Clinical trial NCT02264210
Conditions: Lung Neoplasms Squamous Cell Lung Cancer Adenocarcinoma of the Lung Adenosquamous Cell Lung Cancer Large Cell Lung Cancer Bronchial Neoplasms Stage IB Non-small Cell Lung Cancer
Sponsor: Sun Yat-sen University
Start date: 2015-01-01; Completion date: 2022-07-01
Enrollment: 128 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies how well icotinib works in treating patients with completely resected stage IB NSCLC harboring EGFR mutation.

Detailed description:
Adjuvant chemotherapy have shown little evidence of survival benefit in patients with stages IB non-small cell lung cancer (NSCLC) after complete resection. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) show great efficacy in patients with EGFR mutant non-small cell lung cancer (NSCLC). Icotinib is a novel EGFR-TKI developed by a group of Chinese scientists and clinician. In the phase III ICOGEN trial, icotinib had non-inferiority efficacy to gefitinib with better safety. This study is studying icotinib to see how well it works in treating patients with fully resected stage IB NSCLC harboring EGFR mutation.

Arms: arm 1: Icotinib 125 mg three times daily (375 mg per day) orally for 12 months. arm 2: Observation.
Interventions: intervention 1: Icotinib
Intervention descriptions: intervention 1: Icotinib 125 mg three times daily (375 mg per day) by mouth for 12 months.

Protocol documents:
Prot_000.pdf: 
Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
Clinical Trial Protocol  
 
Randomized, prospective, open-label phase II clinical study of 
adjuvant icotinib (12 months) versus observation in patients 
with stage IB epidermal growth factor receptor 
(EGFR)-mutant non-small cell lung cancer (NSCLC) after 
complete resection (CORIN Study) 
 
 
       
Principal investigator: Si-Yu Wang 
Sponsor: Betta Pharmaceuticals Co., Ltd., Hangzhou, China 
Protocol No.: GASTO 1003 
Registration No.: NCT02264210 
Protocol version No.: 1.1, May, 2020.  
 
 
 
 
 
 
 
Confidentiality statement 
The information contained herein (especially unpublished data) is the property of the Sponsor and 
therefore information provided to you (the Investigator, potential investigator or consultant) is confidential; 
only you, your employees or related Ethics Committee can review them. No information herein can be 
disclosed to others without the written permission of the Sponsor unless the information is provided for 
obtaining the informed consent forms of patients who may have possible medication.    


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
2
  
Synopsis  
 
Title 
Randomized, prospective, open-label phase II clinical study of adjuvant icotinib (12 
months) versus observation in patients with stage IB epidermal growth factor receptor 
(EGFR)-mutant non-small cell lung cancer (NSCLC) after complete resection 
Sponsor 
Betta Pharmaceuticals Co., Ltd., Hangzhou, China 
Objectives 
 
 
To investigate the efficacy of icotinib, an epidermal growth factor receptor tyrosine 
kinase inhibitor (EGFR-TKI) as a postoperative adjuvant therapy for stage IB mutant type 
non-small cell lung cancer (NSCLC) without chemotherapy.  
Primary endpoint: 3-year disease-free survival (DFS). 
Secondary endpoints: disease-free survival (DFS), overall survival (OS), central 
nervous system (CNS)-related DFS, safety and tolerability. 
Study 
Design 
Randomized, prospective, open-label phase II clinical study 
Number 
of 
Subjects  
128 
Target 
Populatio
n 
EGFR-mutant stage IB (based on 7th TNM staging) NSCLC without postoperative 
chemotherapy  
 


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
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Inclusion 
criteria 
Inclusion criteria related to disease:  
• Postoperative histopathology has confirmed stage IB NSCLC with R0 resection by 
TNM staging, accompanied with positive EGFR mutation; 
• Have not received other chemotherapy, radiation therapy or biological therapy; 
• Adjuvant chemotherapy was not planned;  
• The treatment starts within 4 weeks after surgery; 
• No signs of tumor recurrence based on examinations prior to treatment.  
Hematology, Biochemistry and Organ Functions:  
• 
Lung function: FEV1>50; 
• 
Hemoglobin ≥90 g/L (this level can be maintained or exceeded by blood 
transfusion); 
• 
Absolute neutrophil count ≥2.0×109/L; 
• 
Platelet count ≥100×109/L;  
• 
Total bilirubin ≤ 1.5 times the upper limit of normal (ULN); 
• 
ALT and AST ≤ 2.5 times the ULN;  
• 
Creatinine ≤ 1.25 times the ULN; and creatinine clearance ≥ 60 mL/min;  
• 
No pregnancy for women of childbearing age (15 to 49 years).  
General inclusion criteria:  
• 
Subjects have obtained informed consent form signed by the patient or his/her 
legal representative; 
• 
Subjects have good compliance; 
• 
Subjects can take medicines orally;  
• 
Subjects are males or females aged ≥18 years; 
• 
Subjects have ECOG Performance Status Scale of 0-1 and life expectancy of 
greater than 1 year; 
• 
Male and female subjects of childbearing age agree to take reliable measures for 
contraception before entering the study, during the study and up to 8 weeks after 
drug discontinuance.   


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
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Exclusion 
criteria 
• 
Subjects have received any other systemic anticancer therapy for NSCLC, 
including cytotoxic drug therapy, targeted drug therapy (including tyrosine 
kinase inhibitors or monoclonal antibodies), experimental treatment;  
• 
Subjects have received local radiotherapy for NSCLC; 
• 
Subjects have incomplete physiological functions of the upper gastrointestinal 
tract, or malabsorption syndrome, or intolerance to oral medications, or active 
gastrointestinal ulcers; 
• 
There are clinically objective evidences (pathology or imaging evidences) to 
confirm tumor recurrence before the start of treatment; 
• 
Subjects have suffered from cancers other than NSCLC, excluding cervical 
carcinoma in situ, cured basal cell carcinoma, urothelial tumors [including Ta 
and Tis] within the five years prior to the start of treatment in this study;  
• 
Subjects are known to be allergic to icotinib or any components of this drug 
product;  
• 
Subjects have a history of interstitial lung disease, drug-induced interstitial 
disease, radiation pneumonitis requiring hormonal therapy, or any active 
interstitial lung disease with clinical evidences;  
• 
Subjects are found to have idiopathic pulmonary fibrosis by CT scan at the 
baseline;  
• 
Subjects have eye inflammation or eye infection that is not completely 
controlled, or any condition that may cause the above eye diseases;   
• 
Subjects have suffered from any unstable systemic disease, including active 
infection, uncontrolled hypertension, unstable angina, angina occurring within 
the recent 3 months, congestive heart failure (≥New York Heart Association 
[NYHA] Class II), myocardial infarction (6 months before enrollment), severe 
arrhythmia requiring drug therapy, liver, kidney or metabolic diseases;  
• 
Subjects have known HIV infections; 
• 
Subjects combined with additional components of small cell lung cancer; 
• 
Pregnant or breastfeeding women; 
• 
Subjects have a history of definite neurological or psychiatric disorders, 
including epilepsy or dementia; 
• 
Other circumstances deemed inappropriate by the Investigator.   


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
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Duration 
of study 
It is planned to enroll 128 patients based on about 6 patients enrolled each month; and the 
time for enrollment is about 24 months; the minimum survival follow-up period is 3 years, 
and the total study period will last about 60 months.  
Study 
Drug 
Dosage/ 
Route 
of 
Administr
ation/Regi
men 
Group A (icotinib group):   
Patients start to receive oral icotinib 125 mg, tid, for 12 months after R0 resection of 
NSCLC, or discontinue treatment due to tumor recurrence or intolerance.   
Group B (control group)  
Patients are followed up after R0 resection of NSCLC.  
Study 
Procedure 
After patients have signed the informed consent forms (ICFs) and meet the inclusion 
and exclusion criteria, they will be randomly assigned to the icotinib group and the control 
group.  
Patients need to be evaluated. The patients receive the visits once every 3 months 
during the dosing period, and once every 6 months for the survival follow-up until the 
disease recurrence or death.  
The Investigator shall contact the patient, the patient's family, or the patient's current 
physician by phone at least once every 3 months after recurrence, to collect the long-term 
follow-up information on survival. Any patient who withdraws from study treatment for 
reasons other than recurrence (except patient’s withdrawal of informed consent, loss to 
follow-up, death) should continue to receive the objective tumor evaluation every 6 months 
to collect the information on recurrence. 
Safety  
All patients who have received at least one treatment with study drug will be included 
as the effective population for safety analysis. The patient's physical examination results, 
vital signs, adverse events, and abnormal laboratory test results will be summarized. 
Adverse events should be reported and graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
Statistical 
Analysis 
The sample size is 128 for the following considerations: based on previous studies, the 
3-year DFS for stage IB NSCLC is about 60%, the hazard ratio (HR) is 0.5, the test power 
(1-β) is 80%, and the test level (α) is two-sided 10%; enrollment period of 24 months, and 
total study period of 60 months. 
 
 
 
 


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
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 Summary 
Postoperative histopathology 
confirmed stage IB NSCLC with 
R0 resection without adjuvant 
chemotherpay 
Group receiving 
icotinib for 12 months  
Follow-up 
observation group  
Randomization 
1:1 
Three-year DFS 


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
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Table 1 Study Flow Chart 
 
Study period 
Screening  
Randomization 
Follow-up after recurrence M 
Group A (icotinib group) 
Group B (control group)  
 
 
C1-C2 
C=3 months 
5-year survival 
follow-up  
C=6 months 
Survival follow-up 
after 5 years 
C= 12 months 
C1-C2 
C=3 months 
5-year survival 
follow-up  
C=6 months 
Survival follow-up 
after 5 years 
C= 12 months 
 
 
C=3 months 
Day -42 to Day -0 
Day -7 to Day 0  
Day 1  
 
Day 1 
 
 
Screeni
ng 
manage
ment  
Informed Consent/Demographics/ 
Medical History A 
 
 
 
 
 
 
 
Inclusion/exclusion criteria review 
 
 
 
 
 
 
 
Urine pregnancy test B  
 
 
      
      
      
      
 
Safety 
data  
ECG C   
 
 
 
 
 
 
 
ECOG Performance Status/Height/ 
Weight/Vital Signs D 
 
 
 
 
 
 
 
Adverse event E 
 
 
 
 
 
 
 
Subsequent treatment and survival 
 
 
 
 
 
 
Medication record F 
 
 
 
 
 
Preoper
ative 
and 
follow-u
p 
examina
tions  
Physical examination 
 
 
 
 
 
 
 
Enhanced chest CT + enhanced upper 
abdominal CT G 
 
 
G 
G 
G 
G 
 
Assessment of other sitesH 
 
 
  
  
 
 
 
Clinical Biochemistry/Hematology/Urine 
Routine I 
 
 
 
 
 
 
 
FACT-L and LCS Questionnaire J 
 
 
 
 
 
 
 
Tissue specimens or sections for 
biomarker studies K 
 
 
 
 
 
 
 
Blood specimens for biomarkers 
(optional ) L 
 
 
 
 
 
 
 
Pulmonary function/HIV antibody/tumor 
markers 
 
 
 
 
 


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
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Study Process Footnotes 
A. Complete medical history (including a complete medical and surgical history of all relevant diseases), demographics, history of prior surgery, combined medication, concomitant diseases, allergies, and history of 
smoking. In particular, the history of previous and current pulmonary disease and/or systemic disease involving the lungs (e.g., connective tissue disease) should be inquired. 
B. It must be negative for premenopausal women of childbearing potential. For a suspected pregnancy event during the trial, the pregnancy test must be repeated, and a positive result must be reported immediately. 
C. LVEF should be examined for an abnormal ECG with clinical symptoms. 
D. Vital signs including heart rate, blood pressure, respiratory rate, and body temperature. 
E. In case of any spontaneous ocular symptoms, new or worsening respiratory symptoms (e.g., cough, shortness of breath), immediate and appropriate medical assistance should be given to the patient. Any symptoms 
should be treated as clinical routine and, if they meet the definition, are also reported as adverse events or serious adverse events (SAEs). Adverse events are collected from signing of the informed consent of the patient. 
After the study is terminated, all unresolved adverse events or serious adverse events are to be followed until solved, unless the Investigator deems them unlikely to be relieved due to the patient's own disease. All new 
adverse events and serious adverse events within 30 days of the last dose of the study should reported (serious adverse events should be reported to the Ethics Committee of the GASTO Research Center and the National 
Medical Products Administration within 24 hours), and followed up until solved as described above. The most severe level of toxic reaction within each course of treatment is recorded in the CRF. 
F. Data on combined medication are collected, including drug dose, route of administration, schedule of administration, start date, indications, end date, and reason for end, and must be recorded from randomized use of 
the study drug until 1 month after drug discontinuation. The treating physician receives this information from the patient's hospital efficacy follow-up visits every 30 days. By knowing the routinely prescribed 
medications, the treating physician evaluates whether clinically significant improvement in pulmonary symptoms is likely to result from changes in the patient's combined medication over the past 30 days. 
G. Pre-operative and evaluation of tumor recurrence imaging must include chest-enhanced CT, upper abdomen-enhanced CT. Tumor evaluation during the follow-up period is performed every 6 months with a window 
phase of +/- 7 days, covering the chest and upper abdomen. All imaging studies could be replaced by PET/CT. 
H. Brain MRI was scheduled every 12 months. Bone scans and other examinations are "recommended" during the screening period to rule out distant metastases. Usually hospitals will routinely examine them. 
Subsequently, bone scans and other examinations will be done with clinical indications. 
I. Hematology (hemoglobin, erythrocyte pressure, platelets, leukocytes, absolute neutrophil values, absolute lymphocyte values) / blood biochemistry (glucose, calcium, phosphorus, sodium, potassium, chloride, 
creatinine, blood urea nitrogen, total protein, albumin, ALT, AST, alkaline phosphatase, total bilirubin, etc.) / urinalysis (urine specific gravity, pH value, urine glucose, urine protein and occult blood) should be 
completed within 7 days before the first dose, at each follow-up visit and 7 days before and after withdrawal from the study, and when clinically indicated, with specific additional frequency as appropriate. 
J. The patient self-assessment outcome questionnaire FACT-L and LCS Version 4 should be completed at each efficacy evaluation. 
K Tissue specimens will be taken during surgery.  
L. For each efficacy visit cycle, 10 ml of whole blood is taken for biomarker analysis prior to treatment, and the blood sample is processed and transported for storage. 
M. The time window for follow-up after recurrence is every 90 days ± 7 days.  


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
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1. Background 
Lung cancer is the leading cause of cancer deaths worldwide[1], among which non-small cell lung 
cancer (NSCLC) accounts for more than 80% of newly diagnosed lung cancer cases[2]. Even among 
early-stage (stage IB) patients, the 5-year survival rate is only 58%, suggesting that this group of patients is 
still at certain risk of recurrence [3], making combination of local control of the tumor and systemic therapy 
an important treatment modal for patients with surgically resectable NSCLC[4]. 
In studies of postoperative adjuvant therapy for NSCLC, a large meta-analysis made by the 
Non-small Cell Lung Cancer Collaborative Group in 1995 included 4767 patients. Results showed that the 
platinum-containing adjuvant chemotherapy regimen increased the 5-year overall survival (OS) by 5%[5], 
and although the results showed no statistically significant difference (P=0.08), they initially established the 
place of the platinum-containing regimen in adjuvant chemotherapy for NSCLC. In the following decade, 
several randomized controlled clinical trials have compared various postoperative cisplatin-containing 
adjuvant chemotherapy regimens with surgery treatment alone. Several large randomized controlled clinical 
trials have been reported in the 21st century, some of which[6-8] confirmed the overall survival benefit of 
adjuvant chemotherapy, but some[9,10] still yielded negative results. In 2008, LACE made a meta-analysis of 
five large sample clinical trials after 1995[11], with 4584 patients and a median follow-up of 5.2 years. 
Results showed that the overall survival rate was benefited in the chemotherapy group (HR=0.89, p=0.005), 
with a 5-year survival rate increased by 5.4%, and the DFS in the chemotherapy group was also benefited 
(HR=0.84, p<0.001), with a 5-year DFS increased by 5.8%. Such meta-analysis also clarified the role of the 
4-cycle platinum-containing regimen in increasing the 5-year survival rate in patients with stage II-IIIA 
NSCLC after complete resection. It is worth mentioning the CALGB9633 study, a randomized controlled 
study applying paclitaxel + carboplatin for adjuvant chemotherapy in all patients at stage IB, whose 
subgroup analysis confirmed that patients with tumor greater than 4 cm in diameter benefit from 
postoperative adjuvant chemotherapy[12]. 
With the clinical research and progressive application of the targeted drug EGFR-TKI, it plays a more 
and more important role in the treatment of patients with non-small cell lung cancer. In particular, clinical 
studies such as IPASS, OPTIMAL and EURTAC show that EGFR-TKI has a significantly better objective 


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
10 
efficacy than first-line chemotherapy regimens in the treatment of patients with EGFR mutations at stage 
IIIB-IV, and therefore has become the first-line treatment standard for this population. Postoperative 
adjuvant targeted therapy for NSCLC is currently a hot topic of research, for example, a phase III 
randomized clinical trial (BR.19 study) investigated the efficacy of postoperative adjuvant gefitinib therapy 
for NSCLC at stage IB-IIIA[13]. The patients were randomized to receive postoperative gefitinib or placebo 
for 2 years, and 503 patients were enrolled between 2002 and 2005 with median treatment duration of 4.8 
months. The results showed a DFS of 4.2 years and an OS of 5.1 years in the gefitinib-treated group, 
indicating that the lifetime of the patients was not significantly prolonged when compared with that of the 
placebo group, but patients with EGFR mutations were not selected for this trial. Another RADIANT 
phase-III clinical study included patients with positive EGFR at stage I-IIIA (IHC or FISH) with 
postoperative erlotinib for 2 years to evaluate the role of erlotinib in adjuvant therapy, with a placebo 
control group, and the population enrolled in this study was also not selected on the basis of EGFR 
mutations[14]. In 2011, MSKCC retrospectively analyzed 167 lung adenocarcinoma patients with stage I-III 
EGFR mutations from 2002-2008, 56 of whom were treated with targeted therapy in the perioperative 
period, and a survival analysis comparison with patients without targeted therapy showed that the former 
had a higher 2-year DFS than that of the latter (89% vs 70%), and despite that the p-value (0.06) was not 
statistically significantly different, the adjuvant targeted therapy group showed a trend of benefit[15]. A 
phase-II clinical study was reported in the SELECT study at the ASCO meeting in 2012, that is, patients 
with stage IA-IIIA mutant lung cancer were treated with postoperative erlotinib for 2 years following 
standard adjuvant chemotherapy or adjuvant radiotherapy. This study enrolled a total of 36 patients, of 
which 11 patients were on the drug for less than 2 years. After a median follow-up period of 2.5 years, the 
2-year DFS rate was as high as 94%. 
Icotinib (trade name: Conmana®) is a small molecule targeted anti-cancer drug developed 
independently in China for treating advanced NSCLC, and belongs to the same class of EGFR-TKIs as 
gefitinib and erlotinib. with clinical approval from the SFDA in 2006, a series of clinical studies have been 
completed, including the safety and tolerability and pharmacokinetic phase-I clinical studies in patients 
with NSCLC administered three times a day, the results showed good tolerability and determined a 
follow-up dosing regimen of 125 mg repeated over 8 hours[16]. An ICOGEN study[17], namely a 


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
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"randomized, double-blind, double-modeled, parallel-controlled, multicenter phase-III clinical trial 
evaluating the efficacy and safety of erlotinib and gefitinib in patients with locally advanced or metastatic 
non-small-cell lung cancer who had received one or two prior chemotherapies", enrolled 399 patients. The 
primary efficacy evaluation indexes PFS for both were 4.6 months vs. 3.4 months, OS were 13.3 months vs. 
13.9 months, and ORR and DCR were similar between the two groups, as 27.6% vs. 27.2% and 75.4% vs. 
74.9%, respectively. In terms of safety, the incidence rate of adverse reactions was 60.5% in the ectetinib 
group, which was significantly lower than that of 70.4% in the gefitinib group, and the difference between 
the two groups was statistically significant. The incidence rates of rash were 40% and 49.2%, respectively, 
the incidence rates of diarrhea were 18.5% and 27.6%, respectively, and no interstitial pneumonia occurred 
in either group. Therefore, the results of the ICOGEN study showed that erlotinib was comparable to 
gefitinib in terms of efficacy, but had a better safety superior to gefitinib. 
The ICOGEN study found in the exploratory index EGFR gene mutation study 69 cases of positive 
EGFR mutation, with an overall mutation rate of 51%, of which exon 19 accounted for 60.3% of the mutant 
population and exon 21 L858R for 29.1%. Conmana® has an efficacy significantly better in patients with 
EGFR mutations than that in wild-type patients, with an efficacy rate of 59% in mutation patients and 5.1% 
in wild-type patients. Median PFS was 6.6 months in mutation patients and 2.4 months in wild-type 
patients, and median OS was nearly two years in mutation patients, nearly one year longer than that in 
wild-type patients. For this reason, , mutations in EGFR exon 19 and exon 21 are equally predictive of the 
efficacy of erlotinib similar to gefitinib or erlotinib in treating non-small cell lung cancer[18]. 
However, it is unclear whether EGFR-mutant NSCLC at stage IB can benefit from postoperative 
adjuvant treatment with erlotinib. Based on the above study background, we randomized patients after 
stage-IB NSCLC R0 resection with positive EGFR mutation to the study group (with control of adjuvant 
erlotinib for 12 months) to observe the efficacy and safety of erlotinib in this group of patients, and to 
answer whether adjuvant TKI therapy can be used to prolong the survival time of patients after surgery for 
stage-IB EGFR-mutant NSCLC.  


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
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Objectives 
2.1. 
Primary objective 
To investigate the efficacy of icotinib, an epidermal growth factor receptor tyrosine kinase inhibitor 
(EGFR-TKI) as a postoperative adjuvant therapy for stage IB mutant type non-small cell lung cancer 
(NSCLC). Primary endpoint: 3-year DFS. 
3. 
Study Design 
3.1. 
Study design and plan  
This is a randomized, prospective, open-label phase II clinical study to evaluate the efficacy and safety 
of icotinib as adjuvant therapy in patients with stage IB EGFR-mutant non-small cell lung cancer (NSCLC) 
after R0 resection. A total of 128 patients will be enrolled in the study and will be randomly divided into 
icotinib treatment group and control observation group. Patients in the icotinib group are given icotinib 125 
mg, tid, orally, for 12 consecutive months, or discontinue due to disease recurrence or intolerable toxicity 
reaction.   
 
3.2  Selection of subjects  
EGFR-mutant stage IB (based on 7th TNM staging) NSCLC without postoperative chemotherapy.  
3.2.1  Inclusion criteria 
Inclusion criteria related to disease:  
• 
Postoperative histopathology has confirmed stage IB NSCLC with R0 resection by TNM staging, 
accompanied with positive EGFR mutation; 
• 
Have not received other chemotherapy, radiation therapy or biological therapy; 
• 
Adjuvant chemotherapy was not planned;  
• 
The treatment starts within 4 weeks after surgery; 
• 
No signs of tumor recurrence based on examinations prior to treatment. 


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
13 
Hematology, Biochemistry and Organ Functions: 
• 
Lung function: FEV1>50; 
• 
 Hemoglobin ≥90 g/L (this level can be maintained or exceeded by blood transfusion); 
• 
Absolute neutrophil count ≥2.0×109/L; 
• 
 Platelet count ≥100×109/L;  
• 
Total bilirubin ≤ 1.5 times the upper limit of normal (ULN); 
• 
ALT and AST ≤ 2.5 times the ULN;  
• 
 Creatinine ≤ 1.25 times the ULN; and creatinine clearance ≥ 60 mL/min;  
• 
 No pregnancy for women of childbearing age (15 to 49 years).  
General inclusion criteria:  
• 
Subjects have obtained informed consent form signed by the patient or his/her legal 
representative; 
• 
Subjects have good compliance; 
• 
Subjects can take medicines orally;  
• 
Subjects are males or females aged ≥18 years; 
• 
Subjects have ECOG Performance Status Scale of 0-1 and life expectancy of greater than 12 
weeks; 
• 
Male and female subjects of childbearing age agree to take reliable measures for contraception 
before entering the study, during the study and up to 8 weeks after drug discontinuance. 
3.2.2  Exclusion criteria 
• 
Subjects have received any other systemic anticancer therapy for NSCLC, including cytotoxic 
drug therapy, targeted drug therapy (including tyrosine kinase inhibitors or monoclonal 
antibodies), experimental treatment;  
• 
Subjects have received local radiotherapy for NSCLC; 
• 
Subjects have incomplete physiological functions of the upper gastrointestinal tract, or 


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
14 
malabsorption syndrome, or intolerance to oral medications, or active gastrointestinal ulcers; 
• 
There are clinically objective evidences (pathology or imaging evidences) to confirm tumor 
recurrence before the start of treatment; 
• 
Subjects have suffered from cancers other than NSCLC, excluding cervical carcinoma in situ, 
cured basal cell carcinoma, urothelial tumors [including Ta and Tis] within the five years prior to 
the start of treatment in this study;  
• 
Subjects are known to be allergic to icotinib or any components of this drug product;  
• 
Subjects have a history of interstitial lung disease, drug-induced interstitial disease, radiation 
pneumonitis requiring hormonal therapy, or any active interstitial lung disease with clinical 
evidences;  
• 
Subjects are found to have idiopathic pulmonary fibrosis by CT scan at the baseline;  
• 
Subjects have eye inflammation or eye infection that is not completely controlled, or any 
condition that may cause the above eye diseases;   
• 
Subjects have suffered from any unstable systemic disease, including active infection, 
uncontrolled hypertension, unstable angina, angina occurring within the recent 3 months, 
congestive heart failure (≥New York Heart Association [NYHA] Class II), myocardial infarction 
(6 months before enrollment), severe arrhythmia requiring drug therapy, liver, kidney or 
metabolic diseases;  
• 
Subjects have known HIV infections; 
• 
Subjects combined with additional components of small cell lung cancer; 
• 
Pregnant or breastfeeding women; 
• 
Subjects have a history of definite neurological or psychiatric disorders, including epilepsy or 
dementia; 
• 
Other circumstances deemed inappropriate by the Investigator. 
3.3 Duration of study 
It is planned to enroll 128 patients based on about 6 patients enrolled each month; and the time for 


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
15 
enrollment is about 24 months; the minimum survival follow-up period is 3 years, and the total study 
period will last about 60 months. 
3.4 Withdrawal of patient from study treatment 
3.4.1 Withdrawal criteria 
3.4.1.1 Withdrawal time and method 
Patients may withdraw from study treatment and evaluation at any stage of the study, for the 
following reasons: 
Patients are free to withdraw voluntarily from the trial at any time, and future treatment is not 
affected; 
The Investigator and the Sponsor deem that there are any safety reasons (adverse events); 
The Investigator and the Sponsor believe that the patient is poor in compliance to study protocol; 
Death; 
Loss to follow-up; 
Other situations where Investigator believes that the patient should withdraw from the study. 
 
The Investigator deems that the patient should withdraw from the study in the following cases:  
Patients receive antitumor therapy other than this study protocol during the treatment period;  
Patients have severe allergic reactions to investigational drug, such as exfoliative rash or 
hypersensitivity reactions of grade 3 to 4;  
There is any other serious adverse reaction that, in the opinion of the principal investigator or his or 
her designated study personnel, requires a discontinuation of treatment; 
Patients have severe poor compliance;  
The urine β-HCG test results of patients suggest pregnancy. Investigator should report this pregnancy 
as a clinical trial pregnancy report form; 
Other diseases are complicating the study, which in the Investigator’s opinion will significantly affect 
the assessment of the patient's clinical condition and require discontinuation of this treatment regimen; 


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
16 
Other malignancies requiring treatment occur; 
Patients are lost to follow up;  
Prohibited drugs or other substances that in the Investigator’s opinion may cause toxic reactions or 
bias study results are used. 
Icotinib is discontinued for more than 2 consecutive weeks due to adverse reactions. 
Patient dies. 
3.4.1.2 Withdrawal procedure 
For patients who withdraw from the study, the Investigator shall ask about the reasons for withdrawal 
and whether any adverse events occurred. If possible, the Investigator should visit and evaluate patients 
who withdraw from the study. The reason and date of withdrawal (date of last dose) must be documented 
on the case report form (CRF). Patients should return all remaining study drugs. 
Upon withdrawal from the trial, if there is a new or worsening laboratory test result of CTC grade 3 
or 4, the patient must undergo further testing and the results should be documented in the appropriate 
section of the CRF until the laboratory test result returns to CTC grade 1 or 2, unless the test result is 
unlikely to improve due to the disease itself. The Investigator shall document their comments on these 
cases in the CRF and in the medical record. 
All study-related toxicities and SAEs at study discontinuation must be followed until they are 
resolved, unless, in the Investigator's opinion, the condition is unlikely to be relieved because of the disease 
itself. 
After the patient discontinues study treatment, the Investigator shall track all existing or new AEs that 
occur within 30 days of the last dose of study drugs, and report all new AEs and SAEs that occur within 
this period of time (SAE must be reported to the Sponsor within 24 hours) and follow up until the adverse 
event is resolved as described above. If a patient dies during the trial or within 28 days after the trial, the 
Investigator shall document the cause of death in detail on the serious adverse event (SAE) report within 24 
hours. 
3.4.1.3 Substitute of withdrawn cases 


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17 
There is no substitute of patients who withdraw early from the study. 
3.5 Treatment plan 
3.5.1 Treatment schedule 
    The enrolled patients are randomized to a group treated with icotinib for 12 months or a control group. 
Patients of the icotinib group are administrated with 125 mg of icotinib orally, tid, for 12 consecutive 
months after surgery, or discontinued due to disease recurrence or intolerable toxic reactions, and the 
control group is merely followed up. 
3.5.2 Discontinuation of icotinib 
• 
Due to good tolerance when used alone clinically, icotinib generally does not need to be 
discontinued. As reported in the literature, the incidences of interstitial lung disease (ILD) in 
Eastern populations treated with gefitinib and erlotinib are 2-3% and 1-2%, respectively. The 
interstitial lung disease is not observed in the ICOGEN clinical study. 
• 
Patients with interstitial lung disease usually present with acute dyspnea with cough, 
hypothermia, respiratory distress, and arterial oxygen desaturation. The symptoms can be severe 
and fatal in a short period of time. Radiological examination often shows pulmonary infiltrates 
or interstitial ground-glass opacities.  
• 
The treating physician should closely monitor for signs of interstitial lung disease during 
treatment and interrupt icotinib therapy if the patient develops a new acute attack or progressive 
worsening of dyspnea or cough, and perform relevant tests immediately. When interstitial lung 
disease is confirmed, the drug should be discontinued and the patient should be treated 
accordingly. 
3.5.3 Combined treatment and smoking 
All combined medications and treatments (including start/stop dates and indications) must be 
documented in the patient's original data as well as in the appropriate section of the CRF. 


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All patients taking combined drugs metabolized via CYP3A4 should be closely monitored for possible 
adverse effects of these drugs. 
Smoking affects the pharmacokinetics of icotinib, and the smoking status, including the number and 
duration of cigarettes smoked per day, should be recorded during treatment. All patients are advised to quit 
smoking during treatment. 
3.5.4 Concomitant medication 
3.5.4.1 Drugs not allowed to be used 
• 
Bevacizumab and any drug that targets VEGF, VEGFR or EGFR (including registered or 
investigational drugs). 
• 
Any other anti-cancer drug is not allowed except for study-specified icotinib, including 
investigational drugs (e.g., investigational antibiotics, antiemetics, etc.) and herbal medicines 
with anti-tumor indications. 
3.5.4.2 Permissible drugs 
• 
Non-anti-cancer herbal medicines or acupuncture, vitamins/trace elements are also allowed 
without affecting the study endpoints observed and are under the control of the Investigator. 
• 
Patients may receive palliative treatment and supportive treatment for their pre-existing disease. 
3.5.5 Treatment compliance 
The dose and date of administration of icotinib taken for each course of therapy for each patient 
should be documented in the CRF. Reasons for delayed administration, medication reduction, or missed 
doses should also be documented in the CRF. 
Patient compliance with treatment and regimen includes voluntary compliance with all aspects of the 
regimen, including compliance with therapeutic agents, compliance with all blood collections required for 
safety assessment, and compliance with regular follow-up visits. Patients who do not take their medications 
on time, or who do not cooperate with tests, or who do not return to the study on time may be excluded 


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19 
from the study based on the assessment of the principal investigator. Patients who discontinue icotinib due 
to unimprovable adverse reactions that do not resolve even with optimal symptomatic and supportive 
therapy may be withdrawn from the study if the duration of discontinuation is longer than 2 weeks, after 
discussion with and consent from the principal investigator. 
3.6 Study endpoints 
The primary efficacy endpoint in this study is 3-year disease-free survival (DFS). 
Secondary endpoints include disease-free survival (DFS), central nervous system (CNS)-related DFS, 
overall survival (OS), safety, and tolerability.  
Exploratory analysis: to evaluate the efficacy of adjuvant icotinib for patients with completely resected 
stage IB NSCLC based on the AJCC 7th and 8th edition of staging.  
To evaluate the efficacy of adjuvant icotinib for patients with completely resected stage IB NSCLC 
based on sensitive EGFR mutation and all EGFR mutations (including atypical EGFR mutations). 
3.6.1 Efficacy endpoints  
Three-year Disease-Free Survival (DFS) is defined as the proportion of patients who were disease 
free at 3 years. 
Disease-free survival (DFS) is defined as the time between the date of randomization and the first 
confirmation of disease recurrence or death from any cause (whichever occurred first).  
Central nervous system (CNS)-related DFS is defined as the time from randomization to CNS 
recurrence or death, whichever occurred first.  
Overall survival (OS) is defined as the time between randomization and death from any cause. The 
1-year overall survival is defined as the probability that the patient is alive for 1 year from the date of 
randomization. The 2-year overall survival is defined as the probability that the patient is alive for 2 years 
from the date of randomization. The 5-year overall survival is defined as the probability that the patient is 
alive for 5 years from the date of randomization. 
The time that patients who are alive as of the date of analysis and are free of disease recurrence have 


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their last imaging evaluation is taken as the cutoff time. 
3.6.2 Safety indicators 
All patients who have received at least one study drug treatment will serve as a valid population for 
safety analysis. Physical examination findings, vital signs, adverse events and abnormal laboratory test 
results of the patients will be summarized. Adverse events should be reported and graded according to the 
NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. 
3.7 Research process (see Table 1 for flow chart) 
3.7.1 Screening period 
• 
Sign an informed consent prior to any study-related operations. 
• 
Acquire demographic information, and complete medical, surgical and smoking histories. 
• 
Record/confirm the TNM stage of the primary tumor at the time of diagnosis. 
• 
Evaluate tumor at chest-enhanced CT scan, upper abdomen-enhanced CT. 
• 
Perform cranial enhanced MRI. Bone scan is performed only in patients with clinical symptoms. 
All examinations may be replaced by PET/CT. 
• 
Take tumor tissue specimen and perform EGFR detection. 
• 
Confirm that the subject meets the inclusion/exclusion criteria as specified in the study protocol. 
• 
Perform physical examination: heart rate, blood pressure, respiratory rate, body temperature, 
height, weight and ECOG physical status scoring. 
• 
Document all concomitant diseases and combined medications and their indications. 
• 
Carry out routine blood tests: hemoglobin, HCT (hematokrit), platelet count, white blood cell 
count, and neutrophils. 
• 
Perform blood biochemical tests: including blood glucose, calcium, phosphorus, sodium, 
potassium, chloride, creatinine, blood urea nitrogen (BUN), total protein, albumin, ALT, AST, 
alkaline phosphatase, total bilirubin, etc. 


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• 
Carry out a 12-lead electrocardiogram (ECG) examination at baseline stage, and check and sign 
by The Investigator. 
• 
Perform urine pregnancy test on all female patients of childbearing age. Postmenopausal women 
who have been menopausal for at least 2 years and women who have undergone sterilization are 
not required to have the urine pregnancy test. 
• 
Carry out routine urine tests: pH value, urine sugar, urine protein, ketone bodies, occult blood, 
urine bilirubin, red blood cells, and white blood cells. 
• 
Perform HIV antibody tests. 
• 
Perform pulmonary function tests. 
• 
Perform tumor marker screening; collect biomarker blood sample specimen. 
• 
Adverse events: signs and symptoms that exist prior to enrollment (prior to signing informed 
consent) and persist at enrollment should be documented per medical history. Any signs and 
symptoms that develop or worsen after enrollment (even before drug therapy) should be 
recorded as adverse events according to NCI-CTCAE Version 4.0. 
• 
Distribute study drugs. 
3.7.2 Visits 
Efficacy evaluation visits and subsequent visits (every 90 days ± 7 days for the first 6 months and 
every 180 days ± 7 days until 5 years)  
 
Perform physical examinations (heart rate, blood pressure, respiratory rate, temperature, body 
weight and ECOG physical status scoring). 
 
Perform laboratory tests (hematology/blood biochemistry/urinary routine); perform ECG/pregnancy 
test.  
 
Collect biomarker samples (optional): take 10 ml of whole blood for molecular marker screening 
before treatment. 
 
Carry out tumor evaluation: it must include chest enhanced CT and upper abdomen enhanced CT. 
The follow-up period during treatment is every 3 months with an interval of +/- 7 days, covering the 


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22 
chest and upper abdomen. All imaging tests can be replaced by PET/CT. Cranial MRI was 
scheduled every 12 months. Bone scan will be performed only when clinically indicated. 
 
Document adverse events and combined medications since the last visit.  
 
Make an appointment for a next visit. 
 
End of visit/visit at study withdrawal 
If a subject discontinues study drug therapy for any reason (other than death or visit missing), an 
end-of-treatment evaluation should be performed at the time of discontinuation, which includes:   
1. Simple physical and vital signs examination, and ECOG behavioral status assessment 
2. Lab tests: complete blood count (CBC), biochemistry, electrolytes, and urinalysis 
3. 12-lead electrocardiogram 
4. Documentation of adverse events: If an adverse event persists at the end of treatment, or if a new 
adverse event is judged by the Investigator to be related to investigational drug, information about the 
adverse event should be collected until 30 days after the end of treatment (this can be done by 
telephone visit). Follow-up should continue until the adverse event has resolved or stabilized, unless 
the Investigator determines that the adverse event is caused by the patient's own disease. If a patient 
dies within 30 days after the end-of-treatment visit, the Investigator should notify the GASTO within 
24 hours and record the detailed cause of death on the Serious Adverse Event (SAE) form. 
5. Record of combined medications 
6. Preserve biomarker samples (optional): 10 ml of whole blood for molecular marker screening. 
3.7.3 Survival follow-up 
In case of postoperative recurrence, telephone survival follow-up is made every 3 months after 
recurrence until 5 years after surgery or death. The following information should be obtained during each 
follow-up visit:  
• 
Patient survival. 
• 
If dead, record the date of death and cause of death in detail. 


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• 
The disease status, and the date of recurrence after the operation should be recorded in detail (for 
patients without recurrence at the last follow-up). 
• 
Detailed documentation of follow-up anti-cancer treatment. 
Note: Patients who have developed tumor recurrence will be followed up according to local medical 
practice at the discretion of the clinician. 
3.7.4 Temporary visits 
Temporary visits should be performed as clinically indicated. Corresponding clinically significant 
abnormal laboratory tests and adverse events should be documented in the CRF and in the original data. If 
multiple laboratory tests are performed on the same day, only the last set of values from these tests should 
be recorded in the CRF. However, all abnormal values from repeated laboratory tests should be recorded in 
the CRF. 
3.8 Quality of data 
In order to follow the guidelines of the Good Clinical Practice (GCP), the monitor visits each center at 
regular time to ensure compliance with the study protocol, GCP and relevant laws. The visits include 
on-site checks for completeness and clarity of CRFs, cross-checking of CRFs and original documentation, 
and resolving questions regarding data queries. 
3.9 Archiving 
The information entered in the CRF must match the original documentation. Study documents and all 
original information should be retained until 15 years after the end of the trial, until a written notification of 
destruction from the Sponsor is received. 


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4 Study Drug 
4.1 Icotinib 
4.1.1  Name, physicochemical properties, description, strength, ingredients, usage, storage of 
investigational drug 
Drug name 
Trade name: Conmana® 
Generic name: icotinib hydrochloride tablets 
Chemical name: 4-[(3-ethynylphenyl) amino]-quinazolo[6,7-b]-12-crown-4-hydrochloride 
Structural forma: 
O
O
O
O
N
N
NH
HCl
，
 
Molecular formula: C22H21N3O4·HCl  
Molecular weight: 427.88 
Physicochemical properties 
Physicochemical properties: icotinib hydrochloride is an off-white to light yellow crystalline powder; 
odorless and non-hygroscopic. It is soluble in dimethyl sulfoxide, slightly soluble in acetonitrile-water (1:1), 
methanol or chloroform, very slightly soluble in ethanol, and practically insoluble in water and acetonitrile. 
The melting point is 225-228°C. The absorption coefficient (E
1%
1cm) at the wavelength of 340 nm is 500-520.  
Description: Brown-red film-coated tablets, off-white after removing the coating 
Strength: 125 mg. 
Ingredient: The main ingredient is icotinib hydrochloride.  
Administration: Oral, one tablet once, tid.  


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StoragePreserve in tightly closed containers and protected from light.   
5 Ethical and legal issues  
5.1 Independent Ethics Committee (IEC) 
In accordance with the requirements of GCP, Chinese laws and regulations and relevant organizations, 
all study sites participating in this study shall obtain the approval documents of the Ethics Committee 
before the start of the study. Where necessary, the amendments or review of the Ethics Committee shall be 
obtained and forwarded to the Investigator. 
5.2 Ethical guidance for this study 
The procedures for operation, assessment, and documentation covered in this study protocol are 
intended to ensure that the study personnel comply with the clinical practice guidelines and the guiding 
principle detailed in the Declaration of Helsinki. The implementation of this study will also follow Chinese 
Good Clinical Practice.  
The study personnel cannot modify the study protocol without the written consent of the Ethics 
Committee and the Sponsor. However, for the purpose of eliminating the risk factor for patients in an 
emergency, the study personnel can deviate from or modify the study protocol without prior 
consent/support from the Ethics Committee/Institutional Review Board/Sponsor. Deviations or 
modifications and the reasons should be submitted to the Ethics Committee/Institutional Review 
Board/Sponsor as quickly as possible; where appropriate, a proposal for protocol amendments should be 
submitted. The study personnel shall give adequate explanations and describe all deviations or 
modifications to the study protocol.  
5.3 Notice to patients and informed consent 
The study information and ICFs should be provided to patients. Prior to the start of the study, the study 
personnel shall provide ICFs and all other written documentations approved in writing by the Ethics 
Committee to the patients. The approval letter of Ethics Committee, the approved Notice to Patients/ICFs 
must be archived in the study documentation.  


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26 
A signed informed consent must be obtained from patients before any procedure related to this study is 
performed for them. 
5.4 Confidentiality 
All records regarding patient’s identity are kept confidential and will not be made public to the extent 
permitted by applicable laws and/or regulations. Only personnel related to this trial, for example, the 
Investigator and study nurse, can know the patient's identity information. 
The patient's name will not appear in the CRF. Only the patient’s ID and initials are recorded in the 
CRF. A patient's name appearing in any other document (e.g., a pathology report), must be erased in the 
copy of the document. The study reports stored in the computer must comply with the local laws on data 
protection. The patient's identity will also be kept private when the study results are published.  
The Investigator will maintain a name list to identify the patients’ records.   
5.5 Conditions for amendment to the study protocol 
Protocol amendments to the ongoing trial can be made only after mutual consultation between the 
Sponsor and the principal investigator. Materials prepared by the Sponsor for protocol amendment should 
be reviewed in advance by principal investigator, biostatisticians and other relevant personnel. Except for 
the emergency adjustment to eliminate imminent harm to the patients in the study or the adjustment related 
to the logistics and management of the study, such as changes to the monitor, phone number, all protocol 
amendments must be submitted to and approved by the Ethics Committee, and submitted to the regulatory 
authority when necessary. The Investigator can implement adjustments only after the approval of these 
agencies.  
5.6 Conditions for termination of the study 
The Sponsor and principal investigator reserve the right to terminate the study at any time. When the 
study is terminated, both the Sponsor and the principal investigator will ensure that the patient's interests 
and benefits are fully considered.  


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5.7 Preservation of Study Documentation, Medical Report Forms, and Records  
5.7.1  Preservation of Investigator’s documentation 
In order to ensure that the conduct of the study is fully documented and that the study data can be 
validated subsequently, the Investigator shall retain comprehensive and accurate records of the conduct of 
the study. These documents should be divided into two categories: (1) Investigator's study documents, (2) 
original clinical records of patients.  
Investigator’s study documents include the clinical trial protocol and amendments, approval 
documents of the Independent Ethics Committee and the government, ICF sample, drug-related records, 
personnel’s curriculum vitae, and other relevant documents/correspondences, etc.  
Patient’s original clinical records (often pre-defined prior to the start of the study, key efficacy/safety 
parameters recorded other than the medical reports) usually include inpatient/outpatient records, physician 
and nurse’s records, appointment letters, original laboratory reports, ECG, imaging reports, pathology 
reports and specialized assessment reports, signed ICF, consulting letters and correspondences, patient 
screening and recruitment forms. The Investigator shall preserve the two types of documents for at least 15 
years after the study is completed or discontinued. Then these documents can be destroyed in accordance 
with local regulations. The Investigator shall give a prior notice to the Sponsor if he/she intends to hand 
over these study records to other organizations or transport them to other areas. 
If the Investigator cannot guarantee the archiving requirements of any or all documents at the study 
site, the Investigator and the Sponsor should make special arrangement to pack these documents in the 
well-sealed boxes other than the study site, so that these sealed documents can be returned to the 
Investigator in the event of a regulatory audit. If the original records are required for subsequent treatment 
of patients, the corresponding photocopies should be preserved other than the study site. 
5.7.2 Original records and background data 
The Investigator should provide the Sponsor with any background data information from the study 


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28 
documentation and clinical record data as required, which is more important when errors are suspected to 
have occurred in the data transcription. It should also be necessary to be able to access to the complete 
study records in case of special issues and/or government questions or requests for audit and inspection, but 
at the same time the patient’s right to privacy should be protected.  
5.7.3 Audit and inspection 
The Investigator should be aware that, upon formal notification, original records pertaining to the 
study should be prepared and made available to the appropriate qualified person or his/her designee, or the 
inspector of the health department. The data reconciliation in the case report form must be performed 
directly against the original records. 
5.7.4 Case report form 
For each eligible patient, his/her case report form (CRF) must be completed and signed by the 
principal investigator or an authorized representative of the study personnel. This also applies to the CRF of 
patients who fail to complete the clinical trial (even if the CRF has been filled out during the screening 
period). If a patient withdraws from the study treatment, the reason for withdrawal must be recorded in the 
CRF. If a patient withdraws from the study because of a treatment-limiting adverse event, a comprehensive 
effort should be made to clearly document the results. The Investigator shall ensure the data accuracy, 
integrity, legibility and timeliness in the CRF and all required reports reported to the Sponsor.  
6 Monitoring of study 
If the patient confidentiality complies with local requirements, the responsible monitor (or designee) 
will regularly contact and visit the Investigator and will be allowed to review various trial records (CRF 
and other relevant data) as required. 
The monitor is responsible for regularly checking the CRF, verifying compliance with the study 
protocol, and checking input data for integrity, consistency, and accuracy throughout the study. The 
monitor shall be granted access to laboratory test reports and other patient’s records, to check the entries on 
the CRF. The Investigator (or his/her designee) agrees to work with the monitor to ensure that any issues 


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29 
identified during the monitoring visits are resolved. 
7 Statistics and Analysis Plan 
7.1 Statistical analysis 
7.1.1 Baseline and demographic characteristics 
The baseline data include demographic characteristics, tumor stage, medical history, surgical 
approach, concomitant medications, and vital signs, etc. The measurement data are described with the mean, 
standard deviation, median, minimum, and maximum; and the count data are described with frequency and 
percentage. 
7.1.2 Primary efficacy 
The primary efficacy variable in this study is the 3-year disease-free survival (DFS). 
7.1.3 Secondary efficacy 
Analysis of secondary efficacy variables includes: 
 
Disease Free Survival (DFS).  
 
Central nervous system (CNS)-related DFS. 
 
Overall survival (OS). 
 
Safety analysis: Safety and tolerability, quality of life. Adverse events and their most severe 
response grades will be summarized according to the criteria of NCI CTCAE version 4.0, 
and will also be summarized according to the severity and its relationship with the study 
drug. Descriptive summaries of laboratory test results focus on the outliers. Laboratory 
abnormalities will also be summarized by the most severe level in NCI CTCAE version 4.0. 
7.2 Analysis types 


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30 
Intention-to-treat population 
Statistical analysis will be performed in the intention-to-treat (ITT) population. ITT population is 
defined as all enrolled patients.  
Safety analysis population 
All patients who have received the study drug for at least once will be included in the safety analysis. 
Safety parameters will be analyzed and presented based on the treatment the patient has received. 
7.3 Safety analysis 
For all patients in the safety population, the following safety parameters will be analyzed and 
presented based on the treatment the patient has received: 
 
Adverse event 
 
Serious adverse event 
 
Laboratory parameters 
 
Vital signs, including ECOG performance status 
Adverse events and their most severe reaction grades will be summarized according to the criteria of 
the NCI CTC-AE version 4, and will also be summarized by the severity of the event and its relationship 
with the study drug. Descriptive summaries of laboratory test results focus on outliers. Laboratory 
abnormalities will also be summarized by the most severe level in the NCI CTC-AE version 4.  
8. Safety Principles 
8.1 Precautions/warnings 
Icotinib 
The common adverse drug reactions (ADRs) of icotinib are rash (39.5%), diarrhea (18.5%), elevated 
aminotransferase (8.0%), most of which are of grades I and II and usually occur within 1-3 weeks after 
medication. Usually the ADRs are reversible and can disappear automatically, and there is no need of 
special treatment.  
Warnings and precautions for icotinib are as follows: 
1. According to the literature, the incidence of interstitial lung disease (ILD) is 2-3% and 1-2% in the 


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
31 
Eastern population treated with gefitinib and erlotinib, respectively. Interstitial lung disease is not observed 
in the ICOGEN clinical study. Patients with interstitial lung disease usually experience acute dyspnea with 
cough, low-grade fever, respiratory discomfort, and unsaturated arterial oxygen. In a short period of time, 
the symptoms can become severe and cause death. Radiographic examination often shows pulmonary 
infiltration or interstitial ground-glass opacities. 
    During the treatment, the treating physician shall closely monitor the signs of interstitial lung disease; 
and if the patient develops a new acute attack or progressively worsening dyspnea and cough, the treatment 
with this product should be interrupted and relevant examinations should be performed immediately. When 
interstitial lung disease is confirmed, the drug should be discontinued and the patient should be treated 
accordingly.  
High risk factors for ILD reported in the literature include smoking, poor performance status (PS ≥ 2), 
normal lung tissue coverage ≤ 50% on CT scan, and short time since the diagnosis of non-small cell lung 
cancer (<6 months), preexisting interstitial pneumonia, older age (≥55 years old), with heart disease. 
Patients with these high-risk factors should use this product for treatment with caution.  
2. This product should be used with caution in patients with mild transient elevations of hepatic 
aminotransferases that have been observed in a small number of patients. Patients with moderately elevated 
aminotransferase levels or above need to suspend the drug, and monitor the aminotransferase until the 
increase is relieved or disappears, and the drug can be resumed (see [Administration and Dosage]).   
3. Seek medical attention immediately if the following conditions worsen: New acute or progressively 
worsening dyspnea, cough; severe or persistent diarrhea, nausea, vomiting, or anorexia.  
4. Effects on the ability to drive and operate machines: During the treatment with this product, symptoms 
of fatigue may occur, and patients with these symptoms should be reminded when driving or operating 
machines. 
Clinically significant drug-drug interactions may occur with icotinib (see the Instruction for Use of 
Icotinib). 


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32 
8.2 Adverse Events 
Definition of Adverse Events 
An adverse event is any unfavorable medical event that occurs in a patient or a patient receiving 
treatment with the study drug. Adverse events are not necessarily causally related to the drug. Thus, an 
adverse event can be any untoward and unexpected sign (including abnormal laboratory test results), 
symptom, or disease time-related to the study drug used, regardless of whether the event is considered to be 
related to the drug or not. Conditions in which preexisting symptoms are worsened during the study period 
are also reported as AEs.  
Adverse events in humans (regardless of whether they are related to drug or not) include the 
following:  
• 
Adverse events that occur during the use of the drug by professionals; 
• 
Adverse events resulting from drug overdose (intentional or unintentional); 
• 
Adverse events caused by drug abuse; 
• 
Adverse events caused by discontinuation of the drug; 
• 
Adverse events that may arise merely from the patient's participation in the study (e.g., due to 
discontinuation of antihypertensive drugs during the washout period or serious adverse events), 
which must be reported as adverse events even if they are unrelated to the study medication. 
Failure to appear or achieve the clinically expected pharmacological effects will not be 
regarded as adverse events.  
8.2.2 Classification of adverse events  
All adverse events will be graded for severity using a 5-point scale (grades 1 to 5) according to 
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 4.0 
(CTC-AE 4.0) and reported in detail in the CRF.  
8.2.3 Monitoring of adverse events 


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33 
Patients must be closely monitored for adverse events. Such monitoring includes clinical laboratory 
tests. Adverse events should be assessed in terms of seriousness, severity and relationship with the 
investigational drug, etc.  
The Investigator is responsible for evaluating the relationship between all adverse events and the study 
drug. However, the principal investigator can entrust other investigators who participate in this study to 
make the judgment, but he/she remains responsible for it.  
8.2.4 The relationship between adverse events and study drug 
The evaluation of the relationship between an adverse event and the study drug is a comprehensive 
clinical judgment based on all the information obtained when completing the CRF. 
Circumstances assessed as "unrelated" may include: presence of alternative explanations, for example, 
traumatic bleeding at the surgical site; unreasonable, for example, a patient is hit by a car, but there is no 
indication that drug-induced disorientation contributes to the event; or cancer that develops only a few day 
after starting dosing. 
An assessment of "Yes" indicates that there are reasonable reasons to suggest that the adverse event 
may be related to the study medication. 
Factors to be considered when assessing the relationship between the adverse events and the study 
drug include: 
– 
Occurring shortly after administration: This adverse event should occur after administration. 
The length of time between drug administration and the occurrence of the event should be 
considered in the clinical evaluation of this event. 
– 
Disappearance of the event after cessation of dosing (cessation of stimulation) and 
reoccurrence after re-dosing (re-stimulation): full consideration should be given to the 
patient's response after drug withdrawal (cessation of stimulation) or the patient's response 
after re-dosing (re-stimulation).  
– 
Underlying, concomitant, and intermittent diseases: The natural history of the disease, the 
course of treatment, and all other medical conditions the patient may have described in each 
report should be assessed.  


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34 
– 
Concomitant medications or treatments: Other medications the patient is taking or other 
treatments the patient is receiving should be examined to determine if one of these may 
have contributed to the adverse event. 
– 
Known response pattern for a class of drugs: clinical/preclinical. 
– 
Pharmacology and pharmacokinetics of the investigational drug: The pharmacokinetic 
characteristics (absorption, distribution, metabolism, and excretion) of the investigational 
drug should be considered in conjunction with each patient's individual pharmacodynamic 
response. 
8.2.5 Serious adverse events 
Serious adverse events are all unfavorable medical events that meet one of the following conditions 
that occur in any medication situation: 
• 
causing death; 
• 
life threatening; 
• 
leading to patient’s hospitalization or prolonged hospitalization of inpatients;  
• 
leading to persistent or apparent incapacity or disability; 
• 
Major medical event. 
 
Life-Threatening: The term "life-threatening" is defined as "serious" and refers to the risk of 
death of a patient in the event of an adverse event. It does not refer to adverse events that could 
have resulted in death if the situation is assumed to be more exacerbated.  
Hospitalization: Any adverse event leading to hospitalization of a patient or prolonged 
hospitalization of an inpatient is considered serious except for any one of the following:  
– 
Stay in hospital for no more than 12 hours; 
or 
– 
Admission is pre-planned (i.e. surgery or elective surgery that is scheduled prior to the start 
of the study); 


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
35 
or 
– 
Hospital admissions are not associated with adverse events (e.g., hospitalization for 
convalescent purposes). 
It should be noted that invasive treatment performed during hospitalization may meet the 
criteria for a "major medical event" and therefore may need to be reported as a serious adverse 
event based on clinical judgment. Also, if a stricter definition is specifically required by the local 
authority, the local regulations prevail.  
Disability: a person's ability to perform daily life is severely impaired. 
According to the standard definition, the term “sudden death” can only be used when the cause 
of death is cardiac. The terms death and sudden death are distinct and should not be used 
interchangeably. 
Any clinical adverse event or abnormal laboratory test results that occur during the course of the study 
and achieve the degree of severity (as defined above), regardless of the treatment the patient is receiving, 
must be reported to the Sponsor, pharmaceutical regulatory authority, and the Ethics Committee within one 
working day after the Investigator becomes aware of the event.  
Serious adverse events related to study treatment must be collected and reported regardless of how 
long it has been since the last dose, even if the trial has ended.  
Serious adverse events unrelated to study treatment must be collected and reported during the 
study period and within 28 days after the last dose. 
8.2.6 Unexpected adverse events 
An unanticipated adverse event is any adverse drug reaction whose characteristics or severity are 
inconsistent with the Investigator’s Brochure. The suspected unexpected serious adverse reaction (SUSAR) 
refers to an unexpected serious adverse event related to the investigational drug. 
8.2.7 Reporting of adverse events 
All adverse events that occur after signing of the ICF by patients until within 28 days after the last 


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
36 
dose should be recorded in detail.  
Documented records must be supported by raw data. Laboratory abnormalities deemed clinically 
relevant (e.g., those leading to premature withdrawal of patients from the study, requiring treatment, or 
triggering overt clinical manifestations, or those deemed clinically relevant by the study personnel) should 
be recorded as adverse events. A detailed description of each event should be provided, including start and 
end dates, severity, relationship to study drug, actions taken, and outcome of the event. 
SAEs that occur from the signing of the ICF until within 28 days after the last dose and meet the 
definition, including laboratory abnormalities that meet the definition of SAE, must be immediately (within 
24 hours after the study personnel is informed) reported to the personnel specified in the study 
documentation. The SAE report form must also be completed and sent to the specified personnel in the 
study documentation within 24 hours of being informed by the study personnel. SAEs related to study 
treatment must be collected and reported regardless of how long it has been since the last dose, even if the 
trial has ended.  
Each SAE should be followed up until resolution or stabilization and an update should be submitted to 
the designated person. The grade 4 laboratory abnormalities (as per CTC-AE version 4.0) are not reported 
as serious adverse reactions unless the Investigator believes that the abnormality meets the criteria for an 
SAE. Grade 5 laboratory abnormalities as defined in the CTC-AE version 4.0 that occur and are indicative 
of disease at baseline should not be reported as SAEs, especially if these abnormalities are present but are 
still allowed by the protocol or have not been excluded from the study. If it is in doubt as to whether the 
anomaly should be reported as an SAE, the Investigator may consult with the Study Monitor. Laboratory 
abnormalities of CTC-AE grade 4 should be recorded on the page of “Laboratory Information” and 
periodically checked by the medical monitor. If it is uncertain whether an adverse event is caused by the 
study disease, it should be reported as an AE or SAE. 
As required by local laws and regulations, SAEs must be reported to the Ethics Committee and the 
NMPA.  
8.2.8 Treatment and follow-up of adverse events 
Final results for each AE must be recorded on the CRF. All AEs will be followed up according to the 


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
37 
following guidelines: 
About AE 
Follow-up continues until one of the following circumstances has occurred:   
 
Resolved or improved to the extent at the baseline. 
 
Causality is reassessed as irrelevant. 
 
Death. 
 
Starting a new anti-cancer regimen. 
 
No further improvement is expected as confirmed by the Investigator.  
 
Clinical or safety data are no longer collected, or the database is eventually closed. 
Unrelated severe or life-threatening AEs 
Follow-up continues until one of the following circumstances has occurred: 
 
Resolved or improved to the extent at the baseline.   
 
Improvement of the severity to grade 2. 
 
Death. 
 
Starting a new anti-cancer regimen. 
 
No further improvement is expected as confirmed by the Investigator. 
 
Clinical or safety data are no longer collected, or the database is eventually closed. 
Unrelated Grade 1 or 2 AEs : 


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
38 
Follow-up continues until one of the following circumstances has occurred: 
 
Resolved or improved to the extent at the baseline. 
 
Starting a new anti-cancer treatment 
 
No further improvement is expected as confirmed by the Investigator. 
 
Clinical or safety data are no longer collected, or the database is eventually closed. 
8.2.9 Abnormal laboratory test results 
Abnormal laboratory test results will be recorded in the CRF. Any abnormal laboratory test results that 
meet SAE criteria should be reported as SAE in addition to recorded as an AE in the CRF.  
On the AE page of the CRF, any abnormal clinically significant laboratory test results caused by the 
treatment should be recorded as a single diagnostic result, i.e., these results meet one or more of the 
following:  
 
Occurrence of clinical complications.  
 
Leading to a change in the study medication (e.g., dose change, dosing suspension, or permanent 
discontinuation). 
 
Concomitant therapy changes (e.g., additions, interruptions, discontinuations, or any other 
changes of the concomitant medications, treatments, or medications) are required.  
This applies to any laboratory safety and efficacy results that are obtained from the examinations 
performed after administration of the first dose of study drug and are/are not specified in any protocol. 
These results are outside of the laboratory reference range and meet the criteria for clinical significance.  
This does not apply to any abnormal laboratory test results that are outside the laboratory reference 
range but do not meet the criteria for clinical significance (they will be analyzed and reported as laboratory 
abnormalities); AEs that are specifically excluded by the protocol; or results from AEs reported or being 
reported.  


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
39 
If there are medically significant unexplained laboratory abnormalities, the examinations should be 
repeated, and followed up until they return to the normal range and/or they are found to be adequately 
explained. If they have been clearly explained, they should be recorded on the CRF.  
8.3 Pregnancy 
If a female patient becomes pregnant during the study period, the study drug must be discontinued as 
directed and the Investigator shall be notified immediately. The Investigator shall report the pregnancy 
results to the Sponsor, the pharmaceutical regulatory authority, and the Ethics Committee through the 
Clinical Trial Pregnancy Report Form within 24 hours. The Investigator should give medical advices and 
discuss with the patient about the the risks of continuing the pregnancy and possible effects on the fetus. 
The patient should be monitored until the end of the pregnancy, and if the baby is born alive, the baby 
should be followed up. Pregnancy that occurs within 90 days of completion of study dosing should also be 
reported to the Investigator.  
If the spouse of a male patient participating in the study becomes pregnant or becomes pregnant within 
90 days of the end of the study medication, an informed consent form that is signed by the pregnant spouse 
must be obtained from the Pregnant Spouse Data Release Form, and the pregnant spouse should be 
followed up, and the pregnancy outcome should be reported to the Investigator and the Sponsor. The 
spouse should be consulted to discuss the risks of continuing the pregnancy and possible adverse effects on 
the fetus. The patient should be monitored continuously until the end of the pregnancy. If the baby is born 
alive, the baby should also be followed up.  
9 Independent Review Committee (IRC) 
An Independent Review Committee (IRC) consists of two radiologists with the certification for review 
and assessment of radiographic findings and one certified oncologist. They will review patient radiographic 
images (CT, MRI, PET/CT, bone scan) independently in accordance with RECIST 1.1 to confirm 
postoperative local recurrence or metastasis.  
The review by an independent review committee does not determine eligibility for enrolment or the 
treatment of patients. The Investigator makes all treatment decisions based on local assessment results. The 


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
40 
analysis of OS and DFS is based on the Investigator’s assessment results. 
The imaging examinations (CT, MRI, PET/CT, bone scan) of the patients enrolled in this study during 
the baseline period and periodic postoperative follow-up visits need to be collected according to the 
imaging acquisition guidelines of this study, and transferred to the personnel of the Independent Review 
Committee.  


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
41 
10.  References 
[1] 
  Jemal A, Bray F, Center MM et al. Global cancer statistics. CA Cancer J Clin 2011; 61: 69-90. 
[2] 
D'Addario G, Fruh M, Reck M et al. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for 
diagnosis, treatment and follow-up. Ann Oncol 2010; 21 Suppl 5: v116-119.  
[3] 
Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the 
TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac 
Oncol 2007;2:706 –714. 
[4] 
Girard N, Mornex F. Radiotherapy for locally advanced non-small cell lung cancer. Eur J Cancer 2009;45S1:113-25. 
[5] 
Non-Small Cell Lung Cancer Collaborative Group: Chemotherapy in non-small cell lung cancer: A meta analysis 
using updated data on individual patients from 52 randomized clinical trials. BMJ 1995;311:899-909. 
[6] 
The International Adjuvant Lung Cancer Trial Collaborative Group: Cisplatin-based adjuvant chemotherapy in 
patients with completely resected non-small cell lung cancer. N Engl J Med 2004;350:351-60. 
[7] 
Winton T, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung 
cancer. N Engl J Med 2005;352:2589-97. 
[8] 
Douillard JY, Rosell R, De Lena M, et al: Adjuvant vinorelbine plus cisplatin versus observation in patients with 
completely resected stage IB-IIIA non-small cell lung cancer (Adjuvant Navelbine International Trialist Association 
[ANITA]): A randomised controlled trial. Lancet Oncol 2006;7:719-27. 
[9] 
Scagliotti GV, Roldano F, Torri V, et al: Randomized study of adjuvant chemotherapy for completely resected stage I, 
II, or IIIA non-small cell lung cancer. J Natl Cancer Inst 2003;95:1453-1461. 
[10] 
Waller D, Peake RJ, Stephens RJ, et al: Chemotherapy for patients with non-small cell lung cancer: The surgical 
setting of the Big Lung Trial. Eur J Cardiothorac Surg 2004;26:173-82. 
[11] 
Pignon JP, Tribodet H, Scagliotti GV, et al. Lung Adjuvant Cisplatin Evaluation: a pooled analysis by the LACE 
collaborative group. J Clin Oncol, 2008, 26(21): 3552-59. 
[12] 
Strauss GM, Herndon JE 2nd, Maddaus MA, et al. Adjuvant paclitaxel plus carboplatin compared with observation in 
stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy 
Oncology Group, and North Central Cancer Treatment Group Study Groups.J Clin Oncol. 2008;26:5043-51. 
[13] 
Goss GD, Lorimer I, Tsao MS, et al. A phase III randomized, double-blind, placebo-controlled trial of the epidermal 
growth factor receptor inhibitor gefitinb in completely resected stage IB-IIIA non-small cell lung cancer (NSCLC): 
NCIC CTG BR.19. J Clin Oncol. 2010;28(20s Suppl):lba7005. 
[14] 
Richardson F, Richardson K, Sennello G. et al.Biomarker analysis from completely resected NSCLC patients enrolled 
in an adjuvant erlotinib clinical trial (RADIANT). J Clin Oncol. 2009;27(20s Suppl):abstr 7520. 
[15] 
Janjigian YY, Park BJ, Zakowski MF, et al. Impact on disease-free survival of adjuvant erlotinib or gefitinib in 
patients with resected lung adenocarcinomas that harbor EGFR mutations.J Thorac Oncol. 2011;6:569-75. 
[16] 
Zhao Q, Shentu J, Xu N, et al. Phase I study of icotinib hydrochloride (BPI-2009H), an oral EGFR tyrosine kinase 
inhibitor, in patients with advanced NSCLC and other solid tumors. Lung Cancer. 2011. 73(2): 195-202. 
[17] 
Shi Y, Zhang L, Liu X et al. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer 
(ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol 2013; 14: 953-961. 
[18] 
Ren GJ, Zhao YY, Zhu YJ, et al. Tumor gene mutations and messenger RNA expression: correlation with clinical 
response to icotinib hydrochloride in non-small cell lung cancer. Chin Med J (Engl). 2011. 124(1): 19-25. 


Protocol No.: GASTO 1003, Protocol Version: 1.1,  May 1, 2020  
 
 
 
42 
11. Protocol Signature Page  
Investigator’s Statement 
I have read this protocol and the study will be conducted in accordance with the moral, 
ethical and scientific principles stipulated in the Declaration of Helsinki and Chinese GCP. I agree 
to carry out this clinical study in accordance with the design and regulations of this clinical trial 
protocol.  
I will be responsible for making medical decisions related to the clinical trial and ensuring 
that subjects are treated in a timely manner if they experience an AE during the trial. I am aware of 
the procedures and requirements for correct reporting of SAE, and I will document and report 
these events as required.  
I guarantee that the data will be entered into the CRF in an accurate, complete, timely and 
legal manner. I will accept the monitoring or audit of the monitor or auditor dispatched by Sponsor 
and the audit and inspection of the pharmaceutical regulatory department to ensure the quality of 
the clinical trial.  
I agree that the study results are used for application for drug registration. 
I will provide a resume to the Ethics Committee and possibly the Drug Administration 
before the start of the study.  
 
Investigator (signature):                      Date:               
 
 
 
 
 
 
 
 

SAP_001.pdf: 
 1 / 17 
 
STATISTICAL ANALYSIS PLAN 
  
Randomized, prospective, open-label phase II clinical 
study of adjuvant icotinib (12 months) versus 
observation in patients with stage IB epidermal growth 
factor receptor (EGFR)-mutant non-small cell lung 
cancer (NSCLC) after complete resection (CORIN 
Study) 
 
Principal investigator: Si-Yu Wang 
Sponsor: Betta Pharmaceuticals Co., Ltd., Hangzhou, China 
Protocol No.: GASTO 1003 
Registration No.: NCT02264210 
 
Statistical Analysis Plan Version 1.0 electronically signed and approved by GASTO: 
February, 2015. 
Statistical Analysis Plan Version 1.1 electronically signed and approved by GASTO: 
May, 2020. 
 
This confidential document is the property of the sponsor. No unpublished 
information contained in this document may be disclosed without prior written 
approval of the sponsor.  


 2 / 17 
 
Table of contents 
1 Table of Contents........................................................................................................2 
2 Study Objectives.........................................................................................................4 
2.1Primary Objective...................................................................................................4 
2.2Secondary Objective...............................................................................................4 
2.3Exploratory Objectives...........................................................................................4 
3 Study Design and Methods.........................................................................................6 
 3.1 Study Design..........................................................................................................6 
 3.2 Randomization.......................................................................................................6 
 3.3 Blinding..................................................................................................................7 
4 Study Endpoints..........................................................................................................8 
4.1 Efficacy Endpoints...............................................................................................8 
   4.1.1 Primary Efficacy Endpoints............................................................................8 
   4.1.2 Secondary Efficacy Endpoints........................................................................8 
4.2 Safety Endpoints..................................................................................................8 
5 Sample Size.................................................................................................................9 
6 Patient characteristics................................................................................................10 
7 Treatment Compliance..............................................................................................11 
8 Interim Analysis........................................................................................................12 
9 Subgroup Analysis....................................................................................................13 
10 Statistical Considerations........................................................................................14 
 


 3 / 17 
 
11 Variables.................................................................................................................15 
12 Missing data............................................................................................................16 
13 References...............................................................................................................17 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 4 / 17 
 
2 Study Objectives 
2.1 Primary Objective 
To evaluate the efficacy of adjuvant icotinib, in terms of 3-year disease-free survival 
(DFS), for patients with completely resected stage IB non-small cell lung cancer 
(NSCLC).  
 
2.2 Secondary Objectives 
To evaluate the efficacy of adjuvant icotinib, in terms of DFS, for patients with 
completely resected stage IB NSCLC, as compared with observation.  
To evaluate the efficacy of adjuvant icotinib, in terms of central nervous system 
(CNS)-related DFS, for patients with completely resected stage IB NSCLC, as 
compared with observation.  
To evaluate the efficacy of adjuvant icotinib, in terms of overall survival (OS), for 
patients with completely resected stage IB NSCLC, as compared with observation.  
To assess the safety and tolerability of adjuvant 12-month icotinib for patients with 
completely resected stage IB NSCLC, as compared with observation. 
 
2.3Exploratory Objectives 
To evaluate the efficacy of adjuvant icotinib for patients with completely resected 
stage IB NSCLC based on the AJCC 7th and 8th edition of staging.  


 5 / 17 
 
To evaluate the efficacy of adjuvant icotinib for patients with completely resected 
stage IB NSCLC based on sensitive EGFR mutation and all EGFR mutations 
(including atypical EGFR mutations).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 6 / 17 
 
3 Study Design and Methods 
3.1 Study Design 
This is a phase II, open-label, randomized controlled study to evaluate the efficacy 
and safety of adjuvant icotinib for patients with completely resected stage IB NSCLC 
without adjuvant chemotherapy.  
 
The decision of not receiving adjuvant chemotherapy will be according to physician 
and patient choices.  
 
Eligible patients will be randomized in a 1:1 ratio to receive adjuvant therapy with 
icotinib (125 mg, three times daily) or to undergo observation. Treatment with icotinib 
will be given for up to 12 months or until discontinuation criteria are met. Therapy 
will be continued until disease progression or intolerable toxicity occurred. The first 
dose of study treatment should be taken no later than 7 days of randomization.  
 
3.2 Randomization 
Randomization will be performed by the study staff of the GASTO through a 
computer-generated sequence with a minimization method that balanced sex (male vs. 
female) and ECOG PS (0 vs. 1) for random assignment. Randomization will be 
performed just before the initiation of study administration. Eligible patients will be 
randomly assigned in a 1:1 ratio to either receive oral icotinib or undergo observation.  
 


 7 / 17 
 
3.3 Blinding 
Not applicable. This is an open-label study. All investigators, study personnel, and 
patients will be not masked to patient distribution. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 8 / 17 
 
4 Study Endpoints 
4.1 Efficacy Endpoints 
4.1.1 Primary Efficacy Endpoint 
The primary endpoint are 3-year DFS, which is defined as the proportion of patients 
who were disease free at 3 years.  
 
4.1.2 Secondary Efficacy Endpoints 
The secondary endpoints included DFS (time from random assignment to documented 
disease recurrence or death, whichever occurred first), central nervous system 
(CNS)-related DFS (time from randomization to CNS recurrence or death, whichever 
occurred first), overall survival (OS, time from random assignment to death from any 
cause).  
 
4.2 Safety Endpoints 
All patients who receive at least 1 dose of study treatment will be evaluated for safety 
and tolerability. Safety and tolerability will be evaluated at every visit. All adverse 
events (AEs) will be classified according to the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0. Proportion of 
patients with AEs will be recorded for patients in the icotinib group. Grade 3 or 
greater AEs will be recorded. The number and percentage of subjects reporting 
serious adverse events (SAEs) will be summarized. 
AEs will be managed according to the AE management protocol. 


 9 / 17 
 
5 Sample Size 
On the basis of the CALGB 9633 trial [1], we projected a 3-year DFS of 60% for 
patients with stage IB NSCLC. The study is designed to determine whether adjuvant 
icotinib would result in a 17% absolute improvement (from 60% to 77%) in 3-year 
DFS, with 80% power at a two-sided α of 0.1. This improvement corresponded to an 
HR of 0.5. Assuming an accrual time of 2 years, a follow-up time of 3 years, and an 
anticipated dropout rate of 5%, a total of 128 patients would be required to be 
randomly assigned. This sample size is sufficient to power this study at 80% with a 
two-sided type I error rate of 10%.  
 
 
 
 
 
 
 
 
 
 
 
 
 


 10 / 17 
 
6 Patient characteristics 
Patient demographics will be summarized. The patient demographics will include the 
following: 
Age 
Sex 
Baseline ECOG PS 
Smoking status 
 
Disease characteristics will be summarized. Disease characteristics will include the 
following: 
Pathological diagnosis 
Primary tumor size 
Tumor stage 
Tumor grade 
Tumor location 
EGFR mutational status 
 
Tumor stage will be derived based on pathological results.  
 
 
 
 


 11 / 17 
 
7 Treatment Compliance 
Treatment compliance of icotinib will be summarized. Compliance will be calculated 
as the ratio of total dose taken to the total assigned dose (minus any dose adjustments 
and doses omitted/withheld). The treatment time (days and months) will calculated.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 12 / 17 
 
8 Interim Analysis 
Not applicable. No interim analyses were planned.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 13 / 17 
 
9 Subgroup Analysis 
To investigate the interaction between treatment effect and the subpopulation, 
subgroup analyses will be conducted in an exploratory manner with respect to the 
following factors: sex (male vs. female) and EGFR mutation (exon 19 deletion vs. 
exon 21 L858R).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 14 / 17 
 
10 Statistical Considerations 
The Intention-To-Treat Set (ITT) will include all randomized subjects. ITT will be 
used for the analysis of DFS and OS.  
All analyses for efficacy are based on ITT population.  
The Safety Analysis Set will include all subjects who received at least 1 dose of study 
drug and have a safety record after drug administration.  
Descriptive statistics will be defined for continuous variables as number (n), median, 
mean, minimum and maximum, and as frequency and percentage for categorical 
variables. 
The Kaplan-Meier method [2] will be used to estimate the point estimates of 3-year 
DFS for each group. The difference in 3-year DFS between groups will be compared 
by the Z test. The median DFS and OS will be estimated by the Kaplan‒Meier method 
and the differences between median DFS and OS will be compared by the log-rank 
test.    
Hazard ratios and their 95% confidence intervals for treatment effects are estimated 
using Cox proportional hazards models [3].  
Unless otherwise specified, all statistical analyses will be performed using two-sided 
tests with a significance level of 0.05. All statistical analyses will be performed using 
SPSS and R.  
 
 
 


 15 / 17 
 
11 Variables 
Month=365/12 days. 
Year=365 days. 
Time since diagnosis to randomization = date of randomization – date of initial 
diagnosis) +1. 
The duration of treatment was calculated as the (last dose date – first dose date) + 1. 
Duration in study (days) = last day of known to be alive – date of randomization + 1 
Follow-up time (days for DFS) = date of recurrence (patient who had recurrence) or 
date of last follow-up – date of randomization + 1.  
Follow-up time (days for OS) = date of death (patient who died) or date of last 
follow-up – date of randomization + 1.  
 
 
 
 
 
 
 
 
 
 
 


 16 / 17 
 
12 Missing data 
No imputations will be made for missing data. Patients who does not have relapse or 
death will be censored at last follow-up.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 17 / 17 
 
13 References 
1. Strauss GM, Herndon JE, 2nd, Maddaus MA et al. Adjuvant paclitaxel plus 
carboplatin compared with observation in stage IB non-small-cell lung cancer: 
CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology 
Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008; 
26: 5043-5051. 
2. Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J 
Amer Stat Assoc. 1958; 53: 457-481. 
3. Cox D. Regression models and life-tables. J Royal Stat Soc Ser B. 1972; 34: 
187-220.