A Phase 3, Randomised, Double-blind Study to Compare the Efficacy, Safety, PK and Immunogenicity Between SB8 (Proposed Bevacizumab Biosimilar) and Avastin® in Subjects With Metastatic or Recurrent Non-squamous Non-small Cell Lung Cancer
Phase: PHASE3
Conditions: Lung Cancer, Non-small Cell Lung Cancer
Sponsor: Samsung Bioepis Co., Ltd.

SB8 (proposed bevacizumab biosimilar) 
SB8-G31-NSCLC 
Amendment 2, Aug 18, 2016 
 
Samsung Bioepis – Confidential 
Page 1 of 165 
 
 
 
Clinical Study Protocol 
A Phase III, Randomised, Double-blind, Multicentre Study  
to Compare the Efficacy, Safety, Pharmacokinetics and 
Immunogenicity between SB8 (proposed bevacizumab biosimilar) and 
Avastin® in Subjects with Metastatic or Recurrent  
Non-squamous Non-small Cell Lung Cancer 
 
 
 
 
Product 
SB8 (proposed bevacizumab biosimilar) 
EudraCT Number 
2015-004026-34 
US IND Number (if applicable) 
NA 
Protocol Number 
SB8-G31-NSCLC 
Study Phase 
Phase III 
Version and Effective Date 
Amendment 2.0 
Aug 18, 2016 
 
Amendment 1.0 
Dec 17, 2015 
Sponsor 
Samsung Bioepis Co., Ltd. 
107, Cheomdan-daero, Yeonsu-gu, 
Incheon, 21987 
Republic of Korea 
 
This document contains confidential information belonging to Samsung Bioepis Co., Ltd. Your 
acceptance or review of this document constitutes agreement that you will not copy or disclose the 
information contained herein to others or use it for unauthorised purposes without written 
authorisation from the Sponsor. 
 
 
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Page 2 of 165 
 
SYNOPSIS 
Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB8 (proposed bevacizumab biosimilar) 
Name of Active Ingredient: 
Bevacizumab 
Title of Study: 
A Phase III, Randomised, Double-blind, Multicentre Study to Compare the Efficacy, Safety, 
Pharmacokinetics and Immunogenicity between SB8 (proposed bevacizumab biosimilar) and Avastin® 
in Subjects with Metastatic or Recurrent Non-squamous Non-small Cell Lung Cancer 
Protocol No: 
SB8-G31-NSCLC 
Phase: 
III 
Indication: 
Metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC) 
Objectives: 
Primary Objective: 
The primary objective is to demonstrate the equivalence of SB8 to Avastin®, in terms of the best overall 
response rate (ORR) by 24 weeks of chemotherapy in subjects with metastatic or recurrent 
non-squamous NSCLC. 
Secondary Objectives: 
The secondary objectives are: 
• 
To evaluate the efficacy of SB8 compared to Avastin® by 
- Progression free survival (PFS) 
- Overall survival (OS) 
- Duration of response (DOR) 
• 
To evaluate the safety and tolerability of SB8 compared to Avastin® 
• 
To evaluate the pharmacokinetics of SB8 compared to Avastin® 
• 
To evaluate the immunogenicity of SB8 compared to Avastin® 
Exploratory Objective: 
The exploratory objective is: 
• 
To evaluate the best ORR by 11 and 17 weeks 
Study Design: 
This is a Phase III, randomised, double-blind, multicentre study to evaluate the efficacy and safety of 
SB8 compared to Avastin®. Subjects with metastatic or recurrent non-squamous NSCLC without 
known activating epidermal growth factor receptor (EGFR) gene mutations or anaplastic lymphoma 
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Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB8 (proposed bevacizumab biosimilar) 
Name of Active Ingredient: 
Bevacizumab 
kinase (ALK) gene translocations will be randomised in a 1:1 ratio, stratified by age (< 70 and ≥ 70) 
and gender to receive either SB8 or Avastin® (administered intravenously 15 mg/kg every 3 weeks) 
concurrently with chemotherapy (for at least 4 cycles and up to 6 cycles of paclitaxel 200 mg/m2 plus 
carboplatin AUC 6 every 3 weeks). Subjects will undergo radiographic assessment of disease status 
(computed tomography [CT] or magnetic resonance imaging [MRI]) according to the Response 
Evaluation Criteria in Solid Tumours, Version 1.1 (RECIST v1.1) after IP administration of Cycle 2, 4, 
and 6, and before planned Day 1 of Cycle 3, 5, and 7 and then will be performed every four cycles until 
there is radiographic documentation of progressive disease (PD), unacceptable toxicity, death, or end of 
study, whichever occurs first. If subjects show response to treatment, defined as complete 
response (CR)/partial response (PR)/stable disease (SD) after completion of the induction treatment 
period of combination chemotherapy with SB8 or Avastin®, they will receive SB8 or Avastin® 
maintenance therapy as per randomisation until disease progression, unacceptable toxicity, death, or end 
of study (EOS). Adverse Event (AE) information will be collected until end of treatment (EOT) visit (at 
least 21 days after last IP administration and prior to subsequent therapy). 
Approximately 50% of the enrolled subjects will have blood samples collected for PK analysis of SB8 
or Avastin®, at pre-dose and post-dose of Cycle 1, 3, 5, and 7. 
All randomised subjects will be evaluated for ADA against SB8 or Avastin® at Baseline (pre-dose of 
Cycle 1) and during treatment (pre-dose of Cycle 3, 5, and 7) and EOT visit. 
Number of Subjects:  
A total of approximately 678 subjects (339 per treatment group) will be enrolled into this study. 
Target Population: 
Subjects with metastatic or recurrent non-squamous NSCLC without known activating EGFR gene 
mutations or ALK gene translocations  
Eligibility Criteria: 
Inclusion criteria 
Subjects must meet all of the following criteria to be eligible for the study: 
1.  Aged ≥ 18 years (if local regulations are different in this regard, follow the local regulations). 
2.  ECOG performance status of 0-1 at Screening. 
3.  Histologically and/or cytologically confirmed metastatic (AJCC 7th edition TNM stage IV) or 
recurrent non-squamous NSCLC or NSCLC-not otherwise specified (NOS). 
4.  At least one measurable lesion according to RECIST v1.1.  
5.  Adequate haematological function at Screening defined as the following: 
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Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB8 (proposed bevacizumab biosimilar) 
Name of Active Ingredient: 
Bevacizumab 
a. 
Absolute neutrophil count (ANC) ≥ 1,500/mm3 (≥ 1.5 × 109/L). 
b. 
Platelet count ≥ 100,000/mm3 (≥ 100 × 109/L). 
c. 
Haemoglobin ≥ 9 g/dL (without transfusion within 14 days prior to Randomisation). 
6.  Adequate hepatic function at Screening defined as the following: 
a. 
Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (in cases of known Gilbert’s 
syndrome ≤ 3 × ULN). 
b. 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 × ULN (in 
case of liver metastases < 5 × ULN). 
c. 
Alkaline phosphatase (ALP) < 3 × ULN (in case of liver metastases < 5 × ULN). 
7.  Adequate renal function at Screening defined as the following: 
a. 
Serum creatinine ≤ 1.5 × ULN or creatinine clearance (CCr) measured or calculated 
according to Cockcroft-Gault formula ≥ 50 mL/min. 
b. 
Urine dipstick for proteinuria of less than 2+ (other ways of urinalysis are also 
acceptable); if urine dipstick is ≥ 2+, 24 hours urine protein excretion should be < 1 g or 
protein/creatinine ratio in spot urine should be < 1 g/g creatinine (or < 226.0 mg/mmol 
creatinine). 
8.  Subjects and their partners of childbearing potential (female or male) including those with 
history of elective sterilisation (e.g. fallopian tube ligation) who agree to use at least two forms 
of appropriate contraception (e.g., established use of oral, injected or implanted hormonal 
contraceptive, placement of an intrauterine device or intrauterine system, physical barrier, male 
sterilisation or true abstinence) from Screening until 6 months after the last administration of 
investigational product (IP). A pregnancy test result is required for all women of childbearing 
potential including women who had menopause onset within 2 years prior to Randomisation. 
True abstinence will be considered sufficient for subjects who do not have a partner. 
9.  Subjects must be able to provide informed consent, which must be obtained prior to any study 
related procedures. 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for the study: 
1.  Diagnosis of small cell carcinoma of the lung or squamous cell carcinoma of the lung. For 
mixed tumour with the component of squamous cell carcinoma, it should be categorised 
according to predominant histology. Any component of small cell carcinoma of the lung is to 
be excluded. 
2.  Known activating mutations in EGFR gene or transforming re-arrangements of ALK gene. 
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Samsung Bioepis – Confidential 
Page 5 of 165 
 
Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB8 (proposed bevacizumab biosimilar) 
Name of Active Ingredient: 
Bevacizumab 
3.  Radiological or clinical evidence of tumour invasion into blood vessels or close to large 
vessels that may have risk of bleeding at the discretion of Investigator. 
4.  History of systemic anti-cancer therapy administered in the first-line setting for metastatic or 
recurrent disease of NSCLC.  
5.  Any systemic anti-cancer therapy including neoadjuvant or adjuvant chemotherapy 
administered for NSCLC and completed less than 12 months prior to Randomisation. 
6.  Previously treated with a monoclonal antibody and/or molecule targeting VEGFR-related 
and/or EGFR-related signalling pathways. 
7.  Radiotherapy within 14 days prior to Randomisation (tumour lesions situated in a previously 
irradiated area, or in an area subjected to other loco-regional therapy are not considered as 
measurable lesion unless there has been demonstrated progression in the lesion.). 
8.  Major surgical procedure within 28 days prior to Randomisation (e.g., requiring more 
extensive procedure than local anaesthesia [involving general anaesthesia or respiratory 
assistance or regional anaesthesia] or open lung biopsy) or expected major surgical procedure 
during the study. 
9.  Minor surgical procedure within 7 days prior to Randomisation (e.g., requiring local 
anaesthesia or following procedures: mediastinoscopy, percutaneous needle aspiration, core 
biopsy, placement of vascular access device, endobronchoscopy ultra sono & transbronchial 
needle biopsy [EBUS & TBNA], pleural biopsy, thoracentesis, pleurodesis, catheter 
insertions/removal, tooth extraction, superficial incision.  
10.  Subject with non-healing wound. 
11.  Symptomatic brain metastasis and/or leptomeningeal disease. Baseline brain imaging is 
strongly recommended to evaluate for presence of brain metastases. If brain metastases are 
found, they can be treated according to local practice at the discretion of investigator. 
Treatment options for brain metastases may include whole brain radiation, radiosurgery, 
craniotomy, etc. as deemed medically appropriate by the investigator. Subjects should have no 
neurologic symptoms off corticosteroids for at least 1 day to ensure that subjects do not have 
symptomatic brain metastasis. If subjects initially developed symptomatic brain metastases 
that resolved after treatment, they could be considered ‘asymptomatic’ and eligible for the 
study if they have no residual neurological dysfunction off corticosteroids for at least 1 day. 
12.  Previous malignancy other than NSCLC in the last 5 years except for locally curable cancers 
that have been in complete remission and need no subsequent therapy, such as basal or 
squamous cell cancer of the skin, carcinoma in situ of the cervix or breast, or superficial 
bladder cancer. 
13.  Life expectancy is less than 3 months. 
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Page 6 of 165 
 
Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB8 (proposed bevacizumab biosimilar) 
Name of Active Ingredient: 
Bevacizumab 
14.  Evidence of clinically significant haemorrhagic diathesis or underlying coagulopathy. 
15.  Subjects treated with anticoagulant therapy within 10 days prior to Randomisation  
(e.g., clopidogrel [≥ 75 mg/day], regular use of aspirin, dipyridamole, ticlopidine and/or 
cilostazol); anticoagulant therapy within 28 days prior to Randomisation (e.g., with warfarin, 
intravenous heparin, low molecular weight heparin, factor Xa inhibitors, thrombin inhibitor, 
and thrombolytic agent including tissue plasminogen activator, anistreplase, streptokinase, 
urokinase). 
16.  History of active gastroduodenal ulcer within 3 months prior to Randomisation. 
17.  Uncontrolled hypertension (blood pressure: systolic > 150 mmHg and/or diastolic 
> 100 mmHg) despite antihypertensive therapy or hypertensive crisis or hypertensive 
encephalopathy. 
18.  Any of the following events within 6 months prior to Screening:  
a. 
Myocardial infarction or unstable angina. 
b. 
Pulmonary embolism. 
c. 
History of congestive heart failure (CHF) (New York Heart Association, NYHA, 
Class ≥ II). 
d. 
Coronary/peripheral artery bypass graft surgery. 
e. 
Stroke or transient ischemic attack. 
f. 
Deep vein thrombosis. 
g. 
Abdominal fistulae as well as non-GI fistulae, GI perforation and/or fistulae, GI-vaginal 
fistulae, or intra-abdominal abscess. 
h. 
Gastrointestinal bleeding, haematemesis or haemoptysis (≥ 1/2 teaspoon of red blood) or 
any other major bleeding events. 
19.  Symptomatic peripheral sensory, motor, autonomic neuropathy NCI-CTCAE v4.03 grade ≥ 2 
and/or ototoxicity grade ≥ 2, except if due to trauma or mechanical impairment. 
20.  Serologically confirmed active or chronic hepatitis B or hepatitis C (asymptomatic inactive 
carriers are allowed at investigator’s discretion per local standards).  
21.  Acquired immunodeficiency syndrome or known seropositivity for human immunodeficiency 
virus (HIV). 
22.  Live/attenuated vaccine within 12 weeks prior to Randomisation (killed/inactivated or 
recombinant vaccine is allowed.). 
23.  Known allergy or hypersensitivity to any of the treatment components. 
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Amendment 2, Aug 18, 2016 
 
Samsung Bioepis – Confidential 
Page 7 of 165 
 
Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB8 (proposed bevacizumab biosimilar) 
Name of Active Ingredient: 
Bevacizumab 
24.  Risk of osteonecrosis of jaw (ONJ) (e.g., treated with intravenous bisphosphonates and/or 
invasive dental procedures within 28 days prior to Randomisation). 
25.  Uncontrolled malignant pleural effusion (e.g., recurrent despite drainage or sclerosing agents). 
26.  Pregnancy or lactation period. 
27.  Subjects unwilling to follow the study requirements. 
28.  Inappropriate other medical conditions for the study at the discretion of Investigator. 
29.  Currently enrolled in another interventional clinical study. 
30.  Previous administration of other investigational product(s) within 28 days prior to 
Randomisation. 
Planned Study Period: 
Recruitment is expected to last approximately 2 years. Treatment will be given to randomised subjects 
until disease progression, unacceptable toxicity, death, or 12 months from Randomisation of the last 
subject, whichever occurs first. Subjects will be followed for survival status and whether subsequent 
systemic anti-cancer therapy is received or not by clinic visit or telephone contact every 3 months until 
withdrawal of consent or death or 12 months from Randomisation of the last subject. 
Investigational Products: 
• 
Name: SB8 (proposed bevacizumab biosimilar) or EU sourced Avastin® 
• 
Route of administration: intravenous (IV) infusion 
• 
Dose: 15 mg/kg every 3 weeks, the initial dose should be delivered over 90 minutes. If the 
first infusion is well tolerated, the second infusion may be administered over 60 minutes. If 
the 60-minute infusion is well tolerated, all subsequent infusions may be administered over 30 
minutes. 
Non-investigational Products: 
• 
Paclitaxel 200 mg/m2 IV infusion over 3 hours every 3 weeks on Day 1 for at least 4 cycles 
and up to 6 cycles in the absence of disease progression or unacceptable toxicity 
• 
Carboplatin AUC 6 IV infusion over 30 minutes every 3 weeks on Day 1 for at least 4 cycles 
and up to 6 cycles in the absence of disease progression or unacceptable toxicity 
Main Criteria for Evaluation 
Primary endpoint 
• 
The best ORR by 24 weeks of chemotherapy (best ORR is defined as the proportion of 
subjects whose best overall response is either complete response [CR] or partial response 
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Page 8 of 165 
 
Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB8 (proposed bevacizumab biosimilar) 
Name of Active Ingredient: 
Bevacizumab 
[PR] according to RECIST v1.1) 
Tumour assessment will be performed after IP administration of Cycle 2, 4, and 6, and before planned 
Day 1 of Cycle 3, 5, and 7 and then will be performed every 4 cycles according to RECIST v1.1 and 
tumour size will be assessed by both Investigators and independent central reviewer. The primary 
efficacy analysis will be based on the data from the independent central review. 
Secondary endpoints 
The secondary efficacy endpoints are: 
• 
Progression free survival (PFS), defined as the time from the date of Randomisation to the 
date of disease progression or death regardless of the cause of death. Subjects who are not 
progressed at the time of analysis will be censored at the date of EOT visit or the last tumour 
assessment date if the date of EOT is not available. 
• 
Overall survival (OS), defined as the time from the date of Randomisation to the date of death 
regardless of the cause of death. Subjects who are alive at the time of analysis will be 
censored at the date of last known alive. 
• 
Duration of response (DOR), defined as the time from documented tumour response 
(complete or partial) until documented disease progression. Only the subjects who achieve an 
initial tumour response will be evaluated for DOR. 
Safety endpoint is: 
• 
Incidence of adverse events (AEs) and serious adverse events (SAEs) 
Safety of subjects will be monitored by physical examination, ECOG performance status and vital sign 
assessment. Biochemical and haematological laboratory parameters will also be measured. 
AEs will be collected and classified according to NCI-CTCAE v4.03. 
The pharmacokinetic endpoints are: 
• 
Ctrough at pre-dose of Cycle 1, 3, 5, and 7 
• 
Cmax at post-dose of Cycle 1, 3, 5, and 7 
Blood sampling for PK will be collected in approximately 50% of the enrolled subjects. 
The immunogenicity endpoint is: 
• 
Incidence of anti-drug antibodies (ADAs) at pre-dose of Cycle 1, 3, 5, 7, and at the EOT visit 
(at least 21 days after last IP administration and prior to subsequent therapy) 
Exploratory endpoint is: 
• 
Best ORR by 11and 17 weeks 
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Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB8 (proposed bevacizumab biosimilar) 
Name of Active Ingredient: 
Bevacizumab 
Statistical Methods 
Analysis set 
Randomised set (RAN) will consist of all subjects who receive a randomisation number at the 
Randomisation. 
Full analysis set (FAS) will consist of all randomised subjects. The subjects will be analysed based on 
the treatment they were randomised to by intention-to-treat principle. However, subjects who do not 
qualify for randomisation and are inadvertently randomised into the study will be excluded from FAS, 
provided these subjects do not receive any IP during the study. 
Per-protocol set (PPS) will consists of all FAS subjects who complete at least two cycles of 
combination chemotherapy with a tumour assessment and do not have any major protocol deviations 
that impact the primary efficacy assessment. Major protocol deviations that will lead to exclusion from 
the PPS will be pre-specified, and PPS will be determined prior to unblinding the treatment codes. 
Safety set (SAF) will consist of all subjects who received the study drug at least once. This analysis set 
will be used for the safety analyses. The subjects will be analysed based on the actual treatment they 
received. 
PK population will consist of subjects allocated to PK sub-study who have at least one measurable 
serum concentration of bevacizumab. 
Efficacy analysis 
For US FDA or other regulatory agency submissions for those who are in favour of risk ratio, the 
primary efficacy analysis for demonstrating the equivalence of SB8 to Avastin® will be done for the 
ratio of the best ORR (best ORR of SB8/best ORR of Avastin®) by 24 weeks in the FAS. The 
equivalence will be declared if the two-sided 90% confidence interval (CI) of the best ORR ratio is 
contained within the pre-defined equivalence margin of [0.737, 1.357]. The similar analysis will be 
performed for the PPS to support the primary efficacy result. 
For EMA, MFDS or other regulatory agency submissions for those who are in favour of risk difference, 
the primary efficacy analysis will be performed for the difference of the best ORR (best ORR of SB8 – 
best ORR of Avastin®) by 24 weeks between SB8 and Avastin® in the PPS, and the equivalence will be 
declared if the two-sided 95% CI of the best ORR difference is contained within the pre-defined 
equivalence margin of [-12.5%, 12.5%]. The similar analysis will be performed for the FAS to support 
the primary efficacy result. 
Safety analyses 
All reported terms for AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and the grade of severity will be reported by NCI-CTCAE v4.03. AEs will be summarised 
descriptively by treatment group. Changes in vital signs and clinical laboratory measurements will be 
summarised descriptively by treatment group. All other safety variables will be summarised 
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Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB8 (proposed bevacizumab biosimilar) 
Name of Active Ingredient: 
Bevacizumab 
descriptively by treatment group. 
Pharmacokinetic analyses 
The PK blood samples will be collected in approximately 50% of the enrolled subjects. The PK 
parameters will be summarised descriptively by treatment group at selected cycles. 
Immunogenicity analyses 
Incidence of ADAs will be summarised by treatment group and cycle and listed by treatment group. 
Sample size calculation 
Regarding the calculation of the equivalence margin for the ratio of the best ORR by 24 weeks, a meta-
analysis published by Botrel et al. using all of the four published comparative trials that evaluated 
bevacizumab in combination with chemotherapy (i.e. E4599 [Sandler, 2006], AVAiL (BO17704) 
[Reck, 2009], AVF0757 [Johnson, 2004], JO19907 [Niho, 2012]) was considered. 
The overall ratio of the best ORR and its 70% CI from above four studies are calculated to be 
 
using the fixed effect method from meta-analysis. Retaining the 
% of the effect of 
Avastin® over the placebo in the lower margin, the equivalence margin of [0.737, 1.357] will be used 
for the primary analysis with the ratio of the best ORR by 24 weeks. 
For the primary analysis with the difference of the best ORR by 24 weeks, the equivalence margin of [-
12.5%, 12.5%] will be used due to the similar derivation. 
With 305 completers in each treatment group, the two-sided 90% CI of the best ORR ratio is expected 
to lie within [0.737, 1.357] with approximately 80% power, and the two-sided 95% CI of the best ORR 
difference between Avastin® and SB8 is expected to lie within [-12.5%, 12.5%] with 80% power when 
the expected best ORR is assumed to be 35%. Assuming a 10% drop-out rate, a total of 678 subjects 
(339 subjects per treatment group) will be randomised. 
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FLOWCHARTS 
 
Figure 1. Graphical Study Design 
® = Randomisation; ORR = overall response rate; EOT = end of treatment 
1SB8 or Avastin® 15 mg/kg IV infusion every 3 weeks on Day 1. 
2Paclitaxel 200 mg/m2 IV infusion over 3 hours every 3-week on Day 1 for at least 4 cycles and up to 6 cycles. 
Carboplatin AUC 6 IV infusion over 30 minutes every 3-week on Day 1 for at least 4 cycles and up to 6 cycles. 
3Primary endpoint is the best ORR by 24 weeks of chemotherapy with SB8 or Avastin®. 
4Physical examination, vital sign, ECOG performance status, reviewing the laboratory values including haematology, biochemistry, urinalysis, and reviewing IP compliance will be 
performed at each cycle. Tumour assessment will be performed after IP administration of Cycle 2, 4, and 6, and before planned Day 1 of Cycle 3, 5, and 7 and then will be performed 
every 4 cycles since cycle 6 until disease progression or death or end of study. Tumour response will be assessed using CT or MRI following Image Acquisition Guideline that will be 
provided by Sponsor. 
5EOT is defined as discontinuation of treatment due to disease progression, unacceptable toxicity, death, or last administration of IP before end of study. EOT visit will be performed at 
least 21 days after last IP administration and prior to subsequent therapy. Subjects will be followed for survival status and whether subsequent systemic anti-cancer therapy is received or 
not by clinic visit or telephone contact every 3 months from EOT until discontinuation of the subject from the study (e.g., death, withdrawal of consent, lost to follow-up or initiation of 
subsequent therapy for NSCLC) or EOS date, defined as when deaths of all the randomised subjects have been observed, or 12 months from Randomisation of the last subject, whichever 
occurs first. 
 
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Table 1. Schedule of Activities  
Assessments 
Screening 
Induction  
Treatment Period22 
Maintenance  
Treatment Period24 
EOT25 
F/U26 
Cycle 
1 
2 
3 
4 
523 
623 
7 
Every  
cycle since 
Cycle 6 
Every  
4 cycles 
since Cycle 6 
Every  
3 
months 
Day of Cycle 
Within 42 days 
prior to 
Randomisation 
1 
1 
1 
1 
1 
1 
1 
Visit window (days) 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
Informed consent1 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic information2 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history3 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination including height 
(Screening visit only) and weight4 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs5 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG status 
 
 
 
 
 
 
 
 
 
 
 
 
Haematology6 
 
10 
 
 
 
 
 
 
 
 
 
 
Coagulation test7 
 
() 
() () () () () () 
() 
 
() 
 
Biochemistry8 
 
10 
 
 
 
 
 
 
 
 
 
 
Urinalysis9 
 
10 
 
 
 
 
 
 
 
 
 
 
Serology (HBV/HCV infection test)11 
 
() 
() () () () () () 
() 
 
() 
 
Pregnancy test (serum or urine)12 
 
() 
() () () () () () 
() 
 
 
 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
Tumour assessment13 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
14 
 
 
 
 
 
 
 
 
 
 
SB8 or Avastin®16 
 
15 
 
 
 
 
 
 
 
 
 
 
Paclitaxel/Carboplatin17 
 
15 
 
 
 
 
 
 
 
 
 
 
Blood sample for immunogenicity18 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for PK19 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant and previous 
medication20 
 
Continuously 
() 
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Assessments 
Screening 
Induction  
Treatment Period22 
Maintenance  
Treatment Period24 
EOT25 
F/U26 
Cycle 
1 
2 
3 
4 
523 
623 
7 
Every  
cycle since 
Cycle 6 
Every  
4 cycles 
since Cycle 6 
Every  
3 
months 
Day of Cycle 
Within 42 days 
prior to 
Randomisation 
1 
1 
1 
1 
1 
1 
1 
Visit window (days) 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
AEs and SAEs21 
 
Continuously 
() 
Survival status 
 
Continuously 
 
AEs = adverse events; ECG = electrocardiogram; EOT = end of treatment; ECOG = eastern cooperative oncology group; F/U = follow-up; PK = pharmacokinetics; HBV = hepatitis B 
virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; SAEs = serious adverse events 
1.  Written informed consent must be obtained before any study related assessments. 
2.  Demographic data includes the date of birth, gender, race and ethnicity. 
3.  Medical history and major surgical procedures including malignancy other than NSCLC and those medical conditions described in the exclusion criteria, in the last 5 years. 
4.  Complete physical examination for Screening visit, including height and weight; abbreviated physical examination including weight at subsequent visit. Physical examination should 
be performed pre-dose on dosing days. 
5.  Vital signs include blood pressure, pulse rate, and body temperature. If a vital sign result is outside the expected range for the subject’s age, gender and race, then it should be 
repeated after 5 minutes’ rest. 
6.  Blood sampling for haematology and biochemistry should be collected at pre-dose within 3 days prior to the administration of IPs of each cycle. Haematology tests include 
haemoglobin, platelet count, WBC including differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils).  
7.  Blood coagulation test, international normalised ratio (INR) will be performed at Screening. Additional blood coagulation test will be performed at the discretion of Investigator if 
there are any suspicious cases. 
8.  Biochemistry tests include creatinine, urea (blood urea nitrogen [BUN]), serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), total bilirubin, alkaline 
phosphatase (ALP), albumin, and electrolytes (sodium, potassium, chloride). 
9.  If urine dipstick is ≥ 2+ (other ways of urinalysis are also acceptable), 24 hours urine protein excretion is < 1 g or protein/creatinine ratio in spot urine is < 1 g/g creatinine 
(or < 226.0 mg/mmol creatinine). 
10.  Haematology, biochemistry and urinalysis need to be completed within 28 days prior to randomisation. They may not need to be repeated on Day 1 of Cycle 1 if the tests have been 
performed within 14 days prior to administration of IPs. 
11.  Hepatitis B and hepatitis C tests should be performed during Screening period according to local practice. Known history of HIV infection will be confirmed separately at the 
discretion of Investigator. Additional HBV/HCV tests will be performed at the discretion of Investigator if there are any suspicious cases. 
12.  For all women with reproductive potential including women who had menopause onset within 2 years prior to Randomisation, serum or urine pregnancy test must be performed 
within 2 weeks prior to Randomisation. A serum or urine pregnancy test should be performed at EOT visit. Additional pregnancy test will be performed at the discretion of 
Investigator if there are any suspicious cases. 
13.  Tumour assessments should be performed at Screening (within a maximum of 21 days prior to Randomisation) and after IP administration of Cycle 2, 4, and 6, and before planned 
Day 1 of Cycle 3, 5, and 7 and then will be performed every 4 cycles until disease progression, unacceptable toxicity, death, or end of study. If tumour assessment was already 
performed according to the schedule but next IP administration needs to be delayed due to any reasons, tumour assessment does not need to be repeated. At least one measurable 
lesion should be confirmed prior to Randomisation. If the baseline tumour assessment was not performed within 21 days prior to Randomisation, it should be repeated. Tumour 
response will be assessed using CT or MRI following Image Acquisition Guideline that will be provided by Sponsor. The same modality used at Screening will be used throughout 
the study.  
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14.  All screening procedures must be completed and reviewed within 42 days prior to randomisation. All eligibility criteria must be reviewed and confirmed prior to Randomisation.   
15.  The first dose of IP and non-IPs should be administered within 7 days after Randomisation. 
16.  SB8 or Avastin® will be administered via IV infusion before paclitaxel and carboplatin at a dose of 15 mg/kg every 3 weeks for at least 4 cycles and up to 6 cycles, and then SB8 or 
Avastin® maintenance monotherapy will be administered at a dose of 15 mg/kg every 3 weeks until disease progression, unacceptable toxicity, death, or end of study.  
17.  Paclitaxel 200 mg/m2 and carboplatin AUC 6 will be administered as an IV infusion on Day 1 of each cycle every 3 weeks for at least 4 cycles and up to 6 cycles. Subjects will also 
receive the pre-medications (e.g., steroids and anti-emetics) and adequate hydration on dosing days. 
18.  Blood sampling for immunogenicity will be performed in all randomised subjects. Blood sampling for immunogenicity will be taken at pre-dose on Day 1 of Cycle 1, 3, 5, and 7, and 
at the EOT visit (at least 21 days after last IP administration and prior to subsequent therapy). If the administration of IPs is delayed for any reasons after pre-dose blood sampling for 
immunogenicity, blood sampling for immunogenicity does not need to be repeated in delayed visit for the treatment. 
19.  Blood sampling for PK analysis will be performed at pre-dose and post-dose of IP (within 15 minutes after the end of infusion) of Cycle 1, 3, 5, and 7 in approximately 50% of the 
enrolled subjects. If the administration of IPs is delayed for any reasons after pre-dose blood sampling for PK is collected, pre-dose blood sampling for PK does not need to be 
repeated in delayed visit for the treatment, however, post-dose blood sampling for PK analysis should be performed within 15 minutes after the end of infusion. In all cases, the exact 
date and time of PK sampling and administration of IP must be carefully recorded in the source documentation to ensure the data are usable.  
20.  Concomitant and previous (within 28 days prior to Screening) medications will be recorded at Screening and concomitant medications are to be monitored continuously during the 
study treatment and after EOT visit, if such information is related to SAEs. 
21.  All AEs will be reported in the eCRF from the time when the informed consent form is signed until the EOT visit (progression of NSCLC and death due to progression of NSCLC are 
not to be reported as an AE or SAE). After the EOT visit, only SAEs will be reported using the paper SAE report form. 
22.  Subject will receive either SB8 or Avastin® concurrently with chemotherapy for at least 4 cycles and up to 6 cycles. After completion of the induction treatment period, maintenance 
treatment with IPs monotherapy will be a start. 
23.  Induction chemotherapy at Cycle 5 and 6 may be replaced with the maintenance therapy at the discretion of Investigator. In this case, all other activities except for non-IPs infusion 
must follow originally planned activities at each cycle. 
24.  SB8 or Avastin® maintenance monotherapy will be continued every 3 weeks until disease progression, unacceptable toxicity, death, withdrawal of consent, or end of study.  
25.  EOT is defined as discontinuation of treatment due to disease progression, unacceptable toxicity, death, consent withdrawal, or last administration of IP before end of study. EOT visit 
will be performed at least 21 days after last IP administration and prior to subsequent therapy. 
26.  Subjects will be followed for survival status and whether subsequent systemic anti-cancer therapy is received or not by clinic visit or telephone contact every 3 months from EOT 
until discontinuation of the subject from the study (e.g., death, withdrawal of consent, lost to follow-up, or initiation of subsequent therapy for NSCLC) or EOS date, defined as when 
deaths of all the randomised subjects have been observed, or 12 months from randomisation of the last subject, whichever occurs first.
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LIST OF ABBREVIATIONS 
ADA 
Anti-drug Antibody 
AE 
Adverse Event 
AJCC 
American Joint Committee on Cancer 
ALK 
Anaplastic Lymphoma Kinase 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Transaminase 
AUC 
Area Under the Curve 
BSA 
Body Surface Area 
CCr 
Creatinine Clearance 
CHF 
Congestive Heart Failure 
CI 
Confidence Interval 
CL 
Clearance 
Cmax 
Maximum Concentration 
CNS 
Central Nervous System 
CRO 
Contract Research Organisation 
CT 
Computed Tomography 
Ctrough 
Trough Concentration 
CR 
Complete Response 
DOR 
Duration of Response 
DSMB 
Data and Safety Monitoring Board 
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EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EGFR 
Epidermal Growth Factor Receptor 
EMA 
European Medicines Agency 
EOS 
End of Study 
EOT 
End of Treatment 
EPAR 
European Public Assessment Reports 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony-stimulating Factor 
GFR 
Glomerular Filtration Rate 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HR 
Hazard Ratio 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
INR 
International Normalised Ratio 
IP 
Investigational Product 
IRB 
Institutional Review Board 
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IV 
Intravenous 
IWRS 
Interactive Web Recognition System 
MFDS 
Ministry of Food and Drug Safety 
MRI 
Magnetic Resonance Imaging 
NAb 
Neutralising Antibody 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute- Common Terminology Criteria for Adverse Events 
NSCLC 
Non-small Cell Lung Cancer 
NSAID 
Non-steroid Anti Inflammatory Drug 
NYHA 
New York Heart Association 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression-free Survival 
PK 
Pharmacokinetics 
PPS 
Per-protocol Set 
PC 
Paclitaxel/carboplatin 
PR 
Partial Response 
PS 
Performance Status 
RECIST 
Response Evaluation Criteria in Solid Tumours 
SAE 
Serious Adverse Event 
SAF 
Safety Set 
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SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SLD 
Sum of Longest Diameters of Target Lesions 
SmPC 
Summary of Product Characteristics 
TEAE 
Treatment-emergent Adverse Event 
ULN 
Upper Limit of Normal 
US 
United States of America 
Vc 
Volume Distribution of the Central 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Cell Count 
 
 
 
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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................... 2 
FLOWCHARTS ........................................................................................................................... 11 
LIST OF ABBREVIATIONS ...................................................................................................... 15 
TABLE OF CONTENTS ............................................................................................................ 19 
LIST OF TABLES ....................................................................................................................... 23 
LIST OF FIGURES ..................................................................................................................... 23 
LIST OF STUDY STAFF ........................................................................................................... 24 
1. INTRODUCTION ................................................................................................................... 25 
1.1. Background .................................................................................................................... 25 
1.2. Investigational Product: SB8 .......................................................................................... 26 
1.2.1. Overview of SB8 ................................................................................................... 26 
1.2.2. Non-clinical Data of SB8 ...................................................................................... 27 
1.2.3. Clinical Data of SB8 ............................................................................................. 27 
1.3. Comparator Drug: Avastin® ............................................................................................ 27 
1.3.1. Clinical Pharmacokinetics of Avastin® .................................................................. 27 
1.3.2. Clinical Data of Avastin®....................................................................................... 28 
1.4. Rationale for the Study ................................................................................................... 29 
2. STUDY OBJECTIVES ........................................................................................................... 30 
2.1. Primary Objective .......................................................................................................... 30 
2.2. Secondary Objectives ..................................................................................................... 30 
2.3. Exploratory Objective .................................................................................................... 30 
3. STUDY DESIGN .................................................................................................................... 30 
3.1. Overview of Study Design ............................................................................................. 30 
3.2. Rationale for Study Design ............................................................................................ 31 
3.2.1. Rationale for Dose Selection of SB8 or Avastin®.................................................. 31 
3.2.2. Rationale for Selection of Chemotherapy Regimen .............................................. 32 
3.2.3. Rationale for Pharmacokinetic Assessment .......................................................... 32 
3.2.4. Rationale for Immunogenicity Assessments ......................................................... 32 
3.3. Number of Subjects ........................................................................................................ 33 
4. STUDY POPULATION .......................................................................................................... 33 
4.1. Overview ........................................................................................................................ 33 
4.2. Inclusion Criteria ............................................................................................................ 33 
4.3. Exclusion Criteria ........................................................................................................... 34 
4.4. Subject Withdrawal ........................................................................................................ 37 
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5. STUDY PROCEDURES AND ASSESSMENT ..................................................................... 38 
5.1. Procedures by Study Period ........................................................................................... 38 
5.1.1. Screening Period ................................................................................................... 38 
5.1.2. Randomisation ....................................................................................................... 40 
5.1.3. Induction Treatment Period (Cycle 1 to Cycle 6) .................................................. 40 
5.1.4. Maintenance Treatment Period .............................................................................. 42 
5.1.5. End of Treatment (EOT) ....................................................................................... 43 
5.1.6. Follow-up Period ................................................................................................... 43 
5.2. Efficacy Assessment ....................................................................................................... 44 
5.2.1. Measurability of Tumour ....................................................................................... 45 
5.2.2. Timing of Overall Response Rate Evaluation: All Time Points ............................ 48 
5.3. Safety Assessment .......................................................................................................... 48 
5.3.1. Clinical Safety Assessment ................................................................................... 48 
5.3.2. Laboratory Assessment ......................................................................................... 48 
5.4. Other Assessments ......................................................................................................... 49 
5.4.1. Pharmacokinetic Assessments ............................................................................... 49 
5.4.2. Immunogenicity Assessments ............................................................................... 49 
6. TREATMENT AND INVESTIGATIONAL PRODUCT ........................................................ 49 
6.1. Definition of Investigational Products and Non-investigational Products ..................... 49 
6.2. Administration of SB8 or Avastin® ................................................................................ 50 
6.2.1. Dose and Schedule of SB8 or Avastin® ................................................................. 50 
6.2.2. Formulation, Packaging and Labelling ................................................................. 50 
6.2.3. Handling and Storage of SB8 or Avastin® ............................................................. 50 
6.2.4. Preparation and Administration of SB8 or Avastin® ............................................. 50 
6.2.5. Prohibited Concomitant Medications or Therapies ............................................... 51 
6.2.6. Investigational Product Accountability ................................................................. 53 
6.3. Administration of Induction Treatment Period Chemotherapy Regimens ..................... 53 
6.3.1. Paclitaxel ............................................................................................................... 54 
6.3.2. Carboplatin ............................................................................................................ 54 
6.4. Dose and Schedule Modification ................................................................................... 55 
6.4.1. General Considerations ......................................................................................... 55 
6.4.2. Schedule Modification of SB8 or Avastin® ........................................................... 56 
6.4.3. Dose and Schedule Modification of Non-IPs Chemotherapy Agents ................... 58 
6.5. Assessment of Compliance............................................................................................. 61 
6.6. General Concomitant Medication and Supportive Care Guidelines .............................. 61 
6.6.1. Premedication for Study Drugs ............................................................................. 61 
6.6.2. Management for Infusion-related Reactions ......................................................... 62 
6.6.3. Granulocyte Colony-stimulating Factor (G-CSF) Use .......................................... 62 
6.6.4. Antibiotics Use ...................................................................................................... 62 
6.6.5. Other Supportive Care ........................................................................................... 62 
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7. SAFETY MONITORING AND REPORTING ....................................................................... 63 
7.1. Adverse Events ............................................................................................................... 63 
7.1.1. Adverse Event Definition ...................................................................................... 63 
7.1.2. Period of Observation for Adverse Events ............................................................ 64 
7.1.3. Reporting Adverse Events ..................................................................................... 65 
7.1.4. Severity Assessment .............................................................................................. 65 
7.1.5. Causality Assessment ............................................................................................ 65 
7.1.6. Emergency Unblinding for Safety Reasons .......................................................... 66 
7.1.7. Expectedness Assessment ..................................................................................... 66 
7.1.8. Withdrawal Due to Adverse Events....................................................................... 66 
7.2. Serious Adverse Events .................................................................................................. 66 
7.2.1. Serious Adverse Event Definition ......................................................................... 66 
7.2.2. Reporting Serious Adverse Event.......................................................................... 68 
7.3. Adverse Events of Special Interest (AESI) .................................................................... 69 
7.3.1. Hypertension ......................................................................................................... 69 
7.3.2. Proteinuria ............................................................................................................. 69 
7.4. Pregnancy ....................................................................................................................... 69 
7.5. Independent Data and Safety Monitoring Board ............................................................ 69 
8. STATISTICAL CONSIDERATION AND ANALYTICAL PLAN ......................................... 70 
8.1. Analysis Sets .................................................................................................................. 70 
8.2. Statistical Methods and Analytical Plan ......................................................................... 70 
8.2.1. Demographics and Baseline Characteristics ......................................................... 70 
8.2.2. Efficacy ................................................................................................................. 71 
8.2.3. Safety ..................................................................................................................... 72 
8.2.4. Pharmacokinetics .................................................................................................. 73 
8.2.5. Immunogenicity .................................................................................................... 73 
8.3. Determination of Sample Size ........................................................................................ 73 
8.4. Statistical Analysis Timepoints ...................................................................................... 74 
9. DATA COLLECTION AND MANAGEMENT ..................................................................... 75 
9.1. Data Confidentiality ....................................................................................................... 75 
9.2. Monitoring ...................................................................................................................... 75 
9.3. Data Handling and Record Keeping ............................................................................... 76 
9.4. Database Management and Coding ................................................................................ 76 
9.5. Quality Control and Quality Assurance.......................................................................... 77 
10. ETHICAL CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES .................... 77 
10.1. Institutional Review Board or Independent Ethics Committee .................................... 77 
10.2. Ethical Conduct of the Study ....................................................................................... 77 
10.3. Informed Consent ......................................................................................................... 78 
10.4. Investigator Information ............................................................................................... 78 
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10.4.1. Investigator Obligations ...................................................................................... 78 
10.4.2. Coordinating Investigator .................................................................................... 78 
10.4.3. Training of Investigator Site Personnel ............................................................... 79 
10.4.4. Protocol Signatures ............................................................................................. 79 
10.4.5. Financing and Insurance ...................................................................................... 79 
11. STUDY DISCONTINUATION ............................................................................................ 79 
12. PUBLICATION POLICY ..................................................................................................... 80 
13. REFERENCES ...................................................................................................................... 81 
APPENDIX 1: ECOG PERFORMANCE STATUS ................................................................ 84 
APPENDIX 2: LUNG CANCER STAGING (AJCC 7TH EDITION) .................................... 85 
APPENDIX 3: NATIONAL CANCER INSTITUTE-COMMON TERMINOLOGY CRITERIA 
FOR ADVERSE EVENTS VERSION 4.03 (NCI-CTCAE v4.03) (IN PART OF) .................... 88 
APPENDIX 4: WORLD HEALTH ORGANIZATION HISTOLOGICAL CLASSIFICAION OF 
TUMOURS OF THE LUNG ...................................................................................................... 90 
PROTOCOL SIGNATURE PAGES ........................................................................................... 93 
AMENDMENT 1: Dec 17, 2015 ................................................................................................ 96 
AMENDMENT 2: Aug 18, 2016 .............................................................................................. 131 
 
 
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LIST OF TABLES 
Table 1. Schedule of Activities .................................................................................................... 12 
Table 2. Criteria for Response Evaluation ................................................................................... 47 
Table 3. Prohibited Medications and Therapies of NSCLC  ....................................................... 52 
Table 4. Schedule modification of SB8 or Avastin® .................................................................... 56 
Table 5. Dose Levels for Paclitaxel and Carboplatin .................................................................. 58 
Table 6. Dose Modifications and Delays of Paclitaxel and Carboplatin ..................................... 58 
Table 7. Severity Grade of NCI-CTCAE v4.03 .......................................................................... 65 
 
LIST OF FIGURES 
Figure 1. Graphical Study Design ............................................................................................... 11 
 
 
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LIST OF STUDY STAFF 
SPONSOR: 
Samsung Bioepis Co., Ltd. 
107, Cheomdan-daero, Yeonsu-gu, 
Incheon, 21987 
Republic of Korea 
Tel: +82 (32) 455 3114 
Fax: +82 (32) 455 6799  
 
Clinical Project 
Manager  
 
  
 
 
 
Clinical Research 
Physician  
 
 
 
 
Medical Writer 
 
 
  
 
Statistician  
 
 
 
 
Project Safety Lead 
 
  
 
Safety Physician 
 
 
 
 
 
 
 
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1. INTRODUCTION 
1.1. Background 
Lung cancer is the second most common cancer in men and the third most common in women, 
accounting for about 13% of cancer diagnoses, but it is the leading cause of cancer-related 
deaths in industrialised countries. In Europe 2012, estimated new cases of lung cancer are 
410,000 and deaths from lung cancer are 353,000 [Ferlay, 2013]. The 5-year relative survival 
rate varies depending on the stage at diagnosis, from 22.9% to 2.8% for patients with local and 
distant stage disease, respectively [SEER Cancer Statistics, 1975-2009]. 
Approximately half of non-squamous non-small cell lung cancer (NSCLC) patients have 
advanced stage at diagnosis beyond curative resection [Jemal, 2009]. The median overall 
survival with metastatic NSCLC is only 4-5 months and survival rate at one year 10% with best 
supportive care [Rapp, 1988]. A meta-analysis has represented that combination chemotherapy 
leads to improvements of overall survival compared to best supportive care. Current 
combination chemotherapy showed a response rate of 19-32% and a median overall survival of 
7.9 to 11.3 months [NSCLC Collaborative Group, 1995; Schiller, 2002].  
The efficacy and safety of Avastin®, in combination to platinum-based chemotherapy, in the 
first-line treatment of patients with NSCLC, were investigated in studies E4599 [Sandler, 2006] 
and AVAiL (BO17704) [Reck, 2009]. E4599 study reported significantly improved overall 
survival (OS) and progression-free survival (PFS) with bevacizumab plus platinum-based 
chemotherapy versus chemotherapy alone (median OS 12.3 vs. 10.3 months [p = 0.003], median 
PFS 6.2 vs. 4.5months [p < 0.001]). AVAiL study has demonstrated significant PFS 
prolongation with bevacizumab compared with placebo. Adding bevacizumab for chemotherapy 
showed better treatment effect in non-squamous NSCLC.  
Recently, a few tyrosine kinase inhibitors (TKI) demonstrated overwhelming benefit for 
subjects with epidermal growth factor receptor (EGFR) gene mutations and anaplastic 
lymphoma kinase (ALK) gene re-arrangements. In IPASS study, EGFR TKI has shown 
significantly prolonged PFS compared with standard chemotherapy (24.9% with gefitinib vs. 
6.7% with paclitaxel-carboplatin in 12 months PFS rates) [Mok, 2009]. Another study of 
crizotinib versus chemotherapy in advanced ALK-positive lung cancer, the median PFS was 7.7 
months in the crizotinib group and 3.0 months in the chemotherapy group [Shaw, 2013]. 
However, approximately 15% of patients with NSCLC in the United States and European Union 
have EGFR gene mutations and about 5% of patient with NSCLC have ALK gene re-
arrangements. Also patients with unknown genetic alterations or with genetic alterations but 
who cannot receive TKI treatment for various reasons are generally treated with platinum-based 
chemotherapy as first-line chemotherapy.  
Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), has 
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been shown to benefit patients with a variety of cancers. There are studies that the addition of 
bevacizumab to platinum-based chemotherapy of patients with non-squamous NSCLC has a 
significant survival benefit. Considering the proper number of cycles of chemotherapy, no 
survival benefit was shown with administration of more than 4 cycles. Lately, in another study, 
all patients were given 4 cycles of chemotherapy followed by maintenance therapy with 
bevacizumab alone, OS was approximately 13.6 months. This result of OS is not inferior to that 
from another study with 6 cycles of chemotherapy [Patel, 2013].  
Therefore, paclitaxel and carboplatin with bevacizumab for at least 4 and up to 6 cycles and 
then maintenance therapy with bevacizumab is one of rational options for non-squamous 
NSCLC. 
1.2. Investigational Product: SB8 
1.2.1. Overview of SB8 
SB8 is under development as a similar biological medicinal product to Avastin® (bevacizumab, 
Roche Registration Ltd.). Avastin® is currently indicated for the treatment of patients with 
metastatic carcinoma of the colon or rectum, metastatic breast cancer, non-small cell lung cancer, 
advanced and/or metastatic renal cell cancer, epithelial ovarian, fallopian tube or primary 
peritoneal cancer, and carcinoma of the uterine cervix [Avastin® SmPC, 2015]. SB8 and 
Avastin® have identical primary structure and the active substance for both products is 
bevacizumab produced in a Chinese Hamster Ovary (CHO) mammalian cell line transformed by 
recombinant deoxyribonucleic acid (DNA) technology. Bevacizumab is a recombinant 
humanised monoclonal IgG1 antibody that selectively binds to and inhibits the interaction of 
VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of 
VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation 
in in vitro models of angiogenesis. 
SB8 was extensively characterised and compared to Avastin® using “state-of-the-art” methods. 
These studies were in accordance with the principles laid out in the comparability guidelines 
including the ‘Guideline on similar biological medicinal products containing biotechnology-
derived proteins as active substance: Quality issues (revision 1)’ 
[EMEA/CHMP/BWP/49348/2005]. The biosimilarity set of analytical methods is appropriately 
designed and covers the analysis of the primary structure, higher order structure, post-
translational modifications, and bioassays. It was demonstrated that SB8 has similar structural 
and physicochemical characteristics with Avastin®. 
SB8 is presented as a concentrate for infusion in a single-use vial containing either 100 mg of 
bevacizumab in 4 mL or 400 mg of bevacizumab in 16 mL. Both presentations of SB8 contain 
25 mg/mL of bevacizumab and the concentration of the excipients is also identical between the 
100 mg and 400 mg presentations. A 25 mg/mL solution of SB8 is a sterile, clear to slightly 
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opalescent, colourless to pale brown solution for intravenous (IV) infusion and preservative-free 
(pH 5.0). 
1.2.2. Non-clinical Data of SB8 
The summary of the data from non-clinical studies including repeated dose toxicity study in 
non-human primates is described in Investigator’s brochure (IB). 
As outlined in the ‘Guideline on similar biological medicinal products containing monoclonal 
antibodies’ [EMEA/CHMP/BMWP/42832/2005], a risk-based approach was taken to the non-
clinical evaluation of SB8. A series of in vitro pharmacodynamics studies was performed in 
order to demonstrate comparability between SB8 and the reference product (Avastin®). In 
addition, in vivo non-clinical toxicology has been performed in cynomolgus monkeys with SB8 
and Avastin®. Toxicokinetic and in vivo pharmacodynamics evaluation were also performed as a 
part of in vivo toxicity study. 
1.2.3. Clinical Data of SB8 
Based on the biosimilarity between SB8 and Avastin® demonstrated through extensive quality 
and non-clinical similarity exercises, a Phase I study was conducted in healthy male subjects to 
compare the PK, safety, tolerability and immunogenicity of SB8 to Avastin® and a Phase III 
study will be conducted in subjects with metastatic or recurrent non-squamous NSCLC to 
compare the efficacy, safety, PK, and immunogenicity of SB8 to Avastin®. Information on the 
safety of SB8 based on the product information of Avastin® is presented in the Investigator’s 
Brochure (IB). 
1.3. Comparator Drug: Avastin® 
1.3.1. Clinical Pharmacokinetics of Avastin® 
The PK of Avastin® has been studied in patients with solid tumours. Formal drug-drug 
interaction studies have not been performed with Avastin®. 
Distribution: the typical value for central volume (Vc) was 2.73 L and 3.28 L for female and 
male patients respectively, which is in the range that has been described for IgGs and other 
monoclonal antibodies. The typical value for peripheral volume (Vp) was 1.69 L and 2.35 L for 
female and male patients respectively, when bevacizumab is co-administered with anti-
neoplastic agents. After correcting for body weight, male patients had a larger Vc (+ 20%) than 
female patients.  
Metabolism: assessment of bevacizumab metabolism in rabbits following a single IV dose of 
125I-bevacizumab indicated that its metabolic profile was similar to that expected for a native 
IgG molecule which does not bind VEGF. The metabolism and elimination of bevacizumab is 
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similar to endogenous IgG (i.e., primarily via proteolytic catabolism throughout the body, 
including endothelial cells, and does not rely primarily on elimination through the kidneys and 
liver). Binding of the IgG to the FcRn receptor results in protection from cellular metabolism 
and the long terminal half-life.  
Elimination: the value for clearance is, on average, equal to 0.188 and 0.220 L/day for female 
and male patients, respectively. After correcting for body weight, male patients had a higher 
bevacizumab clearance (+ 17%) than females. According to the two-compartmental model, the 
elimination half-life is 18 days for a typical female patient and 20 days for a typical male patient. 
Low albumin and high tumour burden are generally indicative of disease severity. Bevacizumab 
clearance was approximately 30% faster in patients with low levels of serum albumin and 7% 
faster in subjects with higher tumour burden when compared with a typical patient with median 
values of albumin and tumour burden. 
1.3.2. Clinical Data of Avastin® 
1.3.2.1. Avastin® in Non-small Cell Lung Cancer  
Avastin® has clinical activity in patients with NSCLC in combination with chemotherapy. Two 
pivotal Phase III studies demonstrated that the combination of bevacizumab and chemotherapy 
significantly prolonged OS or PFS compared with chemotherapy alone in patients with locally 
advanced metastatic or recurrent NSCLC [Sandler, 2006; Reck, 2009]. Therefore, Avastin® is 
currently approved for use as combination in patients with NSCLC, with platinum-based 
chemotherapy for first-line treatment of unresectable, locally advanced, recurrent or metastatic 
disease. 
Avastin® was investigated in 2 large multicentre, randomised studies in patients with locally 
advanced, metastatic or recurrent NSCLC.  
E4599 Study [Sandler, 2006] 
The E4599 study enrolled 878 patients with locally advanced (stage IIIb with malignant pleural 
effusion), metastatic or recurrent NSCLC other than predominantly squamous cell histology. 
Patients were randomised to platinum-based chemotherapy (paclitaxel 200 mg/m2 and 
carboplatin AUC = 6.0), both by IV infusion (PC) on Day 1 of every 3-week cycle for up to 
6 cycles or PC in combination with Avastin® at a dose of 15 mg/kg IV infusion Day 1 of every 
3-week cycle. After completion of six cycles of PC chemotherapy or upon premature 
discontinuation of chemotherapy, patients on the Avastin® + carboplatin + paclitaxel arm 
continued to receive Avastin® as a single agent every 3 weeks until disease progression.  
The overall response rate was achieved 59 of 392 patients (15%) in the PC group and 133 of 
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381 patients (35%) in the Avastin® + PC group. 
AVAiL study [Reck, 2009] 
In this randomised, Phase III study, patients with locally advanced (stage IIIb with 
supraclavicular lymph node metastases or with malignant pleural or pericardial effusion), 
metastatic or recurrent non-squamous NSCLC, who had not received prior chemotherapy were 
randomly assigned to gemcitabine + cisplatin (GC) or Avastin® 7.5 mg/kg + GC, or Avastin® 
15 mg/kg + GC. Patients were randomised to platinum-based chemotherapy, cisplatin 80 mg/m2 
IV infusion on Day 1 and gemcitabine 1250 mg/m2 IV infusion on Days 1 and 8 of every 
3-week cycle for up to 6 cycles (GC) with placebo or GC with Avastin® at a dose of 7.5 or 
15 mg/kg IV infusion day 1 of every 3-week cycle. In the Avastin® containing arms, patients 
could receive Avastin® as a single-agent every 3 weeks until disease progression or unacceptable 
toxicity.  
The ORR was significantly higher in Avastin® plus GC (34.1% in the Avastin® 7.5 mg/kg + GC, 
30.4% in the Avastin® 15 mg/kg + GC) than GC (20.1%). 
1.4. Rationale for the Study 
Bevacizumab is a vascular endothelial growth factor (VEGF)-specific angiogenesis inhibitor 
indicated for the treatment of non-squamous NSCLC. In 2006 in the US, it was approved for the 
first-line treatment of unresectable, locally advanced, recurrent or metastatic NSCLC in 
combination with paclitaxel and carboplatin [Avastin® Prescribing Information, 2015]. In 2007 
in the EU, it was approved for first-line treatment of patients with metastatic, unresectable 
advanced or recurrent NSCLC other than predominantly squamous cell histology [Avastin® 
SmPC, 2015]. Two drug chemotherapy regimens which combine a platinum agent with 
paclitaxel, docetaxel, vinorelbine, irinotecan, and gemcitabine are usually accepted as standard 
of care for the treatment of advanced NSCLC. Up to date, there is no evidence that one 
platinum-based regimen was superior to another in term of efficacy [Schiller, 2002], indicating 
that determining the platinum compound is mainly based on health care professional’s 
preference. In the community of thoracic oncology there is the perception that the best efficacy 
of anti-angiogenic agents may be achieved in combination with taxanes. In E4599 study, median 
OS and PFS was increased by 2 months and 1.7 months respectively when bevacizumab was 
added to first-line PC therapy compared with PC alone [Sandler, 2006]. In AVAiL study, median 
PFS was significantly increased (6.7 months vs. 6.1 months) in high dose bevacizumab group 
compared with placebo [Reck, 2009]. The purpose of this study is to evaluate the equivalence of 
clinical efficacy of Avastin® combined PC and SB8 combined PC in first-line treatment of non-
squamous NSCLC. 
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2. STUDY OBJECTIVES 
2.1. Primary Objective 
The primary objective of this study is to demonstrate the equivalence of SB8 to Avastin®, in 
terms of the best overall response rate (ORR) by 24 weeks of chemotherapy in subjects with 
metastatic or recurrent non-squamous NSCLC. 
Best ORR is defined as the proportion of subjects whose best overall response is either complete 
response [CR] or partial response [PR] according to RECIST v1.1; tumour assessment will be 
performed after IP administration of Cycle 2, 4, and 6, and before planned Day 1 of Cycle 3, 5, 
and 7 and then will be performed every 4 cycles according to RECIST v1.1 and assessed by 
both Investigators and independent central reviewer. The primary efficacy analysis will be based 
on the data from the independent central review. 
2.2. Secondary Objectives 
The secondary objectives are: 
• 
To evaluate the efficacy of SB8 compared to Avastin® by 
- 
Progression free survival (PFS) 
- 
Overall survival (OS) 
- 
Duration of response (DOR) 
• 
To evaluate the safety and tolerability of SB8 compared to Avastin® 
• 
To evaluate the pharmacokinetics of SB8 compared to Avastin® 
• 
To evaluate the immunogenicity of SB8 compared to Avastin® 
2.3. Exploratory Objective 
The exploratory objective is: 
• 
To evaluate the best ORR by 11 and 17 weeks 
3. STUDY DESIGN 
3.1. Overview of Study Design 
This is a Phase III, randomised, double-blind, multicentre study to evaluate the efficacy and 
safety of SB8 compared to Avastin®. Subjects with metastatic or recurrent non-squamous 
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NSCLC without known activating epidermal growth factor receptor (EGFR) gene mutations or 
anaplastic lymphoma kinase (ALK) gene translocations will be randomised in a 1:1 ratio, 
stratified by age (< 70 and ≥ 70) and gender to receive either SB8 or Avastin® (administered 
intravenously 15 mg/kg every 3 weeks) concurrently with chemotherapy (for at least 4 cycles 
and up to 6 cycles of paclitaxel 200 mg/m2 plus carboplatin AUC 6 every 3 weeks). Subjects 
will undergo radiographic assessment of disease status (computed tomography [CT] or magnetic 
resonance imaging [MRI]) according to the Response Evaluation Criteria in Solid Tumours, 
Version 1.1 (RECIST v1.1) after IP administration of Cycle 2, 4, and 6, and before planned Day 
1 of Cycle 3, 5, and 7 and then will be performed every 4 cycles until there is radiographic 
documentation of progressive disease (PD), unacceptable toxicity, death, or end of study, 
whichever occurs first. If subjects show response to treatment, defined as complete response 
(CR)/partial response (PR)/stable disease (SD) after completion of the induction treatment 
period of combination chemotherapy with SB8 or Avastin®, they will receive SB8 or Avastin® 
maintenance therapy as per randomisation until disease progression or unacceptable toxicity or 
death, or end of study. Adverse Event (AE) information will be collected until end of treatment 
(EOT) visit (at least 21 days after last IP administration and prior to subsequent therapy). 
Approximately 50% of the enrolled subjects will have blood samples collected for PK analysis 
at pre-dose and post-dose of Cycle 1, 3, 5, and 7. 
All randomised subjects will be evaluated for ADA against SB8 or Avastin® at Baseline (pre-
dose of Cycle 1) and during treatment (pre-dose of Cycle 3, 5, and 7) and EOT visit. 
3.2. Rationale for Study Design 
3.2.1. Rationale for Dose Selection of SB8 or Avastin® 
The safety and efficacy of Avastin®, in addition to platinum-based chemotherapy, in the first-
line treatment of patients with non-squamous NSCLC, was investigated in studies E4599 and 
AVAiL. In E4599 study, patients were randomised to platinum-based chemotherapy (paclitaxel 
200 mg/m2 and carboplatin AUC 6), both by IV infusion (PC) on Day 1 of every 3-week cycle 
for up to 6 cycles or PC in combination with Avastin® at a dose of 15 mg/kg IV infusion Day 1 
of every 3-week cycle. After six cycles of paclitaxel-carboplatin chemotherapy or upon 
premature discontinuation of chemotherapy, patients on the Avastin® + PC treatment group 
continued to receive Avastin® as a single agent every 3 weeks until disease progression. Median 
OS and PFS are 12.3 months and 6.4 months in the bevacizumab combined PC group, as 
compared with 10.3 months and 4.8 months in the PC group [Sandler, 2006]. In AVAiL study, 
patients were randomised to platinum-based chemotherapy, cisplatin 80 mg/m2 IV infusion on 
Day 1 and gemcitabine 1250 mg/m2 IV infusion on Days 1 and 8 of every 3-week cycle for up 
to 6 cycles gemcitabine and cisplatin (GC) with placebo or GC with Avastin® at a dose of 7.5 or 
15 mg/kg IV infusion Day 1 of every 3-week cycle. In the Avastin® containing treatment group, 
patients could receive Avastin® as a single-agent every 3 weeks until disease progression or 
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unacceptable toxicity. There are significant PFS prolongation, when bevacizumab group was 
compared with placebo group (placebo 6.1 months, Avastin® 7.5 mg/kg 6.7 months, Avastin® 
15 mg/kg 6.5 months). However, OS was not significantly increased in bevacizumab for the 
7.5 and 15 mg/kg group, respectively, versus placebo, possibly due to high use of efficacious 
second-line therapies [Reck, 2009]. 
3.2.2. Rationale for Selection of Chemotherapy Regimen 
Over the past decade, a number of new agents have become available for the treatment of 
metastatic NSCLC, including the taxanes, gemcitabine, and vinorelbine. The combination of 
one or more of these agents with a platinum compound has resulted in high response rates and 
prolonged survival at one year in Phase II studies [Sandler, 1995; Abratt, 1995; Crino, 1995; 
Langer, 1995; Le Chevalier, 1995]. The improvements offered by cisplatin-based regimens, 
though significant in terms of survival and quality of life, were modest at best. Carboplatin, 
which possesses a toxicity profile favourable to that of its parent analogue cisplatin, yielded 
survival rates superior to that of the cisplatin-combination chemotherapy arms in a large 
randomised study of patients with metastatic NSCLC. With the introduction of taxanes in the 
early 1990s, paclitaxel demonstrated single-agent activity of 21% to 24%, with a 40% 1-year 
survival rate in metastatic disease. The next generation of Phase I/II studies evaluated the 
efficacy of paclitaxel in combination with carboplatin. Results with this regimen have shown 
substantial promise, and 1-year survival rates as high as 54% have been reported [Chandra, 
1998]. Also, taxanes appears to be potent at inhibiting angiogenesis. Sweeney et al., 
demonstrated that docetaxel inhibited endothelial cell proliferation and tubule formation in vitro 
in a dose-dependent fashion [Sweeney, 2001]. 
3.2.3. Rationale for Pharmacokinetic Assessment 
A randomised, three arm, parallel, single-dose comparative PK study was conducted in healthy 
male volunteers to demonstrate similarity in PK profiles of SB8 and EU sourced Avastin® and 
US sourced Avastin®. However, since target-mediated clearance of bevacizumab can be more 
accurately investigated in patients, additional PK assessments will be performed in this 
comparative efficacy study to provide supportive evidence to PK similarity. 
3.2.4. Rationale for Immunogenicity Assessments 
Immune responses may affect both safety and effectiveness such as altering PK, inducing 
anaphylaxis, or promoting development of neutralising antibodies (NAbs) that neutralise the 
product as well as its endogenous protein counterpart. For subject safety and for demonstrating 
biosimilarity, immunogenicity will be assessed in this study according to the recommended 
guideline. 
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3.3. Number of Subjects 
Approximately 678 subjects (339 per treatment group) will be randomised in this study over a 
planned recruitment period of approximately 2 years. 
4. STUDY POPULATION 
4.1. Overview 
The study population for this study is subjects with metastatic or recurrent non-squamous 
NSCLC.  
4.2. Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for the study: 
1. Aged ≥ 18 years (if local regulations are different in this regard, follow the local 
regulations). 
2. ECOG performance status of 0-1 at Screening. 
3. Histologically and/or cytologically confirmed metastatic (AJCC 7th edition TNM stage IV) 
or recurrent non-squamous NSCLC or NSCLC-not otherwise specified (NOS).  
4. At least one measurable lesion according to RECIST v1.1. 
5. Adequate haematological function at Screening defined as the following: 
a. Absolute neutrophil count (ANC) ≥ 1,500/mm3 (≥ 1.5 × 109/L). 
b. Platelet count ≥ 100,000/mm3 (≥ 100 × 109/L). 
c. Haemoglobin ≥ 9 g/dL (without transfusion within 14 days prior to Randomisation). 
6. Adequate hepatic function at Screening defined as the following: 
a. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (in cases of known Gilbert’s 
syndrome ≤ 3 × ULN). 
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 × ULN (in 
case of liver metastases < 5 × ULN). 
c. Alkaline phosphatase (ALP) < 3 × ULN (in case of liver metastases < 5 × ULN). 
7. Adequate renal function at Screening defined as the following: 
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a. Serum creatinine ≤ 1.5 × ULN or creatinine clearance (CCr) measured or calculated 
according to Cockcroft-Gault formula ≥ 50 mL/min. 
b. Urine dipstick for proteinuria of less than 2+ (other ways of urinalysis are also 
acceptable); if urine dipstick is ≥ 2+, 24 hours urine protein excretion should be < 1 g or 
protein/creatinine ratio in spot urine should be < 1 g/g creatinine (or < 226.0 mg/mmol 
creatinine). 
8. Subjects and their partners of childbearing potential (female or male) including those with 
history of elective sterilisation (e.g., fallopian tube ligation) who agree to use at least two 
forms of appropriate contraception (e.g., established use of oral, injected or implanted 
hormonal contraceptive, placement of an intrauterine device or intrauterine system, 
physical barrier, male sterilisation or true abstinence) from Screening until 6 months after 
the last administration of IP. A pregnancy test result is required for all women of 
childbearing potential including women who had menopause onset within 2 years prior to 
Randomisation. True abstinence will be considered sufficient for subjects who do not have 
a partner. 
9. Subjects must be able to provide informed consent, which must be obtained prior to any 
study related procedures. 
4.3. Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for the study: 
1. 
Diagnosis of small cell carcinoma of the lung or squamous cell carcinoma of the lung. For 
mixed tumour with the component of squamous cell carcinoma, it should be categorised 
according to predominant histology. Any component of small cell carcinoma of the lung is 
to be excluded. 
2. Known activating mutations in EGFR gene or transforming re-arrangements of ALK gene. 
3. Radiological or clinical evidence of tumour invasion into blood vessels or close to large 
vessels that may have risk of bleeding at the discretion of Investigator. 
4. 
History of systemic anti-cancer therapy administered in the first-line setting for metastatic 
or recurrent disease of NSCLC. 
5. Any systemic anti-cancer therapy including neoadjuvant or adjuvant chemotherapy 
administered for NSCLC and completed less than 12 months prior to Randomisation. 
6. Previously treated with a monoclonal antibody and/or molecule targeting VEGFR-related 
and/or EGFR-related signalling pathways. 
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7. Radiotherapy within 14 days prior to Randomisation (tumour lesions situated in a 
previously irradiated area, or in an area subjected to other loco-regional therapy are not 
considered as measurable lesion unless there has been demonstrated progression in the 
lesion.). 
8. 
Major surgical procedure within 28 days prior to Randomisation (e.g., requiring more 
extensive procedure than local anaesthesia [involving general anaesthesia or respiratory 
assistance or regional anaesthesia] or open lung biopsy) or expected major surgical 
procedure during the study 
9. 
Minor surgical procedure within 7 days prior to Randomisation (e.g., requiring local 
anaesthesia or following procedures; mediastinoscopy, percutaneous needle aspiration, core 
biopsy, placement of vascular access device, endobronchoscopy ultra sono & 
transbronchial needle biopsy [EBUS & TBNA], pleural biopsy, thoracentesis, pleurodesis, 
catheter insertions/removal, tooth extraction, superficial incision. 
10. Subject with non-healing wound. 
11. Symptomatic brain metastasis and/or leptomeningeal disease. Baseline brain imaging is 
strongly recommended to evaluate for presence of brain metastases. If brain metastases are 
found, they can be treated according to local practice at the discretion of investigator. 
Treatment options for brain metastases may include whole brain radiation, radiosurgery, 
craniotomy, etc. as deemed medically appropriate by the investigator. Subjects should have 
no neurologic symptoms off corticosteroids for at least 1 day to ensure that subjects do not 
have symptomatic brain metastasis. If subjects initially developed symptomatic brain 
metastases that resolved after treatment, they could be considered ‘asymptomatic’ and 
eligible for the study if they have no residual neurological dysfunction off corticosteroids 
for at least 1 day. 
12. Previous malignancy other than NSCLC in the last 5 years except for locally curable 
cancers that have been in complete remission and need no subsequent therapy, such as basal 
or squamous cell cancer of the skin, carcinoma in situ of the cervix or breast, or superficial 
bladder cancer. 
13. Life expectancy is less than 3 months. 
14. Evidence of clinically significant haemorrhagic diathesis or underlying coagulopathy. 
15. Subjects treated with anticoagulant therapy within 10 days prior to Randomisation  
(e.g., clopidogrel [≥ 75 mg/day], regular use of aspirin, dipyridamole, ticlopidine and/or 
cilostazol); anticoagulant therapy within 28 days prior to Randomisation (e.g., with 
warfarin, intravenous heparin, low molecular weight heparin, factor Xa inhibitors, thrombin 
inhibitor, and thrombolytic agent including tissue plasminogen activator, anistreplase, 
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streptokinase, urokinase). 
16. History of active gastroduodenal ulcer within 3 months prior to Randomisation. 
17. Uncontrolled hypertension (blood pressure: systolic > 150 mmHg and/or diastolic 
> 100 mmHg) with antihypertensive therapy, or hypertensive crisis or hypertensive 
encephalopathy. 
18. Any of the following events within 6 months prior to Screening:  
a. Myocardial infarction or unstable angina.  
b. Pulmonary embolism.  
c. History of congestive heart failure (CHF) (New York Heart Association, NYHA, 
Class ≥ II). 
d. Coronary/peripheral artery bypass graft surgery. 
e. Stroke or transient ischemic attack. 
f. Deep vein thrombosis. 
g. Abdominal fistulae as well as non GI fistulae, GI perforation and/or fistulae, GI-vaginal 
fistulae, or intra-abdominal abscess. 
h. Gastrointestinal bleeding and/or haematemesis or haemoptysis (≥ 1/2 teaspoon of red 
blood) or any other major bleeding events. 
19. Symptomatic peripheral sensory, motor, autonomic neuropathy NCI-CTCAE v4.03 grade 
≥ 2 and/or ototoxicity grade ≥ 2, except if due to trauma or mechanical impairment. 
20. Serologically confirmed active or chronic Hepatitis B or Hepatitis C (asymptomatic 
inactive carriers are allowed at investigator’s discretion per local standards) 
21. Acquired immunodeficiency syndrome or known seropositivity for HIV. 
22. Live/attenuated vaccine within 12 weeks prior to Randomisation (killed/inactivated or 
recombinant vaccine is allowed.). 
23. Known allergy or hypersensitivity to any of the treatment components. 
24. Risk of occurrence of osteonecrosis of jaw (ONJ) (e.g., treated with intravenous 
bisphosphonates and/or invasive dental procedures within 28 days prior to Randomisation). 
25. Uncontrolled malignant pleural effusion (e.g., recurrent despite drainage or sclerosing 
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agents). 
26. Pregnancy or lactation period. 
27. Subjects unwilling to follow the study requirements. 
28. Inappropriate other medical conditions for the study at the discretion of Investigator. 
29. Currently enrolled in another interventional clinical study. 
30. Previous administration of other investigational product(s) within 28 days prior to 
Randomisation. 
4.4. Subject Withdrawal 
Once randomised to study treatment, subjects may withdraw from the study or study specific 
procedures at any time. The subject must be discontinued from all study treatment (IPs and/or 
non-IPs) in the event of any of the following, but follow-up for safety information should be 
continued until death or EOT visit (see Sections 5.1.5. and 5.1.6.): 
• 
Radiographic progression of disease at the discretion of Investigator 
• 
Unequivocal clinical progression of disease at the discretion of Investigator 
(e.g., the occurrence of malignancy-associated disseminated intravascular coagulation, 
respiratory failure requiring ventilator care.) 
• 
Death of any cause 
• 
Unacceptable toxicity including AEs not manageable by symptomatic therapy or 
schedule modification or dose modification (see Section 6.4) 
• 
AEs requiring permanent discontinuation of IP (see Section 6.4.2) 
• 
Protocol deviations that may affect the subject’s safety seriously if continued on 
treatment, agreed by the Investigator and the Sponsor 
• 
Pregnancy 
• 
Treatment delay of more than 3 weeks from the schedule, which is counted from the 
planned starting date of each cycle (i.e., 6 weeks from the last administration of IP) 
• 
Lack of subject’s compliance 
• 
Consent withdrawal by subject 
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• 
Unblinding (except unblinding for the purpose of regulatory reporting) 
If subjects withdraw consent, the Investigator must inquire the reason to determine if it is 
related to the study (e.g., documented lack of efficacy, AE or pregnancy). In such cases the 
reason for withdrawal must be recorded clearly and should not be classified as consent 
withdrawal. If the subject does not return for a scheduled visit, every effort should be made to 
contact the individual. Subject’s decision to withdraw consent and discontinue the study 
procedure will not prejudice the future medical treatment in any way. 
All the subjects who withdraw from the study will be asked to return to the Investigational site 
for the EOT visit procedures to be performed (see Section 5.1.5.) and to have a follow-up 
telephone contact or clinic visit. The subject must be reminded that clinical data which have 
been acquired so far will be kept in the study database for the sake of integrity of data, unless 
the subject expresses his/her willingness to remove all of his/her data from the study database. 
5. STUDY PROCEDURES AND ASSESSMENT 
5.1. Procedures by Study Period 
5.1.1. Screening Period 
Screening should be performed within 42 days before Randomisation. All subjects must provide 
written informed consent prior to any study related procedures being performed.  
The following procedures and assessments should be performed within 42 days before 
Randomisation. Retesting or re-evaluation is allowed within the screening period, but the latest 
assessment will be used to determine the eligibility. Re-screening or re-consenting after 42 day 
screening period has elapsed is not allowed.  
• 
Informed consent 
• 
Demographic data  
• 
Medical history and major surgical procedures (see Section 6.2.5.) including 
malignancy other than NSCLC and those medical conditions described in the exclusion 
criteria, in the last 5 years (see Section 4.3.).  
• 
ECOG performance status (see APPENDIX 1) 
• 
Physical examination including vital signs (blood pressure, pulse rate, and body 
temperature), height and weight 
• 
Ongoing AEs from the acquisition of the informed consent 
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• 
Review of previous or concomitant medication (within 28 days prior to informed 
consent; within 12 weeks prior to informed consent in case of vaccines) 
• 
Haematology, biochemistry, urinalysis, and serology (retesting is allowed during the 
Screening period). Haematology, biochemistry and urinalysis need to be completed 
within 28 days before randomisation. 
- 
Haematology: haemoglobin, WBC including differential (neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils), platelet count.  
- 
Blood coagulation test: international normalised ratio (INR). If there is significant 
deviation in the value (i.e., INR > 1.5), it is highly recommended that the 
investigator determine the cause (i.e., warfarin – which would be excluded) and 
reversibility. If the Investigator determines that the subject is at a high risk of 
bleeding as a result of abnormal INR, subject should be excluded according to 
section 4.3 (exclusion criterion 14).  
- 
Biochemistry: serum creatinine, urea (BUN), alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin, 
albumin, sodium, potassium, chloride 
- 
Urinalysis (dipstick): leukocytes, nitrite, urobilinogen, protein, pH, Hb, specific 
gravity, ketone, bilirubin, glucose (other ways of urinalysis are also allowed), if 
urine dipstick is ≥ 2+, 24 hours urine protein excretion should be < 1 g or 
protein/creatinine ratio in spot urine should be < 1 g/g creatinine (or < 
226.0 mg/mmol creatinine)  
- 
Serology: test for Hepatitis B and hepatitis C should be performed during Screening 
period according to local practice. Known history of HIV infection will be 
confirmed separately at the discretion of Investigator. 
- 
If other laboratory tests not listed above are checked by local practice and found to 
be abnormal, it is recommended that Investigator use the best clinical judgement to 
determine if the abnormal values would affect patient safety while participating in 
the study. 
• 
Serum (or urine) pregnancy test for all women of childbearing potential including 
women who had menopause onset within 2 years prior to Randomisation should be 
performed within 2 weeks prior to Randomisation. For all other women, 
documentation of the medical history confirming that the subject is not of childbearing 
potential must be required. 
• 
12-lead ECG 
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• 
Baseline tumour assessment (within a maximum 21 days prior to Randomisation) of 
lung and locoregional lymph nodes by CT scan or MRI. Upper abdominal cavity 
including the adrenal glands must be included in imaging study. If the baseline tumour 
assessment is not performed within 21 days prior to Randomisation, it should be 
repeated. Baseline tumour assessment should be done after allowed surgical procedure 
to suspected target or non-target lesions (see Sections 4.3. and 5.2.1.). Tumour 
assessment before subject signed informed consent will be acceptable to use as 
baselines tumour assessment and may not be repeated if it is done within 21 days prior 
to Randomisation and performed according to Section 5.2.1. 
• 
Additional CT scan, MRI, PET-scan, or bone scan will be performed at the discretion 
of Investigator (optional), if there are symptoms or clinical suspicion of distant 
metastasis. 
5.1.2. Randomisation 
If the subject signs the ICF, the Investigator should check the whole eligibility criteria of the 
subjects prior to Randomisation. 
5.1.2.1. Randomisation Method 
The randomisation numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and site personnel. A subject 
randomisation list will be produced by the interactive web response system (IWRS) provider 
using a validated system that automates the random assignment of subject numbers to 
randomisation numbers. These randomisation numbers are linked to the different treatment arms, 
which in turn are linked to medication numbers. A separate medication randomisation list will 
be produced by or under the responsibility of the Sponsor using a validated system that 
automates the random assignment of medication numbers to medication packs containing each 
of the IPs. 
5.1.2.2. Stratification Factors 
Randomisation will be stratified by 
• 
Age at randomisation: < 70 vs. ≥ 70 
• 
Gender: male vs. female 
5.1.3. Induction Treatment Period (Cycle 1 to Cycle 6) 
The first dose of IPs should be administered within 7 days after Randomisation.  
Induction treatment period consists of 4 to 6 cycles of a 3-week cycle. The Investigator may 
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determine the duration of induction chemotherapy according to tumour response and toxicity 
profiles of individual subject. The visit window allowed for each visit is ± 3 days. 
All procedures and assessments must be performed within 3 days before the administration of 
IPs of each cycle, unless otherwise specified. 
The following procedures and assessments will be performed at each subsequent scheduled visit. 
• 
Physical examination including vital signs (blood pressure, pulse rate, and body 
temperature) and weight 
• 
ECOG performance status 
• 
Haematology, biochemistry, and urinalysis (if urine dipstick is ≥ 2+, see Section 7.3.2.) 
– Repeated laboratory tests may not be needed if tests have been performed within 14 
days prior to Day 1 of Cycle 1. 
• 
Blood coagulation test if clinically suspected 
• 
Pregnancy test (serum or urine) if clinically suspected 
• 
Serology: tests for HBV or HCV will be repeated during the course of the study only 
when clinically suspected. 
• 
AEs assessment from previous cycles 
• 
Review of concomitant medication 
• 
Premedication of IP and/or Non-IPs (if necessary, see Section 6.6.1.) 
• 
Administration of IP and non-IPs on Day 1 of each cycle for at least 4 cycles and up to 
6 cycles 
If a treatment is delayed, concerned laboratory tests will be repeated within 3 days before the 
administration of IPs of each cycle. 
The other assessments will be performed at the following schedule: 
• 
Imaging tumour assessment of target and non-target lesion by CT scan or MRI will be 
performed after IP administration of Cycle 2, 4, and 6 and before planned Day 1 of 
Cycle 3, 5, and 7 (upper abdominal cavity including the adrenal glands must be 
included in imaging study.). If tumour assessment was already performed according to 
the schedule but next IP administration needs to be delayed due to any reasons, tumour 
assessment does not need to be repeated.  
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• 
If progressive disease is suspected clinically, the Investigator may additionally perform 
tumour assessment during the induction treatment period.  
• 
Blood sampling for PK (approximately 50% of enrolled subjects) at pre-dose and post-
dose of IP (within 15 minutes after the end of infusion) of Cycle 1, 3, and 5 
• 
Blood sampling for immunogenicity in all randomised subjects at pre-dose of Cycle 1, 
3, and 5. 
In case of early switch to maintenance treatment period, subject blood sampling will be 
collected as originally planned at Cycle 3 and/or 5, if applicable.  
5.1.4. Maintenance Treatment Period 
If subjects show response to treatment, defined as complete response (CR) or partial response 
(PR), or stable disease (SD) after completion of the induction treatment period of combination 
chemotherapy with SB8 or Avastin® (at least 4 cycles and up to 6 cycles), they will receive SB8 
or Avastin® maintenance therapy as per randomisation until disease progression, unacceptable 
toxicity, death, or end of study. The visit window allowed for each visit is ± 3 days. 
The following procedure and assessments will be performed within 3 days prior to Day 1 of 
each scheduled cycle, unless otherwise specified: 
• 
Physical examination including vital signs (blood pressure, pulse rate, and body 
temperature) and weight 
• 
ECOG performance status 
• 
Haematology, biochemistry, and urinalysis (if urine dipstick is ≥ 2+, see Section 7.3.2.) 
• 
Blood coagulation test if clinically suspected 
• 
Pregnancy test (serum or urine) if clinically suspected 
• 
Serology: tests for HBV or HCV will be repeated during the course of the study only 
when clinically suspected. 
• 
AEs assessments  
• 
Review of concomitant medication 
• 
Administration of IP every 3 weeks on Day 1 of each cycle 
If a treatment is delayed, concerned laboratory tests will be repeated within 3 days before the 
administration of IP of each cycle. 
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The other assessments will be performed at the following schedule: 
• 
Tumour assessment will be performed every 4 cycles (prior to IP administration). 
Upper abdominal cavity including the adrenal glands must be included in imaging 
study. 
• 
If progressive disease is suspected clinically, the Investigator may additionally perform 
tumour assessment during the maintenance treatment period. 
• 
Blood sampling for PK (approximately 50% of enrolled subjects) at pre-dose and post-
dose of IP (within 15 minutes after the end of infusion) of Cycle 3, 5, and 7. 
• 
Blood sampling for immunogenicity at pre-dose of Cycle 3, 5, and 7. 
5.1.5. End of Treatment (EOT) 
EOT is defined as discontinuation of treatment due to disease progression, unacceptable toxicity, 
death, consent withdrawal or last administration of IP before end of study. Other conditions that 
also meet definition of EOT are described in Section 4.4. The EOT visit will be performed at 
least 21 days after last IP administration and prior to subsequent therapy. In case of study 
withdrawal for any reasons, every effort should be made to follow the subject for EOT visit. The 
following procedures will be performed at EOT visit: 
• 
12-lead ECG 
• 
Physical examination including vital sign (including blood pressure, pulse rate, and 
body temperature) and weight 
• 
ECOG performance status 
• 
Haematology, biochemistry, and urinalysis (if urine dipstick is ≥ 2+, see Section 7.3.2.) 
• 
Blood coagulation test if clinically suspected 
• 
AEs assessment 
• 
Pregnancy (serum or urine) test (only for female subjects with childbearing potential) 
• 
Review of concomitant medication 
• 
Blood sampling for immunogenicity 
5.1.6. Follow-up Period 
Subjects will be followed for survival status and whether subsequent therapy is received or not 
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by clinic visit or telephone contact every 3 months (± 7 days) from EOT until discontinuation of 
the subject from the study (e.g., death, withdrawal of consent, lost to follow-up or initiation of 
subsequent therapy for NSCLC) or EOS date, defined as when deaths of all the randomised 
subjects have been observed, or 12 months from Randomisation of the last subject, whichever 
occurs first. 
SAEs will continue to be reported to Sponsor during the follow-up period. (See Section 7.2.2) 
5.2. Efficacy Assessment 
Tumour response will be assessed classified according to RECIST v1.1 criteria. Subject must 
have at least one radiographically measurable lesion in a previously non-irradiated area 
according to RECIST v1.1 to be eligible for randomisation in this study. All tumour 
measurements should be performed with the same method of assessment and made by the same 
Investigator/radiologist for each subject during the study to the extent that this is feasible. Based 
on the independent central review for tumour assessment, the imaging independent central 
reviewer will record their own assessments of each subject’s imaging eligibility at baseline, best 
response, disease progression, and related variables. The primary efficacy analysis will be based 
on the data from the independent central review. 
The primary endpoint is: 
• 
The best ORR by 24 weeks of chemotherapy (best ORR is defined as the proportion of 
subjects whose best overall response is either complete response [CR] or partial 
response [PR] according to RECIST v1.1) 
The secondary endpoints are: 
• 
PFS, defined as the time from the date of Randomisation to the date of disease 
progression or death regardless of the cause of death. Subjects who are not progressed 
at the time of analysis will be censored at the date of the EOT visit or the date of last 
tumour assessment if the EOT visit is not available.  
• 
OS, defined as the time from the date of Randomisation to the date of death regardless 
of the cause of death. Subjects who are alive at the time of analysis will be censored at 
the date of last known alive. 
• 
DOR, defined as the time from documented tumour response (complete or partial) until 
documented disease progression. Only the subjects who achieve an initial tumour 
response will be evaluated for DOR. 
The exploratory endpoint is: 
• 
Best ORR by 11 and 17 weeks 
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5.2.1. Measurability of Tumour  
At baseline, tumour lesion/lymph nodes will be categorised measurable or non-measurable. At 
least one measurable lesion should be confirmed for this study. Tumour lesions must be 
accurately measured in at least one dimension (longest diameter in the plane of measurement is 
to be recorded) with a minimum size of: 
• 
Measurable lesion 10 mm by CT/MRI scan (CT scan slice thickness no greater than 
5 mm) 
Malignant lymph nodes: to be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT/MRI scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed.  
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions are non-
measurable. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin 
or lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
5.2.1.1. Definition of Target and Non-target Lesions 
During the baseline assessment before IP administrations, all lesions detected are classified as 
either target lesions or non-target lesions on CT/MRI scan.  
• 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions total, representative of all involved organs should be identified as target lesions 
and recorded at baseline. Target lesions should be selected based on their size and their 
suitability for accurate repeated measurements by imagaing.  
• 
Non-target lesions: All other lesions including small lesions and other non-measurable 
lesions should be identified as non-target lesions and should be recorded at baseline. 
Measurements of these lesions are not required, but the presence or absence of each 
should be noted throughout follow up.  
For detailed instructions, please refer to Completion Guide for Tumour Assessment Worksheet.  
5.2.1.2. Criteria for Tumour Response Evaluation 
Evaluation of Measurable Lesions 
Tumour response will be evaluated according to the RECIST v1.1 criteria. Subjects should 
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continue to undergo tumour response assessment until PD, unacceptable toxicity, death or end 
of study. 
In this study, tumour response will be measured using CT scan or MRI (other methods such as 
X-ray or ultrasound are not permitted for monitoring target lesions) following Image 
Acquisition Guideline that will be provided by Sponsor. The same method of assessment and 
the same technique should be used to characterise each identified and reported lesion at baseline 
and during the study. 
The use of oral and IV contrast, etc., is highly recommended and should be used consistently 
unless contraindication exists. Tumour evaluations should be made by the same Investigator or 
radiologist for each subject during the study, if possible.  
Baseline total tumour burden must be assessed no more than 21 days prior to Randomisation. If 
the baseline tumour assessment is not performed within 21 days prior to Randomisation, it 
should be repeated. Baseline tumour assessment will include the adrenal glands and the entire 
liver. In case of contrast contraindication, MRI or non-contrast CT scans can be performed. 
Additional PET-scan, or bone scan will be performed at the discretion of the Investigator 
(optional), if there are symptoms or clinical suspicion of distant metastasis. 
Tumour lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are not considered measurable unless there has been demonstrated progression 
in the lesion. 
For baseline brain imaging, MRI with contrast is preferred but CT scan with IV contrast is 
acceptable if MRI cannot be obtained (Ex. pacemaker, unavailable MRI facility, etc.). If brain 
metastases are found but not treated (asymptomatic), they could be potentially listed as target 
and/or non-target lesions at discretion of investigators. However, all target and/or non-target 
lesions should be followed using the same imaging modality throughout the study. 
 
If brain metastases are found and treated, those should be listed as “non-target” lesions for 
tumour response evaluation according to RECIST 1.1. If brain metastases are treated and 
patients are asymptomatic, follow-up brain imaging is not required unless clinically suspected.  
 
Complete Response (CR)  
Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) 
must have reduction in short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
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Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study. 
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of 
at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). 
Table 2. Criteria for Response Evaluation 
Target lesions 
Non-target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PDa 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PDa or not all 
evaluated 
No 
PR 
SD 
Non-PDa or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PDa 
No 
inevaluable 
PD 
Any category 
Yes or No 
PD 
Any category 
PDa  
Yes or No 
PD 
Any category 
Any category 
Yes 
PD 
a For non-target lesions, PD is defined as the unequivocal progression, as determined by the Investigator 
Evaluation of Non-measurable Lesions 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively. 
Complete Response (CR) 
Disappearance of all non-target lesions and normalisation of tumour marker level. All lymph 
nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level 
above the normal limits. 
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesions. (Note: the appearance of one or more 
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new lesions is also considered progression). 
5.2.2. Timing of Overall Response Rate Evaluation: All Time Points 
The overall response is determined once all the data for the subject is known. For best response 
determination in the study, confirmation of complete or partial response is NOT required. Best 
response in this study is defined as the best response across all time points (e.g., a patient who 
has SD at first assessment, PR at second assessment, and PD on last assessment has a best 
overall response of PR).  
5.3. Safety Assessment 
The safety endpoint is: 
• 
Incidence of AEs and SAEs. 
5.3.1. Clinical Safety Assessment 
Safety of subjects will be monitored by physical examination, performance status and vital sign 
assessment. Subjects will be assessed for AEs at each clinical visit and as necessary throughout 
the study. 
5.3.2. Laboratory Assessment 
Haematology and biochemistry laboratory tests will be done as part of regular safety 
assessments. 
• 
Haematology: haemoglobin, WBC including differential (neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils), platelet count.  
• 
A coagulation test (INR) will be performed at Screening and during the study if 
clinically suspected. 
• 
Biochemistry: creatinine, urea (BUN), ALT, AST, ALP, total bilirubin, albumin, 
sodium, potassium, chloride 
• 
Urinalysis (dipstick): leukocytes, nitrite, urobilinogen, protein, pH, Hb, specific gravity, 
ketone, bilirubin, glucose (other ways of urinalysis are also allowed.)  
• 
Pregnancy test in women of childbearing potential (serum or urine) 
• 
Tests for HBV or HCV will be repeated during the course of the study only when 
clinically suspected. 
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5.4. Other Assessments 
5.4.1. Pharmacokinetic Assessments 
Approximately 50% of the enrolled subjects will be participating by default in the PK sub-study 
for PK assessment and those subjects will be defined at the time of randomisation in the IWRS. 
Once the number of subjects is reached to the planned number, all further subjects enrolled will 
not participate in the PK sub-study.  
Blood sampling for PK analysis will be performed at pre-dose and post-dose of IP (within 15 
minutes after the end of infusion) of Cycle 1, 3, 5 and 7. 
If the IP administration is delayed for any reasons after pre-dose blood samples for PK is 
collected, pre-dose blood sampling for PK analysis does not need to be repeated in delayed visit 
for the treatment, however, post-dose blood sampling for PK analysis should be performed 
within 15 minutes after the end of infusion. 
In all cases, the exact date and time of the PK sampling and IP administration must be carefully 
recorded in the source documentation to ensure the data are usable. 
Details of the sampling, handling, storage and shipping for PK samples are described in the 
Study Sample Handling and Logistics Manual. 
5.4.2. Immunogenicity Assessments 
The purpose of immunogenicity testing is to determine whether ADAs and NAbs against SB8 or 
Avastin® occur in similar rate and influence the safety or efficacy. Blood sampling for 
immunogenicity testing will be done as per visiting schedule in all subjects (see Table 1). 
All randomised subjects will be evaluated for ADA against SB8 or Avastin® at Baseline (pre-
dose of Cycle 1) and during treatment (pre-dose of Cycle 3, 5, and 7) and EOT visit. Details of 
sampling, handling, storage and shipping for immunogenicity samples are described in the 
Study Sample Handling and Logistics Manual. 
6. TREATMENT AND INVESTIGATIONAL PRODUCT 
6.1. Definition of Investigational Products and Non-investigational Products 
Throughout the study, the IPs mean SB8 and Avastin®. Combination chemotherapy regimens in 
the induction treatment period are not regarded as IPs since they are considered as standard of 
care. In this study, carboplatin, and paclitaxel are named as non-IPs. 
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6.2. Administration of SB8 or Avastin® 
6.2.1. Dose and Schedule of SB8 or Avastin® 
SB8 or Avastin® will be administered every 3 weeks until disease progression, unacceptable 
toxicity occurs, death, or end of study. SB8 or Avastin® will be administered intravenously at a 
dose of 15 mg/kg. Body weight should be recorded at Screening and at every scheduled visit for 
all subjects.  
6.2.2. Formulation, Packaging and Labelling 
Bevacizumab is supplied for use as a concentrate for solution (100 mg or 400 mg per vial for 
SB8, EU sourced Avastin®). 
Sponsor or the designated representative team will ensure that the test IP is characterised as 
appropriate and are manufactured in accordance with any Good Manufacturing Practice (GMP). 
All IPs will be labelled in accordance with EU, and local regulations and GMP. 
6.2.3. Handling and Storage of SB8 or Avastin® 
SB8 and Avastin® should be stored at 2-8°C. The temperature should be monitored. If 
continuous monitoring is not available then manual temperature logs should be generated and 
recorded to ensure proper storage conditions. If a temperature deviation occurred, responsible 
person should contact the Sponsor to determine if the drug is still appropriate for use. The IPs 
should be stored in a secure area and clearly labelled and stored away from other non-IPs or 
medication to prevent confusion (for example in a clearly marked box on a separate shelf of the 
refrigerator). 
Do not freeze or do not shake SB8 or Avastin® vials. Store the vials within the outer carton to 
protect them from light. The IPs must not be used beyond the expiration date. 
6.2.4. Preparation and Administration of SB8 or Avastin® 
6.2.4.1. Preparation of SB8 or Avastin® 
IPs should be prepared by a pharmacist or properly trained pharmacy delegate using aseptic 
technique to ensure the sterility of the prepared solution. 
Prior to IP preparation, the dose amount will be calculated by the Investigator according to 
subject’s body weight measured and documented at Baseline and every cycle. The dose 
calculation is as follows: 
• 
Dose amount (mg) = actual body weight (kg) × 15 mg/kg 
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• 
Volume (mL) = 
dose amount (mg) 
concentration of bevacizumab (mg/mL) 
Necessary amount of IP will be withdrawn and diluted to a total volume of 100 mL of 0.9% 
sodium chloride injection. Detailed process will be described in the Pharmacy Manual. 
If any quality issue is encountered, the IPs must not be prepared until the discrepancy has been 
completely resolved by checking the documentation with the Investigator. 
After IP preparation is completed, the label with preparation time, subject identifier, dose 
amount, and total infusion volume to be given to a subject will be attached on the infusion bag. 
6.2.4.2. Administration of SB8 or Avastin® 
In the induction treatment period, SB8 or Avastin® will be administered intravenously before 
starting chemotherapy (paclitaxel and carboplatin) at a dose of 15 mg/kg every 3 weeks. In the 
maintenance treatment period, SB8 or Avastin® will be administered intravenously at a dose of 
15 mg/kg every 3 weeks. The first infusion is given over 90 minutes. If the first dose is well 
tolerated, second infusions may be given over 60 minutes and subsequently administered over 
30 minutes. Do not administer SB8 or Avastin® as an IV push or bolus. Investigators or designee 
should observe subjects during administration of IPs and for at least 6 hours after the start of the 
first infusion and for 2 hours after the start of the subsequent infusions for symptoms like fever 
and chills or other infusion-related symptoms. Interruption or slowing of the infusion may help 
to control infusion-related symptoms and may be resumed when symptoms abate. Subjects who 
experience infusion-related reactions may be premedicated with paracetamol and antihistamine 
for subsequent infusions. Subjects should be warned of the possibility of late onset reactions and 
should be instructed to contact their Investigator if these reactions occur. Dose reductions of 
SB8 or Avastin® for toxicity are not permitted. Schedule modifications are permitted as 
described in Section 6.4.2. A detailed guideline for IPs preparation, administration, storage and 
destruction will be provided in the Pharmacy Manual. 
6.2.5. Prohibited Concomitant Medications or Therapies 
All concomitant medication use should be recorded. Details to be recorded include: name 
(generic name preferred), dose number and unit, frequency of administration, route of 
administration, start and stop dates and the AE it relates to (if applicable). 
Medication and therapies that are prohibited prior to Randomisation and/or throughout the study 
are presented in Table 3. 
 
 
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Table 3. Prohibited Medications and Therapies of NSCLC  
Medication or therapies 
Time to be prohibited 
Anticoagulants or thrombolytic agents: 
 
Regular use of aspirin 
Prior to Randomisation 
Aspirin (≥325 mg daily)a 
*After randomisation, low dose aspirin (< 325mg daily) is allowed 
if medically indicated at the discretion of Investigator. 
From Randomisation to EOT 
Antiplatelet agents such as Clopidogrel (≥ 75 mg/day), 
dipyridamole, ticlopidine and/or cilostazolb 
Within 10 days  
prior to Randomisation to EOT 
Warfarin, intravenous heparin, low molecular weight 
heparin, factor Xa inhibitors, thrombin inhibitors, 
thrombolytic agents including tissue plasminogen activator, 
anistreplase, streptokinase, urokinasec 
*After randomisation, anticoagulation is allowed if medically 
indicated 
Within 28 days  
prior to Randomisation to EOT 
Any drugs (include herbal medications) that has not received 
regulatory approval for any indications 
From Randomisation to EOT 
Anticancer systemic therapy other than 
paclitaxel/carboplatin/Avastin®/SB8d 
From Randomisation to EOT 
Major surgical procedure (include open lung biopsy)e 
*If a major surgical procedure is indicated after randomisation, 
treatment needs to be held for at least 28 days after surgery and 
subject needs to completely recover from surgery. The maximum 
allowed delay is 6 weeks from the last IP infusion.  
Within 28 days  
prior to Randomisation 
Minor surgical proceduref 
*If a minor surgical procedure is indicated after randomisation, 
treatment needs to be held for at least 7 days after surgery and subject 
needs to completely recover from surgery. The maximum allowed 
delay is 6 weeks from the last IP infusion. 
Within 7 days  
prior to Randomisation 
Live/attenuated vaccine 
Within 12 weeks  
prior to Randomisation to Cycle 7 Day 1 
Intravenous bisphosphonates and/or invasive dental procedure 
*Allowed after randomisation if determined by investigator as 
clinically necessary (ex. Bone metastases related to NSCLC or tooth 
abscess requiring extraction, etc.) 
Within 28 days 
prior to Randomisation  
Radiotherapyg 
Within 14 days 
prior to Randomisation to EOT 
EOT = end of treatment; NSAIDs = non-steroidal anti-inflammatory drugs 
Local anaesthesia is defined as anaesthesia of a small part of the body such as a tooth or an area of skin. 
a After randomisation, low dose aspirin < 325mg daily is allowed if medically indicated (cardiac prophylaxis, etc.) 
and there is no bleeding diathesis that would increase the risk of therapy at the discretion of Investigator. 
bNon-chronic use of NSAIDS (not including aspirin) for symptom management is permitted if there is no bleeding 
diathesis that would increase the risk of therapy at the discretion of Investigator. 
cAfter randomisation, therapeutic anticoagulation (heparin, warfarin, etc.) is allowed if medically indicated in case of 
new thromboembolic events (i.e., deep venous thrombosis) at the discretion of Investigator. Refer to section 6.4.2 
Table 4 for specific guidelines. Non-systemic use of anticoagulants (ex. heparin flush) to maintain patency of 
intravenous injection devices is allowed. 
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d Nab-paclitaxel or other formulation of paclitaxel is not allowed in this study. 
e Requiring more extensive procedure than local anaesthesia (involving general anaesthesia or respiratory assistance 
or regional anaesthesia) or open lung biopsy. 
f Requiring local anaesthesia or following procedures; mediastinoscopy, percutaneous needle aspiration, core biopsy, 
placement of vascular access device, endobronchoscopy ultra sono & transbronchial needle aspiration (EBUS & 
TBNA), pleural biopsy, thoracentesis, pleurodesis, catheter insertion/removal, tooth extraction, superficial incision. 
g Radiotherapy of palliative purpose to non-progressive non-target lesions is allowed during the treatment period. If 
target lesions are included in irradiated field, then those lesions should not be evaluated as measurable thereafter. It is 
strongly recommended that the Investigator consult to the Sponsor at the timing of planning radiotherapy. IP and non-
IPs should be suspended during radiotherapy and may be resumed at the discretion of the Investigator. 
6.2.6. Investigational Product Accountability 
Information on drug disposition required by applicable regulation may consist of the date 
received, date administered, quantity administered, and the subject to whom the drug was 
administered. The Investigator is responsible for accounting all used/unused IP. The used IP vial 
should be disposed and/or destructed after use according to the local regulation. In case that the 
IP vial is disposed after use, the Investigator is responsible for accounting other materials of 
used IP such as IP container. The Investigator uses this information to maintain an accurate and 
complete dispensing and inventory record provided by the Sponsor. 
IP supplies are shipped to the Investigator site as needed. The monitor will review drug 
accounting during routine monitoring visits with the documents containing relevant information 
provided by the Sponsor. At the completion or termination of the study, a final drug 
accountability review and reconciliation must be completed; any discrepancies must be 
investigated and their resolution documented. 
All full containers of IP must be returned to the Sponsor/contract distribution centre with the 
appropriate form. The site and the site monitor are to contact the Sponsor for detailed 
information before return to the Sponsor is to take place. 
Furthermore, due to the fact that the IP is a hazardous substance, and/or its shipment may cause 
harm to humans, available IP, in an opened vial, may be destroyed at the site with the Sponsor’s 
permission. The site may destroy unused (e.g., left after the vial was opened and/or reconstituted) 
once accountability of the IP is completed. The IP destruction must be documented on the 
relevant records. The site may destroy the IP before the site monitoring visits with the Sponsor’s 
agreement and the site monitors will perform the accountability and reconciliation from the 
records maintained at the site. The accountability, reconciliation, and return procedures also 
apply to all IPs that are required by the protocol and supplied by the Sponsor. 
6.3. Administration of Induction Treatment Period Chemotherapy Regimens 
Doses of chemotherapy will be calculated according to the subject’s body surface area (BSA) or 
body weight. Weight and height should be recorded at Baseline and the BSA calculated, 
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thereafter all subjects should be re-weighted at every cycle. Actual body weights should be used 
in calculating dose at each cycle. For more information of chemotherapy drugs including 
contraindications, special warnings and precautions for use, fertility, pregnancy, and lactation, 
please refer to SmPC of individual drugs. 
6.3.1. Paclitaxel 
6.3.1.1. Preparation and Storage of Paclitaxel 
Refer to the prescribing information in paclitaxel for the formulation, preparation, and storage 
of paclitaxel. Nab-paclitaxel or other formulation of paclitaxel is not allowed in this study.  
6.3.1.2. Dose and Schedule of Paclitaxel 
Paclitaxel will be administered by 200 mg/m2 every 3 weeks for at least 4 and up to 6 cycles 
during the induction treatment period. Actual body weights should be used in calculating BSA at 
each cycle. Paclitaxel will be administered as IV infusion over approximately 3 hours after the 
completion of SB8 or Avastin® administration. Dose and schedule modification for toxicity are 
permitted (see Section 6.4.). 
6.3.2. Carboplatin 
6.3.2.1. Preparation and Storage of Carboplatin 
Refer to the prescribing information in carboplatin for the formulation, preparation, and storage 
of carboplatin. 
6.3.2.2. Dose and Schedule of Carboplatin 
Carboplatin will be administered by Calvert formula (AUC 6) every 3 weeks for at least 4 and 
up to 6 cycles during the induction treatment period. Carboplatin will be administered as IV 
infusion over approximately 30 minutes after the completion of paclitaxel. Dose modification 
and delays for toxicity are permitted (see Section 6.4.). 
The Calvert formula incorporates creatinine clearance (CCr) to calculate the subject’s 
carboplatin dose as following: 
• 
Carboplatin dose (mg) = target AUC × (CCr + 25)  
CCr must be calculated prior to every dosage of carboplatin using below formula (Cockcroft-
Gault equation) and it should NOT exceed 125 ml/min: 
Male: 
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CCr = (140 −𝐴𝐴𝐴[𝑦]) × 𝑏𝑏𝑏𝑏 𝑤𝑤𝑤𝑤ℎ𝑡 [𝑘𝑘]
72 × 𝑠𝑠𝑠𝑠𝑠 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐[𝑚𝑚𝑑𝑑
⁄
]
 
Female: 
CCr = (140 −𝐴𝐴𝐴[𝑦]) × 𝑏𝑏𝑏𝑏 𝑤𝑤𝑤𝑤ℎ𝑡 [𝑘𝑘]
72 × 𝑠𝑠𝑠𝑠𝑠 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐[𝑚𝑔𝑑𝑑
⁄
]
 × 0.85 
6.4. Dose and Schedule Modification 
6.4.1. General Considerations 
Dose and schedule modifications of IPs or non-IPs should follow the guidelines laid out in the 
following sections. In the induction treatment period, the non-IPs (paclitaxel and carboplatin) 
and IPs (SB8 or Avastin®) should be administered at same day. Therefore, if a schedule 
modification for one drug (non-IPs or IPs) is needed, the other drug should be delayed in the 
same time frame. The allowed maximum delay of IPs or non-IPs administration is 3 weeks from 
the schedule, which is counted from the planned Day 1 of each cycle (i.e., 6 weeks from the last 
administration). 
If non-IPs (paclitaxel and carboplatin) should be discontinued due to toxicity, the IPs (SB8 or 
Avastin®) alone can be administered at the discretion of Investigator. 
Dose modification of the IPs is not permitted. Administration of the IPs should follow the 
guidelines as shown in Table 4.  
The guidelines of dose and schedule modifications for common toxicities of non-IPs are 
described in Table 5 and Table 6. If toxicities which are not included in Table 6 occur, dose and 
schedule modifications should be determined at the discretion of Investigator based on the 
following general criteria (see also Section 6.4.2.): 
1.  Dose modifications must be based on the dose level changes in Table 5 and Table 6. 
2.  Dose modifications must be based on the AE requiring the greatest modification.  
3.  Once a dose reduction has occurred, the subject should not be re-escalated to higher doses. 
4.  For grade 3 or 4 toxicities in general, chemotherapy should be held for a maximum of 
6 weeks from the last IP administration until resolution to baseline or ≤ grade 1. 
5.  Subjects may only be re-treated if all related toxicities have resolved to baseline or at the 
discretion of Investigator. 
6.  In the induction period, if a dose delay for one drug (IPs or non-IPs) is needed, the other 
drugs should be delayed in the same time frame.  
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6.4.2. Schedule Modification of SB8 or Avastin® 
Administration of SB8 or Avastin® should follow the guideline as shown in Table 4.  
In the induction period, administration of the IPs and non-IPs should be coupled and schedule 
modification of IPs and non-IPs should follow the same time frame. The allowed maximum 
delay of IP in this period is 3 weeks from the schedule, which is counted from the planned 
Day 1 of each cycle (i.e., 6 weeks from the last administration). For haematologic and non-
haematologic AEs, the schedule modification of non-IP administration should follow the rules 
of dose modification (Table 5 and Table 6). 
In the maintenance period, SB8 or Avastin® is allowed to be delayed within a maximum of 
3 weeks from the schedule, which is counted from the planned Day 1 of each cycle (i.e., 
6 weeks from the last administration). When grade 3 or 4 (excluding cardiac or AEs listed in 
Table 4) AEs are observed within a cycle, hold SB8 or Avastin® until AEs are resolved to ≤ 
grade 2. If toxicity (except haemoptysis) is not resolved to ≤ grade 2 within 6 weeks from the 
last IP administration, discontinuation of SB8 or Avastin® and withdrawal of subject from the 
study may be considered. Continuation of treatment can be decided at the discretion of 
Investigator if the benefits of continuation overweigh the risk of AE. 
Table 4. Schedule modification of SB8 or Avastin® 
Adverse Event 
CTCAE 
Gradea 
Action to be taken 
Haemoptysis 
1  
• If no source was found, and the bleeding resolved 
within 1 week, reinitiate with the same dose.  
• If a source of bleeding was discovered, it will be 
treated according to current medical practice. 
≥2 
• Discontinue 
Hypertension 
≥2 
• Hold SB8 or Avastin® until recovery to resting BP of 
< 150/100 mmHg and then reinitiate with the same 
dose. Anti-hypertensive medications are allowed and 
recommended for blood pressure control at the 
discretion of Investigator.  
4 
• Discontinue 
Congestive heart failure (left 
ventricular systolic dysfunction) 
3 
• Hold until resolution to Grade ≤ 1 
4 
• Discontinue 
Proteinuria 
≥2  
• Hold SB8 or Avastin® until recovery to grade ≤ 1, and 
then reinitiate with the same dose. 
Arterial thromboembolism (New 
onset or worsening CVAs, TIAs, 
MIs, etc.) 
Any 
• Discontinue 
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Adverse Event 
CTCAE 
Gradea 
Action to be taken 
Venous thromboembolism 
≤ 3 
• Closely monitor. Anticoagulation ( heparin, warfarin, 
etc.) is recommended and allowed per local practice at 
the discretion of Investigator and patients should not 
have any grade of pulmonary/CNS haemorrhage or 
grade ≥ 2 haemorrhagic event while on 
anticoagulation.  
4 
• Discontinue 
Increased AST or ALT  
≥ 3  
• Hold SB8 or Avastin® until recovery to grade ≤ 2, and 
then continue SB8 or Avastin®.  
Other clinically significant AEsb 
≥ 3 
• Hold SB8 or Avastin® until recovery to grade ≤ 2, and 
then continue SB8 or Avastin®. 
CVA=cerebrovascular accident; TIA=transient ischemic attack; MI=myocardial infarction; CNS=central nervous 
system; ALT= alanine aminotransferase; AST = aspartate aminotransferase; AE = adverse event 
a NCI-CTCAE v4.03 will be used (see APPENDIX 3) 
b Other clinically significant AEs will be determined at the discretion of Investigator 
 
The investigator should discontinue administration of IP permanently and remove subjects from 
the study if experiencing one of the events specified below: 
• 
Gastrointestinal perforations (gastrointestinal perforation, fistulae formation in the 
gastrointestinal tract, intra-abdominal abscess), fistulae formation involving an internal 
organ 
• 
Wound dehiscence and wound healing complications requiring medical intervention 
• 
Serious haemorrhage requiring medical intervention (grade ≥ 2)  
• 
Arterial thromboembolic events (any grade) 
• 
Life-threatening (grade 4) venous thromboembolic events, including pulmonary 
embolism 
• 
Grade 4 hypertension (hypertensive crisis or hypertensive encephalopathy) 
• 
Grade 4 congestive heart failure (left ventricular systolic dysfunction) 
• 
Nephrotic syndrome (grade ≥ 3 proteinuria or ≥ 3.5 g/24 h) 
• 
Posterior Reversible Encephalopathy Syndrome (PRES)  
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• 
If the investigator determines that situations not listed above but could jeopardise 
safety of subjects with continuation of IP, IP should be permanently discontinued.  
6.4.3. Dose and Schedule Modification of Non-IPs Chemotherapy Agents 
6.4.3.1. Paclitaxel and Carboplatin 
All dose modifications for paclitaxel and carboplatin are based on the dose level changes in 
Table 5. A stepwise dose reduction is permitted. If a reduction to dose level -3 is required then 
subjects must be discontinued from paclitaxel and/or carboplatin treatment. If more than one AE 
requiring dose-reduction is found (e.g. Grade 4 neutrophil count decreased and Grade 3 platelet 
count decreased) during the same evaluation period, one dose level reduction is indicated 
according to Table 6. If both paclitaxel and carboplatin are discontinued due to toxicity, 
continuation of SB8 or Avastin® as monotherapy is allowed at the discretion of Investigator. 
Once a dose reduction has occurred, the subject should not be re-escalated to higher doses. Dose 
modifications must be based on the AE requiring the greatest modification. 
Table 5. Dose Levels for Paclitaxel and Carboplatin 
 
Dose level 0 
Dose level -1 
Dose level -2 
Dose level -3 
Paclitaxel 
200 mg/m2 
150 mg/m2 
100 mg/m2 
Discontinue 
Carboplatin 
AUC 6 
AUC 4.5 
AUC 3 
Discontinue 
 
Table 6. Dose Modifications and Delays of Paclitaxel and Carboplatin 
NCI-CTCAEa 
Category 
AE grade 
Modifications for AEs  
Haematological AE 
Neutrophil count 
decreased 
Grade 3 of any duration 
or 
Grade 4 < 7days 
1st event  
• Hold until ≥ 1.5 × 109/L 
• Once recovers,  
maintain the same dose, but 
the Investigator may 
determine to reduce dose by 
one level based on the 
general status of the subject. 
2nd event  
• Hold until ≥ 1.5 × 109/L. 
• Once recovers, 
reduce dose by one level. 
3rd event despite 
dose reduction 
• Hold until ≥ 1.5 × 109/L. 
• Once recovers,  
reduce dose by one level. 
4th event despite 
dose reduction 
• Discontinue 
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Neutrophil count 
decreased 
Grade 4 ≥ 7 days 
or 
Febrile neutropenia 
with ANC < 1.0 × 109/L 
 
*G-CSF is allowed at the 
discretion of Investigator  
1st event  
• Hold until ≥ 1.5 × 109/L 
and body temperature < 38°C 
• Once recovers, reduce dose 
by one level.  
2nd event despite 
dose reduction 
• Hold until ≥ 1.5 × 109/L 
and body temperature < 38°C 
• Once recovers, 
reduce dose by one level. 
3rd event 
• Discontinue 
Platelets count 
decreased 
Grade 1 or 2 
≥ 50 × 109/L to 
< 100 × 109/L 
• Hold until ≥ 100 × 109/L. 
• Once recovers, 
maintain the same dose. 
Grade 3 
without bleeding 
1st event: 
≥ 25 × 109/L to 
< 50 × 109/L  
• Hold until ≥ 100 × 109/L. 
• Once recovers, 
reduce dose by one level. 
2nd event: 
≥ 25 × 109/L to 
< 50 × 109/L 
• Hold until ≥ 100 × 109/L. 
• Once recovers, 
reduce dose by one level. 
Despite two dose 
reductions: 
< 50 × 109/L 
• Discontinue. 
Grade 4  
or  
Grade 3  
with bleeding 
1st event  
< 25 × 109/L or < 
50 × 109/L with 
bleeding 
• Hold until > 100 × 109/L. 
• Once recovers, 
reduce dose by one level. 
Despite previous 
dose reduction for 
platelet count 
decrease : 
< 25 × 109/L 
• Discontinue. 
Non-hemolytic 
anemia 
Any grade 
Any events time 
• Manage by transfusions  
• Maintain the same dose 
Non-Haematological AE 
Nausea/vomiting 
Grade ≥ 3 
1st event 
• Maintain the same dose. 
2nd event 
• Reduce dose by one level. 
3rd event or later 
• Maintain the reduced dose. 
Diarrhea lasting 
> 24 hours  
despite maximum 
anti-diarrheal 
Grade ≥ 3 
1st event 
• Hold until recovery to ≤ 
grade 1 or baseline.  
• Once recovers,  
maintain the same dose.  
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management 
2nd event 
• Hold until recovery to ≤ 
grade 1 or baseline.  
• Once recovers,  
reduce dose by one level. 
3rd event or later 
• Hold until recovery to ≤ 
grade 1 or baseline.  
• Once recovers, maintain the 
reduced dose.  
Mucositis 
Grade ≥ 3 
1st event 
• Hold until recovery to ≤ 
grade 1 or baseline.  
• Once recovers,  
maintain the same dose.  
2nd event 
• Hold until recovery to ≤ 
grade 1 or baseline.  
• Once recovers,  
reduce dose by one level. 
3rd event or later 
• Hold until recovery to ≤ 
grade 1 or baseline.  
• Once recovers,  
maintain the reduced dose. 
Neurosensory 
toxicity 
Grade 2 
• Hold until recovery to ≤ grade 1 or baseline. 
• Once recovers, 
- Paclitaxel: reduce dose by one level.  
Carboplatin: maintain the same dose. 
Grade 3 or 4 
• Hold until recovery to ≤ grade 1 or baseline. 
• Once recovers,  
- Paclitaxel: discontinue 
Carboplatin: reduce dose by one level.  
AST or ALT or 
blood bilirubin 
increased  
Increased AST or ALT 
Grade ≥ 2  
and  
Increased total bilirubin 
Grade 1 
• Hold until AST/ALT recovery to ≤ grade 1 or 
baseline. 
• Once AST/ALT recovers, 
- Maintain the same dose if bilirubin within 
normal limit. 
- If bilirubin is still increased to grade 1,  
Paclitaxel: reduce dose by one level. 
Carboplatin: maintain the same dose. 
Grade ≥ 3 AST or ALT 
or 
Grade ≥ 2 total bilirubin 
• Hold until AST/ALT and bilirubin recovery to ≤ 
grade 1 or baseline. 
• Once AST/ALT and bilirubin recover, 
- Paclitaxel: reduce dose by one level. 
Carboplatin: maintain the same dose. 
Other clinically 
significant AEsb 
Grade 2 
• Hold until recovery to ≤ grade 1 or baseline. 
• Once recovers, maintain the same dose.  
Grade 3 or 4 
• Hold until recovery to ≤ grade 1 or baseline. 
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• Once recovers, reduce dose by one level. 
AE = adverse event; ANC = absolute neutrophil count; AST = aspartate aminotransferase; ALT = alanine 
transaminase; G-CSF= Granulocyte Colony-stimulating Factor; NCI-CTCAE = national cancer institute common 
terminology criteria for adverse events 
a NCI-CTCAE v4.03 will be used (see APPENDIX 3) 
b Other clinically significant AEs will be determined at the discretion of Investigator 
 
6.5. Assessment of Compliance 
Compliance will be assessed by the subject’s medical records because both IPs and non-IPs are 
IV infusional drugs. All dosing information including any dose reductions should be recorded in 
the subject’s medical records. 
Also any reason for non-compliance should be documented. For example, insufficient 
compliance is defined when a subject missing more than one IP and non-IPs for reasons other 
than toxicity, missed scheduled study activities or overdose. 
IP accountability and dispensing records must be kept current and contain the following 
information: 
• 
The identification of the subjects to whom the drug was dispensed. 
• 
The date(s) and quantity of the drug dispensed and exact package to the subject. 
• 
The dispensing and inventory logs must be available for inspection by the medical 
monitor. 
6.6. General Concomitant Medication and Supportive Care Guidelines 
All concomitant medication(s) (including premedication and antiemetic therapy) must be 
reported. In addition, any diagnostic, therapeutic or surgical procedure performed during the 
treatment period (from Screening to end of treatment), must be recorded. Any medication which 
is necessary for the management of AEs from chemotherapy may be used at the discretion of the 
Investigator. For more information of used drugs including contraindications, special warnings 
and precautions for use, dose modification in case of toxicity, fertility, pregnancy, and lactation, 
please refer to SmPC of individual drugs. 
6.6.1. Premedication for Study Drugs 
6.6.1.1. SB8 or Avastin® 
Routine premedication for SB8 or Avastin® is not permitted. However, subjects who experience 
infusion-related reactions after infusion of SB8 or Avastin® may be premedicated with 
paracetamol and antihistamine for subsequent infusions. Management of infusion-related 
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reactions is described in Section 6.6.2. 
6.6.1.2. Paclitaxel and Carboplatin 
Premedication consisting of ranitidine (or other H2-blocker) 50 mg, pheniramine (or other 
H1-blocker) 4 mg IV slowly, dexamethasone 10 mg IV slowly 30 minutes prior to paclitaxel 
administration, unless contra-indicated, may be used. Modifications of premedication regimen 
are permitted according to local practice. 
6.6.2. Management for Infusion-related Reactions 
SB8 or Avastin® may cause infusion-related reactions such as fever, chills, hypotension, 
shortness of breath, skin rash, headache, nausea, and/or vomiting. Such reactions typically occur 
during or very shortly after an infusion. Administration of SB8 or Avastin® should be performed 
in a setting with emergency equipment and staff who are trained to medical emergencies. If an 
infusion reaction occurs, the SB8 or Avastin® infusion should be discontinued and the subject 
will be monitored until resolution of any observed symptoms. The majority of subjects will be 
resolved for symptoms and subsequently will receive further infusions. Subjects who experience 
infusion-related symptoms may be premedicated with paracetamol and antihistamines for 
subsequent infusions. Subjects should be warned of the possibility of late onset reactions and 
should be instructed to contact their Investigator if these reactions occur. When a severe 
hypersensitivity reaction such as anaphylaxis occurs, the infusion should be interrupted 
immediately and supportive care including oxygen, epinephrine, beta-agonists, and 
corticosteroids should be administered with continuous vital sign monitoring by trained staff 
until the symptoms are resolved. 
6.6.3. Granulocyte Colony-stimulating Factor (G-CSF) Use 
G-CSF may be given at the discretion of Investigator and recommend following NCCN 
Guidelines of Myeloid Growth Factors. In subjects with risk factors for developing febrile 
neutropenia (sepsis syndrome, aged ≥ 65, severe neutropenia [ANC < 0.1 × 109/L], neutropenia 
expected to be more than 10 days in duration, pneumonia, invasive fungal infection, other 
clinically documented infections, hospitalisation at the time of fever, prior episode of febrile 
neutropenia) prophylaxis with G-CSF will be permitted. 
6.6.4. Antibiotics Use 
At the discretion of Investigator, antibiotics may be administered according to NCCN 
Guidelines of Cancer-related Infections or ASCO Guidelines in febrile neutropenia cases. 
6.6.5. Other Supportive Care 
All supportive therapies (e.g., physical therapy, blood transfusions) are permitted as appropriate 
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and according to the local practice.  
Subjects with anemia can be treated according to the local practice. Intravenous bisphosphonate 
therapy is permitted during the study if clinically indicated (e.g., bone metastases for NSCLC) 
(see Section 6.2.5.). 
7. SAFETY MONITORING AND REPORTING 
7.1. Adverse Events 
7.1.1. Adverse Event Definition 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a medicinal (investigational) product or other protocol-imposed intervention and 
which does not necessarily have to have a causal relationship with this treatment or intervention. 
An AE can therefore be an unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of any dose of a medicinal 
(investigational) product or other protocol-imposed intervention, regardless of attribution.  
All AEs during the period of observation (as specified in Section 7.1.2.) including the event that 
occurred prior to administration of an IP should be collected as an AE.  
Pre-existing conditions and any abnormal findings from assessments at the time of screening 
which are not related to protocol-imposed intervention should not be reported as AEs, however 
pre-existing conditions which worsen (i.e., change in severity) that meets the definition of an 
AE during the study are to be reported as AEs. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, the medical condition for which the procedure was performed should 
be reported if it meets the definition of an AE. For example, an acute appendicitis that begins 
during the AE reporting period should be reported as an AE and the resulting appendectomy 
should be recorded as treatment of the AE.  
The AE that emerge during the treatment with an IP (i.e., treatment-emergent adverse event) 
will be analysed for the purposes of safety analyses. 
7.1.1.1. Progression of Underlying Disease 
Progression of NSCLC is not to be reported as an AE if it is clearly consistent with the 
suspected progression of the NSCLC as defined by the criteria as specified in Section 5.2.1.2. 
Such an AE should not be reported as a SAE even if it meets the seriousness criteria. 
However, if there is any uncertainty about an AE being due only to the NSCLC, it should be 
reported as an AE or SAE. 
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In case of local regulations demanding the treating Investigator to report progression of 
underlying disease as AE, then the Investigator must fulfil due diligence to the regulatory 
authorities. However, such cases will not be counted as AE in the Clinical Study Report of this 
study. 
7.1.1.2. Clinically Significant Abnormalities 
If there are any abnormalities discovered during the laboratory test, physical examination, vital 
signs and/or other safety assessments and the abnormality is assessed clinically significant by 
the Investigator, it should be reported as an AE. This does not apply to pre-existing conditions 
which have been documented at Screening or if the abnormality is consistent with a current 
diagnosis. If it is not specified or defined elsewhere in the protocol, clinically significant 
abnormality may include the events that led to an intervention, including withdrawal of the IP, 
dose reduction, significant additional concomitant medication, and others evaluated as clinically 
significant by the Investigator. 
All laboratory abnormalities that require intervention (e.g., transfusion, IV infusion) 
should be reported as clinically significant AEs according to NCI-CTCAE v4.03. If the 
clinically significant laboratory or other abnormality from safety assessment is not a sign of a 
disease or syndrome, the abnormality itself should be collected as an AE. If the abnormality can 
be characterised by a precise clinical term, the clinical term should be recorded as the AE. For 
example, an elevated serum potassium level of 7.0 mEq/L should be recorded as 
“hyperkalemia”. Observations of the same clinically significant abnormality from visit to visit 
should not be repeatedly collected as AEs, unless their severity, seriousness, or etiology changes. 
7.1.2. Period of Observation for Adverse Events  
AEs will be reported from the time the informed consent form (ICF) is signed until the EOT 
visit. After the EOT visit, only SAEs will be reported. 
The Investigator does not need to actively monitor subjects for AEs once the clinical study has 
ended. However, SAEs that occurred after the EOS should be reported to the Sponsor if the 
Investigator becomes aware of the SAEs.  
Unresolved AEs until the EOT should be followed up until discontinuation of the subject from 
the study (e.g., death, withdrawal of consent, lost to follow-up, or initiation of subsequent 
therapy for NSCLC), or EOS date, defined as when deaths of all the randomised subjects have 
been observed, or 12 months from Randomisation of the last subject, whichever occurs first. 
The Investigator should observe the AEs for appropriate medical care of the patient until AE 
resolution or stabilisation. 
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7.1.3. Reporting Adverse Events 
AEs are to be reported and reviewed by the Investigator. When reporting an AE, a diagnosis 
(when possible and appropriate) rather than each individual sign and symptom should be 
reported. 
Each AE is to be assessed to determine if it meets the criteria of an SAE (see Section 7.2.1. for 
SAE definition). If an AE is classed as an SAE, it must be reported to Sponsor, or its designated 
representative, promptly according to the timeline specified in Section 7.2.2.  
For a SAE, a diagnosis with a description of signs and symptoms as well as other supporting 
information that led to the diagnosis should be described in the SAE report form and reported to 
the Sponsor, or its designated representative, according to the procedures described in 
Section 7.2.2. 
7.1.4. Severity Assessment  
The Investigator is responsible for assessing and reporting the severity of AEs in accordance 
with NCI-CTCAE v4.03. 
The following general guideline can be used to describe the severity of the AE. A grading 
(severity) scale for each AE is provided in NCI-CTCAE v4.03 (see APPENDIX 3).  
Table 7. Severity Grade of NCI-CTCAE v4.03 
GRADE 
Clinical Description of Severity 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADLa. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; 
limiting self-care ADLb. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
ADL = activities of daily living 
a Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
7.1.5. Causality Assessment 
The Investigator is responsible for assigning a causal relationship to each AE. The causal 
relationship between the IP and the AE should be defined as not related (no) or related (yes). 
Events should be classified as “related” if there is a reasonable possibility that the IP caused the 
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AE. This means that there are facts (evidence) or arguments to suggest a causal relationship. 
Events should be classified as “not related” if there is no reasonable possibility that the IP 
caused the AE. 
7.1.6. Emergency Unblinding for Safety Reasons 
Unblinding should be considered only when knowledge of the treatment assignment is deemed 
essential for the subject’s safety by their Investigator or a regulatory body. In general, 
unblinding of subjects during the conduct of the clinical study is not allowed unless there are 
compelling medical or safety reasons to do so. The IWRS will be used to break the blind and 
details on how to do this are provided in the IWRS manual. If the blind is broken, it may be 
broken only for the subject in question. The Sponsor must be notified before or immediately 
after a subject and/or the Investigator is unblinded during the course of the study along with the 
reason for breaking the blind. Pertinent information regarding the circumstances of unblinding 
of a subject’s treatment code must be documented in the subject’s source documents. This 
includes who performed the unblinding, the subject(s) affected, the reason for the unblinding, 
the date of the unblinding and the relevant IP information. After unblinding (except unblinding 
for the purpose of regulatory reporting), subjects will be discontinued from the study.  
7.1.7. Expectedness Assessment 
Expectedness of AEs will be assessed by referring to the safety information in IB of the relevant 
safety section. More detailed information on expectedness assessment will be explained in IB. 
The latest SmPC of Avastin®, Annex I of EPAR Product Information posted on EMA website, 
will be used to assess the expectedness for the comparators. 
7.1.8. Withdrawal Due to Adverse Events 
Subject withdrawal from the study due to an AE should be distinguished from withdrawal due to 
personal reasons. Subjects withdrawn due to an AE should be followed up until the time point 
specified in the protocol. When a subject withdraws from the study due to an SAE, the SAE 
must be reported and followed in accordance with the requirements outlined in Section 7.2.2.  
Subjects who discontinue the administration of IPs because of serious or significant safety 
issues should be followed closely until the events are fully and permanently resolved or 
stabilised. 
7.2. Serious Adverse Events 
7.2.1. Serious Adverse Event Definition 
An SAE is any untoward medical occurrence at any dose that: 
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• 
Results in death  
• 
Is life-threatening 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• 
Results in persistent or significant disability/incapacity 
• 
Results in congenital anomaly/birth defects 
• 
Is medically important  
If the SAE is considered progression of NSCLC, it should not be reported as a SAE in 
accordance with Section 7.1.1.1. 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalisation. However, if it is determined that the event 
may jeopardise the subject and may require intervention to prevent one of the other outcomes 
listed in the definition above, the important medical event should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of drug dependency or drug abuse. 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as “serious,” which is 
based on subject/event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning. 
7.2.1.1. Life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe. 
7.2.1.2. Hospitalisation 
AEs reported from clinical studies associated with hospitalisation or prolongation of 
hospitalisation are considered serious. Staying at the observation unit in the emergency room for 
more than 24 h qualifies for hospitalisation. Any events leading to a subsequent emergency 
room visit for less than 24 h should be in the discretion of Investigator to assess seriousness as 
medically important. 
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Hospitalisation or prolongation of hospitalisation in the absence of a precipitating clinical AE is 
not in itself an SAE. Examples include: 
• 
Admission for treatment of a pre-existing condition not associated with the 
development of a new AE or with a worsening of the pre-existing condition (e.g., for 
work-up of persistent pre-treatment laboratory abnormality) 
• 
Social admission for convenience (e.g., admission of a subject who does not have a 
carer) 
• 
Administrative admission (e.g., for a yearly physical exam) 
• 
Protocol-specified admission during a clinical study (e.g., for a procedure required by 
the study protocol) 
• 
Optional admission not associated with a precipitating clinical AE (e.g., for elective 
cosmetic surgery) 
Pre-planned treatments or surgical procedures should be noted in the Screening documentation 
for the individual subject  
7.2.2. Reporting Serious Adverse Event  
SAEs before EOT visit must be immediately reported at least within 24 h of the Investigator 
becoming aware of the event to Sponsor or its designated representative using the SAE report 
form in the eCRF. SAEs that occurred after the EOT visit must be reported at least within 24 h 
of the Investigator becoming aware of the event to Sponsor or its designated representative 
using the paper SAE report form. Contact information for SAE reporting will be provided in 
SAE Report Completion Instruction. 
In particular, if the SAE is fatal or life-threatening, Sponsor must be notified immediately, 
irrespective of the extent of available AE information. This timeframe also applies to additional 
(follow-up) information that becomes available on previously forwarded SAE reports. Sponsor 
will then follow expedited reporting procedures according to local and international regulations 
as appropriate. 
The Investigator is obligated to pursue and provide information to Sponsor on all SAEs in 
accordance with the timeframes for reporting specified above. In addition, an Investigator may 
be requested by Sponsor to obtain specific additional follow-up information in an expedited 
fashion. This information may be more detailed than that captured in the SAE report form. In 
general, this will include a description of the SAE, which should be provided in sufficient detail 
so as to allow for a complete medical assessment of the case and independent determination of 
possible causality. Information on other possible causes of the event, such as concomitant 
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medications and illnesses must be provided. In the case of a subject death, a summary of 
available autopsy findings must be submitted as soon as possible to Sponsor or its designated 
representative. 
All SAEs will be followed until event resolution or stabilisation (for chronic events), if possible, 
even when a subject is withdrawn from treatment. For chronic events that does not fully resolve 
until years later, the outcome should be reported as “resolved with sequelae” as soon as the 
event has stabilised or returned to baseline. Follow-up information for the SAE should be 
actively sought and submitted as the information becomes available. 
7.3. Adverse Events of Special Interest (AESI) 
7.3.1. Hypertension 
Hypertension NCI-CTCAE v4.03 grade ≥ 3 should be classified as AESI. 
7.3.2. Proteinuria 
If subject is discovered to have ≥ 2+ proteinuria on urine dipstick (or other ways of urinalysis) 
and demonstrate 24 hours urine protein excretion ≥ 1 g or protein/creatinine ratio in spot urine 
≥ 1 g/g creatinine (or ≥ 226.0 mg/mmol creatinine), should be classified as AESI. 
7.4. Pregnancy 
Any pregnancy, including those of female partners of male subjects treated with the IP, should 
be reported to the Sponsor. If the female partner of a male subject becomes pregnant, a written 
consent must be obtained from the female partner before collecting any pregnancy-related data. 
All pregnancies associated with the subject, from the time the subject receives the first dose of 
IP until 6 months after the last dose of IP should be reported to Sponsor. Pregnancy reports 
should be made within 24 h of the Investigator becoming aware of the pregnancy using the 
Pregnancy report form. 
Although pregnancy is not an AE, all pregnancies must be followed up until 6-8 weeks after the 
outcome of the pregnancy becomes available, unless the subject is lost to follow-up. The 
pregnancy outcome should be notified to Sponsor by submitting a follow-up Pregnancy report 
form. If the outcome of the pregnancy meets SAE criteria then the Investigator should report 
this case according to the SAE reporting procedure (see Section 7.2.2.). 
7.5. Independent Data and Safety Monitoring Board 
An independent data and safety monitoring board (DSMB) will be assigned for this study. The 
DSMB will consist of external experts (e.g., medical oncologists, clinical pharmacologists or 
biostatisticians) and will review the safety and tolerability data from the study at pre-specified 
intervals. The details of the safety data and time points for review will be described in the 
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DSMB Charter and in the DSMB Statistical Analysis Plan (SAP). 
In addition, an ongoing blinded review of AEs, including clinical laboratory data will be 
continuously undertaken by the Sponsor medical monitor and pharmacovigilance team. 
8. STATISTICAL CONSIDERATION AND ANALYTICAL PLAN 
8.1. Analysis Sets 
The following sets will be used for the analyses performed in the study: 
• 
Randomised set (RAN): RAN will consist of all subjects who receive a randomisation 
number at the randomisation. 
• 
Full analysis set (FAS): FAS will consist of all randomised subjects. The subjects will 
be analysed based on the treatment they were randomised to by intention-to-treat 
principle. However, subjects who do not qualify for randomisation and are 
inadvertently randomised into the study will be excluded from FAS, provided these 
subjects do not receive any IP during the study. 
• 
Per-protocol set (PPS): PPS will consist of all FAS subjects who complete at least two 
cycles of combination chemotherapy with a tumour assessment and do not have any 
major protocol deviations that impact the primary efficacy assessment. Major protocol 
deviations that will lead to the exclusion from the PPS will be pre-specified, and the 
PPS will be determined prior to unblinding treatment codes. 
• 
Safety set (SAF): SAF will consist of all subjects who received the study drug at least 
once. This analysis set will be used for safety analyses. The subjects will be analysed 
based on the treatment they received. 
• 
Pharmacokinetic population: this set will consist of subjects allocated to PK sub-study 
who have at least one measured serum concentration of bevacizumab. 
8.2. Statistical Methods and Analytical Plan 
8.2.1. Demographics and Baseline Characteristics 
The Baseline value will be defined as the last available measurement value prior to the time of 
first IP administration. 
Subject demographics and baseline characteristics will be summarised by treatment group for 
the RAN. Continuous variables (e.g., age, weight, height, disease duration) will be summarised 
with descriptive statistics (n, mean, standard deviation, median, minimum, maximum). 
Categorical variables (e.g., gender, race, ethnicity, ECOG status) will be summarised with 
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counts and percentages.  
Comparison of treatment groups will be performed using the chi-square test or F-test as 
appropriate. The results of these tests will be provided including the p-value for descriptive 
purposes and will not be used as a formal basis to determine the factors to be included in 
statistical models. If baseline imbalances are detected for any of the factors, additional analyses 
may be performed to adjust for these baseline differences. 
Relevant medical history and continuing medical conditions will be summarised by treatment 
group for the RAN. 
Duration of exposure to study drug and number of IV infusions will be summarised by 
treatment group with descriptive statistics using the SAF. Prior and concomitant medications 
and significant non-drug therapies will be summarised by treatment group with frequency and 
percentage. 
8.2.2. Efficacy 
8.2.2.1. Primary Efficacy Analysis 
The primary efficacy endpoint is the best ORR by 24 weeks of chemotherapy. The best ORR is 
defined as the proportion of subjects whose best overall response is either CR or PR according 
to RECIST v1.1 during the induction treatment period. If a subject has either CR or PR at least 
once during the induction treatment period, the subject will be considered as the responder. 
Tumour assessment will be performed after IP administration of Cycle 2, 4, and 6 before 
planned Day 1 of Cycle 3, 5, and 7 and then will be performed every 4 cycles according to 
RECIST v1.1. Tumour size will be assessed by both investigators and independent central 
reviewer. The primary efficacy analysis will be based on the data from the independent central 
review. 
The primary efficacy analysis will aim to demonstrate equivalence in the best ORR between 
SB8 and Avastin®. The null hypothesis tested for the primary efficacy analysis will be either (1) 
SB8 is inferior to Avastin® or (2) SB8 is superior to Avastin® based on a pre-defined equivalence 
margin. 
For US Food and Drug Administration or other regulatory agency submissions for those who 
are in favour of risk ratio, the primary efficacy analysis will be performed in the FAS for the 
ratio of best ORR (best ORR of SB8/ best ORR of Avastin®) by 24 weeks, and the equivalence 
will be declared if the 90% confidence interval (CI) of the best ORR ratio is contained within 
the pre-defined equivalence margin of [0.737, 1.357]. The similar analysis will be performed for 
the PPS to support the primary analysis. 
For EMA, MFDS or other regulatory agency submissions for those who are in favour of risk 
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difference, the primary efficacy analysis will be performed in the PPS for the difference of the 
best ORR (best ORR of SB8 – best ORR of Avastin®) by 24 weeks, and the equivalence 
between the two treatment groups will be declared if the 95% CI of the difference is entirely 
contained within the pre-defined equivalence margin of [-12.5%, 12.5%]. The similar analysis 
will be performed for the FAS to support the primary analysis.  
The primary efficacy analysis will be performed using the log binomial model with treatment. 
The sensitivity analysis will be performed using the log binomial model with the covariates of 
age (< 70, ≥ 70 years), sex (female, male), region (country or pooled centres) and treatment to 
explore the robustness of the primary efficacy results. 
In the primary efficacy analysis for FAS, the response of the patients without any post-baseline 
tumour assessment will be imputed as following: 
• 
Missing data from patients who withdrew the study due to progression disease (PD), 
lack of efficacy and AEs without any tumour assessment will be considered as non-
responder. 
• 
Missing data from patients who withdrew the study with reasons other than PD, lack of 
efficacy and AEs without any tumour assessment will be imputed using multiple 
imputation method. 
• 
Missing data from patients who remained in the study but do not have any valid 
tumour assessment will be imputed using multiple imputation method. 
In the primary efficacy analysis for the PPS, missing data will not be imputed. 
8.2.2.2. Secondary Efficacy Analyses 
The secondary efficacy endpoints of PFS, OS and DOR will be analysed for PPS and FAS. PFS 
and OS will be analysed using the Kaplan-Meier method with median survival time and its 95% 
CI by treatment. The analysis using the stratified Cox proportional hazard model will be 
additionally performed to adjust the covariates used in the sensitivity analysis. DOR will be 
summarised using descriptive statistics by treatment. 
8.2.2.3. Exploratory Efficacy Analysis 
The exploratory efficacy endpoint is the best ORR by 11 and 17 weeks and will be analysed 
with the similar manner of the primary endpoint analysis.  
8.2.3. Safety 
All reported terms for AEs will be coded using MedDRA. No statistical testing will be 
performed for AEs. For all AE and SAE tables, subjects will be counted once for each preferred 
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term and each system organ class.  
A treatment-emergent AE (TEAE) will be defined as any AE with an onset date on or after the 
date of the first administration of IP. AEs which are already present before the first IP and 
increase in severity after the first IP will be considered as TEAEs. Pre-existing AEs before the 
first IP with no increase in severity after the first IP will not be considered as TEAEs.  
All TEAEs and SAEs will be summarised by the frequency and percentage of subjects 
experiencing events by system organ class, preferred term and treatment group. SAEs leading to 
IP discontinuation and TEAEs by causality and severity will be summarised similarly. All AEs 
including those pre-existing during the pre-treatment period will be listed by subject. 
Changes in vital signs and clinical laboratory measurements will be summarised descriptively 
by treatment group. Other safety variables (e.g., infusion reaction) will be summarised and 
listed. 
All safety analyses will be performed using the SAF. 
8.2.4. Pharmacokinetics 
The PK blood samples will be collected in approximately 50% of the enrolled subjects. The PK 
parameters (Ctrough and Cmax) will be summarised descriptively by treatment group at each cycle. 
8.2.5. Immunogenicity 
The incidence of anti-drug antibodies and neutralising antibodies will be summarised by 
treatment group and cycle for SAF.  
8.3. Determination of Sample Size 
Regarding the calculation of the equivalence margin for the ratio of the best ORR by 24 weeks, 
a meta-analysis published by Botrel et al. using all of the four published comparative trials that 
evaluated bevacizumab in combination with chemotherapy (i.e. E4599 [Sandler, 2006], AVAiL 
(BO17704) [Reck, 2009], AVF0757 [Johnson, 2004], JO19907 [Niho, 2012]) was considered. 
The overall response rate for Avastin® was reported as 34.9% (133 of 381 patients), 34.7% (114 
of 329 patients), 32.4% (11 of 34 patients) and 56.2% (68 of 121 patients) compared to the 
overall response rate of 15.1% (59 of 392 patients), 21.7% (71 of 327 patients), 18.8% (6 of 32 
patients) and 33.9% (20 of 59 patients) for chemotherapy, in E4599, AVAiL, AVF0757 and 
JO19907 respectively. 
The overall ratio of the best ORR and the 70% CI from above four studies are calculated to be 
 using the fixed effect method from meta-analysis. Retaining the 
% of 
the effect of Avastin® over the placebo in the lower margin, the equivalence margin of [0.737, 
1.357] will be used for the primary analysis with the ratio of the best ORR by 24 weeks. 
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For the primary analysis with the difference of the best ORR by 24 weeks, the equivalence 
margin of [-12.5%, 12.5%] will be used due to the similar derivation. 
For the calculation of the equivalence margin for the difference of the best ORR by 24 weeks, 
E4599 [Sandler, 2006] and AVAiL [Reck, 2010] studies were considered. The overall response 
rate for Avastin® was reported as 34.9% (133 of 381 patients) and 37.8% (130 of 344 patients), 
compared to the overall response rate of 15.1% (59 of 392 patients) and 21.6% (75 of 347 
patients) for chemotherapy, in E4599 and AVAiL, respectively. 
The overall difference in the best ORR and its 95% CI from these two studies are calculated to 
be 
% [
%, 
%] using the fixed-effect method from meta-analysis, or for 80% CI 
to be [
%, 
%]. The equivalence margin of [-12.5%, 12.5%] will ensure the superiority 
of SB8 over placebo with a small safety margin retaining around 
% for 95% CI and 
% for 
80% CI of the effect over the placebo in the difference of best ORR. 
With 305 completers in each treatment group, the two-sided 90% CI of the best ORR ratio is 
expected to lie within [0.737, 1.357] with approximately 80% power, and the two-sided 95% CI 
of the best ORR difference between Avastin® and SB8 is expected to lie within [-12.5%, 12.5%] 
with 80% power when the expected best ORR is assumed to be 35%. Assuming a 10% drop-out 
rate, a total of 678 subjects (339 subjects per treatment group) will be randomised. 
8.4. Statistical Analysis Timepoints  
Safety endpoint will be assessed for DSMB review during the course of the study. Interim safety 
results will be evaluated by the DSMB, which will be independent of the study conduct. Details 
will be described in the DSMB charter. 
The primary endpoint will be assessed when at least 24 weeks has elapsed since the last subject 
is randomised. Available efficacy and safety data (a full set of the Induction treatment period 
data including available data in the maintenance treatment period from a subset of subjects, i.e., 
those subjects enrolled early) will also be analysed and reported.  
A final CSR will be reported once the full set of the maintenance treatment period is obtained, 
e.g. after EOS. 
After at least 24 weeks from the last subject randomised, or its corresponding date, a limited 
number of individuals of the Sponsor will be unblinded. A formal analysis of the primary 
efficacy data will then be undertaken. Subjects, Investigators, independent central reviewers and 
other study personnel will remain blinded throughout the entire treatment period 
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9. DATA COLLECTION AND MANAGEMENT 
9.1. Data Confidentiality 
Information about study subjects will be kept confidential. Subject identification information 
will be labelled with a code number, and will not include the subject’s name or other 
information that could identify them. A list linking the code and the subject’s name will be kept 
in the site files as required by Good Clinical Practice (GCP) to protect the subject’s 
confidentiality. 
The coded information will be sent to the Sponsor (or designee) who will analyse it and report 
the study results both to regulatory and ethical authorities. The Sponsor may also place data on 
public websites or publish journal articles based upon these results. Subject names or other 
directly identifiable information will not appear on any reports, publications, or other 
disclosures of clinical study outcomes. Care will be taken to prevent subjects being identified 
through these publications. In addition, data may be shared with other companies or researchers 
to aid further research into lung cancer. Such data sharing practices will be covered by 
confidentiality agreements. No-one outside the Investigator site will have access to subject-
identifiable information. 
9.2. Monitoring 
The Sponsor has engaged the services of a contract research organisation (CRO) to perform all 
monitoring functions within this clinical study. The monitors will work in accordance with the 
CRO SOPs and have the same rights and responsibilities as monitors from the Sponsor 
organisation. Monitors will establish and maintain regular contact between the Investigator and 
the Sponsor. 
Monitors will evaluate the competence of each Investigator site and inform the Sponsor about 
any problems relating to facilities, technical equipment or medical staff. During the study, 
monitors will check that written informed consent has been obtained correctly from all subjects 
and that data are recorded correctly and completely. Monitors will also perform source data 
verification by comparing entries in the eCRF with corresponding source data and informing the 
Investigator of any errors or omissions. Monitors will verify adherence to the protocol at the 
Investigator site. All protocol deviations will be reported to the Sponsor via the Monitoring Visit 
Reports. Monitors will arrange for the supply of IP and ensure appropriate storage conditions 
are maintained. 
Monitoring visits will be conducted at regular intervals according to GCP. The monitor will 
provide written reports to the Sponsor on each occasion they make contact with the Investigator 
regardless of whether it is by phone or in person. 
Further details on the monitoring processes and the level of source data verification to be 
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performed will be outlined in the monitoring plan. 
9.3. Data Handling and Record Keeping 
The Investigator must maintain essential study documents (protocol and protocol amendments, 
completed eCRFs, signed informed consent forms, relevant correspondence, and all other 
supporting documentation) until at least 2 years after the last approval of a marketing 
application in an International Conference on Harmonisation (ICH) region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 2 years after the 
formal discontinuation of clinical development of the IP or 15 years from completion of the 
study. These documents should be retained for a longer period if required by the applicable 
regulatory requirements or the Investigator site, institution or private practice in which the study 
is being conducted. Subject identification codes (subject names and corresponding study 
numbers) will be retained for the same period of time. These documents may be transferred to 
another responsible party, deemed acceptable by the Sponsor, and who agrees to abide by the 
retention policies. Written notification of transfer must be submitted to the Sponsor. The 
Investigator must contact the Sponsor prior to disposing of any study records and obtain written 
permission to do so. 
9.4. Database Management and Coding 
Data generated within this clinical study will be handled according to the relevant SOPs of the 
data management and biostatistics departments of the Sponsor (or an appropriate company 
designated by the Sponsor to perform these activities). The study eCRF is the primary data 
collection instrument for the study. Subject data will be captured in an eCRF and reviewed by 
the monitor in order to check adherence to the protocol and to detect any data inconsistency or 
discrepancy. 
The Investigator must ensure that the clinical data required by the study protocol are carefully 
reported in the eCRF. He/she must also check that the data reported in the eCRF correspond to 
those in the medical records. 
Forms should be available during periodic visits by study monitors to enable review for 
completeness and acceptability. Any correction to the data entered into the eCRF must be 
carried out by the Investigator or a designated member of staff. These changes may be made 
either on the initiative of the site staff or in response to monitoring or data queries. Any changes 
to written data must be made using GCP corrections and any change to electronic data should be 
made in a system which can provide an audit trail. Monitors and clinical data managers will 
review the eCRF for accuracy and can generate queries to the investigational staff for resolution. 
Corrections will be recorded in an audit trail that records the old information, the new 
information, and identification of the person making the changes, date of correction made and 
reason for change. The Investigator must sign and date the eCRF pages as indicated. 
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Medical/surgical history and underlying diseases and AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Concomitant medications will be coded using 
the World Health Organization-Drug Dictionary Enhanced (WHO-DDE). The versions of 
coding dictionaries used will be stated in the clinical study report. 
9.5. Quality Control and Quality Assurance 
During the conduct of the study, Sponsor or its agent will conduct periodic monitoring visits to 
ensure that the protocol and GCP are being followed. The monitors may review source 
documents to confirm that the data recorded on the eCRFs are accurate. The Investigator and 
institution will allow the domestic and foreign regulatory authorities, sponsor’s monitors and 
auditors direct access to source documents to perform this verification. The study site may be 
subject to review by the Independent ethics committee (IEC), and/or to quality assurance audits 
performed by Sponsor, and/or to inspection by appropriate regulatory authorities. It is important 
that the Investigator and their relevant personnel are available during the monitoring visits and 
possible audits or inspections and that sufficient time is devoted to the process. 
10. ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES 
10.1. Institutional Review Board or Independent Ethics Committee 
The Investigator and the Sponsor will follow all local laws and regulations relating to contact 
with and approvals from the institutional review board (IRB)/IEC. 
The Investigator must provide the Sponsor with documentation of IRB/IEC approval of the 
protocol and informed consent before the study may begin at the Investigator site. The 
Investigator will supply documentation to the Sponsor relating to the annual renewal of the 
protocol from the IRB/IEC and any approvals of revisions to the ICF or amendments to the 
protocol.  
The Investigator will report promptly to the IRB/IEC any new information that may adversely 
affect the safety of subjects or the conduct of the study. Similarly, the Investigator will submit 
written summaries of the study status to the IRB/IEC on a regular basis and in accordance with 
the timelines required locally. Upon completion of the study, the Investigator will provide the 
ethics committee with a report on the outcome of the study if required by local regulations. 
10.2. Ethical Conduct of the Study 
This study will be conducted in compliance with the protocol, the ICH guidelines, GCP, the 
Declaration of Helsinki (2013) and all applicable and current regulatory requirements. 
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10.3. Informed Consent 
The ICF will be used to explain the risks and benefits of study participation to the subject in 
simple terms before the subject enters into the study. The ICF contains a statement that the 
consent is freely given, that the subject is aware of the risks and benefits of entering the study, 
and that the subject is free to withdraw from the study at any time. Written consent must be 
given by the subject and/or legal representative, after the receipt of detailed information on the 
study. 
The Investigator is responsible for ensuring that informed consent is obtained from each subject 
or legal representative and for obtaining the appropriate signatures and dates on the ICF prior to 
the performance of any protocol procedures and prior to the administration of IP. The 
Investigator will provide each subject with a copy of the signed and dated ICF and this will be 
documented in the subject’s source notes. 
10.4. Investigator Information 
10.4.1. Investigator Obligations 
This study will be conducted in accordance with the ICH Harmonised Tripartite Guideline for 
GCP (1997), the ethical principles that have their origin in the Declaration of Helsinki (2013) 
and local laws and regulations. 
The Investigator is responsible for ensuring that the study is conducted according to the signed 
Investigator statement, the study protocol and applicable regulations; for protecting the rights, 
safety and welfare of subjects under the Investigator’s care; and for the control of drugs under 
investigation. The Investigator must obtain the informed consent of each subject to whom IP is 
administered. 
10.4.2. Coordinating Investigator 
Sponsor will designate a Coordinating Investigator among the Investigators who participate in 
the study. The roles of the Coordinating Investigator are defined as following: 
• 
Provide scientific and medical advice and/or inputs on current medical practice, 
protocol development and site selection 
• 
Review ongoing study activities with Interpretation and presentation of final analyses 
• 
Review clinical study reports 
• 
Involved in development of publication strategy 
• 
The designated Coordinating Investigator will sign the signature page of CSR as a 
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representative of other Investigators. 
10.4.3. Training of Investigator Site Personnel 
Before the first subject is enrolled into the study, a Sponsor representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and will also train them in any study-specific procedures. 
The Investigator will ensure that appropriate training relevant to the study is given to all site 
staff and that any new information relevant to the performance of this study is forwarded to the 
staff involved. 
The Investigator will maintain a record of all individuals involved in the study (medical, nursing 
and other staff). 
10.4.4. Protocol Signatures 
The Investigator must sign the Investigator Signature Page of this protocol prior to starting 
recruitment for the study. By signing the protocol, the Investigator confirms in writing that 
he/she has read, understands and will strictly adhere to the study protocol and will conduct the 
study in accordance with GCP and applicable regulatory requirements. The study will not be 
able to start at any Investigator site where the Investigator has not signed the protocol. 
10.4.5. Financing and Insurance 
Samsung is the Sponsor of this study and will be providing the finances to cover the operation 
of the study. Details of financial agreements are provided in the Clinical Study Agreements with 
the Investigator sites and in contracts with other companies involved in the running of the study. 
The Sponsor has obtained suitable insurance for this study. The insurance details will be 
provided to each Investigator who will be responsible for providing the IRB/IEC with these 
details according to local requirements. 
11. STUDY DISCONTINUATION 
The end of study will occur, when one of the following conditions is met, whichever occurs first; 
• 
Deaths of all the randomised subjects have been reported. 
• 
12 months after Randomisation of the last subject. 
• 
Discontinuation of IP development. 
• 
Occurrence of previously unknown adverse events that could significantly affect 
continuation of the study (e.g., at the discretion of DSMB).  
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• 
Medical or ethical reasons affecting the continued performance of the study. 
After end of study is announced, Sponsor may discontinue supply of IPs and safety follow-up 
will not be performed. 
12. PUBLICATION POLICY 
The Sponsor supports the efforts of health authorities to increase the transparency of medical 
research conducted in human subjects. The Sponsor will register and maintain the information 
of clinical studies on a public registry program such as www.ClinicalTrials.gov. The Sponsor 
will comply with the guidelines of regulatory authorities with regards to public registration and 
disclosure of clinical study data. 
The clinical study data collected during the study are confidential and proprietary to the Sponsor. 
Sponsor shall have the right to delete any confidential or proprietary information contained in 
any proposed abstract or presentation. 
Any publications from this study should be approved by the Sponsor prior to publication or 
presentation. The rights of the Investigator with regard to publication of this study are described 
in the Clinical Study Agreement. 
 
 
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13. REFERENCES 
Abratt RP, Bezwoda WR, Goedhals L, et al. A phase 2 study of gemcitabine with cisplatin in 
patients with non-small cell lung cancer. Prog Proc Am Soc Clin Oncol. 1995; 14: 375. abstract. 
Avastin® Prescribing Information. FDA. (May 07, 2015). Retrieved Aug 07, 2015 
from http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125085s308lbl.pdf. 
Avastin® Summary of Product Characteristics (EMEA/H/C/000582 -II/0082). EMEA (Oct 29, 
2015). Retrieved on Dec 21, 2015 
from http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000582/WC500029271.pdf 
Botrel TEA, Clark O, Clark L, et al. Efficacy of bevacizumab (Bev) plus chemotherapy (CT) 
compared to CT alone in previously untreated locally advanced or metastatic non-small cell 
lung cancer (NSCLC): Systematic review and meta-analysis. Lung Cancer. 2011; 74:89-97 
Chandra P. Belani. Paclitaxel/Carboplatin in the Treatment of Non-Small-Cell Lung Cancer. 
Oncology. 1998; 12: 74-79. 
Crino L, Scagliotti G, Marangolo M, et al. Cisplatin-gemcitabine combination in non-small cell 
lung cancer (NSCLC): a phase II study. Prog Proc Am Soc Clin Oncol. 1995; 14: 352. abstract. 
EMEA/CHMP/BWP/49348/2005. Retrieved Aug 07, 2012 
from http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/W
C500003953.pdf. 
EMEA/CHMP/BMWP/42832/2005. Retrieved Aug 09, 2012 
from http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/W
C500180219.pdf. 
Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns 
in Europe: Estimates for 40 countries in 2012. Eur J Cancer. 2013; 49: 1374– 1403. 
Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management 
of fever and neutropenia in adults treated for malignancy: American Society of Clinical 
Oncology clinical practice guideline. J Clin Oncol. 2013 Feb 20; 31(6): 794-810. 
Jemal A, Siegel R, Ward E, et al. Cancer statistics, CA Cancer J Clin. 2009 Jul-Aug; 59(4): 225-
49. 
Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized Phase II Trial Comparing 
Bevacizumab Plus Carboplatin and Paclitaxel With Carboplatin and Paclitaxel Alone in 
Previously Untreated Locally Advanced or Metastatic Non–Small-Cell Lung Cancer. J Clin 
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Oncol. 2004 Jun 1; 22: 2184-2191. 
Langer CJ, Leighton JC, Comis RL, et al. Paclitaxel and carboplatin in combination in the 
treatment of advanced non-small-cell lung cancer: a phase II toxicity, response, and survival 
analysis. J Clin Oncol. 1995; 13: 1860-70. 
Le Chevalier T, Belli L, Monnier A, et al. Phase II study of docetaxel (Taxotere) and cisplatin in 
advanced non small cell lung cancer (NSCLC): an interim analysis. Prog Proc Am Soc Clin 
Oncol. 1995; 14: 350. abstract.  
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary 
adenocarcinoma. N Engl J Med. 2009 Sep 3; 361(10): 947-57. 
NCCN Guidelines of Myeloid Growth Factor. NCCN. (Version 1, 2015). Retrieved Aug 05, 
2015 from http://www.nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf. 
NCCN Guidelines of Prevention and Treatment of Cancer-Related Infections. NCCN. (Version 
2, 2015). Retrieved Aug 05, 2015 
from http://www.nccn.org/professionals/physician_gls/pdf/infections.pdf. 
Niho S, Kunitoh H, Nokihara H, et al. Randomized phase II study of first-line carboplatin-
paclitaxel with or without bevacizumab in Japanese patients with advanced non-squamous non-
small-cell lung cancer. Lung Cancer. 2012; 362-367 
NSCLC Collaborative Group, Chemotherapy in non-small cell lung cancer: a meta-analysis 
using updated data on individual patients from 52 randomised clinical trials. BMJ. 1995 Oct 7; 
311(7010): 899-909. 
Patel JD, Socinski MA, Garon EB, et al. PointBreak: a randomized phase III study of 
pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and 
bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance 
bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin 
Oncol. 2013 Dec 1; 31(34): 4349-57. 
Rapp E, Pater JL, Willan A, et al. Chemotherapy can prolong survival in patients with advanced 
non-small-cell lung cancer—report of a Canadian multicenter randomized trial. J Clin Oncol. 
1988 Apr; 6(4): 633-41. 
Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either 
placebo or bevacizumab as first-line therapy for nonsquamous non-small cell lung cancer: 
AVAiL. J Clin Oncol. 2009; 27: 1227–1234. 
Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatin–gemcitabine and 
bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: 
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results from a randomised phase III trial (AVAiL). Annals of Oncology. 2010; 21: 1804–1809. 
Sandler AB, Ansari R, McClean J, et al. A Hoosier Oncology Group phase II study of 
gemcitabine plus cisplatin in non-small cell lung cancer (NSCLC). Prog Proc Am Soc Clin 
Oncol. 1995; 14: 357. abstract. 
Sandler AB, Gray R, Michael C. et al. Paclitaxel–Carboplatin Alone or with Bevacizumab for 
Non–Small-Cell Lung Cancer. N Engl J Med. 2006; 355: 2542-2550. 
Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for 
advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10; 346(2): 92-8. 
SEER Cancer Statistics Review. NCI (Apr 23, 2015) from http://seer.cancer.gov/csr/1975_2012/ 
Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-
positive lung cancer. N Engl J Med. 2013 Jun 20; 368(25): 2385-94. 
Sweeney CJ, Miller KD, Sissons SE, et al. The antiangiogenic property of docetaxel is 
synergistic with a recombinant humanized monoclonal antibody against vascular endothelial 
growth factor or 2-methoxyestradiol but antagonized by endothelial growth factors. Cancer Res. 
2001; 61: 3369–72. 
 
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APPENDIX 1: ECOG PERFORMANCE STATUS 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light house work, office 
work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair 
5 
Dead 
 
Reference: 
Oken MM, Creech RH, Tormey DC, et al. Toxicity And Response Criteria of The Eastern 
Cooperative Oncology Group, Am J Clin Oncol. 1982; 5(6):649-55. 
 
 
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APPENDIX 2: LUNG CANCER STAGING (AJCC 7TH EDITION) 
Definitions for T, N, M 
T 
Primary tumour 
 
Tx 
Primary tumour cannot be assessed, or tumour proven by the presence of malignant cells 
in sputum or bronchial washings but not visualized by imaging or bronchoscopy 
 
T0 
No evidence of primary tumour 
 
Tis 
Carcinoma in situ 
 
T1 
Tumour 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, 
without bronchoscopic evidence of invasion more proximal than the lobar bronchus 
(for example, not in the main bronchus)a 
 
T1a 
 
Tumour 2 cm or less in greatest dimension 
 
T1b 
Tumour more than 2 cm but 3 cm or less in greatest dimension 
 
T2 
Tumour more than 3 cm but 7 cm or less or tumour with any of the following features 
(T2 tumours with these features are classified T2a if 5 cm or less): involves main 
bronchus, 2 cm or more distal to the carina; invades visceral pleura (PL1 or PL2); 
associated with atelectasis or obstructive pneumonitis that extends to the hilar region but 
does not involve the entire lung 
 
T2a 
Tumour more than 3 cm but 5 cm or less in greatest dimension 
 
T2b 
Tumour more than 5 cm but 7 cm or less in greatest dimension 
 
T3 
Tumour more than 7 cm or one that directly invades any of the following: parietal pleural 
(PL3), chest wall (including superior sulcus tumours), diaphragm, phrenic nerve, 
mediastinal pleura, parietal pericardium; or tumour in the main bronchus less than 2 cm 
distal to the carina1 but without involvement of the carina; or associated atelectasis or 
obstructive pneumonitis of the entire lung or separate tumour nodule(s) in the same lobe 
 
T4 
Tumour of any size that invades any of the following: mediastinum, heart, great vessels, 
trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, separate tumour 
nodule(s) in a different ipsilateral lobe 
M 
Distant Metastasis 
 
M0 
No distant metastasis 
 
M1 
Distant metastasis 
 
M1a 
Separate tumour nodule(s) in a contralateral lobe, tumour with pleural nodules or 
malignant pleural (or pericardial) effusionb 
 
M1b 
Distant metastasis (in extrathoracic organs) 
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N 
Regional lymph nodes 
 
Nx 
Regional lymph nodes cannot be assessed 
 
N0 
No regional lymph node metastases 
 
N1 
Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and 
intrapulmonary nodes, including involvement by direct extension 
 
N2 
Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s) 
 
N3 
Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral 
scalene, or supraclavicular lymph node(s) 
a The uncommon superficial spreading tumour of any size with its invasive component limited to the bronchial wall, 
which may extend proximally to the main bronchus, is also classified as T1a. 
b Most pleural (and pericardial) effusions with lung cancer are due to tumour. In a few patients, however, multiple 
cytopathologic examinations of pleural (pericardial) fluid are negative for tumour, and the fluid is nonbloody and is 
not an exudate. Where these elements and clinical judgment dictate that the effusion is not related to the tumour, the 
effusion should be excluded as a staging element and the patient should be classified as M0. 
 
Anatomic stage/ Prognostic groups 
Occult carcinoma 
Tx 
N0 
M0 
Stage 0 
Tis 
N0 
M0 
Stage IA 
T1a 
N0 
M0 
T1b 
N0 
M0 
Stage IB 
T2a 
N0 
M0 
Stage IIA 
T2b 
N0 
M0 
T1a 
N1 
M0 
T1b 
N1 
M0 
T2a 
N1 
M0 
Stage IIB 
T2b 
N1 
M0 
T3 
N0 
M0 
Stage IIIA 
T1a 
N2 
M0 
T1b 
N2 
M0 
T2a 
N2 
M0 
T2b 
N2 
M0 
T3 
N1 
M0 
T3 
N2 
M0 
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T4 
N0 
M0 
T4 
N1 
M0 
Stage IIIB 
T1a 
N3 
M0 
T1b 
N3 
M0 
T2a 
N3 
M0 
T2b 
N3 
M0 
T3 
N3 
M0 
T3 
N3 
M0 
T4 
N2 
M0 
T4 
N3 
M0 
Stage IV 
Any T 
Any N 
M1a 
Any T 
Any N 
M1b 
 
Reference: 
Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual, 7th ed. New York: 
Springer 2010. 
 
 
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APPENDIX 3: NATIONAL CANCER INSTITUTE-COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS VERSION 
4.03 (NCI-CTCAE v4.03) (IN PART OF) 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADLa. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; 
limiting self-care ADLb. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
ADL = Activities of Daily Living 
a Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
 
Specific CTCAE Grades for Selected Adverse Events 
AE 
Grade 
1 
2 
3 
4 
5 
Neutrophil count 
decreased 
< LLN-
1,500/mm3 
< 1,500-
1000/mm3 
< 1,000-500/mm3 
< 500/mm3 
- 
Platelet count 
decreased 
< LLN-
75,000/mm3 
< 75,000-
50,000/mm3 
< 50,000-
25,000/mm3 
< 25,000/mm3 
- 
Febrile 
neutropenia 
- 
- 
ANC <1,000/mm3 
with a single 
temperature of 
> 38.3 degrees C 
(101 degrees F) or 
a sustained 
temperature of 
≥ 38 degrees C 
(100.4 degrees F) 
for more than one 
hour. 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
AST/ALT 
> ULN– 
3.0 × ULN 
> 3.0-5.0 × 
ULN 
> 5.0-20.0 × ULN 
> 20.0 × ULN 
- 
Blood bilirubin 
increased 
> ULN– 
1.5 × ULN 
> 1.5-3.0 × 
ULN 
> 3.0-10.0 × ULN 
> 10.0 × ULN 
- 
ALP 
> ULN-2.5 × 
ULN 
> 2.5-5.0 × 
ULN 
> 5.0-20.0 × ULN 
> 20.0 × ULN 
- 
Peripheral motor 
neuropathy 
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Sever symptoms; 
limiting self-care 
ADL; assistive 
device indicated 
Life-
threatening 
consequences; 
urgent 
intervention 
Death 
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AE 
Grade 
1 
2 
3 
4 
5 
intervention not 
indicated 
indicated 
Peripheral 
sensory 
neuropathy 
Asymptomatic; 
loss of deep 
tendon reflexes 
or paresthesia 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Sever symptoms; 
limiting self-care 
ADL 
 
Death 
Mucositis oral 
Asymptomatic 
or mild 
symptoms; 
intervention not 
indicated 
Moderated 
pain; not 
interfering 
with oral 
intake; 
modified diet 
indicated 
Severe pain; 
interfering with 
oral intake 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Vomiting 
1-2 episodes 
(separated by 5 
minutes) in 
24 hrs 
3-5 episodes 
(separated by 5 
minutes) in 24 
hrs 
≥ 6 episodes 
(separated by 5 
minutes) in 24hrs; 
tube feeding, TPN 
or hospitalisation 
indicated 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
ADL = activities of daily living; ANC = absolute neutrophil count TPN = total parenteral nutrition 
 
Reference: 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. NCI. 
from http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf. 
 
 
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APPENDIX 4: WORLD HEALTH ORGANIZATION 
HISTOLOGICAL CLASSIFICAION OF TUMOURS OF THE LUNG 
Epithelial tumours 
Adenocarcinoma 
 Lepidic adenocarcinoma 
 Acinar adenocarcinoma 
 Papillary adenocarcinoma 
 Micropapillary adenocarcinoma 
 Solid adenocarcinoma 
 Invasive mucinous adenocarcinoma – mixed invasive mucinous and 
nonmucinous adenocarcinoma 
 Colloid adenocarcinoma 
 Fetal adenocarcinoma 
 Enteric adenocarcinoma 
 Minimally invasive adenocarcinoma – nonmucinous, mucinous 
 Preinvasive lesions – atypical adenomatous hyperplasia, 
adenocarcinoma in situ (nonmucinous, mucinous) 
Squamous cell carcinoma 
 Keratinizing squamous cell carcinoma 
 Nonkeratinizing squamous cell carcinoma 
 Basaloid squamous cell carcinoma 
 Preinvasive lesion – squamous cell carcinoma in situ 
Neuroendocrine tumours 
 Small cell carcinoma – combined small cell carcinoma 
 Large cell neuroendocrine carcinoma – combined large cell 
neuroendocrine carcinoma 
 Carcinoid tumours – typical carcinoid tumour, atypical carcinoid 
tumour 
 Preinvasive lesion – diffuse idiopathic pulmonary neuroendocrine, 
cell hyperplasia 
Large cell carcinoma 
Adenosquamous carcinoma 
Pleomorphic carcinoma 
Spindle cell carcinoma 
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Giant cell carcinoma 
Carcinosarcoma 
Pulmonary blastoma 
Other and unclassified 
carcinomas 
 Lymphoepithelioma-like carcinoma 
 NUT carcinoma 
Salivary gland-type tumours 
 Mucoepidermoid carcinoma 
 Adenoid cystic carcinoma 
 Epithelial-myoepithelial carcinoma 
 Pleomorphic adenoma 
Papillomas 
 Squamous cell papilloma – exophytic, inverted 
 Glandular papilloma 
 Mixed squamous and glandular papilloma 
Adenomas 
 Sclerosing pneumocytoma 
 Alveolar adenoma 
 Papillary adenoma 
 Mucinous cystadenoma 
 Mucous gland adenoma 
Mesenchymal tumours 
Pulmonary hamartoma 
Chondroma 
PEComatous tumours 
 Lymphangioleiomyomatosis 
 PEComa, benign – clear cell tumour 
 PEComa, malignant 
Congenital peribronchial myofibroblastic tumour 
Inflammatory myofibroblastic tumour 
Epithelioid haemangioendothelioma 
Pleuropulmonary blastoma 
Synovial sarcoma 
Pulmonary artery intimal sarcoma 
Pulmonary myxoid sarcoma with EWSR1–CREB1 translocation 
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Myoepithelial tumours 
 Myoepithelioma 
 Myoepithelial carcinoma 
Lymphohistiocytic tumours 
Extranodal marginal zone 
lymphomas of mucosa-
associated 
 Lymphoid tissue (MALT lymphoma) 
Diffuse large cell lymphoma 
Lymphomatoid granulomatosis 
Intravascular large B cell lymphoma 
Pulmonary langerhans cell histiocytosis 
Erdheim– chester disease 
Tumours of ectopic origin 
Germ cell tumours 
 Teratoma, mature 
 Teratoma, immature 
Intrapulmonary thymoma 
Melanoma 
Meningioma, NOS 
Metastatic tumours 
 
Reference:  
WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart; Volume 7 in 4th 
Edition. 
 
 
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PROTOCOL SIGNATURE PAGES 
SIGNATURE PAGE 
Declaration of Sponsor or Responsible Medical Expert 
Protocol Tille: A P1iase JU, Randomised, Double-blind, Mu1t.icentre Study lo Compare Lhe 
Efficacy, Safety, Pharmacokinetics and lmmuriogenicity between SB8 (proposed bevacizumab 
biosimilar) and Avastin~ in Subjects with Metastatic or Recurrent Non-squamous Non-small 
Cell Lung Cancer 
This clinical study protocol was subjected to critical review. The i.nfonnation it contains is 
consistent with current knowledge of the risks and benefits of the investigalional medicinal 
producr, as well as with the moral, ethical and scientific prindples governing clinical research as 
set out in the Declaration of Helsinki, 2013 and the guidelines on Good Clinical Practice 
applicable to this clinical sludy. 
Sponsor Signatory/Responsible· Medical Expert 
Name: 
Institution: 
Signalure: 
 SB8 Clinical Research Physician 
Samsung Bioepis Cb., Ltd. 
,.. 
: 
Sa.nisuug Bioepis - Confidential 
Page 93-of 165 
PPD
PPD
PPD

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SIGNATURE :PAGE 
Declaration of the Global Princlp:W'Coordinating Inve~tigator 
Protocol Title: A Phase ill, Randomised, Double-blind, Multicetitre Study to Compare the 
Efficacy, Safety, Pbarmacokinetics and Irrununogeuicity between SB8 (proposed bevaci;zumab 
biosimilar) and Avastin® in Subjects with Metastatic-or Re,cummt Non-squamous Non-small 
Cell Lung Cancer 
This clinic-al study protocol was subjected to critical revie1v. Tbelnformation it aontains is 
consistent with current knmvledge of the risks aod benefit> of theinvestigational medicinal 
product, as well as with the moral, ethical and scientific principles governing clinical.research as 
set out in the Declaration ofHe1sinki, 2013 and the guidelines on Good Clinical Practice. 
applicable to tills clinical study. 
Principal/Coordinating lnvestiga:tor 
Name: 
lnstitution: 
Signature: 
Samsung Bioepis - Confid1#ial 
Page 94of165 
PPD
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SIGNATURE PAGE 
Declaration of the Principal/Coordinating Investigator 
Protocol Title: A Phase III, Randomised, Double-blind, Multicentre Study to Compare the 
Efficacy, Safety, Pharmacokinetics and Immunogenicity between SB8 (proposed bevacizumab 
biosimilar) and Avastin® in Subjects with Metastatic or Recurrent Non-squamous Non-small 
Cell Lung Cancer 
This clinical study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational medicinal 
product, as well as with the moral, ethical and scientific principles governing clinical research as 
set out in the Declaration of Helsinki, 2013 and the guidelines on Good Clinical Practice 
applicable to this clinical study. 
Principal/Coordinating Investigator 
Name: 
 
Institution: 
 
Signature: 
 
Date: 
 
 
 
 
(Month, Day, Year) 
 
 
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AMENDMENT 1: Dec 17, 2015 
Section Affected 
Original Content 
Amended/New Content 
Rationale 
 
Version and Effective Date: Version 1.0 Oct 05, 2015 
Version and Effective Date: Amendment 1.0 Dec 17, 
2015 
Version control 
Samsung Bioepis Co., Ltd. 
107, Cheomdan-daero, Yeonsu-gu, 
Incheon, 406-840 
Republic of Korea 
Samsung Bioepis Co., Ltd. 
107, Cheomdan-daero, Yeonsu-gu, 
Incheon, 21987 
Republic of Korea 
New postal 
code 
Change through text 
and figure except for 
AVAiL, E4599 
studies' ORR 
ORR 
Best ORR 
According to 
US FDA 
feedback 
through text 
AvaiL 
AVAiL 
To correct typo 
error 
Synopsis-Study 
Design 
ORR 
best ORR 
According to 
US FDA 
feedback 
Sbjects with metastatic or recurrent non-squamous 
NSCLC with unknown or without activating EGFR gene 
mutations or ALK gene translocations will be 
randomised. 
Subjects with metastatic or recurrent non-squamous 
NSCLC with unknown or without activating without 
known activating EGFR gene mutations or ALK gene 
translocations, will be randomised. 
According to 
US FDA 
feedback 
Approximately 50% of the enrolled subjects will have 
blood samples collected for PK analysis at pre-dose and 
post-dose of Cycle 1, 3, 5, and 7. 
Approximately 50% of the enrolled subjects will have 
blood samples collected for PK analysis of SB8 or 
Avastin®, at pre-dose and post-dose of Cycle 1, 3, 5, 
and 7. 
clarification 
Synopsis-Target 
Population 
Subjects with metastatic or recurrent non-squamous 
NSCLC with unknown or without activating EGFR gene 
Subjects with metastatic or recurrent non-squamous 
NSCLC with unknown or without activating without 
According to 
US FDA 
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mutations or ALK gene translocations  
known activating EGFR gene mutations or ALK gene 
translocations  
feedback 
Synopsis-Eligibility 
Synopsis-Criteria 
Inclusion criteria 
1. Aged ≥ 18 years  
1. Aged ≥ 18 years (if local regulations are different in 
this regard, follow the local regulations). 
Different 
country 
regulations, 
e.g., Taiwan 
7.b. Urine dipstick for proteinuria of less than 2+ (other 
ways of urinalysis are also acceptable); if urine dipstick 
is ≥ 2+, 24 hours urine protein excretion < 1 g or 
protein/creatinine ratio in spot urine < 1 g/g creatinine 
(or < 226.0 mg/mmol creatinine). 
7.b. Urine dipstick for proteinuria of less than 2+ (other 
ways of urinalysis are also acceptable); if urine dipstick 
is ≥ 2+, 24 hours urine protein excretion is < 1 g or 
protein/creatinine ratio in spot urine is < 1 g/g creatinine 
(or < 226.0 mg/mmol creatinine). 
To correct typo 
error 
Synopsis-Criteria 
Exclusion criteria 
7. Radiotherapy within 28 days prior to Randomisation 
(tumour lesions situated in a previously irradiated area, 
or in an area subjected to other loco-regional therapy 
except for pain relief, are not considered as measurable 
lesion.). 
7. Radiotherapy within 28 days prior to Randomisation 
(tumour lesions situated in a previously irradiated area, 
or in an area subjected to other loco-regional 
therapy except for pain relief, are not considered as 
measurable lesion unless there has been demonstrated 
progression in the lesion.). 
According to 
RECIST v1.1 
9. Minor surgical procedure within 7 days prior to 
Randomisation (requiring local anaesthesia or following 
procedures: medianoscopy, percutaneous needle 
aspiration, core biopsy, placement of vascular access 
device, endobronchoscopy ultra sono & transbronchial 
needle biopsy [EBUS & TBNA], pleural biopsy, 
thoracenthesis, pleurodesis, catheter insertions/removal, 
tooth extraction, superficial incision 
9. Minor surgical procedure within 7 days prior to 
Randomisation (requiring local anaesthesia or following 
procedures: mediastinoscopy, percutaneous needle 
aspiration, core biopsy, placement of vascular access 
device, endobronchoscopy ultra sono & transbronchial 
needle biopsy [EBUS & TBNA], pleural biopsy, 
thoracentesis, pleurodesis, catheter insertions/removal, 
tooth extraction, superficial incision 
To correct typo 
error 
11. Known or clinically suspected brain metastasis 
and/or leptomeningeal disease. 
11. Known or clinically suspected Symptomatic brain 
metastasis and/or leptomeningeal disease. 
Investigator’s 
feedback to 
allow 
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incidentaly 
asymptomatic 
findings 
15. Subjects treated with anticoagulant therapy within 10 
days prior to Randomisation  
(e.g., clopidogrel [> 75 mg/day], regular use of aspirin [> 
325 mg/day)], dipyridamole, ticlopidine and/or 
cilostazol); 
15. Subjects treated with anticoagulant therapy within 
10 days prior to Randomisation  
(e.g., clopidogrel [> 75 mg/day], regular use of 
aspirin [> 325 mg/day)], dipyridamole, ticlopidine 
and/or cilostazol);  
No lower limit 
of Aspirin dose 
18.h. Gastrointestinal bleeding, heamatemesis or 
haemoptysis (≥ 1/2 teaspoon of red blood). 
18.h. Gastrointestinal bleeding, haematemesis or 
haemoptysis (≥ 1/2 teaspoon of red blood). 
To correct typo 
error 
Synopsis-Main 
Criteria for 
Evaluation 
Primary endpoint 
• The ORR by 24 weeks of chemotherapy (ORR is 
defined as the proportion of subjects whose best overall 
response is either complete response [CR] or partial 
response [PR] according to RECIST v1.1) 
Tumour assessment will be performed after IP 
administration of Cycle 2, 4, and 6, and before planned 
Day 1 of Cycle 3, 5, and 7 and then will be performed 
every 4 cycles according to RECIST v1.1 and assessed 
by both Investigators and independent central reviewer. 
The primary efficacy analysis will be based on the data 
from the independent central review. 
• The best ORR by 24 weeks of chemotherapy (best 
ORR is defined as the proportion of subjects whose best 
overall response is either complete response [CR] or 
partial response [PR] according to RECIST v1.1) 
Tumour assessment will be performed after IP 
administration of Cycle 2, 4, and 6, and before planned 
Day 1 of Cycle 3, 5, and 7 and then will be performed 
every 4 cycles according to RECIST v1.1 and tumour 
size will be assessed by both Investigators and 
independent central reviewer. The primary efficacy 
analysis will be based on the data from the independent 
central review. 
To correct typo 
error 
For US Food and Drug Administration submission, the 
primary analysis will be performed for the ratio of the 
ORR by 24 weeks. For EMA submission, the primary 
analysis will be performed for the difference of the ORR 
by 24 weeks. 
For US Food and Drug Administration submission, 
the primary analysis will be performed for the ratio 
of the ORR by 24 weeks. For EMA submission, the 
primary analysis will be performed for the difference 
of the ORR by 24 weeks. 
According to 
US FDA 
feedback 
Synopsis-Main 
• Progression free survival (PFS), defined as the time 
• Progression free survival (PFS), defined as the time 
More 
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Criteria for 
Evaluation 
Secondary endpoints 
from the date of Randomisation to the date of disease 
progression or death regardless of the cause of death. 
Subjects who are not progressed at the time of analysis 
will be censored at the date of EOT visit. 
from the date of Randomisation to the date of disease 
progression or death regardless of the cause of death. 
Subjects who are not progressed at the time of analysis 
will be censored at the date of EOT visit or the last 
tumour assessment date if the date of EOT is not 
available.  
sophisticated 
definition of 
PFS 
Synopsis-Statistical  
Methods 
Analysis set 
Full analysis set (FAS) will consist of all randomised 
subjects. The subjects will be analysed based on the 
treatment they were randomised to. 
Full analysis set (FAS) will consist of all randomised 
subjects. The subjects will be analysed based on the 
treatment they were randomised to by intention-to-
treat principle. However, subjects who do not qualify 
for randomisation and are inadvertently randomised 
into the study will be excluded from FAS, provided 
these subjects do not receive any IP during the study.  
According to 
US FDA 
feedback 
 
Per-protocol set (PPS) will consists of all FAS subjects 
who complete at least two cycles of combination 
chemotherapy with a tumour assessment and do not have 
any major protocol deviations that impact the primary 
efficacy assessment. The PPS will be the primary 
analysis set. Major protocol deviations that will lead to 
exclusion from the PPS will be pre-specified, and PPS 
will be determined prior to unblinding the treatment 
codes. 
Per-protocol set (PPS) will consists of all FAS subjects 
who complete at least two cycles of combination 
chemotherapy with a tumour assessment and do not 
have any major protocol deviations that impact the 
primary efficacy assessment. The PPS will be the 
primary analysis set. Major protocol deviations that 
will lead to exclusion from the PPS will be pre-
specified, and PPS will be determined prior to 
unblinding the treatment codes. 
According to 
US FDA 
feedback 
Synopsis-Statistical  
Methods 
Efficacy analysis 
For US FDA submission, the primary efficacy 
analysis for demonstrating the equivalence of SB8 to 
Avastin® will be done for the ratio of the ORR (SB8 
response rate/Avastin® response rate) by 24 weeks. 
The equivalence will be declared if the two sided 90% 
confidence interval (CI) of the ORR ratio lies within 
the pre-defined equivalence margin of [0.742, 1.450]. 
For US FDA submission, the primary efficacy 
analysis for demonstrating the equivalence of SB8 to 
Avastin® will be done for the ratio of best ORR (best 
ORR of SB8/ best ORR of Avastin®) by 24 weeks in 
the FAS. The equivalence will be declared if the two 
sided 90% confidence interval (CI) of the best ORR 
ratio is contained within the pre-defined equivalence 
According to 
US FDA 
feedback, 
recalculate the 
equivalence 
margin 
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For EMA submission, the primary efficacy analysis 
will be performed for the difference in ORR between 
SB8 and Avastin®, and the equivalence will be 
declared if the two-sided 95% CI lies within the pre-
defined equivalence margin of [-12.5%, 12.5%]. The 
secondary efficacy endpoints (PFS, OS, and DOR) 
will be analysed using Cox proportional hazard 
models stratified by age (< 70 and ≥ 70), gender 
(pooled centre).  
margin of [0.737, 1.357]. The similar analysis will be 
performed for the PPS to support the primary 
efficacy result. 
For EMA submission, the primary efficacy analysis 
will be performed for the difference in best ORR by 
24 weeks between SB8 and Avastin® in the PPS, and 
the equivalence will be declared if the two-sided 95% 
CI of the best ORR difference in contained within 
the pre-defined equivalence margin of [-12.5%, 
12.5%]. The Similar analysis will be performed for 
the FAS to support the primary efficacy. 
Synopsis-Statistical  
Methods 
Safety analyses 
All reported terms for AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) 
and the grade of severity will be reported by NCI-
CTCAE v4.03. AEs will be summarised descriptively by 
treatment group. Changes in vital signs and clinical 
laboratory measurements will be summarised 
descriptively by treatment group and visit. All other 
safety variables will be summarised descriptively by 
treatment group. 
All reported terms for AEs will be coded using the 
Medical Dictionary for Regulatory Activities 
(MedDRA) and the grade of severity will be reported by 
NCI-CTCAE v4.03. AEs will be summarised 
descriptively by treatment group. Changes in vital signs 
and clinical laboratory measurements will be 
summarised descriptively by treatment group. and visit. 
All other safety variables will be summarised 
descriptively by treatment group. 
Better term 
Synopsis-Statistical  
Methods 
Immunogenicity 
analyses 
Incidence of ADAs will be summarised by treatment 
group and visit and listed by treatment group 
Incidence of ADAs will be summarised by treatment 
group and cycle and listed by treatment group 
Better term 
Synopsis-Statistical  
Methods 
Sample size 
calculation 
For the calculation of the equivalence margin, AVAiL 
[Reck, 2010] and E4599 [Sandler, 2006] studies of 
Avastin®+ cisplatin/gemcitabine (CG) vs. CG alone 
and of Avastin® + paclitaxel/carboplatin vs. 
paclitaxel/carboplatin alone, respectively, were 
For the calculation of the equivalence margin, a 
meta-analysis published by Botrel et al. using all of 
the four published comparative trials that evaluated 
bevacizumab in combination with chemotherapy (i.e. 
E4599 [Sandler, 2006], AVAiL (BO17704) [Reck, 
According to 
US FDA 
feedback, more 
references are 
cited 
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considered. In AVAiL study, ORR rates were 21.6% 
and 37.8% for placebo and Avastin® + CG groups, 
respectively. In E4599 study, ORR rates were 15.1% 
(out of 392) and 34.9% (out of 381) for placebo and 
Avastin® + paclitaxel/carboplatin groups, 
respectively. 
The overall ratio of ORR and its 95% CI from these 
two studies are calculated to be 2.0217 [1.6943, 
2.4124] using the fixed effect method from meta-
analysis. The equivalence margin of [0.742 1.450] will 
preserve 50% of the effect of Avastin® over the 
placebo in the lower margin. 
The overall difference in ORR and its 80% CI from 
these two studies are calculated to be 
% 
%, 
%] using the fixed-effect method from 
meta-analysis. The equivalence margin of  
[-12.5%, 12.5%] will preserve at least 20% of the 
effect of Avastin® over the placebo in the difference of 
ORR.  
With 305 completers in each treatment group, the 
two-sided 90% CI of the ORR ratio is expected to lie 
within [0.742, 1.450] with 90% power, and the two-
sided 95% CI of the ORR difference between 
Avastin® and SB8 is expected to lie within [-12.5%, 
12.5%] with 80% power when the expected ORR is 
assumed to be 35%. Assuming a 10% drop-out rate, a 
total of 678 subjects (339 subjects per treatment 
group) will be randomised. 
2009], AVF0757 [Johnson, 2004], JO19907 [Niho, 
2012]) was considered. 
The overall ratio of best ORR and its 70% CI from 
above four studies are calculated to be 
 
 using the fixed effect method from 
meta-analysis. Retaining the 
% of the effect of 
Avastin® over the placebo in the lower margin, the 
equivalence margin of [0.737, 1.357] will be used for 
the primary analysis with the ratio of the best ORR 
by 24 weeks. 
For the primary analysis with the difference of the 
best ORR by 24 weeks, the equivalence margin of [-
12.5%, 12.5%] will be used due to the similar 
derivation. 
With 305 completers in each treatment group, the 
two-sided 90% CI of the best ORR ratio is expected 
to lie within [0.737, 1.357] with approximately 80% 
power, and the two-sided 95% CI of the best ORR 
difference between Avastin® and SB8 is expected to 
lie within [-12.5%, 12.5%] with 80% power when the 
expected best ORR is assumed to be 35%. Assuming 
a 10% drop-out rate, a total of 678 subjects (339 
subjects per treatment group) will be randomised. 
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Synopsis-Figure 1 
 
3 Primary endpoint is the ORR by 24 weeks of 
chemotherapy with SB8 or Avastin®. 
 
3 Primary endpoint is the best ORR by 24 weeks of 
chemotherapy with SB8 or Avastin®. 
According to 
US FDA 
feedback 
 
4 Physical examination, vital sign, ECOG performance 
status, reviewing the laboratory values including 
haematology, biochemistry, urinalysis, and reviewing IP 
compliance will be performed at each cycle. Tumour 
assessment will be performed after IP administration of 
Cycle 2, 4, and 6, and before planned Day 1 of Cycle 3, 
5, and 7 and then will be performed every 4 cycles since 
cycle 6 until disease progression or death or end of study. 
Tumour response will be assessed using CT or MRI 
according to local standards. 
4 Physical examination, vital sign, ECOG performance 
status, reviewing the laboratory values including 
haematology, biochemistry, urinalysis, and reviewing IP 
compliance will be performed at each cycle. Tumour 
assessment will be performed after IP administration of 
Cycle 2, 4, and 6, and before planned Day 1 of Cycle 3, 
5, and 7 and then will be performed every 4 cycles since 
cycle 6 until disease progression or death or end of 
study. Tumour response will be assessed using CT or 
MRI according to local standards following Image 
Acquisition Guideline that will be provided by 
Sponsor. 
clarification 
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Table 1 
` 
 
 
 
7. Blood coagulation test including prothrombin 
time/international normalised ratio (PT/INR) will be 
performed at Screening. Additional blood coagulation 
test will be performed at the discretion of Investigator if 
there are any suspicious cases 
7. Blood coagulation test including prothrombin 
time/international normalised ratio (PT/INR) will be 
performed at Screening. Additional blood coagulation 
test will be performed at the discretion of Investigator if 
there are any suspicious cases 
Correct term 
8. Biochemistry tests include creatinine, urea (blood 
urine nitrogen [BUN]), serum aspartate aminotransferase 
(AST), serum alanine aminotransferase (ALT), total 
bilirubin, alkaline phosphatase (ALP), albumin, and 
electrolytes (sodium, potassium, chloride). 
8. Biochemistry tests include creatinine, urea 
(blood urine urea nitrogen [BUN]), serum aspartate 
aminotransferase (AST), serum alanine 
aminotransferase (ALT), total bilirubin, alkaline 
phosphatase (ALP), albumin, and electrolytes (sodium, 
potassium, chloride). 
To correct typo 
error 
9. If urine dipstick is ≥ 2+ (other ways of urinalysis are 
also acceptable), 24 hours urine protein excretion < 1 g 
or protein/creatinine ratio in spot urine < 1 g/g creatinine 
(or < 226.0 mg/mmol creatinine). 
9. If urine dipstick is ≥ 2+ (other ways of urinalysis are 
also acceptable), 24 hours urine protein excretion is < 1 
g or protein/creatinine ratio in spot urine is < 1 g/g 
creatinine (or < 226.0 mg/mmol creatinine). 
To correct typo 
error 
11. Hepatitis B and hepatitis C tests should be performed 
during Screening period. Known history of HIV 
infection will be confirmed separately at the discrietion 
11. Hepatitis B and hepatitis C tests should be 
performed during Screening period according to local 
practice. Known history of HIV infection will be 
clarification 
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of Investigator. Additional HBV/HCV tests will be 
performed at the discretion of Investigator if there are 
any suspicious cases. 
confirmed separately at the discrietion of Investigator. 
Additional HBV/HCV tests will be performed at the 
discretion of Investigator if there are any suspicious 
cases. 
13. Tumour response will be assessed using CT or MRI 
according to local standards. The same modality used at 
Screening will be used throughout the study. 
13. Tumour response will be assessed using CT or 
MRI according to local standards following Image 
Acquisition Guideline that will be provided by 
Sponsor. The same modality used at Screening will be 
used throughout the study. 
clarification 
14. The first dose of IPs and non IPs should be 
administered within 7 days after Randomisation. 
14. The first dose of IP and non-IPs should be 
administered within 7 days after Randomisation. 
plurality 
18. Blood sampling for PK analysis will be performed at 
pre-dose and post-dose (within 15 minutes after the end 
of infusion) of Cycle 1, 3, 5, and 7 in approximately 50% 
of the enrolled subjects. 
18. Blood sampling for PK analysis will be performed at 
pre-dose and post-dose of IP (within 15 minutes after 
the end of infusion) of Cycle 1, 3, 5, and 7 in 
approximately 50% of the enrolled subjects. 
clarification 
19. Concomitant and previous (within 28 days prior to 
Screening) medications will be recorded at Screening 
and concomitant medications are to be monitored 
continuously during the study treatment. 
19. Concomitant and previous (within 28 days prior to 
Screening) medications will be recorded at Screening 
and concomitant medications are to be monitored 
continuously during the study treatment and after EOT 
visit, if such information is related to SAEs. 
PV rules 
20. All AEs will be recorded from the time when the 
informed consent form is signed until the EOT visit 
(progression of NSCLC and death due to progression of 
NSCLC are not to be reported as an AE or SAE). 
20. All AEs will be recorded reported in the eCRF 
from the time when the informed consent form is signed 
until the EOT visit (progression of NSCLC and death 
due to progression of NSCLC are not to be reported as 
an AE or SAE). After the EOT visit, only SAEs will 
be reported using the paper SAE report form. 
aligned to 
7.1.2. 
22. Induction chemotherapy at Cycle 5 and 6 may be 
replaced with the maintenance therapy at the 
22. Induction chemotherapy at Cycle 5 and 6 may be 
replaced with the maintenance therapy at the discretion 
Easier 
language 
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discretion of Investigator. In this case, the schedule of 
activities must follow those of the maintenance 
treatment period. 
of Investigator. In this case, all other activities except 
for non-IPs infusion must follow originally planned 
activities at each cycle. 
25. After completion of study treatment, subjects will be 
followed for survival status and whether subsequent 
therapy is received or not by clinic visit or telephone 
contact every 3 months until discontinuation of the 
subject from the study (e.g., death, withdrawal of 
consent, lost to follow-up), EOS date defined as when 
deaths of all the randomised subjects have been 
observed, or 12 months from randomisation of the last 
subject, whichever occurs first. 
25. After completion of study treatment, subjects will be 
followed for survival status and whether subsequent 
therapy is received or not by clinic visit or telephone 
contact every 3 months until discontinuation of the 
subject from the study (e.g., death, withdrawal of 
consent, lost to follow-up, or initiation of subsequent 
therapy for NSCLC), EOS date defined as when deaths 
of all the randomised subjects have been observed, or 12 
months from randomisation of the last subject, 
whichever occurs first. 
Clarification 
List of Abbreviations ALP Alkaline Phosphate 
ANOVA Anlaysis of Variance 
Cmax Maximum Serum Concentration 
CP Carboplatin/paclitaxel 
CRF Case Report Form 
Ctrough Trough Serum Concentration 
CV Coefficient of Variation 
EMA European Medicinal Agency 
 
 
HBsAg Hepatitis B surface antigen 
HCV-Ab Hepatitis C virus antibody 
IRF Independent Review Facility 
Nab Neutralising Antibody 
 
PTT Partial Thromboplastin Time 
ALP Alkaline Phosphatase 
ANOVA Anlaysis of Variance 
Cmax Maximum Serum Concentration 
CP Carboplatin/paclitaxel  
eCRF Electronic Case Report Form 
Ctrough Trough Serum Concentration 
CV Coefficient of Variation 
EMA European Medicines Agency 
EOT End of Treatment 
EPAR European Public Assessment Reports 
HBsAg Hepatitis B surface antigen 
HCV-Ab Hepatitis C virus antibody 
IRF Independent Review Facility 
NAb Neutralising Antibody 
PC Paclitaxel/carboplatin 
PTT Partial Thromboplastin Time 
To correct typo 
error : removed 
un-used terms 
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RAN Randomised Set 
RAN Randomised Set 
Table of Contents 
6.2.6. Unblinding 
6.2.7. Investigational Product Accountability 
6.2.6. Unblinding 
6.2.6. Investigational Product Accountability 
Editorial 
change: 
Migrate 
“Unblinding” 
to Section 
7.1.6. 
 
7.1.6. Expectedness Assessment 
7.1.7. Withdrawal Due to Adverse Events 
7.1.6. Emergency Unblinding for Safety Reasons 
7.1.6 7.1.7. Expectedness Assessment 
7.1.7 7.1.8. Withdrawal Due to Adverse Events 
Editorial 
change: 
Migrate 
“Unblinding” 
to Section 
7.1.6. 
8.4. Interim Analysis 
8.4. Interim Analysis Statistical Analysis Timepoints 
Better term  
List of Tables 
Table 3. Medications and Therapies of NSCLC 
Prohibited prior to Randomisation and throughout 
the Study 
Table 3. Prohibited Medications and Therapies of 
NSCLC  
Simplification 
List of Study Staff 
SPONSOR 
Samsung Bioepis Co., Ltd. 
107, Cheomdan-daero, Yeonsu-gu, 
Incheon, 406-840 
SPONSOR 
Samsung Bioepis Co., Ltd. 
107, Cheomdan-daero, Yeonsu-gu, 
Incheon, 21987  
New postal 
code 
1. INTRODUCTION 
1.1. Background 
AvaiL 
AVAiL 
To correct typo 
error 
This result of OS is not inferior than that from another 
study with 6 cycles of chemotherapy [Patel, 2013].  
This result of OS is not inferior than to that from 
another study with 6 cycles of chemotherapy [Patel, 
2013].  
To correct typo 
error 
1.2.2. Non-clinical 
Data of SB8 
In addition, in vivo non-clinical toxicology has been 
performed in cynomoulgus monkeys with SB8 and 
In addition, in vivo non-clinical toxicology has been 
performed in cynomoulgus cynomolgus monkeys with 
To correct typo 
error 
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Avastin®. 
SB8 and Avastin®. 
1.2.3. Clinical Data 
of SB8 
Information on the safety of SB8 based on the reference 
product information and non-clinical and work is 
presented in the Investigator’s Brochure (IB). 
Information on the safety of SB8 based on the product 
information of Avastin® is presented in the 
Investigator’s Brochure (IB). 
Better term 
1.3.2.1. Avastin® in 
Non-small Cell Lung 
Cancer 
AvaiL study [Reck, 2009] 
Patients were randomised to platinum-based 
chemotherapy, cisplatin 80 mg/m2 IV infusion on Day 1 
and gemcitabine 1250 mg/m2 IV infusion on Days 1 and 
8 of every 3 week cycle for up to 6 cycles (GC) with 
placebo or CG with Avastin® at a dose of 7.5 or 15 
mg/kg IV infusion day 1 of every 3-week cycle.  
AVAiL study [Reck, 2009] 
Patients were randomised to platinum-based 
chemotherapy, cisplatin 80 mg/m2 IV infusion on Day 1 
and gemcitabine 1250 mg/m2 IV infusion on Days 1 
and 8 of every 3 week cycle for up to 6 cycles (GC) 
with placebo or GC with Avastin® at a dose of 7.5 or 15 
mg/kg IV infusion day 1 of every 3-week cycle. 
Unify to GC 
than mixed use 
of GC and CG 
1.4. Rationale for the 
Study 
Two drug chemotherapy regimen which combine a 
platinum agent with paclitaxel, docetaxel, vinorelbine, 
irinotecan, and gemcitabine are usually accepted as 
standard of care for the treatment of advanced NSCLC. 
In AvaiL study, median PFS was significantly increased 
(6.7 months vs. 6.1 months) in high dose bevacizumab 
group compared with placebo [Reck, 2009]. 
Two drug chemotherapy regimens which combine a 
platinum agent with paclitaxel, docetaxel, vinorelbine, 
irinotecan, and gemcitabine are usually accepted as 
standard of care for the treatment of advanced NSCLC. 
In AVAiL study, median PFS was significantly 
increased (6.7 months vs. 6.1 months) in high dose 
bevacizumab group compared with placebo [Reck, 
2009]. 
Plurality  
2. STUDY 
OBJECTIVES 
2.1. Primary 
Objective 
Overall response rate 
ORR 
Best overall response rate 
best ORR 
According to 
US FDA 
feedback 
2.3. Exploratory 
Objective 
ORR 
best ORR 
According to 
US FDA 
feedback 
3. STUDY DESIGN 
3.1. Overview of 
Subjects with metastatic or recurrent non-squamous 
NSCLC with unknown or without activating epidermal 
Subjects with metastatic or recurrent non-squamous 
NSCLC with unknown or without without known 
According to 
US FDA 
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Study Design 
growth factor receptor (EGFR) gene mutations or 
anaplastic lymphoma kinase (ALK) gene translocations 
will be randomised  
activating epidermal growth factor receptor (EGFR) 
gene mutations or anaplastic lymphoma kinase (ALK) 
gene translocations will be randomised  
feedback 
3.2. Rationale for 
Study Design 
3.2.1. Rationale for Dose Selection of SB8 or Avastin® 
AvaiL 
3.2.1. Rationale for Dose Selection of SB8 or Avastin® 
AVAiL 
To correct typo 
error 
4. STUDY 
POPULATION 
4.2. Inclusion 
Criteria 
1. Aged ≥ 18 years  
1. Aged ≥ 18 years (if local regulations are different in 
this regard, follow the local regulations). 
Different 
country 
regulations, 
e.g. Taiwan 
7.b. Urine dipstick for proteinuria of less than 2+ (other 
ways of urinalysis are also acceptable); if urine dipstick 
is ≥ 2+, 24 hours urine protein excretion < 1 g or 
protein/creatinine ratio in spot urine < 1 g/g creatinine 
(or < 226.0 mg/mmol creatinine). 
7.b. Urine dipstick for proteinuria of less than 2+ (other 
ways of urinalysis are also acceptable); if urine dipstick 
is ≥ 2+, 24 hours urine protein excretion is < 1 g or 
protein/creatinine ratio in spot urine is < 1 g/g creatinine 
(or < 226.0 mg/mmol creatinine). 
To correct typo 
error 
4.3. Exclusion 
Criteria 
7. Radiotherapy within 28 days prior to Randomisation 
(tumour lesions situated in a previously irradiated area, 
or in an area subjected to other loco-regional therapy 
except for pain relief, are not considered as measurable 
lesion.). 
7. Radiotherapy within 28 days prior to Randomisation 
(tumour lesions situated in a previously irradiated area, 
or in an area subjected to other loco-regional 
therapy except for pain relief, are not considered as 
measurable lesion unless there has been demonstrated 
progression in the lesion.). 
According to 
RECIST v.1.1 
9. Minor surgical procedure within 7 days prior to 
Randomisation (requiring local anaesthesia or following 
procedures: medianoscopy, percutaneous needle 
aspiration, core biopsy, placement of vascular access 
device, endobronchoscopy ultra sono & transbronchial 
needle biopsy [EBUS & TBNA], pleural biopsy, 
thoracenthesis, pleurodesis, catheter insertions/removal, 
tooth extraction, superficial incision 
9. Minor surgical procedure within 7 days prior to 
Randomisation (requiring local anaesthesia or following 
procedures: mediastinoscopy, percutaneous needle 
aspiration, core biopsy, placement of vascular access 
device, endobronchoscopy ultra sono & transbronchial 
needle biopsy [EBUS & TBNA], pleural biopsy, 
thoracentesis, pleurodesis, catheter insertions/removal, 
tooth extraction, superficial incision 
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11. Known or clinically suspected brain metastasis 
and/or leptomeningeal disease. 
11. Known or clinically suspected Symptomatic brain 
metastasis and/or leptomeningeal disease. 
Investigator’s 
feedback 
15. Subjects treated with anticoagulant therapy within 10 
days prior to Randomisation  
(e.g., clopidogrel [> 75 mg/day], regular use of aspirin [> 
325 mg/day)], dipyridamole, ticlopidine and/or 
cilostazol); 
15. Subjects treated with anticoagulant therapy within 
10 days prior to Randomisation  
(e.g., clopidogrel [> 75 mg/day], regular use of 
aspirin [> 325 mg/day)], dipyridamole, ticlopidine 
and/or cilostazol);  
No lower limit 
of Aspirin dose 
18.h. Gastrointestinal bleeding, heamatemesis or 
haemoptysis (≥ 1/2 teaspoon of red blood). 
18.h. Gastrointestinal bleeding, haematemesis or 
haemoptysis (≥ 1/2 teaspoon of red blood). 
To correct typo 
error 
5. STUDY 
PROCEDURES 
AND 
ASSESSMENT 
5.1. Procedures by 
Study Period 
5.1.1. Screening 
Period 
- Blood coagulation test including prothrombin 
time/international normalised ratio (PT/INR)  
- Blood coagulation test including prothrombin 
time/international normalised ratio (PT/INR) 
Correct term 
- Urinalysis (dipstick): leukocytes, nitrite, urobilinogen, 
protein, pH, Hb, specific gravity, ketone, bilirubin, 
glucose (other ways of urinalysis are also allowed), if 
urine dipstick is ≥ 2+, 24 hours urine protein excretion < 
1 g or protein/creatinine ratio in spot urine < 1 g/g 
creatinine (or < 226.0 mg/mmol creatitnine)  
- Urinalysis (dipstick): leukocytes, nitrite, urobilinogen, 
protein, pH, Hb, specific gravity, ketone, bilirubin, 
glucose (other ways of urinalysis are also allowed), if 
urine dipstick is ≥ 2+, 24 hours urine protein excretion 
is < 1 g or protein/creatinine ratio in spot urine is < 1 
g/g creatinine (or < 226.0 mg/mmol creatinine)  
Correct term 
- Serology: Hepatitis B surface antigen (HBsAg) and 
Hepatitis C antibody (HCV-Ab) tests, known history 
of HIV infection will be confirmed separately at the 
discretion of Investigator. 
- Serology: test for Hepatitis B and hepatitis C should 
be performed during Screening period according to 
local practice. Known history of HIV infection will be 
confirmed separately at the discretion of Investigator. 
Remove 
specific tests 
• Baseline tumour assessment (within a maximum 21 
days prior to Randomisation) of lung and locoregional 
lymph nodes by CT scan or MRI. Upper abdominal 
cavity including the adrenal glands must be included in 
imaging study. If the case baseline tumour assessment is 
not performed within 21 days prior to Randomisation, it 
should be repeated. In case of negative confirmation of 
• Baseline tumour assessment (within a maximum 21 
days prior to Randomisation) of lung and locoregional 
lymph nodes by CT scan or MRI. Upper abdominal 
cavity including the adrenal glands must be included in 
imaging study. If the case baseline tumour assessment is 
not performed within 21 days prior to Randomisation, it 
should be repeated. In case of negative confirmation 
Clarification 
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measurable lesion(s) by the independent central reviewer 
before subject Randomisation, the concerned subject will 
be considered as screen failure. 
of measurable lesion(s) by the independent central 
reviewer before subject Randomisation, the 
concerned subject will be considered as screen 
failure. Baseline tumour assessment should be done 
after allowed surgical procedure to suspected target 
or non-target lesions (see Sections 4.3. and 5.2.1.).  
5.1.3. Induction 
Treatment Period 
(Cycle 1 to Cycle 6) 
 
• Haematology, biochemistry, and urinalysis (if urine 
dipstick is ≥ 2+, see Section 7.3.2.) – laboratory tests 
may not need to be repeated if tests have been 
performed within 14 days prior to Day 1 of Cycle 1. 
• Haematology, biochemistry, and urinalysis (if urine 
dipstick is ≥ 2+, see Section 7.3.2.) – Repeated 
laboratory tests may not be needed if tests have been 
performed within 14 days prior to Day 1 of Cycle 1. 
To correct typo 
error 
• Serology: HBsAg and HCV-Ab tests will be repeated 
during the course of the study only when clinically 
suspected. 
• Serology: tests for HBV or HCV will be repeated 
during the course of the study only when clinically 
suspected. 
Remove 
specific tests 
• Premedication of IPs and/or Non-IPs (if necessary, see 
Section 6.6.1.) 
• Premedication of IP and/or Non-IPs (if necessary, see 
Section 6.6.1.) 
• Administration of IP and non-IPs on Day 1 of each 
cycle for at least 4 cycles and up to 6 cycles  
Plurality 
• Blood sampling for PK (approximately 50% of enrolled 
subjects) at pre-dose and post-dose (within 15 minutes 
after the end of infusion) of Cycle 1, 3, and 5 
• Blood sampling for PK (approximately 50% of 
enrolled subjects) at pre-dose and post-dose of IP 
(within 15 minutes after the end of infusion) of Cycle 1, 
3, and 5 
Editorial 
change 
In case of early switch to maintenance treatment period, 
subject blood sampling will be collected at Cycle 3 
and/or 5 in the maintenance period, if applicable.  
In case of early switch to maintenance treatment period, 
subject blood sampling will be collected as originally 
planned at Cycle 3 and/or 5, if applicable.  
Easier 
language 
IPs and non-IPs will be administered on Day 1 of each 
cycle for at least 4 cycles and up to 6 cycles 
IPs and non-IPs will be administered on Day 1 of each 
cycle for at least 4 cycles and up to 6 cycles 
Redundant  
5.1.4. Maintenance 
Treatment Period 
• Serology: HBsAg and HCV-Ab tests will be repeated 
during the course of the study only when clinically 
• Serology: tests for HBV or HCV will be repeated 
during the course of the study only when clinically 
Remove 
specific tests 
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suspected. 
suspected. 
• Review of concomitant medication 
• Review of concomitant medication 
• Administration of IP every 3 weeks on Day 1 of 
each cycle 
Clarification 
If a treatment is delayed, concerned laboratory tests will 
be repeated within 3 days before the administration of 
IPs of each cycle. 
If a treatment is delayed, concerned laboratory tests will 
be repeated within 3 days before the administration of 
IPs of each cycle. 
To correct typo 
error 
• Blood sampling for PK (approximately 50% of enrolled 
subjects) at pre-dose and post-dose (within 15 minutes 
after the end of infusion) of Cycle 3, 5, and 7. 
• Blood sampling for PK (approximately 50% of 
enrolled subjects) at pre-dose and post-dose of IP 
(within 15 minutes after the end of infusion) of Cycle 3, 
5, and 7. 
To correct typo 
error 
• Administration of IPs every 3 weeks on Day 1 of each 
cycle  
• Administration of IPs every 3 weeks on Day 1 of 
each cycle 
Editorial 
change 
5.2. Efficacy 
Assessment 
ORR 
best ORR 
According to 
US FDA 
feedback 
• PFS, defined as the time from the date of 
Randomisation to the date of disease progression or 
death regardless of the cause of death. Subjects who are 
not progressed at the time of analysis will be censored at 
the date of the EOT visit. 
• PFS, defined as the time from the date of 
Randomisation to the date of disease progression or 
death regardless of the cause of death. Subjects who are 
not progressed at the time of analysis will be censored at 
the date of the EOT visit or the date of last tumour 
assessment if the EOT visit is not available.  
Clarification of 
PFS 
5.2.1. Measurability 
of Tumour 
All other lesions, including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥ 
10 to < 15 mm short axis) as well as truly non-
measurable lesions 
All other lesions, including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥ 
10 to < 15 mm short axis) as well as truly non-
measurable lesions are non-measurable. 
To correct typo 
error 
5.2.1.2. Criteria for 
Tumour Response 
Evaluation of Measurable Lesions 
Tumour response will be evaluated according to the 
Evaluation of Measurable Lesions 
Tumour response will be evaluated according to the 
To correct typo 
error and 
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Evaluation 
RECIST v1.1 criteria. Subjects should continue to 
undergo tumour response assessment until PD, 
acceptable toxicity, death or end of study. 
In this study, tumour response will be measured using 
CT scan or MRI (other methods such as X-ray, ultra 
sound are not permitted for monitoring target lesions). 
RECIST v1.1 criteria. Subjects should continue to 
undergo tumour response assessment until PD, 
unacceptable toxicity, death or end of study. 
In this study, tumour response will be measured using 
CT scan or MRI (other methods such as X-ray, ultra 
sound are not permitted for monitoring target lesions) 
following Image Acquisition Guideline that will be 
provided by Sponsor. 
clarification 
Table 2 
Target 
lesions 
Non-target 
lesions 
New Lesions 
Overall 
response 
CR 
CR 
No 
CR 
CR 
Non-
CR/Non-PDa 
No 
PR 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-PDa or 
not all 
evaluated 
No 
PR 
SD 
Non-PDa or 
not all 
evaluated 
No 
PR 
Not all 
evaluated 
Non-PDa 
No 
inevaluable 
PD 
Any 
category 
Yes or No 
PD 
Any 
category 
PDa  
Yes or No 
cPD 
Any 
category 
Any 
category 
Yes 
cPD 
 
Target 
lesions 
Non-target 
lesions 
New Lesions 
Overall 
response 
CR 
CR 
No 
CR 
CR 
Non-
CR/Non-
PDa 
No 
PR 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-PDa or 
not all 
evaluated 
No 
PR 
SD 
Non-PDa or 
not all 
evaluated 
No 
PR SD 
Not all 
evaluated 
Non-PDa 
No 
inevaluable 
PD 
Any 
category 
Yes or No 
PD 
Any 
category 
PDa  
Yes or No 
cPD PD 
Any 
category 
Any 
category 
Yes 
cPD PD 
 
To correct typo 
error 
5.2.2. Timing of 
Overall Response 
The overall response is determined once all the data for 
the subject is known. Best response determination in the 
The overall response is determined once all the data for 
the subject is known. For best response determination in 
To correct typo 
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Rate Evaluation: All 
Time Points 
study where confirmation of complete or partial response 
IS NOT required:  
the study, confirmation of complete or partial response 
is NOT required. 
5.3.1. Clinical Safety 
Assessment 
Safety of subjects will be monitored by physical 
examination, performance status and vital sign 
assessment. Subjects will be assessed for AEs at each 
clinical visit and as necessary throughout the study. A 
complete medical history will be performed at 
Screening. 
Safety of subjects will be monitored by physical 
examination, performance status and vital sign 
assessment. Subjects will be assessed for AEs at each 
clinical visit and as necessary throughout the study. A 
complete medical history will be performed at 
Screening. 
Meaningless 
sentence 
5.3.2. Laboratory 
Assessment 
• A coagulation test (PT/INR) will be performed at 
Screening and during the study if clinically suspected. 
• A coagulation test (PT/INR) will be performed at 
Screening and during the study if clinically suspected. 
To correct typo 
error 
• Serology tests (HBsAg and HCV-Ab) will be repeated 
during the course of the study only when clinically 
suspected. 
• Serology tests (HBsAg and HCV-Ab) Tests for HBV 
or HCV will be repeated during the course of the study 
only when clinically suspected. 
Remove 
specific tests 
5.4.1. 
Pharmacokinetic 
Assessments 
Approximately 50% of the enrolled subjects will be 
participating by default in the PK sub-study for PK 
assessment and those subjects will be defined at the time 
of randomisation in the IWR system. Once the number 
of subjects is reached to planned number, all further 
subjects enrolled will not participate the PK sub-study.  
Blood sampling for PK analysis will be performed at 
pre-dose and post-dose (within 15 minutes after the end 
of infusion) of Cycle 1, 3, 5 and 7. 
Approximately 50% of the enrolled subjects will be 
participating by default in the PK sub-study for PK 
assessment and those subjects will be defined at the time 
of randomisation in the IWRS. Once the number of 
subjects is reached to the planned number, all further 
subjects enrolled will not participate in the PK sub-
study.  
Blood sampling for PK analysis will be performed at 
pre-dose and post-dose of IP (within 15 minutes after 
the end of infusion) of Cycle 1, 3, 5 and 7. 
Unify to IWRS 
Table 3 
Table 3. Medications and Therapies of NSCLC 
Prohibited prior to Randomisation and throughout 
the Study 
Table 3. Prohibited Medications and Therapies of 
NSCLC  
Simplification 
Medication or therapies 
Time to be prohibited 
Aspirin or NSAIDs with 
antiplatelet activity 
From Randomisation to 
EOT 
Medication or therapies 
Time to be prohibited 
Aspirin or NSAIDs with 
antiplatelet activity 
From Randomisation 
to EOT 
Clarification of 
time to 
prohibited 
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Anticoagulants or thrombolytic 
agent: 
 
Clopidogrel (> 75 mg/day), 
regular use of aspirin (> 325 
mg/day), dipyridamole, 
ticlopidine and/or cilostazol 
Within 10 days  
prior to Randomisation 
Warfarin, intravenous 
heparin, low molecular 
weight heparin, factor Xa 
inhibitors, thrombin 
inhibitors, thrombolytic 
agents including tissue 
plasminogen activator, 
anistreplase, streptokinase, 
urokinase 
Within 28 days  
prior to Randomisation 
Any drugs (include herbal 
medications) that has not 
received regulatory approval for 
any indications 
From Randomisation to 
EOT 
Anticancer chemotherapy 
regimen other than 
paclitaxel/carboplatina 
From Randomisation to 
EOT 
Major surgical procedure 
(include open lung biopsy)b 
Within 28 days  
prior to Randomisation 
Minor surgical procedurec 
Within 7 days  
prior to Randomisation 
Live/attenuated vaccine 
Within 12 weeks  
prior to Randomisation  
Intravenous bisphosphonates 
and/or invasive dental procedure 
Within 28 days 
prior to Randomisation 
Anticoagulants or thrombolytic 
agent: 
 
Clopidogrel (> 75 mg/day), 
regular use of aspirin (> 325 
mg/day) or NSAID with 
antiplatelet activity, 
dipyridamole, ticlopidine 
and/or cilostazol 
Within 10 days  
prior to Randomisation 
to EOT 
Warfarin, intravenous 
heparin, low molecular 
weight heparin, factor Xa 
inhibitors, thrombin 
inhibitors, thrombolytic 
agents including tissue 
plasminogen activator, 
anistreplase, streptokinase, 
urokinase 
Within 28 days  
prior to Randomisation 
to EOT 
Any drugs (include herbal 
medications) that has not 
received regulatory approval for 
any indications 
From Randomisation to 
EOT 
Anticancer chemotherapy 
regimen other than 
paclitaxel/carboplatina 
From Randomisation to 
EOT 
Major surgical procedure 
(include open lung biopsy)b 
Within 28 days  
prior to Randomisation 
Minor surgical procedurec 
Within 7 days  
prior to Randomisation 
Live/attenuated vaccine 
Within 12 weeks  
prior to Randomisation 
to Cycle 7 Day 1 
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Intravenous bisphosphonates 
and/or invasive dental procedure 
Within 28 days 
prior to Randomisation 
to EOT 
Radiotherapyd 
Within 28 days 
prior to 
Randomisation 
 
a Requiring more extensive procedure than local 
anaesthesia (involving general anaesthesia or respiratory 
assistance or regional anaesthesia) or open lung biopsy. 
b Requiring local anaesthesia or following procedures; 
medianoscopy, percutaneous needle aspiration, core 
biopsy, placement of vascular access device, 
endobronchoscopy ultra sono & transbronchial needle 
aspiration (EBUS & TBNA), pleural biopsy, 
thoracentesis, pleurodesis, catheter insertion/removal, 
tooth extraction, superficial incision. 
a Nab-paclitaxel or other formulation of paclitaxel is 
not allowed in this study. 
ab Requiring more extensive procedure than local 
anaesthesia (involving general anaesthesia or respiratory 
assistance or regional anaesthesia) or open lung biopsy. 
bc Requiring local anaesthesia or following procedures; 
mediastinoscopy, percutaneous needle aspiration, core 
biopsy, placement of vascular access device, 
endobronchoscopy ultra sono & transbronchial needle 
aspiration (EBUS & TBNA), pleural biopsy, 
thoracentesis, pleurodesis, catheter insertion/removal, 
tooth extraction, superficial incision. 
d Radiotherapy of palliative purpose to non-
progressive non-target lesions is allowed during the 
treatment period. If target lesions are included in 
irradiated field, then those lesions should not be 
evaluated as measurable thereafter. It is strongly 
recommended that the Investigator consult to the 
Sponsor at the timing of planning radiotherapy. IP 
and non-IPs should be suspended during 
radiotherapy and may be resumed at the discretion 
of the Investigator. 
Investigator’s 
feedback about 
palliative RT 
during the 
study 
6. TREATMENT 
6.2.6. Unblinding 
7.1.6. Emergency Unblinding for Safety Reasons 
The title of 
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AND 
INVESTIGATION-
AL PRODUCT 
Unblinding should be considered only when knowledge 
of the treatment assignment is deemed essential for the 
subject’s care by their Investigator or a regulatory body. 
In general, unblinding of subjects during the conduct of 
the clinical study is not allowed unless there are 
compelling medical or safety reasons to do so. The 
IWRS will be used to break the blind and details on how 
to do this are provided in the IWRS manual. If the blind 
is broken, it may be broken only for the subject in 
question. The Sponsor must be notified immediately if a 
subject and/or Investigator is unblinded during the 
course of the study along with the reason for breaking 
the blind. Pertinent information regarding the 
circumstances of unblinding of a subject’s treatment 
code must be documented in the subject’s source 
documents. This includes who performed the unblinding, 
the subject(s) affected, the reason for the unblinding, the 
date of the unblinding and the relevant IP information. 
Unblinding should be considered only when knowledge 
of the treatment assignment is deemed essential for the 
subject’s care safety by their Investigator or a 
regulatory body. In general, unblinding of subjects 
during the conduct of the clinical study is not allowed 
unless there are compelling medical or safety reasons to 
do so. The IWRS will be used to break the blind and 
details on how to do this are provided in the IWRS 
manual. If the blind is broken, it may be broken only for 
the subject in question. The Sponsor must be notified 
before or immediately after a subject and/or Investigator 
is unblinded during the course of the study along with 
the reason for breaking the blind. Pertinent information 
regarding the circumstances of unblinding of a subject’s 
treatment code must be documented in the subject’s 
source documents. This includes who performed the 
unblinding, the subject(s) affected, the reason for the 
unblinding, the date of the unblinding and the relevant 
IP information. 
section 6.2.6. is 
changed to 
“Emergency 
Unbliding for 
Safety 
Reasons" and 
the section is 
inserted 
between 
Section 7.1.5. 
and 7.1.6.  
 
6.2.7. Investigational Product Accountability 
6.2.6. Investigational Product Accountability 
Editorial 
change 
6.3.1.1. Preparation 
and Storage of 
Paclitaxel 
Refer to the prescribing information in paclitaxel for the 
formulation, preparation, and storage of paclitaxel. 
Refer to the prescribing information in paclitaxel for the 
formulation, preparation, and storage of paclitaxel. Nab-
paclitaxel or other formulation of paclitaxel is not 
allowed in this study.  
 
6.4.2. Schedule 
Modification of SB8 
or Avastin® 
• Gastointestinal perforations (gastrointestinal 
perforation, fistulae formation in the gastrointestinal 
tract, intra-abdominal abscess), fistulae formation 
involving an internal organ 
• Gastrointestinal perforations (gastrointestinal 
perforation, fistulae formation in the gastrointestinal 
tract, intra-abdominal abscess), fistulae formation 
involving an internal organ 
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Table 6 
 
Non-Haematological AE 
Nausea/vomiting 
Grade 
≥ 3 
1st event 
• 
Maintain the 
same dose. 
2nd 
event 
• 
Reduce dose by 
one level. 
Diarrhea lasting 
> 24 hours  
despite maximum 
anti-diarrheal 
management 
Grade 
≥ 3  
1st event 
• 
Hold until 
recovery to ≤ 
grade 1 or 
baseline.  
• 
Once recovers,  
maintain the 
same dose.  
2nd 
event 
• 
Hold until 
recovery to ≤ 
grade 1 or 
baseline.  
• 
Once recovers,  
reduce dose by 
one level. 
Mucositis 
Grade 
≥ 3  
1st event 
• 
Hold until 
recovery to ≤ 
grade 1 or 
baseline.  
• 
Once recovers,  
maintain the 
same dose.  
2nd 
event 
• 
Hold until 
recovery to ≤ 
grade 1 or 
baseline.  
• 
Once recovers, 
reduce dose by 
one level. 
Non-Haematological AE 
Nausea/vomiting 
Grade 
≥ 3 
1st event 
• 
Maintain the 
same dose. 
2nd event 
• 
Reduce dose by 
one level. 
3rd event 
or later 
• 
Maintain the 
reduced dose 
Diarrhea lasting 
> 24 hours  
despite 
maximum anti-
diarrheal 
management 
Grade 
≥ 3  
1st event 
• 
Hold until 
recovery to ≤ 
grade 1 or 
baseline.  
• 
Once recovers,  
maintain the 
same dose.  
2nd event 
• 
Hold until 
recovery to ≤ 
grade 1 or 
baseline.  
• 
Once recovers,  
reduce dose by 
one level. 
3rd event 
or later 
• 
Hold until 
recovery to ≤ 
grade 1 or 
baseline.  
Once recovers,  
maintain the 
reduced dose. 
Mucositis 
Grade 
≥ 3  
1st event 
• 
Hold until 
recovery to ≤ 
grade 1 or 
baseline.  
• 
Once recovers,  
maintain the 
same dose.  
2nd event 
• 
Hold until 
More 
sophistication 
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recovery to ≤ 
grade 1 or 
baseline.  
• 
Once recovers, 
reduce dose by 
one level. 
3rd event 
or later 
• 
Hold until 
recovery to ≤ 
grade 1 or 
baseline.  
• 
Once recovers,  
maintain the 
reduced dose. 
 
Hepatic 
dysfunction 
Increased 
AST or 
ALT 
Grade ≥ 2  
and  
Increased 
total 
bilirubin 
Grade 1 
• Hold until AST/ALT 
have recovery to ≤ grade 
1 or baseline. 
• Once recovers, 
- Maintain the same dose 
if bilirubin within 
normal limit. 
- If bilirubin is still 
increased to grade 1,  
Paclitaxel: reduce dose 
by one level. 
Carboplatin: maintain 
the same dose. 
Grade ≥ 3 
AST or 
ALT or  
Grade ≥ 2 
total 
bilirubin  
• Hold until AST/ALT and 
bilirubin have returned to 
≤ grade 1 or baseline. 
• Once recover, 
- Paclitaxel: reduce dose 
by one level. 
Carboplatin: maintain 
the same dose. 
 
Biochemistry 
Increased 
AST or 
ALT 
Grade ≥ 2  
and  
Increased 
total 
bilirubin 
Grade 1 
• Hold until 
AST/ALT have recover
y to ≤ grade 1 or 
baseline. 
• Once AST/ALT 
recovers, 
- Maintain the same 
dose if bilirubin 
within normal limit. 
- If bilirubin is still 
increased to grade 1,  
Paclitaxel: reduce 
dose by one level. 
Carboplatin: maintain 
the same dose. 
Grade ≥ 3 
AST or 
ALT or  
Grade ≥ 2 
total 
bilirubin  
• Hold until AST/ALT 
and bilirubin have 
returned recovery to ≤ 
grade 1 or baseline. 
• Once AST/ALT and 
bilirubin recover, 
- Paclitaxel: reduce 
 
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dose by one level. 
Carboplatin: maintain 
the same dose. 
 
6.6. General 
Concomitant 
Medication and 
Supportive Care 
Guidelines 
In addition, any diagnostic, therapeutic or surgical 
procedure performed during the study period (from 
Screening to end of study), must be recorded. 
In addition, any diagnostic, therapeutic or surgical 
procedure performed during the study treatment period 
(from Screening to end of study treatment), must be 
recorded. 
Clarify time 
frame 
6.6.5. Other 
Supportive Care 
Subjects with anemia can be treated according to the 
local practice. Subjects using bisphosphonate therapy for 
their approved labeled indication is not permitted during 
the study (see Section 6.2.5.). 
Subjects with anemia can be treated according to the 
local practice. Subjects using Intravenous 
bisphosphonate therapy for their approved labeled 
indication is not permitted during the study (see Section 
6.2.5.). 
To correct typo 
error 
7. SAFETY 
MONITORING 
AND REPORTING 
7.1.1.2. Clinically 
Significant 
Abnormalities 
Any clinically significant abnormality discovered 
during the laboratory test, physical examination, vital 
signs and/or other safety assessments should be reported 
as an AE.  
If there are any abnormalities discovered during the 
laboratory test, physical examination, vital signs and/or 
other safety assessments should be reported as an AE. 
and the abnormality is assessed clinically significant 
by the Investigator, it should be reported as an AE.  
Broader 
definition of 
AE 
Laboratory Test Abnormalities 
If the Investigator determines a laboratory abnormality 
or out of range result to be clinically significant, it will 
be reported as an AE however, if the laboratory test 
abnormality is consistent with a current diagnosis or pre-
existing conditions, it should be documented accordingly 
and will not be recorded as an AE. 
Vital Signs, Physical Examinations and Other Safety 
Assessments 
If a vital sign result is outside the expected range for the 
subject’s age, gender and race then it should be repeated 
Laboratory Test Abnormalities 
If the Investigator determines a laboratory 
abnormality or out of range result to be clinically 
significant, it will be reported as an AE however, if 
the laboratory test abnormality is consistent with a 
current diagnosis or pre-existing conditions, it should 
be documented accordingly and will not be recorded 
as an AE. 
Vital Signs, Physical Examinations and Other Safety 
Assessments 
If a vital sign result is outside the expected range for 
Simplification 
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after 5 minutes’ rest. If the repeat result is outside the 
expected range and clinically significant then it should 
be reported as an AE.  
Any clinically significant abnormality discovered during 
the physical examination or other safety assessment 
should be reported as an AE. This does not apply to pre-
existing conditions which have been documented at 
Screening. 
the subject’s age, gender and race then it should be 
repeated after 5 minutes’ rest. If the repeat result is 
outside the expected range and clinically significant 
then it should be reported as an AE.  
Any clinically significant abnormality discovered 
during the physical examination or other safety 
assessment should be reported as an AE. This does 
not apply to pre-existing conditions which have been 
documented at Screening. 
7.1.2. Period of 
Observation for 
Adverse Events 
AEs will be recorded from the time the informed 
consent form (ICF) is signed until the EOT visit. During 
the follow-up period after the EOT visit, SAEs that 
are considered to be related to the IP will be 
recorded. 
 
AEs will be reported from the time the informed 
consent form (ICF) is signed until the EOT visit. After 
the EOT visit, only SAEs will be reported. 
 
The Investigator does not need to actively monitor 
subjects for AEs once the clinical study has ended. 
However, SAEs that occurred after the EOS should 
be reported to the Sponsor if the Investigator 
becomes aware of the SAEs. 
Clarification 
about post-
EOT PV rules 
SAEs that are considered to be related to the IP can be 
collected regardless of planned clinical study period. If 
the Investigator detects an SAE in a subject after the 
EOS, and considers the event to be related to the IP, the 
Investigator should contact Sponsor to determine how 
the SAE should be documented and reported. 
SAEs that are considered to be related to the IP can 
be collected regardless of planned clinical study 
period. If the Investigator detects an SAE in a 
subject after the EOS, and considers the event to be 
related to the IP, the Investigator should contact 
Sponsor to determine how the SAE should be 
documented and reported. 
Clarification 
about post-
EOT PV rules 
Unresolved AEs during the study period should be 
followed up until discontinuation of the subject from the 
study (e.g., death, withdrawal of consent, lost to follow-
up), or EOS date, 
Unresolved AEs until the Study EOT should be 
followed up until discontinuation of the subject from the 
study (e.g., death, withdrawal of consent, lost to follow-
up, or initiation of subsequent therapy for NSCLC), 
Clarification 
about post-
EOT PV rules 
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or EOS date, 
 
6.2.6. Unblinding 
Unblinding should be considered only when knowledge 
of the treatment assignment is deemed essential for the 
subject’s care by their Investigator or a regulatory body. 
In general, unblinding of subjects during the conduct of 
the clinical study is not allowed unless there are 
compelling medical or safety reasons to do so. The 
IWRS will be used to break the blind and details on how 
to do this are provided in the IWRS manual. If the blind 
is broken, it may be broken only for the subject in 
question. The Sponsor must be notified immediately if a 
subject and/or Investigator is unblinded during the 
course of the study along with the reason for breaking 
the blind. Pertinent information regarding the 
circumstances of unblinding of a subject’s treatment 
code must be documented in the subject’s source 
documents. This includes who performed the unblinding, 
the subject(s) affected, the reason for the unblinding, the 
date of the unblinding and the relevant IP information. 
7.1.6. Emergency Unblinding for Safety Reasons 
Unblinding should be considered only when knowledge 
of the treatment assignment is deemed essential for the 
subject’s care safety by their Investigator or a 
regulatory body. In general, unblinding of subjects 
during the conduct of the clinical study is not allowed 
unless there are compelling medical or safety reasons to 
do so. The IWRS will be used to break the blind and 
details on how to do this are provided in the IWRS 
manual. If the blind is broken, it may be broken only for 
the subject in question. The Sponsor must be notified 
before or immediately after a subject and/or the 
Investigator is unblinded during the course of the study 
along with the reason for breaking the blind. Pertinent 
information regarding the circumstances of unblinding 
of a subject’s treatment code must be documented in the 
subject’s source documents. This includes who 
performed the unblinding, the subject(s) affected, the 
reason for the unblinding, the date of the unblinding and 
the relevant IP information. 
The title of 
section 6.2.6. is 
changed to 
“Emergency 
Unbliding for 
Safety 
Reasons" and 
the section is 
migrated to 
between 
Section 7.1.5. 
and 7.1.6.  
 
7.1.6. Expectedness Assessment 
7.1.7. Expectedness Assessment 
Editorial 
change 
 
7.1.7. Withdrawal Due to Adverse Events 
Subject withdrawal from the study due to an AE should 
be distinguished from withdrawal due to personal 
reasons. Subjects withdrawn due to an AE should be 
followed up until the time point specified in the protocol. 
Subjects who discontinue the administration of IPs 
7.1.8. Withdrawal Due to Adverse Events 
Subject withdrawal from the study due to an AE should 
be distinguished from withdrawal due to personal 
reasons. Subjects withdrawn due to an AE should be 
followed up until the time point specified in the 
protocol. When a subject withdraws from the study 
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because of serious or significant safety issues should 
be followed closely until the AEs are resolved or 
stabilised. 
When a subject withdraws from the study due to an 
SAE, the SAE must be reported in accordance with 
the requirements outlined in Section 7.2.2. 
due to an SAE, the SAE must be reported and 
followed in accordance with the requirements 
outlined in Section 7.2.2.  
Subjects who discontinue the administration of IPs 
because of serious or significant safety issues should 
be followed closely until the events are fully and 
permanently resolved or stabilised. 
7.2.2. Reporting 
Serious Adverse 
Event 
SAEs must be immediately reported at least within 24 h 
of the Investigator becoming aware of the event to 
Sponsor or its designated representative using the SAE 
report form provided by the Sponsor.  
SAEs before EOT visit must be immediately reported 
at least within 24 h of the Investigator becoming aware 
of the event to Sponsor or its designated representative 
using the SAE report form in the eCRF. provided by 
the Sponsor. SAEs that occurred after the EOT visit 
must be reported at least within 24 h of the 
Investigator becoming aware of the event to Sponsor 
or its designated representative using the paper SAE 
report form. Contact information for SAE reporting 
will be provided in SAE Report Completion 
Instruction. 
Clarification to 
report SAE 
 
The Investigator is obligated to pursue and provide 
information to Sponsor on all SAEs in accordance with 
the timeframes for reporting specified above. In addition, 
an Investigator may be requested by Sponsor to obtain 
specific additional follow-up information in an expedited 
fashion. This information may be more detailed than that 
captured.  
The Investigator is obligated to pursue and provide 
information to Sponsor on all SAEs in accordance with 
the timeframes for reporting specified above. In 
addition, an Investigator may be requested by Sponsor 
to obtain specific additional follow-up information in an 
expedited fashion. This information may be more 
detailed than that captured in the SAE report form. 
Clarification to 
report SAE 
7.3.2. Proteinuria 
If subject is discovered to have ≥ 2+ proteinuria on urine 
dipstick (or other ways of urinalysis) and demonstrate 24 
hours urine protein excretion < 1 g or protein/creatinine 
ratio in spot urine < 1 g/g creatinine (or < 226.0 
If subject is discovered to have ≥ 2+ proteinuria on 
urine dipstick (or other ways of urinalysis) and 
demonstrate 24 hours urine protein excretion ≥ 1 g or 
protein/creatinine ratio in spot urine ≥ 1 g/g creatinine 
To correct typo 
error  
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mg/mmol creatinine), should be classified as AESI. 
(or ≥ 226.0 mg/mmol creatinine), should be classified as 
AESI. 
7.4. Pregnancy 
Although pregnancy is not an AE, all pregnancies must 
be followed up every 2 months until 6-8 weeks after the 
outcome of the pregnancy becomes available, unless the 
subject is lost to follow-up. 
Although pregnancy is not an AE, all pregnancies must 
be followed up every 2 months until 6-8 weeks after 
the outcome of the pregnancy becomes available, unless 
the subject is lost to follow-up. 
More feasible 
to conduct 
8. STATISTICAL 
CONSIDERATION 
AND 
ANALYTICAL 
PLAN 
8.1. Analysis Sets 
• Full analysis set (FAS): FAS will consist of all 
randomised subjects. The subjects will be analysed based 
on the treatment they were randomised to. 
• Full analysis set (FAS): FAS will consist of all 
randomised subjects. The subjects will be analysed 
based on the treatment they were randomised to by 
intention-to-treat principle. However, subjects who 
do not qualify for randomisation and are 
inadvertently randomised into the study will be 
excluded from FAS, provided these subjects do not 
receive any IP during the study. 
According to 
US FDA 
feedback 
• Per-protocol set (PPS): PPS will consists of all FAS 
subjects who complete at least two cycles of 
combination chemotherapy with a tumour assessment 
and do not have any major protocol deviations that 
impact the primary efficacy assessment. The PPS will be 
the primary efficacy analysis set. 
• Per-protocol set (PPS): PPS will consists consist of all 
FAS subjects who complete at least two cycles of 
combination chemotherapy with a tumour assessment 
and do not have any major protocol deviations that 
impact the primary efficacy assessment. The PPS will 
be the primary efficacy analysis set. 
Editorial 
change 
8.2.2.1. Primary 
Efficacy Analysis 
The primary efficacy endpoint is the ORR by 24 weeks 
of chemotherapy. The ORR is defined as the proportion 
of subjects whose best overall response is either CR or 
PR according to RECIST v1.1 during the induction 
treatment period. If a subject has either CR or PR at least 
once during the induction treatment period, the subject 
will be considered as the responder. Tumour assessment 
will be performed after IP administration of Cycle 2, 4, 
and 6, and before planned Day 1 of Cycle 3, 5, and 7 and 
The primary efficacy endpoint is the best ORR by 24 
weeks of chemotherapy. The best ORR is defined as the 
proportion of subjects whose best overall response is 
either CR or PR according to RECIST v1.1 during the 
induction treatment period. If a subject has either CR or 
PR at least once during the induction treatment period, 
the subject will be considered as the responder. Tumour 
assessment will be performed after IP administration of 
Cycle 2, 4, and 6, and before planned Day 1 of Cycle 3, 
According to 
US FDA 
feedback 
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will be performed every 4 cycles according to RECIST 
v1.1 and assessed by both investigators and independent 
central reviewer. The primary efficacy analysis will be 
based on the data from the independent central review. 
The primary efficacy analysis will aim to demonstrate 
equivalence in the ORR between SB8 and Avastin® in 
the PPS. The null hypothesis tested for the primary 
efficacy analysis will be either (1) SB8 is inferior to 
Avastin® or (2) SB8 is superior to Avastin® based on a 
pre-specified equivalence margin. 
For US Food and Drug Administration submission, the 
primary efficacy analysis will be performed for the 
response ratio (SB8 response rate/ Avastin® response 
rate), and the equivalence will be declared if the 90% 
C.I. is contained within the proposed equivalence 
margin of [0.742, 1.450]. 
For EMA submission, the primary efficacy analysis will 
be performed for the difference in the ORR, and the 
equivalence between the two treatment groups will be 
declared if the 95% confidence interval (CI) is entirely 
contained within the pre-justified equivalence margin of 
[-12.5%, 12.5%].  
The analysis method in detail will be described in the 
SAP, and the SAP will be finalised prior to the first 
database lock. 
The same analysis planned for the primary efficacy 
analysis will be repeated for the FAS to explore the 
robustness of the results. In this analysis, subjects 
who withdraw early without any tumour assessment 
5, and 7 and will be performed every 4 cycles according 
to RECIST v1.1. Tumour size will be assessed by both 
investigators and independent central reviewer. The 
primary efficacy analysis will be based on the data from 
the independent central review. 
The primary efficacy analysis will aim to demonstrate 
equivalence in the best ORR between SB8 and 
Avastin® in the PPS. The null hypothesis tested for the 
primary efficacy analysis will be either (1) SB8 is 
inferior to Avastin® or (2) SB8 is superior to Avastin® 
based on a pre-specified pre-defined equivalence 
margin. 
For US Food and Drug Administration submission, the 
primary efficacy analysis will be performed in the FAS 
for the ratio of best ORR by 24 weeks (best ORR of 
SB8/ best ORR of Avastin®), and the equivalence will 
be declared if the 90% confidence interval(CI) of the 
best ORR ratio is contained within the pre-defined 
equivalence margin of [0.737, 1.357]. The similar 
analysis will be performed for the PPS to support the 
primary analysis. 
For EMA submission, the primary efficacy analysis will 
be performed in the PPS for the difference in the best 
ORR by 24 weeks, and the equivalence between the two 
treatment groups will be declared if the 95% confidence 
interval (CI) CI of the difference is entirely contained 
within the pre-justified pre-defined equivalence 
margin of [-12.5%, 12.5%].  
The similar analysis will be performed for the FAS to 
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will be considered as non-responders. 
support the primary analysis. 
The statistical method to get the CI for primary 
analysis will be described in the Statistical Analysis 
Plan (SAP), and the SAP will be finalised prior to the 
first database lock. 
8.2.2.2. Secondary 
Efficacy Analyses 
The secondary efficacy endpoints are as following: 
• Progression free survival (PFS): PFS is defined as the 
time from the date of Randomisation to the date of 
disease progression or death regardless of the cause of 
death. Subjects who are not progressed at the time of 
analysis will be censored at the date of the EOT visit. 
• Overall Survival (OS): OS is defined as the time from 
the date of Randomisation to the date of death regardless 
of the cause of death. Subjects who are alive at the time 
of analysis will be censored at the date of last known 
alive. 
• Duration of response (DOR): DOR is defined as the 
time from documented tumour response (CR or PR) until 
documented disease progression. Only the subjects who 
have the tumour response will be included in the 
analysis. 
The secondary efficacy endpoints will be analyzed using 
Cox proportional hazard model stratified by ECOG 
performance status, gender and region (pooled centres) 
for PPS and FAS 
The secondary efficacy endpoints of PFS, OS and 
DOR will be analysed for PPS and FAS and 
described in the SAP. are as following: 
• Progression free survival (PFS): PFS is defined as 
the time from the date of Randomisation to the date 
of disease progression or death regardless of the 
cause of death. Subjects who are not progressed at 
the time of analysis will be censored at the date of the 
EOT visit. 
• Overall Survival (OS): OS is defined as the time 
from the date of Randomisation to the date of death 
regardless of the cause of death. Subjects who are 
alive at the time of analysis will be censored at the 
date of last known alive. 
• Duration of response (DOR): DOR is defined as the 
time from documented tumour response (CR or PR) 
until documented disease progression. Only the 
subjects who have the tumour response will be 
included in the analysis. 
The secondary efficacy endpoints will be analyzed 
using Cox proportional hazard model stratified by 
ECOG performance status, gender and region 
(pooled centres) for PPS and FAS 
According to 
US FDA 
feedback 
8.2.2.3. Exploratory 
The exploratory efficacy endpoint is the tumour response The exploratory efficacy endpoint is the best ORR by 11 According to 
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Efficacy Analysis 
rate by 11 and 17 weeks.  
The tumour response rate will be computed by the 
number of subjects with either CR or PR by each 
timepoint divided by the total number of patients in the 
analysis population. 
The tumour response rate will be analyzed for PPS and 
FAS.  
and 17 weeks and will be analysed with the similar 
manner of the primary endpoint analysis.  
The tumour response rate will be computed by the 
number of subjects with either CR or PR by each 
timepoint divided by the total number of patients in 
the analysis population. 
The tumour response rate will be analyzed for PPS 
and FAS. 
US FDA 
feedback 
8.2.3. Safety 
 
All reported terms for AEs will be coded using the 
Medical Dictionary for Regulatory Activities 
(MEDDRA). No statistical testing will be performed for 
AEs. 
All reported terms for AEs will be coded using the 
Medical Dictionary for Regulatory Activities 
(MEDDRA) MedDRA. No statistical testing will be 
performed for AEs. 
Follow the 
official name 
Changes in vital signs and clinical laboratory 
measurements will be summarised descriptively by 
treatment group and visit. Other safety variables (e.g., 
infusion reaction) will be summarised and listed. 
Changes in vital signs and clinical laboratory 
measurements will be summarised descriptively by 
treatment group and visit. Other safety variables (e.g., 
infusion reaction) will be summarised and listed. 
Editorial 
change 
8.2.5. 
Immunogenicity 
The incidence of anti-rug antibodies and neutralising 
antibodies will be summarised by treatment group and 
visit for SAF 
The incidence of anti-drug antibodies and neutralising 
antibodies will be summarised by treatment group 
and visit cycle for SAF 
To correct typo 
error 
8.3. Determination 
of Sample Size 
For the calculation of the equivalence margin, AVAiL 
[Reck, 2010] and E4599 [Sandler, 2006] studies of 
Avastin® + cisplatin/gemcitabine (CG) vs. CG alone 
and of Avastin® + paclitaxel/carboplatin vs. 
paclitaxel/carboplatin alone, respectively, were 
considered. In AVAiL study, ORR rates were 21.6% 
and 37.8% for placebo and Avastin® + CG groups, 
respectively. In E4599 study, ORR rates were 15.1% 
(out of 392) and 34.9% (out of 381) for placebo and 
Avastin® + paclitaxel/carboplatin groups, 
For the calculation of the equivalence margin, a 
meta-analysis published by Botrel et al. using all of 
the four published comparative trials that evaluated 
bevacizumab in combination with chemotherapy (i.e. 
E4599 [Sandler, 2006], AVAiL (BO17704) [Reck, 
2009], AVF0757 [Johnson, 2004], JO19907 [Niho, 
2012]) was considered.  
The overall ratio of best ORR and the 70% CI from 
above four studies are calculated to be 
 
using the fixed effect method from 
According to 
US FDA 
feedback, more 
references are 
cited 
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respectively. 
The overall ratio of ORR and its 95% CI from these 
two studies are calculated to be 2.0217 [1.6943, 
2.4124] using the fixed effect method from meta-
analysis. The equivalence margin of [0.742 1.450] will 
preserve 50% of the effect of Avastin® over the 
placebo in the lower margin. 
The overall difference in ORR and its 80% CI from 
these two studies are calculated to be 
% 
[
%, 
%] using the fixed-effect method from 
meta-analysis. The equivalence margin of  
[-12.5%, 12.5%] will preserve at least 20% of the 
effect of Avastin® over the placebo in the difference of 
ORR.  
With 305 completers in each treatment group, the 
two-sided 90% CI of the ORR ratio is expected to lie 
within [0.742, 1.450] with 90% power, and the two-
sided 95% CI of the ORR difference between 
Avastin® and SB8 is expected to lie within [-12.5%, 
12.5%] with 80% power when the expected ORR is 
assumed to be 35%. Assuming a 10% drop-out rate, a 
total of 678 subjects (339 subjects per treatment 
group) will be randomised. 
meta-analysis. Retaining the 
% of the effect of 
Avastin® over the placebo in the lower margin, the 
equivalence margin of [0.737, 1.357] will be used for 
the primary analysis with the ratio of the best ORR 
by 24 weeks. 
For the primary analysis with the difference of the 
best ORR by 24 weeks, the equivalence margin of [-
12.5%, 12.5%] will be used due to the similar 
derivation. 
With 305 completers in each treatment group, the 
two-sided 90% CI of the best ORR ratio is expected 
to lie within [0.737, 1.357] with approximately 80% 
power, and the two-sided 95% CI of the best ORR 
difference between Avastin® and SB8 is expected to 
lie within [-12.5%, 12.5%] with 80% power when the 
expected best ORR is assumed to be 35%. Assuming 
a 10% drop-out rate, a total of 678 subjects (339 
subjects per treatment group) will be randomised. 
8.4. Statistical 
Analysis Timepoints 
8.4. Interim Analysis  
The primary endpoint will be assessed after the last 
subject completes the Induction treatment period. 
Available efficacy and safety data (a full set of the 
Induction treatment period data including available 
data in the maintenance treatment period from a 
8.4. Statistical Analysis Timepoints 
Safety endpoint will be assessed for DSMB review 
during the course of the study. Interim safety results 
will be evaluated by the DSMB, which will be 
independent of the study conduct. Details will be 
described in the DSMB charter. 
The title of 
section 8.4. is 
changed and 
all the 
statement is 
changed 
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subset of subjects, i.e., those subjects enrolled early) 
will also be analysed and reported. A final CSR will 
be reported once the full set of the maintenance 
treatment period is obtained. 
Interim analyses for DSMB review will be performed 
during the course of the study. Interim results will be 
evaluated by the DSMB, which will be independent of 
the study conduct. Details will be described in the 
DSMB charter. 
Subjects, Investigators, independent central 
reviewers and other study personnel will remain 
blinded throughout the entire treatment period. After 
the last subject completes the induction treatment 
period, or its corresponding visit, a limited number of 
prospectively identified individuals of the Sponsor 
will be unblinded. A formal analysis of the primary 
efficacy data will then be undertaken. 
The primary endpoint will be assessed when at least 
24 weeks has elapsed since the last subject is 
randomised. Available efficacy and safety data (a full 
set of the Induction treatment period data including 
available data in the maintenance treatment period 
from a subset of subjects, i.e., those subjects enrolled 
early) will also be analysed and reported.  
A final CSR will be reported once the full set of the 
maintenance treatment period is obtained, e.g. after 
EOS. 
After at least 24 weeks from the last subject 
randomised, or its corresponding date, a limited 
number of individuals of the Sponsor will be 
unblinded. A formal analysis of the primary efficacy 
data will then be undertaken. Subjects, Investigators, 
independent central reviewers and other study 
personnel will remain blinded throughout the entire 
treatment period. 
9. DATA 
COLLECTION 
AND 
MANAGEMENT 
9.1. Data 
Confidentiality 
Care will be taken to prevent subjects being identified 
through these publications. In addition, data may be 
shared with other companies or researchers to aid further 
research into breast cancer.  
Care will be taken to prevent subjects being identified 
through these publications. In addition, data may be 
shared with other companies or researchers to aid 
further research into breast cancer lung cancer. 
To correct typo 
error 
9.4. Database 
Management and 
Coding 
Medical/surgical history and underlying diseases and 
AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MEDDRA).  
Medical/surgical history and underlying diseases and 
AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MEDDRA)(MedDRA).  
To correct typo 
error 
10. ETHICAL 
CONSIDERATIONS 
10.4.5. Financing and Insurance 
A copy of the insurance details will be provided to each 
10.4.5. Financing and Insurance 
A copy of The insurance details will be provided to each 
Some countries 
do not mandate 
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AND 
ADMINISTRATIVE 
PROCEDURES 
10.4. Investigator 
Information 
Investigator who will be responsible for providing the 
IRB/IEC with these details according to local 
requirements. 
Investigator who will be responsible for providing the 
IRB/IEC with these details according to local 
requirements. 
submission of 
Insurance 
documents 
13. REFERENCES 
Avastin® Summary of Product Characteristics 
(EMEA/H/C/000582 -II/0072). EMEA. (May 27, 
2015). Retrieved Aug 07, 2015 
from http://www.ema.europa.eu/docs/en_GB/document_librar
y/EPAR_-
_Product_Information/human/000582/WC500029271.pdf. 
 
Avastin® Summary of Product Characteristics 
(EMEA/H/C/000582 -II/0082). EMEA (Oct 29, 2015). 
Retrieved on Nov 04, 2015 
from http://www.ema.europa.eu/docs/en_GB/document_library/
EPAR_-
_Product_Information/human/000582/WC500029271.pdf 
Botrel TEA, Clark O, Clark L, et al. Efficacy of 
bevacizumab (Bev) plus chemotherapy (CT) 
compared to CT alone in previously untreated locally 
advanced or metastatic non-small cell lung cancer 
(NSCLC): Systematic review and meta-analysis. 
Lung Cancer. 2011; 74:89-97 
Johnson DH, Fehrenbacher L, Novotny WF, et al. 
Randomized Phase II Trial Comparing Bevacizumab 
Plus Carboplatin and Paclitaxel With Carboplatin 
and Paclitaxel Alone in Previously Untreated Locally 
Advanced or Metastatic Non–Small-Cell Lung 
Cancer. J Clin Oncol. 2004 Jun 1; 22: 2184-2191. 
Niho S, Kunitoh H, Nokihara H, et al. Randomized 
phase II study of first-line carboplatin-paclitaxel 
with or without bevacizumab in Japanese patients 
with advanced non-squamous non-small-cell lung 
Updated 
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cancer. Lung Cancer. 2012; 362-367 
APPENDIX 1: 
ECOG 
PERFORMANCE 
STATUS 
Referece: 
Reference: 
To correct typo 
error 
APPENDIX 2: 
LUNG CANCER 
STAGING 
 
T1a 
Tumour 2 cm or less in greatest dimension 
 
T1b 
Tumour more than 2 cm but 3 cm or less in 
greatest dimension 
 
 
T1a 
Tumour 2 cm or less in greatest dimension 
 
T2b 
T1b 
Tumour more than 2 cm but 3 cm or less in 
greatest dimension 
 
To correct typo 
error 
APPENDIX 4: 
WORLD HEALTH 
ORGANIZATION 
HISTOLOGICAL 
CLASSIFICAION 
OF TUMOURS OF 
THE LUNG 
Epithelioid hemangioendothelioma 
Epithelioid haemangioendothelioma 
To correct typo 
error 
 
 
 
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AMENDMENT 2: Aug 18, 2016 
Section Affected 
Original Content 
Amended/New Content 
Rationale 
Synopsis-Eligibility 
Criteria 
Inclusion criteria 
3. Histologically and/or cytologically confirmed 
metastatic (TNM stage IV) or recurrent adenocarcinoma 
of the lung or large cell carcinoma of the lung or 
NSCLC-not otherwise specified (NOS). 
3. Histologically and/or cytologically confirmed 
metastatic (AJCC 7th edition TNM stage IV) or 
recurrent adenocarcinoma of the lung or large cell 
carcinoma of the lung non-squamous NSCLC or 
NSCLC-not otherwise specified (NOS). 
Clarification 
7. b Urine dipstick for proteinuria of less than 2+ (other 
ways of urinalysis are also acceptable); if urine dipstick 
is ≥ 2+, 24 hours urine protein excretion is < 1 g or 
protein/creatinine ratio in spot urine is < 1 g/g creatinine 
(or < 226.0 mg/mmol creatinine). 
7. b Urine dipstick for proteinuria of less than 2+ (other 
ways of urinalysis are also acceptable); if urine dipstick 
is ≥ 2+, 24 hours urine protein excretion is should be < 
1 g or protein/creatinine ratio in spot urine is should be 
< 1 g/g creatinine (or < 226.0 mg/mmol creatinine). 
Grammatical 
change 
8. Subjects and their partners of childbearing potential 
(female or male) who agree to use at least two forms of 
appropriate contraception (e.g., established use of oral, 
injected or implanted hormonal contraceptive, placement 
of an intrauterine device or intrauterine system, physical 
barrier, male sterilisation or true abstinence) from 
Screening until 6 months after the last administration of 
investigational product (IP). A pregnancy test result is 
required for all women of childbearing potential 
including women who had menopause onset within 2 
years prior to Randomisation. True abstinence will be 
considered sufficient for subjects who do not have a 
partner. 
8. Subjects and their partners of childbearing potential 
(female or male) including those with history of 
elective sterilisation (e.g. fallopian tube ligation) who 
agree to use at least two forms of appropriate 
contraception (e.g., established use of oral, injected or 
implanted hormonal contraceptive, placement of an 
intrauterine device or intrauterine system, physical 
barrier, male sterilisation or true abstinence) from 
Screening until 6 months after the last administration of 
investigational product (IP). A pregnancy test result is 
required for all women of childbearing potential 
including women who had menopause onset within 2 
years prior to Randomisation. True abstinence will be 
considered sufficient for subjects who do not have a 
German 
agency’s 
comments. 
“some patients 
may decide to 
reverse elective 
sterilisation” 
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partner. 
Synopsis-Eligibility 
Criteria 
Exclusion criteria 
1. Diagnosis of small cell carcinoma of the lung or 
squamous cell carcinoma of the lung (mixed tumour 
should be categorised according to predominant 
histology). 
1. Diagnosis of small cell carcinoma of the lung or 
squamous cell carcinoma of the lung. For mixed 
tumour with the component of squamous cell 
carcinoma, it should be categorised according to 
predominant histology. Any component of small cell 
carcinoma of the lung is to be excluded. 
Clarification 
on mixed 
histology.  
4. History of systemic chemotherapy administered in the 
first-line setting for metastatic or recurrent disease of 
NSCLC. 
4. History of systemic chemotherapy anti-cancer 
therapy administered in the first-line setting for 
metastatic or recurrent disease of NSCLC. 
Change to 
include 
chemotherapy, 
immunotherap
y, targeted 
agents, etc.  
5. Neoadjuvant or adjuvant chemotherapy for 
administered for NSCLC and completed less than 12 
months prior to Randomisation. 
5. Any systemic anti-cancer therapy including 
neoadjuvant or adjuvant chemotherapy for administered 
for NSCLC and completed less than 12 months prior to 
Randomisation. 
Clarification to 
exclude any 
history of anti-
cancer therapy 
within 12 
months from 
randomisation 
7. Radiotherapy within 28 days prior to Randomisation 
(tumour lesions situated in a previously irradiated area, 
or in an area subjected to other loco-regional therapy are 
not considered as measurable lesion unless there has 
been demonstrated progression in the lesion.). 
7. Radiotherapy within 28 14 days prior to 
Randomisation (tumour lesions situated in a previously 
irradiated area, or in an area subjected to other loco-
regional therapy are not considered as measurable lesion 
unless there has been demonstrated progression in the 
Change made 
to reduce delay 
in systemic 
therapy 
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lesion.). 
8. Major surgical procedure within 28 days prior to 
Randomisation (requiring more extensive procedure than 
local anaesthesia [involving general anaesthesia or 
respiratory assistance or regional anaesthesia] or open 
lung biopsy). 
8. Major surgical procedure within 28 days prior to 
Randomisation (e.g., requiring more extensive 
procedure than local anaesthesia [involving general 
anaesthesia or respiratory assistance or regional 
anaesthesia] or open lung biopsy) or expected major 
surgical procedure during the study. 
Additional 
clarification 
Synopsis-Eligibility 
Criteria 
Exclusion criteria 
11. Symptomatic brain metastasis and/or leptomeningeal 
disease. 
11. Symptomatic brain metastasis and/or 
leptomeningeal disease. Baseline brain imaging is 
strongly recommended to evaluate for presence of 
brain metastases. If brain metastases are found, they 
can be treated according to local practice at the 
discretion of investigator. Treatment options for 
brain metastases may include whole brain radiation, 
radiosurgery, craniotomy, etc. as deemed medically 
appropriate by the investigator. Subjects should 
have no neurologic symptoms off corticosteroids for 
at least 1 day to ensure that subjects do not have 
symptomatic brain metastasis. If subjects initially 
developed symptomatic brain metastases that 
resolved after treatment, they could be considered 
‘asymptomatic’ and eligible for the study if they 
have no residual neurological dysfunction off 
corticosteroids for at least 1 day. 
Additional 
clarification.  
Off-steroid 
requirements to 
determine 
asymptomatic 
brain mets  
12. Previous malignancy other than NSCLC in the last 5 
years except for locally curable cancers that have been 
12. Previous malignancy other than NSCLC in the last 5 
years except for locally curable cancers that have been 
Better 
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complete response and need no subsequent therapy, such 
as basal or squamous cell cancer of the skin, carcinoma 
in situ of the cervix or breast, or superficial bladder 
cancer. 
in complete response remission and need no 
subsequent therapy, such as basal or squamous cell 
cancer of the skin, carcinoma in situ of the cervix or 
breast, or superficial bladder cancer. 
15. Subjects treated with anticoagulant therapy within 10 
days prior to Randomisation  
(e.g., clopidogrel [> 75 mg/day], regular use of aspirin, 
dipyridamole, ticlopidine and/or cilostazol); 
anticoagulant therapy within 28 days prior to 
Randomisation (e.g., with warfarin, intravenous heparin, 
low molecular weight heparin, factor Xa inhibitors, 
thrombin inhibitor, and thrombolytic agent including 
tissue plasminogen activator, anistreplase, streptokinase, 
urokinase). 
15. Subjects treated with anticoagulant therapy within 
10 days prior to Randomisation  
(e.g., clopidogrel [≥ 75 mg/day], regular use of aspirin, 
dipyridamole, ticlopidine and/or cilostazol); 
anticoagulant therapy within 28 days prior to 
Randomisation (e.g., with warfarin, intravenous heparin, 
low molecular weight heparin, factor Xa inhibitors, 
thrombin inhibitor, and thrombolytic agent including 
tissue plasminogen activator, anistreplase, streptokinase, 
urokinase). 
A typo error 
Synopsis-Eligibility 
Criteria 
Exclusion criteria 
18. h. Gastrointestinal bleeding, haematemesis or 
haemoptysis (≥ 1/2 teaspoon of red blood). 
18. h. Gastrointestinal bleeding, haematemesis or 
haemoptysis (≥ 1/2 teaspoon of red blood) or any other 
major bleeding events. 
Additional 
clarification 
20. Serologically confirmed active or chronic hepatitis B 
or hepatitis C 
20. Serologically confirmed active or chronic hepatitis 
B or hepatitis C (asymptomatic inactive carriers are 
allowed at investigator’s discretion per local 
standards) 
Additional 
clarification to 
allow 
asymptomatic 
hepatitis carrier 
29. Currently enrolled in another clinical study. 
29. Currently enrolled in another interventional clinical 
study. 
Additional 
clarification 
Synopsis-Planned 
Subjects will be followed for survival status and whether 
Subjects will be followed for survival status and 
Additional 
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Study Period 
subsequent therapy is received or not by clinic visit or 
telephone contact every 3 months until withdrawal of 
consent or death or 12 months from Randomisation of 
the last subject. 
whether subsequent systemic anti-cancer therapy is 
received or not by clinic visit or telephone contact every 
3 months until withdrawal of consent or death or 12 
months from Randomisation of the last subject. 
Clarification 
Synopsis-Statistical  
Methods 
Analysis set 
 
Randomised set (RAN) will consist of all subjects 
who receive a randomisation number at the 
Randomisation. 
Clarification 
Synopsis-Statistical  
Methods 
Efficacy analysis 
For US FDA submission, the primary efficacy analysis 
for demonstrating the equivalence of SB8 to 
Avastin® will be done for the ratio of the best ORR (best 
ORR of SB8/best ORR of Avastin®) by 24 weeks in the 
FAS. 
For US FDA submission or other regulatory agency 
submissions for those who are in favour of risk ratio, 
the primary efficacy analysis for demonstrating the 
equivalence of SB8 to Avastin® will be done for the 
ratio of the best ORR (best ORR of SB8/best ORR of 
Avastin®) by 24 weeks in the FAS. 
Submission to 
different 
agencies 
For EMA submission, the primary efficacy analysis will 
be performed for the difference in best ORR by 24 
weeks between SB8 and Avastin® in the PPS, and the 
equivalence will be declared if the two-sided 95% CI of 
the best ORR difference in contained within the pre-
defined equivalence margin of [-12.5%, 12.5%]. The 
Similar analysis will be performed for the FAS to 
support the primary efficacy. 
For EMA submission, MFDS or other regulatory 
agency submissions for those who are in favour of 
risk difference, the primary efficacy analysis will be 
performed for the difference in of the best ORR (best 
ORR of SB8 – best ORR of Avastin®) by 24 weeks 
between SB8 and Avastin® in the PPS, and the 
equivalence will be declared if the two-sided 95% CI of 
the best ORR difference in is contained within the pre-
defined equivalence margin of [-12.5%, 12.5%]. The 
Similarsimilar analysis will be performed for the FAS to 
support the primary efficacy result. 
Submission to 
different 
agencies 
Clarification 
Synopsis-Statistical  
Methods 
For the calculation of the equivalence margin, a meta-
analysis published by Botrel et al. using all of the four 
For Regarding the calculation of the equivalence 
margin for the ratio of the best ORR by 24 weeks, a 
Editorial 
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Sample size 
calculation 
published comparative trials that evaluated bevacizumab 
in combination with chemotherapy (i.e. E4599 [Sandler, 
2006], AVAiL (BO17704) [Reck, 2009], AVF0757 
[Johnson, 2004], JO19907 [Niho, 2012]) was considered. 
meta-analysis published by Botrel et al. using all of the 
four published comparative trials that evaluated 
bevacizumab in combination with chemotherapy (i.e. 
E4599 [Sandler, 2006], AVAiL (BO17704) [Reck, 
2009], AVF0757 [Johnson, 2004], JO19907 [Niho, 
2012]) was considered. 
change 
Synopsis-Figure 1 
 
 
Increase 
screening 
period to 42 
days to allow 
some study-
required 
procedures 
 
5EOT is defined as discontinuation of treatment due to 
disease progression, unacceptable toxicity, death, or last 
administration of IP before end of study. After 
completion of study treatment, subjects will be followed 
for survival status and whether subsequent therapy is 
received or not by clinic visit or telephone contact every 
3 months until withdrawal of consent, death, or 12 
months from Randomisation of the last subject. EOT 
visit will be performed at least 21 days after last IP 
administration and prior to subsequent therapy. 
5EOT is defined as discontinuation of treatment due to 
disease progression, unacceptable toxicity, death, or last 
administration of IP before end of study. EOT visit will 
be performed at least 21 days after last IP 
administration and prior to subsequent 
therapy. After completion of study 
treatment,Subjects will be followed for survival status 
and whether subsequent systemic anti-cancer therapy 
is received or not by clinic visit or telephone contact 
every 3 months until from EOT until discontinuation 
of the subject from the study (e.g., death, withdrawal 
of consent, death, lost to follow-up or initiation of 
subsequent therapy for NSCLC) or EOS date, 
Additional 
clarification 
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defined as when deaths of all the randomised 
subjects have been observed. or 12 months from 
Randomisation of the last subject. EOT visit will be 
performed at least 21 days after last IP 
administration and prior to subsequent therapy. 
whichever occurs first 
Table 1 
 
 
Increase 
screening 
period to 42 
days to allow 
some study-
required 
procedures 
7. Blood coagulation test including international 
normalised ratio (INR) will be performed at Screening. 
Additional blood coagulation test will be performed at 
the discretion of Investigator if there are any suspicious 
cases. 
7. Blood coagulation test, including international 
normalised ratio (INR) will be performed at Screening. 
Additional blood coagulation test will be performed at 
the discretion of Investigator if there are any suspicious 
cases. 
Additional 
clarification 
10. Haematology, biochemistry, urinalysis may not need 
to be repeated on Day 1 of Cycle 1 if the tests have been 
performed within 14 days prior to administration of IPs. 
10. Haematology, biochemistry and urinalysis need to 
be completed within 28 days prior to Randomisation. 
They may not need to be repeated on Day 1 of Cycle 1 
if the tests have been performed within 14 days prior to 
Additional 
clarification 
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administration of IPs. 
13. Tumour assessments should be performed at 
Screening (within a maximum 21 days prior to 
Randomisation) and after IP administration of Cycle 2, 4, 
and 6, and before planned Day 1 of Cycle 3, 5, and 7 and 
then will be performed every 4 cycles until disease 
progression, unacceptable toxicity, death, or end of 
study. At least one measurable lesion should be 
confirmed. If the case baseline tumour assessment is not 
performed within 21 days prior to Randomisation, it 
should be repeated. Tumour response will be assessed 
using CT or MRI following Image Acquisition Guideline 
that will be provided by Sponsor. The same modality 
used at Screening will be used throughout the study.  
13. Tumour assessments should be performed at 
Screening (within a maximum of 21 days prior to 
Randomisation) and after IP administration of Cycle 2, 
4, and 6, and before planned Day 1 of Cycle 3, 5, and 7 
and then will be performed every 4 cycles until disease 
progression, unacceptable toxicity, death, or end of 
study. If tumour assessment was already performed 
according to the schedule but next IP administration 
needs to be delayed due to any reasons, tumour 
assessment does not need to be repeated. At least one 
measurable lesion should be confirmed prior to 
Randomisation. If the case baseline tumour 
assessment is was not performed within 21 days prior to 
Randomisation, it should be repeated. Tumour response 
will be assessed using CT or MRI following Image 
Acquisition Guideline that will be provided by Sponsor. 
The same modality used at Screening will be used 
throughout the study. 
Additional 
clarification 
 
14. All screening procedures must be completed and 
reviewed within 42 days prior to Randomisation. All 
eligibility criteria must be reviewed and confirmed 
prior to Rrandomisation 
Additional 
clarification 
25. After completion of study treatment, subjects will be 
followed for survival status and whether subsequent 
therapy is received or not by clinic visit or telephone 
25. 26. After completion of study treatment, Subjects 
will be followed for survival status and whether 
subsequent systemic anti-cancer therapy is received or 
Additional 
clarification 
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contact every 3 months until discontinuation of the 
subject from the study (e.g., death, withdrawal of 
consent, lost to follow-up, or initiation of subsequent 
therapy for NSCLC), EOS date defined as when deaths 
of all the randomised subjects have been observed, or 12 
months from randomisation of the last subject, 
whichever occurs first 
not by clinic visit or telephone contact every 3 months 
from EOT until discontinuation of the subject from the 
study (e.g., death, withdrawal of consent, lost to follow-
up, or initiation of subsequent therapy for NSCLC) or 
EOS date, defined as when deaths of all the randomised 
subjects have been observed, or 12 months from 
randomisation of the last subject, whichever occurs first. 
List of Abbreviations  
AJCC American Joint Committee on Cancer 
CCr Creatinine Clearance 
DOR Duration of Response 
MFDS Ministry of Food and Drug Safety 
Addition of 
abbreviations 
List of Study Staff 
Clinical Research Physician 
 
Medical Write  
 
Statistician 
 
Project Safety Lead 
 
Clinical Research Physician 
 
 
Medical Writer  
 
  
Statistician 
 
 
Project Safety Lead  
 
Change in 
personnel 
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4. STUDY 
POPULATION 
4.2. Inclusion 
Criteria 
3.Histologically and/or cytologically confirmed 
metastatic (TNM stage IV) or recurrent adenocarcinoma 
of the lung or large cell carcinoma of the lung or 
NSCLC-not otherwise specified (NOS). 
3.Histologically and/or cytologically confirmed 
metastatic (AJCC 7th edition TNM stage IV) or 
recurrent adenocarcinoma of the lung or large cell 
carcinoma of the lung non-squamous NSCLC or 
NSCLC-not otherwise specified (NOS). 
Additional 
clarification 
7.b. Urine dipstick for proteinuria of less than 2+ (other 
ways of urinalysis are also acceptable); if urine dipstick 
is ≥ 2+, 24 hours urine protein excretion is < 1 g or 
protein/creatinine ratio in spot urine is < 1 g/g creatinine 
(or < 226.0 mg/mmol creatinine). 
7. b Urine dipstick for proteinuria of less than 2+ (other 
ways of urinalysis are also acceptable); if urine dipstick 
is ≥ 2+, 24 hours urine protein excretion is should be < 
1 g or protein/creatinine ratio in spot urine is should be 
< 1 g/g creatinine (or < 226.0 mg/mmol creatinine). 
Grammatical 
8. Subjects and their partners of childbearing potential 
(female or male) who agree to use at least two forms of 
appropriate contraception (e.g., established use of oral, 
injected or implanted hormonal contraceptive, placement 
of an intrauterine device or intrauterine system, physical 
barrier, male sterilisation or true abstinence) from 
Screening until 6 months after the last administration of 
IP. A pregnancy test result is required for all women of 
childbearing potential including women who had 
menopause onset within 2 years prior to Randomisation. 
True abstinence will be considered sufficient for subjects 
who do not have a partner. 
8. Subjects and their partners of childbearing potential 
(female or male) including those with history of 
elective sterilisation (e.g. fallopian tube ligation) who 
agree to use at least two forms of appropriate 
contraception (e.g., established use of oral, injected or 
implanted hormonal contraceptive, placement of an 
intrauterine device or intrauterine system, physical 
barrier, male sterilisation or true abstinence) from 
Screening until 6 months after the last administration of 
investigational product (IP). A pregnancy test result is 
required for all women of childbearing potential 
including women who had menopause onset within 2 
years prior to Randomisation. True abstinence will be 
considered sufficient for subjects who do not have a 
German 
agency’s 
comments. 
“some patients 
may decide to 
reverse elective 
sterilisation” 
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partner. 
4.3. Exclusion 
Criteria 
 
1.Diagnosis of small cell carcinoma of the lung or 
squamous cell carcinoma of the lung (mixed tumour 
should be categorised according to predominant 
histology). 
1. Diagnosis of small cell carcinoma of the lung or 
squamous cell carcinoma of the lung. For mixed 
tumour with the component of squamous cell 
carcinoma, it should be categorised according to 
predominant histology. Any component of small cell 
carcinoma of the lung is to be excluded. 
Clarification 
on mixed 
histology.  
4.History of systemic chemotherapy for metastatic 
administered in the first-line setting or recurrent disease 
of NSCLC. 
4.History of systemic chemotherapy for 
metastatic anti-cancer therapy administered in the 
first-line setting for metastatic or recurrent disease of 
NSCLC. 
Change to 
include 
chemotherapy, 
immunotherap
y, targeted 
agents, etc.  
5.Neoadjuvant or adjuvant chemotherapy administered 
for NSCLC and completed less than 12 months prior to 
Randomisation. 
5. Any systemic anti-cancer therapy including 
neoadjuvant or adjuvant chemotherapy for administered 
for NSCLC and completed less than 12 months prior to 
Randomisation. 
Clarification to 
exclude any 
history of anti-
cancer therapy 
within 12 
months from 
randomisation 
7.Radiotherapy within 28 days prior to Randomisation 
(tumour lesions situated in a previously irradiated area, 
or in an area subjected to other loco-regional therapy are 
not considered as measurable lesion unless there has 
been demonstrated progression in the lesion.). 
7. Radiotherapy within 28 14 days prior to 
Randomisation (tumour lesions situated in a previously 
irradiated area, or in an area subjected to other loco-
regional therapy are not considered as measurable lesion 
unless there has been demonstrated progression in the 
Change made 
to reduce delay 
in systemic 
therapy 
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lesion.). 
4.3. Exclusion 
Criteria 
 
8. Major surgical procedure within 28 days prior to 
Randomisation (requiring more extensive procedure than 
local anaesthesia [involving general anaesthesia or 
respiratory assistance or regional anaesthesia] or open 
lung biopsy) 
8. Major surgical procedure within 28 days prior to 
Randomisation (e.g., requiring more extensive 
procedure than local anaesthesia [involving general 
anaesthesia or respiratory assistance or regional 
anaesthesia] or open lung biopsy) or expected major 
surgical procedure during the study. 
Additional 
clarification 
11.Symptomatic brain metastasis and/or leptomeningeal 
disease. 
11. Symptomatic brain metastasis and/or 
leptomeningeal disease. Baseline brain imaging is 
strongly recommended to evaluate for presence of 
brain metastases. If brain metastases are found, they 
can be treated according to local practice at the 
discretion of investigator. Treatment options for 
brain metastases may include whole brain radiation, 
radiosurgery, craniotomy, etc. as deemed medically 
appropriate by the investigator. Subjects should 
have no neurologic symptoms off corticosteroids for 
at least 1 day to ensure that subjects do not have 
symptomatic brain metastasis. If subjects initially 
developed symptomatic brain metastases that 
resolved after treatment, they could be considered 
‘asymptomatic’ and eligible for the study if they 
have no residual neurological dysfunction off 
corticosteroids for at least 1 day. 
Additional 
clarification.  
Off-steroid 
requirements to 
determine 
asymptomatic 
brain mets  
12. Previous malignancy other than NSCLC in the last 5 
years except for locally curable cancers that have been 
12. Previous malignancy other than NSCLC in the last 5 
years except for locally curable cancers that have been 
Better 
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complete response and need no subsequent therapy, such 
as basal or squamous cell cancer of the skin, carcinoma 
in situ of the cervix or breast, or superficial bladder 
cancer. 
in complete response remission and need no 
subsequent therapy, such as basal or squamous cell 
cancer of the skin, carcinoma in situ of the cervix or 
breast, or superficial bladder cancer. 
4.3. Exclusion 
Criteria 
 
15. Subjects treated with anticoagulant therapy within 10 
days prior to Randomisation  
(e.g., clopidogrel [> 75 mg/day], regular use of aspirin, 
dipyridamole, ticlopidine and/or cilostazol); 
anticoagulant therapy within 28 days prior to 
Randomisation (e.g., with warfarin, intravenous heparin, 
low molecular weight heparin, factor Xa inhibitors, 
thrombin inhibitor, and thrombolytic agent including 
tissue plasminogen activator, anistreplase, streptokinase, 
urokinase). 
15. Subjects treated with anticoagulant therapy within 
10 days prior to Randomisation  
(e.g., clopidogrel [≥ 75 mg/day], regular use of aspirin, 
dipyridamole, ticlopidine and/or cilostazol); 
anticoagulant therapy within 28 days prior to 
Randomisation (e.g., with warfarin, intravenous heparin, 
low molecular weight heparin, factor Xa inhibitors, 
thrombin inhibitor, and thrombolytic agent including 
tissue plasminogen activator, anistreplase, streptokinase, 
urokinase). 
A typo error 
18. h. Gastrointestinal bleeding, haematemesis or 
haemoptysis (≥ 1/2 teaspoon of red blood). 
18. h. Gastrointestinal bleeding, haematemesis or 
haemoptysis (≥ 1/2 teaspoon of red blood) or any other 
major bleeding events. 
Additional 
clarification 
20. Serologically confirmed active or chronic hepatitis B 
or hepatitis C 
20. Serologically confirmed active or chronic hepatitis 
B or hepatitis C (asymptomatic inactive carriers are 
allowed at investigator’s discretion per local 
standards). 
Additional 
clarification to 
allow 
asymptomatic 
hepatitis carrier 
29. Currently enrolled in another clinical study. 
29. Currently enrolled in another interventional clinical 
study. 
Additional 
clarification 
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4.4 Subject 
Withdrawal 
 
• 
AEs requiring permanent discontinuation of IP (see 
Section 6.4.2) 
• 
Unblinding (except unblinding for the purpose of 
regulatory reporting) 
Additional 
guidelines 
 
All the subjects who withdraw alive from the study will 
be asked to return to the Investigational site for the EOT 
visit procedures to be performed (see Section 5.1.5.) and 
to have a follow-up telephone contact or clinic visit. 
All the subjects who withdraw alive from the study will 
be asked to return to the Investigational site for the EOT 
visit procedures to be performed (see Section 5.1.5.) and 
to have a follow-up telephone contact or clinic visit. 
Grammatical 
5. STUDY 
PROCEDURES 
AND 
ASSESSMENT 
5.1. Procedures by 
Study Period 
5.1.1. Screening 
Period 
Screening should be performed within 28 days before 
Randomisation. All subjects must provide written 
informed consent prior to any study related procedures 
being performed.  
Screening should be performed within 28 42 days 
before Randomisation. All subjects must provide written 
informed consent prior to any study related procedures 
being performed. 
Increase 
screening 
period to 42 
days to allow 
some study-
required 
procedures 
The following procedures and assessments should be 
performed within 28 days before Randomisation. 
The following procedures and assessments should be 
performed within 28 42 days before Randomisation. 
Retesting or re-evaluation is allowed within the 
screening period, but the latest assessment will be 
used to determine the eligibility. Re-screening or re-
consenting after 42 day screening period has elapsed 
is not allowed.  
Increase 
screening 
period to 42 
days to allow 
some study-
required 
procedures 
 
• 
Review of previous or concomitant medication 
(within 28 days prior to informed consent; within 12 
weeks in case of vaccines) 
• 
Review of previous or concomitant medication 
(within 28 days prior to informed consent; within 
12 weeks prior to informed consent in case of 
vaccines) 
Grammatical/C
larification 
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• 
Haematology, biochemistry, urinalysis, and serology 
(retesting is allowed within the Screening period 
within 28 days prior to Randomisation.) 
(…) 
- 
Blood coagulation test including international 
normalised ratio (INR) 
(…) 
- 
Urinalysis (dipstick): leukocytes, nitrite, 
urobilinogen, protein, pH, Hb, specific gravity, 
ketone, bilirubin, glucose (other ways of 
urinalysis are also allowed), if urine dipstick is ≥ 
2+, 24 hours urine protein excretion is < 1 g or 
protein/creatinine ratio in spot urine is < 1 g/g 
creatinine (or < 226.0 mg/mmol creatinine)  
 
• 
Haematology, biochemistry, urinalysis, and 
serology (retesting is allowed during the Screening 
period). Haematology, biochemistry and 
urinalysis need to be completed within 28 days 
before Randomisation. 
(…) 
- 
Blood coagulation test: including international 
normalised ratio (INR). If there is significant 
deviation in the value (i.e., INR > 1.5), it is 
highly recommended that the investigator 
determine the cause (i.e., warfarin – which 
would be excluded) and reversibility. If the 
Investigator determines that the subject is at 
a high risk of bleeding as a result of 
abnormal INR, subject should be excluded 
according to section 4.3 (exclusion criterion 
14).  
(…) 
- 
Urinalysis (dipstick): leukocytes, nitrite, 
urobilinogen, protein, pH, Hb, specific gravity, 
ketone, bilirubin, glucose (other ways of 
urinalysis are also allowed), if urine dipstick is 
≥ 2+, 24 hours urine protein excretion is should 
be < 1 g or protein/creatinine ratio in spot 
urine is should be < 1 g/g creatinine (or < 
226.0 mg/mmol creatinine)  
(…) 
- 
If other laboratory tests not listed above are 
checked by local practice and found to be 
abnormal, it is recommended that 
Investigator use the best clinical judgement 
to determine if the abnormal values would 
Clarification 
on timing of 
laboratory tests 
Additional 
guidelines on 
INR value and 
other 
laboratory tests 
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affect patient safety while participating in 
the study. 
5.1.2. Randomisation If the subject meets all the criteria of eligibility and signs 
off the ICF, the Investigator should check the whole 
eligibility criteria of the subjects prior to Randomisation. 
If the subject meets all the criteria of eligibility and 
signs off the ICF, the Investigator should check the 
whole eligibility criteria of the subjects prior to 
Randomisation. 
Grammatical/ 
Simpler 
5.1.2.2. Stratification 
Factors 
• 
Age: < 70 vs. ≥ 70 
• 
Age at randomisation: < 70 vs. ≥ 70 
Clarification 
5.1.3. Induction 
Treatment Period 
(Cycle 1 to Cycle 6) 
• 
Imaging tumour assessment of target and non-target 
lesion by CT scan or MRI will be performed after IP 
administration of Cycle 2, 4, and 6 and before 
planned Day 1 of Cycle 3, 5, and 7 (upper 
abdominal cavity including the adrenal glands must 
be included in imaging study.). 
• 
Imaging tumour assessment of target and non-target 
lesion by CT scan or MRI will be performed after 
IP administration of Cycle 2, 4, and 6 and before 
planned Day 1 of Cycle 3, 5, and 7 (upper 
abdominal cavity including the adrenal glands must 
be included in imaging study.). Tumour 
assessment does not need to be repeated if IP is 
delayed due to any reasons. 
Additional 
clarification 
5.1.6. Follow-up 
Period 
After completion of study treatment, subjects will be 
followed for survival status and whether subsequent 
therapy is received or not by clinic visit or telephone 
contact every 3 months (± 7 days) until discontinuation 
of the subject from the study (e.g., death, withdrawal of 
consent, lost to follow-up) or EOS date, defined as when 
deaths of all the randomised subjects have been 
observed, or 12 months from Randomisation of the last 
subject, whichever occurs first. 
SAEs that are considered to be related to the IP should 
After completion of study treatment, Subjects will be 
followed for survival status and whether subsequent 
therapy is received or not by clinic visit or telephone 
contact every 3 months (± 7 days) from EOT until 
discontinuation of the subject from the study (e.g., 
death, withdrawal of consent, lost to follow-up or 
initiation of subsequent therapy for NSCLC) or EOS 
date, defined as when deaths of all the randomised 
subjects have been observed, or 12 months from 
Randomisation of the last subject, whichever occurs 
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continue to be reported to Sponsor during the follow-up 
period. 
first. 
SAEs that are considered to be related to the IP 
should will continue to be reported to Sponsor during 
the follow-up period. (see Section 7.2.2) 
 
5.2.1.1. Definition of 
Target and Non-
target Lesions 
During the baseline assessment before IP 
administrations, all lesions detected in the lung are 
classified as either target lesions or non-target lesions on 
CT/MRI scan 
During the baseline assessment before IP 
administrations, all lesions detected in the lung are 
classified as either target lesions or non-target lesions on 
CT/MRI scan 
• 
Target lesions: All measurable lesions up to a 
maximum of 2 lesions per organ and 5 lesions 
total, representative of all involved organs 
should be identified as target lesions and 
recorded at baseline. Target lesions should be 
selected based on their size and their suitability 
for accurate repeated measurements by 
imagaing.  
• 
Non-target lesions: All other lesions including 
small lesions and other non-measurable lesions 
should be identified as non-target lesions and 
should be recorded at baseline. Measurements of 
these lesions are not required, but the presence 
or absence of each should be noted throughout 
follow up.  
For detailed instructions, please refer to Completion 
Guide for Tumour Assessment Worksheet.  
Added more 
details 
5.2.1.2. Criteria for 
The use of oral and IV contrast, etc., should be consistent The use of oral and IV contrast, etc., should be 
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Tumour Response 
Evaluation 
unless contraindication exists. Tumour evaluations 
should be made by the same Investigator or radiologist 
for each subject during the study, if possible.  
Baseline total tumour burden must be assessed no more 
than 21 days prior to Randomisation. If the case baseline 
tumour assessment is not performed within 21 days prior 
to Randomisation, it should be repeated. Baseline tumour 
assessment will include the adrenal glands and the entire 
liver. If case of contrast contraindication, MRI will be 
performed. Additional PET-scan, or bone scan will be 
performed at the discretion of the Investigator (optional), 
if there are symptoms or clinical suspicion of distant 
metastasis. 
Tumour lesions situated in a previously irradiated area, 
or in an area subjected to other loco-regional therapy, are 
not considered measurable unless there has been 
demonstrated progression in the lesion 
consistent is highly recommended and should be 
used consistently unless contraindication exists. 
Tumour evaluations should be made by the same 
Investigator or radiologist for each subject during the 
study, if possible.  
Baseline total tumour burden must be assessed no more 
than 21 days prior to Randomisation. If the case 
baseline tumour assessment is not performed within 21 
days prior to Randomisation, it should be repeated. 
Baseline tumour assessment will include the adrenal 
glands and the entire liver. If In case of contrast 
contraindication, MRI will or non-contrast CT scans 
can be performed. Additional PET-scan, or bone scan 
will be performed at the discretion of the Investigator 
(optional), if there are symptoms or clinical suspicion of 
distant metastasis. 
Tumour lesions situated in a previously irradiated area, 
or in an area subjected to other loco-regional therapy, 
are not considered measurable unless there has been 
demonstrated progression in the lesion. 
For baseline brain imaging, MRI with contrast is 
preferred but CT scan with IV contrast is acceptable 
if MRI cannot be obtained (Ex. pacemaker, 
unavailable MRI facility, etc). If brain metastases are 
found but not treated (asymptomatic), they could be 
potentially listed as target and/or non-target lesions 
at discretion of investigators. However, all target 
on imaging 
modality 
Clarification 
on imaging for 
brain 
metastases 
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and/or non-target lesions should be followed using 
the same imaging modality throughout the study. 
If brain metastases are found and treated, those 
should be listed as “non-target” lesions for tumour 
response evaluation according to RECIST 1.1. If 
brain mets are treated and patients are 
asymptomatic, follow -up brain imaging is not 
required unless clinically suspected. 
6.2.4.1. Preparation 
and Administration 
of SB8 or Avastin® 
• 
Volume (mL) = dose amount (mg) ÷ concentration 
of bevacizumab (mg/mL) 
• 
Volume (mL) = 
dose amount (mg) 
concentration of bevacizumab (mg/mL) 
Graphical  
6.2.5. Prohibited 
Concomitant 
Medications or 
Therapies 
Medication and therapies are prohibited prior to 
Randomisation and throughout the study are presented in 
Table 3. 
Medication and therapies that are prohibited prior to 
Randomisation and/or throughout the study are 
presented in Table 3. 
Grammar 
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Table 3 
 
 
Allowing 
certain 
anticoagulants 
at discretion of 
Investigator 
 
a Nab-paclitaxel or other formulation of paclitaxel is not 
allowed in this study. 
b Requiring more extensive procedure than local 
anaesthesia (involving general anaesthesia or respiratory 
assistance or regional anaesthesia) or open lung biopsy. 
c Requiring local anaesthesia or following procedures; 
mediastinoscopy, percutaneous needle aspiration, core 
biopsy, placement of vascular access device, 
a After randomisation, low dose aspirin < 325mg 
daily is allowed if medically indicated (cardiac 
prophylaxis, etc.) and there is no bleeding diathesis 
that would increase the risk of therapy at the 
discretion of Investigator. 
bNon-chronic use of NSAIDS (not including aspirin) 
for symptom management are permitted if there is 
no bleeding diathesis that would increase the risk of 
 
 
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endobronchoscopy ultra sono & transbronchial needle 
aspiration (EBUS & TBNA), pleural biopsy, 
thoracentesis, pleurodesis, catheter insertion/removal, 
tooth extraction, superficial incision. 
d Radiotherapy of palliative purpose to non-progressive 
non-target lesions is allowed during the treatment period. 
If target lesions are included in irradiated field, then 
those lesions should not be evaluated as measurable 
thereafter. It is strongly recommended that the 
Investigator consult to the Sponsor at the timing of 
planning radiotherapy. IP and non-IPs should be 
suspended during radiotherapy and may be resumed at 
the discretion of the Investigator. 
therapy at the discretion of Investigator. 
cAfter randomisation, therapeutic anticoagulation 
(heparin, warfarin, etc.) is allowed if medically 
indicated in case of new thromboembolic events (i.e., 
deep venous thrombosis) at the discretion of 
Investigator. Refer to section 6.4.2 Table 4 for 
specific guidelines. Non-systemic use of 
anticoagulants (ex. heparin flush) to maintain 
patency of intravenous injection devices is allowed 
d Nab-paclitaxel or other formulation of paclitaxel is not 
allowed in this study. 
e Requiring more extensive procedure than local 
anaesthesia (involving general anaesthesia or respiratory 
assistance or regional anaesthesia) or open lung biopsy. 
f Requiring local anaesthesia or following procedures; 
mediastinoscopy, percutaneous needle aspiration, core 
biopsy, placement of vascular access device, 
endobronchoscopy ultra sono & transbronchial needle 
aspiration (EBUS & TBNA), pleural biopsy, 
thoracentesis, pleurodesis, catheter insertion/removal, 
tooth extraction, superficial incision. 
g Radiotherapy of palliative purpose to non-progressive 
non-target lesions is allowed during the treatment 
period. If target lesions are included in irradiated field, 
then those lesions should not be evaluated as 
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measurable thereafter. It is strongly recommended that 
the Investigator consult to the Sponsor at the timing of 
planning radiotherapy. IP and non-IPs should be 
suspended during radiotherapy and may be resumed at 
the discretion of the Investigator. 
6.3.1.2. Dose and 
Schedule of 
Paclitaxel 
Paclitaxel will be administered as IV infusion over 3 
hours after the completion of SB8 or Avastin® 
administration. Dose and schedule modification for 
toxicity are permitted (see Section 6.4.). 
Paclitaxel will be administered as IV infusion over 
approximately 3 hours after the completion of SB8 or 
Avastin® administration. Dose and schedule 
modification for toxicity are permitted (see 
Section 6.4.). 
Clarification 
6.3.2.2. Dose and 
Schedule of 
Carboplatin 
Carboplatin will be administered as IV infusion over 30 
minutes (± 10) after the completion of paclitaxel. Dose 
modification and delays for toxicity are permitted (see 
Section 6.4.). 
Carboplatin will be administered as IV infusion over 
approximately 30 minutes (± 10) after the completion 
of paclitaxel. Dose modification and delays for toxicity 
are permitted (see Section 6.4.). 
Clarification 
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6.3.2.2. Dose and 
Schedule of 
Carboplatin 
Calvert formula = target AUC × (CCr + 25) mg/day 
CCr must be calculated prior to every dosage of 
carboplatin based on below the formula (Cockcroft-
Gault equation): 
CCr = ([140 – Age[y]] × body weight)/(72 × serum 
creatinine [mg/dL]) × 0.85 (if women) 
 
• 
Carboplatin dose (mg) = target AUC × (CCr + 
25) mg/day 
CCr must be calculated prior to every dosage of 
carboplatin based on using below the formula 
(Cockcroft-Gault equation) and it should NOT exceed 
125 ml/min: 
 
Male: 
𝐂𝐂𝐂=
(𝟏𝟏𝟏−𝐀𝐀𝐀[𝐲]) × 𝐛𝐛𝐛𝐛 𝐰𝐰𝐰𝐰𝐰𝐰 [𝐤𝐤]
𝟕𝟕× 𝐬𝐬𝐬𝐬𝐬 𝐜𝐜𝐜𝐜𝐜𝐜𝐜𝐜𝐜𝐜[𝐦𝐦𝐝𝐝
⁄
]  
Female: 
𝐂𝐂𝐂 =
(𝟏𝟏𝟏−𝑨𝑨𝑨[𝒚]) × 𝒃𝒃𝒃𝒃 𝒘𝒘𝒘𝒘𝒘𝒘 [𝒌𝒌]
𝟕𝟕× 𝒔𝒔𝒔𝒔𝒔 𝒄𝒄𝒄𝒄𝒄𝒄𝒄𝒄𝒄𝒄[𝒎𝒎𝒅𝒅
⁄
]
 × 𝟎. 𝟖𝟖 
 
Typo 
CCr cap based 
on US FDA 
recommenda-
tion 
6.4.1. General 
Consideration 
1. Dose modifications must be based on the dose level 
changes in Table 5 and Table 6 and not in other ways. 
(…) 
5. Subjects may only be re-treated if all related toxicities 
have resolved to baseline or ≤ grade 1. 
1. Dose modifications must be based on the dose level 
changes in Table 5 and Table 6 and not in other ways 
(…) 
5. Subjects may only be re-treated if all related toxicities 
have resolved to baseline or ≤ grade 1 at the discretion 
of Investigator. 
Clarification 
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6.4.2. Schedule 
Modification of SB8 
or Avastin® 
Table 4 
 
 
Additional 
details on IP 
schedule 
modification  
Allowing 
anticoagulation 
for certain 
thrombo-
embolic events 
 
AE = adverse event; ALT = alanine aminotransferase; 
AST = aspartate aminotransferase 
a NCI-CTCAE v4.03 will be used (see APPENDIX 3). 
CVA=cerebrovascular accident; TIA=transient 
ischemic attack; MI=myocardial infarction; 
CNS=central nervous system; ALT= alanine 
aminotransferase; AST = aspartate aminotransferase; AE 
= adverse event 
a NCI-CTCAE v4.03 will be used (see APPENDIX 3) 
b Other clinically significant AEs will be determined 
 
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at the discretion of Investigator 
6.4.2. Schedule 
Modification of SB8 
or Avastin® 
In any subject who experienced one of the events listed 
below, the Investigator should consider to discontinue 
administration of IP permanently, according to the 
approved label of Avastin®: 
(...) 
• 
Severe arterial thromboembolic events (grade ≥ 3) 
• 
Life-threatening (grade 4) venous thromboembolic 
events, including pulmonary embolism 
• 
Grade 4 hypertension (hypertensive crisis or 
hypertensive encephalopathy) 
• 
Nephrotic syndrome (grade ≥ 3 proteinuria or ≥ 3.5 
g/24 h) 
• 
Posterior Reversible Encephalopathy Syndrome 
(PRES) 
In any subject who experienced one of the events 
listed below, The investigator should consider 
to discontinue administration of IP 
permanently, according to the approved label of 
Avastin® and remove subjects from the study if 
experiencing one of the events specified below: 
(...) 
• 
Severe Arterial thromboembolic events (grade ≥ 3 
any grade) 
• 
Life-threatening (grade 4) venous thromboembolic 
events, including pulmonary embolism 
• 
Grade 4 hypertension (hypertensive crisis or 
hypertensive encephalopathy) 
• 
Grade 4 congestive heart failure (left ventricular 
systolic dysfunction) 
• 
Nephrotic syndrome (grade ≥ 3 proteinuria or ≥ 3.5 
g/24 h) 
• 
Posterior Reversible Encephalopathy Syndrome 
(PRES)  
• 
If the investigator determines that situations not 
listed above but could jeopardise safety of 
subjects with continuation of IP, IP should be 
permanently discontinued. 
Change to 
mandate 
discontinuation 
of IP in case of 
certain serious 
events.  
6.4.3.1. Paclitaxel 
and Carboplatin 
All dose modifications for paclitaxel and carboplatin are 
based on the dose level changes in Table 5. A stepwise 
dose reduction is permitted. If a reduction to dose level 3 
All dose modifications for paclitaxel and carboplatin are 
based on the dose level changes in Table 5. A stepwise 
dose reduction is permitted. If a reduction to dose level -
Additional 
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is required then subjects must be discontinued from 
paclitaxel and carboplatin treatment. If paclitaxel and 
carboplatin are discontinued due to toxicity, continuation 
of SB8 or Avastin® as monotherapy is allowed at the 
discretion of Investigator. 
3 is required then subjects must be discontinued from 
paclitaxel and/or carboplatin treatment. If more than 
one AE requiring dose-reduction is found (e.g. Grade 
4 neutrophil count decreased and Grade 3 platelet 
count decreased) during the same evaluation period, 
one dose level reduction is indicated according to 
Table 6. If both paclitaxel and carboplatin are 
discontinued due to toxicity, continuation of SB8 or 
Avastin® as monotherapy is allowed at the discretion of 
Investigator. 
Table 5 
 
Change to 
conventional 
terms.  
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Table 6 
 
Clarification to 
allow G-CSF 
Clarification 
on Grade 3 
platelets count 
decreased 
Change in dose 
reduction for 
neurotoxicity 
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Table 6 
 
 
Table 6 
AE = adverse event; ANC = absolute neutrophil count; 
AST = aspartate aminotransferase; ALT = alanine 
transaminase; NCI-CTCAE = national cancer institute 
common terminology criteria for adverse events 
a NCI-CTCAE v4.03 will be used (see APPENDIX 3). 
AE = adverse event; ANC = absolute neutrophil count; 
AST = aspartate aminotransferase; ALT = alanine 
transaminase; G-CSF= Granulocyte Colony-stimulating 
Factor; NCI-CTCAE = national cancer institute 
common terminology criteria for adverse events 
a NCI-CTCAE v4.03 will be used (see APPENDIX 3) 
b Other clinically significant AEs will be determined 
at the discretion of Investigator 
Additional 
clarifications 
6.6.3. Granulocyte 
Colony-stimulating 
Factor (G-CSF) Use  
Therapeutic or secondary prophylactic use of G-CSF 
may be given at the discretion of Investigator and should 
follow NCCN Guidelines of Myeloid Growth Factors 
Version 1, 2015. In subjects with risk factor developing 
Therapeutic or secondary prophylactic use of G-CSF 
may be given at the discretion of Investigator 
and should follow recommend following NCCN 
Guidelines of Myeloid Growth Factors Version 1, 2015. 
Clarification to 
allow general 
use of G-CSF  
NCCN is a 
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febrile neutropenia (sepsis syndrome, aged ≥ 65, severe 
neutropenia [ANC < 0.1 × 109/L], neutropenia expected 
to be more than 10 days in duration, pneumonia, invasive 
fungal infection, other clinically documented infections, 
hospitalisation at the time of fever, prior episode of 
febrile neutropenia) prophylaxis with G-GSF will be 
permitted. 
In subjects with risk factors for developing febrile 
neutropenia (sepsis syndrome, aged ≥ 65, severe 
neutropenia [ANC < 0.1 × 109/L], neutropenia expected 
to be more than 10 days in duration, pneumonia, 
invasive fungal infection, other clinically documented 
infections, hospitalisation at the time of fever, prior 
episode of febrile neutropenia) prophylaxis with G-GSF 
CSF will be permitted. 
guide that 
continuously 
gets updated.  
6.6.4. Antibiotics 
Use 
At the discretion of Investigator, antibiotics may be 
administered according to NCCN Guidelines of Cancer-
related Infections Version 2, 2015 or ASCO Guidelines 
[Flowers, 2013] in febrile neutropenia cases. 
At the discretion of Investigator, antibiotics may be 
administered according to NCCN Guidelines of Cancer-
related Infections Version 2, 2015 or ASCO 
Guidelines [Flowers, 2013] in febrile neutropenia cases. 
These 
guidelines 
continue to get 
updated.  
6.6.5. Other 
Supportive Care 
Subjects with anemia can be treated according to the 
local practice. Intravenous bisphosphonate therapy for 
their approved labeled indication is not permitted during 
the study (see Section 6.2.5.). 
Subjects with anemia can be treated according to the 
local practice. Intravenous bisphosphonate therapy for 
their approved labeled indication is not permitted 
during the study if clinically indicated (e.g., bone 
metastases for NSCLC) (see Section 6.2.5.). 
Allow IV 
bisphosphonate 
therapy if 
clinically 
indicated 
7.1.1.2. Clinically 
Significant 
Abnormalities 
If the clinically significant laboratory or other 
abnormality from safety assessment is not a sign of a 
disease or syndrome, the abnormality itself should be 
collected as an AE. If the abnormality can be 
characterised by a precise clinical term, the clinical term 
should be recorded as the AE. (…) 
All laboratory abnormalities that require 
intervention (e.g., transfusion, IV infusion) should be 
reported as clinically significant AEs according to 
NCI-CTCAE v4.03. If the clinically significant 
laboratory or other abnormality from safety assessment 
is not a sign of a disease or syndrome, the abnormality 
itself should be collected as an AE. (…) 
Additional 
clarification 
7.1.6. Emergency 
Unblinding for 
(…) This includes who performed the unblinding, the 
subject(s) affected, the reason for the unblinding, the 
(…) This includes who performed the unblinding, the 
subject(s) affected, the reason for the unblinding, the 
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Safety Reasons 
date of the unblinding and the relevant IP information. 
date of the unblinding and the relevant IP information. 
After unblinding (except unblinding for the purpose 
of regulatory reporting), subjects will be 
discontinued from the study. 
on unblinding 
8.1. Analysis Sets 
 
The following sets will be used for the analyses 
performed in the study: 
following sets will be used for the analyses performed in 
the study: 
• 
Randomised set (RAN): RAN will consist of all 
subjects who receive a randomisation number at 
the randomisation. 
Clarification 
8.2.1. Demographics 
and Baseline 
Characteristics 
The Baseline value is defined as that recorded at the 
Randomisation visit (Day 1) for all analyses. If the 
Baseline value is missing at the Randomisation visit, the 
last measurement prior to the time of first IP 
administration will be used. 
Subject demographics and baseline characteristics will 
be summarised by treatment group for the FAS.  
(…) 
Relevant medical history and continuing medical 
conditions will be summarised by treatment group for 
the FAS. 
The Baseline value is will be defined as that recorded 
at the Randomisation visit (Day 1) for all analyses. If 
the Baseline value is missing at the Randomisation 
visit, the last available measurement value prior to the 
time of first IP administration will be used. 
Subject demographics and baseline characteristics will 
be summarised by treatment group for the FAS RAN. 
(…) 
Relevant medical history and continuing medical 
conditions will be summarised by treatment group for 
the FAS RAN 
Clarification 
8.2.2.1. Primary 
Efficacy Analysis 
For US Food and Drug Administration submission, the 
primary efficacy analysis will be performed in the FAS 
for the ratio of best ORR by 24 weeks (best ORR of 
SB8/ best ORR of Avastin®), and the equivalence will be 
declared if the 90% confidence interval (CI) of the best 
For US Food and Drug Administration submission or 
other regulatory agency submissions for those who 
are in favour of risk ratio, the primary efficacy 
analysis will be performed in the FAS for the ratio of 
best ORR by 24 weeks (best ORR of SB8/ best ORR of 
Submission to 
different 
agencies 
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ORR ratio is contained within the pre-defined 
equivalence margin of [0.737, 1.357]. The similar 
analysis will be performed for the PPS to support the 
primary analysis. 
For EMA submission, the primary efficacy analysis will 
be performed in the PPS for the difference in the best 
ORR by 24 weeks, and the equivalence between the two 
treatment groups will be declared if the 95% CI of the 
difference is entirely contained within the pre-defined 
equivalence margin of [-12.5%, 12.5%]. The similar 
analysis will be performed for the FAS to support the 
primary analysis. 
The statistical method to get the CI for primary analysis 
will be described in the Statistical Analysis Plan (SAP), 
and the SAP will be finalised prior to the first database 
lock. 
Avastin®) by 24 weeks, and the equivalence will be 
declared if the 90% confidence interval (CI) of the best 
ORR ratio is contained within the pre-defined 
equivalence margin of [0.737, 1.357]. The similar 
analysis will be performed for the PPS to support the 
primary analysis. 
For EMA submission, MFDS or other regulatory 
agency submissions for those who are in favour of 
risk difference, the primary efficacy analysis will be 
performed in the PPS for the difference in of the best 
ORR (best ORR of SB8 – best ORR of Avastin®) by 
24 weeks, and the equivalence between the two 
treatment groups will be declared if the 95% CI of the 
difference is entirely contained within the pre-defined 
equivalence margin of [-12.5%, 12.5%]. The similar 
analysis will be performed for the FAS to support the 
primary analysis.  
The statistical method to get the CI for primary 
analysis will be described in the Statistical Analysis 
Plan (SAP), and the SAP will be finalised prior to the 
first database lock. 
The primary efficacy analysis will be performed 
using the log binomial model with treatment. The 
sensitivity analysis will be performed using the log 
binomial model with the covariates of age (< 70, ≥ 70 
years), sex (female, male), region (country or pooled 
centres) and treatment to explore the robustness of 
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the primary efficacy results. 
In the primary efficacy analysis for FAS, the 
response of the patients without any post-baseline 
tumour assessment will be imputed as following: 
• 
Missing data from patients who withdrew the 
study due to progression disease (PD), lack of 
efficacy and AEs without any tumour assessment 
will be considered as non-responder. 
• 
Missing data from patients who withdrew the 
study with reasons other than PD, lack of 
efficacy and AEs without any tumour assessment 
will be imputed using multiple imputation 
method. 
• 
Missing data from patients who remained in the 
study but do not have any valid tumour 
assessment will be imputed using multiple 
imputation method. 
In the primary efficacy analysis for the PPS, missing 
data will not be imputed. 
8.2.2.2. Secondary 
Efficacy Analyses 
The secondary efficacy endpoints of PFS, OS and DOR 
will be analysed for PPS and FAS and described in the 
SAP. 
The secondary efficacy endpoints of PFS, OS and DOR 
will be analysed for PPS and FAS and described in the 
SAP. PFS and OS will be analysed using the Kaplan-
Meier method with median survival time and its 
95% CI by treatment. The analysis using the 
stratified Cox proportional hazard model will be 
additionally performed to adjust the covariates used 
in the sensitivity analysis. DOR will be summarised 
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using descriptive statistics by treatment. 
8.3. Determination 
of Sample Size 
For the calculation of the equivalence margin, a meta-
analysis published by Botrel et al. using all of the four 
published comparative trials that evaluated bevacizumab 
in combination with chemotherapy (i.e. E4599 [Sandler, 
2006], AVAiL (BO17704) [Reck, 2009], AVF0757 
[Johnson, 2004], JO19907 [Niho, 2012]) was considered. 
For Regarding the calculation of the equivalence 
margin for the ratio of the best ORR by 24 weeks, a 
meta-analysis published by Botrel et al. using all of the 
four published comparative trials that evaluated 
bevacizumab in combination with chemotherapy (i.e. 
E4599 [Sandler, 2006], AVAiL (BO17704) [Reck, 
2009], AVF0757 [Johnson, 2004], JO19907 [Niho, 
2012]) was considered. The overall response rate for 
Avastin® was reported as 34.9% (133 of 381 
patients), 34.7% (114 of 329 patients), 32.4% (11 of 
34 patients) and 56.2% (68 of 121 patients) 
compared to the overall response rate of 15.1% (59 
of 392 patients), 21.7% (71 of 327 patients), 18.8% (6 
of 32 patients) and 33.9% (20 of 59 patients) for 
chemotherapy, in E4599, AVAiL, AVF0757 and 
JO19907 respectively. 
Clarification 
 
The overall ratio of best ORR and the 70% CI from 
above four studies are calculated to be 
 
 using the fixed effect method from meta-
analysis. Retaining the 
% of the effect of Avastin® 
over the placebo in the lower margin, the equivalence 
margin of [0.737, 1.357] will be used for the primary 
analysis with the ratio of the best ORR by 24 weeks. 
For the primary analysis with the difference of the best 
ORR by 24 weeks, the equivalence margin of [-12.5%, 
The overall ratio of the best ORR and the 70% CI from 
above four studies are calculated to be 
 
using the fixed effect method from meta-
analysis. Retaining the 
% of the effect of Avastin® 
over the placebo in the lower margin, the equivalence 
margin of [0.737, 1.357] will be used for the primary 
analysis with the ratio of the best ORR by 24 weeks. 
For the primary analysis with the difference of the 
best ORR by 24 weeks, the equivalence margin of [-
12.5%, 12.5%] will be used due to the similar 
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12.5%] will be used due to the similar derivation. 
derivation. 
For the calculation of the equivalence margin for the 
difference of the best ORR by 24 weeks, E4599 
[Sandler, 2006] and AVAiL [Reck, 2010] studies were 
considered. The overall response rate for Avastin® 
was reported as 34.9% (133 of 381 patients) and 
37.8% (130 of 344 patients), compared to the overall 
response rate of 15.1% (59 of 392 patients) and 
21.6% (75 of 347 patients) for chemotherapy, in 
E4599 and AVAiL, respectively. 
The overall difference in the best ORR and its 95% 
CI from these two studies are calculated to be 
% [
%, 
%] using the fixed-effect 
method from meta-analysis, or for 80% CI to be 
[
%, 
%]. The equivalence margin of [-
12.5%, 12.5%] will ensure the superiority of SB8 
over placebo with a small safety margin retaining 
around 
% for 95% CI and 
% for 80% CI of the 
effect over the placebo in the difference of best ORR. 
13. REFERENCES 
APPENDIX 1: 
ECOG 
PERFORMANCE 
STATUS 
Avastin® Summary of Product Characteristics 
(EMEA/H/C/000582 -II/0082). EMEA (Oct 29, 2015). 
Retrieved on Nov 04, 2015 from  
http://www.ema.europa.eu/docs/en_GB/document_library/EPA
R_-_Product_Information/human/000582/WC500029271.pdf 
 
Avastin® Summary of Product Characteristics 
(EMEA/H/C/000582 -II/0082). EMEA (Oct 29, 2015). 
Retrieved on Nov 04 Dec 21, 2015 from  
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR
_-_Product_Information/human/000582/WC500029271.pdf 
 
Updated 
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Reck M, von Pwel J, Zatloukal P, et al. Overall 
survival with cisplatin–gemcitabine and 
bevacizumab or placebo as first-line therapy for 
nonsquamous non-small-cell lung cancer: results 
from a randomised phase III trial (AVAiL). Annals of 
Oncology. 2010; 21: 1804–1809 
APPENDIX 2: 
LUNG CANCER 
STAGING 
APPENDIX 2: LUNG CANCER STAGING  
APPENDIX 2: LUNG CANCER STAGING (AJCC 
7TH EDITION) 
Updated 
APPENDIX 3: 
NATIONAL 
CANCER 
INSTITUTE-
COMMON 
TERMINOLOGY 
CRITERIA FOR 
ADVERSE 
EVENTS VERSION 
4.03 (NCI-CTCAE 
v4.03) (IN PART 
OF) 
 
Added a title 
for the table 
PROTOCOL 
SIGNATURE 
PAGES 
 
Declaration of the Global Principal/Coordinating 
Investigator 
Insert signature 
page for global 
PI 
 
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