Clinical trial NCT03676192
Conditions: Adenocarcinoma of Lung
Sponsor: Celltrion
Start date: 2019-02-01; Completion date: 2023-09-19
Enrollment: 689 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To demonstrate that CT-P16 is similar to EU-Approved Avastin in terms of efficacy as determined by objective response rate (ORR) during the Induction Study Period

Detailed description:

Arms: arm 1: Drug: Bevacizumab 15mg/kg IV of CT-P16 will be administered every 3 weeks up to 6 cycles during the Induction Study Period and every 3 weeks until Progressive Disease (PD) or intolerable toxicity during the Maintenance Period. arm 2: Drug: Bevacizumab 15mg/kg IV of EU-approved Avastin will be administered every 3 weeks up to 6 cycles during the Induction Study Period and every 3 weeks until PD or intolerable toxicity during the Maintenance Period.
Interventions: intervention 1: CT-P16 intervention 2: Avastin
Intervention descriptions: intervention 1: 15mg/kg IV of CT-P16 every 3 weeks up to 6 cycles in the induction study period and every 3 weeks until PD occurs in the maintenance study period. intervention 2: 15mg/kg IV of Avastin every 3 weeks up to 6 cycles in the induction study period and every 3 weeks until PD occurs in the maintenance study period.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
A Double-Blind, Randomized, Active-Controlled, Parallel-Group, Phase 3 
Study to Compare Efficacy and Safety of CT-P16 and EU-Approved 
Avastin as First-Line Treatment for Metastatic or Recurrent Non-
Squamous Non-Small Cell Lung Cancer 
 
Protocol Number CT-P16 3.1 
EudraCT Number 
2018-002147-28 
Sponsor: 
CELLTRION, Inc. 
23, Academy-ro, 
Yeonsu-gu, Incheon, 22014, Republic of Korea 
Phone: +82 32 850 5000 
Fax: +82 32 850 5050 
E-mail: contact@celltrion.com 
 
 
 
 
 
 
 
 
 
 
 
Version and Date of Protocol:  
Protocol Version 2.0, 14 June 2019 
 
CONFIDENTIAL 
 
All financial and non-financial support for this study will be provided by CELLTRION, Inc. The concepts and 
information contained in this document or generated during the study are considered proprietary and may not be 
disclosed in whole or in part without the expressed, written consent of CELLTRION, Inc. The study will be 
conducted according to the protocol and in compliance with the International Council for Harmonisation 
harmonized tripartite guideline E6(R2): Good Clinical Practice with the declaration of Helsinki (WMA 2013). 
Throughout this document, symbols indicating proprietary names (®, ™) are not displayed. The appearance of 
product names without these symbols does not imply that these names are not protected. 




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Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Double-Blind, Randomized, 
Active-Controlled, Parallel-Group, Phase 3 Study to Compare Efficacy and Safety of CT-P16 
and EU-Approved Avastin as First-Line Treatment for Metastatic or Recurrent Non-Squamous 
Non-Small Cell Lung Cancer” and the accompanying investigator’s brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Protocol Version 2.0, dated 14 June 2019, the International Council for 
Harmonisation harmonized tripartite guideline E6 (R2): Good Clinical Practice and all 
applicable government regulations. I will not make changes to the protocol before consulting 
with CELLTRION, Inc. or implement protocol changes without independent ethics committee 
approval except to eliminate an immediate risk to patients. I agree to administer study drug 
only to patients under my personal supervision or the supervision of a subinvestigator. 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Patient identity will not be disclosed to third parties or appear 
in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from CELLTRION, Inc. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 


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Table of Contents 
Table of Contents .......................................................................................................................4 
List of Tables ..............................................................................................................................9 
List of Figures ............................................................................................................................9 
Protocol Synopsis.....................................................................................................................10 
List of Abbreviations................................................................................................................18 
1 
Introduction ......................................................................................................................21 
1.1 
Background .............................................................................................................21 
1.2 
CT-P16 ....................................................................................................................22 
1.3 
Non-clinical Studies ................................................................................................23 
1.4 
Clinical Studies .......................................................................................................24 
1.5 
Study Rationale .......................................................................................................25 
1.5.1 
Choice of Study Population .....................................................................25 
1.6 
Benefit and Risk Assessment ..................................................................................26 
2 
Study Objectives...............................................................................................................27 
2.1 
Primary Objective ...................................................................................................27 
2.2 
Secondary Objectives..............................................................................................27 
3 
Investigational Plan ..........................................................................................................28 
3.1 
Study Design ...........................................................................................................28 
3.1.1 
Rationale of Study Design .......................................................................30 
4 
Patient Selection and Withdrawal Criteria .......................................................................31 
4.1 
Selection of Study Population .................................................................................31 
4.1.1 
Inclusion Criteria .....................................................................................31 
4.1.2 
Exclusion Criteria ....................................................................................33 
4.2 
Withdrawal of Patients from the Study ...................................................................36 
4.2.1 
Recruitment of Additional Patients ..........................................................37 
4.3 
Premature Discontinuation of the Study .................................................................37 
5 
Study Treatments ..............................................................................................................38 
5.1 
Method of Assigning Patients to Treatment Groups ...............................................38 


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5.2 
Identity of Investigational Product..........................................................................38 
5.3 
Treatments Administered ........................................................................................40 
5.3.1 
CT-P16 and EU-Approved Avastin ..........................................................41 
5.3.2 
Paclitaxel ..................................................................................................42 
5.3.3 
Carboplatin ..............................................................................................42 
5.4 
Guidelines for Dosing .............................................................................................44 
5.4.1 
Dose Modification and Discontinuation ..................................................44 
5.4.1.1 
CT-P16 or EU-Approved Avastin ............................................................44 
5.4.1.2 
Paclitaxel and Carboplatin .......................................................................46 
5.4.1.2.1 
Re-treatment Criteria for Carboplatin and Paclitaxel ..................46 
5.4.1.2.2 
Dose Modification and Discontinuation of Carboplatin and 
Paclitaxel ......................................................................................46 
5.4.2 
Dose Escalation and Replacement ...........................................................48 
5.5 
Overdose Management ...........................................................................................48 
5.6 
Management of Clinical Supplies ...........................................................................48 
5.6.1 
Study Drug Packaging, Labelling, and Storage .......................................48 
5.6.2 
Study Drug Accountability ......................................................................49 
5.7 
Blinding ..................................................................................................................50 
5.7.1 
Breaking the Blind ...................................................................................50 
5.8 
Treatment Compliance ............................................................................................51 
5.9 
Prior, Concomitant, and Subsequent Therapy.........................................................51 
5.10 Prohibited Therapy ..................................................................................................52 
5.11 Permitted Therapy ...................................................................................................53 
6 
Study Assessments and Procedures ..................................................................................54 
6.1 
Pathological Diagnosis for Eligibility .....................................................................54 
6.2 
Efficacy Assessments ..............................................................................................54 
6.3 
Pharmacokinetic Assessments ................................................................................56 
6.4 
Quality of Life Assessments ...................................................................................57 
6.5 
Safety Assessments .................................................................................................57 
6.5.1 
Adverse Events ........................................................................................58 
6.5.1.1 
Definitions of Adverse Events .................................................................58 
6.5.1.1.1 
Adverse Events of Special Interest ..............................................59 
6.5.1.1.2 
Serious Adverse Events ................................................................59 


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6.5.1.1.3 
Unlisted (Unexpected) Adverse Events .......................................61 
6.5.1.2 
Eliciting and Documenting Adverse Events ............................................61 
6.5.1.3 
Reporting Adverse Events .......................................................................62 
6.5.1.4 
Reporting Serious Adverse Events ..........................................................62 
6.5.1.5 
Suspected Unexpected Serious Adverse Reactions .................................64 
6.5.1.6 
Assessment of Severity ............................................................................64 
6.5.1.7 
Assessment of Causality ..........................................................................65 
6.5.2 
Other Safety Assessment .........................................................................66 
6.5.2.1 
Immunogenicity Testing ..........................................................................66 
6.5.2.2 
Hypersensitivity/Infusion Related Reactions Monitoring .......................66 
6.5.2.3 
Vital Signs, Weight, and Height ...............................................................67 
6.5.2.4 
Electrocardiogram ....................................................................................67 
6.5.2.5 
Physical Examination ..............................................................................67 
6.5.2.6 
Eastern Cooperative Oncology Group .....................................................68 
6.5.2.7 
Hepatitis B, Hepatitis C, and Human Immunodeficiency Viruses ..........68 
6.5.2.8 
Pregnancy ................................................................................................68 
6.5.2.9 
Clinical Laboratory Analyses...................................................................70 
6.6 
Sample Collections .................................................................................................71 
6.6.1 
Pharmacokinetic Blood Sampling ...........................................................71 
6.6.2 
Immunogenicity Blood Sampling ............................................................72 
6.6.3 
Routine Safety Blood Sampling ..............................................................72 
6.7 
Labelling, Storage, and Transportation of Samples ................................................72 
6.7.1 
Sample Labelling .....................................................................................72 
6.7.2 
Sample Storage and Shipment .................................................................72 
7 
Statistical Analysis Plan ...................................................................................................74 
7.1 
Primary Endpoint ....................................................................................................74 
7.2 
Secondary Endpoints ..............................................................................................74 
7.2.1 
Efficacy Endpoints ...................................................................................74 
7.2.2 
Pharmacokinetic Endpoints .....................................................................74 
7.2.3 
Quality of Life Analyses ..........................................................................74 
7.2.4 
Safety Endpoints ......................................................................................74 
7.3 
Sample Size Calculations ........................................................................................75 
7.4 
Analysis Sets ...........................................................................................................75 
7.5 
Description of Subgroups to be Analyzed ..............................................................76 


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7.6 
Statistical Analysis Methodology ...........................................................................76 
7.6.1 
Analysis of Primary Efficacy Endpoint ...................................................77 
7.6.2 
Analysis of Secondary Efficacy Endpoints .............................................77 
7.6.3 
Pharmacokinetic Analyses .......................................................................78 
7.6.4 
Quality of Life Analyses ..........................................................................79 
7.6.5 
Safety Analyses ........................................................................................79 
7.6.6 
Other Analyses .........................................................................................79 
7.6.7 
Interim Analyses ......................................................................................79 
7.7 
Data Quality Assurance...........................................................................................79 
8 
Investigator’s Obligations ................................................................................................81 
8.1 
Confidentiality ........................................................................................................81 
8.2 
Independent Ethics Committee or Institutional Review Board ..............................81 
8.3 
Patient Information and Consent ............................................................................82 
8.4 
Study Reporting Requirements ...............................................................................83 
8.5 
Financial Disclosure and Obligations .....................................................................83 
8.6 
Investigator Documentation ....................................................................................84 
8.7 
Study Conduct .........................................................................................................84 
8.8 
Data Collection .......................................................................................................85 
8.8.1 
Electronic Case Report Forms and Source Documents ...........................85 
8.9 
Adherence to Protocol ............................................................................................85 
8.10 Investigator’s Final Report .....................................................................................86 
8.11 Records Retention ...................................................................................................86 
8.12 Patient Identification Register.................................................................................86 
8.13 Publications .............................................................................................................86 
9 
Study Management ...........................................................................................................88 
9.1 
Sponsor ...................................................................................................................88 
9.2 
Vendor Contact .......................................................................................................88 
9.3 
Monitoring ..............................................................................................................89 
9.3.1 
Data Safety Monitoring Board .................................................................89 
9.3.2 
Independent Tumor Review Committee ..................................................89 
9.3.3 
Monitoring of the Study ...........................................................................89 


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9.3.4 
Inspection of Records ..............................................................................89 
9.4 
Management of Protocol Amendments and Deviations..........................................90 
9.4.1 
Modification of the Protocol ....................................................................90 
9.4.2 
Protocol Deviations .................................................................................90 
9.5 
Study Termination ...................................................................................................91 
9.6 
Final Report ............................................................................................................91 
10 Reference List...................................................................................................................92 
11 Appendices .......................................................................................................................95 
11.1 Appendix: Schedule of Events ................................................................................95 
11.2 Response Evaluation Criteria In Solid Tumors Version 1.1 .................................100 
11.3 American Joint Committee on Cancer Lung Cancer Staging 8th Edition .............104 
11.4 Eastern Cooperative Oncology Group Performance Status ..................................108 
11.5 Quality of Life Questionnaire ...............................................................................109 
11.5.1 
EORTC QLQ-C30 .................................................................................109 
11.5.2 
EORTC QLQ - LC13 ............................................................................. 111 
11.6 Creatinine Clearance Calculation Formula ........................................................... 112 
11.7 New York Heart Association Functional Classification ........................................ 113 
 
 
 


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List of Tables 
Table 5-1 
Bevacizumab Dose Management due to Adverse Events ............................... 44 
Table 5-2 
Dose Adjustment Based on Hematologic Toxicities from the Previous Cycle 47 
Table 5-3 
Dose Adjustment Based on Non-hematologic Toxicities from the Previous 
Cycle ............................................................................................................... 47 
Table 5-4 
Dose Level of Full Dose and Dose Adjustment .............................................. 48 
Table 6-1 
Eligibility Based on Serologic Markers for Hepatitis B Infection .................. 68 
Table 11-1 
Schedule of Events .......................................................................................... 96 
 
List of Figures 
Figure 1 
Study Design Overview .................................................................................. 29 


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Protocol Synopsis 
Protocol Number: CT-P16 3.1 
Title: A Double-Blind, Randomized, Active-Controlled, Parallel-Group, Phase 3 Study to Compare 
Efficacy and Safety of CT-P16 and EU-Approved Avastin as First-Line Treatment for Metastatic or 
Recurrent Non-Squamous Non-Small Cell Lung Cancer 
Study Phase: Phase 3 
Study Centers: It is expected that approximately 150 study centers will participate in the study. 
Test Drug, Dose and Regimen: During the Induction Study Period, 15 mg/kg intravenous (IV) of 
CT-P16 will be administered on Day 1 of each cycle and will be repeated every 3 weeks until 6 cycles. 
Paclitaxel 200 mg/m2 IV and carboplatin area under the curve (AUC) 6 IV also will be administered on 
Day 1 of each cycle and will be repeated every 3 weeks up to 6 cycles (at least 4 cycles). After the 
Induction Study Period, CT-P16 as a monotherapy will be maintained every 3 weeks until progressive 
disease (PD) or intolerable toxicity occurrence. 
Dose reduction of CT-P16 for adverse reactions is not recommended. If indicated, therapy should either be 
permanently discontinued or temporarily suspended. 
CT-P16 will be diluted in a total volume of 100 mL of 0.9% sodium chloride and administered by IV 
infusion with an infusion pump. The dose should be delivered over 90 minutes (±15 minutes) at the 
Cycle 1 of the Induction Study Period. If the infusion is well-tolerated, the infusion of the Cycle 2 of the 
Induction Study Period may be administered over 60 minutes (±10 minutes). If the 60-minute infusion is 
well-tolerated, all subsequent infusions may be administered over 30 minutes (±10 minutes). 
Reference Drug, Dose and Regimen: During the Induction Study Period, 15 mg/kg IV of EU-Approved 
Avastin will be administered on Day 1 of each cycle and will be repeated every 3 weeks until 6 cycles. 
Paclitaxel 200 mg/m2 IV and carboplatin AUC 6 IV also will be administered on Day 1 of each cycle and 
will be repeated every 3 weeks up to 6 cycles (at least 4 cycles). After the Induction Study Period, 
EU-Approved Avastin as a monotherapy will be maintained every 3 weeks until PD or intolerable toxicity 
occurrence. 
Dose reduction of EU-Approved Avastin for adverse reactions is not recommended. If indicated, therapy 
should either be permanently discontinued or temporarily suspended. 
EU-Approved Avastin will be diluted in a total volume of 100 mL of 0.9% sodium chloride and 
administered by IV infusion with an infusion pump. The dose should be delivered over 90 minutes (±15 
minutes) at the Cycle 1 of the Induction Study Period. If the infusion is well-tolerated, the infusion of the 
Cycle 2 of the Induction Study Period may be administered over 60 minutes (±10 minutes). If the 
60-minute infusion is well-tolerated, all subsequent infusions may be administered over 30 minutes (±10 
minutes). 
Objectives: 
Primary Objective 
• 
To demonstrate CT-P16 is similar to EU-Approved Avastin in terms of efficacy as determined by 
objective response rate (ORR) up to Cycle 6 during the Induction Study Period 
Secondary Objectives 
• 
To evaluate additional efficacy profiles including ORR during the Whole Study Period, response 
duration, time to progression (TTP), progression-free survival (PFS), and overall survival (OS) 
• 
To evaluate the pharmacokinetics (PK) of trough serum concentration (Ctrough) 
• 
To evaluate safety profile including immunogenicity 
• 
To evaluate quality of life (QoL) 


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Main Selection Criteria: Patients for stage IV or recurrent non-squamous non-small cell lung cancer 
(nsNSCLC) in this study will be considered for enrollment if they meet all of the inclusion criteria and 
none of the exclusion criteria. 
Inclusion Criteria: 
Each patient must meet all of the following criteria to be randomized in this study: 
1. Patient (male or female) must be ≥ 18 years of age. 
2. Patient must have confirmed predominantly non-squamous non-small cell lung cancer (nsNSCLC) by 
hematoxylin and eosin staining or immunohistochemistry. 
3. Patient must be diagnosed as recurrent disease or stage IV according to the American Joint Committee 
on Cancer (AJCC) Lung Cancer Staging 8th edition. Stage IV is defined as below: 
a. 
Separate tumor nodule(s) in a contralateral lobe, or 
b. Tumor with pleural or pericardial nodules, or  
c. 
Malignant pleural or pericardial effusion related to tumor, or 
d. Single or multiple extrathoracic metastases in a single organ or in multiple organs 
4. Patient must have at least 1 measurable lesion by Response Evaluation Criteria In Solid Tumors 
(RECIST) Version 1.1. Target lesions situated in a previously irradiated area are considered measurable 
if recurrence has been demonstrated in such lesions. 
a. 
Tumor lesions: ≥ 10 mm in long axis by computerized tomography (CT) scan, or 
b. Malignant lymph nodes: ≥ 15 mm in short axis by CT scan 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Oken et al., 1982). 
6. Life expectancy > 6 months based on clinical judgement. 
7. Negative result in both epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma 
kinase (ALK) rearrangement which is confirmed by biopsy or cytology specimens. 
8. Patient must have adequate organ function as follows. These tests must be performed within 14 days 
prior to Day 1 of Cycle 1. 
Bone marrow reserve: 
a. 
Hemoglobin ≥ 9.0 g/dL, and 
b. Absolute neutrophil count ≥ 1,500/mm3, and 
c. 
Platelet count ≥ 100,000/mm3 
Hepatic: 
a. 
Alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase ≤ 3.0 × 
upper limit of normal (ULN) (≤ 5.0 × ULN with liver metastasis), and 
b. Total bilirubin ≤ 1.5 × ULN 
Renal: 
a. 
Serum creatinine ≤ 1.5 × ULN, and 
b. Creatinine clearance (CrCl) rate ≥ 45 mL/min, and 
c. 
Urine dipstick for proteinuria < 1+ (i.e., either 0 or trace); if urine dipstick is ≥ 1+ then 
< 1.0 g of protein in 24 hours urine collection must be confirmed to allow participation in 
the study 
9. Patient and their partner of childbearing potential must agree to use acceptable birth control methods 
throughout the study and for 6 months after the last dose of assigned treatment (see Section 6.5.2.8). 
A man or woman is of childbearing potential if, in the opinion of the investigator, he or she is 


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biologically capable of having children and is sexually active. Male and female patients and their 
partners who have been surgically sterilized for less than 24 weeks prior to the date of informed consent 
must agree to use any medically acceptable methods of contraception. Menopausal females must have 
experienced their last period more than 1 year prior to the date of informed consent to be classified as 
not of childbearing potential. 
10. Patient has the ability to comprehend the full nature and purpose of the study, including possible risks 
and side effects, to cooperate with the investigator, to understand verbal and/or written instructions, and 
to comply with the requirements of the entire study. 
11. Patient and/or their legally authorized representative must be informed and given ample time and 
opportunity to read and/or understand the nature and purpose of this study and must sign the informed 
consent form before any study specific procedures. 
Exclusion Criteria: 
Patients meeting any of the following criteria will be excluded from the study: 
1. Patient who has predominantly squamous cell histology non-small cell lung cancer (NSCLC). If small 
cell elements are present, the patient is ineligible. 
2. Patient who has clinically significant third-space fluid; for example, ascites or pleural effusions that 
cannot be controlled by drainage or other procedures prior to Day 1 of Cycle 1. 
3. Patient who has untreated central nervous system (CNS) metastases or CNS metastasis with bleeding 
risk at investigator's discretion and/or leptomeningeal disease. However, treated and clinically stable 
(asymptomatic; off steroids) brain metastases are allowed.  
4. Patient who has invasion of major blood vessels. Patient with a tumor cavitation in the opinion of the 
investigator is likely to bleed will be excluded as well. 
5. Patient who has received previous anti-cancer systemic therapy including one or more of the 
following(s): 
a. 
Cytotoxic chemotherapy for metastatic nsNSCLC,  
b. 
Cytotoxic chemotherapy for non-metastatic nsNSCLC within 12 months prior to Day 1 of Cycle 
1,  
c. 
Anti-neoplastic biological therapy, immunotherapy or targeted therapy,  
d. 
Bevacizumab (or a bevacizumab proposed biosimilar product).  
6. Patient who has received previous surgical procedure including one or more of the following(s): 
a. 
Surgery for metastatic nsNSCLC, 
b. 
Surgery for non-metastatic nsNSCLC within 6 months prior to Day 1 of Cycle 1,  
c. 
Open biopsy or open pleurodesis within 28 days prior to Day 1 of Cycle 1, 
d. 
Core biopsy or other minor surgical procedure (e.g. placement of vascular access device, closed 
pleurodesis, thoracentesis, and mediastinoscopy) within 14 days prior to Day 1 of Cycle 1. 
7. Patient who has received previous anti-cancer radiotherapy including one or more of the following(s): 
a. 
Radiotherapy for metastatic nsNSCLC, but radiotherapy as part of the palliative therapy and/or 
treatment for CNS metastases completed at least 14 days prior to Day 1 of Cycle 1 is allowed, 
b. 
Radiotherapy for non-metastatic nsNSCLC within 6 months prior to Day 1 of Cycle 1, 
c. 
Any toxicity related with radiotherapy prior to Day 1 of Cycle 1. 
8. Patient who has a medical history of disease including one or more of the following(s): 
a. 
Clinically significant allergic reactions such as asthma, urticaria, angio-oedema, and eczematous 
dermatitis, hypersensitivity to any component of carboplatin, paclitaxel, bevacizumab and 
Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanized 


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antibodies. 
b. 
Cardiac, gastrointestinal, renal, hepatic, hematological (including pancytopenia, aplastic anemia 
or blood dyscrasia), metabolic (including known diabetes mellitus), autoimmune disease, or 
pulmonary diseases classed as significant in the opinion of the investigator. 
c. 
A known infection with hepatitis B (active or carrier of hepatitis B), hepatitis C, or infection with 
human immunodeficiency virus (HIV). However, a patient with past hepatitis B virus is allowed 
if resolved. 
d. 
≥ New York Heart Association (NYHA) class 2 (Appendix 11.7), severe uncontrolled cardiac 
disease (unstable angina, clinically significant electrocardiogram [ECG] abnormalities, etc.), or 
myocardial infarction, within 6 months prior to Day 1 of Cycle 1. 
e. 
Malignancy or history of malignancy other than NSCLC in the past 5 years except adequately 
treated squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix. 
f. 
Any recent infection requiring a course of systemic anti-infectives or a serious infection 
(associated with hospitalization and/or which required intravenous antibiotics) within 14 days 
prior to Day 1 of Cycle 1. 
g. 
Use of oral or parenteral anticoagulants or thrombolytic agent for therapeutic purposes, or 
evidence of bleeding diathesis or coagulopathy. However, a patient who can discontinue regular 
use of aspirin (> 325 mg/day) administration at least 10 days prior to the Day 1 of Cycle 1 or a 
patient who continues with low dose aspirin (≤ 325 mg/day) are allowed for enrollment. 
h. 
Hemoptysis (> 2.5 mL of red blood), thrombotic or hemorrhagic event within the past 6 months 
prior to Day 1 of Cycle 1. 
i. 
Vascular disease history such as cerebrovascular accident, transient ischemic attack, or 
thromboembolic reactions including pulmonary embolism. 
j. 
Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 
6 months prior to Day 1 of Cycle 1. 
k. 
Unhealed wound following surgery, significant traumatic injury within 28 days prior to Day 1 of 
Cycle 1, or an anticipated need for major surgery during the study. 
l. 
Uncontrolled hypertension (defined as either systolic blood pressure ≥ 140 mmHg or diastolic 
blood pressure ≥ 90 mmHg), even after treatment. 
m. Uncontrolled diabetes mellitus, even after insulin treatment. 
9. Patient who has a current or recent treatment (within 30 days before Day 1 of Cycle 1 or 5 half-lives, 
whichever is longer) with any other investigational medicinal product or device. 
10. Female patient who is currently pregnant, breastfeeding, or planning to become pregnant or breastfeed 
and male patient who is planning to have child within 6 months of the last dose of study drug 
administration. 
11. Patient who has evidence of any other coexisting disease or medical or psychological condition, 
metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable 
suspicion of a disease or condition that contraindicates the use of an investigational product, or patient 
is at high risk for treatment complication in the opinion of the investigator. 
Assigning Patients to Treatment Groups: Patients will be randomly assigned to one of two treatment 
groups. The randomization will be balanced by using permuted blocks and will be stratified by country, 
sex (female vs. male), disease status (recurrence vs. metastatic), and ECOG performance score (0 vs. 1).  


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Study Design: 
This study is a double-blind, randomized, active-controlled, parallel-group, Phase 3 study to compare 
efficacy, PK, and overall safety of CT-P16 (15 mg/kg) and EU-Approved Avastin (15 mg/kg) when co-
administered with paclitaxel and carboplatin in patients with metastatic or recurrent nsNSCLC as first-line 
treatment. 
This study will comprise 4 study periods (including Screening Period, Induction Study Period, 
Maintenance Study Period, and Follow-Up Period) and be completed at approximately 3 years from the 
enrollment of the last patient. 
• 
Screening Period 
Screening evaluations will be completed within 28 days prior to randomization. However, 
screening period can be extended to 8 weeks exclusively for treating patients who have CNS 
metastases before starting the study treatment and all other assessments including chest and 
abdomen CT scan should be completed as specified in the protocol (Table 11-1). Approximately 
678 patients will be randomly assigned in a 1:1 ratio to CT-P16 or EU-Approved Avastin 
treatment groups. 
• 
Induction Study Period 
During the Induction Study Period, patients will receive 15 mg/kg IV of either CT-P16 or 
EU-Approved Avastin every 3 weeks up to 6 cycles. Patients will receive paclitaxel 200 mg/m2 
IV and carboplatin AUC 6 IV every 3 weeks up to 6 cycles (at least 4 cycles). Study drug 
administration will be started on the same day as randomization. If a patient has PD during or 
after the completion of the Induction Study Period (assessed at the end of Cycle 6) or does not 
enter the Maintenance Study Period due to any reason, this patient will complete the end of 
treatment (EOT) visit, then will directly enter the Follow-Up Period. 
• 
Maintenance Study Period 
After the completion of 6 cycles during the Induction Study Period, patients with controlled 
disease (complete response [CR], partial response [PR] or stable disease [SD], assessed at the 
end of Cycle 6) will enter the Maintenance Study Period. Patients will receive monotherapy of 
15 mg/kg of CT-P16 or EU-Approved Avastin every 3 weeks until PD or intolerable toxicity, 
whichever occurs first. Then, the patients will perform the EOT visit and then will enter the 
Follow-Up Period. 
• 
Follow-Up Period 
All patients who enter the Follow-Up Period due to any reason will be followed every 9 weeks 
until death or the end of study, whichever occurs first. If PD is not confirmed during the 
Induction Study Period or Maintenance Study Period, tumor response evaluation will be 
performed every 9 weeks during the Follow-Up Period. 
 


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Figure S1 
Study Design Overview 
 
Abbreviations: ECOG, Eastern Cooperative Oncology Group; IV, intravenous; PD, progressive disease. 
Efficacy Assessments: 
Tumor responses will be measured and recorded by using RECIST v.1.1. The primary endpoint, ORR 
during the Induction Study Period, and the secondary endpoint, ORR during the Whole Study Period, will 
be determined by the best overall response (BOR). For CR or PR, BOR must be confirmed by the 
subsequent assessment based on the RECIST v.1.1. 
Primary Efficacy Endpoint: 
• 
Objective response rate (ORR, %) based on BOR during the Induction Study Period by RECIST 
v.1.1 
Secondary Efficacy Endpoints: 
• 
ORR based on BOR during the Whole Study Period by RECIST v.1.1 
• 
Response duration: the time between initial response (CR or PR) and PD/recurrence 
• 
TTP: the time from randomization until PD/recurrence 
• 
PFS: the time from randomization until PD/recurrence or death due to any cause, whichever occurs 
first 
• 
OS: the time from randomization until death due to any cause 
Pharmacokinetic Assessments: 
• 
Induction Study Period (Cycle 1-6): Serum blood samples will be obtained on Day 1 of each cycle 
(prior to the beginning of the study drug administration). 
• 
Maintenance Study Period: Serum blood samples will be obtained on Day 1 of Cycle 1 and every 
3 cycles (end of Cycle 3, Cycle 6, Cycle 9...). 
• 
End of treatment (EOT) visit: Serum blood samples will be obtained any time of the day. 
Secondary PK Endpoints: 
• 
Ctrough: Trough serum concentration 
Safety Assessments: 
Secondary Safety Endpoints: 


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• 
Safety assessments will be performed on immunogenicity, hypersensitivity monitoring (via vital 
sign and ECG), vital sign measurements (blood pressure, heart rates, respiratory rates and body 
temperature), weight, viral assessment, physical examination, clinical laboratory analyses, ECG, 
ECOG, Adverse Events (AEs) (including serious adverse events [SAEs]), adverse events of 
special interest (AESIs) (hypersensitivity/infusion-related reactions, gastrointestinal perforations 
and fistulae, wound healing complications, hypertension, posterior reversible encephalopathy 
syndrome (PRES), proteinuria, arterial thromboembolism (ATE), venous thromboembolism 
(VTE), hemorrhages, congestive heart failure (CHF) and ovarian failure/fertility), pregnancy 
testing, prior and concomitant medications throughout the study. Adverse events will be reported 
for term and grade according to the Common Terminology Criteria for Adverse Events (CTCAE) 
v.5.0. 
Quality of Life Assessments: 
Secondary QoL Endpoints: 
• 
Quality of Life will be assessed using the validated European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ). The QLQ core 30 (QLQ-C30) 
and QLQ lung cancer-specific module (QLQ-LC13) will be used. Patients will complete the 
questionnaires at Screening, end of Cycle 2, Cycle 4, and Cycle 6 of the Induction Study Period, 
and every 3 cycles (end of Cycle 3, Cycle 6, Cycle 9…) of the Maintenance Study Period and 
EOT. 
Sample Size:  
 
A sample size of 305 patients per group will provide 80% power to show similarity in efficacy between 
CT-P16 and EU-Approved Avastin using a 95% confidence interval (CI) (two one-sided alpha 0.025) of 
the difference in ORR for an equivalence margin of (±12.5). 
Approximately 678 patients (339 in each group) will need to be enrolled for the anticipated drop-out rate 
of 10%. 
Statistical Methods: 
Statistical Analysis: 
The statistical methods for this study will be described in a detailed statistical analysis plan (SAP), which 
will be finalized prior to database lock. Changes from analyses planned in this protocol will be 
documented in the SAP. Any deviations from the planned analysis as described in the SAP will be 
justified and recorded in the study report. 
Continuous variables will be summarized by reporting the number of observations (n), mean, standard 
deviation, median, minimum, and maximum. Categorical variables will be summarized using frequency 
tables showing the number and percentage of patients within a particular category. 
Definition of analysis Population: 
Intent-to-treat (ITT) Population: The ITT population is defined as all patients randomly assigned to 
study drug, regardless of whether or not any study treatment dosing is completed. Patients will be assigned 
to treatment groups based on randomization. 
Per-Protocol (PP) Population: The PP population is defined as all randomly assigned patients who have 
at least one response evaluation after receiving at least one full dose of study drug (CT-P16 or 
EU-Approved Avastin) in the Induction Study Period and who do not have any major protocol deviation. 
A major protocol deviation is one that may affect the interpretation of primary endpoint and it will be 
defined in the SAP. Final determinations of the PP population will be made at the blinded data review 
meeting before unblinding. Patients will be assigned to treatment groups based on randomization. 


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PK Population: The PK population is defined as all patients who receive at least one full dose of study 
drug (CT-P16 or EU-Approved Avastin) and who have at least one post treatment PK result. If any 
patients are found to be non-compliant with respect to dosing, a decision will be made on a case-by-case 
basis at the blinded data review meeting before unblinding. Patients will be assigned to treatment groups 
based on treatment actually received. 
Safety Population: The safety population is defined as all randomly assigned patients who receive at least 
one dose (full or partial) of study drug (CT-P16 or EU-Approved Avastin). Patients will be assigned to 
treatment groups based on treatment actually received. 
Data analyses: 
The study will be unblinded to the pre-defined unblinded personnel from the Sponsor and contract 
research organization (CRO) after the completion of Cycle 6 of the Induction Study Period in all patients 
for the reporting purposes. The unblinded personnel will be pre-defined before breaking the study blind. 
The study will remain blinded to the investigators, patients and pre-defined blinded personnel from the 
Sponsor and CRO until all patients have completed the study and the database has been finalized for study 
completion. 
Efficacy Analysis: 
The similarity criterion has been set such that the confidence limits of the 95% CI of the difference in 
ORR will be entirely bounded by the interval (-12.5, 12.5). The primary analysis for the primary endpoint 
will be performed utilizing a logistic regression model considering covariates with treatment groups (CT-
P16 and EU-Approved Avastin) as a fixed effect in the ITT and PP population. For primary analysis, 
central review result will be used. Local review result will be used as supportive data (sensitivity analysis). 
The resulting odds ratio and 95% CI will be converted into difference of proportions using the Delta 
method for the purpose of comparison. Covariates will be described in the SAP. 
The secondary endpoint, both locally reviewed ORR and centrally reviewed ORR during the Whole Study 
Period, will be summarized using proportion and its corresponding 95% CI for each treatment group in the 
ITT and PP population. 
A time-to-event analysis will be undertaken for each of the response duration, TTP, PFS, and OS in the 
ITT and PP population; the median time and its corresponding 95% CI for each treatment group for each 
secondary endpoint of time-to-event analysis will be estimated using the Kaplan-Meier method. 
Pharmacokinetic Analysis: 
The Ctrough (prior to next dose) at each cycle during the Induction Study Period, and Ctrough during the 
Maintenance Study Period will be analyzed. Serum concentrations will be summarized using descriptive 
statistics (including geometric mean and coefficient of variation [CV], as appropriate) by treatment, and 
study visit. Pharmacokinetic parameters will also be summarized using descriptive statistics (including 
geometric mean and CV, as appropriate) by treatment and study visit. All analyses will be performed 
based on the PK population. 
Safety Analysis: 
Adverse events will be coded to system organ class (SOC) and preferred term (PT) using Medical 
Dictionary for Regulatory Activities (MedDRA). Adverse events will be graded for severity according to 
the CTCAE v.5.0. Prior and concomitant medication will be coded to drug class and PT using the World 
Health Organization (WHO) drug dictionary. 
All safety data including immunogenicity will be listed and summarized by treatment group in the safety 
population. 
Quality of Life Analysis: 
Descriptive analysis will be performed on actual score and change from baseline at each visit by treatment 
group in the ITT population. 


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List of Abbreviations 
Abbreviation 
Definition 
Study drug 
CT-P16 or EU-Approved Avastin 
Study treatment 
CT-P16 or EU-Approved Avastin in combination with paclitaxel 
and carboplatin 
ADL 
activity of daily living 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
AJCC 
American Joint Committee on Cancer 
ALK 
anaplastic lymphoma kinase 
ATE 
arterial thromboembolism 
AUC 
area under the curve 
BOR 
best overall response 
CFR 
Code of Federal Regulation 
CHF 
congestive heart failure 
CHO 
Chinese Hamster Ovary 
CI 
confidence interval 
CR 
complete response 
CrCl 
creatinine clearance 
CRO 
Contract Research Organization 
CSR 
clinical study report 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
trough serum concentration 
CV 
coefficient of variation 
DNA 
deoxyribonucleic acid 
DRR 
death rate ratio 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 


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Abbreviation 
Definition 
EORTC QLQ 
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire 
EOT 
end of treatment 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBcAb 
hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HIV 
human immunodeficiency virus 
IB 
Investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
intravenous 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
mCRC 
metastatic carcinoma of the colon or rectum 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NSCLC 
non-small cell lung cancer 
nsNSCLC 
non-squamous non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PP 
per protocol 
PR 
partial response 


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Abbreviation 
Definition 
PRES 
posterior reversible encephalopathy syndrome 
PT 
preferred term 
PVG 
pharmacovigilance 
QLQ-C30 
Quality of Life Questionnaire core 30 
QLQ-LC13 
Quality of Life Questionnaire lung cancer specific module 
QoL 
quality of life 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SCLC 
small cell lung cancer 
SD 
stable disease 
SmPC 
summary of product characteristics 
SOC 
system organ class 
SUSARs 
suspected unexpected serious adverse reactions 
TTP 
time to progression 
ULN 
upper limit of normal 
US 
United States 
USPI 
United States prescribing information 
VEGF 
Vascular Endothelial Growth Factor 
VTE 
venous thromboembolism 
WHO 
World Health Organization 
 


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1 Introduction 
1.1 Background 
In 2018, 1,735,350 new cancer cases and 609,640 cancer deaths are projected to occur in 
the United States (US). Over the past decade of data, the cancer incidence rate (2005-2014) 
was stable in women and declined by approximately 2% annually in men, while the cancer 
death rate (2006-2015) declined by about 1.5% annually in both men and women. The 
combined cancer death rate dropped continuously from 1991 to 2015 by a total of 26%, 
translating to approximately 2,378,600 fewer cancer deaths than would have been expected 
if death rates had remained at their peak. Of the 10 leading causes of death, only cancer 
declined from 2014 to 2015. In 2015, the cancer death rate was 14% higher in non-
Hispanic blacks than non-Hispanic whites overall (death rate ratio [DRR], 1.14; 95% 
confidence interval [95% CI], 1.13-1.15), but the racial disparity was much larger for 
individuals aged <65 years (DRR, 1.31; 95% CI, 1.29-1.32) compared with those aged 
≥ 65 years (DRR, 1.07; 95% CI, 1.06-1.09) and varied substantially by state (Siegel et al., 
2018). 
An estimated 234,030 new cases of lung cancer will be diagnosed in the US in 2018. The 
incidence rate has been declining since the mid-1980s in men, but only since the 
mid-2000s in women, because of gender differences in historical patterns of smoking 
uptake and cessation. From 2005 to 2014, lung cancer incidence rates decreased by 2.5% 
per year in men and 1.2% per year in women. An estimated 154,050 deaths from lung 
cancer will occur in 2018. The lung cancer death rate has declined by 45% since 1990 in 
men and by 19% since 2002 in women due to reductions in smoking, with the pace of 
decline quickening over the past decade; from 2011 to 2015, the rate decreased by 3.8% 
per year in men and by 2.3% per year in women. The 5-year relative survival rate for lung 
cancer is 18% (15% for men and 21% for women). Only 16% of lung cancers are 
diagnosed at a localized stage, for which the 5-year survival rate is 56% (American Cancer 
Society 2018, GLOBOCAN 2012). 
The early signs and symptoms of lung cancer are non-specific and as a consequence the 
majority of cases are diagnosed at an advanced stage, making successful treatment more 
difficult and survival outcomes poor (Barzi and Pennell 2010). There are two main types 
of lung cancer; non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). 


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Non-small cell lung cancer is the most commonly diagnosed type of lung cancer, 
accounting for approximately 85% of all cases (Barzi and Pennell 2010). Non-small cell 
lung cancer comprises a number of different types of lung cancer, which are grouped as 
‘squamous’ or ‘non-squamous’. Non-squamous non-small cell lung cancer (nsNSCLC) 
includes further subtypes such as adenocarcinoma and large cell carcinoma (NCCN - Non-
Small Cell Lung Cancer 2018). Approximately 80% of NSCLC cases are non-squamous 
and 20% are squamous histology. In this study, CT-P16 is being evaluated in patients with 
nsNSCLC. 
Cigarette smoking is by far the most important risk factor for lung cancer; 80% of lung 
cancer deaths in the US are still caused by smoking. Risk increases with both quantity and 
duration of smoking. Cigar and pipe smoking also increase risk. Exposure to radon gas 
released from soil and building materials is thought to be the second-leading cause of lung 
cancer in the US. Other risk factors include occupational or environmental exposure to 
secondhand smoke, asbestos (particularly among smokers), certain metals (chromium, 
cadmium, and arsenic), some organic chemicals, radiation, air pollution, and diesel 
exhaust. Some specific occupational exposures that increase risk include rubber 
manufacturing, paving, roofing, painting, and chimney sweeping. Risk is also probably 
increased among people with a history of tuberculosis. Genetic susceptibility (e.g., family 
history) plays a role in the development of lung cancer, especially in those who develop the 
disease at a young age (American Cancer Society 2018). 
Bevacizumab binds to vascular endothelial growth factor (VEGF), the key driver of 
vasculogenesis and angiogenesis, and thereby inhibits the binding of VEGF to its 
receptors, Flt-1 (VEGFR-1) and KDR (VEGFR-2), on the surface of endothelial cells. 
Neutralizing the biological activity of VEGF regresses the vascularization of tumors, 
normalizes remaining tumor vasculature, and inhibits the formation of new tumor 
vasculature, thereby inhibiting tumor growth (SmPC Avastin 2018). 
1.2 CT-P16 
CT-P16 is a recombinant humanized monoclonal antibody that is being developed and 
manufactured as a biosimilar to Avastin (bevacizumab) by CELLTRION, Inc. CT-P16 will 
have the same pharmaceutical form and strength as Avastin, and is intended to be 
analytically highly similar to Avastin. Bevacizumab, the active ingredient of CT-P16, is 


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produced by recombinant deoxyribonucleic acid (DNA) technology in a Chinese hamster 
ovary (CHO) cell expression system and purified by a suitable process. 
CT-P16, containing the active ingredient of bevacizumab, is a humanized monoclonal 
antibody that targets VEGF, neutralizes human VEGF and inhibits VEGF-induced 
proliferation of endothelial cells that is being developed as a similar biological medicinal 
product to Avastin. Avastin (bevacizumab) was initially authorized in the European Union 
(EU) on 12 January 2005 for the treatment of metastatic carcinoma of the colon or rectum 
(mCRC) in combination with fluoropyrimidine-based chemotherapy. In the EU, it is 
currently approved in combination with other medicines to treat mCRC, metastatic breast 
cancer, NSCLC, advanced and/or metastatic renal cell cancer, epithelial ovarian, fallopian 
tube, primary peritoneal cancer, recurrent glioblastoma, persistent or recurrent cervical 
cancer, and metastatic carcinoma of the cervix (SmPC Avastin 2018). In the US, Avastin 
(bevacizumab) was authorized on 26 February 2004 for the treatment of mCRC in 
combination with 5-fluorouracil–based chemotherapy and is currently approved in 
combination with other medicines to treat mCRC, nsNSCLC, recurrent glioblastoma, 
metastatic renal cell cancer, persistent, recurrent, or metastatic cervical cancer, and 
recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (Avastin USPI 
2018). 
Avastin is supplied as a sterile, preservative-free solution of bevacizumab for intravenous 
(IV) administration. Avastin is supplied in 1 strength, 25 mg/mL, as 100 mg/4 mL vial and 
400 mg/16 mL vial. 
CT-P16 is manufactured using a CHO cell line by fed-batch cell culture, followed by 
harvest, purification, formulation, and subsequent fill-finish operations. The amino acid 
sequences in CT-P16 are identical to that of Avastin. Like Avastin, CT-P16 will be supplied 
as a sterile, clear to opalescent, colorless to brown, preservative-free liquid at a 
concentration of 25 mg/mL in 400 mg (16 mL) vials for IV infusion. CT-P16 will have the 
same pharmaceutical form and strength as Avastin. 
1.3 Non-clinical Studies 
Detailed information regarding the non-clinical pharmacology and toxicology of CT-P16 
can be found in the investigator’s brochure (IB). 


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1.4 Clinical Studies 
CT-P16 has been administered to humans. The pharmacokinetic (PK) of Avastin 
(bevacizumab) in healthy male subjects was assessed in multicenter, randomized, double-
blind, three-arm phase 1 study (NCT03247673). In this study a single dose of 5 mg/kg of 
either CT-P16, EU-Approved Avastin, or US-Licensed Avastin was administered to healthy 
male subjects to demonstrate the similarity of PK. The PK results were contained within 
the pre-defined bioequivalence margin, indicating bioequivalence between CT-P16, EU-
Approved Avastin, and US-Licensed Avastin. The overall safety profiles were similar 
between CT-P16, EU-Approved Avastin, and US-Licensed Avastin. As CT-P16 is being 
developed as a similar biological medicinal product, reference is made to the published 
clinical information on Avastin (bevacizumab). The reference information is summarized 
in the clinical section of the IB. 
In nsNSCLC, the proven efficacy and well-established safety profile of bevacizumab as a 
first-line treatment have been demonstrated in 2 randomized Phase 3 trials. 
The Eastern Cooperative Oncology Group (ECOG) Phase 3 trial E4599 reported 
significantly improved overall survival (OS; study primary endpoint) with bevacizumab 
plus carboplatin–paclitaxel versus carboplatin–paclitaxel alone (hazard ratio 0.79; median 
12.3 versus 10.3 months; P = 0.003). Bevacizumab plus carboplatin–paclitaxel also 
significantly improved progression-free survival (PFS) and response rates versus 
carboplatin–paclitaxel alone and had an acceptable safety profile. The results of E4599 
showed that bevacizumab is the first agent to increase OS beyond the historical 1-year 
benchmark (Sandler et al., 2006). 
AVAiL (BO17704) study, a randomized placebo-controlled Phase 3 trial, evaluated 
bevacizumab (7.5 and 15 mg/kg every 3 weeks) in combination with cisplatin/gemcitabine. 
In AVAiL study, the primary endpoint of PFS was met, further proving the efficacy of 
bevacizumab in NSCLC (Reck et al., 2009). 
The positive results from AVAiL study, together with those from the E4599 study, 
demonstrate that bevacizumab combined with standard platinum-based chemotherapy 
doublets in the first-line setting leads to significantly improved outcomes for patients with 
advanced nsNSCLC. 


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1.5 Study Rationale 
CT-P16 is currently being developed by CELLTRION, Inc., which is intended to be 
formulated as biosimilar to Avastin. For a biosimilar to be approved, it must be shown that 
there are no clinical differences between the two products. The stepwise ‘totality of 
evidence’ approach adopted by regulatory authorities for biosimilars means that the type of 
clinical studies needed varies on a case-by-case basis. However, statistically proven 
equivalence between biosimilar and Avastin in both PK and efficacy are usually required, 
as is a demonstration of acceptable safety and immunogenicity. The PK profile of CT-P16, 
EU-Approved Avastin, and US-Licensed Avastin demonstrated PK equivalence in a 
Phase 1 study in healthy male subjects. An additional assessment of the similarity in 
efficacy, PK, safety, and immunogenicity will be carried out in this proposed comparative 
clinical trial (Study CT-P16 3.1) in patients with metastatic or recurrent nsNSCLC. 
CELLTRION, Inc. considers that the proposed clinical development program will be 
sufficient to demonstrate PK equivalence of CT-P16 (Study CT-P16 1.1; Phase 1; PK 
similarity healthy volunteer study) and therapeutic equivalence and safety (Study CT-P16 
3.1; Phase 3; comparative clinical similarity) to Avastin. 
1.5.1 Choice of Study Population 
International regulations (WHO 2009, European Medicines Agency 2012, FDA 2015) 
suggest that proposed biosimilars should be tested in a population representative of 
approved therapeutic indications of Avastin and sufficiently sensitive for detecting 
potential differences between the biosimilar and Avastin. 
The eligibility criteria for the Study CT-P16 3.1 have been designed to select a 
homogenous patient population appropriate for treatment with Avastin, per the 
US/EU-Approved indication. Avastin is indicated, in addition to platinum-based 
chemotherapy, for first-line treatment of patients with unresectable advanced, metastatic or 
recurrent nsNSCLC (Avastin USPI 2018, SmPC Avastin 2018). Accordingly, eligible 
patients must be diagnosed with stage IV or recurrent nsNSCLC, and planning to initiate 
first-line platinum-based chemotherapy after randomization. These criteria are similar to 
those in the pivotal placebo-controlled study in this indication for the innovator product 
(Sandler et al., 2006), in which a statistically and clinically significant effect was 
demonstrated for bevacizumab versus placebo. Per applicable guidelines, a sponsor should 
consider whether a study in a specific population will be sufficiently sensitive to detect 


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clinically meaningful differences (He et al., 2016). The effect of bevacizumab on objective 
response rate (ORR) in NSCLC patients documented in historical studies was sufficiently 
large and clinically meaningful because of correlations with improvement in PFS and OS 
(Botrel et al., 2011). Recently approved by Food and Drug Administration (FDA), 
bevacizumab biosimilar ABP215 (SmPC MVASI 2019) was evaluated in the pivotal 
comparative efficacy study in patients with nsNSCLC using ORR as a primary endpoint. 
Given these considerations, CELLTRION, Inc. believes that this is a homogenous and 
sensitive population to demonstrate the effect of bevacizumab and to compare the relative 
efficacy and safety of Avastin and CT-P16. 
1.6 Benefit and Risk Assessment 
The CT-P16 will have the same pharmaceutical form and strength as Avastin (25 mg/mL). 
The proposed dosing regimen is in line with the approved labeling for Avastin (SmPC 
Avastin 2018, Avastin USPI 2018). 
The proposed safety monitoring is deemed to be sufficient to monitor potential risks of 
CT-P16 administration. In view of the structural, biological, and toxicological similarity to 
Avastin, CT-P16 is expected to display a similar safety profile.  
Based upon the clinical evidence (Section 1.4) as well as the proven safety profile of 
Avastin, the benefits of the conduct of the proposed clinical study outweigh the associated 
risks. 


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2 Study Objectives 
2.1 Primary Objective 
• To demonstrate CT-P16 is similar to EU-Approved Avastin in terms of efficacy as 
determined by ORR up to Cycle 6 during the Induction Study Period 
2.2 Secondary Objectives 
• To evaluate additional efficacy profiles including ORR during the Whole Study 
Period, response duration, time to progression (TTP), PFS, and OS 
• To evaluate the PK of trough serum concentration (Ctrough) 
• To evaluate safety profile including immunogenicity 
• To evaluate quality of life (QoL) 


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3 Investigational Plan 
3.1 Study Design 
This study is a double-blind, randomized, active-controlled, parallel-group, Phase 3 study 
to compare efficacy, PK, and overall safety of CT-P16 (15 mg/kg) and EU-Approved 
Avastin (15 mg/kg) when co-administered with paclitaxel and carboplatin in patients with 
metastatic or recurrent nsNSCLC as first-line treatment. 
A total of 678 male and female patients with metastatic or recurrent nsNSCLC will be 
enrolled and randomly assigned in a 1:1 ratio (approximately 339 patients per treatment 
group) to CT-P16 or EU-Approved Avastin. 
This study will comprise 4 study periods (including Screening Period, Induction Study 
Period, Maintenance Study Period and Follow-Up Period) and be completed at 
approximately 3 years from the enrollment of last patient. 
An end of treatment (EOT) visit will occur 3 weeks after the last dose of the Induction 
Study Period or Maintenance Study Period regardless of the reason of discontinuation. 
Screening Period 
Screening evaluations will be completed within 28 days prior to randomization. However, 
screening period can be extended to 8 weeks exclusively for treating patients who have 
CNS metastases before starting the study treatment and all other assessments including 
chest and abdomen CT scan should be completed as specified in the protocol (Table 11-1). 
Approximately 678 patients will be randomly assigned in a 1:1 ratio to CT-P16 or 
EU-Approved Avastin treatment groups. 
Induction Study Period 
During the Induction Study Period, patients will receive 15 mg/kg IV of either CT-P16 or 
EU-Approved Avastin every 3 weeks up to 6 cycles. Patients will receive paclitaxel 
200 mg/m2 IV and carboplatin area under the curve (AUC) 6 IV every 3 weeks up to 
6 cycles (at least 4 cycles). Study drug administration will be started on the same day as 
randomization. If a patient has progressive disease (PD) during or after the completion of 
the Induction Study Period (assessed at the end of Cycle 6) or does not enter the 


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Maintenance Study Period due to any reason, this patient will complete the EOT visit, then 
will directly enter the Follow-Up Period. 
Maintenance Study Period 
After the completion of 6 cycles during the Induction Study Period, patients with 
controlled disease (complete response [CR], partial response [PR], or stable disease [SD], 
assessed at the end of Cycle 6) will enter the Maintenance Study Period. Patients will 
receive monotherapy of 15 mg/kg of CT-P16 or EU-Approved Avastin every 3 weeks until 
PD or intolerable toxicity, whichever occurs first. Then, the patients will perform the EOT 
visit and then will enter the Follow-Up Period. 
Follow-Up Period 
All patients who enter the Follow-Up Period due to any reason will be followed every 
9 weeks until death or the end of study, whichever occurs first. If PD is not confirmed 
during the Induction Study Period or Maintenance Study Period, tumor response 
evaluation will be performed every 9 weeks during the Follow-Up Period. 
The study design and patient assessment overview is presented in Figure 1. 
Figure 1 
Study Design Overview 
Abbreviations: ECOG, Eastern Cooperative Oncology Group; IV, intravenous; PD, progressive disease. 


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3.1.1 Rationale of Study Design 
The primary objective of the study is to demonstrate the efficacy equivalence in terms of 
ORR between CT-P16 and EU-Approved Avastin. Taking into account the EU Guideline 
on Similar Biological Medicinal Products Containing Monoclonal Antibody: Non-clinical 
and Clinical Issues (European Medicines Agency 2012) and the FDA Guideline for 
Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (FDA 
2007), ORR is selected as a primary endpoint for this study. Objective response rate is 
considered a clinically relevant, objective and sensitive endpoint for the purpose of the 
clinical similarity assessment of the proposed bevacizumab biosimilar. 


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4 Patient Selection and Withdrawal Criteria 
4.1 Selection of Study Population 
It is expected that approximately 678 patients will be enrolled at approximately 150 study 
centers in around 23 countries. Male or female patients with metastatic or recurrent 
nsNSCLC will be considered for enrollment in the study if they meet all the inclusion 
criteria and none of the exclusion criteria. 
4.1.1 Inclusion Criteria 
Each patient must meet all of the following criteria to be randomized in this study: 
1. Patient (male or female) must be ≥ 18 years of age. 
2. Patient must have confirmed predominantly non-squamous non-small cell lung cancer 
(nsNSCLC) by hematoxylin and eosin staining or immunohistochemistry. 
3. Patient must be diagnosed as recurrent disease or stage IV according to the American 
Joint Committee on Cancer (AJCC) Lung Cancer Staging 8th edition. Stage IV is 
defined as below: 
a. Separate tumor nodule(s) in a contralateral lobe, or 
b. Tumor with pleural or pericardial nodules, or  
c. Malignant pleural or pericardial effusion related to tumor, or 
d. Single or multiple extrathoracic metastases in a single organ or in multiple 
organs 
4. Patient must have at least 1 measurable lesion by Response Evaluation Criteria In Solid 
Tumors (RECIST) Version 1.1. Target lesions situated in a previously irradiated area 
are considered measurable if recurrence has been demonstrated in such lesions. 
a. Tumor lesions: ≥ 10 mm in long axis by computerized tomography (CT) scan, 
or 
b. Malignant lymph nodes: ≥ 15 mm in short axis by CT scan 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Oken et 
al., 1982). 
6. Life expectancy > 6 months based on clinical judgement. 


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7. Negative result in both epidermal growth factor receptor (EGFR) mutation and 
anaplastic lymphoma kinase (ALK) rearrangement which is confirmed by biopsy or 
cytology specimens. 
8. Patient must have adequate organ function as follows. These tests must be performed 
within 14 days prior to Day 1 of Cycle 1. 
Bone marrow reserve: 
a. Hemoglobin ≥ 9.0 g/dL, and 
b. Absolute neutrophil count ≥ 1,500/mm3, and 
c. Platelet count ≥ 100,000/mm3 
Hepatic: 
a. Alkaline 
phosphatase, 
aspartate 
aminotransferase 
and 
alanine 
aminotransferase ≤ 3.0 × upper limit of normal (ULN) (≤ 5.0 × ULN with liver 
metastasis), and 
b. Total bilirubin ≤ 1.5 × ULN 
Renal: 
a. Serum creatinine ≤ 1.5 × ULN, and 
b. Creatinine clearance (CrCl) rate ≥ 45 mL/min, and 
c. Urine dipstick for proteinuria < 1+ (i.e., either 0 or trace); if urine dipstick is 
≥ 1+ then < 1.0 g of protein in 24 hours urine collection must be confirmed to 
allow participation in the study 
9. Patient and their partner of childbearing potential must agree to use acceptable birth 
control methods throughout the study and for 6 months after the last dose of assigned 
treatment (see Section 6.5.2.8). 
A man or woman is of childbearing potential if, in the opinion of the investigator, he or 
she is biologically capable of having children and is sexually active. Male and female 
patients and their partners who have been surgically sterilized for less than 24 weeks 
prior to the date of informed consent must agree to use any medically acceptable 
methods of contraception. Menopausal females must have experienced their last period 
more than 1 year prior to the date of informed consent to be classified as not of 
childbearing potential. 


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10. Patient has the ability to comprehend the full nature and purpose of the study, including 
possible risks and side effects, to cooperate with the investigator, to understand verbal 
and/or written instructions, and to comply with the requirements of the entire study. 
11. Patient and/or their legally authorized representative must be informed and given 
ample time and opportunity to read and/or understand the nature and purpose of this 
study and must sign the informed consent form before any study specific procedures. 
4.1.2 Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the study: 
1. Patient who has predominantly squamous cell histology non-small cell lung cancer 
(NSCLC). If small cell elements are present, the patient is ineligible. 
2. Patient who has clinically significant third-space fluid; for example, ascites or pleural 
effusions that cannot be controlled by drainage or other procedures prior to Day 1 of 
Cycle 1. 
3. Patient who has untreated central nervous system (CNS) metastases or CNS metastasis 
with bleeding risk at investigator's discretion and/or leptomeningeal disease. However, 
treated and clinically stable (asymptomatic; off steroids) brain metastases are allowed. 
4. Patient who has invasion of major blood vessels. Patient with a tumor cavitation in the 
opinion of the investigator is likely to bleed will be excluded as well.  
5. Patient who has received previous anti-cancer systemic therapy including one or more 
of the following(s): 
a. Cytotoxic chemotherapy for metastatic nsNSCLC,  
b. Cytotoxic chemotherapy for non-metastatic nsNSCLC within 12 months prior to 
Day 1 of Cycle 1,  
c. Anti-neoplastic biological therapy, immunotherapy or targeted therapy,  
d. Bevacizumab (or a bevacizumab proposed biosimilar product).  
6. Patient who has received previous surgical procedure including one or more of the 
following(s): 
a. Surgery for metastatic nsNSCLC, 
b. Surgery for non-metastatic nsNSCLC within 6 months prior to Day 1 of Cycle 1,  


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c. Open biopsy or open pleurodesis within 28 days prior to Day 1 of Cycle 1, 
d. Core biopsy or other minor surgical procedure (e.g. placement of vascular access 
device, closed pleurodesis, thoracentesis, and mediastinoscopy) within 14 days prior 
to Day 1 of Cycle 1. 
7. Patient who has received previous anti-cancer radiotherapy including one or more of 
the following(s): 
a. Radiotherapy for metastatic nsNSCLC, but radiotherapy as part of the palliative 
therapy and/or treatment for CNS metastases completed at least 14 days prior to 
Day 1 of Cycle 1 is allowed, 
b. Radiotherapy for non-metastatic nsNSCLC within 6 months prior to Day 1 of Cycle 
1, 
c. Any toxicity related with radiotherapy prior to Day 1 of Cycle 1. 
8. Patient who has a medical history of disease including one or more of the following(s): 
a. Clinically significant allergic reactions such as asthma, urticaria, angio-oedema, and 
eczematous dermatitis, hypersensitivity to any component of carboplatin, paclitaxel, 
bevacizumab and Chinese Hamster Ovary (CHO) cell products or other recombinant 
human or humanized antibodies. 
b. Cardiac, gastrointestinal, renal, hepatic, hematological (including pancytopenia, 
aplastic anemia or blood dyscrasia), metabolic (including known diabetes mellitus), 
autoimmune disease, or pulmonary diseases classed as significant in the opinion of 
the investigator. 
c. A known infection with hepatitis B (active or carrier of hepatitis B), hepatitis C, or 
infection with human immunodeficiency virus (HIV). However, a patient with past 
hepatitis B virus is allowed if resolved. 
d. ≥ New York Heart Association (NYHA) class 2 (Appendix 11.7), severe 
uncontrolled 
cardiac 
disease 
(unstable 
angina, 
clinically 
significant 
electrocardiogram [ECG] abnormalities, etc.), or myocardial infarction, within 6 
months prior to Day 1 of Cycle 1. 
e. Malignancy or history of malignancy other than NSCLC in the past 5 years except 
adequately treated squamous or basal cell carcinoma of the skin or carcinoma in situ 
of the cervix. 


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f. 
Any recent infection requiring a course of systemic anti-infectives or a serious 
infection (associated with hospitalization and/or which required intravenous 
antibiotics) within 14 days prior to Day 1 of Cycle 1. 
g. Use of oral or parenteral anticoagulants or thrombolytic agent for therapeutic 
purposes, or evidence of bleeding diathesis or coagulopathy. However, a patient who 
can discontinue regular use of aspirin (> 325 mg/day) administration at least 10 days 
prior to the Day 1 of Cycle 1 or a patient who continues with low dose aspirin (≤ 
325 mg/day) are allowed for enrollment. 
h. Hemoptysis (> 2.5 mL of red blood), thrombotic or hemorrhagic event within the 
past 6 months prior to Day 1 of Cycle 1. 
i. 
Vascular disease history such as cerebrovascular accident, transient ischemic attack, 
or thromboembolic reactions including pulmonary embolism. 
j. 
Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 
the past 6 months prior to Day 1 of Cycle 1. 
k. Unhealed wound following surgery, significant traumatic injury within 28 days prior 
to Day 1 of Cycle 1, or an anticipated need for major surgery during the study. 
l. 
Uncontrolled hypertension (defined as either systolic blood pressure ≥ 140 mmHg 
or diastolic blood pressure ≥ 90 mmHg), even after treatment. 
m. Uncontrolled diabetes mellitus, even after insulin treatment. 
9. Patient who has a current or recent treatment (within 30 days before Day 1 of Cycle 1 
or 5 half-lives, whichever is longer) with any other investigational medicinal product or 
device. 
10. Female patient who is currently pregnant, breastfeeding, or planning to become 
pregnant or breastfeed and male patient who is planning to have child within 6 months 
of the last dose of study drug administration. 
11. Patient who has evidence of any other coexisting disease or medical or psychological 
condition, metabolic dysfunction, physical examination finding, or clinical laboratory 
finding giving reasonable suspicion of a disease or condition that contraindicates the 
use of an investigational product, or patient is at high risk for treatment complication in 
the opinion of the investigator. 


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4.2 Withdrawal of Patients from the Study 
Patients are free to withdraw from the study at any time for any reason. The investigator 
may also withdraw the patient at any time in the interest of patient safety. The primary 
reason for withdrawal must be recorded in the patient’s medical record and on the 
withdrawal form in the electronic case report form (eCRF) and source documents. 
When possible, the sponsor should be notified of the withdrawal of a patient from the 
study. For patients who withdraw before the end of the study treatment, an EOT visit will 
occur 3 weeks after the last dose of the Induction Study Period or Maintenance Study 
Period regardless of the reason for discontinuation. Any comments (spontaneous or 
elicited) or complaints made by the patient, together with the reason for the study treatment 
termination, and the date of cessation of study drug must be recorded in the eCRF and 
source documents. It is vital to obtain follow-up data on any patient withdrawn because of 
an adverse event (AE) or serious adverse event (SAE). In every case, efforts must be made 
to undertake protocol-specified safety and follow-up procedures. 
Reasons for withdrawal from the study treatment include the following: 
• Patient develops signs of disease progression in the judgement of the investigator. 
• Patient withdraws consent or refuses to continue treatment and/or 
procedures/observations. 
• Patient has any AE that would compromise his or her safety if he or she continues 
to participate in the study. 
• Patient has a significant protocol deviation(s). 
• Patient is lost to follow-up. 
• Patient dies. 
• Study is terminated by the Sponsor. 
• Patient is pregnant. 


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• Investigator’s decision. 
The sponsor may contact or be contacted if clarification is required on a case-by-case 
basis. 
4.2.1 Recruitment of Additional Patients 
Patients who receive study drug and discontinue before study completion will not be 
replaced. Patients who are screen failed, for any reason, can be re-screened only once. 
Re-screened patient will be assigned with new patient identification. 
4.3 Premature Discontinuation of the Study 
The sponsor reserves the right to terminate the study at any time for reasonable medical 
and/or administrative reasons. As much as possible, this should occur after mutual 
consultation. 
If the study is terminated prematurely by the sponsor, all patients will be kept fully 
informed and an appropriate follow-up examination of the patients will be arranged. The 
investigator will inform the institutional review board (IRB) or independent ethics 
committee (IEC) of any premature termination or suspension of the study, where 
applicable. 


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5 Study Treatments 
5.1 Method of Assigning Patients to Treatment Groups 
An interactive voice response system (IVRS) or an interactive web response system 
(IWRS) will be used for the randomization. A randomization schedule will be generated 
for IVRS or IWRS, which will link sequential patient randomization numbers to treatment 
codes. 
Patients who qualify for randomization will be randomly assigned on Day 1 of Cycle 1 of 
the Induction Study Period in a 1:1 ratio to receive CT-P16 or EU-Approved Avastin. The 
randomization will be balanced by using permuted blocks and will be stratified by country, 
sex (female vs. male), disease status (recurrence vs. metastatic), and ECOG performance 
score (0 vs. 1) (Appendix 11.4). 
5.2 Identity of Investigational Product 
CT-P16 is a recombinant humanized monoclonal antibody which is being developed by 
CELLTRION, Inc. as a potential biosimilar to Avastin. 
Dosing instruction described in Avastin prescribing information is to be followed (Avastin 
USPI 2018, SmPC Avastin 2018). 
The company code of the product is CT-P16. The International Nonproprietary Name of 
the commercially available reference material (Avastin) is bevacizumab. Bevacizumab 
contains in total 1,334 amino acids and has an approximate molecular weight of 149 kDa. 
It is composed of 2 identical light chains (214 amino acids each) and 2 heavy chains (453 
amino acids each). The 2 heavy chains are covalently coupled to one another through 2 
inter-chain disulphide bonds, and each light chain is covalently coupled to a heavy chain 
through a disulphide bond (cysteine 214 to cysteine 226, respectively). 
CT-P16 will be supplied as a sterile, clear to opalescent, colorless to brown, 
preservative-free liquid at a concentration of 25 mg/mL in 400 mg (16 mL) vials for IV 
infusion. 




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5.3 Treatments Administered 
During the Induction Study Period, study treatment will be administered in following 
order: 
Hydration (by local practice) 
 
Dexamethasone 20 mg 
Oral, approximately 12 and 6 hours prior to administration of paclitaxel or  
IV infusion, 30 to 60 minutes prior to administration of paclitaxel 
Diphenhydramine (or its equivalent) 50 mg 
IV infusion 30 to 60 minutes prior to administration of paclitaxel 
Cimetidine 300 mg or ranitidine 50 mg 
IV infusion 30 to 60 minutes prior to administration of paclitaxel 
 
Paclitaxel 200 mg/m2 
IV infusion over approximately 3 hours 
 
Carboplatin AUC 6.0 
IV infusion over approximately 30 minutes after administration of paclitaxel 
 
CT-P16 or EU-Approved Avastin 15 mg/kg 
IV infusion over 30 to 90 minutes after administration of carboplatin 
Note: Antiemetic can be used based on local practice. Dose of dexamethasone, diphenhydramine, and 
cimetidine can be adjusted at the investigator’s discretion. 
Uncoupling of study treatment is not allowed until at least 4 cycles of the Induction Study 
Period have been completed. 
 
Study treatment (CT-P16 or EU-Approved Avastin, carboplatin, and paclitaxel) 
should be administered on the same date. 
 
If one of them should be delayed, study treatment should be delayed. 


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 
If one of them should be permanently discontinued, study treatment should be 
discontinued. 
However, paclitaxel and/or carboplatin can be discontinued at Cycle 5 or 6 of Induction 
Study Period based on Section 5.4.1.2. 
Body weight on Day 1 of each cycle during the Induction Study Period and Maintenance 
Study Period will be used for each administration. 
Further information of dosing time and details for Induction Study Period and Maintenance 
Study Period are specified in each section. 
Treatment during the Induction Study Period and Maintenance Study Period can be 
delayed for up to 3 weeks from the planned schedule. If treatment is delayed more than 3 
weeks, then the patient will be discontinued. 
5.3.1 CT-P16 and EU-Approved Avastin 
During the Induction Study Period, patients will receive 15 mg/kg IV of either CT-P16 or 
EU-Approved Avastin every 3 weeks up to 6 cycles. Patients will receive paclitaxel 
200 mg/m2 IV and carboplatin AUC 6 IV every 3 weeks up to 6 cycles (at least 4 cycles). 
After the Induction Study Period, either CT-P16 or EU-Approved Avastin as a 
monotherapy (15 mg/kg IV) will be maintained every 3 weeks until either PD or 
intolerable toxicity occurrence, whichever occurs first. 
CT-P16 or EU-Approved Avastin will be diluted in a total volume of 100 mL of 0.9% 
sodium chloride and administered by IV infusion with an infusion pump. The dose should 
be delivered over 90 minutes (±15 minutes) at the Cycle 1 of the Induction Study Period. If 
the infusion is well-tolerated, the infusion of the Cycle 2 of the Induction Study Period 
may be administered over 60 minutes (±10 minutes). If the 60-minute infusion is 
well-tolerated, all subsequent infusions may be administered over 30 minutes (±10 
minutes). 
The study drug is required to be handled by delegated unblinded staff. 
No premedication is required prior to administration of study drug. 


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5.3.2 Paclitaxel 
Paclitaxel will be administered at a dose of 200 mg/m2 approximately 3 hours through an 
in-line filter with a microporous membrane not greater than 0.22 microns using a single 
infusion, per local practice guidelines. 
Paclitaxel will be diluted in 0.9% sodium chloride or 5% dextrose. Paclitaxel will be 
administered on Day 1 of each cycle in Induction Study Period and will be repeated every 
3 weeks from Cycle 1 through Cycle 6. Paclitaxel can be discontinued at Cycle 5 or 6 of 
Induction Study Period based on Section 5.4.1.2. 
Description for Calculation method 
For dose amount calculation, the body surface area (BSA) should be calculated using either 
Mosteller formula or Dubois formula (Dubois and Dubois 1916, Mostella 1987). 
• Mosteller formula: BSA (m2) = sqrt ([height (cm) x weight (kg)]/3600) 
• Dubois formula: BSA (m2) = 0.007184 x [Weight (kg)]0.425 x [height (cm)]0.725 
All patients should be pre-treated with corticosteroids, antihistamines, and H2 antagonists: 
• Dexamethasone 20 mg: via per oral approximately 12 and 6 hours before 
paclitaxel, or via IV 30 to 60 minutes prior to paclitaxel 
• Diphenhydramine (or its equivalent) 50 mg: via IV 30 to 60 minutes prior to 
paclitaxel 
• Cimetidine 300 mg or ranitidine 50 mg: via IV 30 to 60 minutes before paclitaxel. 
Paclitaxel should be administered only when the hematology and non-hematology toxicity 
criteria described in Section 5.4.1.2.1 are met. 
5.3.3 Carboplatin 
Carboplatin will be administered at a dose of AUC 6 approximately 30 minutes using a 
single infusion, per local practice guidelines.  


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Carboplatin will be diluted in 0.9% sodium chloride or 5% dextrose. Carboplatin will be 
administered after the dose of paclitaxel and before the dose of study drug (Day 1 of each 
cycle in Induction Study Period). Carboplatin will be repeated every 3 weeks from Cycle 1 
through Cycle 6. Carboplatin can be discontinued at Cycle 5 or 6 of Induction Study 
Period based on Section 5.4.1.2. 
Description for Calculation method 
The dose of carboplatin will be calculated based on Calvert equation (Calvert et al., 1989). 
• Maximum carboplatin dose (mg) = target AUC 6 (mg‧min/mL) x (125 mL/min + 
25) = 6 mg‧min/mL x 150 mL/min = 900 mg 
• Carboplatin dose (mg) = target AUC 6 (mg‧min/mL) x (GFR* + 25) 
*Glomerular filtration rate (GFR) estimated by calculated CrCl using Cockcroft-Gault Equation 
Further details about calculated CrCl formula for men and women are provided in 
Appendix 11.6. 
No premedication is required prior to administration of carboplatin.  
Carboplatin should be administered only when the hematology and non-hematology 
toxicity criteria described in Section 5.4.1.2.1 are met. 
 






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5.4.1.2 Paclitaxel and Carboplatin 
5.4.1.2.1 
Re-treatment Criteria for Carboplatin and Paclitaxel 
Minimum laboratory values allowed before administration for carboplatin and paclitaxel 
are as below: 
• Hematology toxicity 
o Absolute neutrophil count: ≥ 1,500/mm3 at the start of each cycle 
o Platelet count: ≥ 100,000/mm3 at the start of each cycle 
• Non-hematology toxicity 
o CrCl: ≥ 45 mL/min at the start of each cycle (see Appendix 11.6) 
o ≤ grade 2 at the start of each cycle (Dose modification for bevacizumab 
should be considered according to Section 5.4.1.1.) 
Administration of carboplatin and paclitaxel can be delayed at maximum up to 3 weeks 
from the planned schedule. If treatment is delayed more than 3 weeks, then patient will be 
discontinued. Uncoupling of study treatment is not allowed until at least 4 cycles of the 
Induction Study Period have been completed (see Section 5.3). 
5.4.1.2.2 
Dose Modification and Discontinuation of Carboplatin and 
Paclitaxel 
Based on the hematology (the lowest platelet and absolute neutrophil count) and the 
non-hematology toxicity from previous cycle, the dose will be modified for the subsequent 
cycle (Table 5-2, Table 5-3, and Table 5-4). 






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• Randomization code/kit number 
• Investigator’s name 
• Storage instructions 
• Caution statement (for study use only) 
• CELLTRION, Inc.’s contact name and address 
• Expiry date 
All study drug supplies must be stored in a secured area (e.g., a locked cabinet), protected 
from light. Both CT-P16 and EU-Approved Avastin must be kept at a controlled 
refrigerated temperature between 2°C and 8°C and it must not be frozen. The immediate 
containers must be kept in the outer carton until use in order to protect the study drug from 
light. The recommended storage conditions, and expiry date where required, are stated on 
the product label approved by each regulatory authority. 
5.6.2 Study Drug Accountability 
It is the responsibility of the clinical investigator to ensure that all study drug received at 
the study center will be inventoried and accounted for throughout the study and the result 
recorded in the drug accountability form maintained at the study center. The study drug 
accountability will be verified by the monitor during on-site monitoring visits and the 
tear-off label will be checked at each visit. Study drug will be stored in a limited-access 
area or in a locked cabinet under appropriate environmental conditions. 
The investigator agrees not to supply the study drug to any person other than 
subinvestigators and designated staff and agrees to administer the study drug to the patients 
participating in the study. 
The investigator will return or destroy all investigational product according to the 
pharmacy manual. The investigator will destroy empty or partially used vials as well as its 
cartons after reconstitution per site standard operating procedure, and keep tear-off labels 
for accountability. This authorization may also be granted to destroy used vials 
immediately after administering to patients. The list of destroyed vials must be recorded. 


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The investigator agrees to neither dispense the study drug from, nor store it at, any study 
center other than the study centers agreed upon with CELLTRION, Inc. 
5.7 Blinding 
This study will be double-blind (i.e., the study is blinded to both the patient and the 
investigator), during the Whole Study Period. The randomization codes will not be 
revealed to study patients, investigators, and study site personnel, except for delegated 
unblinded staff who will handle the study drug and pre-defined unblinded CELLTRION, 
Inc. and 
 until all final clinical data have been entered into the database and the 
database is locked and released for analysis. 
5.7.1 Breaking the Blind 
Under normal circumstances, the blind should not be broken. The blind should be broken 
only if specific emergency treatment would be dictated by knowing the study drug status of 
the patient. The investigator may, in an emergency, determine the identity of the study drug 
by using the applicable procedure in the IWRS or IVRS (see study manual). 
The date, time, and reason for the unblinding must be documented in the appropriate field 
of the eCRF and source documents. The medical monitor will be informed as soon as 
possible. All calls resulting in an unblinding event will be recorded and reported by the 
IWRS or IVRS to the medical monitor and the sponsor. Any patients for whom the blind is 
broken may continue in the study and receive the study treatment at the investigator’s 
discretion. 
pharmacovigilance (PVG) will have access to the randomization code, if suspected 
unexpected serious adverse reactions (SUSARs), which are subject to expedited reporting, 
should be unblinded before submission to the regulatory authorities. 
The data safety monitoring board (DSMB) and the statistical team who provide the safety 
analyses for the DSMB will also be unblinded in the upon request from DSMB members 
during closed session. 


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The overall randomization code will be broken only for reporting purposes (see 
Section 9.6). 
The unblinded team will be pre-defined before breaking the study blind. The study will 
remain blinded to the investigators, study site personnel except for delegated unblinded 
staff who will handle the study drug, patients, and pre-defined CELLTRION, Inc. and 
 
blinded teams until all patients have completed the study and the database has been 
finalized for study termination. 
5.8 Treatment Compliance 
Patient compliance will be determined based on drug accountability as well as source 
documents. 
5.9 Prior, Concomitant, and Subsequent Therapy 
All medications used during the study, as well as all medications taken within 30 days of 
Day 1 of Cycle 1 in the Induction Study Period and until 28 days after the last dose of 
study treatment will be collected. Concomitant medications relevant to serious adverse 
drug reactions (ADR) that occur after the EOT visit will also be collected. For patients who 
do not enter the Follow-Up Period, the last assessed concomitant medication will be 
collected. 
Concomitant medications include all prescription drugs, herbal products, vitamins, 
minerals, and over-the-counter medications. The minimum requirement is that the drug 
name, indication, and the dates of administration are to be recorded. Any changes in 
concomitant medications also will be recorded in the patient’s eCRF and source 
documents. 
Use of all medications and therapy for the treatment of nsNSCLC (e.g., surgery before 
enrollment or salvage treatment), from the diagnosis of disease until the last assessment 
date, will be recorded in the patient’s eCRF and source documents. All treatments of 
nsNSCLC include, but are not limited to, chemotherapy, immunotherapy, targeted therapy, 
hormonal cancer therapy, radiation therapy, surgery, or investigational agents. 
Any concomitant medication deemed necessary for the welfare of the patient during the 
study may be given at the discretion of the investigator. However, it is the responsibility of 


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the investigator to ensure that details regarding the medication are recorded in full in the 
eCRF and source documents. 
5.10 Prohibited Therapy 
The following medications, treatments, or procedures during the Induction Study Period 
and Maintenance Study Period are prohibited: 
• Anticoagulants or thrombolytic agent for therapeutic purpose (use of low dose 
aspirin [≤ 325mg/day] is allowed) 
• Immunosuppressive agents 
• Live or live attenuated vaccines 
• Any concurrent anti-neoplastic therapy (e.g., chemotherapy, immunotherapy, 
targeted therapy, hormonal cancer therapy, radiation therapy, surgery or 
investigational agents for treatment of NSCLC) 
• Any treatment for brain metastasis including whole brain radiotherapy, 
radiosurgery, or a combination of thereof. 
• Herbal medications that have not received regulatory approval 
• Patients with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications 
within 14 days of randomization are excluded. Inhaled or topical steroids, and 
adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are 
permitted in the absence of active autoimmune disease. 
Bevacizumab: 
• Caution should be exercised when administering bevacizumab concomitantly with 
medicines known to have drug interaction (e.g., zoledronic acid, risedronate, 
calcium carbonate/risedronate, alendronate, alendronate/cholecalciferol, 
pamidronate, ibandronate, etidronate, or tiludronate). 


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Paclitaxel: 
• Caution should be exercised when administering paclitaxel concomitantly with 
medicines known to inhibit (e.g., erythromycin, fluoxetine, gemfibrozil) or induce 
(e.g., rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine) 
either CYP2C8 or 3A4. 
Carboplatin: 
• Caution must be exercised when a patient receives aminoglycosides concomitantly. 
• Vancomycin, capreomycin, and diuretics are not recommended. 
• Phenytoin and fosphenytoin are not recommended. 
Concomitant medication use is permitted if indicated by the Investigator for treatment of 
an AE. 
5.11 Permitted Therapy 
The following medications, treatments, or procedures during the study period are 
permitted. 
Patients experiencing febrile neutropenia, especially with diarrhea or dyspnea, should be 
managed in a hospital setting according to standard procedures, with the urgent initiation 
of IV antibiotic therapy. Colony-stimulating factors (CSFs), erythropoiesis-stimulating 
agents (ESAs) or leucovorin can be used for treatment of an AE. However, routine use of 
CSFs, ESAs or leucovorin is not permitted. 
Regular concomitant use of bisphosphonates and receptor activator of nuclear factor 
kappa-B ligand (RANK-L) inhibitors for prevention or reduction of skeletal-related events 
in patients with bone metastases is allowed if initiated prior to the date the informed 
consent form (ICF) is signed. 


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6 Study Assessments and Procedures 
Before performing any study procedures, all potential patients and investigators will sign 
an ICF. Patients will have the opportunity to have any questions answered before signing 
the ICF. The investigator must address all questions raised by the patient. 
All patients will return to the study center at pre-defined time intervals for clinical 
assessments and blood samplings. Patients will undergo the procedures at the time points 
specified in the schedule of events (Table 11-1). 
Disease-related information will be recorded in patients’ eCRF (e.g., smoking history, 
TNM staging, pathological characteristics, etc.). 
6.1 Pathological Diagnosis for Eligibility 
The pathological diagnosis will be evaluated for confirmation of eligibility using a biopsy 
or cytology samples. (Table 11-1). Samples obtained before screening can be used. 
Predominant nsNSCLC should be confirmed by hematoxylin and eosin staining or 
immunohistochemistry before randomization. Gene screening for EGFR mutation and 
ALK rearrangement will be also confirmed before randomization. 
6.2 Efficacy Assessments 
Tumor responses will be measured and recorded by using RECIST v.1.1. The primary 
endpoint, ORR during the Induction Study Period, and the secondary endpoint, ORR 
during the Whole Study Period, will be determined by the best overall response (BOR). 
For CR or PR, BOR must be confirmed by the subsequent assessment based on the 
RECIST v.1.1 (Appendix 11.2). 
Efficacy assessments will be performed as per the time points specified in the schedule of 
events (Table 11-1). 
Tumor assessment will be assessed at Screening and every 2 cycles (end of Cycle 2, Cycle 
4, and Cycle 6) during the Induction Study Period and every 3 cycles (end of Cycle 3, 
Cycle 6, Cycle 9, Cycle 12…) during the Maintenance Study Period, and at the EOT visit. 
During the Follow-Up Period, it will be performed every 9 weeks until PD, death, 
withdrawal or start of new anti-cancer therapy if PD is not confirmed during the Induction 


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or Maintenance Study Periods. For screening, tumor assessment which is obtained within 4 
weeks prior to Day 1 of Cycle 1 can be used as screening data for patient’s convenience. 
These assessments should be performed within 7 days before Day 1 of the next cycle, 
except screening assessment.  
Unequivocal malignant disease not identified before starting study drug, identified on 
additional tumor assessment prompted by symptoms, is considered PD and should be 
recorded as new lesions. If PD is uncertain, patients may continue on treatment until the 
next scheduled assessment or may have an unscheduled assessment earlier than this if 
considered appropriate by the investigator. 
For a BOR of SD, measurements must have met the SD criteria at least once after start of 
study treatment for a minimum interval of 6 weeks (42 days or more after first 
administration of study drug). 
At Screening, spiral CT of the chest and abdomen will be performed with a slice thickness 
of ≤ 5 mm. Brain CT or magnetic resonance imaging (MRI) will be performed at 
Screening as mandatory and will continue to be performed during the study for patients 
with brain metastasis at baseline. Brain metastases detected by the first brain CT or MRI 
must be confirmed treated and clinically stable by the subsequent brain CT or MRI before 
starting study treatment. Bone scans will be performed at Screening. Intravenous contrasts 
should be used for CT scanning. 
Tumor lesions situated in a previously irradiated area are usually not considered 
measurable unless there has been demonstrated recurrence or progression in the lesion. 
Only lesions assessed at Screening will be followed up at subsequent visits. 
If disease progression/recurrence is confirmed by the investigator, the study treatment (or 
study drug) will be discontinued and the patients will directly enter the Follow-Up Period. 
During the Induction Study Period, Maintenance Study Period, and Follow-up Period, the 
same methods for target and non-target lesions should be used. In addition, during the 
study, any method will be performed for any suspected new lesions. 


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Lesion details must be recorded in the eCRF and source documents in the same order as 
they were recorded at the Screening visit. Details of any new lesions will also be collected 
and recorded in the eCRF and source documents. 
Response will be calculated in comparison to the baseline tumor measurements obtained 
before starting study treatment. Disease progression will be calculated in comparison to 
when the tumor burden is at a minimum. Overall response at each visit will be recorded in 
the eCRF and source documents. 
Categorization of overall response at each visit will be based on RECIST v.1.1 using the 
following response categories: CR, PR, SD, PD, and inevaluable (NE) (Appendix 11.2). 
In addition, all tumor assessment images will be evaluated centrally by an independent 
reviewer for reporting purposes for the Whole Study Period (Induction Study Period, 
Maintenance Study Period and Follow-Up Period). Further details regarding the 
independent reviewer will be described in a separate charter. 
Response results by the investigator will be used to determine the eligibility and treatment 
practice. Tumor response evaluation will be performed as per RECIST v.1.1 and anytime 
based on investigator’s decision. 
If an unscheduled tumor assessment is performed, and the patient’s disease has not 
progressed, the next scheduled tumor assessment will be re-calculated based on the date of 
last tumor assessment. However, it should be performed at the end of Cycle 6 of the 
Induction Study Period regardless of when the unscheduled tumor assessment is 
performed. 
Details of the efficacy endpoints and efficacy analysis are presented in Section 7.6.1 and 
Section 7.6.2. 
6.3 Pharmacokinetic Assessments 
Pharmacokinetic samples will be collected on Day 1 of each cycle (prior to the beginning 
of the study drug administration [-3 days as window are allowed]) in the Induction Study 
Period, on Day 1 (-3 days as window are allowed) of Cycle 1 and every 3 cycles (end of 
Cycle 3, Cycle 6, Cycle 9...) in the Maintenance Study Period, and EOT visit. In patients 
whose dose is delayed from the planned schedule, serum blood samples will be obtained 


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on Day 22 of the last cycle (-3 days as window are allowed) (Table 11-1). Pharmacokinetic 
samples will be analyzed at the central laboratory. 
If the blood sample is unable to be analyzed or is missing at Cycle 1, some blood samples 
collected for immunogenicity assessment at Cycle 1 can be used for PK assessment. 
Analysis will be performed at the central laboratory. 
Details of the PK endpoint and PK analysis are presented in Section 7.6.3. 
Actual sampling times for each patient will be recorded in the patient’s eCRF and 
individual source documents. Details for PK blood sampling are provided in Section 6.6.1. 
6.4 Quality of Life Assessments 
Quality of life will be assessed using the validated European Organization for Research 
and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ). The QLQ core 30 
(QLQ-C30) and QLQ lung cancer-specific module (QLQ-LC13) will be used (see 
Appendix 11.5). Patients will complete the questionnaires at Screening, and every 2 cycles 
(end of Cycle 2, Cycle 4, and Cycle 6) of the Induction Study Period, every 3 cycles (end 
of Cycle 3, Cycle 6, Cycle 9…) of the Maintenance Study Period, and EOT. These 
assessments should be performed within 7 days before Day 1 of the next cycle, except 
screening assessment (Table 11-1).  
6.5 Safety Assessments 
Safety assessments will be performed on immunogenicity, hypersensitivity monitoring (via 
vital sign and ECG), vital sign measurements (blood pressure, heart rates, respiratory rates 
and body temperature), weight, viral assessment, physical examination, clinical laboratory 
analyses, ECG, ECOG, AEs (including SAEs), adverse events of special interest (AESIs) 
(hypersensitivity/infusion-related reactions, gastrointestinal perforations and fistulae, 
wound healing complications, hypertension, posterior reversible encephalopathy syndrome 
[PRES], proteinuria, arterial thromboembolism [ATE], venous thromboembolism [VTE], 
hemorrhages, congestive heart failure [CHF] and ovarian failure/fertility), pregnancy 
testing, prior and concomitant medications throughout the study. Adverse events will be 
reported for term and grade according to the Common Terminology Criteria for Adverse 
Events (CTCAE) v.5.0 (Table 11-1). 


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6.5.1 Adverse Events 
6.5.1.1 Definitions of Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during 
the study, regardless of their relationship to study drug or their clinical significance. 
An AE is defined as any untoward medical occurrence in a patient entered in this study 
regardless of its causal relationship to study drug. Patients will be instructed to contact the 
investigator at any time after ICF was signed if any symptoms develop. Any new condition 
noted at Screening would be regarded as an AE, but not a treatment-emergent AE. 
A treatment-emergent AE is defined as any event not present before exposure to study drug 
or any event already present that worsens in either severity or frequency after exposure to 
study drug. This includes any occurrence that is new in onset or aggravated in severity or 
frequency from the baseline condition; abnormal results of diagnostic procedures including 
laboratory test abnormalities are considered AEs if they fulfill the following: 
• Result in discontinuation from the study 
• Require treatment or any other therapeutic intervention 
• Require further diagnostic evaluation (excluding a repetition of the same procedure 
to confirm the abnormality) 
• Are clinically significant as evaluated by the investigator 
Disease progression will not be used as an (S)AE(s) term. If disease progression is decided 
by the investigator, the patient will be discontinued from the study treatment and the 
disease progression will be reported in the appropriate eCRF and source documents. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should 
not be reported as AEs. However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an AE. For example, an acute 
appendicitis that begins during the AE reporting period should be reported as an AE and 
the resulting appendectomy should be recorded as treatment of the AE. 


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6.5.1.1.1 
Adverse Events of Special Interest 
The following AEs are considered AESIs, and will be reported using the same process for 
AEs: 
• Hypersensitivity/infusion-related reactions 
• Gastrointestinal perforations and fistulae 
• Wound healing complications 
• Hypertension 
• PRES 
• Proteinuria 
• ATE 
• VTE 
• Hemorrhages 
• CHF 
• Ovarian failure/fertility 
6.5.1.1.2 
Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death 
• Is immediately life threatening, that is, the patient is at risk of death at the time of 
the event. An event that hypothetically might have caused death if it were more 
severe will not be classified as an SAE. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 


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• Is a congenital anomaly/birth defect 
• Is important medical event that may not result in death, is life threatening, or 
requires hospitalization when, based upon appropriate medical judgment, it may 
jeopardize the patient or may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
Adverse events associated with hospitalization or prolongations of hospitalization are 
considered as SAEs. Any admission (even if less than 24 hours) to a healthcare facility 
meets these criteria. Admission also includes transfer within the hospital to an 
acute/intensive care unit (e.g., from the psychiatric wing to a medical floor, from medical 
floor to a coronary care unit, from neurological floor to a tuberculosis unit). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE. Examples include the following: 
• Admission for treatment of a pre-existing condition not associated with the 
development of a new AE or worsening of the pre-existing condition (e.g., for 
work-up of persistent pre-treatment laboratory abnormality, hospitalization solely 
due to progression of the underlying malignancy) 
• Social admission (e.g., patient has no place to sleep) 
• Purely for convenience (e.g., for easier performance of study assessments) 
• Administrative admission (e.g., for yearly physical examination) 
• Protocol-specified admission during a study (e.g., for a procedure required by the 
study protocol) 
• Optional admission not associated with a precipitating clinical AE (e.g., for elective 
cosmetic surgery) 
• Hospitalization for observation without a medical AE 


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• Pre-planned treatments or surgical procedures; these should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient 
After end of the study, serious ADRs will be reported to CELLTRION, Inc. or its designee. 
6.5.1.1.3 
Unlisted (Unexpected) Adverse Events 
An unlisted or unexpected AE is defined as an event of which the nature or severity is not 
consistent with the applicable product information (e.g., IB) for an unapproved 
investigational product or the label (e.g., package insert or summary of product 
characteristics/US product insert) for an approved product. 
6.5.1.2 Eliciting and Documenting Adverse Events 
Adverse events will be assessed from the date the ICF is signed until up to 28 days from 
last dose of study drug, regardless of the relationship to the study drug. Where an ADR 
(e.g., related to study drug) is ongoing at the EOT visit, the ADR will be followed until one 
of the following: resolution or improvement from baseline, relationship reassessed as 
unrelated, start of new anti-cancer therapy, confirmation from the investigator that no 
further improvement can be expected, end of collection of clinical or safety data, or final 
database closure. Serious ADRs occurring during the Follow-Up Period will be reported 
and followed up. For patients who do not enter the Follow-Up Period, the last assessed 
status of AEs will be collected. 
Adverse events of special interest will be closely monitored (Section 6.5.1.1.1). 
At every study visit, patients will be asked a standard non-leading question to elicit any 
medically related changes in their well-being. They will also be asked if they have been 
hospitalized, had any accidents, used any new medications, or changed concomitant 
medication regimens (both prescription and over the counter medications). 
In addition to patient observations, AEs identified from any study data (e.g., laboratory 
values, physical examination findings, ECG changes) or identified from review of other 
documents that are relevant to patient safety will be documented on the AE page in the 
eCRF and source documents. 


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6.5.1.3 Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page in the 
eCRF and source documents. Information to be collected includes drug treatment, dose, 
event term, time of onset, investigator-specified assessment of severity and relationship to 
study treatment, time of resolution of the event, seriousness, action taken with study 
treatment, any required treatment or evaluations, and outcome. 
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, 
reactions to concurrent medications, or progression of disease states must also be reported. 
All AEs will be followed to adequate resolution. The Medical Dictionary for Regulatory 
Activities (MedDRA) will be used to code all AEs. Adverse events will be graded for 
severity according to the CTCAE v.5.0. 
Any medical condition that is present at the time that the patient is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates at any time during 
the study, it should be recorded as an AE. 
The investigator’s assessment of an AE’s relationship to study treatment is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event will be 
reported. 
The severity and the relationship or association of the study treatment in causing or 
contributing to the AE will be characterized as defined in Section 6.5.1.6 and 
Section 6.5.1.7, respectively. 
6.5.1.4 Reporting Serious Adverse Events 
Any AE considered serious by the investigator or which meets SAE criteria 
(Section 6.5.1.1.2) must be reported to 
PVG within 24 hours from the time study 
center staff first learn about the event. The following contact information is to be used for 
SAE reporting: 
 
 
 


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Data entry should be completed in the eCRF and source documents by the investigator 
within 24 hours of awareness of an SAE. To complete the SAE report, the investigator 
should promptly verify and check the entered SAE in the eCRF and source documents. In 
the event, that this is not possible (e.g., system failure or access problems), the study center 
should complete an SAE report form and fax it to 
PVG within 24 hours of awareness 
of the event, as well as entering the SAE report into the eCRF when the system is 
available. If the patient is hospitalized during an SAE or because of an SAE, a copy of the 
hospital discharge summary will be faxed to 
 PVG as soon as it becomes available. 
Withdrawal from the study and all therapeutic measures will be at the discretion of the 
principal investigator or subinvestigator. All SAEs (regardless of relationship with the 
study treatment) will be followed up until satisfactory resolution or until the principal 
investigator or subinvestigator deems the event to be chronic or not clinically significant or 
the patient to be stable. 
CELLTRION, Inc. or its designee is responsible for reporting relevant SAEs to the 
competent authority, other applicable regulatory authorities, and participating investigators, 
in accordance with European Clinical Trials Directive (Directive 2001/20/EC), 
International Council for Harmonisation (ICH) guidelines, and/or local regulatory 
requirements. 
CELLTRION, Inc. or its designee is responsible for reporting unexpected fatal or 
life-threatening SUSARs (expedited reports) to the regulatory agencies and competent 
authorities by telephone or fax within 7 calendar days after being notified of the event. 
CELLTRION, Inc. or its designee should report other relevant SAEs associated with the 
use of the study drug to the appropriate competent authorities (according to local 
guidelines), investigators, and central ethics committees by a written safety report within 
15 calendar days of notification. 


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6.5.1.5 Suspected Unexpected Serious Adverse Reactions 
The sponsor will promptly evaluate all SUSARs against cumulative product experience to 
identify and expeditiously communicate possible new safety findings to investigators, 
IRBs/IECs, and applicable health authorities based on applicable legislation. 
To determine reporting requirements for single SAE cases, the sponsor will assess the 
expectedness of these events using the applicable reference documents (e.g., study drug 
IB). 
6.5.1.6 Assessment of Severity 
The severity of an AE refers to the extent to which an AE affects the patient’s daily 
activities. The severity of the AE will be graded based on the CTCAE v.5.0, based on the 
following general guidelines (a semicolon indicates “or” within each description): 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2: 
Moderate; minimal, local or non-invasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL)* 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL** 
Grade 4: 
Life-threatening consequences; urgent intervention indicated 
Grade 5: 
Death related to AE 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of severity to be performed. Adverse events 
characterized as intermittent do not require documentation of onset and duration of each 
episode. 


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6.5.1.7 Assessment of Causality 
As discussed in Section 6.5.1.3, the investigator’s assessment of an AE’s relationship to 
study treatment is part of the documentation process, but it is not a factor in determining 
what is or is not reported in the study. If there is any doubt as to whether a clinical 
observation is an AE, the event will be reported. 
The relationship or association between an AE and the study treatment will be assessed 
individually for each of the study treatments administered (e.g., for CT-P16 or 
EU-Approved Avastin, paclitaxel, and carboplatin) 
Unrelated: 
This relationship suggests that there is no association between the study 
treatment and the reported event. 
 
Possible: 
This relationship suggests that treatment with the study treatment caused or 
contributed to the AE, e.g., the event follows a reasonable temporal sequence 
from the time of drug administration or follows a known response pattern to the 
study treatment, but could also have been produced by other factors. 
 
Probable: 
This relationship suggests that a reasonable temporal sequence of the event 
with drug administration exists and, based upon the known pharmacological 
action of the drug, known or previously reported adverse reactions to the drug 
or class of drugs, or judgment based on the investigator’s clinical experience, 
the association of the event with the study treatment seems likely. The event 
disappears or decreases on cessation or reduction of the dose of study 
treatment. 
 
Definite: 
This relationship suggests that a definite causal relationship exists between drug 
administration and the AE, and other conditions (concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do 
not appear to explain the event. The event reappears or worsens if the study 
treatment is re-administered. 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of severity to be performed. If an AE upgrades in 
severity or changes from non-serious to serious, a new AE needs to be reported. If an AE 
downgrades in severity, it should not be reported as a new AE. Adverse events 
characterized as intermittent do not require documentation of onset and duration of each 
episode. 


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6.5.2 Other Safety Assessment 
6.5.2.1 Immunogenicity Testing 
Immunogenicity will be assessed on Day 1 of Cycle 1 (predose), every 2 cycles (end of 
Cycle 2, Cycle 4, and Cycle 6) during the Induction Study Period, every 3 cycles (end of 
Cycle 3, Cycle 6, and Cycle 9, Cycle 12…) during the Maintenance Study Period and EOT 
visit. A window of -3 days before Day 1 of the next cycle are allowed during Induction 
Study Period and Maintenance Study Period. In the Follow-Up period, immunogenicity 
will be assessed once at the first visit of Follow-Up Period (9th week). In patients whose 
dose is delayed from the planned schedule, serum blood samples will be obtained on Day 
22 of the last cycle (-3 days as window are allowed) (Table 11-1). 
If the blood sample is unable to be analyzed or is missing at Cycle 1, some blood samples 
collected for PK assessment at Cycle 1 can be used for immunogenicity assessment. 
Analysis will be performed at the central laboratory. 
6.5.2.2 Hypersensitivity/Infusion Related Reactions Monitoring 
Vital signs for hypersensitivity monitoring will be assessed before beginning the study 
drug infusion on Day 1 of each cycle (within 15 minutes before the beginning of the study 
drug infusion), at the end of study drug infusion (within 15 minutes after the end of the 
study drug infusion), and 60 minutes (±15 minutes) after the end of study drug infusion. In 
addition, ECGs (any type of lead) for hypersensitivity monitoring will be assessed at 
60 minutes (±15 minutes) after the end of study drug infusion (Table 11-1). 
In addition, hypersensitivity will be monitored by routine continuous clinical monitoring 
including patient-reported signs and symptoms. In case of hypersensitivity, emergency 
medication and equipment, such as adrenaline, antihistamines, corticosteroids, and 
respiratory support including inhalational therapy, oxygen, and artificial ventilation must 
be available and any types of ECG can be performed. 
For patients who experience or develop grade 3 or higher treatment-related 
hypersensitivity/infusion related reactions, study drug must be stopped immediately and 
the patient withdrawn from the study (Section 5.4.1.1). 
Details will be recorded in both the source documents and the eCRF. 


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6.5.2.3 Vital Signs, Weight, and Height 
Vital signs and weight measurements will be performed at the time points specified in the 
schedule of events (Table 11-1). Vital signs (including blood pressure, heart and respiratory 
rates, and temperature) will be assessed prior to study treatment administration and be 
measured after 5 minutes of rest (sitting). Height will be assessed at Screening only as a 
baseline measurement. Weight will be assessed on Day 1 of each Cycle for dose 
calculation. All other measurements will be documented at each study center visit. Details 
will be recorded in both the source documents and the eCRF. 
6.5.2.4 Electrocardiogram 
All scheduled 12-lead ECGs will be performed locally after the patient has rested quietly 
for at least 5 minutes in a supine position. A 12-lead ECG will be performed at the time 
points specified in the schedule of events (Table 11-1) and if the patient experienced 
cardiac symptoms during study drug administration. If following the ECG review by the 
investigator there are any ECG findings that would indicate cardiac insufficiency or QT 
prolongation, the patient will be referred to a cardiologist to confirm the abnormality. The 
investigator will then report the event in the source documents and the eCRF. Regardless 
of the 12-lead ECG result, further evaluation with a cardiologist can be done depending on 
the investigator’s discretion. 
In case of hypersensitivity, any type of ECG can be performed (Section 6.5.2.2). 
6.5.2.5 Physical Examination 
Physical examinations will be performed at the time points specified in the schedule of 
events (Table 11-1). 
Physical examinations will be performed before study treatment administration. 
Information about the physical examinations will be recorded by the investigator or 
designee in both the source documents and the eCRF. Any abnormalities will be recorded 
in the source documents. Clinically significant findings and illnesses reported after the start 
of the study that meet the definition of an AE will be recorded as such in the source 
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Maintenance Study Period and EOT visit, or at any time if pregnancy is suspected in 
females of childbearing potential only. (Table 11-1).  
If the urine pregnancy test gives equivocal results, a serum pregnancy test will be 
performed to exclude pregnant women in this study. For the Screening visit, only patients 
who have confirmed negative pregnancy test results will be included in this study. 
Pregnancy test samples will be analyzed at the local laboratory. 
In an event of unexpected pregnancy during study participation and for 6 months after the 
last dose of study drug, patients will be counselled to inform the investigator. If a female 
patient becomes pregnant, the study drug must be discontinued immediately. If a female 
patient or the partner of a male patient becomes pregnant, the pregnancy must be reported 
to CELLTRION, Inc. and 
Safety Department within 24 hours of the study center’s 
knowledge of the pregnancy while confirmation is pending. Once the pregnancy is 
confirmed with a serum pregnancy test, female patients must permanently discontinue the 
study drug and be withdrawn from the study. The study center must complete the supplied 
pregnancy form (female patient or partner of a male patient) and return it to CELLTRION, 
Inc. and 
Safety Department within 24 hours. 
Pregnant patients or the pregnant partners of male patients will be followed until the end of 
the pregnancy (e.g., delivery, stillbirth, miscarriage) and the mother and the baby will be 
followed for 1 year after the birth, provided consent is obtained. 
To prevent pregnancy, birth control methods should be used correctly and consistently 
from screening date to 6 months after the last study drug administration in patients and 
their partner of childbearing potential as below.  
1. Sexual abstinence or, 
2. Use of acceptable contraception 
Acceptable methods of contraception are: 
 Single method (one of following is acceptable): 
a. Intrauterine device 


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b. Vasectomy of a female patient’s male partner 
c. Contraceptive rod implanted into the skin 
 Combination method (use of two of the following is required): 
a. Diaphragm with spermicide (cannot be used in conjunction with 
cervical cap/spermicide) 
b. Cervical cap with spermicide (nulliparous women only) 
c. Contraceptive sponge (nulliparous women only) 
d. Male condom or female condom (cannot be used together) 
e. Hormonal contraceptive: oral contraceptive pill 
(estrogen/progestin pill or progestin –only pill), contraceptive skin 
patch, vaginal contraceptive ring, or subcutaneous contraceptive 
injection 
6.5.2.9 Clinical Laboratory Analyses 
Blood and urine samples for clinical laboratory assessments will be collected at the time 
points specified in the schedule of events (Table 11-1). Blood samples do not need to be 
performed in a fasting state unless required in the opinion of the investigator. 
Clinical laboratory tests for Cycle 1 of the Induction Study Period will be performed 
within 14 days prior to Day 1 of Cycle 1 of the Induction Study Period. Thereafter, clinical 
laboratory tests will be performed within 3 days prior to Day 1 of each cycle. 
 
 


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The following clinical laboratory analyses will be performed: 
Clinical chemistry 
albumin, alkaline phosphatase, alanine aminotransferase, aspartate 
aminotransferase, blood urea nitrogen, calcium, chloride, creatine 
phosphokinase, creatine kinase-myocardial band isoenzyme, total 
cholesterol, creatinine, CrCl (estimated by weight and by 
Cockcroft-Gault formula), gamma-glutamyl transferase, glucose, 
lactate dehydrogenase, triglyceride, high-density lipoprotein 
cholesterol, phosphate, potassium, sodium, total bilirubin, direct 
bilirubin, total protein, uric acid 
Hematology 
hematocrit, hemoglobin, white blood cell count, absolute 
neutrophil count and platelets 
Urinalysis 
• bilirubin, blood, glucose, ketones, leukocytes (white blood 
cells), nitrite, pH, protein, specific gravity, urobilinogen 
and microscopic examination 
• 24 hour urine collection if indicated at Screening 
Coagulation 
Any patients who continue with low dose aspirin (≤ 325 mg/day) 
or any patients who have stopped regular use of aspirin (> 325 
mg/day) should perform prothrombin time and prothrombin time 
international normalized ratio tests. 
• Screening 
• Day 1 of Cycle 1 and Cycle 2 of Induction Study Period 
and when clinically indicated 
Clinical laboratory test samples will be analyzed at the local laboratory. 
6.6 Sample Collections 
The total volume of blood collected for each assessment is discussed in each specific 
laboratory manual. The sample collection tube may be changed during the study and 
details will be provided in the laboratory manual. 
6.6.1 Pharmacokinetic Blood Sampling 
Blood samples for PK assessments collected into serum sample tubes will be obtained 
before study drug administration at the time points specified in the schedule of events 


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(Table 11-1). All samples should be collected at the scheduled time point and the actual 
sampling date and time will be recorded in both the source documents and the eCRF. 
Samples should be stored and shipped as detailed in Section 6.7.2. 
6.6.2 Immunogenicity Blood Sampling 
Blood samples for immunogenicity assessments will be obtained before study drug 
administration at the time points specified in the schedule of events (Table 11-1). All 
samples should be collected at the scheduled time point and the actual sampling date and 
time should be recorded in both the source documents and the eCRF. 
Samples should be stored and shipped as detailed in Section 6.7.2. 
6.6.3 Routine Safety Blood Sampling 
Blood samples for routine safety (clinical laboratory testing) will be collected for analysis 
throughout the study at the time points specified in the schedule of events (Table 11-1). 
6.7 Labelling, Storage, and Transportation of Samples 
6.7.1 Sample Labelling 
Each sample tube will be clearly labelled with the following information: study number, 
patient number, tube identification, and scheduled sampling time point. 
6.7.2 Sample Storage and Shipment 
Samples for PK and immunogenicity will be transferred to and analyzed in the central 
laboratories. 
Where appropriate, the serum should be transferred into a sufficient number of transfer 
vials for transport to assigned testing facilities. Primary and back-up samples will be 
shipped to the central laboratory according to the laboratory manual, and primary samples 
should be shipped separately from the back-up samples. 
Additionally, back-up samples for PK and immunogenicity should be retained at the 
central laboratory as a backup for up to 5 years after the end of the study in case additional 
analysis is required. If additional analysis for PK, and/or immunogenicity is not required, 


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the sample will be stored at CELLTRION, Inc. or a designated biobank for a further 
5 years (from the date the sample is transferred to the biobank) unless a specific 
authorization is given by CELLTRION, Inc. to destroy the sample. Additional tests can be 
conducted at CELLTRION, Inc. or the biobank if it is required from a regulatory or 
medical perspective. Details in storage and shipment will be followed according to the 
laboratory manual. 


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7 Statistical Analysis Plan 
7.1 
Primary Endpoint 
The primary efficacy endpoint will be the ORR based on BOR during the Induction Study 
Period by RECIST v.1.1 (Appendix 11.2). 
7.2 
Secondary Endpoints 
7.2.1 Efficacy Endpoints 
The secondary efficacy endpoints will be the following: 
• ORR based on BOR during the Whole Study Period by RECIST v.1.1 
(Appendix 11.2) 
• Response duration: the time between initial response (CR or PR) and 
PD/recurrence 
• TTP: the time from randomization until PD/recurrence 
• PFS: the time from randomization until PD/recurrence or death due to any cause, 
whichever occurs first 
• OS: the time from randomization until death due to any cause 
7.2.2 Pharmacokinetic Endpoints 
The secondary PK endpoint is trough serum concentration. 
7.2.3 Quality of Life Analyses 
• QLQ-C30 and QLQ-LC13, using EORTC QLQ 
7.2.4 Safety Endpoints 
The secondary safety endpoints will be the following: 
• Incidence and severity of AEs, including SAEs graded according to the NCI 
CTCAE v.5.0. 


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• Incidence and severity of AESIs graded according to the NCI CTCAE v.5.0. 
• Immunogenicity, as assessed by the incidence of antidrug antibody and neutralized 
antidrug antibody. 
• Vital sign measurements 
• ECG 
• Physical examination findings 
• ECOG 
• Pregnancy testing 
• Clinical laboratory analyses 
• Previous and concomitant medications 
7.3 
Sample Size Calculations 
 
 A sample size of 305 patients per group will provide 80% power to 
show similarity in efficacy between CT-P16 and EU-Approved Avastin based on the 
expected ORR of 38% with an equivalence margin of -12.5 to 12.5 using a 95% CI (two 
one-sided alpha 0.025) of the difference in ORR. 
Approximately 678 patients (339 in each group) will need to be enrolled for the anticipated 
drop-out rate of 10%. 
7.4 
Analysis Sets 
The following analysis sets will be used in the statistical analyses. 
Intent-to-treat (ITT) Population: The ITT population is defined as all patients randomly 
assigned to study drug, regardless of whether or not any study treatment dosing is 
completed. Patients will be assigned to treatment groups based on randomization. 


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Per-Protocol (PP) Population: The PP population is defined as all randomly assigned 
patients who have at least one response evaluation after receiving at least one full dose of 
study drug (CT-P16 or EU-Approved Avastin) in the Induction Study Period and who do 
not have any major protocol deviation. A major protocol deviation is one that may affect 
the interpretation of the primary endpoint and it will be defined in the statistical analysis 
plan (SAP). Final determinations of the PP population will be made at the blinded data 
review meeting before unblinding. Patients will be assigned to treatment groups based on 
randomization. 
PK Population: The PK population is defined as all patients who receive at least one full 
dose of study drug (CT-P16 or EU-Approved Avastin) and who have at least one post 
treatment PK result. If any patients are found to be non-compliant with respect to dosing, a 
decision will be made on a case-by-case basis at the blinded data review meeting before 
unblinding. Patients will be assigned to treatment groups based on treatment actually 
received. 
Safety Population: The safety population is defined as all randomly assigned patients who 
receive at least one dose (full or partial) of study drug (CT-P16 or EU-Approved Avastin). 
Patients will be assigned to treatment groups based on treatment actually received. 
7.5 
Description of Subgroups to be Analyzed 
Subgroup analysis could be implemented to reflect medical, regulatory, regional, or ethnic 
considerations. 
7.6 
Statistical Analysis Methodology 
 
 Continuous variables will be summarized using 
the descriptive statistics (the number of observations (n), mean, standard deviation, 
median, minimum value, and maximum value). Categorical variables will be summarized 
using frequency counts and percentages. Data will be listed. 
Details of the statistical analyses, methods, and data conventions are described in the SAP 
which will be finalized before locking of the database. Changes from analyses planned in 


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this protocol will be documented in the SAP. Any deviations from the planned analysis as 
described in the SAP will be justified and recorded in the study report. 
7.6.1 
Analysis of Primary Efficacy Endpoint 
The similarity criterion has been set such that the confidence limits of the 95% CI of the 
difference in ORR will be entirely bounded by the interval (-12.5, 12.5). The primary 
analysis for the primary endpoint will be performed utilizing a logistic regression model 
considering covariates with treatment groups (CT-P16 and EU-Approved Avastin) as a 
fixed effect in the ITT and PP population. For primary analysis, central review result will 
be used. Local review result will be used as supportive data (sensitivity analysis). The 
resulting odds ratio and 95% CI will be converted into difference of proportions using the 
Delta method for the purpose of comparison. Covariates will be described in SAP. 
Categorization of BOR will use the following response categories: CR, PR, SD, PD, and 
NE (see Appendix 11.2). For CR or PR, BOR must be confirmed by the subsequent 
assessment based on the RECIST v.1.1. For a BOR of SD, measurements must have met 
the SD criteria at least once after start of study treatment for a minimum interval of 6 
weeks (42 days or more after first administration of study drug). 
Objective response rate will be calculated as the number of patients with a response of CR 
or PR divided by the number of patients in the corresponding population. Both locally 
reviewed ORR and centrally reviewed ORR will be shown per treatment group and 
overall, including a descriptive analysis. 
7.6.2 
Analysis of Secondary Efficacy Endpoints 
The secondary endpoint, both locally reviewed ORR and centrally reviewed ORR during 
the Whole Study Period, will be summarized using proportion and its corresponding 95% 
CI for each treatment group in the ITT and PP population. 
A time-to-event analysis will be undertaken for each of the response duration, TTP, PFS, 
and OS in the ITT and PP population; the median time and its corresponding 95% CI for 
each treatment group for each secondary endpoint of time-to-event analysis will be 
estimated using the Kaplan-Meier method. 


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Response duration is defined as time from initial response (CR or PR) to determined 
disease progression/or recurrence. 
Time to Progression is defined as time from randomization to determined disease 
progression/or recurrence. 
Progression-free survival is defined as time from randomization to determined disease 
recurrence, progression or death from any cause (whichever occurs first). 
For response duration, TTP, and PFS, if a patient has no event, it will be calculated 
censoring at the date of last adequate radiological assessment, without disease 
progression/or recurrence. If a patient receives another new anticancer therapy, it will be 
censored at the date of adequate radiological assessment, without disease progression/or 
recurrence, before starting another anticancer therapy. Any patient without any tumor 
assessment during the study will be censored at the date of randomization. 
If disease progression or death is documented after missing one tumor assessment, the PFS 
time of these patients will be calculated assuming the event occurred on the date of 
progression (or death). If disease progression or death is documented after missing two or 
more tumor assessments, the patient will be censored for PFS at the date of their last 
adequate tumor assessment, without disease progression/or recurrence. 
Overall survival is defined as time from randomization to death from any cause; for 
patients whose status is unknown, data will be censored at the time when the patient is last 
known to be alive. 
7.6.3 
Pharmacokinetic Analyses 
The Ctrough (prior to next dose) at each cycle during the Induction Study Period, and Ctrough 
during the Maintenance Study Period will be analyzed. Serum concentrations will be 
summarized using descriptive statistics (including geometric mean and coefficient of 
variation [CV], as appropriate) by treatment, and study visit. Pharmacokinetic parameters 
will also be summarized using descriptive statistics (including geometric mean and CV, as 
appropriate) by treatment and study visit. All analyses will be performed based on the PK 
population. 


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7.6.4 
Quality of Life Analyses 
Descriptive analysis will be performed on actual score and change from baseline at each 
visit by treatment group in the ITT population. 
7.6.5 
Safety Analyses 
Adverse events will be coded to system organ class (SOC) and preferred term (PT) using 
MedDRA and graded for severity according to the CTCAE v.5.0. Prior and concomitant 
medication will be coded to drug class and PT using the World Health Organization 
(WHO) drug dictionary. 
All safety data including immunogenicity will be listed and summarized by treatment 
group in the safety population. 
7.6.6 
Other Analyses 
Demographics (age, gender, weight, height, race, ethnicity, weight loss, smoking history 
and lymphovascular invasion), disease-related information and medical history will be 
presented by means of summary tables (descriptive statistics for quantitative variables, or 
frequencies for qualitative variables). 
7.6.7 
Interim Analyses 
No interim analyses are planned for this study. 
7.7 Data Quality Assurance 
This study will be conducted according to the ICH E6 (R2) risk and quality processes 
described in the applicable procedural documents. The quality management approach to be 
implemented in this study will be documented and will comply with the current ICH Good 
Clinical Practice (GCP) guidelines on quality and risk management. 
Steps to be taken to ensure the accuracy and reliability of data include the selection of 
qualified investigators and appropriate study centers, review of protocol procedures with 
the investigator and associated staff before the study, periodic monitoring visits by 
CELLTRION, Inc. or its designee, and direct transmission of clinical laboratory data from 
a central laboratory into the clinical database. The eCRFs will be reviewed for accuracy 


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and completeness by the monitor during on-site monitoring visits and after their return to 
CELLTRION, Inc. or its designee; any discrepancies will be resolved with the investigator 
or designees, as appropriate. The data will be entered into the clinical study database and 
verified for accuracy. 
Quality assurance staff from CELLTRION, Inc. or its designee may visit the study center 
to carry out an audit of the study in compliance with regulatory guidelines and company 
policy. Such audits will require access to all study records, including source documents, for 
inspection and comparison with the eCRF. Patient privacy must, however, be respected. 
Sufficient prior notice will be provided to allow the investigator to prepare properly for the 
audit. 
Similar auditing procedures may also be conducted by agents of any regulatory body 
reviewing the results of this study in support of a licensing application. The investigator 
should immediately notify CELLTRION, Inc. or its designee if he or she has been 
contacted by a regulatory agency concerning an upcoming inspection. 


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8 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of 
the study but may be subject to change based on industry and government standard 
operating procedures, working practice documents, or guidelines. Changes will be reported 
to the IRB/IEC but will not result in protocol amendments. 
8.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in 
a manner designed to maintain patient confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the 
written permission of the patient (or the patient’s legal guardian), except as necessary for 
monitoring and auditing by the sponsor, its designee, the regulatory authorities, or the 
IRB/IEC. 
The investigator, all employees, and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study, any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
8.2 Independent Ethics Committee or Institutional Review Board 
Regulations and the ICH guidelines require that approval be obtained from an IRB/IEC 
before participation of human subjects in research studies. Before study onset, the protocol, 
informed consent, advertisements to be used for the recruitment of study patients, and any 
other written information regarding this study to be provided to the patient or the patient’s 
legal guardian must be approved by the IRB/IEC. Documentation of all IRB/IEC approvals 
and of the IRB/IEC compliance with ICH harmonized tripartite guideline E6 (R2): GCP 
will be maintained by the study center and will be available for review by the sponsor or its 
designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favorable opinion was granted. 


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The investigator is responsible for providing written summaries of the progress and status 
of the study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The 
investigator must promptly supply the sponsor or its designee, the IRB/IEC, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to patients. 
8.3 Patient Information and Consent 
A written informed consent in compliance with the ICH E6 (R2) guidelines shall be 
obtained from each patient before entering the study or performing any unusual or 
non-routine procedure that involves risk to the patient. An informed consent template may 
be provided by the sponsor to the study centers. If any institution-specific modifications to 
study-related procedures are proposed or made by the study center, the consent should be 
reviewed by the sponsor or its designee or both before IRB/IEC submission. Once 
reviewed, the consent will be submitted by the investigator to his or her IRB/IEC for 
review and approval before the start of the study. If the ICF is revised during the course of 
the study, all active participating patients must sign the revised form. 
Before recruitment and enrollment, each prospective patient or his or her legal guardian 
will be given a full explanation of the study and be allowed to read the approved ICF. Once 
the investigator is assured that the patient/legal guardian understands the implications of 
participating in the study, the patient/legal guardian will be asked to give consent to 
participate in the study by signing the ICF. 
In addition to the standard requirements that physicians are currently obliged to observe 
when providing information, the following points must also be covered: 
• A description of the objectives of the study and how it will be organized 
• The type of treatment 
• Any potential negative effects attributable to the study drug 
• The freedom to ask for further information at any time 
• The patient’s right to withdraw from the clinical study at any time without giving 
reasons and without jeopardizing the patient’s further course of medical treatment 


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• The existence of patient insurance coverage and a summary of what is included in 
this coverage 
• Adequate time and opportunity to satisfy questions. 
The investigator will be supplied with an adequate number of ICFs to be used. The forms 
will be signed and dated by both the investigator or subinvestigator and the patient’s legal 
representatives (according to the local regulations) before the beginning of the study. The 
investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the patient or legal guardian. 
To ensure medical confidentiality and data protection, the signed ICFs will be stored in the 
investigator’s study file. The investigator will allow inspection of the forms by authorized 
representatives of the sponsor, IRB/IEC members, and regulatory authorities. The 
investigator will confirm, by signing and dating the eCRFs, that informed consent has been 
obtained. 
8.4 Study Reporting Requirements 
By participating in this study, the principal investigator or subinvestigator agrees to submit 
reports of SAEs according to the timeline and method outlined in Section 6.5.1.4. In 
addition, the principal investigator or subinvestigator agrees to submit annual reports to his 
or her IRB/IEC as appropriate. 
8.5 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the sponsor 
to submit the complete and accurate certification or disclosure statements per regional 
requirements. In addition, the investigator must provide to the sponsor a commitment to 
promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither the sponsor nor its designee is financially responsible for further testing or 
treatment of any medical condition that may be detected during the Screening process. In 
addition, in the absence of specific arrangements, neither the sponsor nor its designee is 
financially responsible for further treatment of the patient’s disease. 


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8.6 Investigator Documentation 
Before beginning the study, the investigator will be asked to comply with ICH E6 (R2) 8.2 
and Title 21 of the Code of Federal Regulation (CFR) by providing the following essential 
documents, including but not limited to: 
• IRB/IEC approval 
• Original investigator-signed investigator agreement page of the protocol 
• Form FDA 1572 or corresponding form, fully executed, and all updates on a new 
fully executed Form FDA 1572 or corresponding form 
• Curriculum vitae for the principal investigator and each subinvestigator listed on 
Form FDA 1572 or corresponding form. Current licensure must be noted on the 
curriculum vitae. The curriculum vitae will be signed and dated by the principal 
investigators and subinvestigators at study start-up, indicating that they are accurate 
and current. 
• Financial disclosure information to allow the sponsor to submit complete and 
accurate certification or disclosure statements required under 21 CFR 54. In 
addition, the investigators must provide to the sponsor a commitment to promptly 
update this information if any relevant changes occur during the course of the 
investigation and for 1 year after the completion of the study. 
• IRB/IEC-approved informed consent, samples of study center advertisements for 
recruitment for this study, and any other written information regarding this study 
that is to be provided to the patient or legal guardian, and 
• Laboratory certifications and normal ranges for any local laboratories used by the 
study center, in accordance with 42 CFR 493 
8.7 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of 
ICH E6 (R2). The investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations. The analytical assays will be conducted 
according to the general principles of the Organization for Economic Cooperation and 


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Development Principles of Good Laboratory Practice for testing of chemicals 
C(81)30(Final). 
8.8 Data Collection 
8.8.1 Electronic Case Report Forms and Source Documents 
It is the intent of this study to acquire study data via electronic format. As part of the 
responsibilities assumed by participating in the study, the principal investigator or 
subinvestigator agrees to maintain adequate case histories for the patients treated as part of 
the research under this protocol. The principal investigator or subinvestigator agrees to 
maintain source documentation (e.g., laboratory reports), enter patient data into the eCRF 
as accurately as possible, and respond to any reported discrepancies rapidly. These source 
documents may include diaries, laboratory reports, ECG strips, etc. 
The analysis data sets will be a combination of these data and data from other sources (e.g., 
laboratory data). 
The eCRFs are accessed through the appropriate system, which allows for on-site data 
entry and data management. Study center users can read from and write to the sponsor’s 
database where the clinical data are collected. This provides immediate, direct data transfer 
to the database, as well as immediate detection of discrepancies, enabling study center 
coordinators to resolve and manage discrepancies in a timely manner. 
Each study center staff involved with the study at each study center will have an individual 
logon account and password that allow for record traceability. Thus, the system, and 
subsequently any investigative reviews, can identify coordinators, investigators, and 
individuals who have entered or modified records. 
8.9 Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6 (R2) and all applicable guidelines and regulations. 


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8.10 Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB/IEC with a summary of the 
study’s outcome and the sponsor and regulatory authority(ies) with any reports required. 
8.11 Records Retention 
All correspondence (e.g., with sponsor, IRB/IEC, or Clinical Research Associates) relating 
to this clinical study will be kept in appropriate file folders. Records of patients, source 
documents, eCRFs, and drug inventory sheets pertaining to the study must be kept on file. 
Essential documents should be retained until at least 15 years after the date on which the 
results of the study are submitted to the regulatory authorities in support of an allocation 
for a research or marketing permit, or completion date for study by approval or disapproval 
of any application, whichever is later. 
These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained. 
If an investigator moves, withdraws from an investigation, or retires, the responsibility for 
maintaining the records may be transferred to another person, who will accept the 
responsibility. Notice of transfer must be made to and agreed upon by the sponsor. 
8.12 Patient Identification Register 
The investigator agrees to complete a patient identification register, which will be used for 
the purpose of long-term follow-up, if needed. This form will be treated as confidential and 
will be filed by the investigator in the Study Center Master File. Otherwise, all reports and 
communications relating to the study will identify patients by assigned number only. 
8.13 Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the sponsor will be 
responsible for these activities and will work with the investigators to determine how the 


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manuscript is written and edited, the number and order of authors, the publication to which 
it will be submitted, and other related issues. The sponsor has final approval authority over 
all such issues. 
Data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. 


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9 Study Management 
9.1 Sponsor 
CELLTRION, Inc. 
23 Academy-ro, Yeonsu-gu 
Incheon, 22014, Republic of Korea 
Phone:  
+82 32 850 5000 
Fax: 
 
+82 32 850 5050 
E-mail: 
contact@celltrion.com 
Sponsor Representative 
 
 
  
 
 
 
 
 
 
9.2 Vendor Contact 
 
 
 
 
 
SAE Reporting 
 
 
 
 
 
 
 
  
 
 


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The names and addresses of the investigators and clinical study centers involved in the 
study are presented separately together with the investigators’ signatures. 
9.3 Monitoring 
9.3.1 Data Safety Monitoring Board 
This study will be monitored by an independent DSMB consisting of a PK specialist, 
statistician, chairing physician, and an independent physician. The DSMB will review and 
evaluate accumulating safety data to ensure the safety of study patients. 
Further details will be provided in the independent DSMB charter. 
9.3.2 Independent Tumor Review Committee 
An independent tumor review committee will be used to review the tumor response for the 
purposes of data analysis and reporting (see Section 6.2). Full details will be provided in a 
separate charter. 
9.3.3 Monitoring of the Study 
The clinical monitor, as a representative of the sponsor, has the obligation to follow the 
study closely. In doing so, the monitor will visit the investigator and study center at 
periodic intervals, in addition to maintaining necessary telephone and letter contact. The 
monitor will maintain current personal knowledge of the study through observation, review 
of study records and source documentation, and discussion of the conduct of the study with 
the investigator and staff. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current ICH E6 (R2) 
and current standard operating procedures. 
9.3.4 Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB/IEC review, and regulatory inspections by providing direct access to all study 
records. In the event of an audit, the investigator agrees to allow the sponsor, 
representatives of the sponsor, or a regulatory agency access to all study records. 


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The investigator should promptly notify the sponsor and 
of any audits scheduled by 
any regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 
9.4 Management of Protocol Amendments and Deviations 
9.4.1 Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the patient, must be reviewed and approved by the sponsor or its 
designee. Amendments to the protocol must be submitted in writing to the investigator’s 
IRB/IEC for approval before patients can be entered into an amended protocol. This will 
be fully documented. 
The investigator must not implement any deviation from or change to the protocol without 
discussion and agreement from CELLTRION, Inc. or its designee, and prior review, 
documented approval, and favorable opinion of the amendment from the relevant IRB/IEC 
and/or regulatory authorities, except where it is necessary to eliminate an immediate 
hazard to patients or where the changes involve only logistical or administrative aspects of 
the clinical study. The eCRF and source documents will describe any departure from the 
protocol and the circumstances requiring it. 
Protocol amendments will be submitted to the appropriate authorities as required by the 
applicable regulatory requirements. 
9.4.2 Protocol Deviations 
The investigator or designee must document and explain in the patient’s source 
documentation any deviation from the approved protocol. The investigator may implement 
a deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
patients without prior IRB/IEC approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol 
amendments should be submitted to the IRB/IEC for review and approval, to the sponsor 
for agreement, and to the regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB/IEC and agreed to by the 


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investigator. A significant deviation occurs when there is non-adherence to the protocol by 
the patient or investigator that results in a significant, additional risk to the patient. 
Significant deviations can include non-adherence to inclusion or exclusion criteria, or 
non-adherence to regulatory regulations or ICH GCP guidelines, and will lead to the 
patient being withdrawn from the study (Section 4.2). 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. Deviations will be defined before unblinding. Principal investigators will 
be notified in writing by the monitor of deviations. The IRB/IEC should be notified of all 
protocol deviations in a timely manner. 
9.5 Study Termination 
Although CELLTRION, Inc. has every intention of completing the study, CELLTRION, 
Inc. reserves the right to discontinue the study at any time for clinical or administrative 
reasons. 
The end of the study is defined as the date of final database lock. 
9.6 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study reports (CSRs) are prepared and provided to the regulatory agency(ies) as 
required by the applicable regulatory requirement(s). The sponsor will also ensure that the 
CSRs in marketing applications meet the standards of the ICH harmonized tripartite 
guideline E3: Structure and content of CSRs. 
The sponsor plans to prepare 3 CSRs to report the following: 
• To report data after completion of the Induction Study Period 
• To report data up to 1-year completion of the last patient 
• To report all data until the end of study. 
If additional CSRs are required for regulatory or academic purposes, CSRs will be 
generated after the first database lock and unblinding process. 


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10 Reference List 
American Cancer Society. Cancer Facts & Figures 2018. Atlanta: American Cancer 
Society. 2018. 
Avastin USPI (Genentech, Inc.). 2018. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125085s324lbl.pdf 
Barzi A and Pennell NA. Targeting Angiogenesis in Non-Small Cell Lung Cancer: Agents 
in Practice and Clinical Development. EJCMO 2010. 2(1):31-42. 
Botrel TE et al. Efficacy of Bevacizumab (Bev) Plus Chemotherapy (CT) Compared to CT 
Alone in Previously Untreated Locally Advanced or Metastatic Non-Small Cell Lung 
Cancer (NSCLC): Systematic Review and Meta-Analysis. 2011. 74(1):89-97. 
Calvert AH et al. Carboplatin Dosage: Prospective Evaluation of a Simple Formula Based 
on Renal Function. J Clin Oncol. 1989. 7:1748-1756. 
Cockcroft DW and Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976. 16(1):31-41. 
Dubois D and Dubois EF. A Formula to Estimate the Approximate Surface Area If Height 
and Weight Be Known. Archives of Internal Medicine. 1916. 17:863-871. 
European Medicines Agency. Guideline on Similar Biological Medicinal Products 
Containing Monoclonal Antibodies – Non-Clinical and Clinical Issues. Committee for 
Medicinal Products for Human Use (CHMP). EMA/CHMP/BMWP/403543/2010. 2012. 
Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/W
C500128686.pdf 
European Parliament and Council. Directive 2001/20/EC of the European Parliament and 
of the Council of 4 April 2001 on the Approximation of the Laws, Regulations and 
Administrative Provisions of the Member States Relating to the Implementation of Good 
Clinical Practice in the Conduct of Clinical Trials on Medicinal Products for Human Use. 
DIRECTIVE 2001/20/EC. 2001. Available from: 


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https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
1/dir_2001_20/dir_2001_20_en.pdf 
Food and Drug Administration (FDA). Center for Drug Evaluation and Research (US). 
Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics. FDA. 2007. Available from: 
https://www.fda.gov/downloads/Drugs/Guidances/ucm071590.pdf 
Food and Drug Administration (FDA). Center for Drug Evaluation and Research (US). 
Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a 
Reference Product. FDA. 2015. Available from: 
https://www.fda.gov/downloads/drugs/guidances/ucm291128.pdf 
GLOBOCAN 2012. Available from: http://globocan.iarc.fr/old/FactSheets/cancers/lung-
new.asp. Accessed 2018. 
He K et al. Statistical Considerations in Evaluating a Biosimilar Product in an Oncology 
Clinical Study. Clinical Cancer Research. 2016. 22(21):5167-5170. 
Lim WH et al. Lean Body Mass-Adjusted Cockcroft and Gault Formula Improves the 
Estimation of Glomerular Filtration Rate in Subjects with Normal-Range Serum 
Creatinine. Nephrology (Carlton). 2006. 11(3):250-6. 
Mostella RD. Simplified Calculation of Body Surface Area. New England Journal of 
Medicine. 1987. 317:1098. 
National Comprehensive Cancer Network. Non-Small Cell Lung Cancer (Version 4. 2018). 
Available from: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.  
Oken et al. Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. 
American Journal of Clinical Oncology. 1982. 5(6):649-656. 
Reck M et al. Phase III Trial of Cisplatin Plus Gemcitabine with either Placebo or 
Bevacizumab as First-Line Therapy for Non-Squamous Non-Small Cell Lung Cancer: 
AVAiL. J Clin Oncol. 2009. 27:1227-1234. 


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Sandler A et al. Paclitaxel-Carboplatin Alone or with Bevacizumab for Non-Small-Cell 
Lung Cancer. N Engl J Med. 2006. 355:2542-2550. 
Siegel RL et al. Cancer Statistics, 2018. CA CANCER J CLIN. 2018. 68:7-30. 
SmPC Avastin®. Summary of Product Characteristics, Annex I. London: EMEA (European 
Medicines Agency). 2018. Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000582/WC500029271.pdf  
SmPC MVASI®. Summary of Product Characteristics. EMEA (European Medicines 
Agency). 2019. Available from: https://www.ema.europa.eu/en/documents/product-
information/mvasi-epar-product-information_en.pdf  
World Health Organization. Guidelines on Evaluation of Similar Biotherapeutic Products 
(SBPs). WHO. 2009. Available from: 
http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR
_WEB_22APRIL2010.pdf?ua 
Zhang et al. Discovering and identifying New York heart association classification from 
electronic health records. BMC medical informatics and decision making. 2018. 18(2):48. 


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11 Appendices 
11.1 Appendix: Schedule of Events 






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normalized ratio) test will be performed at Screening, Day 1 of Cycle 1 and Cycle 2 of Induction Study Period and when clinically indicated for the patient who has 
been administered aspirin. Clinical laboratory test samples will be analyzed at the local laboratory.  
9. 
Urine pregnancy test should be performed at the Screening visit (within 3 days before Day 1 of Cycle 1), within 3 days before Day 1 of Cycle 1 of the Maintenance 
Study Period and EOT visit, or at any time if pregnancy is suspected in females of childbearing potential only. If the urine pregnancy test gives equivocal results, a 
serum pregnancy test will be performed to exclude pregnant women in this study. For the Screening visit, only patients who have confirmed negative pregnancy test 
results will be included in this study. Pregnancy test samples will be analyzed at the local laboratory. 
10. 12-lead ECG at the Screening visit will be performed within 14 days prior to Day 1 of Cycle 1 of the Induction Study Period. For all other cycles, 12-lead ECG will 
be performed within 3 days prior to Day 1 of each cycle. 
11. These assessments should be performed prior to study treatment administration. 
12. Vital signs (including blood pressure, heart and respiratory rates, and temperature) will be assessed prior to study drug administration and be measured after 5 
minutes of rest (sitting). Height will be assessed at Screening only as a baseline measurement. 
13. Paclitaxel and carboplatin will be administered on Day 1 of each cycle in Induction Study Period. 
14. Pharmacokinetic samples will be collected on Day 1 of each cycle (prior to the beginning of the study drug administration [-3 days as window are allowed]) in the 
Induction Study Period, on Day 1 (-3 days as window are allowed) of Cycle 1 and every 3 cycles (end of Cycle 3, Cycle 6, and Cycle 9...) in the Maintenance Study 
Period, and EOT visit. In patients whose dose is delayed from the planned schedule, serum blood samples will be obtained on Day 22 of the last cycle (-3 days as 
window are allowed). Pharmacokinetic samples will be analyzed at the central laboratory. 
15. Tumor evaluation will be assessed at Screening and every 2 cycles during the Induction Study Period and every 3 cycles during the Maintenance Study Period, and 
at the EOT visit. During the Follow-Up Period, it will be performed every 9 weeks until PD, death, withdrawal or start of new anti-cancer therapy if PD is not 
confirmed during the Induction or Maintenance Study Periods. 
16. Tumor assessment will be performed within 4 weeks before the start of study treatment.  
17. Brain CT or MRI will be assessed at Screening as mandatory to assess brain metastasis. During the study, imaging will be performed for patients with brain 
metastasis at baseline or for any suspected new lesions. 
18. Bone scans will be assessed at Screening as mandatory. During the study, scans will be performed for patients with bone metastasis at baseline or for any suspected 
new lesions. 
19. Immunogenicity will be assessed on Day 1 of Cycle 1 (predose), every 2 cycles during the Induction Study Period, every 3 cycles during the Maintenance Study 
Period and EOT visit. In the Follow-Up period, immunogenicity will be assessed once at the first visit of Follow-Up Period (9th week). A window of -3 days before 
Day 1 of the next cycle are allowed. In patients whose dose is delayed from the planned schedule, serum blood samples will be obtained on Day 22 of the last cycle 
(-3 days as window are allowed). 
20. Quality of life should be assessed within 7 days before Day 1 of the next cycle, except screening assessment. 
21. All medications used during the study, as well as all medications taken within 30 days of Day 1 of Cycle 1 in the Induction Study Period and until 28 days after the 
last dose of study treatment. Concomitant medications relevant to serious adverse drug reactions (ADR) occurred after the EOT visit will also be collected. For 
patients who do not enter the Follow-Up Period, the last assessed concomitant medications will be collected. 
22. Adverse events will be assessed from the date the informed consent form is signed until up to 28 days from last dose of study drug, regardless of the relationship to 
the study drug. Where an ADR is ongoing at the EOT visit, the ADR will be followed until one of the following: resolution or improvement from baseline, 
relationship reassessed as unrelated, start of new anti-cancer therapy, confirmation from the investigator that no further improvement can be expected, end of 
collection of clinical or safety data, or final database closure. For patients who do not enter the Follow-Up Period, the last assessed status of AEs will be collected. 


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23. Serious ADRs occurring during the Follow-Up Period will be reported and followed up. 


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11.2 Response Evaluation Criteria In Solid Tumors Version 1.1 
As defined in Eisenhauera et al., 2009; available at 
https://ctep.cancer.gov/protocoldevelopment/docs/recist_guideline.pdf 
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Key Guideline 
[Definition of “Measurable” and “Non-Measurable” Lesions] 
1. Measurable 
•  Tumor lesions: Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of 
10 mm by spiral CT scan (CT scan slice thickness no greater than 5 mm) 
•  Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed by spiral 
CT scan (CT scan slice thickness no greater than 5 mm) 
2. Non-measurable  
All other lesions, including small lesions (longest diameter < 10 mm with spiral CT 
scan for non-nodal lesion or the short axis length of pathological lymph node is with 
10 ≤ - < 15 mm) as well as truly non-measurable lesions including ascites, pleural or 
pericardial effusion, lymphangitic involvement of skin or lung, etc.) 
 
[Definition of “Target” and “Non-Target” Lesions] 
1. Target lesion 
Lesion should be selected based on the largest in size and ease of measurement. 
Maximum of total 5 target lesions can be selected to represent the overall involved 
organs and maximum of 2 within one organ site. 
2. Non-target lesion  
Any lesions or sites of disease not identified as target lesions. 
3. New lesion 


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A new lesion is the appearance of any tumor independent of size clearly visible at the 
same anatomic location in a follow-up scan that was not present in the baseline tumor 
assessment. 
[Definitions of Response] 
Summary of RECIST v.1.1 Response Definitions for Target Lesions 
Complete Response 
(CR) 
Disappearance of all target lesions. 
Any pathological lymph nodes (whether target or non-target) 
must have reduction in short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
Progressive Disease 
(PD) 
At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (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. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum diameters while on study. 
Inevaluable (NE) 
Progression has not been documented and one or more target 
lesions have not been assessed or have been assessed using a 
different method than baseline that makes comparability 
impossible. 
Summary of RECIST v.1.1 Response Definitions for Non-Target Lesions 
CR 
Disappearance of all non-target lesions. All lymph nodes must 
be non-pathological in size (< 10 mm short axis).  
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s)  
PD 
Unequivocal progression of existing non-target lesions  
NE 
Progression has not been documented and one or more non-
target lesions have not been assessed or have been assessed 
using a different method than baseline that makes 
comparability impossible.  
* The appearance of one or more new lesions, which are not present in the baseline tumor assessment is 
considered progression  
 
















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11.5 Quality of Life Questionnaire 
11.5.1 EORTC QLQ-C30 
 


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11.5.2 EORTC QLQ - LC13 
 


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11.6 Creatinine Clearance Calculation Formula 
Note: This formula is to be used for calculating creatinine clearance (CrCl) from local 
laboratory results only. 
Original, Weight-Based Cockcroft and Gault Formula for Calculated Creatinine 
(Clearance for Men) 
 
 
CrCl = 
(mL/min) 
For serum creatinine concentration in mg/dL: 
 
 
(140-agea) x (wtb) x 1.0 
 
72 x serum creatinine (mg/dL) 
 
  
 
 CrCl = 
(mL/min) 
For serum creatinine concentration in µmol/L: 
 
 
(140-agea) x (wtb) x 1.0 
 
0.81 x serum creatinine (µmol/L) 
 
 
Original, Weight-Based Cockcroft and Gault Formula for Calculated Creatinine 
(Clearance for Women) 
 
 
 CrCl = 
(mL/min) 
For serum creatinine concentration in mg/dL: 
 
 
(140-agea) x (wtb) x 0.85 
 
72 x serum creatinine (mg/dL) 
 
  
 
 CrCl = 
(mL/min) 
For serum creatinine concentration in µmol/L: 
 
 
(140-agea) x (wtb) x 0.85 
 
0.81 x serum creatinine (µmol/L) 
 
a Age in years.  
b Weight (wt) in kilograms. 
Source: Cockcroft and Gault 1976, Lim et al., 2006. 
 
 



SAP_001.pdf: 
CELLTRION, Inc. 
 
Statistical Analysis Plan – Version 3.0 Final 
CT-P16 3.1 
Date Issued: December 15, 2023 
 
 
 
I 
Confidential 
 
 
CELLTRION Inc. 
CT-P16 3.1 
 
A Double-Blind, Randomized, Active-Controlled, Parallel-Group, Phase 3 Study to 
Compare Efficacy and Safety of CT-P16 and EU-Approved Avastin as First-Line 
Treatment for Metastatic or Recurrent Non-Squamous Non-Small Cell Lung 
Cancer 
 
 
 
Statistical Analysis Plan 
Version 3.0 Final 
December 15, 2023 
 
 
 
Prepared by: 
 
CELLTRION, Inc. 
20F, IBS Building, 263, Central-ro, Yeonsu-gu, Incheon 
22006 
Republic of Korea 
 
 
Prepared by: 
____________________________      Date: ____/____/____ 
 
 
  
 
 
 
 
 
 
 
 
____________________________      Date: ____/____/____ 
 
 
 
 
 
 
 
 
 
 
Upon review of this document, including table, listing and figure shells, the undersigned 
approves the final statistical analysis plan. The analysis methods and data presentation 
are acceptable, and the table, listing and figure production can begin. 
 
 
Approved by: 
____________________________      Date: ____/____/____ 
 
 
  
 
 
 
 
 
 


CELLTRION, Inc. 
 
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TABLE OF CONTENTS 
1. INTRODUCTION......................................................................................................... 6 
1.1. Data Cut-off for Analysis ......................................................................................... 6 
2. STUDY OBJECTIVES ................................................................................................. 7 
2.1. Primary Objective .................................................................................................... 7 
2.2. Secondary Objective ................................................................................................ 7 
3. OVERALL STUDY DESIGN AND PLAN ................................................................ 7 
4. GENERAL STATISTICAL CONSIDERATIONS ................................................... 9 
4.1. Software ................................................................................................................. 10 
4.2. Sample Size ............................................................................................................ 10 
4.3. Randomization, Stratification, and Blinding .......................................................... 10 
4.4. Population of Analysis ........................................................................................... 11 
4.4.1. Intent-to-Treat Population ............................................................................... 11 
4.4.2. Per-Protocol Population .................................................................................. 11 
4.4.3. Pharmacokinetic Population ............................................................................ 11 
4.4.4. Pharmacokinetic Population – Maintenance Period Subset ............................ 12 
4.4.5. Safety Population ............................................................................................ 12 
4.5. Definition of Baseline and Post-Baseline .............................................................. 12 
4.6. Protocol Deviations ................................................................................................ 12 
4.7. General Comments ................................................................................................. 13 
4.8. Outliers ................................................................................................................... 13 
4.9. Missing Values ....................................................................................................... 13 
5. PATIENT DISPOSITION ......................................................................................... 13 
6. DEMOGRAPHICS, BASELINE, AND BACKGROUND CHARACTERISTICS
 
14 
6.1. Demographics and Stratification Details ............................................................... 14 
6.2. Gene Screening ...................................................................................................... 15 
6.3. Hepatitis B and C and Human Immunodeficiency Virus 1 and 2 .......................... 15 
6.4. Medical History...................................................................................................... 16 
6.5. Disease Characteristic ............................................................................................ 16 
6.6. Previous Treatment for NSCLC ............................................................................. 16 
6.7. Inclusion and Exclusion Criteria ............................................................................ 16 
7. MEDICATIONS AND TREATMENTS ................................................................... 16 
7.1. Prior and Concomitant Medications ...................................................................... 16 
7.2. Exposure to Study Drug ......................................................................................... 18 
8. EFFICACY ANALYSIS ............................................................................................. 19 
8.1. Primary Efficacy Endpoint..................................................................................... 19 
8.2. Secondary Efficacy Endpoint................................................................................. 21 
8.2.1. Objective Response Rate during the Whole Study Period .............................. 21 
8.2.2. Time-To-Event Analysis ................................................................................. 21 
8.2.2.1. Response Duration ..................................................................................... 22 


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8.2.2.2. Time to Progression ................................................................................... 23 
8.2.2.3. Progression-free Survival........................................................................... 23 
8.2.2.4. Overall Survival ......................................................................................... 24 
8.2.2.5. Capture logic for event or censoring with incomplete date of new 
anticancer therapy ................................................................................................... 24 
8.3. Salvage Treatment.................................................................................................. 26 
8.4. Effusion Drainage .................................................................................................. 26 
9. PHARMACOKINETIC ANALYSIS ........................................................................ 26 
9.1. Serum Concentration.............................................................................................. 26 
9.2. Pharmacokinetic Parameter .................................................................................... 26 
10. SAFETY ANALYSIS ............................................................................................... 27 
10.1. Adverse Events .................................................................................................... 27 
10.1.1. Treatment-Emergent Adverse Events ........................................................... 28 
10.1.2. Serious Adverse Events ................................................................................. 29 
10.1.3. Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation ......................................................................................................... 29 
10.1.4. Treatment-Emergent Adverse Event Leading to Deaths ............................... 29 
10.1.5. Treatment-Emergent Adverse Events of Special Interest ............................. 29 
10.2. Clinical Laboratory Evaluations .......................................................................... 30 
10.3. Vital Signs, Weight and Body Surface Area........................................................ 32 
10.4. Electrocardiograms .............................................................................................. 32 
10.5. Hypersensitivity Monitoring ................................................................................ 32 
10.6. Physical Examination ........................................................................................... 33 
10.7. Pregnancy Test ..................................................................................................... 33 
10.8. ECOG Performance Status................................................................................... 33 
10.9. Immunogenicity ................................................................................................... 34 
11. QUALITY OF LIFE ANALYSES ........................................................................... 35 
12. CHANGES FROM PROTOCOL ............................................................................ 36 
13. REFERENCE LIST .................................................................................................. 36 
14. APPENDICES ........................................................................................................... 38 
14.1. Schedule of Events ............................................................................................... 38 
14.2. Table of CTCAE Terms and Grades .................................................................... 41 
14.3. TEAE of Special Interest ..................................................................................... 45 
14.4. Date Imputation.................................................................................................... 52 
14.4.1. Medication ..................................................................................................... 52 
14.4.2. Adverse Events .............................................................................................. 53 
14.4.3. Death ............................................................................................................. 53 
14.5. Best Overall Response Confirmation ................................................................... 54 
 
 
 


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List of Abbreviations 
Abbreviation Definition 
ADA 
Anti-Drug Antibody 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
ATE 
Arterial Thromboembolism 
BOR 
Best Overall Response 
BP 
Blood Pressure 
BSA 
Body Surface Area 
CHF 
Congestive Heart Failure 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CPK 
Creatine Phosphokinase 
CR 
Complete Response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Trough Serum Concentration 
CV 
Coefficient of Variation 
DRM 
Data Review Meeting 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EORTC QLQ European Organization for Research and Treatment of Cancer Qualify 
of Life Questionnaire  
EOT 
End of Treatment 
GCP 
Good Clinical Practice 
HBcAb 
Hepatitis B Core Antibody  
HBsAb 
Hepatitis B Surface Antibody 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B virus  
HIV 
Human Immunodeficiency Virus 
IRR 
Infusion-Related Reaction  
ITT 
Intent-to-Treat 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
LLN 
Lower Limit of Normal 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MNAR 
Missing Not at Random 
N/A 
Not Applicable 
NAb 
Neutralizing Antibody 
NE 
Inevaluable 
NSCLC 
Non-Small Cell Lung Cancer 


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nsNSCLC 
Non-Squamous Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
PR 
Partial Response 
PRES 
Posterior Reversible Encephalopathy Syndrome 
PT 
Preferred Term 
QLQ-C30 
Quality of Life core 30 
QLQ-LC13 
Quality of Life lung cancer-specific module 
QoL 
Quality of Life 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RS 
Raw Score 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
 
 
SD 
Stable Disease 
SMQ 
Standardised MedDRA Queries 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event  
TLF 
Table, Listing and Figure 
TTP 
Time To Progression 
ULN 
Upper Limit of Normal 
VTE 
Venous Thromboembolism 
WHO 
World Health Organization  
 


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1. INTRODUCTION 
This statistical analysis plan (SAP) defines the statistical methods and data presentations 
to be used by CELLTRION Clinical Statistics team in the analysis and presentation of data 
from CELLTRION study number CT-P16 3.1, entitled: A Double-Blind, Randomized, 
Active-Controlled, Parallel-Group, Phase 3 Study to Compare Efficacy and Safety of CT-
P16 and EU-Approved Avastin as First-Line Treatment for Metastatic or Recurrent Non-
Squamous Non-Small Cell Lung Cancer. 
There are three clinical study reports (CSRs) planned: 
• 
To report data after completion of the Induction Study Period (1st CSR) 
• 
To report data up to 1-year completion of the last patient (2nd CSR) 
• 
To report all data until the end of study (3rd CSR) 
This SAP covers data analysis for the final CSR (3rd CSR). The protocol-specified primary 
analysis was completed and reported in the 1st CSR, published on September 13, 2021. 
This SAP for the final CSR is based on the following documents: 
• 
Study Protocol Version 2.0 – 14th June 2019 
• 
Unique Case Report Form (CRF) Version 7.0 – 21 July 2021 
Table, Listing and Figure (TLF) mock shells will be presented as an addendum to this 
document. 
1.1. Data Cut-off for Analysis 
The 1st CSR will contain the data as below: 
- 
Tumor assessment and effusion data obtained up to end of Maintenance Cycle 3 
date prior to cut-off date (22APR2021). For early discontinued patients withdrawn 
prior to end of Maintenance Cycle 3, data obtained up to the End of Treatment 
(EOT). 
- 
European Organization for Research and Treatment of Cancer Qualify of Life 
Questionnaire (EORTC-QLQ) and PK data obtained up to end of Induction Cycle 
6. For early discontinued patients withdrawn prior to Maintenance Study Period, 
data obtained up to the EOT. 
- 
Other (safety, immunogenicity and etc.) data and non-visit based data (e.g 
‘Adverse Event’ or ‘Concomitant Medication’) obtained up to cut-off date 
(22APR2021). 
The 2nd CSR will contain the data as below: 


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- 
Visit based data: All data included in a visit of which the visit date is on or prior 
to cut-off date (21SEP2021) which was 1-year completion of the last patient. 
- 
Non-visit based data: All data up to cut-off date (21SEP2021). 
The final CSR will contain all data obtained up to the end of study. 
2. STUDY OBJECTIVES 
2.1. Primary Objective 
The primary objective of the study is: 
• 
To demonstrate CT-P16 is similar to EU-Approved Avastin in terms of efficacy 
as determined by objective response rate (ORR) during the Induction Study Period 
2.2. Secondary Objective 
The secondary objectives of the study are: 
• 
To evaluate additional efficacy profiles including ORR during the Whole Study 
Period, response duration, time to progression (TTP), progression-free survival 
(PFS), and overall survival (OS) 
• 
To evaluate the Pharmacokinetic (PK) parameter of trough serum concentration 
(Ctrough) 
• 
To evaluate safety profile including immunogenicity 
• 
To evaluate quality of life (QoL) 
3. OVERALL STUDY DESIGN AND PLAN 
This study is a double-blind, randomized, active-controlled, parallel-group, Phase 3 study 
to compare efficacy, PK, and overall safety of CT-P16 (15 mg/kg) and EU-Approved 
Avastin (15 mg/kg) when co-administered with paclitaxel and carboplatin in patients with 
metastatic or recurrent non-squamous non-small cell lung cancer (nsNSCLC) as first-line 
treatment. 
A total of 678 male and female patients with metastatic or recurrent nsNSCLC will be 
enrolled and randomly assigned in a 1:1 ratio (approximately 339 patients per treatment 
group) to CT-P16 or EU-Approved Avastin. 
This study will comprise 4 study periods (including Screening Period, Induction Study 
Period, Maintenance Study Period and Follow-Up Period) and be completed at 
approximately 3 years from the enrollment of last patient. 
An EOT visit will occur 3 weeks after the last dose of the Induction Study Period or 
Maintenance Study Period regardless of the reason of discontinuation. 


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Screening Period 
Screening evaluations will be completed within 28 days prior to randomization. However, 
screening period can be extended to 8 weeks exclusively for treating patients who have 
central nervous system (CNS) metastases before starting the study treatment and all other 
assessments including chest and abdomen computerized tomography (CT) scan should be 
completed as specified in Appendix 14.1. Approximately 678 patients will be randomly 
assigned in a 1:1 ratio to CT-P16 or EU-Approved Avastin treatment groups. 
Induction Study Period 
During the Induction Study Period, patients will receive 15 mg/kg intravenous (IV) of 
either CT-P16 or EU-Approved Avastin every 3 weeks up to 6 cycles. Patients will receive 
paclitaxel 200 mg/m2 IV and carboplatin area under the curve 6 IV every 3 weeks up to 
6 cycles (at least 4 cycles). Study drug administration will be started on the same day as 
randomization. If a patient has progressive disease (PD) during or after the completion of 
the Induction Study Period (assessed at the end of Cycle 6) or does not enter the 
Maintenance Study Period due to any reason, this patient will complete the EOT visit, then 
will directly enter the Follow-Up Period. 
Maintenance Study Period 
After the completion of 6 cycles during the Induction Study Period, patients with 
controlled disease (complete response [CR], partial response [PR], or stable disease [SD], 
assessed at the end of Cycle 6) will enter the Maintenance Study Period. Patients will 
receive monotherapy of 15 mg/kg of CT-P16 or EU-Approved Avastin every 3 weeks until 
PD or intolerable toxicity, whichever occurs first. Then, the patients will perform the EOT 
visit and then will enter the Follow-Up Period. 
Follow-Up Period 
All patients who enter the Follow-Up Period due to any reason will be followed every 
9 weeks until death or the end of study, whichever occurs first. If PD is not confirmed 
during the Induction Study Period or Maintenance Study Period, tumor response 
evaluation will be performed every 9 weeks during the Follow-Up Period. 


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The study design and patient assessment overview is presented in Figure 1. 
Figure 1 Study Design Overview 
Abbreviations: ECOG, Eastern Cooperative Oncology Group; IV, intravenous; PD, progressive disease. 
4. GENERAL STATISTICAL CONSIDERATIONS 
Continuous data will be summarized using descriptive statistics: the number of 
observations (n), mean, standard deviation, minimum, median and maximum unless 
otherwise indicated. Minimum and maximum will be presented to the same number of 
decimal places as the raw data, mean and median will be presented to one more decimal 
place than the raw data, and standard deviation will be presented to two more decimal 
places than the raw data. If the geometric mean is to be presented, it will be set to the same 
precision as the mean. Percent coefficient of variation (CV) will be presented to two more 
decimal places than the raw data.  
Categorical data will be summarized using numbers and percentages of patients. 
Percentages will be presented to one decimal place and will be suppressed when the count 
is zero. A row denoted “Not Done” will be included in count tabulations where necessary 
to account for cases of no assessment or missing values. The denominator for all 
percentages will be the number of patients within the treatment group for the population 
of interest, unless otherwise indicated. 
EOT and unscheduled visit will not be summarized in visit-based tables, unless otherwise 
indicated. But, all data will be displayed in listings. Listings will be sorted by the treatment 
group and then patient number, which is the unique subject identifier and visit, if 
applicable. In cases where more additional sorting is required, other variables will be 
included in sorting as applicable. 
For the purpose of summarization, any numeric values recorded below the lower limit or 
above the upper limit of quantification will be set to the respective limit for all related 


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summaries unless otherwise indicated. In listings, original results containing inequality 
sign will be displayed, unless otherwise specified.  
When combining data from eCRF and analytical facilities 
 
 discrepancy will be handled as following: 
1) Recorded as collected sample in eCRF but no corresponding results from 
analytical facility – listing will display only sample collection visit/date/time from 
eCRF. 
2) No corresponding records in eCRF for results from analytical facility – listing 
will display only specimen collection visit/date and results from analytical facility. 
3) Discrepancy in sample collection date from eCRF and analytical facility – 
listing will display results from analytical facility and visit/date/time from eCRF 
if not missing; if sample collection date/time is missing in eCRF then use 
specimen collection visit/date from analytical facility. 
4.1. Software 
 
 
  
4.2. Sample Size 
 
 A sample size of 305 patients per group will provide 80% power to 
show similarity in efficacy between CT-P16 and EU-Approved Avastin based on the 
expected ORR of 38% with an equivalence margin of -12.5 to 12.5 using a 95% CI (two 
one-sided alpha 0.025) of the difference in ORR. 
Approximately 678 patients (339 in each group) will need to be enrolled for the anticipated 
drop-out rate of 10%. 
4.3. Randomization, Stratification, and Blinding 
An Interactive Web Response System (IWRS) will be used for the randomization and an 
unblinded statistician will generate a computer-generated randomization schedule for 
IWRS, which will link sequential patient randomization numbers to treatment codes.  
Patients who qualify for randomization will be randomly assigned on Day 1 of Cycle 1 in 
the Induction Study Period in a 1:1 ratio to receive CT-P16 or EU-Approved Avastin. The 
randomization will be balanced by using permuted blocks and will be stratified by country, 
sex (female vs. male), disease status (recurrence vs. metastatic), Eastern Cooperative 
Oncology Group (ECOG) performance status (0 vs. 1). 


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This study will be double-blinded during both the Induction Study Period and the 
Maintenance Study Period. The randomization code will not be revealed to study patients, 
investigators, or study site personnel, until all final clinical data have been entered onto 
the database and the database is locked and released for analysis. 
The database will be unblinded for the 1st CSR for a reporting purpose. However, the study 
will remain blinded to the investigators and patients until study termination. 
4.4. Population of Analysis 
Population to be used in analysis will be specified in related sections. The following patient 
populations are defined: Intent-to-Treat (ITT) population, Per-Protocol (PP) population, 
PK population, PK population – Maintenance Period Subset and Safety population.  
The number of patients in each population will be tabulated by treatment group for the ITT 
population. A listing will also be provided displaying this data. 
4.4.1. Intent-to-Treat Population 
The ITT population will consist of all randomized patients who are randomly assigned to 
study drug regardless of whether or not any study treatment dosing is completed and 
successfully screened based on the ‘Screening Pass/Fail’ eCRF page. Patients will be 
assigned to treatment groups based on randomization. The primary population for the 
primary efficacy analysis will be the ITT population. 
4.4.2. Per-Protocol Population 
The PP population will consist of all randomly assigned patients who have at least one 
response evaluation after receiving at least one full dose of study drug (CT-P16 or EU-
Approved Avastin) in the Induction Study Period and who do not have any major protocol 
deviations that may affect the interpretation of the primary endpoint. A patient will be 
considered as receiving full dose if the planned dose is recorded as ‘15mg/kg’ and the 
action taken is recorded as ‘Dose Not Changed’ on ‘Study Treatment Administration’ 
eCRF page. Final determination of the PP population was made at the Data Review 
Meeting (DRM) before unblinding. Patients will be assigned to treatment groups based on 
randomization. A supportive efficacy analysis will be repeated using the PP population.  
4.4.3. Pharmacokinetic Population 
The PK population will consist of all randomly assigned patients who receive at least one 
full dose (as defined in Section 4.4.2) of study drug (CT-P16 or EU-Approved Avastin) 
and who have at least one post treatment PK result. Patients who received incorrect 
treatment during the Induction Study Period will be excluded from the PK population. If 
a patient does not receive full dose, the patient will be discussed during the DRM to 
confirm whether the patient can be considered as receiving full dose or not. Patients will 
be assigned to treatment groups based on treatment they actually received during the 
Induction Study Period.  


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4.4.4. Pharmacokinetic Population – Maintenance Period Subset 
The PK population – Maintenance Period Subset will consist of all patients in PK 
population who received at least 1 dose (full) of either of the study drugs and have at least 
one post treatment PK result during the Maintenance Study Period. Patients who received 
incorrect treatment during the Maintenance Study Period will be excluded from the PK 
population – Maintenance Period Subset. If a patient does not receive full dose, the patient 
will be discussed during the DRM to confirm whether the patient can be considered as 
receiving full dose or not. Patients will be assigned to treatment groups based on treatment 
they actually received. 
4.4.5. Safety Population 
The safety population will consist of all randomly assigned patients who receive at least 
one dose (partial or full) of study drug (CT-P16 or EU-Approved Avastin). A patient will 
be considered to have received study drug if the patient is recorded as having study drug 
administered on the ‘Study Treatment Administration’ eCRF page. Patients will be 
assigned to treatment groups based on treatment they actually received. 
Treatment patients actually received will be based on the kit number recorded on the 
‘Study Treatment Administration’ eCRF page. Patients receiving at least one dose of CT-
P16 will be analyzed under the CT-P16 treatment group. All other patients will be analyzed 
under the EU-Approved Avastin treatment group. 
4.5. Definition of Baseline and Post-Baseline 
The baseline value for all analyses will be the last non-missing value prior to the first 
infusion unless otherwise specified. Post-baseline visits will be considered to be all visits 
after the first infusion. 
4.6. Protocol Deviations 
A major protocol deviation is one that may affect the interpretation of primary endpoint or 
the patient’s rights, safety or welfare. A major protocol deviation occurs when there is 
non-adherence to the protocol by the patient, investigator, or sub-investigator that results 
in a significant and additional risk to the patient or to the integrity of the study data. Major 
protocol deviations include the following: 
• 
Mis-randomizations (defined as patients who received the opposite treatment to 
which they were assigned) 
• 
Non-compliance of Inclusion or Exclusion criteria  
• 
Significant Good Clinical Practice (GCP) non-compliance (to be identified by 
 as sites which have been closed due to scientific misconduct and/or serious 
GCP non-compliance) 
• 
Receiving any prohibited therapies (Section 5.10 of protocol) 


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• 
Missing primary efficacy assessment 
Major protocol deviations will be identified during the DRM. Patients with major protocol 
deviation could be excluded from PP population to minimize the potential impact of the 
deviations. The major protocol deviations will be summarized by treatment group for the 
ITT population and will also be presented in a listing. 
Additionally, if any case of major protocol deviation related to COVID-19 is identified 
during the DRM, primary analysis will be performed excluding patients with major 
protocol deviation related to COVID-19 in ITT population as supportive analysis and the 
patients will be flagged in listing. 
4.7. General Comments 
Data collected on the ‘General Comments’ eCRF page will be presented in a listing for the 
ITT population.  
4.8. Outliers 
Any outliers that are detected during the review of the data will be investigated and 
discussed during the DRM. In general, outliers will not be excluded unless they are 
considered to be erroneous values. Sensitivity analyses and exploratory analyses may be 
conducted using imputation or excluding outliers to ensure robustness of study conclusions.  
4.9. Missing Values 
Missing values in ORR will be considered as ‘Non-responder’ to analyze primary efficacy 
endpoint. 
In order to evaluate the impact of missing data on the primary efficacy endpoint results, 
additional analyses with tipping point analyses will be conducted for the primary efficacy 
endpoint (central review data) for ITT population. 
Tipping point analyses will be conducted under Missing Not at Random (MNAR) 
scenarios. Imputation will be done by gradually shifting the number of responders by 
treatment group to make MNAR scenarios. 95% CI of the difference between two 
proportions (CT-P16 and EU-Approved Avastin group) will be estimated by exact 
binomial approach, and scenarios will be displayed by shift table. No response evaluation 
result or inevaluable (NE) result evaluated in best overall response (BOR) will be 
considered as missing case. All the scenarios will be also provided using 2-dimentional 
plot. 
5. PATIENT DISPOSITION 
The total number of patients who were screened will be displayed. The number of 
screening failures and the primary reason for screening failure will also be summarized. 


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The number of patients who have been randomized and the number and percentage of 
patients who have initiated the study period, have completed the Induction study period, 
and have discontinued the study period will also be displayed for study periods 
respectively, using the following categories for ITT population. 
• 
A patient will be considered to have failed the screening if the screening failure 
date is recorded on the ‘Screening Pass/Fail’ eCRF page. 
• 
A patient will be considered to be randomized if the randomization date is recorded 
on the ‘Randomization’ eCRF page and the response of ‘Is the patient eligible to 
participate in this study?’ on ‘Screening Pass/Fail’ eCRF page is ‘Yes’.  
• 
A patient will be considered to have initiated the Induction Study Period and the 
Maintenance Study Period if the administration date is recorded on the ‘Study 
Treatment Administration’ eCRF page for Induction Study Period and 
Maintenance Study Period, respectively. If the Follow-Up visit date is recorded on 
‘Survival Status’ eCRF page and its ‘Patient Status’ is ‘Alive’, then the patient will 
be considered to have initiated Follow-Up Period. 
• 
A patient will be considered to have completed Induction Study Period if the 
patient administered up to Induction Cycle 6 and performed tumor assessment (i.e. 
‘Response Evaluation’ eCRF page) after the administration date at Induction Cycle 
6. 
• 
A patient will be considered to have discontinued the study period if the 
discontinuation reason is recorded on the ‘Study Treatment Termination’ eCRF 
page. 
The number and percentage of patients who initiated but discontinued study treatment will 
also be displayed by discontinuation reasons in each study period. Time on the study drug 
prior to discontinuation in each study period will be calculated as (Last dose date – First 
dose date + 1) and will also be summarized with descriptive statistics.  
Reason for ending participation in the study will be summarized by reasons on the ‘End of 
Study Participation’ eCRF page. Deaths will be summarized by reasons using the data 
reported on ‘Study Treatment Termination’ or ‘Survival Status’ eCRF page. 
Patient disposition data will be listed for the ITT population. A listing of patients reported 
as screening failure will also be provided with reasons for screening failure. 
6. DEMOGRAPHICS, BASELINE, AND BACKGROUND CHARACTERISTICS 
6.1. Demographics and Stratification Details 
The following demographic measures will be summarized by treatment group for the ITT 
population: Age (years); Fertility status for female patient only (Pre-Menarche, Surgically 
Sterilized (>= 24 weeks prior to the date of informed consent), Post-Menopausal (last 


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menstrual period > 1 year prior to the date of informed consent), Potentially Able to Bear 
Children); Race (American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, White or Caucasian, Not Allowed by 
Investigator Country Regulations, Other); Ethnicity (Hispanic or Latino, Non-Hispanic or 
Non-Latino, Not Allowed by Investigator Country Regulations, Unknown); Smoking 
History (Current Smoker, Former Smoker, Never Smoker); Height (cm) and Weight (kg) 
as recorded at the screening visit. 
Age will be automatically calculated in the eCRF system based on the informed consent 
signed date, the year of birth and information on whether the date of birth has passed or 
not.  
The following stratification details will also be presented: Country (as recorded in the 
clinical database), Sex (Female vs. Male), disease status (Recurrence vs. Metastatic), and 
ECOG performance status (0 vs. 1). The stratification factors collected on the eCRF will 
be used for statistical analysis. 
A table and listing will be produced by treatment group for the ITT population. 
6.2. Gene Screening 
Gene screening is captured at the screening visit on the ‘Gene Screening’ eCRF page. A 
table and listing of gene screening will be provided by treatment group for the ITT 
population. 
6.3. Hepatitis B and C and Human Immunodeficiency Virus 1 and 2 
At scheduled visit, the following assessments will be performed: 
• 
Hepatitis B Surface Antigen (HBsAg) 
• 
Hepatitis B Surface Antibody (HBsAb) 
• 
Hepatitis B Core Antibody (HBcAb) 
• 
Hepatitis C Antibody 
• 
Human Immunodeficiency Virus (HIV) 1&2 
• 
Hepatitis B virus (HBV) DNA (if a patient is HBsAg negative and HBcAb positive) 
Viral serology will be summarized by treatment group, parameter and visit (including 
EOT). For HIV 1&2, summarization will be combined as following: ‘Positive (at least one 
positive)’, ‘Negative (all negative with no positive)’, and ‘Not Done’. A listing of viral 
serology will be produced by treatment group for ITT population. 


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6.4. Medical History 
Medical history is captured at the screening visit and will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) version 24.0 or higher. Medical history 
will be summarized by treatment group, system organ class (SOC) and preferred term (PT) 
for the ITT population. The number and percentage of patients with at least one medical 
history will also be presented in the table by treatment group. A listing of medical history 
will be provided for the ITT population by treatment group. 
6.5. Disease Characteristic 
Disease characteristic is captured at the screening visit on the ‘Disease Characteristic’ 
eCRF page. Disease characteristic will be displayed in a summary table, including: disease 
status, final pathological diagnosis based on immunohistochemistry or hematoxylin and 
eosin staining, current histologic grade, current clinical stage and current TNM stage. A 
listing of Disease characteristic will be provided by treatment group for the ITT population. 
6.6. Previous Treatment for NSCLC 
Previous treatment for NSCLC is captured at the screening visit on the ‘Previous Surgical 
Procedure for NSCLC’, ‘Previous Radiotherapy for NSCLC’ and ‘Previous Anti-Cancer 
Systemic Therapy for NSCLC’ eCRF pages. 
Previous surgical procedure for NSCLC will be coded using MedDRA version 24.0 or 
higher. Previous anti-cancer systemic therapy for NSCLC will be coded using World 
Health Organization (WHO) Drug Dictionary version March, 2021 or later. Previous 
treatment for NSCLC will be summarized by treatment group and, if possible, medical 
term displaying the number and percentage of patients for the ITT population. Previous 
anti-cancer systemic therapy for NSCLC data will also be presented by drug class (using 
Anatomical Therapeutic Chemical [ATC] level 2). Listings for each previous treatment 
will also be provided by treatment group for the ITT population. 
6.7. Inclusion and Exclusion Criteria 
Details of inclusion and exclusion criteria can be found in Sections 4.1.1 and 4.1.2 of the 
protocol. A listing of the inclusion and exclusion criteria along with the corresponding 
protocol version used to assess the eligibility will be presented by treatment group for the 
ITT population.  
7. MEDICATIONS AND TREATMENTS  
Medications and treatments data will be presented for the safety population by treatment 
group. 
7.1. Prior and Concomitant Medications 
All medications used during the study, as well as all medications taken within 30 days 
prior to Day 1 of Cycle 1 in the Induction Study Period and until 28 days after the last dose 


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of study treatment will be collected. Concomitant medications relevant to serious adverse 
drug reactions (ADRs) that occur after the EOT visit will also be collected. For patients 
who do not enter the Follow-Up Period, the last assessed concomitant medication will be 
collected. All medications will be coded using WHO Drug Dictionary version March, 2021 
or later. 
A prior medication is defined as any medication where both the start and stop dates are 
before the date of first infusion. A concomitant medication is defined as any medication 
that has a stop date that is on or after the date of first infusion or missing. The start date of 
a concomitant medication can be before or after the date of first infusion. 
The total number of prior and concomitant medications and the number and percentage of 
patients with at least one prior or concomitant medication will be tabulated for the safety 
population. Prior and concomitant medication data will be presented by drug class (using 
ATC level 2), PT, and treatment group.  
Summaries of concomitant medications will be presented by Whole Study Period, 
Induction Study Period, Maintenance Study period and Follow-up period defined as 
follows: 
• 
Concomitant medications will be summarized in the Induction Study Period if 
patients: 
 
did not enter the Maintenance Study Period and have a medication start date 
on or prior to the last date of EOT (or the last dose date + 28 if the last date of 
EOT is missing). 
 
entered the Maintenance Study Period and have a medication start date prior 
to the date of the first infusion in the Maintenance Study Period. 
• 
Concomitant medications will be summarized in the Maintenance Study Period if 
patients: 
 
have a medication start date on or after the first infusion in the Maintenance 
Study Period and on or prior to the last date of EOT (or the last dose date + 
28 if the last date of EOT is missing) when the discontinuation reason is 
recorded on ‘Study Treatment Termination’ eCRF page. 
 
have a medication start date on or after the first infusion in the Maintenance 
Study Period when the discontinuation reason is not recorded on ‘Study 
Treatment Termination’ eCRF page. 
• 
Concomitant medications will be summarized in Follow-Up Period if patients: 
 
have the last date of EOT and have a medication start date after the last date 
of EOT (or the last dose date + 28 if the last date of EOT is missing) when the 
discontinuation reason is recorded on ‘Study Treatment Termination’ eCRF 
page. 


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For the purpose of inclusion in prior or concomitant medication tables, incomplete 
medication start and stop dates will be imputed respectively as described in Appendix 
14.4.1. 
Prior and concomitant medications will be listed separately by treatment group. 
7.2. Exposure to Study Drug 
The number and percentage of patients with dose administered at each treatment cycle will 
be summarized by treatment group. For those patients who were not administered study 
drug, the number and percentage of patients with each reason why the study drug (CT-P16 
or EU-Approved Avastin) was not administered in ‘Study Treatment Termination’ or 
‘Study Treatment Administration’ eCRF page will be displayed by visit. Information on 
dose delay with the reason and action taken with the reason in ‘Study Treatment 
Administration’ eCRF page will also be presented in the table by visit and treatment group.  
The summary table will also present descriptive statistics for those patients receiving study 
drug: planned dose (mg/kg), weight-adjusted prescribed dose (mg/kg), weight-adjusted 
administered dose (mg/kg), administered dose intensity (weight-adjusted administered 
dose / actual duration of dose) (mg/kg/week) and relative dose intensity (administered dose 
intensity / planned dose intensity * 100) (%) which are based on data collected on the 
‘Study Treatment Administration’ page of the eCRF. The weight-adjusted prescribed dose 
and weight-adjusted administered dose are calculated by dividing the corresponding dose 
recorded on the eCRF, by the patient’s weight at the same visit.  
Actual duration of dose is given by the following formula: 
Actual duration of dose (weeks) = (Start Date of Next Cycle – Start Date of Current Cycle) 
/ 7 
In order to calculate dose intensity, for the last cycle, the duration of dose is assumed to 
be 3 weeks.  
In addition, a listing will be provided by treatment group showing the details of study drug 
exposure. 
Furthermore, a table and listing for exposure of Paclitaxel and Carboplatin will be provided 
in the same manner as the study drug (CT-P16 or EU-Approved Avastin) exposure. 
Paclitaxel will be adjusted by BSA (m2) and carboplatin will be adjusted by CrCl (mL/min) 
instead of weight. Adjusted Carboplatin dose is calculated based on Calvert equation: 
Adjusted Carboplatin Dose (AUC) = Carboplatin Dose (mg)/(CrCl+25). If BSA or CrCl 
is missing at the applicable visit, then the value at the nearest visit to the visit will be used. 
A separate table for overall study drug exposure in each period and a table for overall 
paclitaxel and carboplatin exposure will also be produced, including descriptive statistics 
of the total amount of planned dose, total amount of adjusted prescribed dose, total amount 
of adjusted actual administered dose, administered dose intensity, relative dose intensity 


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(%). Dose intensity in this instance will be calculated as the total sum of adjusted dose 
during each period, divided by duration of dose for that period.  
Actual duration of dose in each period is given by the following formula: 
Actual duration of dose (weeks) = (Start Date of Last Cycle + 21 – Start Date of First 
Cycle) / 7 
For patients who have initiated Maintenance Study Period,  
Actual duration of dose for Induction Study Period = (Start Date of Maintenance Cycle 1 
– Start Date of First Cycle) / 7 
8. EFFICACY ANALYSIS 
Efficacy analyses for the final CSR focus on secondary efficacy endpoints (Section 8.2) 
based on patients’ long-term follow-up data. It is noted that the primary efficacy analysis 
(Section 8.1) was completed in the 1st CSR. In the final CSR, the analysis for the primary 
efficacy endpoint will be performed as a sensitivity analysis using the same method as 1st 
CSR.  
Efficacy will be assessed by response evaluation and time-to-event analyses. 
Response evaluation will be based on tumor responses measured and recorded by using 
Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. The primary 
endpoint, ORR during the Induction Study Period, and the secondary endpoint, ORR 
during the Whole Study Period, will be determined by the BOR. For CR or PR, BOR must 
be confirmed by the subsequent assessment. 
Categorization of BOR will use the following response categories: CR, PR, SD, PD and 
NE. 
Images for tumor assessment will be reviewed separately by central and local, and both 
image review results from central (central independent reviewer) and local (eCRF) will be 
analyzed and listed separately. 
Time-to-event analysis for the study drug (CT-P16 or EU-Approved Avastin) will be 
undertaken for each of the response duration, TTP, PFS, and OS. 
Primary analysis population for the efficacy analysis is the ITT population. A supportive 
analysis will be repeated using the PP population.  
All efficacy data will be listed for the ITT population by treatment group unless otherwise 
specified. 
8.1. Primary Efficacy Endpoint 
In the final CSR, the analysis for the protocol-specified primary efficacy endpoint will be 
performed as a sensitivity analysis using method described in this section. 


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The primary efficacy endpoint is ORR based on BOR during the Induction Study Period 
by RECIST version 1.1 (Appendix 14.5).  
The ORR is defined as the proportion of patients with a confirmed BOR of CR or PR (the 
‘responder’). All other patients in the ITT or PP population except responders will be 
considered as non-responder including patients without post-baseline tumor assessment.   
The similarity criterion has been set such that the confidence limits of the 95% CI of the 
difference in ORR from each treatment group will be entirely bounded by the interval (-
12.5, 12.5). The primary analysis for the primary endpoint will be performed utilizing a 
logistic regression model considering country, sex (female vs. male), disease status at 
baseline (recurrence vs. metastatic), and ECOG performance status at baseline (0 vs. 1) as 
covariates with treatment groups (CT-P16 and EU-Approved Avastin) as a fixed effect. 
Country can be pooled into region (EMEA vs. America vs. Asia) for statistical analysis 
when there are not enough patients within each country. Use of region instead of country 
in statistical analyses was discussed at the blinded DRM. 
A table presenting ORR during the Induction Study Period with the analysis result will be 
produced. The ORR and its corresponding 95% CI for each treatment group will also be 
presented. A point estimate and 95% CI of the risk difference of ORR between CT-P16 
group and EU-Approved Avastin group will be produced. The number and percentage of 
patients in each response category will also be presented by treatment group separately. 
The primary analysis will be conducted in the ITT population. A supportive analysis will 
be conducted in the PP population and also be provided in the table. For the primary 
analysis, central review results will be used. Local review results will be used for a 
sensitivity analysis. Tipping point analysis will also be conducted using central review 
data based on exact binomial approach in the ITT population for a sensitivity analysis.  
The Delta Method for estimating difference of proportion is explained in the following 
process. 
(1) The individual odds and standard errors (SEs) for both treatments will be obtained 
from the model. For the purposes of this algorithm, let the estimate of the odds of 
being a responder in the CT-P16 group be denoted by θa and the estimate of the 
odds of being a responder in the EU-Approved Avastin group be denoted by θb. 
(2) Calculate the variances of these estimates, Var(θa) and Var(θb) respectively from 
the SEs obtained from the model. 
(3) Calculate the estimates of the corresponding proportions, denoted pa and pb 
respectively, for each of the randomized treatment groups, from the estimated odds 
θa and θb using the following formula: 
θ
θ
+
= 1
p
 
and hence calculate the estimate of the difference of proportions pa - pb. 


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(4) Using Taylor expansions and the Delta method, the following formula for 
approximation can be obtained: 
]
[
]))
[
('
(
)]
(
[
2
X
Var
X
E
f
X
f
Var
≈
 
Applying this approximation specifically to this case, and using the formula 
specified in step (3) we obtain the formula 
4)
1(
)
(
)
(
θ
θ
+
= Var
p
Var
 
which should be used to calculate Var(pa) and Var(pb). 
(5) Calculate the variance of the difference in proportions Var(pa - pb) as the sum of 
Var(pa) and Var(pb). Use this to obtain the SE of the difference, and hence 
calculate the 95% CI using the formula:  
95% Confidence Interval = (pa - pb) +/- 1.96(SE(pa - pb)) 
Note: this method assumes that the estimate ORR of CT-P16 group is independent of the 
estimate of EU-Approved Avastin group. 
8.2. Secondary Efficacy Endpoint 
8.2.1. Objective Response Rate during the Whole Study Period 
For the secondary efficacy endpoint, ORR based on BOR during the Whole Study Period 
by RECIST version 1.1 will be analyzed.  
A table will be produced using both central review data and local review data from all 
treatment periods including Induction Study Period, Maintenance Study Period and EOT 
visit in the ITT and PP population. The ORR and its corresponding 95% CI for each 
treatment group will also be presented. The number and percentage of patients within each 
response category will be summarized by treatment group.  
The ORR based on BOR during the Whole Study Period will be analyzed only for the final 
CSR. 
8.2.2. Time-To-Event Analysis 
A time-to-event analysis will be undertaken for each of the response duration, TTP, PFS, 
and OS in the ITT and PP population. 
The number of patients experiencing events and the number of censored patients will be 
summarized by treatment group with reasons for an event/censoring. 
The median survival time and its corresponding 95% CI for each treatment group will be 
estimated using the Kaplan-Meier method. The 25th percentile and 75th percentile for the 


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survival times along with the corresponding 95% CI for the percentiles will also be 
displayed. The Brookmeyer-Crowley methodology will be used to construct the 95% CI 
for each percentile. Survival times and their corresponding 95% CIs will be presented to 
one decimal place. In addition, the estimate of survival rates (at 6, 12, 24, 36 months for 
response duration, TTP, PFS and at 12, 24, 36 months for OS) will be displayed along with 
their corresponding 95% CI. The estimates of survival rates and their corresponding 95% 
CIs will be presented to two decimal places. All time-to-event data will be reported in 
months with reasons for an event/censoring and summarized by treatment group. Time-to-
event in days will be converted to months by dividing the number of days by 30.4 (365.25 
days/12 months). 
For the purposes of inclusion in the survival analysis, incomplete death dates will be 
imputed as described in Appendix 14.4.3. 
To determine ‘event’ or ‘censoring’ for response duration, TTP and PFS, initiation of new 
anticancer therapy will be considered. For missing or incomplete start date of new 
anticancer therapy, the capture logic of event or censoring will be followed in Section 
8.2.2.5. 
A Kaplan-Meier plot will be presented for each of the time-to-event analyses.  
In PFS and OS analyses, an adjusted stratified cox regression model will be used to 
estimate the hazard ratio and its 95% CI for receiving CT-P16 compared with receiving 
EU-Approved Avastin using country, sex (female vs. male), disease status at baseline 
(recurrence vs. metastatic), and ECOG performance score at baseline (0 vs. 1) as 
stratification factors. Country can be pooled into region (EMEA vs. America vs. Asia) for 
statistical analysis when there are not enough patients within each country. 
All time-to-event analyses will be conducted for 2nd CSR and final CSR. 
All time-to-event analyses related to response duration, TTP and PFS will be performed 
based on the central and local review in terms of PD/recurrence, CR and PR. 
Records on ‘Randomization’, ‘Survival Status’, ‘Response Evaluation’, ‘Salvage 
Treatment’ or ‘Study Treatment Termination’ eCRF pages will be used. 
8.2.2.1. Response Duration 
Response duration is defined as the time between initial response (CR or PR) that is 
confirmed by the subsequent assessment after study treatment administration and 
PD/recurrence or death from any cause (whichever occurs first). Time-to-event analysis 
for response duration will be performed for patients who have confirmed BOR of CR or 
PR.  
PD/recurrence or death that occurred on or before beginning another new anticancer 
therapy will be regarded as an event. Censoring will be defined as following: 
Reason for Censoring 
Censoring Date 


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No event and no anticancer therapy 
Last tumor assessment date   
Initiation of New anticancer therapy 
Last 
tumor 
assessment 
date 
before 
anticancer therapy 
Event after missing two or more tumor 
assessment* 
Last tumor assessment date before event 
The last tumor assessment date on which tumor assessment’s is neither ‘missing’ nor ‘NE’ will be used for 
censoring date. 
* If there is only one missing tumor assessment before an event, then it will be considered as an event case. 
Otherwise, it will be considered as a censoring case. 
Response duration will be calculated as follow: 
Response duration (months) = ([Date of Event/Censoring – Date of First known CR/PR 
that is confirmed by the subsequent assessment] +1)/30.4 
8.2.2.2. Time to Progression 
TTP is defined as time from randomization to determined PD/recurrence. 
PD/recurrence that occurred on or before beginning another new anticancer therapy will 
be regarded as an event. Censoring will be defined as following: 
Reason for Censoring 
Censoring Date 
No tumor assessment 
The date of randomization 
No event and no anticancer therapy 
Last tumor assessment date 
Initiation of New anticancer therapy 
Last tumor assessment date before anticancer 
therapy 
Event after missing two or more tumor 
assessment* 
Last tumor assessment date before event 
The last tumor assessment date on which tumor assessment’s is neither ‘missing’ nor ‘NE’ will be used for 
censoring date. 
* If there is only one missing tumor assessment before an event, then it will be considered as an event case. 
Otherwise, it will be considered as a censoring case. 
TTP will be calculated as follow: 
TTP (months) = ([Date of Event/Censoring – Date of Randomization] +1)/30.4 
8.2.2.3. Progression-free Survival 
PFS is defined as time from randomization to determined PD/recurrence or death from any 
cause (whichever occurs first). 
PD/recurrence or death that occurred on or before beginning another new anticancer 
therapy will be regarded as an event. Censoring will be defined as following: 
Reason for Censoring 
Censoring Date 
No tumor assessment 
The date of randomization 


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No event and no anticancer therapy 
Last tumor assessment date 
Initiation of New anticancer therapy 
Last tumor assessment date before anticancer 
therapy 
Event after missing two or more tumor 
assessment* 
Last tumor assessment date before event 
The last tumor assessment date on which tumor assessment’s is neither ‘missing’ nor ‘NE’ will be used for 
censoring date. 
* If there is only one missing tumor assessment before an event, then it will be considered as an event case. 
Otherwise, it will be considered as a censoring case. 
PFS will be calculated as follow: 
PFS (months) = ([Date of Event/Censoring – Date of Randomization] +1)/30.4 
8.2.2.4. Overall Survival 
OS is defined as time from randomization to death from any cause.  
Death will be regarded as an event. Censoring will be defined as following: 
Reason for Censoring 
Censoring Date 
Non-death 
Last known alive date 
OS will be calculated as follow: 
OS (months) = ([Date of Event/Censoring – Date of Randomization] +1)/30.4 
8.2.2.5. Capture logic for event or censoring with incomplete date of new 
anticancer therapy 
A patient will be considered as taking a new anticancer therapy (other than study 
treatments) when there is any record on ‘Salvage treatment’ eCRF pages or a record of 
receiving anticancer therapy on ‘Survival Status’ eCRF page.  
When there is no PD/recurrence (or death) and the start date of new anticancer therapy is 
incomplete, censoring date will be determined as following: 
1) If the last tumor assessment is performed during treatment periods (including EOT 
visit), the censoring date will be the last tumor assessment date during treatment 
periods. 
2) If the last tumor assessment is performed during Follow-Up Period, censoring date 
will be determined as following: 
a. If the day of the start date of new anticancer therapy is missing, then the 
censoring date will be the last tumor assessment date, provided tumor 
assessment date < the partial start date of new anticancer therapy. 


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b. If the day and month of the start date of new anticancer therapy are missing, 
censoring date will be determined as following: 
• 
If all dates of tumor assessments during Follow-Up Period >= the partial 
start date of new anticancer therapy, the censoring date will be the last 
tumor assessment during treatment periods. 
• 
If at least one of tumor assessment during Follow-Up Period < the partial 
start date of new anticancer therapy, the censoring date will be the last 
tumor assessment, provided tumor assessment date < the partial start date 
of new anticancer therapy. 
c. If the start date of new anticancer therapy is completely missing, censoring 
date will be the last tumor assessment date during treatment periods. 
When PD/recurrence (or death) is occurred and the start of new anticancer therapy is 
incomplete, event will be determined as following: 
1) If the first PD/recurrence (or death) is occurred during treatment periods, it will be 
regarded as ‘event’. 
2) If the first PD/recurrence (or death) is occurred during Follow-Up Period, and 
a. If the day of the start date of new anticancer therapy is missing, and 
i. 
If the first PD/recurrence (or death) date < the partial start date of new 
anticancer therapy, it will be regarded as ‘event’.  
ii. 
If the first PD/recurrence (or death) date >= the partial start date of new 
anticancer therapy, it will be censored. The censoring date will be the last 
tumor assessment, provided the tumor assessment date < the partial start 
date of new anticancer therapy. 
b. If the day and month of start date of new anticancer therapy is missing, and 
i. 
If the first PD/recurrence (or death) date < the partial start date of new 
anticancer therapy, it will be regarded as ‘event’. 
ii. 
If the first PD/recurrence (or death) date >= the partial start date of new 
anticancer therapy, it will be censored. The censoring date will be as 
follows:  
• 
If all dates of tumor assessments during Follow-Up Period >= the 
partial start date of new anticancer therapy, the censoring date will be 
the last tumor assessment during treatment periods. 
• 
If at least one of tumor assessment during Follow-Up Period < the 
partial start date of new anticancer therapy, the censoring date will be 


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the last tumor assessment, provided tumor assessment date < the 
partial start date of new anticancer therapy. 
c. If the start date of new anticancer therapy is completely missing, censoring 
date will be the last tumor assessment date during treatment periods. 
8.3. Salvage Treatment 
Salvage treatment during the Follow-Up Period will be recorded in ‘Salvage Treatment’ 
eCRF pages and details will be listed and tabulated by salvage treatment category and 
treatment 
group 
in 
the 
ITT 
population. 
Medications 
used 
for 
chemotherapy/immunotherapy/targeted therapy will be coded using the WHO Drug 
Dictionary version March, 2021 or later and surgery will be coded using MedDRA version 
24.0 or higher. Chemotherapy/immunotherapy/targeted therapy data will also be presented 
by drug class (using ATC level 2). 
Salvage treatment will be summarized for 2nd CSR and final CSR. 
8.4. Effusion Drainage 
Effusion drainage information will be listed by treatment group for ITT population. 
9. PHARMACOKINETIC ANALYSIS   
All PK analysis will be performed in the PK population for the Induction Study Period and 
in the PK population – Maintenance Period subset for the Maintenance Study Period. 
Blood samples for PK analysis will be obtained according to Appendix 14.1. 
9.1. Serum Concentration 
Serum concentration of bevacizumab will be summarized by treatment group at each 
scheduled visit using descriptive statistics: n, mean, standard deviation, geometric mean, 
CV%, minimum, median and maximum. Serum concentration below the lower limit of 
quantification (LLOQ) prior to the first dose will be set to 0, and all other below the LLOQ 
will be set to the LLOQ in the serum concentration descriptive statistics summaries. 
Missing concentrations or post-dose serum concentration will be excluded from the serum 
concentration descriptive statistics summaries.  
Serum concentrations of bevacizumab will be presented in a listing by treatment group. 
All concentrations below the LLOQ will be indicated in the listing.  
9.2. Pharmacokinetic Parameter 
PK parameter is the observed Ctrough following drug administration; calculated from the 
pre-dose concentration of the next dose. The order of samples will be determined based on 
the sampling dates then the scheduled visit order. The samples in following cases are 
excluded from calculation of Ctrough; i) Post-dose concentration in the Induction Study 
Period, ii) interval between the last dose date and sampling date at EOT < 18 days, or iii) 


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duplicated samples at same visit/date/time. Serum concentration below the LLOQ will be 
set to LLOQ in the PK parameter estimation. The Ctrough at each cycle during the Induction 
Study Period, and Ctrough during the Maintenance Study Period will be analyzed. PK 
parameter will also be summarized by treatment and study visit using descriptive statistics: 
n, mean, standard deviation, geometric mean, CV%, minimum, median and maximum. 
PK parameter will be presented in a listing by treatment group. 
10. SAFETY ANALYSIS 
All safety analyses will be performed in the safety population and displayed by treatment 
group.  
10.1. Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a patient enrolled 
into this study (i.e., when the ‘Informed Consent’ eCRF page is signed), regardless of its 
causal relationship to study drug. 
A Treatment-Emergent Adverse Event (TEAE) is defined as any event not present before 
exposure to study drug or any event already present that worsen in either severity or 
frequency after exposure to study drug.  
All AEs will be classified by SOC and PT according to the MedDRA version 24.0 or 
higher. AEs will be graded for severity according to the Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0. 
Listings for AEs will include following information: Study period, SOC, PT and reported 
term; start and stop date; duration of AE in days (Duration = [Stop Date – Start Date] + 1); 
days from last dose on or before AE onset (Date of AE onset – Date of last dose on or 
before AE onset + 1); TEAE flag; infusion-related reactions (IRR) flag; severity (CTCAE 
Grade 1 to 5); frequency (continuous, intermittent, transient); any treatment required (none, 
medication, Non-drug therapy, Medication and Non-drug therapy); outcome 
(recovered/resolved, recovering/resolving, recovered/resolved with sequelae, not 
recovered/not resolved, fatal, unknown); action taken with study treatment (dose not 
changed, drug interrupted, dose reduced, drug withdrawn, not applicable); relationship to 
study treatment (unrelated, possible, probable, definite); whether the event was serious (no, 
yes) and whether a patient terminated from study due to this AE (no, yes). All AEs will be 
listed. 
In summaries, AEs will be considered to be related if relationship is possible, probable or 
definite for study treatment. If relationship or severity is missing, it will be summarized 
separately under a missing category.  
Summaries of TEAEs will be presented by Whole Study Period, Induction Study Period, 
Maintenance Study period and Follow-up period defined as follows: 
• 
TEAEs will be summarized in the Induction Study Period if patients: 


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 
did not enter the Maintenance Study Period and have an AE onset date on or 
prior to the last date of EOT (or the last dose date + 28 if the last date of EOT 
is missing). 
 
entered the Maintenance Study Period and have an AE onset date prior to the 
date of the first infusion in the Maintenance Study Period. 
• 
TEAEs will be summarized in the Maintenance Study Period if patients: 
 
have an AE onset date on or after the first infusion in the Maintenance Study 
Period and on or prior to the last date of EOT (or the last dose date + 28 if the 
last date of EOT is missing) when the discontinuation reason is recorded on 
‘Study Treatment Termination’ eCRF page. 
 
have an AE onset date on or after the first infusion in the Maintenance Study 
Period when the discontinuation reason is not recorded on ‘Study Treatment 
Termination’ eCRF page. 
• 
TEAEs will be summarized in Follow-Up Period if patients: 
 
have the last date of EOT and have an AE onset after the last date of EOT (or 
the last dose date + 28 if the last date of EOT is missing) when the 
discontinuation reason is recorded on ‘Study Treatment Termination’ eCRF 
page. 
For the purpose of inclusion in TEAE tables, incomplete AE start and stop date will be 
imputed as described in Appendix 14.4.2. 
10.1.1. Treatment-Emergent Adverse Events 
Summaries of TEAEs will be presented by Whole Study Period and each study period. 
The total number of TEAEs will be displayed. The number and percentage of patients with 
at least one TEAE will be presented by relationship, severity and treatment group. 
Additionally, the number and percentage of patients will be presented by SOC and PT, and 
by relationship and severity within SOC and PT. At each level of summarization for the 
number of patients with an event, a patient is counted only once if they reported one or 
more events and only the worst severity will be counted at each level of summarization. 
In addition, TEAEs with PT reported at least 5% of patients in either treatment group for 
each period will be summarized. For TEAEs reported for severity of grade 3 or higher, it 
will be summarized regardless of relationship and severity and by relationship, 
respectively. Percentages will be calculated out of the number of patients in the safety 
population. 
The summary of TEAEs will be presented in alphabetical order of SOC. Within each SOC, 
the PTs will be also presented in alphabetical order. 


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10.1.2. Serious Adverse Events 
A serious adverse event (SAE) is defined as any event that is immediately life threatening, 
requires inpatient hospitalization or prolongation of existing hospitalization, results in 
persistent or significant disability/incapacity, is a congenital anomaly/birth defect or 
results in death. Important medical events that may not result in death, be life threatening, 
or require hospitalization may be considered SAEs when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  
TESAEs will be presented in a table in a same manner as the table of TEAEs described in 
Section 10.1.1 .  
All SAEs will be listed including the variables detailed in Section 10.1. Serious criteria 
and SAE description in the ‘Serious Adverse Event’ eCRF page will be presented in an 
additional information listing. 
10.1.3. Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation 
TEAEs for which an action taken with study drug is ‘Drug Withdrawn’ will be considered 
TEAEs leading to study drug discontinuation.  
TEAEs leading to study drug discontinuation will be presented in a table in a same manner 
as the TEAEs table described in Section 10.1.1. 
All TEAEs leading to study drug discontinuation will be listed including the variables 
detailed in Section 10.1. 
10.1.4. Treatment-Emergent Adverse Event Leading to Deaths 
All patients who have an TESAE with serious criteria of ‘Death’ will be listed including 
the following information: study period, date of first/last dose, date of last visit, date of 
death, days on study, days from date of last dose to date of AE onset, SOC/PT/reported 
term, whether an autopsy was performed (yes, no), whether a death certificate was 
completed (yes, no) and relationship to study drug. 
10.1.5. Treatment-Emergent Adverse Events of Special Interest 
The following TEAEs will be considered as TEAEs of special interest: 
Hypersensitivity/IRR, Gastrointestinal perforations and fistulae, Wound healing 
complications, Hypertension, posterior reversible encephalopathy syndrome (PRES), 
Proteinuria, arterial thromboembolism (ATE), venous thromboembolism (VTE), 
Hemorrhages, congestive heart failure (CHF), or Ovarian failure/fertility. 
TEAEs of special interest will be captured using Standardised MedDRA Queries (SMQs) 
and additional PT terms in Appendix 14.3. 
Event of Interest 
Searching Strategy 


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Name 
Category 
Hypersensitivity/infusion-
related reactions 
captured on CRF (recorded as IRR in the AE 
page) 
N/A  
Gastrointestinal 
perforations and fistulae 
Gastrointestinal perforation 
SMQ (Narrow) 
Wound healing 
complications 
selected MedDRA PTs 
N/A 
Hypertension 
Hypertension 
SMQ (Narrow) 
Posterior reversible 
encephalopathy syndrome 
Posterior reversible encephalopathy 
syndrome 
PT 
Proteinuria 
Proteinuria 
SMQ (Narrow) 
Arterial thromboembolism 
Embolic and thrombotic events, arterial 
SMQ (Narrow) 
Venous thromboembolism 
Embolic and thrombotic events, venous 
SMQ (Narrow) 
Hemorrhages (Bleeding) 
Haemorrhage terms (excl laboratory terms) 
SMQ (Narrow) 
Congestive heart failure 
Cardiac failure 
SMQ (Narrow) 
Ovarian failure/fertility 
Ovarian failure 
PT 
TEAEs of special interest will be presented in a table in a same manner as the TEAEs table 
described in Section 10.1.1. 
All TEAEs of special interest will be listed including the variable detailed in Section 10.1.1 
and information recorded on the ‘Adverse Event’ and ‘Hypersensitivity/Infusion Related 
Reactions’ on eCRF page: start date/time and stop date/time of IRR; category; 
SOC/PT/signs and symptoms; severity; systolic blood pressure (BP) [mmHg]; diastolic 
BP; date/time of BP assessment; comments on IRR. 
10.2. Clinical Laboratory Evaluations 
Clinical laboratory test samples will be analyzed at the local laboratory. Reported units 
and normal ranges are various among sites. Reported units will be converted to standard 
units, if applicable. Reported parameters with units that cannot be converted to standard 
units will be summarized separately using the original units. 
Actual result and change from baseline of all numeric laboratory parameters including 
clinical chemistry, hematology, numeric urinalysis and coagulation will be summarized 
using descriptive statistics by treatment group, laboratory category, test parameter and visit.  
The results for all non-numeric urinalysis parameters including microscopic urinalysis 
collected as qualitative format will be categorized into normal and abnormal using the 
local laboratory normal ranges by study site and will be summarized in a shift table. The 
number and percentage of patients within each category will be displayed for baseline and 
each post-baseline visit. 
Clinical laboratory parameters for clinical chemistry, hematology and urinalysis will be 
labeled with a CTCAE term and grading will be applied to baseline values and post-
baseline values for the parameters according to CTCAE version 5.0. Grades that require 
clinical input only will not be assigned to these parameters. Grades which are part numeric 


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and part clinical input will be assigned based on the numeric portion only. The CTCAE 
terms and ranges for applicable parameters are listed in Appendix 14.2. The CTCAE 
grades for this analysis will be Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe) and 
Grade 4 (Life-threatening). The CTCAE Grade 5 (Death) will not be applied in this 
analysis since death cannot be determined from a laboratory result. If the post-baseline 
result for a patient does not satisfy any CTCAE grade, it will be classified as ‘No grade’.  
The number and percentage of patients with a result for each grade will be summarized by 
laboratory category, CTCAE term, visit and CTCAE grade. A shift table will be also 
produced by the Whole Study Period and each study period. Only the most severe case 
during unscheduled and scheduled visits will be included for the post-baseline result in the 
shift table. 
If visit names are ‘Unscheduled’ or ‘EOT’, the post-baseline result of laboratory data will 
be presented by period, defined as follows.  
• 
Laboratory data will be summarized in the Induction Study Period if patients: 
 
entered the Maintenance Study Period and have an assessment date prior to 
the date of the first infusion in the Maintenance Study Period. 
 
did not enter the Maintenance Study Period, entered the Follow-Up Period, 
and have an assessment date prior to the first visit date of Follow-Up Period. 
 
did not enter the Maintenance Study Period, did not enter the Follow-Up 
Period, and have an assessment at any time point. 
• 
Laboratory data will be summarized in the Maintenance Study Period if patients: 
 
entered the Follow-Up Period and have an assessment date on or after the first 
infusion in the Maintenance Study Period and prior to the first visit date of 
Follow-Up Period. 
 
did not enter the Follow-Up Period and have an assessment date on or after 
the first infusion in the Maintenance Study Period. 
• 
Laboratory data will be summarized in Follow-Up Period if patients: 
 
have an assessment date on or after the first visit date of Follow-Up Period. 
Clinical chemistry, hematology, urinalysis and coagulation data will be presented in 
separate listings along with high or low flags for numeric parameter, if applicable, to show 
if a value was outside the normal range, and CTCAE results for applicable parameters will 
be presented. 


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10.3. Vital Signs, Weight and Body Surface Area 
Vital signs (including systolic and diastolic blood pressure, heart rate, respiratory rate, and 
body temperature) and weight will be measured at the time points specified in the 
Appendix 14.1. Height will be collected once at the screening visit and will be listed with 
demographics as specified in Section 6.1. Body surface area (BSA) will be calculated in 
eCRF by using height collected at the screening visit and weight collected at the each 
scheduled visit. 
Weight at Induction cycle 1 will be considered as the baseline value since weight is 
collected for kit number dispensation prior to the infusion, if study drug is administered at 
Induction cycle 1. 
Descriptive statistics for actual values and changes from baseline of vital signs, weight and 
BSA will be presented by treatment group, parameter and visit. 
All vital signs, weight and BSA will be listed for each patient by treatment group and visit. 
10.4. Electrocardiograms 
A 12-lead Electrocardiograms (ECG) will be performed at the time points specified in the 
Appendix 14.1. 
Findings will be classified as ‘Normal’, ‘Abnormal, not clinically significant’, ‘Abnormal, 
clinically significant’ or ‘Not Done’. The number and percentage of patients will be 
presented by treatment group and visit in the form of a shift table to detect changes from 
baseline.  
All ECG data will be listed for each patient by treatment group and visit.  
10.5. Hypersensitivity Monitoring 
Hypersensitivity will be assessed by vital sign monitoring (including systolic and diastolic 
blood pressure, respiratory rate, heart rate, and body temperature) within 15 minutes before 
the beginning of the study drug infusion, within 15 minutes after the end of the study drug 
infusion and 60 minutes (± 15 minutes) after the end of the study drug infusion at each 
visit. The criteria for clinically notable results are defined as follows: 
Parameter 
Low 
High 
Systolic blood pressure (mmHg) 
≤90 
≥160 
Diastolic blood pressure (mmHg) 
≤50 
≥90 
Heart rate (beats per minute) 
≤50 
≥100 
Respiratory rate (breaths per minute) 
≤12 
≥20 
Body temperature (°C) 
≤35.0 
≥38.0 


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The number and percentage of patients who have a clinically notable vital sign 
hypersensitivity result will be presented by treatment group, visit, time point and parameter. 
In addition, hypersensitivity should be monitored by routine continuous clinical 
monitoring including ECG monitoring at 60 minutes (± 15 minutes) after the end of the 
study drug infusion. Findings will be classified as ‘Normal’, ‘Abnormal, not clinically 
significant’, ‘Abnormal, clinically significant’ or ‘Not Done’. The number and percentage 
of patients within each hypersensitivity finding classes will be presented by treatment 
group, visit and time point in the form of a shift table to detect changes from baseline. 
All hypersensitivity data will be listed for each patient by treatment group, visit and time 
point.  
10.6. Physical Examination 
Physical examinations will be performed at the time points specified in the Appendix 14.1. 
Findings will be classified as ‘Normal’, ‘Abnormal, not clinically significant’ and 
‘Abnormal, clinically significant’ or ‘Not Done’. The number and percentage of patients 
within each class will be presented by treatment group, body system and visit in the form 
of a shift table to detect changes from baseline. All physical examination data will be listed 
for each patient by treatment group, visit and body system. 
10.7. Pregnancy Test 
Pregnancy tests of urine and serum in women of childbearing potential will be performed 
at the time points specified in the Appendix 14.1.  
 
Urine pregnancy results will be classified as ‘Positive’, ‘Negative’ or ‘Equivocal’, and 
serum pregnancy results will be classified as ‘Positive’ or ‘Negative’. The number and 
percentage within each class will be presented by treatment group, type of pregnancy test 
and visit (including EOT). All pregnancy testing result will be listed for each patient by 
treatment, visit and type of pregnancy test.  
10.8. ECOG Performance Status 
ECOG performance status is to assess health of oncology patients with score running from 
0 to 5. 
Grade of performance status is as follows: 
Grade 
Performance Status 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of light or sedentary nature, e.g., light house work, office 
work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours 


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3 
Capable of only limited self-care; confined to bed or chair more than 
50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair 
5 
Dead 
ECOG performance status will be assessed at the time points specified in the Appendix 
14.1. Results will be classified as either ‘Grade 0’, ‘Grade 1’, ‘Grade 2’, ‘Grade 3’, ‘Grade 
4’ or ‘Grade 5’ and the number and percentage of patients within each class will be 
provided by treatment group and visit. All ECOG status data will be listed for safety 
population. 
10.9. Immunogenicity 
Blood samples for assessment of immunogenicity will be collected at the time points 
specified in the Appendix 14.1. Immunogenicity assessment consists of both anti-drug 
antibody (ADA) and neutralizing antibody (NAb) assays.  
The ADA assay will follow a three-tiered approach consisting of screening assay, 
confirmatory assay, and titration. The test outcome for the screening assay will be reported 
as ‘Potential Positive’ or ‘Negative’. Samples that are ‘Potential Positive’ in the screening 
assay will be undergone further testing in the confirmatory assay to determine if patients 
are a true positive. The test outcome for the confirmatory assay will be ‘Positive’, 
‘Negative’, and ‘Not applicable (N/A)’. ‘Positive’ indicates a true positive test outcome 
and will be labeled as ‘Positive’ in outputs. ‘Negative’ is considered negative, and ‘N/A’ 
indicates the assay was negative at the screening phase of the process. Patients with a 
‘Negative’ test outcome for either screening or confirmatory assays will be considered 
negative for the overall ADA assessment. Any samples not available for analysis will be 
reported as ‘No Recorded Result (NRR)’. Samples with a ‘NRR’ test outcome for the 
screening assay and ‘N/A’ for the confirmatory assay will be considered ‘N/A’ for the 
overall ADA assessment. For further characterization, the antibody level will be assessed 
by titration in confirmed positive samples. 
The ADA value tagged assay will be transformed using a log transformation. 
Transformed ADA value can be obtained using [log3(X/42)] + 1 transformation. 
Samples that are positive in the ADA confirmatory assay will be analyzed further to 
conduct a NAb assessment. The test outcome for the screening assay will be ‘Positive’ or 
‘Negative’. For further characterization, the antibody level will be assessed by titration in 
NAb positive samples. 
Transformed NAb value can be obtained using [log2(X/5)] + 1 transformation. 
The results of the final ADA and NAb incidence will be summarized. The total number of 
patients with at least one result in timepoints (anytime during the study period, baseline 
and after the first infusion) will be presented. The number and percentage of patient in 
each result will be presented by treatment group, timepoints, visits and test. Additionally, 
the transformed ADA/NAb titer will be summarized by treatment and visits. 


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Immunogenicity test results including actual and transformed ADA and NAb titer will be 
listed for each patient by treatment group and visit.  
11. QUALITY OF LIFE ANALYSES 
QoL will be assessed at the time points specified in the Appendix 14.1 using EORTC QLQ. 
The QLQ core 30 (QLQ-C30) and QLQ lung cancer-specific module (QLQ-LC13) will be 
used. 
Each score for scales will be calculated as per following logic: 
Table 1. QLQ-C30 
Categories  
 Scales 
QLQ-C30 
Item numbers  
Item range* 
Global health status/QoL 
 
 
Global health status/QoL  
29, 30 
6 
Functional scales 
 
 
Physical functioning  
1 to 5 
3 
Role functioning 
6, 7 
3 
Emotional functioning 
21 to 24 
3 
Cognitive functioning 
20, 25 
3 
Social functioning 
26, 27 
3 
Symptom scales/items 
 
 
Fatigue 
10, 12, 18 
3 
Nausea and vomiting 
14, 15 
3 
Pain 
9, 19 
3 
Dyspnoea 
8 
3 
Insomnia 
11 
3 
Appetite loss 
13 
3 
Constipation 
16 
3 
Diarrhea 
17 
3 
Financial difficulties 
28 
3 
*Item range is the difference between the possible maximum and the minimum response 
to individual items; most items take values from 1 to 4, giving range=3. 
 
Table 2. QLQ-LC13 
Categories  
 Scales 
QLQ-LC13 
Item numbers  
Item range* 
Symptom scales/items 
 
 
Dyspnoea** 
3, 4, 5 
3 
Coughing 
1 
3 
Haemoptysis 
2 
3 
Sore mouth 
6 
3 
Dysphagia 
7 
3 
Peripheral neuropathy 
8 
3 
Alopecia 
9 
3 


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Pain in chest 
10 
3 
Pain in arm or shoulder 
11 
3 
Pain in other parts 
12 
3 
* Item range is the difference between the possible maximum and the minimum response 
to individual items; most items take values from 1 to 4, giving range=3.  
** The dyspnea scale should only be used if all three items have been answered. 
 
For all scales, the Raw Score (RS), is the mean of the component items: 
RS = (𝐼𝐼1 + 𝐼𝐼2 + ⋯+ 𝐼𝐼𝑛𝑛)/𝑛𝑛 
Then for Functional scales: 
Score = ቄ1 −
(𝑅𝑅𝑅𝑅−1)
𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟ቅ× 100 
And for Symptom scales/items and Global health status/QoL: 
Score = 
𝑅𝑅𝑅𝑅−1
𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟× 100 
For missing items from multi-item scales, if at least half of the items from the scale have 
been answered, the scale score will be calculated using all the items that were completed 
and apply the logic, otherwise set to missing. For missing single-item, set to missing. 
The scores for each scale will be displayed to two decimal places. Descriptive analysis 
will be performed on actual score and change from baseline at each visit by treatment 
group and scales in the ITT population. The answer for each item will be listed for each 
patient by treatment group and visit in the ITT population. 
12. CHANGES FROM PROTOCOL 
1. The definition of response duration was updated: from ‘Response duration (or 
duration of response) should be defined as the time between the initial response 
(CR or PR) after study treatment administration and PD/recurrence’ to ‘Response 
duration (or duration of response) should be defined as the time between the initial 
response (CR or PR) that is confirmed by the subsequent assessment after study 
treatment administration and PD/recurrence or death from any cause (whichever 
occurs first). 
13. REFERENCE LIST 
Protocol: A Double-Blind, Randomized, Active-Controlled, Parallel-Group, Phase 3 
Study to Compare Efficacy and Safety of CT-P16 and EU-Approved Avastin as First-Line 
Treatment for Metastatic or Recurrent Non-Squamous Non-Small Cell Lung Cancer, 
Version 2.0, 14 June 2019  


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Unique CRF: A Double-Blind, Randomized, Active-Controlled, Parallel-Group, Phase 3 
Study to Compare Efficacy and Safety of CT-P16 and EU-Approved Avastin as First-Line 
Treatment for Metastatic or Recurrent Non-Squamous Non-Small Cell Lung Cancer, 
Version 7.0, 21 July 2021  


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14. APPENDICES 
14.1. Schedule of Events  
Procedure 
Screening1 
(Day -28 to 
Randomization) 
Induction Study Period 
Maintenance Study Period2 
EOT3 
Follow-
Up 
Period4 
Cycle  
Cycle 1 
Day 1 
Each Cycle Day 1 
(except Cycle 1) 
End of Cycles 2 
and 4 
End of 
Cycle 6 
Each Cycle  
Day 1 
End of Cycle 3, 6, 9, 
12… until PD 
Visit window (days) 
 
±3 
 
 
±3 
 
±3 
±7 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics and 
disease-related 
information 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Gene screening5 
X 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion criteria6 
X 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Pathological 
diagnosis7 
X 
 
 
 
 
 
 
 
 
Clinical laboratory 
tests: hematology, 
clinical chemistry, 
urinalysis8 
X 
X 
X 
 
  
X 
 
X 
 
Hepatitis B, C, HIV 
tests 
X 
 
 
 
 
(Cycle 1 only) 
 
(X) 
 
Pregnancy test9 
X 
 
 
 
 
Cycle 1 only 
 
X 
 
12-lead ECG10 
X 
 
 
 
 
Cycle 1 only 
 
X 
 
Physical examination 
X 
X11 
X11 
 
 
X11 
 
X 
X 
ECOG performance 
status 
X 
X11 
X11 
 
 
X11 
 
X 
X 
Vital signs, weight and 
height12 
X 
X11 
X11 
 
 
X11 
 
X 
 
Study drug 
administration 
 
X 
X 
 
 
X 
 
 
 
Concurrent 
chemotherapy13 
 
X 
X 
 
 
 
 
 
 
Hypersensitivity 
monitoring 
 
X 
X 
 
 
X 
 
 
 


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Procedure 
Screening1 
(Day -28 to 
Randomization) 
Induction Study Period 
Maintenance Study Period2 
EOT3 
Follow-
Up 
Period4 
Cycle  
Cycle 1 
Day 1 
Each Cycle Day 1 
(except Cycle 1) 
End of Cycles 2 
and 4 
End of 
Cycle 6 
Each Cycle  
Day 1 
End of Cycle 3, 6, 9, 
12… until PD 
Visit window (days) 
 
±3 
 
 
±3 
 
±3 
±7 
Pharmacokinetic blood 
sampling14 
 
X 
X 
 
X 
 
X 
X 
 
Tumor Evaluation15 
 
 
 
 
 
 
 
 
 
- CT (chest and 
abdomen)  
X16 
 
 
X 
X 
 
X 
X 
(X)15 
- CT or MRI (brain)17 
X16 
 
 
(X) 
(X) 
 
(X) 
(X) 
(X) 
- Bone scan.18 
X16 
 
 
(X) 
(X)  
 
(X) 
(X) 
(X) 
Immunogenicity19 
 
X11 
 
X 
X 
 
X 
X 
FU1 only 
Quality of Life20 
X 
 
 
X 
X 
 
X 
X 
 
Survival and further 
anti-cancer therapy 
 
 
 
 
 
 
 
 
X 
Prior/concomitant 
medications21 
X 
X 
AEs monitoring22 
X 
X23 
Abbreviations: AE, adverse event; CT, computed tomography; ECOG, Eastern Cooperative Oncology Group; ECG, electrocardiogram; EOT, end of treatment; FU1, follow-up 1; HIV, 
human immunodeficiency virus; MRI, magnetic resonance imaging. 
1. 
Screening evaluations will be completed within 28 days prior to randomization. However, screening period can be extended to 8 weeks exclusively for treating patients who have 
CNS metastases before starting the study treatment and all other assessments including chest and abdomen CT scan should be completed as specified in the protocol. 
2. 
Cycle 1 of Maintenance Study Period will occur 3 weeks after Cycle 6 of Induction Study Period. Study drug will be administered every 3 weeks until disease progression (PD) or 
intolerable toxicity occurrence. 
3. 
An end of treatment (EOT) visit will occur 3 weeks after the last dose of the Induction Study Period or Maintenance Study Period regardless of the reason of discontinuation. 
4. 
All patients will be followed every 9 weeks until death or until 36 months from Day 1 of Cycle 1 of the Induction Study Period for the last patient, whichever occurs first. 
5. 
Gene screening results will be used for epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement. 
6. 
The inclusion and exclusion criteria need to be confirmed prior to randomization. 
7. 
A pathological diagnosis results will be used to confirm that the patient has non-squamous cell type. 
8. 
Clinical laboratory tests for Cycle 1 of Induction Study Period will be performed within 14 days prior to Day 1 of Cycle 1 of the Induction Study Period. For all other cycles, clinical 
laboratory tests will be performed within 3 days prior to Day 1 of each cycle. Coagulation (prothrombin time, prothrombin time international normalized ratio) test will be performed 
at Screening, Day 1 of Cycle 1 and Cycle 2 of Induction Study Period and when clinically indicated for the patient who has been administered aspirin. Clinical laboratory test samples 
will be analyzed at the local laboratory.  
9. 
Urine pregnancy test should be performed at the Screening visit (within 3 days before Day 1 of Cycle 1), within 3 days before Day 1 of Cycle 1 of the Maintenance Study Period and 
EOT visit, or at any time if pregnancy is suspected in females of childbearing potential only. If the urine pregnancy test gives equivocal results, a serum pregnancy test will be 
performed to exclude pregnant women in this study. For the Screening visit, only patients who have confirmed negative pregnancy test results will be included in this study. Pregnancy 
test samples will be analyzed at the local laboratory. 


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10. 12-lead ECG at the Screening visit will be performed within 14 days prior to Day 1 of Cycle 1 of the Induction Study Period. For all other cycles, 12-lead ECG will be performed 
within 3 days prior to Day 1 of each cycle. 
11. These assessments should be performed prior to study treatment administration. 
12. Vital signs (including blood pressure, heart and respiratory rates, and temperature) will be assessed prior to study drug administration and be measured after 5 minutes of rest (sitting). 
Height will be assessed at Screening only as a baseline measurement. 
13. Paclitaxel and carboplatin will be administered on Day 1 of each cycle in Induction Study Period. 
14. Pharmacokinetic samples will be collected on Day 1 of each cycle (prior to the beginning of the study drug administration [-3 days as window are allowed]) in the Induction Study 
Period, on Day 1 (-3 days as window are allowed) of Cycle 1 and every 3 cycles (end of Cycle 3, Cycle 6, and Cycle 9...) in the Maintenance Study Period, and EOT visit. In patients 
whose dose is delayed from the planned schedule, serum samples will be obtained on Day 22 of the last cycle (-3 days as window are allowed). Pharmacokinetic samples will be 
analyzed at the central laboratory. 
15. Tumor evaluation will be assessed at Screening and every 2 cycles during the Induction Study Period and every 3 cycles during the Maintenance Study Period, and at the EOT visit. 
During the Follow-Up Period, it will be performed every 9 weeks until PD, death, withdrawal or start of new anti-cancer therapy if PD is not confirmed during the Induction or 
Maintenance Study Periods. 
16. Tumor assessment will be performed within 4 weeks before the start of study treatment.  
17. Brain CT or MRI will be assessed at Screening as mandatory to assess brain metastasis. During the study, imaging will be performed for patients with brain metastasis at baseline or 
for any suspected new lesions. 
18. Bone scans will be assessed at Screening as mandatory. During the study, scans will be performed for patients with bone metastasis at baseline or for any suspected new lesions. 
19. Immunogenicity will be assessed on Day 1 of Cycle 1 (predose), every 2 cycles during the Induction Study Period, every 3 cycles during the Maintenance Study Period and EOT 
visit. In the Follow-Up period, immunogenicity will be assessed once at the first visit of Follow-Up Period (9th week). A window of -3 days before Day 1 of the next cycle are allowed. 
In patients whose dose is delayed from the planned schedule, serum samples will be obtained on Day 22 of the last cycle (-3 days as window are allowed). 
20. Quality of life should be assessed within 7 days before Day 1 of the next cycle, except screening assessment. 
21. All medications used during the study, as well as all medications taken within 30 days of Day 1 of Cycle 1 in the Induction Study Period and until 28 days after the last dose of study 
treatment. Concomitant medications relevant to serious adverse drug reactions (ADRs) occurred after the EOT visit will also be collected. For patients who do not enter the Follow-
Up Period, the last assessed concomitant medications will be collected. 
22. Adverse events will be assessed from the date the informed consent form is signed until up to 28 days after the last dose of study drug, regardless of the relationship to the study drug. 
Where an ADR is ongoing at the EOT visit, the ADR will be followed until one of the following: resolution or improvement from baseline, relationship reassessed as unrelated, start 
of new anti-cancer therapy, confirmation from the investigator that no further improvement can be expected, end of collection of clinical or safety data, or final database closure. For 
patients who do not enter the Follow-Up Period, the last assessed status of AEs will be collected. 
23. Serious ADRs occurring during the Follow-Up Period will be reported and followed up. 
  
 
 


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14.2. Table of CTCAE Terms and Grades 
CTCAE Term 
Laboratory 
Parameter 
 
Level 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Anemia 
Hemoglobin 
Low 
<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 
- 
Alanine 
aminotransferase 
increased 
Alanine 
Aminotransferase 
(ALT) 
High 
>ULN - 3.0 x ULN 
if baseline was 
normal; 1.5 - 3.0 x 
baseline if baseline 
was abnormal 
>3.0 - 5.0 x ULN if 
baseline was normal; 
>3.0 - 5.0 x baseline 
if baseline was 
abnormal 
>5.0 - 20.0 x ULN if 
baseline was normal; 
>5.0 - 20.0 x baseline 
if baseline was 
abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal 
Alkaline 
phosphatase 
increased 
Alkaline 
phosphatase 
High 
>ULN - 2.5 x ULN 
if baseline was 
normal; 2.0 - 2.5 x 
baseline if baseline 
was abnormal 
>2.5 - 5.0 x ULN if 
baseline was normal; 
>2.5 - 5.0 x baseline 
if baseline was 
abnormal 
>5.0 - 20.0 x ULN if 
baseline was normal; 
>5.0 - 20.0 x baseline 
if baseline was 
abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal 
Aspartate 
aminotransferase 
increased 
Aspartate 
Aminotransferase 
(AST) 
High 
>ULN - 3.0 x ULN 
if baseline was 
normal; 1.5 - 3.0 x 
baseline if baseline 
was abnormal 
>3.0 - 5.0 x ULN if 
baseline was normal; 
>3.0 - 5.0 x baseline 
if baseline was 
abnormal 
>5.0 - 20.0 x ULN if 
baseline was normal; 
>5.0 - 20.0 x baseline 
if baseline was 
abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal 
Blood bilirubin 
increased 
Total Bilirubin 
High 
>ULN - 1.5 x ULN 
if baseline was 
normal; 
> 1.0 - 1.5 x 
baseline if baseline 
was abnormal 
>1.5 - 3.0 x ULN if 
baseline was normal; 
>1.5 - 3.0 x baseline 
if baseline was 
abnormal  
>3.0 - 10.0 x ULN if 
baseline was normal; 
>3.0 - 10.0 x baseline 
if baseline was 
abnormal  
>10.0 x ULN if 
baseline was 
normal; >10.0 x 
baseline if baseline 
was abnormal 


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CTCAE Term 
Laboratory 
Parameter 
 
Level 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
CPK increased 
Creatine 
Phosphokinase 
(CPK) 
High 
>ULN - 2.5 x ULN 
>2.5 x ULN - 5 x 
ULN 
>5 x ULN - 10 x 
ULN 
>10 x ULN 
Creatinine 
increased1 
Creatinine 
High 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x baseline; 
>1.5 - 3.0 x ULN 
>3.0 x baseline;  
>3.0 - 6.0 x ULN 
>6.0 x ULN 
GGT increased 
Gamma Glutamyl 
Transferase 
High 
>ULN - 2.5 x ULN 
if baseline was 
normal; 2.0 - 2.5 x 
baseline if baseline 
was abnormal  
>2.5 - 5.0 x ULN if 
baseline was normal; 
>2.5 - 5.0 x baseline 
if baseline was 
abnormal  
>5.0 - 20.0 x ULN if 
baseline was normal; 
>5.0 - 20.0 x baseline 
if baseline was 
abnormal  
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal  
Hemoglobin 
increased 
Hemoglobin 
High 
Increase in >0 - 2 
g/dL 
Increase in >2 - 4 
g/dL  
Increase in >4 g/dL 
- 
Hypercalcemia 
Calcium 
High 
>ULN - 11.5 
mg/dL; >ULN - 2.9 
mmol/L 
>11.5 - 12.5 mg/dL; 
>2.9 - 3.1 mmol/L 
>12.5 - 13.5 mg/dL; 
>3.1 - 3.4 mmol/L 
>13.5 mg/dL; >3.4 
mmol/L 
Hyperkalemia 
Potassium 
High 
>ULN - 5.5 
mmol/L 
>5.5 - 6.0 mmol/L 
>6.0 - 7.0 mmol/L 
>7.0 mmol/L 
Hypernatremia 
Sodium 
High 
>ULN - 150 
mmol/L 
>150 - 155 mmol/L 
>155 - 160 mmol/L; 
>160 mmol/L 
Hypoalbuminemia 
Albumin 
Low 
<LLN - 3 g/dL; 
<LLN - 30 g/L 
<3 - 2 g/dL; 
<30 - 20 g/L 
<2 g/dL; 
<20 g/L 
- 


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CTCAE Term 
Laboratory 
Parameter 
 
Level 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hypocalcemia 
Calcium 
Low 
<LLN - 8.0 mg/dL; 
<LLN - 2.0 
mmol/L 
<8.0 - 7.0 mg/dL; 
<2.0 - 1.75 mmol/L 
<7.0 - 6.0 mg/dL; 
<1.75 - 1.5 mmol/L 
<6.0 mg/dL; <1.5 
mmol/L 
Hypoglycemia 
Glucose 
Low 
<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 
Hypokalemia 
Potassium 
Low 
<LLN - 3.0 
mmol/L 
- 
<3.0 - 2.5 mmol/L 
<2.5 mmol/L 
Hyponatremia 
Sodium 
Low 
<LLN - 130 
mmol/L 
<130 - <124 mmol/L 
<=124 - 120 mmol/L 
<120 mmol/L 
Neutrophil count 
decreased 
Absolute 
neutrophil count 
Low 
<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 
decreased 
Platelets 
Low 
<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 
White blood cell 
decreased 
White blood cell 
count 
Low 
<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 
Cholesterol high 
Total cholesterol 
High 
>ULN - 300 
mg/dL; >ULN - 
7.75 mmol/L  
>300 - 400 mg/dL; 
>7.75 - 10.34 
mmol/L  
>400 - 500 mg/dL; 
>10.34 - 12.92 
mmol/L  
>500 mg/dL; 
>12.92 mmol/L 


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CTCAE Term 
Laboratory 
Parameter 
 
Level 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Proteinuria1  
Protein 
(Urinalysis) 
High 
1+ proteinuria 
2+ and 3+ 
proteinuria  
4+ proteinuria 
- 
Proteinuria1 
24 hours urine 
collection 
(protein) 
High 
≥ ULN - <1.0 g/24 
hrs 
1.0 - <3.5 g/24 hrs 
≥ 3.5 g/24 hrs 
- 
Hypertriglyceride
mia  
Triglyceride 
High 
150 - 300 mg/dL;  
1.71 - 3.42 mmol/L 
>300 - 500 mg/dL; 
>3.42 - 5.7 mmol/L  
>500 - 1000 mg/dL;  
>5.7 - 11.4 mmol/L  
>1000 mg/dL;  
>11.4 mmol/L 
Note: LLN: Lower Limit of Normal, ULN: Upper Limit of Normal. 
A Semi-colon indicates ‘or’ within the description of the grade. 
A single dash (-) indicates a grade is not available. 
1 The most severe grade is counted if the CTCAE grade is discrepant by multiple definitions. 


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14.3. TEAE of Special Interest 
Event of Interest 
SMQ Category/ Capture Logic 
Hypersensitivity/infusion-
related reactions 
captured on CRF (recorded as IRR in the AE page) 
Gastrointestinal 
perforations and fistulae 
SMQ Category: Gastrointestinal perforation 
captured by PTs as follows: Abdominal abscess, Abdominal hernia perforation, Abdominal wall abscess, Abscess intestinal, 
Acquired tracheo-oesophageal fistula, Anal abscess, Anal fistula, Anal fistula infection, Anal fistula repair, Anastomotic ulcer 
perforation, Anovulvar fistula, Aortoenteric fistula, Aorto-oesophageal fistula, Appendiceal abscess, Appendicitis perforated, 
Arterioenteric fistula, Atrio-oesophageal fistula, Chemical peritonitis, Colon fistula repair, Colonic abscess, Colonic fistula, 
Colo-urethral fistula, Diverticular fistula, Diverticular perforation, Diverticulitis intestinal perforated, Douglas' abscess, 
Duodenal perforation, Duodenal ulcer perforation, Duodenal ulcer perforation, obstructive, Duodenal ulcer repair, Enterocolonic 
fistula, Enterocutaneous fistula, Enterovesical fistula, Fistula of small intestine, Focal peritonitis, Gastric fistula, Gastric fistula 
repair, Gastric perforation, Gastric ulcer perforation, Gastric ulcer perforation, obstructive, Gastrointestinal anastomotic leak, 
Gastrointestinal fistula, Gastrointestinal fistula repair, Gastrointestinal perforation, Gastrointestinal ulcer perforation, 
Gastropleural fistula, Gastrosplenic fistula, Ileal perforation, Ileal ulcer perforation, Incisional hernia perforation, Inguinal hernia 
perforation, Intestinal fistula, Intestinal fistula infection, Intestinal fistula repair, Intestinal perforation, Intestinal ulcer 
perforation, Jejunal perforation, Jejunal ulcer perforation, Large intestinal ulcer perforation, Large intestine perforation, Lower 
gastrointestinal perforation, Mesenteric abscess, Neonatal intestinal perforation, Oesophageal abscess, Oesophageal fistula, 
Oesophageal fistula repair, Oesophageal perforation, Oesophageal rupture, Oesophageal ulcer perforation, Oesophageal-
pulmonary fistula, Oesophagobronchial fistula, Oesophagomediastinal fistula, Oesophagopleural fistula, Pancreatic fistula, 
Pancreatic fistula repair, Peptic ulcer perforation, Peptic ulcer perforation, obstructive, Perforated peptic ulcer oversewing, 
Perforated ulcer, Perineal abscess, Perirectal abscess, Peritoneal abscess, Peritoneocutaneous fistula, Peritonitis, Peritonitis 
bacterial, Pneumoperitoneum, Pneumoretroperitoneum, Procedural intestinal perforation, Rectal abscess, Rectal fistula repair, 
Rectal perforation, Rectoprostatic fistula, Rectourethral fistula, Retroperitoneal abscess, Small intestinal perforation, Small 
intestinal ulcer perforation, Umbilical hernia perforation, Upper gastrointestinal perforation 
Wound healing 
complications 
captured by PTs as follows: Abdominal Wound Dehiscence, Anastomotic Complication, Anastomotic Leak, Anastomotic Ulcer 
Perforation, Debridement, Excessive Granulation Tissue, Fungating Wound, Gastrointestinal Stoma Complication, Graft 
Infection, Impaired Healing, Implant Site Abscess, Incision Site Abscess, Incision Site Cellulitis, Incision Site Complication, 
Incision Site Erythema, Incision Site Haematoma, Incision Site Haemorrhage, Incision Site Infection, Incision Site Oedema, 
Incision Site Ulcer, Inflammation Of Wound, Injection Site Ulcer, Intestinal Anastomosis Complication, Necrotising Fasciitis, 
Necrotising Fasciitis Fungal, Necrotising Fasciitis Staphylococcal, Necrotising Fasciitis Streptococcal, Post Procedural 
Cellulitis, Post Procedural Persistent Drain Fluid, Postoperative Wound Complication, Postoperative Wound Infection, 
Reproductive Tract Anastomotic Leak, Skin Graft Detachment, Skin Graft Failure, Urinary Anastomotic Leak, Wound, Wound 
Abscess, Wound Complication, Wound Decomposition, Wound Dehiscence, Wound Evisceration, Wound Haemorrhage, 
Wound Haematoma, Wound Infection, Wound Infection Bacterial, Wound Infection Fungal, Wound Infection Helminthic, 


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Wound Infection Pseudomonas, Wound Infection Staphylococcal, Wound Infection Viral, Wound Necrosis, Wound Secretion, 
Wound Sepsis 
Hypertension 
SMQ Category: Hypertension 
captured by PTs as follows: Accelerated hypertension, Blood pressure ambulatory increased, Blood pressure diastolic increased, 
Blood pressure inadequately controlled, Blood pressure increased, Blood pressure management, Blood pressure orthostatic 
increased, Blood pressure systolic increased, Catecholamine crisis, Dialysis induced hypertension, Diastolic hypertension, 
Eclampsia, Endocrine hypertension, Essential hypertension, Gestational hypertension, HELLP syndrome, Hyperaldosteronism, 
Hypertension, Hypertension neonatal, Hypertensive angiopathy, Hypertensive cardiomegaly, Hypertensive cardiomyopathy, 
Hypertensive cerebrovascular disease, Hypertensive crisis, Hypertensive emergency, Hypertensive encephalopathy, 
Hypertensive end-organ damage, Hypertensive heart disease, Hypertensive nephropathy, Hypertensive urgency, Labile 
hypertension, Malignant hypertension, Malignant hypertensive heart disease, Malignant renal hypertension, Maternal 
hypertension affecting foetus, Mean arterial pressure increased, Metabolic syndrome, Neurogenic hypertension, Orthostatic 
hypertension, Page kidney, Postoperative hypertension, Pre-eclampsia, Prehypertension, Procedural hypertension, Renal 
hypertension, Renal sympathetic nerve ablation, Renovascular hypertension, Retinopathy hypertensive, Secondary 
aldosteronism, Secondary hypertension, Superimposed pre-eclampsia, Supine hypertension, Systolic hypertension, Withdrawal 
hypertension 
Posterior reversible 
encephalopathy syndrome 
captured by PT as follow: Posterior reversible encephalopathy syndrome 
Proteinuria 
SMQ Category: Proteinuria 
captured by PTs as follows: Albumin globulin ratio increased, Albumin urine present, Albuminuria, Bence Jones protein urine 
present, Bence Jones proteinuria, Beta 2 microglobulin urine increased, Globulinuria, Microalbuminuria, Myoglobinuria, 
Orthostatic proteinuria, Protein urine, Protein urine present, Proteinuria, Urine albumin/creatinine ratio increased, Urine 
protein/creatinine ratio abnormal, Urine protein/creatinine ratio increased 
Arterial thromboembolism 
SMQ Category: Embolic and thrombotic events, arterial 
captured by PTs as follows: Acute aortic syndrome, Acute myocardial infarction, Amaurosis, Amaurosis fugax, Angioplasty, 
Aortic bypass, Aortic embolus, Aortic surgery, Aortic thrombosis, Aortogram abnormal, Arterectomy, Arterectomy with graft 
replacement, Arterial angioplasty, Arterial bypass operation, Arterial graft, Arterial occlusive disease, Arterial revascularisation, 
Arterial stent insertion, Arterial therapeutic procedure, Arterial thrombosis, Arteriogram abnormal, Arteriogram carotid 
abnormal, Arteriotomy, Atherectomy, Atherosclerotic plaque rupture, Atrial appendage closure, Atrial appendage resection, 
Basal ganglia infarction, Basilar artery occlusion, Basilar artery thrombosis, Blindness transient, Brachiocephalic artery 
occlusion, Capsular warning syndrome, Carotid angioplasty, Carotid arterial embolus, Carotid artery bypass, Carotid artery 
occlusion, Carotid artery stent insertion, Carotid artery thrombosis, Carotid endarterectomy, Cerebellar artery occlusion, 


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Cerebellar artery thrombosis, Cerebral artery embolism, Cerebral artery occlusion, Cerebral artery stent insertion, Cerebral 
artery thrombosis, Cerebral hypoperfusion, Cerebrovascular insufficiency, Cerebrovascular stenosis, Coeliac artery occlusion, 
Coronary angioplasty, Coronary arterial stent insertion, Coronary artery bypass, Coronary artery embolism, Coronary artery 
occlusion, Coronary artery reocclusion, Coronary artery surgery, Coronary artery thrombosis, Coronary endarterectomy, 
Coronary revascularisation, Coronary vascular graft occlusion, Embolia cutis medicamentosa, Embolism arterial, 
Endarterectomy, Femoral artery embolism, Hepatic artery embolism, Hepatic artery occlusion, Hepatic artery thrombosis, 
Hypothenar hammer syndrome, Iliac artery embolism, Iliac artery occlusion, Internal capsule infarction, Intra-aortic balloon 
placement, Intraoperative cerebral artery occlusion, Ischaemic cerebral infarction, Ischaemic stroke, Lacunar infarction, Left 
atrial appendage closure implant, Leriche syndrome, Mesenteric arterial occlusion, Mesenteric arteriosclerosis, Mesenteric 
artery embolism, Mesenteric artery stenosis, Mesenteric artery stent insertion, Mesenteric artery thrombosis, Myocardial 
infarction, Myocardial necrosis, Ophthalmic artery thrombosis, Papillary muscle infarction, Penile artery occlusion, 
Percutaneous coronary intervention, Peripheral arterial occlusive disease, Peripheral arterial reocclusion, Peripheral artery 
angioplasty, Peripheral artery bypass, Peripheral artery occlusion, Peripheral artery stent insertion, Peripheral artery surgery, 
Peripheral artery thrombosis, Peripheral embolism, Peripheral endarterectomy, Popliteal artery entrapment syndrome, Post 
procedural myocardial infarction, Postinfarction angina, Precerebral artery embolism, Precerebral artery occlusion, Precerebral 
artery thrombosis, Profundaplasty, Pulmonary artery occlusion, Pulmonary artery therapeutic procedure, Pulmonary artery 
thrombosis, Pulmonary endarterectomy, Pulmonary tumour thrombotic microangiopathy, Renal artery angioplasty, Renal artery 
occlusion, Renal artery thrombosis, Renal embolism, Renal-limited thrombotic microangiopathy, Retinal artery embolism, 
Retinal artery occlusion, Retinal artery thrombosis, Silent myocardial infarction, Spinal artery embolism, Spinal artery 
thrombosis, Splenic artery thrombosis, Splenic embolism, Stress cardiomyopathy, Subclavian artery embolism, Subclavian 
artery occlusion, Subclavian artery thrombosis, Thromboembolectomy, Thrombotic microangiopathy, Thrombotic 
thrombocytopenic purpura, Transient ischaemic attack, Truncus coeliacus thrombosis, Vascular pseudoaneurysm thrombosis, 
Vertebral artery occlusion, Vertebral artery thrombosis, Visual acuity reduced transiently 
Venous thromboembolism 
SMQ Category: Embolic and thrombotic events, venous 
captured by PTs as follows: Aseptic cavernous sinus thrombosis, Axillary vein thrombosis, Brachiocephalic vein occlusion, 
Brachiocephalic vein thrombosis, Budd-Chiari syndrome, Catheterisation venous, Cavernous sinus thrombosis, Central venous 
catheterisation, Cerebral venous sinus thrombosis, Cerebral venous thrombosis, Compression garment application, Deep vein 
thrombosis, Deep vein thrombosis postoperative, Embolism venous, Hepatic vein embolism, Hepatic vein occlusion, Hepatic 
vein thrombosis, Homans' sign positive, Iliac vein occlusion, Inferior vena cava syndrome, Inferior vena caval occlusion, 
Jugular vein embolism, Jugular vein occlusion, Jugular vein thrombosis, Mahler sign, May-Thurner syndrome, Mesenteric vein 
thrombosis, Mesenteric venous occlusion, Obstetrical pulmonary embolism, Obstructive shock, Ophthalmic vein thrombosis, 
Ovarian vein thrombosis, Paget-Schroetter syndrome, Pelvic venous thrombosis, Penile vein thrombosis, Peripheral vein 
occlusion, Peripheral vein thrombus extension, Phlebectomy, Portal vein cavernous transformation, Portal vein embolism, Portal 


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vein occlusion, Portal vein thrombosis, Portosplenomesenteric venous thrombosis, Post procedural pulmonary embolism, Post 
thrombotic syndrome, Postoperative thrombosis, Postpartum venous thrombosis, Pulmonary embolism, Pulmonary infarction, 
Pulmonary microemboli, Pulmonary thrombosis, Pulmonary vein occlusion, Pulmonary veno-occlusive disease, Pulmonary 
venous thrombosis, Renal vein embolism, Renal vein occlusion, Renal vein thrombosis, Retinal vein occlusion, Retinal vein 
thrombosis, Septic pulmonary embolism, SI QIII TIII pattern, Splenic vein occlusion, Splenic vein thrombosis, Subclavian vein 
occlusion, Subclavian vein thrombosis, Superior sagittal sinus thrombosis, Superior vena cava occlusion, Superior vena cava 
syndrome, Thrombophlebitis, Thrombophlebitis migrans, Thrombophlebitis neonatal, Thrombophlebitis superficial, 
Thrombosed varicose vein, Thrombosis corpora cavernosa, Transverse sinus thrombosis, Vena cava embolism, Vena cava filter 
insertion, Vena cava filter removal, Vena cava thrombosis, Venogram abnormal, Venoocclusive disease, Venoocclusive liver 
disease, Venous angioplasty, Venous occlusion, Venous operation, Venous recanalisation, Venous repair, Venous stent 
insertion, Venous thrombosis, Venous thrombosis in pregnancy, Venous thrombosis limb, Venous thrombosis neonatal, Visceral 
venous thrombosis 
Hemorrhages (Bleeding) 
 
SMQ Category: Haemorrhage terms (excl laboratory terms) 
captured by PTs as follows: Abdominal wall haematoma, Abdominal wall haemorrhage, Abnormal uterine bleeding, Abnormal 
withdrawal bleeding, Achenbach syndrome, Acute haemorrhagic leukoencephalitis, Acute haemorrhagic ulcerative colitis, 
Administration site bruise, Administration site haematoma, Administration site haemorrhage, Adrenal haematoma, Adrenal 
haemorrhage, Anal fissure haemorrhage, Anal haemorrhage, Anal ulcer haemorrhage, Anastomotic haemorrhage, Anastomotic 
ulcer haemorrhage, Aneurysm ruptured, Angina bullosa haemorrhagica, Anorectal varices haemorrhage, Anticoagulant-related 
nephropathy, Antiplatelet reversal therapy, Aortic aneurysm rupture, Aortic dissection rupture, Aortic intramural haematoma, 
Aortic perforation, Aortic rupture, Aponeurosis contusion, Application site bruise, Application site haematoma, Application site 
haemorrhage, Application site purpura, Arterial haemorrhage, Arterial intramural haematoma, Arterial perforation, Arterial 
rupture, Arteriovenous fistula site haematoma, Arteriovenous fistula site haemorrhage, Arteriovenous graft site haematoma, 
Arteriovenous graft site haemorrhage, Astringent therapy, Atrial rupture, Auricular haematoma, Basal ganglia haematoma, Basal 
ganglia haemorrhage, Basilar artery perforation, Bladder tamponade, Bleeding varicose vein, Blood blister, Blood loss anaemia, 
Blood urine, Blood urine present, Bloody discharge, Bloody peritoneal effluent, Bone contusion, Bone marrow haemorrhage, 
Brain contusion, Brain stem haematoma, Brain stem haemorrhage, Brain stem microhaemorrhage, Breast haematoma, Breast 
haemorrhage, Broad ligament haematoma, Bronchial haemorrhage, Bronchial varices haemorrhage, Bullous haemorrhagic 
dermatosis, Bursal haematoma, Cardiac contusion, Carotid aneurysm rupture, Carotid artery perforation, Catheter site bruise, 
Catheter site haematoma, Catheter site haemorrhage, Central nervous system haemorrhage, Cephalhaematoma, Cerebellar 
haematoma, Cerebellar haemorrhage, Cerebellar microhaemorrhage, Cerebral aneurysm perforation, Cerebral aneurysm 
ruptured syphilitic, Cerebral arteriovenous malformation haemorrhagic, Cerebral artery perforation, Cerebral cyst haemorrhage, 
Cerebral haematoma, Cerebral haemorrhage, Cerebral haemorrhage foetal, Cerebral haemorrhage neonatal, Cerebral 
microhaemorrhage, Cervix haematoma uterine, Cervix haemorrhage uterine, Chest wall haematoma, Choroidal haematoma, 
Choroidal haemorrhage, Chronic gastrointestinal bleeding, Chronic pigmented purpura, Ciliary body haemorrhage, Coital 
bleeding, Colonic haematoma, Conjunctival haemorrhage, Contusion, Corneal bleeding, Cullen's sign, Cystitis haemorrhagic, 
Deep dissecting haematoma, Diarrhoea haemorrhagic, Disseminated intravascular coagulation, Diverticulitis intestinal 


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haemorrhagic, Diverticulum intestinal haemorrhagic, Duodenal ulcer haemorrhage, Duodenitis haemorrhagic, Ear haemorrhage, 
Ecchymosis, Encephalitis haemorrhagic, Enterocolitis haemorrhagic, Epidural haemorrhage, Epistaxis, Exsanguination, Extra-
axial haemorrhage, Extradural haematoma, Extradural haematoma evacuation, Extravasation blood, Eye contusion, Eye 
haematoma, Eye haemorrhage, Eyelid bleeding, Eyelid contusion, Eyelid haematoma, Femoral artery perforation, Femoral vein 
perforation, Foetal-maternal haemorrhage, Fothergill sign positive, Gastric haemorrhage, Gastric ulcer haemorrhage, Gastric 
ulcer haemorrhage, obstructive, Gastric varices haemorrhage, Gastritis alcoholic haemorrhagic, Gastritis haemorrhagic, 
Gastroduodenal haemorrhage, Gastrointestinal haemorrhage, Gastrointestinal polyp haemorrhage, Gastrointestinal ulcer 
haemorrhage, Gastrointestinal vascular malformation haemorrhagic, Genital contusion, Genital haemorrhage, Gingival bleeding, 
Graft haemorrhage, Grey Turner's sign, Haemangioma rupture, Haemarthrosis, Haematemesis, Haematochezia, Haematocoele, 
Haematoma, Haematoma evacuation, Haematoma infection, Haematoma muscle, Haematosalpinx, Haematospermia, 
Haematotympanum, Haematuria, Haematuria traumatic, Haemobilia, Haemoperitoneum, Haemophilic arthropathy, Haemophilic 
pseudotumour, Haemoptysis, Haemorrhage, Haemorrhage coronary artery, Haemorrhage foetal, Haemorrhage in pregnancy, 
Haemorrhage intracranial, Haemorrhage neonatal, Haemorrhage subcutaneous, Haemorrhage subepidermal, Haemorrhage 
urinary tract, Haemorrhagic adrenal infarction, Haemorrhagic arteriovenous malformation, Haemorrhagic ascites, Haemorrhagic 
breast cyst, Haemorrhagic cerebral infarction, Haemorrhagic cyst, Haemorrhagic diathesis, Haemorrhagic disease of newborn, 
Haemorrhagic disorder, Haemorrhagic erosive gastritis, Haemorrhagic gastroenteritis, Haemorrhagic hepatic cyst, Haemorrhagic 
infarction, Haemorrhagic necrotic pancreatitis, Haemorrhagic occlusive retinal vasculitis, Haemorrhagic ovarian cyst, 
Haemorrhagic stroke, Haemorrhagic thyroid cyst, Haemorrhagic transformation stroke, Haemorrhagic tumour necrosis, 
Haemorrhagic urticaria, Haemorrhagic vasculitis, Haemorrhoidal haemorrhage, Haemostasis, Haemothorax, Heavy menstrual 
bleeding, Henoch-Schonlein purpura, Hepatic haemangioma rupture, Hepatic haematoma, Hepatic haemorrhage, Hereditary 
haemorrhagic telangiectasia, Hyperfibrinolysis, Hyphaema, Iliac artery perforation, Iliac artery rupture, Iliac vein perforation, 
Immune thrombocytopenia, Implant site bruising, Implant site haematoma, Implant site haemorrhage, Incision site haematoma, 
Incision site haemorrhage, Increased tendency to bruise, Induced abortion haemorrhage, Inferior vena cava perforation, Infusion 
site bruising, Infusion site haematoma, Infusion site haemorrhage, Injection site bruising, Injection site haematoma, Injection 
site haemorrhage, Instillation site bruise, Instillation site haematoma, Instillation site haemorrhage, Intermenstrual bleeding, 
Internal haemorrhage, Intestinal haematoma, Intestinal haemorrhage, Intestinal varices haemorrhage, Intra-abdominal 
haematoma, Intra-abdominal haemorrhage, Intracerebral haematoma evacuation, Intracranial haematoma, Intracranial tumour 
haemorrhage, Intraocular haematoma, Intrapartum haemorrhage, Intratumoural haematoma, Intraventricular haemorrhage, 
Intraventricular haemorrhage neonatal, Iris haemorrhage, Joint microhaemorrhage, Jugular vein haemorrhage, Kidney contusion, 
Lacrimal haemorrhage, Large intestinal haemorrhage, Large intestinal ulcer haemorrhage, Laryngeal haematoma, Laryngeal 
haemorrhage, Lip haematoma, Lip haemorrhage, Liver contusion, Lower gastrointestinal haemorrhage, Lower limb artery 
perforation, Lymph node haemorrhage, Mallory-Weiss syndrome, Mediastinal haematoma, Mediastinal haemorrhage, Medical 
device site bruise, Medical device site haematoma, Medical device site haemorrhage, Melaena, Melaena neonatal, 
Meningorrhagia, Menometrorrhagia, Mesenteric haematoma, Mesenteric haemorrhage, Mouth haemorrhage, Mucocutaneous 
haemorrhage, Mucosal haemorrhage, Muscle contusion, Muscle haemorrhage, Myocardial haemorrhage, Myocardial rupture, 
Naevus haemorrhage, Nail bed bleeding, Nasal septum haematoma, Neonatal gastrointestinal haemorrhage, Nephritis 


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haemorrhagic, Nipple exudate bloody, Ocular retrobulbar haemorrhage, Oesophageal haemorrhage, Oesophageal intramural 
haematoma, Oesophageal ulcer haemorrhage, Oesophageal varices haemorrhage, Oesophagitis haemorrhagic, Omental 
haemorrhage, Optic disc haemorrhage, Optic nerve sheath haemorrhage, Oral blood blister, Oral contusion, Oral mucosa 
haematoma, Oral purpura, Orbital haematoma, Orbital haemorrhage, Osteorrhagia, Ovarian haematoma, Ovarian haemorrhage, 
Palpable purpura, Pancreatic haemorrhage, Pancreatic pseudocyst haemorrhage, Pancreatitis haemorrhagic, Papillary muscle 
haemorrhage, Paranasal sinus haematoma, Paranasal sinus haemorrhage, Parathyroid haemorrhage, Parotid gland haemorrhage, 
Pelvic haematoma, Pelvic haematoma obstetric, Pelvic haemorrhage, Penile contusion, Penile haematoma, Penile haemorrhage, 
Peptic ulcer haemorrhage, Pericardial haemorrhage, Perineal haematoma, Periorbital haematoma, Periorbital haemorrhage, 
Periosteal haematoma, Peripartum haemorrhage, Peripheral artery aneurysm rupture, Peripheral artery haematoma, Peritoneal 
haematoma, Periventricular haemorrhage neonatal, Petechiae, Pharyngeal contusion, Pharyngeal haematoma, Pharyngeal 
haemorrhage, Pituitary apoplexy, Pituitary haemorrhage, Placenta praevia haemorrhage, Polymenorrhagia, Post abortion 
haemorrhage, Post procedural contusion, Post procedural haematoma, Post procedural haematuria, Post procedural 
haemorrhage, Post transfusion purpura, Postmenopausal haemorrhage, Postpartum haemorrhage, Post-traumatic punctate 
intraepidermal haemorrhage, Premature separation of placenta, Procedural haemorrhage, Proctitis haemorrhagic, Prostatic 
haemorrhage, Pulmonary alveolar haemorrhage, Pulmonary contusion, Pulmonary haematoma, Pulmonary haemorrhage, 
Pulmonary haemorrhage neonatal, Puncture site bruise, Puncture site haematoma, Puncture site haemorrhage, Purpura, Purpura 
fulminans, Purpura neonatal, Purpura non-thrombocytopenic, Purpura senile, Putamen haemorrhage, Radiation associated 
haemorrhage, Rectal haemorrhage, Rectal ulcer haemorrhage, Renal artery perforation, Renal cyst haemorrhage, Renal 
haematoma, Renal haemorrhage, Respiratory tract haemorrhage, Respiratory tract haemorrhage neonatal, Retinal aneurysm 
rupture, Retinal haemorrhage, Retinopathy haemorrhagic, Retroperitoneal haematoma, Retroperitoneal haemorrhage, 
Retroplacental haematoma, Ruptured cerebral aneurysm, Scleral haematoma, Scleral haemorrhage, Scrotal haematocoele, 
Scrotal haematoma, Scrotal haemorrhage, Shock haemorrhagic, Skin haemorrhage, Skin neoplasm bleeding, Skin ulcer 
haemorrhage, Small intestinal haemorrhage, Small intestinal ulcer haemorrhage, Soft tissue haemorrhage, Spermatic cord 
haemorrhage, Spinal cord haematoma, Spinal cord haemorrhage, Spinal epidural haematoma, Spinal epidural haemorrhage, 
Spinal subarachnoid haemorrhage, Spinal subdural haematoma, Spinal subdural haemorrhage, Spleen contusion, Splenic artery 
perforation, Splenic haematoma, Splenic haemorrhage, Splenic varices haemorrhage, Splinter haemorrhages, Spontaneous 
haematoma, Spontaneous haemorrhage, Stoma site haemorrhage, Stomatitis haemorrhagic, Subarachnoid haematoma, 
Subarachnoid haemorrhage, Subarachnoid haemorrhage neonatal, Subcapsular hepatic haematoma, Subcapsular renal 
haematoma, Subcapsular splenic haematoma, Subchorionic haematoma, Subchorionic haemorrhage, Subclavian artery 
perforation, Subclavian vein perforation, Subcutaneous haematoma, Subdural haematoma, Subdural haematoma evacuation, 
Subdural haemorrhage, Subdural haemorrhage neonatal, Subendocardial haemorrhage, Subgaleal haematoma, Subgaleal 
haemorrhage, Subretinal haematoma, Superior vena cava perforation, Testicular haemorrhage, Thalamus haemorrhage, Third 
stage postpartum haemorrhage, Thoracic haemorrhage, Thrombocytopenic purpura, Thrombotic thrombocytopenic purpura, 
Thyroid haemorrhage, Tongue haematoma, Tongue haemorrhage, Tonsillar haemorrhage, Tooth pulp haemorrhage, Tooth 
socket haemorrhage, Tracheal haemorrhage, Traumatic haematoma, Traumatic haemorrhage, Traumatic haemothorax, 
Traumatic intracranial haematoma, Traumatic intracranial haemorrhage, Tumour haemorrhage, Ulcer haemorrhage, Umbilical 


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cord haemorrhage, Umbilical haematoma, Umbilical haemorrhage, Upper gastrointestinal haemorrhage, Ureteric haemorrhage, 
Urethral haemorrhage, Urinary bladder haematoma, Urinary bladder haemorrhage, Urinary occult blood, Urinary occult blood 
positive, Urogenital haemorrhage, Uterine haematoma, Uterine haemorrhage, Vaccination site bruising, Vaccination site 
haematoma, Vaccination site haemorrhage, Vaginal haematoma, Vaginal haemorrhage, Varicose vein ruptured, Vascular access 
site bruising, Vascular access site haematoma, Vascular access site haemorrhage, Vascular access site rupture, Vascular 
anastomotic haemorrhage, Vascular graft haemorrhage, Vascular pseudoaneurysm ruptured, Vascular purpura, Vascular rupture, 
Vein rupture, Venous haemorrhage, Venous perforation, Ventricle rupture, Vertebral artery perforation, Vessel puncture site 
bruise, Vessel puncture site haematoma, Vessel puncture site haemorrhage, Vitreous haematoma, Vitreous haemorrhage, Vulval 
haematoma, Vulval haematoma evacuation, Vulval haemorrhage, Withdrawal bleed, Wound haematoma, Wound haemorrhage 
 
Congestive heart failure 
SMQ Category: Cardiac failure 
captured by PTs as follows: Acute left ventricular failure, Acute pulmonary oedema, Acute right ventricular failure, Cardiac 
asthma, Cardiac failure, Cardiac failure acute, Cardiac failure chronic, Cardiac failure congestive, Cardiac failure high output, 
Cardiogenic shock, Cardiohepatic syndrome, Cardiopulmonary failure, Cardiorenal syndrome, Chronic left ventricular failure, 
Chronic right ventricular failure, Congestive hepatopathy, Cor pulmonale, Cor pulmonale acute, Cor pulmonale chronic, 
Ejection fraction decreased, Hepatojugular reflux, Left ventricular failure, Low cardiac output syndrome, Neonatal cardiac 
failure, Obstructive shock, Pulmonary oedema, Pulmonary oedema neonatal, Radiation associated cardiac failure, Right 
ventricular ejection fraction decreased, Right ventricular failure, Ventricular failure 
Ovarian failure/fertility 
captured by PT as follow: Ovarian failure 


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14.4. Date Imputation 
14.4.1. Medication 
Incomplete medications start and stop dates will be imputed as follows: 
If the stop date is incomplete the following rules will be applied: 
• 
If ‘Yes’ is recorded for ‘If stop date is unknown, was this drug stopped before the 
first administration of study drug?’ on ‘Prior & Concomitant Medications’ eCRF 
page: Assume the first administration date – 1. 
• 
If ‘No’ is recorded for ‘If stop date is unknown, was this drug stopped before the 
first administration of study drug?’ on ‘Prior & Concomitant Medications’ eCRF 
page:   
o 
Missing day: Assume the last day of the month.  
o 
Missing day and month: Assume December 31st. 
o 
Missing day, month and year: Leave it as Missing. 
In the case of the death of a patient and the imputed end date is after the date of death, the 
end date will be imputed as the date of death. 
If the start date is incomplete the following rules will be applied. If the stop date is 
incomplete, imputed end date will be used instead of reported end date:  
• 
Missing day (e.g. XXFEB2019): the month and year of the partial date will be 
compared to the date of the first infusion. 
o If the month and the year are equal for both dates, the start date will be 
imputed as the earlier date of: (i) the date of the first infusion, or (ii) the 
recorded/imputed stop date of the medication. If the recorded/imputed stop 
date is missing, the start date will be imputed as the first infusion. 
o If the month or the year are not equal for both dates, the start date will be 
imputed as the first day of the month (e.g. 01FEB2019). 
• 
Missing day and month (e.g. XXXX2019): the year of the partial date will be 
compared to the date of the first infusion. 
o If the year are equal for both dates, the start date will be imputed as the earlier 
date of: (i) the date of the first infusion, or (ii) the recorded/imputed stop date 
of the medication. If the recorded/imputed stop date is missing, the start date 
will be imputed as the first infusion. 
o If the year are not equal for both dates, the start date will be imputed as the 
first day of January of the year (e.g. 01JAN2019). 


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• 
Missing day, month and year (e.g. XXXXXXXX): the start date will be imputed 
as the earlier date of: (i) the date of first infusion, or (ii) the recorded/imputed stop 
date of the medication. If the recorded/imputed stop date is missing, the start date 
will be imputed as the date of first infusion. 
14.4.2. Adverse Events 
If the AE stop date is incomplete the following rules will be applied. 
• 
Missing day: Assume the last day of the month.  
• 
Missing day and month: Assume December 31st. 
• 
Missing day, month and year: Leave it as Missing. 
In the case of the death of a patient and the imputed stop date is after the date of death, the 
stop date will be imputed as the date of death. 
If the start date is incomplete the following rules will be applied.  
• 
Missing day (e.g. XXFEB2019): the month and year of the partial date will be 
compared to the date of the first infusion. 
o If the month and the year are equal for both dates, the start date will be 
imputed as the earlier date of: (i) the date of the first infusion, or (ii) the 
recorded/imputed stop date of the AE. If the recorded/imputed stop date of 
the AE is missing, the start date will be imputed as the first infusion. 
o If the month or the year are not equal for both dates, the start date will be 
imputed as the first day of the month (e.g. 01FEB2019). 
• 
Missing day and month (e.g. XXXX2019): the year of the partial date will be 
compared to the date of the first infusion. 
o If the year are equal for both dates, the start date will be imputed as the earlier 
date of: (i) the date of the first infusion, or (ii) the recorded/imputed stop date 
of the AE. If the recorded/imputed stop date is missing, the start date will be 
imputed as the first infusion. 
o If the year are not equal for both dates, the start date will be imputed as the 
first day of January of the year (e.g. 01JAN2019). 
• 
Missing day, month and year (e.g. XXXXXXXX): the start date will be imputed 
as the earlier date of: (i) the date of first infusion, or (ii) the recorded/imputed stop 
date of the AE. If the recorded/imputed stop date is missing, the start date will be 
imputed as the date of first infusion. 
14.4.3. Death  
For the purposes of inclusion in the survival analysis, incomplete death dates will be 
imputed as follow: 


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• 
If the reason for end of study participation on the ‘End of Study Participation’ 
eCRF page is ‘Death’ and the death date is incomplete, then death date will be 
imputed as the date of end of study participation on the ‘End of Study Participation’ 
eCRF page. 
• 
If the day of death is missing (e.g. XXFEB2021), the month and year of the partial 
date will be compared to the last known alive date. 
o If month and year are equal for both dates, then death date will be imputed as 
the last known alive date + 1. 
o If the month and year are not equal, the death date will be imputed as the first 
day of the month (e.g. 01FEB2021), provided partial death date > last known 
alive date. Otherwise, death date will be imputed as the last known alive date 
+ 1. 
• 
If the day and month of death date is missing (e.g. XXXXX2021), the year of the 
partial date will be compared to the last known alive date. 
o If year is equal for both dates, then death date will be imputed as the last 
known alive date + 1. 
o If partial year > year of the last known alive date, then death date will be 
imputed as 1st January of that year (e.g. 01JAN2021). Otherwise, death date 
will be imputed as the last known alive date + 1. 
14.5. Best Overall Response Confirmation 
• 
The main goal of confirmation of objective response is to avoid overestimating the 
response rate observed. In cases where confirmation of response is not feasible, it 
should be made clear when reporting the outcome of such studies that the responses 
are not confirmed. 
• 
To be assigned a status of PR or CR as BOR, changes in tumor measurements must 
be confirmed by repeat assessments that should be performed no less than 4 weeks 
after the criteria for response are first met. Longer intervals can be considered as 
12 weeks based on each case. 
• 
In the case of SD, follow-up measurements must have met the SD criteria at least 
once after the first study drug administration at a minimum interval of 6 weeks (42 
days) considering +/- 6 days, which is equivalent to a minimum time of 36 days. 
• 
Subsequent documentation of CR may provide confirmation of a previously 
identified CR for subjects where the second integrated response was NE. 
Subsequent documentation of PR may provide confirmation of a previously 


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identified PR for subjects where the second integrated response was NE or SD. If 
the third time point response confirms the CR (or PR) then the Confirmed 
Response will be CR (or PR). Only one intervening NE is allowed between 
CRs/PRs. For example: CR NE CR = CR; PR NE PR = PR. Additionally, one SD 
is allowed between PRs (e.g., PR SD PR = PR). 
• 
The best overall response is the best response recorded from the start of the study 
treatment to at a subsequent time point as specified in the protocol. The best overall 
response can be interpreted as below table. 
Overall 
Response 
First Time Point 
Overall 
Response 
Subsequent Time Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for 
SD duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for 
SD duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for 
SD duration met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for 
SD duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for 
SD duration met, otherwise, NE 
NE 
NE 
NE 
Source: RECIST v.1.1 (https://ctep.cancer.gov/protocoldevelopment/docs/recist_guideline.pdf) 
Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; 
NE, inevaluable. 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting 
PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after 
CR). Best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ 
may be claimed when subsequent scans suggest small lesions were likely still present and in fact the patient 
had PR, not CR at the first-time point. Under these circumstances, the original CR should be changed to PR 
and the best response is PR. 
 
• 
The overall response of Non-CR/Non-PD at time point will be considered as SD 
when the best overall response is determined.