Clinical trial NCT03329911
Conditions: Non-squamous Non-small Cell Lung Cancer
Sponsor: Bio-Thera Solutions
Start date: 2017-10-20; Completion date: 2021-05-27
Enrollment: 651 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase III, randomized, double blind, multicenter, active comparator, parallel two arm study to compare the efficacy, and to evaluate the safety, and immunogenicity of BAT1706 to EU Avastin® in patients with previously untreated advanced non-squamous non-small cell lung cancer (nsNSCLC) to demonstrate clinical equivalence of BAT1706 and EU Avastin®.

Detailed description:

Arms: arm 1: Drug:EU Avastin® 15 mg/kg IV infusions ,every 3 weeks of a cycle for up to 6 cycles, followed for those with non-progressive disease with maintenance monotherapy with Bevacizumab-EU up to a maximum of 8 months.

Drug: Paclitaxel 200mg/m² via IV infusions, every 3 weeks of a cycle for up to 6 cycles

Drug: Carboplatin AUC 6.0 mg/mL•minute via IV infusions,every 3 weeks of a cycle for up to 6 cycles arm 2: BAT1706 15 mg/kg IV infusions ,every 3 weeks of a cycle for up to 6 cycles, followed for those with non-progressive disease with maintenance monotherapy with BAT1706 up to a maximum of 8 months.

Drug: Paclitaxel 200mg/m² via IV infusions, every 3 weeks of a cycle for up to 6 cycles

Drug: Carboplatin AUC 6.0 mg/mL•minute via IV infusions,every 3 weeks of a cycle for up to 6 cycles
Interventions: intervention 1: EU Avastin® intervention 2: BAT1706 intervention 3: Paclitaxel intervention 4: carboplatin
Intervention descriptions: intervention 1: 100 mg/4 mL intervention 2: 100 mg/4 mL intervention 3: 200 mg/m² intervention 4: target area under the curve \[AUC\] 6 mg/mL•minute

Protocol documents:
Prot_002.pdf: 
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Clinical Study Protocol 
 
 
Protocol Title: 
A Multicenter, Randomized, Double-blind, Phase III 
Study of BAT1706 versus EU-Avastin® plus 
Chemotherapy in Patients with Advanced Non-squamous 
Non-Small Cell Lung Cancer 
 
Protocol Number: 
BAT1706-003-CR 
 
Date of Protocol: 
Version 5.0, 20 June 2019 
Amendment Number: 
4 
 
Replaced Version of Protocol: 
Version 4.0, 08 February 2019 
Product: 
BAT1706 (bevacizumab) 
Study Phase: 
Phase III 
 
IND Number 
To be determined 
 
EudraCT Number 
2017-001286-25 
 
Sponsor: 
Bio-Thera Solutions, Ltd. 
Building A6-5 floor, 11 Kai-Yuan Boulevard, 
Science City, Guangzhou, 510530, China 
 
Medical Monitor: 
Yana Pautova, MD, PhD 
IQVIA 
Frunze 80–612, Novosibirsk, Russia 
+7 9139164867 
 
Leading Principal Investigator: 
Prof. Li Zhang, MD, PhD 
Sun Yat-sen University Cancer Center 
 
 
 
Confidentiality Statement 
 
This confidential information in this document is provided to you as an Investigator or 
consultant for review by you, your staff, and the applicable Institutional Review 
Board/Independent Ethics Committee. Your acceptance of this document constitutes 
agreement that you will not disclose the information contained herein to others without written 
authorization from the Sponsor. 


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Sponsor Signatory: 
PROTOCOL TITLE: A Multicenter, Randomized, Double-blind, Phase III Study of 
BAT1706 versus EU-Avastin® plus Chemotherapy in Patients with Advanced Non-squamous 
Non-Small Cell Lung Cancer 
PROTOCOL NO: BAT1706-003-CR 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
-L--i - -Z--h--a-n--g-------------- 
---------------------- 
Li Zhang 
Signature 
Date 
Chief Medical Officer 
 
21June2019 
 
 


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Synopsis 
 
Name of 
Sponsor/Company: 
Bio-Thera Solutions, Ltd. 
Name of Finished 
Product: 
BAT1706 
Name of Active 
Ingredient: 
Bevacizumab 
Title of Study: 
A Multicenter, Randomized, Double-blind, Phase III Study of BAT1706 versus EU-
Avastin® plus Chemotherapy in Patients with Advanced Non-squamous Non-Small 
Cell Lung Cancer 
Protocol No: 
BAT1706-003-CR 
Investigators: 
Prof. Li Zhang, leading Principal Investigator 
Study centers: 
Multicenter study conducted in approximately 100 study centers 
Study duration: 
The duration of participation for each patient is expected to be about 12 months. There 
will be a 21-day Screening period, followed by the administration of study drugs over a 
maximum of 12 months. A Safety Follow-up Visit (SFUV)/End of Treatment (EoT) Visit 
will take place 28 days ± 2 days after the last dose during the study with a maximum at 
Week 53. Patients who are still benefiting of bevacizumab after 12 months of treatment 
will have the option to continue treatment with BAT1706 (regardless of the arm they were 
assigned to at randomization) in a Long-term extension (LTE) study until disease 
progression, excessive toxicity, withdrawal of consent, Investigator’s decision, or for a 
maximum of 12 additional months (ie, for up to 24 months from initial randomization). 
The end of study is set at 24 months after the Last Patient In (LPI). 
Phase: 
III 
Objectives: 
Primary: 
• 
To compare the efficacy of BAT1706 and European Union (EU)-Avastin® given with chemotherapy 
as first line treatment using the ratio or the difference in overall response rate (ORR) to show clinical 
equivalence. 
Secondary: 
• 
To further evaluate the efficacy of BAT1706 and EU-Avastin® given with chemotherapy using ORR 
at different time points, duration of response (DoR), progression-free survival (PFS) and overall 
survival (OS) (time, and rate at 12 months). 
• 
To evaluate the safety and immunogenicity of BAT1706 and EU-Avastin®. 
• 
To characterize bevacizumab exposure after administration of BAT1706 and EU-Avastin®. 
Exploratory: 
• 
To explore population pharmacokinetics (popPK). 
Methodology: 
This is a Phase III, randomized, double-blind, multicenter, active comparator, parallel two-arm study to 
compare the efficacy, and to evaluate the safety and immunogenicity of BAT1706 to EU-Avastin® in patients 
with previously untreated advanced non-squamous non-small cell lung cancer (nsNSCLC) to demonstrate 
clinical equivalence of BAT1706 and EU-Avastin®. 
After stratification for disease stage, gender and ethnicity (Asian vs non-Asian), eligible patients will be 
randomized in a 1:1 ratio to receive BAT1706 plus paclitaxel and carboplatin (Arm A) or EU-Avastin® plus 


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paclitaxel and carboplatin (Arm B). Patients will be assessed for histology and randomization will occur after 
central imaging review (CIR) to confirm the presence of at least one measurable target lesion according to 
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). 
Combination treatment will be administered every 3 weeks up to 6 cycles, followed for those with non-
progressive disease with maintenance monotherapy with BAT1706 or EU-Avastin® until a maximum of total 
study treatment of 12 months (17 cycles). Patients intolerant to chemotherapy after 2 dose reductions can start 
monotherapy with BAT1706 or EU-Avastin® or start another line of anti-cancer therapy after investigator’s 
judgment. 
A data safety monitoring board (DSMB) will review all safety data after the first 20 patients have been treated 
for 6 weeks in each arm; then after, if no unexpected safety signal was identified, the study will continue and 
the safety data will be reviewed at regular intervals after approximately every 200 patients are evaluated after 
they received the first 4 cycles. 
Patients will undergo tumor assessment at Weeks 6, 12 and 18, regardless of the number of cycles actually 
completed (with a visit window of 1 week maximum during the first 18 weeks), then after every 3 cycles 
(approximately every 9 weeks) and at SFUV/EoT. During the trial, tumor response will be assessed by local 
radiologist/Investigator for immediate therapeutic decision. To comply with the different statistical approaches 
of each regulatory agency, the main efficacy analyses (difference and ratio of ORR) will be based upon tumor 
response at different time points as determined by CIR according to RECIST 1.1. After Week 18, patients with 
responding or stabilized disease will remain in the study until a total study treatment duration of 12 months is 
reached to provide further comparative safety/immunogenicity data as well as other efficacy parameters (such 
as DoR, PFS and OS rates at 12 months for both BAT1706 and EU-Avastin®). All patients will remain in the 
study until Investigator-assessed disease progression, excessive toxicity, Investigator’s judgment, withdrawal 
of consent, lost to follow-up, death, start of a new anticancer therapy, study termination by the Sponsor, or for 
a maximum of 12 months of treatment, whichever occurs first. Then after, all patients who are still benefiting 
of therapy will have the option to continue treatment with BAT1706 in a LTE study (as of Week 53) until 
disease progression, excessive toxicity, withdrawal of consent, Investigator’s decision, or for a maximum of 
12 additional months (ie, for up to 24 months from initial randomization). 
Survival Follow-up will occur every 3 months until 24 months after randomization. A complete clinical study 
report will be submitted to the China Food and Drug Administration (CFDA), United States (US) Food and 
Drug Administration (FDA), and the European Medicines Agency (EMA) when primary efficacy data are 
available in all patients. At the end of the LTE, a complementary study report will be released. The study will 
be conducted according to the national and international ethical standards, the Good Clinical Practice 
guidelines, and the protocol will be approved by the Institutional Review Boards/Independent Ethics 
Committees of the participating sites. 
Planned number of 
patients: 
Approximately 632 patients will be enrolled including a subgroup of 200 patients for 
pharmacokinetics (PK) and population PK (popPK). 
Diagnosis and 
main criteria for 
inclusion: 
Patients ≥ 18 years old, with advanced nsNSCLC (either previously untreated Stage IV 
or recurrent disease that is no longer amenable to curative surgery or local therapy), 
without activating epidermal growth factor receptor (EGFR) mutation or anaplastic 
lymphoma kinase (ALK) receptor alteration, with at least one measurable target lesion 
according to RECIST 1.1, Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1 and life expectancy >3 months based on Investigator’s judgment. 
Test product, dose 
schedule and mode 
of administration: 
BAT1706 will be supplied as 100 mg/4 mL. 
Dose: 15 mg/kg 
Mode 
of 
administration: 
BAT1706 
must 
be 
administered 
prior 
to 
paclitaxel/carboplatin.  Initial  dose for the first infusion should be delivered over     90 
minutes; if well tolerated, the second and subsequent infusion may be administered over 
60 minutes. 


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No dose modifications are allowed. The schedule is every 3 weeks. No more than 6-
week delay (between the end of prior cycle and the start of next cycle) is allowed 
(maximum of 9 weeks between 2 administrations). 
Reference therapy, 
dose, and mode of 
administration: 
EU-Avastin® will be supplied as 100 mg/4 mL. 
Dose: 15 mg/kg 
Mode of administration: Same as that of BAT1706 as specified above. 
Concomitant 
drugs, dose, 
schedule and mode 
of administration: 
Paclitaxel/carboplatin regimen: 
Dose: Paclitaxel 200 mg/m² followed by carboplatin (target area under the curve [AUC] 
6 mg/mL·minute). However, for Chinese patients (according to local label), p aclitaxel 
will be given at a dose of 175 mg/m².  
For all patients in case of anticipated excessive toxicity (eg, elderly patients, prior 
toxicity during chemo-radiotherapy), the Investigator may start the first course of 
chemotherapy using paclitaxel at a dose of 175 mg/m² (or use a paclitaxel dose of  2 00 
mg/m² after prophylactic administration of granulocyte -colony stimulating factor [G-
CSF]), and/or carboplatin AUC 5 mg/mL·minute.  
Mode of administration: paclitaxel is administered intravenously over 3 hours or 
according to local standard practice or package insert after adequate premedication 
before carboplatin is administered. Carboplatin is administered intravenously 
according to local standard practice or package insert. 
The schedule is every 3 weeks (21 days) for up to 6 cycles of combination therapy. 
The drug sequence is as follows: 
Only BAT1706 or EU-Avastin® are administered on Day 1 of Cycle 1, and paclitaxel 
and carboplatin are given on Day 2. As of Cycle 2, BAT1706 or EU-Avastin® is given 
first, then paclitaxel followed by carboplatin on the same day. During the combination 
treatment period, any chemotherapy delay mandates a BAT1706/Avastin® 
administration delay and vice-versa. 


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Criteria for evaluation: 
Primary Endpoint 
Efficacy: 
• 
Overall response rate based on tumor response at Week 18 (ORR18) as assessed by CIR. The response 
is evaluated according to RECIST 1.1 but does not need to be confirmed. 
Secondary Endpoints 
Efficacy: 
• 
Progression-free survival rate at 12 months, defined as the proportion of patients being alive without 
documented progression 12 months after randomization using Kaplan-Meier method. 
• 
Progression-free survival time defined as the time from the date of randomization to the date of 
documented clinical or radiological progression or death due to any cause using Kaplan-Meier 
method. 
• 
Overall survival rate at 12 months, defined as the probability of being alive 12 months after 
randomization using Kaplan-Meier method. 
• 
Overall survival time defined as the time from randomization to death of any cause using Kaplan-
Meier method. 
• 
ORR at Week 6 (ORR6) and at Week 12 (ORR12), based on tumor response as assessed by CIR, and 
best ORR of confirmed responses at end of study assessed by local radiologist/Investigator if after 
Week 18 according to RECIST 1.1. 
• 
Duration of response defined as the time from first documentation of a response (CR or PR) and the 
first documentation of progression (assessed by local radiologist/Investigator if after Week 18) 
according to RECIST 1.1. 
Safety: 
• 
The safety profile of the study drugs as measured by the incidence and severity of adverse events, 
clinical laboratory assessments, vital signs, physical examination, and electrocardiogram parameters. 
Pharmacokinetics: 
• 
Bevacizumab serum exposure following treatments of BAT1706 or EU-Avastin®. 
Immunogenicity: 
• 
Serum level of anti-drug antibodies (ADA) and neutralizing anti-drug antibodies (NADA) correlated 
with bevacizumab serum level. 
Exploratory Endpoint 
Population PK (popPK): 
• 
Bevacizumab serum exposure following treatment with BAT1706. 
Statistical methods: 
To demonstrate equivalence between BAT1706 and EU-Avastin® arms, the ratio of, as well as the difference 
between ORR18 will be analyzed. Equivalence will be declared if the 90% confidence interval (CI) of the ratio 
of ORR18 (BAT1706:EU-Avastin®) is entirely contained within the equivalence margin of (0.75, 1.33) to 
comply with CFDA requirements, and within the equivalence margin of (0.73, 1.36) to comply with US FDA 
requirements. The difference in ORR18 will be calculated, and equivalence will be declared if the 95% CI of 
the difference in the ORR18 between treatments is entirely contained within the asymmetrical equivalence 
margin of (-0.12, 0.15) to comply with EMA requirements. 
Categorical variables will be summarized by the number and percentage of patients in each category. 
Continuous variables will be summarized using number, mean, standard deviation, median, minimum and 
maximum values. Time to event endpoints will be analyzed using Cox proportional hazards models stratified 


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according to the randomization stratification factors. Hazard ratios for the comparison of the two treatment 
arms and corresponding 95% CIs will be reported. 
Pharmacokinetic analyses: 
The PK analysis will be performed on the PK population. The PK and popPK analysis will be explored in a 
subgroup of 200 patients, from samples collected only at designated sites in China, Turkey, and Ukraine. 
Serum bevacizumab concentrations will be listed and summarized by treatment using appropriate descriptive 
statistics. Graphical presentations of concentration-time data by treatment will be provided, as appropriate. 
Additional popPK modeling and/or correlation between bevacizumab exposure and response (safety, 
immunogenicity and/or efficacy) data may be evaluated separately, as appropriate. If performed, a separate 
analysis plan will be prepared and results will be reported separately from the clinical study report. 


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Table of contents 
SPONSOR SIGNATORY ....................................................................................................... 2 
SYNOPSIS ................................................................................................................................ 3 
TABLE OF CONTENTS ........................................................................................................ 8 
LIST OF TABLES ................................................................................................................. 12 
LIST OF FIGURES ............................................................................................................... 12 
1.0 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................ 13 
2.0 
INTRODUCTION...................................................................................................... 16 
2.1 
Background Information............................................................................... 16 
2.1.1 
Overview ........................................................................................... 16 
2.1.2 
Summary of Nonclinical Findings ..................................................... 17 
2.1.3 
Summary of Clinical Findings ........................................................... 18 
2.2 
Rationale ......................................................................................................... 18 
2.3 
Hypothesis ....................................................................................................... 19 
2.4 
Risk Assessment ............................................................................................. 20 
3.0 
STUDY OBJECTIVES .............................................................................................. 23 
3.1 
Primary Objective .......................................................................................... 23 
3.2 
Secondary Objectives..................................................................................... 23 
3.3 
Exploratory Objective ................................................................................... 23 
4.0 
INVESTIGATIONAL PLAN ................................................................................... 24 
4.1 
Summary of Study Design ............................................................................. 24 
4.2 
Discussion of Study Design ............................................................................ 32 
4.3 
Selection of Study Population ....................................................................... 32 
4.3.1 
Inclusion Criteria ............................................................................... 32 
4.3.2 
Exclusion Criteria .............................................................................. 34 
4.3.3 
Subject Restrictions ........................................................................... 37 
4.3.4 
Subject Withdrawal ........................................................................... 37 
5.0 
STUDY TREATMENTS ........................................................................................... 40 
5.1 
Treatments Administered ............................................................................. 40 
5.2 
Identity of Investigational and Comparator Products ............................... 41 
5.3 
Packaging and Labeling ................................................................................ 42 


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5.4 
Method of Assigning Subjects to Treatment Group ................................... 42 
5.5 
Selection of Bevacizumab Dose in the Study ............................................... 43 
5.6 
Treatment Regimen, Schedule, and Mode of Administration ................... 43 
5.6.1 
Chemotherapy .................................................................................... 45 
5.7 
Blinding ........................................................................................................... 50 
5.8 
Prior and Concomitant Treatments ............................................................. 50 
5.8.1 
Excluded Medications ....................................................................... 50 
5.8.2 
Allowed Medications ......................................................................... 51 
5.8.3 
Allowed Radiotherapy ....................................................................... 51 
5.9 
Medical Care of Subjects after End of Study .............................................. 51 
5.10 
Treatment Compliance .................................................................................. 51 
5.11 
Study Medication Accountability ................................................................. 51 
6.0 
EFFICACY, SAFETY, IMMUNOGENICITY, AND 
PHARMACOKINETIC ASSESSMENTS ............................................................... 53 
6.1 
Efficacy............................................................................................................ 53 
6.1.1 
Primary Efficacy Endpoint ................................................................ 53 
6.1.2 
Secondary Efficacy Endpoints ........................................................... 54 
6.2 
Safety ............................................................................................................... 55 
6.2.1 
Adverse Events .................................................................................. 55 
6.2.2 
Clinical Laboratory Evaluations ........................................................ 62 
6.2.3 
Vital   Signs,   Physical   Findings   and    Other    Safety 
Assessments ....................................................................................... 63 
6.2.4 
Safety Monitoring .............................................................................. 64 
6.3 
Immunogenicity.............................................................................................. 65 
6.4 
Pharmacokinetic Assessments ...................................................................... 65 
6.5 
Appropriateness of Measurements ............................................................... 66 
7.0 
STUDY PROCEDURES ........................................................................................... 67 
7.1 
Screening Period ............................................................................................ 67 
7.2 
Treatment Period ........................................................................................... 68 
7.2.1 
Cycle 1 ............................................................................................... 68 
7.2.2 
Cycles 2 to 6 ...................................................................................... 69 
7.2.3 
Cycles 7 to 17: Maintenance Period .................................................. 70 
7.3 
End of Study and Follow-up Period ............................................................. 71 
7.3.1 
End of Treatment Visit/Safety Follow-up Visit ................................ 71 
7.3.2 
Survival Follow-Up ........................................................................... 72 
7.3.3 
Long-Term Extension Study (Cycle 18 onward)............................... 72 
7.3.4 
End of Study Definition ..................................................................... 73 
8.0 
QUALITY CONTROL AND QUALITY ASSURANCE ....................................... 74 
8.1 
Investigator’s Responsibility ......................................................................... 74 
8.2 
Training .......................................................................................................... 75 
8.3 
Monitoring ...................................................................................................... 75 


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8.4 
Non-Compliance with the Protocol .............................................................. 75 
8.5 
Study Documentation and Electronic Case Report Forms ........................ 76 
8.6 
Quality Assurance Audit ............................................................................... 77 
9.0 
STATISTICS .............................................................................................................. 78 
9.1 
Determination of Sample Size ....................................................................... 78 
9.2 
Statistical Methods ......................................................................................... 80 
9.2.1 
Data to be Analyzed .......................................................................... 80 
9.2.2 
Analysis Populations ......................................................................... 80 
9.2.3 
Missing Data ...................................................................................... 81 
9.2.4 
Data Pooling ...................................................................................... 81 
9.3 
Subject Disposition and Characteristics ...................................................... 82 
9.4 
Efficacy Analyses ........................................................................................... 82 
9.4.1 
Primary Efficacy Analyses ................................................................ 82 
9.4.2 
Secondary Efficacy Analyses ............................................................ 83 
9.4.3 
Subgroup Analyses ............................................................................ 83 
9.5 
Safety ............................................................................................................... 83 
9.5.1 
Adverse Events .................................................................................. 84 
9.5.2 
Clinical Laboratory Evaluations ........................................................ 84 
9.5.3 
Vital Signs Measurements, Physical Findings and Other 
Safety Evaluations ............................................................................. 84 
9.6 
Immunogenicity Analyses ............................................................................. 84 
9.7 
Pharmacokinetic Analyses ............................................................................ 85 
10.0 
ETHICS ...................................................................................................................... 86 
10.1 
Institutional Review Board or Independent Ethics Committee ................ 86 
10.2 
Ethical Conduct of the Study ........................................................................ 86 
10.3 
Subject Information and Informed Consent ............................................... 87 
10.4 
Subject Data Protection ................................................................................. 87 
11.0 
STUDY ADMINISTRATION................................................................................... 88 
11.1 
Data Handling and Record Keeping ............................................................ 88 
11.2 
Direct Access to Source Data/Documents .................................................... 88 
11.3 
Investigator Information ............................................................................... 88 
11.3.1 
Investigator Obligations .................................................................... 88 
11.3.2 
Protocol Signatures ............................................................................ 89 
11.3.3 
Publication Policy .............................................................................. 89 
11.4 
Financing and Insurance ............................................................................... 89 
12.0 
REFERENCES ........................................................................................................... 90 
13.0 
APPENDICES ............................................................................................................ 92 
13.1 
Signature of Investigator ............................................................................... 92 


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13.2 
Estimated Blood Sample Volumes per Patient ............................................ 93 
13.3 
Eastern Cooperative Oncology Group (ECOG) — 
Performance Status Scale .............................................................................. 95 
13.4 
Guidelines for Evaluation of Objective Tumor Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria In Solid 
Tumors) ........................................................................................................... 96 
13.5 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
TABLE .......................................................................................................... 104 


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List of Tables 
Table 1 
Schedule of Events ........................................................................................... 27 
Table 2 
Pharmacokinetice, Anti-drug Antibodyf, and Neutralizing Anti- 
drug Antibodyf Sampling Time Points ............................................................ 31 
Table 3 
Investigational and Comparator Products ........................................................ 41 
Table 4 
Treatment Regimen of BAT1706/EU-Avastin® plus Paclitaxel and 
Carboplatin ....................................................................................................... 45 
Table 5 
Dose Modifications for Paclitaxel and Carboplatin according to 
Starting Dose .................................................................................................... 47 
Table 6 
Dose Modifications for Hematologic Toxicities (Regardless of 
Causality) ......................................................................................................... 48 
Table 7 
Dose Modifications for Selected Non-Hematologic Toxicity 
(Regardless of Causality) ................................................................................. 49 
 
List of Figures 
Figure 1 
Schematic of the Study Design ........................................................................ 26 


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1.0 LIST OF ABBREVIATIONS AND DEFINITIONS OF 
TERMS 
 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALK 
Anaplastic lymphoma kinase 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUC0-t 
Area under the concentration-time curve from 0 hour to time t 
BPD 
biosimilar biological product development 
CFDA 
China Food and Drug Administration 
CI 
Confidence interval 
CIR 
Central imaging review 
Cmax 
Maximum concentration 
CNS 
Central nervous system 
CR 
Complete response 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease control rate 
DoR 
Duration of response 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EMA 
European Medicines Agency 


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EoT 
End of Treatment 
EU 
European Union 
FDA 
Food and Drug Administration 
FDG 
Fludeoxyglucose 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
G-CSF 
Granulocyte-colony stimulating factor 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HUVEC 
Human umbilical vein endothelial cells 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
LPI 
Last Patient In 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous(ly) 
IWRS 
Interactive Web Response System 
LTE 
Long-Term Extension 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NADA 
Neutralizing anti-drug antibody 
NCI 
National Cancer Institute 
NSAID 
Non-steroidal anti-inflammatory drug 
NSCLC 
Non-small cell lung cancer 
nsNSCLC 
Non-squamous non-small cell lung cancer 
ORR 
Overall response rate 


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ORR6 
Overall response rate at Week 6 
ORR12 
Overall response rate at Week 12 
ORR18 
Overall response rate at Week 18 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
popPK 
Population pharmacokinetics 
PP 
Per-protocol 
PR 
Partial response 
PRES 
Posterior Reversible Encephalopathy Syndrome 
PT 
Prothrombin time 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SFUV 
Safety Follow-up Visit 
SOP 
Standard operating procedures 
TEAEs 
Treatment-emergent adverse events 
ULN 
Upper limit of normal 
US 
United States 
VEGF 
Vascular endothelial growth factor 
VEGFR 
Vascular endothelial growth factor receptor 


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2.0 INTRODUCTION 
 
2.1 
Background Information 
 
2.1.1 
Overview 
Cancer is associated with a high morbidity and mortality rate worldwide. The incidence and 
mortality of lung cancer is rapidly increasing. Chemotherapy for non-small cell lung cancer 
(NSCLC) is a widely used treatment modality. However, patients undergoing chemotherapy 
often develop chemo-resistance, leading to disease progression; this demonstrates the need for 
more effective treatment. 
Vascular endothelial growth factor (VEGF), binds with VEGF receptors (VEGFR), to promote 
vascular endothelial cell proliferation, migration, lumen formation, and angiogenesis with 
alterations of microvascular permeability. Bevacizumab developed by Genentech is a 
genetically engineered humanized monoclonal antibody directed against human VEGF. The 
antibody selectively binds with high affinity to VEGF A and neutralizes VEGF biologic 
activity through a steric blockade of the binding of VEGF to its receptors on the surface of 
endothelial cells. Based on proven clinical efficacy bevacizumab in combination with 
chemotherapy has been approved for several tumor types such as colon, lung, breast and 
ovarian cancer. 
Use in lung cancer 
Lung cancer is the most common cause of cancer-related death worldwide.1 Less than 15% of 
all lung cancer patients are alive 5 years after diagnosis. At the time of diagnosis, the disease 
is often incurable and when indicated and tolerated, various chemotherapy regimens have yield 
survival of 8-10 months. Recent advances in the characterization of alterations in the epidermal 
growth factor receptor (EGFR) and the anaplastic lymphoma kinase (ALK) gene have allowed 
identifying a subgroup of lung cancer patients who can benefit more of oral targeted agents 
such tyrosine kinase inhibitors than of chemotherapy. This type of gene alteration is present in 
about 15-20% of non-Asian patients and up to 40% in Asian patients. Today, patients with no 
known mutations or with a mutation but no access to the targeted agent are offered a platinum 
based chemotherapy.2,3 Patients with nonsquamous histology, and no risk of major bleeding, 
are offered the addition of bevacizumab, which prolongs survival to about 12-13 months and 
is considered standard of care. In October 2006, the United States (US) Food and Drug 
Administration (FDA) approved the use of chemotherapy protocols combining bevacizumab 
with paclitaxel and carboplatin as a first-line treatment for late-stage NSCLC. In 2015, the 
China FDA (CFDA) approved the use of bevacizumab with paclitaxel and carboplatin as a 


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first-line treatment for late-stage NSCLC. Bevacizumab has now been granted approval in over 
120 countries and regions worldwide, including Europe and North America.4,5 
Based on the results of Sandler’s study6 showing that the addition of bevacizumab significantly 
increased overall response rate (ORR), progression-free survival (PFS) and overall survival 
(OS), the Eastern Cooperative Oncology Group (ECOG; refer to Appendix 13.3) recommends 
bevacizumab in combination with paclitaxel and carboplatin for treatment of selected patients 
with advanced non-squamous NSCLC (nsNSCLC). Sandler’s regimen is proposed for this 
study aimed at demonstrating the biosimilarity between BAT1706 and Avastin®. The optimal 
number of cycles of chemotherapy combined with bevacizumab is of 4 cycles but up to 6 cycles 
have been commonly administered. In studies comparing 4 or 6 cycles of chemotherapy, no 
survival benefit was shown with the administration of more than 4 cycles, and most responses 
are observed after 4 cycles.7 The American Society of Clinical Oncology panel of experts 
recommends not to administer more than 4 cycles in non-responding patients who are then 
given maintenance monotherapy with bevacizumab until progression or intolerance.8 
2.1.2 
Summary of Nonclinical Findings 
Bio-Thera has completed a suite of nonclinical studies using BAT1706. BAT1706 has been 
compared against US-Avastin® and European Union (EU)-Avastin® in a comprehensive 
comparative analytical and nonclinical study program, which provides evidence of the 
structural and functional similarity of BAT1706 to Avastin® as summarized in the 
Investigator’s Brochure (IB).9 
The results of comparative in vitro pharmacodynamic research showed that BAT1706 and 
Avastin® both exhibited specific binding with VEGF-A121 and VEGF-A165, which was 
consistent with literature reports. The biological activity of BAT1706 was measured using 
human umbilical vein endothelial cells (HUVEC) proliferation inhibition testing. The results 
demonstrated that BAT1706 exhibited a similar dose-dependent relationship with the growth 
of HUVEC to Avastin®, with both agents exhibiting potent neutralizing efficacy against VEGF. 
The biological activity of BAT1706 was found to be comparable to that of Avastin® within the 
predetermined range of (1.0 ± 0.2) × 10 4 U/mg. 
The antitumor effect of BAT1706 and Avastin® in several models of human cancer (NSCLC, 
ovarian cancer, and rhabdomyosarcoma) was also investigated. These results showed that 
treatment with BAT1706 and Avastin® at high doses (5 mg/kg in NSCLC and 
rhabdomyosarcoma and 10 mg/kg in ovarian cancer) was effective in all 3 tumor models, and 
none were effective at lower doses (0.5 mg/kg in NSCLC and rhabdomyosarcoma and 1 mg/kg 
in ovarian cancer). Except for the 0.5 mg/kg dose in the rhabdomyosarcoma model, the 
pharmacodynamic effects of BAT1706 and Avastin® were similar, and the tumor growth 


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curves showed a high degree of coincidence. Results from the 2 repeated tests were also 
consistent. 
The results of a pharmacokinetic (PK) study suggested equivalence in in-vivo metabolism of 
BAT1706 and Avastin®. The concentration of the drug in blood plasma revealed extremely 
slow elimination, consistent with literature reports. Toxicokinetic parameters showed no 
significant gender-based difference in the drug exposure; the plasma drug concentration, mean 
area under the plasma concentration-time curve from 0 hours to time t (AUC0-t), and maximum 
concentration (Cmax) were dose-related. The values of AUC0-t, elimination half-life, clearance, 
and Cmax for the same dose (4 mg/kg) of BAT1706 and Avastin® were not notably different. 
Results of the nonclinical toxicology studies demonstrated that BAT1706 has good local 
tolerance for intravenous (IV) administration, and no impact on the central nervous system 
(CNS), cardiovascular or respiratory systems, and no specific binding to non-target tissues in 
the body and no increase in immunogenicity or immunotoxicity when compared with Avastin®. 
A study conducted to observe the irritant effects of BAT1706 on the administration site as well 
as the surrounding tissues did not reveal any irritation reactions at the vascular injection site 
during or after drug administration.9 
 
2.1.3 
Summary of Clinical Findings 
At the time of preparation of this protocol, two Phase I studies conducted with BAT1706 in 
New Zealand (BAT1706-001-CR) and China (BAT1706-002-CR), respectively revealed that 
a single IV infusion of BAT1706 (1 mg/kg) is safe and well tolerated in healthy subjects. There 
were no cases of death reported during either study and there was only 1 serious adverse event 
(SAE [fibula fracture; reported in study BAT1706-001-CR]) which was unrelated to BAT1706 
determined by the Principal Investigator (PI). The key PK parameters of both Phase I studies 
also revealed that BAT1706 is a bioequivalent to Avastin (bevacizumab). No anti-drug 
antibody positive result was reported for any subject included in either study. See Investigator’s 
Brochure (IB) for detailed description of Phase I study results and Appendix B in IB for a 
tabulated summary of each study. 
2.2 
Rationale 
To date, more than a million patients globally have undergone treatment with bevacizumab, 
the world’s first anti-VEGF antibody that has been proven to extend the OS and PFS in multiple 
types of cancer. In the US, China, and Europe, bevacizumab’s patent protection will be expired 
in July 2019, January 2020, and July 2019, respectively. 
Bio-Thera has developed a recombinant humanized anti-VEGF monoclonal antibody injection, 
BAT1706, which is a proposed biosimilar of Avastin® to meet the need for alternatives to 


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high-priced biologic agents. The proposed clinical development is in accordance with 
published guidelines from regulatory authorities for the development of biosimilar monoclonal 
antibodies. The similarity between the biosimilar and the originator compound, will first be 
demonstrated in a Phase I PK study in healthy volunteers. After sufficient evidence is available 
to show PK similarity, and provided no safety signal was reported, the Phase III study can be 
launched to compare the clinical efficacy and demonstrate similarity for safety and 
immunogenicity in a homogenous population of lung cancer patients. 
In this pivotal Phase III clinical study, patients with nsNSCLC will be randomly assigned to 
receive either BAT1706 or EU-Avastin®, plus a selected chemotherapy regimen according to 
standard of care (see Section 4.1). 
Since targeted agents have become standard of care for patients with tumors expressing 
activating mutations in EGFR or alterations in ALK receptor, these patients will not be enrolled 
if the corresponding tyrosine kinase inhibitor is available. Patients with unknown mutation 
status or with activating mutation in EGFR or ALK receptor alteration may be included only 
provided chemotherapy is the study center standard of care and the patient has signed the 
informed consent form stating the superiority of targeted therapy. This study will be performed 
in compliance with the protocol, International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP) and applicable regulatory requirements. The protocol will be approved by the 
Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) of the participating 
sites. 
 
2.3 
Hypothesis 
The null hypothesis is that either (1) BAT1706 is inferior to EU-Avastin® or (2) BAT1706 is 
superior to EU-Avastin® based on a pre-specified equivalence margin. 
To satisfy the different methods used by the regulatory agencies, different endpoints and 
methods of calculations will be used in this global study. 
To satisfy the CFDA and US FDA statistical approaches, the null hypothesis will be rejected 
if the 90% confidence interval (CI) for the ratio of ORR18 (BAT1706: EU-Avastin®) falls 
completely within the predefined equivalence margin of (0.75, 1.33) to comply with CFDA 
requirements and within the predefined equivalence margin of (0.73, 1.36) to comply with 
FDA requirements. To satisfy the European Medicines Agency (EMA) statistical approach, 
the null hypothesis will be rejected if the 95% CI of the difference in the ORR18 between 
treatments (BAT1706 and EU-Avastin®) is entirely contained within the predefined 
equivalence margin of (-0.12, 0.15). 


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The alternative hypothesis is that BAT1706 is equivalent to EU-Avastin®, which can be 
demonstrated by showing that the true treatment ratio/difference is likely to lie between a lower 
and an upper equivalence margin of clinical acceptable difference. The equivalence margins 
have been calculated based on a meta-analysis including the 5 randomized studies6,10-13 
demonstrating the benefit of the addition of bevacizumab over chemotherapy alone in the same 
population as that enrolled in this study. 
 
2.4 
Risk Assessment 
Patient risk is considered equivalent as that when receiving Avastin® as described in package 
insert in the US5 and in the summary of product characteristics in the EU.4 Conservative 
eligibility criteria, regular and long-term safety monitoring, including immunogenicity testing 
will ensure that no abnormal safety signal is observed. The potential for drug-induced liver 
injury requires constant surveillance. To ensure patients’ safety, clinical evaluation and follow-
up of selected liver laboratory parameters are implemented. The Sponsor will immediately 
notify the Principal Investigator if any additional safety or toxicology information becomes 
available during the study. The Sponsor will also notify the Principal Investigator of any new 
information that could potentially impact patient safety or management during the study. 
Gastrointestinal Perforation and Fistulae 
Patients treated with Avastin® have an increased risk of gastrointestinal perforation. The 
incidence of gastrointestinal perforation ranges from 0.3% to 3.2% across clinical studies.9 The 
majority of cases occurred within the first 50 days of initiation of Avastin®. The Investigator 
is required to monitor the patients at regular intervals throughout the study for any new or 
worsening symptoms or signs that may be suggestive of gastrointestinal perforation. 
Surgery and Wound Healing 
Serious and sometimes fatal fistula formation may occur within the first 6 months of Avastin® 
therapy. An increased risk of wound healing complications has been observed in patients who 
underwent surgery during the course of Avastin®. Bevacizumab must be discontinued in 
patients with wound dehiscence. Bevacizumab must be discontinued at least 28 days prior to 
elective surgery and cannot be initiated for at least 28 days after surgery and until the surgical 
wound is fully healed. Restrictions for surgery are detailed in the exclusion criteria. 
Hemorrhage 
Treatment with Avastin® is associated with an increased risk of hemorrhage (including 
hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal 


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bleeding) and arterial thromboembolic events (including cerebral infarction, transient ischemic 
attacks, myocardial infarction, and angina). Patients with prior episodes of hemoptysis, 
thrombotic or hemorrhagic event within 6 months prior to Screening are not eligible. No 
anticoagulation therapy is allowed within 10 days of the first dose of study drug or during the 
study except for venous access or daily aspirin up to 325 mg. Avastin® must be discontinued 
in patients with clinically significant hemorrhage. 
Arterial and Venous Thromboembolic Events 
The incidence is < 5% and depends on the associated chemotherapy, a history of arterial 
thromboembolism, diabetes, or age greater than 65 years. Avastin® must be discontinued in 
patients presenting a severe event, or in case of pulmonary embolism. 
Posterior Reversible Encephalopathy 
The use of Avastin® has been shown to be associated with an increased risk of Posterior 
Reversible Encephalopathy Syndrome (PRES). The incidence is < 0.5%. The Investigator is 
required to monitor the patients at regular intervals throughout the study for any new or 
worsening neurological symptoms or signs that may be suggestive of PRES (typical symptoms 
are diverse and include headache, seizure, lethargy, confusion, blindness, and other visual and 
neurologic disturbances). If a patient develops new or worsening neurological signs or 
symptoms, he/she will be evaluated for PRES. Magnetic resonance imaging (MRI) is necessary 
to confirm the diagnosis of PRES. Any patient who is suspected of developing PRES will be 
discontinued from the study and the adverse event (AE) will be followed closely  (see Section 
6.2.1.1). Symptoms usually resolve or improve within days, although some patients have 
experienced ongoing neurologic sequelae. 
Hypertension 
The incidence of severe hypertension in patients receiving Avastin® is 5-18%. Patients with 
systolic/diastolic blood pressure > 150/100 mmHg (in the presence or absence of a stable 
regimen of antihypertensive therapy) are excluded from this study. Blood pressure will be 
monitored every 3 weeks during the study. Patients who develop hypertension should be 
treated with appropriate antihypertensive therapy at the Investigator’s discretion and should 
continue to have their blood pressure regularly monitored. If the hypertension remains 
uncontrolled, the patient is withdrawn from study. 
Proteinuria 
The incidence and severity of proteinuria is increased in patients receiving Avastin® as 
compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin®. 


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Suspend Avastin® administration for ≥ 2 grams of proteinuria/24 hours and resume when 
proteinuria is < 2 grams/24 hours. Discontinue Avastin® in patients with nephrotic syndrome. 
Infusion reaction 
Infusion reactions with the first dose of Avastin® are uncommon (< 3%) and severe reactions 
occurred in 0.2% of patients. Refer to Section 5.6.1 for premedication and management. 
Due consideration has been given to previous experience with Avastin® in NSCLC patients 
and toxicity management guidance (eg, for hypersensitivity reactions) is provided in this 
protocol. Females of reproductive potential must be informed of the potential of the risk of 
ovarian failure prior to starting treatment with Avastin®. A Data Safety Monitoring Board 
(DSMB) will be established to review the safety and efficacy data of BAT1706 compared with 
data from the active comparator and to review accumulating safety data at regular intervals 
throughout the study (see Section 6.2.4). For details of blinding, please refer to Section 5.7. 
Based on extensive preclinical, analytical, functional and toxicological testing carried out prior 
to initiation of this study, and the Phase I data described above, BAT1706, as a proposed 
biosimilar product, may be seen to provide similar efficacy, safety, immunogenicity and PK to 
EU-Avastin® in patients with advanced nsNSCLC. For more preclinical information please 
refer to the most current IB9 and to Avastin® label for full prescribing information, and 
extensive information on AEs incidence and management. 


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3.0 STUDY OBJECTIVES 
 
3.1 
Primary Objective 
The primary objective of the study is to compare the efficacy of BAT1706 and EU-Avastin® 
given with chemotherapy as first line treatment using the ratio or the difference in ORR to 
show clinical equivalence. 
 
3.2 
Secondary Objectives 
The secondary objectives of the study are as follows: 
• To further evaluate the efficacy of BAT1706 and EU-Avastin® given with 
chemotherapy using ORR at different time points, duration of response (DoR), PFS, 
and OS (time and rate) at 12 months. 
• To evaluate the safety and immunogenicity of BAT1706 and EU-Avastin®. 
• To characterize bevacizumab exposure after administration of BAT1706 and EU-
Avastin®. 
 
3.3 
Exploratory Objective 
• To explore population pharmacokinetics (popPK). 


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4.0 INVESTIGATIONAL PLAN 
 
4.1 
Summary of Study Design 
This is a Phase III, randomized, double-blind, multicenter, active comparator, parallel two-arm 
study to compare BAT1706 plus paclitaxel and carboplatin (Arm A) versus EU-Avastin® plus 
paclitaxel and carboplatin (Arm B). To start the screening procedures and to be enrolled, all 
patients will sign the informed consent form (ICF) and have their target lesion confirmed 
measurable by independent central imaging review (CIR) performed by the imaging vendor. 
After stratification for disease stage, gender, and ethnicity (Asian vs non-Asian), eligible 
patients with previously untreated metastatic, or recurrent nsNSCLC, will be randomized in a 
1:1 ratio to Arm A or Arm B. 
After up to 6 cycles of combination therapy are given, all patients with complete response (CR), 
partial response (PR) or stable disease (SD) will receive maintenance monotherapy with 
BAT1706 or EU-Avastin® until Investigator-assessed disease progression, excessive toxicity, 
Investigator’s judgment, withdrawal of consent, lost to follow-up, death, start of a new 
anticancer therapy, study termination by the  Sponsor,  or  for  a  maximum  of  12 months (17 
cycles)  of treatment,  whichever occurs  first.  Patients intolerant to chemotherapy after  2 dose 
reductions can start monotherapy with BAT1706 or EU-Avastin® or start another line of anti-
cancer therapy after investigator’s judgment. 
A DSMB will review all safety data after the first 20 patients have been treated for 6 weeks in 
each arm; then after, if no unexpected safety signal was identified, the study will continue and 
the safety data will be reviewed at regular intervals after approximately every 200 patients are 
evaluated after they received the first 4 cycles (see Section 6.2.4). 
During the conduct of the study, tumor response will be assessed by the local Investigator 
and/or radiologist according to Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST 1.1; see Appendix 13.4) for immediate therapeutic decision. However, the primary 
efficacy analysis will be based upon the evaluation of tumor response as determined by CIR. 
Patients will undergo tumor assessment at Weeks 6, 12 and 18, regardless of the number of 
cycles actually completed, then after every 3 cycles (approximately every 9 weeks) and at 
Safety Follow-up Visit (SFUV)/End of Treatment (EoT). Window for tumor assessment is    1 
week at the maximum during the first 18 weeks. The main efficacy analyses (difference and 
ratio of ORR) will be based upon tumor response at Week 18 (ORR18) as determined by CIR 
according to RECIST 1.1. Response at Week 6 and at Week 12 will also be evaluated by CIR 
to provide ORR6 and ORR12 to show the pattern of response. After Week 18, patients with 
responding or stabilized disease will remain in the study up to 12 months to provide further 


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comparative safety/immunogenicity data as well as other efficacy parameters (such as DoR, 
PFS and OS rates at 12 months for both BAT1706 and EU-Avastin®). 
A SFUV/EoT visit will take place 28 days ± 2 days after the last dose during the study with a 
maximum at Week 53. Patients who are still benefiting of therapy after 12 months of treatment 
will have the option to continue treatment with BAT1706 as of Week 53 after SFUV 
(regardless of the arm they were assigned to at randomization) in a Long-term extension (LTE) 
study until disease progression, excessive toxicity, withdrawal of consent, Investigator’s 
decision, or for an additional 12-month period (ie, for a maximum of 24 months from initial 
randomization). 
The study will be conducted according to the national and international ethical standards, and 
the protocol will be approved by the IRBs/IECs of the participating sites. 
Planned number of patients 
Approximately 632 patients will be enrolled including a subgroup of 200 patients for PK and 
popPK (from samples collected only at designated sites in China, Turkey, and Ukraine). 
Study duration 
After the patient has signed the ICF, there will be a 21-day Screening period to confirm 
eligibility. All patients will be treated in the study until progression, excessive toxicity, 
withdrawal of consent, Investigator’s decision, or for a maximum total duration of 12 months 
(up to 17 cycles), whichever occurs first. Then after, patients who still benefit of therapy can 
receive BAT1706 as of Week 53 in the LTE study until disease progression, excessive toxicity, 
withdrawal of consent, Investigator’s decision, or for 12 additional months (ie, for up to a 
maximum of 24 months from initial randomization) with the EoT Visit at Week 104 at the 
latest. 
A schematic of the study design is presented in Figure 1. The Schedule of Events is presented 
in Table 1. The schedule of PK, anti-drug antibody (ADA), and neutralizing anti-drug antibody 
(NADA) blood sampling is presented in Table 2. 


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EU-Avastin® 
Maintenance Period 
(up to 12 months from initial 
randomization) 
 
Figure 1 
Schematic of the Study Design 
 
 
 
 
Stratification 
and 
double-blind 
randomization 
Tumor assessment at Weeks 6, 12 and 18, then every 9 weeks 
 
 
Cycle 
C1 
C2 
C3 
C4 
C5 
C6 
C7 
C8 
C9 
C10 
C11 
C17 
 
 
 
 
LTE 
 
 
LTE until up to 
24 months from 
initial randomization 
 
 
BAT1706 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 
31 
49 
53 
Survival Follow-up 
 
 
 
 
 
Combination treatment period up to Week 18 (maximum 6 cycles), and maintenance period for a maximum of 12 months from initial 
randomization (up to a total of 17 cycles); then maintenance with BAT1706 in the LTE study up to 24 months from initial randomization. 
Note: To be eligible, patients must meet all I/E criteria. Patients must have at least one measurable lesion per CIR according to RECIST 1.1. and no known EGFR mutation/ALK 
receptor alteration. If positive or unknown EGFR mutation/ALK receptor alteration, chemotherapy must be standard first line therapy in the institution. 
Abbreviations: ALK = anaplastic lymphoma kinase; CIR = central imaging review; EGFR = epidermal growth factor receptor; EU = European Union; I/E = inclusion/exclusion; 
RECIST 1.1 = Response Evaluation Criteria in Solid Tumors version 1.1; LTE = long-term extension. 
Arm B: (316 patients) 
Combination Treatment Period 
EU-Avastin®+ paclitaxel + carboplatin 
(up to 6 cycles) 
Arm A: (316 patients) 
Combination Treatment Period 
BAT1706 + paclitaxel + carboplatin 
(up to 6 cycles) 
BAT1706 
Maintenance Period 
(up to 12 months from initial 
randomization) 


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Table 1 
Schedule of Events 
 
Assessments 
Screening 
Treatment Perioda 
Maintenance 
Perioda 
SFUVs/ 
EoT Visitb 
LTE Studyc EoT 
Visitb 
Cycle 
NA 
1 
2 
3 
4 
5 
6 
7 to 17 
28 days 
from last 
dose or 
Week 53 at 
the latest 
Cycle 18 onward 
Week 
-3 to -1 
1-3 
4-6 
7-9 
10-12 
13-15 
16-18 
19 to 49 
Week 53 up to 
104 
Day 
-21 to -1 
1-21 
22-42 
43-63 
64-84 
85-105 
106-126 
127 to 343 
Written informed consent 
X 
Eligibility assessment including 
central imaging review 
X 
X 
EGFR mutation and ALK receptor 
alteration status 
X 
Demographicsd 
X 
Relevant medical/surgical historye 
X 
LABORATORY/SAFETY 
ASSESSMENTSf 
Infection Screeng 
X 
Hematologyh 
X 
Day 1 
and 8 
Day 1 
and 8 
Day 1 
and 8 
Day 1 
and 8 
Day 1 
and 8 
Day 1 
and 8 
Day 1 
X 
Day 1 
Chemistry, coagulation, and urine 
test h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Pregnancy Testi 
X 
X 
Urine Pregnancy Testj 
X 
X 
Day 1 Q6W 
Day 1 Q6W 
Vital Signsk 
X 
Day 1 
and 8 
X 
X 
X 
X 
X 
Day 1 
X 
Day 1 
Physical Examinationl 
X 
Day 
1 
and 8 
X 
X 
X 
X 
X 
Day 1 
X 
Day 1 
12-Lead ECGm 
X 
X 
X 
X 
X 
X 
X 
X 
AE/AESI and SAE Reviewn 
X 
Continuous assessment 
Previous/concomitant 
medicationso 
X 
Continuous assessment 


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Assessments 
Screening 
Treatment Perioda 
Maintenance 
Perioda 
SFUVs/ 
EoT Visitb 
LTE Studyc EoT 
Visitb 
Cycle 
NA 
1 
2 
3 
4 
5 
6 
7 to 17 
28 days 
from last 
dose or 
Week 53 at 
the latest 
Cycle 18 onward 
Week 
-3 to -1 
1-3 
4-6 
7-9 
10-12 
13-15 
16-18 
19 to 49 
Week 53 up to 
104 
Day 
-21 to -1 
1-21 
22-42 
43-63 
64-84 
85-105 
106-126 
127 to 343 
DISEASE ASSESSMENTS 
Tumor Assessment 
(RECIST 1.1)p 
X 
Weeks 6, 12, 18 
Weeks 27, 36, 
45 
Xq 
Xr 
ECOG performance status 
X 
X 
X 
Day 1 Q6W 
X 
Survivals 
Every 3 months 
OTHER ASSESSMENTS 
Serum PK samplingt 
X 
Day 1 Q9W 
(X) 
ADA/NADAu before therapy 
X 
Day 1 Q9W 
(X) 
(X) 
STUDY TREATMENT 
Randomizationv 
X 
BAT1706 or EU-Avastin®w 
X 
X 
X 
X 
X 
X 
Day 1 
Day 1 (BAT1706 
only) 
Carboplatin/Paclitaxel after 
premedication and after 
BAT1706 or EU-Avastin® 
Xx 
X 
X 
Xy 
(Xy ) 
(Xy ) 
Abbreviations: ADA = anti-drug antibody; AE = adverse event; AESI = adverse event of special interest; ALK =  anaplastic lymphoma kinase;  ALP  = alkaline phosphatase;  ALT 
= alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; CIR = central imaging review; CT = computed tomography; ECG = 
Electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EGFR = epidermal growth factor receptor; EoT = End of Treatment; EU = 
European Union; HIV = human immunodeficiency virus; INR = international normalized ratio; IV = intravenous(ly); LTE = long-term extension; MRI = magnetic resonance imaging; 
NADA = neutralizing anti-drug antibody; PET = positron emission tomography; PK = pharmacokinetic(s); popPK = population pharmacokinetics; PT = prothrombin time; Q6W = 
every 6 weeks; Q9W = every 9 weeks; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors version 1.1; SAE = serious adverse event; SFUV = Safety Follow-up Visit. 
a Day 1 of each cycle should be planned on Day 22 after the previous cycle was given (ie, an interval of 21 days) with a maximum window of -1 up to +3 days. During the combination 
treatment period, efforts should be made to conduct study visits on the day scheduled with a maximum time window of -1 up to + 3 days for Day 1 of each cycle (except Cycle 
1), and for Day 8 of each cycle. During the maintenance period, visits should occur as scheduled with a maximum window of -1 up to + 3 days for Day 1 of each cycle. Please 
refer Table 2 for time window for PK samplings. 


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b All patients who received at least one infusion of BAT1706 or EU-Avastin® will attend the SFUV/EoT visit while on main study 28 days ± 2 days after last dose. For patients 
continuing in the LTE study after one-year therapy, an SFUV will be conducted at Week 53 before they start therapy in the LTE study. During the LTE study, the EoT Visit 
will take place 28 days ± 2 days after last dose is administered and at the latest at Week 104. 
c Patients who are still benefiting of therapy after 12 months of treatment will be transferred to a LTE study to receive BAT1706 treatment up to a total of 24 months as of 
randomization in initial study. The visit window for LTE visits is -1 to +7 days. All tests are to be performed as indicated until the patient starts another anticancer therapy. 
d Demographics will include the collection of date of birth, gender, and ethnicity. 
e Medical history will include lung cancer history and other past and current medical disease with clinical significance. Prior anticancer treatments, including adjuvant chemo and/or 
radiotherapy, should also be recorded in the eCRF. 
f 
All clinical laboratory tests (hematology [complete blood cell count (CBC) including hemoglobin, hematocrit, platelets, lymphocytes, neutrophils with differential]; serum 
chemistry [creatinine, AST, ALT, ALP, gamma-glutamyl transpeptidase, total bilirubin, direct bilirubin, glucose, total cholesterol, total protein, albumin, sodium, potassium, 
chloride, calcium], coagulation [INR and aPTT or PT], and urinalysis [protein, glucose, and blood]) will be performed at the local laboratory. Laboratory samples must be drawn 
prior to infusion of premedication and study treatment. In case therapeutic doses of anti-coagulants are started during the treatment period, coagulation tests will be repeated no 
more than 3 days prior to each cycle. Urine dipstick will be assessed 7 days prior to randomization and then every 6 weeks during the treatment period. In case proteinuria is 
observed, 24-hour urine test should be performed. 
Written informed consent must be required for performing any study-specific tests or procedures. Results of standard of care tests or examinations performed prior to obtaining 
informed consent and within 28 days prior to Cycle 1 Day 1 may be used for screening assessments rather than repeating such tests. 
g Infection screen will include serum virology of Hepatitis B and C, HIV, syphilis and tuberculosis to be performed according to local practice and local regulatory guidance. 
Infection screen within -21 days of patient consent of screening is acceptable. 
h At Screening, a first set of laboratory tests will take place as soon as a patient starts the screening procedures. In case CBC was done > 7 days prior to Day 1 of Cycle 1, CBC  will 
be repeated to confirm eligibility. For subsequent cycles, all laboratory tests must be performed within a maximum of 3 days prior to Day 1 of each cycle (i.e., before BAT1706 
or EU-Avastin® administration). The results must be available before each study drug infusion. Hematology test will be repeated on Day 8 of each cycle during combination 
therapy. 
i 
For female of child-bearing potential, serum pregnancy test will be performed within 7 days prior to first dose at Screening, during the treatment period in case of positive urine 
test, and at EoT Visit. In case of suspected pregnancy, a serum pregnancy test must be performed. 
j 
For female of child-bearing potential, urine pregnancy test will be performed every 6 weeks. Serum pregnancy test will be performed if a urine pregnancy test is positive. 
k Assessments will include blood pressure (5 minutes rest before start of measurement), pulse rate, and body temperature. 
l 
A comprehensive physical examination (including general appearance, abdomen, head and neck, eyes, ears, nose, throat, chest/respiratory, heart/cardiovascular, 
gastrointestinal/liver, musculoskeletal/extremities, skin, thyroid/neck, lymph nodes, and neurological/psychiatric) will be performed at Screening and at the visits indicated. 
Height will be measured at screening only. Weight will be measured at Screening and then every cycle for body surface area adjustment of dose, if change is ≥ 10%. 
m  A computerized 12-lead ECG will be performed with the patient in a supine position after the patient has rested comfortably for at least 5 minutes (if paper format a copy must be 
available). Additional ECG will be performed if clinically indicated. 
n For AEs, patients will be evaluated from the time of signing informed consent through 28 days after the last study treatment or up to Week 53 after randomization. However, SAEs 
assessed as related to study treatment or study procedures will be collected through the last day of study participation and followed until the events are resolved, return to baseline, 
stabilize, or the patient is lost to follow-up, whichever occurs first. During the LTE study, only AEs of special interest and SAE until 28 days after the subject’s last dose will 
be collected (see Section 6.2.1.2) up to Week 104 after randomization. 
o Concomitant medications will be recorded from the time of signing informed consent through 28 days after last study treatment. 


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p Tumor assessment for confirmation of the presence of a measurable target lesion must be performed at baseline by CIR before the patient can be randomized. Tumor assessment 
includes CT or MRI of at least the chest and abdomen (including the adrenals and the liver using the same method throughout the whole study). Brain CT or MRI scan, and 
bone scans or X-rays should be performed at Screening if clinically indicated and during the treatment period as clinically indicated. If the bone scan is positive at screening, it 
will be repeated at no less than 12-week intervals. Plain X-ray can be used at time of intercurrent regular tumor assessments as clinically indicated. PET scans are not accepted 
as sole method for assessment of efficacy but can be used to identify new lesions if a baseline PET scan was done. Tumor assessments will occur at Weeks 6, 12 and 18, 
regardless of the number of cycles actually received (with a visit window of 1 week maximum during the first 18 weeks), then after every 3 cycles (approximately every 9 weeks 
[assessed within Days 15-21 after the third cycle treatment is given]). The results must be available for treatment decision before the planned next cycle. If a patient is unable 
to undergo a contrast CT due to allergy or renal insufficiency during follow-up, a chest CT without contrast, combined with MRI images of the target lesions with gadolinium 
contrast, is preferred if tolerated by the patient. 
Patients who discontinued study drug without disease progression will continue to undergo tumor assessments until disease progression. 
Tumor imaging (CT or MRI scan) within 28 days before randomization is acceptable if the CT or MRI scan was performed with an imaging format that meets the CIR 
requirements. Bone scan within 3 months before randomization is acceptable if the bone scan was performed with an imaging format that meets the CIR requirements. If the 
patient has bone lesions identified by bone scan within 3 months before randomization he/she will have plain X-ray of bone lesions during the 21-day screening period. X-ray 
will be repeated at each tumor assessment (Weeks 6, 12, 18, etc.) and bone scan will be repeated at no less than 12-week intervals. 
q 
Tumor assessment at the SFUV/EoT Visit is only necessary if more than 4 weeks have passed since the previous assessment. 
r 
During LTE study period, tumor assessment will be performed at Investigator’s discretion until disease progression, withdrawal of consent, Investigator’s decision or up to   
24 months after randomization, whichever occurs first. 
s 
After SFUV/EoT visit, survival will be monitored via telephone call every 3 months up to 24 months after randomization. 
t 
The PK and popPK analysis will be explored in a subgroup of 200 patients. Please refer to Table 2 for more details on the time points of PK blood samples. 
u 
Please refer to Table 2 for the details on the time points of ADA/NADA blood samples. 
v 
Patients will be randomized within 3 days before Day 1 of Cycle 1 (baseline). 
w 
BAT1706/EU-Avastin® will be administered on Day 1 of each cycle (every 21 days) prior to administration of paclitaxel and carboplatin. 
x 
The drug sequence is as follows: Only BAT1706 or EU-Avastin® are administered on Day 1 of Cycle 1, and paclitaxel and carboplatin are given on Day 2. As of Cycle 2, 
BAT1706 or EU-Avastin® is given first, then paclitaxel followed by carboplatin on the same day. 
y 
Patients intolerant to chemotherapy after 2 dose reductions can start monotherapy with BAT1706 or EU-Avastin® or start another line of anti-cancer therapy after investigator’s 
judgment. 


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Table 2 
Pharmacokinetice, Anti-drug Antibodyf, and Neutralizing Anti-drug Antibodyf Sampling Time Points 
 
Date 
Allowed window 
period 
Event 
PK Sampling 
(4 mL per 
sample) 
ADA/NADA 
Sampling 
(6 mL per 
sample) 
Cycle 1 
Day 1 
Up to -7 days 
prior to infusiona 
X 
X 
+15 minutes 
end of infusionc 
X 
Day 4 
±1 day  
at the time equivalent to the prior infusion approximate start time on Day 1b 
X 
Day 8 
±1 day  
at the time of blood sampling for laboratory tests 
X 
Day 15 
±1 day  
at the time equivalent to the prior infusion approximate start time on Day 1b 
X 
X 
Cycle 2 
Day 1 
Up to -3 days 
Prior to the start of the Cycle 2 infusion, at the time of blood sampling for 
laboratory tests 
X 
Cycle 3 
Day 1 
Up to -3 days 
Prior to the start of the Cycle 3 infusion, at the time of blood sampling for 
laboratory tests 
X 
X 
Cycle 4 
Day 1 
Up to -3 days 
Prior to the start of the Cycle 4 infusion, at the time of blood sampling for 
laboratory tests 
X 
Cycle 5 
Day 1 
Up to -3 days 
Prior to the start of the Cycle 5 infusion, at the time of blood sampling for 
laboratory tests 
X 
X 
Cycle 6 
Day 1 
Up to -3 days 
Prior to the start of the Cycle 6 infusion, at the time of blood sampling for 
laboratory tests 
X 
+15 minutes 
end of infusionc 
X 
Day 4 
±1 day  
at the time equivalent to the prior infusion approximate start time on Day 1b 
X 
Day 8 
±1 day  
at the time equivalent to the prior infusion approximate start time on Day 1b 
X 
Day 15 
±1 day  
at the time equivalent to the prior infusion approximate start time on Day 1b 
X 
Cycle 7 
Day 1 
Up to -3 days 
Prior to the start of the Cycle 7 infusion, at the time of blood sampling for 
laboratory tests 
X 
X 
After Cycle 7 
Day 1 
Up to -3 days 
Prior to the start of the cycle infusion, at the time of blood sampling for 
laboratory tests 
Every 9 weeks 
up to Week 53 
Every 9 weeks 
up to Week 53 
SFUV/EoT Visit 
28 days from 
last dose 
±2 days  
at the time of blood sampling for laboratory tests 
Xd 
Xd 
Abbreviations: ADA = anti-drug antibody; NADA = neutralizing anti-drug antibody; PK = pharmacokinetic(s); EoT = End of Treatment; SFUV = Safety Follow-up Visit. 
a. 
Blood samplings at Day 1 of Cycle 1 before infusion can be made within 7 days prior to dosing at time of laboratory tests. 
b. 
Efforts should be made to collect blood samples approximately at the same time as the time of prior infusion on Day 1 at Cycle 1 and on Day 1 at Cycle 6. 
c. 
Blood sampling should be taken from the opposite arm of that used for the infusion. 
d. 
In case a patient is tested positive for ADA/NADA at the EoT visit or at SFUV 12 months after the first dose, whichever comes first, ADA/NADA blood samples should continue to be collected 
every 9 weeks until 2 tests are negative (no later than 24 months after randomization). In case the first positive ADA/NADA result is found at the SFUV/EoT Visit, one PK sampling will be collected. 
e. 
Blood samples will be collected only at designated sites in China, Turkey, and Ukraine. 
f. 
Blood samplings for ADA/NADA will be collected in all patients. 


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4.2 
Discussion of Study Design 
This is a Phase III, randomized, double-blind, multicenter, active comparator, parallel two-arm 
study to compare the efficacy, and to evaluate the safety and immunogenicity of BAT1706 to 
EU-Avastin® in patients with previously untreated advanced nsNSCLC to demonstrate clinical 
equivalence of BAT1706 with EU-Avastin®. The design of the study complies with US FDA, 
CFDA, and EMA guidelines for the demonstration of clinical equivalence of biologic products. 
Eligible patients will be randomized in a 1:1 ratio to receive BAT1706 plus paclitaxel and 
carboplatin or EU-Avastin® plus paclitaxel and carboplatin. To ensure a high degree of 
compliance to eligibility criteria, a CIR is made before randomization to confirm the target 
lesion is measurable according to RECIST 1.1. 
Paclitaxel + carboplatin + Avastin® is one of the standard first-line chemotherapy regimens for 
advanced nsNSCLC patients without known EGFR mutation or ALK receptor alteration. The 
sample size was calculated based on equivalence margins derived from reference studies as 
discussed in Section 9.1. Randomized patients will be assigned to receive either BAT1706 or 
EU-Avastin® throughout the study. No crossover is allowed. The randomization is used to 
ensure that the outcome is not affected by known and unknown differences in prognostic 
factors between treatment arms. Patients will remain in the study for a maximum duration of 
12 months after which, patients who still tolerate and benefit of the treatment will have the 
option to continue treatment with BAT1706 as of Week 53 after SFUV (regardless of the arm 
they were assigned to at randomization) in a LTE open label study until disease progression, 
excessive toxicity, withdrawal of consent, Investigator’s decision, or for a maximum of 12 
additional months (ie, for up to 24 months from initial randomization). 
The double-blind will be maintained throughout the study to avoid bias in the assessment of 
the primary endpoint of tumor measurement and minimize any other bias that could be 
introduced by knowledge of the treatment by either the Investigator or the patient. The blind 
can be broken any time for emergency safety reasons only. 
 
4.3 
Selection of Study Population 
The ICF must be signed before starting any screening procedure. The measurability of the 
target lesion must be confirmed by the independent CIR before randomization can occur. 
 
4.3.1 
Inclusion Criteria 
Patients will be randomized only if they meet all of the following criteria: 
1. Age ≥ 18 years. 


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2. Stage IV nsNSCLC or recurrent disease (any stage at initial diagnosis) no longer amenable 
to curative surgery or local therapy (histologically or cytologically confirmed). 
3. No prior systemic therapy for metastatic disease. Prior systemic therapy and/or 
radiotherapy for locally advanced disease is permitted if completed ≥ 6 months prior to the 
diagnosis of relapsing disease. 
4. Tumors without EGFR mutation or ALK receptor alteration. Patients with unknown 
mutation status or known EGFR mutation or ALK receptor alteration may be included 
provided the corresponding targeted agent is not available and chemotherapy is the 
standard of care of the study center. 
5. At least one measurable target lesion according to RECIST 1.1 (Appendix 13.4) as 
confirmed by CIR; bone-only and brain-only metastases are not allowed. Lesions 
previously treated with radiotherapy are non-target lesions unless clear progression was 
documented. 
6. Eastern Cooperative Oncology Group performance status of 0 or 1 and life expectancy 
> 3 months based on Investigator’s judgment. 
7. Adequate hematological function, defined as: 
• Platelet count ≥ 100,000/µL without the need for transfusion in the 2 weeks prior to 
Screening. 
• Prothrombin time (PT), International normalized ratio (INR) or activated partial 
thromboplastin time (aPTT) < 1.5 × the upper limit of normal  (ULN). 
• Absolute neutrophil count ≥ 1,500/µL  without any medical interventional treatment (ie, 
granulocyte-colony stimulating factors [G-CSFs] and/or herbal remedies). 
• Hemoglobin ≥ 9 g/dL, without the need for transfusion in the 2 weeks prior to 
Screening. 
8. Adequate hepatic function as evidenced by meeting all of the following requirements: 
• Total bilirubin: ≤ 1.5 × ULN. 
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline 
phosphatase (ALP): ≤ 3 × ULN. 
• If liver metastases are present, ALT or AST ≤ 5 × ULN; if liver and/or bone metastases 
ALP ≤ 5 × ULN. 
9. Adequate renal function, as evidenced by meeting all of the following requirements: 


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• Serum creatinine ≤ 1.5 × ULN and creatinine clearance > 50 mL/minute or estimated 
glomerular filtration rate (GFR) > 50 mL/minute. 
• Urine dipstick for proteinuria of less than 2+ (other ways of urinalysis are also 
acceptable); if urine dipstick is ≥ 2+, proteinuria must be < 2 g in 24 hours or an 
equivalent protein/creatinine ratio of < 2000 mg/g creatinine (or < 226.0 mg/mmoL 
creatinine). 
10. Female patients with childbearing potential (excluding women who have undergone 
surgical sterilization or menopause. Menopause is defined as the status where no menstrual 
periods continue for 1 year or more without any other medical reasons), are eligible if they 
have negative serum pregnancy testing within 7 days prior to first dosing and are willing 
to use an  effective  method  of  birth  control/contraception  to  prevent  pregnancy until 3 
months after the end of study. Male patients must consent using effective method of 
contraception until 3 months after the end of study. 
Note: Contraceptive methods that are considered highly effective are, for example, total 
abstinence, an intrauterine device, a double-barrier method (such as condom plus 
diaphragm with spermicide, a contraceptive implant, hormonal contraceptives 
[contraceptive pills, implants, transdermal patches, hormonal vaginal devices, or injections 
with prolonged release], or have a vasectomized partner with confirmed azoospermia). 
 
4.3.2 
Exclusion Criteria 
Patients will not be entered in the study for any of the following reasons: 
1. Diagnosis of small cell carcinoma of the lung, mixed predominant (>50% of tumor cells) 
squamous cell carcinoma of the lung, or NSCLC not otherwise specified. 
2. Known ROS-1 positive tumor. 
3. Tumor cavitation, tumor invading into large blood vessels or close to large vessels with an 
increased risk of bleeding, according to Investigator’s judgment. 
4. Prior therapy with monoclonal antibodies or small molecule inhibitors against VEGF or 
VEGFR, including Avastin®. 
5. Prior systemic therapy for metastatic disease. 
6. Prior systemic anticancer therapy, or radiotherapy for locally advanced nsNSCLC if 
completed < 6 months prior to the diagnosis of relapsing disease. 


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7. Previous malignancy other than NSCLC in the last 5 years except for basal cell cancer of 
the skin or pre-invasive cancer of the cervix. 
8. Known brain metastasis or other CNS metastasis that is either symptomatic or untreated. 
Metastases that have been treated by complete resection and/or radiotherapy demonstrating 
stability or improvement are not an exclusion criterion provided they are stable as shown 
by computed tomography (CT)  or magnetic resonance imaging (MRI)  scan for at least  4 
weeks before Screening without evidence of cerebral edema. Patients on stable dose of 
corticosteroids or anticonvulsants are permitted. 
9. Any unresolved toxicity > Grade 1 (except alopecia) from previous anticancer therapy 
(including radiotherapy). 
10. History of hemoptysis (> 1/2 teaspoons per event over the past 6 months) or evidence of 
inherited bleeding diathesis or coagulopathy with the risk of bleeding. Clinically non-
significant minor bleeding is acceptable. 
11. A significant thrombotic or hemorrhagic event ≤ 6 months prior to Screening (includes 
hemoptysis [> 2.5 mL of red blood], gastrointestinal bleeding, hematemesis, CNS 
hemorrhage, severe epistaxis or vaginal bleeding, cerebral infarction, transient ischemic 
attacks, myocardial infarction, angina, and uncontrolled coronary artery disease). 
12. Current or recent (within 10 days of first dose of study drugs) use of full dose oral or 
parenteral anticoagulants or other thrombolytic agents for therapeutic (as opposed to 
prophylactic) purposes, clinically serious non-healing wounds, or incompletely healed 
bone fracture. 
13. Known hypersensitivity to any of the study drugs or their excipients, or history of clinically 
significant atopic allergy (eg, asthma including childhood asthma, urticarial). 
14. Live/attenuated vaccine within 12 weeks prior to the Screening Visit. 
15. History of myocardial infarction (≤ 6 months prior to Screening), unstable angina, New 
York Heart Association Grade II or greater, congestive heart failure, or serious cardiac 
arrhythmia requiring medication. 
16. History of poorly controlled hypertension or resting blood pressure > 150/100 mmHg in 
the presence of a stable regimen of antihypertensive therapy. 
17. Any major surgical procedure (risk of bleeding or wound healing complications) within 28 
days prior to the first dose or anticipated elective surgery during the  study and until   3 
months after the last dose of study drug. 


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18. History of active gastroduodenal ulcer, abdominal fistula as well as non-gastrointestinal 
fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to 
Screening. 
19. Clinically significant active infection requiring systemic therapy. 
20. Active Hepatitis B infection (according to local site standards) or active Hepatitis C 
infection (Hepatitis C virus [HCV] antibody positive); the patient could be included in the 
study if he/she is HCV RNA negative, details see Section 6.2.2. 
21. Human immunodeficiency virus (HIV) infection, syphilis, or active tuberculosis infection. 
Screening for HIV, syphilis, and tuberculosis to be performed according to local practice 
and local regulatory guidance. 
22. Patient considered unsuitable for inclusion by the Investigator (eg, inability to understand 
and/or comply with study requirements or presence of any condition, which, in the opinion 
of the Investigator, would not allow safe participation in the study). 
23. Pregnant or lactating women. 
24. Poor oral hygiene that may require surgical intervention during the study or any planned 
dental interventions during the study until 1 month after last dose of study drug. 
25. Use of: 
• Anti-infective drugs: within 5 days for drugs from the Western pharmacopeia, 
prior to the first administration of study drug. The patient is eligible provided the 
infection is under control. 
For China sites only: 
• Anti-infective drugs: within 10 days for Chinese herbal medicines or Chinese patent 
medicines prior to the first administration of study drug. The patient is eligible 
provided the infection is under control. 
• Anti-cancer or immune-stimulating agents from Chinese herbal medicines or 
Chinese patent medicines: within 10 days prior to the first administration of study 
drug. In case of relapsing disease, if the anti-cancer Chinese herbal medicines or 
Chinese patent medicines were given for documented new lesions diagnosed less 
than 6 months after prior chemotherapy for local disease, the patient is not eligible. 
26. Patients who required permanent oral anticoagulation (eg, warfarin, rivaroxaban, 
dabigatran, acenocumarol, etc.) treatment. 


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27. Any person who is: 
• an employee of the Principal Investigator, study center, IQVIA or Sponsor. 
• a relative of an employee of the study center, the Investigators, IQVIA or the Sponsor. 
 
4.3.3 
Subject Restrictions 
Patients should agree on the following: 
• Refrain from strenuous exercise (including contact/collision sports) for 72 hours prior 
to randomization and for the duration of the study. 
• Adhere to study requirements for contraceptives. 
• Adhere to the concomitant medication restrictions (excluded medications are specified 
in Section 5.8.1). 
• Ability to stop regular use of aspirin (> 325 mg/day) or other non-steroidal anti-
inflammatory drugs (NSAIDs) with antiplatelet activity or treatment with dipyramidole, 
ticlopidine, clopidogrel or cilostazol within 10 days of first dose of study drug. 
• Ability to stop oral, inhaled or topical corticosteroids, or to limit the dose to not exceed 
10 mg/day prednisolone or equivalent. During the 4 weeks prior to Day 1, the dose 
must be stable. 
• Willingness to stop traditional anticancer or anti-infective remedies after ICF is signed 
during the conduct of the study. 
Surgical procedures 
For elective surgery during the study, the interval between termination of the bevacizumab 
infusion and subsequent elective surgery should be at least 28 days. If emergency surgery is 
performed, precautions should be taken to minimize the potential risk of bleeding and 
thrombosis associated with this class of agents, infusion should be stopped and close 
monitoring for bleeding, wound healing and thromboembolic complications should be initiated. 
Patients with anticipated elective surgery will not be enrolled into the study. 
 
4.3.4 
Subject Withdrawal 
In the event of any of the following conditions, study drug (BAT1706 or Avastin®) should not 
be administered and the patient should be permanently withdrawn from the study: 


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• Gastrointestinal perforations (gastrointestinal perforations, fistula formation in the 
gastrointestinal tract, intra-abdominal abscess) and fistula formation involving an 
internal organ. 
• Wound dehiscence and wound healing complications requiring medical intervention. 
• Serious hemorrhage (ie, requiring medical intervention). 
• Severe arterial thromboembolic events. 
• Life-threatening (Grade 4) venous thromboembolic events, including pulmonary 
embolism. 
• Hypertensive crisis or hypertensive encephalopathy. 
• Posterior Reversible Encephalopathy Syndrome. 
• Nephrotic syndrome. 
• At least 4 weeks prior to elective surgery. 
• Severe hypertension not controlled with medical management. 
• Proteinuria (≥ 2 g/24 hours) persisting despite interruption of BAT1706 or Avastin®. 
• Severe infusion reactions (≥ Grade 3). 
• Patient who become pregnant during the course of the study. 
• Treatment delay of > 6 weeks (> 9 weeks interval between 2 administrations). 
All patients are free to withdraw from participation in the clinical study at any time, for any 
reason, specified or unspecified, and without prejudice to further treatment. The criteria for 
enrollment are to be followed explicitly. If a patient who does not meet enrollment criteria is 
inadvertently enrolled, the Sponsor or Sponsor designee must be contacted. An exception may 
be granted in rare circumstances where there is a compelling safety reason to allow the patient 
to continue. In these rare cases, the Investigator must obtain documented approval from the 
Sponsor or Sponsor designee to allow the patient to continue in the study. 
In addition, patients will be withdrawn from study drug and from the study in the following 
circumstances: 
• The Investigator decides that the patient should be withdrawn. If this decision is made 
because of an intolerable AE or a clinically significant laboratory value, the study drug 


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is to be discontinued and appropriate measures are to be taken. The Sponsor or Sponsor 
designee is to be notified immediately. 
• The patient is unwilling to continue in the study. 
• Lack of compliance with protocol. 
• The Investigator or the Sponsor, for any reason, stops the study. 
If a patient discontinues study treatment, he/she will have the EoT Visit procedures and 
survival follow-up performed as shown in the Schedule of Events (Table 1). All patients will 
be followed for survival, until death or the end of the study 24 months after randomization, 
whichever is earlier. If a patient withdraws consent, the date and primary reason will be 
documented in the source documents. Patients who withdraw consent before the first tumor 
assessment will be replaced. 


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5.0 STUDY TREATMENTS 
 
5.1 
Treatments Administered 
Investigational Medicinal Product 
BAT1706 will be supplied as 100 mg/4 mL. The dose is 15 mg/kg. 
Comparator 
EU-Avastin® will be supplied as 100 mg/4 mL. The dose is 15 mg/kg. 
Concomitant drugs 
The initial dose of paclitaxel is 200 mg/m². However, for Chinese patients (according to local 
label), paclitaxel will be administered at a dose of 175 mg/m².  
In  all  patients,  the  initial  dose  target  of  carboplatin  is  area  under  the  curve  (AUC)    6 
mg/mL·minute.  
For all patients in case of anticipated excessive toxicity (eg, elderly patients, prior toxicity 
during chemo-radiotherapy), the Investigator may start the first course of chemotherapy using 
paclitaxel at a dose of 175 mg/m² (or use a paclitaxel dose of 200 mg/m² after prophylactic 
administration of G-CSF), and/or carboplatin AUC 5 mg/mL·minute.  
Mode of Administration 
• BAT1706 or EU-Avastin® infusion must be administered first, ie, prior to the 
administration of paclitaxel and carboplatin. The prepared infusion solutions will be 
administered as an IV infusion through a dedicated line. It must NOT be administered 
as an IV push or bolus. Drug infusions will take place under the close supervision of 
an experienced physician, and in an environment where full resuscitation facilities are 
immediately available. At the end of each infusion, the IV line must remain in place for 
at least 1 hour to allow administration of IV drugs, if necessary. The initial dose for the 
first BAT1706 or EU-Avastin® infusion should be delivered over 90 minutes. If the first 
infusion is well tolerated, the second and subsequent infusion may be administered over 
60 minutes. Drug administration start/stop and dosing amounts will be recorded in the 
electronic case report form (eCRF). No dose modifications are allowed. No more than 
6-week delay is allowed (maximum of 9 weeks between 2 administrations). 
• Paclitaxel infusion is recommended to be given IV over 3 hours or according to local 
standard practice or package inserts after adequate pre- and concomitant prophylactic 
medication (see details in Section 5.6.1.1). Please refer to the prescribing information 


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for the formulation, preparation, and storage of paclitaxel.14 Dose modifications are 
allowed twice according to the guidelines in Section 5.6.1.3. 
• Carboplatin is administered intravenously according to local standard practice or 
package insert after the end of paclitaxel infusion. Please refer to the prescribing 
information for the formulation, preparation, and storage of carboplatin.15-16 Dose 
modifications are allowed twice according to the guidelines in Section 5.6.1.3. 
 
5.2 
Identity of Investigational and Comparator Products 
Table 3 provides the details of investigational and comparator products. 
 
Table 3 
Investigational and Comparator Products 
 
Investigational product 
Dosage form and strength 
Manufacturer 
BAT1706 
Composition: bevacizumab, trehalose 
dihydrate, sodium phosphate (monobasic, 
monohydrate), sodium phosphate, 
polysorbate 20, and water for injection 
Solution for infusion (25 mg/mL) 
100 mg/4 mL solution in a single 
use vial 
Bio-Thera Solutions, Ltd. 
Comparator 
Dosage form and strength 
Manufacturer 
EU-Avastin®: 
Composition: bevacizumab, trehalose 
dihydrate, sodium phosphate (monobasic, 
monohydrate), sodium phosphate, 
polysorbate 20, and water for injection 
Solution for infusion (25 mg/mL) 
100 mg/4 mL solution in a single 
use vial 
Roche Pharma AG. 
Abbreviation: EU = European Union. 
 
Stability and Storage 
No preservative is used in BAT1706/EU-Avastin®; therefore, the vials are intended for single 
use only. BAT1706/EU-Avastin® is biologically and chemically stable at 2 to 8°C  (36 to 46°F). 
According to the stability report of BAT1706 and SmPC of EU-Avastin®, once reconstituted 
into IV bags, the solution is chemically stable for up to 8 hours at 2 to 25°C (36 to 77°F) in 
sodium chloride 9 mg/mL (0.9%) solution for injection. Diluted solutions must be stored 
refrigerated (2 to 8°C) if not used immediately. Generally, compatibility occurs 48 hours after 
contacted. Site can use disposable infusion bag for BAT1706/EU Avastin® as long as no more 
than 8 hours after reconstituted into IV bags. Do not use vials beyond the expiration date. 
Preparation of BAT1706/EU-Avastin® for Intravenous Administration 
The recommended dose is 15 mg/kg every 3 weeks when used in combination with carboplatin 
and paclitaxel chemotherapy. The dose of BAT1706/EU-Avastin® should be recalculated in 


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case of body weight change ≥ 10% and if not due to fluid retention, which needs to be treated 
appropriately. 
Use appropriate aseptic technique. Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration, whenever solution and container 
permit. It is recommended that the necessary amount of BAT1706/EU-Avastin® will be 
withdrawn and diluted in 0.9% sodium chloride. Recommended concentration is from 
1.4 mg/mL to 16.5 mg/mL. The volume to be administered for each patient will be calculated 
based on the patient’s weight. Discard any unused portion left in the vial, as the product 
contains no preservatives. 
Details of the identity of paclitaxel and carboplatin are provided in the package inserts.14-16 
 
5.3 
Packaging and Labeling 
All study drugs will be supplied to the study center by the Sponsor. 
Both BAT1706 and EU-Avastin® will be packaged and labelled in accordance with text that is 
in full regulatory compliance with each participating country. 
Handling and storage instructions for paclitaxel and carboplatin will be included in a separate 
Pharmacy Manual. 
 
5.4 
Method of Assigning Subjects to Treatment Group 
Once the patient meets all inclusion criteria and no exclusion criteria and has provided an 
informed consent, patient will then be randomly assigned in a blinded manner to either Arm A 
or Arm B with a 1:1 ratio. The randomization will be performed using the Interactive Web 
Response System (IWRS) based on the following stratification factors: 
• NSCLC stage (recurrent disease after any stage at time of primary diagnosis,  or  Stage 
IV). 
• Gender (male or female). 
• Ethnicity (Asian or non-Asian). 
Patients will be assigned a patient number in the order in which they are enrolled in the study. 
Each vial of study drug will be labeled with a unique medication identification number. The 
IWRS will assign the correct vial for the allocated treatment group and visit and the medication 
identification will be linked to an individual patient. 


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Access to the randomization code will be controlled and documented (see Section 5.7 for 
further details). 
 
5.5 
Selection of Bevacizumab Dose in the Study 
In the EU, US, and many other countries, Avastin® has received health authority approval for 
the treatment of nsNSCLC, in combination with carboplatin and paclitaxel, for first-line 
treatment of unresectable, locally advanced, recurrent or metastatic disease. 
The dose of BAT1706 selected for this study is based on the clinically effective dose of the 
currently available dosage form of Avastin® in that indication.4-5 
The primary focus of this study is to demonstrate clinical equivalence of BAT1706 (proposed 
biosimilar to Avastin®) with EU-Avastin®. The recommended dose of Avastin®, administered 
as an IV infusion, is 15 mg/kg of body weight given once every 3 weeks. Therefore in this 
study, patients randomized to receive BAT1706 or EU-Avastin® will receive 15 mg/kg once 
every 3 weeks. 
 
5.6 
Treatment Regimen, Schedule, and Mode of Administration 
The treatment regimen is every 3 weeks (21 days) administrations for up to 6 cycles for 
chemotherapy and BAT1706 or EU-Avastin®, followed by maintenance monotherapy with 
BAT1706 or EU-Avastin® until  progression  or  excessive  toxicity  with  a  maximum  of  12 
months in this study. Thereafter, patients who still benefit and tolerate therapy will be enrolled 
in the LTE study using the same regimen as during maintenance therapy with a maximum of 
12 additional months. 
The duration of participation for each patient of this study is expected to be about 12 months, 
which exceeds the median number of cycles administered in non-Asian patients (7 cycles) 
while it slightly exceeds the  median  number  of  cycles  administered  in  Asian  patients  (11 
cycles).12,13 However, since patients with EGFR mutation are excluded in this study, and the 
mutation confers a longer PFS time, the median number of cycles in Asian patients (in whom 
the mutation is present in up to 50% of adenocarcinoma) is expected to be ≤ 11 cycles.17 
Patients intolerant to chemotherapy after 2 dose reductions can start monotherapy with 
BAT1706 or EU-Avastin® or start another line of anti-cancer therapy after investigator’s 
judgment. The drug sequence is as follows: To better evaluate the tolerability of BAT1706 or 
EU-Avastin® only BAT1706 or EU-Avastin® is administered on Day 1 of Cycle 1, and 
paclitaxel and carboplatin are given on Day 2. As of Cycle 2, BAT1706 or EU-Avastin® is 
given first, then paclitaxel followed by carboplatin on the same day. 


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Patients must be under close surveillance from the start of the infusion to allow detecting 
hypersensitivity reactions which may occur within minutes. Severe hypotension, 
bronchospasm or generalized rash/erythema requires immediate discontinuation of infusion 
and appropriate treatment. The infusion may be slowed for minor symptoms such as flushing 
or local cutaneous reactions. Patients experiencing severe hypersensitivity reactions should be 
discontinued from the study. 
Patients may be hospitalized for observation at the discretion of the Investigator (such instances 
of hospitalization will not be recorded as a serious adverse event [SAE]). 
BAT1706 or EU-Avastin® dose modification for intolerance is NOT permitted during this 
study. Any deviation will be recorded in the eCRF. Dose modifications for intolerance to 
chemotherapy are allowed twice. 
In the event of a life-threatening reaction, including anaphylaxis, hypersensitivity reaction, 
renal failure, severe cardiopulmonary event and severe muco-cutaneous reaction, BAT1706 or 
EU-Avastin® will be discontinued and no additional BAT1706 or EU-Avastin® will be 
administered. 
If extravasation occurs during infusion of the study drug, the infusion must be stopped. Restart 
the remainder of the infusion either in the area of the same arm which is proximal to the body 
or in the other arm. The PK sample will always be drawn from the opposite arm of the infusion 
arm. 
Patients who miss the allocated day for study drug infusion will be contacted and another visit 
will be arranged as soon as practically possible to administer study drug. No dose reduction is 
planned and a maximum of 9 weeks interval between 2 administrations is accepted. If the 
patient has not recovered, he/she is withdrawn from study. In case treatment is delayed for 
intolerance to BAT1706/EU-Avastin®, the chemotherapy must be postponed to coincide with 
the new cycle. 
For more information regarding chemotherapy regimens, please refer to Section 5.6.1. 
The treatment regimen for BAT1706/EU-Avastin® plus chemotherapy is provided in Table 4. 


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Table 4 
Treatment Regimen of BAT1706/EU-Avastin® plus Paclitaxel and 
Carboplatin 
 
Regimen 
Dose 
Mode 
BAT1706/EU-Avastin® 
15 mg/kg 
IV 
Paclitaxel 
200 mg/m2 
(administered according to standard institutional practice) 
IV 
Carboplatin 
target AUC 6 mg/mL·minute  
(according to local standard practice or package insert) 
IV 
Abbreviations: AUC = area under the curve; EU = European Union; IV = intravenous 
Note: BAT1706/EU-Avastin® infusion should be administered prior to paclitaxel and carboplatin. 
 
BAT1706/EU-Avastin® dose and schedule will remain unchanged during the maintenance 
period when given as single agent. The same study drug (BAT1706 or EU-Avastin®) will be 
continued during maintenance therapy based on the allocation at the time of randomization. 
Administered dose of all study drugs, date/time of start of infusion, date/time of end of infusion 
and any interruptions must be documented in the eCRF. Interruptions should be documented 
as the time that infusion is stopped and restarted. 
 
5.6.1 
Chemotherapy 
5.6.1.1 
Premedication 
Systematic premedication is not warranted before BAT1706 or Avastin® infusion on Day 1 of 
Cycle 1. Diphenhydramine (or its equivalent) can be given according to local practice. 
All patients must receive premedication prior to carboplatin/paclitaxel administration to 
prevent severe hypersensitivity reactions. On Day 2 of Cycle 1, and on Day 1 in all subsequent 
cycles, all patients will be given 20 mg dexamethasone IV, diphenhydramine (or its equivalent) 
50 mg IV, and cimetidine (300 mg) or ranitidine (50 mg) IV according to each drug label and 
per local standard practice. Premedication should be completed 30 to 60 minutes before 
paclitaxel infusion. Once BAT1706 or Avastin® is no longer given in combination with 
paclitaxel and the patient has tolerated BAT1706 or Avastin® infusions, premedication can be 
stopped; however, this will depend on each individual case per Investigator’s judgment, and 
local standard practice. 
5.6.1.2 
Chemotherapy Regimen 
Administration of backbone chemotherapy will be according to the standard preparation and 
infusion procedures of each study center. Patients should receive paclitaxel prior to carboplatin. 
All patients will be treated with standard combination chemotherapy consisting of paclitaxel 
(175 mg/m2 initial dose for Chinese patients and 200 mg/m2 for patients from other countries) 


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followed by carboplatin target AUC 6 mg/mL·minute ever y 3 weeks for up to 6 cycles with 
adequate pre- and concomitant medication. For the first course of chemotherapy, in case of 
anticipated excessive toxicity (e.g, elderly patients, prior toxicity during chemo-radiotherapy), 
the Investigator may start paclitaxel at a dose of 175 mg/m2 and/or carboplatin target AUC 5 
mg/mL·minute.  Alternatively, paclitaxel 200 mg/m² can be administered after prophylactic use 
of G-CSF. 
The carboplatin dose will be calculated using the Calvert formula, taking into account the GFR 
and given in dose of AUC: 
Carboplatin-dosage in mg = (target AUC) × (GFR + 25) on Day 1 of each 3 -week cycle. 
Glomerular filtration rate is to be based on the Cockroft-Gault formula for creatinine clearance: 
GFR (mL/min) = C × (140 -age [years]) × (weight  [kg]) 
72 × serum creatinine (mg/dL)  
where C = 0.85 for female patients and C = 1.00 for male patients. 
The Cockcroft–Gault formula will be used to calculate the creatinine clearance/GFR (required 
for the Calvert´s  formula). As clinically recommended, GFR will be capped at 125 mL/minute 
(even if the result obtained is higher) to avoid potential overdosing. Accordingly, the maximum 
total dose of carboplatin would be 900 mg per cycle. 
5.6.1.3 
Dose Modifications in Case of Toxicity 
A maximum of 2 dose reductions is allowed for hematological and non-hematological toxicity 
after paclitaxel and carboplatin (Table 5). Once the dose is reduced, no re-escalation is allowed. 
If toxicity persists despite dose reduction to chemotherapy dose Level-2, the patient must stop 
chemotherapy. Chemotherapy dose reductions can be cumulative from cycle to cycle as 
required based on toxicity. 


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Table 5 
Dose Modifications for Paclitaxel and Carboplatin according to Starting 
Dose 
 
Regimen 
Level-0 
(starting dose) 
Level-1 
Level-2 
Level -3 
Paclitaxel 
(mg/m2) 
200 
150 
100 
Off-treatment 
Carboplatin 
(target AUC [mg/mL·min])  
6 
4.5 
3 
Off-treatment 
Regimen 
Level-0 (starting 
dose) 
Level-1 
Level-2 
Level -3 
Paclitaxel 
(mg/m2) 
175 
130 
90 
Off-treatment 
Carboplatin 
(target AUC [mg/mL·min])  
5 
4 
3 
Off-treatment 
Abbreviation: AUC = area under the curve 
 
Drug toxicity will be assessed using the National Cancer Institute (NCI)-Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 dated 14 Jun 2010. 
In case of insufficient recovery at the planned date for the next cycle, dose modification and 
treatment delay will be made according to Table 6 and Table 7. A maximum treatment delay 
of 6 weeks is accepted (9 weeks interval between administrations); beyond that delay the 
patient is withdrawn from study. Patients with severe hypertension, moderate to severe 
proteinuria, will not receive further treatment with BAT1706/Avastin® if the AE cannot be 
adequately controlled within 14 days. 
During the combination treatment period, any chemotherapy delay mandates a 
BAT1706/Avastin® infusion delay and vice-versa. All 3 drugs of this regimen 
(BAT1706/Avastin® + paclitaxel + carboplatin) should always be administered together during 
the treatment period if the patient fulfills the criteria for receiving the next treatment cycle. 
Recommended dose modifications: 
Please refer to the prescribing information for paclitaxel and carboplatin for details.14-16 


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Table 6 
Dose Modifications for Hematologic Toxicities (Regardless of Causality) 
 
Toxicity 
Paclitaxel/Carboplatin 
Grade 3 Neutropenia of any 
duration or Grade 4 < 7 days 
1st event 
Interrupt until recovery to > 1500/mm3 
Preferably reinitiate at original dose, unless 
Investigator deems dose reduction by one level is 
necessary based on individual patient status. 
Discuss with Medical Monitor Sponsor 
2nd event 
Interrupt until recovery to > 1500/mm3 
Consider dose reduction by one level at 
Investigators discretion, discuss with Medical 
Monitor Sponsor 
3rd event 
Interrupt until recovery to > 1500/mm3 
Use dose reduction by one level 
4th event despite dose 
reduction 
Use dose reduction by one level. Off-treatment if 
2 dose reductions already done 
Grade 4 Neutropenia ≥ 7 days 
1st event 
Interrupt until recovery to > 1500/mm3 
Reinitiate at next lower dose level. 
2nd event despite dose 
reduction 
Interrupt until recovery to > 1500/mm3 
Reinitiate at previous lower dose level. 
3rd event despite dose 
reduction 
Off-Treatment 
Febrile Neutropenia with Absolute 
Neutrophil Count < 1,000/mm3 
1st event 
Hold dose until ANC > 1500/mm3 and T < 37ºC  
Reinitiate at next lower dose level 
2nd event despite dose 
reduction 
Hold dose until ANC > 1500/mm3 and T < 37ºC 
Reinitiate at next lower dose level 
3rd event despite dose 
reduction 
Off-Treatment 
Thrombocytopenia ≥ 50,000 to 
< 100,000/mm3 
all events 
Hold dose until recovery to ≥ 100,000/mm3 
No change in dose 
Grade ≥ 3 Thrombocytopenia 
≥ 25,000/mm3 to 
< 50,000/mm3, 
1st event 
Hold dose until recovery to > 100,000/mm3 
Reinitiate at original dose level 
≥ 25,000/mm3 to 
< 50,000/mm3, 
2nd event 
Hold dose until recovery to >100,000/mm3 
Reinitiate at next lower dose level 
< 50,000/mm3 
despite previous dose 
reduction 
Off-Treatment 
Grade 4 Thrombocytopenia or 
Grade 3 with Bleeding Requiring 
Platelet Transfusion 
< 25,000/mm3, 
1st event 
Hold dose until recovery to > 100,000/mm3 
Reinitiate at next lower dose level 
< 25,000/mm3 
despite previous dose 
reduction 
Off-Treatment 
Any Grade Non-hemolytic Anemia 
Transfusion indicated for Grade ≥ 3 Anemia 
No change in dose. 
Abbreviation: ANC = absolute neutrophil count 
 
If treatment is held for > 1 week for granulocyte recovery, or if a febrile neutropenic episode 
(≥ 38.5℃ with a granulocyte count < 1000/mm3) occurs at any time during therapy, 
prophylactic filgrastim (Neupogen®) or pegfilgrastim (Neulasta®) will be administered 
(according to the package insert) with all subsequent cycles. If other uses of G-CSF are allowed, 
according to regular institutional practice and the Principal Investigator’s judgment. 


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Criteria for dose reductions and discontinuation of therapy for some specific non-hematologic 
toxicities are summarized in Table 7. 
 
Table 7 
Dose Modifications for Selected Non-Hematologic Toxicity (Regardless of 
Causality) 
 
Toxicity 
Paclitaxel/Carboplatin 
Metabolic 
Hyperglycemia 
No Change 
Hypoglycemia 
No Change 
Gastrointestinal-related/Mucositis 
≥ Grade 3 Nausea/Vomiting 
(1st Event) 
No change 
≥ Grade 3 Nausea/Vomiting 
(2nd Event) 
Decrease both drugs dose by one dose level 
Grade 1 - 2 Diarrhea 
No change 
≥ Grade 3 Diarrhea lasting > 24 hours 
despite maximum anti-diarrheal management 
(1st event) 
Hold study drugs until recovery to ≤ Grade 1 or to baseline 
Reinitiate at original dose level 
≥ Grade 3 Diarrhea lasting > 24 hours 
despite maximum anti-diarrheal management 
(2nd Event) 
Hold study drugs until recovery to ≤ Grade 1 or to baseline 
Reinitiate at original dose level 
Grade 1 - 2 Mucositis 
Hold study drugs until recovery to ≤ Grade 1 or to baseline 
Reinitiate at original dose level 
≥ Grade 3 Mucositis 
(1st event) 
Hold study drugs until recovery to ≤ Grade 1 or to baseline 
Decrease current dose by one dose level 
≥ Grade 3 Mucositis 
(2nd event) 
Hold study drugs until recovery to ≤ Grade 1 or to baseline. 
Decrease current dose by one dose level 
Hepatobiliary 
≥ Grade 2 Aspartate aminotransferase or 
Alanine aminotransferase and ≤ Grade 1 Total 
Bilirubin 
Hold until LFTs ≤ Grade 1. Restart paclitaxel at same dose 
when bilirubin is within normal limit. Decrease paclitaxel dose 
by one dose level when bilirubin = Grade 1. No dose 
adjustment for carboplatin 
≥ Grade 3 Aspartate aminotransferase or 
Alanine aminotransferase or ≥ Grade 2 Total 
Bilirubin 
Hold until LFTs ≤ Grade 1. Restart paclitaxel at same dose 
when bilirubin is within normal limit. Decrease paclitaxel dose 
by one dose level when bilirubin = Grade 1. No dose 
adjustment for carboplatin 
Allergic/Hypersensitivity to Paclitaxel 
≥ Grade 3 allergic/ hypersensitivity despite 
adequate premedications 
Off-treatment 
Neuropathy 
Neuropathy Grade 2 
Hold study drugs until recovery to ≤ Grade 1 or to baseline. 
Decrease paclitaxel by one dose level. No dose adjustment for 
carboplatin. 
Neuropathy ≥ Grade 3 
Hold study drugs until recovery to ≤ Grade 1 or to baseline. 
Decrease paclitaxel by two dose levels. No dose adjustment for 
carboplatin. 
Abbreviation: LFT=liver function test 
 
For dose modifications for other events not cited above, it is suggested to follow the hospital 
standards and carefully capture any modification in the eCRF page. 


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5.7 
Blinding 
This is a randomized, double-blind, active comparator study with limited access to the 
randomization code. The treatment each patient will receive will not be disclosed to the 
Investigator, study center staff, patient, Sponsor or Sponsor designee or the DSMB. The 
treatment codes will be held by the Sponsor. 
The process for breaking the blind will be handled through the IWRS. Investigators are 
strongly discouraged from requesting the blind be broken for an individual patient, unless there 
is a patient safety issue that requires unblinding and would change patient management. Any 
center that breaks the blind under inappropriate circumstances may be asked to discontinue its 
participation in the study. If the blind is broken, it may be broken for only the patient in 
question. 
The Sponsor or Sponsor designee must be notified immediately if a patient and/or Investigator 
is unblinded during the course of the study. Pertinent information regarding the circumstances 
of unblinding of a patient’s treatment code must be documented in the patient’s source 
documents and eCRFs. 
Additionally, Sponsor or Sponsor designee may be required to unblind the patient if the AE 
meets criteria of a suspected unexpected serious adverse reaction in order to fulfil expedited 
regulatory reporting requirements. 
The DSMB may assess unblinded data if needed. 
 
5.8 
Prior and Concomitant Treatments 
 
5.8.1 
Excluded Medications 
Patients are not allowed to take the following medications: 
• As of screening and throughout full study including LTE, no anticancer or immune-
stimulating agents should be used (either standard, investigational or Chinese herbal 
medicines). 
• Anti-infectives from Chinese herbal medicines should not be used as the drug-drug 
interaction is unknown but standard antibiotics must be used any time as required from 
screening to end of LTE. 
• Any NSAIDs (including aspirin in doses over 325 mg/day) within 10 days prior to 
administration of the study drug and for the duration of the study; paracetamol, up to 4 
g per day, will be allowed. 


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• Any live/attenuated virus vaccination within 12 weeks before Screening, and during 
study participation until the final Follow-Up Visit. 
• Any oral anticoagulation (eg, warfarin, rivaroxaban, dabigatran, acenocumarol, etc.) 
treatment. 
 
5.8.2 
Allowed Medications 
Patients are allowed to continue with concomitant medication for pre-existing disease as long 
as they are not part of the list of excluded medicines (Section 5.8.1). In the interest of patient 
safety and acceptable standards of medical care, the Investigator will be permitted to prescribe 
treatment(s) at his/her discretion for treatment-emergent adverse events (TEAEs). All 
treatments administered during the patient’s participation in the study (prescription or over-
the-counter, including vitamins and/or herbal supplements) must be recorded in the source 
documents and patients’ eCRF (medication, dose, treatment duration and indication). 
 
5.8.3 
Allowed Radiotherapy 
A short course of local radiotherapy for bone metastasis with palliative intent is allowed during 
participation in the study, but radiotherapy for relapsing or new brain metastases is not allowed. 
In such case, the patient should be withdrawn from study. 
5.9 
Medical Care of Subjects after End of Study 
The Sponsor will not provide any additional care to patients after they leave the study because 
such care should not differ from what is normally expected for patients with advanced 
nsNSCLC. 
5.10 Treatment Compliance 
Records of treatment compliance for each patient will be kept during the study. Any deviations 
from the intended regimen must be recorded in the source document and eCRFs. 
 
5.11 Study Medication Accountability 
The Investigator, a member of the study center staff, or a hospital pharmacist must be 
responsible for the accountability of all study drugs (dispensing, inventory, and record keeping) 
following the Sponsor’s instruction and adherence to GCP guidelines as well as local or 
regional requirements. These forms must be made available, upon request, for inspection at any 
time. 
All study drug supplies should be accounted for at the termination of the study and a written 
explanation provided for discrepancies. All remaining partially used and/or unused study drugs 


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will be returned to the Sponsor or Sponsor’s designee after study completion/termination, or 
destroyed with the permission of the Sponsor in accordance with applicable laws and study 
site procedures. If the study drug is to be destroyed, the Investigator will provide 
documentation in accordance with Sponsor’s specifications. 
Under no circumstances will the Investigator allow the study drugs to be used other than as 
directed by protocol. Study drugs will not be dispensed to any individual who is not enrolled 
in the study. 


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6.0 EFFICACY, SAFETY, IMMUNOGENICITY, AND 
PHARMACOKINETIC ASSESSMENTS 
 
6.1 
Efficacy 
 
6.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is ORR at Week 18 (ORR18) based on tumor response evaluated 
according to RECIST 1.1 (Appendix 13.4) as assessed by CIR. Patients not achieving Week 
18 assessment will be considered non-responders if they dropped out earlier in case of 
intolerance, documented disease progression, withdrawal of consent, lost to follow-up, or death. 
The ORR18 is calculated as the proportion of patients achieving a PR or a CR at Week 
18. Confirmation of response is not required. 
Each patient will be assigned to one of the following RECIST 1.1 categories based on 
independent CIR, irrespective of protocol deviations or missing data: 
• CR: complete response. 
• PR: partial response. 
• SD: stable disease. 
• PD: progressive disease. 
• NE: not evaluable (insufficient data). 
Tumor assessments will be performed at Weeks 6, 12, and 18, regardless of whether a treatment 
cycle is delayed and whether or not this assessment coincides with the completion of the cycle. 
Then after, tumor assessments will be performed after every 3 cycles (approximately every 9 
weeks [assessed within Days 15-21 after the treatment of the third cycle is given]). Window 
for tumor assessment is 1 week at the maximum  during the first  18 weeks. The results must 
be available for treatment decision before the planned next cycle. 
Patients who discontinued study drug without disease progression will continue to undergo 
tumor assessments every 9 weeks until disease progression or a maximum of 12 months. 
Tumor assessment at the EoT Visit is only necessary if more than 4 weeks have passed since 
the previous assessment (window for these assessments is within 1 week of the EoT Visit). 
Contrast-enhanced CT or MRI of at least the chest and abdomen, including the adrenals and 
the liver, and any other areas of disease, as clinically indicated, will be acquired at Screening 
and at all imaging time points. Brain CT or MRI scan, and bone scans or X-rays should be 


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performed at screening if clinically indicated and during treatment period as clinically 
indicated. If the bone scan is positive at screening, it will be repeated at no less than 12-week 
intervals. Plain X-ray of bone lesions are used at time of regular tumor assessments as clinically 
indicated between isotopic bone scans. Positron emission tomography scans are not accepted 
for sole assessment of efficacy but can be used to identify new lesions if a baseline PET scan 
was done. Throughout the study it is critical that the same methodology and scan acquisition 
techniques used at Screening are used throughout the study to ensure comparability. If a patient 
is unable to undergo a contrast CT due to allergy or renal insufficiency during follow-up, a 
chest CT without contrast, combined with MRI images of the target lesions with gadolinium 
contrast, is preferred if tolerated by the patient. Further detail will be provided by CIR 
contracted for this study. 
All imaging for tumor assessments performed until Week 18 will be sent for CIR. The results 
of the CIR (independent blinded assessment of tumor response) will be used for the primary 
efficacy analyses. Details will be described in the imaging charter. 
 
6.1.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
• Progression-free survival rate at 12 months, defined as the proportion of patients being 
alive without documented progression 12 months after randomization, using Kaplan- 
Meier method. 
• Progression-free survival time defined as the time from the date of randomization to 
the date of documented clinical or radiological progression or death due to any cause 
using Kaplan-Meier method. 
• Overall survival rate at 12 months, defined as the proportion of patients being alive 12 
months after randomization using Kaplan-Meier method. 
• Overall survival time defined as the time from randomization to death of any cause 
using Kaplan-Meier method. 
• ORR at Week 6 (ORR6) and ORR at Week 12 (ORR12), based on tumor response as 
assessed by CIR, and best ORR of confirmed responses at end of study assessed by 
local radiologist/Investigator if after Week 18 according to RECIST 1.1. 
• Duration of response defined as the time from first documentation of a response (CR 
or PR) and the first documentation of progression (assessed by local 
radiologist/Investigator if after Week 18) according to RECIST 1.1. 


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6.2 
Safety 
All AEs (non-serious and serious) will be evaluated for safety. Clinical laboratory results, vital 
signs, Electrocardiograms (ECGs) and the performance of physical examination will also be 
evaluated as specified in the Schedule of Events (Table 1). Special attention should be paid for 
anaphylactic reactions/hypersensitivity reactions/infusion related reactions; arterial and venous 
thromboembolic events, febrile neutropenia, gastrointestinal perforations, hypertension, 
proteinuria, 
pulmonary 
hemorrhage, 
other 
hemorrhages, 
and 
wound 
healing 
complications/abscess/fistulas. 
 
6.2.1 
Adverse Events 
Definition of AE: An AE is any untoward medical occurrence in a patient or clinical 
investigation patient administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment. 
The criteria for identifying AEs are: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product. 
• Any new disease or exacerbation of an existing disease. However, worsening of the 
primary disease should be captured under efficacy assessments as disease progression 
rather than as an AE. 
• Any deterioration in non-protocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or X-ray) that results in symptoms, a change in treatment, or 
discontinuation from study drug. 
• Recurrence of an intermittent medical condition (eg, headache) not present at baseline. 
• An abnormal laboratory test result should be considered an AE if the identified 
laboratory abnormality leads to a clinical symptom or any type of intervention, whether 
prescribed in the protocol or not. 
A laboratory result should be considered by the Investigator to be an AE if it: 
1. Results in the withdrawal of study drug. 
2. Results in withholding of study drug pending some investigational outcome. 
3. Results in an intervention, based on medical evaluation (eg, potassium supplement for 
hypokalemia). 


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4. Results in any out of range laboratory value that in the Investigator’s judgment fulfills the 
definitions of an AE with regard to the patient’s medical profile. 
Definition of SAE: An SAE, experience or reaction, is any untoward medical occurrence 
(whether considered to be related to study drug or not) that at any dose: 
• Results in death. However, death due to progressive disease is not reported as an SAE. 
• Is life-threatening (the patient is at a 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). 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
Following hospitalizations are not considered to be SAEs because there is no ‘adverse 
event’ associated with the hospitalization: 
o Surgical operations planned before informed consent (where the illness or 
disease existed before the patient was enrolled in the study and the condition 
requiring the hospitalization has not changed after study drug administration). 
o Hospitalization for administration of chemotherapy. 
o Elective hospitalizations for pre-existing conditions that did not worsen. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital abnormality/birth defect. 
• Other: Medically significant events, which do not meet any of the criteria above, but 
may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the other serious outcomes listed in the definition above. Examples of such 
events are blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc.) 
or convulsions that do not result in hospitalization. 
An overdose is the accidental or intentional use of a drug in an amount higher than the dose 
being studied. An overdose or incorrect administration of study treatment is not itself an AE, 
but it may result in an AE. All AEs associated with an overdose or incorrect administration of 
study drug should be recorded on the AE eCRF. If the associated AE fulfills seriousness criteria, 
the event should be reported to the Sponsor immediately (ie, no more than 24 hours after 
learning of the event) 
An Adverse Drug Reaction (ADR) is defined as all noxious and unintended responses to a 
medicinal product related to any dose. 


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An Unexpected ADR is defined as any adverse reaction, the nature of which is not consistent 
with the applicable product information. 
Each AE is to be evaluated for duration, severity, seriousness and causal relationship to the 
study drug. The action taken and the outcome must also be recorded. 
Severity 
The term severe is a measure of intensity of an event; a severe event is not necessarily serious. 
Severity of all AEs will be graded by the Investigator according to NCI-CTCAE version 4.03, 
dated 14 June 2010. 
Relationship 
Causal relationship assessment to study drug treatments is required for reporting AEs. To 
promote consistency, the following guidelines should be taken into considerations along with 
good clinical and scientific judgment when determining the relationship of study drug 
treatments to an AE: 
 
Definitely 
Related: 
A clinical event, including laboratory test abnormality, occurring in a plausible 
time relationship to the medication administration, and which cannot be 
explained by concurrent disease or other drugs or chemicals. The response to 
the withdrawal of the drug should be clinically plausible. 
Possibly 
Related: 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to the medication administration, but which could also be explained 
by concurrent disease or other drugs or chemicals. Information on the drug 
withdrawal may be lacking or unclear. 
Unlikely 
Related: 
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship to medication administration, and for which other 
drugs, chemicals or underlying disease provide a plausible explanation. 
Not Related: 
A clinical event, including laboratory test abnormality that has no temporal 
relationship to the medication or has more likely the alternative etiology. 
 
Arguments that may suggest that there is a reasonable possibility of a causal relationship could 
be: 
• The event is consistent with the known pharmacology of the drug. 
• The event is known to be caused by or attributed to the drug class. 
• A plausible time to onset of the event relative to the time of drug exposure. 


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• Evidence that the event is reproducible when the drug is re-introduced (positive 
rechallenge). 
• No medically sound alternative etiologies that could explain the event (eg, pre-existing 
or concomitant diseases, or co-medications). 
• The event is typically drug-related and infrequent in the general population not exposed 
to drugs (eg, Stevens-Johnson syndrome). 
• An indication of dose-response (ie, greater effect size if the dose is increased, smaller 
effect size if dose is diminished). 
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be: 
• No plausible time to onset of the event relative to the time of drug exposure is evident 
(eg, pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned). 
• Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (eg, after 5 half-lives) (negative 
dechallenge). 
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger. 
• Additional arguments amongst those stated before, like alternative explanation (eg, 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned). 
• Disappearance of the event even though the study drug treatment continues or remains 
unchanged. 
All efforts should be made to classify the AE according to the above categories. 
Action taken 
The action taken for each AE will be defined as: 
• None. 
• Infusion interrupted. 
• Infusion slowed. 


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• Infusion stopped. 
• Other. 
Outcome 
The outcome of each AE will be defined as: 
• Resolved. 
• Stabilized. 
• Ongoing. 
• Resolved with sequelae. 
• Fatal. 
• Lost to follow-up. 
6.2.1.1 
Reporting of Adverse Events 
Period: From ICF signing to first study medication administration - All AEs related to the study 
procedures (eg, blood withdrawal etc.). 
Period: From the start of the first study medication administration until 28 days after 
discontinuation/completion of the study medication or up to Week 53 after randomization- All 
AEs, regardless of relationship to the study medication/study procedures. During the LTE 
study, only adverse events of special interest (AESIs) and SAEs until 28 days after the subject’s 
last dose will be collected. 
All AEs are to be recorded on the appropriate AE pages in the eCRF. The Investigator should 
complete all the details requested including event’s name, dates of onset, date of resolution, 
severity, action taken, outcome, relationship to study drug. Each event should be recorded 
separately. 
When recording AEs, the diagnosis of the underlying illness or disorder should be used as the 
event term or description on the eCRF, and symptoms of the illness or disorder should not be 
reported as separate AEs. It is expected that whenever possible the clinical term, rather than 
the laboratory term, for the AE will be used by the reporting Investigator (eg, “anemia” versus 
“low hemoglobin value”). 
All AEs must be followed up to resolution, stabilization, or until the patient is lost to follow-up, 
whichever occurs first. 


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6.2.1.2 
Reporting of Serious Adverse Events and Pregnancy 
Any SAE, including death due to any cause (except death due to progressive disease), which 
occurs during this study, whether or not related to the study drug, must be reported immediately 
(within 24 hours of the study center’s knowledge of the event). 
Any SAE, regardless of causality assessment, must be collected from ICF signing till the last 
visit occurring 28 days after the patient’s last dose. All SAEs must be followed to resolution 
or, if resolution is unlikely, to stabilization. Any SAE judged by the Investigator to be related 
to the study drug should be reported to the Sponsor regardless of the length of time that has 
passed since study completion. 
All SAEs must be reported via the Electronic Data Capture (EDC) system by completing the 
relevant eCRF page(s) in English. Criteria for documenting the relationship to study drug as 
well as severity and outcome will be the same as those previously described. Once the SAE 
has been recorded in the EDC system, the Sponsor and other designated recipients will be 
informed of the event automatically. For instances in which the EDC may become unavailable, 
SAEs must be reported using the paper SAE report form to meet the 24-hour timeline 
requirement (contacts and instructions to be provided in separate documentation). Once the 
EDC becomes available, the Investigator must enter all SAE data as reported on the backup 
paper SAE report form on the applicable eCRF pages. 
In the case of fatal or life-threatening events, these should be reported immediately by 
telephone. The immediate report should be followed up within 24 hours by completing the 
relevant page in eCRF. The detail contact information for reporting of SAEs is provided in the 
Investigator Site File. 
The SAE report will contain as much available information concerning the SAE to enable the 
Sponsor (or an authorized representative) to file a report, which satisfies regulatory reporting 
requirements. Any follow-up information received on SAEs should be forwarded within     24 
hours of its receipt. Criteria for documenting the relationship to study drug as well as severity 
and outcome will be the same as those previously described. 
Progression of underlying malignancy 
Progression of the underlying malignancy should not be recorded as an AE. Signs and 
symptoms of the underlying NSCLC should only be reported if: 
• Newly emergent (ie, not present at baseline) and the association with the underlying 
malignancy and old/new metastatic lesions is unclear and/or 


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• The Investigator attributed deterioration of the NSCLC signs and symptoms directly 
to the study drug. Should there be any uncertainty regarding the attribution of the 
NSCLC to the AE, it should be reported as an AE/SAE accordingly. 
Adverse Events of Special Interest (AESIs) 
The following are considered events of interest: 
• Hypertension ≥ Grade 3. 
• Proteinuria ≥ Grade 3. 
• Gastrointestinal perforation, gastrointestinal abscesses and gastrointestinal fistulae 
(any grade). 
• Wound healing complications ≥ Grade 3. 
• Hemorrhage ≥ grade 3 (any grade CNS bleeding; ≥ Grade 2 hemoptysis). 
• Arterial thromboembolic events (any grade). 
• Venous thromboembolic events ≥ Grade 3. 
• Posterior Reversible Encephalopathy Syndrome (any grade). 
• Chronic heart failure ≥ Grade 3. 
• Non-gastrointestinal fistula or abscess ≥ Grade 2. 
These AESIs can be classified as serious or non-serious but require reporting to the Sponsor, 
similar to SAE reporting timeline, even if they do not meet any of the seriousness criteria. 
These events will be captured using the SAE procedure. 
Pregnancy 
Any pregnancy that occurs after administration of study drug must be reported immediately 
(within 24 hours of Investigator’s awareness) on a Pregnancy Report Form. The same 
procedure must be followed if a female partner(s) of a male study patient becomes pregnant 
after the patient has been enrolled. All pregnancies must be followed to outcome. The 
Investigator must obtain written authorization (medical records release) from a female partner 
of a male patient prior to obtaining follow-up. 
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in the 
same format as all other SAEs. 


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A patient who becomes pregnant must be withdrawn from the study. 
6.2.1.3 
Reporting of Serious Adverse Events to Regulatory Authorities and Investigators 
The Sponsor will evaluate reported SAEs for expedited reporting as assessed against the most 
current approved version of the IB. Until an AE is identified in the Reference Safety 
Information of the IB, it is considered unexpected, regardless of whether the AE has been 
submitted previously as an expedited report. 
Expedited reporting will be performed by the Sponsor or Sponsor designee in accordance with 
local and regional law and established guidance. Upon receiving an expedited report, the 
Investigator must review and retain the notice with the IB and shall be responsible for 
submitting expedited reports to their IRBs/IECs in accordance with institutional guidelines. 
Regardless of institutional guidelines, Investigators shall submit expedited reports to their 
IRBs/IECs in the event that the Sponsor identifies an expedited report to represent a new and/or 
unforeseen risk. 
 
6.2.2 
Clinical Laboratory Evaluations 
Clinical laboratory tests during the study will be performed by a local laboratory. The Schedule 
of Events (Table 1) shows the visits and time points at which blood for clinical laboratory tests 
and urine for urine tests will be collected in the study. 
The following laboratory parameters will be measured: 
o 
Infection screen (for Hepatitis B and Hepatitis C): 
o Hepatitis B is defined as active according to local site standards. 
o Active Hepatitis C is defined as positive test for confirmatory HCV RNA. If HCV 
antibody tested positive, the result should be confirmed by a positive HCV RNA. 
Patients with negative HCV RNA could be considered for the study. 
• 
Screening for HIV, syphilis, and tuberculosis to be performed according to local practice 
and local regulatory guidance. 
• 
Hematology: hemoglobin, hematocrit, platelets, white blood cells, lymphocytes, 
neutrophils, and complete blood cell count with differential. 
• 
Serum chemistry: creatinine, AST, ALT, ALP, gamma-glutamyl transpeptidase, total 
bilirubin, direct bilirubin, glucose, total cholesterol, total protein, albumin, sodium, 
potassium, chloride, and calcium. 
• 
Urinalysis: protein, glucose, and blood. 


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• 
Coagulation: INR and aPTT or PT. 
• 
Pregnancy testing for females of child-bearing potential only: Human Chorionic 
Gonadotropin in serum and urine. 
At Screening, a first set of laboratory tests will take place as soon as a patient starts the 
screening procedures. In case CBC was done > 7 days prior to Day 1 of Cycle 1, CBC will be 
repeated to confirm eligibility. And for subsequent cycles, laboratory tests must be performed 
within a maximum of 3 days prior to Day 1 of each cycle (ie, before BAT1706 or Avastin® 
administration). Hematology tests will be repeated on Day 8 of each cycle during combination 
therapy. The results must be available before each study drug infusion. Similarly, unscheduled 
hematology/serum chemistry assessments may be performed whenever clinically indicated. 
In case therapeutic doses of anticoagulants are started during the treatment period, coagulation 
tests will be repeated not more than 3 days prior to each cycle. If anticoagulants are used for 
study-related AE, Investigator should take appropriate actions, including but not limited to 
dose interruption and dose reduction. If the patient has not recovered within the permitted 
window, no further treatment can be administered and the EoT must take place. Urine dipstick 
will be assessed within 7 days prior to randomization and then every cycle during treatment 
period. In case proteinuria is observed, 24-hour urine test should be performed. 
Qualified medical staff at the site will review, initial, and date all laboratory results. Any 
laboratory value outside the reference range that is considered clinically significant by the 
Investigator will be followed as appropriate, at the discretion of the Investigator. Clinically 
significant laboratory values will be recorded as AEs if they meet the criteria as specified in 
Section 6.2.1. 
 
6.2.3 
Vital Signs, Physical Findings and Other Safety Assessments 
6.2.3.1 
Vital signs 
Vital signs (temperature, blood pressure, and pulse rate) will be performed prior to 
administration of study drug at the visits indicated in Table 1. Blood pressure and pulse rate 
will be measured after the patient has rested comfortably for at least 5 minutes using a manual 
or digital sphygmomanometer. 
The Investigator must immediately assess all vital signs findings at each visit. If the 
Investigator finds any clinically relevant abnormalities, these must be reported as AEs/SAEs 
as appropriate. 


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6.2.3.2 
Physical examination 
Physical examination will be performed prior to administration of study drug at Screening and 
at the visits indicated in Table 1. 
Height will only be measured at Screening. Weight will be measured at Screening and then 
every cycle for body surface area adjustment of dose, if change is ≥ 10%. 
Any clinically significant changes from admission will be recorded as AEs. The physical 
examination will be performed by a physician and will include the examination of the 
following: general appearance, abdomen, head and neck, eyes, ears, nose, throat, 
chest/respiratory, heart/cardiovascular, gastrointestinal/liver, musculoskeletal/extremities, 
skin, thyroid/neck, lymph nodes, and neurological/psychiatric. The infusion site will be 
assessed and findings will be recorded as AEs. 
Magnetic resonance imaging may be performed in case there is suspicion for PRES. 
6.2.3.3 
Electrocardiogram 
Electrocardiograms will be performed prior to administration of study drug at the visits 
indicated in Table 1. Additional ECGs will be performed if clinically indicated. Local ECG 
readings will be used throughout the study. 
A computerized 12-lead ECG will be performed with the patient in a supine position after the 
patient has rested comfortably for at least 5 minutes. Standard ECG parameters, including heart 
rate, QRS, PR, RR, QT, and the QT interval corrected for heart rate using Fridericia’s formula 
(QTcF) will be measured. 
The original ECG traces and variables must be stored in the patients’ medical records as source 
data. The Investigator or designee will evaluate the ECG from a clinical perspective and the 
result (whether the ECG result is normal or abnormal) will be recorded on the appropriate 
section of the eCRF and on the ECG trace signed and dated by Investigator or designee. Any 
ECG abnormality that the Investigator considers as an AE should be reported as such. 
 
6.2.4 
Safety Monitoring 
A DSMB consisting of members who are independent from the Sponsor will be established. 
The DSMB analyses will be performed as specified in the DSMB charter. 
The DSMB will review patient safety data on an on-going basis based on descriptive statistics 
of TEAEs after the first 20 patients have been treated for 6 weeks in each arm; then after, if no 
unexpected safety signal was identified, the study will continue and the safety data will be 
reviewed at regular intervals after approximately every 200 patients are evaluated after they 


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received the first 4 cycles. At each DSMB review, if no unexpected changes in the known 
safety profile for Avastin® are observed for BAT1706, the DSMB will recommend continuing 
the study. The blind will be broken only in case a serious safety signal is identified. 
 
6.3 
Immunogenicity 
Blood samples will be collected to test for ADA and NADA at the visits indicated in Table 1 
and Table 2. 
For all immunogenicity samples, the date and time of sampling will be accurately recorded. 
Approximately 6 mL of whole blood per time point for ADA and NADA will be collected. 
Wherever possible, immunogenicity blood samples will be taken at the same time as blood is 
drawn for other analyses to limit repeated venipuncture. The immunogenicity samples should 
be obtained from the forearm not used for the BAT1706 or EU-Avastin® IV administration. 
In case of positive test for ADA/NADA at the EoT visit or at SFUV 12 months after the first 
dose, whichever comes first, ADA/NADA blood sample should continue to be collected every 
9 weeks until 2 tests are negative (no later than 24 months after randomization); one PK 
sampling will be collected in case the first positive ADA/NADA result is found at the 
SFUV/EoT Visit. 
In the event of early withdrawal from treatment, every effort should be made to take 
immunogenicity samples as part of the EoT Visit procedures, if possible, with date/time of 
sample and date/time of dose prior to this sample recorded. 
Blood sample, collection, processing, storage, and shipment handling details will be presented 
in a separate Laboratory Manual. 
 
6.4 
Pharmacokinetic Assessments 
The PK and popPK analysis will be explored in a subgroup of 200 patients, from samples 
collected only at designated sites in China, Turkey, and Ukraine. 
Blood samples for the determination of serum concentrations of bevacizumab will be taken by 
venipuncture at the times specified in the schedule of assessments (Table 1 and Table 2). 
Approximately 4 mL of whole blood per time point for PK will be collected. 
The exact date/time of each blood sample collection will be recorded in the patient’s eCRF. 
Blood samples for PK analyses should be collected in appropriate blood collection tubes as 
defined in the study manuals. The Sponsor will provide the Investigator with a manual 


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containing details for the preparation of blood samples to be collected. Shipment and analysis 
instructions will be provided to the Investigator in a separate manual. 
The following information will be captured for blood sample collection in each patient’s eCRF: 
1. Patient’s number. 
2. Start date/time and stop date/time of the most recent dose administration prior to the PK 
sample, if applicable. 
3. Date and time of each blood sample collected for PK analysis. 
4. Start date/time and stop date/time of subsequent dose administration, if applicable. 
 
6.5 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in studies of NSCLC. 
The safety assessments to be performed in this study, including hematology analyses, serum 
chemistry tests, urine test, and assessment of TEAEs, are standard evaluations to ensure patient 
safety. Early assessments of ADA/NADA at Days 15 and 43 will be done in order to detect an 
early immune response, followed by assessments every 6 to 9 weeks. Serum level of 
bevacizumab will be measured at the same time points as ADA/NADA and up to 3 months 
after last dose in case ADA/NADA are positive at EoT visit. 
The RECIST 1.1 guideline (Appendix 13.4) is well established and scientifically accepted and 
will be used for the evaluation of tumor  response.  The  NCI-CTCAE  version  4.03  dated 14 
Jun 2010, a standard for assessment of safety in oncology clinical studies, will be used for the 
assessment of AEs in nsNSCLC patients. 


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7.0 STUDY PROCEDURES 
 
7.1 
Screening Period 
Screening (Day -21 to -1) 
Patients must be screened within 21 days prior to randomization. The purpose of screening 
period is to obtain informed consent and to establish protocol eligibility. Informed consent will 
be obtained after the study has been fully explained to each patient and prior to the conduct of 
any screening procedures or assessments. Re-screening is allowed to re-evaluate eligibility of 
the patient if prior exclusion criteria could be resolved. Medical monitor’s approval is required. 
At Screening, a first set of laboratory tests will take place as soon as a patient starts the 
screening procedures. In case CBC was done > 7 days prior to Day 1 of Cycle 1, CBC will be 
repeated to confirm eligibility. 
During the Screening visit, the following procedures will be performed/collected: 
• Informed consent. 
• Eligibility assessment including CIR to confirm the presence of at least one measurable 
target lesion according to RECIST 1.1 (Appendix 13.4). 
• EGFR and ALK mutation status if applicable. 
• Demographics (including date of birth, gender, and ethnicity). 
• Relevant medical/surgical history (including lung cancer history and other past and 
current medical disease with clinical significance; prior anticancer treatments, 
including adjuvant chemo and/or radiotherapy). 
• Laboratory/safety assessments: 
o Infection screen (serum virology of Hepatitis B and C, and HIV, syphilis, and 
tuberculosis). 
o Laboratory testing (hematology, chemistry, coagulation and urine test). 
o Serum pregnancy test (for females of child-bearing potential): within 7 days 
of prior to first dosing. 
o Vital signs (see Section 6.2.3.1). 
o Physical examination including height (see Section 6.2.3.2). 


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o 12-lead ECG (see Section 6.2.3.3). 
o Assessment of AEs. 
o Previous and concomitant therapy/medications assessments. 
• Disease assessments: 
o Tumor assessment (see Section 6.1). 
o ECOG performance status. 
 
7.2 
Treatment Period 
 
7.2.1 
Cycle 1 
Eligible patients with confirmed measurable target lesion by CIR will be randomized and 
allocated to treatment as per the IWRS within 3 days before Day 1 of Cycle 1 (baseline). The 
following procedures will also be performed/collected: 
• Assessment of eligibility. 
• Laboratory/safety assessments: 
o Hematology: Days 1 and 8. 
o Chemistry, coagulation and urine test: Day 1. 
o Vital signs (see Section 6.2.3.1): Days 1 and 8. 
o Physical examination (see Section 6.2.3.2): Days 1 and 8. 
Note: Weight is measured at every cycle. If weight change is ≥ 10%, the dose 
will be adjusted according to the new body surface area. 
o 12-lead ECG (see Section 6.2.3.3): Day 1. 
o Assessment of AEs – continuous. 
o Concomitant therapy/medications assessments – continuous. 
• Disease assessment: 
o Survival – continuous. 
• Other assessments: 
o Blood PK (if applicable) and ADA/NADA samples: Refer to Table 2. 


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Blood samplings on Day 1 before infusion can be made within 7 days prior to 
dosing at time of laboratory tests. 
• Study treatment (see Section 5.0): 
o Randomization (within 3 days before Day 1 of Cycle 1). 
o Administration of BAT1706 or EU-Avastin®: Day 1. 
o Administration of premedication: prior to carboplatin/paclitaxel administration: 
On Day 2 (see Section 5.6.1.1). 
o Administration of carboplatin/paclitaxel: Day 2. 
 
7.2.2 
Cycles 2 to 6 
The following procedures will be performed/collected: 
• Laboratory/safety assessments: 
o Hematology: Days 1 and 8. 
o Chemistry, coagulation and urine test: Day 1. 
o Urine pregnancy test (for females of child-bearing potential): Day 1 of Cycles 3 
and 5 (serum pregnancy test to be performed in case of positive urine pregnancy 
test). 
o Vital signs (see Section 6.2.3.1): Day 1. 
o Physical examination, including weight (see Section 6.2.3.2): Day 1 
Note: Weight is measured at every cycle to adjust body surface area if change 
is ≥ 10%. 
o 12-lead ECG (see Section 6.2.3.3): Day 1. 
o Assessment of AEs – continuous. 
o Concomitant therapy/medications assessments – continuous. 
• Disease assessments: 
o Tumor assessment (see Section 6.1): Weeks 6, 12, and 18. 
o ECOG performance status: Day 1 of Cycles 3 and 5. 
o Survival – continuous. 


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• Other assessments: 
o Blood PK (if applicable) and ADA/NADA samples: Refer to Table 2. 
• Study treatment (see Section 5.0): 
o Administration of BAT1706 or EU-Avastin®: Day 1. 
o Administration of premedication: Day 1. 
o Administration of carboplatin/paclitaxel: Day 1. 
 
7.2.3 
Cycles 7 to 17: Maintenance Period 
The following procedures will be performed/collected: 
• Laboratory/safety assessments: 
o Laboratory testing (hematology, chemistry, coagulation and urine test): Day 1. 
o Urine pregnancy test (for females of birth potential): Day 1 every 6 weeks 
(serum pregnancy test to be performed in case of positive urine pregnancy test). 
o Vital signs (see Section 6.2.3.1): Day 1. 
o Physical examination, including weight (see Section 6.2.3.2): Day 1 
Note: Weight is measured at every cycle to adjust body surface area if change 
is ≥ 10%. 
o Assessment of AEs – continuous. 
o Concomitant therapy/medications assessments – continuous. 
• Disease assessments: 
o Tumor assessment (see Section  6.1): Weeks 27,  36, and 45  or  after every    
3 cycles. 
o ECOG performance status: Day 1 every 6 weeks. 
o Survival – continuous. 
• Other assessments: 
o Blood PK (if applicable) and ADA/NADA samples: Refer to Table 2. 


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• Study treatment (see Section 5.0): BAT1706 or EU-Avastin® every 3 weeks until 
disease progression or until the total duration of study treatment reaches 12 months, 
then BAT1706 only in the LTE study for an additional 12 months (ie, for up to a total 
of 24 months after initial randomization). 
 
7.3 
End of Study and Follow-up Period 
 
7.3.1 
End of Treatment Visit/Safety Follow-up Visit 
All patients who receive at least one infusion of BAT1706 or EU-Avastin® and who 
discontinue the study at any time after Day 1 (but do not withdraw their consent) will be 
required to undergo all of the evaluations at SFUV/EoT that will take place 28 days ± 2 days 
after they received the last dose during the study with a maximum at Week 53. 
The following procedures will be performed/collected: 
• Laboratory/safety assessments: 
o Laboratory testing (hematology, chemistry, coagulation, and urine test). 
o Serum pregnancy test (for females of child-bearing potential). 
o Vital signs (see Section 6.2.3.1). 
o Physical examination (see Section 6.2.3.2). 
o 12-lead ECG (see Section 6.2.3.3). 
o Assessment of AEs – continuous. 
o Previous and concomitant therapy/medications assessments – continuous. 
• Disease assessments: 
o Tumor assessment (see Section 6.1): Only required if more than 4 weeks have 
passed since the previous assessment (window for  this assessment is  within  1 
week of the EoT Visit). 
o ECOG performance status. 
• Other assessments: 
o Blood PK (if applicable) and ADA/NADA samples: at the time of hematology’s 
blood sampling (if tested positive for ADA/NADA at the SFUV/EoT visit, 
ADA/NADA blood samples should continue to be collected every 9 weeks until 


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2 consecutive tests are negative [no later than 24 months after randomization]). 
In case the first positive ADA/NADA result is found at the SFUV/EoT Visit, 
one PK sampling will be collected. 
 
7.3.2 
Survival Follow-Up 
After the SFUV/EoT Visit, all patients who do not withdraw consent will be monitored for 
survival status via telephone call every 3 months up to 24 months after randomization. 
The Sponsor may also elect to discontinue clinical investigations under this study for any 
reason, at any time. 
 
7.3.3 
Long-Term Extension Study (Cycle 18 onward) 
Patients who are still benefiting of therapy after 12 months will be offered to continue to 
receive BAT1706 in the LTE study (regardless of the arm patient was assigned at 
randomization), until disease progression, excessive toxicity, withdrawal of consent, 
Investigator’s decision, or for a maximum of 12 additional months (ie, for up to 24 months 
from initial randomization). The same treatment regimen of every 3 weeks (21 days) will be 
followed. Patients who enter in the LTE study will undergo the EoT visit within 28 ± 2 days 
after they receive the last dose of study drug with a maximum at Week 104. 
The visit window for LTE visits are -1 to +7 days. 
The following will be performed/collected: 
• Laboratory/safety assessments: 
o Laboratory testing (hematology, chemistry, coagulation and urine test): Day 1. 
o Urine pregnancy test (for females of birth potential): Day 1 every 6 weeks 
(serum pregnancy test to be performed in case of positive urine pregnancy test). 
o Vital signs (see Section 6.2.3.1): Day 1. 
o Physical examination, including weight (see Section 6.2.3.2): Day 1. 
Note: Weight is measured at every cycle to adjust body surface area if change 
is ≥ 10%. 
o Continuous assessment of AESIs and SAEs until 28 days after the subject’s last 
dose. 
o Concomitant therapy/medications assessments – continuous. 


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• Disease assessments: 
o Tumor assessment (see Section 6.1): Patient should be assessed at Investigator’s 
discretion until disease progression, excessive toxicity, withdrawal of consent, 
Investigator’s decision or up to 24 months after randomization, whichever 
occurs first. 
o Survival: monitored via telephone call every 3 months. 
• Study treatment (see Section 5.0): BAT1706 only every 3 weeks until disease 
progression or up to 12 months. 
• 
Other assessments: 
o ADA/NADA blood samples: Refer to Table 1. 
 
7.3.4 
End of Study Definition 
The study will be closed when all randomized and treated patients have either died, are lost to 
follow-up, or have withdrawn consent, or for a maximum of 24 months after the last patient 
randomized, whichever occurs earlier. 


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8.0 QUALITY CONTROL AND QUALITY ASSURANCE 
According to the Guidelines of GCP (CPMP/ICH/135/95), the Sponsor is responsible for 
implementing and maintaining quality assurance and quality control systems with written 
Standard Operating Procedures (SOPs). 
Quality control will be applied to each stage of data handling. 
The following steps will be taken to ensure the accuracy, consistency, completeness, and 
reliability of the data: 
• Investigator meeting(s). 
• Local laboratories for clinical laboratory parameters and ECGs. 
• Center Initiation visit. 
• Early center visits post-enrollment. 
• Routine center monitoring. 
• Ongoing center communication and training. 
• Data management quality control checks. 
• Continuous data acquisition and cleaning. 
• Internal review of data. 
• Quality control check of the final clinical study report. 
In addition, Sponsor and/or Sponsor designee may conduct periodic audits of the study 
processes, including, but not limited to study center, center visits, local laboratories, vendors, 
clinical database, and final clinical study report. When audits are conducted, access must be 
authorized for all study-related documents including medical history and concomitant 
medication documentation to authorized Sponsor’s representatives and regulatory authorities. 
 
8.1 
Investigator’s Responsibility 
The Investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), ICH GCP, and applicable regulatory requirements as described in the 
Clinical Study Agreement. The Investigator is ultimately responsible for the conduct of all 
aspects of the study at the study site and verifies by signature the integrity of all data transmitted 
to the Sponsor. The term “Investigator” as used in this protocol as well as in other study 
documents, refers to the Investigator or authorized study personnel that the Investigator 


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has designated to perform certain duties. Sub-Investigators or other authorized study personnel 
are eligible to sign for the Investigator, except where the Investigator’s signature is specifically 
required. 
 
8.2 
Training 
The study monitor will ensure that the Investigator and study site personnel understand all 
requirements of the protocol, the investigational status of the study drug, and his/her regulatory 
responsibilities as an Investigator. Training may be provided at an Investigator’s meeting, at 
the study site, and/or by instruction manuals. In addition, the study monitor will be available 
for consultation with the Investigator and will serve as the liaison between the study site and 
the Sponsor. 
 
8.3 
Monitoring 
The study monitor is responsible for ensuring and verifying that each study site conducts the 
study according to the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable regulatory guidelines/requirements. 
Monitoring visits to each site will be conducted by the assigned study monitor as described in 
the clinical monitoring plan. Monitoring will be in the form of personal visits with the 
Investigator and their staff as well as any appropriate communications by telephone, fax, mail, 
or E-mail transmission. The frequency of monitoring may vary depending on enrollment rate 
and the quality of data collected. The Investigator and staff are expected to cooperate and 
provide all relevant study documentation in detail at each site visit on request for review. The 
Investigator agrees to cooperate with the monitor to ensure any problems detected in the course 
of these monitoring visits are resolved. 
In order for the Investigator to participate in this study, the study monitor must have direct 
access to source data for data verification. This will be done by comparing data from the eCRFs 
with data from the patient’s clinic or hospital records (permission will be sought from the 
patient as part of the consent process). 
 
8.4 
Non-Compliance with the Protocol 
The Investigator may deviate from the protocol only to eliminate an apparent immediate hazard 
to the patient. In the event(s) of an apparent immediate hazard to the patient, the Investigator 
will notify the Sponsor immediately by phone and confirm notification to the Sponsor in 
writing as soon as possible, but within 1 calendar day after the change is implemented. The 
Sponsor will also ensure the responsible IEC is notified of the urgent measures taken in such 
cases according to local regulations. 


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If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the Sponsor may terminate the Investigator’s participation. The Sponsor will notify 
the IEC and applicable regulatory authorities of any Investigator termination. 
 
8.5 
Study Documentation and Electronic Case Report Forms 
The Investigator is responsible for maintaining complete and accurate source documents. 
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to, the 
following: 
• Clinic, office, or hospital charts. 
• Copies or transcribed health care provider notes that have been certified for accuracy 
after production. 
• Recorded data from automated instruments such as IWRS, X-rays, and other imaging 
reports (eg, sonograms, CT scans, magnetic resonance images, ECGs, rhythm strips) 
regardless of how these images are stored, including microfiche and photographic 
negatives. 
• Records of telephone contacts. 
• Diaries or evaluation checklists. 
• Drug distribution and accountability logs maintained in pharmacies or by research 
personnel. 
• Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation). 
• Correspondence regarding a study patient’s treatment between physicians or 
memoranda sent to the IRBs/IECs. 
• CRF components that are completed directly by patients and serve as their own source. 
The Investigator will comply with the procedures for data recording and reporting. Any 
corrections to paper study documentation must be performed as follows: 1) the first entry will 
be crossed out entirely, remaining legible; and 2) each correction must be dated and initialed 
by the person correcting the entry; the use of correction fluid and erasing are prohibited. 
Electronic case report form will be used for this study, meaning that all eCRF data will be 
entered in electronic forms at the study center. Only authorized study site personnel will record 
or change data on the eCRFs. All data must be entered in English. The eCRF is essentially 


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considered a data entry form and should not constitute the original (or source) medical records 
unless otherwise specified. 
The Investigator has ultimate responsibility for the collection and reporting of all clinical data 
entered on the eCRF. The Investigator or designee as identified on Form FDA 1572 must sign 
the CRF to attest to its accuracy, authenticity, and completeness. 
The handling of data by the Sponsor, including data quality assurance, will comply with 
regulatory guidelines (eg, ICH GCP) and the standard operating procedures of the Sponsor or 
Sponsor designee. Data management and control processes specific to the study will be 
described in the data management plan. 
Adverse events will be coded using current Medical Dictionary for Regulatory Activities 
(MedDRA). Concomitant medications will be coded using World Health Organization Drug 
Dictionary. Concomitant diseases/medical history will be coded using MedDRA. 
 
8.6 
Quality Assurance Audit 
The Sponsor and/or Sponsor’s designee may conduct audits to evaluate study conduct and 
compliance with the protocol, SOPs, other written instructions/agreements, ICH GCP, and 
applicable regulatory guidelines/requirements. In addition, inspections may be conducted by 
regulatory authority at their discretion during the study or after its completion. The Investigator 
must inform the Sponsor immediately of such request. 


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9.0 STATISTICS 
 
9.1 
Determination of Sample Size 
The expected ORR used for this study is based on the ORR calculated from our meta-analysis 
that includes a population of Western and Asian patients (with approximately 23% of Asian 
patients) with nsNSCLC cancer and unknown EGFR/ALK mutation status. Such an ORR is 
derived from the reported best ORR in the intent-to-treat (ITT) population or in the subgroup 
of patients with measurable disease. Although enrolling a higher rate of Asian patients, which 
would yield an ORR of about 45%, we expect the ORR in our study to be approximately 40% 
since we will exclude patients with known EGFR mutation or ALK receptor alteration 
(conferring slightly higher, non-statistically significant, responsiveness) in regions where the 
targeted agents are available.17 
To satisfy all regulatory agencies (CFDA, EMA, and US FDA), results will be presented using 
the risk ratio or the risk difference method to show equivalence. 
Sample Size Justification Based on Risk Ratio 
To satisfy the CFDA and US FDA, equivalence will be demonstrated using the risk ratio 
method. The net treatment effect of Avastin® as measured by the ratio of ORRs is 1.97 with a 
corresponding 70% CI of (1.81, 2.14). Preserving 52% net effect of Avastin®, the equivalence 
margin will be set to 1.33 on the ratio of ORRs. Preserving 48% net effect of Avastin®, the 
equivalence margin will be set to 1.36 on the ratio of ORRs. 
 
 
 
Abbreviations: CI = confidence interval; RR = risk ratio. 
The null hypothesis is that either (1) BAT1706 is inferior to Avastin® or (2) BAT1706 is 
superior to Avastin® based on a pre-specified equivalence margin of (0.75, 1.33) for CFDA, 
and based on a pre-specified equivalence margin of (0.73, 1.36) for US FDA. The alternative 
hypothesis is that BAT1706 is equivalent to Avastin®, which can be demonstrated by showing 


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that the true treatment ratio is likely to lie between a lower and an upper equivalence margin 
of clinical acceptable difference. In other words, equivalence will be declared if the 2-sided 
90% CI of the ratio of ORRs (BAT1706: Avastin®) is entirely contained within the equivalence 
margin of (0.75, 1.33) for CFDA, and within the equivalence margin of (0.73, 1.36) for US 
FDA. Based on these equivalence margins and reference effect size of 40%, 316 patients per 
arm (632 patients total) will achieve 80% power for CFDA, and will achieve 87% power for 
US FDA. The primary analysis will be based on the ITT population, and the supportive analysis 
will be based on the per-protocol (PP) population. With an expected ORR of 42% in the PP 
set, 83% power will be achieved with the equivalence margin of (0.75, 1.33), and 90% power 
will be achieved with the equivalence margin of (0.73, 1.36). 
Sample Size Justification Based on Risk Difference 
To satisfy the EMA, equivalence will be demonstrated using the risk difference method. The 
net treatment effect of Avastin® as measured by the difference between ORRs is 0.21 with 70% 
CI of (0.17, 0.26). Preserving 29% net effect of Avastin®, the equivalence margin will be set 
to (-0.12, +0.15) for the difference of ORRs. 
 
 
Abbreviations: CI = confidence interval; RD = risk difference. 
 
The null hypothesis is that either (1) BAT1706 is inferior to EU-Avastin® or (2) BAT1706 is 
superior to EU-Avastin® based on a pre-specified asymmetrical equivalence margin of (-0.12, 
0.15). The alternative hypothesis is that BAT1706 is equivalent to EU-Avastin®, which can be 
demonstrated by showing that the true treatment difference is likely to lie between a lower and 
an upper equivalence margin of clinical acceptable difference. In other words, equivalence will 
be declared if the 2-sided 95% CI of the difference in the ORR between treatments (BAT1706 
and EU-Avastin®) is entirely contained within the equivalence margin of (-0.12, 0.15). 
Based on that margin and a reference effect size of 40% at Week 18, 316 patients per arm (632 
patients total) will achieve 85% power and 2-side control type I error within 5%. The primary 
analysis will be based on the ITT population, and the supportive analysis will be based 


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on the PP population. With an expected ORR of 42% in the PP set, 84% power will be achieved. 
 
9.2 
Statistical Methods 
Categorical variables will be summarized by the number and percentage of patients in each 
category. Continuous variables will be summarized using number, mean, standard deviation, 
median, minimum, and maximum values. Time to event endpoints will be analyzed using Cox 
proportional hazards models stratified according to the randomization stratification factors. 
Hazard ratios for the comparison of the 2 treatment arms and corresponding 95% CIs will be 
reported. 
Generally, 
the 
baseline 
value 
to 
be 
used 
in 
any 
change 
from 
baseline, 
listings/summaries/graphical presentations or as a covariate in a statistical analysis is defined 
as the latest available pre-randomization value. If necessary, detailed baseline definitions of 
specific parameters or assessments will be defined in the Statistical Analysis Plan (SAP). 
 
9.2.1 
Data to be Analyzed 
Data handling will be the responsibility of IQVIA. The data will be inspected for 
inconsistencies by performing validation checks. 
All details regarding the statistical analysis and the preparation of tables, listings and figures 
will be described in the SAP prepared by IQVIA and approved by the Sponsor before database 
lock. The statistical analysis will be performed by IQVIA. 
 
9.2.2 
Analysis Populations 
The efficacy analyses will be applied for both the PP and ITT population. 
Intention-to-Treat (ITT) Population 
The ITT population will consist of all randomized patients in accordance with the intended 
treatment arm, regardless of the treatment actually received. For the primary efficacy analysis 
of the ITT population, patients who discontinued prior to Week 18 for any reason will be 
counted as non-responders. 
Per-protocol (PP) Population 
The PP population is defined as patients who have received at least 3 cycles of study drugs as 
allocated (BAT1706 or EU-Avastin® and paclitaxel/carboplatin) or less due to early 
progression, death, or excessive toxicity and have one tumor assessment with no major 


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protocol deviations that would have significantly impact on primary efficacy or safety 
outcomes. 
All decisions to exclude patients from PP population will be made prior to database release. 
For the PP efficacy analysis, patients for whom the efficacy endpoint is missing, ie, patients 
without at least 1 valid post treatment evaluation, are excluded from the PP population, except 
those who are withdrawn due to excessive toxicity, early progression or death, in which case 
the patients will be classified as non-responders. It is anticipated that approximately 10% of 
patients in the ITT population will be excluded from the PP Population. 
Safety Population 
The safety population will consist of all randomized patients who received at least one dose of 
study drug (BAT1706 or EU-Avastin®) and allocated into actual-received treatment arm. The 
safety population will be used as the basis for all safety analyses. 
Pharmacokinetic (PK) Population 
Pharmacokinetic population is a subgroup of 200 patients from samples collected only at 
designated sites in China, Turkey, and Ukraine who receive at least one dose of study drug, 
have at least one measured concentration at a scheduled post-dose PK time point, and have no 
major protocol deviations that may significantly affect the PK assessment. The PK and popPK 
analysis will be performed on the PK population. 
 
9.2.3 
Missing Data 
For the primary efficacy analysis as well as all analyses of responder/survivor proportion 
endpoints performed on ITT and PP population, patients who do not provide data for the 
responder/survivor endpoint will be considered non-responders/censor, ie, assigned to the less 
favorable outcome for the endpoint. Sensitivity analyses to assess the robustness of conclusions 
to missing data will be carried out if there are more than 5% of patients missing evaluations in 
either treatment arm. Sensitivity analyses will include an analysis that assumes that outcomes 
are missing at random. Details of the method for dealing with missing data and of the 
implementation of the sensitivity analyses will be described in the SAP. 
 
9.2.4 
Data Pooling 
This is a multi-center study and centers may be pooled together in a country/region level for 
subgroup or center effect analysis in an exploratory manner if applicable. 


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9.3 
Subject Disposition and Characteristics 
Patient disposition will be summarized for patients in ITT population. The total number of 
patients for each defined analysis population will also be tabulated. The demographic and 
baseline characteristics will be summarized descriptively for the ITT population. Study drug 
and study duration will be summarized using descriptive statistics for the safety population. 
 
9.4 
Efficacy Analyses 
 
9.4.1 
Primary Efficacy Analyses 
The primary efficacy endpoint is ORR18 based on tumor response at Week 18 evaluated 
according to RECIST 1.1 (Appendix 13.4) as assessed by CIR. 
The primary efficacy analyses aim to demonstrate the equivalence between BAT1706 and EU-
Avastin® arms. The null hypothesis tested for the primary efficacy analyses is that either 
(1) BAT1706 is inferior to EU-Avastin® or (2) BAT1706 is superior to EU-Avastin® based on 
a pre-defined equivalence margin. 
For the CFDA and US FDA, to demonstrate equivalence between the 2 treatment groups, the 
ratio of ORRs will be used. The ratio of ORR18 will be calculated. Equivalence will be declared 
if the 90% CI of the ratio of the ORR18 between treatments (BAT1706:EU-Avastin®) is entirely 
contained within the equivalence margin of (0.75, 1.33) to comply with CFDA requirements, 
and within the equivalence margin of (0.73, 1.36) to comply with US FDA requirements. For 
the EMA, the difference between ORR18 will be calculated. Equivalence will be declared if the 
95% CI of the difference of ORR18 between treatments is entirely contained within the 
asymmetrical equivalence margin of (-0.12, 0.15). 
The 2-sided 90% CI of risk ratio or 95% CI of risk difference will be estimated including 
covariates of stratification factors: NSCLC stage (recurrent disease after any stage at time of 
primary diagnosis, or Stage IV), Gender (male or female), and Ethnicity (Asian or non-Asian), 
for the ITT population as primary analyses and for the PP population as supportive analyses. 
The multivariate-adjusted risk ratio and the 90% CI will be estimated by the log-binomial 
regression model including stratification factors. When the log-binomial model fails to 
converge, the Poisson regression with robust error variance will be used. 
The multivariate-adjusted risk difference and the 95% CI will be estimated by the binomial 
regression model including stratification factors. If this binomial model for the risk difference 
fails to converge, the modified Poisson approach can be used as above. 


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The primary efficacy analyses will take place after all patients have been evaluated for response 
at Week 18. 
 
9.4.2 
Secondary Efficacy Analyses 
The secondary efficacy endpoints include ORR6, ORR12, best ORR of confirmed responses at 
end of study, DoR, PFS rate at 12 months, PFS time, OS rate at 12 months, and OS time. 
The secondary binary efficacy endpoints will be summarized descriptively and analyzed 
similarly to the primary efficacy endpoint. For time to event variables such as PFS, OS, and 
DoR, Kaplan-Meier curves will be calculated and displayed. Median survival times and the 
corresponding 95% CI will be provided. The estimated hazard ratio with 95% CI will be 
obtained from Cox regression model. The secondary analyses will be conducted based on up 
to 12-month exposure. A complementary report for safety and survival data will be made 2 
years after LPI. 
 
9.4.3 
Subgroup Analyses 
The primary endpoint and secondary endpoints will be also analyzed in subgroups breaking 
down by, but not limited to, country/region/demographic, dose of paclitaxel and carboplatin, 
or stratification factors: Stage (IV or other), gender and ethnicity (Asian or non-Asian). In each 
subgroup, the analysis will be carried out using the same type of methodology as described for 
corresponding endpoint. These results will be considered exploratory because of the 
multiplicity issue and also smaller sample sizes that cannot be pre-specified. For subgroups 
without an adequate number of patients, the analysis may not be performed. One additional 
exploratory analysis to assess the effect of paclitaxel dose differences and carboplatin dose 
differences on the primary endpoint will be conducted by fitting a logistic regression model of 
ORR18 with independent factors including paclitaxel dose (200 vs 175 mg/m2), carboplatin 
dose (AUC 6 vs 5 mg/mL·minute),  treatment group, and ethnicity (Asian vs non-Asian). Odds 
ratios and 95% confidence intervals will be presented. Another exploratory analysis to assess 
the effect of reduced dose of paclitaxel and carboplatin on the primary endpoint will be 
conducted by a logistic regression model of ORR18 with independent factors including 
paclitaxel dose (>80% vs ≤80% of initial dose at cycle 6), carboplatin dose (AUC >80% vs 
≤80% of initial dose at cycle 6), treatment group, and ethnicity (Asian vs non-Asian). 
 
9.5 
Safety 
The safety population will be applied for all safety analyses. 


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9.5.1 
Adverse Events 
Treatment-emergent AEs are AEs that occur, having been absent before the first dose of study 
drug, or have worsened in severity after the initiating the study drug. Treatment-emergent AEs 
will be coded using MedDRA version 19.0 and assigned grades based on NCI-CTCAE version 
4.03 dated 14 Jun 2010. The number and percentage of patients reporting TEAEs will be 
tabulated by the worst CTCAE grade, System Organ Class, and Preferred Term as well as the 
relationship to study drug. Similarly, the number and percentage of patients reporting interested 
TEAEs (please refer to Section 6.2.1), treatment-emergent SAEs, and TEAEs leading to 
discontinuation of study treatments will be summarized by CTCAE grade and relationship to 
study drug. 
 
9.5.2 
Clinical Laboratory Evaluations 
Descriptive statistics will be provided for both laboratory assessment value and change from 
baseline by scheduled visits. 
Abnormal clinical laboratory results will be graded according to NCI-CTCAE version 4.03, if 
applicable. A shift table, presenting the frequency tabulation for baseline and the worst post 
treatment value according to the NCI-CTCAE grade or clinical judgment, will be provided for 
each clinical laboratory tests. 
Abnormal clinical laboratory results deemed of clinical significance or of Grade 3 or 4 will be 
listed and reported as AEs. 
Viral serology and immunodeficiency virus test will be presented in patient characteristics 
summary table. 
 
9.5.3 
Vital Signs Measurements, Physical Findings and Other Safety Evaluations 
Descriptive statistics will be provided for vital sign and electrocardiogram parameters by 
scheduled visits. Physical examination data will be listed. 
 
9.6 
Immunogenicity Analyses 
The safety population will be used for the immunogenicity analyses associated with number 
and percentage of patients with positive ADA/NADA will be summarized. The PK population 
will be used for correlation between serum level of ADA/NADA and bevacizumab exposure; 
results will be presented by scatter plot as well as Pearson/Spearman correlation coefficient. 


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9.7 
Pharmacokinetic Analyses 
The PK and popPK analyses will be explored in a subgroup of 200 patients, from samples 
collected only at designated sites in China, Turkey, and Ukraine. 
The PK analyses will be performed on the PK population. Serum bevacizumab concentrations 
will be listed and summarized by treatment using appropriate descriptive statistics. Graphical 
presentations of concentration-time data by treatment will be provided, as appropriate. 
Additional population PK modeling and/or correlation between bevacizumab exposure and 
response (safety, immunogenicity and/or efficacy) data may be evaluated separately, as 
appropriate. If performed, a separate analysis plan will be prepared and results will be reported 
separately from the clinical study report. 


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10.0 ETHICS 
 
10.1 Institutional Review Board or Independent Ethics Committee 
An Ethics Committee should approve the final protocol, including the final version of the ICF 
and any other written information and/or materials to be provided to the patients. The 
Investigator will provide the Sponsor or Sponsor designee with documentation of IRB/IEC 
approval of the protocol and informed consent before the clinical study may begin at the study 
centers. The Investigator should submit the written approval to Sponsor or representative 
before enrollment of any patient into the study. 
Sponsor or representative should approve any modifications to the ICF that are needed to meet 
local requirements. 
The Investigator will supply documentation to the Sponsor or IQVIA of required IRB/IEC’s 
annual renewal of the protocol, and any approvals of revisions to the informed consent 
document or amendments to the protocol. 
The Investigator will report promptly to the IRB/IEC, any new information that may adversely 
affect the safety of patients or the conduct of the clinical study. Similarly, the Investigator will 
submit written summaries of the study status to the IRB/IEC annually, or more frequently if 
requested by the IRB/IEC. Upon completion of the clinical study, the Investigator will provide 
the IEC with a brief report of the outcome of the clinical study, if required. 
 
10.2 Ethical Conduct of the Study 
This study will be conducted and the informed consent will be obtained according to the ethical 
principles stated in the Declaration of Helsinki (64th General Assembly, Fortaleza, Brazil, 
October 2013), the applicable guidelines for GCP (CPMP/ICH/135/95), or the applicable drug 
and data protection laws and regulations of the countries where the clinical study will be 
conducted. 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording and reporting studies that involve the participation of human patients. 
The study will be conducted in compliance with GCP and the applicable national regulations 
to assure that the rights, safety and well-being of the participating study patients are protected 
consistent with the ethical principles that have their origin in the Declaration of Helsinki. 


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10.3 Subject Information and Informed Consent 
The ICF will be used to explain the risks and benefits of study participation to the patient in 
simple terms before the patient will be entered into the clinical study. The ICF contains a 
statement that the consent is freely given, that the patient is aware of the risks and benefits of 
entering the clinical study, and that the patient is free to withdraw from the clinical study at 
any time. Written consent must be given by the patient and/or legal representative, after the 
receipt of detailed information on the clinical study. 
The Investigator is responsible for ensuring that informed consent is obtained from each patient 
or legal representative and for obtaining the appropriate signatures and dates on the informed 
consent document prior to the performance of any protocol procedures and prior to the 
administration of study drug. The Investigator will provide each patient with a copy of the 
signed and dated consent form. 
 
10.4 
Subject Data Protection 
The contents of this protocol and any amendments and results obtained during the study should 
be kept confidential by the Investigator, the Investigator’s staff, and the IRB/IEC and will not 
be disclosed in whole or in part to others, or used for any purpose other than reviewing or 
performing the study, without the written consent of the Sponsor. No data collected as part of 
this study will be used in any written work, including publications, without the written consent 
of the Sponsor. These obligations of confidentiality and non-use shall in no way diminish such 
obligations as set forth in either the Confidentiality Agreement or Clinical Study Agreement 
executed between the Sponsor/Contract Research Organization and the institution/Investigator. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Study 
Agreement executed between the institution/Investigator and the Sponsor or Sponsor designee. 


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11.0 STUDY ADMINISTRATION 
 
11.1 Data Handling and Record Keeping 
It is the Investigator’s responsibility to maintain essential study documents (protocol and 
protocol amendments, completed eCRFs, signed ICFs, relevant correspondence, and all other 
supporting documentation). The study center should plan on retaining such documents for 
approximately 15 years after study completion. The study center should retain such documents 
until at least 2 years after the last approval of a marketing application in an 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 study drug. These 
documents should be retained for a longer period if required by the applicable regulatory 
requirements or the hospital, institution, or private practice in which the clinical study is being 
conducted. Patient identification codes (patient names and corresponding study numbers) will 
be retained for this same period of time. These documents may be transferred to another 
responsible party, acceptable to the Sponsor, 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. 
No records should be disposed of without the written approval of the Sponsor. 
 
11.2 Direct Access to Source Data/Documents 
The Investigator will prepare and maintain adequate and accurate source documents to record 
all observations and other pertinent data for each patient randomized into the clinical study. 
The Investigator will allow the Sponsor, IQVIA, and authorized regulatory authorities to have 
direct access to all documents pertaining to the clinical study, including individual patient 
medical records, as appropriate. 
 
11.3 Investigator Information 
 
11.3.1 
Investigator Obligations 
This study will be conducted in accordance with the ICH Harmonized Tripartite Guideline for 
GCP (GCP, 1997); the US CFR Title 21 parts 50, 56, and 312; and European Legislation; and 
the ethical principles that have their origin in the Declaration of Helsinki. 


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The Investigator agrees to conduct the clinical study in compliance with this protocol after the 
approval of the protocol by the IEC/IRB in compliance with local regulatory requirements. The 
Investigator and the Sponsor will sign the protocol to confirm this agreement. 
 
11.3.2 
Protocol Signatures 
After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or representative (Appendix 13.1). 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 clinical study in accordance with ICH 
Tripartite Guidelines for GCP and applicable regulatory requirements. The study will not be 
able to start at any center where the Investigator has not signed the protocol. 
 
11.3.3 
Publication Policy 
The data generated by this clinical study are confidential information of the Sponsor. The 
Sponsor will make the results of the study publicly available. The publication policy with 
respect to the Investigator and study center will be set forth in the Clinical Study Agreement. 
 
11.4 Financing and Insurance 
The Sponsor will provide insurance in accordance with local guidelines and requirements as a 
minimum for the patients participating in this clinical study. The terms of the insurance will 
be kept in the study files. 


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12.0 REFERENCES 
1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide 
burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010 Dec 
15;127(12):2893-917. 
2. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib 
versus standard chemotherapy as first-line treatment for European patients with 
advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a 
multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-
46. 
3. Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, et al. Crizotinib versus 
chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013 Jun 
20;368(25):2385-94. 
4. Avastin® Summary of Product Characteristics (European Union). Roche Registration 
Limited. 14 January 2015. 
5. Avastin® Package Insert (United States). Genentech, Inc. May 2015. 
6. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-
carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 
2006 Dec 14;355(24):2542-50. 
7. Socinski MA, Schell MJ, Peterman A, Bakri K, Yates S, Gitten R, et al. Phase III trial 
comparing a defined duration of therapy versus continuous therapy followed by 
second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol. 
2002 Mar 1;20(5):1335-43. 
8. Azzoli CG, Temin S, Aliff T, Baker S Jr, Brahmer J, Johnson DH, et al. 2011 Focused 
Update of 2009 American Society of Clinical Oncology Clinical Practice Guideline 
Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer. J Clin Oncol. 
2011 Oct 1; 29(28):3825-31. 
9. Investigator’s Brochure: BAT1706: Proposed Biosimilar to Avastin® (Bevacizumab). 
Edition 01 dated 28 October 2015. 
10. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, 
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(11):2184-91. 


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11. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, 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 Mar 
10;27(8):1227-34. 
12. Niho S, Kunitoh H, Nokihara H, Horai T, Ichinose Y, Hida T, 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 
Jun;76(3):362-7. 
13. Zhou C, Wu YL, Chen G, Liu X, Zhu Y, Lu S, et al. BEYOND: A Randomized, 
Double-Blind, Placebo-Controlled, Multicenter, Phase III Study of First-Line 
Carboplatin/Paclitaxel Plus Bevacizumab or Placebo in Chinese Patients With 
Advanced or Recurrent Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 
2015 Jul 1;33(19):2197-204. 
14. Taxol® (paclitaxel) Injection (Patient Information Included): Package Insert. Bristol-
Myers Squibb Company. 
15. Paraplatin® (carboplatin aqueous solution) Injection: Package Insert. Bristol-Myers 
Squibb Company. 
16. Physician Prescribing Information of Paraplatin Injection. Bristol-Myers Squibb 
Company. 
17. Liang WH, Zhang YX, Kang SY, Pan H, Shao WL, Deng QH, et al. Impact of EGFR 
mutation status on tumor response and progression free survival after first-line 
chemotherapy in patients with advanced non-small-cell lung cancer: a meta-analysis. J 
Thorac Dis. 2014 Sep; 6(9): 1239–1250. 


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13.0 APPENDICES 
 
13.1 Signature of Investigator 
PROTOCOL TITLE: A Multicenter, Randomized, Double-blind, Phase III Study of 
BAT1706 versus EU-Avastin® plus Chemotherapy in Patients with Advanced Non-squamous 
Non-Small Cell Lung Cancer 
PROTOCOL NO: BAT1706-003-CR 
This protocol is a confidential communication of Bio-Thera Solutions, Ltd. I confirm that I 
have read this protocol, I understand it, and I will work according to this protocol. I will also 
work consistently with the ethical principles that have their origin in the Declaration of 
Helsinki and that are consistent with GCP and the applicable laws and regulations. Acceptance 
of this document constitutes my agreement that no unpublished information contained herein 
will be published or disclosed without prior written approval from Bio-Thera Solutions, Ltd. 
 
 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
 
 
Signature of Investigator: 
   
  
Printed Name: 
  
 
Investigator Title: 
  
 
Name of Center: 
  
 
 
Date:    
 
 
 
 
 
 
 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the 
name of the center in which the study will be conducted. Return the signed copy to Bio-Thera Solutions, Ltd/ 
IQVIA. 


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13.2 Estimated Blood Sample Volumes per Patient 
 
Time Points 
Evaluation Indexes 
Total Blood Volume (mL) 
Screening Period 
Infection screen 
5 
Hematology 
2 
Serum chemistry 
5 
Coagulation 
3 
Serum Pregnancy Test (if applicable) 
2 
Approximate Total 
17 
Treatment Period 
Cycle 1 
Hematology 
2 × 2  
Serum Chemistry 
5 
Coagulation 
3 
ADA/NADA 
6 × 2  
PK (if applicable) 
4 × 5  
Approximate Total 
44 
Cycles 2, 4 
Hematology 
2 × 2  
Serum Chemistry 
5 
Coagulation 
3 
PK (if applicable) 
4 
Approximate Total for each cycle 
16 
Cycles 3, 5 
Hematology 
2 × 2  
Serum Chemistry 
5 
Coagulation 
3 
ADA/NADA 
6 
PK (if applicable) 
4 
Approximate Total for each cycle 
22 
Cycle 6 
Hematology 
2 × 2  
Serum Chemistry 
5 
Coagulation 
3 
ADA/NADA 
6 
PK (if applicable) 
4 × 5  
Approximate Total for each cycle 
38 
Cycles 7, 10, 13, 16 
Hematology 
2 
Serum Chemistry 
5 
Coagulation 
3 
ADA/NADA 
6 
PK (if applicable) 
4 
Approximate Total for each cycle 
20 
Cycles 8, 9, 11, 12, 14, 15, 17 
Hematology 
2 
Serum Chemistry 
5 
Coagulation 
3 


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Approximate Total for each cycle 
10 
End of Treatment Visit/ 
Safety Follow up Visit 
Hematology 
2 
Serum Chemistry 
5 
Coagulation 
3 
Serum Pregnancy Test (if applicable) 
2 
ADA/NADA (if applicable) 
6 
PK (if applicable) 
4 
Approximate Total 
22 
LTE Study (if applicable) 
Hematology 
2 
Serum Chemistry 
5 
Coagulation 
3 
Serum Pregnancy Test (if applicable) 
2 
ADA/NADA (if applicable) 
6 
Approximate Total 
18 
Abbreviations: ADA =  anti-drug  antibody;  LTE  =  long-term  extension;  NADA  =  neutralizing  anti-drug  antibody;  
PK = pharmacokinetic(s). 


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13.3 Eastern Cooperative Oncology Group (ECOG) — Performance 
Status Scale 
 
Classification 
Criteria 
0 
Fully active, able to carry on all pre-disease performance without restriction 
(Karnofsky 90-100) 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work 
(Karnofsky 70-80) 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; 
up and about more than 50% of waking hours 
(Karnofsky 50-60) 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours 
(Karnofsky 30-40) 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
(Karnofsky 10-20) 


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13.4 Guidelines for Evaluation of Objective Tumor Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria In Solid Tumors) 
INTRODUCTION 
This appendix details the implementation of Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 Guidelines for the BAT1706-003-CR study with regards to Investigator 
assessment of tumor burden including protocol-specific requirements for this trial. 
DEFINITION 
OF 
MEASURABLE, 
NON-MEASURABLE, 
TARGET 
AND 
NON-TARGET LESIONS 
Only patients with measurable disease at baseline should be included in the study. 
Measurable disease is defined by the presence of at least one measurable lesion which has not 
been irradiated within 12 weeks prior to the date of randomization. 
Measurable: 
• For tumor lesions: the longest diameter in the plane of measurement has to be recorded 
with a minimum size of 10 mm by CT scan when CT scan slice thickness is no greater 
than 5 mm or by magnetic resonance imaging (MRI) and which is suitable for accurate 
repeated measurements. 
• For nodal lesions: at baseline and in the follow-up, only the short axis of lymph node 
will be measured and followed. To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed at baseline. 
Non-measurable: 
• All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis at baseline). Nodes with < 10 mm short 
axis are considered non-pathological and should not be recorded or followed as non-
target lesions (NTL). 
• Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by 
physical examination that is not measurable by CT or MRI. 
• Measurable previously irradiated lesions where other measurable lesions are available 
for assessment as target lesions and lesions irradiated within 12 weeks of randomization. 


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• Skin lesions assessed by clinical examination. 
Special Cases: 
• Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability. Blastic lesions are considered non-measurable. 
• Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present in 
the same patient, these should be selected as target lesions. 
Target lesions: 
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as 
target lesions (TL) at baseline. 
Non-Target lesions: 
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at baseline. 
METHODS OF ASSESSMENT 
The same method of assessment and the same technique should be used to characterize each 
identified and recorded lesion at baseline and during follow-up visits. 
CT and MRI 
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TL selected for response assessment and to assess NTL and identification 
of any new lesions. 
In the BAT1706-003-CR study, CT or MRI examinations of the chest and abdomen, including 
adrenals, will be used to assess tumor burden at baseline and follow-up visits. CT examination 
with intravenous contrast media administration is the preferred method. MRI with contrast 
(Gadolinium) should be used where CT is not feasible or it is medically contra-indicated. For 
brain lesion assessment, MRI is the preferred method. 
Clinical examination 
In the BAT1706-003-CR study, clinical examination will not be used for assessment of TL. 
Clinically detected lesions can be selected as target lesions if they are assessed by CT or MRI 


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scans. Clinical examination can be used to assess NTL and to identify the presence of new 
lesions. 
X- ray 
Chest X-ray 
In the BAT1706-003-CR study, chest X-ray assessment will not be used for assessment of TL 
as they will be assessed by CT examination or MRI examination. Chest X-ray can, however, 
be used to assess NTL and to identify the presence of new lesions. 
Plain X-ray 
In the BAT1706-003-CR study, plain X-ray may be used as a method of assessment for bone 
NTL and to identify the presence of new bone lesions. 
Ultrasound 
In the BAT1706-003-CR study, ultrasound examination will not be used for assessment of TL 
and NTL as it is not a reproducible method, does not provide an accurate assessment of tumor 
size and it is patientive and operator dependent. Ultrasound examination can, however, be used 
to identify the presence of new lesions. If new clinical symptoms occur and an ultrasound is 
performed then new lesions should be confirmed by CT or MRI examination. 
Endoscopy and laparoscopy 
In the BAT1706-003-CR study, endoscopy and laparoscopy will not be used for tumor 
assessments as they are not validated in the context of tumor assessment. 
Tumor markers 
In the BAT1706-003-CR study, tumor markers will not be used for tumor response 
assessments as per RECIST 1.1. 
Cytology and histology 
In the BAT1706-003-CR study, histology will not be used as part of the tumor response 
assessment as per RECIST 1.1. 
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment is required when the measurable tumor has met criteria for response or stable 
disease. In such circumstances, the cytology is necessary to differentiate between 
response/stable disease (an effusion may be a side effect of the treatment) and progressive 
disease (PD) (if the neoplastic origin of the fluid is confirmed). Where cytology findings are 
not available, any effusion that significantly worsens (from trace to large) or appearance of 


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clinically significant effusion (requiring change in drug therapy) during the study treatment 
will be considered to be progression of NTL, or disease progression due to new lesions. 
Isotopic bone scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI or X-
ray at baseline should be recorded as NTL and followed by the same method as per baseline 
assessment. 
In the BAT1706-003-CR study, isotopic bone scans may be used as a method of assessment to 
identify the presence of new bone lesions at follow-up visits. New lesions will be recorded 
where a positive hot-spot that was not present on the baseline bone scan assessment is identified 
on a bone scan performed at any time during the study. The Investigator should consider the 
positive hot-spot to be a significant new site of malignant disease and represent true disease 
progression in order to record the new lesion. Confirmation by CT, MRI and X-ray is 
recommended where bone scan findings are equivocal. 
Fludeoxyglucose-Positron emission tomography scan 
In the BAT1706-003-CR study, fludeoxyglucose (FDG)-positron emission tomography (PET) 
scans may be used as a method for identifying new lesions if a baseline FDG-PET scan is done, 
according with the following algorithm: New lesions will be recorded where there is positive 
FDG uptake not present on baseline FDG-PET scan or in a location corresponding to a new 
lesion on CT/MRI at the same follow-up visit. Only combined PET/CT with full diagnostic 
CT part can be used. A positive FDG-PET scan lesion should be reported only when an uptake 
greater than twice that of the surrounding tissue is observed. If there is no baseline FDG-PET 
scan available, and no evidence of new lesions on CT/MRI scans then follow-up CT/MRI 
assessments should be continued, scheduled as per protocol or clinical indicated, in order to 
confirm new lesions. 
TUMOR RESPONSE EVALUATION 
Refer to Table 1 Schedule of Events on the tumor assessment time point. 
Target lesions (TL) 
Documentation of target lesions 
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including lymph 
nodes), representative of all lesions involved should be identified as TL at baseline. Target 
lesions should be selected on the basis of their size (longest diameter for non-nodal lesions or 
short axis for nodal lesions), but in addition should be those that lend themselves to 
reproducible repeated measurements. 


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The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes). All measurements should be recorded in 
millimeters. At baseline the sum of the diameters for all TL will be calculated and reported as 
the baseline sum of diameters. At follow-up visits the sum of diameters for all TL will be 
calculated and reported as the follow-up sum of diameters. 
Special cases: 
• For TL measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis. 
• If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable disease 
at baseline should be twice the slice thickness of the baseline scan. 
• If  a lesion has completely disappeared, the longest diameter should be recorded  as   0 
mm. 
• If a TL splits into two or more parts, then the sum of the diameters of those parts should 
be recorded. 
• If two or more TL merge then the sum of the diameters of the combined lesion should 
be recorded for one of the lesions and 0 mm recorded for the other lesion(s). 
• If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned. If an accurate measure can be given, this should be 
recorded, even if it is below 5 mm. 
• If a TL cannot be measured accurately due to it being too large, an estimate of the size 
of the lesion should be provided. 
• When a TL has had any intervention eg, radiotherapy, embolization, surgery etc., 
during the study, the size of the TL should still be provided where possible. 
Evaluation of target lesions 
This section provides the definitions of the criteria used to determine objective tumor visit 
response for TL. 
Complete Response (CR) Disappearance of all target lesions since baseline. Any pathological 
lymph nodes selected as target lesions must have a reduction in short axis to <10 mm. 
Partial Response (PR) At least a 30% decrease in the sum of the diameters of TL, taking as 
reference the baseline sum of diameters. 


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Stable Disease (SD) Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD. 
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. 
Not Evaluable (NE) Only relevant if any of the target lesions were not assessed or not 
evaluable or had a lesion intervention at this visit. Note: If the sum of diameters meets the PD 
criteria, PD overrides not evaluable as a target lesion response. 
Non-Target lesions 
Evaluation of non-target lesions 
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at baseline. 
Measurements are not required for these lesions, but their status should be followed at 
subsequent visits. At each visit an overall assessment of the NTL response should be recorded 
by the Investigator. This section provides the definitions of the criteria used to determine and 
record overall response for NTL at the investigational site at each visit. 
Complete Response (CR) Disappearance of all non-target lesions since baseline. All lymph 
nodes must be non-pathological in size (<10 mm short axis). 
Non CR/Non PD Persistence of one or more NTL. 
Progression (PD) Unequivocal progression of existing NTL. Unequivocal progression may 
be due to an important progression in one lesion only or in several lesions. In all cases the 
progression MUST be clinically significant for the physician to consider changing (or stopping) 
therapy. 
Not Evaluable (NE) Only relevant when one or some of the non-target lesions were not 
assessed and, in the Investigator's opinion, they are not able to provide an evaluable overall 
non-target lesion assessment at this visit. 
To achieve ‘unequivocal progression’ on the basis of non-target lesions, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. 


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New Lesions 
Details of any new lesions will also be recorded with the date of assessment. The presence of 
one or more new lesions is assessed as progression. 
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
The finding of a new lesion should be unequivocal: ie, not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumor. 
If a new lesion is equivocal, for example because of its small size, the treatment and tumor 
assessments should be continued until the new lesion has been confirmed. If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan. 
Symptomatic deterioration 
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy. 
Patients with ‘symptomatic deterioration’ requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumor 
assessments where possible until objective disease progression is observed. 
Evaluation of Overall Visit Response 
The overall visit response will be derived using the algorithm shown in the table below. 
Overall visit response 
 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
NA 
No 
CR 
NA 
CR 
No 
CR 
CR 
Non CR/Non PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non PD or NE 
No 
PR 
SD 
Non PD or NE 
No 
SD 
NA 
Non CR/Non PD 
No 
SD (Non CR/Non PD) 
NE 
Non PD or NE 
No 
NE 
NA 
NE 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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Target lesions 
Non-target lesions 
New lesions 
Overall response 
Abbreviations: CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = not 
evaluable; NA = not applicable (only relevant if there were no target lesions/non-target lesions at baseline). 
 
CENTRAL REVIEW 
Radiological examinations performed in the conduct of this study for RECIST response 
assessments must be retained at the study site as source data and a copy anonymized for 
personal identifiers eg, name, initials, be available for collection by the Sponsor for centralized 
review if required. 


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13.5 PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Document History 
 
Document 
Date 
Substantial 
Region 
Amendment 4 
20-Jun-2019 
Yes 
Global 
Amendment 3 
08-Feb-2019 
No 
Global 
Amendment 2 
19-Sep-2018 
Yes 
Global 
Amendment 1 
26-Feb-2018 
Yes 
Global 
Original Protocol 
23-Mar-2017 
- 
- 
 
 
Amendment [4] (20 June 2019) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
Requested by FDA Advise/Information Letter for IND #138278 dated 25 March 2019: 
• To delete the phrase “with the 2-sided control type I error within 10%” on page 79 of 
the protocol because the comparative evaluation of overall response rates for BAT1706 
and EU-Avastin® will be based on whether the 90% CI of the risk ratio falls entirely 
between the predetermined similarity margins. 
• To revise the following statement, “The main conclusion shall be driven from both the 
ITT and per-protocol (PP) analysis sets,” to be consistent with the statement, “The 2- 
sided 90% CI of risk ratio or 95% CI of risk difference will be estimated for the ITT 
population as primary analyses and for the PP population as supportive analyses.” The 
primary analysis should be based on the ITT population, which includes all randomized 
patients. 
• To specify that the stratification factors to be used in the primary analysis will be based 
on the stratification variables for randomization as recorded in the IWRS. 
List of Main Changes in Amendment: 
Protocol text: 
• Section 9.1: “with the 2-sided control type I error within 10%” is deleted. 


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105 
Version 5.0, 20 June 2019 
Confidential 
 
 
• Section 9.1: The statement “The main conclusion shall be driven from both the ITT and 
per-protocol (PP) analysis sets,” is replaced with the statement “The primary analysis 
will be based on the ITT population and the supportive analysis will be based on the 
per-protocol (PP) population.” 
• Section 9.4.1: The stratification factors are added in the primary analysis and it is 
updated to “The 2-sided 90% CI of risk ratio or 95% CI of risk difference will be 
estimated including covariates of stratification factors: NSCLC stage (recurrent disease 
after any stage at time of primary diagnosis, or Stage IV), Gender (male or female), and 
Ethnicity (Asian or non-Asian), for the ITT population as primary analyses and for the 
PP population as supportive analyses.” 
In addition, minor corrections of typographical errors and inconsistencies have been made. 
Such changes are not listed in this protocol amendment summary. 

SAP_003.pdf: 
 
 
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Statistical Analysis Plan 
 
 
BAT1706-003-CR 
 
A MULTICENTER, RANDOMIZED, DOUBLE BLIND, PHASE III STUDY OF 
BAT1706 VERSUS EU AVASTIN® PLUS CHEMOTHERAPY IN PATIENTS WITH 
ADVANCED NON-SQUAMOUS NON-SMALL CELL LUNG CANCER 
 
 
 
Author: Aiqin Zhang, Senior Biostatistician, IQVIA 
Todd Dumas, Research Pharmacokineticist, IQIVA 
Version Number and Date: 28Nov2019 / Final V2.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Modification History 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from Previous Authorized Version 
0.1 
10Nov2017 
Jesse Lee 
Not Applicable – First Version 
0.2 
13Mar2018 
Jesse Lee 
Updated as the protocol Version 2.0, 26 February 
2018. 
0.3 
18May2018 
Jesse Lee 
Updated as the comments received from SBR and SPL 
received on 22Mar2018. 
The PK/PD analysis were Included. 
0.4 
19Dec2018 
Aiqin Zhang 
Updated as the comments received from sponsor 
received on 24Jul2018. 
Updated as the Protocol V3.0, 19Sep2018. 
0.5 
25Jul2019 
Aiqin Zhang 
Updated per protocol amendment 4, version 5.0 
20Jun2019. 
1.0 
01Aug2019 
Aiqin Zhang 
Updated sponsor comments. 
1.0 
14Aug2019 
Aiqin Zhang 
Remove the 2nd interim analysis 
2.0 
28Nov2019 
Aiqin Zhang 
Removed interim analysis and replaced with final 
analysis, with timing as defined by U.S. FDA. 
A few other minor changes are made in the SAP to 
make it in total accordance with the protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Contents 
Statistical Analysis Plan Signature Page ......................................................................................................... 2 
Output Shells Signature Page ........................................................................................................................ 3 
1. 
LIST OF ABBREVIATIONS ............................................................................................................. 9 
2. 
INTRODUCTION ............................................................................................................................. 12 
2.1. 
Primary Objective ............................................................................................................................ 12 
2.2. 
Secondary Objectives ....................................................................................................................... 12 
2.3. 
Exploratory Objectives ..................................................................................................................... 12 
3. 
STUDY DESIGN ............................................................................................................................... 12 
3.1. 
General Description ......................................................................................................................... 12 
3.2. 
Method of Assigning Subjects to Treatment Groups ......................................................................... 12 
3.3. 
Treatments Administered ................................................................................................................ 13 
3.4. 
Schedule of Events ........................................................................................................................... 13 
3.5. 
Changes to Analysis from Protocol ................................................................................................... 13 
4. 
PLANNED ANALYSES ................................................................................................................... 14 
4.1. 
DSMB Analysis and Data Monitoring ................................................................................................ 14 
4.2. 
Primary efficacy endpoint and secondary endpoints final Analysis ................................................... 15 
4.3. 
Follow-up Analysis .......................................................................................................................... 15 
5. 
ANALYSIS SETS AND SUBGROUPS ......................................................................................... 15 
5.1. 
Screened Analysis Set (SCR) ............................................................................................................. 15 
5.2. 
Intention-to-Treat Population (ITT) .................................................................................................. 15 
5.3. 
Per-protocol Population (PP) ............................................................................................................ 15 
5.4. 
Safety Population (SAF) .................................................................................................................... 16 
5.5. 
Pharmacokinetic (PK) Population ..................................................................................................... 16 
 
 
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5.6. 
Population Pharmacokinetic (popPK) Population ............................................................................. 16 
6. 
GENERAL CONSIDERATIONS ................................................................................................... 16 
6.1. 
Treatment Arms ............................................................................................................................... 16 
6.2. 
Reference Start Date and Study Day ................................................................................................. 16 
6.3. 
Baseline ........................................................................................................................................... 17 
6.4. 
End of Treatment ............................................................................................................................. 17 
6.5. 
Retests, Unscheduled Visits and Early Termination Data .................................................................. 17 
6.6. 
Statistical Tests ................................................................................................................................ 17 
6.7. 
Common Calculations ...................................................................................................................... 17 
6.8. 
Software Version ............................................................................................................................. 18 
7. 
STATISTICAL CONSIDERATIONS ............................................................................................ 18 
7.1. 
Hypothesis ....................................................................................................................................... 18 
7.2. 
Sample Size ...................................................................................................................................... 18 
7.2.1. 
Determination of Sample Size .............................................................................................................. 18 
7.2.2. 
Sample Size Justification Based on Risk Ratio ..................................................................................... 19 
7.2.3. 
Sample Size Justification Based on Risk Difference............................................................................. 19 
7.3. 
Multi-center Studies ........................................................................................................................ 20 
7.4. 
Missing data .................................................................................................................................... 20 
7.5. 
Examination of Subgroups ............................................................................................................... 20 
8. 
OUTPUT PRESENTATIONS ........................................................................................................ 21 
9. 
DISPOSITION AND WITHDRAWALS & PROTOCOL DEVIATION ............................... 21 
9.1. 
Disposition and Withdrawals ........................................................................................................... 21 
9.2. 
Protocol Deviation ........................................................................................................................... 21 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ..................................... 22 
10.1. 
Demographics .............................................................................................................................. 22 
10.2. 
Other Baseline Characteristics ...................................................................................................... 22 
10.3. 
Mutation Status at Baseline ......................................................................................................... 23 
 
 
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10.4. 
Derivations ................................................................................................................................... 23 
11. 
SURGICAL AND MEDICAL HISTORY ...................................................................................... 23 
11.1. 
Lung Cancer History ...................................................................................................................... 23 
11.2. 
Surgical History ............................................................................................................................ 24 
12. 
CONCOMITANT ILLNESSES ....................................................................................................... 24 
13. 
MEDICATIONS AND PROCEDURES ........................................................................................ 24 
13.1. 
Prior Oncology Therapies and Surgeries ....................................................................................... 24 
13.2. 
Prior Medications and Procedures ................................................................................................ 24 
13.3. 
Concomitant Medications and Procedures ................................................................................... 25 
14. 
STUDY MEDICATION EXPOSURE ............................................................................................ 25 
14.1. 
Treatment Exposure ..................................................................................................................... 25 
14.2. 
Derivations of Treatment Exposure .............................................................................................. 25 
15. 
STUDY MEDICATION COMPLIANCE ...................................................................................... 26 
16. 
EFFICACY OUTCOMES ................................................................................................................. 26 
16.1. 
Primary Efficacy ........................................................................................................................... 26 
16.1.1. 
Primary Efficacy Variable & Derivation .................................................................................................26 
16.1.2. 
Primary Efficacy Analyses ......................................................................................................................27 
16.2. 
Secondary Efficacy........................................................................................................................ 27 
16.2.1. 
Secondary Efficacy Variables & Derivations ........................................................................................ 27 
16.2.2. 
Secondary Efficacy Analyses ................................................................................................................. 28 
16.3. 
Subgroup Analyses ....................................................................................................................... 30 
16.4. 
Missing Data Methods of Efficacy ................................................................................................. 30 
17. 
QUALITY OF LIFE ANALYSIS ..................................................................................................... 31 
18. 
SAFETY OUTCOMES ..................................................................................................................... 31 
18.1. 
Adverse Events ............................................................................................................................. 31 
18.1.1. 
All TEAEs................................................................................................................................................. 32 
18.1.2. 
TEAEs Leading to IMP Discontinuation ................................................................................................ 34 
18.1.3. 
Serious TEAEs ........................................................................................................................................ 34 
18.1.4. 
Treatment Emergent Adverse Events of Special Interest (TEAESI) .................................................... 34 
18.2. 
Deaths.......................................................................................................................................... 34 
 
 
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18.3. 
Laboratory Evaluations ................................................................................................................. 36 
18.4. 
ECG Evaluations ........................................................................................................................... 37 
18.5. 
Vital Signs .................................................................................................................................... 38 
18.6. 
Physical Examination .................................................................................................................... 38 
18.7. 
Immunogenicity Assessments ...................................................................................................... 38 
18.8. 
ECOG Performance ....................................................................................................................... 39 
19. 
GENETIC ANALYSIS ...................................................................................................................... 39 
20. 
DATA NOT SUMMARIZED OR PRESENTED ........................................................................ 39 
21. 
PHARMACOKINETIC ANALYSIS .............................................................................................. 39 
21.1. 
Precision ...................................................................................................................................... 39 
21.2. 
Concentration Data ...................................................................................................................... 39 
21.3. 
Pharmacokinetic Parameters ........................................................................................................ 40 
21.4. 
Exposure Response Correlation .................................................................................................... 40 
22. 
REFERENCES ................................................................................................................................... 41 
23. 
APPENDICES .................................................................................................................................... 42 
APPENDIX 1. 
Programming Conventions for Outputs ............................................................................. 42 
APPENDIX 2. 
Partial Date Conventions ................................................................................................... 43 
APPENDIX 3. 
Confirmation of Best Overall Response ............................................................................. 46 
APPENDIX 4. 
CTCAE V4.03 Grade of Hematology and Chemistry ............................................................ 47 
APPENDIX 5. 
Sample Code for Efficacy Analysis ..................................................................................... 50 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1. LIST OF ABBREVIATIONS 
 
Abbreviation
Definition 
ADA 
Anti-drug antibody 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALK 
Anaplastic lymphoma kinase 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
CFDA 
China food and drug administration 
CI 
Confidence interval 
CIR 
Central imaging review 
CNS 
Central nervous system 
CR 
Complete response 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease control rate 
DoR 
Duration of response 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
CRF 
Electronic case report form 
EDC 
Electronic Data Capture 
EGFR 
Epidermal growth factor receptor 
EMA 
European Medicines Agency 
EoT 
End of Treatment 
EU 
European Union 
FDA 
Food and Drug Administration 
FDG 
Fludeoxyglucose 
GCP 
Good Clinical Practice 
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HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous(ly) 
IWRS 
Interactive Web Response System 
LTE 
Long-Term Extension 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NADA 
Neutralizing anti-drug antibody 
NCI 
National Cancer Institute 
NSCLC 
Non-small cell lung cancer 
nsNSCLC 
Non-squamous non-small cell lung cancer 
ORR 
Overall response rate 
ORR6 
Overall response rate at Week 6 
ORR12 
Overall response rate at  Week 12 
ORR18 
Overall response rate at  Week 18 
OS 
Overall survival 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
popPK 
population pharmacokinetics 
PP 
Per-protocol 
PR 
Partial response 
PRES 
Posterior Reversible Encephalopathy Syndrome 
 
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PT 
Prothrombin time 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SOP 
Standard operating procedures 
TEAEs 
Treatment-emergent adverse events 
ULN 
Upper limit of normal 
US 
United States 
VEGF 
Vascular endothelial growth factor 
VEGFR 
Vascular endothelial growth factor receptor 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2. INTRODUCTION 
The purpose of this SAP is to document technical and detailed specifications for the final analysis of data 
collected for protocol BAT1706 003-CR, Version 5.0, 20Jun2019. 
Results of the analyses described in this SAP will be included in the Clinical Study Report (CSR). Additionally, the 
planned analyses identified in this SAP will be included in regulatory submissions or future manuscripts. Any 
post-hoc, or unplanned analyses performed to provide results for inclusion in the CSR but not identified in this 
prospective SAP will be clearly identified in the CSR. 
The SAP is based upon section 9 (Statistics) of the trial protocol and prepared in compliance with ICH E9. 
 
2.1. PRIMARY OBJECTIVE 
 
The primary objectives are to: 
 
Compare the efficacy of BAT1706 and EU-Avastin® given with chemotherapy as first line treatment 
using the ratio or the difference in ORR to show clinical equivalence. 
 
2.2. SECONDARY OBJECTIVES 
 
The secondary objectives are to: 
 
Evaluate the efficacy of BAT1706 and EU-Avastin® given with chemotherapy using ORR at different time 
points, duration of response (DoR), PFS, and OS (time, and rate at 12 months). 
 
Evaluate the safety and immunogenicity of BAT1706 and EU-Avastin®. 
 
Characterize bevacizumab exposure after administration of BAT1706 and EU-Avastin®. 
 
2.3. 
EXPLORATORY OBJECTIVES 
 
 
To explore population pharmacokinetics (popPK). 
 
3. STUDY DESIGN 
 
3.1. GENERAL DESCRIPTION 
 
This is a Phase III, randomized, double-blind, multi-center, active comparator, parallel two-arm study to compare 
the efficacy, and to evaluate the safety and immunogenicity of BAT1706 to EU-Avastin® in patients with 
previously untreated advanced non-squamous non-small cell lung cancer (nsNSCLC) to demonstrate clinical 
equivalence of BAT1706 and EU-Avastin®. 
 
3.2. METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS 
 
After stratification for disease stage (IV vs. other), gender (male vs. female) and ethnicity (Asian vs non-Asian), 
eligible patients will be randomized in a 1:1 ratio to receive BAT1706 plus paclitaxel and carboplatin (Arm A) or 
EU-Avastin® plus paclitaxel and carboplatin (Arm B). Patients will be assessed for histology and randomization 
will occur after central imaging review (CIR) to confirm the presence of at least one measurable target lesion 
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according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). 
 
3.3. TREATMENTS ADMINISTERED 
 
Combination treatment will be administered every 3 weeks up to 6 cycles, followed for those with non-
progressive disease with maintenance monotherapy with BAT1706 or EU-Avastin® until a maximum of total 
study treatment of 12 months (17 cycles). Patients intolerant to chemotherapy after 2 dose reductions can start 
monotherapy with BAT1706 or EU-Avastin® or start another line of anti-cancer therapy after investigator’s 
judgment. 
A data safety monitoring board (DSMB) will review all safety data after the first 20 patients have been treated 
for 6 weeks in each arm; then after, if no unexpected safety signal was identified, the study will continue, and 
the safety data will be reviewed at regular intervals after approximately every 200 patients are evaluated after 
they received the first 4 cycles. 
 
3.4. SCHEDULE OF EVENTS 
 
Patients will undergo tumor assessment at Weeks 6, 12 and 18, regardless of the number of cycles actually 
completed (with a visit window of 1 week maximum during the first 18 weeks), then after every 3 cycles 
(approximately every 9 weeks) and at SFUV/EoT. During the trial, tumor response will be assessed by local 
radiologist/Investigator for immediate therapeutic decision. 
To comply with the different statistical approaches of each regulatory agency, the main efficacy analyses 
(difference and ratio of ORR) will be based upon tumor response at different time points as determined by CIR 
according to RECIST 1.1. After Week 18, patients with responding or stabilized disease will remain in the study 
until a total study treatment duration of 12 months is reached to provide further comparative 
safety/immunogenicity data as well as other efficacy parameters (such as DoR, PFS and OS rates at 12 months 
for both BAT1706 and EU Avastin®). 
All patients will remain in the study until Investigator assessed disease progression, excessive toxicity, 
Investigator’s judgment, withdrawal of consent, lost to follow-up, death, start of a new anticancer therapy, study 
termination by the Sponsor, or for a maximum of 12 months of treatment, whichever occurs first. Then after, all 
patients who are still benefiting of therapy will have the option to continue treatment with BAT1706 in a LTE 
study (as of Week 53) until disease progression, excessive toxicity, withdrawal of consent, Investigator’s 
decision, or for a maximum of 12 additional months (ie, for up to 24 months from initial randomization). 
Survival Follow up will occur every 3 months until 24 months after randomization. A complete clinical study 
report will be submitted to the China Food and Drug Administration (CFDA), United States (US) Food and Drug 
Administration (FDA), and the European Medicines Agency (EMA) when primary efficacy data are available in all 
patients. At the end of the LTE, a complementary study report will be released. The study will be conducted 
according to the national and international ethical standards, the Good Clinical Practice guidelines, and the 
protocol will be approved by the Institutional Review Boards/Independent Ethics Committees of the 
participating sites. 
The schedule of events can be found in Table 1 and Table 2 in the protocol BAT1706 003-CR, Version 5.0, 
20Jun2019. 
 
3.5. CHANGES TO ANALYSIS FROM PROTOCOL 
 
NOT APPLICABLE. 
 
 
 
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4. PLANNED ANALYSES 
The following formal analyses are planned for the study: 
 
4.1. DSMB ANALYSIS AND DATA MONITORING 
 
A Data Safety Monitoring Board (DSMB) will be established for the study. The DSMB will be responsible to 
monitor patient’s safety data during the study. The DSMB will review unblinded treatment data. 
Specifically, the DSMB will be responsible for the following: 
 
Review of safety data that will include: SAEs, drug exposure, deaths. 
 
Review of the conduct of the study, including enrolment. 
 
Review of the efficacy data will include: primary and secondary efficacy endpoints. 
Two separate biostatistics study teams will be used to perform the DSMB analysis: The study team who remain 
blinded, and an unblinded team. The unblinded team will be located in a geographically separate office from the 
study team. Unblinded data will be maintained in a separate secured directory accessed only by the unblinded 
team. 
The study team will prepare the blinded analysis using a dummy randomization code, and then deliver the data 
and programs to the unblinded team. The unblinded team will receive the true randomization code from the 
IWRS provider and apply this for the unblinded analysis. The results of the analysis will be reviewed by the DSMB 
members at a scheduled DSMB meeting. The DSMB will make a recommendation to the Sponsor based on these 
results in accordance with the DSMB Charter. 
The full study team will remain blind to these results and to discussions between the DSMB and the sponsor 
regarding any recommendations to terminate the study or make major changes to the protocol. These should 
be discussed with a designated member of the Sponsor senior management. The study team will then implement 
actions as necessary, while retaining confidentiality as appropriate. 
The DSMB will evaluate the safety data periodically or as needed and make a recommendation to the Sponsor 
whether to continue, revise, or terminate the study based on the safety findings. Summaries of laboratory data, 
vital signs, ECGs, adverse events (AEs), serious adverse events (SAEs), and other relevant safety information will 
be sent to the DSMB. Details of the DSMB responsibilities and logistics are documented in the Charter. 
DSMB will review all safety data after the first 20 patients have been treated for 6 weeks in each arm; then after, 
if no unexpected safety signal was identified, the trial will continue, and the safety data will be reviewed after 
every 200 patients are evaluated after they received the first 4 cycles. At each DSMB review, if no unexpected 
changes in the known safety profile for Avastin® are observed for BAT1706, the DSMB will recommend 
continuing the study. The blind will be broken only in case a serious safety signal is identified. 
 
1st DSMB - 20 subjects with completed 6 weeks. 
 
2nd DSMB - 200 subjects with completed 12 weeks (4 cycles). 
 
3rd DSMB - 400 subjects with completed 12 weeks (4 cycles). 
 
4th DSMB - 600 subjects with completed 12 weeks (4 cycles). 
 
5th DSMB – efficacy data (up to a maximum of one year of treatment) available after the last patient 
enrolled has completed the Week 18 evaluation, provided there are safety and immunogenicity 
data for one year from enrollment for at least one-third of the study population. 
 
 
 
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4.2. PRIMARY EFFICACY ENDPOINT AND SECONDARY ENDPOINTS FINAL ANALYSIS 
 
A final analysis of efficacy, safety, pharmacokinetics, immunogenicity and survival data will be performed by 
IQVIA Biostatistics following Sponsor authorization based on all data (up to a maximum of one year of treatment) 
available after the last patient enrolled has completed the Week 18 evaluation, provided there are safety and 
immunogenicity data for one year from enrollment for at least one-third of the study population. Data through 
the above said data cut off point will be locked, the unblinded team will produce the results, and the results will 
be shared with the Sponsor. Following Sponsor authorization, a complete clinical study report will be released. 
 
 
 
4.3. 
FOLLOW-UP ANALYSIS 
 
A follow-up analysis including all secondary efficacy (survival and duration of response), safety, 
pharmacokinetics and immunogenicity will be performed by IQVIA Biostatistics after the last patient has 
completed the Long-Term Extension (LTE) study or at the latest 24 months after randomization of the last 
patient. Following Sponsor authorization, a complementary clinical study report will be released and archived. 
The data collected in the LTE study will be presented using separate TFLs based on corresponding TFLs of 
secondary endpoints analysis. 
 
5. ANALYSIS SETS AND SUBGROUPS 
The following subject sets are applicable to this study: 
 
5.1. SCREENED ANALYSIS SET (SCR) 
 
The Screened Analysis Set will consist of all subjects who signed the informed consent. 
 
5.2. INTENTION-TO-TREAT POPULATION (ITT) 
 
The ITT Population will consist of all randomized patients in accordance with the intended treatment arm, 
regardless of the treatment actually received. For the primary efficacy analysis of the ITT population, patients 
who discontinued prior to Week 18 for any reason will be counted as non-responders. 
 
5.3. PER-PROTOCOL POPULATION (PP) 
 
The PP population is defined as patients who have received at least 3 cycles of study drugs as allocated (BAT1706 
or EU Avastin® and paclitaxel/carboplatin) or less due to early progression, death, or excessive toxicity and have 
one tumor assessment with no major protocol deviations that would have significantly impact on primary 
efficacy or safety outcomes. 
All decisions to exclude patients from PP population will be made prior to database release. For the PP efficacy 
analysis, patients for whom the efficacy endpoint is missing, i.e., patients without at least 1 valid post treatment 
evaluation, are excluded from the PP population, except those who are withdrawn due to excessive toxicity, 
early progression or death, in which case the patients will be classified as non-responders. It is anticipated that 
approximately 10% of patients in the ITT population will be excluded from the PP Population. 
If the Per Protocol analysis set includes at least 90% of subjects in the ITT Population, additional efficacy 
analyses on the Per Protocol analysis set will be omitted as the differences in the results based upon these 
 
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two analysis sets are expected to be negligible. 
 
5.4. SAFETY POPULATION (SAF) 
 
The Safety Population will consist of all randomized patients who received at least one dose of study drug 
(BAT1706 or EU-Avastin®) and allocated into actual-received treatment arm. The safety population will be used 
as the basis for all safety analyses. 
 
5.5. PHARMACOKINETIC (PK) POPULATION 
 
Pharmacokinetic population is a subgroup of 200 patients from samples collected only at designated sites in 
China, Turkey, and Ukraine who receive at least one dose of study drug, have at least one measured 
concentration at a scheduled post dose PK time point, and have no major protocol deviations that may 
significantly affect the PK assessment. The PK and optional popPK analysis will be performed on the PK 
population. 
 
5.6. POPULATION PHARMACOKINETIC (POPPK) POPULATION 
 
Optional exploratory popPK analyses may be conducted to support drug approval for other countries. Details 
and criteria for popPK population would be outlined in a separate standalone modelling analysis plan with the 
results reported separately from the Clinical Study Report if conducted. 
 
6. GENERAL CONSIDERATIONS 
 
6.1. TREATMENT ARMS 
 
 
Treatment Arm A: BAT1706 plus carboplatin and paclitaxel. 
 
Treatment Arm B: EU-Avastin® plus carboplatin and paclitaxel. 
 
6.2. REFERENCE START DATE AND STUDY DAY 
 
Reference start date is defined as the day of the first administration of study treatment, (Day 1 is the day of the 
first dose of study treatment) and will appear in every listing where an assessment date or event date appears. 
Study day will be calculated from the reference start date and will be used to show start/stop day of the 
assessments and events relative to the first administration of study treatment. 
 
If the date of the event is on or after the reference date, then: 
Study day = (date of event – reference date) + 1. 
 
If the date of the event is prior to the reference date, then: 
Study day = (date of event – reference date). 
In the situation where the event date is partial or missing, the date will appear partial or missing in the 
listings, and Study Day, and any corresponding durations will be presented based on the imputations 
specified in Appendix 2; Partial Date Conventions. 
 
 
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6.3. BASELINE 
 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to reference 
treatment start date (including unscheduled assessments). In case where the last non-missing measurement and 
the reference treatment start date coincide, that measurement will be considered as baseline, but AEs and 
medications commencing on the reference start date will be considered post-baseline, that is, treatment- 
emergent or concomitant (“worst case” approach). 
For ECG results, if last non-missing measurement and the reference treatment start date coincide, that 
measurement must be pre-treatment in order to be considered as baseline. 
 
6.4. END OF TREATMENT 
 
All patients who receive at least one infusion of BAT1706 or EU-Avastin® and who discontinue the study at any 
time after Day 1 (but do not withdraw their consent) will be required to undergo all of the evaluations for the 
SFUV/EoT that will take place 28 days ± 2 days after they received the last dose during the study with a maximum 
at Week 53. 
 
6.5. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. Unscheduled 
measurements will not be included in by-visit (cycle X day X) summaries but will contribute to best/worst case 
value where required (e.g., shift table). 
In the case of a retest (visit-specific unscheduled visit number assigned), the latest non-missing measurement 
among all scheduled and unscheduled measurements for that visit will be used for by-visit summaries. 
For any subject with early withdrawal assessments available, all early withdrawal assessments related to the 
specific subject are to be considered in chronological order and are to be: 
 
Considered as unscheduled. 
 
Not summarized in the by-visit summaries. 
 
Only listed in the by-subject data listings. 
Listings will include scheduled, unscheduled, retest, and early discontinuation data. 
 
6.6. STATISTICAL TESTS 
 
The significant level will be (5%); confidence intervals will be 95% and all tests will be two-sided, unless otherwise 
specified in the description of the analyses. 
 
6.7. COMMON CALCULATIONS 
 
For quantitative measurements, change from Baseline will be calculated as: 
 
Change from baseline = Test Value at Visit X – Baseline Value 
For quantitative measurements, % change from baseline will be calculated as: 
 
(Test value at visit X – test value on baseline)/test value on baseline * 100% 
 
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The time from Date of Event A to Date of Event B (years) is calculated as: 
 
(Date of Event B - Date of Event A + 1)/365.25. 
The time from Date of Event A to Date of Event B (months) is calculated as: 
 
(Date of Event B - Date of Event A + 1)/30.4375. 
 
6.8. SOFTWARE VERSION 
 
All analyses will be conducted using SAS Version 9.4, except for the PK analysis. Non-compartmental PK 
parameter calculations will be performed using Phoenix® WinNonlin® 6.4 or higher (Certara, Princeton, New 
Jersey, United States). Figures may be prepared using SAS®, Phoenix® WinNonlin®, or SigmaPlot 12.5 or higher 
(Systat Software, Inc., San Jose, California, United States). 
 
7. STATISTICAL CONSIDERATIONS 
 
7.1. HYPOTHESIS 
 
The null hypothesis is that either (1) BAT1706 is inferior to EU-Avastin® or (2) BAT1706 is superior to EU-Avastin® 
based on a pre-specified equivalence margin. 
To satisfy the different methods used by the regulatory agencies, different endpoints and methods of 
calculations will be used in this global study. 
To satisfy the CFDA and US FDA statistical approaches, the null hypothesis will be rejected if the 90% confidence 
interval (CI) for the ratio of ORR18 (BAT1706: EU-Avastin®) fall completely within the predefined equivalence 
margin of (0.75, 1.33) to comply with CFDA requirements and within the predefined equivalence margin of (0.73, 
1.36) to comply with FDA requirements. To satisfy the European Medicines Agency (EMA) statistical approach, 
the null hypothesis will be rejected if the 95% CI of the difference in the ORR18 between treatments (BAT1706 
and EU-Avastin®) is entirely contained within the predefined equivalence margin of (-0.12, 0.15). 
The alternative hypothesis is that BAT1706 is equivalent to EU-Avastin®, which can be demonstrated by showing 
that the true treatment ratio/difference is likely to lie between a lower and an upper equivalence margin of 
clinical acceptable difference. 
 
7.2. SAMPLE SIZE 
 
Approximately 632 patients will be enrolled including a subgroup of 200 patients for PK and popPK, from samples 
collected only at designated sites in China, Turkey, and Ukraine. 
 
7.2.1. DETERMINATION OF SAMPLE SIZE 
 
The expected ORR used for this study is based on the ORR calculated from our meta-analysis that includes a 
population of Western and Asian patients (with approximately 23% of Asian patients) with nsNSCLC cancer and 
unknown EGFR/ALK mutation status. Such an ORR is derived from the reported best ORR in the intent-to-treat 
(ITT) population or in the subgroup of patients with measurable disease. Although enrolling a higher rate of 
Asian patients, which would yield an ORR of about 45%, we expect the ORR in our study to be approximately 
40% since we will exclude patients with known EGFR mutation or ALK receptor alteration (conferring slightly 
higher, non-statistically significant, responsiveness) in regions where the targeted agents are available. 
To satisfy all regulatory agencies (CFDA, EMA, and US FDA), results will be presented using the risk ratio or the 
 
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risk difference method to show equivalence. 
 
7.2.2. SAMPLE SIZE JUSTIFICATION BASED ON RISK RATIO 
 
To satisfy the CFDA and US FDA, equivalence will be demonstrated using the risk ratio method. The net 
treatment effect of Avastin® as measured by the ratio of ORRs is 1.97 with a corresponding 70% CI of (1.81, 2.14). 
Preserving 52% net effect of Avastin®, the equivalence margin will be set to 1.33 on the ratio of ORRs. Preserving 
48% net effect of Avastin®, the equivalence margin will be set to 1.36 on the ratio of ORRs. 
Abbreviations: CI = confidence interval; RR = risk ratio. 
The null hypothesis is that either (1) BAT1706 is inferior to Avastin® or (2) BAT1706 is superior to Avastin® based 
on a pre-specified equivalence margin of (0.75, 1.33) for CFDA, and based on a pre-specified equivalence margin 
of (0.73, 1.36) for US FDA. The alternative hypothesis is that BAT1706 is equivalent to Avastin®, which can be 
demonstrated by showing that the true treatment ratio is likely to lie between a lower and an upper equivalence 
margin of clinical acceptable difference. In other words, equivalence will be declared if the 2-sided 90% CI of the 
ratio of ORRs (BAT1706: Avastin®) is entirely contained within the equivalence margin of (0.75, 1.33) for CFDA, 
and within the equivalence margin of (0.73, 1.36) for US FDA. Based on these equivalence margins and reference 
effect size of 40%, 316 patients per arm (632 patients total) will achieve 80% power for CFDA and will achieve 
87% power for US FDA. The primary analysis will be based on the ITT population, and the supportive analysis will 
be based on the per-protocol (PP) population. With an expected ORR of 42% in the PP set, 83% power will be 
achieved with the equivalence margin of (0.75, 1.33), and 90% power will be achieved with the equivalence 
margin of (0.73, 1.36). 
 
7.2.3. SAMPLE SIZE JUSTIFICATION BASED ON RISK DIFFERENCE 
 
To satisfy the EMA, equivalence will be demonstrated using the risk difference method. The net treatment effect 
of Avastin® as measured by the difference between ORRs is 0.21 with 70% CI of (0.17, 0.26). Preserving 29% net 
effect of Avastin®, the equivalence margin will be set to (-0.12, +0.15) for the difference of ORRs. 
 
 
 
 
 
 
 
 
 
 
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Abbreviations: CI = confidence interval; RD = risk difference. 
The null hypothesis is that either (1) BAT1706 is inferior to EU Avastin® or (2) BAT1706 is superior to EU Avastin® 
based on a pre-specified asymmetrical equivalence margin of (-0.12, 0.15). The alternative hypothesis is that 
BAT1706 is equivalent to EU Avastin®, which can be demonstrated by showing that the true treatment difference 
is likely to lie between a lower and an upper equivalence margin of clinical acceptable difference. In other words, 
equivalence will be declared if the 2-sided 95% CI of the difference in the ORR between treatments (BAT1706 
and EU Avastin®) is entirely contained within the equivalence margin of (-0.12, 0.15). 
Based on that margin and a reference effect size of 40% at Week 18, 316 patients per arm (632 patients total) 
will achieve 85% power and 2-side control type I error within 5%. The primary analysis will be based on the ITT 
population, and the supportive analysis will be based on the PP population. With an expected ORR of 42% in the 
PP set, 84% power will be achieved. 
 
7.3. MULTI-CENTER STUDIES 
 
This is a multi-center study and centers may be pooled together in a country/region level for subgroup or center 
effect analysis in an exploratory manner if applicable. 
 
7.4. MISSING DATA 
 
Missing safety data will not be imputed. 
Missing efficacy data will be handled as described in section 16.4 of this analysis plan. 
 
7.5. EXAMINATION OF SUBGROUPS 
 
The following subgroups are considered of interest to comparatively explore the treatment effect for the 
definition of subgroups, data as documented in the CRF will be taken. 
 
Age: <65 years vs. ≥ 65 years 
 
Baseline ECOG performance status: 0 vs. 1 
 
nsNSCLC Stage: IV vs. Recurrent disease 
 
Sex: Male vs. Female 
 
Ethnicity: Asian vs. Non-Asian 
 
Planned dose of Paclitaxel (200 vs. 175 mg/m2) 
 
Planned dose of Carboplatin (AUC 6 vs. 5 mg/mL·minute) 
 
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 
Reduced Percentage of paclitaxel dose at cycle 6 from initial dose (>80% vs. ≤80%) 
 
Reduced Percentage of carboplatin dose at cycle 6 from initial dose (AUC >80% vs. ≤80%) 
 
8. OUTPUT PRESENTATIONS 
Appendix 1 details the conventions for presentation of data in outputs. 
The templates provided with this SAP describe the presentations for this study and therefore the format and 
content of the summary tables, figures, and listings to be provided by IQVIA Biostatistics. 
Continuous variables will be summarized using descriptive statistics, i.e. 
 
Number of subjects (N), number of subjects with non-missing values 
 
Mean, standard deviation (SD) 
 
Median, 
 
25th Percentile - 75th Percentile (Q1-Q3) 
 
Minimum and maximum. 
Qualitative variables will be summarized by counts and percentages. 
Unless otherwise stated the calculation of proportions will be based on the number of subjects of the analysis 
set of interest. Therefore, counts of missing observations will be included in the denominator and presented as 
a separate category. 
 
9. DISPOSITION AND WITHDRAWALS & PROTOCOL DEVIATION 
 
9.1. DISPOSITION AND WITHDRAWALS 
 
Patient disposition will be summarized for patients in ITT population. The total number of patients for each 
defined analysis population will also be tabulated. The demographic and baseline characteristics will be 
summarized descriptively for the ITT population. Study drug and study duration will be summarized using 
descriptive statistics for the safety population. 
 
9.2. 
PROTOCOL  DEVIATION 
 
Protocol deviation will be summarized for patients in ITT population. Protocol deviations will be presented in a 
listing including date, severity and action of population exclusion if any. The protocol deviation which impacts 
subject safety, ICH-GCP compliance and study endpoints will be marked as important protocol deviation per 
suggestion’s approval prior to database lock. The type of protocol deviations includes the following categories 
based on IQVIA’ SOP: 
 
Informed consent 
 
Eligibility and entry criteria 
 
Concomitant medication criteria 
 
Laboratory assessment criteria 
 
Study procedures criteria 
 
Serious adverse event criteria 
 
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 
Randomization Criteria 
 
Visit schedule criteria 
 
IP compliance 
 
Efficacy criteria 
 
Administrative criteria 
 
Source document criteria 
 
Regulatory or ethics approvals criteria 
 
Other criteria 
 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be summarized for the ITT. No statistical testing will be 
carried out for demographic or other baseline characteristics. 
 
10.1. DEMOGRAPHICS 
 
The following demographic data is derived from CRF page “Demographics”. 
 
 Age (years) = (Date of ICF signed – Date of Birth +1)/365.25 
• 
< 65 years 
• 
>= 65 years 
 
•
65 - < 75 years
•
75 - < 85 years
•
>= 85 years
 
Sex: 
 
 


Male 
Female
 
 
Ethnicity: 
 
 
Hispanic or Latino 
 
Not Hispanic or Latino 
 
Unknown 
 
Race: 
 
American Indian or Alaska Native 
 
Asian 
 
Black or African American 
 
Native Hawaiian or Other Pacific Islander 
 
White 
 
Other 
 
10.2. OTHER BASELINE CHARACTERISTICS 
 
 
ECOG Performance Status 
 
0 
 
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 
1 
 
>1 
 
Height (cm) 
 
Weight (kg) 
 
BMI (kg/m2) = Weight (kg)/ Height (m)2 
 
The following infection screen will be summarized for the ITT for overall subjects (“Infection Screen” on eCRF). 
 
Hepatitis B: positive, negative, unknown. 
 
Hepatitis C: positive, negative, unknown. 
 
Human Immunodeficiency Virus (HIV): positive, negative, unknown. 
 
Syphilis: positive, negative, unknown. 
 
Tuberculosis: positive, negative, unknown. 
 
10.3. MUTATION STATUS AT BASELINE 
 
The following mutation screen will be summarized for the ITT for overall subjects (“EGFR, ALK and ROS-1 
Mutation Status” on eCRF). 
 
EGFR Mutation: positive, negative, unknown. 
 
ALK Mutation: positive, negative, unknown. 
 
ROS-1 Mutation: positive, negative, unknown. 
 
10.4. DERIVATIONS 
 
 
1 week = 7 days 
 
1 month = 30.4375 days 
 
1 year = 365.25 days 
 
Duration (Years) = (Date of Informed Consent Signed – Date of Event + 1)/365.25 
 
11. 
SURGICAL AND MEDICAL HISTORY 
 
11.1. LUNG CANCER HISTORY 
 
 
Time since Initial nsNSCLC diagnosis (months) – calculated relative to date of ICF 
 
Stage of the disease at the time of initial diagnosis 
 
Stage I 
 
Stage II 
 
Stage III 
 
Stage IV 
 
nsNSCLC Pathology Classification 
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 
Adenocarcinoma 
 
Large cell carcinoma 
 
Adenosquamous NSCLC mixed predominant Adenocarcinoma 
 
Other 
 
nsNSCLC Stage at Enrolment 
Lung cancer history are record on the “Lung Cancer History” CRF page. 
 
11.2. SURGICAL HISTORY 
 
Surgical History are recorded on the “Medical / Surgical History” CRF page. 
Medical history still ongoing will be summarized by system organ class (SOC) and preferred term (PT) for the 
SAF. Medical Dictionary for Regulatory Activities (MedDRA) central coding dictionary (MedDRA latest version) 
will be used for coding. Records will be sorted alphabetically. 
Medical history still ongoing at enrolment or ended prior to enrolment will be listed together for the ITT. 
 
12. 
CONCOMITANT ILLNESSES 
 
Concomitant Illnesses are conditions (other than the indication being studied) which started prior to or at 
screening and are ongoing at the date of screening, which will be summarized by system organ class (SOC) and 
preferred term (PT) for the SAF Population. Medical Dictionary for Regulatory Activities (MedDRA) central coding 
dictionary (MedDRA latest version) will be used for coding. Records will be sorted alphabetically. Concomitant 
Illnesses will be coded using “Medical / Surgical History”. 
Medical history still ongoing at enrolment or ended prior to enrolment will be listed together for the ITT. 
 
13. 
MEDICATIONS AND PROCEDURES 
 
13.1. PRIOR ONCOLOGY THERAPIES AND SURGERIES 
 
Prior oncology therapies including chemotherapy, medications, radiotherapy, and procedures will be captured 
on “Prior Radiotherapy”, “Prior Anticancer Therapy” and “Prior Cancer-related Surgeries/Procedures” CRF pages 
respectively. Only therapies and procedures starting prior to screening visit will be collected. Otherwise the 
therapy will be presented together with concomitant medications whilst procedures will be considered 
concomitant procedures. 
In addition to coded terms, number of prior oncology chemotherapy and medication per subject will be 
summarized together with best response for each subject. 
Radiotherapies (including best response), surgeries and procedures will be presented and listed for the ITT. In 
addition, tumor history of surgery and procedures will be coded according to MedDRA (latest version), and 
summarized by SOC/PT for the ITT. 
Prior oncology therapies will be listed for SAF. 
 
13.2. PRIOR MEDICATIONS AND PROCEDURES 
 
WHO drug dictionary (latest version) will be used to classify prior medications by preferred term. 
 
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Prior medication is defined as any medication taken prior to the date of first dose of investigational product, will 
be summarized separately by the number and percentage of subjects receiving each medication within each 
preferred term by treatment group and overall for the Safety population. 
Prior medication usage will be summarized separately by the number and percentage of subjects receiving each 
medication within each preferred term by treatment group and overall for the ITT. Multiple medication usage 
by a subject in the same category will be counted only once for the purpose of the summaries. 
All prior medications and procedures will be listed for the ITT. 
 
13.3. CONCOMITANT MEDICATIONS AND PROCEDURES 
 
Concomitant medication is defined as all medications taken by the subject from signed informed consent 
through 28 days after last study treatment. 
Concomitant medication (CRF page “Concomitant Medications”) usage will be summarized separately by the 
number and percentage of subjects receiving each medication within each preferred term by treatment group 
and overall for the Safety population. Medications can be counted both as prior and concomitant medication. 
Multiple medication usage by a subject in the same category will be counted only once for the purpose of the 
summaries. 
Concomitant Procedures are captured on CRF page “Concomitant Procedures”. Medical Dictionary for 
Regulatory Activities (MedDRA) central coding dictionary, latest version will be used for coding. 
Relevant information for procedures will be listed for the ITT. 
 
14. 
STUDY MEDICATION EXPOSURE 
 
14.1. TREATMENT EXPOSURE 
 
 
BAT1706 will be supplied as 100 mg/4 mL. The dose is 15 mg/kg every 3 weeks. 
 
EU-Avastin® will be supplied as 100 mg/4 mL. The dose is 15 mg/kg every 3 weeks. 
 
The initial dose of paclitaxel is 200 mg/m². For Chinese patients (according to local label), paclitaxel will 
be administered at a dose of 175 mg/m². 
 
In all patients, the initial dose target of carboplatin is area under the curve (AUC) 6 mg/mL·minute. 
 
For all patients in case of anticipated excessive toxicity (e.g., elderly patients, prior toxicity during 
chemo-radiotherapy), the Investigator may start the first course of chemotherapy using paclitaxel at a 
dose of 175 mg/m² (or use a paclitaxel dose of 200 mg/m² after prophylactic administration of G-CSF), 
and/or carboplatin AUC 5 mg/mL·minute. 
 
14.2. DERIVATIONS OF TREATMENT EXPOSURE 
 
The summary of treatment exposure and compliance for study drugs will include the following information in 
the SAF for overall. 
 
 
 
Treatment duration (week): 
 
 
Duration of Drug = ( 
date of last dose of Drug - date of first dose of Drug + 21 ) 
7 
 
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 
Total number of infusions received (n) 
 
 
Cumulative actual treatment dose (mg/kg): the sum of the calculated actual dose levels of each 
drug that the subject received (i.e. total dose administered (mg/kg)) 
 
 
Dose intensity (DI) (mg/kg/week) per subject is defined as: 
 
 
DI = ( 
Cumulative dose of Drug from 1st infusion 
) 
(date of last dose of Drug – date of first dose of Drug + 21) / 7 
 
 
Relative dose intensity (RDI) (%) per subject is defined as the actual dose intensity divided by the 
planned dose per week and expressed in %. 
 
Dose Intensity 
RDI =  100 X ( 
) 
15/3 
 
 
15. 
STUDY MEDICATION COMPLIANCE 
Compliance to study medication will be presented for the Safety Population. 
Compliance to study medication will adopt the relative dose intensity (RDI) in section 14.2. 
 
16. 
EFFICACY OUTCOMES 
The efficacy analyses will be applied for both the PP and ITT Population. 
Treatment efficacy will be evaluated using tumor responses. Tumor response will be assessed by the local 
Investigator and/or radiologist according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1; 
see protocol Appendix 13.4) for immediate therapeutic decision. However, the primary efficacy analysis will be 
based upon the evaluation of tumor response as determined by CIR. Patients will undergo tumor assessment at 
Weeks 6, 12 and 18, regardless of the number of cycles actually completed, then after every 3 cycles 
(approximately every 9 weeks) and at Safety Follow-up Visit (SFUV)/End of Treatment (EoT). Window for tumor 
assessment is 1 week at the maximum during the first 18 weeks. 
Tumor responses data are captured on CRF page “Tumor Evaluation Target Lesions”, “Tumor Evaluation Non- 
Target Lesions”, “Tumor Evaluation New Lesions”, and “Overall Tumor Response (According to RECIST 1.1)”. 
Tumor assessment results from each scheduled visit will be listed for SAF. Tumor assessment for target lesion 
including sum of diameters for each cycle will be summarized for the SAF. 
 
16.1. PRIMARY EFFICACY 
 
16.1.1. PRIMARY EFFICACY VARIABLE & DERIVATION 
 
The primary efficacy endpoint is ORR at Week 18 (ORR18) based on tumor response evaluated according to 
RECIST 1.1 (Appendix 13.4 in protocol) as assessed by CIR. 
To demonstrate equivalence between BAT1706 and EU-Avastin® arms, the ratio of, as well as the difference 
between ORR18 will be analyzed. Equivalence will be declared if the 90% confidence interval (CI) of the ratio of 
ORR18 (BAT1706:EU-Avastin®) is entirely contained within the equivalence margin of (0.75, 1.33) to comply with 
CFDA requirements, and within the equivalence margin of (0.73, 1.36) to comply with US FDA requirements. The 
 
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difference in ORR18 will be calculated, and equivalence will be declared if the 95% CI of the difference in the 
ORR18 between treatments is entirely contained within the asymmetrical equivalence margin of (-0.12, 0.15) to 
comply with EMA requirements. 
Response Week 18 will be based on tumor assessment obtained at Week 18. Patients not achieving Week 18 
assessment will be considered non-responders if they dropped out earlier in case of intolerance, documented 
disease progression, withdrawal of consent, lost to follow up, or death. 
The ORR18 is calculated as the proportion of patients achieving a PR or a CR at Week 18. Confirmation of response 
is not required. 
 
16.1.2. PRIMARY EFFICACY ANALYSES 
 
The primary efficacy analyses aim to demonstrate the equivalence between BAT1706 and EU Avastin® arms. The 
null hypothesis tested for the primary efficacy analyses is that either (1) BAT1706 is inferior to EU Avastin® or 
(2) BAT1706 is superior to EU Avastin® based on a predefined equivalence margin. 
For the CFDA and US FDA, to demonstrate equivalence between the 2 treatment groups, the ratio of ORR will 
be used. The ratio of ORR18 will be calculated. 
The 2-sided 90% CI of risk ratio or 95% CI of risk difference will be estimated including covariates of stratification 
factors: NSCLC stage (recurrent disease after any stage at time of primary diagnosis, or stage IV), gender (male 
or female), and ethnicity (Asian or non-Asian) for the ITT population as primary analyses and for the PP 
population as supportive analyses. 
The multivariate-adjusted risk ratio and the 90% CI will be estimated by the log-binomial regression model 
including stratification factors. When the log-binomial model fails to converge, the Poisson regression with 
robust error variance will be used. 
The multivariate-adjusted risk difference and the 95% CI will be estimated by the binomial regression model 
including stratification factors. If this binomial model for the risk difference fails to converge, the modified 
Poisson approach can be used as above. 
The primary efficacy analyses will take place after all patients have been evaluated for response at Week 18. 
The sample code can be found in appendix 5: Sample Code for Efficacy Analysis. 
 
16.2. SECONDARY EFFICACY 
 
16.2.1. SECONDARY EFFICACY VARIABLES & DERIVATIONS 
 
The secondary efficacy endpoints include ORR6 , ORR12 , best ORR of confirmed responses at end of study, DoR, 
PFS rate at 12 months, PFS time, OS rate at 12 months, and OS time. 
Response at Week 6 will also be evaluated by CIR to provide ORR6 to show the pattern of response. After Week 
18, patients with responding or stabilized disease will remain in the study up to 12 months to provide further 
comparative safety/immunogenicity data as well as other efficacy parameters (such as DoR, PFS and OS rates at 
12 months for both BAT1706 and EU-Avastin®). 
A SFUV/EoT visit will take place 28 days ± 2 days after the last dose during the study with a maximum at Week 
53. Patients who are still benefiting of therapy after 12 months of treatment will have the option to continue 
treatment with BAT1706 as of Week 53 after SFUV (regardless of the arm they were assigned to at 
randomization) in a Long term extension (LTE) study until disease progression, excessive toxicity, withdrawal of 
consent, Investigator’s decision, or for an additional 12-month period (ie, for a maximum of 24 months from 
initial randomization). 
 
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The secondary binomial efficacy endpoints will be summarized descriptively and analyzed similarly to the 
primary efficacy endpoint. For time to event variables such as PFS, OS, and DoR, Kaplan Meier curves will be 
calculated and displayed. Median survival times and the corresponding 95% CI will be provided. The estimated 
hazard ratio with 95% CI will be obtained from Cox regression model. The secondary analyses will be conducted 
based on data from up to 12-month exposure. For both analyses, data from all 632 randomized patients will be 
analyzed. A complementary report for safety and survival data will be made 2 years after LPI. 
The secondary efficacy endpoints are as follows: 
• 
Progression free survival rate at 12 months, defined as the proportion of patients being alive without 
documented progression 12 months after randomization, using Kaplan-Meier method. 
• 
Progression free survival time defined as the time from the date of randomization to the date of 
documented clinical or radiological progression or death due to any cause using Kaplan-Meier method. 
• 
Overall survival rate at 12 months, defined as the proportion of patients being alive 12 months after 
randomization using Kaplan-Meier method. 
• 
Overall survival time defined as the time from randomization to death of any cause using Kaplan-Meier 
method. 
• 
ORR at Week 6 (ORR6) and ORR at Week 12 (ORR12), based on tumor response as assessed by CIR, and 
best ORR of confirmed responses at end of study assessed by local radiologist/Investigator if after Week 
18 according to RECIST 1.1. 
• 
Duration of response defined as the time from first documentation of a response (CR or PR) and the 
first documentation of progression (assessed by local radiologist/Investigator if after Week 18) 
according to RECIST 1.1. 
 
16.2.2. SECONDARY EFFICACY ANALYSES 
 
23.1.1.1. 
Overall Response Rate (ORR) 
Overall response rate will be the proportion of subject with a best overall response of CR or PR. The ORR and its 
95% confidence interval (CI) will be presented. The 95% (exact) CI will be calculated based on the binomial 
method. When no imaging/measurement is done at all at a particular time point, the patient is not evaluable at 
that time-point. ORR6 and ORR12 will be analysed base on CIR assessment. 
 
23.1.1.2. 
Progression Free Survival (PFS) 
Progression-free survival is defined as the time from the date of randomization to disease progression or death 
whichever occurs first in subjects. Subjects without event (no disease progression or death) will be censored at 
the date of ‘last tumor assessment’. Subjects for whom no post-baseline tumor assessments are available are 
censored at the time of first dose. Kaplan Meier methodology will be used to estimate median PFS and its 95% 
confidence interval. Kaplan Meier curves will be constructed to provide a visual description of the PFS change 
with time. PFS will be analysed based on Investigator assessment. 
 
Define date of PFS event / censoring: 
 
Status 
Censoring 
Date of event / censoring 
Progressed or 
died 
Within two subsequent scheduled 
tumor assessments after last response 
assessment of CR, PR or SD or 
randomization 
Event 
Minimum(Date of PD, Date of death) 
 
 
 
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Otherwise 
Censored 
Date of last tumor assessment with 
outcome CR, PR or SD or date of 
randomization, whatever is later 
Neither progressed nor died 
Censored 
Date of last tumor assessment with 
outcome CR, PR or SD or date of 
randomization, whatever is later 
 
23.1.1.3. 
Overall Survival (OS) 
Overall survival is defined as the time from randomization to the date of death (any cause). Subjects who were 
alive at the time of analysis or end of study will be censored at the date of the last available visit. Kaplan-Meier 
methodology will be used to estimate the median survival time and its 95% confidence interval. Kaplan Meier 
curves will be constructed to provide a visual description of the OS change with time. OS will be analysed based 
on Investigator assessment. 
 
Define date of OS event / censoring: 
 
Survival Status 
Censoring 
Date of event/censoring
Died 
Before cut-off 
Event 
Date of death 
After cutoff 
Censored 
Date of cutoff 
Alive 
(no date of death) 
Alive after cut-off 
Censored 
Date of cut-off 
Otherwise 
Censored 
Last date known to be alive
 
23.1.1.4. 
Duration of Response (DoR) 
Duration of response for responders (CR or PR) is defined as the time interval between the date of the earliest 
qualifying response and the date of disease progression of death for any cause, whichever occurs earlier. For 
subjects who are alive without disease progression following the qualifying response, duration of response will 
be censored on the date of last evaluable tumor assessment or last follow-up for progression of disease. Kaplan 
Meier methodology will be used to estimate median duration of response or duration of stable disease and its 
95% confidence interval. Kaplan Meier curves will be constructed to provide a visual description of the DoR. 
DOR will be analysed based on CIR assessment before week 18 and investigator assessment after week 18. 
 
23.1.1.5. 
Best Overall Response (BOR) 
The BOR for each subject is defined as the best result obtained among all tumor assessments from the 
randomization until documented disease progression. The overall response will be based on imaging, classified 
according to RECIST version 1.1 criteria. 
The best possible overall response is CR, followed by PR, SD and PD. If a subject has missing baseline tumor 
assessment and/or no tumor assessment on-treatment, BOR will be Not Evaluable (NE). In the case the single 
response is SD, SD must have been assessed no less than 6 weeks (at least 42 days) after randomization, 
otherwise the best response will be NE. In case of different dates of scans within the same tumor assessment, 
the latest date will be used for diagnosis of response and the earliest date for date of progression. 
The BOR rate is defined as the number of subjects, whom BOR was either Complete Response (CR) or Partial 
Response (PR), confirmed at end of treatment (EoT) assessed by local radiologist/Investigator if after Week 18 
according to RECIST 1.1. BOR will be analysed based on CIR assessment before week 18 and investigator 
assessment after week 18. 
 
 
 
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16.3. SUBGROUP ANALYSES 
 
The primary endpoint and secondary endpoints will be also analyzed in subgroups breaking down by, but not 
limited to, country/region/demographic, dose of paclitaxel and carboplatin, or stratification factors: Stage (IV or 
other), gender and ethnicity (Asian or non-Asian). 
In each subgroup, the analysis will be carried out using the same type of methodology as described for 
corresponding endpoint. These results will be considered exploratory because of the multiplicity issue and also 
smaller sample sizes that cannot be pre-specified. For subgroups without an adequate number of patients, the 
analysis may not be performed. 
One additional exploratory analysis to assess the effect of paclitaxel dose differences and carboplatin dose 
differences on the primary endpoint will be conducted by fitting a logistic regression model of ORR18 with 
independent factors including paclitaxel dose (200 vs 175 mg/m2), carboplatin dose (AUC 6 vs 5 mg/mL·minute), 
treatment group, and ethnicity (Asian vs non-Asian). Odds ratios and 95% confidence intervals will be presented. 
Another exploratory analysis to assess the effect of reduced dose of paclitaxel and carboplatin on the primary 
endpoint will be conducted by a logistic regression model of ORR18 with independent factors including paclitaxel 
dose (>80% vs ≤80% of initial dose at cycle 6), carboplatin dose (AUC >80% vs ≤80% of initial dose at cycle 6), 
treatment group, and ethnicity (Asian vs non-Asian). 
The primary endpoint and secondary endpoints will be also analyzed in subgroups breaking down by 
stratification factors: 
 
Age (<65 vs. ≥65 years), 
 
ECOG Performance Status (0 vs. 1), 
 
nsNSCLC Stage (IV vs. Recurrent disease) 
 
Sex (male vs. female) 
 
Ethnicity (Asian vs. non-Asian). 
 
Planned dose of Paclitaxel (200 vs. 175 mg/m2) 
 
Planned dose of Carboplatin (AUC 6 vs. 5 mg/mL·minute) 
 
Reduced Percentage of paclitaxel dose at cycle 6 from initial dose (>80% vs. ≤80%) 
 
Reduced Percentage of carboplatin dose at cycle 6 from initial dose (AUC >80% vs. ≤80%) 
These results will be considered exploratory because of the multiplicity issue and also smaller sample sizes that 
cannot be pre-specified. For subgroups without an adequate number of patients, the analysis may not be 
performed. 
 
16.4. MISSING DATA METHODS OF EFFICACY 
 
For the primary efficacy analysis as well as all analyses of responder/survivor proportion endpoints performed 
on ITT and PP population, patients who do not provide data for the responder/survivor endpoint will be 
considered non-responders/censor, i.e., assigned to the less favorable outcome for the endpoint. 
Sensitivity analyses to assess the robustness of conclusions to missing data will be carried out if there are more 
than 5% of patients missing evaluations in either treatment arm. Sensitivity analyses will include an analysis that 
assumes that outcomes are missing at random. 
• 
For imputing missing parts of dates for the efficacy analyses (except OS) the missing day in a date 
will be imputed as the 15th of the month, if month and year is documented. If the imputation is 
earlier than the date of randomization, the day of randomization is taken. In all other cases missing 
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or incomplete dates will not be imputed. 
• 
For imputing missing day of death date, if month and year is available, the day will be imputed by 
15, unless this results in a date not later as a date the subject is known to be alive. In that case the 
date of death will be imputed by the last date known to be alive + 1. 
 
17. QUALITY OF LIFE ANALYSIS 
NOT APPLICABLE. 
 
18. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the SAF. There will be no statistical comparisons between the 
dosing cohorts for safety data. 
 
18.1. ADVERSE EVENTS 
 
A clinical study AE is any untoward medical occurrence in a subject or clinical investigation subject administered 
a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE 
can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease (new or exacerbated) temporally associated with the use of medicinal (investigational) product, 
whether related to the medicinal (investigational) product. Relevant information is recorded on CRF page 
“Adverse Events”. 
AE Report period: 
 
From ICF signing to first study medication administration - All AEs related to the study procedures (eg, 
blood withdrawal etc.). 
 
From 
the 
start 
of 
the 
first 
study 
medication 
administration 
until 
28 
days 
after 
discontinuation/completion of the study medication or up to Week 53 after randomization - All AEs, 
regardless of relationship to the study medication/study procedures. During the LTE study, only adverse 
events of special interest (AESIs) and SAEs until 28 days after the subject’s last dose will be collected. 
 
 
All Treatment-Emergent Adverse Events (TEAEs) are defined as AEs that started or worsened on or after the first 
dose of study medication through 28 days after last dose. 
Prior AEs are AEs that started or worsened (where a new record shall be reported) prior to the first dose of IMP. 
If for reasons such as partial/missing dates, it is not possible to define an AE as prior or treatment-emergent, it 
will be classified as a TEAE. All AEs other than prior AEs will be considered TEAEs. 
When AE start date coincides with first dose date, relevant timing can be obtained by comparing infusion start 
time and AE start time. Where it is still not possible to classify an AE as treatment-emergent or not, the AE will 
be classified by the worst case; i.e. treatment-emergent. 
An overall summary of number of subjects within each of the categories described in the sub-section below, will 
be provided as specified in the output templates. 
For all SOC/PT summaries, all AEs will be presented in alphabetic order. 
Listings will include TEAEs. 
 
 
 
 
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18.1.1. ALL TEAES 
 
Adverse events will be summarized by worst severity (according to NCI-CTCAE version 4.03) per subject, using 
MedDRA (latest version) PT as event category and MedDRA (latest version) SOC body term as Body System 
category. 
Unless otherwise stated adverse events will be displayed in terms of frequency tables: PT and primary SOC in 
alphabetical order. 
If an adverse event is reported for a given subject more than once during treatment, the worst severity and the 
worst relationship to trial treatment will be tabulated. 
Adverse events related to trial treatment are those events with relationship missing, unknown or CRF listed as 
possibly related and definitely related. 
In case a subject had events with missing and non-missing grades, the maximum of the non-missing grades will 
be displayed. 
An overview table of TEAEs will be provided detailing the number and percentage of subjects with: 
 
Any TEAE 
 
Any related TEAE 
 
Any BAT1706 related TEAE 
 
Any EU-Avastin related TEAE 
 
Any Carboplatin related TEAE 
 
Any Paclitaxel related TEAE 
 
Any serious TEAE 
 
Any related serious TEAE 
 
Any BAT1706 related serious TEAE 
 
Any EU-Avastin related serious TEAE 
 
Any Carboplatin related serious TEAE 
 
Any Paclitaxel related serious TEAE 
 
Any TEAE by NCI-CTCAE severity grade (3, 4) 
 
Trial treatment related TEAE by NCI-CTCAE severity grade (3, 4) 
 
Treatment BAT1706 related TEAE by NCI-CTCAE severity grade (3, 4) 
 
Treatment EU-Avastin related TEAE by NCI-CTCAE severity grade (3, 4) 
 
Treatment Carboplatin related TEAE by NCI-CTCAE severity grade (3, 4) 
 
Treatment Paclitaxel related TEAE by NCI-CTCAE severity grade (3, 4) 
 
Any TEAE leading to death 
 
Any related TEAE leading to death 
 
Any BAT1706 related TEAE leading to death 
 
Any EU-Avastin related TEAE leading to death 
 
Any Carboplatin related TEAE leading to death 
 
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 
Any Paclitaxel related TEAE leading to death 
 
The following summary tables will also be provided for TEAEs detailing the number and percentage of subjects 
by MedDRA primary SOC (ordered alphabetically) and PT (ordered alphabetically): 
 
TEAEs 
 
Trial drug related TEAEs 
 
Non-serious TEAEs at a frequency threshold of 5% (Events that occurred at least among 5% of 
subjects) 
 
TEAEs by worst grade (for each subject, maximal grade within the same preferred term) 
 
Trial drug related by worst grade 
 
Grade 3 TEAEs 
 
Grade 3 related TEAEs 
 
BAT1706 Grade 3related TEAEs 
 
EU-Avastin Grade 3 related TEAEs 
 
Carboplatin Grade 3 related TEAEs 
 
Paclitaxel Grade 3 related TEAEs 
 
TEAEs leading to death 
 
Trial drug related TEAEs leading to death 
 
BAT1706 related TEAEs leading to death 
 
EU-Avastin related TEAEs leading to death 
 
Carboplatin related TEAEs leading to death 
 
Paclitaxel related TEAEs leading to death 
All TEAEs will be listed to support these tables. A listing of TEAEs leading to death will also be provided 
including all relevant information. 
 
18.1.1.1. 
Severity 
The severity of all TEAEs will be graded according to 5 grades (Grade 1 to Grade 5) in accordance with the national 
cancer institute common terminology criteria for adverse event (NCI-CTCAE) V4.03. 
TEAEs starting with a missing severity will be treated as missing severity and presented wherever applicable. 
Severity will be listed for TEAEs in the SAF. 
 
18.1.1.2. 
Relationship to Study Medication 
As indicated by the Investigator, causal relationship between AEs and study treatment is classed as “Definitely 
Related” “Possibly Related”, “Unlikely Related” or “Not Related”. TEAEs with a missing relationship to study 
medication will be regarded as “Definitely Related” to the question. 
Incidence of related TEAEs will be presented by SOC and then PT. TEAEs of each causal relationship level will be 
listed. 
 
 
 
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18.1.2. TEAES LEADING TO IMP DISCONTINUATION 
 
TEAEs leading to permanent discontinuation of IMP will be identified according to the item “Action Taken with 
Investigational Product” on the “Adverse Events” form of the CRF, such as, “IP was permanently stopped due 
to this AE”, etc. 
TEAEs leading to IMP discontinuation will be listed. 
 
18.1.3. SERIOUS TEAES 
 
A serious adverse event (SAE) is defined as any adverse event resulting in death, life-threatening, requires 
inpatient hospitalization (initial or prolonged), persistent or significant Disability/Incapacity, congenital anomaly 
or birth defect or any other important medical events 
Detailed definition of SAEs can be found in protocol section 6.2.1. 
On CRF, SAEs are those events with a response of “Yes” for the item “Serious”. Summaries of incidence rates 
(frequencies and percentages) of serious TEAEs by SOC and PT will be prepared. 
 
18.1.4. TREATMENT EMERGENT ADVERSE EVENTS OF SPECIAL INTEREST (TEAESI) 
 
According to the mechanism of IMP, the TEAESI include following ≥ Grade 2 renal, hepatic, cardiac and 
hematologic AEs: 
 
Hypertension >= Grade 3 
 
Proteinuria >= Grade 3 
 
Gastrointestinal perforation, gastrointestinal abscesses and gastrointestinal fistulae (any grade) 
 
Wound healing complications >= Grade 3 
 
Hemorrhage >=grade 3 (any grade CNS bleeding; >= Grade 2 haemoptysis) 
 
Arterial thromboembolic events (any grade) 
 
Venous thromboembolic events >= Grade 3 
 
Posterior reversible encephalopathy syndrome (any grade) 
 
Chronic heart failure >= Grade 3 
 
Non-gastrointestinal fistula or abscess >= Grade 2 
Protocol section 6.2.1.1 provides a detailed description of all AESIs. 
TEAESI can be identified on the “Adverse Events” CRF page with question “Is this an Adverse Events of Special 
Interest (AESIs)?” Summaries of incidence rates (frequencies and percentages) of TEAESIs by SOC and PT will be 
prepared. 
 
18.2. DEATHS 
 
All deaths, deaths within 30 days after last dose of study treatment (BAT1706, EU-Avastin, carboplatin, or 
paclitaxel), deaths within 60 days after first dose of study treatment (BAT1706, EU-Avastin, carboplatin, or 
paclitaxel) as well as the primary reason for death, will be tabulated based on information from the “Report on 
Death” CRF page: 
 
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 
Any subject who died and primary reason for death 
 
Progressive disease and/or disease related condition 
 
Related to study treatment(s) 
 
BAT1706 
 
EU-Avastin 
 
Carboplatin 
 
Paclitaxel 
 
Event unrelated to study treatment 
 
Unknown 
 
Subjects who died within 30 days after last dose of treatment and primary reason for death 
 
Progressive disease and/or disease related condition 
 
Related to study treatment(s) 
 
BAT1706 
 
EU-Avastin 
 
Carboplatin 
 
Paclitaxel 
 
Event unrelated to study treatment 
 
Unknown 
 
Subjects who died within 60 days after first dose of treatment and primary reason for death 
 
Progressive disease and/or disease related condition 
 
Related to study treatment(s) 
 
BAT1706 
 
EU-Avastin 
 
Carboplatin 
 
Paclitaxel 
 
Event unrelated to study treatment 
 
Unknown 
In addition, date and cause of death will be provided in individual subject data listing together with selected 
dosing information (date of first / last administration, separately for cetuximab, cisplatin, carboplatin, and 5- 
FU). 
This listing will also include: 
 
Data from “Report on Death” CRF page 
 
Flag for death within 30 days after last dose of trial treatment (BAT1706, EU-Avastin, carboplatin, or 
paclitaxel) 
 
Flag for death within 60 days after first dose of trial treatment (BAT1706, EU-Avastin, carboplatin, or 
paclitaxel) 
 
 
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18.3. LABORATORY EVALUATIONS 
 
Laboratory samples will be analyzed at the study site’s local laboratory. Laboratory assessments will include the 
following: 
 
Hematology: Hemoglobin, Hematocrit, Platelets, White Blood Cell, Lymphocytes, Neutrophils 
(recorded on CRF page “Hematology”) 
 
Chemistry: Creatinine, AST, ALT, ALP, Gamma-Glutamyl Transpeptidase, Total Bilirubin, Direct Bilirubin, 
Glucose, Total Cholesterol, Total Protein, Albumin, Sodium, Potassium, Chloride, Calcium. (recorded on 
CRF page “Chemistry”) 
 
Coagulation: INR, aPTT, PT. (recorded on CRF page “Coagulation”). Coagulation data will be presented 
together with hematology records. 
 
Serology: Test results for Hepatitis B Virus (HBV) antigen, Hepatitis B Virus (HBV) antibody, Hepatitis C 
Virus (HCV) antibody, Human Immunodeficiency Virus (HIV) will be summarized in terms of number of 
subject being positive/negative. A listing will also be provided. 
 
Urinalysis: Recorded on CRF page “Urinalysis”. 
 
24 hours urine test: Urine protein and creatinine ratio (UPCR), which are captured on CRF page “24- 
hour Urine Test”, will be summarized together with serum chemistry. 
 
Pregnancy test: For females of child-bearing potential only: Human Chorionic Gonadotropin in serum 
and urine Recorded on CRF page “Serum Pregnancy Test”. 
Test normal ranges of all quantitative tests above, if applicable, are also recorded in the EDC system. 
Data recorded by the laboratory will be converted to the International System of Units (SI) and all presentations 
will use SI units. Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of normal 
range (LLN), or “> X”, i.e. above the upper limit of normal range (ULN), will be converted to X for the purpose of 
quantitative summaries, but will be presented as recorded, i.e. as “< X” or “> X” in the listings. 
For HematoIogy, Coagulation, and Chemistry parameters that are CTCAE gradable, shift tables of baseline CTCAE 
grade versus the worst CTCAE grade will be presented. Unscheduled measurements will be included in 
summaries. 
Changes over time will be described using descriptive statistics, and the percentage of subjects with values 
outside the normal range will be presented. 
For Urinalysis parameters, actual value of each scheduled visit, change from baseline for each post-baseline 
scheduled measurement will be presented by visit. 
NCI-CTCAE grades available: 
The laboratory toxicities will be tabulated by the worst on-treatment CTCAE grade or the shift of CTCAE grade 
from baseline to worst grade during on-treatment period using descriptive statistics (count and percentage). 
The highest CTCAE grade during the on-treatment period is considered as the worst grade for the summary. 
• The worst grade during the on-treatment period will be summarized considering only patients with post 
baseline laboratory samples: Laboratory tests by NCI-CTCAE grade (0, 1, 2, 3, 4, and missing). 
The shift table will summarize baseline CTCAE grade vs. the worst on-treatment CTCAE grade (grade = 0, 1, 2, 3, 
4, missing). The above analyses apply to the following hematology and biochemistry parameters which can be 
graded per NCI-CTCAE (Appendix 4): 
• 
Hematology – Hemoglobin, Platelet, White Blood Cells, Neutrophils (Absolute), Lymphocytes 
(Absolute) 
 
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• 
Chemistry – Albumin, Alkaline phosphatase (ALP), Aspartate Aminotransferase (AST), Alanine 
Aminotransferase (ALT), Total Bilirubin, Calcium, Glucose, Potassium, Sodium, Creatinine, Gamma- 
Glutamyl Transpeptidase. 
Tables will summarize, separately for hematology and biochemistry parameters, the shift from baseline 
grade to worst on-treatment grade by parameters and treatment group. 
NCI-CTCAE grades not available: 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges in SI 
units and categorized as: 
• 
Low: Below the lower limit of the laboratory reference range. 
• 
Normal: Within the laboratory reference range (upper and lower limit included). 
• 
High: Above the upper limit of the laboratory reference range. 
The worst on-treatment value for hematology and biochemistry parameters which cannot be graded per NCI- 
CTCAE will be summarized by parameter according to the local laboratories normal ranges as follows: 
• Shift from baseline value (low, normal, high) to above normal during on-treatment period 
Shift from baseline value (low, normal, high) to below normal during on-treatment period. The above analyses 
apply to the following hematology and biochemistry parameters which cannot be graded per NCI-CTCAE: 
 
Hematology: Red Blood Cells, Monocytes, Eosinophils, Basophils. 
 
Biochemistry: Direct Bilirubin, Total Protein, Chloride. 
All parameters will be listed with abnormality and CTCAE grade for SAF when applicable. 
 
18.4. ECG EVALUATIONS 
 
The following measurements will be presented and listed for SAF, and change from baseline will be prepared for 
quantitative parameters: 
 
Heart Rate (beats/min) 
 
RR Interval (msec) 
 
PR Interval (msec) 
 
QRS Interval (msec) 
 
QT Interval (msec) 
 
QTcF Interval (msec) – corrected by Fridericia method 
 
Overall ECG evaluation 
 
Abnormal, clinical significance 
 
Abnormal, not clinical significance 
 
Normal 
Conclusions are sorted as Normal/Abnormal non-clinically significant/Abnormal clinically significant, the latest 
one being considered as the worst. If no post-baseline data are available, the worst on-treatment result will be 
accounted as missing. If significance is not provided, the conclusion will be classified as “Abnormal ECG”. This 
“Abnormal ECG” category will count abnormal conclusion with missing significance only. A listing of all ECG 
parameters results will be provided. 
 
 
 
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18.5. VITAL SIGNS 
 
The following vital signs measurements will be reported for this study: 
 
Body Temperature (⁰C) 
 
Systolic Blood Pressure (mmHg) 
 
Diastolic Blood Pressure (mmHg) 
 
Pulse Rate (bpm) 
The following summaries will be provided for vital signs data: Actual and change from baseline by visit 
 
18.6. PHYSICAL EXAMINATION 
 
The following physical examination and neurological examination will be reported for this study: 
 
Height (cm) 
 
Weight (kg) 
 
General appearance 
 
Abdomen 
 
HEENT (Head, Eyes, Ears, Nose and Throat) 
 
Neck 
 
Chest/Respiratory 
 
Heart/Cardiovascular 
 
Gastrointestinal/Liver 
 
Musculoskeletal/Extremities 
 
Skin 
 
Thyroid/Neck 
 
Lymph Nodes 
 
Neurological/Psychiatric 
The summaries of examination results will be provided in listing. 
 
18.7. IMMUNOGENICITY ASSESSMENTS 
 
Samples collected for immunogenicity assessments will initially be screened for antidrug antibodies (ADA) 
against the IMP. A confirmation assay will be used to confirm the positive status for samples which scored 
potentially positivity by the screening assay. In confirmed positive samples, the relative titer of the antibody will 
be determined as well as whether the confirmed positive sample represent a neutralizing antibody. A 
neutralizing ADA assay will be performed on the confirmed positive samples. 
Immunogenicity results including overall ADA results (screening, confirmatory and titers, as appropriate), 
neutralizing ADA results. 
The immunogenicity results will be listed for anti-drug antibodies and neutralizing antibodies for each patient 
 
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and time point (CRF: “ADA/NADA Blood Samples”). 
 
ADA/NADA Status 
 
Positive 
 
Negative 
 
Unknown 
 
18.8. ECOG PERFORMANCE 
 
The Eastern Cooperative Oncology Group/ECOG performance status of each subject will be reviewed at the time 
points outlined in the Table 1 of protocol. Shifts in ECOG performance status from baseline to worst on- 
treatment performance status will be summarized by treatment group. Missing category will also be included 
(CRF” ECOG Performance Status”). A listing will also be provided for ECOG performance status. 
 
19. GENETIC ANALYSIS 
 
NOT APPLICABLE. 
 
20. DATA NOT SUMMARIZED OR PRESENTED 
 
NOT APPLICABLE. 
 
21. PHARMACOKINETIC ANALYSIS 
 
21.1. PRECISION 
 
All PK concentrations will be reported and analyzed with the same precision as the source data provided by the 
bio-analytical laboratory regardless of how many significant figures or decimals the data carry. Derived PK 
parameters (if any) will be rounded for reporting purposes in by-subject listings. The rounded derived PK data 
will be considered the source data for the calculation of descriptive statistics and the statistical analysis. For 
most derived PK parameters, 3 significant digits will be used as the standard rounding procedure, with the 
following exceptions: 
• 
Parameters, if determined, directly derived from source data (eg Cmin) will be reported and 
analyzed with the same precision as the source data. 
• 
Parameters, if determined, derived from actual elapsed sample collection times (eg, tmax ) will 
be reported with the same precision as the actual elapsed sampling time value of the source data. 
For the reporting of descriptive statistics, the mean, standard deviation, standard error, and CIs will be presented 
to one digit more precision than the source data. The minimum, median, and maximum will be presented to the 
same precision as the source data. Coefficient of variation will always be reported to 1 decimal place. Ratios of 
means for PK parameters will be presented with two decimal places (as a percentage) to meet regulatory 
requirements and P-values, if any, shall be reported to four decimal places or as <0.0001. 
 
21.2. CONCENTRATION DATA 
 
A descriptive comparison of bevacizumab concentrations between treatments will be used to evaluate the 
 
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secondary objective. 
Subjects with partial data will be evaluated on a case-by-case basis to determine if sufficient data are available 
for reliable inclusion in descriptive statistics summaries. Missing concentrations will be treated as missing. 
A listing of PK blood sample collection times as well as derived sampling time deviations (typically relative to the 
infusion start time, end time where called for based on the nominal description of the sampling timepoint) will 
be provided. Plasma concentrations will be summarized using descriptive statistics by treatment. Concentrations 
that are below the limit of quantitation (BLQ) will be treated as zero for the computation of descriptive statistics. 
If average concentrations are BLQ, they will be presented as 0 or LLOQ. 
A subject listing of all concentration-time data for each treatment will be presented. Figures of arithmetic mean 
concentration-time data (± STD, as appropriate) will be presented by treatment on linear and semi-logarithmic 
scales. Individual subject concentration-time data will be graphically presented on linear and semi-logarithmic 
scales. 
 
21.3. PHARMACOKINETIC PARAMETERS 
 
Given the morbidity of patients with advanced lung cancer, the post dose blood sampling profile for Cycle 1 and 
Cycle 6 is limited and missing data and out of window sampling is anticipated; therefore, no traditional PK 
parameter determination using noncompartmental analysis is planned. However, PK parameters (e.g., AUC, 
maximum concentration, and time to maximum concentration) may be determined to if the data allow if 
appropriate. 
 
21.4. EXPOSURE RESPONSE CORRELATION 
 
Data from this study could be used to support future exploratory population PK modelling and/or correlation 
analysis if warranted to interpret the data. If performed, a separate analysis plan will be prepared, and results 
will be reported separately from the clinical study report. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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22. REFERENCES 
Protocol version 5.0,20Jun2019. 
 
BAT1706-003-CR CRF Version 05 - Annotated Trial Design, Dated 12Mar2019. 
BAT1706-003-CR CRF Version 05 - Unique Form, Dated 12Mar2019. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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23. APPENDICES 
 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
 
IQVIA Output Conventions 
Outputs will be presented according to the IQVIA’s general guidelines and template for outputs conventions. 
 
General Rules 
The following conventions will be applied for reporting descriptive statistics of all continuous data (except PK 
values): 
Mean, Median, Q1, Q3, Minimum, and Maximum will have the same precision as SDTM data (number of digits) 
for non-derived data (e.g. weight). 
SD will be presented with one digit more than mean. 
Statistics on derived data (e.g. treatment exposure time in days) will be rounded to reasonable number of digits. 
Maximal digits should be available in ADaM datasets. 
Qualitative variables will be summarized by counts and percentages. A missing category should always be 
displayed at baseline – even when there are no missing data. A missing category, at other endpoints than 
baseline, should only be displayed when there are missing data. Unless otherwise stated, the calculation of 
proportions will be based on the number of subjects of the analysis set of interest. Therefore, counts of missing 
observations will be included in the denominator and presented as a separate category. 
Total of missing and non-missing observations at each time-point will reflect the population still in the trial 
at that time. For example, if a subject is still in the trial at the time-point but with missing data, it should be 
counted in the number of missing observations. 
 
Dates & Times 
Depending on data available, dates and times will take the form DDMMMYYYY and HH:MM:SS. 
 
Spelling Format 
English US 
 
Presentation of Treatment Groups 
All listings will be ordered by the following (unless otherwise indicated in the template): 
 
Treatment arm 
 
Center-subject ID 
 
Date (where applicable) 
All tables containing coded terms (CM, MH, AE, etc), coded records will be sorted in alphabetic order. 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX 2. PARTIAL DATE CONVENTIONS 
 
Algorithm for Treatment Emergence of Adverse Events: 
 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If start date < study med start date, then not TEAE 
If start date >= study med start date and start 
date<=study med stops date +28 days, then TEAE 
Partial 
If start date < study med start date, then not TEAE 
If start date >= study med start date and start 
date<=study med stops date +28 days, then TEAE 
Missing 
If start date < study med start date, then not TEAE 
If start date >= study med start date and start 
date<=study med stops date +28 days, then TEAE 
 
 
 
Partial, but known 
components show that it 
cannot be on or after 
study med start date 
Known 
Not TEAE 
Partial 
Not TEAE 
Missing 
Not TEAE 
 
 
 
Partial, could be on or 
after study med start date 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
Partial 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and 
month are unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
Partial 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and 
month are unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
Missing 
Assumed TEAE 
 
 
 
 
 
 
 
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 
Algorithm for Prior / Concomitant Medications/Concomitant procedures: 
 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If stop date < the time of signing informed consent , assign as prior 
If stop date >= the time of signing informed consent and start date <= end 
of treatment +28 days, assign as concomitant 
If stop date >= the time of signing informed consent and start date > end of 
treatment + 28 days, assign as post study 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < the time of signing informed consent, assign as prior 
If stop date >= the time of signing informed consent and start date <= end 
of treatment + 28 days, assign as concomitant 
If stop date >= the time of signing informed consent and start date > end of 
treatment + 28 days, assign as post treatment 
Missing 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment + 28 days, assign as concomitant 
If start date > end of treatment + 28 days, assign as post treatment 
 
 
 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date < the time of signing informed consent, assign as prior 
If stop date >= the time of signing informed consent and start date <= end 
of treatment + 28 days, assign as concomitant 
If stop date >= the time of signing informed consent and start date > end of 
treatment + 28 days, assign as post treatment 
Partial 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown) and impute stop 
date as latest possible date (i.e. last day of month if day unknown or 31st 
December if day and month are unknown), then: 
If stop date < the time of signing informed consent, assign as prior 
If stop date >= the time of signing informed consent and start date <= end 
of treatment + 28 days, assign as concomitant 
If stop date >= the time of signing informed consent and start date > end of 
treatment + 28 days, assign as post treatment 
Missing 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment + 28 days, assign as concomitant 
If start date > end of treatment + 28 days, assign as post treatment 
 
 
 
Missing 
Known 
If stop date < the time of signing informed consent, assign as prior 
If stop date >= the time of signing informed consent, assign as concomitant
Cannot be assigned as ‘post treatment’ 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < the time of signing informed consent, assign as prior 
If stop date >= the time of signing informed consent, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
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START DATE 
STOP DATE 
ACTION 
 
Missing 
Assign as concomitant 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX 3. CONFIRMATION OF BEST OVERALL RESPONSE 
 
Initial 
overall response 
Subsequent 
overall response 
Confirmed time point 
overall response 
CR 
CR 
CR provided subsequent CR is ≥ 28 days away 
from the first timepoint 
CR 
PR 
SD provided minimum criteria for SD duration met; 
otherwise, PD 
CR 
SD 
SD provided minimum criteria for SD duration met; 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met; 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
PR 
CR 
PR provided subsequent CR is ≥ 28 days away from the 
first timepoint 
PR 
PR 
PR provided subsequent PR is ≥ 28 days away from the 
first timepoint 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
SD 
Any 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
SD 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PD 
Any 
PD 
NE 
NE 
NE 
Footnote: 
(a) CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
not evaluable. 
(b) CR and PR need to be confirmed by subsequent tumor assessment at least 28 days later. 
(c) SD minimum evaluation interval will be at least 35 days. 
(d) If a subject only has a response value of NE or the only response value is SD and is within 36 
days of the first administration date, the best response will be NE. 
 
 
 
 
 
 
 
 
 
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APPENDIX 4. CTCAE V4.03 GRADE OF HEMATOLOGY AND CHEMISTRY 
 
 
Lab Test 
Name 
Direction 
toxicity 
CTCAE 
v4.0 SOC 
CTCAE 
v4.0 Term 
Grade 
1 
Grade 
2 
Grade 
3 
Grade 
4 
Grade 
5 
Hematology
 
 
 
 
 
 
 
 
Hemoglobin - 
Low 
Decrease 
Blood and 
lymphatic 
system 
disorders 
Anemia 
<LLN - 10.0 g/dL; 
<LLN - 6.2 mmol/L; 
<LLN - 100 g/L 
<10.0 - 8.0 g/dL; 
<6.2 - 4.9 mmol/L; 
<100 - 80g/L 
<8.0 g/dL; 
<4.9 mmol/L; 
<80 g/L; 
transfusion indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Hemoglobin -
High 
Increase 
Investigations 
Hemoglobin 
increased 
Increase in >0 - 2 gm/dL 
above ULN or 
above baseline if 
baseline is above ULN 
Increase in >2 - 4 
gm/dL above ULN or 
above baseline if 
baseline is above ULN
Increase in >4 gm/dL 
above ULN or above 
baseline if baseline is 
above ULN 
- 
- 
Leukocytes/ 
White blood cell 
Decrease 
Investigations 
White blood 
cell 
decreased 
<LLN - 3000/mm3; 
<LLN - 3.0 x 10e9 /L 
<3000 - 2000/mm3; 
<3.0 - 2.0 x 10e9 /L 
<2000 - 1000/mm3; 
<2.0 - 1.0 x 10e9 /L 
<1000/mm3; 
<1.0 x 10e9 /L 
- 
Lymphocyte - 
Low 
Decrease 
Investigations 
Lymphocyte 
count 
decreased 
<LLN - 800/mm3; 
<LLN - 0.8 x 10e9/L 
<800 - 500/mm3; 
<0.8 - 0.5 x 10e9 /L 
<500 - 200/mm3; 
<0.5 - 0.2 x 10e9 /L 
<200/mm3; 
<0.2 x 10e9 /L 
- 
Lymphocyte - 
High 
Increase 
Investigations 
Lymphocyte 
count 
increased 
- 
>4000/mm3 - 
20,000/mm3 
>20,000/mm3 
- 
- 
Neutrophils 
Decrease 
Investigations 
Neutrophil 
count 
decreased 
<LLN - 1500/mm3; 
<LLN - 1.5 x 10e9 /L 
<1500 - 1000/mm3; 
<1.5 - 1.0 x 10e9 /L 
<1000 - 500/mm3; 
<1.0 - 0.5 x 10e9 /L 
<500/mm3; 
<0.5 x 10e9 /L 
- 
Platelet count 
(PLT) 
Decrease 
Investigations 
Platelet 
count 
decreased 
<LLN - 75,000/mm3; 
<LLN - 75.0 x 10e9 /L 
<75,000 - 
50,000/mm3; 
<75.0 - 50.0 x 10e9 /L 
<50,000 - 25,000/mm3; 
<50.0 - 25.0 x 10e9 /L 
<25,000/mm3; 
<25.0 x 10e9 /L 
- 
 
 
 
 
 
 
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Lab Test
Name 
Direction
toxicity
CTCAE
v4.0 SOC 
CTCAE
v4.0 Term 
Grade
1 
Grade
2 
Grade
3 
Grade
4 
Grade 5
Chemistry
Albumin
Decrease
Metabolism 
and nutrition 
disorders 
Hypoalbuminemia
<LLN - 3 g/dL;
<LLN - 30 g/L 
<3 - 2 g/dL;
<30 - 20 g/L 
<2 g/dL;
<20 g/L 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death
Alkaline 
phosphatase 
(ALP) 
Increase
Investigations
Alkaline 
phosphatase 
increased 
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
-
Alanine 
aminotransferase 
(ALT) 
Increase
Investigations
Alanine 
aminotransferase 
increased 
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
-
Aspartate 
aminotransferase 
(AST) 
Increase
Investigations
Aspartate 
aminotransferase 
increased 
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
-
Total
Bilirubin 
Increase
Investigations
Blood
bilirubin 
increased 
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 10.0 x ULN
>10.0 x ULN
-
Creatinine
Increase
Investigations
Creatinine
increased 
>1 - 1.5 x baseline;
>ULN - 1.5 x ULN 
>1.5 - 3.0 x baseline;
>1.5 - 3.0 x ULN 
>3.0 baseline;
>3.0 - 6.0 x ULN 
>6.0 x ULN
-
Potassium
- Low 
Decrease
Metabolism 
and nutrition 
disorders 
Hypokalemia
<LLN - 3.0 mmol/L
<LLN - 3.0 mmol/L; 
symptomatic; 
intervention 
indicated 
<3.0 - 2.5 mmol/L; 
hospitalization 
indicated 
<2.5 mmol/L; 
life-threatening 
consequences 
Death
Potassium
- High 
Increase
Metabolism 
and nutrition 
disorders 
Hyperkalemia
>ULN - 5.5 mmol/L
>5.5 - 6.0 mmol/L
>6.0 - 7.0 mmol/L; 
hospitalization 
indicated 
>7.0 mmol/L; 
life-threatening 
consequences 
Death
Sodium
- Low 
Decrease
Metabolism
and nutrition 
disorders 
Hyponatremia
<LLN - 130 mmol/L
-
<130 - 120 mmol/L
<120 mmol/L;
life-threatening 
consequences 
Death
 
 
 
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Lab Test 
Name 
Direction 
toxicity
CTCAE 
v4.0 SOC 
CTCAE 
v4.0 Term 
Grade 
1 
Grade 
2 
Grade 
3 
Grade 
4 
Grade 
5 
Sodium
- High 
Increase 
Metabolism 
and nutrition 
disorders 
Hypernatremia 
>ULN - 150 mmol/L 
>150 - 155 mmol/L 
>155 - 160 mmol/L; 
hospitalization 
indicated 
>160 mmol/L; 
life-threatening 
consequences 
Death
Calcium
- Low 
Decrease
Metabolism 
and nutrition 
disorders 
Hypocalcemia 
Corrected serum 
calcium of 
<LLN - 8.0 mg/dL; 
<LLN - 2.0 mmol/L; 
Ionized calcium 
<LLN - 1.0 mmol/L 
Corrected serum 
calcium of <8.0 - 7.0 
mg/dL; <2.0 - 1.75 
mmol/L; 
Ionized calcium 
<1.0 - 0.9 mmol/L; 
symptomatic 
Corrected serum 
calcium of 
<7.0 - 6.0 mg/dL; 
<1.75 - 1.5 mmol/L; 
Ionized calcium 
<0.9 - 0.8 mmol/L; 
hospitalization 
indicated 
Corrected serum 
calcium of <6.0 mg/dL; 
<1.5 mmol/L; 
Ionized calcium 
<0.8 mmol/L; 
life-threatening 
consequences 
Death
Calcium 
- High 
Increase 
Metabolism 
and nutrition 
disorders 
Hypercalcemia 
Corrected serum 
calcium of 
>ULN - 11.5 mg/dL;
>ULN - 2.9 mmol/L; 
Ionized calcium 
>ULN - 1.5 mmol/L 
Corrected serum 
calcium of >11.5 - 
12.5 mg/dL; >2.9 - 3.1
mmol/L; Ionized 
calcium >1.5 - 1.6 
mmol/L; 
symptomatic 
Corrected serum 
calcium of 
>12.5 - 13.5 mg/dL; 
>3.1 - 3.4 mmol/L; 
Ionized calcium 
>1.6 - 1.8 mmol/L; 
hospitalization 
indicated 
Corrected serum 
calcium of >13.5 mg/dL; 
>3.4 mmol/L; 
Ionized calcium 
>1.8 mmol/L; 
life-threatening 
consequences 
Death
Glucose
- Low 
Decrease
Metabolism 
and nutrition 
disorders 
Hypoglycemia 
<LLN - 55 mg/dL; 
<LLN - 3.0 mmol/L 
<55 - 40 mg/dL; 
<3.0 - 2.2 mmol/L 
<40 - 30 mg/dL; 
<2.2 - 1.7 mmol/L 
<30 mg/dL; 
<1.7 mmol/L; 
life-threatening 
consequences; 
seizures 
Death
Glucose
- High 
Increase 
Metabolism 
and nutrition 
disorders 
Hyperglycemia 
Fasting glucose 
value 
>ULN - 160 mg/dL; 
>ULN - 8.9 mmol/L 
Fasting glucose value
>160 - 250 mg/dL; 
>8.9 - 13.9 mmol/L 
>250 - 500 mg/dL; 
>13.9 - 27.8 mmol/L; 
hospitalization 
indicated 
>500 mg/dL; 
>27.8 mmol/L; 
life-threatening 
consequences 
Death
Gamma 
glutamyl 
transferase 
Increase 
Investigations
GGT 
increased 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
- 
 
 
 
 
 
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APPENDIX 5. SAMPLE CODE FOR EFFICACY ANALYSIS 
 
data rs; 
set sasdata.adrs; 
where ittfl='Y' and paramcd='ORESW18'; 
keep usubjid trtp trtpn avalc sex mhnsclc ethnicsf; 
run; 
proc freq data=rs; 
tables sex*mhnsclc*ethnicsf*trtp*avalc/relrisk cmh riskdiff(common); 
ods output CommonPdiff=riskdiff;/* for common risk difference*/ 
ods output CommonRelRisks=relrisk; /* for common relative risk*/ 
run; 
 
**for multivariate-adjusted risk ratio; 
 
* log-binomial regression; 
proc genmod data=rs; 
class trtp sex mhnsclc ethnicsf; 
 
model avalc(event='Y’) =trtp sex mhnsclc ethnicsf/dist=bin link=log; 
estimate 'BAT1706 vs EU-Avastin' trtp 1 -1/exp alpha=0.1; 
ods output Estimates=Estimates_90; 
run; 
 
 
 
 
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*possion regression with the robust variance; 
proc genmod data=rs; 
class trtp sex mhnsclc ethnicsf usubjid; 
 
model avalc(event='Y’) =trtp sex mhnsclc ethnicsf/dist=possion link=log; 
repeated subject=usubjid/ type=ind; 
estimate 'BAT1706 vs EU-Avastin' trtp 1 -1/exp alpha=0.1; 
ods output Estimates=Estimates_90; 
run; 
 
 
 
 
data riskratio; 
 
set estimates_90(where=(index(label,'Exp')>0)); 
rr=strip(put(lbetaestimate,7.3)); * risk ratio; 
rrci=strip(put(lbetaLowerCL,7.3)) ||','||strip(put(lbetaUpperCL,7.3)) ||')'; *90% CI for risk ratio; 
run; 
 
** for multivariate-adjusted risk difference; 
 
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* log-binomial regression; 
proc genmod data=rs; 
class trtp sex mhnsclc ethnicsf; 
 
model avalc(event='Y’) =trtp sex mhnsclc ethnicsf/dist=bin link=identity; 
lsmeans trtp / diff cl; 
ods output diffs=diffs; 
run; 
 
 
 
*possion regression with the robust variance; 
proc genmod data=rs; 
class trtp sex mhnsclc ethnicsf usubjid; 
 
model avalc(event='Y’) =trtp sex mhnsclc ethnicsf/dist=possion link=identity; 
repeated subject=usubjid/type=ind; 
lsmeans trtp / diff cl; 
 
ods output diffs=diffs; 
run; 
 
 
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data diff; 
 
set diffs; 
 
df=strip(put(estimate,7.3)); * risk difference; 
 
dfci=strip (put (Lower,7.3))||','||strip(put(Upper,7.3))||')'; *95% CI for risk difference; 
run; 
 
 
logistic regression model: 
proc logistic data=rs; 
class Trtpn pdoscar pdospac ethnicsf; 
model avalc=Trtpn pdoscar pdospac ethnicsf/ expb; 
run; 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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