Clinical trial NCT03247673
Conditions: Healthy
Keywords: safety Pharmacokinetics Immunogenicity
Sponsor: Celltrion
Start date: 2017-08-07; Completion date: 2018-01-17
Enrollment: 141 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a Phase 1 Randomized, Double-blind, Three-arm, Parallel Group, Single-dose Study to compare the PK, safety and immunogenicity of the proposed biosimilar test product CT-P16 with EU-approved Avastin and US-licensed Avastin after a single IV infusion of 5mg/kg of each product to healthy male subjects

Detailed description:
This study is a double-blind, three-arm, parallel group, single-dose study. A total of 141 subjects will be enrolled; 47 subjects in each of the 3 arms of the clinical study. In each arm, all subjects will receive a single dose (5 mg/kg) of either CT-P16, EU-approved Avastin, or US-licensed Avastin by intravenous (IV) infusion for 90 min (±5 min) on Day 1 followed by 15 weeks during which the PK, safety, and immunogenicity measurements will be made. The randomization will be stratified by body weight and site.

Arms: arm 1: CT-P16 will be administrated once in IV infusion of 5mg/KG to healthy male subjects arm 2: EU-approved Avastin will be administrated once in IV infusion of 5mg/KG to healthy male subjects arm 3: US-licensed Avastin will be administrated once in IV infusion of 5mg/KG to healthy male subjects
Interventions: intervention 1: CT-P16 intervention 2: EU-approved Avastin intervention 3: US-licensed Avastin
Intervention descriptions: intervention 1: CT-P16 is a biosimilar product for Avastin intervention 2: EU-approved Avastin intervention 3: US-licensed Avastin

Protocol documents:
SAP_002.pdf: 
 
 
 
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STATISTICAL ANALYSIS PLAN 
Protocol Name 
A Randomized, Double-blind, Three-arm, Parallel Group, Single-dose Study to Compare the 
Pharmacokinetics and Safety of Three Formulations of Bevacizumab (CT-P16, EU-approved 
Avastin and US-licensed Avastin) in Healthy Male Subjects 
 
Protocol No. 
CT-P16 1.1 Version 1.0 
Investigational Product 
CT-P16 
Version No (Date) 
V2.0 (29 MAR 2018) 
Written By 
Kim, Alyoung / Biostatistician 
 
C&R Research 
 


 
 
 
 
 
 
 
 
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Signature page 
 
The Statistical Analysis Plan was written by C&R Research according to ICH guideline, Local regulation 
and a related SOP (SOP 0400 Statistical Analysis Plan), after training related SOPs. 
 
Prepared by: 
 
 
 
 
 
 
 
 
 
Date (DD-MMM-YYYY) 
 
Name/Position 
 
Signature 
 
Reviewed by: (from C&R) 
 
 
 
 
 
 
 
Date (DD-MMM-YYYY) 
 
Name/Position 
 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
The Statistical Analysis Plan was approved by Sponsor. 
 
Approved by: 
 
 
 
 
 
 
 
 
 
Date (DD-MMM-YYYY) 
 
Name/Position 
 
Signature 
 


 
 
 
 
 
 
 
 
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Version Information (Document revision history) 
Version 
Effective Date 
Prepared by Name 
Details 
V1.0 
Sponsor’s final approved date 
Kim, Alyoung 
First Version 
V2.0 
Sponsor’s final approved date 
Kim, Alyoung 
Second Version 
 


 
 
 
 
 
 
 
 
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Abbreviation 
Term 
Definition 
ADA 
AE 
Anti-Drug Antibody 
Adverse Event  
AESI 
Adverse Event of Special Interest  
ATC  
Anatomical Therapeutic Chemical code 
AUC 
Area Under the Concentration-time curve  
AUC0-inf 
Area Under the Concentration-time curve from time zero to infinity  
AUC0-last 
Area Under the Concentration-time curve from time zero to the last quantifiable 
concentration  
BMI 
Body Mass Index 
CI 
Confidence Interval  
CL 
Total Body Clearance 
CTCAE 
Common Terminology Criteria for Adverse Events  
CV 
Coefficient of Variation  
Cmax 
Maximum serum concentration  
DRM 
Data Review Meeting 
ECG 
Electrocardiogram  
eCRF 
Electronic Case Report Form 
EOI 
End of Infusion 
EOS 
End of Study 
EU 
European Union  
ICH  
International Council for Harmonization 
IMP 
Investigational Medicinal Product 
IRR 
Infusion-Related Reaction 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
λz 
Terminal elimination rate constant  
MedDRA 
Medical Dictionary for Regulatory Activities 
NAb 
Neutralizing Antibody 
NCI 
National Cancer Institute 
PK 
Pharmacokinetic (s) 
PT  
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan  
SOC 
System Organ Class 


 
 
 
 
 
 
 
 
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Term 
Definition 
SOI 
Start of Infusion 
SOP 
Standard Operating Procedure 
t1/2 
Terminal half-life  
TEAE 
Treatment-Emergent Adverse Event  
TESAE 
Treatment-Emergent Serious Adverse Event 
Tmax 
Time to Cmax  
US 
United States 
Vz 
Volume of distribution during the terminal phase  
WHODD 
World Health Organization Drug Dictionary 


 
 
 
 
 
 
 
 
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Contents 
 
Signature page ............................................................................................................................... 2 
Version Information (Document revision history) ........................................................................ 3 
Abbreviation ................................................................................................................................... 4 
1. 
INTRODUCTION ........................................................................................................................ 8 
2. 
STUDY OBJECTIVES .................................................................................................................. 8 
2.1 
Primary Objective ......................................................................................................... 8 
2.2 
Secondary Objective(s) ................................................................................................ 8 
3. 
STUDY DESIGN ......................................................................................................................... 8 
4. 
ENDPOINTS .............................................................................................................................. 9 
4.1 
Primary Endpoints ........................................................................................................ 9 
4.2 
Secondary Endpoints ................................................................................................... 9 
5. 
GENERAL CONSIDERATIONS ................................................................................................. 10 
5.1 
General Considerations .............................................................................................. 10 
5.2 
Sample Size ................................................................................................................ 10 
5.3 
Randomization, Stratification and Unblinding .......................................................... 11 
5.4 
Analysis Populations .................................................................................................. 11 
5.5 
Protocol Deviation ..................................................................................................... 12 
5.6 
General Comments .................................................................................................... 12 
5.7 
Outlier ......................................................................................................................... 13 
6. 
SUBJECT DISPOSITION ........................................................................................................... 13 
6.1 
Screening Failure ........................................................................................................ 13 
6.2 
Subject Disposition .................................................................................................... 13 
6.3 
Subject Disposition and Analysis Population by Study Site ..................................... 13 
7. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ............................................................. 13 
7.1 
Demographics ............................................................................................................ 13 
7.2 
Medical History .......................................................................................................... 14 
7.3 
Inclusion and Exclusion Criteria ................................................................................. 14 
7.4 
Viral Serology ............................................................................................................. 15 
7.5 
Urine Drug Test .......................................................................................................... 15 
8. 
TREATMENTS AND MEDICATIONS ........................................................................................ 15 
8.1 
Prior and Concomitant Medications ......................................................................... 15 
8.2 
Extent of Exposure ..................................................................................................... 16 
9. 
PHARMACOKINETIC ANALYSIS .............................................................................................. 16 
9.1 
Handling of Values Below the Limit of Quantification (BLQ) ................................... 16 
9.2 
Serum Concentration ................................................................................................. 17 


 
 
 
 
 
 
 
 
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9.3 
Serum Pharmacokinetic Parameters .......................................................................... 18 
9.4 
Statistical Analysis of Pharmacokinetic Data ............................................................. 20 
10. SAFETY ANALYSIS ................................................................................................................... 20 
10.1 
Adverse Events .......................................................................................................... 20 
10.2 
Clinical Laboratory Tests ........................................................................................... 22 
10.3 
Hypersensitivity Monitoring ...................................................................................... 23 
10.4 
Vital Signs .................................................................................................................. 24 
10.5 
12-Lead Electrocardiogram ....................................................................................... 24 
10.6 
Physical Examination ................................................................................................. 24 
10.7 
Immunogenicity Analysis .......................................................................................... 25 
10.8 
Restriction Assessment ............................................................................................. 26 
11. APPENDICES ........................................................................................................................... 27 
11.1 
Schedule of Assessments .......................................................................................... 27 
11.2 
CTCAE Grades ............................................................................................................ 30 
11.3 
Laboratory Grades .................................................................................................... 31 
11.4 
Date Imputation for Prior and Concomitant Medication ........................................ 35 
11.5 
Tables, Listings, Figures ............................................................................................. 37 
12. ROLE & RESPONSIBILITIES ..................................................................................................... 42 
13. APPLIED SOPs ......................................................................................................................... 42 
 


 
 
 
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1. 
INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of data 
collected within the scope of CELLTRION, Inc., protocol CT-P16 1.1 (A Randomized, Double-blind, 
Three-arm, Parallel-group, Single-dose Study to Compare the Pharmacokinetics and Safety of Three 
Formulations of Bevacizumab [CT-P16, European Union (EU)-approved Avastin and United States (US)-
licensed Avastin] in Healthy Male Subjects) Version 1.0 dated 07 June 2017 and electronic case report 
form (eCRF) Version 3.0 dated 28 July 2017. The purpose of this plan is to provide specific guidelines 
for which the analyses will proceed. Any deviations from these guidelines will be documented in the 
clinical study report (CSR). The analyses described in this plan are considered a priori, in that they have 
been defined prior to database lock. Any analyses performed subsequent to database lock will be 
considered post-hoc and exploratory.  
 
2. 
STUDY OBJECTIVES  
2.1 
Primary Objective 
To demonstrate the similarity of the pharmacokinetics (PK) in terms of area under the concentration-
time curve from time zero to infinity (AUC0-inf), area under the concentration-time curve from time zero 
to the last quantifiable concentration (AUC0-last), and maximum serum concentration (Cmax) of CT-P16, 
EU-approved Avastin and US-licensed Avastin in healthy male subjects (CT-P16 to EU-approved Avastin, 
CT-P16 to US-licensed Avastin, and EU-approved Avastin to US-licensed Avastin). 
 
2.2 
Secondary Objective(s) 
• 
To assess the additional PK parameters of CT-P16, EU-approved Avastin and US-licensed Avastin in 
healthy male subjects. 
 
• 
To evaluate the safety and immunogenicity of CT-P16, EU-approved Avastin and US-licensed 
Avastin in healthy male subjects. 
 
3. 
STUDY DESIGN 
This study is a double-blind, three-arm, parallel group, single-dose study. A total of 141 healthy male 
subjects aged between 19 and 55 years will be enrolled; 47 subjects in each of the 3 arms of the 
clinical study. In each arm, all subjects will receive a single dose of CT-P16, EU-approved Avastin, or 
US-licensed Avastin by intravenous (IV) infusion for 90 min (±5 min) on Day 1 followed by 15 weeks 
during which the PK, safety and immunogenicity measurements will be made. 
Subjects will be screened for eligibility within 21 to 2 days before the infusion of the Investigational 
Medicinal Product (IMP) after they have signed an informed consent. Multiple visits may be needed 
during the screening period to complete study-related assessment. 
Eligible subjects will be admitted to the clinical unit on Day –1 to undergo baseline assessments and 
will be randomized on Day –1 to receive one of CT-P16, EU-approved Avastin, or US-licensed Avastin 


 
 
 
 
 
 
 
 
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once all eligibility criteria have been confirmed. Subjects will be confined to the clinical unit until 
completion of the 24-hour assessments after IMP administration. The consecutive study visits will be 
carried out on an out-patient basis. Blood for PK analysis will be collected up to Day 99. Safety will be 
assessed throughout the study by collection of information about AEs and concomitant medication, by 
clinical laboratory testing, measurement of vital signs, recording of 12-lead Electrocardiograms (ECGs), 
physical examination and assessment of the immunogenicity of CT-P16, EU-approved Avastin, and US-
licensed Avastin. An end-of-study (EOS) examination will take place on Day 99. 
The total duration of the participation will be up to 15 weeks for each individual subject who 
completes the entire clinical trial. 
 
4. 
ENDPOINTS 
4.1 
Primary Endpoints 
Pharmacokinetics 
• 
Area under the concentration-time curve from time zero to infinity (AUC0-inf) 
• 
Area under the concentration-time curve from time zero to the last quantifiable concentration 
(AUC0-last) 
• 
Maximum serum concentration (Cmax) 
 
4.2 
Secondary Endpoints 
Pharmacokinetics 
• 
Time to Cmax (Tmax) 
• 
Volume of distribution during the terminal phase (Vz) 
• 
Terminal elimination rate constant (λz) 
• 
Terminal half-life (t1/2) 
• 
Total body clearance (CL) 
• 
Percentage of AUC0-inf obtained by extrapolation (%AUCext) 
Safety and Immunogenicity 
• 
Vital signs (blood pressure [BP], heart rate [HR], body temperature [BT], and respiratory rate [RR]) 
• 
Physical examination 
• 
Clinical laboratory tests including hematology, chemistry, coagulation, and urinalysis 
• 
12-lead electrocardiogram (ECG) 
• 
Adverse events (AEs) and concomitant medication 
• 
Adverse event of special interest (AESI)  
• 
Immunogenicity of CT-P16, EU-approved Avastin and US-licensed Avastin 
 


 
 
 
 
 
 
 
 
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5. 
GENERAL CONSIDERATIONS 
5.1 
General Considerations 
Statistical analyses will be performed using SAS (SAS Institute Inc., Cary, North Carolina, United States 
of America [USA]), version 9.4.  
Continuous data will be summarized by treatment group using descriptive statistics (number, 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 Variance (CV) will be presented to 
two decimal places. Confidence Intervals (CIs) obtained from statistical procedures will be displayed to 
the same number of decimal places as the associated estimate is presented. 
If minimum value from the data is zero, geometric mean will not be calculated. 
Categorical data will be summarized by treatment group using frequency tables (number and 
percentage). Percentages will be suppressed when the count is zero. A row denoted “Missing” will be 
included in count tabulations where necessary to account for missing values. The denominator for all 
percentages will be the number of subjects within the randomized treatment group or the actual 
treatment group for the population of interest, unless otherwise indicated. Percentages will be 
presented to one decimal place.  
Data will be displayed in all listings sorted by treatment group and then subject 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 the sort order as applicable. 
EOS visit of early termination results will not be included in the summaries, but will be presented in 
data listings. Unscheduled results will not be included in the summary tables except for determining 
baseline, but will be presented in data listings. 
Baseline will be the latest available measurement including unscheduled assessment prior to the 
administration of IMP, unless otherwise indicated. 
This Statistical Analysis Plan (SAP) will be updated prior to unblinding after Data Review Meeting 
(DRM). 
 
5.2 
Sample Size 
This study is powered to demonstrate PK equivalence of CT-P16, EU-approved Avastin and US-licensed 
Avastin in AUC0-inf, AUC0-last, and Cmax. Assuming a CV of 30% and ratio of geometric means of 1.03, 42 
subjects for each arm are needed to achieve 90% power for a 90% CI for the ratio of AUC0-inf, AUC0-last, 
and Cmax to satisfy the equivalence margin of 80% to 125%. The sample size is calculated from two 
one-sided tests with each 5% significant level using geometric mean ratio. A 10% dropout rate is 
anticipated so approximately 141 subjects (47 subjects in each of 3 study arms; CT-P16, EU-approved 


 
 
 
 
 
 
 
 
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Avastin or US-licensed Avastin) will be enrolled. Sample size was calculated using nQuery Advisor 7.0 
(Statistical Solutions, Ltd., Cork, Ireland). 
 
5.3 
Randomization, Stratification and Unblinding 
Randomization will occur at Day -1 after all baseline assessments have been performed and eligibility 
for the study has been confirmed. Subjects will be randomly assigned to treatment groups (1:1:1 ratio 
to CT-P16, EU-approved Avastin, or US-licensed Avastin) using the Interactive Web Response System 
(IWRS). The randomization will be balanced by using permuted blocks and will be stratified by body 
weight (<70 kg vs ≥70 kg) and site. 
The study will be performed in a double-blind manner. All IMPs will be diluted by a designated 
unblinded pharmacist, and will be supplied to the treating physician or designee in a blinded manner, 
in identical infusion bags, thereby enabling double-blind conditions.  
The study blind should not be broken except in a medical emergency (where knowledge of the IMP 
administered would affect the treatment of the emergency) or regulatory requirement (e.g., for serious 
adverse events [SAEs] or death).  
If a subject is unblinded, the subject must be withdrawn from the clinical study and procedures 
accompanying withdrawal are to be performed. 
Suspected unexpected serious adverse reactions (SUSARs), which are subject to expedited reporting, 
should be unblinded before submission to the Competent Authorities. 
The overall randomization code will be broken only for reporting purposes once all final clinical data 
have been entered into the database and all data queries have been resolved, and the assignment of 
subjects to the analysis sets has been completed. The randomization code will not be revealed to 
study subjects, parents or guardians, study site staff, or Investigators. 
 
5.4 
Analysis Populations 
The following subject population are defined: all-randomized, safety, and PK. A summary table 
reflecting the numbers of subjects who comprised all-randomized, safety and PK population will be 
summarized by treatment group and overall. The number of subjects for all-randomized population is 
displayed using treatment to which they were randomized. For other populations, counts are based on 
the actual treatment they received. If a subject receives two or more kinds of IMPs including any dose 
of CT-P16 then the actual treatment of the subject will be CT-P16. A listing for analysis population will 
be provided. 
 
 All-randomized population 
The all-randomized population is defined as all randomly assigned subjects. A subject will be 
considered to be assigned randomly if the subject is allocated a randomization number as 
recorded on the ‘Randomization’ eCRF page. Subjects in the all-randomized population will be 


 
 
 
 
 
 
 
 
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analyzed according to the treatment to which they were randomized and not according to what 
they actually received, in the event there will be a discrepancy between the actual treatment 
received and the randomized treatment. 
 
 Safety population 
The safety population will include all randomized subjects who received a complete or partial dose 
of IMP. A subject will be considered to have received IMP if the subject is recorded as having IMP 
administered (IMYN=’Yes’) on the ‘Infusion of IMP’ eCRF page. All subjects in the safety population 
will be analyzed according to the actual treatment they received. All safety analyses will be based 
on the safety population, unless otherwise specified. 
 
 Pharmacokinetic population 
The PK population will include all subjects who have received a complete dose of IMP with 
collection of at least one post-treatment PK sample with a concentration above the lower limit of 
quantification for bevacizumab. A subject, however, who has received two or more different kinds 
of IMPs, accidentally, will be excluded from the PK population. A subject will be considered to 
have received a complete dose of IMP if the subject is recorded as having IMP administered fully 
(IMFULL=’Yes’) on the ‘Infusion of IMP’ eCRF page. Subjects in the PK population will be analyzed 
according to the actual treatment they received, unless otherwise specified. 
 
5.5 
Protocol Deviation 
The major protocol deviations are defined as follows: 
• 
Protocol deviations thought to interfere with the absorption, distribution, metabolism, and 
excretion of the compound to be measured; 
• 
Protocol deviations that may affect the interpretation of study results or the subject’s rights, 
safety, or welfare. 
 
A decision will be made during the blinded DRM to classify protocol deviations as major based on the 
underlying protocol deviations.  
Major protocol deviations will be summarized by treatment group for the all-randomized population 
and they will also be presented in a listing. 
 
5.6 
General Comments 
General Comments collected on eCRF will be presented in a listing for the all-randomized population. 
 


 
 
 
 
 
 
 
 
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5.7 
Outlier 
Any outliers that are detected during the blind review of the data will be investigated. 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. 
 
6. 
SUBJECT DISPOSITION 
6.1 
Screening Failure 
A listing of subjects reported as screening failures will be provided. 
6.2 
Subject Disposition 
A summary table reflecting the number of subjects who were randomized, who initiated administration 
of IMP and who completed the study will be presented by treatment group and overall. This table will 
also present the number of subjects who did not complete the study, both overall and according to 
reasons for withdrawal from the study.  
A subject will be considered to have been randomized if the subject is allocated a randomization 
number as recorded on the ‘Randomization’ eCRF page. A subject will be considered to have initiated 
treatment in the study if it is recorded that IMP was administered (IMYN='Yes') on the 'Infusion of IMP' 
page of the eCRF. A subject will be considered to have completed the study if it is recorded that they 
completed (DSCOMPL='Yes') on the 'End of Study' page of the eCRF. A subject will be considered to 
have discontinued the study if it is recorded that they did not complete (DSCOMPL='No') on the 'End 
of Study' page of the eCRF. 
Subject disposition data will be summarized and listed by treatment group in all-randomized 
population. 
 
6.3 
Subject Disposition and Analysis Population by Study Site 
The number and percentage of subjects who comprised all-randomized, safety and PK populations and 
who completed the study will be presented by treatment group and study site. This table will also 
present the number of subjects who did not complete the study, both overall and according to reasons 
for withdrawal from the study by study site. 
Subject disposition by study site data will be summarized by treatment group in all-randomized 
population. 
 
7. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
7.1 
Demographics 
Demographics and other background characteristics listed below will be presented in summary tables 
for the PK population and safety population.  


 
 
 
 
 
 
 
 
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The following continuous variables will be summarized by treatment group using descriptive statistics 
(number, mean, standard deviation, minimum, median and maximum): 
• 
Age (years) 
• 
Height (cm) 
• 
Weight (kg) 
• 
Body Mass Index (kg/m2) 
 
The following categorical data will be summarized by treatment group using frequency tables (number 
and percentage): 
• 
Race 
• 
Gender 
• 
Weight (< 70 kg vs ≥ 70 kg) 
• 
Smoking history 
• 
Alcohol history 
• 
Caffeine history 
• 
(Abuse History) Drug 
• 
(Abuse History) Alcohol 
 
Subject demographics and baseline characteristics will be presented in a data listing for the safety 
population. 
 
7.2 
Medical History 
Medical histories will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 20.1, and the version number will be shown as a footnote on the corresponding tables. 
Medical history will be summarized for the safety population by treatment group, system organ class 
(SOC) and preferred term (PT) displaying the total number of medical history events, and the number 
and percentage of subjects with at least one medical history term. SOC and PT will be sorted by 
alphabetical order. At each level of summarization, a subject is counted once if he reported one or 
more medical histories. 
A listing of medical history will also be provided by treatment group for the safety population.  
 
7.3 
Inclusion and Exclusion Criteria 
Details of the inclusion and exclusion criteria can be found in sections 4.2 and 4.3 of the study 
protocol. A listing of the inclusion and exclusion criteria will be presented for each subject by 
treatment group for the all-randomized population.  
 


 
 
 
 
 
 
 
 
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7.4 
Viral Serology 
The following viral serology items will be listed by treatment group for the safety population: 
• 
Hepatitis B surface antigen (HBsAg) 
• 
Hepatitis B surface antibody (HBsAb) 
• 
Hepatitis C virus antibody 
• 
Human immunodeficiency virus-1 or -2 (HIV-1 or -2) antibodies 
• 
Syphilis 
 
7.5 
Urine Drug Test 
The following urine drug test items will be listed by treatment group for the safety population: 
• 
Amphetamines 
• 
Barbiturates 
• 
Benzodiazepines 
• 
Cocaine 
• 
Opiates 
• 
Cannabinoids 
 
8. 
TREATMENTS AND MEDICATIONS 
8.1 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the Anatomical Therapeutic Chemical (ATC) 
classification of World Health Organization Drug Dictionary (WHODD) version 01Sep2017, and the 
version number will be shown as a footnote on the corresponding tables. 
All medications used within 30 days prior to screening visit until the EOS visit will be collected on the 
eCRF. Prior medication is defined as any medication with end date prior to the first administration of 
IMP date. Concomitant medication is defined as any medication that is ongoing, or has an end date 
that is on or after the date of IMP infusion. The start date of a concomitant medication can be before 
or after the date of first administration.    
The total number of prior and concomitant medications and the number and percentage of subjects 
with at least one prior or concomitant medication will be tabulated for the safety population. Prior and 
concomitant medication data will be presented separately by treatment group, drug class and PT. Drug 
class will be displayed using ATC Level 2. ATC and PT will be sorted by alphabetical order. At each level 
of subject summarization, a subject is counted only once if one or more medication was reported at 
that level. 
Additionally, prior and concomitant medications will be listed by treatment group for the safety 
population. 
For the purpose of inclusion in prior or concomitant medication, incomplete medication start dates 
and end dates will be imputed respectively as described in Appendix 11.4. 


 
 
 
 
 
 
 
 
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8.2 
Extent of Exposure 
Extent of exposure table will be summarized for the safety population by treatment group with number 
and percentage of subjects who administered IMP and who received a complete dose or partial dose. 
Planned dose (mg), prescribed dose (mg) and administered dose (mg) of IMP (CT-P16, EU-approved 
Avastin, and US-licensed Avastin) will also be summarized for the safety population by treatment group 
using descriptive statistics (number, mean, standard deviation, minimum, median and maximum).   
All IMP administration data will be presented in a data listing for the safety population. 
 
9. 
PHARMACOKINETIC ANALYSIS 
All pharmacokinetic analyses will be performed using all data on the PK population unless otherwise 
specified. Derivation of PK parameters will be the responsibility of Early Phase, Quantitative Clinical 
Development, PAREXEL International. The PK parameters will be determined for analyte in serum 
following single dose administration. 
 
9.1 
Handling of Values Below the Limit of Quantification (BLQ) 
The values below the limit of quantification values will be imputed in the PK concentration dataset 
used for serum concentration summarization, and the derivation of PK parameters.  
The BLQ values prior to the IMP administration will be treated as zero. For the BLQ values after IMP 
administration, the following rules will be applied; 
 
The BLQ values at the beginning of a subject profile (i.e. before the first incidence of a 
measurable concentration) will be assigned to zero. 
 
The BLQ values at the end of a subject profile (i.e. after the last incidence of a measurable 
concentration) will be set to missing. 
 
Single BLQs which fall between two measurable concentrations will be set to missing.  
 
Consecutive BLQs which fall between measurable concentrations will be set to missing. 
Measurable concentrations after consecutive BLQs will also be set to missing. 
 


 
 
 
 
 
 
 
 
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9.2 
Serum Concentration 
Venous blood samples will be collected from each subject during this study for the determination of 
the PK of bevacizumab administered as CT-P16, EU-approved Avastin, and US-licensed Avastin. Blood 
samples for PK analysis will be drawn according to the following schedule: 
Day of study period 
Time point 
Window 
Day 1 
Pre-dose 
Before IMP infusion 
End of infusion 
Immediately end of infusion 
(Within +5 minutes after EOI) 
1 hour after EOI 
± 15 minutes 
4 hours after SOI 
8 hours after SOI 
12 hours after SOI 
Day 2 
24 hours after SOI 
Day 3 
48 hours after SOI 
± 1 hour 
Day 4 
72 hours after SOI 
Day 8 
168 hours after SOI 
± 4 hours 
Day 15 
336 hours after SOI 
Day 29 
672 hours after SOI 
± 1 day 
Day 43 
1,008 hours after SOI 
Day 57 
1,344 hours after SOI 
Day 71 
1,680 hours after SOI 
± 3 days 
Day 85 
2,016 hours after SOI 
Day 99 
2,352 hours after SOI 
 
Serum samples will be analyzed to determine the concentrations of bevacizumab using a validated 
immunoassay. 
Serum concentrations, serum collection times, and deviations from scheduled collection times of 
bevacizumab will be listed for safety population. Serum concentrations of bevacizumab will be 
summarized for PK population by treatment group and scheduled sampling time point using 
descriptive statistics (number, mean, geometric mean, standard deviation, CV, minimum, median, and 
maximum). 
The individual serum concentration versus time profiles for bevacizumab, as well as the mean serum 
concentration versus time profiles will be presented graphically in both linear and semi-logarithmic 
scales by treatment group. The individual serum concentration versus time profiles for bevacizumab 
will be presented by treatment group as spaghetti plots showing all data from subjects in the same 
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presented. For ease of presentations, scheduled sampling times will be used to present results in mean 
figures. For individual figures, actual times will be used. 
 
9.3 
Serum Pharmacokinetic Parameters 
The following serum PK parameters will be calculated for bevacizumab administered as CT-P16, EU-
approved Avastin, and US-licensed Avastin by non-compartmental method using Phoenix® WinNonlin® 
version 6.3 (Certara USA, Inc., Princeton, NJ) with following guidelines: 
• 
Actual sampling times relative to dosing rather than nominal times will be used in the 
calculation of all derived PK parameters. 
• 
There will be no imputation of missing data.  
• 
Any subjects with missing concentration data will be included in the PK population provided 
that at least Cmax and AUC0-last can be reliably calculated. 
 
The serum PK parameters are defined as the following table. 
Parameter 
Definition 
AUC0-inf 
AUC from time zero extrapolated to infinity 
AUC0-last 
AUC from time zero to the time of the last quantifiable concentration 
Cmax 
Maximum observed serum concentration 
Tmax 
Time corresponding to occurrence of Cmax 
Vz 
Volume of distribution during terminal phase (after IV) 
λz 
Terminal elimination rate constant 
t½ 
Apparent terminal elimination half life 
CL 
Total body clearance 
%AUCext 
Percentage of AUC0-inf obtained by extrapolation 
 
PK parameters will be estimated according to the following guidelines: 
• 
Cmax will be obtained directly from the concentration-time data. 
• 
Tmax is the time at which Cmax is observed. 
• 
λz will be estimated at terminal phase by linear regression after log-transformation of the 
concentrations: 
- 
Only those data points that are judged to describe the terminal log-linear decline will be 
used in the regression.  
- 
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λz with the line of regression starting at any post-Cmax data point (Cmax should not be part 
of the regression slope). The adjusted coefficient of determination (R2 adjusted) in general 
should be greater than 0.85. Any value < 0.85 will be flagged but may be used at the PK 
Scientist’s best knowledge and judgment. All the derived parameters (i.e. λz, t½, AUC0-inf, 
CL, Vz, and %AUCext) will need to be flagged in the individual data listing and excluded 
from statistical analysis and descriptive summary accordingly. 
- 
The interval used to determine λz should be equal or greater than 1.5-fold the estimated 
half-life or otherwise flagged and used at the PK Scientist’s best knowledge and judgment. 
All the derived parameters (i.e. t½, AUC0-inf, CL, Vz, and %AUCext) will need to be flagged in 
the individual data listing and excluded from statistical analysis and descriptive summary 
accordingly. 
• 
t½ will be calculated as ln2/λz. 
• 
AUC is calculated by the linear up/log down method (linear method will be employed for all 
incremental trapezoids arising from increasing concentrations and the logarithmic method will 
be used for those arising from decreasing concentrations. 
- 
AUC0-t=∫
 t
0
dt
t
C
)
(
 
- 
AUC0-inf =∫
 t
0
dt
t
C
)
(
＋∫
∞
t
dt
t
C
)
(
=AUC0-last＋Clast/λz. 
- 
Clast is last observed quantifiable concentration.  
- 
If a subject withdraws after the IMP infusion but before last planned PK sampling time 
then the calculated PK parameters will be flagged (i.e. AUC0-last) and used at the PK 
Scientist’s best knowledge and judgment. This kind of AUC0-last will be flagged in 
individual data listing and excluded from statistical analysis and descriptive summary 
accordingly. 
• 
%AUCext will be calculated as (1－[AUC0-last/AUC0-inf])×100. The %AUCext should not exceed 20% 
for each individual profile. If the %AUCext is more than 20%, the individual result should be 
flagged and mentioned in the report and all derived parameters (i.e. AUC0-inf and CL) will be 
flagged in the individual data listing and excluded from statistical analysis and descriptive 
summary accordingly.  
• 
CL will be calculated as dose/AUC0-inf. 
• 
Vz will be calculated as dose/(λz* AUC0-inf). 
 
PK parameters will be presented in data listings and summarized in tables for PK population by 
treatment group, using descriptive statistics (number, mean, standard deviation, CV, geometric mean, 
minimum, median, and maximum). The decimal places of the raw data for each PK parameter will be 
considered as following table. 
 


 
 
 
 
 
 
 
 
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PK parameter 
Unit 
The decimal places of  
the raw data 
AUC0-inf 
hㆍμg/mL 
1 
AUC0-last 
hㆍμg/mL 
1 
Cmax 
μg/mL 
1 
Tmax 
h 
2 
Vz 
L 
2 
λz 
1/h 
5 
t½ 
h 
1 
CL 
L/h 
4 
%AUCext 
% 
1 
 
9.4 
Statistical Analysis of Pharmacokinetic Data 
The statistical analysis of the log-transformed primary endpoints (AUC0-inf, AUC0-last, and Cmax) will be 
based on an analysis of covariance (ANCOVA) model with treatment as a fixed effect and body weight 
(<70kg vs ≥70kg) assessed on day -1 and study site as covariates. The difference in least squares 
means between the CT-P16 and EU-approved Avastin, CT-P16 and US-licensed Avastin, and EU-
approved Avastin and US-licensed Avastin, and the associated 90% CIs will be determined. Back 
transformation will provide the ratio of geometric means and 90% CIs for these ratios. 
Similarity of systemic exposure (AUC0-inf, AUC0-last, and Cmax) will be determined if 90% CI for the ratio 
of geometric means is within the acceptance interval of 0.8 to 1.25 for the following comparisons: 
• 
CT-P16 vs EU-approved Avastin 
• 
CT-P16 vs US-licensed Avastin 
• 
EU-approved Avastin vs US-licensed Avastin 
 
 
10. SAFETY ANALYSIS 
This section provides details of safety analysis. All analyses of safety data will be conducted using the 
safety population, unless otherwise specified. 
 
10.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this product. Concomitant illnesses, which existed prior to entry into the clinical study, 
will not be considered as AEs unless they worsen during the treatment period. Pre-existing conditions 
will be recorded in the eCRF on the Medical History. All AEs will be collected from the date the 
informed consent form is signed and will continue until the end of the subject’s participation in the 


 
 
 
 
 
 
 
 
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study. A treatment-emergent adverse event (TEAE) is defined as an AE that begins or that worsens in 
severity after administration of the IMP. 
A SAE is defined in the protocol as any event that: results in death; is life threatening; requires at least 
24-hour hospitalization or prolongation of expected length of stay; results in persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions; is a congenital 
anomaly or birth defect, or is another important medical event other than listed above which may be 
considered SAEs when, based on appropriate medical judgment, they may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
An AESI is defined as AE classified as an infusion-related reaction (IRR)/ hypersensitivity, which is 
checked (AEIRR='Yes') on the 'Adverse Events' eCRF page. 
Adverse events will be coded to SOC and PT according to the MedDRA version 20.1. AEs will be 
graded for intensity according to the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) v4.03.  
A summary table of overall AEs will be presented with the number and percentage of subjects with at 
least one AE, TEAE, SAE, treatment-emergent serious adverse event (TESAE), TEAE leading to 
permanent discontinuation of IMP, AE leading to death and TEAE of special interest. 
For summarization of TEAEs, a subject will be counted only once if one or more events are reported 
and only the worst intensity will be counted at each level of summarization. The summary of TEAEs will 
be presented in alphabetical order of SOC. Within each SOC, the PTs will be also presented in 
alphabetical order. 
AEs will be considered to be related if relationship is possible, probable or definite for IMP. AEs with no 
relationship or intensity recorded will be summarized separately under a missing category. 
The following TEAE summary tables will include the total number of each corresponding TEAEs and the 
number and percentage of subjects experiencing TEAEs by treatment group, SOC, PT, relationship, and 
maximum intensity. 
 
Treatment-emergent Adverse Events 
 
Treatment-emergent Serious Adverse Events 
 
Treatment-Emergent Adverse Events Leading to Permanent Discontinuation of IMP 
 
Treatment-Emergent 
Adverse 
Events 
of 
Special 
Interest 
(Infusion-related 
reaction/hypersensitivity) 
 
The following TEAE summary tables will include the total number of each corresponding TEAEs and the 
number and percentage of subjects experiencing TEAEs by treatment group, SOC, PT, and maximum 
intensity regardless of relationship. 
 
Treatment-emergent Adverse Events  
 
Treatment-emergent Serious Adverse Events 
 
Treatment-Emergent Adverse Events Leading to Permanent Discontinuation of IMP 


 
 
 
 
 
 
 
 
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Listings for AE, SAE, TEAE leading to permanent discontinuation of IMP and TEAE of special interest will 
be provided by actual treatment received. The listings will include the following information from the 
eCRF: SOC, reported term and PT; start and end date; outcome (recovered, recovered with sequelae, 
recovering, not recovered, fatal, unknown); severity/intensity (Grade 1 [mild], Grade 2 [moderate], 
Grade 3 [severe], Grade 4 [life-threatening], Grade 5 [death]); relationship/causality to IMP (unrelated, 
possible, probable, definite); action taken with study treatment (no action taken, IMP interrupted, IMP 
withdrawn, not applicable); other treatment (no treatment, medication treatment, non-medication 
treatment, specify, both medication and non-medication treatment, specify), and whether a subject was 
discontinued from study due to AE (no, yes) . For IRR only, start time and end time will also be 
included in the listing.  Additionally, following listings will be provided; signs and symptoms of 
infusion-related reaction/hypersensitivity, additional AEs with an outcome of “Death”, and additional 
information on SAEs.  
    
10.2 Clinical Laboratory Tests 
Clinical laboratory tests (hematology, clinical chemistry, coagulation, and urinalysis) will be summarized 
by laboratory test type, treatment group using descriptive statistics (number, mean, standard deviation, 
minimum, median and maximum) at each scheduled collection time. For continuous parameters, 
change from baseline will also be summarized for all post infusion scheduled collection times. For 
neutrophil, lymphocyte, monocyte, eosinophil, and basophil, minimum and maximum will be presented 
to three decimal places, mean and median will be presented to four decimal places, and standard 
deviation will be presented to five decimal places. For all other items except neutrophil, lymphocyte, 
monocyte, eosinophil, and basophil, minimum and maximum will be presented to the two decimal 
places, mean and median will be presented to three decimal places, and standard deviation will be 
presented to four decimal places. A shift table comparing the categorical results classified as either 
“Normal”, “Abnormal, not clinically significant”, “Abnormal, clinically significant” or “Not done” at each 
scheduled post-baseline visit with those at baseline will be summarized by treatment group and visit 
except for urinalysis. It is considered as “Not done” if it is recorded that the sample was not collected 
(LBYN='No') on the 'Clinical Laboratory Assessment-Hematology', 'Clinical Laboratory Assessment-
Clinical Chemistry', 'Clinical Laboratory Assessment-Coagulation', or 'Clinical Laboratory Assessment-
Urinalysis' page of the eCRF or the actual result of the item has been not collected at each scheduled 
collection time. For summaries using shift tables, ‘Not done’ will also be regarded as a baseline value. 
All laboratory results will be listed by treatment group. If any continuous parameter of clinical 
laboratory tests is collected with inequality signs (>, <) the inequality signs will be removed and the 
numeric values will be used for analyses (e.g., [>3, ≥3, <3, ≤3] will be analyzed as 3). 
The items will be summarized as following: 
 
Hematology: Hemoglobin, Hematocrit, Red Blood Cell, White Blood Cell, Neutrophil, 


 
 
 
 
 
 
 
 
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Lymphocyte, Monocyte, Eosinophil, Basophil, absolute neutrophil count, and Platelets 
 
Clinical Chemistry: Albumin, Alkaline phosphatase, Alanine aminotransferase, Aspartate 
aminotransferase, Blood urea nitrogen, Calcium, Chloride, Total cholesterol, Creatine 
phosphokinase, Creatine kinase–myocardial band isoenzyme, Creatinine, Creatinine clearance, 
C reactive protein, Gamma-glutamyl transferase, Glucose, Lactate dehydrogenase, Magnesium, 
Phosphate, Potassium, Sodium, Total bilirubin, Direct bilirubin, Total protein, Uric acid, 
Triglyceride, and Troponin I 
 
Coagulation: Fibrinogen, International normalized ratio, Prothrombin time, and Activated 
partial thromboplastin time 
 
Urinalysis: Color, pH, Specific gravity, Ketones, Protein, Glucose, Bilirubin, Nitrite, Urobilinogen, 
and Occult blood 
 
All numeric parameters will be labeled with a CTCAE term and grading will be applied to post-baseline 
values for all numeric parameters where possible according to CTCAE v 4.03. Grades that require 
clinical input only will not be assigned to these parameters. Grades which are part numeric 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 11.3. 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 numeric 
laboratory result. If the post-baseline result for a subject does not satisfy any CTCAE grade, it will be 
classified as “No Grade”. The number and percentage of subjects with a result for each grade will be 
summarized by CTCAE term, visit (overall period and all post-baseline scheduled visits), and treatment 
group for safety population. In addition, a listing will be provided showing the CTCAE results for each 
subject by treatment group in the safety population. 
A listing showing only subjects with abnormal values will be provided. 
 
10.3 Hypersensitivity Monitoring 
Hypersensitivity monitoring in vital signs of systolic and diastolic BP, HR, BT, RR will be summarized by 
treatment group at each scheduled collection time using descriptive statistics (number, mean, standard 
deviation, minimum, median and maximum). Change from baseline will also be summarized for all 
scheduled collection times. The baseline value on the 'Vital Signs' page of the eCRF for each 
corresponding item will be used as the baseline of hypersensitivity monitoring in vital signs. 
The number and percentage of subjects who have a clinically significant vital sign hypersensitivity will 
be presented by treatment group and parameter.  
The criteria for clinically notable results are defined as follows: 
 


 
 
 
 
 
 
 
 
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Parameter 
Low 
High 
Systolic blood pressure (mmHg) 
≤ 90 
≥ 160 
Diastolic blood pressure (mmHg) 
≤ 50 
≥ 90 
Respiratory rate (breaths per minute) 
≤ 12 
≥ 20 
Heart rate (beats per minute) 
≤ 50 
≥ 100 
Body temperature (oC) 
≤ 35.0 
≥ 38.0 
 
Hypersensitivity monitoring finding in 12-lead ECG will be classified as either “Normal”, “Abnormal, not 
clinically significant”, “Abnormal, clinically significant”, "Not Done", or "Missing". It is considered as “Not 
done” if it is recorded that the ECG was not performed (HGYN='No') on the 'Hypersensitivity 
Monitoring-12-lead ECG' page of the eCRF. It is considered as “Missing” if it is recorded that the ECG 
was performed (HGYN='Yes') on the 'Hypersensitivity Monitoring-12-lead ECG' page of the eCRF but 
the actual result has been not collected. Results will be summarized by treatment group, in the form of 
a shift table comparing the categorical results of hypersensitivity monitoring finding in 12-lead ECG 
with ECG at baseline. The baseline value on the '12-lead ECGs' page of the eCRF will be used as the 
baseline of hypersensitivity monitoring in 12-lead ECG. 
All hypersensitivity monitoring results in vital signs, 12-lead ECG, and continuous monitoring will be 
listed by treatment group. 
 
10.4 Vital Signs 
Vital signs of systolic and diastolic BP, HR, BT, RR will be listed and summarized by treatment group at 
each scheduled collection time using descriptive statistics (number, mean, standard deviation, minimum, 
median and maximum). Change from baseline will also be summarized for all post-infusion scheduled 
collection times.  
 
10.5 12-Lead Electrocardiogram 
12-lead electrocardiograms (ECGs) findings will be classified as either “Normal”, “Abnormal, not 
clinically significant”, “Abnormal, clinically significant”, “Not done”, or "Missing". A subject will be 
considered “Not done” if ‘No’ was recorded for the question, ‘Was the ECG performed?’ in the ‘12-lead 
ECG’ page of the eCRF. A subject will be considered “Missing” if ‘Yes’ was recorded for the question, 
‘Was the ECG performed?' in the ‘12-lead ECG’ page of the eCRF but the actual result was not 
collected. Results will be listed and summarized by treatment group and visit, in the form of a shift 
table comparing the categorical results at each scheduled post-baseline visit with those at baseline. For 
summaries using shift tables, ‘Not done’ and ‘Missing’ will also be regarded as a baseline value. 
 
10.6 Physical Examination 
Physical examinations should be based on the following body systems: general appearance, 


 
 
 
 
 
 
 
 
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head/ears/eyes/nose/throat, urogenital system, skin, cardiovascular system, respiratory system, 
abdominal system, neurological system, musculoskeletal system and lymph nodes. Findings will be 
classified as either “Normal”, “Abnormal, not clinically significant”, “Abnormal, clinically significant”, “Not 
done”, or "Missing". A subject will be considered “Not done” if ‘No’ was recorded for the question, 
‘Was the physical examination performed?’ or if ‘Not done’ was recorded for 'Interpretation' for each 
body system in the ‘Physical Examinations’ page of the eCRF. A subject will be considered “Missing” if 
‘Yes’ was recorded for the question, ‘Was the physical examination performed?' in the ‘Physical 
Examinations’ page of the eCRF but the actual result for each body system has been not collected. A 
shift table comparing the categorical results at each scheduled post-baseline visit with those at 
baseline will be summarized by treatment group and visit. For summaries using shift tables, ‘Not done’ 
and ‘Missing’ will also be regarded as a baseline value. All physical examination findings will be 
presented in a data listing.  
 
10.7 Immunogenicity Analysis 
Immunogenicity assessment consists of both anti-drug antibody (ADA) and neutralizing antibody (NAb) 
assay. The test outcome will be reported as “Positive” or “Negative” and the titer values will be 
reported as the reciprocal of the dilution able to yield a background just at or above the cut point. 
ADA assay result will be considered as “Positive” only when the confirmatory assay result using CT-P16 
as inhibition drug is “Positive”. NAb assay result will be summarized only when the ADA result is 
considered as “Positive”. 
 
ADA Screening/Confirmatory assay results 
ADA 
Result 
NAb Result 
Screening 
Confirmatory 
CT-P16 
EU-Approved 
Avastin 
US-Licensed 
Avastin 
Negative 
N/A 
N/A 
N/A 
Negative 
N/A 
Positive 
Positive  
Positive/Negative  
Positive/Negative 
Positive 
The result will be 
summarized as 
reported. 
Positive 
Negative 
Positive/Negative  
Positive/Negative  
Negative 
The result will not be 
summarized. 
 
The number and percentage of subject will be presented by treatment group and visit for the safety 
population. A listing showing immunogenicity test results for each subject will be provided by 
treatment group and visit. The ADA result will involve both a screening and a confirmatory assay using 
3 Inhibition drugs (CT-P16, EU-approved Avastin and US-licensed Avastin) and the NAb result will 
involve a screening assay. The listing will also include actual results of ADA titer and NAb titer and 


 
 
 
 
 
 
 
 
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transformed results of ADA titer for each visit. ADA titer, NAb screening assay, and NAb titer results will 
be listed when any of 3 drug inhibition results is positive in ADA confirmatory assay. The ADA titer 
values will be transformed using a logarithmic transformation. Transformed ADA titer values can be 
obtained using 
 transformation. If the values in the data are in inequality forms, the sign 
of inequality will be removed and then the values will be transformed. 
 
10.8 
Restriction Assessment 
Restriction assessment should be based on the following categories: alcohol, caffeine, nicotine, meals, 
activity, medications, and contraception. Compliance of restriction for each category will be classified 
as either “Yes” or “No”. A listing showing restriction assessment results for each subject will be 
provided by treatment group and visit. 


 
 
 
 
 
 
 
 
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11. APPENDICES 
11.1 Schedule of Assessments 
 
Assessments 
Screening 
In-House Stay 
Out-patient Visits 
EOS1 
Day of Study Period 
Day 
-21 to -2 
Day 
-1 
Day 
1 
Day 
2 
Day 
32 
Day 
42 
Day 
8 
Day 
15 
Day 
29 
Day 
43 
Day 
57 
Day 
71 
Day 
85 
Day 
99 
Visit window (day) 
- 
- 
- 
- 
- 
- 
± 1 
± 1 
± 1 
± 3 
± 3 
± 3 
Informed consent 
X 
Medical and medication history 
X 
X 
Demographics 
X 
Inclusion / exclusion criteria3 
X 
X 
Body weight & Height4 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
Viral serology test5 
X 
Drugs of abuse / alcohol / 
nicotine check6 
X 
X 
Randomization 
X 
Clinical laboratory tests7 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogram9 
X 
X 
X 
X 
X 
X 
X 
Infusion of IMP 
X 
Pharmacokinetic sampling10 
X
11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hypersensitivity monitoring12 
X 


 
 
 
 
 
 
 
 
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Immunogenicity13 
X
11 
X 
X 
X 
X 
Restriction assessment 
X 
X 
Concomitant medication14 
X 
X 
Adverse events 
X 
X 
 Abbreviations: ECG, electrocardiogram; EOS, end of study; IMP, investigational medicinal product; PK, pharmacokinetic; 
1. 
End-of-study visit procedures will be performed for subjects who completed the study as well as subjects who terminated the clinical study prematurely. After the 
EOS visit, serious adverse drug reactions will be reported to the Sponsor or its designee. 
2. 
Assessments on Day 3 and 4 can be carried out either during the In-House Stay or on an out-patient basis according to Investigator decision. 
3. 
Inclusion and exclusion criteria should be checked before randomization. 
4. 
Height will be measured at screening only. 
5. 
Serology tests will be performed at the screening visit for human immunodeficiency virus (HIV) -1 or -2 antibodies, hepatitis B surface antigen (HBsAg) and hepatitis B 
surface antibody (HBsAb), hepatitis C antibody and syphilis. 
6. 
Drug abuse testing includes the followings: amphetamines, barbiturates, benzodiazepines, cocaine, opiates, and cannabinoids during the screening period only. The 
history of Drug abuse, alcohol and nicotine will be checked by medical history taking by Investigator during the screening period and Day -1. 
7. 
Clinical laboratory tests will be carried out at screening, on Day –1, Day 3, 8, 15, 43, 71, and 99; Hematology (hematocrit, hemoglobin, red blood cell count, white 
blood cell count with differential, absolute neutrophil count, and platelets), Clinical chemistry (albumin, alkaline phosphatase, alanine aminotransferase, aspartate 
aminotransferase, blood urea nitrogen, calcium, chloride, total cholesterol, creatine phosphokinase, creatine kinase–myocardial band isoenzyme, creatinine, creatinine 
clearance [estimated by Modification of Diet in Renal Disease [MDRD]], C reactive protein, gamma-glutamyl transferase, glucose, lactate dehydrogenase, magnesium, 
phosphate, potassium, sodium, total bilirubin, direct bilirubin, total protein, uric acid, triglyceride, and Troponin I), Urinalysis (color, pH, specific gravity, ketones, 
protein, glucose, bilirubin, nitrite, urobilinogen, occult blood, and microscopic examination), Coagulation (Fibrinogen, international normalized ratio, prothrombin 
time, and activated partial thromboplastin time) 
8. 
Vital signs will be measured at screening, on Day –1, before dosing on Day 1, on Day 3, 4, 8, 15, 29, 43, 57, 71, 85, and 99. 
9. 
Twelve-lead ECG will be performed at the screening visit, on Day 3, 8, 15, 43, 71, and 99. 
10. Blood samples for PK analysis will be collected as specified in CT-P16 1.1 SAP section 9.2. 
11. Pre-dose blood sample for PK and immunogenicity assessment will be collected before start of infusion on Day 1. 


 
 
 
 
 
 
 
 
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12. For hypersensitivity monitoring, vital signs measurement and 12-lead ECG will be done as specified in CT-P16 1.1 Protocol Table 3. 
13. Immunogenicity will be assessed on before dosing on Day 1, on Day 15, 43, 71 and 99. 
14. Prior and concomitant medication use will be recorded for the 30 days prior to the screening visit until the EOS visit.


 
 
 
 
 
 
 
 
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11.2 CTCAE Grades 
 
Grade 1 
Mild; asymptomatic or mild symptoms;  
clinical or diagnostic observations only;  
intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental Activities of Daily Living (ADL1) 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self care ADL2 
Grade 4 
Life-threatening consequences; 
urgent intervention indicated. 
Grade 5 
Death related to AE. 
Source: CTCAE Version 4.03 
Note: a semicolon indicates “or” within each description. 
1. 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
2. 
Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
 
 


 
 
 
 
 
 
 
 
CONFIDENTIAL 
SD 0400 A v1.0 
Statistical Analysis Plan 
       31/42 page 
 
 
 
 SAP V2.0 
Effective Date: 29-MAR-2018 
11.3 Laboratory Grades 
CTCAE Term 
Laboratory Parameter 
Level 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Anemia 
Hemoglobin  
Low 
<LLN - 10.0 g/dL; 
<LLN - 100 g/L 
<10.0 - 8.0 g/dL; 
<100 - 80 g/L 
<8.0 g/dL; 
<80 g/L; 
- 
Alanine 
aminotransferase 
increased 
Alanine 
Aminotransferase (ALT) 
High 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Alkaline phosphatase 
increased 
Alkaline phosphatase 
High 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Aspartate 
aminotransferase 
increased 
Aspartate 
Aminotransferase 
(AST) 
High 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Blood bilirubin 
increased 
Total Bilirubin 
High 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 10.0 x ULN 
>10.0 x ULN 
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 increased 
Creatinine 
High 
>1 - 1.5 x baseline; 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x baseline; 
>1.5 - 3.0 x ULN 
>3.0 baseline; 
>3.0 - 6.0 x ULN 
>6.0 x ULN 


 
 
 
 
 
 
 
 
CONFIDENTIAL 
SD 0400 A v1.0 
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       32/42 page 
 
 
 
 SAP V2.0 
Effective Date: 29-MAR-2018 
CTCAE Term 
Laboratory Parameter 
Level 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
GGT increased 
Gamma Glutamyl 
Transferase 
High 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Hemoglobin 
increased 
Hemoglobin 
High 
Increase in >0 - 2 
gm/dL above ULN or 
above baseline if 
baseline is above ULN 
Increase in >2 - 4 
gm/dL above ULN or 
above baseline if 
baseline is above ULN 
Increase in >4 gm/dL 
above ULN or above 
baseline if baseline is 
above ULN 
- 
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 
Hyperuricemia 
Uric acid 
High 
>ULN - 10 mg/dL 
(0.59 mmol/L) without 
physiologic 
consequences 
- 
- 
>10 mg/dL; >0.59 
mmol/L; 
life-threatening 
consequences 
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 
- 


 
 
 
 
 
 
 
 
CONFIDENTIAL 
SD 0400 A v1.0 
Statistical Analysis Plan 
       33/42 page 
 
 
 
 SAP V2.0 
Effective Date: 29-MAR-2018 
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 - 120 mmol/L 
<120 mmol/L 
Lymphocyte count 
decreased 
Lymphocytes 
Low 
<LLN - 800/mm3; 
<LLN - 0.8 x 10e9/L 
<800 - 500/mm3; 
<0.8 - 0.5 x 10e9 /L 
<500 - 200/mm3; 
<0.5 - 0.2 x 10e9 /L 
<200/mm3; 
<0.2 x 10e9 /L 
Lymphocyte count 
increased 
Lymphocytes 
High 
- 
>4000/mm3 - 
20,000/mm3 
>20,000/mm3 
- 
Neutrophil count 
decreased 
Total Neutrophils 
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 


 
 
 
 
 
 
 
 
CONFIDENTIAL 
SD 0400 A v1.0 
Statistical Analysis Plan 
       34/42 page 
 
 
 
 SAP V2.0 
Effective Date: 29-MAR-2018 
CTCAE Term 
Laboratory Parameter 
Level 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Platelet count 
decreased 
Platelet count 
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 Cells 
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 
Note: The LLN and ULN values will be the normal ranges as provided by the central laboratory at each relevant transfer. 
A Semi-colon indicates ‘or’ within the description of the grade. 
A single dash (-) indicates a grade is not available. 
 


 
 
 
 
 
 
 
 
CONFIDENTIAL 
SD 0400 A v1.0 
Statistical Analysis Plan 
                 35/42 page 
 
 
SAP V2.0 
Effective Date: 29-MAR-2018 
11.4 Date Imputation for Prior and Concomitant Medication 
Prior and concomitant medications will be coded using the WHO Drug Dictionary version 01Sep2017 or later. 
For the purpose of inclusion in prior and/or concomitant medication tables, incomplete medication start and 
end dates will be imputed as follows:  
 
• 
Missing day: Assume the day is 1st of the month. If the partial date and the date of IMP infusion 
(defined as the date recorded on ‘Infusion of IMP’ eCRF page) lie within the same month and year, set to 
the date of first infusion, if not after the end date for the medication, otherwise set to end date of the 
medication. 
 
• 
Missing day and month: Assume 1st January. If the partial date and the date of first infusion lie within 
the same year, set to the date of first infusion, if not after the end date for the medication, otherwise set 
to end date of the medication. 
 
• 
Missing day, month and year: Assume date of first infusion, if not after the end date for the medication, 
otherwise set to the end date for the medication. 
 
For the missing day imputation, the following examples should be used for reference: 
 
• 
Example 1:  
Medication start: JUN2015 
Medication end: 20OCT2015 
Date of first infusion: 16OCT2015 
Medication start imputed: 01JUN2015 
 
• 
Example 2:  
Medication start: OCT2015  
Medication end: 20OCT2015 
Date of first infusion: 16OCT2015 
Medication start imputed: 16OCT2015 
 
• 
Example 3:  
Medication start: OCT2015  
Medication end: 20OCT2015 
Date of first infusion: 24OCT2015 
Medication start imputed: 20OCT2015 
 
Partial end dates will be imputed as follows: 
• 
Missing day: Assume the last day of the month  
• 
Missing day and month: Assume December 31st  
• 
Missing day, month and year: Assume that the medication is continuing. 


 
 
 
 
 
 
 
 
CONFIDENTIAL 
SD 0400 A v1.0 
Statistical Analysis Plan 
                 36/42 page 
 
 
SAP V2.0 
Effective Date: 29-MAR-2018 
 
In the case of the death of a subject, and the imputed end date is after the date of death, the end date will 
be imputed as the date of death.


 
 
 
 
 
 
 
 
CONFIDENTIAL 
SD 0400 A v1.0 
Statistical Analysis Plan 
                        37/42 page 
SAP V2.0 
Effective Date: 29-MAR-2018 
11.5   Tables, Listings, Figures 
 
List of Tables 
Table Number 
Title 
Population 
Table 14.1.1 
Population of Analysis 
All-Randomized Population 
Table 14.1.2 
Summary of Subject Disposition 
All-Randomized Population 
Table 14.1.3 
Subject Disposition and Analysis Population by Study Site 
All-Randomized Population 
Table 14.1.4 
Major Protocol Deviations 
All-Randomized Population 
Table 14.1.5.1 
Demographics and Baseline Characteristics  
Safety Population 
Table 14.1.5.2 
Demographics and Baseline Characteristics  
Pharmacokinetic Population 
Table 14.1.6 
Medical History  
Safety Population 
Table 14.1.7 
Prior Medications 
Safety Population 
Table 14.1.8 
Concomitant Medications 
Safety Population 
Table 14.1.9 
Extent of Exposure 
Safety Population 
Table 14.2.1 
Summary of Serum Concentration (μg/mL) at Nominal Time Point 
Pharmacokinetic Population 
Table 14.2.2 
Summary of Serum Pharmacokinetic Parameters 
Pharmacokinetic Population 
Table 14.2.3 
Statistical Analysis of Serum Pharmacokinetic Parameters 
Pharmacokinetic Population 
Table 14.3.1.1 
Summary of Overall Adverse Event  
Safety Population 
Table 14.3.1.2 
Treatment-Emergent Adverse Events by Relationship and Intensity 
Safety Population 
Table 14.3.1.3 
Treatment-Emergent Serious Adverse Events by Relationship and Intensity 
Safety Population 
Table 14.3.1.4 
Treatment-Emergent Adverse Events Leading to Permanent Discontinuation of  
Investigational Medicinal Product by Relationship and Intensity 
Safety Population 
Table 14.3.1.5 
Treatment-Emergent Adverse Events of Special Interest (Infusion-Related 
Safety Population 


 
 
 
 
 
 
 
 
CONFIDENTIAL 
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                        38/42 page 
SAP V2.0 
Effective Date: 29-MAR-2018 
Reaction/Hypersensitivity) by Relationship and Intensity 
Table 14.3.1.6 
Treatment-Emergent Adverse Events by Intensity 
Safety Population 
Table 14.3.1.7 
Treatment-Emergent Serious Adverse Events by Intensity 
Safety Population 
Table 14.3.1.8 
Treatment-Emergent Adverse Events Leading to Permanent Discontinuation of  
Investigational Medicinal Product by Intensity 
Safety Population 
Table 14.3.5.1.1 
Descriptive Statistics for Actual Result and Change from Baseline of Hematology  Safety Population 
Table 14.3.5.1.2 
Shift from Baseline in Hematology  
Safety Population 
Table 14.3.5.1.3 
Descriptive Statistics for Actual Result and Change from Baseline of Clinical 
Chemistry  
Safety Population 
Table 14.3.5.1.4 
Shift from Baseline in Clinical Chemistry  
Safety Population 
Table 14.3.5.1.5 
Summary of CTCAE Grading 
Safety Population 
Table 14.3.5.1.6 
Descriptive Statistics for Actual Result and Change from Baseline of Coagulation  Safety Population 
Table 14.3.5.1.7 
Shift from Baseline in Coagulation  
Safety Population 
Table 14.3.5.1.8 
Descriptive Statistics for Actual Result and Change from Baseline of Urinalysis  
Safety Population 
Table 14.3.6.1.1 
Descriptive Statistics for Actual Result and Change from Baseline of 
Hypersensitivity Monitoring in Vital Signs  
Safety Population 
Table 14.3.6.1.2 
Summary of Clinically Notable Vital Sign Results during Hypersensitivity 
Monitoring 
Safety Population 
Table 14.3.6.2 
Shift from Baseline in Hypersensitivity Monitoring in 12-lead ECG 
Safety Population 
Table 14.3.6.3 
Descriptive Statistics for Actual Result and Change from Baseline of Vital Signs 
Safety Population 
Table 14.3.6.4 
Shift from Baseline in 12-Lead Electrocardiogram Results 
Safety Population 
Table 14.3.6.5 
Shift from Baseline in Physical Examination 
Safety Population 
Table 14.3.6.6 
Summary of Immunogenicity Results 
Safety Population 


 
 
 
 
 
 
 
 
CONFIDENTIAL 
SD 0400 A v1.0 
Statistical Analysis Plan 
                        39/42 page 
SAP V2.0 
Effective Date: 29-MAR-2018 
 
List of Data Listings 
Listing Number 
Title 
Population 
Listing 16.2.2.1.1 
Analysis Population 
All-Randomized Population 
Listing 16.2.2.1.2 
Screening Failure 
Subject who Failed of Screening 
Listing 16.2.2.1.3 
Subject Disposition 
All-Randomized Population 
Listing 16.2.2.1.4 
Inclusion/Exclusion Criteria 
All-Randomized Population 
Listing 16.2.2.1.5 
Major Protocol Deviations 
All-Randomized Population 
Listing 16.2.2.1.6 
General Comments 
All-Randomized Population 
Listing 16.2.4.1 
Demographics  
Safety Population 
Listing 16.2.4.2 
Baseline Characteristics 
Safety Population 
Listing 16.2.4.3 
Medical History 
Safety Population 
Listing 16.2.4.4 
Viral Serology 
Safety Population 
Listing 16.2.4.5 
Urine Drug Test 
Safety Population 
Listing 16.2.4.6 
Prior and Concomitant Medications 
Safety Population 
Listing 16.2.5.1 
Infusion of Investigational Medicinal Product 
Safety Population 
Listing 16.2.6.1 
Individual Serum Sampling Times and Concentration (μg/mL) of Bevacizumab 
Safety Population 
Listing 16.2.6.2 
Individual Serum Pharmacokinetic Parameters of Bevacizumab 
Pharmacokinetic Population 
Listing 16.2.7.1 
Adverse Events 
Safety Population 
Listing 14.3.2.1 
Serious Adverse Events 
Safety Population 
Listing 14.3.2.2 
Serious Adverse Event: Additional Information 
Safety Population 
Listing 14.3.2.3 
Treatment-Emergent Adverse Event Leading to Permanent Discontinuation of  
Investigational Medicinal Product 
Safety Population 


 
 
 
 
 
 
 
 
CONFIDENTIAL 
SD 0400 A v1.0 
Statistical Analysis Plan 
                        40/42 page 
SAP V2.0 
Effective Date: 29-MAR-2018 
Listing 14.3.2.4 
Adverse Events Leading to Death 
Safety Population 
Listing 14.3.2.5 
Treatment-Emergent Adverse Event of Special Interest: Infusion-Related 
Reaction/Hypersensitivity 
Safety Population 
Listing 14.3.2.6 
Infusion-Related Reaction: Sign and Symptom 
Safety Population 
Listing 14.3.4.1 
Abnormal Laboratory Test 
Safety Population 
Listing 16.2.8.1 
Hematology 
Safety Population 
Listing 16.2.8.2 
Clinical Chemistry 
Safety Population 
Listing 16.2.8.3 
Coagulation 
Safety Population 
Listing 16.2.8.4 
Urinalysis-Categorical Parameters 
Safety Population 
Listing 16.2.8.5 
Urinalysis-Numeric Parameters 
Safety Population 
Listing 16.2.9.1.1 
Hypersensitivity Monitoring - Vital Signs  
Safety Population 
Listing 16.2.9.1.2 
Hypersensitivity Monitoring - 12-Lead Electrocardiogram 
Safety Population 
Listing 16.2.9.1.3 
Hypersensitivity Monitoring - Continuous Monitoring 
Safety Population 
Listing 16.2.9.2 
Vital Signs 
Safety Population 
Listing 16.2.9.3 
12-Lead Electrocardiogram 
Safety Population 
Listing 16.2.9.4 
Physical Examination 
Safety Population 
Listing 16.2.9.5 
Immunogenicity 
Safety Population 
Listing 16.2.9.6 
Restriction Assessment 
Safety Population 
 
List of Figures 
Figure Number 
Title 
Population 
Figure 14.2.1.1 
Mean (+/-SD) Serum Concentrations of Bevacizumab by Treatment 
Pharmacokinetic Population 
Figure 14.2.1.2 
Individual Serum Concentrations of Bevacizumab Versus Time (Spaghetti Plot) 
Pharmacokinetic Population 


 
 
 
 
 
 
 
 
CONFIDENTIAL 
SD 0400 A v1.0 
Statistical Analysis Plan 
                        41/42 page 
SAP V2.0 
Effective Date: 29-MAR-2018 
Figure 14.2.1.3 
Individual Serum Concentrations of Bevacizumab Versus Time 
Pharmacokinetic Population 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
SD 0400 A v1.0 
Statistical Analysis Plan 
42/42 page 
 
 
SAP V2.0 
Effective Date: 29-MAR-2018 
12. ROLE & RESPONSIBILITIES 
Role 
Name 
Responsibilities 
Biostatistician 
Kim, Alyoung 
Responsible for conducting statistical analysis and 
managing all the relevant tasks 
Biostatistician 
Bae, Suhyun 
Responsible for reviewing the statistical analysis results 
conducted by the Project Biostatistician 
Biostatistician 
Kim, Jieun 
Responsible for reviewing the statistical analysis results 
conducted by the Project Biostatistician 
Biostatistician 
Park, Joeun 
Responsible for conducting double programming for 
statistical analysis 
 
13. APPLIED SOPs 
SOP No. 
SOP Version_Effective date 
SOP Name 
0400 
1.0_17-Aug-2015 
Statistical Analysis Plan 
0401 
2.0_15-Apr-2016 
Statistical Analysis Process 
0406 
2.0_01-Sep-2016 
Definition of Analysis Population 
 
SD No. 
SD Version_Effective date 
SD Name 
0400 A 
1.0_17-Aug-2015 
Statistical Analysis Plan 
0406 A 
3.0_01-Sep-2016 
Definition of Analysis Population 
 
 
 
 
 
 

Prot_003.pdf: 
CELLTRION, Inc. 
CT-P16 1.1 
Clinical Study Protocol 
CONFIDENTIAL 
 
Version 1.0 
Page 1 of 65 
07 June 2017 
 
Clinical Study Protocol 
A Randomized, Double-blind, Three-arm, Parallel Group, Single-
dose Study to Compare the Pharmacokinetics and Safety of Three 
Formulations of Bevacizumab (CT-P16, EU-approved Avastin and 
US-licensed Avastin) in Healthy Male Subjects 
 
 
 
Sponsor: 
CELLTRION, Inc. 
 
23, Academy-ro, 
 
Yeonsu-gu, Incheon 
 
22014 Republic of Korea 
 
Clinical Research Organization: 
xxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxl 
xxxxxxxxxxxxxxxxxxxxa 
 
Principal Investigator: 
xxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx5 
xxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxx 
 
Sponsor Protocol No.: 
CT-P16 1.1 
 
IMP Name: 
CT-P16 
 
Development Phase: 
Phase I 
 
Date of Protocol: 
07 June 2017 
 
Version of Protocol 
1.0 
 
 
 
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 harmonised 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. 
Confidentiality Statement 
This document contains confidential information of CELLTRION, Inc. Do not copy or distribute 
without written permission from the Sponsor. 


CELLTRION, Inc. 
CT-P16 1.1 
Clinical Study Protocol 
CONFIDENTIAL 
 
Version 1.0 
Page 2 of 65 
07 June 2017 
 
SIGNATURE PAGE 
Declaration of Sponsor or Responsible Medical Expert 
Protocol Title: A Randomized, Double-blind, Three-arm, Parallel Group, Single-dose 
Study to Compare the Pharmacokinetics, Safety of Three Formulations of Bevacizumab 
(CT-P16, EU-approved Avastin and US-licensed Avastin) in Healthy Male Subjects 
This clinical study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational medicinal 
product, as well as with the moral, ethical and scientific principles governing clinical research 
as set out in the Declaration of Helsinki (WMA 2013), and the guidelines on Good Clinical 
Practices (GCP) applicable to this clinical study. 
Sponsor Signatory/Responsible Medical Expert 
 
 
 
 
 
xxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxx 
CELLTRION, Inc. 
 
Date 
 


CELLTRION, Inc. 
CT-P16 1.1 
Clinical Study Protocol 
CONFIDENTIAL 
 
Version 1.0 
Page 3 of 65 
07 June 2017 
 
SIGNATURE PAGE 
Declaration of the Principal Investigator 
Protocol Title: A Randomized, Double-blind, Three-arm, Parallel Group, Single-dose 
Study to Compare the Pharmacokinetics, Safety of Three Formulations of Bevacizumab 
(CT-P16, EU-approved Avastin and US-licensed Avastin) in Healthy Male Subjects 
I have read and understand all sections of the protocol entitled “A Randomized, Double-blind, 
Three-arm, _Parallel Group, Single-dose Study to Compare the Pharmacokinetics and Safety 
of Three Formulations of Bevacizumab (CT-P16, EU-approved Avastin and US-licensed 
Avastin) in Healthy Male Subjects” and the accompanying current investigator’s brochure.  
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the xxxxxxxxxxxxxxxxxxxxxxx, the International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use 
harmonised 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. 
Principal Investigator 
 
 
Signature of Principal Investigator  
 
Date 
 
Printed Name of Principal Investigator  
 
 
 


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• Arm 2 (n=47) EU-approved Avastin 
• Arm 3 (n=47) US-licensed Avastin 
Study Population: 
Healthy male subjects, 19 to 55 years of age with a body weight of ≥ 50 kg and a 
body mass index between 18.0 and 29.9 kg/m2 (both inclusive) are planned for 
enrollment. 
Inclusion and Exclusion 
Criteria 
Inclusion Criteria 
Subjects who meet the following criteria will be considered eligible to participate 
in the clinical study: 
1. Subject is able to understand and to comply with protocol requirements, 
instructions, and restrictions. 
2. Subject voluntarily agrees to participate in this study and has given a written 
informed consent prior to performing any of the screening procedures. 
3. Healthy male subjects between the ages of 19 and 55 years, both inclusive 
(healthy is defined as no clinically relevant abnormalities identified by a 
detailed medical history, full physical examination, including blood pressure 
[BP] and heart rate [HR] measurement, 12-lead electrocardiogram [ECG] and 
clinical laboratory tests prior to the administration of investigational medicinal 
product [IMP]). 
4. Body Mass Index (BMI) between 18.0 and 29.9 kg/m2 (both inclusive) and a 
body weight ≥ 50 kg. 
5. Male subject, unless surgically sterile for at least 6 months before the time of 
the administration of the IMP, must be willing to abstain from sexual 
intercourse or willing to use a condom in addition to having his female partner 
of childbearing potential use an additional form of contraception such as an 
intra-uterine device, barrier method with spermicide, oral contraceptive, 
injectable progesterone, sub-dermal implant from Day 1 until at least 6 months 
after the administration of the IMP. The female partner of the participating 
subject should be familiar with the use of the respective contraceptive methods. 
Intra-uterine devices and hormonal methods for contraceptive should have 
been used for at least one menstruation cycle before infusion. 
Exclusion Criteria 
Subjects who meet one or more of the following criteria will not be considered 
eligible to participate in the clinical study: 
1. Subject is a female. 
2. Subject has a medical history of disease including one or more of the 
following(s): 
- 
Clinically significant allergic reactions (spontaneous, atopic allergy, or 
following drug administration) such as asthma, urticaria, angio-
oedema, and eczematous dermatitis, hypersensitivity, also including 
known or suspected clinically relevant drug hypersensitivity to benzyl 
alcohol or any components of the test and reference IMP formulation 
or other similar drugs. 
- 
Cardiac, gastrointestinal, renal, hepatic, hematological (including 
pancytopenia, aplastic anaemia or blood dyscrasia), metabolic 
(including known diabetes mellitus), neurologic or pulmonary diseases 
classed as significant by the Investigator. 
- 
Non-healing wound, ulcer, bone fracture, or with a major surgical 
procedure, or significant traumatic injury within 28 days before 
administration of the IMP or plans a surgical procedure during the 
clinical trial. 
- 
History or any concomitant active malignancy. 
- 
A known infection with human immunodeficiency virus (HIV),  
hepatitis B or hepatitis C. 
- 
Any recent infection requiring a course of systemic anti-infective that 
was completed within 28 days before randomization or a serious 
infection (associated with hospitalization and/or which required 


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intravenous antibiotics) within 6 months before administration of the 
IMP. 
- 
Inherited bleeding diathesis or coagulopathy with the risk of bleeding. 
- 
Haemoptysis, thrombotic or haemorrhagic event within 6 months prior 
to the administration of IMP. 
- 
Cerebral vascular accident, transient ischemic attack, or subarachnoid 
haemorrhage within 6 months prior to administration of the IMP. 
- 
History and/or sign/symptoms of abdominal fistula, gastrointestinal 
perforation, or intra-abdominal abscess within 6 months prior to 
administration of the IMP. 
- 
Abnormal blood pressure (normal range; systolic BP 90 ~ 139 mmHg 
and diastolic BP 60 ~ 89 mmHg) 
3. Subject has an illness within 28 days prior to randomization that is classed as 
clinically significant by the Investigator. 
4. Subject used prescription or non-prescription drugs and dietary supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the dose of the IMP 
and/or subject used live or live attenuated vaccinations within 30 days prior to 
the dose of the IMP. Herbal supplements must be discontinued 28 days prior 
to the administration of the IMP. 
5. Subject has undergone treatment with an investigational drug or participated 
in another clinical trial within 3 months or 5 half-lives (whichever is longer) 
prior to the administration of the IMP.  
6. Subject has the previous treatment with an anti-VEGF antibody, or any other 
antibody or protein targeting the VEGF receptor. 
7. Subjects who have previously been exposed to a biologic agent within 3 
months prior to the administration of the IMP. 
8. A male subject plans to father a child or donates sperms within a 6 month 
period following study drug administration. 
9. Subject shows reasonable evidence of drug abuse including alcohol prior to 
the administration of the IMP (positive result for drug urine test and/or the 
opinion of the Investigator). Subject consumes more than 10 cigarettes or 
equivalent per day within 3 weeks prior to the administration of the IMP and/or 
is unable to refrain from smoking during in-house stays. 
10. Subject donated whole blood or lost 400 mL or more blood within 8 weeks 
(plasma/platelets donation within 4 weeks) prior to the administration of the 
IMP. 
11. Subject is vulnerable (e.g., employees of the clinical trial site or any other 
individuals involved with the conduct of the study, or immediate family 
members of such individuals, persons kept in prison or other institutionalized 
persons by law enforcement). 
12. Subject shows evidence of a condition (psychological, emotional problems, 
any disorders or resultant therapy) that is likely to invalidate informed consent, 
or limit the ability of the subject to comply with the protocol requirements in 
the opinion of the Investigator. 
13. Subject is not likely to complete the study for whatever reason in the opinion 
of the Investigator. 
Study Procedures: 
Screening (Day -21 to Day -2): 
Subjects will sign the informed consent and undergo procedures to determine 
eligibility. 
Adverse events (AEs) and concomitant medications will be monitored from the 
date when the informed consent form (ICF) is signed throughout the study. 
 
Admission (Day -1):  
Eligible subjects will be admitted to the clinical unit on Day -1 to undergo baseline 
assessments: re-check of inclusion and exclusion criteria, medical and medication 
history, concomitant medications, clinical laboratory, vital signs, body weight, 


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physical examination, and check for illicit drugs, history of drug abuse, nicotine 
and alcohol. 
In case of all pertaining tests have been concluded to confirm the eligibility during 
screening period, randomization will be done on Day -1.  
 
Study Period (Day 1 [Week 1] to Day 98 [Week 14]): 
CT-P16, EU-approved Avastin, or US-licensed Avastin will be administered to 
subjects on Day 1. Subjects will be confined to the clinical unit until completion 
of the 24-hour assessments after IMP administration. The consecutive study visits 
will be carried out on an out-patient basis. Acceptable tolerance windows for each 
assessments are described in Section 7.1. 
• PK analysis will be collected at pre-dose, at the end of infusion (EOI), 1 hour 
after the EOI, and at 4, 8, 12, and 24 hours (Day 2) after start of infusion 
(SOI), and on Days 3, 4, 8, 15, 29, 43, 57, 71, and 85.  
• Clinical laboratory testing will be performed on Day 3, 8, 15, 43, and 71. 
• Vital signs will be measured before dosing on Day 1, and on Day 3, 4, 8, 15, 
29, 43, 57, 71 and 85.  
• A 12-lead ECG will be performed on Day 3, 8, 15, 43, and 71.  
• Physical examinations will be performed on Day 3.  
• Hypersensitivity monitoring (vital signs measurement and 12-lead ECG) will 
be done on Day 1. 
• Immunogenicity of CT-P16, EU-approved Avastin and US-licensed Avastin 
will be assessed at pre-dose on Day 1, Day 15, 43 and Day 71. 
 
End-of-Study Visit (Day 99 [Week 15]): 
The end-of-study visit will be performed on Day 99 (Week 15).  
Subjects will return to the research unit and undergo the following PK and safety 
assessments: PK sampling and immunogenicity for CT-P16, EU-approved Avastin 
and US-licensed Avastin, collection of information related to AEs and concomitant 
medications, body weight, vital signs, 12-lead ECG, clinical laboratory tests and 
physical examination. 
The total duration of the participation will be up to 15 weeks for each individual 
subject who completes the entire clinical trial. 
Criteria for Evaluation: 
Primary Endpoints 
Pharmacokinetics  
• Area under the concentration-time curve from time zero to infinity (AUC0-inf) 
• Area under the concentration-time curve from time zero to the last 
quantifiable concentration (AUC0-last) 
• Maximum serum concentration (Cmax) 
 
Secondary Endpoints 
Pharmacokinetics 
• Time to Cmax (Tmax) 
• Volume of distribution during the terminal phase (Vz) 
• Terminal elimination rate constant (λz) 
• Terminal half-life (t1/2) 
• Total body clearance (CL)  
• Percentage of AUC0-inf obtained by extrapolation (%AUCext) 
Safety and Immunogenicity 
• Vital signs (blood pressure [BP], heart rate [HR], body temperature [BT], and 
respiratory rate [RR]) 
• Physical examination 


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• Clinical laboratory tests including hematology, chemistry, coagulation, and 
urinalysis 
• Twelve-lead electrocardiogram (ECG) 
• AEs and concomitant medication 
• Adverse event of Special interest (AESI) (e.g., hypersensitivity/infusion-
related reaction)  
• Immunogenicity of CT-P16, EU-approved Avastin and US-licensed Avastin 
Sample size 
assumption: 
A sample size of 42 completing subjects from each arm of the clinical study will 
provide 90% power to show similarity in PKs among the test product, EU-
approved Avastin and US-licensed Avastin using 90% confidence interval (CI) 
approach based on 80%-125% equivalence margin. A coefficient of variation (CV) 
of 30% is assumed based upon historical PK data. The sample size is calculated 
from two one-sided tests with each 5% significance level using geometric mean 
ratio. A 10% dropout rate is anticipated so approximately 141 subjects (47 in each 
arm) will be enrolled. By assuming that EU-approved Avastin and US-licensed 
Avastin are identical, the multiplicity problem is not considered in the calculation 
of the sample size. 
Statistical Methods: 
Pharmacokinetic analyses 
The statistical analysis of the log-transformed primary endpoints (AUC0-inf, AUC0-
last and Cmax) will be based on an analysis of covariance (ANCOVA) model. The 
difference in least squares means between the CT-P16 and EU-approved Avastin, 
CT-P16 and US-licensed Avastin, EU-approved Avastin and US-licensed Avastin, 
and the associated 90% CIs will be determined. Back transformation will provide 
the ratio of geometric means and 90% CIs for these ratios.  
Similarity of systemic exposure (AUC0-inf, AUC0-last and Cmax) will be determined 
if 90% CI for the ratio of geometric means is within the acceptance interval of 80% 
to 125% for the following comparisons: 
• CT-P16 vs EU-approved Avastin 
• CT-P16 vs US-licensed Avastin 
• EU-approved Avastin vs US-licensed Avastin 
For secondary endpoints, following PK parameters will be assessed: 
Time to Cmax (Tmax), volume of distribution during the terminal phase (Vz), 
terminal elimination rate constant (λz), terminal half-life (t1/2), total body clearance 
(CL) and percentage of AUC0-inf obtained by extrapolation (%AUCext). 
Pharmacokinetic parameters will be presented in listings and summarized in tables. 
The tables will display the following descriptive statistics: n, mean, median, 
standard deviation (SD), minimum, maximum, the geometric mean and CV. 
Safety and immunogenicity analyses 
All safety and immunogenicity analyses will be conducted on the safety 
population, and listed and summarized by treatment group. All reported terms for 
AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Terminology and severity grading of AEs will be recorded based on 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Prior 
and concomitant medications will be coded using the World Health Organization 
(WHO) Drug Dictionary. All safety data will be analyzed descriptively.  


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................... 4 
TABLE OF CONTENTS .................................................................................................... 9 
List of Tables ....................................................................................................... 11 
LIST OF ABBREVIATIONS ........................................................................................... 12 
1. 
INTRODUCTION ............................................................................................... 15 
1.1 
Background............................................................................................. 15 
1.2 
Rationale for the Clinical Study ............................................................. 16 
1.3 
Risk-Benefit Assessment ........................................................................ 17 
2. 
STUDY OBJECTIVES ....................................................................................... 22 
2.1 
Primary Objective ................................................................................... 22 
2.2 
Secondary Objective(s) .......................................................................... 22 
3. 
OVERALL DESIGN AND PLAN OF THE STUDY ......................................... 23 
3.1 
Overview ................................................................................................ 23 
3.2 
Endpoints ................................................................................................ 23 
3.2.1 
Primary endpoints .............................................................................. 23 
3.2.2 
Secondary endpoints .......................................................................... 24 
3.3 
Justification of the Study Design ............................................................ 24 
4. 
STUDY POPULATION ...................................................................................... 25 
4.1 
Number of Subjects ................................................................................ 25 
4.2 
Inclusion Criteria .................................................................................... 25 
4.3 
Exclusion Criteria ................................................................................... 25 
4.4 
Subject Withdrawal and Replacement .................................................... 27 
4.5 
Premature Termination of the Clinical Trial .......................................... 28 
5. 
INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 30 
5.1 
Identity of the Investigational Medicinal Products ................................ 30 
5.2 
Dose Rationale Including Time of Dosing ............................................. 30 
5.3 
Supply, Packaging, Labeling and Storage .............................................. 30 
5.4 
Drug Accountability, Dispensing and Destruction ................................. 31 
5.5 
Method of Assigning Subjects to Treatment Group ............................... 31 
5.5.1 
Screening numbers ............................................................................. 31 
5.5.2 
Randomization ................................................................................... 31 
5.6 
Administration of Investigational Medicinal Products........................... 32 
5.7 
Compliance ............................................................................................. 32 
5.8 
Blinding and Breaking the Blind ............................................................ 32 
5.9 
Concomitant Medications ....................................................................... 33 
5.10 
Treatment of Overdose ........................................................................... 33 
6. 
VARIABLES AND METHODS OF ASSESSMENT ........................................ 34 
6.1 
Pharmacokinetic Variables ..................................................................... 34 
6.2 
Safety Variables...................................................................................... 34 
6.2.1 
Medical History, Demographic and Other Baseline Information ...... 34 
6.2.2 
Adverse Events .................................................................................. 35 


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6.2.2.1 Definitions .......................................................................... 35 
6.2.2.2 Recording of Adverse Events ............................................. 36 
6.2.2.3 Assessment of Adverse Events ........................................... 36 
6.2.2.4 Reporting of Serious Adverse Events................................. 39 
6.2.2.5 Follow-up of Adverse Events ............................................. 40 
6.2.2.6 Procedure for Notification of Serious Adverse Event and 
Suspected Unexpected Serious Adverse Reactions to 
Institutional Review Boards ............................................... 40 
6.2.2.7 Pregnancy ........................................................................... 41 
6.2.3 
Hypersensitivity Assessment ............................................................. 41 
6.2.4 
Clinical Laboratory Assessments ....................................................... 41 
6.2.5 
Vital Signs ......................................................................................... 42 
6.2.6 
Electrocardiograms ............................................................................ 43 
6.2.7 
Physical Examinations ....................................................................... 43 
6.3 
Immunogenicity Variables ..................................................................... 43 
6.4 
Sample Collection, Storage and Shipment ............................................. 44 
6.4.1 
Pharmacokinetic Sampling ................................................................ 44 
6.4.2 
Clinical Laboratory Testing ............................................................... 44 
6.4.3 
Immunogenicity Sampling ................................................................. 44 
7. 
STUDY CONDUCT ............................................................................................ 45 
7.1 
Schedule of Assessments ........................................................................ 45 
7.2 
Assessments by Visit .............................................................................. 49 
7.2.1 
Screening Visit (Days –21 to –2) ....................................................... 49 
7.2.2 
In-House Stay (Day –1 to Day 2) and Out-Patient Visits (Day 3 to Day 
85) ...................................................................................................... 50 
7.2.3 
End-of-Study Visit (Day 99).............................................................. 50 
7.2.4 
Early Termination Visit ..................................................................... 51 
7.3 
Restrictions ............................................................................................. 51 
7.3.1 
Dietary and Fluid Restrictions ........................................................... 51 
7.3.2 
Other Restrictions .............................................................................. 52 
8. 
STATISTICAL METHODS ................................................................................ 53 
8.1 
Study Population .................................................................................... 53 
8.1.1 
Disposition of Subjects ...................................................................... 53 
8.1.2 
Protocol Deviations ........................................................................... 53 
8.1.3 
Analysis Populations ......................................................................... 53 
8.2 
General Considerations .......................................................................... 54 
8.3 
Safety Analyses ...................................................................................... 54 
8.3.1 
Adverse Events .................................................................................. 54 
8.3.2 
Clinical Laboratory Tests................................................................... 54 
8.3.3 
Vital Signs ......................................................................................... 55 
8.3.4 
Electrocardiogram .............................................................................. 55 
8.3.5 
Physical Examination ........................................................................ 55 
8.3.6 
Immunogenicity analysis ................................................................... 55 
8.4 
Pharmacokinetic Analyses ...................................................................... 55 
8.5 
Interim Analyses ..................................................................................... 57 
8.6 
Determination of Sample Size ................................................................ 57 
9. 
DATA COLLECTION AND QUALITY ASSURANCE ................................... 58 
9.1 
Data Quality Assurance .......................................................................... 58 
9.2 
Data Collection ....................................................................................... 58 


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9.3 
Case Report Forms and Source Documents ........................................... 59 
9.4 
Access to Source Documents ................................................................. 59 
9.5 
Data Management ................................................................................... 59 
9.6 
Archiving Study Documents .................................................................. 60 
10. 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ............................. 61 
10.1 
Good Clinical Practice ............................................................................ 61 
10.2 
Informed Consent ................................................................................... 61 
10.3 
Protocol Approval and Amendment(s) ................................................... 61 
10.4 
Confidentiality Data Protection .............................................................. 62 
10.5 
Liability and Insurance ........................................................................... 62 
10.6 
Publication Policy ................................................................................... 62 
11. 
REFERENCE LIST ............................................................................................. 64 
 
List of Tables 
Table 1. 
Identity of Investigational Products ............................................................. 30 
Table 2. 
Blood sampling time points for PK assessment ........................................... 45 
Table 3.  
Schedule of Assessment for Hypersensitivity Monitoring .......................... 46 
Table 4. 
Schedule of Assessments ............................................................................. 47 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC0-inf 
Area under the concentration-time curve from time zero to infinity 
AUC0-last 
Area under the concentration-time curve from time zero to the last 
quantifiable concentration 
BMI 
Body mass index 
BP 
Blood pressure 
BT 
Body temperature 
bpm 
Beats per minute 
CDMP 
Clinical Data Management Plan 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CK-MB 
Creatine kinase–myocardial band isoenzyme 
CL 
Total body clearance 
CNS 
Central nervous system 
CPK 
Creatine phosphokinase 
CRO 
Clinical research organization 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
Cmax 
Maximum serum concentration 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
EOI 
End of infusion 
EOS 
End of study 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 


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GI 
Gastrointestinal 
HBsAg 
Hepatitis B surface antigen 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IB 
Investigator's brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
IV 
Intravenous 
λz 
Terminal elimination rate constant 
LDH 
Lactate dehydrogenase 
mBC 
Metastatic breast cancer 
mCRC 
Metastatic colorectal cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
Millimeter mercury 
MRI 
Magnetic resonance imaging 
NSCLC 
Non-small cell lung cancer 
OTC 
Over-the-counter 
ONJ 
Osteonecrosis of the jaw 
PK 
Pharmacokinetic(s) 
PRES 
Posterior Reversible Encephalopathy Syndrome 
PT 
Prothrombin time 
RBC 
Red blood cell 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis Plan 
SD 
Standard deviation 
SmPC 
Summary of product characteristics 
SOI 
Start of infusion 
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected serious adverse reactions  
t1/2 
Terminal half-life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to Cmax 


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ULN 
Upper limit of normal (laboratory range) 
US 
United States 
USPI 
United States Prescribing Information 
VEGF 
Vascular endothelial growth factor 
Vz 
Volume of distribution during the terminal phase 
WBC 
White blood cell 
WHO 
World Health Organization 
 


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1. 
INTRODUCTION 
1.1 
Background 
Vascular endothelial growth factor (VEGF), a diffusible glycoprotein produced by normal and 
neoplastic cells, is an important regulator of physiologic and pathologic angiogenesis (Ferrara 
et al. 2003). It is a highly conserved, homodimeric, heparin-binding glycoprotein that exists in 
several isoforms (Ferrara et al. 1997). VEGF mediates its effects by interacting with the 
membrane-bound tyrosine kinase receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR, flk-1), 
activating specific downstream survival and proliferation pathways. VEGF is considered 
essential for normal developmental vasculogenesis, and there is substantial evidence 
implicating VEGF as a critical factor in tumor angiogenesis (Ferrara et al. 2003). Transfection 
of Chinese hamster ovary cells with expression vectors encoding VEGF allows these cells to 
form tumors in nude mice (Ferrara et al. 1993). Increased VEGF expression has been described 
in most human tumors and in many instances is correlated with an adverse prognosis (increased 
risk of tumor recurrence and metastasis and decreased survival) (Takahashi et al. 1995; 
Takahashi et al. 1997; Warren et al. 1995). 
Bevacizumab is a humanized monoclonal antibody directed against VEGF. Bevacizumab binds 
VEGF and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of 
endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell 
proliferation and new blood vessel formation in in vitro models of angiogenesis. By blocking 
the endothelial interaction of VEGF and its receptors, bevacizumab serves as an antiangiogenic 
agent. 
The reference product, Avastin, is formulated as a 25 mg/mL concentrate for solution for 
infusion, presented in single-use, type 1 glass vials containing 100 mg or 400 mg of 
bevacizumab. The Avastin drug product is a clear to slightly opalescent, colourless to pale 
brown liquid containing the excipients, α, α-trehalose dihydrate (60 mg/ml), sodium phosphate 
(51 mM, pH 6.2), polysorbate 20 (0.04%), and water for injections. The product is to be diluted 
in 0.9% sodium chloride solution prior to administration. 
CT-P16, containing the active ingredient bevacizumab, is being developed as a similar 
biological medicinal product to Avastin, which currently has received approval in both 
European Union (EU) and United States (US) for the indications shown in the Avastin 
Summary of Product Characteristics (SmPC, 2017) and Avastin United States Prescribing 
Information (USPI, 2016). 
CT-P16 drug product will have the same pharmaceutical form and strength as the EU-
approved/US-licensed Avastin, and is intended to be highly analytically comparable to EU-
approved/US-licensed Avastin. As for EU-approved/US-licensed Avastin, the bevacizumab 


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active ingredient of CT-P16 is produced by recombinant DNA technology in a CHO cell 
expression system and purified by a suitable process. 
Avastin has been approved in a variety of tumor types, including metastatic carcinoma of the 
colon or rectum; metastatic breast cancer (mBC) (EU only); unresectable, advanced, metastatic, 
or recurrent non-small cell lung cancer (NSCLC) other than predominantly squamous histology; 
advanced and/or metastatic renal cell cancer; epithelial ovarian, fallopian tube or primary 
peritoneal cancer; persistent, recurrent, or metastatic carcinoma of the cervix; and glioblastoma 
(US only). 
As CT-P16 is being developed under a global development plan, the pharmacokinetic (PK) 
profile of CT-P16 and two reference products from different sources (EU-approved Avastin 
and US-licensed Avastin) will be compared to demonstrate PK equivalence in this Phase 1 
study. 
1.2 
Rationale for the Clinical Study 
The introduction of biosimilar (follow-on) medicinal products is desirable as they will enhance 
patient access by expanding the field of competing biotechnological treatments. The purpose 
of this clinical study is to compare the PK, safety, tolerability and immunogenicity of the 
proposed biosimilar test product CT-P16 with EU-approved Avastin and US-licensed Avastin 
after a single intravenous (IV) infusion of 5 mg/kg of each product to healthy adult subjects 
following the recommendations of the Food and Drug Administration (FDA) guidance 
“Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (FDA 2015)” 
and EMA guidance “Similar biological medicinal products containing monoclonal antibodies: 
non-clinical and clinical issues” (EMA/CHMP/BMWP/403543/2010) (CHMP 2012). 
With regards to the selection of dose, doses of Avastin between 5 and 15 mg/kg are used in 
clinical practice. From a safety perspective, it is considered best to administer the lowest 
recommended therapeutic dose in studies of healthy subjects. Also, the 5 mg/kg dose is 
proposed in this Phase 1 PK study, since bevacizumab PK is linear at doses between 1 and 10 
mg/kg and use of 5 mg/kg is further supported in terms of assessment of immunogenicity as 
higher doses are theoretically expected to be less immunogenic. According to clinicaltrials.gov, 
5 mg/kg has been administered to healthy male volunteers in another study of a biosimilar 
bevacizumab (Pfizer’s PF-06439535) and has been shown to be well tolerated, with no signs 
of unexpected side effects or cardiotoxicity (Knight et al. 2016). 
Healthy subjects have been selected for this study in order to avoid potentially high variability 
of the exposure of bevacizumab if administered to patients with metastatic colorectal cancer or 
non-squamous non-small cell lung cancer, which would introduce a bias into the attainment of 


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the primary study objective. A parallel-group design will be used in this study to prevent 
potential crossover effects. 
1.3 
Risk-Benefit Assessment 
Information about the risk following the administration of bevacizumab was taken from the 
Avastin SmPC (2017) and Avastin USPI (2016) of EU-approved and US-licensed Avastin. 
Gastrointestinal (GI) perforations and Fistulae: Patients may be at an increased risk for the 
development of gastrointestinal perforation and gall bladder perforation when treated with 
Avastin. Intra-abdominal inflammatory process may be a risk factor for gastrointestinal 
perforations in patients with metastatic carcinoma of the colon or rectum, therefore, caution 
should be exercised when treating these patients. Prior radiation is a risk factor for GI 
perforation in patients treated for persistent, recurrent or metastatic cervical cancer with 
Avastin and all patients with GI perforation had a history of prior radiation. Therapy should be 
permanently discontinued in patients who develop gastrointestinal perforation. 
Non-GI Fistulae: Patients may be at increased risk for the development of fistulae when 
treated with Avastin. Avastin should be permanently discontinued in patients with 
tracheoesophageal fistula or any Grade 4 fistula [US National Cancer Institute - Common 
Terminology Criteria for Adverse Events (CTCAE) Version 3)]. Limited information is 
available on the continued use of Avastin in patients with other fistulae. In cases of internal 
fistula not arising in the gastrointestinal tract, discontinuation of Avastin should be considered. 
Wound healing complications: Avastin may adversely affect the wound healing process. 
Serious wound healing complications, including anastomotic complications, with a fatal 
outcome have been reported. Therapy should not be initiated for at least 28 days following 
major surgery or until the surgical wound is fully healed. In patients who experienced wound 
healing complications during therapy, treatment should be withheld until the wound is fully 
healed. Therapy should be withheld for elective surgery. Necrotising fasciitis, including fatal 
cases, has rarely been reported in patients treated with Avastin. This condition is usually 
secondary to wound healing complications, gastrointestinal perforation or fistula formation. 
Avastin therapy should be discontinued in patients who develop necrotising fasciitis, and 
appropriate treatment should be promptly initiated. 
Hypertension: An increased incidence of hypertension was observed in Avastin-treated 
patients. Clinical safety data suggest that the incidence of hypertension is likely to be dose-
dependent. Pre-existing hypertension should be adequately controlled before starting Avastin 
treatment. There is no information on the effect of Avastin in patients with uncontrolled 
hypertension at the time of initiating therapy. Monitoring of blood pressure (BP) is generally 
recommended during therapy. In most cases hypertension was controlled adequately using 


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standard antihypertensive treatment appropriate for the individual situation of the affected 
patient. The use of diuretics to manage hypertension is not advised in patients who receive a 
cisplatin-based chemotherapy regimen. Avastin should be permanently discontinued if 
medically significant hypertension cannot be adequately controlled with antihypertensive 
therapy, or if the patient develops hypertensive crisis or hypertensive encephalopathy. 
Posterior Reversible Encephalopathy Syndrome (PRES): There have been rare reports of 
Avastin-treated patients developing signs and symptoms that are consistent with PRES, a rare 
neurologic disorder, which can present with the following signs and symptoms among others: 
seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or 
without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, 
preferably magnetic resonance imaging (MRI). In patients developing PRES, treatment of 
specific symptoms including control of hypertension is recommended along with 
discontinuation of Avastin. The safety of reinitiating Avastin therapy in patients previously 
experiencing PRES is not known. 
Proteinuria: Patients with a history of hypertension may be at increased risk for the 
development of proteinuria when treated with Avastin. There is evidence suggesting that all 
Grade (CTCAE Version 3) proteinuria may be related to the dose. Monitoring of proteinuria 
by dipstick urinalysis is recommended prior to starting and during therapy. Therapy should be 
permanently discontinued in patients who develop Grade 4 proteinuria (nephrotic syndrome) 
(CTCAE Version 3). 
Arterial thromboembolism: In clinical trials, the incidence of arterial thromboembolic 
reactions including cerebrovascular accidents, transient ischaemic attacks and myocardial 
infarctions was higher in patients receiving Avastin in combination with chemotherapy 
compared to those who received chemotherapy alone. Patients receiving Avastin plus 
chemotherapy, with a history of arterial thromboembolism, diabetes or age greater than 65 
years have an increased risk of developing arterial thromboembolic reactions during therapy. 
Caution should be taken when treating these patients with Avastin. Therapy should be 
permanently discontinued in patients who develop arterial thromboembolic reactions. 
Venous thromboembolism: Patients may be at risk of developing venous thromboembolic 
reactions, including pulmonary embolism under Avastin treatment. Patients treated for 
persistent, recurrent, or metastatic cervical cancer with Avastin in combination with paclitaxel 
and cisplatin may be at increased risk of venous thromboembolic events. Avastin should be 
discontinued in patients with life-threatening (Grade 4) thromboembolic reactions, including 
pulmonary embolism (CTCAE Version 3). Patients with thromboembolic reactions ≤ Grade 3 
need to be closely monitored (CTCAE Version 3). 


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Haemorrhage: Patients treated with Avastin have an increased risk of haemorrhage, especially 
tumor-associated haemorrhage. Avastin should be discontinued permanently in patients who 
experience Grade 3 or 4 bleeding during Avastin therapy (CTCAE Version 3). Patients with 
untreated central nervous system (CNS) metastases were routinely excluded from clinical trials 
with Avastin, based on imaging procedures or signs and symptoms. Therefore, the risk of CNS 
haemorrhage in such patients has not been prospectively evaluated in randomized clinical trials. 
Patients should be monitored for signs and symptoms of CNS bleeding, and Avastin treatment 
discontinued in cases of intracranial bleeding. There is no information on the safety profile of 
Avastin in patients with congenital bleeding diathesis, acquired coagulopathy or in patients 
receiving full dose of anticoagulants for the treatment of thromboembolism prior to starting 
Avastin treatment, as such patients were excluded from clinical trials. Therefore, caution 
should be exercised before initiating therapy in these patients. However, patients who 
developed venous thrombosis while receiving therapy did not appear to have an increased rate 
of Grade 3 or above bleeding when treated with a full dose of warfarin and Avastin 
concomitantly (CTCAE Version 3). 
Pulmonary haemorrhage/haemoptysis: Patients with non-small cell lung cancer treated with 
Avastin may be at risk of serious, and in some cases fatal, pulmonary haemorrhage 
/haemoptysis. Patients with recent pulmonary haemorrhage/haemoptysis (> 2.5 mL of red 
blood) should not be treated with Avastin.  
Congestive heart failure (CHF): Reactions consistent with CHF were reported in clinical trials. 
The findings ranged from asymptomatic declines in left ventricular ejection fraction to 
symptomatic CHF, requiring treatment or hospitalization. Caution should be exercised when 
treating patients with clinically significant cardiovascular disease such as pre-existing coronary 
artery disease, or congestive heart failure with Avastin. Most of the patients who experienced 
CHF had mBC and had received previous treatment with anthracyclines, prior radiotherapy to 
the left chest wall or other risk factors for CHF were present. CHF Grade 3 or higher reactions 
were somewhat more frequent among patients receiving bevacizumab in combination with 
chemotherapy than in patients receiving chemotherapy alone. This is consistent with results in 
patients in other studies of mBC who did not receive concurrent anthracycline treatment 
(CTCAE Version 3). 
Neutropenia and infections: Increased rates of severe neutropenia, febrile neutropenia, or 
infection with or without severe neutropenia (including some fatalities) have been observed in 
patients treated with some myelotoxic chemotherapy regimens plus Avastin in comparison to 
chemotherapy alone. This has mainly been seen in combination with platinum- or taxane-based 
therapies in the treatment of NSCLC, mBC, and in combination with paclitaxel and topotecan 
in persistent, recurrent, or metastatic cervical cancer. 


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Hypersensitivity reactions/infusion reactions: Patients may be at risk of developing 
infusion/hypersensitivity reactions. Close observation of the patient during and following the 
administration of bevacizumab is recommended as expected for any infusion of a therapeutic 
humanized monoclonal antibody. If a reaction occurs, the infusion should be discontinued and 
appropriate medical therapies should be administered. A systematic premedication is not 
warranted. 
Osteonecrosis of the jaw (ONJ): Cases of ONJ have been reported in cancer patients treated 
with Avastin, the majority of whom had received prior or concomitant treatment with 
intravenous bisphosphonates, for which ONJ is an identified risk. Caution should be exercised 
when Avastin and intravenous bisphosphonates are administered simultaneously or 
sequentially. Invasive dental procedures are also an identified risk factor. A dental examination 
and appropriate preventive dentistry should be considered prior to starting the treatment with 
Avastin. In patients who have previously received or are receiving intravenous 
bisphosphonates invasive dental procedures should be avoided, if possible. 
Ovarian failure/fertility: Avastin may impair female fertility. Therefore fertility preservation 
strategies should be discussed with women of child-bearing potential prior to starting treatment 
with Avastin. 
Embryo-fetal Toxicity: Avastin may cause fetal harm based on the drug’s mechanism of action 
and findings from animal studies. Congenital malformations were observed with the 
administration of bevacizumab to pregnant rabbits during organogenesis every 3 days at a dose 
as low as a clinical dose of 10 mg/kg. Furthermore, animal models link angiogenesis and VEGF 
and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryo-fetal 
development, and postnatal development. Advise pregnant women of the potential risk to a 
fetus. Advise females of reproductive potential to use effective contraception during treatment 
with and for 6 months after the last dose of Avastin. 
This study will therefore include close monitoring of safety and toxicity reactions. Subjects 
who received monoclonal antibody or biologic agent within 3 months prior to the 
administration of the Investigational medicinal product (IMP) (in a clinical trial or as treatment) 
will be excluded from study participation as they may have developed antibodies against 
bevacizumab, which might be a trigger adverse reaction. Antibodies against bevacizumab may 
also interfere with the primary study objective as the exposure to the IMP may be precluded 
due to antibody binding and therefore may distort the PK endpoints. Further, the potential 
immunogenicity of CT-P16, EU-approved and US-licensed Avastin will be evaluated. 
The safety monitoring practices employed by this protocol are adequate to protect the subjects’ 
safety and should detect all expected treatment-emergent adverse events (TEAEs). As 


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bevacizumab is infused only once over 90 minutes (± 5 min) in treatment-relevant dose, the 
overall risk of the study for healthy subjects is considered to be acceptable. 


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2. 
STUDY OBJECTIVES 
2.1 
Primary Objective 
• To demonstrate the similarity of the PK in terms of area under the concentration-time curve 
from time zero to infinity (AUC0-inf), area under the concentration-time curve from time 
zero to the last quantifiable concentration (AUC0-last), and maximum serum concentration 
(Cmax) of CT-P16, US-licensed Avastin and EU-approved Avastin in healthy male subjects 
(CT-P16 to EU-approved Avastin, CT-P16 to US-licensed Avastin, and EU-approved 
Avastin to US-licensed Avastin). 
2.2 
Secondary Objective(s) 
• To assess the additional PK parameters of CT-P16, US-licensed Avastin, and EU-approved 
Avastin in healthy male subjects. 
• To evaluate the safety and immunogenicity of CT-P16, US-licensed Avastin, and EU-
approved Avastin in healthy male subjects. 


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3. 
OVERALL DESIGN AND PLAN OF THE STUDY 
3.1 
Overview 
This study is a double-blind, three-arm, parallel group, single-dose study. A total of 141 healthy 
male subjects aged between 19 and 55 years will be enrolled; 47 subjects in each of the 3 arms 
of the clinical study. In each arm, all subjects will receive a single dose of CT-P16, EU-
approved Avastin, or US-licensed Avastin by IV infusion for 90 min (±5 min) on Day 1 
followed by 15 weeks during which the PK, safety and immunogenicity measurements will be 
made. 
Subjects will be screened for eligibility within 21 to 2 days before the infusion of the IMP after 
they have signed an informed consent. Multiple visits may be needed during the screening 
period to complete study-related assessments. 
Eligible subjects will be admitted to the clinical unit on Day –1 to undergo baseline assessments 
and will be randomized on Day –1 to receive one of CT-P16, EU-approved Avastin, or US-
licensed Avastin once all eligibility criteria have been confirmed. Subjects will be confined to 
the clinical unit until completion of the 24-hour assessments after IMP administration. The 
consecutive study visits will be carried out on an out-patient basis. Blood for PK analysis will 
be collected up to Day 99. Safety will be assessed throughout the study by collection of 
information about AEs and concomitant medication, by clinical laboratory testing, 
measurement of vital signs, recording of 12-lead ECGs, physical examination and assessment 
of the immunogenicity of CT-P16, EU-approved Avastin, and US-licensed Avastin. An end-
of-study (EOS) examination will take place on Day 99. 
The total duration of the participation will be up to 15 weeks for each individual subject who 
completes the entire clinical trial. 
Please refer to Section 7.2, Table 2, Table 3, and Table 4 for a detailed list of procedures 
performed on each study day/visit. 
3.2 
Endpoints 
3.2.1 
Primary endpoints 
Pharmacokinetics 
• Area under the concentration-time curve from time zero to infinity (AUC0-inf) 
• Area under the concentration-time curve from time zero to the last quantifiable 
concentration (AUC0-last) 
• Maximum serum concentration (Cmax) 


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3.2.2 
Secondary endpoints 
Pharmacokinetics 
• Time to Cmax (Tmax) 
• Volume of distribution during the terminal phase (Vz) 
• Terminal elimination rate constant (λz) 
• Terminal half-life (t1/2) 
• Total body clearance (CL) 
• Percentage of AUC0-inf obtained by extrapolation (%AUCext) 
Safety and Immunogenicity 
• Vital signs (blood pressure [BP], heart rate [HR], body temperature [BT], and respiratory 
rate [RR]) 
• Physical examination 
• Clinical laboratory tests including hematology, chemistry, coagulation, and urinalysis 
• Twelve-lead electrocardiogram (ECG) 
• Adverse events (AEs) and concomitant medication 
• Adverse event of special interest (AESI) (e.g., hypersensitivity/infusion-related reaction 
[IRR]) 
• Immunogenicity of CT-P16, EU-approved Avastin and US-licensed Avastin 
3.3 
Justification of the Study Design 
The purpose of this clinical trial is to compare the PK, safety and immunogenicity of the 
proposed biosimilar test product CT-P16 with EU-approved Avastin and US-licensed Avastin 
after a single IV infusion of 5 mg/kg of each product to healthy male subjects. The clinical trial 
will be conducted according to the recommendations of the FDA guidance “Scientific 
Considerations in Demonstrating Biosimilarity to a Reference Product (US FDA guidance 
2015)” and EMA guidance “Similar biological medicinal products containing monoclonal 
antibodies: non-clinical and clinical issues” (EMA/CHMP/BMWP/403543/2010) (CHMP 
2012). 


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4. 
STUDY POPULATION 
The study population will consist of healthy male subjects. Subjects must be able to provide 
written informed consent and meet all the inclusion criteria and none of the exclusion criteria, 
according to the criteria outlined below (Sections 4.2 and 4.3). 
4.1 
Number of Subjects 
A total of 141 subjects will be enrolled in the clinical study, and 47 subjects will be randomized 
into each of 3 study arms (CT-P16, EU-approved Avastin or US-licensed Avastin). 
4.2 
Inclusion Criteria 
Subjects who meet the following criteria will be considered eligible to participate in the clinical 
study: 
1. Subject is able to understand and to comply with protocol requirements, instructions, and 
restrictions. 
2. Subject voluntarily agrees to participate in this study and has given a written informed 
consent prior to performing any of the screening procedures. 
3. Healthy male subjects between the ages of 19 and 55 years, both inclusive (healthy is 
defined as no clinically relevant abnormalities identified by a detailed medical history, full 
physical examination, including BP and HR measurement, 12-lead ECG and clinical 
laboratory tests prior to the administration of IMP). 
4. Body Mass Index (BMI) between 18.0 and 29.9 kg/m2 (both inclusive) and a body weight 
≥50 kg.  
5. Male subject, unless surgically sterile for at least 6 months before the time of the 
administration of IMP, must be willing to abstain from sexual intercourse or willing to use 
a condom in addition to having his female partner of childbearing potential use an 
additional form of contraception such as an intra-uterine device, barrier method with 
spermicide, oral contraceptive, injectable progesterone, sub-dermal implant from Day 1 
until at least 6 months after the administration of the IMP. The female partner of the 
participating subject should be familiar with the use of the respective contraceptive 
methods. Intra-uterine devices and hormonal methods for contraceptive should have been 
used for at least one menstruation cycle before infusion. 
4.3 
Exclusion Criteria 
Subjects who meet one or more of the following criteria will not be considered eligible to 
participate in the clinical study: 


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1. Subject is a female. 
2. Subject has a medical history and/or current presence of disease including one or more of 
the following(s): 
− Clinically significant allergic reactions (spontaneous, atopic allergy, or following drug 
administration) such as asthma, urticaria, angio-oedema, and eczematous dermatitis, 
hypersensitivity, also including known or suspected clinically relevant drug 
hypersensitivity to benzyl alcohol or any components of the test and reference IMP 
formulation or other similar drugs. 
− Cardiac, gastrointestinal, renal, hepatic, hematological (including pancytopenia, 
aplastic anaemia or blood dyscrasia), metabolic (including known diabetes mellitus), 
neurologic or pulmonary diseases classed as significant by the Investigator. 
− Non-healing wound, ulcer, bone fracture, or with a major surgical procedure, or 
significant traumatic injury within 28 days before administration of the IMP or plans a 
surgical procedure during the clinical trial. 
− History or any concomitant active malignancy. 
− History of and/or current immunodeficiency including infection with hepatitis B, 
hepatitis C, human immunodeficiency virus (HIV) or positive result to the screening 
test for those infections. 
− Any recent infection requiring a course of systemic anti-infective that was completed 
within 28 days before randomization or a serious infection (associated with 
hospitalization and/or which required intravenous antibiotics) within 6 months before 
administration of the IMP. 
− Inherited bleeding diathesis or coagulopathy with the risk of bleeding. 
− Haemoptysis, thrombotic or haemorrhagic event within 6 months prior to the 
administration of IMP. 
− Cerebral vascular accident, transient ischemic attack, or subarachnoid haemorrhage 
within 6 months prior to administration of the IMP. 
− History and/or sign/symptoms of abdominal fistula, gastrointestinal perforation, or 
intra-abdominal abscess within 6 months prior to administration of the IMP. 
− Abnormal blood pressure (normal range; systolic BP 90 ~ 139 mmHg and diastolic BP 
60 ~ 89 mmHg). 
3. Subject has an illness within 28 days prior to randomization that is classed as clinically 
significant by the Investigator. 


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4. Subject used prescription or non-prescription drugs and dietary supplements within 7 days 
or 5 half-lives (whichever is longer) prior to the administration of the IMP and/or subject 
used live or live attenuated vaccinations within 30 days prior to the dose of the IMP. Herbal 
supplements must be discontinued 28 days prior to the administration of the IMP. 
5. Subject has undergone treatment with an investigational drug or participated in another 
clinical trial within 3 months or 5 half-lives (whichever is longer) prior to the administration 
of the IMP. 
6. Subject has the previous treatment with an anti-VEGF antibody, or any other antibody or 
protein targeting the VEGF receptor. 
7. Subjects who have previously been exposed to a biologic agent within 3 months prior to 
the administration of the IMP. 
8. A male subject plans to father a child or donates sperms within a 6-month period following 
study drug administration. 
9. Subject shows reasonable evidence of drug abuse including alcohol prior to the 
administration of the IMP (positive result for drug urine test and/or the opinion of the 
Investigator). Subject consumes more than 10 cigarettes or equivalent per day within 3 
weeks prior to the administration of the IMP and/or is unable to refrain from smoking 
during in-house stays. 
10. Subject donated whole blood or lost 400 mL or more blood within 8 weeks 
(plasma/platelets donation within 4 weeks) prior to the administration of the IMP. 
11. Subject is vulnerable (e.g., employees of the clinical trial site or any other individuals 
involved with the conduct of the study, or immediate family members of such individuals, 
persons kept in prison or other institutionalized persons by law enforcement). 
12. Subject shows evidence of a condition (psychological, emotional problems, any disorders 
or resultant therapy) that is likely to invalidate informed consent, or limit the ability of the 
subject to comply with the protocol requirements in the opinion of the Investigator. 
13. Subject is not likely to complete the study for whatever reason in the opinion of the 
Investigator. 
4.4 
Subject Withdrawal and Replacement 
Subjects will be withdrawn from the study prematurely for the following reasons: 
• Withdrawal of consent: Subjects have the right to withdraw from the study at any time for 
any reason. If the withdrawal occurs following IMP dosing, the subject will be asked to 
attend the clinical unit for safety assessments at the EOS examination. 


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• Protocol violation of concern: The subject will be withdrawn by the Investigator after 
discussion with the Sponsor: 
−  If protocol violations or intercurrent illnesses that may affect study objectives occur, or 
−  If it is discovered that the subject has entered the study in violation of the protocol. 
• Adverse event: If a subject reports symptoms that are considered unacceptable by the 
Investigator and/or Sponsor, he will be withdrawn from the study, e.g. abnormal laboratory 
values such as alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) elevated >5 times of upper limit of normal (ULN) laboratory range 
or uric acid >10 mg/dL or > 0.59 mmol/L with physiological consequences (according to 
Grade 4, CTCAE Version 4.03). 
The appropriate AE page in electronic case report form (eCRF) is to be completed. If premature 
withdrawal occurs for any reason, the Investigator must determine the primary reason for a 
subject's premature withdrawal from the study and record this information in the eCRF. 
Subjects who discontinue the study will be asked to participate in the safety assessments of the 
EOS procedures including a physical examination, vital sign measurements, 12-lead ECG and 
standard safety laboratory tests, if possible. All subjects who withdraw from the study because 
of an AE or clinical laboratory abnormality will be followed-up at suitable intervals in order to 
evaluate the course of the AE or laboratory abnormality and to ensure resolution or stabilization 
of the event. The subsequent outcomes of these events will be recorded in the eCRF. 
Subjects will be allowed to rescreen only once, however, subjects withdrawn (after 
randomization) will not be replaced. 
For subjects who are lost to follow-up (i.e. those subjects whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the Investigator should 
show due diligence by documenting in the source documents steps taken to contact the subject, 
e.g. dates of telephone calls, registered letters, etc. 
4.5 
Premature Termination of the Clinical Trial 
If the Investigator, the Sponsor, or the Medical Monitor becomes aware of conditions or events 
that suggest a possible hazard to subjects if the clinical study continues, then the clinical study 
may be terminated after appropriate consultation among the involved parties. The clinical study 
may be terminated at the Sponsor’s discretion also in the absence of such a finding. 
Conditions that may warrant termination of the clinical study include, but are not limited to: 
• The discovery of an unexpected, relevant, or unacceptable risk to the subjects enrolled in 
the clinical study (including but not limited to AEs, laboratory and/or vital sign 


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abnormalities that in the opinion of the Investigator/Sponsor are unacceptable for a further 
conduct of the study); 
• Failure to enroll subjects at the required rate; 
• A decision of the Sponsor to suspend or discontinue development of the IMP. 
Should the study be terminated and/or the site closed for whatever reason, Study related 
documents should be archived at the site according to the section 9.6. Used/unused IMP should 
be managed according to section 5.4. Any actions of the Investigator required for assessing or 
maintaining study subject safety will continue as required, despite termination of the study by 
the Sponsor.  
If the study is terminated for whatever reason, all subjects will be kept fully informed. 


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5. 
INVESTIGATIONAL MEDICINAL PRODUCT 
5.1 
Identity of the Investigational Medicinal Products 
The IMPs that will be used in this study are outlined in Table 1. 
Table 1. 
Identity of Investigational Products 
IMP Name 
Dosage form 
Strength 
Route 
CT-P16 
Liquid for concentrate for solution for infusion 
400 mg 
IV 
EU-approved Avastin 
Liquid for concentrate for solution for infusion 
400 mg 
IV 
US-licensed Avastin 
Liquid for concentrate for solution for infusion 
400 mg 
IV 
IMP = investigational medicinal product; IV = intravenous. 
5.2 
Dose Rationale Including Time of Dosing 
The IMP (CT-P16, EU-approved Avastin, or US-licensed Avastin) will be dosed once as an IV 
infusion over 90 min (±5 min). The lowest approved dose for Avastin indications is 5 mg/kg 
body weight which is the typical dose used for treatment of metastatic colorectal cancer (mCRC) 
as lined out in the prescribing information of Avastin. 
5.3 
Supply, Packaging, Labeling and Storage 
The test IMP (CT-P16, EU-approved Avastin and US-licensed Avastin) will be supplied by 
CELLTRION, Inc. The IMPs will be packaged and labeled according to applicable local and 
regulatory requirements. 
A label will be attached to the outside of each subject kit, as well as to the immediate container. 
The text will be compliant with local regulatory requirements and may include some of the 
following information: 
• 
Protocol number 
• 
Subject number/site number 
• 
Contents and quantity 
• 
Lot number 
• 
Randomization code/kit number 
• 
Investigator’s name 
• 
Storage instructions 
• 
Caution statement (for clinical trial use only) 
• 
CELLTRION’s contact name and address 
• 
Expiry date 


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All IMP supplies must be stored in accordance with the manufacturer’s instructions and will 
be stored in a refrigerator at 2°C to 8°C and the vials will be protected from light. Until 
dispensed to the subjects, the IMPs will be stored in a securely locked area, accessible to 
authorized personnel only. 
5.4 
Drug Accountability, Dispensing and Destruction 
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 drug accountability will be 
verified by the monitor during on-site monitoring visits.  
The Investigator agrees not to supply the study drug to any person other than sub-Investigator, 
designated staff, and the subjects participating in the study. Study drug may not be relabeled 
or reassigned for use by other subjects unless approved by CELLTRION, Inc. 
During the study, study drugs may need to be returned to the depot of origin. Unused study 
drug vials should be returned to the depot of origin. Accountability of the product must be 
completed at the site level and discrepancies, if any, need to be resolved prior to return. Only 
if it is written in standard operating procedures (SOPs) or documentation in place, the used 
vials can be destroyed locally. The list of destroyed vials must be recorded. 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.  
Details in study drugs accountability and destruction will be followed according to the 
pharmacy manual. 
5.5 
Method of Assigning Subjects to Treatment Group 
5.5.1 
Screening numbers 
All screened subjects are assigned unique screening or run-in numbers. These numbers will be 
used to identify subjects during study period. 
5.5.2 
Randomization 
Randomization will occur at Day -1 after all baseline assessments have been performed and 
eligibility for the study has been confirmed. Subjects will be randomly assigned to treatment 
groups (1:1:1 ratio to CT-P16, EU-approved Avastin, or US-licensed Avastin) using the 
Interactive Web Response System (IWRS). The randomization will be balanced by using 
permuted blocks and will be stratified by body weight (<70 kg vs ≥70 kg) and site. 


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5.6 
Administration of Investigational Medicinal Products 
On Day 1, a subject will receive an IV infusion of CT-P16, EU-approved Avastin, or US-
licensed Avastin over 90 minutes (± 5 min) with an infusion pump. The infusion will take 
place starting in the morning under consideration of dietary and fluid restrictions (see 
Section 7.3.1). 
Subject will be residing in a semi-recumbent position while they receive the infusion of the 
IMP. By exception, the subject may get up (e.g., toilet visit) but he has to be instructed to call 
the study staff for assistance. Appropriate medical measures must be directly available in case 
of IRRs. The infusion must be interrupted if the intensity of the IRRs does not justify the 
continuation of the administration and would impose the subject to an unbearable risk as 
deemed by the Investigator or if a situation arises where the stopping rules apply (see Sections 
4.4 and 4.5). 
The infusion of CT-P16, EU-approved Avastin or US-licensed Avastin can be stopped 
immediately in the case of safety issues occurring during the infusion period at the 
Investigator’s discretion. An interruption of the infusion is permitted if the Investigator deems 
this appropriate (e.g., in case of signs dyspnea or clinically significant hypertension). The 
infusion will be resumed as soon as the cause of the interruption is resolved. If feasible, subjects 
will be followed for the safety and PK assessments given by the study design after they have 
received the infusion. 
5.7 
Compliance 
The infusion will be performed by trained, qualified personnel designated by the Investigator. 
The date and time of start of infusion (SOI) and end of infusion (EOI) will be documented. 
Comments will be recorded if there are any deviations from the planned dosing procedures. 
5.8 
Blinding and Breaking the Blind 
The study will be performed in a double-blind manner. All IMPs will be diluted by a designated 
unblinded pharmacist, and will be supplied to the treating physician or designee in a blinded 
manner, in identical infusion bags, thereby enabling double-blind conditions. 
The study blind should not be broken except in a medical emergency (where knowledge of the 
IMP administered would affect the treatment of the emergency) or regulatory requirement (e.g., 
for serious adverse events [SAEs] or death). 
The decision to break the blind will be made on a case-by-case basis, at the discretion of the 
Investigator/Sponsor. If the blind is broken, the date, time and reason must be recorded in the 
eCRF, and any associated AE report. 


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If an emergency unblinding becomes necessary, the Investigator should notify the 
Sponsor/Medical Monitor prior to unblinding, if possible, unless identification of the IMP is 
required for emergency therapeutic measures. If the Investigator is unable to contact the 
Sponsor/Medical Monitor, the Investigator may, in an emergency, determine the identity of the 
treatment by using the applicable procedure in the IWRS.  
If a subject is unblinded, the subject must be withdrawn from the clinical study and procedures 
accompanying withdrawal are to be performed. 
Suspected unexpected serious adverse reactions (SUSARs), which are subject to expedited 
reporting, should be unblinded before submission to the Competent Authorities. 
The overall randomization code will be broken only for reporting purposes once all final 
clinical data have been entered into the database and all data queries have been resolved, and 
the assignment of subjects to the analysis sets has been completed. The randomization code 
will not be revealed to study subjects, parents or guardians, study site staff, or Investigators. 
5.9 
Concomitant Medications 
Any medicinal product, prescribed or over-the-counter (OTC) drug, including herbal and other 
non-traditional remedies, is considered a concomitant medication. Prior and concomitant 
medication use will be recorded for the 30 days prior to the screening visit until the EOS visit. 
Concomitant medication use is permitted if indicated by the Investigator for premedication or 
treatment of an AE. 
Subjects who had an exposure to a monoclonal antibody or currently used a biologic (including 
but not limited to anti-VEGF antibody) within 3 months prior to the administration of the IMP 
must be excluded. The use of OTC medications (including vitamins), or prescription 
medications within 7 days or 5 half-lives (whichever is longer) prior to the dose of the IMP 
until EOS will not be permitted. For live or attenuated vaccines, the vaccination within 30 days 
prior to the dose of the IMP until EOS will not be permitted. Herbal supplements must be 
discontinued 28 days prior to the administration of the IMP until EOS. Refer to Section 4.3 for 
exclusion criteria on concomitant medications and timing. 
5.10 Treatment of Overdose 
An overdose is defined as 10% or more than the dose prescribed. Overdose may be 
symptomatic or asymptomatic. Sign and Symptoms associated with an overdose must be 
recorded as an AE and recorded as detailed in Section 6.2.2.2, and an overdose without signs 
or symptoms must be documented in the IMP section in the eCRF. 
Although not strictly due to an overdose, IRR are possible and hypersensitivity must be 
monitored according to the details in Section 6.2.3. 


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6. 
VARIABLES AND METHODS OF ASSESSMENT 
6.1 
Pharmacokinetic Variables 
The following PK parameters will be determined for CT-P16, EU-approved Avastin and US-
licensed Avastin in serum following single dose administration: 
Primary Endpoints 
• Area under the concentration-time curve from time zero to infinity (AUC0-inf)  
• Area under the concentration-time curve from time zero to the last quantifiable 
concentration (AUC0-last)  
• Maximum serum concentration (Cmax) 
Secondary Endpoints 
• Time to Cmax (Tmax)  
• Volume of distribution during the terminal phase (Vz)  
• Terminal elimination rate constant (λz) 
• Terminal half-life (t1/2) 
• Total body clearance (CL)  
• Percentage of AUC0-inf obtained by extrapolation (%AUCext) 
Blood will be processed and serum analyzed by a validated method for concentrations of CT-
P16, EU-approved Avastin and US-licensed Avastin. The PK parameters listed above will be 
calculated from the serum concentration-actual time profiles. The non-compartmental analysis 
will be performed using xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx. 
6.2 
Safety Variables 
6.2.1 
Medical History, Demographic and Other Baseline Information 
The medical history comprises the following: 
• General medical history 
• Medication history 
The following demographic information will be recorded: 
• Age 
• Gender 
• Race 


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• Height [cm], without shoes 
• Body weight [kg], without shoes 
• Body Mass Index [kg/m²] 
Other baseline characteristics will be recorded as follows: 
• History of drug abuse 
• History of alcohol abuse 
• Smoking history 
• History of caffeine use (or other stimulating beverages) 
• Special diet (vegetarian) 
• History of blood or plasma/platelets donation or loss 
6.2.2 
Adverse Events 
All AEs will be collected from the date the informed consent form (ICF) is signed and AE 
reporting will continue until the end of the subject's participation in the study. 
6.2.2.1 
Definitions 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this product. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
All AEs, including intercurrent illnesses, occurring during the clinical study will be 
documented in the eCRF. Concomitant illnesses, which existed prior to signing the ICF, will 
not be considered AEs unless they worsen during the study period. Pre-existing conditions will 
be recorded in the eCRF on the Medical History or appropriate page. 
A TEAE is defined as an AE that begins or that worsens in severity after administration of the 
IMP. If laboratory test abnormalities occur after IMP infusion, only the clinically significant 
cases should be considered TEAEs. The clinically significant cases are ones that: 
• 
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) 


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• 
Require dose modification or dose delay 
• 
Are associated with clinical signs or symptoms judged by the Investigator to have a 
clinically significant impact 
Medical intervention such as surgery, diagnostic procedures, and therapeutic procedures are 
not AEs. The event term of primary cause should be recorded and reported instead of the term 
of surgery, diagnostic procedure, or therapeutic procedure. 
6.2.2.2 
Recording of Adverse Events 
Adverse events may be volunteered spontaneously by the study subject or discovered by the 
study staff during physical examinations or by asking an open, non-leading question such as 
“How have you been feeling since you were last asked?” All AEs and any required remedial 
action will be recorded. The nature of AE, date (and time, if known) of AE onset, date (and 
time, if known) and status of AE outcome, severity, and action taken of the AE will be 
documented together with the Investigator’s assessment of the seriousness of the AE and causal 
relationship to the IMP. 
All AEs should be recorded individually in the study subject’s own words (verbatim) unless, 
in the opinion of the Investigator, the AEs constitute components of a recognized condition, 
disease or syndrome. In the latter case, the condition, disease or syndrome should be named 
rather than each individual symptom. The AEs will subsequently be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). 
6.2.2.3 
Assessment of Adverse Events 
Terminology and severity grading of AEs will be recorded based on CTCAE Version 4.03. 
MedDRA version 20.0 or later will be recorded in statistical analysis plan (SAP) and used for 
reporting purpose (i.e. clinical study report and regulatory requirement). 
Each AE will be assessed by the Investigator with regard to the categories discussed in the 
sections below. 
6.2.2.3.1 
Intensity 
Investigator will assess all AEs for severity in accordance with the following criteria:  


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Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental 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. 
Source: CTCAE Version 4.03 
Note: a semicolon indicates “or” within each description. 
*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. 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the event should be noted for that day. Any change in severity of signs and 
symptoms over a number of days will be captured by recording the change of intensity of the 
respective AE, with the amended severity grade, and the date (and time, if known) of the change. 
In the case of any event requiring medical intervention occurring during the in-house stay, the 
Investigator will institute general supportive measures including, where necessary, respiratory 
assistance and cardiopulmonary resuscitation. 
6.2.2.3.2 
Causality 
The Investigator will assess the causality/relationship between the IMP and the AE and record 
that assessment results in the eCRF. 
The most likely cause of an AE will be indicated in the eCRF with details of the concomitant 
disease or medication or other cause. 
The causal relationship of the AE to IMP will be described using following classification: 
• Definite: 
− This relationship suggests that a definite causal relationship exists between drug 
administration and the AE, and other conditions do not appear to explain the event. 
• 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 drug seems likely. 


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• Possible: 
− This relationship suggests that treatment with the IMP caused or contributed to the AE, 
i.e., the event follows a reasonable temporal sequence from the time of drug 
administration or follows a known response pattern to the IMP, but could also have 
been produced by other factors. 
• Unrelated: 
− This relationship suggests that there is no association between the IMP and the reported 
event. 
6.2.2.3.3 
Expectedness 
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. Investigator’s brochure [IB]) for an 
unapproved investigational product or the label (e.g. prescribing information or SmPC) for an 
approved product. If the IB for CT-P16 is delayed, the SmPC or prescribing information will 
take precedence. 
6.2.2.3.4 
Seriousness 
An SAE is defined as any untoward medical occurrence that: 
• Results in death; 
• Is life-threatening; this means that the subject is at risk of death at the time of the event; it 
does not mean that the event hypothetically might have caused death if it were more severe; 
• Requires at least 24-hour hospitalization or prolongation of expected length of stay. 
Hospitalization for elective medical/surgical procedures, scheduled treatments, or routine 
check-ups are not serious adverse events by these criteria; 
• Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
• Is a congenital anomaly or birth defect; 
• Is another important medical event (see below). 
Important medical events that do not result in death, are not life-threatening, or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of 
the outcomes listed above. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or in a physician’s office, blood dyscrasias 
or seizures that do not result in in-patient hospitalization, and the development of drug 
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A distinction should be drawn between SAEs and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria above. For example, a mild degree of 
gastrointestinal bleeding requiring an overnight hospitalization for monitoring purposes would 
be considered an SAE, but is not necessarily severe. Similarly, an AE that is severe in intensity 
is not necessarily an SAE. For example, alopecia may be assessed as severe in intensity but 
would not be considered an SAE. 
Medical and scientific judgment should be exercised in deciding if an AE is serious and if 
expedited reporting is appropriate. 
6.2.2.3.5 
Adverse Events of Special Interest 
An ‘adverse event of special interest’ is an AE or occurrence that is designated to be of special 
interest and must be reported to the Sponsor using the same reporting process as an AE. 
The following events are considered events of clinical interest for this study: 
• Infusion-related reaction/hypersensitivity 
All AEs related to infusion include but are not limited to the following: urticaria, hypotension 
or hypertension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory 
distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, or 
anaphylactoid events. 
6.2.2.4 
Reporting of Serious Adverse Events 
The Investigator will review each SAE and evaluate the intensity and the causal relationship of 
the event to IMP. All SAEs will be recorded from signing of informed consent until the EOS 
visit. Serious AEs occurring after the EOS visit and coming to the attention of the Investigator 
must be reported only if there is (in the opinion of the Investigator) reasonable causal 
relationship with the IMP. 
The Investigator is responsible for data entry in the electronic data capture system within 24 
hours of awareness of an SAE. In the event that is not possible (e.g., system failure or access 
problems), the study center should complete an SAE report form and fax to clinical research 
organization (CRO) Pharmacovigilance team within 24 hours of awareness of the event. 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
As a minimum requirement, the initial notification should provide the following information: 
• Study number 


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• Subject number 
• Gender 
• Age 
• Name of Investigator and full study center address 
• SAE term 
• Criterion for classification as ‘serious’ 
• Name of IMP and treatment start date 
• Date of SAE onset 
• Causality assessment (if sufficient information is available to make this classification) 
The Sponsor will request clarification of omitted or discrepant information from the initial 
notification. The Investigator or an authorized delegate is responsible for faxing the requested 
information to the Sponsor within 24 hours of the Sponsor’s request.  
Initial reports of SAEs must be followed later with detailed descriptions, including clear 
photocopies of other documents as necessary (e.g. hospital reports, consultant reports, autopsy 
reports etc.), with the study subject’s personal identifiers removed. All relevant information 
obtained by the Investigator through review of these documents will be recorded and faxed to 
the Sponsor within 24 hours of receipt of the information. If a new SAE Report Form is 
received, then the Investigator must sign and date the form. The Sponsor may also request 
additional information on the SAE, which the Investigator or an authorized delegate must fax 
to the Sponsor within 24 hours of the request. 
6.2.2.5 
Follow-up of Adverse Events 
All AEs experienced by a subject, irrespective of the suspected causality, will be monitored 
until the event has been resolved, until any abnormal laboratory values have returned to 
baseline or stabilized at a level acceptable to the Investigator and Sponsor/Medical Monitor, 
until there is a satisfactory explanation for the changes observed, or until the subject is lost to 
Follow-up. 
6.2.2.6 
Procedure for Notification of Serious Adverse Event and Suspected 
Unexpected Serious Adverse Reactions to Institutional Review Boards 
If required by applicable local regulations, the Investigator shall promptly notify the relevant 
Institutional Review Board (IRB) (in addition to the Sponsor) of any SAE (including follow-
up SAEs) and SUSARs that occurred at his/her site or brought to his/her attention by the 
Sponsor. The Investigator shall verify that the IRB acknowledges receipt of the information. 


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The Sponsor will provide annual safety reports to the competent authorities and ethics 
committees responsible for the clinical study. These updates will include information on 
SUSARs and other relevant safety findings. 
6.2.2.7 
Pregnancy 
Women will be excluded from this study (see Section 4.3). However, the following directives 
describe the procedures and measurements that are to be considered if women of childbearing 
potential become pregnant who are partners of male subjects participating in this study. 
- If a female partner of a male subject who has been exposed to the IMP becomes pregnant, the 
course and outcome of the pregnancy should be monitored and documented. The baby will be 
followed for 1 year after the birth, provided consent from the pregnant partner of the subject is 
obtained. 
- The Sponsor or its designee has a responsibility to monitor the outcome of all pregnancies 
reported during the clinical study. 
- Each pregnancy must be reported by the Investigator to the Sponsor on the initial pregnancy 
report form within 24 hours after becoming aware of the pregnancy. The Investigator must 
follow up and document the course and the outcome of all pregnancies even if the subject was 
withdrawn from the clinical study or if the clinical study has finished. 
- All outcomes of pregnancy must be reported by the Investigator to the Sponsor on the 
pregnancy outcome report form within 24 hours after he/she has gained knowledge of the 
normal delivery or elective abortion. 
- The site must complete the supplied pregnancy form (the partner of a male subject) and return 
it to CRO Pharmacovigilance team within 24 hours (see Section 6.2.2.4). 
6.2.3 
Hypersensitivity Assessment 
Hypersensitivity will be assessed by routine clinical monitoring including BP, HR, RR and BT 
measurement and 12-lead ECG and recorded in accordance with the Schedule of Assessment 
for Hypersensitivity Monitoring (Table 3). Emergency equipment such as adrenaline, 
antihistamines, and respiratory support including inhalational therapy, oxygen, and artificial 
ventilation must be available. Subjects who develop a life-threatening IRR must be withdrawn 
from study. 
6.2.4 
Clinical Laboratory Assessments 
The safety laboratory analyses of blood including hematology, coagulation, and clinical 
chemistry, as well as urine drug screen will be performed according to validated methods and 
procedures. Laboratory analyses will be performed by the local laboratories.  


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The following laboratory variables will be determined in accordance with the Schedule of 
Assessments (Table 4): 
• Hematology: The following hematology parameters were assessed: hemoglobin, 
hematocrit, red blood cell (RBC) count, white blood cell (WBC) count with differential, 
absolute neutrophil count (ANC), and platelets. 
• Clinical chemistry: The following clinical chemistry parameters were assessed: albumin, 
alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), blood urea nitrogen (BUN), calcium, chloride, total cholesterol, creatine 
phosphokinase (CPK), creatine kinase–myocardial band isoenzyme (CK-MB), creatinine, 
creatinine clearance (estimated by Modification of Diet in Renal Disease [MDRD]), C-
reactive protein (CRP), gamma-glutamyl 
transferase (GGT), 
glucose, lactate 
dehydrogenase (LDH), triglycerides, magnesium, phosphate, potassium, sodium, total 
bilirubin, direct bilirubin, total protein, uric acid, Troponin I. 
• Coagulation: Fibrinogen, international normalized ratio (INR), prothrombin time (PT), 
activated partial thromboplastin time (aPTT). 
• Urinalysis: Color, pH, specific gravity, ketones, protein, glucose, bilirubin, nitrite, 
urobilinogen, occult blood, and microscopic examination. 
• Urine drug, alcohol and nicotine: screen for drugs of abuse including the following: 
amphetamines, barbiturates, benzodiazepines, cocaine, opiates, and cannabinoids. The test 
for drugs of abuse will be performed during the Screening Period only. The history of Drug 
abuse, Alcohol and nicotine will be checked by medical history taking by the Investigator 
during the Screening Period and Day -1. 
Any value outside the normal range will be flagged for the attention of the Investigator or 
designee at the site. The Investigator or designee will indicate whether or not the value is of 
clinical significance. If the result of any test (or repeat test, if done) from the samples taken 
during the screening period is indicated as clinically significant, the study subject will NOT be 
allowed into the study without permission of the Sponsor/Medical Monitor. However, retest is 
permitted only once during screening period by the Investigator’s judgment. Additional testing 
during the study period may be done if medically indicated. If a clinically significant 
abnormality is found in the samples taken after dosing, during the study, and/or at the EOS 
visit, it should be recorded as an AE and the study subject will be followed until the test(s) has 
(have) normalized or stabilized. 
6.2.5 
Vital Signs 
Vital signs will be assessed at time points specified in the Schedule of Assessments (Table 4). 
The following vital signs will be measured: 


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• Blood pressure (systolic and diastolic [mmHg]); 
• Heart rate (beats per minute [bpm]); 
• Body temperature (°C); 
• Respiratory rate (breaths per minute). 
Blood pressure (BP), HR, RR and BT recordings will be made after the study subject has been 
resting for at least 5 minutes. 
6.2.6 
Electrocardiograms 
The 12-lead ECGs will be obtained after the subject has been rested for at least 5 minutes and 
will be performed at the time points specified in the Schedule of Assessments (Table 4). 
Twelve-lead ECG for hypersensitivity monitoring will also be performed according to the 
Schedule of Assessment for Hypersensitivity Monitoring (Table 3). 
If, following ECG review by the Investigator, there are any ECG findings that would indicate 
cardiac insufficiency or QT prolongation, the subject will be referred to a cardiologist and the 
event will be recorded in the source documents and the eCRF. 
6.2.7 
Physical Examinations 
Physical examinations will be performed at time points specified in the Schedule of 
Assessments (Table 4). 
The physical examination includes an assessment of general appearance and a review of 
systems. Information about the physical examination 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. 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 documents. 
6.3 
Immunogenicity Variables 
The potential immunogenicity of CT-P16, EU-approved Avastin and US-licensed Avastin will 
be assessed in samples collected at the time points specified in the Schedule of Assessments 
(Table 4). 
The immunogenicity of CT-P16, EU-approved Avastin and US-licensed Avastin will be 
assessed at baseline and post-treatment serum measures by anti-drug antibodies in a validated 
immunoassay. 


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6.4 
Sample Collection, Storage and Shipment 
6.4.1 
Pharmacokinetic Sampling 
Blood will be collected per blood sampling time points for PK assessment sample at the time 
points specified in the Schedule of Assessments (Table 2). All samples will be collected as 
close as possible to the scheduled time point and the actual sampling time will be recorded. 
The samples will be split into separate containers or tubes, and processed, stored, and shipped 
under the appropriate conditions as outlined in a separate laboratory manual. xxxxxxxxxxxxxx. 
6.4.2 
Clinical Laboratory Testing 
Clinical testing will be performed locally at the time points specified in the Schedule of 
Assessments (Table 4). 
6.4.3 
Immunogenicity Sampling 
Serum will be collected at the time points specified in the Schedule of Assessments (Table 4). 
The samples will be split into separate containers or tubes, and processed, stored, and shipped 
under the appropriate conditions as outlined in a separate laboratory manual. xxxxxxxxxxxx. 


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7. 
STUDY CONDUCT 
7.1 
Schedule of Assessments 
The study consists of a screening visit (Day –21 to Day –2), in-house stay (Day –1 to Day 2), 
and further visits on an out-patient basis which will be conducted on Day 3, Day 4, Day 8, Day 
15, Day 29, Day 43, Day 57, Day 71, Day 85, and Day 99. The subjects will receive the study 
drug on Day 1, and assessments for PK and safety will be carried out during the in-house stay 
and further out-patient visits. 
The EOS visit for safety and PK assessments will take place on Day 99. The approximate study 
duration for an individual subject will be 15 weeks. 
Study procedures can be performed within the allowed flexibility range without protocol 
violation. Details of blood sampling time points and acceptable tolerance windows for PK 
assessments are described in Table 2.  
Table 2. 
Blood sampling time points for PK assessment 
Day of study period 
Time point 
Window 
Day 1 
Pre-dose 
Before study drug infusion 
End of infusion 
Immediately end of infusion  
(within +5 minutes after EOI) 
1 hour after EOI 
± 15 minutes 
4 hours after SOI 
8 hours after SOI 
12 hours after SOI 
Day 2 
24 hours after SOI 
± 15 minutes 
Day 3 
48 hours after SOI 
± 1 hour 
Day 4 
72 hours after SOI 
Day 8 
168 hours after SOI 
± 4 hours 
Day 15 
336 hours after SOI 
Day 29 
672 hours after SOI 
± 1 day 
Day 43 
1,008 hours after SOI 
Day 57 
1,344 hours after SOI 
Day 71 
1,680 hours after SOI 
± 3 days 
Day 85 
2,016 hours after SOI 
Day 99 
2,352 hours after SOI 
Abbreviation: EOI = End of infusion, SOI = Start of infusion 
 


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For hypersensitivity monitoring, vital signs and 12-lead ECG will be done. Assessment time 
points and acceptable tolerance windows for hypersensitivity monitoring are described in Table 
3. 
Table 3.  
Schedule of Assessment for Hypersensitivity Monitoring 
Assessment 
Day of study 
period 
Time points 
Window 
Vital sign 
Day 1 
15 minutes after SOI 
± 5 minutes 
30 minutes after SOI 
1 hour after SOI 
Immediately EOI 
within +10 minutes after EOI 
2 hours after SOI 
± 15 minutes 
3 hours after SOI 
4 hours after SOI 
12-lead ECG 
Day 1 
1 hour after EOI1 
± 15 minutes 
Abbreviation: ECG= Electrocardiogram, EOI = End of infusion, SOI = Start of infusion 
1. Continuous monitoring can be performed until 1hour after EOI at the investigator’s discretion. 
For safety assessments other than hypersensitivity monitoring (Vital signs, physical 
examination, clinical laboratory tests, 12-lead ECG and post-infusion immunogenicity 
assessments), assessment time points and visit windows will be applied according to the Table 
4. Pre-dose assessment for Immunogenicity will be collected prior to the infusion on Day 1.  
Even if an assessment takes place using the given tolerance window, the consecutive 
assessment will be performed from the baseline time point. 
The assessment that will be performed during the study are shown in the Table 4. 


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Table 4. 
Schedule of Assessments 
Assessments 
Screening 
In-House Stay 
Out-patient Visits 
EOS1 
Day of Study Period 
Day  
-21 to -2 
Day 
-1 
Day 
1 
Day 
2 
Day 
32 
Day 
42 
Day 
8 
Day 
15 
Day 
29 
Day 
43 
Day 
57 
Day 
71 
Day 
85 
Day 
99 
Visit window (day) 
 
 
- 
- 
- 
- 
- 
- 
± 1  
± 1  
± 1  
± 3 
± 3 
± 3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and medication history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight & Height4 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Physical examination 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
Viral serology test5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drugs of abuse / alcohol / nicotine 
check6 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests7 
X 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
Vital signs8 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogram9 
X 
 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
Infusion of IMP 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic sampling10 
 
 
X11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hypersensitivity monitoring12 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity13 
 
 
X11 
 
 
 
 
X 
 
X 
 
X 
 
X 
Restriction assessment 
X 
X 
Concomitant medication14 
X 
X 
Adverse events 
X 
X 
Abbreviations: EOI = End of infusion, EOS = End of study, IMP = Investigational medicinal product, SOI = Start of infusion 
 


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1. 
End-of-study visit procedures will be performed for subjects who completed the study as well as subjects who terminated the clinical study prematurely. After the EOS visit, 
serious adverse drug reactions will be reported to the Sponsor or its designee. 
2. 
Assessments on Day 3 and 4 can be carried out either during the In-House Stay or on an out-patient basis according to Investigator decision. 
3. 
Inclusion and exclusion criteria should be checked before randomization.  
4. 
Height will be measured at screening only. 
5. 
Serology tests will be performed at the screening visit for human immunodeficiency virus (HIV) -1 or -2 antibodies, hepatitis B surface antigen (HBsAg) and hepatitis B surface 
antibody (HBsAb), hepatitis C antibody and syphilis. 
6. 
Drug abuse testing includes the followings: amphetamines, barbiturates, benzodiazepines, cocaine, opiates, and cannabinoids during the screening period only. The history of 
Drug abuse, alcohol and nicotine will be checked by medical history taking by Investigator during the screening period and Day -1. 
7. 
Clinical laboratory tests will be carried out at screening, on Day –1, Day 3, 8, 15, 43, 71, and 99; Hematology (hematocrit, hemoglobin, red blood cell count, white blood cell 
count with differential, absolute neutrophil count, and platelets), Clinical chemistry (albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, 
blood urea nitrogen, calcium, chloride, total cholesterol, creatine phosphokinase, creatine kinase–myocardial band isoenzyme, creatinine, creatinine clearance [estimated by 
Modification of Diet in Renal Disease [MDRD]], C reactive protein, gamma-glutamyl transferase, glucose, lactate dehydrogenase, magnesium, phosphate, potassium, sodium, 
total bilirubin, direct bilirubin, total protein, uric acid, triglyceride, and Troponin I), Urinalysis (color, pH, specific gravity, ketones, protein, glucose, bilirubin, nitrite, 
urobilinogen, occult blood, and microscopic examination), Coagulation (Fibrinogen, international normalized ratio, prothrombin time, and activated partial thromboplastin 
time) 
8. 
Vital signs will be measured at screening, on Day –1, before dosing on Day 1, on Day 3, 4, 8, 15, 29, 43, 57, 71, 85, and 99. 
9. 
Twelve-lead ECG will be performed at the screening visit, on Day 3, 8, 15, 43, 71, and 99. 
10. Blood samples for PK analysis will be collected as specified in Table 2.  
11. Pre-dose blood sample for PK and immunogenicity assessment will be collected before start of infusion on Day 1. 
12. For hypersensitivity monitoring, vital signs measurement and 12-lead ECG will be done as specified in Table 3. 
13. Immunogenicity will be assessed on before dosing on Day 1, on Day 15, 43, 71 and 99.  
14. Prior and concomitant medication use will be recorded for the 30 days prior to the screening visit until the EOS visit. 


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7.2 
Assessments by Visit 
7.2.1 
Screening Visit (Days –21 to –2) 
All screening assessments will be the same for subjects in all parts of the study (unless otherwise 
indicated). 
Potential subjects for the inclusion in the study will be asked to attend the screening visit fasting 
apart from water (duration of the fast approximately 4 hours). Written informed consent will be 
obtained from all subjects before any screening procedures are performed. Subjects will be fully 
informed of their responsibilities (in terms of attending the study visits, dietary and lifestyle 
restrictions) of all the procedures expected to be performed in the study, the possible risks and 
disadvantages of being dosed with bevacizumab and their rights while participating in the study. 
They will have the opportunity to ask questions and have time to consider participation. If the 
subject wishes to participate in the study, they will be asked to sign and date the ICF. 
The screening visit will take place within the 21 days prior to dosing (Day –21 to Day -2) unless 
otherwise approved by the Sponsor/Medical Monitor or Investigator. If more tests or assessments 
are required to check the subject's eligibility for study participation, a subject may be invited to 
additional visits within the screening period at the discretion of the Investigator. 
During the screening visit, the following evaluations will be performed: 
• Obtain written informed consent 
• Medical and medication history 
• Demographics: race, gender, age (years) 
• Review inclusion/exclusion criteria 
• Body height (cm), weight (kg), and BMI (kg/m²) 
• Physical examination  
• Serology (hepatitis B, hepatitis C, HIV testing, and venereal disease research laboratory 
[VDRL] testing) 
• Screen for drugs of abuse, the history of drugs of abuse, alcohol and nicotine 
• Twelve-lead ECG 
• Vital signs (BP, HR, BT, and RR) 
• Clinical laboratory tests (hematology, clinical chemistry, coagulation, and urinalysis)  


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• AEs, concomitant medications and restriction assessments 
If in the opinion of the Investigator, the subject has any clinically significant abnormality, he will 
be excluded from the study. 
7.2.2 
In-House Stay (Day –1 to Day 2) and Out-Patient Visits (Day 3 to Day 85) 
Subjects who successfully complete the screening visit will be domiciled in the study center as 
scheduled on Day –1. Inclusion and exclusion criteria will be reviewed to confirm subject 
eligibility on admission. Subjects will enter the study center for the in-patient stay on Day –1. If 
the subject is eligible, he will be randomized on Day –1.  
Meals will be served during the in-house stay. The in-house stay will provide an enhanced level 
of subject supervision and safety; it will also facilitate the maintenance of compliance and ensure 
that all study procedures are completed at the appropriate time intervals. The subjects can be 
discharged from the clinical unit on Day 2 after all study procedures have been completed. 
Assessments on Day 3 and 4 can be carried out either during the In-House Stay or on an out-patient 
basis according to the Investigator decision. Thereafter, all study-related procedures and 
assessments will take place on an out-patient basis. Refer to Table 4 for a presentation of the single 
study procedures. 
7.2.3 
End-of-Study Visit (Day 99) 
On Day 99, subjects will return to the clinical unit for an EOS visit. The following evaluations will 
be performed: 
• Body weight 
• Physical examination 
• Clinical laboratory testing (hematology, clinical chemistry, coagulation and urinalysis)  
• Vital signs (BP, HR, BT, and RR) 
• Twelve-lead ECG 
• PK sampling 
• Sampling for immunogenicity against CT-P16, EU-approved Avastin and US-licensed Avastin 
• AEs, concomitant medications and restriction assessments 


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7.2.4 
Early Termination Visit 
If a subject withdraws prematurely after dosing, all data normally to be collected at EOS 
(Section 7.2.3) will be collected at the time of premature discontinuation or at the scheduled EOS. 
If deemed necessary by the Investigator, then the subject will be asked to return at the regularly 
scheduled EOS visit. 
7.3 
Restrictions 
7.3.1 
Dietary and Fluid Restrictions 
Alcohol: 
Alcohol consumption must be avoided from 48 hours before any study visit and 
while subjects are confined to the study center. Subjects will abstain from 
alcohol-containing products for 24 hours prior to each PK sample time point.  
Subject will not exceed an alcohol consumption of 7 units per week. One unit 
is equivalent to a half-pint (285 mL) of beer/lager, one measure (25 mL) of 
spirits, or one small glass (125 mL) of wine. The Investigator will check if 
subject is complying with these restraints. 
Caffeine: 
Subjects will not be permitted to drink caffeine-containing products (e.g., 
coffee, black tea, cola) or use caffeine or xanthine-containing products for 
48 hours prior to infusion of the investigational product and during the 
confinement period of the study. Subjects will abstain from caffeine-containing 
products for 24 hours prior to each PK sample time point. 
Nicotine: 
Subjects will be permitted to smoke less than 10 cigarettes or equivalent per 
day until the end of the study period, but will not be allowed to smoke during 
the confinement period of the study. 
Meals: 
Subjects must abstain from all food and drink (except water) at least 8 hours 
prior to the IMP infusion and at least 4 hours prior to any safety laboratory 
evaluations. Water is permitted until 1 hour prior to the SOI and may be 
consumed without restriction beginning 1 hour after the EOI. Lunch will be 
provided approximately 2 hours after the EOI. No outside food or drink is 
permitted at the study center. All meals and snacks will be provided by the study 
center. 


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7.3.2 
Other Restrictions 
Activity: 
Strenuous activity (e.g., heavy lifting, weight training, calisthenics, and 
aerobics) is prohibited from 96 hours prior to admission until discharge. After 
discharge, mild physical activity can be resumed, but strenuous physical 
activity is prohibited until EOS. Subjects will remain in a semi-recumbent 
position starting from administration of IMP until the EOI of the IMP. Measures 
are to be administered to minimize toilet visits (e.g., emptying bladder before 
infusion). In case the subject has to get up, he should call the study staff for 
assistance. 
Medications: 
The use of herbal supplements is prohibited within 28 days prior to the study 
drug administration until EOS. Use of prescription, OTC medications, or 
dietary supplements is prohibited within 7 days or 5 half-lives (whichever is 
longer) prior to the study drug administration until EOS will not be permitted. 
For live or attenuated vaccines, the vaccination within 30 days prior to the dose 
of the IMP until EOS will not be permitted. Concomitant medication use is 
permitted if indicated by the Investigator for premedication or treatment of an 
AE. 
Contraception: 
Men with childbearing potential female partner must agree to use a highly 
effective method of contraception throughout the study and for 6 months after 
the administration of assigned treatment. Subject is not permitted to donate 
sperm or plan to have a child within a 6-month period following IMP 
administration. 


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8. 
STATISTICAL METHODS 
Statistical analyses will be performed using xxxxxxxxxxxx. PK parameters will be calculated 
using Phoenix xxxxxxx. 
The statistical methods for this study will be described in a detailed SAP, which will be finalized 
prior to locking of the database. 
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 final study 
report. 
8.1 
Study Population 
8.1.1 
Disposition of Subjects 
The number and percentage of subjects entering and completing the clinical study will be presented 
by treatment. 
8.1.2 
Protocol Deviations 
Deviations from the protocol, including deviations of inclusion/exclusion criteria will be assessed 
as “minor” or “major” in agreement with the Sponsor. Deviations will be defined prior to 
unblinding. 
8.1.3 
Analysis Populations 
All-randomized population: 
The all-randomized population is defined as all randomly 
assigned subjects. 
Safety population: 
The safety population will include all randomized subjects 
who received a complete or partial dose of IMP. Subjects 
will be included in the analysis according to the dose and 
IMP received. All safety analyses will be based on the safety 
population. 
Pharmacokinetic population: 
The PK population will include all subjects who have 
received a complete dose of IMP with collection of at least 
one post-treatment PK sample. Subjects in the PK 
population will be analyzed according to the treatment they 
received. 


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8.2 
General Considerations 
Continuous data will be summarized by treatment group using descriptive statistics (number, mean, 
standard deviation [SD], minimum, median and maximum). Categorical data will be summarized 
by treatment group using frequency tables (number and percentage). 
Any outliers that are detected during the blind review of the data will be investigated. Methods for 
dealing with outliers will be defined in the SAP, prior to unblinding. 
8.3 
Safety Analyses 
8.3.1 
Adverse Events 
Adverse events will be graded for intensity and the terminology of AEs will be described according 
to the CTCAE v4.03. All safety data will be listed and summarized by treatment group as 
appropriate. Adverse events will be coded to system organ class and preferred term according to 
the Medical Dictionary for Regulatory Activities. 
The following TEAE summaries will be reported by system organ class, preferred term, and 
treatment group: 
• 
The number and percentage of subjects reporting at least 1 TEAE 
• 
The number and percentage of subjects reporting at least 1 TESAE 
• 
The number and percentage of subjects leading to permanent discontinuation due to an 
TEAE 
• 
The number and percentage of subjects with AESI  
If more than 1 TEAE is recorded for a subjects within any system organ class or preferred term, 
the subject will be counted only once within the respective summary. 
Adverse events will also be summarized by maximum intensity and relationship to IMP with the 
percentage of subjects in each category. 
Adverse events of special interest will also be summarized by intensity. 
8.3.2 
Clinical Laboratory Tests 
Clinical laboratory tests will be summarized by treatment group at each scheduled collection time. 
For continuous parameters, change from baseline will also be summarized for all post infusion 
scheduled collection times. All laboratory results will be listed. 


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8.3.3 
Vital Signs 
Vital signs will be listed and summarized, by treatment group at each scheduled collection time. 
Change from baseline will also be summarized for all post-infusion scheduled collection times. 
8.3.4 
Electrocardiogram 
Overall assessment and ECG parameters will be listed and summarized by treatment group and 
visit. In addition, change from baseline in ECG parameters will be summarized by treatment. 
8.3.5 
Physical Examination 
A shift table comparing the categorical results at each scheduled post-baseline visit with those at 
baseline will be summarized by treatment group and visit. All physical examination findings will 
be presented in a data listing. 
8.3.6 
Immunogenicity analysis 
Immunogenicity will be summarized by treatment. 
8.4 
Pharmacokinetic Analyses 
The PK analysis will be conducted on the PK population. 
PK concentration data and parameters will be listed by subject including actual sampling times 
relative to dosing. Serum concentrations and parameters will be summarized by treatment. The 
following descriptive statistics will be presented for serum concentrations and parameters obtained 
at each nominal time point: n, mean, SD, coefficient of variation (CV), geometric mean, median, 
minimum and maximum values. 
The non-compartmental PK parameters listed in Sections 3.2.1 and 3.2.2 will be calculated using 
xxxxxxxxxxxxxxxxxx based on the following guidelines: 
• Cmax will be obtained directly from the concentration-time data. 
• Tmax is the time at which Cmax is observed. 
• λz will be estimated at terminal phase by linear regression after log-transformation of the 
concentrations: 
− Only those data points that are judged to describe the terminal log-linear decline will be 
used in the regression.  


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− A minimum number of 3 data points in the terminal phase will be used in calculating λz 
with the line of regression starting at any post-Cmax data point (Cmax will not be part of the 
regression slope) and including Clast and tlast. The adjusted coefficient of determination (R2 
adjusted) in general should be greater than 0.85. All the derived parameters (i.e. λz, t1/2, 
AUC0-inf, CL, and Vz) will need to be flagged accordingly. 
− An appropriate number of decimal places will be used for λz to enable the reported value 
of t1/2 to be calculated. 
• t1/2 will be calculated as ln2/λz. 
• AUC0-last and AUC0-inf will be calculated as follows: 
− The linear trapezoidal method will be employed for all incremental trapezoids arising from 
increasing concentrations and the logarithmic trapezoidal method will be used for those 
arising from decreasing concentrations. 
− AUC0-last=
. 
− AUC0-inf =∫
 t
0
)
( dt
t
C
＋∫
∞
t
dt
t
C )
(
= AUC0-last＋Clast/λz. 
− Clast is last observed quantifiable concentration. 
• CL will be calculated as dose/AUC0-inf 
• Vz will be calculated as CL/λz 
• %AUCext will be calculated as (1 ￚ [AUC0-last/AUC0-inf]) × 100. The %AUCext should not 
exceed 20% for each individual profile. If the %AUCext is more than 20%, the individual result 
should be flagged as well as all parameters depending on AUC0-inf. All the derived parameters 
(i.e. AUC0-inf, Vd and CL) will need to be flagged accordingly. 
The statistical analysis of the log-transformed primary endpoints (AUC0-inf, AUC0-last, and Cmax) 
will be based on an analysis of covariance (ANCOVA) model. The difference in least squares 
means between the CT-P16 and EU-approved Avastin, CT-P16 and US-licensed Avastin, and EU-
approved Avastin and US-licensed Avastin, and the associated 90% CIs will be determined. Back 
transformation will provide the ratio of geometric means and 90% CIs for these ratios. 
Similarity of systemic exposure (AUC0-inf, AUC0-last, and Cmax) will be determined if 90% CI for 
the ratio of geometric means is within the acceptance interval of 80% to 125% for the following 
comparisons: 
∫
 t
0
)
( dt
t
C


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• CT-P16 vs EU-approved Avastin 
• CT-P16 vs US-licensed Avastin 
• EU-approved Avastin vs US-licensed Avastin 
8.5 
Interim Analyses 
No formal interim analysis is planned. 
8.6 
Determination of Sample Size 
This study is powered to demonstrate PK equivalence of CT-P16, EU-approved Avastin and 
US-licensed Avastin in AUC0-inf, AUC0-last, and Cmax. Assuming a CV of 30% and ratio of 
geometric means of 1.03, 42 subjects for each arm are needed to achieve 90% power for a 90% CI 
for the ratio of AUC0-inf, AUC0-last, and Cmax to satisfy the equivalence margin of 80% to 125%. 
The sample size is calculated from two one-sided tests with each 5% significant level using 
geometric mean ratio. A 10% dropout rate is anticipated so approximately 141 subjects (47 in each 
arm) will be enrolled. 
 


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9. 
DATA COLLECTION AND QUALITY ASSURANCE 
9.1 
Data Quality Assurance 
The Sponsor or designee will conduct a study initiation visit to verify the qualifications of the 
investigator, inspect the facilities, and inform the Investigator of responsibilities and procedures 
for ensuring adequate and correct documentation. 
The Investigator must prepare and maintain adequate and accurate records of all observations and 
other data pertinent to the clinical study for each study participant. Frequent communication 
between the clinical site and the Sponsor is essential to ensure that the safety of the study is 
monitored adequately. The Investigator will make all appropriate safety assessments on an ongoing 
basis. All information recorded in the eCRF for this clinical study must be consistent with the 
subject’s source documentation. The Sponsor’s Medical Monitor may review safety information 
as it becomes available throughout the study. 
All aspects of the study will be carefully monitored with respect to Good Clinical Practice (GCP) 
for compliance with applicable government regulations (ICH 2016). The Study Monitor will be an 
authorized individual designated by the Sponsor. The Study Monitor will have access to all records 
necessary to ensure integrity of the data and will periodically review the progress of the study with 
the Investigator. 
9.2 
Data Collection 
Electronic Data Capture (EDC) will be used for this study, meaning that all eCRF data will be 
entered in electronic forms at the study site. Data collection will be completed by authorized study 
site staff designated by the Investigator. Appropriate training and security measures will be 
completed with the Investigator and all authorized study site staff prior to the study being initiated 
and any data being entered into the system for any study subjects. The Investigator will ensure that 
the data collected are accurate, complete and legible. 
The responsible study monitor will check data at the monitoring visits to the clinical study site. 
Data will be monitored within the eCRF by the study monitor before being exported. Any changes 
made during monitoring will be documented with a full audit trail within the eCRF. 
All clinical work conducted under this protocol is subject to GCP regulations. 


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9.3 
Case Report Forms and Source Documents 
All data obtained during the clinical study will be promptly recorded in the eCRF. All source 
documents from which eCRF entries are derived will be placed in the subject’s personal records. 
The original eCRF entries for each subject will be checked against source documents by the 
monitor. Instances of missing or uninterpretable data will be discussed with the Investigator for 
resolution. 
9.4 
Access to Source Documents 
During the course of the study, a monitor will make clinical study center visits to review protocol 
compliance, compare eCRF entries and individual subject’s personal records, assess IMP 
accountability and ensure that the clinical study is being conducted according to pertinent 
regulatory requirements. The eCRF entries will be verified against source documents. The review 
of medical records will be handled confidentially to ensure subject anonymity. 
Checking of the eCRF entries for completeness and clarity and verifying with source documents, 
will be required to monitor the clinical study for compliance with GCP and other regulations. 
Moreover, competent authorities of certain countries and IRBs may wish to carry out source data 
inspections on-site, and the Sponsor’s Clinical Quality Assurance Group may wish to carry out 
audits. Direct access to source data will be required for these inspections and audits; they will be 
carried out giving due consideration to data protection and subject confidentiality. The Investigator 
assures the Sponsor of the necessary support at all times. 
9.5 
Data Management 
Data management of all data documented will be performed under the responsibility of CRO or 
CELLTRION, Inc. 
A Clinical Data Management Plan (CDMP) will be provided to the Sponsor describing the work 
and data flow within this clinical study which will be using an EDC System. The EDC System will 
be customized for this study. Both the EDC System and CDMP will be sent to the Sponsor for 
review and approval. The CDMP must be finalized before database lock. 
For the EDC, a database structure that will host this study will be created and an interface to access 
it will be implemented. The system will establish and maintain the use of the computerized system 
according to the relevant SOP. Practical training sessions will be conducted on site to system users 
to teach them how to use the system. 


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Data will be collected individually in eCRFs. After all study materials are delivered and the eCRF 
is completed and validated, data will be entered in the clinical data storage system. Data will be 
available immediately to the data manager after it has been entered and therefore the data 
verification and validation process can start earlier contributing to data quality. 
Any missing, implausible, or inconsistent recordings will be referred back to the Investigator using 
a data query form and will be documented for each individual subject before clean file is declared. 
The AEs will subsequently be coded using the MedDRA, and prior and concomitant medications 
will be coded using the World Health Organization (WHO) Drug Dictionary. 
9.6 
Archiving Study Documents 
According to International Conference for Harmonization (ICH) guidelines, essential documents 
should be retained for a minimum of 2 years after the last approval of a marketing application in 
an ICH region and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical development of 
the IMP. However, these documents should be retained for a longer period if required by the 
applicable legal requirements. 
 


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10. 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
10.1 Good Clinical Practice 
The procedures set out in this clinical study protocol are designed to ensure that the Sponsor and 
the Investigator abide by the principles of the ICH guidelines on GCP and the Declaration of 
Helsinki (WMA 2013). The clinical study also will be carried out in keeping with national and 
local legal requirements. 
10.2 Informed Consent 
Before each subject is enrolled in the clinical study, written informed consent will be obtained 
from the subject according to the regulatory and legal requirements of the participating country 
and will be retained as part of the clinical study records. The Investigator will not undertake any 
investigation specifically required only for the clinical study until written consent has been 
obtained. The terms of the consent and when it was obtained must also be documented in the eCRF. 
The Investigator must ensure that the subject received full and adequate oral and written 
information about the nature, purpose, possible risk, and benefit of the study. Subjects must also 
be notified that they are free to withdraw from the study at any time without prejudice to future 
care. The subject should be given the opportunity to ask questions and allowed time to consider 
the information provided. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol. If the ICF is revised, it must be reviewed and approved by the responsible IRB and signed 
by all subjects subsequently enrolled in the clinical study as well as those currently enrolled in the 
clinical study. 
10.3 Protocol Approval and Amendment(s) 
Before the start of the clinical study, the clinical study protocol and other relevant documents will 
be approved by the IRB, in accordance with local legal requirements. The Sponsor must ensure 
that all ethical and legal requirements have been met before the first subject is enrolled in the 
clinical study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, which 
must be released by the responsible staff, and receive IRB approval prior to implementation (as 
appropriate). 


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Administrative changes may be made without the need for a formal amendment but will also be 
mentioned in the integrated clinical study report. All amendments will be distributed to all study 
protocol recipients, with appropriate instructions. 
10.4 Confidentiality Data Protection 
All clinical study findings and documents will be regarded as confidential. Study documents 
(protocols, IB, and other material) will be stored appropriately to ensure their confidentiality. The 
Investigator and members of his/her research team (including the IRB) must not disclose such 
information without prior written approval from the Sponsor, except to the extent necessary to 
obtain informed consent from subjects who wish to participate in the study or to comply with 
regulatory requirements. 
The anonymity of participating subjects must be maintained. Subjects will be specified on study 
documents by their subject number. Documents that identify the subject (e.g., the signed ICF) must 
be maintained in confidence by the Investigator. 
10.5 Liability and Insurance 
The Sponsor will take out reasonable third party liability insurance cover in accordance with all 
local legal requirements. The civil liability of the Investigator; the persons instructed by him/her 
and the hospital, practice, or institute in which they are employed; and the liability of the Sponsor 
with respect to financial loss due to personal injury and other damage that may arise as a result of 
the carrying out of this study are governed by the applicable laws and GCP guidelines. 
The Sponsor will arrange for subjects participating in this study to be insured against financial loss 
due to personal injury caused by the pharmaceutical products being tested or by medical steps 
taken in the course of the study. 
The method and manner of compensation to subjects should comply with applicable regulatory 
requirement(s). 
10.6 Publication Policy 
By signing the clinical study protocol, the Investigator agrees with the use of results of the clinical 
study for the purposes of national and international registration, publication and information for 
medical and pharmaceutical professionals. If necessary, the competent authorities will be notified 
of the Investigator’s name, address, qualifications and extent of involvement. 


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An Investigator or CRO shall not publish, or present for publication any articles or papers or make 
any presentations, or assist any other person in publishing any articles or papers or making any 
presentations, or making any public declaration relating or referring to the clinical study, the results 
of the clinical study, in whole or in part, without the prior written consent of the Sponsor. 


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11. 
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