should be held.   
• 
If hypertension resolves to grade 1 
or baseline level within 14 days, 
resume treatment with a dose 
reduction to the next lower dose 
level. 
Treatment objective: lower the 
blood pressure to <140/90 mmHg 
(or <130/80 mm Hg in subject 
with chronic renal disease and/or 
diabetes).  
 
Refer to Appendix 8. 
Grade 4:  
Permanently discontinue study 
treatment. 
Emergent medical treatment. 
BP = Blood pressure 
 
Table 12 
Dose Modifications for Decreased Platelet Count 
AE Grading 
Dose Adjustment 
Treatment Suggestions 
Grade 1:  
 
None. 
Perform follow up visit as scheduled. 
Grade 2:  
 
• 
Hold treatment.   
• 
If the AE recovers to grade 1 or 
baseline level within 7 days, 
resume treatment at the same 
dose level. 
Hematology test should be monitored every 
2-3 days; active treatment for platelet 
elevation is recommended. 
• 
Hold treatment.   
• 
If the AE recovers to grade 1 or 
baseline level within 14 days, 
resume treatment with a dose 
Hematology test should be monitored every 
2-3 days; active treatment for platelet 
elevation is recommended. 


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Table 12 
Dose Modifications for Decreased Platelet Count 
AE Grading 
Dose Adjustment 
Treatment Suggestions 
reduction to the next lower 
dose level. 
Grade 3:  
 
• 
Hold treatment.   
• 
If the AE recovers to grade 1 or 
baseline level within 14 days, 
resume treatment with a dose 
reduction to the next lower 
dose level. 
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:  
 
Permanently discontinue study 
treatment. 
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  
AE = Adverse event 
 
Table 13 
Dose Modifications for Hemorrhage at Any Site 
AE Grading 
Dose Adjustment 
Treatment Suggestions 
Grade 1 
None 
Perform follow up visit as 
scheduled. 
Grade 2 
• 
Hold treatment. 
• 
If the AE recovers to grade 1 or baseline level within 14 
days, resume treatment with a dose reduction to the next 
lower dose level. 
Provide active treatment 
Grade 3 or 
above a 
Permanently discontinue study treatment. 
Emergent medical 
intervention 
AE = Adverse event 
a Refer to Appendix 7 for clinical management of severe or serious hemorrhage. 
 
 
Table 14 
Dose Modifications for Abnormal Liver Function 
AE Gradinga 
Dose Adjustment 
Treatment Suggestions 
Grade 1 
None. 
Follow up per planned 
schedule. 
Grade 2 or 3 (Liver 
function is abnormal but 
the biochemical criteria for 
Hy’s Lawb are not met) 
• 
Hold treatment. 
• 
If the AE recovers to grade 1 or baseline 
level within 14 days, resume treatment 
with a dose reduction to the next lower 
dose level. 
 
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. 


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Table 14 
Dose Modifications for Abnormal Liver Function 
AE Gradinga 
Dose Adjustment 
Treatment Suggestions 
Grade 4 
The study drug should be terminated. 
Urgent medical intervention 
indicated. 
AE = adverse event. 
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 alkaline phosphatase 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 8.2.2 for special 
reporting requirements and Appendix 6 for additional information regarding Hy’s Law. 


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8 
SAFETY MONITORING 
8.1 
Definitions 
8.1.1 
Adverse Event 
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 v5.0. 
8.1.2 
Serious Adverse Event 
An AE is considered “serious” if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes:  
• Death 
• A life-threatening AE.  An event is considered “life-threatening” if, in the view of the 
investigator, its occurrence places the subject at immediate risk of death.  It does not 
include an AE or suspected adverse reaction (AR) that, had it occurred in a more severe 
form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject or patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
8.2 
Adverse Event Reporting 
8.2.1 
Adverse Event Reporting Period 
After informed consent, but prior to initiation of study drug, all serious adverse events (SAEs) 
regardless of attribution will be collected.  After initiation of study drug, all SAEs and AEs 
regardless of attribution will be collected until 30 days after 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. 
8.2.2 
Expedited Reporting 
Certain events require immediate reporting to allow the sponsor to take appropriate measures to 
address potential new risks in a clinical 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 


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the investigator must report to the sponsor within 24 hours after first learning of the event, 
regardless of relationship to study drug: 
• SAEs (from informed consent to 30 days following the last dose of study drug or a new 
treatment of anti-tumor therapy), 
• Abnormal hepatic function is defined as serum AST or ALT ≥3 × ULN together with total 
bilirubin ≥2 × ULN, regardless of seriousness. 
o For management for hepatic function abnormal event, refer to Table 14 (Dose 
Adjustment for Abnormal Liver Function).  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 
Appendix 6 (Clinical Evaluation of Possible Drug-Induced Liver Injury [DILI]) for 
additional information regarding Hy’s Law. 
• CTCAE grade ≥3 hemorrhagic event, 
o When there is a grade ≥3 hemorrhagic event per NCI CTCAE (Version 5.0).  The 
management of severe or serious hemorrhagic events will be conducted according 
to Appendix 7 (Clinical Management of Severe or Serious Hemorrhagic Events).   
• Pregnancy, 
8.3 
Eliciting Adverse Events 
A consistent methodology of non-directive questioning for eliciting AEs at all subject 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?” 
8.4 
Assessment of Severity 
Investigators will seek information on AEs and SAEs at each subject contact.  All AEs and 
SAEs, whether reported by the subject or noted by authorized study personnel, will be recorded 
in the subject’s medical record and on the appropriate AE/SAE form. 
For each AE and SAE recorded on the applicable eCRF, the investigator will make an assessment 
of severity through clinical description by referring to the five-grade determination standard in the 
NCI CTCAE v5.0.  Please use the guideline below for the assessment of severity when the 
observed or reported AE is not listed in the NCI CTCAE v5.0: 


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• 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. 
Note: 
*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. 
8.5 
Causality assessment 
Investigators should use their knowledge of the subject, the circumstances surrounding the AE, 
and an evaluation of any potential alternative causes to determine whether or not an AE is 
considered to be related to the study drug.  To ensure consistency of causality assessments, 
investigators should apply the general guidelines in provided as below: 
 
• Related: There is a reasonable possibility that the event may have been caused by the 
product under investigation.  Factors that point toward this assessment include but are not 
limited to: a positive re-challenge, a reasonable temporal sequence between administration 
of the drug and the event, a known response pattern of the suspected drug, improvement 
following discontinuation or dose reduction, a biologically plausible relationship between 
the drug and the AE, or a lack of an alternative explanation for the AE. 
 
• Not Related: There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established. 
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this.  Causal relationship in cases 
where the disease under study has deteriorated due to lack of effect should be classified as no 
reasonable possibility. 
8.6 
Documenting Adverse Events 
When an AE or SAE is recorded, the preferred medical terminology or concept should be used.  
Abbreviations and colloquialisms (eg, jargon or slang) should be avoided. 
All AEs (including SAEs) should be recorded on the AE eCRF, and the check box for “Serious” 
should be ticked for entries that fit the criteria for SAEs.  The investigator should also complete 
an SAE report and submit this to the sponsor or its designee within 24 hours of knowledge of the 
event.  


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Only one medical concept should be recorded in the event field on the eCRF. 
8.6.1 
Diagnosis versus Symptoms and Signs 
If known, a diagnosis should be recorded on the eCRF rather than individual signs and symptoms 
(eg, hepatic failure should be recorded instead of jaundice, asterixis, and elevated transaminases).  
However, if a constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded as an AE 
or SAE on the eCRF.  If a diagnosis is subsequently established, it should be reported as follow-
up information. 
8.6.2 
Adverse Event Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (eg, cascade events or clinical sequelae) 
should be identified by their primary cause with the exception of severe or serious secondary 
events.  For example, if severe diarrhea is known to have resulted in dehydration, it is sufficient to 
record only diarrhea as an AE or SAE on the eCRF 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 eCRF.  For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the eCRF. 
8.6.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution between subject evaluation 
time points.  Such events should only be recorded once in the eCRF unless the severity changes.  
If a persistent AE becomes more or less severe, it should be recorded again in a new eCRF entry.  
Please refer to the eCRF Completion Guidelines for information on completing each eCRF.  
A recurrent AE is one that occurs and resolves between subject evaluation time points and 
subsequently recurs.  All recurrent AEs should be recorded on the eCRF respectively. 
8.6.4 
Abnormal Laboratory Values or Abnormal Vital Signs 
Not every laboratory abnormality/abnormal vital sign qualifies as an AE.  A laboratory test 
result/abnormal vital sign must be reported as an AE if it is a change from baseline and meets any 
of the following criteria:  
• Accompanied by clinical symptoms,  
• Results in a change in study treatment (eg, dosage modification, treatment interruption, or 
treatment discontinuation),  
• Results in a medical intervention (eg, potassium supplementation for hypokalemia) or a 
change in concomitant therapy,  
• Clinically significant in the investigator’s judgment.  
Investigators are responsible for reviewing all laboratory findings and abnormal vital signs and 
determining whether or not each abnormality should be reported as an AE. 


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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 eCRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the eCRF.  If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE.  For example, an elevated serum potassium level of 7.0 mmol/L should be recorded as 
“hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the eCRF, unless their severity, seriousness, or 
etiology changes. 
8.6.5 
Preexisting Medical Condition 
A preexisting medical condition is one that is present at screening.  Such conditions should be 
recorded on the eCRF 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 eCRF, it is important to convey the concept that the preexisting condition has changed by 
including applicable descriptors (eg, “more frequent headaches”). 
8.6.6 
Pregnancy 
A female subject 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 of awareness to the sponsor (the reporting period for pregnancy 
continues up to 30 days after completion of the study drug).  The investigator should counsel the 
subject and discuss the risks of continuing with the pregnancy and the possible effects on the fetus.  
Monitoring of the subject should continue until outcome of the pregnancy.  Pregnancies occurring 
up to 30 days after the completion of the study drug must also be reported to the investigator. 
Male subjects 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. 
Pregnancy loss of any kind should always be classified as serious AE (as the sponsor considers 
these medically significant), recorded on the eCRF, and expeditiously reported to sponsor. 
Any congenital anomaly/birth defect in a child born to a female subject or female partner of a male 
subject exposed to the investigational product should be recorded and reported as an SAE. 
8.6.7 
Worsening of Solid Tumor 
Worsening and/or progression of the subject’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. 


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8.6.8 
Death 
All deaths that occur during the protocol-specified AE reporting period must have the underlying 
cause reported to the sponsor as an SAE with death listed as the outcome.  Deaths due to the 
progression of disease must also be reported to the sponsor as an SAE.  Death events that occur 
after 30 days following last dose of study drug must be reported to the sponsor as an SAE only if 
it is confirmed as related to study drug.  If the primary cause of death is unknown and cannot be 
ascertained at the time of reporting, please record “Unknown cause death” on the eCRF, and the 
“unexplained/unknown death” should be reported expeditiously as an SAE.  The SAE should be 
reported before the specific cause of death has been determined. 
8.7 
Duration of Follow-up for Adverse Events 
The investigator will follow all unresolved AEs and SAEs until the events are resolved or 
stabilized, the subject is lost to follow-up, subject death, or end of study.  Resolution of AEs and 
SAEs (with dates) should be documented on the appropriate eCRF and in the subject’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 eCRF. 
For some SAEs, additional case details deemed necessary to appropriately evaluate the SAE report 
(eg, hospital discharge summary, consultant report, or autopsy report) may be followed-up by 
telephone, fax, email, and/or a monitoring visit. 
All pregnancies that occur during the study should be followed until pregnancy outcome.  
 


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9 
STATISTICAL ANALYSIS 
9.1 
Statistics and Analysis Method 
A separate statistical analysis plan (SAP) will provide specific details on analytical methods. 
9.1.1 
Statistical Hypothesis 
This study is designed to demonstrate superiority of fruquintinib plus BSC (fruquintinib arm) over 
placebo plus BSC (placebo arm) in prolonging OS for subjects with refractory mCRC.  The study 
is designed to test the null hypothesis H0: λ=1.0 versus the alternative hypothesis Ha: λ < 1.0, 
where λ is the hazard ratio (treatment arm/placebo arm). 
9.1.2 
Sample Size Rationale 
The total sample size and number of OS events required for efficacy assessment in the ITT 
population is calculated based on the following assumptions:  
• A one-sided significance level of 0.025;  
• Assuming an OS HR (fruquintinib arm/placebo arm) of 0.73, this sample size yields 
approximately 90% statistical power to detect superiority of the fruquintinib arm over 
placebo arm.  If the true median OS for the placebo arm is 5 months, then the HR of 0.73 
corresponds to median OS of 6.8 months in the fruquintinib arm (median OS improvement 
of 1.8 months);   
• An enrollment rate of 30 subjects per month during the first 3 months and 50 subjects per 
month thereafter; 
• Yearly dropout rate of 10%; 
• Randomization ratio = 2:1 (fruquintinib arm vs placebo arm).     
• Data maturity = 70%; 
• One interim futility analysis when 1/3 of the total number of OS events (ie, 160 OS 
events) have occurred, the Lan-DeMets spending function is used in the calculation.  
Under the premise of these assumptions, approximately 687 subjects will be randomized to this 
study over approximately 15 months in this study.  OS will be analyzed when 480 OS events are 
observed, which is expected to occur in approximately 7 months after the end of enrollment. East® 
version 6.5 software (www.cytel.com) was utilized for the calculation.  In clinical practice, 
TAS-102 is used more commonly than regorafenib.  To ensure that the subject population is 
representative of clinical practice, post-regorafenib subjects will be capped at 344 subjects if there 
is an unanticipated enrichment of that population.  This will ensure that at least 50% of the subjects 
will be post-TAS.  Subjects are considered in post-TAS-102 or post-regorafenib populations if 
they have received at least one dose of either agent, respectively, prior to entering the study.  Based 
on the similar mechanisms of action between regorafenib and fruquintinib, it will be of clinical 
interest to evaluate the magnitude of benefit in each of the populations when compared to the ITT 
population. 
 


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9.1.3 
Analysis Sets 
Intent-to-Treat (ITT) Population  
All randomized subjects will be included in the ITT population.  Subjects will be analyzed by 
treatment arm as randomized.  The ITT population will be the primary population for evaluating 
all efficacy endpoints and patient characteristics.   
Safety Analysis Population 
All randomized subjects who received at least one dose of study treatment will be included in the 
safety analysis population.  Subjects in this population will be analyzed according to the treatment 
they actually received.  This population will be used for all safety analyses. 
9.2 
Primary and Secondary Endpoints 
9.2.1 
Primary Endpoint 
The primary endpoint of the study is OS, defined as the time (months) from date of randomization 
to death from any cause.  Subjects without report of death at the time of analysis will be censored 
at the date last known alive.  Subjects lacking data beyond the date of randomization will have 
their survival time censored at the date of randomization.  OS will not be censored if a subject 
receives subsequent anticancer treatments after discontinuation of the study drugs.  
9.2.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include PFS, ORR, DCR, and DoR.  
9.2.2.1 
Key Secondary Endpoint: Progression-free Survival 
PFS is defined as the time (months) from randomization until the first radiographic documentation 
of objective progression as assessed by investigator using RECIST v1.1, or death from any cause, 
whichever comes first.  More specifically, PFS will be determined using all data until the last 
evaluable visit prior to or on the date of: (i) radiographic disease progression per RECIST v1.1; 
(ii) withdrawal of consent to obtain additional scans on study; or (iii) initiation of subsequent 
anticancer therapy other than the study drugs, whichever is earlier.  Censoring rules for subjects 
who do not experience PD or death will be described in the study SAP.  Additional sensitivity 
analyses may be conducted and will be specified in the SAP.   
9.2.2.2 
Objective Response Rate 
Objective response rate is defined as the proportion of subjects achieving a best overall response 
of confirmed complete response (CR) or partial response (PR), per RECIST v1.1, as determined 
by the investigator.  


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9.2.2.3 
Disease Control Rate 
Disease control rate is defined as proportion of subjects achieving a best overall response of 
confirmed CR, PR, or SD, per RECIST v1.1, as determined by the investigator.  To be qualified 
for SD, the duration of SD should last for at least 7 weeks. 
9.2.2.4 
Duration of Response 
Duration of response is defined as the time (months) from the first occurrence of PR or CR, 
whichever comes first, until the date of radiographic PD or death.  The duration of response will 
be determined for subjects with best overall response of confirmed CR or PR. 
9.2.3 
Secondary Safety Endpoints 
Safety 
endpoints 
include 
AE, 
laboratory 
tests, 
vital 
signs 
and 
weight, 
ECG, 
echocardiogram/MUGA (especially LVEF) and ECOG PS.  
All AEs, whether related to the drug or not, will be recorded in the eCRF including the start/end 
date, measures taken, treatment affected (yes versus no) and the outcome.  For all the events, the 
causality with the treatment and the severity will be determined by the investigator. 
9.2.4 
Other Endpoints 
9.2.4.1 
Patient Reported Outcomes 
Quality of life will be assessed using European Organization for Research and Treatment of Cancer 
(EORTC) QLQ-C30 and EQ-5D-5L questionnaires.  Quality of life score, change from baseline, 
subjects achieving minimally important difference (MID) cut-off, and time to deterioration (TTD) 
will be assessed. 
9.2.4.2 
Assessment of Resource Utilization 
Health care resource utilization assessments such as physician visits, emergency room visits, 
hospital care (eg, inpatient and outpatient), drug prescriptions etc. will be assessed. 
9.2.5 
Statistical Methods 
9.2.5.1 
Analysis of Efficacy Endpoints 
Efficacy analyses will be based on ITT population.  All secondary endpoints based on radiological 
assessments of tumor burden will be derived from investigator assessment using RECIST v1.1.  
Additional sensitivity analyses may be performed and will be outlined in the SAP. 
9.2.5.1.1 
Primary Endpoint - Overall Survival 
A 1-sided stratified log-rank test will be used for the comparison of OS of the fruquintinib with 
placebo group at a significance level of 0.025.  The same stratification factors used for 
randomization (Section 7.3.1) will be used for analysis.  Kaplan-Meier methodology will be used 
to estimate the median OS and its 2-sided 95% Confidence Interval (CI) for each treatment arm.  
Plots will be produced by treatment arm.  The HR between the 2 treatment groups (fruquintinib vs 
placebo), together with its 95% CI, will be calculated from a stratified Cox proportional hazard 
model stratified by the randomization stratification factors. 


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9.2.5.1.2 
Secondary Efficacy Endpoints (PFS, ORR, DCR, DoR)  
First secondary endpoint is to evaluate PFS in subjects with refractory mCRC treated with 
fruquintinib plus BSC versus placebo plus BSC.  Kaplan-Meier methodology will be used to 
estimate the median PFS and its 2-sided 95% CI for each treatment arm.  Plots will be produced 
by treatment arm. 
The hazard ratio (HR) between the 2 treatment groups (fruquintinib vs placebo), together with its 
95% CI, will be calculated from a stratified Cox proportional hazard model stratified by the 
randomization stratification factors.    
The estimates of DCR and ORR in each treatment group and their 2-sided 95% CIs will be 
presented.  Comparison of DCR and ORR between treatment groups will be performed using 
stratified Cochran-Mantel-Haenszel test.  The CI of difference in DCR and ORR between 
treatment groups will be calculated using the approximate normal distribution method of binomial 
distribution. 
Duration of response (DoR) will only be determined for subjects who responded (confirmed best 
overall response of CR or PR).  Statistical test will not be conducted, as subjects with response are 
not randomized.  Descriptive analysis will be adopted for DoR.  For each treatment group, results 
will be presented by Kaplan-Meier estimates and distribution curve. 
9.2.5.1.3 
Multiplicity Adjustment for the Primary Endpoint OS and Key Secondary 
Endpoint PFS  
To ensure strong control of family-wise Type I error rate among the analyses for the primary 
endpoint OS and the key secondary endpoint PFS at a 2-sided 𝛼= 0.05 level, a fixed-sequence 
procedure will be applied.  In this testing procedure, the analyses of OS will be conducted first and 
once the statistical significance is established for OS at a 2-sided 0.05 level, the analysis of PFS 
can then be performed at a 2-sided 0.05 level. 
9.2.5.1.4 
Subgroup Analyses 
Subset analyses may be conducted, for example, by age, performance status, prior lines of therapy, 
prior use of TAS-102, prior use of regorafenib, region, and others as deemed appropriate. 
9.2.5.2 
Analysis of Safety Endpoints 
All safety parameters will be summarized and listed by using the safety population.  
TEAEs will be summarized by MedDRA system organ class (SOC) and PT.  The incidence and 
percentage of subjects with at least 1 occurrence of a preferred term will be included according to 
the most severe NCI-CTCAE version 5.0.  Relationship to study therapy (causality) will be 
summarized separately.  If more than one AE was recorded for a subject within a PT, the subject 
will be counted once in the most severe grade.   
Laboratory data will be summarized by visit.  All TEAEs and abnormal laboratory variables shall 
be evaluated by the NCI CTC AE Version 5.0 Classification System.  Other safety data including 
vital signs, ECG, ECOG PS will be summarized using descriptive statistics. 


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9.2.5.3 
Analysis of Other Endpoints 
9.2.5.3.1 
Subject Reported Outcomes 
Subject reported outcomes will be assessed using EORTC QLQ-C30 and EQ-5D-5L 
questionnaires.  The number and percentage of subjects who completed the questionnaires will be 
summarized for each treatment arm by visit.  Reasons for non-completion will be presented.  
Quality of life scores and change from baseline scores will be compared between treatment arms 
using mixed model repeated measures approach adjusting for covariates.  For each scale, 
appropriate minimally important difference (MID) cut-off will be determined and number and 
percent of subjects achieving the MID will be presented.  In addition, time to deterioration (TTD) 
will be summarized using Kaplan-Meier methodology.  
9.2.5.3.2 
Resource Utilization 
Health care resource utilization data including number and percent of subjects hospitalized, 
reasons for hospitalizations, emergency room visits, drug prescriptions will be summarized. 
9.3 
Pharmacokinetic and Pharmacodynamic Analyses 
9.3.1 
Population PK and Exposure-Response Analyses 
Descriptive statistics (including but not limited to arithmetic mean, standard deviation, coefficient 
of variation, median, minimum, maximum and geometric mean) will be provided for the observed 
concentrations for fruquintinib and metabolite M11. 
Population PK analysis of plasma concentration-time data of fruquintinib and metabolite M11 will 
be performed using nonlinear mixed-effects modeling.  The population PK modeling will include 
all subjects with sufficient and interpretable PK assessments.  The data from the population PK 
samples may be combined together with the data from other studies for the population PK analysis.  
If relevant and sufficient data are available, the relationship of exposure to fruquintinib and M11 
to measures of efficacy and AEs may also be analyzed.  Details of the population PK and/or 
exposure-response analysis will be given in a population PK/pharmacodynamic analysis plan.  The 
results of the population PK/pharmacodynamic analysis will be presented in a separate report. 
9.3.2 
Pharmacodynamic (ECG) Analysis 
Subjects who 1) receive at least 1 dose of study drug, and 2) have baseline and at least 1 post-dose 
ECG measurement will be evaluable for pharmacodynamic (ECG) evaluation.  Subjects who had 
reduced dosage, prolonged dose interruption of >2 days in cycle 1, or who had any dose 
interruption within 7 days before cycle 1 day 21, or were discontinued from the study prior to the 
completion of ECG data collection (cycle 1 day 21) will be excluded.  For each of the ECG 
parameters, the average values from the 3 readings of a triplicate ECG set will be used in the 
analysis. 
For all ECG parameters, the baseline will be defined as the mean values of the triplicate ECG 
measurements taken at pre-dose on cycle 1 day 1. 


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9.3.2.1 
QTc Intervals 
The terminology QTc is used in this section as a general notation for corrected QT intervals using 
any of the specified methods. 
The QT interval data will be corrected for heart rate using 2 correction methods (Fridericia – QTcF 
and Bazett – QTcB).  For each QTc correction method, the relationship between QTc and RR at 
baseline will be evaluated graphically by plotting the logarithm of baseline QTc values against the 
logarithm of corresponding RR intervals.  Fridericia will be used as the primary correction method 
for statistical analysis.  If the correlation between QTc and RR intervals remains significant using 
the Fridericia correction method, an alternative correction method may be considered for statistical 
analysis in addition to QTcF. 
For the statistical analysis based on the primary correction method (QTcF), the mean changes from 
baseline (ΔQTc) at each time point will be summarized (mean, standard deviation, median and 
range, 2-sided 90% confidence interval).  The difference in ΔQTc between fruquintinib and 
placebo (ΔΔQTc) for each individual will also be calculated at each time point (individual ΔQTc 
for fruquintinib – mean ΔQTc for placebo at the same time point).  Mean values for the difference 
and 2-sided 90% CI for mean difference will be calculated at each time point. 
The primary analysis will focus on the maximum mean change from baseline in QTc (ΔQTc) on 
cycle 1 day 21, which will be estimated by the mean QTc change at around Tmax, the time when 
the maximum plasma concentration is reached (ie, steady state).  The same analysis will be 
performed for ΔQT data using other correction methods if data warrant.  The mean change from 
baseline in QTc (±standard deviation) over time will be plotted. 
In addition, QTc will be categorized based on ICH E14 guidelines.  Tables will present the number 
and percentage of subjects meeting or exceeding the following categories: 
• QTc interval prolongation: 
− Absolute values > 450 to ≤ 480 msec 
− Absolute values > 480 to ≤ 500 msec 
− Absolute values > 500 msec 
• QTc interval change from baseline: 
− Increase from baseline > 30 to ≤ 60 msec 
− Increase from baseline > 60 msec 
9.3.2.2 
Heart Rate, QRS, and PR intervals 
For each treatment and time point of measurement, heart rate , QRS interval and PR interval, as 
well as the change from baseline in heart rate, QRS and PR (HR, QRS, PR), will be 
summarized using descriptive statistics (mean, standard deviation, median, range, and 90% CI).  
The number and percentage of subjects with heart rate >100 bpm will be tabulated for each time 
point.  The number and percentage of subjects with QRS >110 msec will be tabulated for each 
time point.  The number and percentage of subjects with PR >200 msec will be tabulated for each 
time point. 


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9.3.2.3 
T-wave and U-wave Morphology 
The number and percentage of subjects having T-wave morphology changes from baseline and/or 
the occurrence of abnormal U-waves that represent the appearance or worsening of the 
morphological abnormality will be summarized.  Subjects with abnormal ECG findings will be 
listed.  Additional analyses will be performed if deemed necessary. 
9.3.3 
QTc-PK Analysis 
The potential relationship between QTc and PK will be evaluated using data from all evaluable 
subjects who have data from baseline and at least 1 post-dose ECG measurement following the 
first dose.  QTc change from baseline before and after correction for placebo (ΔQTc and ΔΔQTc) 
using the primary correction method (see Section 9.3.2.1) at each time point of measurement will 
be plotted against the corresponding plasma concentrations of fruquintinib and M11 separately.  
Additional plots will be produced, if deemed necessary. 
A linear mixed effects model will be fitted to the QTc and ΔΔQTc data from cycle 1 day 1 and 
cycle 1 day 21 with either parent or metabolite concentration as a predictor and subject as a random 
effect; if the intercept term is not significant, the model will be re-fitted with a zero intercept term.  
Based upon these relationships, the predicted population average ΔQTc and ΔΔQTc as well as 
their corresponding upper 90% 2-sided confidence interval bound will be computed at the mean 
maximum plasma concentrations (ie, Cmax) of fruquintinib and M11, or other concentrations of 
interest. 
9.4 
Interim Analysis 
An independent data monitoring committee (IDMC) will be convened to review accumulating 
safety data.  During the study, safety interim analyses will be performed approximately every 
6 months.  The frequency of safety interim analysis may be modified upon IDMC 
recommendation.   
One interim non-binding futility analysis will be performed when approximately 1/3 of the total 
number of OS events (ie, 160 OS events) has occurred.  The IDMC will be instructed to 
recommend stopping the study for futility if the 1-sided p-value from a stratified log-rank test is at 
least 0.772 (corresponding to an observed HR of at least 1.133).  Otherwise, the study will continue 
with full enrollment.  There is a 22.8% chance of terminating the study for futility at the interim 
analysis if the true median OS in fruquintinib arm is 5 months, ie, fruquintinib is ineffective.  There 
is a 0.4% chance of stopping for futility, declaring fruquintinib ineffective at the interim if the true 
median OS in fruquintinib arm is 6.8 months, ie, fruquintinib is effective in our study population.  
Although there are no plans to stop the study early for efficacy based on OS data at the interim 
analysis, to protect the integrity of the study and to preserve the type 1 error, a fraction of alpha 
(0.0001) will be spent at the interim analysis based on an O’Brien-Fleming stopping boundary. 


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10 
ETHICAL CONSIDERATIONS 
10.1 
Good Clinical Practice 
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct, consensus and the ethical principles 
derived from international guidelines, including the Declaration of Helsinki and Council for 
International Organizations of Medical Sciences  International Ethical Guidelines, Applicable ICH 
GCP Guidelines that have their origin in the Declaration of Helsinki, and applicable regulations 
and guidelines governing clinical study conduct. 
10.2 
Ethics Review 
The Independent Ethics Committee (IEC)/Institutional Review Board (IRB) must review the 
protocol and amendments, investigator’s brochure, informed consent form, study-relevant 
materials (such as advertisements for subject recruitment) and any other essential documents.  
IEC/IRB approval is to be obtained prior to the study. 
All amendments are to be reviewed and approved by the IEC/IRB and applicable regulatory 
authorities (as required) and documented.  All unexpected SAEs should be reported to the sponsor, 
IEC/IRB and applicable regulatory authorities as required.  During the study, protocol deviations 
that may increase a subject’s risk should be reported to the IEC/IRB in a timely manner. 
Protocols and any substantial amendments to the protocol will require health authority approval 
(as required) prior to initiation, except for changes necessary to eliminate an immediate hazard to 
study subjects. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC. 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, European 
Regulation 536/2014 for Clinical Studies (if applicable), European Medical Device 
Regulation 2017/745 for Clinical Device Research (if applicable), and all other applicable 
local regulations. 
10.3 
Informed Consent 
The following will be followed for informed consent: 
• Investigators or designees, if locally permissible, must obtain the signed ICF from 
subjects prior to conducting any study-related procedures.  
• The Investigator or his/her representative will explain the nature of the study to the 
subject or to their legally authorized representative, if locally permissible, and answer all 
questions regarding the study. 


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• Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative, if locally permissible, will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act requirements, where 
applicable, and the IRB/IEC or study center. 
• Subjects must be informed that they may withdraw consent to participate in the study 
without any limitations.  If the subject cannot sign the ICF, a legally acceptable 
representative of the subject must sign the ICF if locally permissible.  
• If the subject and the legally acceptable representative are not able to read and write, an 
impartial witness should be present throughout the whole process of providing informed 
consent. Once the subject and the legally acceptable representative, if locally permissible, 
give their oral consent, the ICF should be signed by the impartial witness to confirm that 
the subject and the legally acceptable representative fully understand the study and their 
right to withdraw informed consent without any limitations. 
• Informed consent should be recorded in the eCRF.  
• If the risk/benefit assessment changes after the safety analysis, the ICF must be reviewed 
and updated, and all updated information should be provided to subjects (including subjects 
who have already received the study drug). 
10.4 
Data Privacy 
All information about fruquintinib (such as patent application, formulation, manufacturing process 
and basic study information) is considered confidential as long as it is unpublished. 
All information obtained in the study is considered confidential.  Hutchison MediPharma Limited 
will open the information to investigational personnel, the National Medical Products 
Administration, and any other regulatory authority when necessary.  To ensure the completeness 
of the study analysis data, investigational personnel are accountable for providing all results and 
data to the sponsor. 
Investigators must guarantee the privacy of subjects by not disclosing subject-related information 
to third parties without authorization.  eCRFs and other documents submitted to the sponsor should 
not contain the subject’s name.   
• Subjects will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information that would make the subject identifiable will not be transferred. 
• Subjects are identified only by the unique identifier.  Investigators may retain the 
identification forms, which include subject numbers, names, and addresses.  ICFs and 
other documents should be documented properly, and should not be given to the Sponsor. 
• Subjects must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection laws.  The level of disclosure must also 
be explained to the subject who will be required to give consent for their data to be used 
as described in the informed consent.  


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• Subjects must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.5 
Disclosure 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations. 
10.6 
Biological Specimens and Data 
For subjects who provide informed consent agreeing to participate in future biomedical research, 
any unused samples for study-related research, as well as unused PK samples, may be stored for 
no longer than 15 years, or other period as per local requirements, after the final date of the 
database lock.  After this storage period, any residual samples will be destroyed.  The Sponsor will 
store the samples in a secure storage space with adequate measures to protect confidentiality. 
The results of these future biomedical research analyses will not be shared with subjects and will 
not be presented in the CSR. 
If there are specific site or country requirements involving the pharmacogenomic analyses that the 
sponsor is unable to comply with, samples will not be collected at those sites. 
All samples will be single/double coded as defined by ICH guideline E15. 
10.7 
Data Quality Assurance 
• To ensure the safety of subjects in the study, and to ensure accurate, complete, and 
reliable data, the Investigator will keep records of laboratory tests, clinical notes, and 
subject medical records in the subject files as original source documents for the study. 
• All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data).  The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
• Guidance on completion of CRFs will be provided in the CRF Completion Guidelines. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities, and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan. 
• The Sponsor or designee is responsible for the data management of this study, including 
quality review of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (eg, 
CROs). 


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11 
OVERSIGHT 
11.1 
Independent Monitoring 
11.1.1 
Independent Data Monitoring Committee 
An IDMC will be established in this study.  The IDMC will consist of at least 4 independent 
clinical oncology physicians and 1 independent statistician with no conflicts of interest with the 
sponsor.  The IDMC will evaluate the safety data regularly, and the subjects’ safety will be 
determined by the evaluation of the risk/benefit at a regular review meeting.  The responsibilities 
of the IDMC will include: 
• 
Regular (approximately every 6 months) unblinded review of the study data to provide 
suggestions such as “continue as planned, suspend, protocol amendment, terminate study” 
so as to prevent subjects from being exposed to unsafe dose and treatment regimes. 
• 
Review of interim analysis data to provide suggestions such as “continue as planned, 
suspend, protocol amendment, terminate study.” 
Upon completion of the data review, the IDMC will provide suggestions on whether or not to 
continue the study, if modification of the protocol is recommended or if study termination is 
required.  The final decision shall be made by Hutchison MediPharma Limited.  The IDMC 
membership and governance is outlined in a separate IDMC charter. 
11.2 
Quality Control and Assurance 
The clinical study will be executed and reported following GCPs, all applicable regulatory 
requirements, and applicable standard operating procedures, including quality control of 
documents.  
The investigator is responsible for supervising any individual or party to whom the investigator 
delegates trial-related duties and functions conducted at the trial site.  The sponsor and investigator 
ensure that any individual or party who performs trial-related duties or functions on behalf of the 
sponsor/investigator is qualified to perform the trial-related duties or functions. 
The overall procedures for quality assurance of clinical study data are described in the sponsor or 
designee’s standard operational procedures.  The planned quality assurance and quality control 
procedures for the study are described in the following sections. 
11.2.1 
Monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, the Sponsor’s 
personnel (or designated CRO) will review the protocol and eCRFs with the Investigators and their 
staff.  During the study, the field monitor will visit the site regularly to check the completeness of 
subject records, the accuracy of entries on the eCRFs, the adherence to the protocol to GCP, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and accounted 
for according to specifications.  Key study personnel, including the Investigator, must be available 
to assist the field monitor during these visits. 
The Investigator must give the field monitor access to all relevant source documents to confirm 
their consistency with the eCRF entries.  The Sponsor’s monitoring standards require full 
verification of the informed consent, adherence to the inclusion/exclusion criteria, and 


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documentation of SAEs.  Additional checks of the consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan. 
11.2.2 
Audits 
Authorized representatives of the sponsor, a regulatory/competent authority, and/or an IRB/IEC 
representative may visit the site to perform audits or inspections, including source data verification.  
Should this occur, the Investigator is responsible for: 
• Informing the sponsor of a planned inspection by the authorities as soon as notification is 
received and authorizing the Sponsor’s participation in the inspection 
• Providing access to all necessary facilities, study data, and documents for the inspection 
or audit 
• Communicating any information arising from inspection by the regulatory authorities to 
the Sponsor immediately 
• Taking all appropriate measures requested by the Sponsor to resolve the problems found 
during the audit or inspection 
• Documents subject to audit or inspection include but are not limited to all source 
documents, CRFs, medical records, correspondence, ICFs, IRB/EC files, documentation 
of certification and quality control of supporting laboratories, and records relevant to the 
study maintained in any supporting pharmacy facilities.  Conditions of study material 
storage are also subject to inspection.  In addition, representatives of the Sponsor may 
observe the conduct of any aspect of the clinical study or its supporting activities both 
within and outside of the Investigator’s institution. 
In all instances, the confidentiality of the data must be respected. 
11.2.3 
Records 
11.2.3.1 
Data Capture and Management 
The term case report form (CRF) or eCRF should be understood to refer to electronic data capture 
(EDC) system.  The EDC system is the database where pertinent study data are collected.  For all 
subjects, including screen failures, data will be collected on source documents first.  The Principal 
Investigator is responsible for assuring that the data entered into eCRFs is complete, accurate, and 
that entry and updates are performed in a timely manner.  Blood and tumor samples for PK and 
biomarkers assessments will be collected by study sites and sent to the designated central 
laboratory for processing.  Data from ECG assessments will be collected at the study sites, and the 
data will be transmitted to a designated CRO for centralized analysis, as well as for further 
processing and data reconciliation.  Imaging data will be collected at the study sites, and a 
designated CRO will perform further processing, data reconciliation, and holding. 
At all times, the Principal Investigator has final responsibility for the accuracy and authenticity of 
all clinical and laboratory data entered in the EDC.  Subject source documents are the 
Investigator's/physician's subject records maintained at the study site.  In cases where the source 
documents are the hospital or the physician's chart, the information collected in the EDC must 
match those charts.  All final data recorded in EDC system will be copied onto CDs and kept by 


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the Sponsor.  A copy of these CDs will also be kept at the clinical site.  All data recorded on source 
documents will be kept at the clinical site. 
The completed pages of the EDC system are the sole property of the Sponsor and should not be 
made available in any form to third parties without written permission from the Sponsor, except 
for authorized representatives of the Sponsor or appropriate regulatory authorities. 
11.2.3.2 
Source Documentation 
• The Investigator/institution should maintain adequate and accurate source documents and 
study records for all subjects that support the information entered in the CRF. 
• Source data should be attributable, legible, contemporaneous, original, accurate, and 
complete.  Changes to source data should be traceable and not obscure the original entry.   
• All information recorded on eCRFs must be traceable to source documents in the 
subject’s file.  Any changes should be explained if necessary (eg, via an audit trail). 
11.2.3.3 
Records Retention 
Records and documents, including signed ICFs, source documents, study drug documents, 
monitoring visit records, regulatory documents, and all other correspondence and documents 
pertaining to the conduct of this study must be retained by the Investigator for at least 5 years after 
study completion, unless local regulations or institutional policies require a longer retention period. 
If the documents cannot be stored properly at the investigational site, the documents can be 
transferred by the Investigator and Sponsor to an approved storage facility.  The documents must 
be sealed for storage and easily found for review in the case of a regulatory authority audit.  No 
records may be transferred to another location or party without written notification to the Sponsor. 
No records may be destroyed during the retention period following study completion or 
discontinuation without the written approval of the Sponsor.  Records must be destroyed in a 
manner that ensures confidentiality.   
11.3 
Study Termination or Study Site Closure 
The Sponsor and the Investigator have the right to close out a site prematurely. 
Investigator’s Decision  
The Investigator must notify the Sponsor of a desire to close out a site in writing, providing at least 
30 days’ notice.  The final decision should be made through mutual agreement with the 
Sponsor.  Both parties will arrange the close out procedures after review and consultation 
Sponsor’s Decision 
The Sponsor will notify the Investigator(s) of a decision to close out a study site in writing.  
Reasons may include the following, among others:   
• The Investigator has received all items and information necessary to perform the 
study, but has not enrolled any subject within a reasonable period of time  
• The Investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines   


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• The total number of subjects required for the study are enrolled earlier than expected  
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CROs used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements.  The 
investigator shall promptly inform the subject and should assure appropriate subject therapy and/or 
follow-up.  
 


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


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


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14 
REFERENCES 
American Cancer Society, Key Statistics for Colorectal Cancer, 2019. URL:  www.cancer.org/ 
cancer/ colon-rectal-cancer/about/key-statistics.html; accessed February 12, 2019. 
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: 
GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.  
CA Cancer J Clin.  2018 Nov;68(6):394-424  
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31-41. 
Duda DG, Batchelor TT, Willett CG, Jain RK.  VEGF-targeted cancer therapy strategies: current 
progress, hurdles and future prospects.  Trends Mol Med. 2007 Jun;13(6):223-30. 
Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, 
Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, GoldbergRM, Sargent DJ, 
Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group.  Regorafenib monotherapy 
for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, 
randomised, placebo-controlled, phase 3 trial.  Lancet 2013 Jan 26;381(9863):303-12. 
Izzedine H, Ederhy S, Goldwasser F, Soria JC, Milano G, Cohen A, Khayat D, Spano JP. 
Management of hypertension in angiogenesis inhibitor-treated patients.  Ann Oncol. 2009 
May;20(5):807-15. 
Jayson GC, Kerbel R, Ellis LM, Harris AL. Antiangiogenic therapy in oncology: current status 
and future directions.  Lancet.  2016 Jul 30;388 (10043):518-29. 
Koopman M, Kortman GA, Mekenkamp L, Ligtenberg MJ, Hoogerbrugge N, Antonini NF, Punt 
CJ, van Krieken JH.  Deficient mismatch repair system in patients with sporadic advanced 
colorectal cancer.  Br J Cancer.  2009 Jan 27;100(2):266-73. 
Li J, Qin S, Xu R, et al. Effect of fruquintinib vs placebo on overall survival in patients with 
previously treated metastatic colorectal cancer.  JAMA. 2018;319(24):2486-96. 
LONSURF® (trifluridine and tipiracil) Prescribing Information.  Taiho Pharmaceutical Co, Taiho 
Oncology, Inc. Princeton NJ, USA.  Revised Feb 2019 
Mayer R, Van Cutsem E, Falcone A, et al. Randomized Trial of TAS-102 for Refractory 
Metastatic Colorectal Cancer (RECOURSE). N Engl J Med 2015; 372: 1909-19. 
National Comprehensive Cancer Network (NCCN), Version 2019.  
STIVARGA® (regorafenib) Prescribing Information.  Bayer HealthCare Pharmaceuticals, Inc, 
Whippany NJ, USA.  Revised Apr 2017. 
Sun Q, Zhou J, Zhang Z, Guo M et al., Discovery of fruquintinib, a potent and highly selective 
small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy. Cancer Biol 
Ther. 2014;15 (12):1635-45. 


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15 
APPENDICES 


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APPENDIX 1 
COVID-19 RISK ASSESSMENT 
Hutchison MediPharma acknowledges that the subjects to be enrolled in this study are patients 
with refractory cancer, and therefore, may be at higher risk for complications if they contract 
COVID-19.  Available data indicate that the elderly and people with underlying health conditions 
such as chronic respiratory, cardiovascular, or kidney disease; diabetes; active cancer; and more 
generally severe chronic diseases are more vulnerable to experience complications.  However, 
there is an unmet medical need for new medications that are safe and effective in patients with 
refractory cancer who have limited treatment options. 
During the COVID-19 pandemic, patients may be at additional risk as a result of going to a 
healthcare facility and interacting with healthcare staff and providers.  Patients may be screened 
and enrolled if the site has procedures in place to test and appropriately follow new patients on 
trial and to ensure patient safety and data integrity.  Potential patients with a known or suspected 
COVID-19 infection are ineligible.  Patients with a known COVID-19 infection may be considered 
for participation following 2 subsequent negative tests per guidelines. It is at the principal 
investigator’s discretion to balance the risk/benefit to determine when enrollment is appropriate, 
and patient safety should always be considered. 
The risk management and mitigation steps being taken by Hutchison MediPharma Limited and its 
designee are as follows.  These steps were developed to align with COVID-19 guidance on clinical 
trials issued by the US Food and Drug Administration and European Medicines Agency. 
1. Subject safety 
a. Patient education on COVID-19-related risks will be provided by the principal 
investigator (ie, using cancer patient guidelines at European Society for Medical 
Oncology web site). 
− Patient time in clinic should be minimized when possible.  Blood sampling/visits may 
be performed at another location if this can be done within local restrictions on social 
distancing to reduce site burden and risk for infection (eg, utilizing a local laboratory, 
a home nurse, or a satellite site).  The laboratory results must be reviewed by the 
principal investigator, and laboratory normal ranges must be collected and 
documented.  
− Study visits may be conducted with patients using telemedicine, where the principal 
investigator and site personnel can videoconference with the patient.  In this setting, 
the principal investigators should perform as many assessments as possible, including 
any adverse events (AEs), concomitant medications, and Eastern Cooperative 
Oncology Group performance status.  
b. Reduce the risk for COVID-19 infection associated with traveling to and from the 
clinic by providing a safer option to avoid public transportation (eg, car/taxi service) 
if necessary and permitted by local process.  
c. If a patient enrolled into the study subsequently tests positive for COVID-19, the data 
will be entered into the eCRF as an AE, with proper source documentation. 
2. Investigational Medicinal Product handling 


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Investigational Product may be delivered to the patient’s house if permitted under the 
site’s Standard Operating Procedures and patient chain of custody and patient privacy is 
protected. 
3. Management of protocol deviations due to the COVID-19 pandemic 
Hutchison MediPharma and its designee will adhere to all applicable health authority 
guidelines for documenting and reporting any protocol deviations due to the COVID-19 
pandemic.  The deviations will be reported to the authorities or institutional review 
boards/independent ethics committees as instructed. 
4. Remote monitoring 
Hutchison MediPharma and its designee agree to perform remote monitoring where 
feasible and permitted.  For remote source data verification, country legislation will be 
followed and performed only where allowed with written agreement of the principal 
investigator.  The planned site-level procedures will be described in detail and approvals 
sought as required.  If a site cannot support remote monitoring with Electronic Medical 
Record access, the site will not be permitted to consent new patients.  Remote visits will 
also be conducted to facilitate site selection, initiation and training. 
5. External factors related to COVID-19  
Central supply chains may be affected, and tubes used for ctDNA may not reach the 
study sites in adequate time for the enrollment of subjects.  In these cases, tests should be 
performed, if possible, using investigator site-supplied equipment.  If this is not possible, 
deviations should be appropriately documented as in number 3 above.  If other tests are 
problematic due to local conditions related to COVID-19, please check with the sponsor.  
The benefit-risk balance for patients to enroll into this study according to the inclusion and 
exclusion criteria defined in the protocol and according to the defined COVID-19 risk mitigation 
measures in this document remains favorable. 
Hutchison MediPharma and its designee will continue to evaluate the impact of COVID-19 on the 
ability of each site to initiate and execute the trial.  Site-specific positions will be evaluated prior 
to the site initiation visit, with the outcomes and any resultant actions documented and filed in the 
Trial Master File. 
As the COVID-19 situation may be temporary, regulatory guidance will be continuously 
reevaluated and any changes will be communicated when necessary. 


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APPENDIX 2 
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 house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled, cannot carry on any self-care, totally confined to bed or 
chair 
5 
Death 
 
 


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APPENDIX 3 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST V1.1) 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, 
are presented below. 
1 Measurability of Tumor at Baseline 
1.1 Definitions 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
described below. 
1.1.1 Measurable Tumor Lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size as follows: 
• 10  mm by CT or magnetic resonance imaging (MRI) scan (CT/MRI scan slice 
thickness/interval no greater than 5 mm) 
• 10-mm caliper measurement by clinical examination (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 the short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and follow-up, only the 
short axis will be measured and followed.  
1.1.2 Non-Measurable Tumor Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter  10 mm or pathological 
lymph nodes with short axis  10 but  15 mm) as well as truly non-measurable lesions.  Lesions 
considered truly non-measurable include leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, peritoneal 
spread, and abdominal mass/abdominal organomegaly identified by physical examination that is 
not measurable by reproducible imaging techniques. 
1.1.3 Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment, as outlined below. 
Bone Lesions: 
• Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques for measuring bone lesions.  However, these techniques can 
be used to confirm the presence or disappearance of bone lesions. 
• 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 as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 


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• Blastic bone lesions are non-measurable. 
Cystic Lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
• Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
Lesions with Prior Local Treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
1.2 Specifications by Methods of Measurements 
1.2.1 Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as close as possible to the treatment start and never more 
than 4 weeks before the beginning of the treatment. 
1.2.2 Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during the study.  Imaging-based evaluation should 
always be the preferred option. 
Clinical Lesions.  Clinical lesions will only be considered measurable when they are superficial 
and  10 mm in diameter as assessed using calipers (eg, skin nodules).  For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. 
Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung. 
CT, MRI.  CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 5 mm or less.  When CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  MRI is 
also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with intravenous 
(IV) contrast because of allergy or renal insufficiency, the decision as to whether a non-contrast 
CT or MRI (without IV contrast) will be used to evaluate the patient at baseline and during the 


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


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be considered non-target lesions.  Nodes that have a short axis of 10 mm are considered non-
pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum of diameters.  If lymph nodes are to be 
included in the sum, then, as noted above, only the short axis is added into the sum.  The baseline 
sum of diameters will be used as a reference to characterize further any objective tumor regression 
in the measurable dimension of the disease. 
All other lesions (or sites of disease), including pathological lymph nodes, should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required and 
these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal progression.” 
In addition, it is possible to record multiple non-target lesions involving the same organ as a single 
item on the Case Report Form (eCRF) (eg, “multiple enlarged pelvic lymph nodes” or “multiple 
liver metastases”). 
2.3 Response Criteria 
2.3.1 Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
• 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 (nadir), including baseline.  In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.  
The appearance of one or more new lesions is also considered progression. 
• Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum on study 
2.3.2 Special Notes on the Assessment of Target Lesions 
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even 
if the nodes regress to  10 mm on study.  This means that when lymph nodes are included as 
target lesions, the sum of lesions may not be 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.  During the study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that the radiologist 


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may not feel comfortable assigning an exact measure and may report them as being too small to 
measure.  When this occurs, it is important that a value be recorded on the eCRF, as follows: 
• If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.  If the lesion is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned and 
BML (below measurable limit) should be ticked. (BML is equivalent to a “less than” 
sign.) (Note: It is less likely that this rule will be used for lymph nodes since they usually 
have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm should be assigned in this circumstance 
as well and BML should also be ticked). 
To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm, and in that case BML should not be ticked. 
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum.  
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly coalesced 
such that they are no longer separable, the vector of the longest diameter in this instance should be 
the maximum longest diameter for the coalesced lesion. 
2.3.3 Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions.  While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol. 
• Complete response (CR): Disappearance of all non-target lesions and (if applicable) 
normalization of tumor marker level.  All lymph nodes must be non-pathological in size 
( 10 mm short axis). 
• Non-CR/Non-PD: Persistence of one or more non-target lesions and/or (if applicable) 
maintenance of tumor marker level above the normal limits 
• Progressive disease (PD): Unequivocal progression of existing non-target lesions.  The 
appearance of one or more new lesions is also considered progression. 
2.3.4 Special Notes on Assessment of Progression of Non-Target Disease 
When the Patient Also Has Measurable Disease.  In this setting, to achieve unequivocal 
progression on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease in a magnitude that, even in the presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy.  A 
modest increase in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 


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When the Patient Has Only Non-Measurable Disease.  This circumstance arises in some phase 3 
trials when it is not a criterion of study entry to have measurable disease.  The same general 
concepts apply here as noted above; however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden.  
Because worsening in non-target disease cannot be easily quantified (by definition: if all lesions 
are truly non-measurable), a useful test that can be applied when assessing patients for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in non-
measurable disease is comparable in magnitude to the increase that would be required to declare 
PD for measurable disease, that is, an increase in tumor burden representing an additional 73% 
increase in volume (which is equivalent to a 20% increase in diameter in a measurable lesion).  
Examples include an increase in a pleural effusion from “trace” to “large” or an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols as “sufficient 
to require a change in therapy.”  If unequivocal progression is seen, the patient should be 
considered to have had overall PD at that point.  While it would be ideal to have objective criteria 
to apply to non-measurable disease, the very nature of that disease makes it impossible to do so; 
therefore, the increase must be substantial. 
2.3.5 New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important.  There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal, that is, not 
attributable to differences in scanning technique, change in imaging modality, or findings thought 
to represent something other than tumor (for example, some “new” bone lesions may be simply 
healing or flare of preexisting lesions).  This is particularly important when the patient’s baseline 
lesions show partial or complete response.  For example, necrosis of a liver lesion may be reported 
on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease.  If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
(18) F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly, possible “new” disease).  New lesions on the basis of FDG-PET imaging 
can be identiﬁed according to the following algorithm: 
A negative FDG-PET scan at baseline with a positive FDG-PET scan during the study is a sign of 
PD based on a new lesion. 
In the case of no FDG-PET scan at baseline and a positive FDG-PET scan during the study: 
• If the positive FDG-PET scan during the study corresponds to a new site of disease 
conﬁrmed by CT, this will be considered PD. 
• If the positive FDG-PET scan during the study is not conﬁrmed as a new site of disease on 
CT, additional follow-up CT scans are needed to determine whether there is truly 


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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 scan during the study corresponds to a preexisting site of disease 
on CT that is not progressing on the basis of the anatomic images, this will not be 
considered PD. 
2.4 Evaluation of Response 
2.4.1 Time Point Response (Overall Response) 
It is assumed that at each protocol-specified time point, a response assessment occurs.  Table 15 
provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 16 is to be used. 
Table 15 
Time Point Response: Patients with Target Lesions (with or without Non-
Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable 
disease. 
 


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Table 16 
Time Point Response: Patients with Non-Target Lesions Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease. 
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable disease is increasingly 
used as an endpoint for assessment of efficacy in some trials; thus, assigning “stable disease” when no lesions can 
be measured is not advised. 
2.4.2 Missing Assessments and Not-Evaluable Designation 
When no imaging/measurement is done at all at a particular time point, the patient is not evaluable 
at that time point.  If only a subset of lesion measurements are made at an assessment, usually the 
case is also considered not evaluable at that time point, unless a convincing argument can be made 
that the contribution of the individual missing lesion(s) would not change the assigned time point 
response.  This would be most likely to happen in the case of PD.  For example, if a patient had a 
baseline sum of 50 mm with 3 measured lesions and, during the study, only 2 lesions were 
assessed, but those gave a sum of 80 mm, the patient will have achieved PD status, regardless of 
the contribution of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done or the scan 
could not be assessed because of poor image quality or obstructed view, the response for target 
lesions should be “unable to assess” since the patient is not evaluable.  Similarly, if one or more 
non-target lesions are not assessed, the response for non-target lesions should be “unable to assess” 
except where there is clear progression.  Overall response would be “unable to assess” if either the 
target response or the non-target response is “unable to assess” except where this is clear evidence 
of progression, as this equates with the case being not evaluable at that time point. 
2.4.3 Best Overall Response: All Time Points 
The best overall response is determined once all the data for the patient is known.  Best response 
determination in trials where confirmation of complete or partial response IS NOT required: Best 
response in these trials is defined as the best response across all time points (for example, a patient 
who has SD at first assessment, PR at second assessment, and PD on last assessment has a best 
overall response of PR).  When SD is believed to be best response, it must also meet the protocol 
specified minimum time from baseline.  If the minimum time is not met when SD is otherwise the 
best time point response, the patient’s best response depends on the subsequent assessments.  For 
example, a patient who has SD at first assessment, PD at second and does not meet minimum 
duration for SD, will have a best response of PD.  The same patient lost to follow-up after the first 
SD assessment would be considered inevaluable. 
Best response determination in trials where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the criteria for each are met at a 


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subsequent time point as specified in the protocol (generally 4 weeks later).  In this circumstance, 
the best overall response can be interpreted as in Table 17. 
Table 17 
Best Overall Response When Confirmation of Complete Response and 
Partial Response is Required 
Overall response 
First time point 
Overall response 
Subsequent time point 
BEST overall response 
CR 
CR 
CR 
CR 
PR 
SD，PD or PRa 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
NE 
NE 
NE 
 
CR = complete response, PR = partial response, SD = stable disease, PD =progressive disease, and NE = inevaluable. 
a: If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR).  Best 
response would depend on whether minimum duration for SD was met.  However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the first 
time point.  Under these circumstances, the original CR should be changed to PR and the best response is PR. 
 
Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size ( 0 mm), they may still have a measurement reported on scans.  This measurement should be 
recorded even though the nodes are normal in order not to overstate progression should it be based 
on increase in size of the nodes.  As noted earlier, this means that patients with CR may not have 
a total sum of “zero” on the eCRF. 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document objective progression even after 
discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an objective 
response; it is a reason for stopping study therapy.  The objective response status of such patients 


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is to be determined by evaluation of target and non-target disease as shown in Table 15 and 
Table 16. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If at the 
next scheduled assessment, progression is confirmed, the date of progression should be the earlier 
date when progression was suspected. 
In studies for which patients with advanced disease are eligible (ie, primary disease still or partially 
present), the primary tumor should also be captured as a target or non-target lesion, as appropriate.  
This is to avoid an incorrect assessment of complete response if the primary tumor is still present 
but not evaluated as a target or non-target lesion. 
2.5 Frequency of Tumor Re-evaluation 
Frequency of tumor re-evaluation while on treatment should be protocol specific and adapted to 
the type and schedule of treatment.  However, in the context of phase 2 studies where the beneficial 
effect of therapy is not known, follow-up every 6–8 weeks (timed to coincide with the end of a 
cycle) is reasonable.  Smaller or greater time intervals than these could be justified in specific 
regimens or circumstances.  The protocol should specify which organ sites are to be evaluated at 
baseline (usually those most likely to be involved with metastatic disease for the tumor type under 
study) and how often evaluations are repeated.  Normally, all target and non-target sites are 
evaluated at each assessment.  In selected circumstances certain non-target organs may be 
evaluated less frequently.  For example, bone scans may need to be repeated only when complete 
response is identified in target disease or when progression in bone is suspected. 
After the end of the treatment, the need for repetitive tumor evaluations depends on whether the 
trial has as a goal the response rate or the time to an event (progression/death).  If ‘time to an event’ 
(eg, time to progression, disease-free survival, progression-free survival) is the main endpoint of 
the study, then routine scheduled re-evaluation of protocol specified sites of disease is warranted.  
In randomized comparative trials in particular, the scheduled assessments should be performed as 
identified on a calendar schedule (for example: every 6–8 weeks on treatment or every 3–4 months 
after treatment) and should not be affected by delays in therapy, drug holidays or any other events 
that might lead to imbalance in a treatment arm in the timing of disease assessment. 
2.6 Confirmatory measurement/duration of response 
2.6.1 Confirmation 
In non-randomized 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 (see the paper by Bogaerts et al. in this Special 
Issue10).  However, in all other circumstances, for example in randomized trials (phase 2 or 3) or 
in 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. 


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2.6.2 Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study). 
The duration of overall complete response is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented. 
2.6.3 Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and diseases.  If 
the proportion of patients achieving stable disease for a minimum period of time is an endpoint of 
importance in a particular trial, the protocol should specify the minimal time interval required 
between two measurements for determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation.  It is not in the scope of this 
guideline to define a standard follow-up frequency.  The frequency should take into account many 
parameters including disease types and stages, treatment periodicity and standard practice.  
However, these limitations of the precision of the measured endpoint should be taken into account 
if comparisons between trials are to be made. 
 


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APPENDIX 4 
PROHIBITED MEDICATION 
A series of strong inducers and strong inhibitors of CYP3A are listed in Table 18 and Table 19 
below.  Examples of sensitive substrates of P-gp and BCRP are listed in Table 20. 
Patients who received a CYP3A strong inducer or strong inhibitor within 2 weeks (3 weeks for 
hyperforin perforatum/St. John’s Wort treatment) prior to the first dose of the study drug will not 
be allowed to participate in the study.  During the study, co-administration of strong inducers and 
inhibitors of CYP3A with fruquintinib should be avoided unless investigators consider it 
necessary.  In this case, fruquintinib efficacy reduction or toxicity increases resulting from the 
interaction should be closely monitored. 
Not all the medications are listed in the following tables.  Other drugs known possibly to affect 
CYP3A activity and to be substrates of P-gp and BCRP should be used with caution.  When 
combining fruquintinib with other drugs the prescription information of all concomitant 
medications should be reviewed. 
 
 


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Table 18 
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, Seville oranges, 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. 
 
 


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Table 19 
Typical Strong Inducers of CYP3A4 
Strong Inducers of CYP3A4 
Apalutamide 
Avasimibe 
Carbamazepine 
Enzalutamide 
Mitotane 
Phenobarbital 
Phenytoin 
Rifabutin 
Rifampin (or rifampicin) 
St. John’s wort 
 
 


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Table 20 
Sensitive Substrates of P-gp or 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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Table 21 
Summary of Clinical Trial Program of Fruquintinib in China and the US* 
Study Number 
NCT# 
(Name) 
Indication 
Study Title 
Study Objectives 
and Phase  
Study Subjects 
 
Study Design 
2012-013-00CH1 
NCT02691299 
3rd line mCRC 
A Randomized, Double-blind, 
Placebo-controlled, Multi-
center Phase II Clinical Trial 
to Evaluate the Efficacy and 
Safety of Fruquintinib  Plus 
Best Supportive Care in 
advanced colorectal cancer 
patients who have progressed 
after second-line 
chemotherapy 
PFS (Fruquintinib 
versus PBO), OS, 
ORR, safety Phase 2 
Fruquintinib: 
N=47; Placebo: 
N=24  
Total N=71 
Randomized, 
double-blind, 
placebo-controlled, 
multicenter study 
 
2014-013-00CH1 
NCT02590965 
3rd line NSCLC 
A Randomized, Double-blind, 
Placebo-controlled, Multi-
center Phase II Clinical Trial 
to Evaluate the Efficacy and 
Safety of Fruquintinib Plus 
Best Supportive Care in 
Patients With Advanced Non-
squamous Non-small Cell 
Lung Cancer 
(Fruquintinib versus 
PBO), OS, ORR, 
safety Phase 2 
Fruquintinib 
N=61. Placebo: 
N=30  
Total N=91 
Randomized, 
double-blind, 
placebo-controlled, 
multicenter study 
 
2015-013-00CH1 
NCT02691299 
(FALUCA) 
3rd line NSCLC 
A Randomized, Double-blind, 
Placebo-controlled, Multi-
center Phase III Clinical Trial 
in Patients With Advanced 
Non-squamous Non-small 
Cell Lung Cancer Treated 
With Fruquintinib 
Confirmatory efficacy 
and safety NSCLC. 
Phase 3 
Fruquintinib 
N=352 
Placebo N= 171 
Total N=523 
Randomized, 
double-blind, 
placebo-controlled, 
multicenter study 
 
2017-013-00CH1 
NCT03223376 
2nd line gastric 
cancer 
A Phase III Study to Evaluate 
the Efficacy and Safety of 
Fruquintinib in Combination 
With Paclitaxel Versus 
Paclitaxel Alone in Second 
Line Gastric Cancer 
Phase 3 
N=544 
(planned) 
 
Randomized, 
double-blind, 
placebo-controlled, 
multicenter study 
 
2014-013-00CH3 
NCT02415023 
2nd line gastric 
cancer 
 
A Phase Ib/2 Clinical Study 
to Evaluate the Safety, 
Pharmacokinetic 
Characteristics and 
Preliminary Efficacy of 
Fruquintinib Combined With 
Paclitaxel in Patients With 
Advanced Gastric Cancer 
(Fruquintinib + 
paclitaxel combo), 
safety, tolerability, 
PK, preliminary 
efficacy Phase 1b/2 
N=34 
Two-stage, open-
label, multicenter 
study. Stage 1: dose 
escalation. Stage 2: 
selected dose 
regimen expansion 
(combination  + 
paclitaxel)  




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Table 21 
Summary of Clinical Trial Program of Fruquintinib in China and the US* 
Study Number 
NCT# 
(Name) 
Indication 
Study Title 
Study Objectives 
and Phase  
Study Subjects 
 
Study Design 
2014-013-00CH5 
 
A Single Center, Open-label, 
Randomized, Two-period 
Crossover Study to Evaluate 
the Pharmacokinetics and 
Bioequivalence in Healthy 
Male Chinese Volunteers 
Following Single Doses of 
Fruquintinib Capsules 
Produced by Two Different 
Manufacturers 
Primary: to assess the 
bioequivalence of 
fruquintinib produced 
at two manufacturers; 
Secondary: safety, 
explore metabolism 
and excretion 
Phase 1 
Healthy Males 
N=24 
Randomized, open-
label, two-period 
crossover, two-stage, 
single center study. 
 
2015-013-00CH2 
NCT02689752 
 
Absorption, Metabolism and 
Excretion of [14C] 
Fruquintinib in Healthy Male 
Volunteers after a Single Oral 
Administration of 5mg/100 
μCi/Subject of [14C] 
Fruquintinib 
Evaluate mass 
balance in healthy 
male volunteers 
following a single 
oral administration of 
5 mg/100 μCi/Subject 
of [14C] fruquintinib 
Phase 1 
Healthy Males  
N=6 
To investigate the 
absorption, drug 
biotransformation 
and mass balance 
and to evaluated the 
PK and safety of 
fruquintinib. To 
identify the 
compound's major 
metabolites  
Source:  Fruquintinib Investigator’s Brochure 
*See the Fruquintinib Investigator’s Brochure for up-to-date information. 
 
 


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APPENDIX 6 
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, treatment should be discontinued immediately, and supportive treatment should be given.  
This 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 8.1), 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 eCRFs 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 Hematology 
o Clinical biochemistry: ALT, AST, bilirubin (including total bilirubin and direct 
bilirubin), ALP, albumin, PTT or INR, amylase, lipase, 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). 
• 
Complete appropriate auxiliary examination: 


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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, 
consultation with a gastroenterologist or hepatologist should be considered ;  
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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APPENDIX 7 
CLINICAL MANAGEMENT OF SEVERE OR SERIOUS 
HEMORRHAGIC EVENTS 
If hemorrhagic events are evaluated as severe (CTCAE grade ≥3) or SAEs,  study treatment should 
be discontinued or interrupted immediately, and appropriate treatment measures initiated to control 
bleeding (eg 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 7.5.6.2).  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. 
If a hemorrhagic event is evaluated as a severe (CTCAE grade ≥3) or SAE after taking fruquintinib, 
the investigator is required to report the event in an expedited fashion (within 24 hours of first 
awareness) to sponsor (see Section 8.2.2).  
See Figure 2 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 (eg warfarin) 
▪ NSAIDs (eg aspirin) 
▪ Anti-platelet drugs (eg, clopidogrel/glycoprotein GPIIb/IIIa 
inhibitors/dipyridamole) 
▪ Other anticoagulants (eg heparin/thrombolytics/SSRIs) 
▪ Food and herbal supplements with anticoagulant property 
▪ 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, PTT, 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.  


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o If suspected cardiovascular causes exist, cardiac ultrasonography is recommended to 
exclude cardiovascular dysfunction (ie, right heart failure). 
 




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APPENDIX 8 
MANAGEMENT OF HYPERTENSION IN PATIENTS RECEIVING 
FRUQUINTINIB 
Hypertension is a common AE that has been reported in patients taking angiogenesis inhibitors 
(Izzedine 2009), 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 (Figure 3), please see a summary of the most recent AHA/ACC hypertension 
treatment guidelines. 
 


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Figure 3 
Schema from American Heart Association/ American College of Cardiology 
for Controlling Hypertension in Adults 






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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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APPENDIX 9 
CONVERSION TABLES FOR URINALYSIS RESULTS 
Blood 
Leucocytes 
Negative 
0 
0 cells/μL 
Negative 
0 
<10 mg/dL 
Trace 
1+ 
1-24 cells/μL 
Trace 
1+ 
11-99 mg/dL 
Small 
2+ 
25-79 cells/μL 
Small 
2+ 
99-299 mg/dL 
Medium 
3+ 
80-199 cells/μL Medium 
3+ 
300-999 mg/dL 
Large 
4+ 
≥ 200 cells/μL 
large 
4+ 
>1000 mg/dL 
 
Proteinuria 
NCI-CTCAE Grade 
Protein by urinalysis 
24-hour protein quantitation 
1 
1+ 
<1.0g 
2 
2+ 
<2.0g 
2 
≥2+ 
<3.5 g (excluding 3.5 g) 
3 
N/A 
≥3.5 g 


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APPENDIX 10 
COCKGROFT GAULT FORMULA 
 
The Cockcroft-Gault formulas are as follows: 
• CrCl (male) = ([140-age] × weight in kg)/(serum creatinine × 72) 
• CrCl (female) = CrCl (male) × 0.85 
 
Source:  Cockcroft 1976 


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APPENDIX 11 
AMENDMENT HISTORY 
Amendment 3.1 (25 March 2021) 
This 2019-013-GLOB1 Protocol Amendment 3.1 was an administrative amendment to correct a 
formatting numbering error in the Inclusion Criteria (Section 5.3) and to add a clarification in 
Table 14 in the 2019-013-GLOB1 Protocol Amendment 3.   
 
Amendment 3 (16 March 2021) 
Section 
Summary of Change 
Rationale for Change 
Section 4.1.2.3 - Temporary 
Change of Pharmacokinetic 
Sampling, Holter Monitor QTc 
Evaluations, and Circulating Tumor 
DNA Sample Collection 
Addition of notes regarding 
temporary change of PK sampling, 
electrocardiogram (ECG) 
collection, and ctDNA sample 
collection 
Delays in laboratory kit production 
and delivery resulting from 
COVID-19-related disruptions 
Section 6.1.1.17 - 
Electrocardiograms Monitoring 
Addition of notes regarding 
temporary change of PK sampling, 
ECG collection, and ctDNA sample 
collection 
Delays in laboratory kit production 
and delivery resulting from 
COVID-19-related disruptions 
Table 2 Schedule of Events for 
Dense Pharmacokinetic and 
Electrocardiogram Evaluations for 
the Subset of Approximately 120 
Patients (revised title) 
Table 3 Schedule of Events for 
Sparse Pharmacokinetic and 
Electrocardiogram Evaluations for 
Patients Not Included in the 
Approximately 120 Patients in the 
Subset in Table 2 (revised title) 
Revised table titles to reflect that 
first 120 patients did not have dense 
PK sampling 
Due to COVID-related supply chain 
issues, dense PK sampling and 
concurrent Holter ECG monitoring 
were not performed on first 120 
patients in the study but will be 
sampled in approximately 120 
patients 
Section 1 - Synopsis, Exclusion 
Criteria #5 
Section 5.4 - Exclusion Criteria #5  
Added urinalysis along with urine 
dipstick for initial evaluation for 
protein in urine during screening 
To align with current clinical 
practice as dipsticks are not used 
universally 
Section 9.2.5.1.1 - Primary 
Endpoint - Overall Survival 
Specified that the hazard ratio 
between the fruquintinib and 
placebo groups will be calculated 
from a stratified Cox proportional 
hazard model stratified by the 
randomization stratification factors 
Clarification 
Section 1 - Synopsis, Exclusion 
Criteria #14 
Section 5.4 - Exclusion Criteria #14 
Deleted the reference to 
Appendix 4 for concomitant 
medications with a known risk of 
causing QT prolongation and/or 
torsades de pointes as these details 
are not located in the appendix 
Clarification of the location from a 
reference to Appendix 4 to 
appropriate web site 


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Section 
Summary of Change 
Rationale for Change 
Table 1 Schedule of Events 
Added the option of conducting 
some assessments up to and 
including Cycle 1, Day 1 
Providing the sites with flexibility 
for timing of assessments 
Section 7.1 - Study Drug 
Administration 
Specified that study drug should be 
administered around the same time 
each day and that a missed dose can 
be administered within 12 hours of 
usual administration time 
Clarification 
Section 7.3.3.1 - Emergency 
Unblinding 
Language changed to encourage, 
but not require, consultation with 
the sponsor prior to emergency 
unblinding of a patient’s study 
treatment allocation 
Request by the UK Medicines and 
Healthcare Products Regulatory 
Agency (MHRA) 
Section 7.5.1 - Prohibited Therapies 
Added specification to prohibit live 
vaccines during the study and for 
3 months after the last dose of study 
drug(s) 
Request by the UK MHRA 
Section 9.2.5.1.2 - Secondary 
Efficacy Endpoints (PFS, ORR, 
DCR, DoR) 
Clarified statistical methods 
Request by the US Food and Drug 
Administration (FDA) 
Section 2.1 - Study Rationale 
(formerly Section 2.2) 
Section 2.2 - Background (formerly 
Section 2.1) 
Moved Study Rationale to the 
beginning of the Introduction, 
revised and removed text that was 
redundant with Background 
To align with sponsor-approved 
template text across all clinical 
study protocols  
Section 10.1 - Good Clinical 
Practice (revised section header) 
Section 10.2 - Ethics Review 
Section 10.3 - Informed Consent  
Section 10.4 - Data Privacy 
Section 10.7 - Data Quality 
Assurance (formerly Section 10.6) 
Revised and updated text in Ethical 
Considerations section. 
To align with sponsor-approved 
template text across all clinical 
study protocols  
Section 10.3 – Ethical Conduct of 
the Study (deleted section) 
Section 11.2.3 – Protocol Deviation 
(deleted section) 
Section 11.2.4.2 – Study Files 
(deleted section) 
Deleted sections 
To remove text that was redundant 
with other sections in other section 
of Section 10 and align with 
sponsor-approved template text 
across all clinical study protocols   
Section 10.6 - Biological 
Specimens and Data 
Added section 
To align with sponsor-approved 
template text across all clinical 
study protocols  


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Section 
Summary of Change 
Rationale for Change 
Section 11.2 - Quality Control and 
Assurance  
Section 11.2.1 - Monitoring 
Section 11.2.2 - Audits 
Section 11.2.3.2 - Source 
Documentation 
Section 11.2.3.3 - Records 
Retention 
Revised subsections under 
Oversight 
To align with sponsor-approved 
template text across all clinical 
study protocols 
Section 2.1.1 – Administration 
Regimen (deleted section) 
Deleted section 
To remove text that was redundant 
with information in Section 7.1 and 
align with sponsor-approved 
template text across all clinical 
study protocols 
 
Amendment 2 (30 October 2020) 
Section 
Summary of Change 
Rationale for Change 
Section 1 - Synopsis - Study Design 
Section 5.1 - Recruitment 
Section 9.1.2 - Sample Size 
Rationale 
Changed estimated number of 
subjects to 687. 
Change made to increase the 
statistical power of the study from 
80% to 90%. 
Section 1 - Synopsis – Inclusion 
Criteria #3 
Section 5.3 - Inclusion Criteria #3 
Provided country level flexibility 
for molecular characterization of 
MSI/MMR status. 
MSI/MMR status not available for 
determination in every country.  
Section 1 - Synopsis – Inclusion 
Criteria #6 
Section 5.3 - Inclusion Criteria #6 
Added clarifying language for the 
inclusion of subjects post receipt of 
oxaliplatin in the adjuvant setting.  
Clarified language.  
Section 1 - Synopsis – Inclusion 
Criteria #11 
Section 5.3 - Inclusion Criteria #11 
Clarified contraception language.  
Change made per Belgian Health 
Authority (HA) request. 
Section1 - Synopsis - Inclusion 
Criteria #12 
Section 5.3 - Inclusion Criteria #12 
Added new inclusion criterion to 
address previous treatment with 
BRAF inhibitor. 
Per German HA request.  BRAF 
inhibitors are not approved and 
available in every country. 
Section1 - Synopsis - Exclusion 
Criteria #5 
Section 5.4 - Exclusion Criteria #5 
Added clarifying language. 
To correct inconsistency 
Section 1 - Synopsis - Exclusion 
Criteria #19 
Section 5.4 - Exclusion Criteria #19 
Added “(or 5 half-lives)” to the 
“within 2 weeks” amount of time 
from use of CYP3A4 inhibitors 
prior to first dose of study drug.  
Belgian HA request 
Section 1 - Synopsis - Exclusion 
Criteria #31 
Section 5.4 - Exclusion Criteria #31 
Added “including the azo dyes 
Tartrazine - FD&C Yellow 5 and 
Sunset yellow FCF - FD&C Yellow 
6” to the Exclusion Criteria. 
Belgian and German HA request 


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Section 
Summary of Change 
Rationale for Change 
Section 1 - Synopsis - Exclusion 
Criteria #32 
Section 5.4 - Exclusion Criteria #32 
Added in Exclusion Criteria for 
previous treatment with 
fruquintinib. 
Clarification  
Section 1 - Synopsis - Exclusion 
Criteria #33 
Section 5.4 - Exclusion Criteria #33 
Added in an exclusion criterion for 
vaccine use prior to enrollment. 
Additional detail 
Section 1 - Synopsis - Number of 
Sites 
Increased planned number of sites 
from 100 sites to 140 sites. 
Change to reflect the planned 
increase in number of patients in 
study. 
Section 1 - Synopsis - Study 
Duration 
Increased study duration.   
Change to reflect the planned 
increase in number of subjects.  
Section 1.1 - Study Schematic 
Updated Figure 1 by adding “Prior 
treatment with an immune 
checkpoint inhibitor of BRAF 
inhibitor, if indicated”. 
Clarified language for alignment. 
Table 1 Schedule of Events and 
Footnote 2 
Section 6.1.1.3 - Tumor Diagnosis 
and Treatment History 
Added in characterization of 
MSI/MMR and BRAF mutation in 
the Tumor Diagnosis and Treatment 
History assessment. 
Clarified language for alignment. 
Table 1 Schedule of Events and 
Footnote 11 (footnote added) 
Section 6.1.1.12 - Blood Amylase 
and Lipase (section added) 
Added assessments for amylase and 
lipase. 
Per German HA request. 
Table 1 Schedule of Events 
Section 6.1.1.16 - Pregnancy Test 
Added “or an equivocal urine 
pregnancy test” in pregnancy 
testing requirements. 
To ensure an equivocal urine test is 
followed-up by a more sensitive 
serum pregnancy test. 
Table 2 Schedule of Events for 
Dense Pharmacokinetic and 
Electrocardiogram Evaluations for 
the Subset of Approximately 120 
Patients 
Table 3 Schedule of Events for 
Sparse Pharmacokinetic and 
Electrocardiogram Evaluations for 
Patients Not Included in the 
Approximately 120 Patients in the 
Subset in Table 2 
Added in a ±10-minute time 
window for acquisition of PK 
samples. 
Provide more flexibility for sites 
and less chance of deviations. 
Section 4.1.1 - Enrollment in Study 
Added additional rationale for 2:1 
randomization.   
Belgian HA request 
Section 5.2 - Definitions 
Additional details of randomization. 
Belgian HA request 
Section 6.1.1.17 - 
Electrocardiograms Monitoring 
Added “All ECGs for the purposes 
of screening will be performed 
using standard, local equipment.” 
Clarified language 
Section 6.1.1.3 - Tumor Diagnosis 
and Treatment History 
Clarified requirements for RAS, 
BRAF, MSI/MMR status. 
Italian HA request, to align with IC 
#3.   


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Section 
Summary of Change 
Rationale for Change 
Section 6.2.1 - Permanent 
Discontinuation of Treatment 
reason #3 
Added discontinuation details to 
intolerable toxicity  
German HA request 
Section 7.1 - Study Drug 
Administration 
Added instructions for study drug if 
subject vomits 
Added for clarity 
Section 7.3.3.1 - Emergency 
Unblinding 
Added language to request sponsor 
medical monitor notification if 
possible before emergency 
unblinding 
German HA request 
Section 7.5.2 - Permitted Therapies 
– Permitted Therapies 
Table 13 Dose Adjustment for 
Hemorrhage at Any Site 
Appendix 6 
Clinical 
Evaluation of Possible Drug-
Induced Liver Injury (DILI) 
Removed paragraph and footnote 
about monitoring subjects receiving 
anti-platelet and/or anti-thrombotic 
drugs. 
Belgian HA request 
Section 7.5.6.2 - Dose Modification 
for Important Identified Risks and 
Potential Risks 
Changed title of section to “Dose 
Modification for Important 
Identified Risks and Potential Risks 
Belgian HA request 
Section 7.5.6.2 - Dose Modification 
for Important Identified Risks and 
Potential Risks 
Table 9 Dose Modification for 
Dermatological Toxicity (revised 
table heading) 
Changed Palmar Plantar 
Erythrodysethesia and abbreviation 
of PPE to more broad term of 
Dermatological Toxicity. 
Belgian HA request 
Section 9.1.2 - Sample Size 
Rationale 
Section 9.2.1 - Primary Endpoint 
Section 9.2.2.1 - Key Secondary 
Endpoint: Progression-free Survival 
Section 9.2.5.1.1 - Primary 
Endpoint - Overall Survival 
Section 9.2.5.1.2 - Secondary 
Efficacy Endpoints (PFS, ORR, 
DCR, DoR) 
Section 9.2.5.1.3 - Multiplicity 
Adjustment for the Primary 
Endpoint OS and Key Secondary 
Endpoint PFS 
Section 9.4 - Interim Analysis 
Additional details added 
Clarification of statistical methods 
Section 11.3.2 – Protocol 
Deviations 
Edited language 
Clarification of responsibilities 
Table 1 Schedule of Events 
Removed the visit window for 
cycle 1 day 21 
Reflect need for PK sampling 1 day 
before and 1 day after cycle 1 day 
21 visit 


Clinical Study Protocol 2019-013-GLOB1 
Fruquintinib 
Amendment 4 
 
 
 
Hutchison MediPharma 
 
Page 131 
 
CONFIDENTIAL 
 
 
 
 
Amendment 1 (08 April 2020) 
Section 
Summary of Change 
Rationale for Change 
Section 1 Synopsis - Inclusion 
Criteria, #3 
Section 5.3 Inclusion Criteria, #3 
Provided additional detail for 
molecular characterization of RAS, 
BRAF, and MSI/MMR status 
Requested by CHMP 
Section 6.2.1 Permanent 
Discontinuation of Treatment 
Added statement that patients may 
continue to receive treatment 
following progressive disease by 
RECIST 
Provide clarity as requested by 
FDA 
Section 1 Synopsis - Inclusion 
Criteria, #4 
Section 5.3 Inclusion Criteria, #4 
Modified requirement for prior 
treatment with TAS-102 or 
regorafenib 
Provide additional clarity as 
requested by FDA 
Section 7.5.6.2 Dose Modification 
for Important Identified Risks 
Table 9 Dose Modification for 
Dermatological Toxicity 
Table 10 Dose Modification for 
Proteinuria 
Table 11 Dose Modification for 
Hypertension 
Table 12 Dose Adjustment for 
Decreased Platelet Count 
Table 13 Dose Adjustment for 
Hemorrhage at Any Site 
Edited “Dose Adjustment” 
requirements in Table 8, Table 9, 
Table 10, Table 11, and Table 12 to 
provide clear guidance 
Provide clarity for dose 
modification requirements for 
specific adverse events as requested 
by FDA 
Section 1 Synopsis - Exclusion 
Criteria, #4 
Section 5.4 Exclusion Criteria, #4 
(deleted) 
Removed exclusion criterion #4 
Revised in response to FDA 
comment.  Exclusion criterion #4 
was redundant with criterion #22 
(currently #21), which provides 
appropriate guidance for resolution 
of toxicity from prior therapy 
Section 1 Synopsis - Inclusion 
Criteria, #5 
Section 5.3 Inclusion Criteria, #5 
Added additional detail regarding 
prior treatment with immune 
checkpoint inhibitors 
Provide additional clarity 
Section 8.6.3 Persistent or 
Recurrent Adverse Events 
Removed section 
Avoid potential confusion.  Details 
on data entry will be addressed in 
CRF Completion Guidelines. 
 


Signature Page for VV-CLIN-000381 v1.0
Signature Page for VV-CLIN-000381 v1.0
Approval
MO
01-Jul-2021 21:21:57 GMT+0000
Approval
CSO
02-Jul-2021 14:47:22 GMT+0000


Statistical Analysis Plan Summary of Changes 
 
Amendment 4 
Section 
Summary of Change 
Section 7.5.3 - Drug-Drug Interactions 
(Therapies to Avoid or Use with Special Caution)  
Removed instruction that subjects should avoid proton pump 
inhibitor drugs and H2 blockers  
Section 1 - Synopsis  
Section 5.1 - Recruitment  
Revised the planned estimated number of study sites from 
140 to 160  
Section 1 - Synopsis, Inclusion Criterion #4  
Section 5.3 - Inclusion Criteria, #4  
For the inclusion criterion requiring patients must have 
received treatment with prior therapy, including anti-VEGF or 
anti-EGFR, examples of these treatments were added  
Section 1 - Synopsis, Exclusion Criterion #5  
Section 5.4 - Exclusion Criteria, #5  
Changed the protein level for which a 24-hour urine 
assessment is required.  
Section 1 - Synopsis, Exclusion Criterion #6  
Section 5.4 - Exclusion Criteria, #6  
Added in details for blood pressure assessment process.  
Section 1.2 – Schedule of Events  
Table 1 Schedule of Events  
Removed visit window day 21 of cycle 2 and cycle 3  
Table 2 Schedule of Events for Dense 
Pharmacokinetic and Electrocardiogram 
Evaluations for the Subset of Approximately 
120 Patients with Evaluable ECGs  
Revised title  
Table 3 Schedule of Events for Sparse 
Pharmacokinetic and Electrocardiogram 
Evaluations for Patients Not Included in the 
Approximately 120 Evaluable Patients in the 
Subset in Table 2  
Revised title  
Table 1 Schedule of Events  
Section 1.2.1 - Footnotes for Schedule of Events 
Table 1, #21 (footnote removed)  
Section 6.1.1.21 - Circulating Tumor DNA  
Removed requirement for the collection of blood to evaluate 
ctDNA. Further noted that analysis of ctDNA samples 
collected would be performed according to the statistical 
analysis plan  
Section 6.1.1.17 - Electrocardiograms 
Monitoring  
Added that any subject with a pacemaker should undergo PK 
and safety ECG evaluations according to the schedule 
outlined in Table 3  
Section 6.1.1.18 - Echocardiogram  
Added that echocardiograms completed as standard of care 
prior to signing the informed consent, but within 28 days of 
first dose of study treatment, may be used as baseline 
assessment.  
Section 1.2.2 - Footnotes for the Schedule of 
Events Tables 2 and 3, #4 (footnote added)  
Added instruction to refer to the Holter Monitor instruction 
manual for appropriate timing of the start of the ECG 
recording.  
Appendix 9 Conversion Tables for Urinalysis 
Results  
Added table to aid in conversion of proteins measured by 
urinalysis for assessment of proteinuria  
 
 
Amendment 3.1 (25 March 2021) 
This 2019-013-GLOB1 Protocol Amendment 3.1 was an administrative amendment to correct a formatting 
numbering error in the Inclusion Criteria (Section 5.3) and to add a clarification in Table 14 in the 2019-013-GLOB1 
Protocol Amendment 3. 


 
Amendment 3 (16 March 2021) 
Section 
Summary of Change 
Section 4.1.2.3 - Temporary Change of 
Pharmacokinetic Sampling, Holter Monitor QTc 
Evaluations, and Circulating Tumor DNA Sample 
Collection  
Addition of notes regarding temporary change of PK 
sampling, electrocardiogram (ECG) collection, and ctDNA 
sample collection  
Section 6.1.1.17 - Electrocardiograms 
Monitoring  
Addition of notes regarding temporary change of PK 
sampling, ECG collection, and ctDNA sample collection  
Table 2 Schedule of Events for Dense 
Pharmacokinetic and Electrocardiogram 
Evaluations for the Subset of Approximately 
120 Patients (revised title)  
Table 3 Schedule of Events for Sparse 
Pharmacokinetic and Electrocardiogram 
Evaluations for Patients Not Included in the 
Approximately 120 Patients in the Subset in 
Table 2 (revised title)  
Revised table titles to reflect that first 120 patients did not 
have dense PK sampling  
Section 1 - Synopsis, Exclusion Criteria #5  
Section 5.4 - Exclusion Criteria #5  
Added urinalysis along with urine dipstick for initial 
evaluation for protein in urine during screening  
Section 9.2.5.1.1 - Primary Endpoint - Overall 
Survival  
Specified that the hazard ratio between the fruquintinib and 
placebo groups will be calculated from a stratified Cox 
proportional hazard model stratified by the randomization 
stratification factors  
Section 1 - Synopsis, Exclusion Criteria #14  
Section 5.4 - Exclusion Criteria #14  
Deleted the reference to Appendix 4 for concomitant 
medications with a known risk of causing QT prolongation 
and/or torsades de pointes as these details are not located in 
the appendix  
Table 1 Schedule of Events  
Added the option of conducting some assessments up to and 
including Cycle 1, Day 1  
Section 7.1 - Study Drug Administration  
Specified that study drug should be administered around the 
same time each day and that a missed dose can be 
administered within 12 hours of usual administration time  
Section 7.3.3.1 - Emergency Unblinding  
Language changed to encourage, but not require, 
consultation with the sponsor prior to emergency unblinding 
of a patient’s study treatment allocation  
Section 7.5.1 - Prohibited Therapies  
Added specification to prohibit live vaccines during the study 
and for 3 months after the last dose of study drug(s)  
Section 9.2.5.1.2 - Secondary Efficacy Endpoints 
(PFS, ORR, DCR, DoR)  
Clarified statistical methods  
Section 2.1 - Study Rationale (formerly Section 
2.2)  
Section 2.2 - Background (formerly Section 2.1)  
Moved Study Rationale to the beginning of the Introduction, 
revised and removed text that was redundant with 
Background  
Section 10.1 - Good Clinical Practice (revised 
section header)  
Section 10.2 - Ethics Review  
Section 10.3 - Informed Consent  
Section 10.4 - Data Privacy  
Revised and updated text in Ethical Considerations section.  


Section 10.7 - Data Quality Assurance (formerly 
Section 10.6)  
Section 10.3 – Ethical Conduct of the Study 
(deleted section)  
Section 11.2.3 – Protocol Deviation (deleted 
section)  
Section 11.2.4.2 – Study Files (deleted section)  
Deleted sections  
Section 10.6 - Biological Specimens and Data  
Added section  
Section 11.2 - Quality Control and Assurance  
Section 11.2.1 - Monitoring  
Section 11.2.2 - Audits  
Section 11.2.3.2 - Source Documentation  
Section 11.2.3.3 - Records Retention  
Revised subsections under Oversight  
Section 2.1.1 – Administration Regimen 
(deleted section)  
Deleted section  
 
 
Amendment 2 (30 October 2020) 
Section 
Summary of Change 
Section 1 - Synopsis - Study Design  
Section 5.1 - Recruitment  
Section 9.1.2 - Sample Size Rationale  
Changed estimated number of subjects to 687.  
Section 1 - Synopsis – Inclusion Criteria #3  
Section 5.3 - Inclusion Criteria #3  
Provided country level flexibility for molecular 
characterization of MSI/MMR status.  
Section 1 - Synopsis – Inclusion Criteria #6  
Section 5.3 - Inclusion Criteria #6  
Added clarifying language for the inclusion of subjects post 
receipt of oxaliplatin in the adjuvant setting.  
Section 1 - Synopsis – Inclusion Criteria #11  
Section 5.3 - Inclusion Criteria #11  
Clarified contraception language.  
Section1 - Synopsis - Inclusion Criteria #12  
Section 5.3 - Inclusion Criteria #12  
Added new inclusion criterion to address previous treatment 
with BRAF inhibitor.  
Section1 - Synopsis - Exclusion Criteria #5  
Section 5.4 - Exclusion Criteria #5  
Added clarifying language.  
Section 1 - Synopsis - Exclusion Criteria #19  
Section 5.4 - Exclusion Criteria #19  
Added “(or 5 half-lives)” to the “within 2 weeks” amount of 
time from use of CYP3A4 inhibitors prior to first dose of study 
drug.  
Section 1 - Synopsis - Exclusion Criteria #31  
Section 5.4 - Exclusion Criteria #31  
Added “including the azo dyes Tartrazine - FD&C Yellow 5 
and Sunset yellow FCF - FD&C Yellow 6” to the Exclusion 
Criteria.  
Section 1 - Synopsis - Exclusion Criteria #32  
Section 5.4 - Exclusion Criteria #32  
Added in Exclusion Criteria for previous treatment with 
fruquintinib.  
Section 1 - Synopsis - Exclusion Criteria #33  
Section 5.4 - Exclusion Criteria #33  
Added in an exclusion criterion for vaccine use prior to 
enrollment.  
Section 1 - Synopsis - Number of Sites  
Increased planned number of sites from 100 sites to 140 
sites.  
Section 1 - Synopsis - Study Duration  
Increased study duration.  
Section 1.1 - Study Schematic  
Updated Figure 1 by adding “Prior treatment with an 
immune checkpoint inhibitor of BRAF inhibitor, if indicated”.  


Table 1 Schedule of Events and Footnote 2  
Section 6.1.1.3 - Tumor Diagnosis and 
Treatment History  
Added in characterization of MSI/MMR and BRAF mutation in 
the Tumor Diagnosis and Treatment History assessment.  
Table 1 Schedule of Events and Footnote 11 
(footnote added)  
Section 6.1.1.12 - Blood Amylase and Lipase 
(section added)  
Added assessments for amylase and lipase.  
Table 1 Schedule of Events  
Section 6.1.1.16 - Pregnancy Test  
Added “or an equivocal urine pregnancy test” in pregnancy 
testing requirements.  
Table 2 Schedule of Events for Dense 
Pharmacokinetic and Electrocardiogram 
Evaluations for the Subset of Approximately 
120 Patients  
Table 3 Schedule of Events for Sparse 
Pharmacokinetic and Electrocardiogram 
Evaluations for Patients Not Included in the 
Approximately 120 Patients in the Subset in 
Table 2  
Added in a ±10-minute time window for acquisition of PK 
samples.  
Section 4.1.1 - Enrollment in Study  
Added additional rationale for 2:1 randomization.  
Section 5.2 - Definitions  
Additional details of randomization.  
Section 6.1.1.17 - Electrocardiograms 
Monitoring  
Added “All ECGs for the purposes of screening will be 
performed using standard, local equipment.”  
Section 6.1.1.3 - Tumor Diagnosis and 
Treatment History  
Clarified requirements for RAS, BRAF, MSI/MMR status.  
Section 6.2.1 - Permanent Discontinuation of 
Treatment reason #3  
Added discontinuation details to intolerable toxicity  
Section 7.1 - Study Drug Administration  
Added instructions for study drug if subject vomits  
Section 7.3.3.1 - Emergency Unblinding  
Added language to request sponsor medical monitor 
notification if possible before emergency unblinding  
Section 7.5.2 - Permitted Therapies – Permitted 
Therapies  
Table 13 Dose Adjustment for Hemorrhage at 
Any Site  
Appendix 6 Clinical Evaluation of Possible Drug-
Induced Liver Injury (DILI)  
Removed paragraph and footnote about monitoring subjects 
receiving anti-platelet and/or anti-thrombotic drugs.  
Section 7.5.6.2 - Dose Modification for 
Important Identified Risks and Potential Risks  
Changed title of section to “Dose Modification for Important 
Identified Risks and Potential Risks  
Section 7.5.6.2 - Dose Modification for 
Important Identified Risks and Potential Risks  
Table 9 Dose Modification for Dermatological 
Toxicity (revised table heading)  
Changed Palmar Plantar Erythrodysethesia and abbreviation 
of PPE to more broad term of Dermatological Toxicity.  
Section 9.1.2 - Sample Size Rationale  
Section 9.2.1 - Primary Endpoint  
Section 9.2.2.1 - Key Secondary Endpoint: 
Progression-free Survival  
Section 9.2.5.1.1 - Primary Endpoint - Overall 
Survival  
Section 9.2.5.1.2 - Secondary Efficacy Endpoints 
(PFS, ORR, DCR, DoR)  
Additional details added  


Section 9.2.5.1.3 - Multiplicity Adjustment for 
the Primary Endpoint OS and Key Secondary 
Endpoint PFS  
Section 9.4 - Interim Analysis  
Section 11.3.2 – Protocol Deviations  
Edited language  
Table 1 Schedule of Events  
Removed the visit window for cycle 1 day 21  
 
 
Amendment 1 (08 April 2020) 
Section 
Summary of Change 
Section 1 Synopsis - Inclusion Criteria, #3  
Section 5.3 Inclusion Criteria, #3  
Provided additional detail for molecular characterization of 
RAS, BRAF, and MSI/MMR status  
Section 6.2.1 Permanent Discontinuation of 
Treatment  
Added statement that patients may continue to receive 
treatment following progressive disease by RECIST  
Section 1 Synopsis - Inclusion Criteria, #4  
Section 5.3 Inclusion Criteria, #4  
Modified requirement for prior treatment with TAS-102 or 
regorafenib  
Section 7.5.6.2 Dose Modification for Important 
Identified Risks  
Table 9 Dose Modification for Dermatological 
Toxicity  
Table 10 Dose Modification for Proteinuria  
Table 11 Dose Modification for Hypertension  
Table 12 Dose Adjustment for Decreased 
Platelet Count  
Table 13 Dose Adjustment for Hemorrhage at 
Any Site  
Edited “Dose Adjustment” requirements in Table 8, Table 9, 
Table 10, Table 11, and Table 12 to provide clear guidance  
Section 1 Synopsis - Exclusion Criteria, #4  
Section 5.4 Exclusion Criteria, #4 (deleted)  
Removed exclusion criterion #4  
Section 1 Synopsis - Inclusion Criteria, #5  
Section 5.3 Inclusion Criteria, #5  
Added additional detail regarding prior treatment with 
immune checkpoint inhibitors  
Section 8.6.3 Persistent or Recurrent Adverse 
Events  
Removed section  
 






Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
Th s document s conf dent a . 
SAP Text Vers on: 1.0 dated 25 Mar 2021 
Contro ed Document ID: 3903A.02, Effect ve Date 31 Aug 2020 
F ng requ rements: TMF 
Page 3 of 99 
 
I conf rm that I have rev ewed th s document and agree w th the content. 
Approvals 
Syneos Health Approval 
 
 
 
 
 
 
Name, T t e 
Lead  B ostat st c an / Support 
B ostat st c an 
 
S gnature 
 
Date (DD Mmm YYYY) 
 
 
 
 
 
 
Name, T t e 
Lead  Pharmacok net c st 
 
S gnature 
 
Date (DD Mmm YYYY) 
 
 
 
 
 
 
Name, T t e 
 
S gnature 
 
Date (DD Mmm YYYY) 
Hutchison MediPharma Limited Approval 
 
 
 
 
 
 
 
Sponsor Contact 
 
S gnature 
 
Date (DD Mmm YYYY) 
 
 
 
 
 
 
 
Sponsor Contact 
 
S gnature 
 
Date (DD Mmm YYYY) 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor Contact 
 
S gnature 
 
Date (DD Mmm YYYY) 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
Th s document s conf dent a . 
SAP Text Vers on: 1.0 dated 25 Mar 2021 
Contro ed Document ID: 3903A.02, Effect ve Date 31 Aug 2020 
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Page 4 of 99 
 
Table of Contents 
Revision History ............................................................................................................................ 2 
Approvals .................................................................................................................................... 3 
 
Glossary of Abbreviations .................................................................................................... 9 
 
Purpose .............................................................................................................................. 13 
 
Study Objectives ................................................................................................................ 15 
 
Study Details/Design .......................................................................................................... 17 
 
Endpoints ........................................................................................................................... 23 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
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Analysis Populations .......................................................................................................... 27 
 
General Aspects for Statistical Analysis ............................................................................ 28 
 
Demographic, Other Baseline Characteristics and Medication .......................................... 35 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
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Efficacy .............................................................................................................................. 43 
 
Pharmacokinetics ............................................................................................................... 56 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
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Safety ................................................................................................................................. 58 
 
IDMC Review ..................................................................................................................... 69 
 
Changes from Analysis Planned in Protocol ...................................................................... 70 
 
Reference List .................................................................................................................... 71 
 
Programming Considerations ............................................................................................ 72 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
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Quality Control ................................................................................................................... 78 
 
Appendix ............................................................................................................................ 79 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
Th s document s conf dent a . 
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Contro ed Document ID: 3903A.02, Effect ve Date 31 Aug 2020 
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Glossary of Abbreviations 
Abbreviation 
Description 
AE 
Adverse event 
ADaM 
Analysis Data Model 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
aPTT 
Activated Partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATC 2 
Anatomical therapeutic class 2 
AR (1) 
Autoregressive (1)  
BMI 
Body mass index 
BLQ 
Below the lower limit of quantification 
BRAF 
B-Raf proto-oncogene 
BSC 
Best supportive care 
CEA 
Carcino-embryonic antigen 
CI 
Confidence interval 
CMH 
Cochran-Mantel Haenszel 
COVID-19 
Coronavirus 2019 
ctDNA 
Circulating tumor DNA 
CTMS 
Clinical trial management system 
CR 
Complete response 
CS 
Clinically significant 
CSR 
Clinical study report 
CV 
Coefficient of variation 
CRO 
Clinical research organization 
CT 
Computed tomography 
CTCAE  
Common Terminology Criteria for Adverse Event 
dMMR 
Deficient mismatch repair 
DCR 
Disease control rate 
DoR 
Duration of response 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
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Abbreviation 
Description 
eCRF 
Electronic case report form 
ECHO 
Echocardiogram 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End of treatment 
ERT 
eResearchTechnology, Inc. 
HR 
Hazard ratio 
ICF 
Informed consent form 
IDMC 
Independent data monitoring committee 
IND 
Investigational new drug 
INR 
International normalized ratio 
IRT 
Interactive response technology 
ITT 
Intent-to-Treat 
IWRS 
Interactive web response system 
JSMC 
Japanese safety monitoring committee 
LDH 
Lactate dehydrogenase 
LS 
Least-square 
mCRC 
Metastatic colorectal cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSI 
Microsatellite instability 
MSI-H 
Microsatellite instability-high 
MID 
Minimally important difference 
MMR 
Mismatch repair  
MSS 
Microsatellite stable 
MMRM 
Mixed model repeated measures 
MRI 
Magnetic resonance imaging 
MUGA 
Multigated acquisition  


Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
Th s document s conf dent a . 
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Abbreviation 
Description 
NA 
Not available 
NCS 
Not clinically significant 
NE 
Not evaluable 
ORR 
Objective response rate 
OS 
Overall survival 
pMMR 
Proficient mismatch repair 
PD  
Progressive disease 
PID 
Percentage intended dose 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PO 
Per os (oral administration) 
PR 
Partial response 
PR 
PR Interval (ECG Parameter) 
PT 
Preferred term 
Q1 
Lower quartile 
Q3 
Upper quartile 
QoL 
Quality of life 
QD 
Quaque die (once daily) 
QTcB 
QT correction Bazett formula 
QTcF 
QT correction Fridericia formula 
QRS 
A combination of the Q wave, R wave and S wave 
RAS  
Rat sarcoma 
REML 
Restricted maximum likelihood 
RD 
Relative dose 
RDI 
Relative dose intensity  
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE  
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SD 
Stable disease 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
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SAP Text Vers on: 1.0 dated 25 Mar 2021 
Contro ed Document ID: 3903A.02, Effect ve Date 31 Aug 2020 
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Abbreviation 
Description 
StdDev 
Standard deviation 
SDTM 
Study Data Tabulation Model 
SE 
Standard error 
SI 
International System of Units 
SOC 
System organ class 
TLFs 
Tables, listings and figures 
TSH 
Thyroid-stimulating hormone 
TTD 
Time to deterioration 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
VAS 
Visual analogue scale 
VEGF 
Vascular Endothelial Growth Factor 
WHODD 
World Health Organization Drug Dictionary 
 
 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
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Purpose 
The purpose of this statistical analysis plan (SAP) for the study is to ensure that the data listings, summary 
tables and figures that are to be produced, and the statistical methodologies that are used, are complete 
and appropriate to allow valid conclusions regarding the study objectives.  The SAP adheres to the proper 
regulatory guidelines and most recent International Council for Harmonisation guidelines (E3, E6, E9). All 
decisions regarding the final analyses, as defined in this SAP document, have been made prior to locking 
the database; any deviations from these guidelines will be documented in the clinical study report (CSR).  
A separate SAP is to be developed for the protocol Japanese Specific Addendum (Safety Lead-In for 
Japan).  
 
Responsibilities 
Syneos Health is to perform the statistical analyses and are responsible for the production and quality 
control of all Study Data Tabulation Model (SDTM) datasets, Analysis Data Model (ADaM) datasets, and 
the tables, listings, and figures (TLFs) for efficacy and safety, as well as tabulation of fruquintinib and M11 
concentrations from PK  (pharmacokinetic) plasma samples.  Details for analysis of circulating tumor DNA 
and pharmacogenomics will be prepared in a separate document. The SAP for population PK, 
Electrocardiogram (ECG) (pharmacodynamics) and QTc-PK analysis will be prepared separately by 
another contract research organization (CRO). 
 
Timings of Analyses 
An independent data monitoring committee (IDMC) is to review descriptive summaries of accumulating 
safety and subject disposition every 6 months, or at a frequency recommended by the IDMC, as described 
in the IDMC Charter Final Version 1.0 dated 25-Aug-2020.  An unblinded team from Syneos Health 
Biostatistics is to perform the analyses as described in Section 18, Content of Open and Closed Sessions 
of the IDMC Charter, in order to maintain the blinding of the study. 
 
Interim Analyses 
One interim non-binding futility analysis is to be performed once 1/3 of the total number of overall survival 
(OS) events (i.e., 160 OS events) have occurred. This interim analysis is for futility only, there are no plans 
to stop the study early for efficacy based on OS data at the interim analysis.  
The IDMC is to be instructed to recommend stopping the study for futility if the 1-sided p-value from a 
stratified log-rank test is at least 0.772 (corresponding to an observed HR of 1.133).  Otherwise, the study 
is to be continued with full enrollment.  
There is a 22.8% chance of terminating the study for futility at the interim analysis if the true median OS in 
fruquintinib arm is 5 months, i.e., fruquintinib is ineffective.  There is a 0.4% chance of stopping for futility, 
declaring fruquintinib ineffective at the interim if the true median OS in fruquintinib arm is 6.8 months, i.e., 
fruquintinib is effective in the study population. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
Th s document s conf dent a . 
SAP Text Vers on: 1.0 dated 25 Mar 2021 
Contro ed Document ID: 3903A.02, Effect ve Date 31 Aug 2020 
F ng requ rements: TMF 
Page 14 of 99 
 
 
Final Analysis 
If the study does not stop based on the futility analysis, the final analysis for the CSR will be conducted 
when at least 480 OS events have been observed. All study data collected up through the time of the final 
analysis will be summarized, unless otherwise specified. Unblinding will occur at the time of the final 
analysis.  


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Study Objectives 
 
Primary Objective 
• 
To evaluate the overall survival (OS) of fruquintinib plus best supportive care (BSC) compared to 
placebo plus BSC in subjects with refractory metastatic colorectal cancer (mCRC). 
 
Secondary Objective(s) 
• 
To evaluate progression-free survival (PFS) of fruquintinib plus BSC compared to placebo plus 
BSC. 
• 
To evaluate the objective response rate (ORR), disease control rate (DCR), and duration of 
response (DoR). 
• 
To assess the safety and tolerability of fruquintinib plus BSC compared to placebo plus BSC. 
• 
To characterize the PK exposure of fruquintinib and metabolite M11 in subjects with refractory 
mCRC. 
• 
To evaluate the effect of fruquintinib on cardiac repolarization, as detected by changes in 
electrocardiogram (ECG) QTc intervals, and the potential relationship with fruquintinib and M11 
plasma concentrations. 
• 
To explore the relationship between fruquintinib exposure and endpoints for efficacy and safety. 
• 
To evaluate quality of life (QoL) as assessed by using European Organisation for Research and 
Treatment of Cancer (EORTC) QLQ-C30: cancer-specific; and EQ-5D-5L questionnaires. 
• 
To assess resource utilization (for example, hospitalizations, concomitant medications). 
 
Exploratory Objective 
• 
To assess potential predictive biomarkers of response to fruquintinib. 
Details of the study objectives and correspondent endpoints is provided in Table 1. 
Table 1. Objectives and Corresponding Endpoints 
Tier 
Objectives 
Endpoints 
Primary 
To evaluate the overall survival of  
fruquintinib plus BSC compared to placebo 
plus BSC in subjects with refractory mCRC 
OS 
Secondary 
To evaluate progression-free survival  of 
fruquintinib plus BSC compared to placebo 
plus BSC 
PFS 
To evaluate the objective response rate, 
disease control rate, and duration of response  
• ORR 
• DCR 
• DoR 


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Tier 
Objectives 
Endpoints 
To assess the safety and tolerability of 
fruquintinib plus BSC compared to placebo 
plus BSC 
Safety including treatment-emergent 
adverse events (TEAEs), serious 
adverse events (SAEs), deaths, ECG’s, 
and clinical laboratory abnormalities 
To characterize the PK profile of fruquintinib in 
subjects with refractory mCRC 
Observed plasma concentrations, 
estimated population PK and exposure 
parameters of fruquintinib and M11 
To evaluate the effect of fruquintinib on 
cardiac repolarization, as detected by 
changes in electrocardiogram (ECG) QTc 
intervals, and the potential relationship with 
fruquintinib and M11 plasma concentrations 
QTc interval and plasma concentrations 
of fruquintinib and M11 at specified time 
points  
To evaluate the relationship between 
fruquintinib exposure and endpoints for 
efficacy and safety 
Parameters describing exposure-
response with efficacy (e.g., OS) and 
safety (e.g., adverse events [AEs]) 
endpoints 
To evaluate quality of life (QoL) as 
assessed by using QLQ-C30: cancer specific; 
and EQ-5D-5L questionnaires 
Changes in health status (QLQ-C30: 
cancer specific; and EQ-5D-5L) 
To assess resource utilization (for example, 
hospitalizations, medications) 
Resource utilization including all 
concomitant medications, days in 
hospital 
Exploratory To assess potential predictive biomarkers of 
response to fruquintinib 
• Change from baseline in circulating 
tumor DNA (ctDNA) 
• Change from baseline in tumor 
markers (carcino-embryonic antigen 
[CEA]) 
• Pharmacogenomics 
 
 
 


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Study Details/Design 
 
Brief Description 
The study is a global, randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial to 
compare the efficacy and safety of fruquintinib plus BSC versus placebo plus BSC in subjects with mCRC.  
Approximately 687 subjects are to be randomized in a 2:1 ratio to either the fruquintinib plus BSC treatment 
group or the placebo plus BSC treatment group. 
Randomization is stratified by the following factors: 
• 
Prior therapy with trifluridine/tipiracil (TAS-102) versus regorafenib versus both trifluridine/tipiracil 
(TAS-102) and regorafenib. 
• 
RAS (rat sarcoma) status (wild type versus mutant). 
• 
Duration of metastatic disease (≤18 months versus >18 months). 
Subjects are to receive study treatment, with each 4-week cycle consisting of 3 weeks of daily oral study 
medication and 1 week of study treatment interruption (3 weeks on/1 week off).  Tumor evaluation is 
performed by imaging (computed tomography [CT] or magnetic resonance imaging [MRI] scan) every 8 
weeks until there is progressive disease (PD), death, new anti-cancer treatment, study treatment 
discontinuation or study completion, whichever comes first.  Safety parameters include assessment of 
adverse events (AE), laboratory tests, vital signs, ECG, Echocardiogram (ECHO), physical examination, 
Eastern Cooperative Oncology Group (ECOG) performance status, EORTC QLQ-C30 and EQ-5D-5L 
questionnaires.  Post-discontinuation anti-tumor treatment and survival follow-up after PD is also recorded. 
 
Subject Selection 
The study is conducted at approximately 140 international study sites with a study population of subjects 
≥18 years of age with histologically and/or cytologically documented metastatic colorectal adenocarcinoma 
who progressed on, or were intolerant to, all standard chemotherapies and relevant biologics and TAS-102 
and/or regorafenib. 
 
Inclusion Criteria 
Refer to Section 5.3 Inclusion Criteria of the study protocol. 
 
Exclusion Criteria 
Refer to Section 5.4 Exclusion Criteria of the study protocol. 
 
Statistical Hypothesis  
This study is designed to demonstrate superiority of fruquintinib plus BSC (fruquintinib arm) over placebo 
plus BSC (placebo arm) in prolonging OS for subjects with refractory mCRC. The study is designed to test 
the null hypothesis H0: λ=1.0 versus the alternative hypothesis Ha: λ < 1.0, where λ is the hazard ratio 
(treatment arm/placebo arm). 


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Determination of Sample Size 
With regards to the study, the total sample size and number of OS events required for efficacy assessment 
in the intent-to-treat population is calculated based on the following assumptions: 
• 
A one-sided significance level of 0.025; 
• 
Assuming an OS hazard ratio (HR) of 0.73 (fruquintinib arm/placebo arm), this sample size yields 
approximately 90% statistical power to detect superiority of the fruquintinib arm over placebo arm.  
If the true median OS for the placebo arm is 5 months, then the HR of 0.73 corresponds to median 
OS of 6.8 months in the fruquintinib arm (median OS improvement of 1.8 months).   
• 
An enrollment rate of 30 subjects per month during the first 3 months and 50 subjects per month 
thereafter; 
• 
Yearly dropout rate of 10%; 
• 
Randomization ratio = 2:1 (fruquintinib arm/placebo arm); 
• 
Data maturity = 70%; 
• 
One interim futility analysis when 1/3 of the total number of OS events (i.e., 160 OS events) have 
occurred, the Lan-DeMets spending function is used in the calculation. 
Under the premise of these assumptions, approximately 687 subjects are to be randomized to this study 
over approximately 15 months in this study.  OS is to be analyzed when 480 OS events have been 
observed, which is expected to occur in approximately 7 months after the end of enrollment.  EAST version 
6.5 was utilized for the calculation. 
In clinical practice, TAS-102 is used more commonly than regorafenib.  To ensure that the subject 
population is representative of clinical practice, post-regorafenib (regorafenib or both trifluridine/tipiracil 
(TAS-102) and regorafenib) subjects are to be capped at 344.  This ensures that at least 50% of the subjects 
are post-TAS.   
Subjects are considered in post-TAS-102 or post-regorafenib populations if they have received at least one 
dose of either agent, respectively, prior to entering the study.  Based on the similar mechanisms of action 
between regorafenib and fruquintinib, it is to be of clinical interest to evaluate the magnitude of benefit in 
each of the populations when compared to the intent-to-treat population. 
 
Treatment Assignment and Blinding 
The study subject, investigators, and study site personnel are to remain blinded to all randomization 
assignments throughout the study.  The sponsor’s study director, study monitor, and any other sponsor and 
Syneos Health personnel who are in regular contact with the study site are to remain blinded to all subject 
randomization assignments, except sponsor pharmacovigilance personnel for the purpose of 
Investigational New Drug (IND) safety reports.  Treatment is allocated using Interactive Web Response 
System (IWRS) randomization strategy and procedure defined in the IWRS manual.    


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Unblinding can occur in emergency cases.  If unblinding is required for treatment of a subject for an SAE, 
the investigator must first contact the sponsor’s medical monitor before unblinding, and then unblind the 
subject using the IWRS.  Once unblinded, the subject should discontinue the treatment but continue to be 
followed for safety and efficacy.  The investigator should record the event in the source document. 
The interim futility analysis maintains blinding at IDMC meetings during the Open Sessions following the 
procedures described in Section 18, Content of Open and Closed Sessions of the latest version of the 
IDMC Charter. 
 
Administration of Study Medication 
Fruquintinib (HMPL-013) capsule 5 mg is administered orally (PO) once daily (QD), 3 weeks on, 1 week off 
(4-week cycles).  Subjects are randomized into either fruquintinib in combination with BSC group (treatment 
group) or placebo in combination with BSC group (control group) in a 2:1 ratio (Figure 1). 
If study treatment dose adjustment is required, the site must log into the IWRS, adjust the dose, reassign 
the drug serial number, and dispense new study treatment dose (in 1 mg capsules) to the subject.  If the 
dose is adjusted a second time, i.e., from 4 mg QD to 3 mg QD, the site must log into the IWRS and record 
the second dose adjustment.  On this occasion, it is not necessary to reassign a new drug serial number. 
If tumor evaluation shows PD during the previous cycle and new drug has been dispensed, the subject 
must return all unused study treatment on the 30-day safety visit after end of treatment (EOT). 
• 
Treatment group: fruquintinib 5 mg PO, QD, plus BSC, 3 weeks on/ 1 week off, every 4-week cycle. 
• 
Control group: Matching placebo 5 mg PO, QD plus BSC, 3 weeks on/ 1 week off, every 4-week 
cycle. 
Subjects are allowed to have no more than 2 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.  Once a dose has been reduced, 
it cannot be re-escalated.  The dose reduction sequence by starting dose is shown in Table 2 below.   
Table 2.  Dose Modification Sequence by Starting Dose 
Dose Level 0* 
(Original dose) 
5 mg QD 3 weeks on, 1 week off 
fruquintinib of 5 mg, 1 capsule, or 1 
capsule of the matching placebo 
Dose Level -1* 
(the 1st dose reduction) 
4 mg QD 3 weeks on, 1 week off 
fruquintinib of 1 mg, 4 capsules, or 4 
capsules of the matching placebo 
Dose Level -2* 
(the 2nd dose reduction) 
3 mg QD 3 weeks on, 1 week off 
fruquintinib of 1 mg, 3 capsules, or 3 
capsules of the matching placebo 
 
Reasons for dose modifications includes the following:  
• 
Hematologic and non-hematologic toxicity. 


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• 
Palmar-Plantar Erythrodysethesia. 
• 
Proteinuria. 
• 
Hypertension. 
• 
Decreased platelet count. 
• 
Hemorrhage at any site. 
• 
Abnormal live function. 
Dose modification guidelines are detailed in Section 7.5.6 of the protocol. 
 
Study Procedures and Flowchart 
The study contains the following procedures. 
• 
Screening Period: This period contains two visits windows of -28 to -1 days and -7 to -1.  
• 
Study Treatment Period: This period contains treatment cycles, with a visit window of +/- 3 days for 
each scheduled visit starting at Cycle 2 day 1.  
o 
Cycle 1 includes cycle 1 day 1 and cycle 1 day 21 visits;  
o 
Cycle 2 includes cycle 2 day 1 and cycle 2 day 21 visits; 
o 
Cycle 3 includes cycle 3 day 1 and cycle 3 day 21 visits;  
o 
Cycle 4 and beyond include cycle 4 day 1, cycle 5 day 1, etc.   
• 
Follow-Up: This period contains the following. 
o 
Post treatment: 7 days after last dose with a visit window of +/- 3 days,  
o 
Safety Follow-up: 30 days after EOT visit with a visit window of +/- 7 days, and 
o 
Survival Follow-up: 12 weeks from EOT visit with a visit window of +/- 14 days. 
o 
EOT: last non-missing assessment during the treatment period (treatment period is from 
the date of the first study drug administration until 37 days after last dose) 
The protocol activities include the following throughout the periods listed above.  
• 
Informed Consent. 
• 
Demographics. 


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• 
Medical History, Disease History, and molecular characterization of RAS, B-Raf proto-oncogene 
(BRAF), Microsatellite Instability (MSI)/ Mismatch Repair (MMR) status. 
• 
Prior and Concomitant Medication/Concomitant Procedure. 
• 
Comprehensive Physical Examination. 
• 
Limited Physical Examination. 
• 
ECOG. 
• 
Vital Signs. 
• 
Hematology. 
• 
Blood Chemistry. 
• 
Blood amylase and lipase. 
• 
Coagulation. 
• 
Thyroid Function. 
• 
Urinalysis. 
• 
Serum Pregnancy Test. 
• 
Urine Pregnancy Test. 
• 
12-lead ECG. 
• 
ECHO/Multigated acquisition (MUGA). 
• 
Tumor Evaluation/Imaging. 
• 
Tumor Markers. 
• 
Circulating Tumor DNA, excluded from Japanese Specific Addendum.  
• 
PK Plasma Sampling. 
• 
Subject Randomization, excluded from Japanese Specific Addendum. 
• 
Drug/Dispense/Return. 
• 
Study Treatment. 
• 
Adverse Event. 


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• 
Survival Follow-up. 
• 
EORTC  QLQ-C30 Questionnaire, excluded from Japanese Specific Addendum. 
• 
EQ-5D-5L Questionnaire, excluded from Japanese Specific Addendum. 
Details of study procedures can be found in the following tables within the protocols. 
• 
Table 1. Schedule of Events. 
• 
Table 2. Schedule of Events for Pharmacokinetic and Electrocardiogram Evaluations for the First 
Approximately 120 Subjects, and  
• 
Table 3.  Schedule of Events for Pharmacokinetic and Electrocardiogram Evaluations for Subjects 
Enrolled After the First Approximately 120.  
The study schematic is presented in Figure 1. 
Figure 1.  Study Design Schema 
 


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Endpoints   
 
Primary Efficacy Endpoint 
The primary endpoint of the study is OS, defined as the time (months) from date of randomization to death 
from any cause. That is, OS is calculated as (date of death or last known alive – date of randomization + 
1)/30.4375.   Subjects without report of death at the time of analysis are censored at the date last known 
alive.  Subjects lacking data beyond the date of randomization have their survival time censored at the date 
of randomization.  OS will not be censored if a subject receives subsequent anticancer treatments after 
discontinuation of the study treatments. Date of last known alive defined in Section 7.2.4 and date of death 
is defined in Section 7.2.5 of the SAP. 
 
Secondary Efficacy Endpoints 
• 
Key secondary efficacy endpoint: PFS.  
PFS is defined as the time (months) from randomization until the first radiographic documentation of 
objective progression as assessed by investigator using Response Evaluation Criteria In Solid Tumors 
(RECIST) v1.1, or death from any cause. More specifically, PFS will be determined using all the assessment 
data up until the last evaluable visit prior to or on the date of (i) disease progression as defined by RECIST 
Version 1.1 or death; or (ii) withdrawal of consent; or (iii) receiving subsequent anti-cancer therapy, 
whichever is earlier. Subjects without report of PD or death from any cause at the time of analysis are 
censored as described in Table 3 below. 
The PFS time will always be derived based on scan dates not tumor assessment dates. If PD is documented 
between scheduled visits, the actual date of documented progression will be used as an uncensored value 
in the analysis of PFS. RECIST assessments/scans contributing towards a particular visit may be performed 
on different dates. The following rules are applied: 
1. Date of progression is determined based on the earliest of the dates of the component that triggered 
the progression. 
2. When censoring a subject for PFS, the subject is censored at the latest of the dates contributing to 
a particular overall visit assessment. 




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• 
The additional anti-tumor secondary efficacy endpoints include ORR, DCR, and DoR. The 
derivation of the best overall response is detailed in Section 9.2.3.  
o 
ORR is defined as the proportion of subjects achieving a best overall response of confirmed 
complete response (CR) or partial response (PR), per RECIST v1.1, as determined by the 
investigator. 
Objective response rate (ORR) will be calculated using two different ways: 
§ 
Scenario #1: ORR will be calculated using a strict interpretation of RECIST Version 
1.1. Objective response will be derived as no/yes variable. Subjects with a BOR of 
confirmed CR or PR will be assigned ‘Yes’. Subjects not having a BOR of 
confirmed CR or PR will be assigned ‘No’. Hence, ORR is defined as the proportion 
of subjects with objective response being “Yes”.  
§ 
Scenario #2: ORRUNCONF RMED will be calculated using all responses regardless of 
confirmation. Objective response will be derived as no/yes variable.  Subjects with 
a BOR of confirmed CR, confirmed PR, unconfirmed CR or unconfirmed PR will 
be assigned “Yes”.  All subjects with other BOR values will be assigned “No”.  
Hence, ORRUNCONF RMED is defined as the proportion of subjects with objective 
response being “Yes”. 
o 
DCR is defined as proportion of subjects achieving a best overall response of confirmed 
CR, PR, or SD (for at least 7 weeks), within each treatment group, per RECIST v1.1, as 
determined by the investigator.  To be qualified for SD, the duration of SD should last for 
at least 7 weeks. 
o 
DoR is defined as the time (months) from the first occurrence of PR or CR by RECIST 
Version 1.1, until the first date that progressive disease is documented by RECIST Version 
1.1, or death, whichever comes first. Only those subjects with confirmed responses of CR 
or PR will be included in this analysis. Censoring will follow the rules outlined for PFS in 
Table 3 in this section for those subjects who do not have censored DoR, it is calculated 
as (date of death or PD or last assessment – date of first occurrence of confirmed CR or 
PR + 1)/30.4375. 
• 
Changes in health status (QLQ-C30: cancer specific; and EQ-5D-5L). 
• 
Resource utilization including all concomitant medications, days in hospital. 
 
Exploratory Endpoints 
• 
Change from baseline in circulating tumor DNA (ctDNA), analysis to be included in a separate 
document. 
• 
Change from baseline in tumor markers (carcino-embryonic antigen [CEA]). 
• 
Pharmacogenomics,  analysis to be included in a separate document. 


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Safety Endpoints 
• 
Safety including treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), 
deaths, ECG’s, and clinical laboratory abnormalities. 
 
Pharmacokinetic Endpoints 
• 
Observed plasma concentrations, estimated population PK and exposure parameters of 
fruquintinib and M11. 
• 
QTc interval and plasma concentrations of fruquintinib and M11 at specified time points.  
 
Pharmacodynamic Endpoints 
• 
Parameters describing exposure-response with efficacy (e.g., OS) and safety (e.g., AEs) 
endpoints. 


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Analysis Populations 
 
Screened Population 
The Screened population includes all subjects who signed informed consent form (ICF).   
 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population includes all randomized subjects.  Subjects are analyzed by treatment 
group as randomized.  The ITT population is the primary population for evaluating all efficacy endpoints 
and subject characteristics.   
 
Safety Population 
The Safety population includes all randomized subjects who received at least one dose of study treatment.  
Subjects in this population are analyzed according to the treatment they actually received.  This population 
is used for all safety analyses.   
 
Pharmacokinetic (PK) Population 
The PK population includes all subjects who receive at least one dose of study treatment and have at least 
one post-dose PK sample obtained and analyzed.  The PK population is used for tabulation of fruquintinib 
and M11 concentrations from PK plasma samples. 
 
Non-COVID-19 Impacted Population 
The Non-COVID-19 Impacted population includes all randomized subjects who do not have any 
Coronavirus 2019 (COVID-19)-related protocol deviations.  The Non-COVID-19 Impacted population is 
used for sensitivity analyses for the primary and secondary efficacy endpoints. 
 
Per Protocol (PP) Population 
The per-protocol (PP) analysis set will include only those subjects in ITT who have no major protocol 
deviations (as described in Section 6.7) and who received the treatment to which they were randomized or 
assigned. For subjects who took the wrong treatment for part of the study, their data will be excluded from 
the PP population. PP population is used for sensitivity analyses of OS and PFS, and may be used to 
analyze selected endpoints to test the robustness of results. The criteria for inclusion in the PP subset will 
be finalized and documented prior to unblinding of the study. 
 
Protocol Deviations 
Protocol deviations are recorded in the clinical trial management system (CTMS) as outlined in the latest 
version of the Protocol Deviation and Non-compliance Management Plan.  Protocol deviations are 
categorized as minor or major before database lock. 
Protocol deviations including deviations that are related to COVID-19 are recorded in the CTMS as outlined 
within the Protocol Deviation and Non-Compliance Plan.   


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General Aspects for Statistical Analysis 
 
General Methods 
• 
Summaries are presented for each treatment group and overall for subjects’ disposition, 
demographics and baseline characteristics, medical history, disease history, prior medications, and 
concomitant medications tables.  Summaries are presented for each treatment group for other 
tables. 
• 
All data listings that contain an evaluation date contains a relative study day as defined in Section 
7.2.3. 
• 
For categorical variables, summary tabulations of the number and percent of subjects within each 
category of the parameter as seen on the electronic case report form (eCRF) are to be presented.  
Percentage calculations are based on the number of subjects within treatment group and overall, 
unless otherwise specified.  Percentages are rounded to 1 decimal place, unless otherwise 
specified.  The category Missing is included in subject-level demographics and disease history 
tables when the count is greater than zero for missing subjects.  
• 
For continuous variables, the number of subjects, mean, standard deviation (StdDev), median, 
lower quartile (Q1), upper quartile (Q3), minimum, and maximum values are presented.  The 
precision of summary statistics, unless otherwise specified, is as follows:  
o 
Minimum, maximum: same decimal places as the raw data. 
o 
Mean, median, Q1, and Q3 : 1 more decimal place than the raw data. 
o 
Standard deviation, standard error:  2 decimal places more than the raw data.  
• 
For results from a mixed model repeated measures, least-square (LS) mean and LS mean 
difference are presented with one decimal place, and standard error (SE) of LS means and SE of 
LS mean difference are presented with two decimal places.   
• 
Comparison between treatment groups are calculated as fruquintinib plus BSC versus placebo plus 
BSC. 
• 
Two-sided 95% confidence intervals (CI) are provided and rounded to 2 decimal places, unless 
otherwise specified. 
• 
2-sided p-values are presented with 3 decimal places. 
• 
Any rounding will be done after all calculations are made. 
 
Key Definitions 
 
First Dose Date 
First dose date is defined as the day of first dose of study treatment received after randomization. 


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Last Dose Date 
Last dose date is defined as day of the last dose of study treatment.   
For subjects ongoing for the treatment period at time of analysis prior to database lock, the last dose date 
is the date of the most recent study visit in the database for that subject. 
 
Study Day 
The study day is determined relative to the date of first dose of study treatment, unless otherwise specified.  
The day of the first dose of study treatment is defined as study day 1.  The day prior to the first dose of 
study treatment is study day -1.  There is no study day 0. 
For events that occur before the first dose of study treatment,  
study day = date of the event – first dose date;  
for events that occur on or after the first dose of study treatment,  
study day = date of the event – first dose date + 1. 
 
Date of Last Known Alive 
The date of last known alive is defined as the last alive date of contact from the Survival Follow-up page on 
the eCRF.  For subjects ongoing at time of analysis, the date of last known alive is the date of the most 
recent study visit in the database for that subject. 
More specifically, the last known alive date will be derived for subjects not known to have died at the 
analysis cut-off date using the latest date (including complete and partial date with Month and Year 
information) among the following data: 
- 
All assessment dates (e.g. laboratory, vital signs assessments, ECG, ECOG, performance status 
assessment, tumor assessment dates etc.). 
- 
Medication dates including study medication, concomitant medications, anticancer therapies 
administered after study treatment discontinuation. 
- 
Adverse events start and end date, and the date of adverse event becoming serious. 
- 
Date latest known alive collected during the survival follow-up. 
- 
Randomization date.   
 
Date of Death 
Date of death is defined as the date of death from the Death Detail page on the eCRF.  Date of death is 
cross-checked with AEs where outcome is ‘Fatal’, if applicable. In rare case, if year and month of death 
date are known but the day is unknown, day will be imputed as 15. For example, if a subject is reported to 
die on Dec2017, the death date will be imputed as 15 Dec2017. 


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Baseline and Change from Baseline  
For all change from baseline variables, the baseline is defined as the last non-missing assessment prior to 
or on the day of randomization, and must be prior to the first administration of study treatment, including 
scheduled and unscheduled visits, unless otherwise specified.  Hence, change from baseline = post-
baseline value – baseline value.  
The baseline value for analyses of qualitative parameters (e.g., normal/abnormal) is defined as the last 
evaluation prior to or on the day of randomization, and must be prior to the first administration of study 
treatment. 
 
Treatment-emergent Events  
An AE is considered a TEAE if the onset date is on or after the start of study treatment or if the onset date 
is missing, or if the AE has an onset date before the start of study treatment but worsened in severity after 
the study treatment until 37 days after the last dose of study treatment or a new treatment of anti-tumor 
therapy, whichever is earlier. After this period, treatment-related SAEs will also be considered as TEAEs. 
AEs with an unknown/not reported onset date will also be included. 
 
Missing Data 
All available data of the subjects who withdraw from the study for any reasons is analyzed.  Missing data is 
assumed to be missing at random.  Category ‘Missing’ is displayed for qualitative assessments, where 
applicable. 
For demographic and baseline characteristics, each variable will be analyzed and/or summarized using the 
available data. Unless otherwise specified, subjects with missing data will be excluded only from analyses 
for which data are not available. 
There is no imputation of missing data for the analysis purpose, unless otherwise stated. 
 
Imputation of the Missing Dates 
Imputation rules described in this section are applicable to partial dates of AEs, concomitant medications, 
anti-cancer therapy, primary diagnosis and metastatic disease diagnosis. However, imputation of missing 
AE and concomitant medication onset and stop dates will be used to determine the status of each AE and 
the prior/concomitant status of each medication, the imputed dates should not be shown in listings. 
Incomplete Start Date of AEs: 
- 
If the AE onset date is completely missing, the AE start date will be imputed as the reference start 
date (i.e. first dosing date); 
- 
If the AE onset date is partial missing, then  
§ 
If both the year and the month are available and the year and the month are the corresponding 
year and month of the reference start date, then the AE start date will be imputed as the 
reference start date;  


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§ 
If both the year and the month are available and the year and the month are not equal to the 
corresponding year and month of the reference start date, then the AE start date will be imputed 
as the 1st day of the month; 
§ 
If only the year is available and the available year is the corresponding year of the reference start 
date, then the AE start date will be imputed as the reference start date; 
§ 
If only the year is available, and the available year is not equal to the corresponding year of the 
reference start date, then the AE start date will be imputed as the January 1st of the year. 
Incomplete Stop Date of AEs:  
AE end date will be imputed as below for the partial date only, the imputation rules only apply when the 
AE is not ongoing: 
- 
If both the year and the month are available, AE end date will be imputed as the last day of the 
month; 
- 
If only the year is available, AE end date will be imputed as the December 31st of the year. 
If the imputed AE end date is after the death date for subjects is know to be dead at end of study or cut 
off date, the date of the death will be used for AE end date. If the imputed AE end date is after the last 
known alive date for subjects alive at the end of study or cut off date, the date of last known alive date will 
be use for AE end date.  
For AE continuing at the cut-off date, the end date will not be imputed and instead will be reported as 
“ongoing”. 
Concomitant Medication/Procedure/Surgery with onset/end dates  
Concomitant Medication/Procedure/Surgery with onset/end dates that are partially/completely missing will 
be imputed as follows. 
(i) start date: 
- 
1st day of the month will be used to impute the start date if only the day is missing. 
- 
January 1st will be used to impute the start date if both the day and month are missing. 
- 
If the date is completely missing, then the day before the reference start date will be imputed as the 
start date. 
(ii) end date: 
- 
Last day of the month will be used to impute the end date if only the day is missing. 
- 
December 31st of the year will be used to impute the end date if both the day and month are missing. 
- 
If the date is completely missing, assign ‘continuing’ status to the end date. 
If the imputed end date is after the death date or last known alive date, the date of the death or last known 
alive date will be imputed as the Concomitant medication/procedure/surgery end date. 


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Subsequent Anti-cancer Therapy Date (collected during Survival Follow-Up) 
When a partial new anti-tumor therapy start date is reported, every effort will be made to identify the 
precedence relationship of starting date of new anti-tumor therapy relative to the reference end date (i.e. 
last dose date). Below rules will be used: 
- 
If the date is completely missing, new anti-tumor therapy date will be imputed as reference end date + 
1; 
- 
If only the day is missing, 15th day will be imputed as the new anti-tumor therapy date; 
- 
If both the day and the month are missing, then July 1st will be imputed as the new anti-tumor therapy. 
If the imputed start date is prior to the reference end date for subjects, the reference end date + 1 will be 
used as the imputed start date of the subsequent anti-cancer therapy.   
Primary Diagnosis Date and Metastatic Disease Diagnosis Date 
When a partial date of primary diagnosis for advanced colorectal cancer or a partial date of first 
metastatic disease diagnosis is reported, the below imputation rules will be used: 
- 
If the date is completely missing, no imputation will be conducted; 
- 
If only the day is missing, 15th day will be assigned; 
- 
If both the day and the month are missing, then July 1st will be assigned. 
 
 
Visit Windows 
It is expected that there will be a variation between subjects in the actual number of study days from the 
start of administration of study drug within each cycle - defined as Day 1 - to the dates that the scheduled 
visits occurs. To handle this, for tables and figures where data are grouped by visit, assessments will be 
categorized using visit windows based on study days (relative to the Day 1 of each cycle). The visit-window 
mapping is described in Table 4. Visit-based summaries will be based on the windowed visits. All data, 
whether or not within the visit windows, will be presented in subjects listings.  
For windowed visits during the treatment cycles, if more than 1 visit occurs during a visit window, the visit 
closest to the scheduled day will be assigned to the windowed visit. If two visits are equidistant from the 
scheduled day, the later visit will be assigned to the windowed visit. If there are multiple assessments on 
the same day, the worst case will be used.  For the treatment completion visit, the last assessment in the 
window will be included in the summary.  
For a subject who prematurely discontinues the study, the premature visit will be slotted accordingly. The 
window for post treatment visit will be "last dose date of last cycle to last dose date of last cycle + 10 days" 
and the window for safety follow-up visit will be “Last dose date of last cycle + 11 days to last dose date of 
last cycle + 37 days”.




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Pooling of Centers 
Data from all study centers is combined for analysis.   
 
Outliers 
Data Management are to be notified of outliers, if identified during TLF reviews, for query.  Syneos Health 
Biostatistics and Programming do not change or remove outliers from the data.  
 
Data Sources 
Randomization numbers, stratification factors, and treatment assignments derived from IWRS are 
reconciled with the dummy randomization schedule prior to database lock and unblinding, and with the 
actual randomization schedule after database lock and unblinding. 
After the study is unblinded, fruquintinib and M11 concentrations from PK plasma samples are provided by 
Covance and mapped onto SDTM PC domain.  Syneos Health then transfers SDTM PC domain to Certara. 
Protocol deviations are recorded in the clinical trial management system and provided as an Excel 
document.  Protocol deviations are to be reviewed prior to database lock.  
CRF data are extracted from Rave database. 
Laboratory data are provided by local labs. 
Imaging data are provided by eResearchTechnology, Inc. (ERT). 
Interactive Response Technology (IRT) data are provided by Endpoint. 
Quality of life data using EORTC QLQ-C30 and EQ-5D-5L questionnaires are collected via Electronic 
Clinical Outcome Assessment (eCOA) and provided by ERT.  
 
 


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Demographic, Other Baseline Characteristics and Medication 
 
Subject Disposition and Withdrawals 
The following summaries will be presented for all enrolled subjects to reflect the subject disposition: 
- 
Number of subjects who signed the informed consent.  
- 
Number of screen failures. 
- 
Reason for screen failure. 
- 
Number of subjects who are randomized.  
- 
Number of subjects who do not receive study drug. 
- 
Number of subjects who received study drug. 
- 
Subjects still on treatment (i.e., missing end-of treatment information). 
- 
Reason for study drug discontinuation (for study drug). 
- 
Number of subjects going into Survival follow-up if there are any assessments after the last dose 
date + 37 days.  
- 
Number and percentage of subjects still on study (i.e., missing end-of-study information). 
- 
Number and percentage of subjects who discontinued the study. 
- 
Reason for study discontinuation. 
A separate table will be presented for the ITT population to show the subjects included in each analysis set 
and proper reasons for exclusion from an analysis set.  
A separate table will be presented for the ITT population to show the concordance of randomization 
schedule stratification factors and CRF collected factors of prior therapy, duration of metastatic disease, 
and RAS status. The following summaries will be presented: 
- 
Number of subjects with all randomization schedule stratification factors concordant with CRF 
collected factors. 
- 
Number of subjects with at least one randomization schedule stratification factor discordant with 
CRF collected factors. 
o 
Number of subjects with discordance in prior therapy, duration of metastatic disease, and 
RAS status. 
- 
Prior therapy (Trifluridine/Tipiracil (TAS-102), Regorafenib, or Both Trifluridine/Tipiracil (TAS-102) 
and Regorafenib) based on randomization schedule stratification factors and prior therapy based 
on CRF collected factors. 
- 
Duration of metastatic disease (≤ 18 months, > 18 months) based on randomization schedule 
stratification factors, and duration of metastatic disease based on CRF collected factors. 
- 
RAS status (Wild Type, Mutant) based on randomization schedule stratification factors, and RAS 
status based on CRF collected factors. 
Subject discontinuation status and analysis population are also listed. 
 
Protocol Deviations 
Protocol deviations are summarized descriptively for subjects with at least 1 major protocol deviation and 
subjects with at least 1 minor protocol deviation for each treatment group and overall.  Each protocol 
deviation is also summarized descriptively within major and minor protocol deviations for each treatment 
group and overall of the ITT population.  A subject can have multiple major and/or minor deviations and 


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counted once per major and/or minor deviation. COVID-19-related protocol deviations are summarized 
descriptively for each treatment group and overall of the ITT population. 
A listing of protocol deviations, including COVID-19-related protocol deviations, is provided. 
 
Demographic and Baseline Characteristics 
The following parameters are summarized descriptively for each treatment group and overall for the ITT 
population. 
• 
Age (years) at ICF date, Age Categories (< 65 years, ≥ 65 years). 
• 
Sex (Female, Male); If female, Child Bearing Potential.  
• 
Race (American Indian or Alaskan Native, Asian, Black or African American, Native Hawaiian or 
Other Pacific Islander, White, Other, Multiple Races, Not Reported, Unknown). A subject can have 
multiple races and is summarized in the multiple race category.  
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown).  
• 
Region (North America, Europe, and Asia).  
• 
Baseline Height (cm). 
• 
Baseline Weight (kg). 
• 
Baseline body mass index [BMI] (kg/m2): it is calculated as Weight at Baseline (kg)/ [Height at 
Baseline (m)]2. 
o 
BMI category: < 18.5, ≥ 18.5 and < 24, ≥ 24 kg/m2. 
• 
Baseline ECOG Performance Status: 0, 1. 
Age (years) at ICF date is calculated by site personnel as the number of years from date of birth up to date 
of informed consent.  For example, 
Date of Birth 
Date of Informed 
Consent 
Original Age 
Age to be entered into 
IWRS 
01MAR1985 
01JUL2020 
35 years 4 months 
35 
01AUG1985 
01JUL2020 
34 years 11 months 
34 
 
A separate table presenting number and percentage of subjects by site and country will be produced for 
the ITT population. 


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Demographic data and baseline characteristics, randomization scheme and codes, informed consent data, 
and inclusion/exclusion criteria are listed by subject. 
 
Disease History  
History of colorectal cancer of the ITT population is summarized descriptively for each treatment group and 
overall for the following. 
• 
Time (months) since First Diagnosis of Colorectal Cancer: it is calculated as (date of randomization 
– date of first diagnosis of colorectal cancer)/30.4375.   
• 
Stage of Colorectal Cancer at First Diagnosis (stage I, stage II, stage III, stage IV). 
• 
Primary Tumor Location at First Diagnosis. 
o 
Colon.  
§ 
Colon – Right (cecum, ascending colon, and hepatic flexure). 
§ 
Colon – Left (splenic flexure, descending colon, transverse colon, sigmoid colon). 
§ 
Colon – Right and Left. 
§ 
Colon – Unknown. 
o 
Rectum. 
o 
Colon and Rectum. 
§ 
Colon – Right (cecum, ascending colon, and hepatic flexure). 
§ 
Colon – Left (splenic flexure, descending colon, transverse colon, sigmoid colon).  
§ 
Colon – Right and Left. 
§ 
Colon – Unknown. 
o 
Unknown. 
• 
Primary Site at First Diagnosis (Colon Left, Colon Right, Both Colon Left and Right, Colon 
Unknown, Rectum Only, Unknown). 
• 
Duration of Metastatic Disease (months): it is calculated as (date of randomization – date of 
diagnosis of metastasis disease)/30.4375. 
o 
Duration of Metastatic Disease Categories (≤ 18 months, > 18 months). 
• 
Prior Oncology Treatments (Prior Anti-cancer Medication, Prior Anti-cancer Radiotherapy, Prior 
Anti-cancer Procedures). 


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• 
RAS Status (Wild Type, Mutant). 
• 
BRAF Status (Wild Type, V600 E Mutation, Other). 
• 
Microsatellite/Mismatch Repair Status (Microsatellite stable [MSS] and/or proficient mismatch 
repair [pMMR], microsatellite instability-high [MSI-H] and/or deficient mismatch repair [dMMR]). 
• 
Prior Therapy with Trifluridine/Tipiracil (TAS-102) and/or Regorafenib (Trifluridine/Tipiracil (TAS-
102), Regorafenib, Both Trifluridine/Tipiracil (TAS-102) and Regorafenib). 
• 
Number of Prior Treatment Lines (≤ 3, > 3). 
• 
Number of Prior Treatment Lines for Metastatic Disease (≤ 3, > 3). 
• 
Prior Treatment with Vascular Endothelial Growth Factor (VEGF) Inhibitors (Yes, No). 
• 
Prior Treatment with Epidermal Growth Factor Receptor (EGFR) Inhibitors (Yes, No). 
• 
Prior Treatment with EGFR/VEGF Inhibitors.  
o 
No anti-VEGF and no anti-EGFR. 
o 
Anti-VEGF, or anti-EGFR, or both. 
§ 
Anti-VEGF and no anti-EGFR. 
§ 
Anti-EGFR and no anti-VEGF. 
§ 
Both anti-VEGF and anti-EGFR. 
• 
Prior Treatment with Immune Checkpoint Inhibitors for MSI-H/dMMR (Yes, No). 
• 
Prior Treatment with BRAF Inhibitors for BRAF V600E Mutation (Yes, No). 
• 
Liver Metastases at Baseline (Yes, No): obtained based on whether the liver organ was involved 
in the target and non-target lesion tumor scan assessment at the baseline. 
• 
Number of Metastatic Sites Other than Colon or Rectum (Single, Multiple): obtained based on the 
number of sites/organs was involved in the target and non-target lesion tumor scan assessment at 
the baseline. If only one is involved, that would be single; if more than one are involved, it will be 
multiple. For this derivation, paired organs, such as lung, kidney, ovaries, and lymph nodes will be 
considered as one organ, irrespective of the number of parts they may be made up of (i.e. tumors 
in the left lung and right lung will be counted as in one site).  
• 
Number of Metastatic Sites (Single, Multiple): obtained based on the number of sites/organs was 
involved in the target and non-target lesion tumor scan assessment at the baseline. If only one is 
involved, that would be single; if more than one are involved, it will be multiple. For this derivation, 
paired organs, such as lung, kidney, ovaries, and lymph nodes will be considered as one organ, 
irrespective of the number of parts they may be made up of (i.e. tumors in the left lung and right 
lung will be counted as in one site).   


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Medical History 
The conditions/diseases from medical history are those conditions/diseases that stopped prior to the study 
entry. Medical history is coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 
23.0 or higher.  Medical history is summarized using discrete summary statistics for each MedDRA system 
organ class (SOC) and preferred term (PT) by treatment group and overall for the ITT population.  Subjects 
with multiple medical histories in the same SOC or PT are counted only once for the respective SOC or PT.   
Summaries are ordered in alphabetical order of SOC and then, within an SOC, in decreasing frequencies 
by PT in overall column. If the frequencies tie, an alphabetic order will be applied.  
A listing of medical history by subject is provided.   
 
Prior and Concomitant Medication  
Prior and concomitant medications are classified by Anatomical Therapeutic Classification (ATC) 
therapeutic subgroup (Level 2) and PT using the World Health Organization Drug Dictionary (WHODD) 
version March2020 or later.  Medications with partial start or stop dates are imputed as described in Section 
7.3.1 prior to be determined whether the medication is prior or concomitant medication. 
Medications taken prior to the first dose of study treatment are denoted “Prior”. Medications taken prior to 
the first dose of study treatment and continuing beyond the first dose of study treatment or those 
medications started on or after the first dose of study treatment but no later than 37 days after the last dose 
are denoted “Concomitant”. Medication with start date/time being partially or completely missing will be 
assumed to be concomitant if it cannot be definitely shown that the medication did not occur during the 
treatment period. 
The use of prior and concomitant medications will be summarized using discrete summary statistics in each 
treatment group and overall for the ITT population.  If a subject took a specific medication multiple times or 
took multiple medications within a specific ATC or PT, the subject is counted only once for the respective 
ATC or PT. 
Summaries are ordered in alphabetical order of ATC and then, within an ATC , in decreasing frequencies 
by PT in overall column. If the frequencies tie, an alphabetic order will be applied. 
A listing of prior medication and concomitant medication by subject is provided. 
 
Concomitant Medical or Surgical Procedure 
Medical or surgical procedures that occurs after first dose date but no later than 37 days after the last dose 
are denoted “Concomitant”.  Concomitant medical or surgical procedures are classified using the MedDRA 
version 23.0 or higher.  
The use of concomitant medical or surgical procedures will be summarized using discrete summary 
statistics in each treatment group and overall for the ITT population.  If a subject took a specific medication 
multiple times or took multiple medications within a specific SOC or PT, the subject is counted only once 
for the respective SOC or PT. 


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Summaries are ordered in alphabetical order of SOC and then, within an SOC , in decreasing frequencies 
by PT in overall column. If the frequencies tie, an alphabetic order will be applied. 
A listing of concomitant medical or surgical procedures by subject is provided. 
 
Prior Oncology Treatment 
Prior oncology treatments including prior anti-cancer mediation, prior anti-cancer radiotherapy,  prior anti-
cancer procedure or surgery are summarized descriptively for each treatment group and overall for the ITT 
population.   
 
Prior Anti-cancer Medication 
Summary of prior anti-cancer medication for the ITT population includes the following: 
• 
The number and percent of subjects with at least one prior anti-cancer medication. 
• 
The total number of prior anti-cancer medications. 
• 
The number of prior lines of therapy and its categories of 0, 1, 2, 3, > 3.  
Prior anti-cancer medications are classified using the WHODD version March 2020 or later. 
The use of prior anti-cancer medications will be summarized by ATC and PT using discrete summary 
statistics in each line of therapy, each treatment group and overall for the ITT population. Within each line 
of therapy, a subject with multiple prior medication entries in the same ATC (PT) is only counted once within 
a particular ATC (PT).With each line of therapy, results are sorted by ATC followed by PT in decreasing 
order of frequency (by Total column). If the frequencies are tied, an alphabetic order is applied. 
 
Prior Anti-cancer Radiotherapy 
Summary of prior anti-cancer radiotherapy for the ITT population includes the following. 
• 
The number and percent of subjects with at least one prior anti-cancer radiotherapy. 
• 
The total number of prior anti-cancer radiotherapy. 
 
Prior Anti-cancer Procedure or Surgery 
Summary of prior anti-cancer procedure or surgery for the ITT population includes the following 
• 
The number and percent of subjects with at least one prior anti-cancer procedure or surgery. 
• 
The total number of prior anti-cancer procedures or surgery. 
The number and percent of subjects for each purpose of prior anti-cancer procedure or surgery. A 
subject with multiple occurrences of the same purpose will be counted only once for the purpose, 
and a subject with multiple purposes will be counted once in each category of purpose.   
Prior anti-cancer procedure or surgery is coded (MedDRA) version 23.0 or higher. 
The number and percent of subjects with each procedure or surgery will be summarized using discrete 


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summary statistics in each treatment group and overall for the ITT population by SOC and PT. If a subject 
had a procedure multiple times or had multiple procedures within a specific SOC or PT, the subject is 
counted only once for the respective SOC or PT. Summaries are ordered in alphabetical order of SOC and 
then, within an SOC, in decreasing frequencies by PT in overall column. If the frequencies tie, an alphabetic 
order will be applied. 
 
Extent of Exposure  
Exposure of study treatment is descriptively summarized for each treatment group as follows. Table 5 
details the parameters of study treatment exposure. 
Table 5. Extent of Exposure Parameters 
Parameter 
Definition  
Duration of Exposure (days) 
Last dose date of study drug – first dose date of study drug + 8. 
Number of Days with Recorded 
Dose  
Sum of days with recorded doses 
Number of Cycles Treatment 
Received 
Subjects are considered to have started a cycle if they have 
received at least one dose of any study treatment. 
Number of Cycles Treatment 
Received Categories 
1, 2, 3, 4, 5, 6 and > 6 
Cumulative Dose (mg) 
Sum of doses administered in all cycles. The total dose 
administered in each cycle is defined as: the sum of (number of 
5 mg capsules taken × 5 + number of 1 mg capsules taken)  
where number of capsules taken = total capsules dispensed – 
total capsules returned. 
Dose Intensity (mg/day) 
Cumulative Dose (mg) / Duration of Exposure (day) 
Target dose intensity is 3.75 mg 
Relative dose intensity (RDI) (%) 
100 * [Dose Intensity (mg/day) / (5 × 21/28 (mg/day))]   
RDI Categories 
< 50% 
50 - < 70% 
70 - < 90% 
90 - < 110% 
 ≥ 110%. 
Relative Dose (RD) (%) 
100 * [Cumulative dose (mg) / (5×21× number of cycles 
treatment received (mg)] 
 
RD Categories 
< 50% 
50 - < 70% 
70 - < 90% 
90 - < 110% 
 ≥ 110%. 
Percentage Intended Dose (PID) (%) 
100 * [(number of days with any recorded doses) /duration of 
exposure ] 
Target PID is 75%. 
Number of days with any recorded doses  
 
 


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The following summary for dose adjustment will be summarized for each treatment group. 
o 
Study drug is administered orally on days 1-21 of each 28-day cycle. A cycle will be called 
cycle delay if the duration of the cycle is longer than 28 days. However, the last cycle will 
not be evaluated for cycle delay. Reason for delay is not collected. Hence, the total number 
of cycle delay will be calculated for each subject.  Number of subjects with any cycle delay, 
and the frequency of cycle delay (0, 1, 2, 3, 4, 5, 6, > 6) will be summarized.  
o 
Number of subjects with any dose modification (including both drug interruption and dose 
reduction); 
o 
Frequency of dose modification: 0, 1, 2, 3, 4, 5, 6, > 6. 
o 
Drug interrupted (number of subjects experienced drug interruption and reasons for drug 
interruption; frequency of drug interruptions: 0, 1, ≥ 2). 
o 
Drug withdrawn (number of subjects experienced drug withdrawn and reasons for drug 
withdrawn). 
o 
Dose reduced (Number of subjects with any dose reduction and reasons for dose 
reduction; and frequency of dose reduction: 0, 1, 2, ≥ 3), also the dose reduction category 
below will be summarized.  
§ 
Reduction from 5mg to 4mg.  
§ 
Reduction from 4mg to 3mg.  
Study treatment accountability, study treatment administration are extent of exposure are listed by subject 
and visit. 


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Efficacy 
Efficacy analyses are based on the ITT population.  All secondary endpoints based on radiological 
assessments of tumor burden are derived from investigator assessment using Response Evaluation 
Criteria In Solid Tumors (RECIST) version 1.1 (Eisenhauer et al 2009). 
 
Primary and Key Secondary Efficacy Endpoint and Analysis 
 
Primary Efficacy Endpoint and Analysis 
The primary endpoint of the study is OS, defined in Section 5.1 of the SAP and calculated as (date of death 
or last known alive – date of randomization + 1)/30.4375. 
The Kaplan-Meier plots will be produced and the median, 25% and 75% percentile of time-to-event will be 
estimated using Kaplan-Meier method with their corresponding 95% CI which are calculated from a log-log 
transformation based on the method by Brookmeyer and Crowley (1982). Additionally, estimates will be 
provided for the survival probability along with their 95% CIs which are calculated using linear 
transformation based on the method by Brookmeyer and Crowley (1982) at selected landmarks, for 
example, at 3, 6, 9, 12, and 18 months. Example Statistical Analysis System (SAS) code is provided in 
Appendix 5. 
The two-sided p-value to test the treatment effect will be calculated using a stratified log-rank test 
accounting for randomization schedule stratification factors. Example SAS code is provided in Appendix 6. 
The hazard ratio (HR) between the 2 treatment groups (fruquintinib vs placebo), together with its 95% CIs, 
will be calculated from a stratified Cox proportional hazard model (i.e. accounting for randomization 
schedule stratification factors) in which the treatment group is the only covariate in the model. A HR < 1 
indicates a favorable clinical benefit from fruquintinib over the placebo group. Example SAS code is 
provided in Appendix 7. 
Duration of follow-up is defined as the time (months) from date of randomization to the last date known to 
be alive for subjects who have not yet been reported to have died by the time of the analysis. Subjects who 
were reported to have died by the time of the analysis are censored at date of death. That is, duration of 
follow-up is calculated as (date of death or last known alive – date of randomization + 1)/30.4375. The 
duration of follow-up will be calculated using the Kaplan-Meier method.  
All OS data are provided in listings by subject. 
 
Key Secondary Efficacy Endpoint and Analysis 
The key secondary efficacy endpoint is PFS. PFS is defined in Section 5.2 and calculated as (date of death 
or radiographic PD or last assessment – date of randomization + 1)/30.4375. 
The number and percent of subjects who had progression-free events, the number and percent of 
subjects censored, and reasons for censoring are presented for each treatment group.  Reasons for 
censoring include the following. 
a. No baseline nor post-baseline assessment 


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b. No death nor PD  
c. Drop-out before end of study 
d. New anti-tumor therapy started prior to PD 
e. Death or PD occurred after two or more consecutive missed assessment 
The Kaplan-Meier plots will be produced and the median, 25% and 75% percentile of time-to-event will be 
estimated using Kaplan-Meier method with their corresponding 95% CI which are calculated from a log-log 
transformation based on the method by Brookmeyer and Crowley (1982). Additionally, estimates will be 
provided for the survival probability along with their 95% CIs which are calculated using linear 
transformation based on the method by Brookmeyer and Crowley (1982) at selected landmarks, for 
example, at 3, 6, 9, 12, and 18 months.  
The two-sided p-value to test the treatment effect will be calculated using a stratified log-rank test 
accounting for randomization schedule stratification factors. The hazard ratio (HR) between the 2 treatment 
groups (fruquintinib vs placebo), together with its 95% CIs, will be calculated from a stratified Cox 
proportional hazard model (i.e. accounting for randomization schedule stratification factors) in which the 
treatment group is the only covariate in the model. A HR < 1 indicates a favorable clinical benefit from 
fruquintinib over the placebo group. 
A Kaplan-Meier plot of the time to censoring, where the censoring indicator of the primary PFS analysis is 
reversed, will be presented.  
All PFS data is provided in listings by subject. 
 
Multiplicity Adjustments 
The clinical trial evaluates the objectives defined in terms of the comparison of fruquintinib + BSC versus 
placebo + BSC on the primary and key secondary efficacy endpoints in Section 9.1.1 and Section 9.1.2. 
The multiplicity problem includes 2 hypotheses of no effect: 
• 
Hypothesis 𝐻!. Comparison of fruquintinib + BSC versus placebo + BSC for OS. 
• 
Hypothesis 𝐻". Comparison of fruquintinib + BSC versus placebo + BSC for PFS. 
The 2-sided p-values for the 2 comparisons will be used for the multiple testing procedure. Example SAS 
code in Appendix 6. 
A fixed-sequence (hierarchical) testing procedure is used to control the overall type I error rate at 0.05.  If 
the resulting 2-sided p-value from the analysis of primary endpoint OS is ≤ 0.05, then, a superiority test of 
for PFS will be conducted at the two-sided significance level of 0.05.  
 
Sensitivity Analysis for OS and PFS 
The following sensitivity analyses for OS and PFS will be performed, in which the p-value will always be 
obtained from the stratified log-rank test and the hazard ratio (HR) between the 2 treatment groups 
(fruquintinib vs placebo), together with its 95% CIs will be calculated from the model in Section 9.1.1 and 
Section 9.1.2 for OS and PFS, respectively, unless otherwise specified.  


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- 
using ITT population, unstratified Cox proportional hazard model in which the randomization 
schedule stratification factors and treatment group are included in the model as covariates; 
- 
using ITT population, stratified analysis for both log-rank test and Cox proportional hazard model, 
but using the stratification factors collected on the case report form (CRF); 
- 
using ITT population, unstratified Cox proportional hazard model in which the stratification factors 
collected on the CRF and treatment group are included in the model as covariates; 
- 
using Non-COVID-19 Impacted population, 
- 
using ITT population, subjects with primary cause of death attributed to COVID-19 will be censored 
at the last known alive date prior to the death date for OS; and will follow the censoring rule defined 
in Table 3 for PFS and will use the data prior to the date of death.  
- 
using PP population 
- 
using PP population, unstratified Cox proportional hazard model in which the randomization 
schedule stratification factors and treatment group are included in the model as covariates;  
- 
using PP population, stratified analysis for both log-rank test and Cox proportional hazard model 
using the stratification factors collected on the CRF; 
- 
using ITT population, multivariate Cox’s proportion hazard model with treatment and randomization 
schedule stratification factors (i.e. prior therapy, RAS status, and duration of metastatic disease) 
included in the model as covariate and, adjust for key prognostic factors using stepwise selection 
process with level of enter alpha= 0.15 and level of remove alpha= 0.15.  Key prognostic factors 
include a set of potential prognostics/predictive factors as described in Section 9.1.5. 
An additional sensitivity analyses for OS will be performed 
- 
using ITT population, based on the first exact 480 deaths and the additional dead subjects will be 
censored at the date of last known alive before their death. 
- 
using ITT population, subjects who take the subsequent anti-cancer therapy and are still alive will 
be censored at the date of initiating the subsequent anti-cancer therapy for OS.  
The following additional sensitivity analyses for PFS will be performed, and all those sensitivity analyses 
defines the PFS event in an alternative way. 
- 
For Rule 7 of Table 3, subjects who take new anti-cancer therapy are considered as a progression, 
and the date of progression is on the date of initiating the new anti-cancer therapy. However, if the 
new anti-cancer therapy is initiated after two or more consecutive missed/non-evaluable tumor 
assessments, the subjects will still be censored at date of last radiological assessment before the 
missed assessments. Then, the same analysis methods outlined in Section 9.1.2 will be conducted.  


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- 
For Rule 8 of Table 3, ignore the missing tumor assessments, that is, subjects with PD or death 
after two or more consecutive missed/non-evaluable tumor assessments will be considered as PFS 
event, and the event date for PD or death will be obtained as usual. Then, the same analysis 
methods outlined in Section 9.1.2 will be conducted.  
 
Examination of Subgroups 
Subgroup analyses will be conducted as stated in the OS analysis and progression free survival sections. 
It should be noted that the study was not designed to detect treatment differences with high statistical 
power within subgroups. For OS and PFS subgroup analysis, if a subgroup is too small, it may be pooled 
with others. If the number of events in a subgroup is not sufficient, analysis will not be performed. 
The following subgroups will be assessed for OS and PFS: 
• 
Age: < 65 years, >= 65 years 
• 
Sex: Female, Male 
• 
Region: North America, Europe, Asia  
• 
Race: White, Asian, Black or African American, Other (including American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Other as recorded on the Demographics eCRF, and 
subjects with multiple races selected)  
• 
Baseline ECOG Performance Status: 0, 1 
• 
Prior Therapy with Trifluridine/Tipiracil (TAS-102) and/or Regorafenib: Trifluridine/Tipiracil (TAS-
102), Regorafenib, Both Trifluridine/Tipiracil (TAS-102) and Regorafenib 
• 
RAS Gene Status: Wild Type, Mutant 
• 
BRAF Status: Wild Type, V600 E Mutation, Other 
• 
Microsatellite/Mismatch Repair Status: Microsatellite Stable (MSS) and/or proficient mismatch 
repair (pMMR), Microsatellite Instability-High (MSI-H) and/or deficient mismatch repair (dMMR) 
• 
Duration of metastatic disease (time from 1st Metastatic Diagnosis to Randomization): ≤ 18 months, 
> 18 months 
• 
Number of Prior Chemotherapy Treatment Lines: ≤ 3, > 3 
• 
Number of Prior Chemotherapy Treatment Lines for Metastatic Disease: ≤ 3, > 3 
• 
Prior Treatment with Vascular Endothelial Growth Factor (VEGF) Inhibitors: Yes, No 
• 
Prior Epidermal Growth Factor Receptor (EGFR) Inhibitors: Yes, No 
• 
Prior target treatment  


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o 
No anti-VEGF and no anti-EGFR 
o 
Anti-VEGF, or anti-EGFR, or both 
§ 
Anti-VEGF and no anti-EGFR 
§ 
Anti-EGFR and no anti-VEGF 
§ 
Both anti-VEGF and anti-EGFR 
• 
Prior Treatment with Immune Checkpoint Inhibitors for MSI-H/dMMR: Yes, No 
• 
Prior Treatment with BRAF Inhibitors for BRAF V600E Mutation: Yes, No 
• 
Primary Tumor Location at First Diagnosis:  
o 
Colon, Rectum, Colon and Rectum, Unknown 
• 
Primary Tumor Site at First Diagnosis:  
o 
Colon Left (Splenic flexure, descending colon, transverse colon, sigmoid colon and 
rectum), Colon Right (Cecum, ascending colon and hepatic flexure), Colon Left and Right, 
Colon Unknown, Rectum Only, Unknown 
• 
Liver Metastases at Baseline: Yes, No  
• 
Number of Metastatic Tumor Sites Other than Colon or Rectum: Single, Multiple 
• 
Number of Metastatic Tumor Sites: Single, Multiple 
The values of stratification factors used for subgroup analysis are actual values of strata collected through 
eCRF. 
 
All the sensitivity and the subgroup analysis for both OS and PFS will be considered exploratory and may 
only be supportive of the primary analysis of OS and PFS. Forest plot will also be used to graphically show 
the results.  
 
Secondary Efficacy Endpoints and Analyses 
Secondary efficacy endpoints include ORR, DCR, and DoR. 
 
Objective Response Rate and Disease Control Rate 
The 95% CIs of ORR and ORRUNCONF RMED are calculated using the Clopper-Pearson exact binomial method 
for each treatment group. 
The adjusted proportion difference and along with its 95% CI in ORR between treatment groups will  be 
calculated using the Wald method to account for the randomization schedule stratification factors, and p-
value of comparing treatment groups is based on a stratified Cochran-Mantel Hanzel (CMH) test stratified 
by the randomization schedule stratification factors.  If the number of objective responses is not sufficient 
to utilize the CMH test, a stratified exact CMH test is performed instead. Example SAS code is provided in 
Appendix 8 and Appendix 9. 






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2. Five functional scales: Physical functioning, Role functioning, Emotional functioning, Cognitive 
functioning, Social functioning  
3. Three symptom scales: Fatigue, Nausea and vomiting, Pain 
4. Six single items: Dyspnea, Insomnia, Appetite loss, Constipation, Diarrhea, Financial difficulties 
Each subscale/single item is scored in accordance to the EORTC QLQ-C30 Scoring Manual (Aaronson et 
al, 1993).  All scales and single-item measures range in score from 0 to 100 after linear transformation.  A 
technical summary of scoring can be found in Appendix 1.  Higher score for the Global health status/QoL 
and functioning scales represent higher functioning (i.e. a better state).  However, the direction is opposite 
in symptom scales and single items. Higher scores on symptom and single-item scales represent higher 
levels of symptoms (i.e. a worse state). 
The number and percent of subjects who completed the questionnaires are summarized by visit and each 
treatment group.   
9.2.5.1. 
Analysis of Change from Baseline in 15 Subscales 
Change from baseline in the scores of each of the 15 subscales are summarized by visit and each treatment 
group.   
Analysis of change from baseline in the scores of each of the 15 subscales are performed by visit (i.e. 
cycle), using a restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) 
approach. The MMRM model will include treatment group, visit (i.e. cycle), treatment group by visit 
interaction, baseline value of scale, and randomization schedule stratification factors as fixed effects. An 
unstructured variance-covariance structure will be used to model within-subject errors. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom and adjust standard errors.  MMRM 
is based on the assumption of missing at random and the assumption that dropouts would behave similarly 
to other subjects in the same treatment group, and possibly with similar covariate values, had they not 
dropped out. Example SAS code is provided in Appendix 10. To ensure the proper amount of data utilized 
in the model for each visit, the following steps will be implemented to identify data to be included in the 
model.  
(1) Calculate the number of subjects with non-missing assessments for each cycle. 
(2) Identify the last cycle with at least 20 subjects in any of the treatment groups  and no subsequent cycles 
having at least 20 subjects in any of the treatment groups.  
(3) Assessments after the cycle identified in Step 2 will not be included in the model.  
If there is a convergence issue with the unstructured covariance model, Toeplitz, Autoregressive (1) (AR 
(1)) covariance structure is used, following this sequence until convergence is achieved.  If the model still 
does not converge with AR (1) structure, no results are reported. When the covariance structure is not 
unstructured, the sandwich estimator for the variance-covariance matrix is derived, using the EMPIRICAL 
option in the PROC MIXED statement in SAS.  


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The visit windowing rules defined in Section 7.4 will be applied to identify the record for a cycle of each 
subject, and hence to be included in the analysis. The comparison are between fruquintinib plus BSC to 
placebo plus BSC at each scheduled post-baseline visit.  The tabulation of MMRM includes estimates of 
least-square (LS) means, standard errors (SE), and 2-sided 95% CIs for each treatment group.  Estimates 
of the LS mean difference, SE of the difference, 2-sided 95% CI of the difference between treatment groups, 
and p-value are also presented. As a sensitivity analysis, subjects who have more than one assessment in 
a cycle (i.e., a quality of life assessment at an unscheduled visit), the worst score for that cycle is used in 
the analysis of change from baseline in the 15 subscales.  The above analysis is replicated using these 
substituted values.  
9.2.5.2. 
Analysis of Minimally Important Difference and Time to Deterioration 
Depending on each scale and item, the minimally important difference (MID) cut-off for QoL improvement 
is defined as a change of at least 6.35 to 14.24 points from baseline, based on a recent validation study on 
subjects with mCRC (Musoro et al., 2020) and the study (Osoba et al., 1998) cited in the EORTC-QLQ-30 
Scoring Manual.  The MID cut-off for QoL deterioration, stable, and improvement and in each scale and 
item are listed in Table 8.  
Table 8. Summary of MID for EORTC QLQ-C30 Questionnaire 
Scale/item 
Deterioration 
Stable 
Improvement 
Global health status/QoL 
-6.38 
-6.38 < and < 8.34 
8.43 
Physical functioning 
-7.47 
-7.47 < and < 7.81 
7.81 
Role functioning 
-10.66 
-10.66 < and < 14.24 
14.24 
Emotional functioning* 
-10 
-10 < and <10  
10 
Cognitive functioning* 
-10 
-10 < and < 10 
10 
Social functioning 
-6.18 
-6.18 < and < 9.23 
9.23 
Fatigue 
-7.38 
-7.38 < and < 10.79 
10.79 
Nausea and vomiting 
-6.62 
-6.62 < and < 7.75 
7.75 
Pain* 
-10 
-10 < and < 10 
10 
Dyspnoea* 
-10 
-10 < and < 10 
10 
Insomnia* 
-10 
-10 < and < 10 
10 
Appetite loss 
-9.78 
-9.78 < and < 12.28 
12.28 
Diarrhea 
-7.96 
-7.96 < and 6.35 
6.35 
Constipation 
-10* 
-10* < and <12.75 
12.75 
Financial difficulties* 
-10 
-10 < and < 10 
10 
*The MID of these sca e/ tems were not reported n (Musoro et a ., 2020). Instead, the MID for these sca e/ tems were arb trar y 
determ ned at 10 po nts, fo ow ng the study (Osoba et a ., 1998) c ted n EORTC QLQ 30 Scor ng Manua . Osoba et a . reported “a 
tt e” change as a change of 5 10 po nts, and “moderate” change as 10 20 po nts.     
The number and percent of subjects achieving MID for each scale (by categories defined in Table 8) are 
summarized by visit and treatment group.   
In addition, for each scale and single item, time to deterioration (TTD) is defined as the time (months) from 
randomization until the first change of at least 6.18 to 10.66 points (depending on each scale and item) 
from baseline (Table 8), or death, whichever comes first.  Any subject who does not experience TTD at the 
time of analysis is censored at the date of the most recent study visit in the database for that subject.   


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TTD is calculated as (date of the first reduction of at least 6.18 to 10.66 points from baseline, death or most 
recent visit – date of randomization + 1)/30.4375. 
Kaplan-Meier estimates for TTD are tabulated by treatment group, using 25th, 50th (median), and 75th 
percentiles with associated 2-sided 95% CIs. In addition, the two-sided p-value will be obtained from the 
stratified Kaplan-Meier method to account for the stratification factors. The hazard ratio (HR) between the 
two treatments (fruquintinib vs placebo), together with its 95% CIs will be calculated from a stratified (i.e. 
accounting for randomization schedule stratification factors) Cox hazard model in which treatment and 
baseline value of scale will be included as fixed effects. 
Data of EORTC QLQ-C30 questionnaire and subscales are listed by subject and visit. 
9.2.5.3. 
Handling Missing Data for EORTC QLQ-C30 Questionnaire 
The number of and percent subjects of missing data on each of the 15 subscales are presented by visit and 
also for the overall trial.  Subjects who have died are included in this count.  
As a simple sensitivity analysis of the impact of intercurrent events such as death and drop-out, an analysis 
of covariance (ANCOVA) will be conducted using the change from baseline to the last available assessment 
for each subject during the period from the date of randomization to the 37 days after the date of last dose. 
The ANCOVA model, include baseline scale score, randomization schedule stratification factors, treatment, 
and a baseline score and treatment interaction as fixed-effect variables.    
 
EQ-5D-5L Questionnaire  
The EQ-5D is a generic preference-based measure that indirectly measures the utility for health that 
generates an index-based summary score based upon societal preference weights (Pickard et al 2007).The 
EQ-5D-5L consists of 5 items that cover 5 main dimensions including mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression, and a general visual analogue scale (VAS) for health status. The 
range of VAS scoring is from 0 (the worst health imaginable) to 100 (the best health imaginable).   
Each of the 5 dimensions comprising the EQ-5D descriptive system is divided into 5 levels of perceived 
problems as follows. 
• 
Level 1: indicating no problem  
• 
Level 2: indicating slight problems  
• 
Level 3: indicating moderate problems 
• 
Level 4: indicating severe problems  
• 
Level 5: indicating extreme problems  
The response levels collected from the EQ-5D-5L five dimensions  as a health profile are converted into an 
EQ-5D-5L index (utility) scores to represent subjects’ utility value.  The EQ-5D-5L index-based score is 
typically interpreted along a continuum where a utility value of 1 represents perfect health, 0 represents a 
state equal to death and a negative value represents a state worse than dead.    


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The UK value set and scoring algorithm are used to derive the EQ-5D-5L index score for this analysis 
(Devlin et al., 2018).  The detailed scoring algorithm can be found in Appendix 2.  
The number and percent of subjects who completed the questionnaires are summarized by visit for each 
treatment group. 
9.2.6.1. 
Analysis of Change from Baseline in VAS and Index Scores 
Change from baseline in VAS and index scores are summarized by visit and for each treatment group. The 
MMRM analysis and the sensitivity analysis described in Section 9.2.5.1 can be similarly applied to the 
endpoints of  
- 
change from baseline in VAS with the baseline VAS score as covariate; 
- 
change from baseline in EQ-5D-5L index score with the baseline EQ-5D-5L index score as 
covariate 
To ensure the proper amount of data utilized in the model for each visit, the following steps will be 
implemented to identify data to be included in the model.  
(1) Calculate the number of subjects with non-missing assessments for each cycle. 
(2) Identify the last cycle with at least 20 subjects in any of the treatment groups and no subsequent cycles 
having at least 20 subjects in any of the treatment groups.  
(3) Assessments after the cycle identified in Step 2 will not be included in the model.  
9.2.6.2. 
Analysis of Minimally Important Difference and Time to Deterioration 
The appropriate MID cut-off for VAS is defined as a reduction of at least 7 points from baseline, based on 
a study of 534 cancer subjects evaluated by UK-based scoring algorithm (Pickard et al, 2007).  
The appropriate MID cut-off for index score is defined as a reduction of at least 0.063 points from baseline, 
based on the study on the scoring algorithm from England (McClure et al., 2017). McClure et al. reported 
the MID in the England population has a mean (standard deviation) of 0.063 (0.013), and a median of 0.064 
(interquartile range: 0.055 to 0.073).  
The MID cut-off for VAS and index scores for QoL deterioration, stable, and improvement are listed in Table 
9.  
Table 9. Summary of MID for EQ-5D-5L Questionnaire 
Scale/item 
Deterioration 
Stable 
Improvement 
VAS 
-7 
-7 < and < 7 
7 
Index Score 
-0.063 
-0.063 < and <0.063 
0.063 
 
The number and percent of subjects achieving MID are summarized by visit for each treatment group.   
In addition, TTD of VAS is defined as the time (month) from randomization until the first reduction of at least 
7 points from baseline or death, whichever comes first. TTD of index score is defined as the time (month) 


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from randomization until the first reduction of at least 0.063 points from baseline or death, whichever comes 
first.  
TTD for VAS is calculated as (date of the first reduction of at least 7 points from baseline, PD, death or 
most recent visit – date of randomization + 1)/30.4375. 
TTD for EQ-5D-5L index score is calculated as (date of the first reduction of at least 0.063 points from 
baseline, PD, death or most recent visit – date of randomization + 1)/30.4375. 
Subjects who does not experience TTD at the time of analysis are censored at the last visit.  Then, for the 
two time-to event endpoints 
- 
TTD for VAS  
- 
TTD for EQ-5D-5L index score  
The Kaplan-Meier method will be used to obtain the descriptive statistics of median, 25% and 75% 
percentiles along with their 95% CIs by treatment group. In addition, the two-sided p-value will be obtained 
from the stratified Kaplan-Meier method to account for the randomization stratification factors. The hazard 
ratio (HR) between the two treatments (fruquintinib vs placebo), together with its 95% CIs will be calculated 
from a stratified (i.e. accounting for randomization schedule stratification factors) Cox hazard model in which 
treatment and baseline value of scale will be included as fixed effects. 
Results from the descriptive system of 5 dimensions are summarized descriptively by visit for each 
treatment group.  A shift table from baseline for the levels within each of the 5 dimensions is provided by 
visit and treatment group. 
Data of EQ-5D-5L questionnaire are listed by subject and visit. 
9.2.6.3. 
Handling Missing Data for EQ-5D-5L Questionnaire 
The number of and percent subjects of missing data on the VAS and index score are presented by visit and 
for the overall trial.  Subjects who have died are included in this count. 
The sensitivity ANCOVA analysis described in Section 9.2.5.3 will be similarly applied to the endpoints of  
- 
change from baseline in VAS for each subject during the period from the date of randomization to 
the 37 days after the date of last dose with the baseline VAS score as covariate; 
- 
change from baseline in EQ-5D-5L index score for each subject during the period from the date of 
randomization to the 37 days after the date of last dose with the baseline EQ-5D-5L index score 
as covariate 
 
Health Resource Utilization 
Data of heath resource utilization including primary reason for visit, type of resource, duration of visit (days) 
which is calculated as stop date – start date +1, number of visits, concomitant medication prescribed 
(Yes/No), and special transportation required are summarized descriptively for each treatment group. Each 
subject may have multiple health care visit during the study period, and the non-missing value from each 
visit will be utilized in the analysis.  


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In addition, in the analysis of primary reason for visit, type of resource, concomitant medication prescribed 
(Yes/No), and special transportation required (Yes/No), only the unique response categories for a subject 
will be summarized. For example, a subject may have 10 health care visits, the response categories from 
those 10 visits are just 8 times of “Adverse Event” and 2 times of “Management of mCRC”, hence, this 
subject will only be counted in those two categories instead of summarizing 10 times in the aforementioned 
analysis.  
Data of heath resource utilization are listed by subject. 
 
Exploratory Efficacy Endpoints  
 
Circulating Tumor DNA 
The analysis of ctDNA will be documented separately, and is not covered in this SAP. 
 
Tumor Marker 
Change from baseline in serum CEA will be summarized by visit and for each treatment group. 
Data of CEA is listed by subject and visit.  
 
 


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Pharmacokinetics 
PK population is used for tabulation as specified in this section.   
 
PK Sampling Schedule  
The PK sampling schedule for the first approximately 120 subjects is displayed in Table 2 in the study 
protocol.  Furthermore, the PK sampling schedule for subjects enrolled after the first approximately 120 
subjects is displayed in Table 3 in the protocol.  
 
Data Handling 
 
Handling of Missing Data  
Missing concentration data for all subjects who are administered scheduled study treatments is considered 
as non-informative missing and is not imputed.  No concentration estimates are provided for missing sample 
values. 
 
Handling of below the lower limit of quantification (BLQ) Data 
For PK concentration summary, the following rules apply: 
• 
PK concentrations below the lower limit of quantification (BLQ) in pre-dose samples and in samples 
taken before the time of the first quantifiable value are set to zero;  
• 
The PK concentrations BLQ after quantifiable concentration are set to zero 
 
Handling of the Difference between the Scheduled (nominal time) and the Actual Sampling 
Times (actual time) 
For all sampling times, the actual sampling times relative to dosing are calculated as the difference 
between the actual clock time of sampling and the actual clock time of dosing.  The actual post-dose 
sampling times relative to dosing expressed in hours and rounded off to two decimal digits are used, except 
for pre-dose samples occurring prior to dosing, which are reported as zero (0.00), regardless of the time 
difference.  Scheduled sampling times are listed but will not be summarized. If the actual time of sampling 
is missing, it is reported as NR (not recorded) in the listing, the nominal time is used for summary statistics. 
 
Listing and Presentation of Individual PK Data  
PK data are presented by subject, cycle and day (for instance, C1D1, C1D21, C2D1, etc.), and time 
point. 
1. Concentration data for fruquintinib and M11 are presented to the same decimal place and in original 
units as reported by the bioanalytical lab, e.g., ng/mL;  
2. Listing of PK sampling times including nominal and actual time elapsed from dose with the deviation 
from the nominal time. 


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Summary of PK Concentration Data 
The observed concentrations for fruquintinib and metabolite M11 are summarized descriptively at each 
scheduled timepoint and dose level including. Summaries are presented by cycle and day (for instance, 
C1D1, C1D21, C2D1, etc.) and time point using descriptive statistics.  
• 
If the time deviation is greater than ± 20%, the PK concentration value is excluded from the 
summary descriptives. 
PK plasma concentration data at each scheduled timepoint and dose level is presented using the following 
descriptive statistics. 
• 
n  
• 
arithmetic mean and StdDev 
• 
coefficient of variation (CV)% 
• 
median 
• 
minimum and maximum 
• 
geometric mean and geometric CV% 
• 
number and percent of subject with BLQ 
The conventions presented in Table 10 below are used for the presentation of the descriptive statistics of 
plasma concentrations. 
Table 10. PK Reporting Precision 
Variable 
Summarized with: 
Minimum, Maximum 
3 significant digits or as needed based on actual 
measured values  
Mean (arithmetic and geometric), Median 
3 significant digits 
StdDev 
3 significant digits 
CV% and Geometric CV% 
1 decimal point 
 
 
 


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Safety 
The Safety population is used to evaluate the safety endpoints including AEs, clinical laboratory data, vital 
signs, single 12-lead ECG parameters, ECHO/MUGA parameters, physical examinations, ECOG 
performance status, extent of exposure and compliance, survival follow-up, and death. Unless otherwise 
specified, the safety data during the treatment period will be evaluated, and the treatment period is defined 
as the duration from the date of the first study drug administration until 37 days after last dose. 
 
Adverse Events 
AEs are collected throughout the study, commencing from the time the ICF is signed until 30 ± 7 days after 
the last dose day of study treatment, or start of a new treatment of anti-tumor therapy, whichever is earlier.  
AEs related to COVID-19 are determined by sites and recorded in electronic data capture (EDC), as 
deemed appropriate. 
AEs are coded by SOC and PT using MedDRA version 23.0 or higher.  An AE is considered a TEAE if  
1. the onset date is on or after the start of study treatment or if the onset date is missing, or  
2. if the AE has an onset date before the start of study treatment but worsened in severity after the 
study treatment until 37 days after the last dose of study treatment or a new treatment of anti-tumor 
therapy, whichever is earlier. After this period, treatment-related SAEs will also be considered as 
TEAEs.    
TEAEs related to COVID-19 are also flagged in AE analysis dataset.  
An AE is considered treatment-related in the summaries if it is assessed as related to the study treatment 
by the investigator or if the assessment of relationship to study treatment is missing. 
Severity of AEs is graded from Grade 1 to Grade 5 according to the National Cancer Institute Common 
Terminology Criteria for Adverse Event (CTCAE) version 5.0. Missing severity grade is imputed as Grade 
3.   
AESIs 
including 
hepatotoxicity, 
haemorrhage, 
hypertension, 
thyroid 
dysfunction, 
proteinuria, 
dermatological toxicity, cardiac ischemia and infarction, arterial or venous thromboembolic events, and 
gastrointestinal perforation are listed in Appendix 3. 
 
Overview of TEAEs  
An overall summary of the number and percent of subjects along with the total number of adverse events 
each treatment group is provided for the categories listed in Table 11. 
 
 


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Table 11. Overview of TEAEs 
Category 
Sub-category 
All TEAEs 
CTCAE Grade ≥3 
Treatment-related 
Leading to Dose Reduction 
Leading to Dose Interruption 
Leading to Treatment Discontinuation 
Treatment-related Leading to Dose Reduction 
Treatment-related Leading to Dose Interruption 
Treatment-related Leading to Treatment Discontinuation 
Leading to Death 
Serious TEAEs 
CTCAE Grade ≥ 3 
Treatment-related 
Leading to Dose Reduction 
Leading to Dose Interruption 
Leading to Treatment Discontinuation 
Treatment-related Leading to Dose Reduction 
Treatment-related Leading to Dose Interruption 
Treatment-related Leading to Treatment Discontinuation 
Leading to Death 
Treatment-emergent AESIs 
 
CTCAE Grade ≥ 3 
Serious 
Treatment-related 
Leading to Dose Reduction 
Leading to Dose Interruption 
Leading to Treatment Discontinuation 
Treatment-related Leading to Dose Reduction 
Treatment-related Leading to Dose Interruption 
Treatment-related Leading to Treatment Discontinuation 
Leading to Death 
COVID-19-related TEAEs 
CTCAE Grade ≥ 3 
Serious 
Treatment-related 
Leading to Dose Reduction 
Leading to Dose Interruption 
Leading to Treatment Discontinuation 
Treatment-related Leading to Dose Reduction 
Treatment-related Leading to Dose Interruption 
Treatment-related Leading to Treatment Discontinuation 
Leading to Death 
 
A subject with two or more AEs in a category is counted only once for the subject count. 
 
TEAEs by SOC and PT 
The number and percent of subjects experiencing a TEAE within each of the categories and sub-categories 
listed in Table 11 are also summarized by SOC, PT, and highest CTCAE grade for each treatment group. 


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A subject with two or more adverse events for each combination of SOC and PT is counted only once for 
the combination.   
The summary is sorted in descending order of frequency of SOC according to the sum of Fruquintinib + 
BSC and Placebo + BSC columns. Within SOC, sort by descending frequency of PT in according to the 
sum of Fruquintinib + BSC and Placebo + BSC columns. 
In addition, the number and percent of subjects are summarized by PT and highest CTCAE grade and by 
PT and CTCAE grade >=3  for each treatment group.  
 
Treatment-emergent Adverse Events of Special Interest 
Treatment-emergent AESI are also summarized by highest CTCAE grade for each treatment group and 
the subgroups listed below. 
Time (days) to onset of first treatment-emergent AESI are descriptively summarized for each AESI and 
treatment group. Time to first AESI 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 subject 
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.  
Adverse events of special interest (AESI) are summarized for the following subgroups. 
• 
Age: < 65 years, >= 65 years 
• 
Sex: Female, Male 
• 
Region: North America (including USA), Europe (including Austria, Belgium, France, Germany, 
Hungary, Italy, Spain, and United Kingdom); Asia (including Japan) 
• 
Race: White, Asian, Black or African American, Other 
• 
BMI (kg/m2): < 18.5, >= 18.5 to < 24, >= 24 
• 
Prior Therapy: Trifluridine/Tipiracil (TAS-102), Regorafenib , Both Trifluridine/Tipiracil (TAS-102) 
and Regorafenib  
• 
RAS Status: Wild Type, Mutant 
• 
Duration of metastatic disease: <= 18 months, > 18 months 
• 
Liver Metastases at Baseline: Yes, No  
For AEs falling into the AESI category “hepatotoxicity”, a summary table will also be provided by SOC, PT, 
and highest CTCAE for subjects with the following liver function category at baseline. Each liver function 
category will be evaluated separately to identify the subjects meeting the criteria. A listing of hepatotoxicity 
AEs will also be produced for subjects who meet any of the liver function category criteria at baseline (i.e. 


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aspartate aminotransferase [AST] or alanine aminotransferase [ALT] >3x upper limit of normal [ULN] or 
total bilirubin >2xULN, or alkaline phosphatase [ALP] <2xULN).  
• 
AST or ALT >3xULN  & ≤ 5xULN;  
• 
AST or ALT > 5xULN;  
• 
Total bilirubin  >2xULN;  
• 
AST or ALT > 3xULN and Total bilirubin  >2xULN;  
• 
AST or ALT >3xULN, Total bilirubin  >2xULN and ALP <2xULN 
 
Subgroup analysis of AE 
Analysis by BMI category (<18.5, ≥18.5 and <24 and ≥24 ) will be performed for the following AE summary: 
 
• 
TEAE overview summary 
• 
SAE summary 
• 
Summary of TEAE leading to drug discontinuation 
• 
Summary of TEAE with CTCAE grade ≥3. 
 
Laboratory Evaluations 
Blood and urine samples for the determination of clinical chemistry, hematology, and urinalysis laboratory 
variables described in Table 12 will be measured.  
Clinical laboratory results will be graded according to CTCAE criteria, Version 5.0.Any graded changes that 
occurs following the initiation of study drug and represents at least a 1-grade change from the baseline 
assessment is defined as treatment emergent. Any assessment, for which CTCAE toxicity grades are not 
available, will not be included in any analyses for which toxicity grades are required. Grade 0 is assigned 
to all laboratory values except missing values and not already assigned another grade.  Missing values are  
considered missing. 
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 first dose administration and up to 37 days 
following the last dose of study medication will be used for analysis.  


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Table 12. List of Laboratory Parameters 
Laboratory Category 
Parameters 
Hematology 
Hemoglobin, Hematocrit, Red Blood Cell Count (RBC), Platelet Count, White 
Blood Cell Count (WBC), Absolute Neutrophil Count, Neutrophils %, Absolute 
Lymphocyte Count, Lymphocytes %, Absolute Monocyte Count, Monocytes %, 
Absolute Eosinophil Count, Eosinophils %, Absolute Basophil Count, Basophils 
% 
Blood Chemistry 
Albumin, Blood urea nitrogen (BUN), Creatinine, Aspartate transaminase 
(AST), Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), Total 
Bilirubin, Lactate dehydrogenase (LDH), Uric acid, Sodium, Potassium, 
Chloride, Bicarbonate, Glucose, Calcium, Magnesium, Phosphorus, Total 
cholesterol, Triglycerides, Total Protein 
Blood 
Chemistry 
– 
Thyroid Function 
Free triiodothyronine (fT3), Serum free thyroxine (fT4), Thyroid-stimulating 
hormone (TSH) 
Urinalysis 
pH, Glucose, Protein, White blood cell, Red blood cell 
Urinalysis Microscopy 
Microscopic White Blood cell count, Microscopic Red Blood cell count, Other 
Coagulation 
Activated Partial thromboplastin time (aPTT), Prothrombin time, International 
normalized ratio (INR) 
 
All summaries of hematology, blood chemistry (including thyroid function), urinalysis and coagulation 
parameters are based on the results of SI units, where applicable.  Thyroid function parameters are 
analyzed under blood chemistry category. 
Summary tables for hematology, blood chemistry, coagulation, and urinalysis (pH only) laboratory variables 
include descriptive statistics for result values and change from baseline for all continuous variables by visit 
and treatment group.   
Toxicities for clinical labs will be characterized according to CTCAE, Version 5.0 (Table 18 of Appendix 4 
when possible), and the frequency and percentage of subjects with each CTCAE grade for each visit during 
the treatment period will be described. Moreover, any occurrence of grade 3 or grade 4 during the treatment 
period will be summarized, and shift in grade from baseline to the worst post-baseline value will be 
summarized.  
Summary table and listing are also provided for treatment-emergent hepatotoxicity and subjects with or 
without liver metastasis by each treatment group. Hepatotoxicity is based on the pre-specified thresholds 
below: 
1. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3x upper limit of normal 
(ULN) and ≤ 5x ULN 


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2. AST > 3,5,8,10, and 20x ULN, AST > 5x ULN for more than 5 weeks 
3. ALT > 3,5,8,10, and 20x ULN, ALT > 5x ULN for more than 5 weeks 
4. AST and/or ALT > 3,5,8,10, and 20x ULN, > 5x ULN for more than 5 weeks 
5. Total bilirubin elevations > 1.5x, 2x ULN 
6. Potential Drug-Induced Liver Injury  (DILI): AST and/or ALT > 3x ULN and total bilirubin > 2x ULN 
7. Hy's Law criteria: AST and/or ALT > 3x ULN and total bilirubin > 2x ULN and ALP < 2x ULN 
An edish plot presenting peak total bilirubin and peak ALT values will also be produced. 
Qualitative assessments of urinalysis parameters are summarized for all subjects using the number of 
subjects with results of negative, trace, or positive. 
Summary of clinical significance (Abnormal not clinically significant [NCS] and Abnormal clinically significant 
[CS]) is also provided by visit and treatment group. Shift from baseline to the worst post-baseline 
investigators’ assessment (i.e. normal, NCS, and CS for quantitative measurements and categorical 
measurements) will be presented. 
All laboratory results (including hematology, blood chemistry, blood chemistry – thyroid function, urinalysis, 
coagulation, hepatitis, amylase and lipase, and serum/urine pregnancy test data) in SI units are presented 
in data listings.  Tests are listed in alphabetical order within their respective panels (hematology, blood 
chemistry, urinalysis, and coagulation).   
 
Vital Signs 
Vital signs include systolic blood pressure, diastolic blood pressure, respiratory rate, body temperature, 
pulse rate, weight, body mass index (BMI) will be computed as weight (kg)/[height (m)]2.   
For vital signs, change from baseline to each post-baseline visit and timepoint will be calculated. The 
potentially clinically significant findings of vital signs will also be defined based on criteria defined in Table 
13.  
Vital signs are summarized with descriptive statistics for the observed values at each visit and change from 
baseline to post-baseline visits values by treatment group. The criteria of potentially clinically significant 
findings are defined in Table 13. The frequency and percentage of subjects with any potentially clinically 
significant findings during the treatment period will be presented.  
 
 
 


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Table 13.  Potentially Clinically Significant Criteria for Vital Signs  
Variable 
Criterion value   
SBP (mmHg) 
Increase from baseline of 
˃ 0 - ≤ 20  
˃ 20 - ≤ 40  
˃ 40  
Decrease from baseline of 
˃ 0 - ≤ 20  
˃ 20 - ≤ 40  
˃ 40  
 
DBP (mmHg) 
Increase from baseline of 
˃ 0 - ≤ 20  
˃ 20 - ≤ 40  
˃ 40  
Decrease from baseline of 
˃ 0 - ≤ 20  
˃ 20 - ≤ 40  
˃ 40  
 
Heart rate (bpm) 
Increase from baseline of 
˃ 0 - ≤ 20  
˃ 20 - ≤ 40  
˃ 40  
Decrease from baseline of 
˃ 0 - ≤ 20  
˃ 20 - ≤ 40  
˃ 40  
 
Weight (kg) 
Percentage increase from baseline of 
˂ 5%  
≥ 5 – < 10%  
≥ 10 - < 20%  
≥ 20% 
Percentage decrease from baseline of 
˂ 5%  
≥ 5 – < 10%  
≥ 10 - < 20%  
≥ 20% 
 
 
Vital signs are listed by subject and visit. 
 
Electrocardiogram  
Electrocardiogram (ECG) parameters include heart rate, PR interval, and QT, QT correction Bazett formula 
(QTcB), QT correction Fridericia formula (QTcF) and a combination of the Q wave, R wave and S wave 
(QRS) intervals. Potentially clinically significant ECG findings will be identified using the criteria which are 
included in Table 14.  




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Echocardiogram  
ECHOs are performed at Screening, cycle 2 day 1, and on day 1, every 3 cycles thereafter.  Assessment 
parameters include left ventricular ejection fraction and overall interpretation of cardiac function.  MUGAs 
are permitted if ECHOs cannot be performed.   
Categorical summaries of overall interpretation and change from baseline of left ventricular ejection fraction 
of ECHO/MUGA results at each visit are summarized.  A shift from baseline to the worst post-baseline table 
for overall interpretation is also provided.   
ECHO/MUGA data is listed by subject and visit.   
 
Physical Examination  
A comprehensive physical examination at Screening includes subject general appearance, eyes, ears, 
nose and throat, head and neck, respiratory, cardiovascular, abdomen (gastrointestinal), skin, genitourinary 
system, lymph nodes, musculoskeletal, neurological assessments. 
Limited physical examination at scheduled visits is a subset the comprehensive physical examination as 
deemed appropriate by the investigator. 
Results of physical examination are listed by subject and visit. 
 
ECOG Performance Status 
ECOG performance status is be summarized descriptively using counts and percentages by visit for each 
treatment group.  A shift from baseline to worst post-baseline value table is also provided.   
ECOG performance status is listed by subject and visit.  
 
Other Safety Endpoints 
 
Survival Follow-up  
Subjects received any anti-cancer medications, radiotherapy, and procedures during survival follow-up and 
survival status are summarized descriptively for each treatment group.   
Data of survival follow-up are listed by subject and visit. 
 
Anti-cancer Medication during Survival Follow-up 
Anti-cancer medication during survival follow-up are classified using the WHODD version March 2020 or 
later. 
The use of anti-cancer medication during survival follow-up will be summarized using discrete summary 
statistics, each treatment group and overall for the safety population.  If a subject took a specific medication 
multiple times or took multiple medications within a specific ATC or PT, the subject is counted only once for 
the respective ATC or PT. 


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Summaries are ordered in alphabetical order of ATC and then, within an ATC, in decreasing frequencies 
by PT in overall column. If the frequencies tie, an alphabetic order will be applied. 
Data of anti-cancer medication during survival follow-up are listed by subject. 
 
Anti-cancer Procedure during Survival Follow-up 
The anti-cancer procedures during survival follow-up are coded using MedDRA version 23.0 or higher.  
The use of anti-cancer procedures during survival follow-up will be summarized using discrete summary 
statistics in each treatment group and overall for the safety population.  If a subject had a specific procedure 
multiple times or had multiple procedures within a specific SOC or PT, the subject is counted only once for 
the respective SOC or PT. 
Summaries are ordered in alphabetical order of SOC and then, within an SOC, in decreasing frequencies 
by PT in overall column. If the frequencies tie, an alphabetic order will be applied. 
Data of anti-cancer procedure during survival follow-up are listed by subject. 
 
Anti-cancer Radiotherapy during Survival Follow-up 
The number and percent of subjects with at least one anti-cancer radiotherapy during survival follow-up are  
summarized for each treatment group. 
Data of anti-cancer radiotherapy during survival follow-up are listed by subject. 
 
Deaths  
Primary cause of death and whether autopsy was performed are summarized descriptively for each 
treatment group.  Similarly, the deaths happening during the treatment period, defined as the period from 
the date of the first study drug administration until 37 days after last dose, will also be tabulated. Data of 
deaths are listed by subject. On-treatment death will be flagged.  
 
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 subjects and study staff due to the COVID-19 pandemic while ensuring 
subjects safety and maintaining data integrity, subjects are allowed remote visits during the pandemic.  
The planned protocol deviation analyses are described in Section 8.2; planned sensitivity analyses for the 
PFS and OS are described in Section 9.1.4, and the summary for COVID-19-related TEAEs are included 
in Section 11.1.1.  
 
Additional summaries related to the COVID-19 pandemic from the following aspects will be produced for 
ITT:  
• 
Type of impact on study visit (missing entire visit; Interrupted and/or out of window in-person visit at 
site; remote visit (virtual or telephone); or other) 


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• 
Reason related to COVID-19 (subject diagnosed with COVID-19; quarantined due to COVID-19; site 
closed or access restricted due to COVID-19; site open but subject unwilling or unable to come to site 
due to COVID-19; or other) 
• 
Study drug discontinuation due to COVID-19 
ITT population will be used for the planned analyses described above. The number of subjects impacted 
by COVID-19 during the study investigation period as well as at any time will be summarized by treatment 
group and overall. The study investigation period is defined as the period from the date of randomization 
to the 37 days after the date of last study treatment administration.  
Supporting listings for the described analyses above will be provided.   
 
Interstitial Lung Disease 
Interstitial lung disease data collected, including chest x-ray results and oxygen saturation, are listed by 
subject. 
 


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IDMC Review  
A subset of TLFs for the study final analysis will be used for IDMC meetings.  The specific content of the 
TLFs submitted to the IDMC are determined by the IDMC members.  The results to be reviewed by the 
IDMC will be primarily based on the safety data.  Efficacy data is also provided for the purpose of the 
planned interim futility analysis after 1/3 of OS events has occurred.  
For open sessions, the tables are presented with column Total only and the listings contains no treatment 
header. For closed sessions, the tables are presented with columns Treatment A + BSC, Treatment B + 
BSC, and Total, and the listings contain treatment headers. The unblended statistician to be involved in the 
closed sessions of the IDMC will share the actual treatment information for Treatment A an Treatment B.  
The IDMC may request to be unblinded by treatment group or per-subject basis at any time.  The unblinded 
biostatistician provides the information to unmask.  These communications are maintained in the IDMC 
workspace and submitted to the Trial Master File at the end of the study. 
The study is to be terminated in the case of confirmed futility after evaluation of 1/3 of OS events (i.e., 160 
OS events). 
At any time, the IDMC may request any other safety-related information deemed necessary to contribute 
to an appropriate review of safety. 
Further details of content for open and closed sessions are provided in Section 18, “Content of Open and 
Closed Sessions”, of the IDMC Charter in order to maintain the blinding of the study. 


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Changes from Analysis Planned in Protocol 
• 
Not applicable. 


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Reference List 
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman 
SB, de Haes JCJM, Kaasa S, Klee MC, Osoba D, Razavi D, Rofe PB, Schraub S, Sneeuw KCA, Sullivan 
M, Takeda F. The European Organisation for Research and Treatment of Cancer A quality-of-life instrument 
for use in international clinical trials in oncology. Journal of the National Cancer Institute 1993; 85: 365-376. 
Brookmeyer R., and Crowley J. (1982). A confidence interval for the median survival time. Biometrics, 29-
41. 
Devlin et al., Valuing health-related quality of life: An EQ-5D-5L value set for England. Health Economics. 
2018;27:7–22. https://doi.org/10.1002/hec.3564 
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. 
European Organization for Research and Treatment of Cancer. EORTC QLQ-C30 Scoring Manual. 
https://www.eortc.org/app/uploads/sites/2/2018/02/SCmanual.pdf 
EuroQol 
Research 
Foundation. 
EQ-5D-5L 
User 
Guide. 
Version 
3.0; 
September 
2019. 
https://euroqol.org/wp-content/uploads/2019/09/EQ-5D-5L-English-User-Guide_version-3.0-Sept-2019-
secured.pdf 
Kim, Y., & Won, S. (2013). Adjusted proportion difference and confidence interval in stratified randomized 
trials. PharmaSUG 2013. https://www.pharmasug.org/proceedings/2013/SP/PharmaSUG-2013-SP04.pdf 
McClure et al., Instrument-Defined Estimates of the Minimally Important Difference for EQ-5D-5L Index 
Scores. Value Health. 2017 Apr;20(4):644-650. doi: 10.1016/j.jval.2016.11.015. Epub 2017 Jan 10. PMID: 
28408007. 
Musoro et al., Minimally important differences for interpreting European Organisation for Research and 
Treatment of Cancer (EORTC) Quality of life Questionnaire core 30 scores in subjects with ovarian 
cancer, Gynecologic Oncology, 10.1016/j.ygyno.2020.09.007, (2020). 
Osoba et al., Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol. 
1998 Jan;16(1):139-44. doi: 10.1200/JCO.1998.16.1.139. PMID: 9440735. 
Pickard et al., Estimation of minimally important differences in EQ-5D utility and VAS scores in 
cancer. Health Qual Life Outcomes. 2007;5:70. doi: 10.1186/1477-7525-5-70. 
Pickard AS, Wilke CT, Lin HW, Lloyd A. Health Utilities Using the EQ-5D in Studies of Cancer. 
PharmacoEconomics 2007;25:365–84 


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Programming Considerations 
All TLFs and statistical analyses are generated using SAS for Windows, Release 9.4 (SAS Institute Inc., 
Cary, NC, USA). Computer-generated table, listing and figure outputs adhere to the following specifications.   
 
General Considerations 
• 
One SAS program can create several outputs 
• 
Each output is stored in a separate file 
• 
Output files are delivered as follows 
o 
Two compiled pdf files (with bookmark and TOC) – one for tables and figures, and one for 
listings]; 
o 
Individual rtf file for the TLFs (this is only applicable to the final delivery, e.g. final interim 
analysis delivery, final database lock delivery for clinical study report); 
o 
For figures, include the individual .tiff file (this is only applicable to the final delivery, e.g. 
final IA delivery, final DBL delivery for CSR) 
• 
Numbering of TLFs follows ICH E3 guidance  
 
Table, Listing, and Figure Format 
 
General 
• All TLFs are produced in landscape format on American letter paper size. 
• All TLFs are produced using the Courier New font, size 8 which is the smallest acceptable point size 
for the Regulatory Authorities. 
• The data displays for all TLFs have a minimum blank 1-inch margin on all 4 sides. 
• Headers and footers for figures are in Courier New font, size 8 which is the smallest acceptable point 
size for the Regulatory Authorities. 
• Legends are used for all figures with more than 1 variable, group, or item displayed. 
• Table and listings are in black and white (no color).  Figures are in colors, where applicable. 
• Only standard keyboard characters are used in the TLFs.  Special characters, such as non-printable 
control characters, printer-specific, or font-specific characters, are not used.  Hexadecimal-derived 
characters are used, where possible, if they are appropriate to help display math symbols (e.g., μ).  
Certain subscripts and superscripts (e.g., cm2, Cmax) are employed on a case-by-case basis. 
• Mixed case is used for all titles, footnotes, column headers, and programmer-supplied formats, as 
appropriate. 


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Headers 
• TLFs are internally paginated in relation to the total length (i.e., the page number should appear 
sequentially as page n of N, where N is the total number of pages in the table). 
• The date output was generated should appear along with the program name as a footer on each 
page. 
15.2.2.1. 
Headers for Study 
• All output should have the following header at the top of each page: 
Hutchison MediPharma Limited 
 
Protocol No.: 2019-013-GLOB1 
Page X of Y 
 
 
  Data Cut-off Date: DDMMMYYYY 
15.2.2.2. 
Headers for Study – Interim Analysis 
• All output should have the following header at the top of each page: 
Hutchison MediPharma Limited 
 
Protocol No.: 2019-013-GLOB1 – Interim Analysis 
 
Page X of Y 
Data Cut-off Date: DDMMMYYYY 
15.2.2.3. 
Headers for IDMC Meeting 
• All output should have the following header at the top of each page: 
Hutchison MediPharma Limited 
 
Protocol No.: 2019-013-GLOB1 - IDMC Meeting 
 
Page X of Y 
 
  Data Cut-off Date: DDMMMYYYY 
15.2.2.4. 
Headers for Japan Safety Lead-in Cohort 
• All output should have the following header at the top of each page: 
Hutchison MediPharma Limited 
 
Protocol No.: 2019-013-GLOB1 - Japan Safety Lead-in Cohort 
 
Page X of Y 
Data Cut-off Date: DDMMMYYYY 
15.2.2.5. 
Headers for Japan Safety Monitoring Committee (JSMC) Meeting 
• All output should have the following header at the top of each page: 
Hutchison MediPharma Limited 
 
Protocol No.: 2019-013-GLOB1 – JSMC Meeting 
 
Page X of Y 
Data Cut-off Date: DDMMMYYYY 
 
Display Titles 
• Each TLF are identified by the designation and a numeral.  (i.e., Table 14.1.1).  A decimal system 
(x.y and x.y.z) are used to identify TLFs with related contents.  The title is centered.  The analysis 
set are identified on the line immediately following the title.  The title and table designation are single-
spaced.  A solid line spanning the margins separate the display titles from the column headers.  
There is 1 blank line between the last title and the solid line.  Parameters or Visits, if applicable, are 
between the last title and the solid line. 


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Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
(Intent-to-Treat Population) 
 
Column Headers 
• Column headings are displayed immediately below the solid line described above in initial upper-
case characters.  
• In the case of efficacy tables, the variable (or characteristic) column is on the far left followed by the 
treatment group columns.  P-values are presented under the ‘Fruquintinib + BSC’ column. 
• For numeric variables, include “unit” in column or row heading when appropriate. 
• Analysis set sizes are presented for each treatment group in the column heading as (N=xx) (or in the 
row headings, if applicable).  This is distinct from the ‘n’ used for the descriptive statistics representing 
the number of subjects in the analysis set. 
• The order of treatments in the tables and listings is ‘Placebo + BSC’ first then ‘Fruquintinib + BSC’, 
followed by a ‘Total’ column, where applicable. 
 
Body of the Data Display 
15.2.5.1. 
General Conventions 
Data in columns of a table or listing are formatted as follows: 
• Alphanumeric values are left-justified; 
• Whole numbers (e.g., counts) are right-justified; and 
• Numbers containing fractional portions are decimal aligned. 
15.2.5.2. 
Table Conventions 
• Units are included where available 
• If the categories of a parameter are ordered, then all categories between the maximum and minimum 
category are presented in the table, even if n=0 for all treatment groups in a given category that is 
between the minimum and maximum level for that parameter.  For example, the frequency 
distribution for symptom severity would appear as: 
Severity Rating N 
severe 
0 
moderate 
8 
mild 
3 
 


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Where percentages are presented in these tables, zero percentages are presented and so counts of 0 are 
presented as 0 and not as 0 (0%). 
• If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the Study, 
etc.), then only those categories for which there is at least 1 subject represented in 1 or more groups 
are included. 
• An Unknown or Missing category are added to each parameter for which information is not available 
for 1 or more subjects.   
• Unless otherwise specified, the estimated mean, median, Q1, and Q3 for a set of values are printed 
out to 1 more significant digit than the original values, and standard deviations are printed out to 2 
more significant digits than the original values.  The minimum and maximum should report the same 
significant digits as the original values.  For example, for systolic blood pressure: 
N 
  XX 
Mean (StdDev) 
XXX.X (X.XX) 
Median 
XXX.X 
Min, Max 
XXX, XXX 
Q1, Q3 
XXX, XXX 
Missing 
XXX 
 
• P-values are output in the format: “0.xxx”, where xxx is the value rounded to 3 decimal places.  Every 
p-value less than 0.001 is presented as <0.  If the p-value is returned as >0.999, then present as 
>0.999. 
• Percentage values are printed to one decimal place, in parentheses with no spaces, one space after 
the count (e.g., 7 (12.8), 13 (5.4)).  Unless otherwise noted, for all percentages, the number of 
subjects in the analysis set for the treatment group who have an observation is the denominator.  
Percentages after zero counts should not be displayed and percentages equating to 100% are 
presented as 100, without decimal places.   
• Tabular display of data for medical history, prior/concomitant medications, and all tabular displays of 
AE data are presented by the body system, treatment class, or SOC with the highest occurrence in 
the active treatment group in decreasing order, assuming all terms are coded.  Within the body 
system, drug class and SOC, medical history (by preferred term), drugs (by ATC 2 code), and AEs 
(by preferred term) are displayed in decreasing order.  If incidence for more than 1 term is identical, 
they should then be sorted alphabetically.   
• Missing descriptive statistics or p-values which cannot be estimated are reported as “-”. 
• The percentage of subjects is normally calculated as a proportion of the number of subjects assessed 
in the relevant treatment group (or overall) for the analysis set presented.  However, careful 
consideration is required in many instances due to the complicated nature of selecting the 
denominator, usually the appropriate number of subjects exposed.  Describe details of this in 
footnotes or programming notes. 


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• For categorical summaries (number and percent of subjects) where a subject can be included in 
more than one category, describe in a footnote or programming note if the subject are included in 
the summary statistics for all relevant categories or just 1 category and the criteria for selecting the 
criteria. 
• Where a category with a subheading (such as system organ class) has to be split over more than 
one page, output the subheading followed by “(cont.)” at the top of each subsequent page.  The 
overall summary statistics for the subheading should only be output on the first relevant page. 
15.2.5.3. 
Listing Conventions 
• Listings are sorted for presentation in order of treatment groups as above, subject number, 
visit/collection day, and visit/collection time. 
• Missing data are represented on subject listings as either a hyphen (“-”) with a corresponding 
footnote (“- = unknown or not evaluated”), or as “N/A”, with the footnote “N/A = not applicable”, 
whichever is appropriate. 
• Dates are printed in SAS DATE9.format (“ddMMMyyyy”: 01JUL2000).  Missing portions of dates are 
represented on subject listings as dashes (--JUL2000).  Dates that are missing because they are not 
applicable for the subject are output as “N/A”, unless otherwise specified. 
• All observed time values are to be presented using a 24-hour clock HH:MM.  Time is reported if it 
was measured as part of the study. 
• Units are included where available 
15.2.5.4. 
Figure Conventions 
• Unless otherwise specified, for all figures, study visits are displayed on the X-axis and endpoint (e.g., 
treatment mean change from baseline) values are displayed on the Y-axis. 
 
Footnotes 
• A solid line spanning the margins separates the body of the data display from the footnotes.   
• All footnotes are left justified with single-line spacing immediately below the solid line underneath the 
data display. Each footnote will end with a period “.”. 
• Footnotes should always begin with “Note:” if an informational footnote, or a, b, c, etc.  if a reference 
footnote.  Each new footnote should start on a new line, where possible. 
• Subject specific footnotes are avoided, where possible. 
• Footnotes are used sparingly and add value to the table, figure, or listing.  If more than six lines of 
footnotes are planned, then a cover page is strongly recommended to be used to display footnotes, 
and only those essential to comprehension of the data are repeated on each page.   


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• The order of different types of footnotes need to follow the proper order as shown below 
1. Subject specific footnote, such as [a], [b], *, 1, 2, 3, and etc.; 
2. General footnote starting with “Note: …”, also the text of the footnotes will be properly 
aligned at the place after the phrase “Note:” if the line of footnote will wrap to the next row.  
3. Abbreviation footnote. The abbreviation of the footnote will be ordered alphabetically, In 
addition, each word spelling the abbreviation will use uppercase for the first letter unless it 
is the convention to use lowercase, e.g. “of”, “and”, etc. Each abbreviation will be separated 
by a “;” 
4. The last line of the footnote section is standard source line that indicates the name of the 
program used to produce the data display, date the program was run, and the listing source. 
For example, 
   
  Source: Listing 16.2.x.x 
  Program: xxxx.sas 
 
 
 
 
Table Generation: DDMMMYYYY HH:MM 
 
 
 


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Quality Control 
SAS programs are developed to produce output such as analysis data sets, summary tables, data listings, 
figures or statistical analyses.  An overview of the development of programs is detailed in Syneos Health 
SOP Developing Statistical Programs (3907). 
Syneos Health SOPs Developing Statistical Programs (3907) and Conducting the Transfer of Biostatistical 
Deliverables (3908) describes the quality control procedures that are performed for all SAS programs and 
output.  Quality control is defined here as the operational techniques and activities undertaken to verify that 
the SAS programs produce the output by checking for their logic, efficiency and commenting and by review 
of the produced output. 
Syneos Health SOP Pharmacokinetic and Related Data Analyses  (3913.01) describes the procedure for 
the generation and reporting of PK and pharmacodynamics data.  


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Appendix 
 
Appendix 1. EORTC QLQ-C30 Scoring Algorithm  
The principle for scoring these scales is the same in all cases. The steps for scoring are:     1) Estimate 
the average of the items that contribute to the scale. (i.e. the raw score);  
    2) Use a linear transformation to standardize the raw score, so that scores range from 0 to 100.  
More specifically, if items 𝐼!, 𝐼", … , 𝐼# are included in a scale, the RawScore, RS, is the mean of the 
component items: 
𝑅𝑎𝑤𝑆𝑐𝑜𝑟𝑒
𝑅𝑆
(𝐼! + 𝐼" + ⋯+ 𝐼#)/𝑛 
Then apply the linear transformation to 0-100 to obtain the desired score for the scale, i.e.  
- 
for Functional scales:  
𝑆𝑐𝑜𝑟𝑒
51
(𝑅𝑆
1)
𝑟𝑎𝑛𝑔𝑒9 × 100 
- 
for Symptom scales/items and Global health status/QoL: 
𝑆𝑐𝑜𝑟𝑒
 =(𝑅𝑆
1)
𝑟𝑎𝑛𝑔𝑒> × 100 
where Range in the formula is the difference between the maximum possible value of RS and the minimum 
possible value. The QLQ-C30 has been designed so that all items in any scale take the same range of 
values. Therefore, the range of RS equals the range of the item values. Most items are scored 1 to 4, giving 
range = 3. The exceptions are the items contributing to the global health status / QoL, which are 7-point 
questions with range = 6. More detailed information about the items to be included in each scale is 
summarized in Table 15 below.  
To calculate the score for a scale following the aforementioned principles, it is required to at least half of 
the items have been answered, otherwise, the score will be set as missing. However, for single-item scale, 
set the score to missing if it is not answered. For example, role functioning and cognitive functioning each 
contain 2 items, and so these scales can be estimated whenever one of their constituent items is present; 
physical functioning contains 5 items, and so at least 3 need to have been completed.   
 
 


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Table 15. Scoring the EORTC QLQ-C30 version 3.0 
 
Scale 
Number of 
items 
Item range 
Version 3.0 
Item numbers 
Global health status / QoL 
 
 
 
 
Global health status/QoL (revised)  
QL2 
2 
6 
29, 30 
Functional scales 
 
 
 
 
Physical functioning (revised) 
PF2 
5 
3 
1 to 5 
Role functioning (revised) 
RF2 
2 
3 
6, 7 
Emotional functioning 
EF 
4 
3 
21 to 24 
Cognitive functioning 
CF 
2 
3 
20, 25 
Social functioning 
SF 
2 
3 
26, 27 
Symptom scales / items 
 
 
 
 
Fatigue 
FA 
3 
3 
10, 12, 18 
Nausea and vomiting 
NV 
2 
3 
14, 15 
Pain 
PA 
2 
3 
9, 19 
Dyspnoea 
DY 
1 
3 
8 
Insomnia 
SL 
1 
3 
11 
Appetite loss 
AP 
1 
3 
13 
Constipation 
CO 
1 
3 
16 
Diarrhoea 
DI 
1 
3 
17 
Financial difficulties 
FI 
1 
3 
28 


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Appendix 2. Scoring the EQ-5D-5L Descriptive System 
The EQ-5D-5L descriptive system can be scored as an example in Figure 2 below. There should be only 
one response for each dimension.  
Figure 2. Example of Scoring the EQ-5D-5L Descriptive System 
 


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Then, the EQ-5D-5L index score is a weighted linear combination over 5 dimensions of health status. The 
coefficient for the weighting for each level of domains are presented in Table 16. 
Table 16. EQ-5D-5L weighting coefficient scheme from England for the response of each 
dimension (Devlin et al., 2018) 
Score level of dimension 
Coefficient for each level of dimension 
Mobility 
 
Self-care 
Usual 
activities 
Pain/ 
discomfort 
Anxiety/ 
depression 
Level 1: no problem 
0 
0 
0 
0 
0 
Level 2: slight 
0.027 
0.023 
0.023 
0.029 
0.036 
Level 3: moderate 
0.035 
0.037 
0.029 
0.039 
0.048 
Level 4: severe 
0.096 
0.076 
0.075 
0.128 
0.132 
Level 5: unable or extreme [a] 
0.127 
0.094 
0.085 
0.155 
0.134 
[a] For dimensions (Mobility, Self-care, and Usual activities), it takes value “Unable”. For dimensions 
(Pain/discomfort and Anxiety/depression), it takes value “Extreme”.  
The EQ-5D-5L index score is calculated using the equation  
EQ-5D-5L index score 
1
2.159 × ∑coefficient value assigned to the response of each dimention 
If any of the 5 dimension scores is missing, the index score will be set to missing.  
For example, for a value of health state 23245, the EQ-5D-5L index score is calculated as 
EQ-5D-5L index score = 1 −2.159 ×
∑coefficient value assigned to the response of each dimention =  1 −2.159 ×
∑(0.027 + 0.037 + 0.023 + 0.128 + 0.134) = 0.247  
 
 
 




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Preferred Terms: 
Acute hepatic failure,  
Acute yellow liver atrophy,  
Ascites,  
Asterixis,  
Bacterascites,  
Biliary cirrhosis,  
Biliary cirrhosis primary,  
Biliary fibrosis,  
Cholestatic liver injury,  
Chronic hepatic failure,  
Coma hepatic,  
Cryptogenic cirrhosis,  
Diabetic hepatopathy,  
Drug-induced liver injury,  
Duodenal varices,  
Gallbladder varices,  
Gastric varices,  
Gastric varices haemorrhage,  
Hepatectomy,  
Hepatic atrophy,  
infiltration eosinophilic,  
Hepatic lesion,  
 
Hepatic necrosis,  
Gastroduodenal haemorrhage,  
Gastric ulcer haemorrhage,  
Duodenal ulcer haemorrhage,  
Gastrointestinal ulcer 
haemorrhage,  
Hepatic calcification,  
Hepatic cirrhosis,  
Hepatic encephalopathy,  
Hepatic encephalopathy 
prophylaxis,  
Hepatic failure,  
Hepatic fibrosis,  
Hepatic hydrothorax,  
Hepatic Hepatic steatosis,  
Hepatitis fulminant,  
Hepatobiliary disease,  
Hepatocellular foamy cell 
syndrome,  
Hepatocellular injury,  
Hepatopulmonary syndrome,  
Hepatorenal failure,  
 
Hepatorenal syndrome,  
Hepatotoxicity,  
Intestinal varices,  
Liver and small intestine transplant,  
Liver disorder,  
Liver injury,  
Liver operation,  
Liver transplant,  
Lupoid hepatic cirrhosis,  
Mixed liver injury,  
Nodular regenerative hyperplasia,  
Non-alcoholic steatohepatitis,  
Oedema due to hepatic disease,  
Oesophageal varices 
haemorrhage,  
Peripancreatic varices,  
Portal fibrosis, Portal hypertension,  
Portal hypertensive enteropathy,  
Portal hypertensive gastropathy,  
Portal triaditis,  
 
Portal vein cavernous 
transformation,  
Portal vein dilatation,  
Portopulmonary hypertension,  
Renal and liver transplant,  
Retrograde portal vein flow,  
Reye's syndrome,  
Reynold's syndrome,  
Splenic varices,  
Splenic varices haemorrhage,  
Subacute hepatic failure,  
Varices oesophageal,  
Varicose veins of abdominal wall,  
Anorectal varices,  
Anorectal varices haemorrhage,  
Intrahepatic portal hepatic venous 
fistula,  
Peritoneovenous shunt,  
Portal shunt,  
Small-for-size liver syndrome,  
Spider naevus. 
  
  
  
  


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Haemorrhage 
Description: 
Any bleeding event, including skin, respiratory, gastrointestinal, genitourinary tracts, brain, tumor or any other 
site bleeding, or PLT decreased or PT\APTT\INR prolongation with corresponding PT as listed in “Preferred 
Term” column, without a bleeding symptom.  
 
Analysis method: 
The overall incidence of the risk of hemorrhage with Fruquintinib compared to placebo will be evaluated using 
the standardized categories of Hemorrhages, and categorized by CTCAE grades.  
Preferred Terms: 
Blood urine present,  
Blood urine,  
Gastric occult blood positive, 
Occult blood positive, 
Haemorrhage,  
Haematoma,  
Haemorrhagic diathesis, 
Haemorrhagic disorder, 
Spontaneous haemorrhage, 
Haemorrhagic stroke, 
Gastrointestinal haemorrhage, 
Upper gastrointestinal 
haemorrhage,  
Lower gastrointestinal 
haemorrhage,  
Gastric haemorrhage,  
Ulcer haemorrhage,  
Rectal haemorrhage, 
 
Anal haemorrhage, 
Haematochezia,  
Melaena, 
Gingival bleeding,  
Lip haemorrhage,  
Mouth haemorrhage,  
Mucosal haemorrhage,  
Epistaxis,  
Haemoptysis,  
Pulmonary haemorrhage, 
Respiratory tract haemorrhage, 
Haemothorax,  
Pericardial haemorrhage, 
Haematuria,  
Renal haemorrhage,  
Urethral haemorrhage,  
Urinary bladder haemorrhage, 
Menorrhagia, 
 
Metrorrhagia, 
Postmenopausal haemorrhage, 
Uterine haemorrhage,  
Vaginal haemorrhage,  
Skin haemorrhage,  
Skin ulcer haemorrhage,  
Soft tissue haemorrhage, 
Subcutaneous haematoma, 
Haemorrhage subcutaneous,  
Nail bed bleeding,  
Ear haemorrhage,  
Eye contusion,  
Eye haemorrhage,  
Eyelid bleeding,  
Retinal haemorrhage,  
Hepatic haemorrhage,  
Splenic haemorrhage, 
Haemarthrosis,  
 
 
Retroperitoneal haematoma, 
Blood blister, 
Bloody discharge,  
Ecchymosis,  
Contusion,  
Purpura,  
Thrombocytopenic purpura, 
Injection site haemorrhage, 
Injection site haematoma,  
Injection site bruising,  
Infusion site haemorrhage,  
Infusion site haematoma,  
Infusion site bruising,  
Traumatic haemorrhage,  
Wound haemorrhage,  
Tumor haemorrhage, 
Disseminated intravascular 
coagulation. 
  
  
  
  


Statistical Analysis Plan for Interventional Studies 
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Hypertension 
Description:  
Any event of hypertension or blood pressure increased, with or without any sign or symptom, corresponding PT 
are listed in “Preferred Term” column. 
 
Analysis method: 
The overall incidence of hypertension with Fruquintinib compared to placebo will be evaluated using the 
standardized categories of Hypertension. It will be categorized by CTCAE grades. 
Preferred Terms: 
Hypertension,  
Blood pressure increased,  
Blood pressure diastolic increased,  
Blood pressure systolic increased,  
Blood pressure inadequately 
controlled,  
 
Blood pressure management,  
Blood pressure orthostatic 
increased,  
Orthostatic hypertension,  
Essential hypertension,  
Hypertensive crisis,  
 
Hypertensive emergency,  
Malignant hypertension,  
Hypertensive encephalopathy,  
Labile hypertension,  
Prehypertension,  
Procedural hypertension,  
 
Renal hypertension,  
Secondary hypertension,  
Systolic hypertension,  
Withdrawal hypertension,  
Blood pressure fluctuation. 
  
  
  
  
Thyroid Dysfunction 
Description: 
Any event of hypothyroidism or other thyroid dysfunction; or 
Lab TSH increase with T3 or T4 decrease, with or without any symptom. Corresponding PT are listed in 
“Preferred Term” column 
 
Analysis method: 
The overall incidence of thyroid dysfunction with Fruquintinib compared to placebo will be evaluated using the 
MedDRA SMQ of Hypothyroidism. It will be categorized by CTCAE grades. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
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Page 87 of 99 
 
Preferred Terms: 
Hypothyroidism,  
Thyroid disorder,  
Thyroxine therapy,  
Thyroid therapy,  
Thyroid atrophy,  
 
Thyroid function test abnormal,  
Thyroxine abnormal,  
Thyroxine decreased,  
Thyroxine free abnormal,  
Thyroxine free decreased,  
 
Tri-iodothyronine abnormal,  
Tri-iodothyronine free decreased,  
Iodine uptake abnormal,  
Iodine uptake decreased,  
Tri-iodothyronine uptake abnormal, 
 
Tri-iodothyronine uptake 
decreased,  
Anti-thyroid antibody positive,  
Anti-thyroid antibody. 
  
  
  
  
Proteinuria 
Description: 
Any event of proteinuria, 24hrs urinary protein high, urinary protein test positive, corresponding PT are listed in 
“Preferred Term” column. 
 
Analysis method: 
The overall incidence of proteinuria with Fruquintinib compared to placebo will be evaluated using a group of 
MedDRA PTs regarding proteinuria (PT listing will be defined upon the cleaned and coded AE data). It will also 
be categorized by CTCAE grades. 
Preferred Terms: 
Protein urine present,  
Proteinuria.  
  
  
  
  
  
Dermatological Toxicity 
Description: 
Any event of hand-foot syndrome or other severe skin reactions, corresponding PT are listed in “Preferred 
Term” column. 
 
Analysis method: 
The overall incidence of HFS and rash with Fruquintinib compared to placebo will be evaluated using a group of 
MedDRA PTs regarding HFS and rash (PT listing will be defined upon the cleaned and coded AE data). It will 
also be categorized by CTCAE grades. 


Statistical Analysis Plan for Interventional Studies 
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Preferred Terms: 
Palmar-plantar 
erythrodysaesthesia syndrome,  
Palmar erythema,  
Dermatitis bullous,  
Dermatitis allergic,  
Dermatitis psoriasiform,  
Dermatitis acneiform,  
Blister,  
Rash,  
Rash erythematous,  
 
Rash maculo-papular, 
Skin reaction,  
Skin disorder,  
Skin exfoliation,  
Erythrosis,  
Nail disorder,  
Nail bed bleeding,  
Acute generalised exanthematous 
pustulosis,  
Cutaneous vasculitis,  
 
Dermatitis exfoliative generalized,  
Dermatitis exfoliative,  
Drug reaction with eosinophilia and 
systemic symptoms,  
Epidermal necrosis,  
Erythema multiforme,  
Exfoliative rash,  
Oculomucocutaneous syndrome,  
Skin necrosis,  
Stevens-johnson syndrome, 
 
Toxic epidermal necrolysis,  
Toxic skin eruption,  
Acquired epidermolysis bullosa,  
Blister rupture,  
Bullous impetigo,  
Drug eruption,  
Epidermolysis bullosa,  
Epidermolysis,  
Skin erosion. 
  
  
  
  
Cardiac Ischemia and Infarction 
Description: 
A group of Acute Cardiac Syndrome (ACS) relevant symptoms, such as chest pain, tightness or discomfort, 
accompanied with dyspnoea, nausea, vomiting…, OR 
Any diagnosis event of angina, ACS ,or cardiac ischemia or infarction. Corresponding PT are listed in 
“Preferred Term” column. 
 
Analysis method: 
The overall incidence of cardiac ischemia and infarction with Fruquintinib compared to placebo will be 
evaluated using the MedDRA SMQ of Ischaemic heart disease. It will be categorized by CTCAE grades. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
Th s document s conf dent a . 
SAP Text Vers on: 1.0 dated 25 Mar 2021 
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Page 89 of 99 
 
Preferred Terms: 
Acute coronary syndrome,  
Acute myocardial infarction,  
Angina unstable,  
Blood creatine phosphokinase MB 
abnormal,  
Blood creatine phosphokinase MB 
increased,  
Coronary artery embolism,  
Coronary artery occlusion,  
Coronary artery thrombosis,  
Myocardial infarction,  
 
Myocardial necrosis ,  
Troponin increased,  
Troponin I increased,  
Troponin T increased,  
Infarction,  
Blood creatine phosphokinase 
abnormal,  
Blood creatine phosphokinase 
increased,  
Cardiac enzymes increased,  
 
Electrocardiogram ST segment 
elevation,  
Electrocardiogram ST-T segment 
elevation,  
Angina pectoris,  
Angina unstable,  
Arteriosclerosis coronary artery,  
Arteriospasm coronary,  
Coronary angioplasty,  
Coronary arterial stent insertion,  
Coronary artery bypass,  
 
Percutaneous coronary 
intervention,  
Coronary artery disease,  
Coronary artery insufficiency,  
Coronary artery stenosis,  
ECG signs of myocardial 
ischaemia,  
Ischaemic cardiomyopathy,  
Myocardial ischaemia,  
Prinzmetal angina,  
Subendocardial ischaemia.  
  
  
  
  
Arterial/Venous 
Thromboembolic Events 
Description: 
Any arterial or venous thromboembolic event, including but not limited to, arterial thrombosis, pulmonary 
embolism, deep vein thrombosis, retinal vein occlusion or thrombosis.  Corresponding PT are listed in 
“Preferred Term” column 
 
Analysis method: 
The overall incidence of thromboembolic events with Fruquintinib compared to placebo will be evaluated using 
the MedDRA SMQ of Embolic and thrombotic events. It will be categorized by CTCAE grades. 
Preferred Terms: 
Acute aortic syndrome,  
Acute myocardial infarction,  
Aortic embolus,  
Aortic thrombosis,  
Arterial occlusive disease,  
Arterial thrombosis,  
Basal ganglia infarction,  
Basilar artery occlusion,  
 
Ischaemic stroke,  
Lacunar infarction,  
Leriche syndrome,  
Mesenteric arterial occlusion,  
Mesenteric arteriosclerosis,  
Mesenteric artery embolism,  
Mesenteric artery stenosis,  
Mesenteric artery thrombosis,  
 
Subclavian artery occlusion,  
Subclavian artery thrombosis,  
Superior mesenteric artery 
syndrome,  
Thrombotic microangiopathy,  
Thrombotic thrombocytopenic 
purpura,  
Transient ischaemic attack,  
 
Portal vein thrombosis,  
Post procedural pulmonary 
embolism,  
Post thrombotic syndrome,  
Postoperative thrombosis,  
Pulmonary embolism,  
Pulmonary infarction,  
Pulmonary microemboli,  


Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
Th s document s conf dent a . 
SAP Text Vers on: 1.0 dated 25 Mar 2021 
Contro ed Document ID: 3903A.02, Effect ve Date 31 Aug 2020 
F ng requ rements: TMF 
Page 90 of 99 
 
Basilar artery thrombosis,  
Blindness transient,  
Brachiocephalic artery occlusion,  
Carotid arterial embolus,  
Carotid artery occlusion,  
Carotid artery thrombosis,  
Cerebellar artery occlusion,  
Cerebellar artery thrombosis,  
Cerebral artery embolism,  
Cerebral artery occlusion,  
Cerebral artery thrombosis,  
Cerebral hypoperfusion,  
Cerebrovascular insufficiency,  
Cerebrovascular stenosis,  
Coeliac artery occlusion,  
Coronary artery embolism,  
Coronary artery occlusion,  
Coronary artery reocclusion,  
Coronary artery thrombosis,  
Embolism arterial,  
Femoral artery embolism,  
Femoral artery occlusion,  
Hepatic artery embolism,  
Hepatic artery occlusion,  
Hepatic artery thrombosis,  
Iliac artery embolism,  
Iliac artery occlusion,  
Intraoperative cerebral artery 
occlusion,  
Ischaemic cerebral infarction, 
 
Myocardial infarction,  
Myocardial necrosis,  
Papillary muscle infarction,  
Penile artery occlusion,  
Peripheral arterial occlusive 
disease,  
Peripheral arterial reocclusion,  
Peripheral artery thrombosis,  
Peripheral embolism,  
Popliteal artery entrapment 
syndrome,  
Post procedural myocardial 
infarction,  
Pulmonary artery thrombosis,  
Renal artery occlusion,  
Renal artery thrombosis,  
Renal embolism,  
Retinal artery embolism,  
Retinal artery occlusion,  
Retinal artery thrombosis,  
Silent myocardial infarction,  
Spinal artery embolism,  
Spinal artery thrombosis,  
Splenic artery thrombosis,  
Splenic embolism,  
Stress cardiomyopathy,  
Subclavian artery embolism,  
Subclavian artery occlusion,  
Stress cardiomyopathy,  
Subclavian artery embolism, 
Truncus coeliacus thrombosis,  
Vertebral artery occlusion,  
Vertebral artery thrombosis,  
Visual acuity reduced transiently,  
Axillary vein thrombosis,  
Cavernous sinus thrombosis,  
Cerebral venous thrombosis,  
Deep vein thrombosis,  
Deep vein thrombosis 
postoperative,  
Embolism venous,  
Hepatic vein occlusion,  
Hepatic vein thrombosis,  
Iliac vein occlusion,  
Inferior vena cava syndrome,  
Inferior vena caval occlusion,  
Intracranial venous sinus 
thrombosis,  
Jugular vein thrombosis,  
May-Thurner syndrome,  
Mesenteric vein thrombosis,  
Mesenteric venous occlusion,  
Obstetrical pulmonary embolism,  
Obstructive shock,  
Ophthalmic vein thrombosis,  
Ovarian vein thrombosis,  
Paget-Schroetter syndrome,  
Pelvic venous thrombosis,  
Penile vein thrombosis, 
Portal vein occlusion,   
Pulmonary thrombosis,  
Pulmonary vein occlusion,  
Pulmonary veno-occlusive disease,  
Pulmonary venous thrombosis,  
Renal vein embolism,  
Renal vein occlusion,  
Renal vein thrombosis,  
Retinal vein occlusion,  
Retinal vein thrombosis,  
Splenic vein occlusion,  
Splenic vein thrombosis,  
Subclavian vein thrombosis,  
Superior sagittal sinus thrombosis,  
Superior vena cava occlusion,  
Superior vena cava syndrome,  
Thrombophlebitis, 
Thrombophlebitis migrans,  
Thrombophlebitis neonatal,  
Thrombophlebitis superficial,  
Thrombosed varicose vein,  
Thrombosis corpora cavernosa,  
Transverse sinus thrombosis,  
Vena cava embolism,  
Vena cava thrombosis,  
Venogram abnormal,  
Venoocclusive disease,  
Venoocclusive liver disease,  
Venous occlusion,  
Venous thrombosis,  
Venous thrombosis limb. 
  
  
  
  


Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
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Page 91 of 99 
 
Gastrointestinal Perforation 
Description: 
Any event of gastrointestinal perforation. 
 
Analysis method: 
The overall incidence of gastrointestinal perforation with Fruquintinib compared to placebo will be evaluated 
using the MedDRA SMQ of Gastrointestinal perforation. It will be categorized by CTCAE grades. 
Preferred Terms: 
Abdominal abscess,  
Abdominal hernia perforation,  
Abdominal wall abscess,  
Abscess intestinal,  
Acquired tracheo-oesophageal 
fistula,  
Anal abscess,  
Anal fistula,  
Anal fistula excision,  
Anastomotic ulcer perforation,  
Anovulvar fistula,  
Aorto-duodenal fistula,  
Aorto-oesophageal fistula,  
Appendiceal abscess,  
Appendicitis perforated,  
Chemical peritonitis,  
Colon fistula repair,  
Colonic abscess,  
Colonic fistula,  
Diverticular fistula,  
Diverticular perforation,  
Douglas' abscess,  
 
Duodenal fistula,  
Duodenal perforation,  
Duodenal ulcer perforation,  
Duodenal ulcer perforation,  
obstructive,  
Duodenal ulcer repair,  
Enterocolonic fistula,  
Enterocutaneous fistula,  
Enterovesical fistula,  
Gastric fistula,  
Gastric fistula repair,  
Gastric perforation,  
Gastric ulcer perforation,  
Gastric ulcer perforation,  
obstructive,  
Gastrointestinal anastomotic leak,  
Gastrointestinal fistula,  
Gastrointestinal fistula repair,  
Gastrointestinal perforation, 
Gastrointestinal ulcer perforation,  
Gastropleural fistula,  
 
Ileal fistula,  
Ileal perforation,  
Ileal ulcer perforation,  
Intestinal fistula,  
Intestinal fistula repair,  
Intestinal perforation,  
Intestinal ulcer perforation,  
Jejunal fistula,  
Jejunal perforation,  
Jejunal ulcer perforation,  
Large intestinal ulcer perforation,  
Large intestine perforation,  
Neonatal intestinal perforation,  
Oesophageal fistula,  
Oesophageal fistula repair,  
Oesophageal perforation,  
Oesophageal rupture,  
Oesophageal ulcer perforation,  
Oesophagobronchial fistula,  
Paraoesophageal abscess,  
 
Peptic ulcer perforation,  
Peptic ulcer perforation,  
obstructive,  
Perforated peptic ulcer oversewing,  
Perforated ulcer,  
Perineal abscess,  
Perirectal abscess,  
Peritoneal abscess,  
Peritonitis,  
Peritonitis bacterial,  
Procedural intestinal perforation,  
Rectal abscess,  
Rectal fistula repair,  
Rectal perforation,  
Rectoprostatic fistula,  
Rectourethral fistula,  
Retroperitoneal abscess,  
Small intestinal perforation,  
Small intestinal ulcer perforation. 
 
 










Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
Th s document s conf dent a . 
SAP Text Vers on: 1.0 dated 25 Mar 2021 
Contro ed Document ID: 3903A.02, Effect ve Date 31 Aug 2020 
F ng requ rements: TMF 
Page 96 of 99 
 
 
Appendix 5. Kaplan Meier Estimates and 95% CI from Brookmeyer and Crowley method 
 
SAS Code example for KM estimates and 95% CI from a log-log transformation based on 
Brookmeyer-Crowley method 
Example SAS code for 95% CI calculated from a log-log transformation based on the method by 
Brookmeyer and Crowley, for median, 25th and 75th percentiles: 
*** KM Estimates - Quartiles ***; 
ods output quartiles=quartiles1; 
proc lifetest  
 
data=ADTTE(where=(PARAMCD="OS")) 
 
conftype=loglog; 
 
time AVAL*CNSR(1); 
 
strata TRTPN; 
run; 
 
AVAL is the time in months, CNSR is the censoring variable, TRTPN is the treatment group variable. 
The output dataset (quartiles1) contains by treatment group, the estimate for median (ESTIMATE, where 
PERCENT=50), 25% (ESTIMATE, where PERCENT=25), and 75% (ESTIMATE, where PERCENT=75), 
along with the corresponding 95% CI calculated from a log-log transformation (for each corresponding 
PERCENT=25, =50 and =75, the CI values are stored in LowerLimit and UpperLimit). 
 
SAS Code example for KM estimates and 95% CI from a linear transformation based on 
Brookmeyer-Crowley method at selected landmarks 
Example SAS code for 95% CI calculated from a linear transformation based on the method by Brookmeyer 
and Crowley at selected landmarks, for example, at 3, 6, 9, 12, and 18 months: 
*** KM Estimates - Timelist ***; 
proc lifetest  
 
data=ADTTE(where=(PARAMCD="OS")) 
 
conftype=linear method=km atrisk timelist=(3, 6, 9, 12, 18) 
reduceout outsurv=tlist; 
 
time AVAL*CNSR(1); 
 
strata TRTPN;  
run; 
 
AVAL is the time in months, CNSR is the censoring variable, TRTPN is the treatment group variable. 
The outsurv dataset (tlist) will provide by treatment group, the estimate (SURVIVAL*100) at specified time 
points (variable TIMELIST) and the corresponding 95% CIs (SDF_LCL*100, SDF_UCL*100). 


Statistical Analysis Plan for Interventional Studies 
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Page 97 of 99 
 
 
Appendix 6. Stratified Log-Rank Test 
Example SAS code for Stratified Log-Rank Test, accounting for randomization schedule stratification 
factors. 
*** Stratified Log rank test ***; 
ods output LogUniChisq=logunichisq1; 
proc lifetest  
 
data=ADTTE(where=(PARAMCD="OS")) 
 
method=km; 
 
time AVAL*CNSR(1); 
strata STRAT1RN STRAT2RN STRAT3RN; 
test TRTPN; 
run; 
 
AVAL is the time in months, CNSR is the censoring variable, TRTPN is the treatment group variable, and 
STRAT1RN, STRAT2RN and STRAT3RN are placeholder variables representing the randomization 
schedule stratification factors.  
The output dataset (logunichisq1) contains the p-value for the Log-Rank Test (ProbChiSq) comparing the 
treatment groups. 
 
Multiplicity Adjustment for Log-Rank Tests for OS and PFS 
A fixed-sequence (hierarchical) testing procedure is used to control the overall type I error rate at 0.05.  If 
the resulting 2-sided p-value from the analysis of primary endpoint OS is ≤ 0.05, then, a superiority test of 
for PFS will be conducted at the two-sided significance level of 0.05.  
If the resulting p-value from the analysis of primary endpoint OS is ≤ 0.05 then the adjusted p-values are 
the maximum value between the p-values produced for the OS and PFS procedures. 
data pvalue; 
   input p @@; 
   if (_n_ = 1) then 
      pseq = 0; 
   pseq = max(pseq, p); 
   retain pseq; 
   cards; 
0.021 0.043; 
run; 
The raw p-values used to calculate the adjusted p-value will be obtained from the SAS programming for 
OS and PFS, then, this sample program will be tailored in the production.  


Statistical Analysis Plan for Interventional Studies 
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Appendix 7. Stratified Cox Proportional Hazard Model 
Example SAS code for hazard ratio between the 2 treatment groups (fruquintinib vs placebo), and 
corresponding 95% CIs, calculated from a stratified Cox proportional hazard model (i.e. accounting for 
randomization schedule stratification factors) in which the treatment group is the only covariate in the model:  
*** Hazard ratio ***; 
ods output hazardratios=hazrat1; 
proc phreg 
 
data=ADTTE(where=(PARAMCD="OS")) 
alpha=0.05;  
 
model AVAL*CNSR(1)=TRTPN; 
strata STRAT1RN STRAT2RN STRAT3RN; 
hazardratio TRTPN; 
run; 
 
AVAL is the time in months, CNSR is the censoring variable, TRTPN is the treatment group variable, and 
STRAT1RN, STRAT2RN and STRAT3RN are placeholder variables representing the randomization 
schedule stratification factors.  
The output dataset (hazrat1) contains the hazard ratio (HazardRatio) and the corresponding 95% CI 
(WaldLower, WaldUpper). Confirm the order of TRTPN variables is coded so HR < 1 indicates a favorable 
clinical benefit from fruquintinib over the placebo group. 
 
Appendix 8. Cochran-Mantel Haenszel test stratified by randomization schedule 
stratification factors 
Example SAS code for p-value of comparing treatment groups based on a Cochran-Mantel Hanzel test 
stratified by the randomization schedule stratification factors. 
 
 *** stratified Cochran-Mantel Haenszel (CMH) test ***; 
ods output CMH=cmh1; 
proc freq 
 
data=ADEFF(where=(PARAMCD="ORR")); 
table STRAT1RN*STRAT2RN*STRAT3RN*TRTPN*AVAL/cmh; 
run; 
 
TRTPN is the treatment group variable and STRAT1RN, STRAT2RN and STRAT3RN are placeholder 
variables representing the randomization schedule stratification factors.  
The output dataset (cmh1) contains the p-value (Prob, corresponding to the Statistic=3, for General 
Association). If the number of objective   responses is not sufficient to utilize the CMH test, a stratified exact 
CMH test will be performed instead. 
 
Appendix 9. Adjusted proportion difference between treatment groups with 95% CI using 
the Wald method to account for randomization schedule stratification factors 
Example SAS code for adjusted proportion difference between treatment groups with 95% CI using the 
Wald method to account for randomization schedule stratification factors: 


Statistical Analysis Plan for Interventional Studies 
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Page 99 of 99 
 
ods output CommonPdiff=pdiff1; 
proc freq data = ADEFF(where=(PARAMCD="ORR")); 
      tables STRAT1RN*STRAT2RN*STRAT3RN*TRTPN*AVAL/riskdiff(column=2 
common cl=wald); 
run; 
 
Using ADEFF and variable AVAL, the outcome of interest is ORR (i.e. Objective response rate), TRTPN is 
the treatment group variable and STRAT1RN, STRAT2RN and STRAT3RN are placeholder variables 
representing the randomization schedule stratification factors. The above example assumes the response 
is coded in column 2 (i.e. AVAL is coded as 0, 1, where 1 is response), and that fruquintinib is presented in 
row 1, and placebo is presented in row 2. The above code will be adjusted for correct presentation based 
on the actual coding in ADEFF if necessary. 
The output (pdiff1) provides an adjusted proportion difference between treatment groups (the variable 
Value, when Method="Mantel-Haenszel") with a 95% CI (the variables LowerCL, UpperCL, when 
Method="Mantel-Haenszel") using the Wald method to account for randomization schedule stratification 
factors. 
 Appendix 10. REML-based MMRM 
Example SAS code for REML-based MMRM: 
 
proc mixed  
data=ADQS(where=(PARAMCD="PHYSF" and ANL20FL="Y")) 
method=reml; 
class USUBJID TRTPN AVISITN STRAT1RN STRAT2RN STRAT3RN; 
model CHG = BASE TRTPN AVISITN TRTPN*AVISITN STRAT1RN STRAT2RN 
STRAT3RN/solution ddfm=kr;  
repeated AVISITN/subject=USUBJID type=UN; 
lsmeans TRTPN*AVISITN/diff cl slice = AVISITN; 
run;  
 
CHG is the change from baseline in score of the subscale, USUBJID is the subject identification variable, 
TRTPN is the treatment group variable, AVISITN is a placeholder variable for visit, TRTPN*AVISITN is the 
treatment group-by-visit interaction, BASE is a placeholder variable for baseline value of scale, and 
STRAT1RN, STRAT2RN, and STRAT3RN are placeholder variables representing the randomization 
schedule stratification factors.  
Prior to performing this analysis, the visits for each subject are limited within the dataset up to the last cycle 
with at least 20 subjects in any of the treatment groups (i.e. all subsequent cycles have less than 20 patients 
in each of the treatment groups). If there is a convergence issue with the unstructured covariance model, 
Toeplitz, Autoregressive (1) (AR (1)) covariance structure is used, following this sequence until 
convergence is achieved.  If the model still does not converge with AR (1) structure, no results are reported. 
When the covariance structure is not unstructured, the sandwich estimator for the variance-covariance 
matrix is derived, using the EMPIRICAL option in the PROC MIXED statement in SAS. 








Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
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Page 4 of 134 
 
I conf rm that I have rev ewed th s document and agree w th the content. 
Approvals 
Syneos Health Approval 
 
 
 
 
 
 
Name, T t e 
Lead  B ostat st c an / Support 
B ostat st c an 
 
S gnature 
 
Date (DD Mmm YYYY) 
 
 
 
 
 
 
Name, T t e 
 
S gnature 
 
Date (DD Mmm YYYY) 
Hutchison MediPharma Limited Approval 
 
 
 
 
 
 
 
Sponsor Contact 
 
S gnature 
 
Date (DD Mmm YYYY) 
 
 
 
 
 
 
 
Sponsor Contact 
 
S gnature 
 
Date (DD Mmm YYYY) 
 
 
 
 
 
 
 
 
 
 
Sponsor Contact 
 
S gnature 
 
Date (DD Mmm YYYY) 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
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Page 5 of 134 
 
Table of Contents 
Revision History ............................................................................................................................ 2 
Approvals .................................................................................................................................... 4 
 
Glossary of Abbreviations .................................................................................................. 10 
 
Purpose .............................................................................................................................. 14 
 
Study Objectives ................................................................................................................ 16 
 
Study Details/Design .......................................................................................................... 18 
 
Endpoints ........................................................................................................................... 24 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
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Page 6 of 134 
 
 
Analysis Populations .......................................................................................................... 28 
 
General Aspects for Statistical Analysis ............................................................................ 30 
 
Demographic, Other Baseline Characteristics and Medication .......................................... 39 


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Efficacy .............................................................................................................................. 47 
 
Pharmacokinetics ............................................................................................................... 60 


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Safety ................................................................................................................................. 62 
 
IDMC Review ..................................................................................................................... 73 
 
Changes from Analysis Planned in Protocol ...................................................................... 74 
 
Reference List .................................................................................................................... 75 
 
Programming Considerations ............................................................................................ 76 


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Quality Control ................................................................................................................... 82 
 
Appendix ............................................................................................................................ 83 
 


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Glossary of Abbreviations 
Abbreviation 
Description 
AE 
Adverse event 
ADaM 
Analysis Data Model 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
aPTT 
Activated Partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATC 2 
Anatomical therapeutic class 2 
AR (1) 
Autoregressive (1)  
BMI 
Body mass index 
BLQ 
Below the lower limit of quantification 
BRAF 
B-Raf proto-oncogene 
BSC 
Best supportive care 
CEA 
Carcino-embryonic antigen 
CI 
Confidence interval 
CMH 
Cochran-Mantel Haenszel 
COVID-19 
Coronavirus 2019 
ctDNA 
Circulating tumor DNA 
CTMS 
Clinical trial management system 
CR 
Complete response 
CS 
Clinically significant 
CSR 
Clinical study report 
CV 
Coefficient of variation 
CRO 
Clinical research organization 
CT 
Computed tomography 
CTCAE  
Common Terminology Criteria for Adverse Event 
dMMR 
Deficient mismatch repair 
DCR 
Disease control rate 
DoR 
Duration of response 


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Abbreviation 
Description 
eCRF 
Electronic case report form 
ECHO 
Echocardiogram 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End of treatment 
ERT 
eResearchTechnology, Inc. 
HR 
Hazard ratio 
ICF 
Informed consent form 
IDMC 
Independent data monitoring committee 
IND 
Investigational new drug 
INR 
International normalized ratio 
IRT 
Interactive response technology 
ITT 
Intent-to-Treat 
IWRS 
Interactive web response system 
JSMC 
Japanese safety monitoring committee 
LDH 
Lactate dehydrogenase 
LS 
Least-square 
mCRC 
Metastatic colorectal cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSI 
Microsatellite instability 
MSI-H 
Microsatellite instability-high 
MID 
Minimally important difference 
MMR 
Mismatch repair  
MSS 
Microsatellite stable 
MMRM 
Mixed model repeated measures 
MRI 
Magnetic resonance imaging 
MUGA 
Multigated acquisition  


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Abbreviation 
Description 
NA 
Not available 
NCS 
Not clinically significant 
NE 
Not evaluable 
ORR 
Objective response rate 
OS 
Overall survival 
pMMR 
Proficient mismatch repair 
PD  
Progressive disease 
PID 
Percentage intended dose 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PO 
Per os (oral administration) 
PR 
Partial response 
PR 
PR Interval (ECG Parameter) 
PT 
Preferred term 
Q1 
Lower quartile 
Q3 
Upper quartile 
QoL 
Quality of life 
QD 
Quaque die (once daily) 
QTcB 
QT correction Bazett formula 
QTcF 
QT correction Fridericia formula 
QRS 
A combination of the Q wave, R wave and S wave 
RAS  
Rat sarcoma 
REML 
Restricted maximum likelihood 
RD 
Relative dose 
RDI 
Relative dose intensity  
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE  
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SD 
Stable disease 


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Abbreviation 
Description 
StdDev 
Standard deviation 
SDTM 
Study Data Tabulation Model 
SE 
Standard error 
SI 
International System of Units 
SOC 
System organ class 
TLFs 
Tables, listings and figures 
TSH 
Thyroid-stimulating hormone 
TTD 
Time to deterioration 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
VAS 
Visual analogue scale 
VEGF 
Vascular Endothelial Growth Factor 
WHODD 
World Health Organization Drug Dictionary 
 
 
 


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Purpose 
The purpose of this statistical analysis plan (SAP) for the study is to ensure that the data listings, summary 
tables and figures that are to be produced, and the statistical methodologies that are used, are complete 
and appropriate to allow valid conclusions regarding the study objectives.  The SAP adheres to the proper 
regulatory guidelines and most recent International Council for Harmonisation guidelines (E3, E6, E9). All 
decisions regarding the final analyses, as defined in this SAP document, have been made prior to locking 
the database; any deviations from these guidelines will be documented in the clinical study report (CSR).  
A separate SAP is to be developed for the protocol Japanese Specific Addendum (Safety Lead-In for 
Japan).  
 
Responsibilities 
Syneos Health is to perform the statistical analyses and are responsible for the production and quality 
control of all Study Data Tabulation Model (SDTM) datasets, Analysis Data Model (ADaM) datasets, and 
the tables, listings, and figures (TLFs) for efficacy and safety, as well as tabulation of fruquintinib and M11 
concentrations from PK  (pharmacokinetic) plasma samples.  Details for analysis of circulating tumor DNA 
and pharmacogenomics will be prepared in a separate document. The SAP for population PK, 
Electrocardiogram (ECG) (pharmacodynamics) and QTc-PK analysis will be prepared separately by 
another contract research organization (CRO). 
 
Timings of Analyses 
An independent data monitoring committee (IDMC) is to review descriptive summaries of accumulating 
safety and subject disposition every 6 months, or at a frequency recommended by the IDMC, as described 
in the IDMC Charter Final Version 1.0 dated 25-Aug-2020.  An unblinded team from Syneos Health 
Biostatistics is to perform the analyses as described in Section 18, Content of Open and Closed Sessions 
of the IDMC Charter, in order to maintain the blinding of the study. 
 
Interim Analyses 
One interim non-binding futility analysis is to be performed once 1/3 of the total number of overall survival 
(OS) events (i.e., 160 OS events) have occurred. This interim analysis is for futility only, there are no plans 
to stop the study early for efficacy based on OS data at the interim analysis.  
The IDMC is to be instructed to recommend stopping the study for futility if the 1-sided p-value from a 
stratified log-rank test is at least 0.772 (corresponding to an observed HR of 1.133).  Otherwise, the study 
is to be continued with full enrollment.  
There is a 22.8% chance of terminating the study for futility at the interim analysis if the true median OS in 
fruquintinib arm is 5 months, i.e., fruquintinib is ineffective.  There is a 0.4% chance of stopping for futility, 
declaring fruquintinib ineffective at the interim if the true median OS in fruquintinib arm is 6.8 months, i.e., 
fruquintinib is effective in the study population. 


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Final Analysis 
If the study does not stop based on the futility analysis, the final analysis for the CSR will be conducted 
when at least 480 OS events have been observed. All study data collected up through the time of the final 
analysis will be summarized, unless otherwise specified. Unblinding will occur at the time of the final 
analysis.  


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Study Objectives 
 
Primary Objective 
• 
To evaluate the overall survival (OS) of fruquintinib plus best supportive care (BSC) compared to 
placebo plus BSC in subjects with refractory metastatic colorectal cancer (mCRC). 
 
Secondary Objective(s) 
• 
To evaluate progression-free survival (PFS) of fruquintinib plus BSC compared to placebo plus 
BSC. 
• 
To evaluate the objective response rate (ORR), disease control rate (DCR), and duration of 
response (DoR). 
• 
To assess the safety and tolerability of fruquintinib plus BSC compared to placebo plus BSC. 
• 
To characterize the PK exposure of fruquintinib and metabolite M11 in subjects with refractory 
mCRC. 
• 
To evaluate the effect of fruquintinib on cardiac repolarization, as detected by changes in 
electrocardiogram (ECG) QTc intervals, and the potential relationship with fruquintinib and M11 
plasma concentrations. 
• 
To explore the relationship between fruquintinib exposure and endpoints for efficacy and safety. 
• 
To evaluate quality of life (QoL) as assessed by using European Organisation for Research and 
Treatment of Cancer (EORTC) QLQ-C30: cancer-specific; and EQ-5D-5L questionnaires. 
• 
To assess resource utilization (for example, hospitalizations, concomitant medications). 
 
Exploratory Objective 
• 
To assess potential predictive biomarkers of response to fruquintinib. 
Details of the study objectives and correspondent endpoints is provided in Table 1. 
Table 1. Objectives and Corresponding Endpoints 
Tier 
Objectives 
Endpoints 
Primary 
To evaluate the overall survival of  
fruquintinib plus BSC compared to placebo 
plus BSC in subjects with refractory mCRC 
OS 
Secondary 
To evaluate progression-free survival  of 
fruquintinib plus BSC compared to placebo 
plus BSC 
PFS 
To evaluate the objective response rate, 
disease control rate, and duration of response  
• ORR 
• DCR 
• DoR 


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Tier 
Objectives 
Endpoints 
To assess the safety and tolerability of 
fruquintinib plus BSC compared to placebo 
plus BSC 
Safety including treatment-emergent 
adverse events (TEAEs), serious 
adverse events (SAEs), deaths, ECG’s, 
and clinical laboratory abnormalities 
To characterize the PK profile of fruquintinib in 
subjects with refractory mCRC 
Observed plasma concentrations, 
estimated population PK and exposure 
parameters of fruquintinib and M11 
To evaluate the effect of fruquintinib on 
cardiac repolarization, as detected by 
changes in electrocardiogram (ECG) QTc 
intervals, and the potential relationship with 
fruquintinib and M11 plasma concentrations 
QTc interval and plasma concentrations 
of fruquintinib and M11 at specified time 
points  
To evaluate the relationship between 
fruquintinib exposure and endpoints for 
efficacy and safety 
Parameters describing exposure-
response with efficacy (e.g., OS) and 
safety (e.g., adverse events [AEs]) 
endpoints 
To evaluate quality of life (QoL) as 
assessed by using QLQ-C30: cancer specific; 
and EQ-5D-5L questionnaires 
Changes in health status (QLQ-C30: 
cancer specific; and EQ-5D-5L) 
To assess resource utilization (for example, 
hospitalizations, medications) 
Resource utilization including all 
concomitant medications, days in 
hospital 
Exploratory To assess potential predictive biomarkers of 
response to fruquintinib 
• Change from baseline in circulating 
tumor DNA (ctDNA) 
• Change from baseline in tumor 
markers (carcino-embryonic antigen 
[CEA]) 
• Pharmacogenomics 
 
 
 


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Study Details/Design 
 
Brief Description 
The study is a global, randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial to 
compare the efficacy and safety of fruquintinib plus BSC versus placebo plus BSC in subjects with mCRC.  
Approximately 687 subjects are to be randomized in a 2:1 ratio to either the fruquintinib plus BSC treatment 
group or the placebo plus BSC treatment group. 
Randomization is stratified by the following factors: 
• 
Prior therapy with trifluridine/tipiracil (TAS-102) versus regorafenib versus both trifluridine/tipiracil 
(TAS-102) and regorafenib. 
• 
RAS (rat sarcoma) status (wild type versus mutant). 
• 
Duration of metastatic disease (≤18 months versus >18 months). 
Subjects are to receive study treatment, with each 4-week cycle consisting of 3 weeks of daily oral study 
medication and 1 week of study treatment interruption (3 weeks on/1 week off).  Tumor evaluation is 
performed by imaging (computed tomography [CT] or magnetic resonance imaging [MRI] scan) every 8 
weeks until there is progressive disease (PD), death, new anti-cancer treatment, study treatment 
discontinuation or study completion, whichever comes first.  Safety parameters include assessment of 
adverse events (AE), laboratory tests, vital signs, ECG, Echocardiogram (ECHO), physical examination, 
Eastern Cooperative Oncology Group (ECOG) performance status, EORTC QLQ-C30 and EQ-5D-5L 
questionnaires.  Post-discontinuation anti-tumor treatment and survival follow-up after PD is also recorded. 
 
Subject Selection 
The study is conducted at approximately 140 international study sites with a study population of subjects 
≥18 years of age with histologically and/or cytologically documented metastatic colorectal adenocarcinoma 
who progressed on, or were intolerant to, all standard chemotherapies and relevant biologics and TAS-102 
and/or regorafenib. 
 
Inclusion Criteria 
Refer to Section 5.3 Inclusion Criteria of the study protocol. 
 
Exclusion Criteria 
Refer to Section 5.4 Exclusion Criteria of the study protocol. 
 
Statistical Hypothesis  
This study is designed to demonstrate superiority of fruquintinib plus BSC (fruquintinib arm) over placebo 
plus BSC (placebo arm) in prolonging OS for subjects with refractory mCRC. The study is designed to test 
the null hypothesis H0: λ=1.0 versus the alternative hypothesis Ha: λ < 1.0, where λ is the hazard ratio 
(treatment arm/placebo arm). 


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Determination of Sample Size 
With regards to the study, the total sample size and number of OS events required for efficacy assessment 
in the intent-to-treat population is calculated based on the following assumptions: 
• 
A one-sided significance level of 0.025; 
• 
Assuming an OS hazard ratio (HR) of 0.73 (fruquintinib arm/placebo arm), this sample size yields 
approximately 90% statistical power to detect superiority of the fruquintinib arm over placebo arm.  
If the true median OS for the placebo arm is 5 months, then the HR of 0.73 corresponds to median 
OS of 6.8 months in the fruquintinib arm (median OS improvement of 1.8 months).   
• 
An enrollment rate of 30 subjects per month during the first 3 months and 50 subjects per month 
thereafter; 
• 
Yearly dropout rate of 10%; 
• 
Randomization ratio = 2:1 (fruquintinib arm/placebo arm); 
• 
Data maturity = 70%; 
• 
One interim futility analysis when 1/3 of the total number of OS events (i.e., 160 OS events) have 
occurred, the Lan-DeMets spending function is used in the calculation. 
Under the premise of these assumptions, approximately 687 subjects are to be randomized to this study 
over approximately 15 months in this study.  OS is to be analyzed when 480 OS events have been 
observed, which is expected to occur in approximately 7 months after the end of enrollment.  EAST version 
6.5 was utilized for the calculation. 
In clinical practice, TAS-102 is used more commonly than regorafenib.  To ensure that the subject 
population is representative of clinical practice, post-regorafenib (regorafenib or both trifluridine/tipiracil 
(TAS-102) and regorafenib) subjects are to be capped at 344.  This ensures that at least 50% of the subjects 
are post-TAS.   
Subjects are considered in post-TAS-102 or post-regorafenib populations if they have received at least one 
dose of either agent, respectively, prior to entering the study.  Based on the similar mechanisms of action 
between regorafenib and fruquintinib, it is to be of clinical interest to evaluate the magnitude of benefit in 
each of the populations when compared to the intent-to-treat population. 
 
Treatment Assignment and Blinding 
The study subject, investigators, and study site personnel are to remain blinded to all randomization 
assignments throughout the study.  The sponsor’s study director, study monitor, and any other sponsor and 
Syneos Health personnel who are in regular contact with the study site are to remain blinded to all subject 
randomization assignments, except sponsor pharmacovigilance personnel for the purpose of 
Investigational New Drug (IND) safety reports.  Treatment is allocated using Interactive Web Response 
System (IWRS) randomization strategy and procedure defined in the IWRS manual.    


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Unblinding can occur in emergency cases.  If unblinding is required for treatment of a subject for an SAE, 
the investigator must first contact the sponsor’s medical monitor before unblinding, and then unblind the 
subject using the IWRS.  Once unblinded, the subject should discontinue the treatment but continue to be 
followed for safety and efficacy.  The investigator should record the event in the source document. 
The interim futility analysis maintains blinding at IDMC meetings during the Open Sessions following the 
procedures described in Section 18, Content of Open and Closed Sessions of the latest version of the 
IDMC Charter. 
 
Administration of Study Medication 
Fruquintinib (HMPL-013) capsule 5 mg is administered orally (PO) once daily (QD), 3 weeks on, 1 week off 
(4-week cycles).  Subjects are randomized into either fruquintinib in combination with BSC group (treatment 
group) or placebo in combination with BSC group (control group) in a 2:1 ratio (Figure 1). 
If study treatment dose adjustment is required, the site must log into the IWRS, adjust the dose, reassign 
the drug serial number, and dispense new study treatment dose (in 1 mg capsules) to the subject.  If the 
dose is adjusted a second time, i.e., from 4 mg QD to 3 mg QD, the site must log into the IWRS and record 
the second dose adjustment.  On this occasion, it is not necessary to reassign a new drug serial number. 
If tumor evaluation shows PD during the previous cycle and new drug has been dispensed, the subject 
must return all unused study treatment on the 30-day safety visit after end of treatment (EOT). 
• 
Treatment group: fruquintinib 5 mg PO, QD, plus BSC, 3 weeks on/ 1 week off, every 4-week cycle. 
• 
Control group: Matching placebo 5 mg PO, QD plus BSC, 3 weeks on/ 1 week off, every 4-week 
cycle. 
Subjects are allowed to have no more than 2 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.  Once a dose has been reduced, 
it cannot be re-escalated.  The dose reduction sequence by starting dose is shown in Table 2 below.   
Table 2.  Dose Modification Sequence by Starting Dose 
Dose Level 0* 
(Original dose) 
5 mg QD 3 weeks on, 1 week off 
fruquintinib of 5 mg, 1 capsule, or 1 
capsule of the matching placebo 
Dose Level -1* 
(the 1st dose reduction) 
4 mg QD 3 weeks on, 1 week off 
fruquintinib of 1 mg, 4 capsules, or 4 
capsules of the matching placebo 
Dose Level -2* 
(the 2nd dose reduction) 
3 mg QD 3 weeks on, 1 week off 
fruquintinib of 1 mg, 3 capsules, or 3 
capsules of the matching placebo 
 
Reasons and guidelines for dose modifications are detailed in Section 7.5.6 of the protocol.  


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Study Procedures and Flowchart 
The study contains the following procedures. 
• 
Screening Period: This period contains two visit windows of -28 to -1 days and -7 to -1.  
• 
Study Treatment Period: This period contains treatment cycles, with a visit window of +/- 3 days for 
each scheduled visit starting at Cycle 2 day 1.  
o 
Cycle 1 includes cycle 1 day 1 and cycle 1 day 21 visits;  
o 
Cycle 2 includes cycle 2 day 1 and cycle 2 day 21 visits; 
o 
Cycle 3 includes cycle 3 day 1 and cycle 3 day 21 visits;  
o 
Cycle 4 and beyond include cycle 4 day 1, cycle 5 day 1, etc.   
• 
Follow-Up: This period contains the following. 
o 
Post treatment: 7 days after last dose with a visit window of +/- 3 days,  
o 
Safety Follow-up: 30 days after EOT visit with a visit window of +/- 7 days, and 
o 
Survival Follow-up: 12 weeks from EOT visit with a visit window of +/- 14 days. 
o 
EOT: last non-missing assessment during the treatment period (treatment period is from 
the date of the first study drug administration until 37 days after last dose) 
The protocol activities include the following throughout the periods listed above.  
• 
Informed Consent. 
• 
Demographics. 
• 
Medical History, Disease History, and molecular characterization of RAS, B-Raf proto-oncogene 
(BRAF), Microsatellite Instability (MSI)/ Mismatch Repair (MMR) status. 
• 
Prior and Concomitant Medication/Concomitant Procedure. 
• 
Comprehensive Physical Examination. 
• 
Limited Physical Examination. 
• 
ECOG. 
• 
Vital Signs. 
• 
Hematology. 


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• 
Blood Chemistry. 
• 
Blood amylase and lipase. 
• 
Coagulation. 
• 
Thyroid Function. 
• 
Urinalysis. 
• 
Serum Pregnancy Test. 
• 
Urine Pregnancy Test. 
• 
12-lead ECG. 
• 
ECHO/Multigated acquisition (MUGA). 
• 
Tumor Evaluation/Imaging. 
• 
Tumor Markers. 
• 
Circulating Tumor DNA, excluded from Japanese Specific Addendum.  
• 
PK Plasma Sampling. 
• 
Subject Randomization, excluded from Japanese Specific Addendum. 
• 
Drug/Dispense/Return. 
• 
Study Treatment. 
• 
Adverse Event. 
• 
Survival Follow-up. 
• 
EORTC  QLQ-C30 Questionnaire, excluded from Japanese Specific Addendum. 
• 
EQ-5D-5L Questionnaire, excluded from Japanese Specific Addendum. 
Details of study procedures can be found in the following tables within the protocols. 
• 
Table 1. Schedule of Events. 
• 
Table 2. Schedule of Events for Pharmacokinetic and Electrocardiogram Evaluations for the First 
Approximately 120 Subjects, and  
• 
Table 3.  Schedule of Events for Pharmacokinetic and Electrocardiogram Evaluations for Subjects 


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Enrolled After the First Approximately 120.  
The study schematic is presented in Figure 1. 
Figure 1.  Study Design Schema 
 


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Endpoints   
 
Primary Efficacy Endpoint 
The primary endpoint of the study is OS, defined as the time (months) from date of randomization to death 
from any cause. That is, OS is calculated as (date of death or last known alive – date of randomization + 
1)/30.4375.   Subjects without report of death at the time of analysis are censored at the date last known 
alive.  Subjects lacking data beyond the date of randomization have their survival time censored at the date 
of randomization.  OS will not be censored if a subject receives subsequent anticancer treatments after 
discontinuation of the study treatments. Date of last known alive defined in Section 7.2.4 and date of death 
is defined in Section 7.2.5 of the SAP. 
 
Secondary Endpoints 
• 
Key secondary efficacy endpoint: PFS.  
PFS is defined as the time (months) from randomization until the first radiographic documentation of 
objective progression as assessed by investigator using Response Evaluation Criteria In Solid Tumors 
(RECIST) v1.1, or death from any cause. More specifically, PFS will be determined using all the assessment 
data up until the last evaluable visit prior to or on the date of (i) disease progression as defined by RECIST 
Version 1.1 or death; or (ii) withdrawal of consent or lost to follow-up; or (iii) receiving subsequent anti-
cancer therapy, whichever is earlier. Subjects without report of PD or death from any cause at the time of 
analysis are censored as described in Table 3 below. 
The PFS time will always be derived based on scan dates not tumor assessment dates. RECIST 
assessments/scans contributing towards a particular visit may be performed on different dates. The 
following rules are applied: 
1. Date of progression is determined based on the earliest of the dates of the component that triggered 
the progression. 
2. When censoring a subject for PFS, the subject is censored at the latest of the dates contributing to 
a particular overall visit assessment. 




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Objective response rate (ORR) will be calculated using two different ways: 
§ 
Scenario #1: ORR will be calculated using a strict interpretation of RECIST Version 
1.1. Objective response will be derived as no/yes variable. Subjects with a BOR of 
confirmed CR or PR will be assigned ‘Yes’. Subjects not having a BOR of 
confirmed CR or PR will be assigned ‘No’. Hence, ORR is defined as the proportion 
of subjects with objective response being “Yes”.  
§ 
Scenario #2: ORRUNCONF RMED will be calculated using all responses regardless of 
confirmation. Objective response will be derived as no/yes variable.  Subjects with 
a BOR of confirmed CR, confirmed PR, unconfirmed CR or unconfirmed PR will 
be assigned “Yes”.  All subjects with other BOR values will be assigned “No”.  
Hence, ORRUNCONF RMED is defined as the proportion of subjects with objective 
response being “Yes”. 
o 
DCR is defined as proportion of subjects achieving a best overall response of confirmed 
CR, PR, or SD (for at least 7 weeks)per RECIST v1.1, as determined by the investigator.  
To be qualified for SD, the duration of SD should last for at least 7 weeks. 
o 
DoR is defined as the time (months) from the first occurrence of PR or CR by RECIST 
Version 1.1, until the first date that progressive disease is documented by RECIST Version 
1.1, or death, whichever comes first. Only those subjects with confirmed responses of CR 
or PR will be included in this analysis. Censoring will follow the rules outlined for PFS in 
Table 3 in this section. For those subjects who do not have censored DoR, it is calculated 
as (date of death or PD or last assessment – date of first occurrence of confirmed CR or 
PR + 1)/30.4375. 
• 
Changes in health status (QLQ-C30: cancer specific; and EQ-5D-5L). 
• 
Resource utilization including all concomitant medications, days in hospital. 
 
Exploratory Endpoints 
• 
Change from baseline in circulating tumor DNA (ctDNA), analysis plan to be included in a 
separate document. 
• 
Change from baseline in tumor markers (carcino-embryonic antigen [CEA]). 
• 
Pharmacogenomics,  analysis plan to be included in a separate document. 
 
Safety Endpoints 
• 
Safety including treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), 
deaths, ECG’s, and clinical laboratory abnormalities. 


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Pharmacokinetic Endpoints 
• 
Observed plasma concentrations, estimated population PK and exposure parameters of 
fruquintinib and M11. 
• 
QTc interval and plasma concentrations of fruquintinib and M11 at specified time points.  
 
Pharmacodynamic Endpoints 
• 
Parameters describing exposure-response with efficacy (e.g., OS) and safety (e.g., AEs) 
endpoints. 


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Analysis Populations 
 
Screened Population 
The Screened population includes all subjects who signed informed consent form (ICF).   
 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population includes all randomized subjects.  Subjects are analyzed by treatment 
group as randomized.  The ITT population is the primary population for evaluating all efficacy endpoints 
and subject characteristics.   
 
Safety Population 
The Safety population includes all randomized subjects who received at least one dose of study treatment.  
Subjects in this population are analyzed according to the treatment they actually received.  This population 
is used for all safety analyses.   
In the event that there are protocol deviations reported during the conduct of the study leading to a patient 
receiving mixed treatment (ie, receiving both placebo and fruquintinib), the actual treatment assigned for 
the patient will be the most frequently used treatment. For example, if a patient received 42 days of placebo 
and 21 days of fruquintinib during the treatment period, then the actual treatment for the patient will be 
PLACEBO. However, if the duration of treatment for placebo and fruquintinib tie, then the assigned 
treatment at the time of randomization for the patient will be the actual treatment used for the patient in the 
summary. For example, a patient was randomized to fruquintinib, but received 21 days of placebo and 21 
days of fruquintinib during the treatment period, then the actual treatment for the patient will be 
FRUQUINTINIB which is the assigned treatment at randomization. 
 
Per Protocol (PP) Population 
The per-protocol (PP) analysis set will include only those subjects in ITT who received the treatment to 
which they were randomized to and have no major protocol deviations that preclude the assessment of 
efficacy and/or data integrity. Subjects who took the wrong treatment at any time during the study  will be 
excluded from the PP population. PP population is used for sensitivity analyses of OS and PFS, and may 
be used to analyze selected endpoints to test the robustness of results. The criteria for inclusion in the PP 
subset will be finalized and documented prior to unblinding of the study. 
 
Pharmacokinetic (PK) Population 
The PK population includes all subjects who receive at least one dose of study treatment and have at least 
one post-dose PK sample obtained and analyzed (i.e. valid result being available).  The PK population is 
used for tabulation of fruquintinib and M11 concentrations from PK plasma samples. 
 
Protocol Deviations 
Protocol deviations including deviations that are related to COVID-19 are recorded in the clinical trial 
management system (CTMS) as outlined in the latest version of the Protocol Deviation and Non-compliance 
Management Plan. During the course of the study, a list of key programmable PDs will be produced and 
reviewed periodically, these PDs will be reconciled into the CTMS. These programmable PDs include but 


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not limited to the (i) programmable inclusion criteria 1-5, 7-9, 12, exclusion criteria 1-7, 13, 21, 26; (ii) 
randomized but failed to receive treatment; (iii) treated without randomization; (iv) other PDs that may affect 
efficacy evaluation.   All major and minor protocol deviations will be reviewed and confirmed during blind 
data review meeting prior to database lock. Out of all major protocol deviations identified, a subset of 
protocol deviations leading to exclusion of subjects from PP population will be determined.  


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General Aspects for Statistical Analysis 
 
General Methods 
• 
Summaries are presented for each treatment group and overall for subjects’ disposition, 
demographics and baseline characteristics, medical history, disease history, prior medications, and 
concomitant medications tables.  Summaries are presented for each treatment group for other 
tables. 
• 
All data listings that contain an evaluation date contains a relative study day as defined in Section 
7.2.3. 
• 
For categorical variables, summary tabulations of the number and percent of subjects within each 
category of the parameter as seen on the electronic case report form (eCRF) are to be presented.  
Percentage calculations are based on the number of subjects within treatment group and overall, 
unless otherwise specified.  Percentages are rounded to 1 decimal place, unless otherwise 
specified.  The category Missing is included in subject-level demographics and disease history 
tables when the count is greater than zero for missing subjects.  
• 
For continuous variables, the number of subjects, mean, standard deviation (StdDev), median, 
lower quartile (Q1), upper quartile (Q3), minimum, and maximum values are presented.  The 
precision of summary statistics, unless otherwise specified, is as follows:  
o 
Minimum, maximum: same decimal places as the raw data. 
o 
Mean, median, Q1, and Q3 : 1 more decimal place than the raw data. 
o 
Standard deviation, standard error:  2 decimal places more than the raw data.  
• 
For results from a mixed model repeated measures, least-square (LS) mean and LS mean 
difference are presented with one decimal place, and standard error (SE) of LS means and SE of 
LS mean difference are presented with two decimal places.   
• 
Comparison between treatment groups are calculated as fruquintinib plus BSC versus placebo plus 
BSC. 
• 
Two-sided 95% confidence intervals (CI) are provided and rounded to 2 decimal places, unless 
otherwise specified. 
• 
2-sided p-values are presented with 3 decimal places. 
• 
Any rounding will be done after all calculations are made. 
 
Key Definitions 
 
First Dose Date 
First dose date is defined as the day of first dose of study treatment received on or after date of 


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randomization. 
 
Last Dose Date 
Last dose date is defined as day of the last non-zero dose of study treatment. The last dose date is typically 
obtained from the study drug administration records. For the situation that the last non-zero dose record 
has a partial end date (i.e. only missing day) for a patient, the following algorithm will be implemented to 
impute the partial end date.  
1. Calculate the date that is 21 days after the start date of the record; 
2. Obtain the end date of the month for the month of partial end date; 
3. Get the end of study date; 
4. Get the death date; 
5. The partial end date will be imputed to be the earliest among those dates from Item 1 to 4.  
For example, for a patient, the last non-zero dosing record has the start date being 19 Aug 2020, and the 
end date being partial as Sep 2020. With the end of study and death date being 13 Sep 2020, after 
implementing the algorithm above, the partial end date will be imputed to be 08 Sep 2020 which is the 
earliest date among (08 Sep 2020, 30 Sep 2020, and 13 Sep 2020).  
For subjects ongoing for the treatment period at time of analysis prior to database lock, the last dose date 
is the date of the most recent study visit in the database for that subject. 
 
Study Day 
The study day is determined relative to the date of first dose of study treatment, unless otherwise specified.  
The day of the first dose of study treatment is defined as study day 1.  The day prior to the first dose of 
study treatment is study day -1.  There is no study day 0. 
For events that occur before the first dose of study treatment,  
study day = date of the event – first dose date;  
for events that occur on or after the first dose of study treatment,  
study day = date of the event – first dose date + 1. 
 
Date of Last Known Alive 
The date of last known alive is defined as the last alive date of contact from the Survival Follow-up page on 
the eCRF.  For subjects ongoing at time of analysis, the date of last known alive is the date of the most 
recent study visit in the database for that subject. 


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More specifically, the last known alive date will be derived for subjects not known to have died at the 
analysis cut-off date using the latest date (including complete and partial date with Month and Year 
information) among the following data: 
- 
All assessment dates (e.g. laboratory, vital signs assessments, ECG, ECOG, performance status 
assessment, tumor assessment dates etc.). 
- 
Medication dates including study medication, concomitant medications, anticancer therapies 
administered after study treatment discontinuation. 
- 
Adverse events start and end date, and the date of adverse event becoming serious. 
- 
Date latest known alive collected during the survival follow-up. 
- 
Randomization date.   
 
After sorting properly for all those available dates, if the last last known alive date is a partial date with 
Month and Year information, day will be imputed as 15, unless this is after the cut off date in which case 
the cut off date will be used as last alive date. 
 
 
Date of Death 
Date of death is defined as the date of death from the Death Detail page on the eCRF.  Date of death is 
cross-checked with AEs where outcome is ‘Fatal’, if applicable. In rare case, if year and month of death 
date are known but the day is unknown, day will be imputed as 15. For example, if a subject is reported to 
die on Dec2017, the death date will be imputed as 15 Dec2017. In the case of the imputed death date being 
after the end of study date and the death date and end of study date being the same month, the death date 
will be assigned to be the date of end of study.  
 
Baseline and Change from Baseline  
For all change from baseline variables, the baseline is defined as the last non-missing assessment prior to 
or on the day of randomization, and must be prior to the first administration of study treatment, including 
scheduled and unscheduled visits, unless otherwise specified.  Hence, change from baseline = post-
baseline value – baseline value.  
The baseline value for analyses of qualitative parameters (e.g., normal/abnormal) is defined as the last 
evaluation prior to or on the day of randomization, and must be prior to the first administration of study 
treatment. 
 
Treatment-emergent Events  
An AE is considered a TEAE if the onset date is on or after the start of study treatment or if the onset date 
is missing, or if the AE has an onset date before the start of study treatment but worsened in severity after 
the study treatment until 37 days after the last dose of study treatment or a new treatment of anti-tumor 
therapy, whichever is earlier. After this period, treatment-related SAEs will also be considered as TEAEs. 
AEs with an unknown/not reported onset date will also be included. 


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Missing Data 
All available data of the subjects who withdraw from the study for any reason is analyzed.  Missing data is 
assumed to be missing at random.  Category ‘Missing’ is displayed for qualitative assessments, where 
applicable. 
For demographic and baseline characteristics, each variable will be analyzed and/or summarized using the 
available data. Unless otherwise specified, subjects with missing data will be excluded only from analyses 
for which data are not available. 
There is no imputation of missing data for the analysis purpose, unless otherwise stated. 
 
Imputation of the Missing Dates 
Imputation rules described in this section are applicable to partial dates of AEs, concomitant medications, 
anti-cancer therapy, primary diagnosis and metastatic disease diagnosis. However, imputation of missing 
AE and concomitant medication onset and stop dates will be used to determine the status of each AE and 
the prior/concomitant status of each medication, the imputed dates should not be shown in listings. 
Incomplete Start Date of AEs: 
- 
If the AE onset date is completely missing, the AE start date will be imputed as the reference start 
date (i.e. first dosing date); 
- 
If the AE onset date is partial missing, then  
§ 
If both the year and the month are available and the year and the month are the corresponding 
year and month of the reference start date, then the AE start date will be imputed as the 
reference start date;  
§ 
If both the year and the month are available and the year and the month are not equal to the 
corresponding year and month of the reference start date, then the AE start date will be imputed 
as the 1st day of the month; 
§ 
If only the year is available and the available year is the corresponding year of the reference start 
date, then the AE start date will be imputed as the reference start date; 
§ 
If only the year is available, and the available year is not equal to the corresponding year of the 
reference start date, then the AE start date will be imputed as the January 1st of the year. 
Incomplete Stop Date of AEs:  
AE end date will be imputed as below for the partial date only, the imputation rules only apply when the 
AE is not ongoing: 
- 
If both the year and the month are available, AE end date will be imputed as the last day of the 
month; 
- 
If only the year is available, AE end date will be imputed as the December 31st of the year. 
If the imputed AE end date is after the death date for subjects is know to be dead at end of study or cut 
off date, the date of the death will be used for AE end date. If the imputed AE end date is after the last 


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known alive date for subjects alive at the end of study or cut off date, the date of last known alive date will 
be use for AE end date.  
For AE continuing at the cut-off date, the end date will not be imputed and instead will be reported as 
“ongoing”. 
Concomitant Medication/Procedure/Surgery with onset/end dates  
Concomitant Medication/Procedure/Surgery with onset/end dates that are partially/completely missing will 
be imputed as follows. 
(i) start date: 
- 
1st day of the month will be used to impute the start date if only the day is missing. 
- 
January 1st will be used to impute the start date if both the day and month are missing. 
- 
If the date is completely missing, then the day before the reference start date will be imputed as the 
start date. 
(ii) end date: 
- 
Last day of the month will be used to impute the end date if only the day is missing. 
- 
December 31st of the year will be used to impute the end date if both the day and month are missing. 
- 
If the date is completely missing, assign ‘continuing’ status to the end date. 
If the imputed end date is after the death date or last known alive date, the date of the death or last known 
alive date will be imputed as the Concomitant medication/procedure/surgery end date. 
Subsequent Anti-cancer Therapy Date (collected during Survival Follow-Up) 
When a partial new anti-tumor therapy start date is reported, every effort will be made to identify the 
precedence relationship of starting date of new anti-tumor therapy relative to the reference end date (i.e. 
last dose date). Below rules will be used: 
- 
If the date is completely missing, new anti-tumor therapy date will be imputed as reference end date + 
1; 
- 
If only the day is missing, 15th day will be imputed as the new anti-tumor therapy date; 
- 
If both the day and the month are missing, then July 1st will be imputed as the new anti-tumor therapy. 
If the imputed start date is prior to the reference end date for subjects, the reference end date + 1 will be 
used as the imputed start date of the subsequent anti-cancer therapy.   
Primary Diagnosis Date and Metastatic Disease Diagnosis Date 
When a partial date of primary diagnosis for advanced colorectal cancer or a partial date of first 
metastatic disease diagnosis is reported, the below imputation rules will be used: 
- 
If the date is completely missing, no imputation will be conducted; 
- 
If only the day is missing, 15th day will be assigned; 
- 
If both the day and the month are missing, then July 1st will be assigned. 


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Visit Windows 
It is expected that there will be a variation between subjects in the actual number of study days from the 
start of administration of study drug within each cycle  defined as Day 1  to the dates that the scheduled 
visits occurs. To handle this, for tables and figures where data are grouped by visit, assessments will be 
categorized using visit windows based on study days (relative to the Day 1 of each cycle). The visit-window 
mapping is described in Table 4. Visit-based summaries will be based on the windowed visits. All data, 
whether or not within the visit windows, will be presented in subjects listings.  
For windowed visits during the treatment cycles, if more than 1 visit occurs during a visit window, the visit 
closest to the scheduled day will be assigned to the windowed visit. If two visits are equidistant from the 
scheduled day, the later visit will be assigned to the windowed visit. If there are multiple assessments on 
the same day, the worst case will be used.  For the treatment completion visit, the last assessment in the 
window will be included in the summary.  
For a subject who prematurely discontinues the study, the premature visit will be slotted accordingly. The 
window for post treatment visit will be "last dose date of last cycle + 4 days to last dose date of last cycle + 
10 days" and the window for safety follow-up visit will be “Last dose date of last cycle + 11 days to last dose 
date of last cycle + 37 days”.






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Pooling of Centers 
Data from all study centers is combined for analysis.   
 
Outliers 
Data Management are to be notified of outliers, if identified during TLF reviews, for query.  Syneos Health 
Biostatistics and Programming do not change or remove outliers from the data.  
 
Data Sources 
Randomization numbers, stratification factors, and treatment assignments derived from IWRS are 
reconciled with the dummy randomization schedule prior to database lock and unblinding, and with the 
actual randomization schedule after database lock and unblinding. 
After the study is unblinded, fruquintinib and M11 concentrations from PK plasma samples are provided by 
Covance and mapped onto SDTM PC domain.  Syneos Health then transfers SDTM PC domain to Certara. 
Protocol deviations are recorded in the CTMS and provided as an Excel document.  Protocol deviations 
are to be reviewed prior to database lock.  
CRF data are extracted from Rave database. 
Laboratory data are provided by local labs. 
Imaging data are provided by eResearchTechnology, Inc. (ERT). 
Interactive Response Technology (IRT) data are provided by Endpoint. 
Quality of life data using EORTC QLQ-C30 and EQ-5D-5L questionnaires are collected via Electronic 
Clinical Outcome Assessment (eCOA) and provided by ERT.  


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Demographic, Other Baseline Characteristics and Medication 
 
Subject Disposition and Withdrawals 
The following summaries will be presented for all enrolled subjects to reflect the subject disposition: 
- 
Number of subjects who signed the informed consent.  
- 
Number of screen failures. 
- 
Reason for screen failure. 
- 
Number of subjects who are randomized.  
- 
Number of subjects who do not receive study drug. 
- 
Number of subjects who received study drug. 
- 
Subjects still on treatment (i.e., missing end-of treatment information). 
- 
Reason for study drug discontinuation (for study drug). 
- 
Number of subjects going into Survival follow-up if there are any assessments after the last dose 
date + 37 days.  
- 
Number and percentage of subjects still on study (i.e., missing end-of-study information). 
- 
Number and percentage of subjects who discontinued the study. 
- 
Reason for study discontinuation. 
Since there is no designated CRF field to collect the reasons at the end of Study (EoS) page of the CRF, 
the following algorithm will be implemented to derive the reason for EoS.  
1. If a patient died on the study, the reason for EoS will be “death.”  
2. If a patient did not die on the study,  
a. Check the Survival Follow-Up (SFU) page, extract the value (eg, Lost to Follow-up and 
Withdrawal of Consent) in the field of Survival Status from the last available SFU page, and it will 
be assigned as the EoS reason. 
b. When 2.a is not available, check the Visit Information page where SFU visit was not performed, 
extract the last available value in the field of reason not conducting the visit, and it will be assigned 
as the EoS reason or “Missing” if the visit information is there but reason is missing before 
proceeding to the next step. 
c. When 2.a and 2.b are both not available, check the End of Treatment (EoT), extract the reason of 
EoT, and it will be assigned as the EoS reason. 
A separate table will be presented to show the subjects included in each analysis set and proper reasons 
for exclusion from an analysis set.  
A separate table will be presented for the ITT population to show the concordance of randomization 
schedule stratification factors and CRF collected factors of prior therapy [i.e. Trifluridine/Tipiracil (TAS-102), 
Regorafenib, or Both Trifluridine/Tipiracil (TAS-102) and Regorafenib], duration of metastatic disease (≤ 18 
months, > 18 months), and RAS status (Wild Type, Mutant). The following summaries will be presented: 
- 
Number of subjects with all randomization schedule stratification factors concordant with CRF 
collected factors. 
- 
Number of subjects with at least one randomization schedule stratification factor discordant with 
CRF collected factors. 
o 
Number of subjects with discordance in prior therapy [i.e. Trifluridine/Tipiracil (TAS-102), 
Regorafenib, or Both Trifluridine/Tipiracil (TAS-102) and Regorafenib], duration of 
metastatic disease, and RAS status. 


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Subject discontinuation status and analysis population are also listed. 
 
Protocol Deviations 
Protocol deviations are summarized descriptively for subjects with at least 1 major protocol deviation and 
subjects with at least 1 minor protocol deviation for each treatment group and overall.  Each protocol 
deviation is also summarized descriptively by categories within major and minor protocol deviations for 
each treatment group and overall for the ITT population.  A subject can have multiple major and/or minor 
deviations and counted once per major and/or minor deviation. COVID-19-related protocol deviations are 
summarized descriptively for each treatment group and overall for the ITT population. 
A listing of protocol deviations, including COVID-19-related protocol deviations, is provided. 
 
Demographic and Baseline Characteristics 
The following parameters are summarized descriptively for each treatment group and overall for the ITT 
population. 
• 
Age (years) at ICF date, Age Categories (< 65 years, ≥ 65 years). 
• 
Sex (Female, Male); If female, Child Bearing Potential.  
• 
Race (American Indian or Alaskan Native, Asian, Black or African American, Native Hawaiian or 
Other Pacific Islander, White, Other, Multiple Races, Not Reported, Unknown). A subject can have 
multiple races and is summarized in the multiple race category.  
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown).  
• 
Region (North America, Europe, and Asia).  
• 
Baseline Height (cm). 
• 
Baseline Weight (kg). 
• 
Baseline body mass index [BMI] (kg/m2): it is calculated as Weight at Baseline (kg)/ [Height at 
Baseline (m)]2. 
o 
BMI category: < 18.5, ≥ 18.5 and < 24, ≥ 24 kg/m2. 
• 
Baseline ECOG Performance Status: 0, 1. 
Age (years) at ICF date is calculated by site personnel as the number of years from date of birth up to date 
of informed consent.  For example, 
Date of Birth 
Date of Informed 
Consent 
Original Age 
Age to be entered into 
IWRS 
01MAR1985 
01JUL2020 
35 years 4 months 
35 


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01AUG1985 
01JUL2020 
34 years 11 months 
34 
 
A separate table presenting number and percentage of subjects by site and country will be produced for 
the ITT population. 
Demographic data and baseline characteristics, randomization scheme and codes, informed consent data, 
and inclusion/exclusion criteria are listed by subject. 
 
Disease History  
History of colorectal cancer of the ITT population is summarized descriptively for each treatment group and 
overall for the following: 
• 
Time (months) since First Diagnosis of Colorectal Cancer: it is calculated as (date of randomization 
– date of first diagnosis of colorectal cancer)/30.4375.   
• 
Stage of Colorectal Cancer at First Diagnosis (stage I, stage II, stage III, stage IV). 
• 
Primary Tumor Location at First Diagnosis. 
o 
Colon.  
§ 
Colon – Right (cecum, ascending colon, and hepatic flexure). 
§ 
Colon – Left (splenic flexure, descending colon, transverse colon, sigmoid colon). 
§ 
Colon – Right and Left. 
§ 
Colon – Unknown. 
o 
Rectum. 
o 
Colon and Rectum. 
§ 
Colon – Right (cecum, ascending colon, and hepatic flexure). 
§ 
Colon – Left (splenic flexure, descending colon, transverse colon, sigmoid colon).  
§ 
Colon – Right and Left. 
§ 
Colon – Unknown. 
o 
Unknown. 
• 
Primary Site at First Diagnosis (Colon Left, Colon Right, Both Colon Left and Right, Colon 
Unknown, Rectum Only, Unknown). 


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• 
Duration of Metastatic Disease (months): it is calculated as (date of randomization – date of 
diagnosis of metastasis disease)/30.4375. 
o 
Duration of Metastatic Disease Categories (≤ 18 months, > 18 months). 
• 
Prior Oncology Treatments (Prior Anti-cancer Medication, Prior Anti-cancer Radiotherapy, Prior 
Anti-cancer Procedures). 
• 
RAS Status (Wild Type, Mutant). 
• 
BRAF Status (Wild Type, V600 E Mutation, Other). 
• 
Microsatellite/Mismatch Repair Status (Microsatellite stable [MSS] and/or proficient mismatch 
repair [pMMR], microsatellite instability-high [MSI-H] and/or deficient mismatch repair [dMMR]). 
• 
Prior Therapy with Trifluridine/Tipiracil (TAS-102) and/or Regorafenib (Trifluridine/Tipiracil (TAS-
102), Regorafenib, Both Trifluridine/Tipiracil (TAS-102) and Regorafenib). 
• 
Number of Prior Treatment Lines (≤ 3, > 3). 
• 
Number of Prior Treatment Lines for Metastatic Disease (≤ 3, > 3). 
• 
Prior Treatment with Vascular Endothelial Growth Factor (VEGF) Inhibitors (Yes, No). 
• 
Prior Treatment with Epidermal Growth Factor Receptor (EGFR) Inhibitors (Yes, No). 
• 
Prior Treatment with EGFR/VEGF Inhibitors.  
o 
No anti-VEGF and no anti-EGFR. 
o 
Anti-VEGF, or anti-EGFR, or both. 
§ 
Anti-VEGF and no anti-EGFR. 
§ 
Anti-EGFR and no anti-VEGF. 
§ 
Both anti-VEGF and anti-EGFR. 
• 
Prior Treatment with Immune Checkpoint Inhibitors for MSI-H/dMMR (Yes, No). 
• 
Prior Treatment with BRAF Inhibitors for BRAF V600E Mutation (Yes, No). 
• 
Liver Metastases at Baseline (Yes, No): obtained based on whether the liver organ was involved 
in the target and non-target lesion tumor scan assessment at the baseline. 
• 
Number of Metastatic Sites Other than Colon or Rectum (Single, Multiple): obtained based on the 
number of sites/organs was involved in the target and non-target lesion tumor scan assessment at 
the baseline. If only one is involved, that would be single; if more than one are involved, it will be 
multiple. For this derivation, paired organs, such as lung, kidney, ovaries, and lymph nodes will be 
considered as one organ, irrespective of the number of parts they may be made up of (i.e. tumors 
in the left lung and right lung will be counted as in one site).  


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• 
Number of Metastatic Sites (Single, Multiple): obtained based on the number of sites/organs was 
involved in the target and non-target lesion tumor scan assessment at the baseline. If only one is 
involved, that would be single; if more than one are involved, it will be multiple. For this derivation, 
paired organs, such as lung, kidney, ovaries, and lymph nodes will be considered as one organ, 
irrespective of the number of parts they may be made up of (i.e. tumors in the left lung and right 
lung will be counted as in one site).   
 
Medical History 
The conditions/diseases from medical history are those conditions/diseases that stopped prior to the study 
entry. Medical history is coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 
25.0.  Medical history is summarized using discrete summary statistics for each MedDRA system organ 
class (SOC) and preferred term (PT) by treatment group and overall for the ITT population.  Subjects with 
multiple medical histories in the same SOC or PT are counted only once for the respective SOC or PT.   
Summaries are ordered in alphabetical order of SOC and then, within an SOC, in decreasing frequencies 
by PT in overall column. If the frequencies tie, an alphabetic order will be applied.  
A listing of medical history by subject is provided.   
 
Prior and Concomitant Medication  
Prior and concomitant medications are classified by Anatomical Therapeutic Classification (ATC) 
therapeutic subgroup (Level 2) and PT using the World Health Organization Drug Dictionary (WHODD) 
version March2020 or later.  Medications with partial start or stop dates are imputed as described in Section 
7.3.1 prior to be determined whether the medication is prior or concomitant medication. 
Medications taken prior to the first dose of study treatment are denoted “Prior”. Medications taken prior to 
the first dose of study treatment and continuing beyond the first dose of study treatment or those 
medications started on or after the first dose of study treatment but no later than 37 days after the last dose 
are denoted “Concomitant”. Medication with start date/time being partially or completely missing will be 
assumed to be concomitant if it cannot be definitely shown that the medication did not occur during the 
treatment period. 
The use of prior and concomitant medications will be summarized using discrete summary statistics in each 
treatment group and overall for the ITT population.  If a subject took a specific medication multiple times or 
took multiple medications within a specific ATC or PT, the subject is counted only once for the respective 
ATC or PT. 
Summaries are ordered in alphabetical order of ATC and then, within an ATC , in decreasing frequencies 
by PT in overall column. If the frequencies tie, an alphabetic order will be applied. 
A listing of prior medication and concomitant medication by subject is provided. 


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Concomitant Medical or Surgical Procedure 
Medical or surgical procedures that occurs after first dose date but no later than 37 days after the last dose 
are denoted “Concomitant”.  Concomitant medical or surgical procedures are classified using the MedDRA 
version 25.0.  
The use of concomitant medical or surgical procedures will be summarized using discrete summary 
statistics in each treatment group and overall for the ITT population.  If a subject took a specific medication 
or surgical procedures multiple times or took multiple medications or surgical procedures within a specific 
SOC or PT, the subject is counted only once for the respective SOC or PT. 
Summaries are ordered in alphabetical order of SOC and then, within an SOC , in decreasing frequencies 
by PT in overall column. If the frequencies tie, an alphabetic order will be applied. 
A listing of concomitant medical or surgical procedures by subject is provided. 
 
Prior Oncology Treatment 
Prior oncology treatments including prior anti-cancer mediation, prior anti-cancer radiotherapy,  prior anti-
cancer procedure or surgery are summarized descriptively for each treatment group and overall for the ITT 
population.   
 
Prior Anti-cancer Medication 
Summary of prior anti-cancer medication for the ITT population includes the following: 
• 
The number and percent of subjects with at least one prior anti-cancer medication. 
• 
The total number of prior anti-cancer medications. 
• 
The number of prior lines of therapy and its categories of 0, 1, 2, 3, > 3.  
Prior anti-cancer medications are classified using the WHODD version March 2022. 
The use of prior anti-cancer medications will be summarized by ATC and PT using discrete summary 
statistics, each treatment group and overall for the ITT population. A subject with multiple prior medication 
entries in the same ATC (PT) is only counted once within a particular ATC (PT).Results are sorted by ATC 
followed by PT in decreasing order of frequency (by Total column). If the frequencies are tied, an alphabetic 
order is applied. 
 
Prior Anti-cancer Radiotherapy 
Summary of prior anti-cancer radiotherapy for the ITT population includes the following. 
• 
The number and percent of subjects with at least one prior anti-cancer radiotherapy. 
• 
The total number of prior anti-cancer radiotherapy. 
 
Prior Anti-cancer Procedure or Surgery 
Summary of prior anti-cancer procedure or surgery for the ITT population includes the following 


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• 
The number and percent of subjects with at least one prior anti-cancer procedure or surgery. 
• 
The total number of prior anti-cancer procedures or surgery. 
The number and percent of subjects for each purpose of prior anti-cancer procedure or surgery. A 
subject with multiple occurrences of the same purpose will be counted only once for the purpose, 
and a subject with multiple purposes will be counted once in each category of purpose.   
Prior anti-cancer procedure or surgery is coded (MedDRA) version 25.0. 
The number and percent of subjects with each procedure or surgery will be summarized using discrete 
summary statistics in each treatment group and overall for the ITT population by SOC and PT. If a subject 
had a procedure multiple times or had multiple procedures within a specific SOC or PT, the subject is 
counted only once for the respective SOC or PT. Summaries are ordered in alphabetical order of SOC and 
then, within an SOC, in decreasing frequencies by PT in overall column. If the frequencies tie, an alphabetic 
order will be applied. 
 
Extent of Exposure  
Exposure of study treatment is descriptively summarized for each treatment group as follows. Table 5 
details the parameters of study treatment exposure. 
Table 5. Extent of Exposure Parameters 
Parameter 
Definition  
Duration of Exposure (days) 
(Last dose date of study drug or death, whichever comes 
earlier) – first dose date of study drug + 8 or the date of death 
while on study, whichever comes first. 
Number of Days with Recorded 
Dose  
Sum of days with recorded doses 
Number of Cycles Treatment 
Received 
Subjects are considered to have started a cycle if they have 
received at least one dose of any study treatment. 
Number of Cycles Treatment 
Received Categories 
1, 2, 3, 4, 5, 6 and > 6 
Cumulative Dose (mg) 
Sum of doses administered in all cycles. The total dose 
administered in each cycle is defined as: the sum of (number of 
5 mg capsules taken × 5 + number of 1 mg capsules taken)  
where number of capsules taken = total capsules dispensed – 
total capsules returned. 
Dose Intensity (mg/day) 
Cumulative Dose (mg) / Duration of Exposure (day) 
Target dose intensity is 3.75 mg 
Relative dose intensity (RDI) (%) 
100 * [Dose Intensity (mg/day) / (5 × 21/28 (mg/day))]   
RDI Categories 
< 50% 
50 - < 70% 
70 - < 90% 
90 - < 110% 
 ≥ 110%. 
Relative Dose (RD) (%) 
100 * [Cumulative dose (mg) / (5×21× number of cycles 
treatment received (mg)] 
 


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Parameter 
Definition  
RD Categories 
< 50% 
50 - < 70% 
70 - < 90% 
90 - < 110% 
 ≥ 110%. 
Percentage Intended Dose (PID) (%) 
100 * [(number of days with any recorded doses) /duration of 
exposure ] 
Target PID is 75%. 
Number of days with any recorded doses  
The following summary for dose adjustment will be summarized for each treatment group. 
o 
Study drug is administered orally on days 1-21 of each 28-day cycle. A cycle will be called 
cycle delay if the duration of the cycle is longer than 28 days. However, the last cycle will 
not be evaluated for cycle delay. Reason for delay is not collected. Hence, the total number 
of cycle delay will be calculated for each subject.  Number of subjects with any cycle delay, 
and the frequency of cycle delay (0, 1, 2, 3, 4, 5, 6, > 6) will be summarized.  
o 
Number of subjects with any dose modification (including both drug interruption and dose 
reduction); 
o 
Frequency of dose modification: 0, 1, 2, 3, 4, 5, 6, > 6. 
o 
Drug interrupted (number of subjects experienced drug interruption and reasons for drug 
interruption; frequency of drug interruptions: 0, 1, ≥ 2). 
o 
Drug withdrawn (number of subjects experienced drug withdrawn and reasons for drug 
withdrawn). 
o 
Dose reduced (Number of subjects with any dose reduction and reasons for dose 
reduction; and frequency of dose reduction: 0, 1, 2, ≥ 3), also the dose reduction category 
below will be summarized.  
§ 
Reduction from 5mg to 4mg.  
§ 
Reduction from 4mg to 3mg.  
Study treatment accountability, study treatment administration are extent of exposure are listed by subject 
and visit. 
 
 
 


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Efficacy 
Efficacy analyses are based on the ITT population.  All secondary endpoints based on radiological 
assessments of tumor burden are derived from investigator assessment using Response Evaluation 
Criteria In Solid Tumors (RECIST) version 1.1 (Eisenhauer et al 2009). 
 
Primary and Key Secondary Efficacy Endpoint and Analysis 
 
Primary Efficacy Endpoint and Analysis 
The primary endpoint of the study is OS, defined in Section 5.1 of the SAP and calculated as (date of death 
or last known alive – date of randomization + 1)/30.4375. 
The Kaplan-Meier plots will be produced and the median, 25% and 75% percentile of time-to-event will be 
estimated using Kaplan-Meier method with their corresponding 95% CI which are calculated from a log-log 
transformation based on the method by Brookmeyer and Crowley (1982). Additionally, estimates will be 
provided for the survival probability along with their 95% CIs which are calculated using linear 
transformation based on the method by Brookmeyer and Crowley (1982) at selected landmarks, for 
example, at 3, 6, 9, 12, and 18 months. Example Statistical Analysis System (SAS) code is provided in 
Appendix 6. 
The two-sided p-value to test the treatment effect will be calculated using a stratified log-rank test 
accounting for randomization schedule stratification factors. Example SAS code is provided in Appendix 7. 
The hazard ratio (HR) between the 2 treatment groups (fruquintinib vs placebo), together with its 95% CIs, 
will be calculated from a stratified Cox proportional hazard model (i.e. accounting for randomization 
schedule stratification factors) in which the treatment group is the only covariate in the model. A HR < 1 
indicates a favorable clinical benefit from fruquintinib over the placebo group. Example SAS code is 
provided in Appendix 8. 
Duration of follow-up is defined as the time (months) from date of randomization to the last date known to 
be alive for subjects who have not yet been reported to have died by the time of the analysis. Subjects who 
were reported to have died by the time of the analysis are censored at date of death. That is, duration of 
follow-up is calculated as (date of death or last known alive – date of randomization + 1)/30.4375. The 
duration of follow-up will be calculated using the Kaplan-Meier method.  
All OS data are provided in listings by subject. 
 
Key Secondary Efficacy Endpoint and Analysis 
The key secondary efficacy endpoint is PFS. PFS is defined in Section 5.2 and calculated as (date of death 
or radiographic PD or last assessment – date of randomization + 1)/30.4375. 
The number and percent of subjects who had progression-free events, the number and percent of 
subjects censored, and reasons for censoring are presented for each treatment group.  Reasons for 
censoring include the following. 
a. No baseline nor post-baseline assessment 


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b. No death nor PD  
c. Lost to follow-up without death or PD 
d. Withdrawal of consent without death or PD 
e. New anti-tumor therapy started prior to PD 
f. 
Death or PD occurred after two or more consecutive missed assessment 
The Kaplan-Meier plots will be produced and the median, 25% and 75% percentile of time-to-event will be 
estimated using Kaplan-Meier method with their corresponding 95% CI which are calculated from a log-log 
transformation based on the method by Brookmeyer and Crowley (1982). Additionally, estimates will be 
provided for the survival probability along with their 95% CIs which are calculated using linear 
transformation based on the method by Brookmeyer and Crowley (1982) at selected landmarks, for 
example, at 3, 6, 9, 12, and 18 months.  
The two-sided p-value to test the treatment effect will be calculated using a stratified log-rank test 
accounting for randomization schedule stratification factors. The hazard ratio (HR) between the 2 treatment 
groups (fruquintinib vs placebo), together with its 95% CIs, will be calculated from a stratified Cox 
proportional hazard model (i.e. accounting for randomization schedule stratification factors) in which the 
treatment group is the only covariate in the model. A HR < 1 indicates a favorable clinical benefit from 
fruquintinib over the placebo group. 
A Kaplan-Meier plot of the time to censoring, where the censoring indicator of the primary PFS analysis is 
reversed, will be presented.  
All PFS data is provided in listings by subject. 
 
Multiplicity Adjustments 
The clinical trial evaluates the objectives defined in terms of the comparison of fruquintinib + BSC versus 
placebo + BSC on the primary and key secondary efficacy endpoints in Section 9.1.1 and Section 9.1.2. 
The multiplicity problem includes 2 hypotheses of no effect: 
• 
Hypothesis 𝐻!. Comparison of fruquintinib + BSC versus placebo + BSC for OS. 
• 
Hypothesis 𝐻". Comparison of fruquintinib + BSC versus placebo + BSC for PFS. 
The 2-sided p-values for the 2 comparisons will be used for the multiple testing procedure. Example SAS 
code in Appendix 7. 
A fixed-sequence (hierarchical) testing procedure is used to control the overall type I error rate at 0.05.  If 
the resulting 2-sided p-value from the analysis of primary endpoint OS is ≤ 0.05, then, a superiority test of 
for PFS will be conducted at the two-sided significance level of 0.05.  
 
Sensitivity Analysis for OS and PFS 
The following sensitivity analyses for OS and PFS will be performed, in which the p-value will always be 
obtained from the stratified log-rank test and the hazard ratio (HR) between the 2 treatment groups 


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(fruquintinib vs placebo), together with its 95% CIs will be calculated from the model in Section 9.1.1 and 
Section 9.1.2 for OS and PFS, respectively, unless otherwise specified.  
- 
using ITT population, unstratified Cox proportional hazard model in which the randomization 
schedule stratification factors and treatment group are included in the model as covariates; 
- 
using ITT population, stratified analysis for both log-rank test and Cox proportional hazard model, 
but using the stratification factors collected on the case report form (CRF); 
- 
using ITT population, unstratified Cox proportional hazard model in which the stratification factors 
collected on the CRF and treatment group are included in the model as covariates; 
- 
using ITT population, subjects with primary cause of death attributed to COVID-19 will be censored 
at one day before the death date (i.e. death date – 1).; and will follow the censoring rule defined in 
Table 3 for PFS and will use the data prior to the date of death.  
- 
using PP population 
- 
using PP population, unstratified Cox proportional hazard model in which the randomization 
schedule stratification factors and treatment group are included in the model as covariates;  
- 
using PP population, stratified analysis for both log-rank test and Cox proportional hazard model 
using the stratification factors collected on the CRF; 
- 
using ITT population, multivariate Cox’s proportion hazard model with treatment and randomization 
schedule stratification factors (i.e. prior therapy, RAS status, and duration of metastatic disease) 
included in the model as covariate and, adjust for key prognostic factors using stepwise selection 
process with level of enter alpha= 0.15 and level of remove alpha= 0.15.  Key prognostic factors 
include a set of potential prognostics/predictive factors as described in Section 9.1.5. 
An additional sensitivity analyses for OS will be performed 
- 
using ITT population, based on the first exact 480 deaths and the additional  subjects who died will 
be censored at one day before the death date (i.e. death date – 1). 
- 
using ITT population, subjects who take the subsequent anti-cancer therapy and are still alive will 
be censored at the date of initiating the subsequent anti-cancer therapy for OS.  
The following additional sensitivity analyses for PFS will be performed, and all those sensitivity analyses 
defines the PFS event in an alternative way. 
- 
For Rule 6 of Table 3, subjects who take new anti-cancer therapy are considered as a progression, 
and the date of progression is on the date of initiating the new anti-cancer therapy. However, if the 
new anti-cancer therapy is initiated after two or more consecutive missed/non-evaluable tumor 
assessments, the subjects will still be censored at date of last radiological assessment before the 
missed assessments. Then, the same analysis methods outlined in Section 9.1.2 will be conducted.  


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- 
For Rule 7 of Table 3, ignore the missing tumor assessments, that is, subjects with PD or death 
after two or more consecutive missed/non-evaluable tumor assessments will be considered as PFS 
event, and the event date for PD or death will be obtained as usual. Then, the same analysis 
methods outlined in Section 9.1.2 will be conducted.  
 
Examination of Subgroups 
Subgroup analyses will be conducted based on the unstratified Cox proportional hazard model in which the 
applicable randomization schedule stratification factors and treatment group are included in the model as 
covariates. It should be noted that the study was not designed to detect treatment differences with high 
statistical power within subgroups. For OS and PFS subgroup analysis, if a subgroup is too small, it may 
be pooled with others. If the number of events in a subgroup is not sufficient, analysis will not be performed. 
The following subgroups will be assessed for OS and PFS: 
• 
Age: < 65 years, >= 65 years 
• 
Sex: Female, Male 
• 
Region: North America, Europe, Asia  
• 
Race: White, Asian, Black or African American, Other (including American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Other as recorded on the Demographics eCRF, and 
subjects with multiple races selected)  
• 
Baseline ECOG Performance Status: 0, 1 
• 
Prior Therapy with Trifluridine/Tipiracil (TAS-102) and/or Regorafenib: Trifluridine/Tipiracil (TAS-
102), Regorafenib, Both Trifluridine/Tipiracil (TAS-102) and Regorafenib. This is a stratification 
factor which will not be included in the model for subgroup analysis. 
• 
RAS Gene Status: Wild Type, Mutant. This is a stratification factor which will not be included in the 
model for subgroup analysis.   
• 
BRAF Status: Wild Type, V600 E Mutation, Other 
• 
Microsatellite/Mismatch Repair Status: Microsatellite Stable (MSS) and/or proficient mismatch 
repair (pMMR), Microsatellite Instability-High (MSI-H) and/or deficient mismatch repair (dMMR) 
• 
Duration of metastatic disease (time from 1st Metastatic Diagnosis to Randomization): ≤ 18 months, 
> 18 months. This is a stratification factor which will not be included in the model for subgroup 
analysis. 
• 
Number of Prior Chemotherapy Treatment Lines: ≤ 3, > 3 
• 
Number of Prior Chemotherapy Treatment Lines for Metastatic Disease: ≤ 3, > 3 
• 
Prior Treatment with Vascular Endothelial Growth Factor (VEGF) Inhibitors: Yes, No 


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• 
Prior Epidermal Growth Factor Receptor (EGFR) Inhibitors: Yes, No 
• 
Prior target treatment  
o 
No anti-VEGF and no anti-EGFR 
o 
Anti-VEGF, or anti-EGFR, or both 
§ 
Anti-VEGF and no anti-EGFR 
§ 
Anti-EGFR and no anti-VEGF 
§ 
Both anti-VEGF and anti-EGFR 
• 
Prior Treatment with Immune Checkpoint Inhibitors for MSI-H/dMMR: Yes, No 
• 
Prior Treatment with BRAF Inhibitors for BRAF V600E Mutation: Yes, No 
• 
Primary Tumor Location at First Diagnosis:  
o 
Colon, Rectum, Colon and Rectum, Unknown 
• 
Primary Tumor Site at First Diagnosis:  
o 
Colon Left (Splenic flexure, descending colon, transverse colon, sigmoid colon and 
rectum), Colon Right (Cecum, ascending colon and hepatic flexure), Colon Left and Right, 
Colon Unknown, Rectum Only, Unknown 
• 
Liver Metastases at Baseline: Yes, No  
• 
Number of Metastatic Tumor Sites Other than Colon or Rectum: Single, Multiple 
• 
Number of Metastatic Tumor Sites: Single, Multiple 
The values of stratification factors used for subgroup analysis are actual values of strata collected through 
eCRF. 
 
All the sensitivity and the subgroup analysis for both OS and PFS will be considered exploratory and may 
only be supportive of the primary analysis of OS and PFS. Forest plot will also be used to graphically show 
the results.  
 
Secondary Efficacy Endpoints and Analyses 
Secondary efficacy endpoints include ORR, DCR, and DoR. 
 
Objective Response Rate and Disease Control Rate 
The 95% CIs of ORR and ORRUNCONF RMED are calculated using the Clopper-Pearson exact binomial method 
for each treatment group. 
The adjusted proportion difference and along with its 95% CI in ORR between treatment groups will  be 
calculated using the Wald method to account for the randomization schedule stratification factors, and p-






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EORTC QLQ-C30 Questionnaire  
The EORTC QLQ-C30 questionnaire, composed of both multi-item scales and single-item measures, is a 
30-item cancer-specific instrument (Aaronson et al, 1993) which are grouped into 15 subscales as detailed 
below.  
1. Global health status/QoL scale 
2. Five functional scales: Physical functioning, Role functioning, Emotional functioning, Cognitive 
functioning, Social functioning  
3. Three symptom scales: Fatigue, Nausea and vomiting, Pain 
4. Six single items: Dyspnea, Insomnia, Appetite loss, Constipation, Diarrhea, Financial difficulties 
Each subscale/single item is scored in accordance to the EORTC QLQ-C30 Scoring Manual (Aaronson et 
al, 1993).  All scales and single-item measures range in score from 0 to 100 after linear transformation.  A 
technical summary of scoring can be found in Appendix 1.  Higher score for the Global health status/QoL 
and functioning scales represent higher functioning (i.e. a better state).  However, the direction is opposite 
in symptom scales and single items. Higher scores on symptom and single-item scales represent higher 
levels of symptoms (i.e. a worse state). 
The number and percent of subjects who completed the questionnaires will be summarized by visit and 
each treatment group.   
9.2.5.1. 
Analysis of Change from Baseline in 15 Subscales 
Change from baseline in the scores of each of the 15 subscales will be summarized by visit and each 
treatment group.   
Analysis of change from baseline in the scores of each of the 15 subscales will be performed by visit (i.e. 
cycle), using a restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) 
approach. The MMRM model will include treatment group, visit (i.e. cycle), treatment group by visit 
interaction, baseline value of scale, and randomization schedule stratification factors as fixed effects. An 
unstructured variance-covariance structure will be used to model within-subject errors. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom and adjust standard errors.  MMRM 
is based on the assumption of missing at random and the assumption that dropouts would behave similarly 
to other subjects in the same treatment group, and possibly with similar covariate values, had they not 
dropped out. Example SAS code is provided in Appendix 10. To ensure the proper amount of data utilized 
in the model for each visit, the following steps will be implemented to identify data to be included in the 
model.  
(1) Calculate the number of subjects with non-missing assessments for each cycle. 
(2) Identify the last cycle with at least 20 subjects in any of the treatment groups  and no subsequent cycles 
having at least 20 subjects in any of the treatment groups.  
(3) Assessments after the cycle identified in Step 2 will not be included in the model.  


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If there is a convergence issue with the unstructured covariance model, Toeplitz, Autoregressive (1) (AR 
(1)) covariance structure is used, following this sequence until convergence is achieved.  If the model still 
does not converge with AR (1) structure, no results are reported. When the covariance structure is not 
unstructured, the sandwich estimator for the variance-covariance matrix is derived, using the EMPIRICAL 
option in the PROC MIXED statement in SAS.  
The visit windowing rules defined in Section 7.4 will be applied to identify the record for a cycle of each 
subject, and hence to be included in the analysis. The comparison are between fruquintinib plus BSC to 
placebo plus BSC at each scheduled post-baseline visit.  The tabulation of MMRM includes estimates of 
least-square (LS) means, standard errors (SE), and 2-sided 95% CIs for each treatment group.  Estimates 
of the LS mean difference, SE of the difference, 2-sided 95% CI of the difference between treatment groups, 
and p-value are also presented. As a sensitivity analysis, subjects who have more than one assessment in 
a cycle (i.e., a quality of life assessment at an unscheduled visit), the worst score for that cycle is used in 
the analysis of change from baseline in the 15 subscales.  The above analysis is replicated using these 
substituted values.  
9.2.5.2. 
Analysis of Minimally Important Difference and Time to Deterioration 
Depending on each scale and item, the minimally important difference (MID) cut-off for QoL improvement 
is defined as a change of at least 6.35 to 14.24 points from baseline, based on a recent validation study on 
subjects with mCRC (Musoro et al., 2020) and the study (Osoba et al., 1998) cited in the EORTC-QLQ-30 
Scoring Manual.  The MID cut-off for QoL deterioration, stable, and improvement and in each scale and 
item are listed in Table 8 based on change scores.  
Table 8. Summary of MID for EORTC QLQ-C30 Questionnaire 
 
Scale/item 
Deterioration 
Stable 
Improvement 
Global health status/QoL 
≤-6.38 
-6.38 < and < 8.43 
≥8.43 
Physical functioning 
≤-7.47 
-7.47 < and < 7.81 
≥7.81 
Role functioning 
≤-10.66 
-10.66 < and < 14.24 
≥14.24 
Emotional functioning* 
≤-10 
-10 < and <10  
≥10 
Cognitive functioning* 
≤-10 
-10 < and < 10 
≥10 
Social functioning 
≤-6.18 
-6.18 < and < 9.23 
≥9.23 
Fatigue 
≥10.79 
-7.38 < and < 10.79 
≤-7.38 
Nausea and vomiting 
≥7.75 
-6.62 < and < 7.75 
≤-6.62 
Pain* 
≥10 
-10 < and < 10 
≤-10 
Dyspnoea* 
≥10 
-10 < and < 10 
≤-10 
Insomnia* 
≥10 
-10 < and < 10 
≤-10 
Appetite loss 
≥12.28 
-9.78 < and < 12.28 
≤-9.78 
Diarrhea 
≥6.35 
-7.96 < and 6.35 
≤-7.96 
Constipation 
≥12.75 
-10* < and <12.75 
≤-10 
Financial difficulties* 
≥10 
-10 < and < 10 
≤-10 
*The MID of these sca e/ tems were not reported n (Musoro et a ., 2020). Instead, the MID for these sca e/ tems were arb trar y 
determ ned at 10 po nts, fo ow ng the study (Osoba et a ., 1998) c ted n EORTC QLQ 30 Scor ng Manua . Osoba et a . reported “a 
tt e” change as a change of 5 10 po nts, and “moderate” change as 10 20 po nts.     


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The number and percent of subjects achieving MID for each scale (by categories defined in Table 8) are 
summarized by visit and treatment group.   
In addition, for each scale and single item, time to deterioration (TTD) is defined as the time (months) from 
randomization until the first change of at least -10.66 to 12.75 points (depending on each scale and item) 
from baseline (Table 8, “Deterioration” column value), or death, whichever comes first.  Any subject who 
does not experience TTD at the time of analysis is censored at the date of the most recent study visit in the 
database for that subject.   
TTD is calculated as (date of the first reduction of at least -10.66 to 12.75 points from baseline, death or 
most recent visit – date of randomization + 1)/30.4375. 
When no post-baseline assessments available, date of randomization will be used for this calculation. 
 
Kaplan-Meier estimates for TTD will be tabulated by treatment group, using 25th, 50th (median), and 75th 
percentiles with associated 2-sided 95% CIs. In addition, the two-sided p-value will be obtained from the 
stratified Kaplan-Meier method to account for the stratification factors. The hazard ratio (HR) between the 
two treatments (fruquintinib vs placebo), together with its 95% CIs will be calculated from a stratified (i.e. 
accounting for randomization schedule stratification factors) Cox hazard model in which treatment and 
baseline value of scale will be included as fixed effects. 
Data of EORTC QLQ-C30 questionnaire and subscales are listed by subject and visit. 
9.2.5.3. 
Handling Missing Data for EORTC QLQ-C30 Questionnaire 
The number of and percent subjects of missing data on each of the 15 subscales will be presented by visit 
and also for the overall trial.  Subjects who have died are included in this count.  
As a simple sensitivity analysis of the impact of intercurrent events such as death and drop-out, an analysis 
of covariance (ANCOVA) will be conducted using the change from baseline to the last available assessment 
for each subject during the period from the date of randomization to the 37 days after the date of last dose. 
The ANCOVA model, include baseline scale score, randomization schedule stratification factors, treatment, 
and a baseline score and treatment interaction as fixed-effect variables.    
 
EQ-5D-5L Questionnaire  
The EQ-5D is a generic preference-based measure that indirectly measures the utility for health that 
generates an index-based summary score based upon societal preference weights (Pickard et al 2007).The 
EQ-5D-5L consists of 5 items that cover 5 main dimensions including mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression, and a general visual analogue scale (VAS) for health status. The 
range of VAS scoring is from 0 (the worst health imaginable) to 100 (the best health imaginable).   
Each of the 5 dimensions comprising the EQ-5D descriptive system is divided into 5 levels of perceived 
problems as follows. 
• 
Level 1: indicating no problem  
• 
Level 2: indicating slight problems  


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• 
Level 3: indicating moderate problems 
• 
Level 4: indicating severe problems  
• 
Level 5: indicating extreme problems  
The response levels collected from the EQ-5D-5L five dimensions  as a health profile are converted into an 
EQ-5D-5L index (utility) scores to represent subjects’ utility value.  The EQ-5D-5L index-based score is 
typically interpreted along a continuum where a utility value of 1 represents perfect health, 0 represents a 
state equal to death and a negative value represents a state worse than dead.    
The UK value set and scoring algorithm are used to derive the EQ-5D-5L index score for this analysis 
(Devlin et al., 2018).  The detailed scoring algorithm can be found in Appendix 2.  
The number and percent of subjects who completed the questionnaires are summarized by visit for each 
treatment group. 
9.2.6.1. 
Analysis of Change from Baseline in VAS and Index Scores 
Change from baseline in VAS and index scores are summarized by visit and for each treatment group. The 
MMRM analysis and the sensitivity analysis described in Section 9.2.5.1 can be similarly applied to the 
endpoints of  
- 
change from baseline in VAS with the baseline VAS score as covariate; 
- 
change from baseline in EQ-5D-5L index score with the baseline EQ-5D-5L index score as 
covariate 
To ensure the proper amount of data utilized in the model for each visit, the following steps will be 
implemented to identify data to be included in the model.  
(1) Calculate the number of subjects with non-missing assessments for each cycle. 
(2) Identify the last cycle with at least 20 subjects in any of the treatment groups and no subsequent cycles 
having at least 20 subjects in any of the treatment groups.  
(3) Assessments after the cycle identified in Step 2 will not be included in the model.  
9.2.6.2. 
Analysis of Minimally Important Difference and Time to Deterioration 
The appropriate MID cut-off for VAS is defined as a reduction of at least 7 points from baseline, based on 
a study of 534 cancer subjects evaluated by UK-based scoring algorithm (Pickard et al, 2007).  
The appropriate MID cut-off for index score is defined as a reduction of at least 0.063 points from baseline, 
based on the study on the scoring algorithm from England (McClure et al., 2017). McClure et al. reported 
the MID in the England population has a mean (standard deviation) of 0.063 (0.013), and a median of 0.064 
(interquartile range: 0.055 to 0.073).  
The MID cut-off for VAS and index scores for QoL deterioration, stable, and improvement are listed in Table 
9.  


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Table 9. Summary of MID for EQ-5D-5L Questionnaire 
Scale/item 
Deterioration 
Stable 
Improvement 
VAS 
≤-7 
-7 < and < 7 
≥7 
Index Score 
≤-0.063 
-0.063 < and <0.063 
≥0.063 
 
The number and percent of subjects achieving MID are summarized by visit for each treatment group.   
In addition, TTD of VAS is defined as the time (month) from randomization until the first reduction of at least 
7 points from baseline or death, whichever comes first. TTD of index score is defined as the time (month) 
from randomization until the first reduction of at least 0.063 points from baseline or death, whichever comes 
first.  
TTD for VAS is calculated as (date of the first reduction of at least 7 points from baseline, death or most 
recent visit – date of randomization + 1)/30.4375. 
TTD for EQ-5D-5L index score is calculated as (date of the first reduction of at least 0.063 points from 
baseline, death or most recent visit – date of randomization + 1)/30.4375. 
Subjects who does not experience TTD at the time of analysis are censored at the last visit.  Then, for the 
two time-to event endpoints 
- 
TTD for VAS  
- 
TTD for EQ-5D-5L index score  
When no post-baseline assessments are available, the date of randomization will be used for this 
calculation, that is, subjects will be censored at the date of randomization. 
 
The Kaplan-Meier method will be used to obtain the descriptive statistics of median, 25% and 75% 
percentiles along with their 95% CIs by treatment group. In addition, the two-sided p-value will be obtained 
from the stratified Kaplan-Meier method to account for the randomization stratification factors. The hazard 
ratio (HR) between the two treatments (fruquintinib vs placebo), together with its 95% CIs will be calculated 
from a stratified (i.e. accounting for randomization schedule stratification factors) Cox hazard model in which 
treatment and baseline value of scale will be included as fixed effects. 
Results from the descriptive system of 5 dimensions are summarized descriptively by visit for each 
treatment group.  A shift table from baseline for the levels within each of the 5 dimensions is provided by 
visit and treatment group. 
Data of EQ-5D-5L questionnaire are listed by subject and visit. 
9.2.6.3. 
Handling Missing Data for EQ-5D-5L Questionnaire 
The number of and percent subjects of missing data on the VAS and index score are presented by visit and 
for the overall trial.  Subjects who have died are included in this count. 
The sensitivity ANCOVA analysis described in Section 9.2.5.3 will be similarly applied to the endpoints of  


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- 
change from baseline in VAS for each subject during the period from the date of randomization to 
the 37 days after the date of last dose with the baseline VAS score as covariate; 
- 
change from baseline in EQ-5D-5L index score for each subject during the period from the date of 
randomization to the 37 days after the date of last dose with the baseline EQ-5D-5L index score 
as covariate 
 
Health Resource Utilization 
Data of heath resource utilization including primary reason for visit, type of resource, duration of visit (days) 
which is calculated as stop date – start date +1, number of visits, concomitant medication prescribed 
(Yes/No), and special transportation required are summarized descriptively for each treatment group. Each 
subject may have multiple health care visits during the study period, and the non-missing value from each 
visit will be utilized in the analysis.  
In addition, in the analysis of primary reason for visit, type of resource, concomitant medication prescribed 
(Yes/No), and special transportation required (Yes/No), only the unique response categories for a subject 
will be summarized. For example, a subject may have 10 health care visits, the response categories from 
those 10 visits are just 8 times of “Adverse Event” and 2 times of “Management of mCRC”, hence, this 
subject will only be counted in those two categories instead of summarizing 10 times in the aforementioned 
analysis.  
Data of heath resource utilization are listed by subject. 
 
Exploratory Efficacy Endpoints  
 
Circulating Tumor DNA 
The analysis of ctDNA will be documented separately, and is not covered in this SAP. 
 
Tumor Marker 
Change from baseline in serum CEA will be summarized by visit and for each treatment group. 
Data of CEA is listed by subject and visit.  
 
 


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Pharmacokinetics 
PK population is used for tabulation as specified in this section.   
 
PK Sampling Schedule  
The PK sampling schedule for for the subset of approximately 120 subjects with evaluable ECGs is 
displayed in Table 2 in the study protocol.  Furthermore, the PK sampling schedule for for subjects not 
included in the approximately 120 subjects with evaluable ECGs in the subset in Table 2 is displayed in 
Table 3 in the protocol.  
 
Data Handling 
 
Handling of Missing Data  
Missing concentration data for all subjects who are administered scheduled study treatments is considered 
as non-informative missing and is not imputed.  No concentration estimates are provided for missing sample 
values. 
 
Handling of below the lower limit of quantification (BLQ) Data 
For PK concentration summary, the following rules apply: 
• 
PK concentrations below the lower limit of quantification (BLQ) in pre-dose samples and in samples 
taken before the time of the first quantifiable value are set to zero;  
• 
The PK concentrations BLQ after quantifiable concentration are set to zero 
 
Handling of the Difference between the Scheduled (nominal time) and the Actual Sampling 
Times (actual time) 
For all sampling times, the actual sampling times relative to dosing are calculated as the difference 
between the actual clock time of sampling and the actual clock time of dosing.  The actual post-dose 
sampling times relative to dosing expressed in hours and rounded off to two decimal digits are used. Actual 
predose time in sampling times will not be set to 0. Scheduled sampling times are listed but will not be 
summarized. If the actual time of sampling is missing, it is reported as NR (not recorded) in the listing, the 
nominal time is used for summary statistics. 
 
Listing and Presentation of Individual PK Data  
PK data are presented by subject, cycle and day (for instance, C1D1, C1D21, C2D1, etc.), and time 
point. 
1. Concentration data for fruquintinib and M11 are presented to the same decimal place and in original 
units as reported by the bioanalytical lab, e.g., ng/mL;  
2. Listing of PK sampling times including nominal and actual time elapsed from dose with the deviation 
from the nominal time. 


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Summary of PK Concentration Data 
The observed concentrations for fruquintinib and metabolite M11 are summarized descriptively at each 
scheduled timepoint and dose level including. Summaries are presented by cycle and day (for instance, 
C1D1, C1D21, C2D1, etc.) and time point using descriptive statistics.  
• 
If the time deviation is greater than ± 20%, the PK concentration value is excluded from the 
summary descriptives. 
• 
Predose samples collected after C1D1, will be excluded from summary statistics if the time 
deviation is greater than ± 20% from 24 hours of the last dose. 
PK plasma concentration data at each scheduled timepoint and dose level is presented using the following 
descriptive statistics. 
• 
n  
• 
arithmetic mean and StdDev 
• 
coefficient of variation (CV)% 
• 
median 
• 
minimum and maximum 
• 
geometric mean and geometric CV% 
• 
number and percent of subject with BLQ 
Geometric mean and geometric CV% will not be reportable in the summary statistics if there is a BLQ value 
at a timepoint. The conventions presented in Table 10 below are used for the presentation of the descriptive 
statistics of plasma concentrations. 
Table 10. PK Reporting Precision 
Variable 
Summarized with: 
Minimum, Maximum 
3 significant digits or as needed based on actual 
measured values  
Mean (arithmetic and geometric), Median 
3 significant digits 
StdDev 
3 significant digits 
CV% and Geometric CV% 
1 decimal point 
 
 
 






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Category 
Sub-category 
Leading to Death 
Treatment-emergent AESIs 
 
CTCAE Grade ≥ 3 
Serious 
Treatment-related 
Treatment-related CTCAE Grade ≥3 
Leading to Dose Reduction 
Leading to Dose Interruption 
Leading to Treatment Discontinuation 
Treatment-related Leading to Dose Reduction 
Treatment-related Leading to Dose Interruption 
Treatment-related Leading to Treatment Discontinuation 
Leading to Death 
COVID-19-related TEAEs* 
CTCAE Grade ≥ 3 
Serious 
Treatment-related 
Leading to Dose Reduction 
Leading to Dose Interruption 
Leading to Treatment Discontinuation 
Treatment-related Leading to Dose Reduction 
Treatment-related Leading to Dose Interruption 
Treatment-related Leading to Treatment Discontinuation 
Leading to Death 
* COVID-19-related TEAEs will be characterized according to Table 19 Appendix 4 
A subject with two or more AEs in a category is counted only once for the subject count. 
 
TEAEs by SOC and PT 
The number and percent of subjects experiencing a TEAE within each of the categories and sub-categories 
listed in Table 12 are also summarized by SOC, PT, and highest CTCAE grade for each treatment group. 
A subject with two or more adverse events for each combination of SOC and PT is counted only once for 
the combination.   
The summary is sorted in descending order of frequency of SOC according to the sum of Fruquintinib + 
BSC and Placebo + BSC columns. Within SOC, sort by descending frequency of PT in according to the 
sum of Fruquintinib + BSC and Placebo + BSC columns. 
In addition, the number and percent of subjects are summarized by PT and highest CTCAE grade and by 
PT and CTCAE grade >=3  for each treatment group.  
 
Treatment-emergent Adverse Events of Special Interest 
Treatment-emergent AESI are also summarized by highest CTCAE grade for each treatment group and 
the subgroups listed below. 
Time (days) to onset of first treatment-emergent AESI are descriptively summarized for each AESI and 
treatment group. Time to first AESI 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 subject 


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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.  
Adverse events of special interest (AESI) are summarized for the following subgroups. 
• 
Age: < 65 years, >= 65 years 
• 
Sex: Female, Male 
• 
Region: North America (including USA), Europe (including Austria, Belgium, France, Germany, 
Hungary, Italy, Spain, and United Kingdom); Asia (including Japan) 
• 
Race: White, Asian, Black or African American, Other 
• 
BMI (kg/m2): < 18.5, >= 18.5 to < 24, >= 24 
• 
Prior Therapy: Trifluridine/Tipiracil (TAS-102), Regorafenib , Both Trifluridine/Tipiracil (TAS-102) 
and Regorafenib  
• 
RAS Status: Wild Type, Mutant 
• 
Duration of metastatic disease: <= 18 months, > 18 months 
• 
Liver Metastases at Baseline: Yes, No  
For AEs falling into the AESI category “Hepatic function abnormal”, a summary table will also be provided 
by SOC, PT, and highest CTCAE for subjects with the following liver function category at baseline. Each 
liver function category will be evaluated separately to identify the subjects meeting the criteria. A listing of 
hepatotoxicity AEs will also be produced for subjects who meet any of the liver function category criteria at 
baseline (i.e. aspartate aminotransferase [AST] or alanine aminotransferase [ALT] >3x upper limit of normal 
[ULN] or total bilirubin >2xULN, or alkaline phosphatase [ALP] <2xULN).  
• 
AST or ALT >3xULN  & ≤ 5xULN;  
• 
AST or ALT > 5xULN;  
• 
Total bilirubin  >2xULN;  
• 
AST or ALT > 3xULN and Total bilirubin  >2xULN;  
• 
AST or ALT >3xULN, Total bilirubin  >2xULN and ALP <2xULN 
 
Subgroup analysis of AE 
Analysis by BMI category (<18.5, ≥18.5 and <24 and ≥24 ) will be performed for the following AE summary: 
 
• 
TEAE overview summary 


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• 
SAE summary 
• 
Summary of TEAE leading to drug discontinuation 
• 
Summary of TEAE with CTCAE grade ≥3. 
 
Laboratory Evaluations 
Blood and urine samples for the determination of clinical chemistry, hematology, and urinalysis laboratory 
variables described in Table 13 will be measured.  
Clinical laboratory results will be graded according to CTCAE criteria, Version 5.0.Any graded changes that 
occur following the initiation of study drug and represents at least a 1-grade change from the baseline 
assessment is defined as treatment emergent. Any assessment, for which CTCAE toxicity grades are not 
available, will not be included in any analyses for which toxicity grades are required. Grade 0 is assigned 
to all laboratory values except missing values and not already assigned another grade.  Missing values are  
considered missing. 
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 first dose administration and up to 37 days 
following the last dose of study medication will be used for analysis.  
Table 13. List of Laboratory Parameters 
Laboratory Category 
Parameters 
Hematology 
Hemoglobin, Hematocrit, Red Blood Cell Count (RBC), Platelet Count, White 
Blood Cell Count (WBC), Absolute Neutrophil Count, Neutrophils %, Absolute 
Lymphocyte Count, Lymphocytes %, Absolute Monocyte Count, Monocytes %, 
Absolute Eosinophil Count, Eosinophils %, Absolute Basophil Count, Basophils 
% 
Blood Chemistry 
Albumin, Blood urea nitrogen (BUN), Creatinine, Aspartate transaminase 
(AST), Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), Total 
Bilirubin, Lactate dehydrogenase (LDH), Uric acid, Sodium, Potassium, 
Chloride, Bicarbonate, Glucose, Calcium, Magnesium, Phosphorus, Total 
cholesterol, Triglycerides, Total Protein 
Blood 
Chemistry 
– 
Thyroid Function 
Free triiodothyronine (fT3), Serum free thyroxine (fT4), Thyroid-stimulating 
hormone (TSH) 
Urinalysis 
pH, Glucose, Protein, White blood cell, Red blood cell 


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Laboratory Category 
Parameters 
Urinalysis Microscopy 
Microscopic White Blood cell count, Microscopic Red Blood cell count, Other 
Coagulation 
Activated Partial thromboplastin time (aPTT), Prothrombin time, International 
normalized ratio (INR) 
 
All summaries of hematology, blood chemistry (including thyroid function), urinalysis and coagulation 
parameters are based on the results of SI units, where applicable.  Thyroid function parameters are 
analyzed under blood chemistry category. 
Summary tables for hematology, blood chemistry, coagulation, and urinalysis (pH only) laboratory variables 
include descriptive statistics for result values and change from baseline for all continuous variables by visit 
and treatment group.   
Toxicities for clinical labs will be characterized according to CTCAE, Version 5.0 (Table 20 of Appendix 5 
when possible), and the frequency and percentage of subjects with each CTCAE grade for each visit during 
the treatment period will be described. Moreover, any occurrence of grade 3 or grade 4 during the treatment 
period will be summarized, and shift in grade from baseline to the worst post-baseline value will be 
summarized.  
Summary tables and listings are also provided for treatment-emergent hepatotoxicity and subjects with or 
without liver metastasis by each treatment group. Hepatotoxicity is based on the pre-specified thresholds 
below: 
1. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3x upper limit of normal 
(ULN) and ≤ 5x ULN 
2. AST > 3,5,8,10, and 20x ULN, AST > 5x ULN for more than 5 weeks 
3. ALT > 3,5,8,10, and 20x ULN, ALT > 5x ULN for more than 5 weeks 
4. AST and/or ALT > 3,5,8,10, and 20x ULN, > 5x ULN for more than 5 weeks 
5. Total bilirubin elevations > 1.5x, 2x ULN 
6. ALP >1.5×, 2 × ULN 
7. Potential Drug-Induced Liver Injury  (DILI): AST and/or ALT > 3x ULN and (total bilirubin > 1.5×, > 
2x ULN) 
8. AST and/or ALT >3 × ULN and (TBL >2xULN or international normalized ratio [INR] >1.5) 
9. Hy's Law criteria: AST and/or ALT > 3x ULN and total bilirubin ≥ 2x ULN and ALP < 2x ULN 
An eDISH plot presenting peak total bilirubin and peak ALT values will also be produced. 


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Qualitative assessments of urinalysis parameters are summarized for all subjects using the number of 
subjects with results of negative, trace, or positive. 
For the urinalysis parameters, if the test result is “-“ or “negative”, the investigation interpretation for the lab 
test will be considered to be “normal”. The information of converting urinalysis parameters (i.e. WBC, RBC, 
and protein) results is provided in Table 21 of Appendix 5. 
Summary of clinical significance (Abnormal not clinically significant [NCS] and Abnormal clinically significant 
[CS]) is also provided by visit and treatment group. Shift from baseline to the worst post-baseline 
investigators’ assessment (i.e. normal, NCS, and CS for quantitative measurements and categorical 
measurements) will be presented. 
All laboratory results (including hematology, blood chemistry, blood chemistry – thyroid function, urinalysis, 
coagulation, hepatitis, amylase and lipase, and serum/urine pregnancy test data) in SI units are presented 
in data listings.  Tests are listed in alphabetical order within their respective panels (hematology, blood 
chemistry, urinalysis, and coagulation).   
 
Vital Signs 
Vital signs include systolic blood pressure, diastolic blood pressure, respiratory rate, body temperature, 
pulse rate, weight, body mass index (BMI) will be computed as weight (kg)/[height (m)]2.   
For vital signs, change from baseline to each post-baseline visit and timepoint will be calculated. The 
potentially clinically significant findings of vital signs will also be defined based on criteria defined in Table 
14.  
Vital signs are summarized with descriptive statistics for the observed values at each visit and change from 
baseline to post-baseline visits values by treatment group. The criteria of potentially clinically significant 
findings are defined in Table 14. The frequency and percentage of subjects with any potentially clinically 
significant findings during the treatment period will be presented.  
Table 14.  Potentially Clinically Significant Criteria for Vital Signs  
Variable 
Criterion value   
SBP (mmHg) 
Increase from baseline of 
˃ 0 - ≤ 20  
˃ 20 - ≤ 40  
˃ 40  
Decrease from baseline of 
˃ 0 - ≤ 20  
˃ 20 - ≤ 40  
˃ 40  
 
DBP (mmHg) 
Increase from baseline of 
˃ 0 - ≤ 20  
˃ 20 - ≤ 40  
˃ 40  
Decrease from baseline of 
˃ 0 - ≤ 20  




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QTcF, QTcB  (msec) 
> 450  
 
> 480  
 
> 500 
 
≤ 300 
 
Increase from baseline > 30  
 
Increase from baseline > 60 
 
> 450 and increase from baseline > 30  
 
> 450 and increase from baseline > 60  
 
> 480 and increase from baseline > 30  
 
> 480 and increase from baseline > 60  
 
> 500 and increase from baseline > 30  
 
> 500 and increase from baseline > 60  
 
Single 12-lead ECG are collected in all subjects using standardized equipment during cycles 1 to 3.  From 
cycle 4 onward, ECG is only performed as clinically indicated.   
For each ECG parameter, the observed values and change from baseline will be summarized. The 12-lead 
ECG interpretation by investigator are summarized at each visit descriptively, including the number and 
percent of subjects with normal, abnormal not clinically significant, and abnormal clinically significant results 
at baseline and each evaluation.  
The criteria of potentially clinically significant findings are defined in Table 15. The frequency and 
percentage of subjects with any potentially clinically significant findings during the treatment period will be 
presented. Shift table from baseline to worst post-baseline ECG results is provided. 
Single 12-lead ECG interpretations by investigator data are listed by subject and visit. 
 
Echocardiogram  
ECHOs are performed at Screening, cycle 2 day 1, and on day 1, every 3 cycles thereafter.  Assessment 
parameters include left ventricular ejection fraction and overall interpretation of cardiac function.  MUGAs 
are permitted if ECHOs cannot be performed.   
Categorical summaries of overall interpretation and change from baseline of left ventricular ejection fraction 
of ECHO/MUGA results at each visit are summarized.  A shift from baseline to the worst post-baseline table 
for overall interpretation is also provided.   
ECHO/MUGA data is listed by subject and visit.   


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Physical Examination  
A comprehensive physical examination at Screening includes subject general appearance, eyes, ears, 
nose and throat, head and neck, respiratory, cardiovascular, abdomen (gastrointestinal), skin, genitourinary 
system, lymph nodes, musculoskeletal, neurological assessments. 
Limited physical examination at scheduled visits is a subset the comprehensive physical examination as 
deemed appropriate by the investigator. 
Results of physical examination are listed by subject and visit. 
 
ECOG Performance Status 
ECOG performance status will be summarized descriptively using counts and percentages by visit for each 
treatment group.  A shift from baseline to worst post-baseline value table is also provided.   
ECOG performance status will be listed by subject and visit.  
 
Other Safety Endpoints 
 
Anti-cancer Medication during Survival Follow-up 
Anti-cancer medication during survival follow-up are classified using the WHODD version March 2022. 
The use of anti-cancer medication during survival follow-up will be summarized using discrete summary 
statistics, each treatment group and overall for the safety population.  If a subject took a specific medication 
multiple times or took multiple medications within a specific ATC or PT, the subject is counted only once for 
the respective ATC or PT. 
Summaries are ordered in alphabetical order of ATC and then, within an ATC, in decreasing frequencies 
by PT in overall column. If the frequencies tie, an alphabetic order will be applied. 
Data of anti-cancer medication during survival follow-up are listed by subject. 
 
Anti-cancer Procedure during Survival Follow-up 
The anti-cancer procedures during survival follow-up are coded using MedDRA version 25.0.  
The use of anti-cancer procedures during survival follow-up will be summarized using discrete summary 
statistics in each treatment group and overall for the safety population.  If a subject had a specific procedure 
multiple times or had multiple procedures within a specific SOC or PT, the subject is counted only once for 
the respective SOC or PT. 
Summaries are ordered in alphabetical order of SOC and then, within an SOC, in decreasing frequencies 
by PT in overall column. If the frequencies tie, an alphabetic order will be applied. 
Data of anti-cancer procedure during survival follow-up are listed by subject. 


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Anti-cancer Radiotherapy during Survival Follow-up 
The number and percent of subjects with at least one anti-cancer radiotherapy during survival follow-up are  
summarized for each treatment group. 
Data of anti-cancer radiotherapy during survival follow-up are listed by subject. 
 
Deaths  
Primary cause of death and whether autopsy was performed will be summarized descriptively for each 
treatment group.  Similarly, the deaths happening during the treatment period, defined as the period from 
the date of the first study drug administration until 37 days after last dose, will also be tabulated. Data of 
deaths are listed by subject. On-treatment death will be flagged.  
 
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 subjects and study staff due to the COVID-19 pandemic while ensuring 
subjects safety and maintaining data integrity, subjects are allowed remote visits during the pandemic.  
The planned protocol deviation analyses are described in Section 8.2; planned sensitivity analyses for the 
PFS and OS are described in Section 9.1.4, and the summary for COVID-19-related TEAEs are included 
in Section 11.1.1.  
 
Additional summaries related to the COVID-19 pandemic from the following aspects will be produced for 
ITT population:  
• 
Type of impact on study visit (missing entire visit; Interrupted and/or out of window in-person visit at 
site; remote visit (virtual or telephone); or other) 
• 
Reason related to COVID-19 (subject diagnosed with COVID-19; quarantined due to COVID-19; site 
closed or access restricted due to COVID-19; site open but subject unwilling or unable to come to site 
due to COVID-19; or other) 
• 
Study drug discontinuation due to COVID-19 
The number of subjects impacted by COVID-19 during the study investigation period as well as at any 
time will be summarized by treatment group and overall. The study investigation period is defined as the 
period from the date of randomization to the 37 days after the date of last study treatment administration.  
Supporting listings for the described analyses above will be provided.   
 
Interstitial Lung Disease 
Interstitial lung disease data collected, including chest x-ray results and oxygen saturation, are listed by 
subject. 
 


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IDMC Review  
A subset of TLFs for the study final analysis will be used for IDMC meetings.  The specific content of the 
TLFs submitted to the IDMC are determined by the IDMC members.  The results to be reviewed by the 
IDMC will be primarily based on the safety data.  Efficacy data is also provided for the purpose of the 
planned interim futility analysis after 1/3 of OS events has occurred.  
For open sessions, the tables are presented with column Total only and the listings contains no treatment 
header. For closed sessions, the tables are presented with columns Treatment A + BSC, Treatment B + 
BSC, and Total, and the listings contain treatment headers. The unblinded statistician to be involved in the 
closed sessions of the IDMC will share the actual treatment information for Treatment A and Treatment B.  
The IDMC may request to be unblinded by treatment group or per-subject basis at any time.  The unblinded 
biostatistician provides the information to unmask.  These communications are maintained in the IDMC 
workspace and submitted to the Trial Master File at the end of the study. 
The study is to be terminated in the case of confirmed futility after evaluation of 1/3 of OS events (i.e., 160 
OS events). 
At any time, the IDMC may request any other safety-related information deemed necessary to contribute 
to an appropriate review of safety. 
Further details of content for open and closed sessions are provided in Section 18, “Content of Open and 
Closed Sessions”, of the IDMC Charter in order to maintain the blinding of the study. 


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Changes from Analysis Planned in Protocol 
• 
Not applicable. 


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Reference List 
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman 
SB, de Haes JCJM, Kaasa S, Klee MC, Osoba D, Razavi D, Rofe PB, Schraub S, Sneeuw KCA, Sullivan 
M, Takeda F. The European Organisation for Research and Treatment of Cancer A quality-of-life instrument 
for use in international clinical trials in oncology. Journal of the National Cancer Institute 1993; 85: 365-376. 
Brookmeyer R., and Crowley J. (1982). A confidence interval for the median survival time. Biometrics, 29-
41. 
Devlin et al., Valuing health-related quality of life: An EQ-5D-5L value set for England. Health Economics. 
2018;27:7–22. https://doi.org/10.1002/hec.3564 
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. 
European Organization for Research and Treatment of Cancer. EORTC QLQ-C30 Scoring Manual. 
https://www.eortc.org/app/uploads/sites/2/2018/02/SCmanual.pdf 
EuroQol 
Research 
Foundation. 
EQ-5D-5L 
User 
Guide. 
Version 
3.0; 
September 
2019. 
https://euroqol.org/wp-content/uploads/2019/09/EQ-5D-5L-English-User-Guide_version-3.0-Sept-2019-
secured.pdf 
Kim, Y., & Won, S. (2013). Adjusted proportion difference and confidence interval in stratified randomized 
trials. PharmaSUG 2013. https://www.pharmasug.org/proceedings/2013/SP/PharmaSUG-2013-SP04.pdf 
McClure et al., Instrument-Defined Estimates of the Minimally Important Difference for EQ-5D-5L Index 
Scores. Value Health. 2017 Apr;20(4):644-650. doi: 10.1016/j.jval.2016.11.015. Epub 2017 Jan 10. PMID: 
28408007. 
Musoro et al., Minimally important differences for interpreting European Organisation for Research and 
Treatment of Cancer (EORTC) Quality of life Questionnaire core 30 scores in subjects with ovarian 
cancer, Gynecologic Oncology, 10.1016/j.ygyno.2020.09.007, (2020). 
Osoba et al., Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol. 
1998 Jan;16(1):139-44. doi: 10.1200/JCO.1998.16.1.139. PMID: 9440735. 
Pickard et al., Estimation of minimally important differences in EQ-5D utility and VAS scores in 
cancer. Health Qual Life Outcomes. 2007;5:70. doi: 10.1186/1477-7525-5-70. 
Pickard AS, Wilke CT, Lin HW, Lloyd A. Health Utilities Using the EQ-5D in Studies of Cancer. 
PharmacoEconomics 2007;25:365–84 


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Programming Considerations 
All TLFs and statistical analyses are generated using SAS for Windows, Release 9.4 (SAS Institute Inc., 
Cary, NC, USA). Computer-generated table, listing and figure outputs adhere to the following specifications.   
 
General Considerations 
• 
One SAS program can create several outputs 
• 
Each output is stored in a separate file 
• 
Output files are delivered as follows 
o 
Two compiled pdf files (with bookmark and TOC) – one for tables and figures, and one for 
listings]; 
o 
Individual rtf file for the TLFs (this is only applicable to the final delivery, e.g. final interim 
analysis delivery, final database lock delivery for clinical study report); 
o 
For figures, include the individual .tiff file (this is only applicable to the final delivery, e.g. 
final IA delivery, final DBL delivery for CSR) 
• 
Numbering of TLFs follows ICH E3 guidance  
 
Table, Listing, and Figure Format 
 
General 
• All TLFs are produced in landscape format on American letter paper size. 
• All TLFs are produced using the Courier New font, size 8 which is the smallest acceptable point size 
for the Regulatory Authorities. 
• The data displays for all TLFs have a minimum blank 1-inch margin on all 4 sides. 
• Headers and footers for figures are in Courier New font, size 8 which is the smallest acceptable point 
size for the Regulatory Authorities. 
• Legends are used for all figures with more than 1 variable, group, or item displayed. 
• Table and listings are in black and white (no color).  Figures are in colors, where applicable. 
• Only standard keyboard characters are used in the TLFs.  Special characters, such as non-printable 
control characters, printer-specific, or font-specific characters, are not used.  Hexadecimal-derived 
characters are used, where possible, if they are appropriate to help display math symbols (e.g., μ).  
Certain subscripts and superscripts (e.g., cm2, Cmax) are employed on a case-by-case basis. 
• Mixed case is used for all titles, footnotes, column headers, and programmer-supplied formats, as 
appropriate. 


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Headers 
• TLFs are internally paginated in relation to the total length (i.e., the page number should appear 
sequentially as page n of N, where N is the total number of pages in the table). 
• The date output was generated should appear along with the program name as a footer on each 
page. 
15.2.2.1. 
Headers for Study 
• All output should have the following header at the top of each page: 
Hutch son Med Pharma L m ted 
 
Protoco  No.: 2019 013 GLOB1 
Page X of Y 
 
 
  Data Cut off Date: DDMMMYYYY 
15.2.2.2. 
Headers for Study – Interim Analysis 
• All output should have the following header at the top of each page: 
Hutch son Med Pharma L m ted 
 
Protoco  No.: 2019 013 GLOB1  Inter m Ana ys s 
 
Page X of Y 
Data Cut off Date: DDMMMYYYY 
15.2.2.3. 
Headers for IDMC Meeting 
• All output should have the following header at the top of each page: 
Hutch son Med Pharma L m ted 
 
Protoco  No.: 2019 013 GLOB1  IDMC Meet ng 
 
Page X of Y 
 
  Data Cut off Date: DDMMMYYYY 
15.2.2.4. 
Headers for Japan Safety Lead-in Cohort 
• All output should have the following header at the top of each page: 
Hutch son Med Pharma L m ted 
 
Protoco  No.: 2019 013 GLOB1  Japan Safety Lead n Cohort 
 
Page X of Y 
Data Cut off Date: DDMMMYYYY 
15.2.2.5. 
Headers for Japan Safety Monitoring Committee (JSMC) Meeting 
• All output should have the following header at the top of each page: 
Hutch son Med Pharma L m ted 
 
Protoco  No.: 2019 013 GLOB1  JSMC Meet ng 
 
Page X of Y 
Data Cut off Date: DDMMMYYYY 
 
Display Titles 
• Each TLF are identified by the designation and a numeral.  (i.e., Table 14.1.1).  A decimal system 
(x.y and x.y.z) are used to identify TLFs with related contents.  The title is centered.  The analysis 
set are identified on the line immediately following the title.  The title and table designation are single-
spaced.  A solid line spanning the margins separate the display titles from the column headers.  
There is 1 blank line between the last title and the solid line.  Parameters or Visits, if applicable, are 
between the last title and the solid line. 


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Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
(Intent-to-Treat Population) 
 
Column Headers 
• Column headings are displayed immediately below the solid line described above in initial upper-
case characters.  
• In the case of efficacy tables, the variable (or characteristic) column is on the far left followed by the 
treatment group columns.  P-values are presented under the ‘Fruquintinib + BSC’ column. 
• For numeric variables, include “unit” in column or row heading when appropriate. 
• Analysis set sizes are presented for each treatment group in the column heading as (N=xx) (or in the 
row headings, if applicable).  This is distinct from the ‘n’ used for the descriptive statistics representing 
the number of subjects in the analysis set. 
• The order of treatments in the tables and listings is ‘Placebo + BSC’ first then ‘Fruquintinib + BSC’, 
followed by a ‘Total’ column, where applicable. 
 
Body of the Data Display 
15.2.5.1. 
General Conventions 
Data in columns of a table or listing are formatted as follows: 
• Alphanumeric values are left-justified; 
• Whole numbers (e.g., counts) are right-justified; and 
• Numbers containing fractional portions are decimal aligned. 
15.2.5.2. 
Table Conventions 
• Units are included where available 
• If the categories of a parameter are ordered, then all categories between the maximum and minimum 
category are presented in the table, even if n=0 for all treatment groups in a given category that is 
between the minimum and maximum level for that parameter.  For example, the frequency 
distribution for symptom severity would appear as: 
Severity Rating N 
severe 
0 
moderate 
8 
mild 
3 
 


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Where percentages are presented in these tables, zero percentages are presented and so counts of 0 are 
presented as 0 and not as 0 (0%). 
• If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the Study, 
etc.), then only those categories for which there is at least 1 subject represented in 1 or more groups 
are included. 
• An Unknown or Missing category are added to each parameter for which information is not available 
for 1 or more subjects.   
• Unless otherwise specified, the estimated mean, median, Q1, and Q3 for a set of values are printed 
out to 1 more significant digit than the original values, and standard deviations are printed out to 2 
more significant digits than the original values.  The minimum and maximum should report the same 
significant digits as the original values.  For example, for systolic blood pressure: 
N 
  XX 
Mean (StdDev) 
XXX.X (X.XX) 
Median 
XXX.X 
Min, Max 
XXX, XXX 
Q1, Q3 
XXX, XXX 
Missing 
XXX 
 
• P-values are output in the format: “0.xxx”, where xxx is the value rounded to 3 decimal places.  Every 
p-value less than 0.001 is presented as <0.  If the p-value is returned as >0.999, then present as 
>0.999. 
• Percentage values are printed to one decimal place, in parentheses with no spaces, one space after 
the count (e.g., 7 (12.8), 13 (5.4)).  Unless otherwise noted, for all percentages, the number of 
subjects in the analysis set for the treatment group who have an observation is the denominator.  
Percentages after zero counts should not be displayed and percentages equating to 100% are 
presented as 100, without decimal places.   
• Tabular display of data for medical history, prior/concomitant medications, and all tabular displays of 
AE data are presented by the body system, treatment class, or SOC with the highest occurrence in 
the active treatment group in decreasing order, assuming all terms are coded.  Within the body 
system, drug class and SOC, medical history (by preferred term), drugs (by ATC 2 code), and AEs 
(by preferred term) are displayed in decreasing order.  If incidence for more than 1 term is identical, 
they should then be sorted alphabetically.   
• Missing descriptive statistics or p-values which cannot be estimated are reported as “-”. 
• The percentage of subjects is normally calculated as a proportion of the number of subjects assessed 
in the relevant treatment group (or overall) for the analysis set presented.  However, careful 
consideration is required in many instances due to the complicated nature of selecting the 
denominator, usually the appropriate number of subjects exposed.  Describe details of this in 
footnotes or programming notes. 


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• For categorical summaries (number and percent of subjects) where a subject can be included in 
more than one category, describe in a footnote or programming note if the subject are included in 
the summary statistics for all relevant categories or just 1 category and the criteria for selecting the 
criteria. 
• Where a category with a subheading (such as system organ class) has to be split over more than 
one page, output the subheading followed by “(cont.)” at the top of each subsequent page.  The 
overall summary statistics for the subheading should only be output on the first relevant page. 
15.2.5.3. 
Listing Conventions 
• Listings are sorted for presentation in order of treatment groups as above, subject number, 
visit/collection day, and visit/collection time. 
• Missing data are represented on subject listings as either a hyphen (“-”) with a corresponding 
footnote (“- = unknown or not evaluated”), or as “N/A”, with the footnote “N/A = not applicable”, 
whichever is appropriate. 
• Dates are printed in SAS DATE9.format (“ddMMMyyyy”: 01JUL2000).  Missing portions of dates are 
represented on subject listings as dashes (--JUL2000).  Dates that are missing because they are not 
applicable for the subject are output as “N/A”, unless otherwise specified. 
• All observed time values are to be presented using a 24-hour clock HH:MM.  Time is reported if it 
was measured as part of the study. 
• Units are included where available 
15.2.5.4. 
Figure Conventions 
• Unless otherwise specified, for all figures, study visits are displayed on the X-axis and endpoint (e.g., 
treatment mean change from baseline) values are displayed on the Y-axis. 
 
Footnotes 
• A solid line spanning the margins separates the body of the data display from the footnotes.   
• All footnotes are left justified with single-line spacing immediately below the solid line underneath the 
data display. Each footnote will end with a period “.”. 
• Footnotes should always begin with “Note:” if an informational footnote, or a, b, c, etc.  if a reference 
footnote.  Each new footnote should start on a new line, where possible. 
• Subject specific footnotes are avoided, where possible. 
• Footnotes are used sparingly and add value to the table, figure, or listing.  If more than six lines of 
footnotes are planned, then a cover page is strongly recommended to be used to display footnotes, 
and only those essential to comprehension of the data are repeated on each page.   


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• The order of different types of footnotes need to follow the proper order as shown below 
1. Subject specific footnote, such as [a], [b], *, 1, 2, 3, and etc.; 
2. General footnote starting with “Note: …”, also the text of the footnotes will be properly 
aligned at the place after the phrase “Note:” if the line of footnote will wrap to the next row.  
3. Abbreviation footnote. The abbreviation of the footnote will be ordered alphabetically, In 
addition, each word spelling the abbreviation will use uppercase for the first letter unless it 
is the convention to use lowercase, e.g. “of”, “and”, etc. Each abbreviation will be separated 
by a “;” 
4. The last line of the footnote section is standard source line that indicates the name of the 
program used to produce the data display, date the program was run, and the listing source. 
For example, 
   
  Source: L st ng 16.2.x.x 
  Program: xxxx.sas  
 
 
 
Tab e Generat on: DDMMMYYYY HH:MM 
 
 
 


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Quality Control 
SAS programs are developed to produce outputs such as analysis data sets, summary tables, data listings, 
figures or statistical analyses.  An overview of the development of programs is detailed in Syneos Health 
SOP Developing Statistical Programs (SOP Number:3907). 
Syneos Health SOPs Developing Statistical Programs (3907) and Conducting the Transfer of Biostatistical 
Deliverables (3908) describes the quality control procedures that are performed for all SAS programs and 
output.  Quality control is defined here as the operational techniques and activities undertaken to verify that 
the SAS programs produce the output by checking for their logic, efficiency and commenting and by review 
of the produced output. 
Syneos Health SOP Pharmacokinetic and Related Data Analyses  (3913.01) describes the procedure for 
the generation and reporting of PK and pharmacodynamics data.  


Statistical Analysis Plan for Interventional Studies 
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Appendix 
 
Appendix 1. EORTC QLQ-C30 Scoring Algorithm  
The principle for scoring these scales is the same in all cases. The steps for scoring are:     1) Estimate 
the average of the items that contribute to the scale. (i.e. the raw score);  
    2) Use a linear transformation to standardize the raw score, so that scores range from 0 to 100.  
More specifically, if items 𝐼!, 𝐼", … , 𝐼# are included in a scale, the RawScore, RS, is the mean of the 
component items: 
𝑅𝑎𝑤𝑆𝑐𝑜𝑟𝑒
𝑅𝑆
(𝐼! + 𝐼" + ⋯+ 𝐼#)/𝑛 
Then apply the linear transformation to 0-100 to obtain the desired score for the scale, i.e.  
- 
for Functional scales:  
𝑆𝑐𝑜𝑟𝑒
51
(𝑅𝑆
1)
𝑟𝑎𝑛𝑔𝑒9 × 100 
- 
for Symptom scales/items and Global health status/QoL: 
𝑆𝑐𝑜𝑟𝑒
 =(𝑅𝑆
1)
𝑟𝑎𝑛𝑔𝑒> × 100 
where Range in the formula is the difference between the maximum possible value of RS and the minimum 
possible value. The QLQ-C30 has been designed so that all items in any scale take the same range of 
values. Therefore, the range of RS equals the range of the item values. Most items are scored 1 to 4, giving 
range = 3. The exceptions are the items contributing to the global health status / QoL, which are 7-point 
questions with range = 6. More detailed information about the items to be included in each scale is 
summarized in Table 16 below.  
To calculate the score for a scale following the aforementioned principles, it is required to at least half of 
the items have been answered, otherwise, the score will be set as missing. However, for single-item scale, 
set the score to missing if it is not answered. For example, role functioning and cognitive functioning each 
contain 2 items, and so these scales can be estimated whenever one of their constituent items is present; 
physical functioning contains 5 items, and so at least 3 need to have been completed.   
 
 


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Table 16. Scoring the EORTC QLQ-C30 version 3.0 
 
Scale 
Number of 
items 
Item range 
Version 3.0 
Item numbers 
Global health status / QoL 
 
 
 
 
Global health status/QoL (revised)  
QL2 
2 
6 
29, 30 
Functional scales 
 
 
 
 
Physical functioning (revised) 
PF2 
5 
3 
1 to 5 
Role functioning (revised) 
RF2 
2 
3 
6, 7 
Emotional functioning 
EF 
4 
3 
21 to 24 
Cognitive functioning 
CF 
2 
3 
20, 25 
Social functioning 
SF 
2 
3 
26, 27 
Symptom scales / items 
 
 
 
 
Fatigue 
FA 
3 
3 
10, 12, 18 
Nausea and vomiting 
NV 
2 
3 
14, 15 
Pain 
PA 
2 
3 
9, 19 
Dyspnoea 
DY 
1 
3 
8 
Insomnia 
SL 
1 
3 
11 
Appetite loss 
AP 
1 
3 
13 
Constipation 
CO 
1 
3 
16 
Diarrhoea 
DI 
1 
3 
17 
Financial difficulties 
FI 
1 
3 
28 


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Appendix 2. Scoring the EQ-5D-5L Descriptive System 
The EQ-5D-5L descriptive system can be scored as an example in Figure 2 below. There should be only 
one response for each dimension.  
Figure 2. Example of Scoring the EQ-5D-5L Descriptive System 
 


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Then, the EQ-5D-5L index score is a weighted linear combination over 5 dimensions of health status. The 
coefficient for the weighting for each level of domains are presented in Table 17. 
Table 17. EQ-5D-5L weighting coefficient scheme from England for the response of each 
dimension (Devlin et al., 2018) 
Score level of dimension 
Coefficient for each level of dimension 
Mobility 
 
Self-care 
Usual 
activities 
Pain/ 
discomfort 
Anxiety/ 
depression 
Level 1: no problem 
0 
0 
0 
0 
0 
Level 2: slight 
0.027 
0.023 
0.023 
0.029 
0.036 
Level 3: moderate 
0.035 
0.037 
0.029 
0.039 
0.048 
Level 4: severe 
0.096 
0.076 
0.075 
0.128 
0.132 
Level 5: unable or extreme [a] 
0.127 
0.094 
0.085 
0.155 
0.134 
[a] For dimensions (Mobility, Self-care, and Usual activities), it takes value “Unable”. For dimensions 
(Pain/discomfort and Anxiety/depression), it takes value “Extreme”.  
The EQ-5D-5L index score is calculated using the equation  
EQ-5D-5L index score 
1
2.159 × ∑coefficient value assigned to the response of each dimention 
If any of the 5 dimension scores is missing, the index score will be set to missing.  
For example, for a value of health state 23245, the EQ-5D-5L index score is calculated as 
EQ-5D-5L index score = 1 −2.159 ×
∑coefficient value assigned to the response of each dimention =  1 −2.159 ×
∑(0.027 + 0.037 + 0.023 + 0.128 + 0.134) = 0.247  
 
 
 




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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 




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Aldosterone urine increased 
Ectopic renin secretion 
Metanephrine urine increased 
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 


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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 




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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 


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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 
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 


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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 


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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 
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 


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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 


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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 
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 


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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 


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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 
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 


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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 


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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 
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 


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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 
  




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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 




Statistical Analysis Plan for Interventional Studies 
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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 


Statistical Analysis Plan for Interventional Studies 
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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 
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 


Statistical Analysis Plan for Interventional Studies 
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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 


Statistical Analysis Plan for Interventional Studies 
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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 
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 


Statistical Analysis Plan for Interventional Studies 
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Page 112 of 134 
 
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 


Statistical Analysis Plan for Interventional Studies 
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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 
Cerebral microinfarction 
Paradoxical embolism 
Truncus coeliacus thrombosis 
Cerebral septic infarct 
Paraneoplastic thrombosis 
Tumour embolism 


Statistical Analysis Plan for Interventional Studies 
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Page 114 of 134 
 
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 


Statistical Analysis Plan for Interventional Studies 
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Page 115 of 134 
 
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 
Deep vein thrombosis 
Portal vein embolism 
Venous operation 


Statistical Analysis Plan for Interventional Studies 
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SAP Text Vers on: 1.4 dated 21 Ju 2022 
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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 




Statistical Analysis Plan for Interventional Studies 
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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 


Statistical Analysis Plan for Interventional Studies 
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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 


Statistical Analysis Plan for Interventional Studies 
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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 


Statistical Analysis Plan for Interventional Studies 
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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 


Statistical Analysis Plan for Interventional Studies 
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Coagulation factor V level decreased 
Hepatobiliary neoplasm 
Renal and liver transplant 
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 




Statistical Analysis Plan for Interventional Studies 
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Cardiac failure 
Chronic right ventricular failure 
Obstructive shock 
Cardiac failure acute 
Congestive hepatopathy 
Pulmonary oedema 
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 
 
 
 


Statistical Analysis Plan for Interventional Studies 
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Page 125 of 134 
 
 
Appendix 4. COVID related AE 
Table 19. MedDRA (Version 25.0) Preferred Term List for COVID-19 Related AE 
 
 
 
Asymptomatic COVID-19 
Occupational exposure to SARS-CoV-2 
Breakthrough COVID-19 
Post-acute COVID-19 syndrome 
Congenital COVID-19 
SARS-CoV-2 antibody test positive 
Coronavirus infection 
SARS-CoV-2 carrier 
Coronavirus pneumonia 
SARS-CoV-2 RNA decreased 
Coronavirus test positive 
SARS-CoV-2 RNA fluctuation 
COVID-19 
SARS-CoV-2 RNA increased 
COVID-19 immunisation 
SARS-CoV-2 sepsis 
COVID-19 pneumonia 
SARS-CoV-2 test false negative 
COVID-19 prophylaxis 
SARS-CoV-2 test positive 
COVID-19 treatment 
SARS-CoV-2 viraemia 
Exposure to SARS-CoV-2 
Suspected COVID-19 
Multisystem inflammatory syndrome 
Thrombosis with thrombocytopenia syndrome 
Multisystem inflammatory syndrome in adults 
Vaccine derived SARS-CoV-2 infection 
Multisystem inflammatory syndrome in children 
 










Statistical Analysis Plan for Interventional Studies 
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Page 130 of 134 
 
 
Appendix 6. Kaplan Meier Estimates and 95% CI from Brookmeyer and Crowley method 
 
SAS Code example for KM estimates and 95% CI from a log-log transformation based on 
Brookmeyer-Crowley method 
Example SAS code for 95% CI calculated from a log-log transformation based on the method by 
Brookmeyer and Crowley, for median, 25th and 75th percentiles: 
*** KM Estimates - Quartiles ***; 
ods output quartiles=quartiles1; 
proc lifetest  
 
data=ADTTE(where=(PARAMCD="OS")) 
 
conftype=loglog; 
 
time AVAL*CNSR(1); 
 
strata TRTPN; 
run; 
 
AVAL is the time in months, CNSR is the censoring variable, TRTPN is the treatment group variable. 
The output dataset (quartiles1) contains by treatment group, the estimate for median (ESTIMATE, where 
PERCENT=50), 25% (ESTIMATE, where PERCENT=25), and 75% (ESTIMATE, where PERCENT=75), 
along with the corresponding 95% CI calculated from a log-log transformation (for each corresponding 
PERCENT=25, =50 and =75, the CI values are stored in LowerLimit and UpperLimit). 
 
SAS Code example for KM estimates and 95% CI from a linear transformation based on 
Brookmeyer-Crowley method at selected landmarks 
Example SAS code for 95% CI calculated from a linear transformation based on the method by Brookmeyer 
and Crowley at selected landmarks, for example, at 3, 6, 9, 12, and 18 months: 
*** KM Estimates - Timelist ***; 
proc lifetest  
 
data=ADTTE(where=(PARAMCD="OS")) 
 
conftype=linear method=km atrisk timelist=(3, 6, 9, 12, 18) reduceout outsurv=tlist; 
 
time AVAL*CNSR(1); 
 
strata TRTPN;  
run; 
 
AVAL is the time in months, CNSR is the censoring variable, TRTPN is the treatment group variable. 
The outsurv dataset (tlist) will provide by treatment group, the estimate (SURVIVAL*100) at specified time 
points (variable TIMELIST) and the corresponding 95% CIs (SDF_LCL*100, SDF_UCL*100). 


Statistical Analysis Plan for Interventional Studies 
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Appendix 7. Stratified Log-Rank Test 
Example SAS code for Stratified Log-Rank Test, accounting for randomization schedule stratification 
factors. 
*** Stratified Log rank test ***; 
ods output LogUniChisq=logunichisq1; 
proc lifetest  
 
data=ADTTE(where=(PARAMCD="OS")) 
 
method=km; 
 
time AVAL*CNSR(1); 
strata STRAT1RN STRAT2RN STRAT3RN; 
test TRTPN; 
run; 
 
AVAL is the time in months, CNSR is the censoring variable, TRTPN is the treatment group variable, and 
STRAT1RN, STRAT2RN and STRAT3RN are placeholder variables representing the randomization 
schedule stratification factors.  
The output dataset (logunichisq1) contains the p-value for the Log-Rank Test (ProbChiSq) comparing the 
treatment groups. 
 
Multiplicity Adjustment for Log-Rank Tests for OS and PFS 
A fixed-sequence (hierarchical) testing procedure is used to control the overall type I error rate at 0.05.  If 
the resulting 2-sided p-value from the analysis of primary endpoint OS is ≤ 0.05, then, a superiority test of 
for PFS will be conducted at the two-sided significance level of 0.05.  
The multiplicity adjusted p-value for OS is its raw p-value, and the adjusted p-values for PFS is the 
maximum value between the p-values produced for the OS and PFS.  
data pvalue; 
   input p @@; 
   if (_n_ = 1) then 
      pseq = 0; 
   pseq = max(pseq, p); 
   retain pseq; 
   cards; 
0.021 0.043  
run; 
The raw p-values used to calculate the adjusted p-value will be obtained from the SAS programming for 
OS and PFS, then, this sample program will be tailored in the production.  


Statistical Analysis Plan for Interventional Studies 
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Page 132 of 134 
 
 
Appendix 8. Stratified Cox Proportional Hazard Model 
Example SAS code for hazard ratio between the 2 treatment groups (fruquintinib vs placebo), and 
corresponding 95% CIs, calculated from a stratified Cox proportional hazard model (i.e. accounting for 
randomization schedule stratification factors) in which the treatment group is the only covariate in the model:  
*** Hazard ratio ***; 
ods output hazardratios=hazrat1; 
proc phreg 
 
data=ADTTE(where=(PARAMCD="OS")) 
alpha=0.05;  
 
model AVAL*CNSR(1)=TRTPN; 
strata STRAT1RN STRAT2RN STRAT3RN; 
hazardratio TRTPN; 
run; 
 
AVAL is the time in months, CNSR is the censoring variable, TRTPN is the treatment group variable, and 
STRAT1RN, STRAT2RN and STRAT3RN are placeholder variables representing the randomization 
schedule stratification factors.  
The output dataset (hazrat1) contains the hazard ratio (HazardRatio) and the corresponding 95% CI 
(WaldLower, WaldUpper). Confirm the order of TRTPN variables is coded so HR < 1 indicates a favorable 
clinical benefit from fruquintinib over the placebo group. 
 
Appendix 9. Cochran-Mantel Haenszel test stratified by randomization schedule 
stratification factors 
Example SAS code for p-value of comparing treatment groups based on a Cochran-Mantel Hanzel test 
stratified by the randomization schedule stratification factors. 
 
 *** stratified Cochran-Mantel Haenszel (CMH) test ***; 
ods output CMH=cmh1; 
proc freq 
 
data=ADEFF(where=(PARAMCD="ORR")); 
table STRAT1RN*STRAT2RN*STRAT3RN*TRTPN*AVAL/cmh; 
run; 
 
TRTPN is the treatment group variable and STRAT1RN, STRAT2RN and STRAT3RN are placeholder 
variables representing the randomization schedule stratification factors.  
The output dataset (cmh1) contains the p-value (Prob, corresponding to the Statistic=3, for General 
Association). If the number of objective   responses is not sufficient to utilize the CMH test, a stratified exact 
CMH test will be performed instead. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
Th s document s conf dent a . 
SAP Text Vers on: 1.4 dated 21 Ju 2022 
Contro ed Document ID: 3903A.02, Effect ve Date 31 Aug 2020 
F ng requ rements: TMF 
Page 133 of 134 
 
 Appendix 10. Adjusted proportion difference between treatment groups with 95% CI using 
the Wald method to account for randomization schedule stratification factors 
Example SAS code for adjusted proportion difference between treatment groups with 95% CI using the 
Wald method to account for randomization schedule stratification factors: 
ods output CommonPdiff=pdiff1; 
proc freq data = ADEFF(where=(PARAMCD="ORR")); 
      tables STRAT1RN*STRAT2RN*STRAT3RN*TRTPN*AVAL/riskdiff(column=2 common 
cl=wald); 
run; 
 
Using ADEFF and variable AVAL, the outcome of interest is ORR (i.e. Objective response rate), TRTPN is 
the treatment group variable and STRAT1RN, STRAT2RN and STRAT3RN are placeholder variables 
representing the randomization schedule stratification factors. The above example assumes the response 
is coded in column 2 (i.e. AVAL is coded as 0, 1, where 1 is response), and that fruquintinib is presented in 
row 1, and placebo is presented in row 2. The above code will be adjusted for correct presentation based 
on the actual coding in ADEFF if necessary. 
The output (pdiff1) provides an adjusted proportion difference between treatment groups (the variable 
Value, when Method="Mantel-Haenszel") with a 95% CI (the variables LowerCL, UpperCL, when 
Method="Mantel-Haenszel") using the Wald method to account for randomization schedule stratification 
factors. 
 Appendix 11. REML-based MMRM 
Example SAS code for REML-based MMRM: 
 
proc mixed  
data=ADQS(where=(PARAMCD="PHYSF" and ANL20FL="Y")) 
method=reml; 
class USUBJID TRTPN AVISITN STRAT1RN STRAT2RN STRAT3RN; 
model CHG = BASE TRTPN AVISITN TRTPN*AVISITN STRAT1RN STRAT2RN 
STRAT3RN/solution ddfm=kr;  
repeated AVISITN/subject=USUBJID type=UN; 
lsmeans TRTPN*AVISITN/diff cl slice = AVISITN; 
run;  
 
CHG is the change from baseline in score of the subscale, USUBJID is the subject identification variable, 
TRTPN is the treatment group variable, AVISITN is a placeholder variable for visit, TRTPN*AVISITN is the 
treatment group-by-visit interaction, BASE is a placeholder variable for baseline value of scale, and 
STRAT1RN, STRAT2RN, and STRAT3RN are placeholder variables representing the randomization 
schedule stratification factors.  
Prior to performing this analysis, the visits for each subject are limited within the dataset up to the last cycle 
with at least 20 subjects in any of the treatment groups (i.e. all subsequent cycles have less than 20 patients 
in each of the treatment groups). If there is a convergence issue with the unstructured covariance model, 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Hutch son Med Pharma L m ted; Protoco  No.: 2019 013 GLOB1 
 
 
 
Th s document s conf dent a . 
SAP Text Vers on: 1.4 dated 21 Ju 2022 
Contro ed Document ID: 3903A.02, Effect ve Date 31 Aug 2020 
F ng requ rements: TMF 
Page 134 of 134 
 
Toeplitz, Autoregressive (1) (AR (1)) covariance structure is used, following this sequence until 
convergence is achieved.  If the model still does not converge with AR (1) structure, no results are reported. 
When the covariance structure is not unstructured, the sandwich estimator for the variance-covariance 
matrix is derived, using the EMPIRICAL option in the PROC MIXED statement in SAS. 


Statistical Analysis Plan Summary of Changes 
 
Version # 
Date 
(DD-Mmm-YYYY) 
Revision Summary 
1.0 
25-Mar-2021 
Original Draft 
1.1 
15-Nov-2021 
Update to address sponsor comments on draft delivery 
Stable document signed for IA. 
1.2 
25-Mar-2022 
Update to address sponsor comments on v1.0 and v1.1. 
Some listed below: 
• Change in visit windows 
• Clarifications on Exposure duration calculation 
• Summary of MID for EORTC QLQ-C30 Questionnaire 
• Table updated 
• Update on TTD calculation for questionnaires 
1.3 
09-Jun-2022 
Update to address sponsor comments on v1.2.: 
Some listed below: 
• Censoring Rules for PFS Table updated 
• Non COVID population removed 
• Change in Exposure duration calculation 
• Change in sensitivity and subgroup analyses for OS and 
• PFS 
• Change in AESI definition 
• AESI Categories and Preferred Term Table updated 
• MedDRA (Version 25.0) Preferred Term List for COVID-19  
• Related AE Table added 
• PK updates and Change in partial know alive date 
• imputation rules 
1.4 
21-Jul-2022 
• Section 6.4 and 6.6 about the protocol deviation (just 
language changes) 
• Table 4 about the visit window 
• Section 11.2 some hepatic evaluation criteria added 
• Table 14.3.4.1.5 to reflect the hepatic criteria changes in 
the SAP 
• Listing 16.2.3.3 updates the title; adding a new Listing 
16.2.3.4 by site. 
• Section 7.2.2 last dose date definition 
• Section 6.5 PK population additional detail 
• Table 12 additional raw with Treatment-related CTCAE 
Grade ≥3