Conditions: Gastric Cancer Gastric Adenocarcinoma
Keywords: Gastric Cancer Gastric Adenocarcinoma Gastro-esophageal Cancer Gastro-esophageal Junction Cancer Stomach Cancer Tumor Oncology Antiangiogenesis Metastatic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 460
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of rivoceranib plus best supportive care (BSC) compared to placebo plus BSC in participants with advanced or metastatic gastric cancer (GC).

Detailed description:

Arms:
arm 1: Participants will receive rivoceranib 700 milligrams (mg) orally once per day during each cycle plus BSC. BSC is defined as palliative, non-cancer therapy. Each cycle duration is 28 days. arm 2: Participants will receive matching placebo to rivoceranib orally once per day during each cycle plus BSC. BSC is defined as palliative, non-cancer therapy. Each cycle duration is 28 days.

Interventions: intervention 1: Rivoceranib intervention 2: Placebo
Intervention descriptions: intervention 1: Oral tablet intervention 2: Oral tablet

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
A Prospective, Randomized, Double-Blinded, Placebo-Controlled, Multinational, Multicenter, 
Parallel-group, Phase III Study to Evaluate the Efficacy and Safety of Apatinib plus Best 
Supportive Care (BSC) compared to Placebo plus BSC in Patients with Advanced or 
Metastatic Gastric Cancer (GC) 
Protocol No. 
LSK-AM301 
Version No. 
5.0 
Version date 
20181116 
Sponsor 
LSK BioPartners, Inc. 
8 East Broadway, Suite 611, Salt Lake City, 
Utah, USA 84111 
Sponsor Medical Monitor 
 
Phone: 
 
Email: 
 
EudraCT No. 
2016-003984-20 
IND No. 
111963 
NCT No. 
NCT03042611 
The contents included in this document are confidential and proprietary information of the company 
sponsoring the study. This document is provided to you as an Investigator, your staff, and the 
applicable Institutional Review Board/Independent Ethics Committee. Any other use, copying, 
disclosure of information in this document is strictly prohibited without written authorization of the 
sponsor. Any supplemental information (e.g., amendments) that may be added to this document is 
also confidential and proprietary to the sponsor and must be kept confidential in the same manner 
as the contents of this document. This protocol has been written in accordance with current ICH-
GCP guidelines. 
CONFIDENTIAL 
NCT #NCT03042611




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PROTOCOL REVISION HISTORY  
Version 
Date 
Comment 
1.0 
13 JUN 2016 
Initial Release for Regulatory Authority Review and Scientific Input 
– Not approved for or implemented for patient treatment. 
2.0 
28 OCT 2016 
Protocol version under which patient enrollment to begin. Updated 
based on FDA, CHMP/EMA and PMDA comments and advice to 
adjust inclusion/exclusion and study evaluations and to clarify and 
require study activity that address these comments. 
3.0 
03 Feb 2017 
Protocol version to clarify and make slight modifications to 
inclusion/exclusion criteria. Updated to include Japan specific 
PMDA requirements to global protocol version and to add more 
clear parameters for patients to qualify and consent to continued 
study treatment after disease progression. 
3.1 
28 APR 2017 
Protocol amendment to clarify contraception method and to 
accommodate request for earlier confirmation of disease 
progression for patients who continue study treatment beyond initial 
progression, according to FDA and MHRA comments.  
3.1DEU 
28 JUN 2017 
Germany specific protocol amendment to clarify contraception 
method and to add additional pregnancy testing according to BfArM 
(Germany) comments. 
3.1FRA 
28 JUN 2017 
France specific protocol amendment to modify inclusion and 
exclusion criteria, treatment suspension and discontinuation plan, 
and additional pregnancy tests according to ANSM request. 
3.1UK 
19 OCT 2017 
UK specific amendment to clarify wording per UK REC comments. 
3.1POL 
16 NOV 2017 
Poland specific protocol amendment to add additional pregnancy 
testing according to Poland competent authority comments. 
4.0 
07 FEB 2018 
Change of inclusion criteria to allow for later line study treatment in 
some study regions where recent approval of therapy or 
standardization of therapy in later line has occurred. This is to 
maintain the target study population to be subjects who failed 
approved standard therapies.   
4.0 Country 
Specific 
22 MAR 2018 
Country specific cascaded versions to reflect changes made in V4.0 
from V3.1, including 4.0DEU, 4.0FRA, 4.0UK, and 4.0POL 
4.0ROM 
29 MAR 2018 
Romania specific protocol amendment to add additional pregnancy 
testing according to Romania competent authority comments. 
4.1 
(Japan only) 
04 JUN 2018 
Extended trial period estimation as required by PMDA. 
5.0 
16 NOV 2018 
Created open-label extension period for patients taking apatinib 
after unblinding study results during final analysis. Extended trial 
period estimation. Clarified ECG data collection. Integrated 
previous country specific protocol versions.  
5.0FRA 
16 NOV 2018 
France specific version to reflect changes made in V5.0 from V4.0. 
 
 


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SYNOPSIS 
 
Name of Sponsor 
LSK BioPartners, Inc. 
Protocol No. 
LSK-AM301 
Study Title 
A Prospective, Randomized, Double-Blinded, Placebo-Controlled, 
Multinational, Multicenter, Parallel-group, Phase III Study to Evaluate 
the Efficacy and Safety of Apatinib plus Best Supportive Care (BSC) 
compared to Placebo plus BSC in Patients with Advanced or Metastatic 
Gastric Cancer (GC) 
Indication 
Advanced or Metastatic Gastric Cancer 
Investigational 
Product 
YN968D1 (apatinib mesylate) will be supplied as 100 mg and 200 mg 
tablets for oral (PO) administration 
Coordinating 
Investigator(s) 
 
 Korea 
For UK: 
 
 UK 
Study Centers 
The study will be performed in approximately 90 sites in Asia Pacific, 
North America and Europe. 
Study Duration 
Total study duration will be approximately 30 months: 21 months of 
recruitment period + 9 months of treatment period, approximately from 
January 15th, 2017 to June30th, 2020. The extension period may 
continue beyond these dates. The study data will be analyzed when the 
required number of events (approximately 325 deaths) are observed. 
This is projected to occur approximately 9 months after the last subject 
is randomized. All subjects will be treated and/or followed after 
randomization until the study data analysis is performed, and then they 
will be monitored for survival status until death. Patients continuing to 
benefit from apatinib treatment, after final analysis and subsequent 
unblinding, will be given an option to consent to continue treatment with 
apatinib. Placebo patients will stop taking the placebo and will be 
monitored for survival status until death.   
Study Phase 
Phase III 
Objective 
Primary objective 
To evaluate the overall survival (OS) of Apatinib compared to Placebo 
in patients with Advanced or Metastatic Gastric Cancer (GC) 
Secondary objectives 
• To evaluate progression-free survival (PFS) 
• To evaluate objective response rate (ORR) 


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• To evaluate disease control rate (DCR) 
• To evaluate EORTC QLQ-C30 and EORTC QLQ-STO22 
• To evaluate EQ-5D-5L 
• To explore pharmacodynamic markers: 
Vascular 
Endothelial 
Growth 
Factor 
(VEGF), sVEGFR-1, 
sVEGFR2, sVEGFR3 
• To evaluate pharmacokinetics 
• To evaluate the safety: 
Adverse events, laboratory tests, vital signs, physical examination, 
12-lead ECG, ECOG performance status 
Study Design 
Prospective, 
Randomized, 
Double-Blinded, 
Placebo-Controlled, 
Multinational, Multicenter, Parallel-group 
Sample Size 
Approximately 459 subjects (among them, the anticipated number of 
Japanese patients is at least 50 and up to 100 will be enrolled.) 
Test Drug 
Apatinib 700 mg p.o. qd (as 869 mg apatinib mesylate) 
Control Drug 
Matching Placebo to Apatinib 
Treatments 
Apatinib or Placebo, qd, p.o. should be continued until disease 
progression, intolerable toxicity or subject’s withdrawal of consent. 
Dose Adjustment 
Scheme 
During each administration cycle (28 days/cycle), only a single dose 
reduction (Apatinib 700 mg qd to 600 mg qd or 600 mg qd to 400 mg 
qd) is permitted; A total of two dose reductions are permitted during the 
entire study period; and dose reduction below 400 mg qd will not be 
permitted. 
・ In case of Grade I non-hematological treatment related toxicity and 
Grade I or II hematologic toxicity, no dose adjustment needs to be 
done.  
・ In case of Grade II non-hematological treatment related toxicity, 
study treatment is continued without modification and with required 
symptomatic treatment. The investigator may reduce the dose by 
one level in the next cycle if they determine that continuing Grade 
II treatment related toxicity or a significant potential of worsening 
should be avoided. 
・ In case of potentially related or related anti-angiogenic treatment 
Grade II AEs, pre-emptive dose reduction is recommended and the 
investigator may reduce the dose by one level at any time to reduce 
the risk of potential significant worsening that may cause the 
patient to discontinue the study. If the AE Grade stabilizes or 
decreases with dose reduction, the investigator may choose to 


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increase the dose by one level at any time within the cycle or at the 
start of the next cycle to maximize potential study treatment 
exposure.  The investigator may decrease or increase the dose 
according to tolerability of the patient of Grade II AEs, but may not 
decrease below the 400 mg qd dose level and may not increase 
above the 700 mg qd dose level. 
・ In case of Grade III or IV non-hematological treatment related 
toxicity, study treatment will be temporarily withheld and resumed 
upon recovery to ≤ Grade I within 3 weeks. If treatment is resumed 
upon recovery, the dose should be reduced by one level. If recovery 
takes longer than 3 weeks, the investigator should contact the 
sponsor to determine if the patient may continue on study 
treatment.  
・ In case of Grade III or IV hematological treatment related toxicity, 
study treatment will be temporarily withheld and resumed upon 
recovery to ≤ Grade II within 3 weeks. If treatment is resumed upon 
recovery, the dose should be reduced by one level. If recovery 
takes longer than 3 weeks, the investigator should contact the 
sponsor to determine if the patient may continue on study 
treatment. 
Criteria for 
Discontinuation of 
Study Treatment 
If any of the following criteria is met during the treatment period, the 
study treatment will be discontinued. The subject will undergo end-of-
treatment examination (at completion/ discontinuation) and proceed to 
the post-treatment observation period to the full extent possible.  
1. Subject withdraws his/her consent. 
2. The development of disease progression is confirmed according to 
the RECIST guideline (version 1.1) that makes it inappropriate to 
continue with study treatment according to the investigator’s 
discretion or consent for continued treatment beyond RECIST 
confirmed disease progression is not obtained.  
3. Clinical symptoms determined to be due to disease progression that 
makes it inappropriate to continue with study treatment according to 
the investigator’s discretion or consent for continued treatment 
beyond clinical symptoms that are determined to be due to disease 
progression is not obtained. 
4. Onset of CTCAE grade ≥ 3 hypertension for which a causal 
relationship to the investigational product cannot be ruled out. 
(However, the judgment on whether or not to continue the treatment 


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will be made by the investigator.) 
5. Not having received a dose of the investigational product within the 
past consecutive 3 weeks for specific reasons, such as the onset of 
a treatment related adverse event.  
6. Treatment with prohibited concomitant medication of sufficient dose 
and duration to confound the study results or to make continuation 
or restarting of treatment within 3 weeks unsafe for the patient. 
7. Intolerable toxicity even after 2 dose reductions. 
8. Confirmed positive pregnancy test. 
9. The subject is lost to follow-up. 
10. The subject is dead. 
11. The investigator determines that continuation of study treatment is 
not appropriate.  
Eligibility Criteria 
Inclusion Criteria: 
1. Male or female at least 18 years old or older.  
2. Documented primary diagnosis of histologic- or cytologic-confirmed 
adenocarcinoma of the stomach or gastroesophageal junction. 
3. Patients have locally advanced unresectable or metastatic disease 
that has progressed since last treatment. 
4. One or more measurable or nonmeasurable evaluable lesions per 
RECIST 1.1. 
5. Patients should have failed or were intolerant to at least two prior 
lines of standard chemotherapies with each containing one or more 
of the following agents:  
o 
Fluoropyrimidine (IV 5-FU, capecitabine, or S-1), 
o 
platinum (cisplatin or oxaliplatin), 
o 
taxanes (paclitaxel or docetaxel) or epirubicin, 
o 
irinotecan, 
o 
trastuzumab in case of HER2-positive, 
o 
ramucirumab 
o 
nivolumab 
o 
pembrolizumab  
Previous treatments with experimental agents (except experimental 
antiangiogenic agents) alone or as part of the prior therapy lines are 
allowed but not mandatory. A maximum number of three prior 
therapy lines are allowed, unless nivolumab or pembrolizumab was 
used in a prior line, for which case a maximum of four prior therapy 
lines are allowed.  


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(For the patients whose disease recurred within 24 weeks from the 
last dose of adjuvant anticancer chemotherapy, that adjuvant 
anticancer chemotherapy is counted as 1 prior chemotherapy line.) 
6. Disease progression within 6 months after the last treatment. 
7. Patients who have adequate bone-marrow, renal and liver function 
including; 
a. Hematologic: Absolute neutrophil count ≥ 1,500/mm3, Platelets ≥ 
100,000/mm3, Hemoglobin ≥ 9.0 g/dL (Blood transfusion to meet 
the inclusion criteria within 2 weeks is not allowed.). 
b. Renal: Creatinine clearance (according to Cockcroft-Gault 
Equation or by 24 hr urine collection) > 50 mL/min and serum 
creatinine < 1.0 x ULN. 
c. Hepatic: Serum bilirubin < 1.5 x ULN, AST and ALT ≤ 3.0 x ULN 
(≤ 5.0 x UNL, if with liver metastasis). 
d. Blood coagulation tests: PTT and INR ≤ 1.5 x ULN and ≤ 1.5 x 
ULN, respectively. 
e. The patient’s urinary protein should be < 2+ on dipstick or routine 
urinalysis. If urine dipstick or routine analysis indicates 
proteinuria ≥ 2+, then a 24-hour urine or urine protein/creatinine 
ratio must be collected and must demonstrate < 2 g of protein in 
24 hours to allow participation in the study. 
8. Patients whose Eastern Cooperative Oncology Group (ECOG) 
performance status are evaluated to be ≤ 1. 
9. Expected survival of ≥ 12 weeks, in the opinion of the investigator. 
10. Ability to swallow the investigational product tablets.  
11. Female patients of child-bearing potential must have a negative 
serum or urine pregnancy test at the Screening Visit. Females must 
be surgically sterile, postmenopausal for at least 1 year prior to 
Screening Visit (no other medical cause involved) or must be using 
a highly effective method of birth control according to applicable 
guidelines. Acceptable methods of birth control include: combined 
estrogen-progestogen 
or 
progestogen-only 
hormone 
contraceptives 
[oral, 
non-oral, 
or 
implants], 
intrauterine 
contraceptive device or Intrauterine Contraceptive System that are 
approved or certified in Japan or applicable country. Other 
intrauterine contraceptive device, contraception double barrier 
methods such as condom, sponge, cervical cap and diaphragm with 
spermicides, if locally determined to be highly effective outside of 


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Japan or applicable country, may be considered as acceptable. 
12. Ability and willingness to comply with the study protocol for the 
duration of the study and with follow-up procedures. 
 
Exclusion Criteria: 
1. History of another malignancy within 2 years prior to randomization. 
Subjects with the following are eligible for this study if, in the opinion 
of the investigator, they do not pose a significant risk to life 
expectancy: 
o 
Bladder 
tumors 
considered 
superficial 
such 
as 
noninvasive (T1a) and carcinoma in situ (Tis) 
o 
Curatively treated cervical carcinoma in situ 
o 
Thyroid papillary cancer with prior treatment 
o 
Carcinoma of the skin without melanomatous features 
o 
Prostate cancer which has been surgically or medically 
treated and not likely to recur within 2 years 
2.  CNS metastases as shown by radiology records or clinical 
evidence of symptomatic CNS involvement in the last 3 months prior 
to randomization.  Patients are eligible if metastases have been 
treated and have returned to neurologic baseline or are 
neurologically stable (except for residual signs or symptoms related 
to the CNS treatment). 
3. Cytotoxic chemotherapy, surgery, immunotherapy, radiotherapy or 
other targeted therapies within 3weeks (4 weeks in cases of 
ramucirumab, mitomycin C, nitrosourea, lomustine; 1 week in case 
of biopsy) prior to randomization (Adjuvant radiotherapy given to 
local area for non-curative symptom relief is allowed until 2 weeks 
before randomization.). 
4. Therapy with clinically significant systemic anticoagulant or 
antithrombotic agents within 7 days prior to randomization that may 
prevent blood clotting and, in the investigator’s opinion, could place 
the subject at risk. Maximum dose of 325 mg/day of aspirin is 
allowed. 
5. Patients who had therapeutic paracentesis of ascites (> 1L) within 
the 3 months prior to starting study treatment or who, in the opinion 
of the investigator, will likely need therapeutic paracentesis of 
ascites (> 1L) within 3 months of starting study treatment. 
6. Previous treatment with Apatinib. 


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7. Known hypersensitivity to Apatinib or components of the 
formulation. 
8. Concomitant treatment with strong inhibitors or inducers of 
CYP3A4, CYP2C9 and CYP2C19. 
9. Active bacterial infections. 
10. Patients with substance abuse or medical, psychological, or social 
conditions that may interfere with the patient’s participation in the 
study or evaluation of the study results. Conditions include but are 
not limited to; 
- Known history of human immunodeficiency virus (HIV) infection. 
- Active hepatitis B or C infection or chronic hepatitis B or C 
infection requiring treatment with antiviral therapy or prophylactic 
antiviral therapy unless evidence of viral suppression has been 
documented and the patient will remain on appropriate antiviral 
therapy throughout the study. 
11. Patients who participated, within 4 weeks prior to randomization, or 
are participating in any other clinical trial.  
12. Pregnant or breast-feeding women. 
13. History of drug or alcohol abuse within past 5 years. 
14. Medical or psychiatric illnesses that, in the investigator’s opinion, 
may impact the safety of the subject or the objectives of the study. 
15. History of uncontrolled hypertension (Blood pressure ≥ 140/90 
mmHg and change in antihypertensive medication within 7 days 
prior to randomization) that is not well managed by medication and 
the risk of which may be precipitated by a VEGF inhibitor therapy. 
16. Patients who have known history of symptomatic congestive heart 
failure (New York Heart Association III-IV), symptomatic or poorly 
controlled cardiac arrhythmia, complete left bundle branch block, 
bifascicular block, or any clinically significant ST segment and/or T-
wave abnormalities, QTcF > 450 msec for males or QTcF > 470 
msec for females prior to randomization. 
17. Prior major surgery or fracture within 3 weeks prior to randomization 
or presence of any non-healing wound (procedures such as 
catheter placement is not considered to be major). 
18. History of bleeding diathesis or clinically significant bleeding within 
14 days prior to randomization. 
19. History of clinically significant thrombosis (bleeding or clotting 
disorder) within the past 3 months prior to randomization that, in the 


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investigator’s opinion, may place the patient at risk of side effects 
from anti-angiogenesis products.  
20. History of gastrointestinal bleeding, gastric stress ulcerations, or 
peptic ulcer disease within the past 3 months prior to randomization 
that, in the investigator’s opinion, may place the patient at risk of 
side effects from anti-angiogenesis products.  
21. Myocardial infarction or unstable angina pectoris within 6 months 
prior to randomization. 
22. History of severe adverse events including uncontrolled HTN or 
other common anti-angiogenesis class drug effects that were 
related to ramucirumab discontinuation and/or may indicate a higher 
risk to the safety of the patient if provided further anti-angiogenesis 
treatment, in the investigator’s opinion. 
23. History of other significant cardiovascular diseases or vascular 
diseases within the last 6 months prior to randomization (e.g. 
hypertensive crisis, hypertensive encephalopathy, stroke or 
transient ischemic attack [TIA], or significant peripheral vascular 
diseases) that, in the investigator’s opinion, may pose a risk to the 
patient on VEGF inhibitor therapy.  
24. History of clinically significant glomerulonephritis, biopsy-proven 
tubulointerstitial nephritis, crystal nephropathy, or other renal 
insufficiencies.  
25. Gastrointestinal malabsorption, or any other condition that in the 
opinion of the investigator might affect the absorption of the study 
drug. 
Study Overview 
This is a prospective, randomized, double-blinded, placebo-controlled, 
multinational, multicenter, parallel-group, phase III study to evaluate the 
efficacy and safety of Apatinib plus Best Supportive Care (BSC) 
compared to Placebo plus BSC in patients with advanced or metastatic 
gastric cancer who failed two or more prior treatment regimens.  
After informed consent and screening procedures, eligible subjects will 
be randomized in a 2:1 ratio to Apatinib or Placebo group. All subjects 
will receive best supportive care (BSC). The randomization will be 
stratified by the following factors; Geographic region (Asia vs. North 
America/Europe), 
Disease 
measurability 
(measurable 
vs. 
nonmeasurable), Prior ramucirumab treatment (Yes vs. No), and 
Treatment therapy line (3rd vs. ≥4th).  
Randomized subjects will receive either the test product Apatinib at 700 


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mg/day plus BSC or Placebo plus BSC and will be evaluated at regular 
site visits, which will be made every 2 weeks till the death of the subject 
or discontinuation of the study treatment due to disease progression, 
intolerable toxicity or subject’s withdrawal of consent. If treatment 
related toxicity is detected, two steps of dose reductions (600 mg and 
400 mg for Apatinib) are allowed during the entire study period 
according to the dose adjustment plan (refer to Section 4.4) 
Tumor response and progression will be assessed every other cycle (8 
weeks interval) by a local imaging facility.  Patient treatment decisions 
will be made based on local imaging results and investigator opinion 
which will be entered into the case report forms.  Scans will be 
obtained at baseline and throughout the study and will be analyzed 
post-study by a central imaging analysis facility. Centrally imaging 
results will determine the patient’s best tumor response and time of 
progression according to RECIST 1.1. 
Post-treatment follow-up visit will be made at 4 weeks after the end of 
treatment (EOT) and then survival follow-ups will follow at 8 weeks 
interval till the death of the subject or closure of the study. 
 
Extension Period: 
Continued treatment with apatinib and best supportive care or best 
supportive care alone during the extension period of the study is only 
for those subjects that are taking either apatinib or placebo at the time 
of unblinding, respectively.   For all other subjects that have not been 
considered as reaching the end of study (i.e. subjects in survival follow-
up) and are not taking study medication at the time of unblinding, they 
will be followed for survival status only.  It is anticipated that less than 
40 subjects will be taking study medication at the time of unblinding of 
which less than 30 will be taking apatinib. 
 
Subjects taking apatinib at the time of unblinding:  
After the End of the Study (EOS) when the study is unblinded, subjects 
still on apatinib treatment with best supportive care, if determined to be 
safe to continue therapy by the investigator, may consent to continue 
this treatment until disease progression, intolerability, death, withdrawal 
of consent, or, if none of those has occurred, apatinib becomes 
available through other methods acceptable to the applicable 
regulatory authority. Site visit and evaluation for safety should be 


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performed approximately every four weeks (± 3 days). Safety 
assessment may be performed more frequently, if clinically indicated. 
Tumor assessments will be performed per standard care approximately 
every 6-8 weeks. Subjects who reached end of treatment should be 
followed for survival per section 3.4.6. For apatinib subjects not willing 
to consent for further treatment after the study is unblinded or for those 
where the protocol extension period has not been approved locally or 
nationally, will stop the apatinib administration and perform the End of 
Treatment visit, Post-treatment Follow-up for safety, and Survival 
Follow-up as appropriate. A study schedule for subjects continuing 
apatinib treatment in the extension period is provided in Table 2. 
 
Subjects taking placebo at the time of unblinding: 
Subjects who are determined to be taking the placebo and best 
supportive care when the study is unblinded may consent to continue 
to be followed for survival status and continued best supportive care. 
For those subjects that were taking placebo, no End of Treatment visit 
is required. Best supportive care may be continued for patients no 
longer taking placebo, if appropriate, and only until other anti-cancer 
therapy is administered, disease progression, intolerability, death, or 
withdrawal of consent. The study schedule for subjects receiving only 
best supportive care in the extension period is to be determined by the 
investigator as standard of care for managing that supportive care. 
 
Japan Specific Safety Run-In: 
The AM104 ethnic bridging study determined that there is no 
statistically significant difference in Japanese ethnic population 
pharmacokinetics as compared to Chinese and/or Caucasians that 
would make it unsafe to proceed at the study starting dose.  The 
AM104 study evaluated the pharmacokinetics of a single dose of 201 
mg of Apatinib in 18 healthy volunteers of each of three specific ethnic 
populations; Japanese, Chinese and Caucasian. Initiation of enrollment 
in Japan will have a safety run-in approach to further confirm the safety 
of the study starting dose in this ethnic population. [Detail explanation 
is provided in Section 3.1.1] 
 


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1) Post-treatment follow-up will be done at 4 weeks (± 7 days) after the end of 
treatment (EOT).
2)
Survival follow-up will be done at 8 weeks (± 7 days) interval after the Post-
treatment follow-up visit. Survival follow-ups will continue till the death of the subject 
or until the study closure.
Endpoints
Primary Outcome Measure: 
・Overall Survival (OS): Time from randomization to death. Subjects 
alive or lost to follow-up at the end of study (EOS) are censored.
Secondary Outcome Measures: 
・Progression Free Survival (PFS): Time from randomization to either 
radiological progression or death. Subjects alive and free of 
progression at the end of study (EOS) are censored.
・Objective Response Rate (ORR): Percentage of subjects with a 
Best Overall Response of Complete Response (CR) or Partial 
Response (PR). 
・Disease Control Rate (DCR): Proportion of subjects with a Best 
Overall Response of complete, partial response, or stable disease. 
・Global health status/quality of life score according to European 
Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 (EORTC QLQ-C30) and EORTC QLQ-
STO22. 
・Each dimension response according to EuroQol 5-Dimension 5-
Level (EQ-5D-5L) Questionnaire. 
Safety Measures:
・Adverse events, laboratory tests, vital signs, physical examination, 
EOS is defined as the end of the 
primary analysis period when the 
patients are unblinded. 
After EOS
• Tumor assessment Information
• Safety assessment 
- 28 days 
from BSLN
Treatment Period
Screening Period
After EOT
Apatinib 700 mg qd, po
Follow-up Period
Matching Placebo to apatinib qd, po
Post-Tx F/u 1)
• At 4 weeks after EOT
• Exams and tests 
• for eligibility 
assessment
• Baseline tumor 
evaluation
• Informed consent
• Demography
• Medical/medication 
history
• GC history
Randomization (2:1)
Apatinib + BSC
Placebo + BSC
EOS
SCRN
(-28 days)
BSLN
EOT
Post-TX 
f/u
End of Extension period
Extension Period
• Subjects in the apatinib group 
who are not confirmed as 
disease progression at EOS or 
are otherwise eligible to 
continue apatinib treatment until
end of treatment or study 
withdraw (section 6.2)
• Other subjects will be followed 
for survival status until death.
Survival F/u 2)
• At 8 weeks interval
(by telephone or 
direct visit)
28 day cycles
• Tumor assessment every other cycle
• QoL assessment once every cycle
• Safety assessments every two weeks


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12-lead ECG, and ECOG performance status. 
Exploratory Measures:  
・ Pharmacodynamic marker: Vascular Endothelial Growth Factor 
(VEGF), sVEGFR-1, sVEGFR2 and sVEGFR3. 
・ Pharmacokinetics 
Statistical 
Methods 
Efficacy analysis 
The primary analysis of OS will be conducted in the ITT population (all 
randomized subjects) using a stratified (by the randomization 
stratification factors) logrank test at the two-sided alpha=0.05 level of 
significance.  
If the primary analysis of OS is statistically significant, then the key 
secondary endpoints of PFS and ORR will be analyzed using a fixed-
sequence testing procedure. First, PFS will be analyzed using the same 
statistical methods that are used in the primary efficacy analysis of OS. 
If the analysis of PFS is statistically significant, then ORR will be 
analyzed using the Cochran-Mantel-Haenszel test stratified by the 
randomization stratification factors. However, if a prior test is not 
statistically significant, then the subsequent analyses will be 
exploratory rather than confirmatory.  
All other secondary efficacy endpoints will be analyzed using two-sided 
tests at the alpha=0.05 level of significance, with no adjustments for 
multiplicity DCR will be analyzed using the same methodology as 
described for ORR. 
For the European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and EuroQol 
5-Dimension 5-Level (EQ-5D-5L) Questionnaire, the treatment groups 
will be compared using analysis of covariance (ANCOVA) models with 
treatment group and the randomization stratification variables as 
factors, and with the baseline value of the corresponding endpoint as a 
covariate. 
Safety analysis 
Safety parameter data will be summarized and listed by patient. 
Summary tables will show incidence rates (number of subjects with at 
least one event) of AE, SAE, etc., as well as summaries of severity 
(CTCAE v4.03) and causal relationship. Change from baseline tables 
will be presented for clinical laboratory assessments, vital signs and 
ECOG performance score. Laboratory abnormalities will also be 


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summarized in tables showing shifts in grade. 
Interim Analysis 
and IDMC 
An interim analysis for futility will be conducted with collected clinical 
data when approximately 163 events (death) are observed. 
The independent data monitoring committee (IDMC) will review the 
result of the interim analysis and recommend to the sponsor whether 
or not to terminate for futility. Final decision regarding study termination 
will be made by the sponsor. 
Early termination will be considered if the calculated conditional power 
based on primary efficacy endpoint is less than 0.2.  


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Table 1. Study Schedule 
Visit 
SCRN 
Treatment Period  
EOT/DC 
Post-Tx F/U 
Survival F/U 
Cycle 1 
All subsequent Cycles 
- 
EOT + 4 wks 
Every 8 wks  
after Post-Tx F/U 
Visit date 
≤ 28 
≤ 14 
1 (BSLN) 
15 
29* 
1* 
15 
29 
- 
EOT + 28 days 
- 
Visit window 
- 
- 
- 
± 3 days 
± 7 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Medical history1 
X 
 
 
 
 
 
 
 
 
 
 
GC history2 
X 
 
 
 
 
 
 
 
 
 
 
Height & weight3 
 
X 
X￥ 
X 
 
X￥ 
X 
 
X 
X 
 
Physical examination 
 
X 
X￥ 
X 
 
X￥ 
X 
 
X 
X 
 
Vital signs4 
 
X 
X￥ 
X 
 
X￥ 
X 
 
X 
X 
 
ECOG performance 
 
X 
X￥ 
X 
 
X￥ 
X 
 
X 
X 
 
12-lead ECG 
 
X 
X￥20 
X20 
 
X￥20 
 
 
X 
X 
 
Chest X-ray 
 
 
As clinically indicated 
 
Hematology5 
 
X 
 
X 
 
X￥ 
X 
 
X 
X 
 
Blood chemistry6 
 
X 
 
X 
 
X￥ 
X 
 
X 
X 
 
Coagulation tests7 
 
X 
 
X 
 
X￥ 
X 
 
X 
X 
 
Urinalysis8 
 
X 
 
X 
 
X￥ 
X 
 
X 
X 
 
Pregnancy test9 
 
X 
As clinically indicated or per local regulatory requirement10 
 
Serological test11 
 
X 
 
 
 
 
 
 
 
 
 
QOL12 
 
 
X￥ 
 
 
X￥ 
 
 
X 
 
 
CT (or PET-CT) or MRI 
 
X 
 
 
 
 
 
X13 
X13 
 
 


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Visit 
SCRN 
Treatment Period  
EOT/DC 
Post-Tx F/U 
Survival F/U 
Cycle 1 
All subsequent Cycles 
- 
EOT + 4 wks 
Every 8 wks  
after Post-Tx F/U 
Visit date 
≤ 28 
≤ 14 
1 (BSLN) 
15 
29* 
1* 
15 
29 
- 
EOT + 28 days 
- 
Visit window 
- 
- 
- 
± 3 days 
± 7 days 
Biopsy14 
 
As clinically indicated 
 
 
Eligibility review 
 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
IP administration (qd) 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse Events15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Previous/Concomitant 
Medication16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PD markers17 
 
 
X￥ 
 
 
X￥ 
 
 
X 
 
 
PK sampling 18 
 
 
X 
X 
 
X 
 
 
 
 
 
Survival F/U19 
 
 
 
 
 
 
 
 
 
 
X 
1 cycle = 28 days, SCRN, Screening; BSLN, Baseline; W, Week; wks, weeks; EOT, End of Treatment; F/U, Follow-Up; Tx, Treatment; DC, Discontinuation; EOS, End of Study 
*Note: Typically, Day 29 evaluations (adverse events and concomitant medication) of each cycle will not require a clinic visit and will not be performed if the patient is returning 
for Day 1 of the next cycle within the visit window (+ or – 3 days). 
￥Procedures should be performed before IP administration on the day of start. 
1) 
Medical history within 1 year (within 3 years for cancer) from signing on the ICF should be collected. Medical history includes clinically significant past and 
current diagnosis including surgical procedures. Any surgical procedures done for treatment of GC will be collected separately regardless when those were 
carried out.  
2) 
Full history of GC including date of initial diagnosis, primary location ([≥ 5 cm below GEJ] vs. GEJ), stage, metastatic and prior treatment information should 
be collected. 
3) 
Height is measured once at Screening visit. 


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4) 
Vital signs include weight, sitting systolic/diastolic blood pressure, heart rate, respiration rate, and body temperature. 
5) 
Hematology test (complete blood count, CBC) to be performed locally must include white blood cell (WBC) with 5-part differential (neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils), platelet count, absolute neutrophil count (ANC), red blood cell (RBC), hemoglobin (Hb), and hematocrit (Hct). If 
hematological treatment related toxicity occurs, the hematological test can be performed more frequently at the investigator’s discretion during the treatment 
period. 
6) 
Chemistry test to be performed locally must include sodium, potassium, chloride, carbon dioxide or bicarbonate (if required), blood urea nitrogen (BUN), 
creatinine, glucose (Fasting glucose at the Screening visit. Further fasting glucose only if necessary in the opinion of the investigator), total protein, albumin, 
calcium, amylase, lipase, phosphorous, magnesium, creatinine kinase (CK), uric acid, total bilirubin, AST, ALT, and ALP. If non-hematological treatment 
related toxicity occurs, the chemistry test can be performed at the investigator’s discretion during the treatment period. 
7) 
Coagulation test to be performed locally includes prothrombin time expressed as either prothrombin time (PT) or international normalized ratio (INR) and 
partial thromboplastin time (PTT or aPTT). 
8) 
Urinalysis test to be performed locally includes specific gravity, protein, glucose, occult blood, and, only if indicated, with microscopic examination. 
9) 
This will be ordered only for women of child-bearing potential (serum or urine) including women who have not been surgically sterile, or post-menopausal 
for at least 1 year prior to Screening visit (no other medical cause involved).  
10) Additional pregnancy test may be performed if required by local health authorities. Additional pregnancy test is required at the beginning every treatment 
cycle, and at EOT visit for Germany and Romania. Additional pregnancy test is required at the beginning of every treatment cycle, at EOT visit, and at post-
treatment follow-up visit for Poland.  
11) Serological tests to be performed locally include HIV antibody (if HIV antibody result is positive, HIV-1 antibody and HIV-2 antibody should be conducted), 
HBs antigen, and HCV antibody.  
12) Subjects will complete two questionnaires; EORTC-QLQ-30 with EORTC QLQ-STO22 and EQ-5D-5L at baseline and then approximately every 4 weeks 
typically either at the end of the cycle or at the beginning of the next cycle. 
13) Tumor will be assessed based on chest, abdominal and pelvic CT (or PET-CT) scan or MRI approximately every 8 weeks at the end of every other cycle. 
The same method should be used for the assessment of tumor response throughout the study. RECIST Guideline Version 1.1 will be used to assess tumor 
response. CT (or PET-CT) scan/MRIs after Baseline are allowed to perform within 7 days prior to the planned visit date.  Scans to confirm progression of 
disease or for other reasons not per schedule as determined by the investigator may be performed when needed. 
14) If a diagnosis cannot be made with chest, abdominal and pelvic CT (or PET-CT)/MRI due to atypical radiological appearance, primary or metastatic biopsy 
is recommended. Subsequent biopsies are carried out based on the investigator’s discretion but it should be considered in case of growth or change in the 
enhancement pattern identified during follow-up. Histopathologic examination of the biopsy specimen should be assessed by an expert pathologist. 


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15) Adverse events will be documented for any untoward medical occurrence in a patient from the time they sign the informed consent form and until study 
completion per the Study Schedule. 
16) Any medications administered within 28 days prior to signing the ICF and current medications should be collected. Medications for treatment of GC will be 
collected separately regardless when those were administered. 
17) PD markers include vascular endothelial growth factor (VEGF), sVEGFR-1, sVEGFR2 and sVEGFR3. 
18) PK sampling will be performed once prior to dosing on Day 1 of every cycle until EOT and at further timepoints on Day 1 of Cycle 1 and Day 15 of Cycle 
1. Details are provided in Section 5.4.4 and in the PK Sampling Manual. 
19) Subjects who prematurely discontinue study treatment but who are not withdrawn from the study will be followed every 8 weeks (± 7 days) for tracking of 
their survival until death or the end of the study. This survival follow-up should be performed via telephone, certified letter or during subjects’ visit to the 
investigational site or other clinic site where confirmation of survival information documentation can be obtained. In addition, publicly accessible data may 
be used to document death. More frequent follow-up may be necessary at the time of the interim and final analysis to provide the most up-to-date survival 
information. 
20) 12-lead ECG will be performed within 14 days before the date of randomization, at Day 1 of every cycle (before IP administration), at EOT visit and at the 
post-treatment follow-up visit. In addition to this, 12-lead ECG should be performed approximately 4 hours after IP administration on Cycle 1 Day 1 and 
Cycle 1 Day 15 corresponding to the same time when the PK Cmax blood is drawn. 
 
 


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Table 2. Study Schedule for Subjects Continuing Apatinib Treatment into the Extension Period 
Visit 
Treatment Period during Extension  
All Cycles 
EOT/DC 
Post-Tx F/U 
EOT + 4 wks 
Survival F/U  
Every 8 wks after Post-Tx F/U 
Visit date 
1* 
- 
EOT + 28 days 
- 
Visit window 
± 3 days 
± 7 days 
Informed consent for extension period 
X1 
 
 
 
IP dispensation 
X 
 
 
 
Adverse Events 
X 
X 
X 
 
Concomitant Medication 
X 
X 
X 
 
CT (or PET-CT) or MRI2 
X2 
X2 
 
 
Targeted Physical examination 
X￥ 
 
X 
 
Vital signs3 
X￥ 
 
X 
 
12-lead ECG 
X￥ 
 
X 
 
Hematology4 
X￥ 
 
X 
 
Blood chemistry5 
X￥ 
 
X 
 
Coagulation tests6 
X￥ 
 
X 
 
Urinalysis7 
X￥ 
 
X 
 
Survival F/U8 
 
 
 
X 
Chest X-ray 
As clinically indicated 
 
Pregnancy test9 
As clinically indicated or per local regulatory requirement10 
 
￥Procedures should be performed before IP administration on the day of start. 
1) 
Additional informed consent is required to enter extension study for placebo and apatinib subjects. After consent, placebo subjects will continue best 
supportive care and survival follow-up only. 
2) 
Tumor will be assessed based on chest, abdominal and pelvic CT (or PET-CT) scan or MRI with a frequency as determined by standard of care 


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approximately every 8 weeks at the end of every other cycle. It is recommended, but not required, that the same tumor assessment criteria used during 
the study continue in the extension period. The same method should be used for the assessment of tumor response throughout the study. RECIST Guideline 
Version 1.1 will be used to assess tumor response. CT (or PET-CT) scan/MRIs after Baseline are allowed to be performed per standard of care. Scans to 
confirm progression of disease or for other reasons not per schedule as determined by the investigator may be performed when needed. 
3) 
Vital signs include weight, sitting systolic/diastolic blood pressure, heart rate, respiration rate, and body temperature. 
4) 
Hematology test (complete blood count, CBC) to be performed locally must include white blood cell (WBC) with 5-part differential (neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils), platelet count, absolute neutrophil count (ANC), red blood cell (RBC), hemoglobin (Hb), and hematocrit (Hct). If 
hematological treatment related toxicity occurs, the hematological test can be performed more frequently at the investigator’s discretion during the treatment 
period. 
5) 
Chemistry test to be performed locally must include sodium, potassium, chloride, carbon dioxide or bicarbonate (if required), blood urea nitrogen (BUN), 
creatinine, glucose (Fasting glucose at the Screening visit. Further fasting glucose only if necessary in the opinion of the investigator), total protein, albumin, 
calcium, amylase, lipase, phosphorous, magnesium, creatinine kinase (CK), uric acid, total bilirubin, AST, ALT, and ALP. If non-hematological treatment 
related toxicity occurs, the chemistry test can be performed at the investigator’s discretion during the treatment period. 
6) 
Coagulation test to be performed locally includes prothrombin time expressed as either prothrombin time (PT) or international normalized ratio (INR) and 
partial thromboplastin time (PTT or aPTT). 
7) 
Urinalysis test to be performed locally includes specific gravity, protein, glucose, occult blood, and, only if indicated, with microscopic examination. 
8) 
Subjects who discontinue apatinib treatment during the extension period but who are not withdrawn from the study will be followed approximately every 8 
weeks (± 7 days) for tracking of their survival until death or the end of the study. This survival follow-up should be performed via telephone, certified letter 
or during subjects’ visit to the investigational site or other clinic site where confirmation of survival information documentation can be obtained. In addition, 
publicly accessible data may be used to document death. More frequent follow-up may be necessary at the time of the end of the study or for periodic 
updates to provide the most up-to-date survival information. 
9) 
This will be ordered only for women of child-bearing potential (serum or urine) including women who have not been surgically sterile, or post-menopausal 
for at least 1 year prior to Screening visit (no other medical cause involved). 
10) Additional pregnancy test may be performed if required by local health authorities. Additional pregnancy test is required at the beginning every treatment 
cycle, and at EOT visit for Germany and Romania. Additional pregnancy test is required at the beginning of every treatment cycle, at EOT visit, and at post-
treatment follow-up visit for Poland.  


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TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE .............................................................................................. 2 
PROTOCOL REVISION HISTORY ........................................................................................ 3 
SYNOPSIS ................................................................................................................................... 4 
TABLE OF CONTENTS .......................................................................................................... 23 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................... 27 
1. 
INTRODUCTION ............................................................................................................. 30 
1.1. 
BACKGROUND ............................................................................................................... 30 
1.2. 
GENERAL INFORMATION ............................................................................................... 32 
1.3. 
STUDY RATIONALE ....................................................................................................... 37 
2. 
STUDY OBJECTIVE ....................................................................................................... 38 
2.1. 
PRIMARY OBJECTIVE..................................................................................................... 38 
2.2. 
SECONDARY OBJECTIVES .............................................................................................. 39 
3. 
INVESTIGATIONAL PLAN ........................................................................................... 39 
3.1. 
OVERALL STUDY DESIGN AND PLAN ............................................................................ 39 
3.1.1. 
Additional Information for Japan Specific Safety Run-In ..................................... 41 
3.2. 
STUDY POPULATION ...................................................................................................... 43 
3.2.1. 
Inclusion Criteria ................................................................................................... 43 
3.2.2. 
Exclusion Criteria .................................................................................................. 44 
3.3. 
DISCUSSION OF STUDY DESIGN .................................................................................... 47 
3.4. 
STUDY PROCEDURES ..................................................................................................... 48 
3.4.1. 
Screening Visit ....................................................................................................... 49 
3.4.2. 
Baseline Visit (Day 1 in Cycle 1) .......................................................................... 50 
3.4.3. 
Treatment Visits After Baseline ............................................................................. 51 
3.4.4. 
End of Treatment (EOT) Visit/Discontinuation ..................................................... 52 
3.4.5. 
Post-Treatment Follow-Up Visit ............................................................................ 53 
3.4.6. 
Survival Follow-Up Visit....................................................................................... 53 
3.4.7. 
Extension period study visits ................................................................................. 54 
4. 
STUDY TREATMENTS ................................................................................................... 56 
4.1. 
INVESTIGATIONAL PRODUCTS ....................................................................................... 56 
4.1.1. 
Identity and Storage of Investigational Products ................................................... 56 


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4.1.2. 
Return of Unused Investigational Products ........................................................... 57 
4.1.3. 
Discontinuation of Investigational Products Supply ............................................. 57 
4.2. 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP (RANDOMIZATION METHOD)
 ..................................................................................................................................... 57 
4.3. 
ADMINISTRATION OF INVESTIGATIONAL PRODUCT ...................................................... 58 
4.4. 
DOSE ADJUSTMENT PLAN ............................................................................................. 58 
4.5. 
DOUBLE-BLINDING METHOD ....................................................................................... 59 
4.5.1. 
Double-Blinding .................................................................................................... 59 
4.5.2. 
Maintenance of Blinding ....................................................................................... 59 
4.5.3. 
Unblinding Procedure in Emergency Situations .................................................... 60 
4.6. 
TREATMENT COMPLIANCE ............................................................................................ 60 
4.7. 
PRIOR AND CONCOMITANT MEDICATIONS .................................................................... 60 
4.7.1. 
Contraindicated Treatment .................................................................................... 60 
4.7.2. 
Permitted Concomitant Treatment ......................................................................... 62 
5. 
ASSESSMENT MEASURES ........................................................................................... 62 
5.1. 
BASELINE ASSESSMENT ................................................................................................ 62 
5.1.1. 
Demographics ........................................................................................................ 62 
5.1.2. 
Medical and Surgical History ................................................................................ 62 
5.1.3. 
Prior Medications History ..................................................................................... 62 
5.2. 
EFFICACY ASSESSMENT ................................................................................................ 63 
5.2.1. 
Tumor Evaluation (Chest, abdominal and pelvic CT/MRI) .................................. 63 
5.2.2. 
Patient Reported Outcome ..................................................................................... 63 
5.3. 
SAFETY ASSESSMENT ................................................................................................... 64 
5.3.1. 
Adverse Event ....................................................................................................... 64 
5.3.2. 
Clinical Laboratory Tests ....................................................................................... 65 
5.3.3. 
Vital Signs and Physical Findings ......................................................................... 65 
5.3.4. 
Weight and Height ................................................................................................. 66 
5.3.5. 
Eastern Cooperative Oncology Group Performance Status................................... 66 
5.3.6. 
ECG Monitoring .................................................................................................... 66 
5.3.7. 
Chest X-Ray .......................................................................................................... 66 
5.4. 
EXPLORATORY ASSESSMENT ........................................................................................ 67 
5.4.1. 
Pharmacodynamic (PD) marker ............................................................................ 67 
5.4.2. 
Biological Sample Storage .................................................................................... 67 
5.4.3. 
Tumor Biopsy ........................................................................................................ 67 
5.4.4. 
Pharmacokinetics ................................................................................................... 68 


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6. 
CRITERIA FOR STUDY DISCONTINUATION OR SUBJECT WITHDRAWAL .. 69 
6.1. 
EARLY TERMINATION OF THE STUDY ............................................................................ 69 
6.2. 
CRITERIA FOR TREATMENT DISCONTINUATION ............................................................ 69 
6.3. 
TREATMENT CONTINUATION AFTER DISEASE PROGRESSION ......................................... 70 
6.4. 
HANDLING EARLY WITHDRAWALS ............................................................................... 71 
6.5. 
MEDICAL CARE AFTER THE END OF TREATMENT FOR WITHDRAWN SUBJECTS........... 71 
7. 
SAFETY REPORT ........................................................................................................... 72 
7.1. 
DEFINITION ................................................................................................................... 72 
7.1.1. 
Adverse Event (AE) .............................................................................................. 72 
7.1.2. 
Serious Adverse Event (SAE) ............................................................................... 72 
7.2. 
ASSESSMENT CRITERIA ................................................................................................. 73 
7.2.1. 
Severity Evaluation ............................................................................................... 73 
7.2.2. 
Causality Evaluation .............................................................................................. 74 
7.3. 
SERIOUS ADVERSE EVENT REPORTING ......................................................................... 75 
7.4. 
EXPOSURE DURING PREGNANCY .................................................................................. 76 
8. 
STATISTICAL METHODS ............................................................................................. 77 
8.1. 
SAMPLE SIZE CALCULATION AND RATIONALE ............................................................. 77 
8.1.1. 
Hypothesis ............................................................................................................. 77 
8.1.2. 
Background and assumptions ................................................................................ 77 
8.1.3. 
Sample Size calculation ......................................................................................... 78 
8.2. 
EVALUATION CRITERIA AND METHODS ........................................................................ 79 
8.2.1. 
Primary Efficacy Endpoint .................................................................................... 79 
8.2.2. 
Secondary Efficacy Endpoints ............................................................................... 79 
8.2.3. 
Safety Endpoints .................................................................................................... 79 
8.2.4. 
Exploratory Endpoints ........................................................................................... 79 
8.3. 
STATISTICAL ANALYSIS ................................................................................................. 80 
8.3.1. 
General Principles of Data Analysis ...................................................................... 80 
8.3.2. 
Analysis Population ............................................................................................... 80 
8.3.3. 
Demographic and Baseline Characteristics ........................................................... 80 
8.3.4. 
Primary Efficacy Analysis ..................................................................................... 80 
8.3.5. 
Key Secondary Efficacy Analyses ......................................................................... 81 
8.3.6. 
Other Secondary Efficacy Analyses ...................................................................... 83 
8.3.7. 
Safety Analysis ...................................................................................................... 83 
8.3.8. 
Exploratory Analysis ............................................................................................. 84 
8.3.9. 
Extension Period Analysis ..................................................................................... 84 


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8.4. 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) AND INTERIM ANALYSIS ..... 84 
8.4.1. 
IDMC ..................................................................................................................... 84 
8.4.2. 
Interim Analysis .................................................................................................... 85 
9. 
QUALITY CONTROL AND QUALITY ASSUARANCE ............................................ 85 
9.1. 
MONITORING ................................................................................................................. 85 
9.2. 
AUDIT AND INSPECTION ................................................................................................ 86 
10. ETHICS ............................................................................................................................. 86 
10.1. INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE .................... 86 
10.2. ETHICAL CONDUCT OF THE STUDY ............................................................................... 86 
10.3. WRITTEN INFORMED CONSENT .................................................................................... 87 
10.4. PATIENT DATA PROTECTION .......................................................................................... 88 
10.5. PROTECTION FOR SUBJECTS AFTER END OF STUDY ..................................................... 88 
11. COLLECTION AND DOCUMENTATION OF DATA ................................................. 88 
11.1. COLLECTION OF STUDY DATA....................................................................................... 88 
11.2. DOCUMENTATION OF STUDY RESULTS .......................................................................... 89 
12. ADMINISTRATIVE INFORMATION ........................................................................... 89 
12.1. PATIENT INJURY AND INSURANCE ................................................................................. 89 
12.2. CONFIDENTIALITY ........................................................................................................ 90 
12.3. RECORD RETENTION ..................................................................................................... 90 
12.4. PUBLICATION POLICY ................................................................................................... 90 
13. REFERENCES .................................................................................................................. 92 
14. APPENDICES ................................................................................................................... 95 
APPENDIX 1: EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORM
ANCE STATUS ......................................................................................................................... 95 
APPENDIX 2: TUMOR RESPONSE CRITERIA ................................................................. 96 
 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
5-FU 
5-Fluorouracil 
ADL 
Activity of Daily Living 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
ANC 
Absolute Neutrophil Count 
ANCOVA 
Analysis of covariance 
aPTT 
activated Partial Thromboplastin Time 
AST 
Aspartate Transaminase 
AUC0-24  
Area under plasma concentration-time curve 
BP 
Blood Pressure 
BSC 
Best Supportive Care 
BSLN 
Baseline 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CF 
Cisplatin; 5-fluorouracil 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CK 
Creatinine Kinase 
Cmax 
maximum plasma concentration 
CNS  
Central Nervous System 
CR 
Complete Response 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DC 
Discontinuation 
DCF  
Docetaxel; Cisplatin; 5-fluorouracil 
DCR 
Disease Control Rate 
DLT 
Dose Limiting Toxicity 
ECF  
Epirubicin; Cisplatin; 5-fluorouracil 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 


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EDC 
Electronic Data Capture 
EGFR 
Epidermal Growth Factor Receptor 
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire-Core 30 
EOS 
End of Study 
EOT 
End of Treatment 
EQ-5D-5L 
EuroQol 5-Dimension 5-Level 
F/U 
Follow-Up 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GC 
Gastric Cancer  
GCP 
Good Clinical Practice 
GIST 
Gastrointestinal Stromal Tumor  
Hb 
Hemoglobin 
HBc antibody 
Hepatitis B core antibody 
HBs antibody 
Hepatitis B surface antibody 
HBs antigen 
Hepatitis B surface antigen 
HCV 
Hepatitis C Virus 
HFS 
Hand-Foot Syndrome  
HIV 
Human Immunodeficiency Virus 
HR 
Hazard Ratio 
IB 
Investigational Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for 
Adverse Events 
NDA 
New Drug Application 


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ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PD 
Pharmacodynamic 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PK  
Pharmacokinetics 
PPS 
Per Protocol Set 
PR 
Partial Response 
PT 
Prothrombin Time 
PT 
Preferred Term 
PTT 
Partial Thromboplastin Time 
PVDC 
Polyvinylidene Chloride 
q.d. 
Once a Day 
QOL 
Quality of Life 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria for Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SCRN 
Screening 
SD 
Stable Disease 
SD 
Standard Deviation 
SNPs 
Single-Nucleotide Polymorphisms  
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TIA 
Transient Ischemic Attack 
TKI 
Tyrosine Kinase Inhibitor 
Tx 
Treatment 
ULN 
Upper Limit of Normal 
USA 
United States of America 
VAS 
Visual Analogue Scale 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR 
Vascular Endothelial Growth Factor Receptor 
vs 
versus 
 
 


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1. 
INTRODUCTION 
1.1. Background 
Gastric cancer is the 4th most common cancer world-wide and is the 4th most common 
cause of cancer-related death.1 The prevalence rate of gastric cancer is higher in Asian, 
South America and Eastern Europe than in Western Europe and North America.2 
Surgical resection is effective for complete cure of gastric cancer, but is only applicable 
to localized disease. A majority of patients have locally advanced, metastatic, or recurrent 
cancer that is inoperable. For such patients, extending the duration of survival by 
systemic chemotherapy is the primary treatment, and platinum and/or 5-FU based 
combination chemotherapy is widely used globally. As a first-line standard chemotherapy, 
multiple-agent combination chemotherapy is used, such as DCF (docetaxel; cisplatin; 5-
fluorouracil) in the US, ECF (epirubicin; cisplatin; 5-fluorouracil) in Europe, CF (cisplatin; 
5-fluorouracil either as infusional 5-FU or oral fluoropyrimidines like capecitabine or S-1) 
in Korea.3 
According to several recent meta-analyses which analyzed the role of chemotherapy in 
patients with inoperable or metastasized gastric cancer, conservative chemotherapy is 
reported to improve survival and quality of life compared to the best supportive care.4, 5, 
6 However, the response rate for first-line therapy in advanced gastric patients is below 
50%, and even in those fortunate cases that respond to the first-line chemotherapy, many 
patients re-experience tumor progression over time, often developing peritoneal 
metastasis and experiencing rapid exacerbation of systemic conditions. This results in 
20~50% of patients requiring second-line chemotherapy in actual clinical practice.7 A 
typical treatment therapy of advanced and metastatic gastric cancer is a combination 
therapy of capecitabine and oxaliplatin, which was not inferior in overall survival 
compared to 5-FU-based therapy with no significant difference in response rate. Such 
results indicate that capecitabine, an oral 5-FU analog, may replace the continuous 
intravenous infusion of 5-FU and supported that the combination therapy of capecitabine 
and oxaliplatin is a globally acceptable standard therapy.8, 9 
As such, existing cytotoxic chemotherapies are based on fluoropyrimidine, cisplatin and 
anthracycline which can increase the oncological effect by combining two or three drugs 
rather than one, but improvement in 5-year survival is around 30–35%10 , 11 , 12 and 
median overall survival only reaches 9~11 months for inoperable advanced gastric 
cancer.8 In addition, combination therapy of chemotherapy agents may increase 


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anticancer effect but also increases the risk of toxicity. Many gastric cancer patients are 
elderly and also have other diseases which may limit the use of chemotherapy agents. 
Therefore, to improve disadvantages of the existing anticancer therapies such as 
treatment toxicity, inconvenient administration method, limited survival extension, 
development of new chemotherapies and drugs for targeted treatment is warranted.13 
Drugs developed for targeted therapy of gastric cancer can be functionally broken into 
(1) HER2 signaling pathway inhibitors, (2) EGFR signaling pathway inhibitors and (3) 
Neovascular inhibitors, while the inhibitors for fibroblast growth factors (FGFs), mTOR 
and MET pathway have also been developed recently and are being studied for clinical 
application.14 
Trastuzumab (Herceptin®) among the molecular targeted therapies of gastric cancer is 
anti-HER2 monoclonal antibody, a HER2 signaling pathway inhibitor, and a combination 
therapy of Trastuzumab and chemotherapy in gastric cancer patients with HER2 
overexpression has been approved by the US FDA, Europe’s EMEA and Korea in 2010. 
This was based on the result drawn from the ToGA (Trastuzumab for Gastric Cancer) 
study in gastric cancer patients with HER2 overexpression that adding Trastuzumab 
significantly improves the duration of survival (13.8 months vs. 11.1 months, p = 
0.0046).15 
Gefitinib and Erlotinib, Epidermal growth factor receptor (EGFR) signaling pathway 
inhibitors, did not show a significant effect on gastric cancer as a tyrosine kinase inhibitor 
of EGFR-1. 16 , 17  In addition, cetuximab and panitumumab, anti-EGFR monoclonal 
antibodies, were assessed in phase III study. The median PFS for patients allocated 
capecitabine-cisplatin plus cetuximab was 4.4 months (95% CI 4.2-5.5) compared with 
5.6 months (95% CI 5.1-5.7) for patients allocated capecitabine-cisplatin alone (HR 1.09, 
95% CI 0.92-1.29; p-value=0.32) in cetuximab phase III study, EXPAND study.18 For 
panitumumab phase III study, REAL-3 study, the median overall survival in patients 
allocated EOC (epirubicin, oxaliplatin, capecitabine) was 11.3 months (95% CI 9.6-13.0) 
compared with 8.8 months (95% CI 7.7-9.8) in patients allocated modified-dose EOC 
plus panitumumab (HR 1.37, 95% CI 1.07-1.76; p-value=0.013). These studies showed 
negative results.19 
However, vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor, 
Ramucirumab is a fully human monoclonal antibody (IgG1) and has recently obtained 
approval in the US and is being used because the mean overall survival was at least 20% 
greater for the Ramucirumab (5.2 months) group than for the Placebo group (3.8 months) 


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in a phase III study (REGARD study). 20 , 21 , 22  In addition, the combination of 
ramucirumab with paclitaxel significantly increases overall survival compared with 
placebo plus paclitaxel (9.6 months vs. 7.4 months, HR 0.807 [95% CI 0.678-0.962; p-
value=0.017]) in a phase III study (RAINBOW study). Based on the results, ramucirumab 
is recommended as a standard second-line treatment for patients with advanced gastric 
cancer.23 
These drugs have less toxicity than existing anticancer drugs and have an advantage of 
allowing patient-tailored treatment as they are designed to react to signaling pathways 
specific to cancer. Lately in addition, clinical studies on new compounds of tyrosine 
kinases receptor inhibitors which suppress vascular angiogenesis, growth and 
metastasis are being carried out. Vascular endothelial cell growth factor (VEGF) is a 
circulating signal protein and because it induces a number of vascular angiogenesis-
related responses such as cell proliferation or migration, vascular infiltration, and 
movement from bone marrow to stem cells when combined with a VEGF receptor 
(VEGFR), VEGF and VEGFR become physiologically important targets. An anti-VEGF 
monoclonal antibody, Bevacizumab, was evaluated in phase III study, and the AVAGAST 
study is the first antiangiogenic agents trial in gastric cancer. Even though the study did 
not show significant improvement of the OS (bevacizumab plus chemotherapy: 12.1 
months vs. placebo plus chemotherapy: 10.1 months; HR 0.87 [95% CI 0.79 – 1.03; p-
value=0.1002]), adding bevacizumab to chemotherapy was associated with significant 
increases in both PFS (6.7 months vs. 5.3 months; HR 0.80 [95% CI 0.68 – 0.93]) and 
ORR (46.0% vs. 37.4%; p-value=0.0315) in the first-line treatment of advanced gastric 
cancer.24  
The VEGFR family is comprised of VEGFR1/Flt-1, VEGFR2/KDR/Flk-1 and 
VEGFR3/Flt-4. Various inhibitors which target the VEGFR family, including sorafenib, 
vandetanib, cediranib, and sunitinib, have been developed to date. These are all non-
specific VEGF receptor small molecule inhibitors. Sorafenib achieved an approval for 
advanced renal cancer 25  and liver cancer 26 . Sunitinib achieved approval for 
gastrointestinal stromal tumor27 and advanced renal cell cancer28 and has been studied 
for advanced or metastatic gastric cancer.29  
1.2. General Information 
The family members of VEGF receptors include: VEGFR-1(Flt-1), VEGFR-2 (KDR/Flk-
1), VEGFR-3 (Flt-4). Vascular angiogenesis in tumors is mainly induced by VEGF binding 
to VEGFR-2 (KDR/Flk-l). VEGFR-2 signaling in tumor vascular endothelial cells is now 


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recognized as a pivotal and rate-limiting step in tumor angiogenesis, and much research 
has focused on generating novel agents that inhibit this pathway. Most human tumors 
produce a high level of VEGF to trigger production of vasculature necessary to sustain 
tumor growth. Recently there have been several new drug candidates targeting inhibition 
of tyrosine kinase activity by inhibiting the VEGF receptors. 
Apatinib is an orally administered small molecule receptor tyrosine kinase inhibitor (TKI) 
which selectively inhibits VEGFR-2 to suppress endothelial cell migration and 
proliferation and, by reducing the tumor microvascular density, induces an antiangiogenic 
effect and antineoplastic effect. Clinical study results of Apatinib are summarized in the 
following. 
YN968D1 is the mesylate salt of apatinib freebase.  Many prior studies were conducted 
referring to dose of apatinib as the weight of apatinib including the mesylate salt. In this 
study and in future studies, LSK will refer to apatinib dose strength as the weight of the 
apatinib freebase alone instead of weight of the apatinib mesylate salt.  The freebase 
dosage is approximately 81% of the mesylate dosage.  The formulation is the same. 
Referring to apatinib dose strength as freebase is more aligned with standards for 
referencing total active product. 
1)
Phase I, dose escalation, PK study in subjects with advanced cancer30
A phase I dose escalation study was conducted in China from August 2007 to March 
2009, which enrolled 46 subjects at 
. Of these, 
19 subjects were enrolled in a dose-escalation study. Another 27 subjects were enrolled 
in the PK study. The subjects enrolled primarily were gastrointestinal tumor (73.9%). All 
subjects had received at least one prior chemotherapy regimen, 84.7% had prior surgery 
and 27% had radiation treatment. Measurable lesions were documented in 45 of the 
subjects at baseline. Subjects were treated for up to 56 days of continuous therapy and 
all subjects in the study received a total of 133 cycles of therapy.  
The study was conducted at five dose levels (250 mg, 500 mg, 750 mg, 850 mg, and 
1,000 mg of YN968D1 [as apatinib mesylate]). One (1) additional subject was included 
in the 250 mg-cohort due to withdrawal of consent of another participant. Two (2) DLTs 
at the dose level of 1,000 mg/day were documented. One (1) subject had Grade 3 
hypertension and the other had Grade 3 hand-foot syndrome (HFS). Three additional 
subjects were enrolled in the 850 mg group. None of the total six (6) subjects in the 850 
mg-cohort experienced DLTs. Therefore, the MTD for this dosing schedule was 


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determined to be 850 mg daily of YN968D1.  
Pharmacokinetic assessments were also conducted on eleven (11) subjects in the 750 
mg-single-dose cohort who continued to the 750 mg-multiple-dose cohort after a 7-day-
washed-out period while one withdrew consent. Thus, the PK analysis population for 
single-dosing was n = 8 for 500 mg-cohort, n = 12 for 750 mg-cohort, n = 8 for 850 mg-
cohort (one subject from the dose-escalation cohort provided consent to participate in 
the PK cohort), and for multiple-dosing 750 mg-cohort (n = 11) for 56 days. 
The overall mean pharmacokinetic parameters of YN968D1 after single and multiple oral 
dose administration are summarized in Table 3 below. For single dose evaluation, Cmax 
was achieved in 3 to 4 hours after oral administration. The plasma level of YN968D1 
varied considerably between patients. The concentration of YN968D1 in plasma 
increased with dose. Cmax and AUC0-24 showed a dose-dependent increase at doses from 
500 to 850 mg, whereas increased slightly more than dose proportionally at dose of 850 
mg dose, and showed high inter-individual variability. The elimination half-life of the 
terminal phase (t1/2λz), estimated to be approximately 9 hours, was consistent over the 
three dose levels. 
For multiple-dose at 750 mg, the mean Cmax was 2,421 ng/mL on Day 1, which increased 
to 2,553 ng/mL by Day 6, and the mean AUC0-24 was 19,399 ng·h/mL on Day 1, which 
increased to 25,449 ng·h/mL by Day 6. There was no further increase in Cmax and AUC 
beyond 6 days of multiple dosing, and this was similar for the mean elimination t1/2. 
Steady-state conditions were achieved by Day 6, suggesting no accumulation during 56 
days of once-daily dosing.  
Table 3. Noncompartmental Mean Pharmacokinetic Parameters of YN968D1 after 
Single or Multiple Oral Doses 
PK 
Parameter 
Single Oral Dose 
Multiple Oral Dose of 750 mg 
500 mg 
(n=8) 
750 mg 
(n=12) 
850 mg 
(n=8) 
Day 1 
(n=11) 
Day 6 
(n=11) 
Day 28 
(n=11) 
Day 56 
(n=11) 
Cmax ng/mL 
(%CV) 
1,521 
(75.1) 
2,379 
(55.9) 
2,833 
(90.0) 
2,421 
(68.5) 
2,553 
(52.8) 
2,210 
(45.5) 
1,854 
(51.2) 
tmax hour 
(range) 
3.5 
(3.0-8.0) 
3.0 
(2.0-4.0) 
4.0 
(1.5-8.0) 
3.0 
(2.0-8.0) 
4.0 
(3.0-8.0) 
4.0 
(2.0-6.0) 
3.0 
(2.0-6.0) 


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PK 
Parameter 
Single Oral Dose 
Multiple Oral Dose of 750 mg 
500 mg 
(n=8) 
750 mg 
(n=12) 
850 mg 
(n=8) 
Day 1 
(n=11) 
Day 6 
(n=11) 
Day 28 
(n=11) 
Day 56 
(n=11) 
AUC0-24 
ng.hr/mL 
(%CV) 
11,295 
(68.7) 
18.172 
(59.3) 
21,975 
(80.8) 
19,399 
(60.5) 
25,449 
(59.2) 
19,946 
(43.2) 
15,629 
(63.2) 
t1/2λz  
hours 
(%CV) 
8.1 
(30.7) 
9.0 
(15.1) 
9.1 
(33.1) 
8.9 
(25.8) 
11.0 
(56.7) 
11.3 
(66.5) 
8.3 
(61.0) 
Abbreviations: Cmax, maximum plasma concentration; CV, coefficient of variation; tmax, time to reach Cmax; 
AUC0-24, area under plasma concentration-time curve; t1/2λz, half-life associate with terminal slope of a 
semilogarithmic concentration-time curve 
 
The safety population comprised all subjects who had received at least 1 dose of 
YN968D1 (N=46). The most frequently observed adverse drug reactions were 
hypertension (69.5%, 29 grade 1-2 and 3 grade 3-4), proteinuria (47.8%, 16 grade 1-2 
and 6 grade 3-4), and hand-foot syndrome (45.6%, 15 grade 1-2 and 6 grade 3-4). 
Hypertension was generally manageable with antihypertensive agents. Approximately 
10 % of the subjects who developed HFS progressed to Grade 3. Other treatment-related 
AEs were generally mild or moderate in severity and were manageable. The treatment 
was discontinued for both of the two subjects who experienced DLT. After recovery, one 
(1) subject was able to reinitiate treatment at a reduced dose. A total of 15 subjects 
received at least one cycle of YN968D1 at the initial dose. Four (4) subjects discontinued 
the treatment during Cycle 1, of which 1 subject in the 250 mg dose group due to disease 
progression and 3 in the 1,000 mg dose group due to intolerable toxicity. Eighteen (18) 
subjects had a dose reduction for different toxicities during the extended treatment (1 in 
1,000 mg group, 13 in 850 mg group, and 4 in 750 mg group). For those subjects who 
experienced dose reduction, the mean duration of treatment with YN968D1 was 5.4 
months.  
Among the 45 subjects with measurable lesions, 4 withdrew consent due to receiving 
other therapy, 1 experienced intolerable toxicity, and 3 were lost to follow-up. Therefore, 
37 subjects were evaluable for best overall response. Partial response (PR) was 
observed in 7 (18.9%) subjects, stable disease (SD) in 24 subjects (64.9%), resulting in 
a disease control rate of 83.8% at 8 weeks. Subject’s response at each dose level is 
provided in Table 4. Out of 7 subjects who achieved a partial response (PR), 1 was 


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diagnosed as gastrointestinal stromal tumor (GIST), 1 as cancer of unknown primary site, 
1 as renal cell cancer, 1 as gastric cancer and 3 as colon cancer. 
Table 4. Objective Response Observed in phase I YN968D1 Trial 
Dose Cohort 
Response in Evaluable Subjects 
Disease 
Control (%) 
CR 
PR 
SD 
PD 
CR+PR+SD 
250 mg 
0 
1 
1 
1 
2 (66.7) 
500 mg 
0 
2 
4 
3 
6 (66.7) 
750 mg 
0 
2 
9 
0 
11 (100) 
850 mg 
0 
2 
8 
1 
10 (90.9) 
1,000 mg 
0 
0 
2 
1 
2 (66.7) 
Total 
0 
7 
24 
6 
31 (83.8) 
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease 
The results of this study showed that YN968D1 was safe and well tolerated and exhibited 
substantial antitumor activity at the YN968D1 (apatinib mesylate) dose of 750 mg and 
850 mg once daily. 
2) Phase II clinical study in patients with advanced or metastatic gastric cancer31 
In the phase II study conducted in patients with advanced or metastatic gastric cancer 
who did not respond to the second-line anticancer therapy or had disease recurred, a 
total of 144 patients were randomized to 3 groups; placebo group (Group A), 850mg of 
YN968D1 (as apatinib mesylate) qd group (Group B) and 425mg of YN968D1 bid group 
(Group C). 
Median overall survival (OS) of Group A, B and C was 2.50 months (95 % CI, 1.87-3.70 
months), 4.83 months (95 % CI, 4.03-5.97 months) and 4.27 months (95 % CI, 3.83-4.77 
months), respectively, and median progression-free survival (PFS) was 1.40 months (95 % 
CI, 1.20-1.83 months), 3.67 months (95 % CI, 2.17-6.80 months) and 3.20 months (95 % 
CI, 2.37-4.53 months), respectively. Both the PFS (P <0.001) and OS (P <0.001, P = 
0.0017) showed a statistically significant difference between the YN968D1 group and the 
Placebo group. Nine patients had a PR (Group B n=3, Group C n=6). Toxicities were 
tolerable. Toxicities of Grade 3 or over were hand-foot syndrome and hypertension, and 
hematologic toxicities of Grade 3 or over were rare. Considering the safety profile of 
YN968D1 at the two dose levels of 850 mg and 425 mg, the dosing regimen of 850 mg 


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once daily of YN968D1 was recommended. To sum up, YN968D1 increased PFS and 
OS in patients with advanced gastric cancer who failed to second-line or higher 
anticancer therapy. 
3) Phase III clinical study in patients with advanced or metastatic gastric cancer32 
A multicenter, randomized, double-blind, phase III study was conducted in patients who 
failed to second-line therapy. The study was designed as 28 days/cycle, consisting of 
YN968D1 850 mg (as apatinib mesylate) group and Placebo group. The primary efficacy 
endpoint was overall survival. Randomization was done centrally and was stratified by 
the number of metastatic sites (≤2 or >2). A total of 267 randomly assigned subjects were 
included in FAS population; 176 in the YN968D1 group and 91 in the Placebo group. As 
for the efficacy, mean overall survival was statistically greater for the YN968D1 group 
than for the Placebo group (6.5 months versus 4.7 months; HR= 0.709; 95% CI 
(0.537~0.937); p< 0.0149). mPFS also showed the same result (2.6 months versus 1.8 
months; HR= 0.444, 95%CI (0.331~0.595), P<0.001). ORR was 2.84% and 0.00% for 
the YN968D1 group and the Placebo group, respectively. As for the safety, YN968D1 
was mostly controlled by treatment discontinuation or reduction. The most common 
adverse events were hand-foot skin reaction (HFSR), proteinuria and hypertension. In 
conclusion, the efficacy and safety of YN968D1 850 mg were confirmed in advanced and 
metastatic gastric cancer.  
1.3. Study Rationale 
In this phase III study, we will assess the benefit of YN968D1 treatment in advanced and 
metastatic gastric cancer patients who failed standard of treatment at 700 mg/day of 
YN968D1 (as apatinib mesylate), which was within the maximum tolerated dose in the 
phase I study30, in terms of overall survival (OS), progression free survival (PFS), tumor 
response rate, disease control rate and quality of life. The target population will be 
advanced and metastatic gastric cancer patients who have failed approved standard 
treatments (disease progression or intolerant to available approved drugs).  
YN968D1 is known to selectively inhibit VEGFR-2 and angiogenesis of cancer. Various 
laboratory tests showed results that YN968D1 highly selectively inhibits protein tyrosine 
kinase VEGFR-2/KDR (IC50 about 1 nM) receptor, and YN968D1 demonstrated an 
anticancer effect in gastric cancer cell line (NCI-N87 cell line) implanted-nude mouse. In 
mouse with hypodermic implantation of colorectal, liver, kidney, breast or non-small cell 
cancer cells, YN968D1 also demonstrated an anticancer effect. Also, a combination 


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therapy of oxaliplatin and YN968D1 showed a high cancer cell growth inhibitory effect 
while having no increase in toxicity. 
As a result of phase I clinical study conducted in patients with advanced solid tumor30, 
Apatinib mesylate had the MTD of 850 mg and the clinically recommended dose of 750 
mg. The most common side effects were hypertension, proteinuria, and hand-foot 
syndrome but were all mild to moderate in severity and were manageable. In terms of 
effectiveness, a total 83.8% of patients had disease controlled; partial response in 18.9% 
and stable disease in 64.9%. Out of 22 patients with gastric-colorectal cancer who were 
included in the study, 18 showed a disease control effect where 4 of them were partial 
responses indicating an outstanding effect. Phase II and phase III clinical studies 
conducted in China showed a great effect of increasing overall survival compared to the 
Placebo group in patients with advanced gastric cancer31. 32. Based on the positive 
outcome, Apatinib has been approved in China for treatment of advanced gastric cancer 
in 2014. 
Previous studies show clinical benefits in OS and PFS, however, there is no more 
treatment option for patients who failed approved standards therapies. As described 
above, Apatinib has shown potential survival benefit in patients with gastric cancer; 
therefore, its efficacy and safety need to be ascertained in this controlled and properly 
powered phase III study. This study will be the steppingstone to continue the clinical 
development of Apatinib as a treatment agent for advanced and metastatic gastric cancer. 
Moreover, the data to be obtained from this study will contribute to our understanding of 
this disease.  
2. 
STUDY OBJECTIVE 
The overall objective of this study is to evaluate the efficacy and safety of Apatinib plus 
Best Supportive Care (BSC) compared to Placebo plus BSC in patients with advanced 
or metastatic gastric cancer (GC).  
2.1. Primary Objective 
The primary objective of this study is to evaluate the efficacy of Apatinib administered 
with best supportive care (BSC) in the target population in terms of improving overall 
survival compared with that of placebo administered with best supportive care (BSC). 


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2.2. Secondary Objectives 
The secondary objectives of this study are as follows; 
• To evaluate progression-free survival (PFS) 
• To evaluate objective response rate (ORR) 
• To evaluate disease control rate (DCR) 
• To evaluate EORTC QLQ-C30 and EORTC QLQ-STO22 
• To evaluate EQ-5D-5L 
• To explore pharmacodynamic markers: 
Vascular Endothelial Growth Factor (VEGF), sVEGFR-1, sVEGFR2, and 
sVEGFR3 
• To evaluate pharmacokinetics 
Moreover, the safety of Apatinib will be evaluated and safety measures are as follows; 
• Adverse events, laboratory tests, vital signs, physical examination, 12-lead ECG, 
and ECOG performance status 
3. 
INVESTIGATIONAL PLAN 
3.1. Overall Study Design and Plan 
This is a prospective, randomized, double-blinded, placebo-controlled, multinational, 
multicenter, parallel-group, phase III study to evaluate the efficacy and safety of Apatinib 
plus Best Supportive Care (BSC) compared to Placebo plus BSC in patients with 
advanced or metastatic gastric cancer who failed two or more prior treatment regimens. 
After informed consent and screening procedures, eligible subjects will be randomized 
in a 2:1 ratio to Apatinib or Placebo group. All subjects will receive best supportive care 
(BSC). The randomization will be stratified by the following factors: Geographic region 
(Asia 
vs. 
North 
America/Europe), 
Disease 
measurability 
(measurable 
vs. 
nonmeasurable), Prior ramucirumab treatment (Yes vs. No), and Treatment therapy line 
(3rd vs. ≥4th). 
Randomized subjects will receive either the test product Apatinib (freebase) at 700 
mg/day plus BSC or Placebo plus BSC and will be evaluated at regular site visits, which 
will be made every 2 weeks till the death of the subject or discontinuation of the study 
treatment due to disease progression, intolerable toxicity or subject’s withdrawal of 


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consent. If treatment related toxicity is detected, two steps of dose reductions (600 mg, 
400 mg for Apatinib) are allowed during the entire study period according to the dose 
adjustment plan (refer to Section 4.4). 
The intent of the study is to have subjects receive a dose every day continuously. The 
actual dose received will be captured and the start and stop of dosing will be used to 
calculate dose intensity and duration of treatment. A cycle length is determined by either 
the calendar days or days on treatment, whichever is appropriate for the individual 
subject. Dose interruptions such as for management of adverse events may elongate 
the cycle days as needed, however, the subject should be evaluated at reasonable 
intervals to ensure the subjects safety such as follow-up for adverse events and 
laboratory value monitoring. While continuously receiving study investigational product, 
per the protocol schedule, subjects should be evaluated at regular site visits, which will 
be made approximately every 2 weeks as described above. 
Tumor response and progression will be assessed every other cycle (8 weeks interval) 
by a local imaging facility. Patient treatment decisions will be made based on local 
imaging results and investigator opinion which will be entered into the case report forms. 
Scans will be obtained at baseline and throughout the study and will be analyzed post-
study by a central imaging analysis facility. Centrally imaging results will determine the 
patient’s best tumor response and time of progression according to RECIST 1.1. 
Post-treatment follow-up visit will be made at 4 weeks after the end of treatment (EOT) 
and then survival follow-ups will follow at 8-week intervals till the death of the subject or 
closure of the study.  More frequent intervals of survival follow-up may be performed to 
provide for the most accurate survival data at the time of interim and final analysis or 
during periodic updates. 
In this trial, approximately 459 subjects will be enrolled (among them, the anticipated 
number of Japanese patients is at least 50 and up to 100 will be enrolled.) 
The study data will be analyzed when the required number of events (approximately 325 
deaths) are observed. This is projected to occur approximately 9 months after the last 
subject is randomized. All subjects will be treated and/or followed after randomization 
until the study data analysis is performed, and then they will be monitored for survival 
status until death. 
Subjects continuing to benefit from apatinib treatment, after final analysis and 


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subsequent unblinding, will be allowed to consent for extension of treatment with apatinib, 
if determined safe to continue treatment by the investigator, and best supportive care 
until proven intolerable, disease progression, death, the drug is commercially available 
or other reason for subject treatment withdrawal. Subjects who have been receiving 
placebo will be allowed to consent for extension of best supportive care only until the 
extension period is completed or the study is stopped by the sponsor. All subjects who 
are taking investigational product at the time of unblinding will be asked to consent for 
continued survival follow-up during the extension phase of the study.  Subjects who 
were off treatment at the time of unblinding, but are still participating in the study (i.e. in 
survival follow-up) do not require a new consent after unblinding to continue participation. 
3.1.1. Additional Information for Japan Specific Safety Run-In 
The AM104 ethnic bridging study determined that there is no statistically significant 
difference in Japanese ethnic population pharmacokinetics as compared to Chinese 
and/or Caucasian that would make it unsafe to proceed at the study starting dose. The 
AM104 study evaluated the pharmacokinetics of a single dose of 201 mg of Apatinib in 
18 healthy volunteers of each of three specific ethnic populations; Japanese, Chinese 
and Caucasian. Initiation of enrollment in Japan will have a safety run-in approach to 
further confirm the safety of the study starting dose in this ethnic population. Initially, in 
Japan, only 6 patients will be enrolled and assigned either Apatinib or Placebo to 
investigate 
the 
safety 
at 
the 
same 
starting 
dose 
and 
with 
the 
same 
randomization/enrollment criteria as all other study patients. The treatment assignment, 
as with all patients, will not be known to any study personnel with the following exceptions. 
During the observation period, the independent data monitoring committee or an 
appropriately unblinded and separate study personnel who would perform no other study 
activity or duties that would jeopardize the integrity of the study, will determine whether 
at least 3 of the 6 patients have been assigned to Apatinib treatment. The patients will 
be hospitalized and monitored during the 14 days of DLT evaluation period including 
performing the following evaluations once on either study day 7, 8 or 9 that is not noted 
in the standard study schedule,  
・ Physical examination 
・ Measurement of vital signs including weight 
・ Assessment of ECOG performance score 
・ Assessment of adverse event 
・ Collection of concomitant medication information 
・ Hematology, blood chemistry, coagulation test and urinalysis 


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If at least 3 have been assigned Apatinib treatment, the Apatinib treated patients will be 
observed for a minimum of 14 days of therapy.  If less than 3 patients are randomized 
to Apatinib treatment, 3 more patients (bringing the total to 9 patients) may be enrolled 
immediately to ensure that the DLT evaluation in Japan patients is performed on at least 
3 Apatinib treated patients.  
If no DLT occurs during the DLT evaluation period (at least 0/3 Apatinib treated patients), 
the study may proceed in Japan with further enrollment per protocol and the IDMC and 
PMDA will be notified. 
If there is only 1 DLT during the DLT evaluation period (at least 1/3), another 3 patients 
may be enrolled to ensure that at least 6 Apatinib patients are observed for the 14 day 
DLT evaluation period.  
If there remains only 1 DLT during the DLT evaluation period after at least 6 Apatinib 
treated patients are observed (at most 1/6 Apatinib treated patients), the study may 
proceed in Japan with further enrollment per protocol and the IDMC and PMDA will be 
notified. 
If there are 2 DLT events in the 14 day DLT evaluation period (either at most 2/3 or at 
least 2/6 Apatinib treated patients), the enrollment in Japan will temporarily stop until a 
decision to discontinue or continue enrollment with or without modifications is decided 
after consultation with the IDMC and PMDA. 
For the purposes of the Japanese safety run-in, a DLT is defined as any of the following 
events assessed by the Investigator as probably or possibly related to Apatinib that 
occurs during or after the initial dose on Day 1 through Day 14. 
1. CTCAE Grade 4 event 
2. Grade 3 febrile neutropenia (<1,000 neutrophils/mm3) 
3. Grade 3 anemia or thrombocytopenia with duration > 7 days 
4. Grade 3 non-hematologic toxicity including Grade 3 nausea, vomiting and 
diarrhea that continues despite optimal medical management 
5. Anemia or thrombocytopenia that requires transfusion 
6. When the study treatment was withheld based on the protocol 4.4 dose 
adjustment plan more than three days 


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3.2. Study Population 
3.2.1. Inclusion Criteria 
If a patient is to be eligible to participate in the study, the patient must meet all of the 
following inclusion criteria.  
1. Male or female at least 18 years old or older.  
2. Documented 
primary 
diagnosis 
of 
histologic- 
or 
cytologic-confirmed 
adenocarcinoma of the stomach or gastroesophageal junction. 
3. Patients have locally advanced unresectable or metastatic disease that has 
progressed since last treatment. 
4. One or more measurable or nonmeasurable evaluable lesions per RECIST 1.1. 
5. Patients should have failed or were intolerant to at least two prior lines of standard 
chemotherapies with each containing one or more of the following agents:  
o 
fluoropyrimidine (IV 5-FU capecitabine, or S-1), 
o 
platinum (cisplatin or oxaliplatin), 
o 
taxanes (paclitaxel or docetaxel) or epirubicin, 
o 
irinotecan, 
o 
trastuzumab in case of HER2-positive 
o 
ramucirumab  
o 
nivolumab 
o 
pembrolizumab 
Previous 
treatments 
with 
experimental 
agents 
(except 
experimental 
antiangiogenic agents) alone or as part of the prior therapy lines are allowed but 
not mandatory. A maximum number of three prior therapy lines are allowed, 
unless nivolumab or pembrolizumab was used in a prior line, for which case a 
maximum of four prior therapy lines are allowed.  
(For the patients whose disease recurred within 24 weeks from the last dose of 
adjuvant anticancer chemotherapy, that adjuvant anticancer chemotherapy is 
counted as 1 prior chemotherapy line.)  
6. Disease progression within 6 months after the last treatment. 
7. Patients who have adequate bone-marrow, renal and liver function including; 
a. Hematologic: Absolute neutrophil count ≥ 1,500/mm3, Platelets ≥ 100,000/mm3, 
Hemoglobin ≥ 9.0 g/dL (Blood transfusion to meet the inclusion criteria within 
2 weeks is not allowed.). 
b. Renal: Creatinine clearance (according to Cockcroft-Gault Equation or by 24 
hr urine collection) > 50 mL/min and serum creatinine < 1.0 x ULN. 


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c. Hepatic: Serum bilirubin < 1.5 x ULN, AST and ALT ≤ 3.0 x ULN (≤ 5.0 x UNL, 
if with liver metastasis). 
d. Blood coagulation tests: PTT and INR ≤ 1.5 x ULN and ≤ 1.5 x ULN, 
respectively. 
e. The patient’s urinary protein should be < 2+ on dipstick or routine urinalysis. If 
urine dipstick or routine analysis indicates proteinuria ≥ 2+, then a 24-hour 
urine or urine protein/creatinine ratio must be collected and must demonstrate 
< 2 g of protein in 24 hours to allow participation in the study. 
8. Patients whose Eastern Cooperative Oncology Group (ECOG) performance 
status are evaluated to be ≤ 1. 
9. Expected survival of ≥ 12 weeks, in the opinion of the investigator. 
10. Ability to swallow the investigational product tablets. 
11. Female patients of child-bearing potential must have a negative serum or urine 
pregnancy test at the Screening Visit. Females must be surgically sterile, 
postmenopausal for at least 1 year prior to Screening Visit (no other medical 
cause involved) or must be using a highly effective method of birth control 
according to applicable guidelines. Acceptable methods of birth control include: 
combined estrogen-progestogen or progestogen-only hormone contraceptives 
[oral, non-oral, or implants], intrauterine contraceptive device or Intrauterine 
Contraceptive System that are approved or certified in Japan or applicable 
country. Other intrauterine contraceptive device, contraception double barrier 
methods such as condom, sponge, cervical cap and diaphragm with spermicides, 
if locally determined to be highly effective outside of Japan or applicable country, 
may be considered as acceptable. Abstinence is not an acceptable method of 
contraception for the study. 
12. Ability and willingness to comply with the study protocol for the duration of the 
study and with follow-up procedures. 
3.2.2. Exclusion Criteria 
If a patient is to be eligible to participate in the study, the patient must not meet any of 
the following exclusion criteria. 
1. History of another malignancy within 2 years prior to randomization. Subjects with 
the following are eligible for this study if, in the opinion of the investigator, they do 
not pose a significant risk to life expectancy: 
о Bladder tumors considered superficial such as noninvasive (T1a) and 
carcinoma in situ (Tis) 


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о Curatively treated cervical carcinoma in situ 
о Thyroid papillary cancer with prior treatment 
о Carcinoma of the skin without melanomatous features 
о Prostate cancer which has been surgically or medically treated and not 
likely to recur within 2 years 
2.  CNS metastases as shown by radiology records or clinical evidence of 
symptomatic CNS involvement in the last 3 months prior to randomization. 
Patients are eligible if metastases have been treated and have returned to 
neurologic baseline or are neurologically stable (except for residual signs or 
symptoms related to the CNS treatment). 
3. Cytotoxic chemotherapy, surgery, immunotherapy, radiotherapy or other targeted 
therapies within 3 weeks (4 weeks in cases of ramucirumab, mitomycin C, 
nitrosourea, lomustine; 1 week in case of biopsy) prior to randomization (Adjuvant 
radiotherapy given to local area for non-curative symptom relief is allowed until 2 
weeks before randomization.). 
4. Therapy with clinically significant systemic anticoagulant or antithrombotic agents 
within 7 days prior to randomization that may prevent blood clotting and, in the 
investigator’s opinion, could place the subject at risk. Maximum dose of 325 
mg/day of aspirin is allowed. 
5. Patients who had therapeutic paracentesis of ascites (> 1L) within the 3 months 
prior to starting study treatment or who, in the opinion of the investigator, will likely 
need therapeutic paracentesis of ascites (> 1L) within 3 months of starting study 
treatment. 
6. Previous treatment with Apatinib. 
7. Known hypersensitivity to Apatinib or components of the formulation. 
8. Concomitant treatment with strong inhibitors or inducers of CYP3A4, CYP2C9 
and CYP2C19. 
9. Active bacterial infections. 
10. Patients with substance abuse or medical, psychological, or social conditions that 
may interfere with the patient’s participation in the study or evaluation of the study 
results. Conditions include but are not limited to; 
- Known history of human immunodeficiency virus (HIV) infection. 
- Active hepatitis B or C infection or chronic hepatitis B or C infection requiring 
treatment with antiviral therapy or prophylactic antiviral therapy unless evidence 
of viral suppression has been documented and the patient will remain on 
appropriate antiviral therapy throughout the study. 


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11. Patients who participated, within 4 weeks prior to randomization, or are 
participating in any other clinical trial. 
12. Pregnant or breast-feeding women. 
13. History of drug or alcohol abuse within past 5 years. 
14. Medical or psychiatric illnesses that, in the investigator’s opinion, may impact the 
safety of the subject or the objectives of the study. 
15. History of uncontrolled hypertension (Blood pressure ≥ 140/90 mmHg and 
change in antihypertensive medication within 7 days prior to randomization) that 
is not well managed by medication and the risk of which may be precipitated by 
a VEGF inhibitor therapy. 
16. Patients who have known history of symptomatic congestive heart failure (New 
York Heart Association III-IV), symptomatic or poorly controlled cardiac 
arrhythmia, complete left bundle branch block, bifascicular block, or any clinically 
significant ST segment and/or T-wave abnormalities, QTcF > 450 msec for males 
or QTcF > 470 msec for females prior to randomization. 
17. Prior major surgery or fracture within 3 weeks prior to randomization or presence 
of any non-healing wound (procedures such as catheter placement is not 
considered to be major). 
18. History of bleeding diathesis or clinically significant bleeding within 14 days prior 
to randomization. 
19. History of clinically significant thrombosis (bleeding or clotting disorder) within the 
past 3 months prior to randomization that, in the investigator’s opinion, may place 
the patient at risk of side effects from anti-angiogenesis products.   
20. History of gastrointestinal bleeding, gastric stress ulcerations, or peptic ulcer 
disease within the past 3 months prior to randomization that, in the investigator’s 
opinion, may place the patient at risk of side effects from anti-angiogenesis 
products. 
21. Myocardial infarction or unstable angina pectoris within 6 months prior to 
randomization. 
22. History of severe adverse events including uncontrolled HTN or other common 
anti-angiogenesis class drug effects that were related to ramucirumab 
discontinuation and/or may indicate a higher risk to the safety of the patient if 
provided further anti-angiogenesis treatment, in the investigator’s opinion. 
23. History of other significant cardiovascular diseases or vascular diseases within 
the last 6 months prior to randomization (e.g. hypertensive crisis, hypertensive 
encephalopathy, stroke or transient ischemic attack [TIA], or significant peripheral 


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vascular diseases) that, in the investigator’s opinion, may pose a risk to the 
patient on VEGF inhibitor therapy. 
24. History of clinically significant glomerulonephritis, biopsy-proven tubulointerstitial 
nephritis, crystal nephropathy, or other renal insufficiencies. 
25. Gastrointestinal malabsorption, or any other condition that in the opinion of the 
investigator might affect the absorption of the study drug. 
3.3. Discussion of Study Design 
This study is a prospective, randomized, double-blinded, placebo-controlled, 
multinational, multicenter, parallel-group, phase III study to evaluate the efficacy and 
safety of Apatinib in patients with advanced or metastatic gastric cancer.  
In the Chinese phase I study30, Apatinib mesylate demonstrated noteworthy efficacy with 
18 of 22 patients with gastro-colorectal cancer showing disease control. Of those 18 
patients with disease control, 4 subjects showed partial response. The mean treatment 
duration in this phase I study was 5.4 months. In the phase I study30, treatment with 
apatinib was given until disease progression, death, an intolerable toxicity or withdrawal 
of consent and the most frequent adverse events were hypertension, proteinuria and 
hand-foot syndrome, which were mild to moderate in severity and manageable. The 
phase I efficacy data showed that partial response was seen in 18.9% of patients and 
stable disease in 64.9%, totaling an 83.8% disease control rate. In other words, out of 
22 patients with gastric-colorectal cancer in total who were included in this phase I study, 
18 subjects had disease control including 4 subjects with partial response, which 
indicates an excellent efficacy profile. In the phase II and III studies recently conducted 
in China as mentioned above, Apatinib demonstrated an excellent efficacy that it 
increased overall survival compared to the Placebo group when administered to patients 
with advanced gastric cancer who failed two or more lines of therapy. Based on the 
results from the clinical studies, this phase III study is planned to confirm the effects of 
Apatinib in patients with advanced or metastatic gastric cancer. The subjects will be 
randomized at 2:1 ratio to receive either Apatinib (freebase) 700 mg qd or Placebo qd 
and then the safety and efficacy will be assessed during the treatment period. 
In addition, this study has been designed as a double-blind, placebo-controlled, and 
multinational, multicenter study. The target population—advanced or metastatic gastric 
cancer patients who have failed standard therapies—is an appropriate candidate who 
will possibly benefit from Apatinib treatment considering there is no recommended or 
accessible further treatment. To reserve objectivity and credibility of the study results, a 


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double-blind design has been adopted. Patients will be stratified according to the 
geographic region (Asia vs. North America/Europe). Region was employed as a 
stratification factor in order to avoid an imbalance among regions in the randomization 
to the Apatinib group and the Placebo group. In addition, disease measurability
(measurable vs. nonmeasurable), Prior ramucirumab treatment (Yes vs. No), and 
Treatment therapy line (3rd vs. ≥4th) will be employed as stratification factors. The primary 
endpoint is overall survival (OS), which is considered the most reliable cancer endpoint
and is the preferred endpoint from a regulatory perspective. Thus, OS was selected as 
the primary endpoint in this phase III trial. EORTC and EQ-5D questionnaires were 
selected in order to assess the quality of life of subjects because these questionnaires
are being used in cancer patients worldwide.
3.4.
Study Procedures
Protocol-specific evaluations and their schedule in detail during the whole study period 
are summarized in Table 1. in the protocol synopsis section. Figure 1 shows the overview 
of the study scheme. 
Figure 1. Study Scheme
1) Post-treatment follow-up will be done at 4 weeks (± 7 days) after the end of treatment (EOT). 
2)
Survival follow-up will be done at 8 weeks (± 7 days) interval after the Post-treatment follow-up visit. 
Survival follow-ups will continue until the death of the subject or till the study closure.
EOS is defined as the end of the 
primary analysis period when the 
patients are unblinded. 
After EOS
• Tumor assessment Information
• Safety assessment 
- 28 days 
from BSLN
Treatment Period
Screening Period
After EOT
Apatinib 700 mg qd, po
Follow-up Period
Matching Placebo to apatinib qd, po
Post-Tx F/u 1)
• At 4 weeks after EOT
• Exams and tests 
• for eligibility 
assessment
• Baseline tumor 
evaluation
• Informed consent
• Demography
• Medical/medication 
history
• GC history
Randomization (2:1)
Apatinib + BSC
Placebo + BSC
EOS
SCRN
(-28 days)
BSLN
EOT
Post-TX 
f/u
End of Extension period
Extension Period
• Subjects in the apatinib group 
who are not confirmed as 
disease progression at EOS or 
are otherwise eligible to 
continue apatinib treatment until
end of treatment or study 
withdraw (section 6.2)
• Other subjects will be followed 
for survival status until death.
Survival F/u 2)
• At 8 weeks interval
(by telephone or 
direct visit)
28 day cycles
• Tumor assessment every other cycle
• QoL assessment once every cycle
• Safety assessments every two weeks


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3.4.1. Screening Visit 
Upon signing on the informed consent form, the screening period will start. Screening 
should be completed within 28 days before the date of randomization. Within this period, 
following procedures are to be carried out. Any procedures or assessments associated 
with the study should be initiated only after obtaining the written informed consent from 
potential subjects. If procedures within the 28-day window were performed as part of 
standard of care prior to consent, those evaluations may be used as screening period 
results. 
・ Informed consent1 
・ Collection of demographic information 
・ Collection of medical history2 
・ Collection of GC history3 
・ Collection of previous/concomitant medication information4 
・ Assessment of adverse events5 
1) In Japan, when the patient is under 20 years old, informed consent will be obtained 
from both the patient and the legal guardian. 
2) Medical history within 1 year (within 3 years for cancers) from signing on the ICF 
should be collected. Medical history includes clinically significant past and current 
diagnosis including surgical procedures. Any surgical procedures done for treatment 
of GC will be collected separately regardless when those were carried out.  
3) Full history of GC including date of initial diagnosis, primary location ([≥ 5 cm below 
GEJ] vs. GEJ), stage, and metastatic information should be collected. 
4) Any medications administered within 28 days from signing the ICF and current 
medications should be collected. Medications for treatment of GC will be collected 
separately regardless of when those were administered. 
5) Any untoward medical occurrence in a patient who has signed the informed 
consent form will be collected as an adverse event.  
The following should be completed within 14 days before the baseline visit. These data 
except vital signs, which will be measured again in the baseline visit, will be used as 
baseline data for determination of eligibility of subjects in the study. 
・ Measurement of height 
・ Physical examination 
・ Measurement of vital signs including weight 


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・ Assessment of ECOG performance score 
・ 12-lead ECG 
・ Hematology, blood chemistry, serological test, coagulation test and urinalysis1 
・ Pregnancy test2 
・ CT/MRI for GC evaluation3 
・ Biopsy for GC evaluation4 
・ Collection of concomitant medication information 
・ Assessment of adverse event 
・ Eligibility review by the registration center5) 
1) Please refer to 5.3.2 for specific item of each test panel. 
2) This will be ordered only for women of child-bearing potential (serum or urine) 
including women who have not been post-menopausal for at least 1 year prior to 
Screening visit. 
3) Tumor will be assessed based on CT (or PET-CT) scan or MRI. The same method 
should be used for the assessment of tumor response throughout the study. 
4) If a diagnosis cannot be made with CT (or PET-CT)/MRI due to atypical 
radiological appearance, primary or metastatic tumor biopsy is recommended. 
Histopathologic examination of the biopsy specimen should be assessed by an 
expert pathologist. 
5) Among the screened patients, the registration center will review those fulfilling the 
criteria in Section 3.2.1, not meeting any of the criteria in Section 3.2.2 and judged 
to be appropriate for the study. 
3.4.2. Baseline Visit (Day 1 in Cycle 1) 
Randomized subjects will receive the assigned investigational product as instructed. The 
following procedures are carried out at this visit. 
・ Physical examination 
・ Measurement of vital signs including weight 
・ Assessment of ECOG performance score 
・ 12-lead ECG (Before IP administration)  
・ Chest X-ray, pregnancy test (serum or urine), biopsy1 
・ Collection of concomitant medication information 
・ Randomization 
・ Completion of patient reported outcome (EORTC QLQ-C30, EORTC QLQ-
STO22, EQ-5D-5L) 


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・ Pharmacodynamic (PD) marker test 
・ Dispense of investigational product 
・ Administration of investigational product 
・ Blood sampling for Cycle 1 Day 1 PK 
・ 12-lead ECG (Approximately 4 hours after IP administration and corresponding 
to PK sampling) 
・ Assessment of adverse events 
1) Only done when clinically indicated. The following countries require a pregnancy 
test at the beginning of each treatment cycle for the applicable subjects: Germany, 
Romania, and Poland.  
If a randomized subject is found not to meet any of the eligibility criteria before the first 
administration of the investigational product, the subject will not be started on the study 
treatment and will be withdrawn from the study. Subjects who are randomized but never 
receive the investigational product or subjects who are withdrawn from the study before 
randomization will not be allowed to re-consent. 
3.4.3. Treatment Visits After Baseline 
A treatment cycle is composed of 28 days (4 weeks) and the study treatment will be 
continued until the death of the subject or discontinuation of the study treatment due to 
disease progression, intolerable toxicity or subject’s withdrawal of consent. Subjects are 
required to visit the investigational site every 2 weeks (± 3 days) till the death of the 
subject or discontinuation of the study treatment due to disease progression, intolerable 
toxicity or subject’s withdrawal of consent. The following procedures are carried out at 
each treatment visit after baseline. 
・ Physical examination 
・ Measurement of vital signs including weight 
・ Assessment of ECOG performance score 
・ Assessment of adverse event 
・ Collection of concomitant medication information 
・ Chest X-ray, pregnancy test (serum or urine), biopsy1 
・ 12-lead ECG and Pharmacodynamic (PD) marker test2 
・ Blood sampling for PK (See Section 5.4.4) 
・ Hematology, blood chemistry, coagulation test and urinalysis 
・ Completion of patient reported outcome (EORTC QLQ-C30, EORTC QLQ-
STO22, and EQ-5D-5L)2 


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・ CT/MRI3 
・ Dispense of investigational product at the first day of every cycle (as long as the 
study treatment is continued) 
1) Only done when clinically indicated. Biopsies are carried out based on the 
investigator’s discretion, but it should be considered in case of growth or change in 
the enhancement pattern identified during follow-up. Histopathologic examination of 
the biopsy specimen should be assessed by an expert pathologist. The following 
countries require a pregnancy test at the beginning of each treatment cycle for the 
applicable subjects: Germany, Romania, and Poland. 
2) Measured at the first day of every cycle (4 weeks interval) prior to dosing. In 
addition, a 12-lead ECG should be performed approximately 4 hours after IP 
administration on Day 15 of Cycle 1 corresponding to the Cmax PK blood draw 
timepoint. 
3) Measured approximately every 8 weeks at the end of every other cycle from 
Baseline 
3.4.4. End of Treatment (EOT) Visit/Discontinuation 
Subjects who discontinue study treatment (see Section 6.2) or subjects permanently 
withdrawn from the study are required to make this visit within 7 days from their final 
administration of the investigational product. Following procedures are carried out at this 
visit. 
・ Physical examination 
・ Measurement of vital signs including weight 
・ Assessment of ECOG performance score 
・ Assessment of adverse event 
・ Collection of concomitant medication information 
・ Chest X-ray, pregnancy test (serum or urine), biopsy1 
・ 12-lead ECG 
・ Hematology, blood chemistry, coagulation test and urinalysis 
・ Pharmacodynamic (PD) marker test 
・ CT/MRI2 
・ Completion of patient reported outcome (EORTC QLQ-C30, EORTC QLQ-
STO22, EQ-5D-5L) 
1) Only done when clinically indicated. Biopsies are carried out based on the 
investigator’s discretion but it should be considered in case of growth or change in 


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the enhancement pattern identified during follow-up. Histopathologic examination of 
the biopsy specimen should be assessed by an expert pathologist. The following 
countries require a pregnancy test at the end of treatment visit for applicable 
subjects: Germany, Romania, and Poland. 
2) If CT/MRI is performed within 4 weeks prior to EOT or disease progression is
clearly confirmed by previous CT/MRI, tumor evaluation is not required at EOT.
3.4.5. Post-Treatment Follow-Up Visit 
For the purpose of safety follow-up, a post-treatment visit should be made at 28 days (± 
7 days) after the end of treatment visit. The following procedures are carried out at this 
visit. 
・
Physical examination
・
Measurement of vital signs including weight
・
Assessment of ECOG performance score
・
12-lead ECG
・
Hematology, blood chemistry, coagulation test and urinalysis
・
Assessment of adverse event
・
Collection of concomitant medication information
・
Chest X-ray, pregnancy test (serum or urine)1
1)
Only done when clinically indicated. A pregnancy test for applicable subjects is
required at post-treatment follow up visit for Poland.
3.4.6. Survival Follow-Up Visit 
Subjects who prematurely discontinue study treatment (see Section 6.2) but who are not 
withdrawn from the study will be followed-up at 8 weeks (± 7 days) interval for tracking 
of their survival until they meet the following criteria:  
・
The subject withdraws his/her consent on the study.
・
The subject is dead.
・
The entire study has been completed or discontinued.
・
The investigator judges that it is necessary to discontinue the follow-up.
This survival follow up can be performed via telephone, certified letter or during subjects’ 
visit to the investigational site or other clinic site where confirmation of survival 
information documentation can be obtained. In addition, publicly accessible data may be 
used to document death. The survival status and follow up date should be recorded in 


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the electronic case report form (eCRF). 
The following parameters shall be recorded in the follow-up period (Post-Treatment 
Follow-Up Visit and Survival Follow Visit): 
・ The onset time of death or disease progression (if disease progression is not 
confirmed at EOT) 
・ Other tumor treatments (if applicable) 
3.4.7. Extension period study visits 
After the study is unblinded and the extension period of the study begins, all subjects 
taking study medication at that time should have their study treatment assignment 
unblinded and determined to be either apatinib or placebo. For subjects that are not 
taking study medication at the time of unblinding, the investigator may request to know 
their treatment assignment. Subjects who have stopped taking study medication or best 
supportive care prior to unblinding will not be given the option to restart taking apatinib 
or begin receiving best supportive care.  
Subjects taking placebo at the time of unblinding: 
Subjects who are determined to be taking the placebo and best supportive care when 
the study is unblinded may consent to continue to be followed for survival status and to 
continue best supportive care. For those subjects that were taking placebo, no End of 
Treatment visit is required. Best supportive care may be continued for patients no longer 
taking placebo, if appropriate, and only until other anti-cancer therapy is administered, 
disease progression, intolerability, death, or withdrawal of consent. No AE’s or SAE’s will 
be gathered for subjects receiving only best supportive care. Survival status will continue 
to be requested until withdrawal of consent. The study schedule for subjects receiving 
only best supportive care in the extension period is to be determined by the investigator 
as standard of care for managing that supportive care. 
 
  
Subjects taking apatinib at the time of unblinding:  
After the End of the Study (EOS) when the study is unblinded, for those subjects taking 
apatinib, if the investigator determines that it is safe to continue apatinib treatment, they 
should obtain consent from the subject to continue to administer apatinib and perform 
safety evaluations, tumor assessments and survival follow-up. Subjects will continue 
apatinib treatment until disease progression, intolerability, death, withdrawal of consent, 
or, if none of those has occurred, apatinib becomes available through other methods 


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acceptable to the applicable regulatory authority. Site visit and evaluation for safety 
should be performed approximately every four weeks (± 3 days). Safety assessment may 
be performed more frequently, if clinically indicated. Tumor assessments will be 
performed per standard care approximately every 6-8 weeks. Subjects who reached 
end of treatment should be followed for survival per section 3.4.6. For apatinib 
subjects not willing to consent for further treatment after the study is unblinded or for 
those where the protocol extension period has not been approved locally or 
nationally, will stop the apatinib administration and perform the End of Treatment visit, 
Post-treatment Follow-up for safety, and Survival Follow-up as appropriate.  
Treatment Visits during Extension Period: 
The following procedures are carried out at each treatment visit after the start of the 
extension period for each subject continuing apatinib treatment: 
・
Assessment of adverse event
・
Dispense investigational product1
・
Tumor assessment by CT/MRI2
・
Targeted Physical examination, if needed
・
Measurement of vital signs including weight
・
12-lead ECG
・
Laboratory testing: Hematology, blood chemistry, coagulation test and urinalysis
1) Dispensed a 30-day supply when needed for as long as the study treatment is
continued
2) Measured at standard of care intervals
If clinically indicated or regulatory required and as part of standard of care: 
・
Chest X-ray
・
Pregnancy test (serum or urine)1
1) Additional pregnancy test is required at the beginning of every treatment cycle,
and at EOT visit for Germany and Romania. Additional pregnancy test is required
at the beginning of every treatment cycle, at EOT visit, and at post-treatment follow
up visit for Poland.


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Best Supportive Care during Extension Period (former placebo subjects): 
Only subjects that were actively taking placebo at the time of unblinding will be given the 
option to continue with best supportive care treatment after discontinuation of the 
placebo. No procedures are required for subjects receiving only best supportive care 
during the extension period. The site and investigator should provide best supportive 
care as they were providing while the subject was on blinded placebo study medication.  
Best supportive care and any further evaluations of these subjects should be per 
standard of care and are not required to be reported. Best supportive care may be 
provided until beginning another anti-cancer therapy, disease progression or subject’s 
withdrawal of consent. Survival follow-up should continue until the extension study is 
completed, the subject has expired or the subject withdraws consent. 
4. 
STUDY TREATMENTS 
4.1. Investigational Products 
4.1.1. Identity and Storage of Investigational Products 
All investigational products will be supplied by LSK BioPartners, Inc. in a polyvinylidene 
chloride (PVDC), heat-sealed foil-laminated blister pack. The outer packaging and the 
relevant unit of each pack of the investigational products will be labelled according to the 
applicable law to indicate these drugs are to be used only for investigational purposes. 
Apatinib is supplied as 200 mg and 100 mg tablets and the matching placebo will be also 
provided with the tablets of the same size. 
Table 5. Identity of the Test Drug 
Common Name 
Apatinib  
Chemical Name 
N-(4-(1-cyanocyclopentyl) phenyl)-2-(4- 
pyridinylmethyl) amino-3-pyridinecarboxamide 
methanesulfonate 
Molecular Formula 
C25H27N5O4S 
Molecular Weight 
493.58 
 
Matching placebos will be manufactured to appear the same as the equivalent strength 
Apatinib tablet with the same ingredients (only excipients are included). 
The investigational products should be kept in a locked storage area at 15-25 °C (59-77 
˚F) with excursions allowed to 40 °C (104 ˚F) for up to 24 hours. Investigators or 


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designated personnel should check the temperature of the storage room daily and 
ensure that temperature monitoring devices are working correctly. Any deviations from 
the storage condition, including any actions taken, must be documented and reported to 
the sponsor or its sponsor representative. Once a deviation is identified, the 
investigational product must be stored separately and not used until the sponsor or its 
sponsor representative provides written permission to use the investigational product. 
4.1.2. Return of Unused Investigational Products 
Subjects are required to bring all used packs and any unused investigational product (IP) 
when they visit to the site at the end of each cycle. The IP returned by subjects or any 
unused IP (that is, never dispensed to any subject) must be returned to the sponsor or 
its representative at the end of the study or destroyed after accountability has been 
performed and only after written authorization from the sponsor or sponsors 
representative has been received. 
4.1.3. Discontinuation of Investigational Products Supply 
During the Treatment period, all subjects will be provided with investigational products 
(Apatinib or Placebo) until treatment discontinuation.  
If one of the following criteria is met, sponsor can discontinue IP supply. 
1) The country applicable regulatory agency declines New Drug Application (NDA) 
for the indication. 
2) This trial is terminated due to safety issue. 
3) Apatinib becomes commercially available to the patients in the applicable 
country. 
4) Other alternative standard treatment can be available. 
5) The trial is unblinded and the extension period of the study is not approved by 
applicable regulatory or local ethics authorities. 
4.2. Method of Assigning Patients to Treatment Group (Randomization method) 
Subjects will be randomized in a 2:1 ratio to the Apatinib group or the Placebo group, 
and the randomization will be stratified according to the following factors.  
1) Geographic region (Asia pacific vs. North America/Europe) 
2) Disease measurability (measurable vs. nonmeasurable) 
3) Prior ramucirumab treatment (Yes vs. No) 
4) Treatment therapy line (3rd vs. ≥4th) 


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For each subject who has provided written consent and whose eligibility is confirmed, a 
registration number will be assigned by the Interactive Web Response System (IWRS), 
and the subject will be enrolled in the study (enrollment). Detailed procedures for IWRS 
use will be specified in a separate document. 
4.3. Administration of Investigational Product 
Investigational products will be administered orally once a day, approximately 1 hour 
after breakfast. It is recommended that the administration time should be consistent 
throughout the study period (that is, the administration interval should be approximately 
24 hours). The investigational product should not be taken until during the clinic visit of 
Day 1 of each cycle. 
Subjects should take 3 tablets of 200 mg and 1 tablet of 100 mg in strength at a time. If 
the dose is reduced to 600 mg, 3 tablets of 200 mg in strength should be taken. If the 
dose is reduced further to 400 mg, only 2 tablets of 200 mg in strength should be taken 
at a time. If the subject vomits after swallowing the IP, the dose will not be replaced and 
there will be no replacement of a missed dose of IP.   
4.4. Dose Adjustment Plan 
To ensure safety of subjects, the dose of study treatment may be reduced for the 
toxicities described below as related to treatment, including ‘Certain, Probable or 
Possible’ causality. 
・ In case of Grade I non-hematological treatment related toxicity and Grade I or II 
hematologic toxicity, no dose adjustment needs to be done.  
・ In case of Grade II non-hematological treatment related toxicity, study treatment is 
continued without modification and with required symptomatic treatment. The 
investigator may reduce the dose by one level in the next cycle if they determine that 
continuing Grade II treatment related toxicity or a significant potential of worsening 
should be avoided. 
・ In case of potentially related or related anti-angiogenic treatment Grade II AEs, pre-
emptive dose reduction is recommended and the investigator may reduce the dose 
by one level at any time to reduce the risk of potential significant worsening that may 
cause the patient to discontinue the study. If the AE Grade stabilizes or decreases 
with dose reduction, the investigator may choose to increase the dose by one level 
at any time within the cycle or at the start of the next cycle to maximize potential 
study treatment exposure. The investigator may decrease or increase the dose 


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according to tolerability of the patient of Grade II AEs, but may not decrease below 
the 400 mg qd dose level and may not increase above the 700 mg qd dose level.  
・ In case of Grade III or IV non-hematological treatment related toxicity, study 
treatment will be temporarily withheld and resumed upon recovery to ≤ Grade I within 
3 weeks. If treatment is resumed upon recovery, the dose should be reduced by one 
level. If recovery takes longer than 3 weeks, the investigator should contact the 
sponsor to determine if the patient may continue on study treatment.  
・ In case of Grade III or IV hematological treatment related toxicity, study treatment 
will be temporarily withheld and resumed upon recovery to ≤ Grade II within 3 weeks. 
If treatment is resumed upon recovery, the dose should be reduced by one level. If 
recovery takes longer than 3 weeks, the investigator should contact the sponsor to 
determine if the patient may continue on study treatment. 
During each administration cycle (28 days/cycle), only a single dose reduction (700 mg 
qd to 600 mg qd or 600 mg qd to 400 mg qd) is permitted; A total of two dose reductions 
are permitted during the entire study period; and dose reduction below 400 mg qd will 
not be permitted. 
4.5. Double-Blinding Method 
4.5.1. Double-Blinding 
All investigational products that were made indistinguishable between study drug and 
matching placebo in appearance for the purpose of double-blinding will be supplied to 
the investigators and will be identified by code numbers. 
4.5.2. Maintenance of Blinding 
Allocation to either the Apatinib group or the Placebo group will be double-blinded. As 
Apatinib-matching placebo will be supplied, the Apatinib group and the Placebo group 
cannot be distinguished at the time of the delivery and dispensing of the investigational 
product. Double-blindness of the study is maintained by prohibiting subjects and 
investigators as well as any study personnel of the sponsor or CRO except for the 
persons in charge of randomization codes and labelling of IP from accessing 
randomization codes. 
The allocation code of a given subject can be broken according to the unblinding 
procedures described in Section 4.5.3 only if medically necessary to treat intercurrent 
illness or medical emergency, or according to the sponsor’s judgment that the code must 
be broken to protect the rights and safety of the subject. 


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4.5.3. Unblinding Procedure in Emergency Situations 
Unblinding should only occur when medically necessary to treat an intercurrent illness 
or medical emergency. When the treatment information assigned to a subject need to be 
revealed emergently in order to appropriately treat an intercurrent illness or medical 
emergency, the investigator will request an emergency code break for the subject by 
entering the necessary data into IWRS according to a written procedure prepared 
separately. A discussion with the medical monitor for the sponsor (or sponsor’s designee) 
should occur when possible to review alternatives to unblinding that could be taken. If 
there can be no discussion with the medical monitor for the sponsor (or sponsor’s 
designee) before unblinding the emergency code, this should be documented.  
In response to the request for an emergency code break, the emergency code for the 
subject will immediately be unblinded via IWRS. IWRS will notify the investigator of the 
treatment information assigned to the subject, and will also notify the sponsor and its 
representative of the unblinding. 
4.6. Treatment Compliance 
The investigator and/or the designated person responsible for dispensing investigational 
products (IP) must be able to account for all IP provided to the site. The person 
responsible for dispensing the IP must document the dispensing detail (the subject 
number, the date, the amount of dispensed IP, the lot number of IP, the IP code on each 
IP package dispensed, etc.) and have access to the Interactive Web Response System 
(IWRS). Dose modification, interruptions, and reason for these actions must be recorded 
in the source documents. No IP is to be used other than for the purpose of this study. 
4.7. Prior and Concomitant Medications 
4.7.1. Contraindicated Treatment 
The following treatments or medications are contraindicated during the Treatment period. 
If any of these treatments/medications is administered, the subject should be withdrawn 
from the study treatment. 
・ While patients are on treatment cycle of this study, other anticancer therapy, 
systemic chemotherapy, radiotherapy (Radiation as a palliative therapy to treat 
bone metastasis will be allowed.), immunotherapy, cancer-related hormone 
therapy (cancer unrelated alternative hormone therapy that was initiated prior to 
the study enrollment is allowed) or herbal medicines that have official indication 
as anticancer drugs, or administration of investigational products from other 


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clinical studies are not permitted. 
・
The use of hematopoietic factors such as G-CSF etc. during the Japan DLT 
assessment period will be prohibited in the protocol.
・
Packed red blood cell transfusion or erythropoietin therapy are not permitted 
within 14 days prior to the study enrollment (however, permitted if stable 
condition was maintained by erythropoietin therapy for at least 1 month prior to 
the enrollment). Packed red blood cell transfusion or erythropoietin therapy can 
be used after the initiation of the treatment at the investigator’s discretion and 
their use must be recorded in the eCRF. (Erythropoietin therapy is not approved 
for the anemia associated with cancer chemotherapy in Japan)
・
Medications known or suspected to prolong the QT/QTc interval, with the 
exception of drugs with low risk of QT/QTc prolongation. This includes but not 
limited to the following drugs;
-
Antibacterial drugs: Clarithromycin, Azithromycin, Erythromycin, 
Roxithromycin, Metronidazole, Moxifloxacin
-
Antiarrhythmic drugs: Quinidine, Sotalol, Amiodarone, Disopyramide, 
Procainamide
-
Antipsychotics: Risperidone, Fluphenazine, Droperidol, Haloperidol, 
Thioridazine, Pimozide, Olanzapine, Clozapine
-
Antifungals: Fluconazole, Ketoconazole
-
Antimalarials: Mefloquine, Chloroquine
-
Antidepressants: Amitriptyline, Imipramine, Clomipramine, Dothiepin, 
Doxepin
・
Strong inducers or inhibitors of CYP3A4, CYP2C9, and CYP2C19. This 
includes but not limited to the following drugs (refer to
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Development    
Resources/DrugInteractionsLabeling/ucm093664.htm);
-
CYP3A4 inducers or inhibitors: Diltiazem, Itraconazole, Ketoconazole, 
Posaconazole, Voriconazole, Clarithromycin
-
CYP2C9:Phenytoin, Piroxicam
-
CYP2C19: Rifampin, Fluconazole, Fluoxetine, Fluvoxamine
・
During the treatment period, the intake of following food and supplements are 
prohibited in principle. If the patients are not under the control of hospital, the 
patients will be informed that following foods are to be avoided;
-
Supplements St. John's wort (Hypericum perforatum)


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-
Foods and drinks that contains grapefruit, seville orange or orange
marmalade
4.7.2. Permitted Concomitant Treatment 
Any medications that are considered necessary for the subject’s welfare may be given 
at the discretion of the investigator and are permitted. Medications for treatment of 
underlying disease and symptomatic treatment of adverse events are permitted.  
Best supportive care (BSC) will be given to subjects in the both treatment groups at the 
discretion of the investigators. BSC is defined as palliative, non-cancer therapy. There 
should be no difference in the practice of administering BSC between the two groups 
and BSC will be continuously provided after the study treatment is discontinued.  
5.
ASSESSMENT MEASURES
5.1. Baseline Assessment 
5.1.1. Demographics  
At the time of screening, demographic information including age, sex, body mass index, 
race will be collected from those who were identified as potential subjects. 
5.1.2. Medical and Surgical History 
At the Screening Visit, the subject’s treatment history of gastric cancer as well as his/her 
medical and surgical history will be recorded. All medical history within 1 year prior to 
screening (within 3 years for cancers) from signing on the ICF will be collected. History 
of gastric cancer shall include date of diagnosis, diagnosis result, location of primary 
tumor at diagnosis (Gastric [≥ 5 cm below GEJ] vs. GEJ), information of metastasis 
(metastases to other organs such as lung, liver metastasis), surgical history etc. 
5.1.3. Prior Medications History 
Any medications or therapies that the subject was taking or receiving at the time of study 
participation (Screening visit) shall be recorded as concomitant medications. 
Medications that the subject took within 28 days from signing on the ICF shall also be 
recorded in the eCRF. Any changes or additions in concomitant medications or therapies 
shall be indicated in the eCRF.  
Any prior anticancer treatments used for the management of advanced or metastatic 
gastric cancer (e.g. anticancer chemotherapy and/or radiotherapy) and number of lines 
shall be identified and recorded in the eCRF. 


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5.2. Efficacy Assessment 
5.2.1. Tumor Evaluation (Chest, abdominal and pelvic CT/MRI)  
Tumor imaging will be further explained in an Imaging manual. A CT should be used with 
slice thickness ≤ 5 mm. Tumor will be assessed CT (or PET-CT) scan or MRI—whichever 
is used, the same method and the same equipment should be used throughout the 
study—at the following time points: 
・ Within 14 days before Baseline visit (baseline measurement) 
・ The end of every other cycle thereafter 
・ End of treatment (EOT) visit1) 
1) If CT/MRI is performed within 4 weeks prior to EOT or disease progression is 
clearly confirmed by previous CT/MRI, tumor evaluation is not required at EOT. 
If a subject is withdrawn from the IP treatment due to any reason except for disease 
progression, tumor evaluation will be continued every 8 weeks until disease 
progression is confirmed or other tumor treatment is initiated.  
The change of imaging equipment will be allowed only if subjects become hypersensitive 
to the contrast medium for CT or if there is concern about too much radiation exposure. 
In addition to these planned tumor evaluations, unscheduled imaging is allowed as 
clinically indicated at the Investigator's discretion. The key images to be used for 
determination of disease progression will be reviewed by a central imaging analysis 
facility based on objective tumor assessments using the RECIST guidelines (version 1.1). 
The tumor response criteria is presented in Appendix 2. 
If a diagnosis cannot be made with CT/MRI due to atypical radiological appearance, 
primary or metastatic biopsy is recommended. Subsequent biopsies are carried out 
based on the investigator’s discretion, but it should be considered in case of growth or 
change in the enhancement pattern identified during follow-up. Histopathologic 
examination of the biopsy specimen should be assessed by an expert pathologist. 
5.2.2. Patient Reported Outcome 
Following two questionnaires will be used as tools to collect patient reported outcomes. 
These questionnaires will be completed at the first day of every cycle (4 weeks interval). 
・ European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 (EORTC QLQ-C30) with the European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire-the gastric cancer 


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specific module (EORTC QLQ-STO22): EORTC QLQ-C30 is a 30-item core-cancer-
specific questionnaire-integrating system for assessing the health-related QOL of 
cancer patients participating in international clinical trials. The questionnaire 
incorporates 5 functional scales (physical, role, cognitive, emotional and social), 4 
symptom scales (fatigue, pain, nausea/vomiting, appetite), a global QOL scale and 
single items for the assessment of additional systems commonly reported by cancer 
patients (e.g., constipation, diarrhea, sleep disturbance and financial). All items are 
scored on 4-point Likert scales, ranging from 1 (‘not at all’) to 4 (‘very much’), with 
the exception of two items in the global QOL scale which use modified 7-point linear 
analog scales.33 , 34 The questionnaire is widely used in cancer patients including 
gastric cancer23, 35 ,36 and has been translated in various languages. It should be 
completed by subjects. In addition, EORTC QLQ-STO22 is a 22-item gastric cancer-
specific questionnaire-integrating system for assessing the health-related QOL of 
gastric cancer patients. 
・ EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire: it has been developed by 
EuroQol Group from the EQ-5D-3L, which has 3 levels in each dimension, to improve 
the instrument’s sensitivity and to reduce ceiling effects. It consists of EQ-5D-5L 
descriptive system and the visual analogue scale (VAS). The descriptive system 
comprises the 5 dimensions (mobility, self care, usual activities, pain/discomfort, 
anxiety/depression) and each dimension has 5 levels. Its validity and reliability have 
been proven in many different populations, including subjects with gastric cancer.37, 
38 It should be completed by subjects. 
5.3. Safety Assessment 
5.3.1. Adverse Event 
Assessments will be made on the adverse events (AEs) including any sign, symptom, 
disease or illness that occurred newly or if present at baseline, worsened in a subject 
and may impair the well-being of the subject. Clinical laboratory findings and any other 
findings from the diagnostic procedures that are considered clinically significant (e.g. 
requiring unscheduled diagnostic procedures or treatment modalities or resulting in 
discontinuation of the study) will also be included in the AE assessment. 
AEs will be collected and evaluated at each visit after informed consent is signed until 
28 calendar days after the last administration of the investigational product. Any AEs that 
emerged following administration of IP will be evaluated in comparison to the baseline 
level of AEs determined at screening. 


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See Section 7 for detailed information on SAFETY REPORT of this study. 
5.3.2. Clinical Laboratory Tests 
The following tests will be performed locally at individual investigational sites. 
Hematology, chemistry, coagulation and urinalysis will be performed at Day 1 (before IP 
administration) and Day 15 of every cycle, the end of treatment (EOT) visit and the post-
tx F/U visit. If hematological or non-hematological treatment related toxicity occurs, 
laboratory tests can be performed at the investigator’s discretion during the treatment 
period. Serological tests will be performed only at the screening visit and additional tests 
can be performed as clinically indicated or as required by local health authorities. 
・
Hematology (complete blood count, CBC: white blood cell (WBC) with 5-part
differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils),
platelet count, absolute neutrophil count (ANC), red blood cell count (RBC),
hemoglobin (Hb), hematocrit (Hct)
・
Blood chemistry: sodium, potassium, chloride, carbon dioxide or bicarbonate (if
required), blood urea nitrogen (BUN), creatinine, glucose (fasting), total protein,
albumin, calcium, amylase, lipase, phosphorous, magnesium, creatinine kinase
(CK), uric acid, total bilirubin, AST, ALT, and ALP
・
Serological tests: HIV antibody (if HIV antibody result is positive, HIV-1 antibody
and HIV-2 antibody should be conducted), HBs antigen, HBs antibody, HBc
antibody, HCV antibody
・
Coagulation tests: prothrombin time expressed as either prothrombin time (PT)
or international normalized ratio (INR) and partial thromboplastin time (PTT or
aPTT)
・
Urinalysis: specific gravity, protein, glucose, occult blood, and microscopic
examination if indicated
・
Pregnancy test: it will be carried out only for female subjects with child-bearing
potential (serum or urine).
5.3.3. Vital Signs and Physical Findings 
Body temperature (oral, axillary, core, temporal, or tympanic), blood pressure 
(systolic/diastolic), heart rate, and respiratory rate will be collected as vital signs. Vital 
signs will be measured at every visit with the subject in a sitting position at rest for at 
least 5 minutes. Systemic physical examination will be performed within 14 days before 
the date of randomization and at every study visit thereafter.  


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5.3.4. Weight and Height 
Weight (kg) will be measured at each visit and height (cm) will be measured only at the 
screening visit. 
5.3.5. Eastern Cooperative Oncology Group Performance Status  
ECOG Performance Status (refer to Appendix 1) will be assessed at every visit. 
5.3.6. ECG Monitoring 
A 12-lead ECG should be performed within 14 days before the date of randomization, at 
Day 1 of every cycle (before IP administration), at EOT visit and at the post-treatment 
follow-up visit. In addition, a 12-lead ECG should be performed approximately 4 hours 
after IP administration on Cycle 1 Day 1 and Cycle 1 Day 15. Additional ECG should be 
performed as clinically indicated. Any abnormal findings in ECG measurements with 
clinical significance should be reported as adverse events. 
To facilitate the safety analysis in section 8.3.7 of the ECG data, if approved by 
country and local regulatory authorities, duplicate copies (either digital or hard 
copies) of the ECG tracing and the evaluation report should be transferred to the 
Sponsor after de-identifying the subject information for further clinical evaluation of 
ECG data as per regulatory recommendations. The original ECG results will be kept 
on file at the site as source documentation. Handling of this information/data will be 
done in accordance with the applicable data protection laws. (US government CFR 
21 Part 11 for electronic records; US government Health Insurance Portability and 
Accountability Act (HIPPA), etc.)  
As the request for the ECG copies is during an amendment, it is typically necessary to 
either ensure that informed consent is obtained to facilitate submittal of these ECG 
copies to the sponsor (or sponsor representatives) or in the case where consent cannot 
be updated (i.e. subject has expired), appropriate local ethics committee approval is 
obtained to authorize the submittal of these ECG copies. 
5.3.7. Chest X-Ray 
A chest x-ray should be performed as clinically indicated. Any abnormal findings in chest 
x-ray measurements with clinical significance should be reported as adverse events.


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5.4. Exploratory Assessment 
5.4.1. Pharmacodynamic (PD) marker 
At baseline, all subjects will be tested for Single-Nucleotide Polymorphisms (SNPs) to 
identify genotypes associated with the response to therapy with VEGFR-2 inhibitor.  
Vascular Endothelial Growth Factor (VEGF) will be evaluated at; 
・ The 1st day of 1st cycle 
・ The 1st day of 2nd cycle and each cycle thereafter (prior to IP administration) 
・ End of Treatment visit 
In addition, plasma samples for sVEGFR-1, sVEGFR2 and sVEGFR3 will be taken.  
Guidelines for collection and handling of blood specimen and materials will be provided 
by the sponsor or sponsor’s designee. Each study site collects and ships the specimens 
to the central laboratory according to the guidelines provided. 
Genetic test will be conducted including the gene information that specifies the patient 
and will be used only for research purpose. Therefore, the results of genetic test will not 
be disclosed to the patient, patient’s family, investigators, or other third parties and will 
not be recorded in the patient’s medical record.   
In Japan, if the patient is under 20 years old and the patient or legal guardian withdraws 
consent, the collection and sampling of blood sample will be stopped.  However, the 
information and blood samples already collected and sampled can be used to evaluate 
the result of the clinical trial. 
5.4.2. Biological Sample Storage 
The sponsor may wish to analyze blood samples in the future for the research purpose. 
Blood samples will be tested and stored for up to 10 years after the end of the study and 
then destroyed, unless other time limitations are required by local regulations or ethical 
requirements. Samples should be frozen at site and will be shipped to the sponsor or its 
designee during or at the end of the study as requested by the sponsor. 
5.4.3. Tumor Biopsy 
The sponsor may wish to analyze tumor biopsy samples in the future for the research 
purpose. Tumor biopsy (primary or metastatic tumor) will be collected whenever possible 
during the treatment period.  


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Tumor samples remaining after analysis will be stored for up to 10 years after the end of 
the study and then destroyed, unless other time limitations are required by local 
regulations or ethical requirements. Tumor tissue samples should be fixed by formalin at 
site and will be shipped to the sponsor or its designee during or at the end of the study 
as requested by the sponsor. 
Testing of biologic and/or tumor tissue samples may include but is not limited to the 
following tests; 
・ Growth factors; EGFR, VEGFR, HER2, c-MET  
・ Cytokines  
・ Cell cycle regulators, apoptosis-associated factors 
・ miRNAs; Let-7g, miR-433, miR-214, miR-21 
・ Epigenetic alterations, Genetic polymorphisms 
5.4.4. Pharmacokinetics 
Pharmacokinetic parameters (Cmax, Tmax, AUC, half-life, etc.) will be evaluated for 
apatinib. Blood samples for determination of plasma PK profiles of apatinib will be 
collected during the study per the time table below. The allowed time window for sampling 
is ± 10 minutes. 
Time Point 
Sample Number 
Time (h) 
Cycle 1/Day 1 
1 
2 
Predose 
3–4 h postdose (Tmax) 
Cycle 1/Day 15 
3 
4 
5 
6 (from 20±5% of patients) 
Predose on Day 15 
0.5–1 h postdose 
3–4 h postdose (Tmax) 
8–12 h postdose 
Cycle 2/Day 1 –  
Cycle 9/Day 1* 
7–14* 
Predose only (trough) 
* or until drug discontinuation or study completion 
For PK sample for each pharmacokinetic evaluation, a total of 5~10 mL of blood will be 
collected at each time point. Collection, handling and storage of blood samples for 
determination of plasma PK profiles of apatinib will be explained in the study instructional 
manual. 


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6. 
CRITERIA FOR STUDY DISCONTINUATION OR SUBJECT WITHDRAWAL 
6.1. Early Termination of the Study 
The study may be terminated at any time by the sponsor for any reason. Some reasons 
may be due to new safety information, non-compliance issues, or judgment of study 
futility. In this event, the sponsor will inform the study Investigators, investigational sites, 
and all regulatory authorities. The extension period of the study may be terminated by 
the sponsor for any reason.  
6.2. Criteria for Treatment Discontinuation 
Subjects may voluntarily withdraw their consent from the study or the investigator may 
terminate a subject's participation if the investigator judges that the subject can no longer 
fully comply with the study requirements or if any of the study procedures are deemed 
potentially harmful to the subject. 
If any of the following criteria is met during the treatment period, the study treatment will 
be discontinued.  
1. Subject withdraws his/her consent. 
2. The development of disease progression is confirmed according to the RECIST 
guideline (version 1.1) that makes it inappropriate to continue with study 
treatment according to the investigator’s discretion or consent for continued 
treatment beyond RECIST confirmed disease progression is not obtained. (see 
Section 6.3) 
3. Clinical symptoms determined to be due to disease progression that makes it 
inappropriate to continue with study treatment according to the investigator’s 
discretion or consent for continued treatment beyond clinical symptoms that are 
determined to be due to disease progression is not obtained. (see Section 6.3) 
4. Onset of CTCAE grade ≥ 3 hypertension for which a causal relationship to the 
investigational product cannot be ruled out. (However, the judgment on whether 
or not to continue the treatment will be made by the investigator.) 
5. Not having received a dose of the investigational product within the past 
consecutive 3 weeks for specific reasons, such as the onset of a treatment 
related adverse event.  
6. Treatment with prohibited concomitant medication of sufficient dose and duration 
to confound the study results or to make continuation or restarting of treatment 
within 3 weeks unsafe for the patient. 


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7. Intolerable toxicity even after 2 dose reductions. 
8. Confirmed positive pregnancy test. 
9. The subject is lost to follow-up. 
10. The subject is dead. 
11. The investigator determines that continuation of study treatment is not 
appropriate. 
6.3. Treatment continuation after disease progression 
Patients who will be treated beyond disease progression must review and sign a 
supplemental informed consent form before continuing on study drug. In addition, the 
following activity must be performed and the investigator must provide documentation of 
their opinion with supporting laboratory evaluation data that: 
• The patient demonstrates investigator-assessed potential for clinical benefit and 
does not have rapid disease progression. 
• It is safe to continue study drug and the patient, by evidence of signing consent, is 
tolerant of any continuing adverse events. 
• ECOG performance status of 0 or 1 or stable ECOG performance status of 2 with 
no signs of rapid deterioration (ECOG status of 2 for past three months or more 
where the investigator feels that the deterioration of ECOG performance status from 
baseline at study entry is not indicative of potential to have serious adverse events 
within at least 30 days from beginning of continuation study treatment). 
• The patient has a life expectancy of more than 30 days. 
• Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (e.g., CNS metastases). 
• A radiographic assessment/scan should be performed approximately 8 weeks (±7 
days), 
or 
earlier 
if 
the 
patient 
is 
exhibiting 
symptoms 
that 
may 
indicate continued progression, after initial Investigator-assessed progression to 
determine whether there has been a decrease in the tumor size or continued 
progressive disease. The assessment of clinical benefit should be balanced by 
clinical judgment as to whether the patient is clinically deteriorating and unlikely to 
receive any benefit from continued treatment with study therapy. 
For the patients who continue receive study therapy beyond progression, further 
progression is defined as an additional 15% increase in tumor burden from time of initial 
progression. This includes an increase in the sum of diameters of all target lesions and/or 
the diameters of new measurable lesions compared to the time of initial progression or 


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rapid deterioration in the performance status. Study treatment should be discontinued 
permanently upon documentation of further progression. 
Laboratory tests will continue with other study evaluations as described in the 
subsequent cycle study schedule to adequately ensure subject safety and further 
evaluations to ensure the subjects safety and continued benefit may be performed at the 
investigator’s discretion.  
After the decision to end study treatment permanently, an end of treatment (EOT) 
examination will be performed (at completion/discontinuation) and the subject will 
proceed to the post-treatment follow-up and survival follow-up. However, subjects in 
either treatment group will be withdrawn from the study if they meet any of the following 
criteria:  
1. Subject withdraws his/her consent on the follow-up period. 
2. Subject is lost to follow-up. 
Post-treatment follow-up can be carried out before withdrawal if the subject agrees to it. 
Data that have already been collected on withdrawn subjects will be retained and used 
for analysis but no new data will be collected after withdrawal. When subjects withdraw 
from the study, they will be asked whether the study center can continue to contact them 
or family members for survival status only. If this consent is withdrawn, publicly 
accessible records may be used for documentation of death. 
6.4. Handling Early Withdrawals 
In any case of early withdrawal from the study, the date and reason should be recorded 
in the subject’s eCRF and source documents. If the reason for early withdrawal was an 
AE, the outcome of the AE should be reported according to Section 7.2 and 7.3. All 
subjects who have received at least one dose of IP should complete all tests scheduled 
for the EOT wherever possible.  
Screening numbers and randomization numbers, once allocated, cannot be reused. Any 
new subject will always receive new subject numbers (screening number and 
randomization number). 
6.5. Medical Care After the End of Treatment for Withdrawn Subjects  
Subjects for whom the study is terminated or suspended or who are withdrawn from the 
study due to disease progression or intolerable toxicity will be provided with or directed 


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to medical care and treatment, as deemed best for the study by the investigator.  
After being withdrawn from the treatment, subjects will be monitored for survival status 
(See Section 3.4.5 and 3.4.6). 
7. 
SAFETY REPORT 
7.1. Definition 
7.1.1. Adverse Event (AE) 
An adverse event (AE) is defined as any untoward medical occurrence in a patient who 
has signed the informed consent form. The event need not necessarily have a causal 
relationship with the investigational product.  
Examples of AEs include but are not limited to:  
• 
Abnormal test findings that are clinically significant. 
• 
Clinically significant symptoms and signs. 
• 
Clinically significant changes in physical examination findings. 
• 
Signs or symptoms resulting from drug overdose, misuse, or withdrawal. 
Disease progression assessed by measurement of malignant lesions on imaging studies 
should not be reported as an AE. Treatment-emergent adverse event (TEAE) is defined 
as an AE that has a start date on or after the first dose of the investigational product until 
the final subject visit or, if it has a start date before the date of the first dose of study drug, 
increase in severity on or after the date of the first dose of investigational product until 
the final subject visit. The safety analysis will be carried out with TEAE. Adverse events 
collected during screening period (from the time of informed consent until right before 
the first administration of the investigational product) will be separately listed and 
reviewed. 
7.1.2. Serious Adverse Event (SAE) 
A serious adverse event (SAE) is any untoward medical occurrence that: 
• Results in death. 
• Is life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization.1) 


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•
Results in persistent or significant disability/incapacity.
•
Results in a congenital anomaly/birth defect.
1) This does not include any of the following:
•
Hospitalization or prolongation of existing hospitalization for a procedure (e.g.,
surgery, examination) that had been planned before the study
•
Hospitalization or prolongation of existing hospitalization for follow-up
observation of an already healed or improved condition
•
Hospitalization or prolongation of existing hospitalization for examination or
education
•
Hospitalization or prolongation of existing hospitalization for non-medical reason
(e.g., temporary absence of a family member)
•
Admission to a hospice facility, nursing care facility, or rehabilitation facility
7.2. Assessment Criteria 
7.2.1. Severity Evaluation 
The severity of adverse events will be assessed according to the Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.03 issued by National Cancer Institute 
(NCI) [39]. Adverse events which cannot be graded by the NCI-CTCAE version 4.03 will 
be classified as follows based on the maximum intensity (See Table 6). 
Table 6. Definition of Severity Grade of Adverse Events 
Grade 
Description of Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
2 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL* 
3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL** 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death Related to AE 
ADL, activity of daily living 
* Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the
telephone, managing money, etc.
** Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking


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medications, and not bedridden. 
7.2.2. Causality Evaluation 
The investigator should assess the causality of AEs and record the causal relationship, 
along with the ground that such an assessment is made on, in the eCRF. In addition, if 
the investigator determines an SAE is associated with study procedures, the investigator 
must record this causal relationship in the source documents and eCRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable. 
The causality of AEs and SAEs to study treatment should be determined using the 
following definitions as guidelines[40]. AEs with at least possible relationship and AEs with 
conditional and unassessable relationship are considered causally related to the study 
treatment. 
Table 7. Definition of Causality Assessment Criteria 
Term 
Assessment Criteria 
Certain 
• 
Event or laboratory test abnormality, with plausible time 
relationship to drug intake 
• 
Cannot be explained by disease or other drugs 
• 
Response to withdrawal plausible (pharmacologically, 
pathologically) 
• 
Event definitive pharmacologically or phenomenologically  
(i.e. an objective and specific medical disorder or a 
recognized pharmacological phenomenon) 
• 
Rechallenge satisfactory, if necessary 
Probable 
/Likely 
• 
Event or laboratory test abnormality, with reasonable time 
relationship to drug intake 
• 
Unlikely to be attributed to disease or other drugs 
• 
Response to withdrawal clinically reasonable 
• 
Rechallenge not required 
Possible 
• 
Event or laboratory test abnormality, with reasonable time 
relationship to drug intake 
• 
Could also be explained by disease or other drugs 
• 
Information on drug withdrawal may be lacking or unclear 
Unlikely 
• 
Event or laboratory test abnormality, with a time to drug 
intake that makes a relationship improbable (but not 
impossible) 


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Term 
Assessment Criteria 
• 
Disease or other drugs provide plausible explanations 
Conditional 
/Unclassified 
• 
Event or laboratory test abnormality 
• 
More data for proper assessment needed, or 
• 
Additional data under examination 
Unassessable 
/Unclassifiable 
• 
Report suggesting an adverse reaction 
• 
Cannot be judged because information is insufficient or 
contradictory 
• 
Data cannot be supplemented or verified 
 
7.3. Serious Adverse Event Reporting 
All SAE must be reported to the sponsor without delay from the time of investigator’s 
acknowledgement on the event, whether or not the SAE has a causal relationship to the 
investigational product. The investigator is responsible for informing the IRB/IEC of the 
SAE, as per local requirements. If a non-serious AE becomes serious, this and other 
relevant follow-up information must also be provided to the sponsor without delay, 
whether or not it has a causal relationship to the investigational product. All SAE will be 
recorded in the eCRF. The site should fax or e-mail the SAE Report Form within 24 hours 
from the time of discovery of the SAE with as much information as possible to the sponsor.  
During the extension period, new SAE should only be reported for subjects who are 
taking apatinib and have not completed Post-treatment Follow-up visit.   
The SAE form should have the following information: 
• Study title, protocol number, and sponsor name  
• Reporter’s name, investigator’s name, and contact number  
• Site name, site number, and subject’s identification code (subject’s study 
number) 
• SAE name, start and stop dates of the event  
• Causality to the investigational product, action taken in regard to investigational 
product, and treatments (any procedures or medications given) to manage the 
SAE, and the outcome of the event 
If the site obtains additional information regarding the event after submitting the Initial 
SAE Report Form, the site should prepare a Follow-up SAE Report Form and send it to 


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the sponsor through fax or e-mail. Only new or corrected information should be added to 
the Follow-up SAE Report Form, along with identifying information regarding the subject 
and the event. All AE other than SAE, will be reported on the AE page of the eCRF. 
The contact information for SAE reporting is as follows; 
Main address: 
• 
Name: LSK Global PS, PV department 
• 
Email: 
 
• 
Fax Number: 
 
Sub address for Japan patients only (cc): 
• 
Name: Department of Pharmacovigilance, Mediscience Planning Inc. 
• 
Email: 
 
• 
Fax: 
 
7.4. Exposure During Pregnancy 
Apatinib is not intended for use during pregnancy or lactation. Reproductive studies in 
animals have not been performed to date with Apatinib and there have been no data 
regarding the exposure during human pregnancy. Angiogenesis is critical to fetal 
development and the inhibition of angiogenesis following administration of Apatinib is 
likely to result in adverse effects on pregnancy. If a potential subject is a female of 
childbearing potential, a negative pregnancy test (urine or serum) must be obtained 
before she can be enrolled as a subject. A female subject or a male subject’s female 
sexual partner must use effective contraception consistently and correctly during the 
study and for at least 28 days after they have stopped taking the investigational products. 
It is not known whether Apatinib is secreted in human milk. Because drugs are commonly 
excreted in human milk and because of the potential for serious adverse reactions in 
nursing infants, a female subject or a male subject’s female sexual partner must not 
breastfeed while receiving the investigational products during this study and for at least 
28 days after they have stopped taking the investigational products. Nonetheless, if any 
pregnancy or breastfeeding occurs to a female subject or a male subject’s female sexual 
partners, during the study period and for at least 28 days after the end of treatment, the 


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event must be reported to the sponsor without delay. In addition, the follow-up survey will 
be conducted when pregnancy occurs and the outcome of the pregnancy must be 
reported to the sponsor using the Pregnancy Report Form. Assessment of the event will 
be conducted by the investigator with consultation from sponsor and actions may be 
taken on a case by case basis. Potential action may include unblinding the involved 
subject’s treatment assignment following unblinding procedure and discontinuing study 
treatment. Subsequent reporting of such event and the following action will be submitted 
to relevant ethic committee and regulatory in accordance to local regulation and standard 
procedures. 
Please send the Pregnancy Report Form for reporting exposure during pregnancy or 
breastfeeding to the following e-mail, or fax if not available; 
Main address: 
• 
Name: LSK Global PS, PV department 
• 
Email: 
 
• 
Fax Number: 
 
Sub address for Japan patients only (cc): 
• 
Name: Department of Pharmacovigilance, Mediscience Planning Inc. 
• 
Email: 
 
• 
Fax: 
 
8. 
STATISTICAL METHODS 
8.1. Sample Size Calculation and Rationale 
 
 
 
  
 
 
 
 


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8.2. Evaluation Criteria and Methods 
8.2.1. Primary Efficacy Endpoint 
Overall Survival (OS): Time from randomization to death. Subjects alive or lost to follow-
up at the end of study (EOS) are censored. 
For the purposes of analysis, the end of study (EOS) is defined as a designated date 
soon after the 325th death event has been confirmed. All data prior to this date will be 
used for efficacy and safety analysis.  
8.2.2. Secondary Efficacy Endpoints 
・ Progression Free Survival (PFS): Time from randomization to either radiological 
progression or death. Subjects alive and free of progression at the end of study (EOS) 
are censored. 
・ Objective Response Rate (ORR): Percentage of subjects with a Best Overall 
Response of Complete Response (CR) or Partial Response (PR). 
・ Disease Control Rate (DCR): Proportion of subjects with a Best Overall Response of 
complete or partial response, or stable disease. 
・ Global health status/quality of life score according to European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC 
QLQ-C30) and EORTC QLQ-STO22 
・ Each dimension response according to EuroQol 5-Dimension 5-Level (EQ-5D-5L) 
Questionnaire 
8.2.3. Safety Endpoints 
Safety analyses will be based on the Safety Set and the assessments will be made with 
regard to AEs, abnormalities in laboratory tests, ECOG performance, 12-Lead ECG, 
physical examination and vital signs, etc.   
8.2.4. Exploratory Endpoints 
The relationship between efficacy measure and pharmacodynamic parameters (VEGF, 
sVEGFR-1, sVEGFR2 and sVEGFR3) will be explored. In addition to this, 
pharmacokinetic parameters (Cmax, Tmax, AUC, half-life, etc.) will be evaluated for apatinib.  


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8.3. Statistical Analysis 
LSK Global Pharma Services Co., Ltd. will perform statistical analysis. Outlines of 
analysis are described below, and details of analysis methods will be provided in the 
Statistical Analysis Plan (SAP). 
Version 1.0 of the SAP will be finalized before EOS.   
8.3.1. General Principles of Data Analysis 
Statistical analyses will be performed using SAS software (SAS Institute, SAS Circle, 
Cary, NC, USA) and all statistical tests, unless otherwise specified, will be two-sided at 
a 5% significance level.   
8.3.2. Analysis Population 
Data obtained from subjects in this study will be analyzed by intent to treat (ITT) set, 
safety set, full analysis set (FAS) or per protocol set (PPS). 
・ ITT set consists of data from all subjects who are randomized. In the ITT set, subjects 
will be included in the group to which they were randomized. The analysis for primary 
endpoint, OS and the secondary endpoints of PFS and ORR will be conducted in the 
ITT set. 
・ Safety set consists of data from all subjects who received at least one dose of Apatinib 
or placebo. In the Safety set, subjects will be included in the group based on the 
treatment that was received. Safety data will be analyzed by safety set. 
・ FAS consists of data from all subjects who received at least one dose of the Apatinib 
or placebo. The FAS will be used for all efficacy analyses. 
・ PPS consists of data from subjects included in FAS who completed the study per 
protocol without major violation such as inclusion/exclusion criteria violation and use 
of prohibited concomitant medication during the study. The PPS will be used for all 
efficacy analyses. 
8.3.3. Demographic and Baseline Characteristics 
Demographic and Baseline Characteristics will be summarized by descriptive statistics 
by treatment group for the ITT set. The number of subjects, mean, standard deviation, 
minimum and maximum will be presented for continuous data, and the number and 
percentage (%) of subjects will be presented for categorical data.  
8.3.4. Primary Efficacy Analysis 
The primary efficacy analysis will be conducted using the ITT set. 


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Overall Survival (OS): Time from randomization to death. Subjects alive or lost to follow-
up at the end of study (EOS) are censored. 
The comparison of OS between the two treatment groups will be performed with a 
stratified logrank test at the two-sided alpha=0.05 level of significance. 
In order to estimate the hazard ratio, a Cox proportional hazards regression model will 
be fitted with treatment group and the randomization stratification variables as factors 
[Geographic region (Asia vs. North America/Europe), Disease measurability 
(measurable vs. nonmeasurable), Prior ramucirumab treatment (Yes vs. No), and 
Treatment therapy line (3rd vs. ≥4th)].  
Kaplan-Meier estimates will be calculated for each treatment group to construct the 
survival curve. The median overall survival and its 95% CI will also be presented. 
8.3.5. Key Secondary Efficacy Analyses 
If the primary analysis of OS is statistically significant, then the key secondary endpoints 
of PFS and ORR will be analyzed using a fixed-sequence testing procedure.  These 
analyses will be conducted using the ITT set. First, PFS will be analyzed using the same 
statistical methods that are used in the primary efficacy analysis of OS. If the analysis of 
PFS is statistically significant, then ORR will be analyzed using the Cochran-Mantel-
Haenszel test stratified by the randomization stratification factors.  However, if a prior 
test is not statistically significant, then the subsequent analyses will be exploratory rather 
than confirmatory. 
 
・ Progression Free Survival (PFS): Time from randomization to either radiological 
progression (determined by the central imaging analysis facility) or death from 
any cause. Subjects alive and free of progression at the end of study (EOS) are 
censored. Options for PFS assessment for each situation are as shown in Table 
7, and censoring date will be based on the last tumor assessment date. 
・ Objective Response Rate (ORR): Percentage of subjects with a Best Overall 
Response (determined by the central imaging analysis facility) of Complete 
Response (CR) or Partial Response (PR). 
 
For PFS, the same statistical method that is used in primary efficacy analysis (OS) will 
be performed. 
For the ORR (CR or PR), the frequency and percentage of subjects will be calculated 


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and the 95% confidence interval will be provided. Response in both treatment groups 
will be compared with the Cochran-Mantel-Haenszel test stratified by the randomization 
stratification factors. 
Table 8. PFS censoring rule (applies only disease progression documented by 
imaging data) 
Situation 
Disease progression  
or censoring date 
Outcome 
No baseline tumor 
assessment data 
Time of enrollment 
Censored 
Progression documented 
between scheduled visits 
Whichever comes first: 
• 
Date of tumor assessment 
indicating new lesion (disease 
progression based on new 
lesion) or 
• 
Date of last tumor assessment 
measuring lesions (disease 
progression based on the 
increase of total sum of lesions)  
Progressed 
No progression 
Date of last tumor assessment of the 
measured lesions 
Censored 
Treatment discontinuation 
due to disease progression 
without documented 
progression 
Date of last tumor assessment of the 
measured lesions 
Censored 
Treatment discontinuation 
due to toxicity or other 
reasons 
Date of last tumor assessment of the 
measured lesions 
Censored 
Initiation of new anticancer 
therapy 
Date of last tumor assessment of the 
measured lesions 
Censored 
Death before the first 
disease progression 
assessment 
Date of death 
Progressed 
Death between 
appropriate assessment 
Date of death 
Progressed 


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Situation 
Disease progression  
or censoring date 
Outcome 
visits 
Death or disease 
progression after two or 
more missing visits 
Date of last tumor assessment of the 
measured lesions 
Censored 
 
8.3.6. Other Secondary Efficacy Analyses 
The primary and key secondary endpoints will also be analyzed using the FAS and PP 
sets. All other secondary efficacy endpoints will be analyzed in the ITT, FAS, and PP sets 
using two-sided test at the alpha=0.05 level of significance, with no adjustments for 
multiplicity.  
 
・ Disease Control Rate (DCR): Proportion of subjects with a Best Overall 
Response (determined by the central imaging analysis facility) of complete or 
partial response, or stable disease.  
・ Global health status/quality of life score according to European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 
(EORTC QLQ-C30) and EORTC QLQ-STO22. 
・ Each dimension response according to EuroQol 5-Dimension 5-Level (EQ-5D-
5L) Questionnaire. 
For the DCR, the same statistical method that is used in ORR will be performed. 
The European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 (EORTC QLQ-C30), EORTC QLQ-STO22 and EuroQol 5-
Dimension 5-Level (EQ-5D-5L) Questionnaire will be analyzed using analysis of 
covariance (ANCOVA) models with treatment group and the randomization stratification 
variables as factors, and the baseline value of the corresponding endpoint as a covariate. 
8.3.7. Safety Analysis 
Adverse event 
Summary and analysis of adverse events will be performed for treatment-emergent 
adverse events. Treatment-emergent adverse events are adverse events that were 
absent before the drug administration but occurred after the administration, or if present 
at baseline worsened in severity after drug administration. 


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For the occurrence of treatment-emergent adverse events, the occurrence of adverse 
drug reactions (ADR), and the occurrence of serious adverse events (SAE), the 
frequency and percentage will be presented. Treatment-emergent adverse events, ADR 
and SAE will be coded using System Organ Class (SOC) and Preferred Term (PT) based 
on MedDRA and the AE severity will be classified according to NCI-CTCAE. Also, the 
number of subjects, incidence rate and number of incidences will be presented for the 
coded adverse events. 
Other safety endpoints including laboratory test results and vital signs 
For the analysis of safety data, including laboratory values, vital signs, physical 
examination, 12-lead ECG and ECOG performance status, continuous variables will be 
summarized using descriptive statistics (mean, median, SD, minimum and maximum) 
and categorical variables will be summarized using numbers and percentages of 
subjects. If it is necessary, a normal/abnormal shift of the safety endpoint will be 
summarized. 
8.3.8. Exploratory Analysis 
The relationship between efficacy measures and pharmacodynamic parameters (VEGF, 
sVEGFR-1, sVEGFR2 and sVEGFR3) will be evaluated. Detailed methodology of 
statistical analysis for the exploratory variables will be described in the statistical analysis 
plan (SAP).  
In addition, detailed methodology of statistical analysis for pharmacokinetic parameters 
will be provided in an additional document described by the PK analysis facility. 
8.3.9. Extension Period Analysis 
Efficacy and safety data conducted during the extension period will be summarized 
descriptively. No formal statistical analyses will be conducted.  Additional details 
concerning the extension period analyses will be provided in a separate Extension Period 
Statistical Analysis Plan.   
8.4. Independent Data Monitoring Committee (IDMC) and Interim Analysis 
8.4.1. IDMC 
Independent data monitoring committee (IDMC) is composed of 3 members (2 clinicians 
and 1 statistician) who are fully independent of the entity conducting the trial. The IDMC 
should comply with IDMC charter in the ICH GCP guideline. 
The IDMC will convene when approximately 163 events are observed to review 


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unblinded results of the interim analysis. The IDMC can also convene when unexpected 
adverse drug reaction with a Grade 3 or more (based on NCI-CTCAE 4.03) are observed. 
The IDMC can also convene, if necessary, to ensure appropriate review of the Japan 
specific safety run-in. 
8.4.2. Interim Analysis 
An interim analysis will be conducted with collected clinical data when approximately 163 
(approximately 50% of the required 325 events) events are observed. All planned study 
procedures such as patient enrollment, treatment and follow-up visit should be performed 
regardless of the interim analysis. If it is necessary to change the timing of the interim 
analysis, in consultations with sponsor, the IDMC can change interim analysis time and 
its corresponding statistical criteria for early termination. 
The interim analysis will assess the primary efficacy endpoint. The IDMC will review the 
results of the interim analysis and recommend to the sponsor whether or not to terminate 
the trial for futility. Final decision regarding study termination will be made by the sponsor. 
The IDMC and statisticians involved in the interim analysis should keep the interim 
analysis result completely confidential. The results of the interim analysis should be kept 
unknown to all staff involved in the conduct of the trial. If early termination is decided, the 
IDMC delivers the interim analysis report to the sponsor after the official unblinding 
procedure. 
Early termination will be considered if the interim analysis is futile, that is when the 
calculated conditional power based on primary efficacy endpoint is less than 0.2. Early 
stopping for futility interim analysis does not inflate the Type-I error, thus Type I-error 
adjustment is not needed. 
9. 
QUALITY CONTROL AND QUALITY ASSUARANCE 
9.1. Monitoring 
During the study conduct, study monitors of the sponsor or designated personnel must 
be allowed to visit all study sites periodically to assess the data quality and study integrity 
and to ensure that the protocol and Good Clinical Practice (GCP) are being followed. 
The monitors may review source documents to confirm that the data recorded on eCRFs 
is accurate. The investigator and institution will allow monitors/auditors or its agents and 
appropriate regulatory authorities direct access to source documents to perform this 
source verification. 


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9.2. Audit and Inspection 
The sponsor or representative may conduct audits at the trial site(s). Audits will include, 
but are not limited to protocol compliance, drug supply, presence of required documents, 
the informed consent process, and comparison of eCRFs with source documents. The 
investigator agrees to participate with audits conducted at a reasonable time in a 
reasonable manner.  
Regulatory authorities worldwide may inspect the trial site during or after the trial. The 
investigator should contact the sponsor immediately if this occurs, and must fully 
cooperate with the inspections conducted at a reasonable time in a reasonable manner. 
10. ETHICS 
10.1. Institutional Review Board or Independent Ethics Committee 
Before initiating the study, the investigator is responsible for ensuring that the protocol 
including its amendments, ICF, patient recruitment procedures (e.g. advertisements), 
written information to be provided to the subjects, IB, available safety information, and 
information about payment and compensation available to subjects have been reviewed 
and approved by a relevant IEC/IRB. The IEC/IRB should be appropriately constituted 
and perform its functions in accordance with the principles of GCP and applicable local 
regulatory requirements.  
10.2. Ethical Conduct of the Study 
The study will be conducted in accordance with the relevant regulatory requirements, 
this protocol, and ethical principles that are consistent with the Good Clinical Practice 
(GCP) guideline developed by the International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The 
clinical trial will also be conducted in compliance with Declaration of Helsinki, protocol, 
Standard specified in the Section 3 in the Article 14 and the Section 2 in the Article 80 in 
Pharmaceutical Law, Notification 28 from MHLW dated March 27th, 1997 “Ordinance on 
the criteria for the implementation of clinical trials of the drug (GCP)”. In addition, 
investigational site personnel and CRO(s) will comply to their regional or country 
standard operating procedures and local regulatory and ethic requirements. Prior to 
initiation of the study, the investigator and the sponsor should obtain approval/favorable 
opinion from the IRB/IEC on this protocol and any further amendments, and the subject 
information and informed consent form.  


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Any suspected serious breaches must be immediately reported to the sponsor. A serious 
breach is a breach of the conditions and principles of GCP in connection with the study 
or the protocol, which is likely to affect, to a significant degree, the safety of the subjects 
or the scientific value of the study. 
Personnel involved in the study will be qualified by education, training, and experience 
to perform their respective tasks. 
10.3. Written Informed Consent 
The nature and purpose of the study should be fully explained to each patient. Written 
informed consent must be obtained from each patient prior to any study procedures 
being carried out. The Patient Information Sheet and Consent Form, advertisement flyer 
for recruitment, and any other documents to be handed out to the subjects should be 
reviewed and approved by the appropriate IRB/IEC prior to use.  
For UK subjects only:   
Each patient will be given a minimum of 24 hours to ask questions regarding the 
trial and review the informed consent form before signing.  
For all subjects: 
Only participants who understand the information in the Participant information 
Sheet and the Informed Consent Form will be allowed to take part in the trial. If 
during the course of the trial new information becomes available on the drug that 
is being studied, this information will be discussed with the participant and a 
decision will be made whether or not the participant wants to continue in the 
study. If the participant decides to continue in the study, he/she will be asked to 
sign an amended, REC approved patient information sheet and consent form. 
Extension period subjects: 
Subjects who are not taking study medication at the time of unblinding should be followed 
with their original consent in place for survival status. A separate informed consent will 
be required at the beginning of the extension period for each subject that is taking study 
medication at that time.  Placebo subjects should be consented to allow for continued 
survival reporting and best supportive care according to standard of care.  Apatinib 
subjects should be consented to allow for continued apatinib administration, best 


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supportive care, survival reporting and adverse event monitoring approximately every 
two weeks and tumor assessment at intervals based on standard of care intervals. 
10.4. Patient Data Protection 
All parties involved in the study will take utmost consideration to protect the privacy of 
subjects. Subject’s name, address, or any identifiable data will not be present on any 
sponsor documents, reports, publications, or in any other disclosures, except where 
required by law. Subject identification codes will be used in place of subject’s names to 
distinguish individuals on case report forms and in other data. Completed case report 
forms will not be used for purposes other than this study. In case of data transfer, the 
sponsor will maintain high standards of confidentiality and protection of subject’s 
personal data. 
10.5. Protection for Subjects After End of Study 
After EOS, all subjects will be provided with or directed to medical care and treatment, 
as deemed best for the study by the investigator.  
11. Collection and Documentation of Data 
11.1. Collection of Study Data 
For all subjects who provide written consent and are enrolled via the Interactive Web 
Response System (IWRS), the investigator (or designated personnel) will enter data into 
the electronic case report form (eCRF) of each subject after completion of each 
assessment procedure without delay. The data entered into the EDC system should be 
made timely, accurate and complete. The investigator or a person designated by the 
principal investigator will use the EDC system to enter the data into the eCRFs and to 
correct the data. Any data entries and corrections shall be tracked in an electronic audit 
trail of the EDC system that captures the history of changes, including user identifications 
of the persons who made corrections and the changes made. The investigator will 
confirm that all entries in the eCRF (including audit trails and query responses) are 
accurate and complete and ensure the accuracy and completeness by electronically 
signing the eCRF. Separate documents to guide the procedures for eCRF data entries, 
changes and corrections, and electronic signatures will be provided to the investigator. 
The investigator or designated personnel who is in charge of completing eCRF should 
receive appropriate training prior to use of eCRF or IWRS system and they should use 
the unique user account provided by the sponsor to access to this system. User accounts 


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must not be shared or reassigned to other individuals.  
The requirements for the EDC system will conform to the guidance on EDC stipulated in 
the Code of Federal Regulations (CFR) Title 21, Part 11 (Guidelines for the Electronic 
Data Handling and Management) and any applicable local regulation. 
End of Study and Extension Period Study Data 
The primary EDC system will be completed with safety data through to the designated 
End of Study date that is determined after the study team is aware of the 325th death 
event.  All data prior to this designated date will be made accurate and complete 
through normal monitoring and data cleaning practices prior to locking the primary 
database for analysis.  SAE (until 28 days after last dose of apatinib) and survival data 
will continue to be gathered within this primary EDC system until a supplemental 
extension period EDC system is made available to the investigators before or after 
locking of the primary EDC system database. Survival data may continue to be allowed 
into the primary data set for analysis after the designated EOS date and until unblinding 
has occurred. Any safety data after the designated EOS date should be entered in the 
extension period EDC system when it becomes available. 
11.2. Documentation of Study Results 
All original eCRF data captured in the EDC system and their copy reproduced accurately 
and completely from the original data will be saved in CDs or other storage media. A 
copy of the completed eCRF data for their subjects will be provided to each site at the 
end of the study. 
12. ADMINISTRATIVE INFORMATION 
12.1. Patient Injury and Insurance 
In general, if a patient is injured as a direct result of the investigational products, the 
sponsor or its contracted insurance company will pay for reasonable and necessary 
medical treatment for the injury. If laws or regulations of the locality in which the study is 
taking place require additional payment of expenses, the sponsor should comply with 
such laws or regulations. Where applicable, the sponsor will arrange for specific 
insurance coverage. If health damage occurred in patient participating the clinical trial 
due to the willful or gross negligence of investigator’s site, indemnification will be 
discussed based on the contract with the site. The indemnification for the health damage 


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and the payment to patients will be described in the ICF. 
12.2. Confidentiality 
The names of all subjects will be kept confidential. In the evaluation and documentation 
of the study, all subjects will be identified by the numbers assigned to them. Subject 
numbers will be used in the CRFs. Source documents may or may not be de-identified 
for inspection/monitoring, however, any documents (pathology reports, radiology reports, 
etc.) that are provided for the sponsors record keeping that have the subject’s name on 
them or other subject identification will only be provided to the sponsor after the subject’s 
name or other identification is redacted and appropriate study identification (i.e., subject 
number) is attached. The subjects should be informed that all study materials will be kept 
in strict confidence. The signed ICFs will be retained by the site personnel responsible 
for storing records after the EOS. By signing the protocol, the principal investigator 
agrees to properly obtain informed consent from the subjects participating in the study 
and to permit inspection as requested. The subjects shall be informed that the sponsor’s 
representative, IRBs or other governments including Korea, U.S and EU, etc. may audit 
the subject’s medical records for verification of collected information and any information 
accessed during the audit will be handled strictly confidential. 
12.3. Record Retention 
Essential documents should be retained until 2 years, 3 years (for Korean sites), or as 
long as required by local law following the date a marketing application is approved for 
the drug for the indication for which it is being investigated; or, if no application is to be 
filed or if the application is not approved for such indication, until 2 years, 3 years (for 
Korean sites), or as long as required by local law after the investigation is discontinued 
and relevant regulatory agency is notified. At the end of such period, the investigator 
should notify the sponsor in writing of its intent to destroy all such material; however, 
these essential documents must not be destroyed or transferred to another location 
without written notification of the sponsor. The sponsor is responsible for informing the 
investigator or institution when these documents no longer need to be retained. If the 
sponsor wants these essential documents to be retained for longer than such period, 
such materials should be retained at the sponsor’s expense.  
12.4. Publication Policy 
Any data from the study conducted according to this protocol are the property of the 
sponsor. Publication of the study data requires prior written approval of the sponsor and 


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will be carried out in collaboration between the investigators and the sponsor. 
 
 


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13. REFERENCES 
 
1  Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulen J, Jemal A. Global cancer 
statistics, 2012. CA Cancer J Clin. 2015;65:87-108. 
2  Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and 
prevalence across five continents: defining priorities to reduce cancer disparties in 
different geographic regions of the world. J Clin Oncol. 2006;24(14):2137-50. 
3  Kang YK, Yoon DH, Ryoo BY, Ryu MH. Recent advances in Chemotherapy for 
Advanced Gastric Cancer. Asia-Pacific J Oncol & Hematol 2010; 2:67-74. 
4  Wagner AD, Grothe W, Haerting J, Kleber G, Grothey A, Fleig WE. Chemotherapy in 
advanced gastric cancer: a systematic review and meta-analysis based on 
aggregate data. J Clin Oncol. 2006;24(18):2903-9. 
5  Wagner AD, Unverzagt S, Grothe W, et al. Chemotherapy for advanced gastric 
cancer. Cochrane Database Syst Rev. 2010;17(3):CD004064. 
6  Wesolowski R, Lee C, Kim R. Is there a role for second-line chemotherapy in 
advanced gastric cancer. Lancet Oncol. 2009; 10: 903-912. 
7  Jung JT. Chemotherapy of advanced gastric cancer. The Korean Journal of 
Helicobacter and Upper Gastrointestinal Research. 2013;13(3):142-6. 
8  Cunningham D, Starling N, Rao S, et al. Upper Gastrointestinal Clinical Studies 
Group of the National Cancer Research Institute of the United Kingdom. 
Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 
2008;358(1):36-46. 
9  Park YH, Lee JL, Ryoo BY, et al. Capecitabine in combination with Oxaliplatin 
(XELOX) as a first-line therapy for advanced gastric cancer. Cancer Chemother 
Pharmacol. 2008;61(4):623-9. 
10  Kim TH, Park SR, Ryu KW, et al. Phase 3 trial of postoperative chemotherapy alone 
versus chemoradiation therapy in stage III-IV gastric cancer treated with R0 
gastrectomy and D2 lymph node dissection. Int J Radiat Oncol Biol Phys. 
2012;84(5):e585-92. 
11  Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus 
surgery alone for resectable gastroesophageal cancer. N Engl J Med. 
2006;355(1):11-20. 
12  Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery 
compared with surgery alone for adenocarcinoma of the stomach or 
gastroesophageal junction. N Engl J Med. 2001;345(10):725-30. 
13  Zang DY, A New Option for Advanced Gastric Cancer-Docetaxel and Novel Oral 
Fluoropyrimidine Combination Chemotherapy. J Korean Med Assoc 2007; 50(6): 
556-60. 
14  Cheung DY, Kim JK. Molecularly Targeted Therapy for Stomach Cancer. Korean 
Journal of Gastroenterology. 2013;61(3):117-27. 
15  Bang YJ, Van Cutsem E, Feyereislova A, et al. ToGA Trial Investigators. 
Trastuzumab in combination with chemotherapy versus chemotherapy alone for 
treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer 
(ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 
2010;376(9242):687-97. 
16  Ferry DR, Anderson M, Beddard K, et al. A phase II study of gefitinib monotherapy in 
advanced esophageal adenocarcinoma: evidence of gene expression, cellular, and 
clinical response. Clin Cancer Res. 2007;13:5869-5875. 
 
                                               


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17  Dragovich T, McCoy S, Fenoglio-Preiser CM, et al. Phase II trial of erlotinib in 
gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J Clin 
Oncol. 2006; 24: 4922-7. 
18  Lordick F, Kang YK, Chung HC, et al. Capecitabine and cisplatin with or without 
cetuximab for patients with previously untreated advanced gastric cancer 
(EXPAND): a randomised, open-label phase 3 trial. Lancet. 2013;14:490-99. 
19  Waddell T, Chau L, Cunningham D, et al. Epirubicin, oxalipaltin, and capecitabine 
with or without panitumumab for patients with previously untreated advanced 
oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet 
Oncol. 2013;14:481-89. 
20  FDA.gov press release for ramucirumab approval, accessed April 22, 2014. 21  
Ramucirumab gastric cancer regimen & reference. 
22  Fuchs CS, Tomasek J, et al. Ramucirumab monotherapy for previously treated 
advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an 
international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 
2014 Jan 4; 383 (9911):31-9. 
23  Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo 
plus paclitaxel in patients with previously treated advaned gastric or gastro-
oesophageal junction adenocarcinoma (RAINBOW): a double-bline, randomised 
phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224-35. 
24  Ohtsu A, Shah MA, Cutsem EV, et al., Bevacizumab in combination with 
chemotherapy as first-line therapy in advanced gastric cancer: a ranomized, double-
blind, placebo-controlled phase III study. J Clin Oncol 2011;29(30):3968-76. 
25  Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, et al. Sorafenib in 
advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356: 125–13. 
26  Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, et al. Sorafenib in advanced 
hepatocellular carcinoma. N Engl J Med. 2008;359: 378–390. 
27  Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, 
McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, 
Bello CL, Huang X, Baum CM, Casali PG. Efficacy and safety of sunitinib in patients 
with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised 
controlled trial. Lancet. 2006;368:1329–1338.  
28  Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard 
S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA . Sunitinib 
versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007; 
356:115–124. 
29  Bang YJ, et al. Phase II Study of sunitinib as second-line treatment for advanced 
gastric cancer. Invest New Drugs. 2011;29:1449-58. 
30  Jin Li, Xinmin Zhao, et al. Safety and pharmacokinetics of novel selective vascular 
endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced 
malignancies. BMC Cancer. 2010;50:529. 
31  Jin Li, Qin S, Xu J, et al. Apatinib for chemotherapy-refractory advanced metastatic 
gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II 
trial. J Clin Oncol. 2013 Sep 10;31 (26):3219-25. 
32  Li J, Qin S, Xu J, et al. Randomized, double-blind, placebo-controlled Phase III trial 
of Apatinib in patients with chemotherapy-refractory advanced or metastatic 
adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol. 
2016;Feb 16. pii: JCO635995. 
33  EORTC QLQ-C30 Scoring Manual, EORTC Quality of Life Group, 2001. 


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34  Guidelines for assessing Quality of Life in EORTC clinical trials, EORTC Quality of 
Life, 2002. 
35 Lim HS, Cho GS, Park YH, Kim SK. Comparison of quality of life and nutritional 
status in gastric cancer patients undergoing gastrectomies. Clin Nutr Res. 
2015;4:153-9. 
36 Yun YH1, Park YS, Lee ES, et al., Validation of the Korean version of the EORTC 
QLQ-C30, Qual Life Res. 2004 May;13(4):863-8. 
37 Janssen MF1, Pickard AS, Golicki D, et al., Measurement properties of the EQ-5D-
5L compared to the EQ-5D-3L across eight patient groups: a multi-country study, 
Qual Life Res. 2013 Sep;22(7):1717-27. 
38 Kim SH, Hwang JS, Kim TW, et al., Validity and reliability of the EQ-5D for cancer 
patients in Korea, Support Care Cancer. 2012 Dec;20(12):3155-60. 
39 NCI CTCAE version 4.03.http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf. 
40 The use of the WHO-UMC system for standardised case causality assessment. 
http://www.who-umc.org/Graphics/26649.pdf. The Uppsala monitoring centre. 


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14. APPENDICES
Appendix 1: Eastern Cooperative Oncology Group (ECOG) Performance Status 
ECOG Grade 
Description 
0 
Fully active, able to carry on all pre-disease activities without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature (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. 


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Appendix 2: Tumor Response Criteria 
Tumor assessment will be performed based on the revised RECIST guideline (version 1.1)  
[Reference: Eisenhauer EA, Therasse P, Bogaerts J, et al., New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1), European Journal of Cancer 2009;45:228-247] 
 
1. Baseline assessment 
The baseline tumor lesions assessed within 14 days before randomization will be categorized 
as measurable lesions (lesions that can be accurately measured in at least one dimension as 
≥10 mm) or as non-measurable lesions (all other lesions, including lesions <10mm in longest 
diameter, infiltrating type of GC, and truly non-measurable lesions). Specific criteria for 
determination for measurability will be provided in a separate imaging guideline.  
All measurable lesions should be identified as target lesions, and should be evaluated by 
measurement of the sum of the longest diameters of measurable and viable lesions. 
 
2. Definitions 
Measurable lesions: must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of; 
・ 10 mm by CT/MRI scan (CT/MRI scan slice thickness no greater than 5 mm) 
・ 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
・ 20 mm by chest X-ray 
 
Non-measurable lesions: All other lesions, including small lesions (longest diameter <10mm 
or pathological lymph nodes with ≥ 10 to < 15 mm short axis), as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin 
or lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques 
 
Target lesions: All measurable lesions up to a maximum of five lesions in total and two lesions 
per organ with the greatest size (a long axis for non-nodal lesions and a short axis for nodal 
lesions) should be identified as target lesions. Target lesions should be representative of all 
involved organs and in addition be those that lend themselves to reproducible repeated 
measurements (with large lesions that are difficult to measure avoided). 
 
Non-target lesions: All lesions not selected as target lesions will be handled as non-target 
lesions, regardless of whether measurement is possible. Multiple non-target lesions in the 
same organ or site may be recorded as a single item (e.g., multiple enlarged pelvic lymph 


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nodes, multiple liver metastases). 
 
3. Response criteria 
 
Table 1. Response Criteria of Target Lesions 
Response of 
Target Lesions 
Definition 
Complete response (CR) 
The disappearance of all target lesions and reduction in short 
axis of any nodal target lesions to < 10 mm 
Partial Response (PR) 
At least a 30% decrease in the sum of the longest diameters 
of the target lesions, taking as a reference the baseline sum 
diameters  
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as a reference the smallest 
sum diameter while on study.  
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of the 
target lesions, taking as a reference the smallest sum on 
study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 
mm. (Note: the appearance of one or more new lesions is 
also considered progression).  
 
 
 
 


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Table 2. Response Criteria of Non-Target Lesions 
Response of 
Non-Target Lesions 
Definition 
CR 
Disappearance of all non-target lesions and normalisation 
of tumour marker level. All lymph nodes must be non-
pathological in size (<10mm short axis). 
non-CR/non-PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal upper 
limits 
PD 
Unequivocal progression of existing non-target lesions 
(Note: the appearance of one or more new lesions is also 
considered progression). 
 
 
 
Table 3. Time Point Response 
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 evaluated 
No 
PR 
SD 
Non-PD or 
not evaluated 
No 
SD 
Not evaluated 
Non-PD 
No 
Inevaluable (NE) 
PD 
Any response 
Yes or No 
PD 
Any response 
PD 
Yes or No 
PD 
Any response 
Any response 
Yes 
PD 
 
 
 


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Table 4. Best Overall Response When Confirmation Of CR And PR 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 
a If a CR is truly met at the 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). The 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.  
 
 

SAP_001.pdf: 
Form DA-05-03.03 Statistical Analysis Plan 
Protocol No.: LSK-AM301 
Sponsor: LSK BioPartners, Inc. 
SAP_LSK-AM301_V1_2019-02-01 
Page 1 of 48 
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Statistical Analysis Plan 
Protocol No.: LSK-AM301 
A Prospective, Randomized, Double-Blinded, Placebo-Controlled, Multinational, 
Multicenter, Parallel-group, Phase III Study to Evaluate the Efficacy and Safety of 
Apatinib plus Best Supportive Care (BSC) compared to Placebo plus BSC in 
Patients with Advanced or Metastatic Gastric Cancer (GC) 
Sponsor: LSK BioPartners, Inc. 
Author: 
 
Protocol Version: LSK-AM301_V5.0, 2018-11-16 
SAP Version No & Date: SAP_LSK-AM301_V1_2019-02-01 
NCT #NCT03042611


Form DA-05-03.03 Statistical Analysis Plan 
Protocol No.: LSK-AM301 
Sponsor: LSK BioPartners, Inc. 
SAP_LSK-AM301_V1_2019-02-01 
Page 2 of 48 
2/48 
 
 
 
Signature Page 
 
 
 
Prepared by 
 
Signature 
Date(YYYY-MM-DD) 
 
 
Reviewed by 
 
Signature 
Date(YYYY-MM-DD) 
 
 
 
Signature 
Date(YYYY-MM-DD) 
 
 
 
Approved by 
 
 
LSK BioPartners, Inc. 
 
 
 
 
Signature 
Date(YYYY-MM-DD) 
 
LSK BioPartners, Inc. 
Signature 
Date(YYYY-MM-DD) 
 
 
LSK BioPartners, Inc. 
Signature 
Date(YYYY-MM-DD) 


Form DA-05-03.03 Statistical Analysis Plan 
Protocol No.: LSK-AM301 
Sponsor: LSK BioPartners, Inc. 
SAP_LSK-AM301_V1_2019-02-01 
Page 3 of 48 
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History of Revision 
 
 
Protocol No. 
LSK-AM301 
Sponsor 
LSK BioPartners, Inc. 
CRO 
LSK Global PS 
Prepared by 
 
Approval Date 
Amended Version 


Form DA-05-03.03 Statistical Analysis Plan 
Protocol No.: LSK-AM301 
Sponsor: LSK BioPartners, Inc. 
SAP_LSK-AM301_V1_2019-02-01 
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List of Contents 
1. 
INTRODUCTION ....................................................................................................................................... 10 
2. 
STUDY OBJECTIVES .............................................................................................................................. 11 
2.1 
Primary Objective ........................................................................................................................... 11 
2.2 
Secondary Objective ...................................................................................................................... 11 
3. 
INVESTIGATIONAL PLAN...................................................................................................................... 11 
3.1 
Overall Study Design and Plan .................................................................................................... 11 
3.2 
Study Duration ................................................................................................................................ 12 
3.3 
Administration of Investigational Product ................................................................................... 13 
3.4 
Randomization ................................................................................................................................ 13 
3.5 
Japan Specific Safety Run-in ....................................................................................................... 13 
3.6 
Study Scheme ................................................................................................................................ 15 
3.7 
Determination of the Sample Size ............................................................................................... 15 
3.7.1 
Hypothesis ......................................................................................................................... 15 
3.7.2 
Background and Assumptions ........................................................................................ 16 
3.7.3 
Sample Size Calculation ................................................................................................. 16 
4. 
ANALYSIS SETS ...................................................................................................................................... 17 
4.1 
Intention-To Treat Set .................................................................................................................... 17 
4.2 
Safety Set ........................................................................................................................................ 17 
4.3 
Full Analysis Set ............................................................................................................................. 17 
4.4 
Per-Protocol Set ............................................................................................................................. 17 
5. 
STUDY VARIABLES AND DEFINITIONS ............................................................................................ 17 
5.1 
Efficacy Variables ........................................................................................................................... 17 
5.1.1 
Efficacy Variables Primary Endpoint ............................................................................. 19 
5.1.2 
Efficacy Variables Secondary Endpoints ...................................................................... 19 
5.2 
Pharmacodynamic Variables ........................................................................................................ 19 
5.3 
Patient Reported Outcome ........................................................................................................... 20 
5.3.1 
EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire ......................................... 21 
5.4 
Patient Reported Outcome Secondary Endpoints .................................................................... 22 
5.5 
Gastric Cancer History and Current Cancer Status .................................................................. 22 
5.5.1 
Gastric Cancer History .................................................................................................... 22 
5.5.2 
Current Cancer Status ..................................................................................................... 22 
5.6 
Anti-Cancer Therapy, Surgeries and Radiotherapy .................................................................. 22 
5.6.1 
Prior Anti-Cancer Therapy .............................................................................................. 22 
5.6.2 
Post Anti-Cancer Therapy ............................................................................................... 22 
5.6.3 
Surgeries and procedures ............................................................................................... 22 
5.6.4 
Radiotherapy ..................................................................................................................... 23 
5.7 
Medical History ............................................................................................................................... 23 
5.8 
Prior, Concomitant and Post Medication .................................................................................... 23 
5.9 
Safety Variables ............................................................................................................................. 23 
5.9.1 
Adverse Events ................................................................................................................ 23 
5.9.2 
Treatment-Emergent Adverse Events ........................................................................... 24 
5.9.3 
Serious Adverse Event (SAE) ........................................................................................ 24 
5.9.4 
Adverse Drug Reaction (ADR) ....................................................................................... 24 


Form DA-05-03.03 Statistical Analysis Plan 
Protocol No.: LSK-AM301 
Sponsor: LSK BioPartners, Inc. 
SAP_LSK-AM301_V1_2019-02-01 
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5.9.5 
Does Limiting Toxicity (DLT)........................................................................................... 25 
5.9.6 
Vital Signs.......................................................................................................................... 25 
5.9.7 
12-Lead Electrocardiogram (ECG) ................................................................................ 25 
5.9.8 
Laboratory Data ................................................................................................................ 25 
5.9.9 
Physical Examination ...................................................................................................... 25 
5.9.10 ECOG performance ......................................................................................................... 26 
6. 
DISPOSITION AND PROTOCOL DEVIATIONS ................................................................................. 26 
6.1 
Subject Disposition ........................................................................................................................ 26 
6.2 
Protocol Deviations ........................................................................................................................ 27 
7. 
EFFICACY EVALUATION ....................................................................................................................... 27 
7.1 
Demographics and baseline characteristics .............................................................................. 27 
7.2 
Cancer History and Cancer Therapy/Surgeries/Procedures/Radiotherapy ........................... 28 
7.3 
Medical History ............................................................................................................................... 28 
7.4 
Prior and Concomitant Medications ............................................................................................ 29 
7.5 
Efficacy Analysis ............................................................................................................................. 29 
7.5.1 
Multiple Comparison Procedure on Primary and Key Secondary Endpoints .......... 29 
7.5.2 
Primary Efficacy Analysis ................................................................................................ 29 
7.5.3 
Key Secondary Efficacy Analysis ................................................................................... 30 
7.5.4 
Other Secondary Efficacy Analysis ................................................................................ 31 
7.6 
Pharmacodynamic Analysis .......................................................................................................... 32 
8. 
SAFETY EVALUATION ........................................................................................................................... 33 
8.1 
Extent of Exposure......................................................................................................................... 33 
8.2 
Adverse Events .............................................................................................................................. 33 
8.2.1 
Overall Summary of Adverse Events ............................................................................. 33 
8.2.2 
Display of Adverse Events .............................................................................................. 33 
8.2.3 
Death and Serious Adverse Events and Other Significant Adverse Events ............ 34 
8.2.4 
Dose Limiting Toxicity (DLT) ........................................................................................... 35 
8.3 
Clinical Laboratory Evaluation ...................................................................................................... 35 
8.4 
Chest X-ray and Pregnancy Test ................................................................................................. 36 
8.5 
Other Safety Measures ................................................................................................................. 36 
8.5.1 
Vital Signs.......................................................................................................................... 36 
8.5.2 
Physical Examination ...................................................................................................... 36 
8.5.3 
12-lead Electrocardiogram .............................................................................................. 36 
8.5.4 
ECOG performance ......................................................................................................... 37 
9. 
SUBGROUP ANALYSIS .......................................................................................................................... 37 
10. GENERAL PRESENTATION OF SUMMARIES AND ANALYSES .................................................. 40 
10.1 
Significance level ........................................................................................................................... 40 
10.2 
Summary Statistics ........................................................................................................................ 41 
10.3 
Decimals .......................................................................................................................................... 41 
10.4 
Statistical Analysis Methods ......................................................................................................... 41 
10.5 
Baseline ........................................................................................................................................... 41 
10.6 
Study Period and Visit Window Definitions ................................................................................ 41 
10.7 
Software for Statistical Analysis ................................................................................................... 42 
11. DATA HANDLING COVENTIONS ......................................................................................................... 42 
11.1 
Handling of Missing Data .............................................................................................................. 42 
11.1.1 Missing Value of Efficacy Variables ............................................................................... 42 


Form DA-05-03.03 Statistical Analysis Plan 
Protocol No.: LSK-AM301 
Sponsor: LSK BioPartners, Inc. 
SAP_LSK-AM301_V1_2019-02-01 
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11.1.2 Missing Value of Safety Variables ................................................................................. 42 
11.2 
Repeated or Unscheduled Assessments ................................................................................... 42 
11.3 
Handling of Incomplete Date ........................................................................................................ 42 
12. INDEPENDENT DATA MONITORING COMMITTEE (IDMC) AND INTERIM ANALYSIS ............. 43 
12.1 
IDMC ................................................................................................................................................ 43 
12.2 
Interim Analysis and Stopping Rules ........................................................................................... 43 
13. CHANGE FROM PROTOCOL ................................................................................................................ 44 
14. SAS PROCEDURE FOR TESTING ....................................................................................................... 47 
14.1 
Test of Categorical Variable for Comparison of Treatment Groups ........................................ 47 
14.2 
Test for shift from baseline to post-baseline within treatment group ...................................... 47 
14.3 
Cochran-Mantel-Haenszel test ..................................................................................................... 47 
14.4 
Logrank test and Kaplan-Meier estimates .................................................................................. 47 
14.5 
Stratified Logrank test ................................................................................................................... 47 
14.6 
Cox proportional hazard regression model ................................................................................ 47 
14.7 
Analysis of Covariance (ANCOVA) ............................................................................................. 48 
15. REFERENCES .......................................................................................................................................... 48 
Appendix. ........................................................................................................................................................... 48 
 


Form DA-05-03.03 Statistical Analysis Plan 
Protocol No.: LSK-AM301 
Sponsor: LSK BioPartners, Inc. 
SAP_LSK-AM301_V1_2019-02-01 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
ANC 
Absolute Neutrophil Count 
ANCOVA 
Analysis of covariance 
aPTT 
activated Partial Thromboplastin Time 
AST 
Aspartate Transaminase 
BP 
Blood Pressure 
BSC 
Best Supportive Care 
BSLN 
Baseline 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
CK 
Creatinine Kinase 
Cmax 
maximum plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete Response 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DC 
Discontinuation 
DCF 
Docetaxel; Cisplatin; 5-fluorouracil 
DCR 
Disease Control Rate 
DLT 
Dose Limiting Toxicity 
ECF 
Epirubicin; Cisplatin; 5-fluorouracil 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture 
EGFR 
Epidermal Growth Factor Receptor 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer Quality 
of Life Questionnaire-Core 30 
EOS 
End of Study 
EOT 
End of Treatment 
EQ-5D-5L 
EuroQol 5-Dimension 5-Level 
F/U 
Follow-Up 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GC 
Gastric Cancer 


Form DA-05-03.03 Statistical Analysis Plan 
Protocol No.: LSK-AM301 
Sponsor: LSK BioPartners, Inc. 
SAP_LSK-AM301_V1_2019-02-01 
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GCP 
Good Clinical Practice 
GEJ 
Gastroesophageal Junction 
GIST 
Gastrointestinal Stromal Tumor 
Hb 
Hemoglobin 
HBc antibody 
Hepatitis B core antibody 
HBs antibody 
Hepatitis B surface antibody 
HBs antigen 
Hepatitis B surface antigen 
HCV 
Hepatitis C Virus 
HFS 
Hand-Foot Syndrome 
HIV 
Human Immunodeficiency Virus 
HR 
Hazard Ratio 
IB 
Investigational Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
INR 
International Normalized Ratio 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed effect Model Prepeat Measurement 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events 
NDA 
New Drug Application 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PD 
Pharmacodynamic 
PET 
Positron Emission Tomograhy 
PFS 
Progression Free Survival 
PK 
Pharmacokinetics 
PPS 
Per Protocol Set 
PR 
Partial Response 
PT 
Prothrombin Time 
PT 
Preferred Term 
PTT 
Partial Thromboplastin Time 
PVDC 
Polyvinylidene Chloride 
q.d. 
Once a Day 
QOL 
Quality of Life 


Form DA-05-03.03 Statistical Analysis Plan 
Protocol No.: LSK-AM301 
Sponsor: LSK BioPartners, Inc. 
SAP_LSK-AM301_V1_2019-02-01 
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RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria for Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SCRN 
Screening 
SD 
Stable Disease 
SD 
Standard Deviation 
SNPs 
Single-Nucleotide Polymorphisms 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TKI 
Tyrosine Kinase Inhibitor 
Tx 
Treatment 
ULN 
Upper Limit of Normal 
USA 
United States of America 
VAS 
Visual Analogue Scale 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR 
Vascular Endothelial Growth Factor Receptor 
vs 
versus 


Form DA-05-03.03 Statistical Analysis Plan 
Protocol No.: LSK-AM301 
Sponsor: LSK BioPartners, Inc. 
SAP_LSK-AM301_V1_2019-02-01 
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1. INTRODUCTION 
Gastric cancer is the 4th most common cancer world-wide and is the 4th most common cause of cancer- 
related death. The prevalence rate of gastric cancer is higher in Asia, South America and Eastern Europe 
than in Western Europe and North America. 
Rivoceranib mesylate (also known as apatinib mesylate) is a novel angiogenesis inhibitor and is being 
developed for the treatment of advanced gastric cancer. The generic name has been now established as 
rivoceranib mesylate in consultation with the USAN and INN naming conventions. Rivoceranib mesylate 
was previously referred to by the laboratory code, YN968D1, and the nonproprietary name in China, 
apatinib mesylate. Rivoceranib mesylate will be manufactured as an oral tablet in 100 mg and 200 mg 
strengths of rivoceranib freebase. Many prior studies were conducted referring to the dose of rivoceranib 
as the weight of rivoceranib including the mesylate salt. In this study and in future studies, LSK will refer to 
rivoceranib dose strength as the weight of the rivoceranib freebase alone instead of weight of the 
rivoceranib mesylate salt. The freebase dosage is approximately 81% of the mesylate dosage. 
This phase III study assesses the benefit of rivoceranib treatment at 700 mg/day of YN968D1 (as 
rivoceranib mesylate). . This dose was selected because it was the maximum dose investigated in the 
phase I study. This study will assess the benefit of rivoceranib plus best supportive care versus placebo 
plus best supportive care in regards to overall survival (OS), progression free survival (PFS), tumor 
response rate, disease control rate and quality of life. The target population is advanced and metastatic 
gastric cancer subjects who have failed at least two approved standard treatments (disease progression or 
intolerant to available approved drugs). 
Rivoceranib is administered as a mesylate salt and was designed based on computer modeling to develop 
a molecule that was specific for the vascular endothelial growth factor receptor (VEGFR)-2. Rivoceranib 
selectively binds to and inhibits vascular endothelial growth factor receptor-2 (VEGFR-2), which is believed 
to be principally responsible for inhibition of VEGF-stimulated endothelial cell migration, proliferation and 
decreases in tumor microvascular density (MVD). Results from various laboratory tests showed that 
rivoceranib highly selectively inhibited protein tyrosine kinase VEGFR-2/KDR (IC50 about 1 nM) receptor, 
and rivoceranib demonstrated an anticancer effect in gastric cancer cell line (NCI-N87 cell line) implanted- 
nude mouse. In mice with hypodermic implantation of colorectal, liver, kidney, breast or non-small cell 
cancer cells, rivoceranib also demonstrated an anticancer effect. Also, a combination therapy of oxaliplatin 
and rivoceranib showed a high cancer cell growth inhibitory effect while having no increase in toxicity. 
As a result of a phase I clinical study conducted in subjects with advanced solid tumors, rivoceranib 
mesylate had an MTD of 850 mg and the clinically recommended dose was 750 mg. The most common 
side effects were hypertension, proteinuria, and hand-foot syndrome. These side effects were mild to 
moderate in severity and were manageable. In terms of effectiveness, 83.8% of subjects had controlled 
disease; with partial response in 18.9% of subjects and stable disease in 64.9% of subjects. Out of 22 
subjects with gastric-colorectal cancer who were included in the study, 18 showed controlled disease with 
4 partial responses indicating a promising effect. Phase II and phase III clinical studies conducted in China 
showed an increase of overall survival compared to the placebo group in subjects with advanced gastric 
cancer. Based on the positive outcome, rivoceranib (known as apatinib in China) was approved in China 
for treatment of advanced gastric cancer in 2014. 


Form DA-05-03.03 Statistical Analysis Plan 
Protocol No.: LSK-AM301 
Sponsor: LSK BioPartners, Inc. 
SAP_LSK-AM301_V1_2019-02-01 
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Previous studies have shown clinical benefits in OS and PFS, however, there is no treatment option for 
patients who have failed approved standard therapies for advanced or metastatic gastric cancer. As 
described above, rivoceranib has shown a potential survival benefit in patients with gastric cancer; therefore, 
its efficacy and safety will be ascertained in this controlled and properly powered phase III study. This study 
will be the steppingstone to continue the clinical development of rivoceranib as a treatment agent for 
advanced and metastatic gastric cancer. Moreover, the data to be obtained from this study will contribute 
to our understanding of this disease. 
This document describes the methods that will be used in summarizing and analyzing the efficacy, safety, 
and correlative pharmacodynamic biomarker and genetic polymorphism data that will be collected in this 
study. The methods for analyzing pharmacokinetic and extension period data will be addressed in separate 
analysis plans. 
Note: For purposes of this SAP, Rivoceranib will be used as the nonproprietary name throughout the 
document. Apatinib was formerly used in other supporting documents, such as the protocol. 
2. STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of rivoceranib administered with best 
supportive care (BSC) in the target population in terms of improving overall survival compared with that of 
placebo administered with best supportive care (BSC). 
2.2 
Secondary Objective 
The secondary objectives of this study are as follows: 
• 
To evaluate progression-free survival (PFS) 
• 
To evaluate objective response rate (ORR) 
• 
To evaluate disease control rate (DCR) 
• 
To evaluate EORTC QLQ-C30 and EORTC QLQ-STO22 
• 
To evaluate EQ-5D-5L 
• 
To explore pharmacodynamic markers: 
Vascular Endothelial Growth Factor (VEGF), sVEGFR-1, sVEGFR2, and sVEGFR3 
• 
To evaluate pharmacokinetics 
Moreover, the safety of rivoceranib will be evaluated and safety measures are as follows: 
• 
Adverse events, laboratory tests, vital signs, physical examination, 12-lead ECG, and ECOG 
performance status 
3. INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a prospective, randomized, double-blinded, placebo-controlled, multinational, multicenter, parallel- 
group, phase III study to evaluate the efficacy and safety of Rivoceranib plus Best Supportive Care (BSC) 


Form DA-05-03.03 Statistical Analysis Plan 
Protocol No.: LSK-AM301 
Sponsor: LSK BioPartners, Inc. 
SAP_LSK-AM301_V1_2019-02-01 
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compared to Placebo plus BSC in subjects with advanced or metastatic gastric cancer who failed two or ≥ 
three prior treatment regimens. 
After informed consent and screening procedures, eligible subjects will be randomized in a 2:1 ratio to 
Rivoceranib or Placebo group. All subjects will receive best supportive care (BSC). The randomization will 
be stratified by the following factors: Geographic region (Asia vs. North America/Europe), Disease 
measurability (measurable vs. nonmeasurable), Prior ramucirumab treatment (Yes vs. No), and Treatment 
therapy line (3rd vs. ≥ 4th). 
Randomized subjects will receive either the test product Rivoceranib (freebase) at 700 mg/day plus BSC 
or Placebo plus BSC and will be evaluated at regular site visits, which will be made every 2 weeks till the 
death of the subject or discontinuation of the study treatment due to disease progression, intolerable toxicity 
or subject’s withdrawal of consent. If treatment related toxicity is detected, two steps of dose reductions 
(600 mg, 400 mg for Rivoceranib) are allowed during the entire study period according to the dose 
adjustment plan. 
Tumor response and progression will be assessed every other cycle (8 weeks interval) by a local imaging 
facility. Subject treatment decisions will be made based on local imaging results and investigator opinion 
which will be entered into the case report forms. Scans will be obtained at baseline and throughout the 
study and will be analysed post-study by a central imaging analysis facility. Centrally imaging results will 
determine the subjects best tumor response and time of progression according to RECIST 1.1. 
Post-treatment follow-up visit will be made at 4 weeks after the end of treatment (EOT) and then survival 
follow-ups will follow at 8-week intervals till the death of the subject or closure of the study. 
The study data will be analysed when the required number of events (approximately 325 deaths) are 
observed. This is projected to occur approximately 9 months after the last subject is randomized. All 
subjects will be treated and/or followed after randomization until the study data analysis is performed, and 
then they will be monitored for survival status until death. 
Subjects on treatment after analysis will be provided an option to enroll in a treatment maintenance (the 
Extension period) protocol if approved by country and local regulatory authorities. 
3.2 
Study Duration 
Total study duration was designed to be approximately 18 months: 9 months of recruitment period + 9 
months of treatment period. The study recruitment period extended to 21 months thus total study duration 
became 30 months in Protocol version 4.1 and in subsequent Protocol version 5.0. The extension period 
may continue beyond 30 months. The study data will be analysed when the required number of events 
(approximately 325 deaths) are observed. This is projected to occur approximately 9 months after the last 
subject is randomized. All subjects will be treated and/or followed after randomization until the study data 
analysis is performed, and then they will be monitored for survival status until death. Patients continuing to 
benefit from rivoceranib treatment, after final analysis and subsequent unblinding, will be given an option 
to consent to continue treatment with rivoceranib. Placebo patients will stop taking the placebo and will be 
monitored for survival status until death. 


Form DA-05-03.03 Statistical Analysis Plan 
Protocol No.: LSK-AM301 
Sponsor: LSK BioPartners, Inc. 
SAP_LSK-AM301_V1_2019-02-01 
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3.3 
Administration of Investigational Product 
Investigational products will be administered orally once a day, approximately 1 hour after breakfast. It is 
recommended that the administration time should be consistent throughout the study period (that is, the 
administration interval should be approximately 24 hours). The investigational product should not be taken 
until during the clinic visit of Day 1 of each cycle. 
Subjects should take 3 tablets of 200 mg and 1 tablet of 100 mg in strength at a time. If the dose is reduced 
to 600 mg, 3 tablets of 200 mg in strength should be taken. If the dose is reduced further to 400 mg, only 2 
tablets of 200 mg in strength should be taken at a time. If the subject vomits after swallowing the IP, the 
dose will not be replaced and there will be no replacement of a missed dose of IP. 
3.4 
Randomization 
Subjects will be randomized in a 2:1 ratio to the Rivoceranib group or the Placebo group, and the 
randomization will be stratified according to the following factors. 
1. 
Geographic region (Asia pacific vs. North America/Europe) 
2. 
Disease measurability (Measurable vs. Non-measurable) 
3. 
Prior ramucirumab treatment (Yes vs. No) 
4. 
Treatment therapy line (3rd vs. ≥ 4th) 
For each subject who has provided written consent and whose eligibility is confirmed, a registration number 
will be assigned by the Interactive Web Response System (IWRS), and the subject will be enrolled in the 
study (enrollment). Detailed procedures for IWRS use will be specified in a separate document. 
3.5 
Japan Specific Safety Run-in 
The AM104 ethnic bridging study determined that there is no statistically significant difference in Japanese 
ethnic population pharmacokinetics as compared to Chinese and/or Caucasian that would make it unsafe 
to proceed at the study starting dose. The AM104 study evaluated the pharmacokinetics of a single dose 
of 201 mg of Rivoceranib in 18 healthy volunteers of each of three specific ethnic populations; Japanese, 
Chinese and Caucasian. Initiation of enrollment in Japan included a safety run-in approach to further 
confirm the safety of the study starting dose in this ethnic population. 
Initially, in Japan, only 6 subjects were enrolled and assigned either Rivoceranib or Placebo to investigate 
the safety at the same starting dose and with the same randomization/enrollment criteria as all other study 
subjects. The treatment assignments were not known to any study personnel with the following exceptions. 
During the observation period, an appropriately unblinded and separate study personnel in the study team 
who would perform no other study activity or duties that would jeopardize the integrity of the study, 
determined whether at least 3 of the first 6 subjects were assigned to Rivoceranib treatment. These specific 
subjects were hospitalized and monitored during the 14 days of DLT evaluation period including performing 
the following evaluations once on either study day 7, 8 or 9 that was not noted in the standard study 
schedule, 
• 
Physical examination 
• 
Measurement of vital signs including weight 


Form DA-05-03.03 Statistical Analysis Plan 
Protocol No.: LSK-AM301 
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• 
Assessment of ECOG performance score 
• 
Assessment of adverse event 
• 
Collection of concomitant medication information 
• 
Hematology, blood chemistry, coagulation test and urinalysis 
If at least 3 were assigned Rivoceranib treatment, the Rivoceranib treated subjects would be observed for 
a minimum of 14 days of therapy. If less than 3 subjects were randomized to Rivoceranib treatment, 3 
more subjects (bringing the total to 9 subjects) could have been enrolled immediately to ensure that the 
DLT evaluation in Japan subjects was performed on at least 3 Rivoceranib treated subjects. 
If no DLT occurred during the DLT evaluation period (at least 0/3 rivoceranib treated subjects), the study 
could proceed in Japan with further enrollment per protocol and the IDMC and PMDA would be notified. 
If there was only 1 DLT during the DLT evaluation period (at least 1/3), another 3 subjects could have been 
enrolled to ensure that at least 6 Rivoceranib subjects were observed for the 14 day DLT evaluation period. 
If there remained only 1 DLT during the DLT evaluation period after at least 6 Rivoceranib treated subjects 
were observed (at most 1/6 Rivoceranib treated subjects), the study could proceed in Japan with further 
enrollment per protocol and the IDMC and PMDA would be notified. 
If there were 2 DLT events in the 14 day DLT evaluation period (either at most 2/3 or at least 2/6 Rivoceranib 
treated subjects), then the subject data (AE, SAE, DLT, etc) in EDC with randomization information would 
be sent to the independent contract research organization for interim analyses (AXIO Research, LLC). 
AXIO would merge the subject information with the randomization information for presentation to the IDMC. 
AXIO would schedule a teleconference to review the information with the IDMC, which would discuss 
recommendation regarding whether discontinue or continue enrollment with or without study design 
modifications. Such a study design modification could be but not limited to: 
• 
Dose modification 
• 
Extended safety run-in 
• 
Request for additional safety monitoring 
Then AXIO would transfer the IDMC’s recommendation to LSKB and LSKG. The enrollment in Japan would 
temporarily stop until sponsor’s decision to discontinue or continue enrollment with or without modifications 
after consultation with PMDA. 
The notification of the outcome of the Japan Safety Run-in would also be given to each site. In addition, if 
a DLT occurred, a notification would be made in a timely manner to all investigators that had subjects being 
treated on study. 
For the purposes of the Japanese safety run-in, a DLT is defined as any of the following events assessed 
by the Investigator as probably or possibly related to Rivoceranib that occurs during or after the initial dose 
on Day 1 through Day 14. 
1. CTCAE Grade 4 event 
2. Grade 3 febrile neutropenia (<1,000 neutrophils/mm3) 
3. Grade 3 anemia and thrombocytopenia with duration > 7 days 
4. Grade 3 non-hematologic toxicity including Grade 3 nausea, vomiting and diarrhea that 


Form DA-05-03.03 Statistical Analysis Plan
Protocol No.: LSK-AM301
Sponsor: LSK BioPartners, Inc.
SAP_LSK-AM301_V1_2019-02-01
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Extension Period
- 28 days
from BSLN
28 day cycles
After EOT
After EOS
EOS is defined as the end of the
primary analysis period when the
Apatinib + BSC
patients are unblinded.
Post-Tx F/u 1)
Apatinib 700 mg qd, po
• At 4 weeks after EOT
• Subjects in the apatinib group
who are not confirmed as
ndomization (2:1)
disease progression at EOS or
are otherwise eligible to
Placebo + BSC
Matching Placebo to apatinib qd, po
Survival F/u 2)
• At 8 weeks interval
(by telephone or
direct visit)
continue apatinib treatment until
end of treatment or study
withdraw (section 6.2)
• Other subjects will be followed
for survival status until death.
• Tumor assessment every other cycle
• QoL assessment once every cycle
• Safety assessments every two weeks
• Tumor assessment Information
• Safety assessment
Ra
Screening Period
Treatment Period
Follow-up Period
• Informed consent
• Demography
• Medical/medication
history
• GC history
• Exams and tests
• for eligibility
assessment
• Baseline tumor
evaluation
continues despite optimal medical management
5.
Anemia or thrombocytopenia that requires transfusion
6.
When the study treatment was withheld based on the protocol 4.4 dose adjustment plan more
than three day
Of note, the first 6 subjects enrolled in Japan were evaluable, were confirmed that at least 3 were
administered rivoceranib and no DLT was observed in any of these subjects.
3.6
Study Scheme
Overview of study design is summarized in Figure 1. 
SCRN
(-28 days)
BSLN
EOT
Post-TX
f/u
EOS
End of Extension period
Figure 1. Study Scheme
1)    Post-treatment follow-up will be done at 4 weeks (± 7 days) after the end of treatment (EOT). 
2)    Survival follow-up will be done at 8 weeks (± 7 days) interval after the Post-treatment follow-up visit. Survival
follow-ups will continue until the death of the subject or till the study closure.
3.7
Determination of the Sample Size


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4. ANALYSIS SETS 
4.1 
Intention-To Treat Set 
ITT set consists of data from all subjects who are randomized into the study. In the ITT set, subjects will be 
included in the group to which they were randomized. The ITT set will be used for the primary efficacy 
analyses. 
4.2 
Safety Set 
Safety set consists of data from all subjects in the ITT population who received at least one dose of 
Rivoceranib or placebo. In the Safety set, subjects will be included in the group based on the treatment that 
was received. Safety data will be analyzed by safety set. 
4.3 
Full Analysis Set 
FAS consists of data from subjects included in ITT Set who received at least one dose of Rivoceranib or 
placebo. The FAS will be used for supportive efficacy analyses. 
4.4 
Per-Protocol Set 
PPS consists of data from subjects included in FAS who completed the study per protocol without major 
violation such as inclusion/exclusion criteria violation and use of prohibited concomitant medication during 
the study. The PPS will be used for supportive efficacy analyses. Whether each subject is included in the 
PPS will be decided in a blinded meeting based on the protocol deviations and violations before data base 
lock. 
5. STUDY VARIABLES AND DEFINITIONS 
5.1 
Efficacy Variables 
Based on the definition of target and non-target lesion, response of target lesions and response of non- 
target lesion are defined in Table 1 and Table 2 in the RECIST1.1. Centrally imaging results will determine 
the subjects best tumor response and time of progression according to RECIST 1.1. 
 
Table 1. Response Criteria of Target Lesions 
 
 
Complete response (CR) 
Partial Response (PR) 
Stable Disease (SD) 
The disappearance of all target lesions and reduction in short axis of 
any nodal target lesions to < 10 mm 
At least a 30% decrease in the sum of the longest diameters of the 
target lesions, taking as a reference the baseline sum diameters 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as a reference the smallest sum diameters while 
on study. 
 
 
Response of 
Target Lesions 
Definition 


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Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of the target 
lesions, taking as a reference the smallest sum on study (this includes 
the baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new 
lesions is also considered progression). 
 
 
 
 
Table 2. Response Criteria of Non-Target Lesions 
 
 
 
CR 
 
 
non-CR/non-PD 
 
 
PD 
Disappearance of all non-target lesions and normalisation of 
tumour marker level. All lymph nodes must be non-pathological in 
size (<10mm short axis). 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal upper limits 
Unequivocal progression of existing non-target lesions (Note: the 
appearance of one or more new lesions is also considered 
progression). 
 
 
With the tumor response of target, non-target and new lesion, overall response is defined in Table 3. 
Table 3. Time Point Response (subjects with target and 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 
SD 
Non-PD or 
not evaluated 
Non-PD or 
not evaluated 
No 
No 
PR 
SD 
Not evaluated 
Non-PD 
No 
Inevaluable (NE) 
PD 
Any response 
Yes or No 
PD 
Any response 
PD 
Yes or No 
PD 
Any response 
Any response 
Yes 
PD 
 
With the tumor response of non-target and new lesion, overall response is defined in Table 4 
Response of 
Non-Target Lesions 
Definition 
Response of 
Target Lesions 
Definition 


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Table 4. Time Point Response (subjects with non-target lesions only) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not evaluated 
No 
Inevaluable (NE) 
Unequivocal PD 
Yes or No 
PD 
Any response 
Yes 
PD 
 
The best overall response without confirmation of complete or partial response is defined as the best 
response across all time points. When there are more than one response, it will be selected as the best 
overall response according to the order of CR > PR > SD > NON-CR / NON-PD > PD > NE. The minimum 
duration for SD to decide best response is 6 weeks. 
5.1.1 
Efficacy Variables Primary Endpoint 
Overall Survival (OS): Time from randomization to death. Subjects alive or lost to follow-up are censored at 
the date the subject was last known to be alive. 
5.1.2 
Efficacy Variables Secondary Endpoints 
Centrally imaging results will determine the subject’s best tumor response and time of progression 
according to RECIST 1.1. for the following endpoints. In addition, supportive tumor response and 
progression will be analyzed based on investigator assessment. 
• 
Progression Free Survival (PFS): Time from randomization to either documented radiological 
progression (PD) or death. Subjects alive and free of progression are censored at the last tumor 
assessment date when alive and free of progression were known. And if there is no baseline tumor 
assessment data for subjects, the subjects are censored at the date of randomization. 
• 
Objective Response Rate (ORR): Proportion of subjects with a Best Overall Response of Complete 
Response (CR) or Partial Response (PR). 
• 
Disease Control Rate (DCR): Proportion of subjects with a Best Overall Response of complete 
response (CR) or partial response (PR), or stable disease (SD). 
5.2 
Pharmacodynamic Variables 
Levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor-1 (sVEGFR-1), sVEGFR-2, 
and sVEGFR-3 will be evaluated at baseline (on Cycle 1 Day 1 prior to first dose), on Day 1 (±3 days) of 
each subsequent treatment cycle, and at the End of Treatment/Discontinuation visit. 
All subjects will be evaluated at baseline for single nucleotide polymorphisms (SNPs) in VEGFR-2 
(rs1870377, rs2305948, and rs17709898) that may provide genotype information that correlates to 
response to VEGFR-2 inhibition therapy. 


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5.3 
Patient Reported Outcome 
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 
(EORTC QLQ-C30) and the European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire-the gastric cancer specific module (EORTC QLQ-STO22) were used to evaluate patient 
reported outcome. 
EORTC QLQ-C30 is a 30-item core-cancer-specific questionnaire-integrating system for assessing the 
health-related QOL of cancer subjects participating in international clinical trials. The questionnaire 
incorporates 5 functional scales (physical, role, cognitive, emotional and social), 4 symptom scales (fatigue, 
pain, nausea/vomiting, appetite), a global QOL scale and single items for the assessment of additional 
systems commonly reported by cancer subjects (e.g., constipation, diarrhoea, sleep disturbance and 
financial). All items are scored on 4-point Likert scales, ranging from 1 (‘not at all’) to 4 (‘very much’), with 
the exception of two items in the global QOL scale which use modified 7-point linear analog scales. 
Table 5. Scoring the QLQ-C30 version 3.0 
 
Scale 
Number 
of items 
Item 
range* 
Version 3.0 
Item 
numbers 
Function 
scales 
Global health status / QoL 
Global health status/QoL 
QL2 
2 
6 
29, 30 
Functional scales 
Physical functioning 
PF2 
5 
3 
1 to 5 
F 
Role functioning 
RF2 
2 
3 
6, 7 
F 
Emotional functioning 
EF 
4 
3 
21 to 24 
F 
Cognitive functioning 
CF 
2 
3 
20, 25 
F 
Social functioning 
SF 
2 
3 
26, 27 
F 
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 
* Item range is the difference between the possible maximum and the minimum response to individual items; most 
items take values from 1 to 4, giving range=3. 
 
For all scales, the RawScore (i.e., RS) is the mean of the component items: 
RawScore = RS = (I1 + I2 + … + In) /n 


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Using the RawScore, Functional scales: 
Scale = [1- (RS – 1) / range] * 100 
 
Symptom scales / items and Global health status / QoL: 
Score = [(RS - 1) / range] * 100 
 
EORTC QLQ-STO22 is a 22-item gastric cancer-specific questionnaire-integrating system for assessing 
the health-related QOL of gastric cancer subjects. 
 
 
Table 6. Scoring the QLQ-STO22 
 
Scale name 
Number 
of items 
Item 
range 
QLQ-STO22 Item 
numbers 
Functional scales 
Body image 
STOBI 
1 
3 
19 
Symptom scales 
Dyspnoea 
STODYS 
3 
3 
1-3 
Pain 
STOPAIN 
4 
3 
4-7 
Reflux symptoms 
STORFX 
3 
3 
8-10 
Eating restrictions 
STOEAT 
4 
3 
11-13,16 
Anxiety 
STOANX 
3 
3 
17,18,20 
Dry mouth 
STODM 
1 
3 
14 
Taste 
STOTA 
1 
3 
15 
Body image 
STOBI 
1 
3 
19 
Hair loss 
STOHL 
2/1 
3 
21, 22* 
* Item 22 is an optional item and depends on the answer to item 21. Item 22 should 
only be answered and assessed if ‘yes’ has been answered to item 21. 
 
For all scales, the RawScore (i.e., RS) is the mean of the component items: 
RawScore = RS = (I1 + I2 + … + In) /n 
 
Using the RawScore, Functional scales and Symptom scales: 
Score = [(RS - 1) / range] * 100 
Only when at least half of the items for each sub-scale have been answered, RawScore of the scale will be 
calculated. The RawScore is defined as the average of the items that are answered from the respondent 
excluding the unanswered items. When less than half of the items are answered, the corresponding score 
is considered as missing. 
5.3.1 
EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire 
It consists of EQ-5D-5L descriptive system and the visual analogue scale (VAS). The descriptive system 
comprises the 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and 


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each dimension has 5 levels. 
5.4 
Patient Reported Outcome Secondary Endpoints 
The following secondary endpoints will be analyzed based on patient reported outcomes. 
• 
Global health status/quality of life score according to European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and EORTC QLQ- 
STO22 
• 
Each dimension response according to EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire 
 
5.5 
Gastric Cancer History and Current Cancer Status 
5.5.1 
Gastric Cancer History 
All gastric cancer history within 3 year prior to screening will be collected. History of gastric cancer shall 
include date of diagnosis, method for diagnosis, stage at initial diagnosis, location of primary tumor at 
diagnosis (Gastric [≥ 5 cm below GEJ] vs. GEJ), location of metastases (metastases to other organs such 
as lung, liver metastasis) etc. 
5.5.2 
Current Cancer Status 
Current disease presentation (locally advanced, metastatic or local), cancer stage at screening and location 
of metastases will be collected. 
5.6 
Anti-Cancer Therapy, Surgeries and Radiotherapy 
5.6.1 
Prior Anti-Cancer Therapy 
Any prior anti-cancer treatments used for the management of advanced or metastatic gastric cancer (e.g. 
anticancer chemotherapy and/or radiotherapy) will be collected. Specifically, line of therapy, best response, 
reason for stopping, date of progression and agent will be collected. 
5.6.2 
Post Anti-Cancer Therapy 
Anti-cancer treatments that is used in post-treatment follow up (after end of treatment (EOT)) will also be 
collected. Regimen number, reason for the regimen and agent will be collected. 
5.6.3 
Surgeries and procedures 
Cancer-related or general surgeries/procedures will be collected in the eCRF. Location and intent of surgery 
will be collected. Location and result of procedures and whether the result is normal/abnormal with clinically 
significant or not will also be collected. 
Surgeries/Procedures will be classified as prior surgeries/procedures if it meets the following conditions: 
• 
The date of procedures is prior to first administration of study drug; 
Surgeries/Procedures are defined as concomitant surgeries/procedures that meet the following conditions: 
• 
The date of procedures is on or after the first administration of study drug and on or before the date 
of End of Treatment (EOT); 


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Surgeries/Procedures are defined as post surgeries/procedures that meet the following conditions: 
• 
The date of procedures is after the date of End of Treatment (EOT); 
Note: In the 
above 
definitions 
of 
prior, concomitant and 
post 
surgeries/procedures, 
the 
surgeries/procedures may be considered as prior, concomitant and post. 
In the event of partial dates, the algorithm in Section 12.3 will be followed to determine whether the 
surgeries/procedures are to be considered as prior / concomitant / post. 
5.6.4 
Radiotherapy 
Body site and intent of radiotherapy and its cumulative dose will be collected. Radiotherapy will be classified 
as prior, concomitant and post based on check box in the eCRF. 
5.7 
Medical History 
General medical history within 1 year prior to screening will be collected. 
5.8 
Prior, Concomitant and Post Medication 
Any medications or therapies that the subject was taking or receiving at the time of study participation 
(Screening visit) shall be recorded as concomitant medications. Medications that the subject took within 28 
days from signing on the ICF shall also be recorded in the eCRF. 
Medication will be classified as prior medication if it meets the following conditions: 
• 
The start and stop date are prior to first administration of study drug; 
Medication is defined as concomitant medication that meets the following conditions: 
• 
The start date is on or after the first administration of study drug and on or before the date of End 
of Treatment (EOT); or 
• 
The start date is prior to the first administration of study drug, but the stop date is on or after the 
first administration of study drug (or the medication is listed as ongoing); 
Medication is defined as post medication that meets the following conditions: 
• 
The start date is after the date of End of Treatment (EOT); 
Note: In the above definitions of prior, concomitant and post medication, a medication may be considered 
as prior, concomitant and post in the same time. 
In the event of partial dates, the algorithm in Section 12.3 will be followed to determine whether the 
medication is to be considered as prior/concomitant /post. 
5.9 
Safety Variables 
5.9.1 
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a subject who has signed the 
informed consent form. The event need not necessarily have a causal relationship with the investigational 
product. 


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Examples of AEs include but are not limited to: 
• 
Abnormal test findings that are clinically significant. 
• 
Clinically significant symptoms and signs. 
• 
Clinically significant changes in physical examination findings. 
• 
Signs or symptoms resulting from drug overdose, misuse, or withdrawal. 
Disease progression assessed by measurement of malignant lesions on imaging studies should not be 
reported as an AE. 
5.9.2 
Treatment-Emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as AEs that have a start date on or after the first 
dose of the investigational product until the final subject visit or, if it has a start date before the date of the 
first dose of study drug, increase in severity on or after the date of the first dose of investigational product 
until the final subject visit. If there are partial or missing dates, the imputation algorithm in Section 11.3 will 
be followed to decide whether the AE is TEAE. 
Adverse events collected during screening period (from the time-point of informed consent until right before 
the first administration of the investigational product) will be separately listed and reviewed. 
5.9.3 
Serious Adverse Event (SAE) 
A serious adverse event (SAE) is any untoward medical occurrence that: 
• 
Results in death. 
• 
Is life-threatening. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization.1) 
• 
Results in persistent or significant disability/incapacity. 
• 
Results in a congenital anomaly/birth defect. 
 
1) This does not include any of the following: 
• 
Hospitalization or prolongation of existing hospitalization for a procedure (e.g., surgery, 
examination) that had been planned before the study 
• 
Hospitalization or prolongation of existing hospitalization for follow-up observation of an already 
healed or improved condition 
• 
Hospitalization or prolongation of existing hospitalization for examination or education 
• 
Hospitalization or prolongation of existing hospitalization for non-medical reason (e.g., 
temporary absence of a family member) 
• 
Admission to a hospice facility, nursing care facility, or rehabilitation facility 
5.9.4 
Adverse Drug Reaction (ADR) 
An adverse drug reaction is defined as an AE that is considered certain, probable/likely, possible, unlikely, 
conditional/unclassified or unassessable/unclassifiable related to study medication. 


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5.9.5 
Does Limiting Toxicity (DLT) 
Dose Limiting Toxicity data was collected only for the subjects enrolled in Japan Run-in. Whether the DLT 
occurred or not (Yes/No), and any of the following event occurred will be collected: 
1. CTCAE Grade 4 event 
2. Grade 3 febrile neutropenia (<1,000 neutrophil/mm3) 
3. Grade 3 anemia and thrombocytopenia with duration >7 days 
4. Grade 3 non-hematologic toxicity including Grade 3 nausea, vomiting and diarrhea that 
continues despite optimal medical management 
5. Anemia or thrombocytopenia that requires transfusion 
6. When the study treatment was withheld based on the protocol 4.4 dose adjustment plan 
more than three days 
5.9.6 
Vital Signs 
Systolic blood pressure, diastolic blood pressure, pulse, body temperature, respiratory rate, weight, height 
and BMI will be collected. Weight (kg) will be measured at each visit and height (cm) will be measured only 
at the screening visit. 
5.9.7 
12-Lead Electrocardiogram (ECG) 
Heart rate, PR interval, QTcF, RR interval, ST segment, T-wave, Heart rate, and whether the result is 
normal/abnormal and clinically significant/not-significant will be collected. For Day 1 of Cycle 1 and 2, 12- 
lead ECG will be collected before the IP administration and approximately 4 hours after IP administration 
which corresponds to the time when the PK Cmax blood is drawn. 
5.9.8 
Laboratory Data 
• 
Hematology (complete blood count, CBC: white blood cell (WBC) with 5-part differential 
(neutrophils, lymphocytes, monocytes, eosinophils, and basophils), platelet count, absolute 
neutrophil count (ANC), red blood cell count (RBC), hemoglobin (Hb), hematocrit (Hct) 
• 
Blood chemistry: sodium, potassium, chloride, carbon dioxide or bicarbonate (if required), blood 
urea nitrogen (BUN), creatinine, glucose (fasting), total protein, albumin, calcium, amylase, lipase, 
phosphorous, magnesium, creatinine kinase (CK), uric acid, total bilirubin, AST, ALT, and ALP 
• 
Serological tests: HIV antibody (if HIV antibody result is positive, HIV-1 antibody and HIV-2 
antibody should be conducted), HBs antigen, HBs antibody, HBc antibody, HCV antibody 
• 
Coagulation tests: prothrombin time expressed as either prothrombin time (PT) or international 
normalized ratio (INR) and partial thromboplastin time (PTT or aPTT) 
• 
Urinalysis: specific gravity, protein, glucose, occult blood, and microscopic examination if indicated 
• 
Pregnancy test: it will be carried out only for female subjects with child-bearing potential (serum or 
urine). 
5.9.9 
Physical Examination 
Any abnormal physical findings on eye, ears, nose, throat, neck, thyroid, cardiovascular system, respiratory 
system, gastrointestinal system or mouth, dermatologic system, extremities, musculoskeletal system, 


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ECOG Grade 
Description 
central and peripheral nervous system, lymph nodes will be collected. Whether the finding is clinically 
significant will also be checked. 
5.9.10 ECOG performance 
ECOG performance score (0,1,2,3,4) will be collected. 
 
 
Table 7. ECOG Grade 
 
0 
Fully active, able to carry on all pre-disease activities without restriction. 
 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
1 
or sedentary nature (light house work, office work). 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
2 
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. 
Completely disabled. Cannot carry on any self-care. 
4 
Totally confined to bed or chair. 
 
6. DISPOSITION AND PROTOCOL DEVIATIONS 
6.1 
Subject Disposition 
Subjects in each analysis set (ITT Set, FAS, PPS and Safety Set) will be summarized with counts and 
percent by treatment group for all enrolled subjects. Reason excluded from each analysis set will be 
summarized with counts by treatment group. Subjects excluded from each analysis set will be listed. 
The disposition of all screened subjects will be summarized by treatment group. The number of subjects 
who are randomized (treated/Non-treated) and the number of subjects who are completed/Withdrawn will 
be summarized by treatment group. The withdrawn subject will be listed. 
In addition, for subjects who prematurely discontinue from the study, the reasons for withdrawn will be 
summarized with counts by treatment group and for the ITT set. The number of randomized subject will 
also be summarized by region, country and by investigator. The number of randomized subject will be 
summarized with counts and percent by the stratification. 
The disposition tables will include the following summaries by treatment and overall: 
• 
Analysis populations (all subjects) 
• 
Enrollment by region, country and site (ITT population) 
• 
Summary of randomization stratification per IWRS (ITT population) 
• 
Study Treatment Disposition and Discontinuation (ITT population) 
• 
Study Status, Duration of Treatment and Study Exit (ITT population). 
 
 
Duration of Treatment (month) = (Date of last treatment admin.– Date of first treatment admin. +1) 


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x 12/365.25 
 
Duration of Study (month) 
= Date of (End of study – Date of Randomization +1) x 12/365.25; for study 
discontinued/completed. 
= Date of (the last visit – Date of Randomization +1) x 12/365.25; for study ongoing. 
 
 
Data will be summarized in the following tables: 
- Table. Subject Disposition – All Screened Subjects 
- Table. Subject Population – All Enrolled Subjects 
- Table. Enrollment by Geographic Region – ITT 
- Table. Enrollment by Country– ITT 
- Table. Enrollment by Site – ITT 
- Table. Summary of Randomization Stratification – ITT 
- Table. Duration of Treatment - ITT 
 
- List. Analysis Set – ITT 
- List. Withdrawn Subjects – ITT 
 
 
6.2 
Protocol Deviations 
The study team will conduct reviews of the protocol deviation and violation (PDV) data and resulting set of 
PPS population subjects throughout the study, adjusting the PDV criteria as seems appropriate. The PPS 
population subjects set will be finalized at the blind meeting (or earlier), prior to database lock. 
All protocol deviations and violations data will be listed. 
Data will be summarized in the following table and list. 
- Table. Major Protocol Deviation – ITT Set 
- List. Subjects with Major Protocol Deviation – ITT Set 
 
 
7. EFFICACY EVALUATION 
7.1 
Demographics and baseline characteristics 
Demographics and baseline characteristics will be summarized by descriptive statistics by treatment group 
for the ITT set. The number of subjects, mean, standard deviation, minimum and maximum will be 
presented for continuous data, and the number and percentage (%) of subjects will be presented for 
categorical data. 
For the demographics, the following variables will be summarized: 
• 
Continuous Variables: Age (years), Weight (Kg) at baseline, Height(cm), BMI(Kg/𝑚𝑚2) at baseline 
• 
Categorical Variables: Sex(Male, Female), History of drug abuse (Yes, No), History of alcohol 


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abuse(Yes, No), Ethnicity (Hispanic of Latino, Not Hispanic or Latino), Race(American Indian or 
Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White, 
Others), Geographic Region (Asia pacific, North America/Europe), Disease Measurability 
(Measurable, Nonmeasurable), Prior Ramucirumab Treatment (Yes, No), Treatment Therapy Line 
(3rd, ≥ 4th) 
 
 
 
Age(years) = Year of consent – year of birth; If consent date is after birth date 
Year of consent – year of birth-1; If consent date is before birth date 
 
BMI(kg/m2) = Weight(kg)/[height (cm)/100]2 
Data will be summarized in the following tables. 
-Table. Demographic and baseline characteristics – ITT 
- List. Demographic data – ITT 
7.2 
Cancer History and Cancer Therapy/Surgeries/Procedures/Radiotherapy 
Gastric cancer history, current cancer status, anti-cancer therapy, surgeries, procedures and radiotherapy 
will be summarized presenting descriptive statistics by treatment group for the ITT set. For anti-cancer 
therapy will be coded using WHO-DDE 2017(ATC code). The number and percentage (%) of subjects will 
be presented based on ‘Anatomical main group(level 1)’ and ‘Therapeutic subgroup(level 2)’ by treatment 
group. For surgeries/procedures, the number and percentage (%) of subjects will be presented based on 
Preferred Term(PT) and System Organ Class(SOC) using Medical Dictionary of Regulatory Activities 
(MedDRA) version 19.0 or higher. For anti-cancer therapy, surgeries/procedures and radiotherapy, p-value 
that tests homogeneity of proportions between treatment groups (chi-square test or Fisher’s exact test) will 
be presented. 
Data will be summarized in the following tables. 
-Table. Gastric Cancer History – ITT 
-Table. Current Cancer Status – ITT 
-Table. Prior Anti Cancer – ITT 
-Table. Prior Anti Cancer Therapy by Anatomical and Therapeutic Class – ITT 
-Table. Post Anti Cancer Therapy by Anatomical and Therapeutic Class – ITT 
-Table. Prior Surgeries and Procedures by SOC and PT – ITT 
-Table. Concomitant Surgeries and Procedures by SOC and PT – ITT 
-Table. Post Surgeries and Procedures by SOC and PT – ITT 
-Table. Prior Radiotherapy – ITT 
-Table. Concomitant Radiotherapy – ITT 
-Table. Post Radiotherapy – ITT 
7.3 
Medical History 
Medical History will be summarized by treatment group for the ITT set. The number and percentage (%) of 
subjects will be presented based on Preferred Term (PT) and System Organ Class(SOC) using Medical 


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Dictionary of Regulatory Activities (MedDRA) version 19.0 or higher. P-value that tests homogeneity of 
proportions between treatment groups (chi-square test or Fisher’s exact test) will be presented. 
Data will be summarized in the following tables. 
- Table. Medical History by SOC and PT – ITT 
 
 
7.4 
Prior and Concomitant Medications 
All collected medications will be classified as Prior or Concomitant Medications according to Section 5.5, 
and coded by using WHO-DDE 2017(ATC code). For ITT set, the number and percentage (%) of subjects 
will be presented based on ‘Anatomical main group (level 1)’ and ‘Therapeutic subgroup(level 2)’ by 
treatment group. P-value that tests homogeneity of proportions between treatment groups (chi-square test 
or Fisher’s exact test) will be presented 
Data will be summarized in the following tables. 
- Table. Prior Medication by Anatomical and Therapeutic Class – ITT 
- Table. Concomitant Medication by Anatomical and Therapeutic Class – ITT 
- Table. Post Medication by Anatomical and Therapeutic Class – ITT 
 
 
7.5 
Efficacy Analysis 
7.5.1 
Multiple Comparison Procedure on Primary and Key Secondary Endpoints 
To control the family-wise error rate (FWER) on testing multiple hypotheses of interest, the fixed sequence 
closed testing procedure will be used. In this fixed sequence procedure, each hypothesis will be sequentially 
tested with two-sided 5% level only if higher level hypothesis is rejected. For this fixed sequential testing, 
the primary and key secondary efficacy endpoints will be tested using the ITT set. Specifically, 
1. Test OS with two-sided 5% level 
2. If OS is significant, test PFS (based on central review) with two-sided 5% level 
3. If OS and PFS are significant, test ORR (based on central review) with two-sided 5% level 
If a prior test is not statistically significant, then the subsequent analyses will be exploratory rather than 
confirmatory. 
7.5.2 
Primary Efficacy Analysis 
• 
Overall Survival (OS): Time from randomization to death. Subjects alive or lost to follow-up are 
censored at the date the subject was last known to be alive. 
The primary efficacy endpoint (OS) will be analyzed using ITT, FAS and PPS. The primary efficacy analysis 
will be conducted using the ITT set. The final analysis will be conducted when approximately 325 events 
are observed. 
The comparison of OS between the two treatment groups will be performed with a logrank test stratified on 
the randomization stratification variables Geographic region (Asia vs. North America/Europe), Prior 


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ramucirumab treatment (Yes vs. No), and Treatment therapy line (3rd vs. ≥ 4th) at the two-sided alpha=0.05 
level of significance. 
In order to estimate the hazard ratio, a Cox proportional hazards regression model will be fitted with 
treatment group as a factor and the randomization stratification variables [Geographic region (Asia vs. North 
America/Europe), Disease measurability (measurable vs. nonmeasurable), Prior ramucirumab treatment 
(Yes vs. No), and Treatment therapy line (3rd vs. ≥ 4th)] as covariates. The hazard ratio and its 95% 
confidence interval will be presented. 
Kaplan-Meier estimates will be calculated for each treatment group to construct the survival curve. The 
median overall survival and its 95% CI (based on Greenwood formula) will be presented. The primary 
endpoints will also be analyzed using the FAS and PPS. 
Data will be summarized in the following tables and figures. 
-Table. Overall Survival – ITT 
-Table. Overall Survival – FAS 
-Table. Overall Survival – PPS 
 
-Figure. Kaplan Meier Plot for Overall Survival – ITT 
-Figure. Kaplan Meier Plot for Overall Survival – FAS 
-Figure. Kaplan Meier Plot for Overall Survival – PPS 
7.5.3 
Key Secondary Efficacy Analysis 
The key secondary efficacy endpoints (PFS, ORR) will be analyzed using ITT, FAS and PPS. The key 
secondary efficacy analyses will be conducted using the ITT set. 
• 
Progression Free Survival (PFS): Time from randomization to either documented radiological 
progression (determined by the central imaging analysis facility) or death from any cause. Subjects 
alive and free of progression are censored at the last tumor assessment date when alive and free 
of progression were known. 
• 
Objective Response Rate (ORR): Percentage of subjects with a Best Overall Response 
(determined by the central imaging analysis facility) of Complete Response (CR) or Partial 
Response (PR). 
PFS will be analyzed using the same statistical methods that are used in the primary efficacy analysis of 
OS. 
ORR will be analyzed using the Cochran-Mantel-Haenszel test stratified by the randomization stratification 
factors Geographic region (Asia vs. North America/Europe), Prior ramucirumab treatment (Yes vs. No), and 
Treatment therapy line (3rd vs. ≥ 4th). For the ORR, the frequency and percentage (with 95% CI) of subjects 
will also be provided. 
Data will be summarized in the following tables and figures. 
-Table. Progression Free Survival [Independent Central Review] – ITT 


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-Table. Progression Free Survival [Independent Central Review] – FAS 
-Table. Progression Free Survival [Independent Central Review] – PPS 
 
-Figure. Kaplan Meier Plot for Progression Free Survival [Independent Central Review] - ITT 
-Figure. Kaplan Meier Plot for Progression Free Survival [Independent Central Review] - FAS 
-Figure. Kaplan Meier Plot for Progression Free Survival [Independent Central Review] – PPS 
 
-Table. Objective Response Rate [Independent Central Review] – ITT 
-Table. Objective Response Rate [Independent Central Review] – FAS 
-Table. Objective Response Rate [Independent Central Review] – PPS 
 
-Table. Progression Free Survival - [Investigator Review] – ITT 
-Table. Progression Free Survival - [Investigator Review] – FAS 
-Table. Progression Free Survival - Investigator Review] – PPS 
 
-Table. Objective Response Rate - [Investigator Review] – ITT 
-Table. Objective Response Rate - [Investigator Review] – FAS 
-Table. Objective Response Rate - [Investigator Review] – PPS 
 
- List. Time to Event Parameters by Subjects – ITT Set 
- List. Objective Response by Subject – ITT Set 
 
 
7.5.4 
Other Secondary Efficacy Analysis 
All other secondary efficacy endpoints will be analyzed in the ITT, FAS, and PPS using two-sided test at 
the alpha=0.05 level of significance, with no adjustments for multiplicity. 
• 
Disease Control Rate (DCR): Proportion of subjects with a Best Overall Response (determined by 
the central imaging analysis facility) of complete or partial response (CR or PR), or stable disease 
(SD). 
• 
Global health status/quality of life score according to European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and EORTC QLQ- 
STO22. 
• 
Each dimension response according to EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire. 
For the DCR, the same statistical method that is used in ORR will be performed. 
Each derived score from the European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 (EORTC QLQ-C30) and EORTC QLQ-STO22 will be summarized by descriptive 
statistics by treatment group for each cycle. Each derived score from EORTC QLQ-C30 and EORTC QLQ- 
STO22 will also be analyzed using analysis of covariance (ANCOVA) models for each cycle with the derived 
change from baseline score as dependent variable, treatment group and the randomization stratification 
variables as factors, and the baseline score of the corresponding questionnaire as a covariate. Least 


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squares mean difference and 95% confidence interval with corresponding p-value for comparing two 
treatment groups will be presented. 
For EuroQol 5-Dimension 5-Level (EQ-5D-5L), the number and percentage (%) of subjects for each level 
of each dimension will be presented for each cycle for both treatment groups. EQ VAS data will be analyzed 
using analysis of covariance (ANCOVA) models for each cycle with the derived change from baseline score 
as dependent variable, treatment group as a factor and the randomization stratification variables, the 
baseline score of the corresponding questionnaire as covariates. Least squares mean difference and 95% 
Confidence interval with corresponding p-value for comparing two treatment groups will be presented. 
Data will be summarized in the following tables. 
-Table. Disease Control Rate [Independent Central Review] – ITT 
-Table. Disease Control Rate [Independent Central Review] – FAS 
-Table. Disease Control Rate - [Investigator Review] – ITT 
-Table. Disease Control Rate - [Investigator Review] – FAS 
 
 
-Table. EORTC QLQ-C30 [Parameter]] – ITT 
-Table. EORTC QLQ-C30 [Parameter] - FAS 
-Table. EORTC QLQ-STO22[Parameter] – ITT 
-Table. EORTC QLQ-STO22 [Parameter]- FAS 
-Table. EQ-5D-5L [Parameter] – ITT 
-Table.EQ-5D-5L [Parameter] – FAS 
 
- List. EORTC QLQ-C30 – ITT Set 
- List. EORTC QLQ-STO22 – ITT Set 
- List. EQ-5D-5L – ITT Set 
7.6 
Pharmacodynamic Analysis 
All pharmacodynamic parameters (VEGF, sVEGFR-2, sVEGFR-2, and sVEGFR-3) will be summarized by 
visit (baseline, completion of each 28-day cycle and end of treatment/discontinuation) and will also be listed. 
Summaries will include descriptive statistics including number of observations (n), mean, standard deviation 
(SD), median, minimum (min), and maximum (max). 
All SNP data will be summarized with a table detailing the distribution of SNPs at baseline with the number 
of subjects and corresponding percentage of each polymorphism for each SNP analyzed (i.e. rs1870377, 
rs2305948, and rs17709898). Each SNP analyzed will also be listed for each subject. 
-Table. Summary of Pharmacodynamic Factors – ITT 
-Table. Summary of SNP Distribution – ITT 
 
-List. Pharmacodynamic Factors – ITT 
-List. Subject SNP Status – ITT 


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8. SAFETY EVALUATION 
All safety evaluation is based on Safety Set and summarized by treatment group. 
8.1 
Extent of Exposure 
To access the extent of exposure to the treatment, descriptive statistics will be presented for number of 
cycles, total cumulative dose (mg), duration of treatment (days), delivered dose intensity (mg/day) and 
relative dose intensity (RDI) by treatment group. Also, subjects with one or more dose interruptions, subjects 
with one or more dose adjustment and subjects off treatment will be summarized. The number of cycles will 
refer to all cycles started, including those discontinued or temporarily suspended. 
Exposure related variables are defined as: 
• 
The duration of treatment (days) = Date of last treatment admin.– Date of first treatment admin. +1 
• 
Delivered Dose Intensity (mg/day) = Total dose delivered / The duration of treatment 
• 
Relative Dose Intensity (RDI) = Delivered Dose Intensity (mg/day) / 700 mg/day 
Data will be summarized in the following tables. 
- Table. Treatment Exposure – Safety Set 
 
- List. Drug Concentration Data – Safety Set 
- List. Subjects with Dose Adjustment – Safety Set 
8.2 
Adverse Events 
AEs will be coded by Preferred Term (PT) and System Organ Class(SOC) using version 19.0 or newer of 
Medical Dictionary of Regulatory Activities (MedDRA). All AE tables will reflect only TEAEs defined in 5.6.2. 
Adverse events severity will be classified according to NCI-CTCAE (version 4.03). Adverse events that 
have 
relationship 
with 
investigational 
product 
such 
as 
certain, 
probable/likely, 
possible, 
conditional/unclassified or unassessable/unclassifiable will be defined as adverse drug reaction (ADRs). 
8.2.1 
Overall Summary of Adverse Events 
The number of subjects, incidence rate with its 95% CI and number of events will be presented for TEAEs, 
adverse drug reaction (ADR) and serious adverse event by treatment group during the study. Chi-square 
test or Fisher’s exact test will be used for comparison of AE incidence between groups. 
Data will be summarized in the following tables. 
- Table. Overall Summary of TEAEs – Safety Set 
- Table. Overall Summary of Serious TEAEs – Safety Set 
- Table. Overall Summary of ADRs – Safety Set 
- Table. Overall Summary of Serious ADRs – Safety Set 
8.2.2 
Display of Adverse Events 
All TEAEs and ADR will be presented according to standardized SOC and PT. The following conventions 
will be used in summarizing AEs: 


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• 
For subject incidence summaries, a subject will be counted only once within each SOC and within 
each PT. 
• 
Summaries by NCI-CTCAE grade – if a subject reports more than 1 AE within an SOC and/or PT, 
the AE will the highest severity within each SOC and within each PT will be included. 
• 
When the number of events is calculated, more than 1 AE counted as different events 
Data will be summarized in the following tables and listings. 
- Table. Incidence of TEAEs by SOC and PT – Safety Set 
- Table. Incidence of ADRs by SOC and PT – Safety Set 
- Table. Incidence of TEAEs by the Worst NCI-CTC Grade, SOC and PT [Rivoceranib + BSC] – Safety Set 
- Table. Incidence of TEAEs by the Worst NCI-CTC Grade, SOC and PT [Placebo + BSC] – Safety Set 
- Table. Number of TEAEs by NCI-CTCAE, SOC and PT [Rivoceranib + BSC] – Safety Set 
- Table. Number of TEAEs by NCI-CTCAE, SOC and PT [Placebo + BSC] – Safety Set 
- Table. Incidence of ADRs by the Worst NCI-CTC Grade, SOC and PT [Rivoceranib + BSC] – Safety Set 
- Table. Incidence of ADRs by the Worst NCI-CTC Grade, SOC and PT [Placebo + BSC] – Safety Set 
- Table. Number of ADRs by NCI-CTCAE, SOC and PT [Rivoceranib + BSC] – Safety Set 
- Table. Number of ADRs by NCI-CTCAE, SOC and PT [Placebo + BSC] – Safety Set 
 
- List. Subjects with TEAEs – Safety Set 
8.2.3 
Death and Serious Adverse Events and Other Significant Adverse Events 
For Serious adverse events (SAEs, Sec 5.6.3), AEs leading to IP discontinuation and AEs leading to death, 
separate listings and summaries of subject counts and percents together with the number of events will be 
presented by treatment group and by SOC and PT. Also, subjects who died and primary reason of death 
will be summarized with counts and percents by treatment group. 
Data will be summarized in the following tables and lists. 
- Table. Incidence of Serious TEAEs by SOC and PT – Safety Set 
- Table. Incidence of Serious ADRs by SOC and PT – Safety Set 
- Table. Incidence of TEAEs Leading to IP Discontinuation by SOC and PT – Safety Set 
 
- Table. Incidence of ADRs Leading to IP Discontinuation by SOC and PT – Safety Set 
- Table. Incidence of TEAEs Leading to IP Dose Reduction/Interruption by SOC and PT – Safety Set 
- Table. Incidence of ADRs Leading to IP Dose Reduction/Interruption by SOC and PT – Safety Set 
- Table. Incidence of TEAEs Leading to Fatal Outcome by SOC and PT – Safety Set 
- Table. Incidence of ADRs Leading to Fatal Outcome by SOC and PT – Safety Set 
- Table. Death Summary – Safety Set- List. Subjects with Serious TEAEs – Safety Set 
 
- List. Subjects with Serious TEAEs – Safety Set 
- List. Subjects with TEAEs Leading to IP Discontinuation – Safety Set 
- List. Subjects with TEAEs Leading to IP Dose Reduction/Interruption – Safety Set 
- List. Subjects with TEAEs Leading to Fatal – Safety Set 


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8.2.4 
Dose Limiting Toxicity (DLT) 
Dose Limiting Toxicity data (Sec 5.6.5) will be collected only for the subjects enrolled in Japan Run-in. The 
incidence of DLT will be summarized and relevant subjects will be listed. 
- Table. Incidence of DLT in Japan Run-in – Safety Set 
- List. Subjects with DLT in Japan Run-in – Safety Set 
8.3 
Clinical Laboratory Evaluation 
Laboratory data will be classified according to CTC Grade (NCI-CTCAE version 4.03). A shift table from 
baseline to worst NCI-CTC grade will be presented. 
- Table. Shift from Baseline of Hematology Tests by Worst NCI-CTC Grade: Rivoceranib + BSC [Parameter] 
– Safety Set 
- Table. Shift from Baseline of Hematology Tests by Worst NCI-CTC Grade: Placebo + BSC [Parameter] – 
Safety Set 
- Table. Shift from Baseline of Blood Chemistry Tests – serum electrolyte by Worst NCI-CTC Grade: 
Rivoceranib + BSC [Parameter] – Safety Set 
- Table. Shift from Baseline of Blood Chemistry Tests – serum electrolyte by Worst NCI-CTC Grade: Placebo 
+ BSC [Parameter] – Safety Set 
- Table. Shift from Baseline of Blood Chemistry Tests – liver enzymes by Worst NCI-CTC Grade: 
Rivoceranib + BSC [Parameter] – Safety Set 
- Table. Shift from Baseline of Blood Chemistry Tests – liver enzymes by Worst NCI-CTC Grade: Placebo 
+ BSC [Parameter] – Safety Set 
- Table. Shift from Baseline of Blood Chemistry Tests – others by Worst NCI-CTC Grade: Rivoceranib + 
BSC [Parameter] – Safety Set 
- Table. Shift from Baseline of Blood Chemistry Tests – others by Worst NCI-CTC Grade: Placebo + BSC 
[Parameter] – Safety Set 
 
- Table. Shift from Baseline of Coagulation Tests by Worst NCI-CTC Grade: Rivoceranib + BSC [Parameter] 
– Safety Set 
- Table. Shift from Baseline of Coagulation Tests by Worst NCI-CTC Grade: Placebo + BSC [Parameter] – 
Safety Set 
To investigate a normal/abnormal shift from baseline by visit, results will be classified as Normal, Abnormal 
NCS, or Abnormal CS and presented with a shift table. Subjects who were ‘Normal’ or ‘Abnormal - not 
clinically significant (NCS)’ at baseline but shifted to ‘Abnormal - clinically significant (CS)’ will be 
summarized in the following tables and listings. Significant shift from baseline will be tested using 
McNemar’s or Bowker’s test. 
- Table. Shift from Baseline of Hematology Tests [Parameter] – Safety Set 
- Table. Shift from Baseline of Blood Chemistry Tests – serum electrolyte [Parameter] – Safety Set 
- Table. Shift from Baseline of Blood Chemistry Tests – liver enzymes [Parameter] – Safety Set 
- Table. Shift from Baseline of Blood Chemistry Tests – others [Parameter] – Safety Set 
 
- Table. Shift from Baseline of Coagulation Tests [Parameter] – Safety Set 


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- Table. Shift from Baseline of Urinalysis Tests [Parameter] – Safety Set 
- List. Listing of individual laboratory measurements – Safety Set 
- List. Subjects Shifting from Normal or NCS at Baseline to CS at Post-treatment on Laboratory – Safety 
Set 
8.4 
Chest X-ray and Pregnancy Test 
Data for Chest X-ray and Pregnancy Test will be collected whenever there is clinical indication. Clinically 
significant result of Chest X-ray and positive result of Pregnancy Test will be presented in the following lists. 
- List. Clinically Significant Chest X-ray – Safety Set 
- List. Positive Pregnancy Test – Safety Set 
8.5 
Other Safety Measures 
8.5.1 
Vital Signs 
Vital Sign parameters (Systolic Blood Pressure, Diastolic Blood Pressure, Pulse, Body Temperature, 
Respiratory Rate, and Weight) and the change from baseline at each scheduled visit will be summarized 
with descriptive statistics by visit and treatment group. 
Data will be summarized in the following table. 
- Table. Vital Signs [Parameter] – Safety Set 
8.5.2 
Physical Examination 
Subjects with at least once clinically significant abnormal result at all time points after first IP administration 
on physical examination will be summarized by treatment group. Clinically significant result of physical 
examination will be listed. 
Data will be summarized in the following table and list. 
- Table. Clinically Significant Physical Examination – Safety Set 
- List. Subjects with Clinically Significant Abnormal on Physical Examination – Safety Set 
8.5.3 
12-lead Electrocardiogram 
Values for ECG parameters (Heart rate, PR interval, QTcF and RR Interval) and the change from baseline 
will be summarized with descriptive statistics by time point and treatment group. The ECG result will be 
presented in shift tables (Normal, Abnormal NCS, or Abnormal CS) from baseline to each scheduled time 
point by time point and treatment group. Significant shift from baseline will be tested using McNemar’s test. 
Data will be summarized in the following tables and list. 
- Table. 12-lead Electrocardiogram [Parameter] – Safety Set 
- Table. Shift from baseline on 12-lead ECG – Safety Set 
- List. Subjects Shifting from Normal or NCS at baseline to CS at Post-Treatment on 12-lead ECG – Safety 
Set 


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8.5.4 
ECOG performance 
ECOG performance grade (0,1,2,3,4) will be presented in shift tables from baseline to each scheduled visit 
by visit and treatment group. Significant shift from baseline will be tested using Bowker’s test. 
Data will be summarized in the following table. 
- Table. Shift Table on ECOG grade – Safety Set 
9. SUBGROUP ANALYSIS 
Subgroup analyses will be conducted on randomization stratification factors. In the event of any 
randomization errors, the correct classification of the factor will be used.; 
1. 
Geographic region (Asia vs. North America/Europe) 
2. 
Disease measurability (Measurable vs. Non-measurable) 
3. 
Prior ramucirumab treatment (Yes vs. No) 
4. 
Treatment therapy line (3rd vs. ≥ 4th) 
In addition, a subgroup analysis will also be conducted for treatment therapy line comparing 3rd vs 4th vs. 
5th. The 5th line subjects will be identified based on recorded prior lines of therapy as this was not a 
stratification factor. 
The analysis for the efficacy endpoints OS, PFS, ORR, DCR using ITT population will be repeated for 
each subgroup. Descriptive statistics by visit for the efficacy endpoint will also be produced by subgroup. 
Note that subgroup analysis will be performed if there are sufficient subjects within a subgroup for 
statistical analysis. Otherwise, only descriptive statistics will be displayed. 
The study has been sized to provide adequate power for the primary analysis. The subgroup analyses may 
not necessarily reach statistical significance at the 5% level. P-values and 95% confidence intervals will be 
provided but will not be considered inferential. However, a consistency of treatment effect is expected 
across the primary and all subgroup analyses. Subgroup analyses are mainly to demonstrate trend and 
assess internal consistency of any treatment benefit and/or safety signal. Only the analyses that provide 
meaningful information will be presented for the CSR. 
Additional subgroup analyses will be performed to assess the consistency of treatment benefit per the 
primary outcome of overall survival. A forest plot displaying the hazard ratio and its 95% confidence interval 
will be generated for all the subgroups, including the four stratification groups mentioned above: 
1. Treatment therapy line (3rd vs. 4th vs. 5th) 
2. Age category (<65 vs. ≥ 65) 
3. ECOG status (0 vs. 1 at baseline) 
4. Race (white, Asian, black, and others) 
5. Sex (male vs. female) 
6. Previous gastrectomy (Yes vs. No) 
7. Number of organs with metastases (<2 vs. ≥ 2) 
8. Liver metastases (Yes vs. No) 


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Data will be summarized in the following tables. 
-Table. Overall Survival [Asia] – ITT 
-Table. Overall Survival [North America/Europe] – ITT 
-Table. Overall Survival [Measurable] – ITT 
-Table. Overall Survival [Non-measurable] – ITT 
-Table. Overall Survival [Prior ramucirumab] – ITT 
-Table. Overall Survival [No prior ramucirumab] – ITT 
-Table. Overall Survival [3rd line therapy] – ITT 
-Table. Overall Survival [≥ 4th line therapy] – ITT 
-Table. Overall Survival [4th line therapy] – ITT 
-Table. Overall Survival [5th line therapy] – ITT 
-Table. Overall Survival [< 65 ages] – ITT 
-Table. Overall Survival [≥ 65 ages] – ITT 
-Table. Overall Survival [ECOG status at baseline: 0] – ITT 
-Table. Overall Survival [ECOG status at baseline: 1] – ITT 
-Table. Overall Survival [White] – ITT 
-Table. Overall Survival [Asian] – ITT 
-Table. Overall Survival [Black] – ITT 
-Table. Overall Survival [Others] – ITT 
-Table. Overall Survival [Male] – ITT 
-Table. Overall Survival [Female] – ITT 
-Table. Overall Survival [Previous gastrectomy] – ITT 
-Table. Overall Survival [Non-previous gastrectomy] – ITT 
-Table. Overall Survival [Organs with metastases: <2] – ITT 
-Table. Overall Survival [Organs with metastases: ≥2] – ITT 
-Table. Overall Survival [Liver metastases] – ITT 
-Table. Overall Survival [Non-liver metastases] – ITT 
 
 
-Table. Progression Free Survival [Asia] – ITT 
-Table. Progression Free Survival [North America/Europe] – ITT 
-Table. Progression Free Survival [Measurable] – ITT 
-Table. Progression Free Survival [Non-measurable] – ITT 
-Table. Progression Free Survival [Prior ramucirumab] – ITT 
-Table. Progression Free Survival [No prior ramucirumab] – ITT 
-Table. Progression Free Survival [3rd line therapy] – ITT 
-Table. Progression Free Survival [≥ 4th line therapy] – ITT 
-Table. Progression Free Survival [4th line therapy] – ITT 
-Table. Progression Free Survival [5th line therapy] – ITT 


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-Table. Progression Free Survival [< 65 ages] – ITT 
-Table. Progression Free Survival [≥ 65 ages] – ITT 
-Table. Progression Free Survival [ECOG status at baseline: 0] – ITT 
-Table. Progression Free Survival [ECOG status at baseline: 1] – ITT 
-Table. Progression Free Survival [White] – ITT 
-Table. Progression Free Survival [Asian] – ITT 
-Table. Progression Free Survival [Black] – ITT 
-Table. Progression Free Survival [Others] – ITT 
-Table. Progression Free Survival [Male] – ITT 
-Table. Progression Free Survival [Female] – ITT 
-Table. Progression Free Survival [Previous gastrectomy] – ITT 
-Table. Progression Free Survival [Non-previous gastrectomy] – ITT 
-Table. Progression Free Survival [Organs with metastases: <2] – ITT 
-Table. Progression Free Survival [Organs with metastases: ≥2] – ITT 
-Table. Progression Free Survival [Liver metastases] – ITT 
-Table. Progression Free Survival [Non-liver metastases] – ITT 
 
 
-Table. Objective Response Rate [Asia] – ITT 
-Table. Objective Response Rate [North America/Europe] – ITT 
-Table. Objective Response Rate [Measurable] – ITT 
-Table. Objective Response Rate [Non-measurable] – ITT 
-Table. Objective Response Rate [Prior ramucirumab] – ITT 
-Table. Objective Response Rate [No prior ramucirumab] – ITT 
-Table. Objective Response Rate [3rd line therapy] – ITT 
-Table. Objective Response Rate [≥ 4th line therapy] – ITT 
-Table. Objective Response Rate vival [4th line therapy] – ITT 
-Table. Objective Response Rate [5th line therapy] – ITT 
-Table Objective Response Rate [< 65 ages] – ITT 
-Table. Objective Response Rate [≥ 65 ages] – ITT 
-Table. Objective Response Rate [ECOG status at baseline: 0] – ITT 
-Table. Objective Response Rate [ECOG status at baseline: 1] – ITT 
-Table. Objective Response Rate [White] – ITT 
-Table. Objective Response Rate [Asian] – ITT 
-Table. Objective Response Rate [Black] – ITT 
-Table. Objective Response Rate [Others] – ITT 
-Table. Objective Response Rate [Male] – ITT 
-Table. Objective Response Rate [Female] – ITT 
-Table. Objective Response Rate [Previous gastrectomy] – ITT 
-Table. Objective Response Rate [Non-previous gastrectomy] – ITT 


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-Table. Objective Response Rate [Organs with metastases: <2] – ITT 
-Table. Objective Response Rate [Organs with metastases: ≥2] – ITT 
-Table. Objective Response Rate [Liver metastases] – ITT 
-Table. Objective Response Rate [Non-liver metastases] – ITT 
 
 
-Table. Disease Control Rate [Asia] – ITT 
-Table. Disease Control Rate [North America/Europe] – ITT 
-Table. Disease Control Rate [Measurable] – ITT 
-Table. Disease Control Rate [Non-measurable] – ITT 
-Table. Disease Control Rate [Prior ramucirumab] – ITT 
-Table. Disease Control Rate [No prior ramucirumab] – ITT 
-Table. Disease Control Rate [3rd line therapy] – ITT 
-Table. Disease Control Rate [≥ 4th line therapy] – ITT 
-Table. Disease Control Rate [4th line therapy] – ITT 
-Table. Disease Control Rate [5th line therapy] – ITT 
-Table. Disease Control Rate [< 65 ages] – ITT 
-Table. Disease Control Rate [≥ 65 ages] – ITT 
-Table. Disease Control Rate [ECOG status at baseline: 0] – ITT 
-Table. Disease Control Rate [ECOG status at baseline: 1] – ITT 
-Table. Disease Control Rate [White] – ITT 
-Table. Disease Control Rate [Asian] – ITT 
-Table. Disease Control Rate [Black] – ITT 
-Table. Disease Control Rate [Others] – ITT 
-Table. Disease Control Rate [Male] – ITT 
-Table. Disease Control Rate [Female] – ITT 
-Table. Disease Control Rate [Previous gastrectomy] – ITT 
-Table. Disease Control Rate [Non-previous gastrectomy] – ITT 
-Table. Disease Control Rate [Organs with metastases: <2] – ITT 
-Table. Disease Control Rate [Organs with metastases: ≥2] – ITT 
-Table. Disease Control Rate [Liver metastases] – ITT 
-Table. Disease Control Rate [Non-liver metastases] – ITT 
 
 
-Figure. Forest plot of Hazard Ratio for all subgroups – ITT 
 
 
10. GENERAL PRESENTATION OF SUMMARIES AND ANALYSES 
10.1 Significance level 
Unless otherwise specified, all statistical tests will be 2-sided hypothesis tests performed at the 5% level of 


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significance and all confidence intervals will be 2-sided 95% confidence intervals. 
10.2 Summary Statistics 
Summary statistics for continuous variables/endpoints will be presented with number of observations (n), 
mean, standard deviation (SD), median, minimum (min), and maximum (max). Summary statistics for 
categorical variables/endpoints will be presented with counts (n) and percents. Unless otherwise 
specified, denominator of percentage is number of subjects included in the analysis set by each group. 
10.3 Decimals 
Mean, standard deviation, median, minimum, maximum for descriptive statistics of continuous data, and 
percentage for categorical data will be presented down to 2 decimal places. P-values will be reporter to 4 
decimal places. If the calculated p-value is below 0.0001, it will be presented as ‘<0.0001’. 
Results for clinical laboratory tests and vital signs will be presented to significant digits, in other words, 
rounded to the maximum decimal places for each item. 
10.4 Statistical Analysis Methods 
For a between-group comparison of categorical data, a chi-square test will be basically used and when 
more than 20% of the table cells have expected frequencies that are less than 5, Fisher’s exact test will be 
presented. For confidence intervals of proportion of categorical data, if more than 20% of the table cells 
have expected frequencies that are less than 5, then exact 95% CIs will be calculated, otherwise 
approximate 95% CIs will be calculated. 
10.5 Baseline 
Baseline is defined as the value at Cycle 1 Day 1, or the last value observed prior to randomization if this 
is not available. 
10.6 Study Period and Visit Window Definitions 
Unless otherwise specified, data for regular scheduled visits will be summarized. 
Table 8. Visit Window 
 
Visit Name 
Actual Time Point 
Visit Window 
Screening 
~ -Week 2 
- 
Cycle 1 Day 1 
Day 1 
- 
Cycle 1 Day 15 
Day 15 
±3 days 
… 
Cycle Z Day 1 
Day (28×Z + 1) 
±3 days 
Cycle Z Day 15 
Day (28×Z + 15) 
±3 days 
End of Treatment (EOT) 
- 
±7 days 
Post Treatment Follow-Up 
EOT + 28 days 
±7 days 
Survival Follow-Up 
Every 8 weeks after 
Post-Tx F/U 
±7 days 


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10.7 Software for Statistical Analysis 
SAS® Version 9.4 or higher (SAS institute, Cary, NC, USA) 
 
 
11. DATA HANDLING COVENTIONS 
11.1 Handling of Missing Data 
11.1.1 Missing Value of Efficacy Variables 
If any value is missing at any time point or a subject was withdrawn prior to study completion so that there 
are no data, they will be handled as missing without imputation. 
11.1.2 Missing Value of Safety Variables 
For safety endpoints, observed data will be used for analysis without imputation of missing values. 
11.2 Repeated or Unscheduled Assessments 
In case there are measurements from an unscheduled visit after the first dose of the investigational product, 
measurements at scheduled and unscheduled visit are chronologically presented in the subject list whereas 
summary of descriptive statistic by time point will only include measurements at scheduled visits. 
11.3 Handling of Incomplete Date 
For AE data, in case day or month is omitted from the start date, only collected date units will be used 
without any imputation of date. 
When the entire start date is missing or the format of the collected AE date does not allow for comparison, 
the AE will be assumed to be TEAE. 
For surgeries/procedures, in case day or month is omitted from the date thus collected as ‘UK’, only 
collected date units will be used without any imputation of date. When the entire date is missing or the 
format of the collected date does not allow for comparison with the first IP administration date, the 
surgeries/procedures are assumed to being used prior to the first dose administration date of the 
investigational product. When the format of the collected date does not allow for comparison with the EOT 
date, the surgeries/procedures are assumed to being used on or before the EOT date. 
 
 
For medication, in case day or month is omitted from the start or end date thus collected as ‘UK’, only 
collected date units will be used without any imputation of date. When the entire start date is missing or the 
format of the collected start date does not allow for comparison with the first IP administration date, the 
medication is assumed to being used prior to the first dose administration date of the investigational product. 
When the format of the collected start date does not allow for comparison with the EOT date, the medication 
is assumed to being used on or before the EOT date. In case end date is missing or format of the collected 
end date does not allow for comparison, medications assumed to be ‘ongoing’. 


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12. INDEPENDENT DATA MONITORING COMMITTEE (IDMC) AND INTERIM 
ANALYSIS 
12.1 IDMC 
Independent data monitoring committee (IDMC) is composed of 3 members (2 clinicians and 1 statistician) 
who are fully independent of the entity conducting the trial. The IDMC should comply with IDMC charter in 
the ICH GCP guideline. 
The IDMC will meet at least once prior to trial initiation (organizational meeting) and then at least three 
additional times at specific milestones (one for the formal interim analysis and two for the safety review) in 
the trial. The detailed schedule and purpose of the IDMC meetings is described in IDMC charter. 
For the formal interim analysis, the IDMC will convene when approximately 163 events are observed to 
review unblinded results of the interim analysis. The IDMC can convene when unexpected adverse drug 
reaction with a Grade 3 or more (based on NCI-CTCAE 4.03) are observed. The IDMC can also convene, 
if necessary, to ensure appropriate review of the Japan specific safety run-in (Sec 3.5). 
12.2 Interim Analysis and Stopping Rules 
The interim analysis for futility will be conducted with collected clinical data when approximately 163 
(approximately 50% of the required 325 events) events are observed. The independent contract research 
organization for the interim analysis (AXIO Research, LLC) will conduct all the interim analysis for the study. 
All planned study procedures such as subject enrollment, treatment and follow-up visit should be performed 
regardless of the interim analysis. If it is necessary to change the timing of the interim analysis, in 
consultations with sponsor, the IDMC can change interim analysis time and its corresponding statistical 
criteria for early termination. 
The interim analysis for futility will assess the primary (OS) and key secondary (PFS, ORR) efficacy 
endpoints using the statistical methods planned for the final analysis but only for ITT population. The interim 
analysis for futility and two safety reviews will assess adverse events and safety endpoints. The IDMC will 
review the results of the interim analysis and recommend to the sponsor whether or not to terminate the 
trial for futility. Final decision regarding study termination will be made by the sponsor. 
The IDMC and independent statisticians involved in the interim analysis should keep the interim analysis 
result completely confidential. The results of the interim analysis should be kept unknown to all staff involved 
in the conduct of the trial. If early termination is decided, the IDMC delivers the interim analysis report to 
the sponsor after the official unblinding procedure. 
Early termination will be considered if the interim analysis is futile, that is when the calculated conditional 
power based on primary efficacy endpoint, overall survival (OS), is less than 0.2. The main/official futility 
analysis will assume future data is distributed as the current data to calculate conditional power (Pepe- 
Anderson-Betensky test). For additional sensitivity check, conditional power will be calculated assuming 
future data are distributed according to the alternative hypothesis, specifically hypothesized effect of 
HR=0.72 (Lan-Simon-Halperin test). 
Early stopping for futility interim analysis does not inflate the Type-I error, thus Type I-error adjustment is 
not needed. 


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13. CHANGE FROM PROTOCOL 
 
Protocol v5.0 
Location(s) 
SAP 
Location(s) 
Protocol v5.0 Language 
SAP Language Changed from 
Protocol v5.0 
Reason of Change 
Section. 8.1.1 
p.73 
Section 3.7.1 
p.15 
“Where HR (hazard ratio) 
is the ratio of median 
overall survival of Placebo 
and Rivoceranib* group.” 
“where HR (hazard ratio) is the ratio of 
median overall survival of denotes the 
hazard ratio for Rivoceranib group 
relative to Placebo group.” 
Clarify language in the protocol. 
Section 8.1.3 
p.74 
Section 3.7.3 
p.16 
“325 events (413 subjects) 
are needed.” 
“a total of 325 events (413 subjects) are 
needed to provide approximately 80% 
power for Overall Survival.” 
Clarify language in the protocol. 
Section 8.3.2 
p.75 
Section 4.1 
Section 4.2 
Section 4.3 
Section 4.4 
p.17 
“ITT set consists of data 
from all subjects who are 
randomized.” 
“The analysis for primary 
endpoint, OS and the 
secondary endpoints of 
PFS and ORR will be 
conducted in the ITT set.” 
“Safety set consists of data 
from all subjects who 
received at least one dose 
of Rivoceranib or placebo.” 
“The FAS will be used for 
all efficacy analyses.” 
“The PPS will be used for 
all efficacy analyses.” 
“ITT set consists of data from all 
subjects who are randomized into the 
study.” 
“The analysis The ITT set will be used 
for the primary efficacy analyses 
endpoint, OS and the secondary 
endpoints of PFS and ORR will be 
conducted in the ITT set.” 
“Safety set consists of data from all 
subjects in the ITT population who 
received at least one dose of 
Rivoceranib or placebo.” 
“The FAS will be used for all supportive 
efficacy analyses.” 
“The PPS will be used for all supportive 
efficacy analyses.” 
Clarification that ITT set will be 
used for the primary efficacy 
analyses, and FAS and PPS will 
be used for supportive efficacy 
analyses. 


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Protocol v5.0 
Location(s) 
SAP 
Location(s) 
Protocol v5.0 Language 
SAP Language Changed from 
Protocol v5.0 
Reason of Change 
Appendix 2: 
Table 3 
p.91 
Section 5.1 
Table 4 
Table 5 
p.18 
Table title: Time Point 
Response 
Table title: Time Point Response 
(subjects with target and non-target 
lesion) 
Added table 5: Time Point Response 
(subjects with non-target lesion only) 
Clarified on the original table 
and added a table to define 
response for subjects with non- 
target lesion only. 
Section 8.2.1 
p.74 
Section 8.3.4 
p.76 
Section 5.1.1 
p.19 
Section 7.5.2 
p.29 
“Overall Survival (OS): 
Time from randomization 
to death. Subjects alive or 
lost to follow-up at the end 
of study (EOS) are 
censored.” 
“Overall Survival (OS): Time from 
randomization to death. Subjects alive 
or lost to follow-up at the end of study 
(EOS) analysis cut-off point are 
censored at the date the subject was 
last known to be alive.” 
Clarified overall survival 
censoring. 
Section 8.2.2 
p.74 
Section 8.3.5 
p.76 
Section 5.1.2 
p.19 
Section 7.5.3 
p.30 
“Subjects alive and free of 
progression at the end of 
study (EOS) are 
censored.” 
“Subjects alive and free of progression 
at the end of study (EOS) are censored 
at the last tumor assessment date when 
alive and free of progression were 
known.” 
Clarified progression free 
survival censoring. 
Section 8.3.5 
p.76 
Section 5.1.2 
p.19 
“Progression Free Survival 
(PFS): Time from 
randomization to either 
radiological progression 
(determined by the central 
imaging analysis facility) or 
death from any cause.” 
Centrally imaging results will determine 
the subject’s best tumor response and 
time of progression according to 
RECIST 1.1. for PFS, ORR and DCR. 
In addition, supportive tumor response 
and progression will be analyzed based 
on investigator assessment. 
Added supportive tumor 
response and progression 
analyses based on investigator 
assessment. 
Section 8.3.4 
p.76 
Section 7.5.2 
p.29 
“The comparison of OS 
between the two treatment 
groups will be performed 
with a stratified log-rank 
“The comparison of OS between the 
two treatment groups will be performed 
with a log-rank test stratified on the 
randomization stratification variables 
Due to the occurrence of 
several very small strata for 
non-measurable subjects, it is 
not meaningful to conduct 


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Protocol v5.0 
Location(s) 
SAP 
Location(s) 
Protocol v5.0 Language 
SAP Language Changed from 
Protocol v5.0 
Reason of Change 
test at the two-sided 
alpha=0.05 level of 
significance.” 
[Geographic region (Asia vs. North 
America/Europe), Prior ramucirumab 
treatment (Yes vs. No), and Treatment 
therapy line (3rd vs. ≥ 4th)] at the two- 
sided alpha=0.05 level of significance.” 
stratified analyses using all four 
randomization stratification 
variables. The measurable vs. 
non-measurable stratification 
criteria will not be utilized in all 
stratified analyses. 
Section 8.3.4 
p.77 
Section 7.5.2 
p.29-30 
“For the ORR (CR or PR), 
…Response in both 
treatment groups will be 
compared with the 
Cochran-Mantel-Haenszel 
test stratified by the 
randomization stratification 
factors.” 
“ORR will be analyzed using the 
Cochran-Mantel-Haenszel test stratified 
by the randomization stratification 
factors Geographic region (Asia vs. 
North America/Europe), Prior 
ramucirumab treatment (Yes vs. No), 
and Treatment therapy line (3rd vs. ≥ 
4th).” 
Due to the occurrence of 
several very small strata for 
non-measurable subjects, it is 
not meaningful to conduct 
stratified analyses using all four 
randomization stratification 
variables. The measurable vs. 
non-measurable stratification 
criteria will not be utilized in all 
stratified analyses. 
Section 8.3.4 
p.82 
Section 5.1.2 
p.19 
Entire table: Table 8. PFS 
censoring rule 
Entire table: Table 8. PFS censoring 
rule. 
“Subjects alive and free of progression 
are censored at the last tumor 
assessment date when alive and free of 
progression were known.” 
Scenarios in Table 8 in the 
protocol is redundant and not 
entirely accurate, so the entire 
table is removed and replaced 
by the censoring guideline 
described in this SAP. 
Specifically, death for any cause 
should always be a PFS event. 
* Note: For purposes of this SAP, Rivoceranib will be used as the nonproprietary name throughout the document. Apatinib was formerly used in the 
protocol. In addition, grammatical and typographical changes are not included in the table. 


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14. SAS PROCEDURE FOR TESTING 
14.1 Test of Categorical Variable for Comparison of Treatment Groups 
 
 
14.2 Test for shift from baseline to post-baseline within treatment group 
 
 
14.3 Cochran-Mantel-Haenszel test 
 
 
14.4 Logrank test and Kaplan-Meier estimates 
 
 
14.5 Stratified Logrank test 
 
 
14.6 Cox proportional hazard regression model 
 


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14.7 Analysis of Covariance (ANCOVA) 
 
 
15. REFERENCES 
1 Li J, Qin S, Xu J, et al. Randomized, double-blind, placebo-controlled Phase III trial of Apatinib in patients 
with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal 
junction. J Clin Oncol. 2016;Feb 16. pii: JCO635995. 
Appendix. 
Appendix 1. LIST OF TABLES, LISTINGS AND FIGURES 
Appendix 1.1. Mock-up Tables 
Appendix 1.2. Mock-up Figures 
Appendix 1.3. Mock-up Listings