A Randomized, Double-blind, Single-dose, Three-arm, Parallel-group, Phase 1 Study to Compare Pharmacokinetic and Safety of TRS003 to China-approved Bevacizumab and US-licensed Avastin®，When Administered to Healthy Male Participants
Phase: PHASE1
Conditions: Healthy
Sponsor: Zhejiang Teruisi Pharmaceutical Inc.

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  1 | 50 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
This study will be conducted according to this protocol, including protocol amendments 
and in compliance with Good Clinical Practice, the ethical principles, and other 
applicable regulatory requirements 
 
 
 
 
 
 
 
Protocol Number: 
TRS00301001 
Clinical Phase: 
Phase 1 
 
IND Number: 
136545 
Sponsor: 
Zhejiang Teruisi Pharmaceutical Inc. 
Version:                                 1.0 
Effective Date:                      May 12, 2018 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
This document contains confidential information, which should not be copied, referred to, released or published 
without written approval from Zhejiang Teruisi Pharmaceutical Inc. In the event of any actual or suspected 
breach of this obligation, Zhejiang Teruisi Pharmaceutical Inc. must be promptly notified. These restrictions 
on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential. 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  2 | 50 
 
TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ................................................................................................. 1 
TABLE OF CONTENTS ................................................................................................................ 2 
SPONSOR SIGNATURE ............................................................................................................... 5 
INVESTIGATOR AGREEMENT .............................................................................................. 6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................. 8 
Synopsis ........................................................................................................................................ 10 
1 
Introduction ............................................................................................................................ 16 
1.1 
Background .............................................................................................................. 16 
1.2 
Rational of the Study ............................................................................................... 17 
1.3 
Preclinical Studies .................................................................................................... 18 
2 
Study Objectives .................................................................................................................... 21 
2.1 
Primary Objective .................................................................................................... 21 
2.2 
Secondary Objective ................................................................................................ 21 
3 
STUDY POPULATION AND SUBJECT ENROLLMENT ................................................ 22 
3.1 
Eligibility Criteria .................................................................................................... 22 
3.1.1 
Inclusion Criteria: ............................................................................................. 22 
3.1.2 
Exclusion Criteria: ............................................................................................ 22 
3.2 
Lifestyle Considerations .......................................................................................... 24 
3.2.1 
Meals and Dietary Restrictions ......................................................................... 24 
3.2.2 
Alcohol .............................................................................................................. 24 
3.2.3 
Activity ............................................................................................................. 24 
3.3 
Overall study Design................................................................................................ 24 
3.4 
Dose Selection Rational ........................................................................................... 25 
3.5 
Screening Visit ......................................................................................................... 25 
3.6 
Randomization and blinding .................................................................................... 26 
3.7 
Confinement Period ................................................................................................. 26 
3.8 
Duration of Treatment.............................................................................................. 27 
3.9 
Outpatient Visits ...................................................................................................... 27 
3.10 
End of Study (EOS) Visit ........................................................................................ 27 
4 
Study Drug and Treatment Allocations ................................................................................. 28 
4.1 
Treatment Compliance ............................................................................................. 28 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  3 | 50 
 
4.2 
Study Drug Description, Storage and Handling ...................................................... 28 
4.3 
Drug Administration ................................................................................................ 29 
4.4 
Special Precautions and Clinical Interventions ........................................................ 30 
4.4.1 
Infusion Reactions ............................................................................................ 30 
4.4.2 
Extravasation..................................................................................................... 31 
4.5 
Warnings and precautions of Bevacizumab ............................................................. 31 
4.6 
Contraindications ..................................................................................................... 32 
4.7 
Protocol Therapy and off Study Criteria .................................................................. 32 
4.7.1 
Criteria for removal from protocol therapy: ..................................................... 33 
4.7.2 
Off Study Criteria ............................................................................................. 33 
4.7.3 
Subject Replacement ......................................................................................... 33 
4.8 
Study Closure ........................................................................................................... 33 
5 
Study Assestments and Evaluations....................................................................................... 35 
5.1 
Blood Samples for PK Evaluations.......................................................................... 35 
5.2 
Blood Samples for Immunogenicity Evaluations .................................................... 35 
5.3 
Safety assessments ................................................................................................... 35 
5.4 
Conflict of Interest ................................................................................................... 36 
6 
Data Collection and Management .......................................................................................... 37 
6.1 
Study Record Retentions.......................................................................................... 37 
6.2 
Protocol Deviations .................................................................................................. 38 
6.3 
Publication and Data Sharing................................................................................... 39 
7 
Human Subject Protection and Regulatory Oversight ........................................................... 40 
7.1 
Informed Consent Processes and Documentation.................................................... 40 
7.2 
Confidentiality and Privacy ..................................................................................... 40 
8 
Safety Reporting .................................................................................................................... 41 
8.1 
Definitions................................................................................................................ 41 
8.2 
Causality of AEs ...................................................................................................... 42 
8.3 
Categorization of AEs .............................................................................................. 43 
8.4 
Reporting of SAEs and Suspected Unexpected Serious Adverse Reactions 
(SUSARs) ............................................................................................................................. 43 
8.5 
IRB Reporting .......................................................................................................... 44 
8.6 
Quality Assurance and Quality Control ................................................................... 44 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  4 | 50 
 
8.7 
Clinical Monitoring Plan.......................................................................................... 45 
9 
Statistical Considerations ....................................................................................................... 47 
9.1 
General Statistical Considerations ........................................................................... 47 
9.2 
Pharmacokinetic analysis ......................................................................................... 47 
9.3 
Immunogenicity analysis ......................................................................................... 47 
9.4 
Determination of Sample Size ................................................................................. 48 
9.5 
Population Analysis ................................................................................................. 48 
9.5.1 
Safety Population Analysis ............................................................................... 48 
9.5.2 
PK Population Analysis .................................................................................... 48 
9.6 
Safety Analysis ........................................................................................................ 48 
9.7 
Tabulation of Individual Participation Data ............................................................ 49 
10 
References ....................................................................................................................... 50 
 
 
LIST OF TABLES 
 
Table 1 
Schedule of Activities ............................................................................................. 13 
Table 2 
Approximate Blood Volumes (mL) Sampled During the Study ........................ 15 
Table 3 
Management of Infusion-Related Reactions/Hypersensitivity Reactions (NCI 
CTCAE Grade) ........................................................................................................................... 31 
 
 
 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  5 | 50 
 
 
 
SPONSOR SIGNATURE 
 
Study Title: A randomized, double-blind, single-dose, three-arm, parallel-group, phase 
1 study to compare pharmacokinetic and safety of TRS003 to China-approved 
bevacizumab and US-licensed Avastin, when administered intravenously to healthy 
male subjects. 
 
Protocol Number:  TRS00301001 
 
Version: 1.0  
 
Person authorized to sign the protocol and protocol amendment(s) for the Sponsor, Zhejiang 
Teruisi Pharmaceutical Inc. 
 
 
 
____________________________________ 
Signature by: Youling Wu, Ph.D. 
 
____________________________________ 
Date 
 
 
 
 
 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  6 | 50 
 
 
 
INVESTIGATOR AGREEMENT 
 
I have read Protocol TRS00301001: A randomized, double-blind, single-dose, three-arm, 
parallel-group, phase 1 study to compare pharmacokinetic and safety of TRS003 to China-
approved bevacizumab and US-licensed Avastin, when administered intravenously to healthy 
male subjects  and agree to conduct the study as described therein in compliance with ICH 
Guidelines for Good Clinical Practice and applicable regulatory requirements and to inform 
all who assist me in the conduct of this study of their responsibilities and obligations. 
 
The signature below constitutes my agreement to the contents of this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
  
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name (please type or print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Institution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Address 
 
 
 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  7 | 50 
 
 
 
Sponsor Study Contacts 
 
Name  
Title/Role 
Contact Information 
Ruben Zhao 
Medical Director 
Phone: +86 18001098786 
Fax: +86 5722126820 
Email: libin.zhao@teruisipharm.com 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  8 | 50 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse Event 
AHA 
Autoimmune Hemolytic Anemia 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase  
aPTT 
activated Partial Thromboplastin Time 
AST 
Aspartate Transaminase 
AUC 
Area under the serum concentration-time curve 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
EOI 
End-of-Infusion  
EOS 
End-of-Study Visit 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCV 
Hepatitis C virus 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  9 | 50 
 
HBsAg 
Hepatitis B Surface antigen 
HbcAb 
Hepatitis B core antibody 
IB 
Investigato s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRR 
Infusion Related Reaction 
IV 
Intravenously 
MedDRA 
Medical Dictionary for Regulatory Activities 
PE 
Physical Examination  
PK 
Pharmacokinetics  
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
ULN 
Upper Limit of Normal 
UP/CR 
Urine Protein to Creatinine Ratio 
WBC 
White Blood Cells 
 
 
 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  10 | 50 
 
SYNOPSIS 
Title 
A randomized, double-blind, single-dose, three-arm, parallel-group, 
phase 1 study to compare pharmacokinetic and safety of TRS003 to 
China-approved bevacizumab and US-licensed Avastin, when 
administered intravenously to healthy male subjects. 
Sponsor 
Zhejiang Teruisi Pharmaceutical Inc. 
Study Drug 
TRS003 
Clinical Trial Phase 
Phase 1 
Proposed Indication 
Metastatic colorectal cancer (mCRC); First-line Non-Squamous 
Non-small cell lung cancer (NSCLC); Recurrent Glioblastoma (GB)
in adults; Metastatic renal cell carcinoma (mRCC); Persistent, 
Recurrent or Metastatic carcinoma of the cervix ; recurrent epithelial 
ovarian, fallopian tube or primary peritoneal cancer. 
Objectives 
 
Primary 
 To demonstrate pharmacokinetic (PK) similarity between 
TRS003, China-approved bevacizumab   and US-licensed 
Avastin, as measured by AUC0-inf in healthy male subjects after 
a single 3 mg/kg dose.  
 
Secondary  
 
To assess other PK parameters such as but not limited to Cmax
and AUClast, following a single dose of TRS003, China-
approved bevacizumab and US-licensed Avastin in healthy 
male subjects. 
 
To determine the incidence of immunogenicity against 
TRS003, China-approved bevacizumab, and US-licensed 
Avastin in healthy male subjects. 
 
To evaluate the safety of TRS003, China-approved 
bevacizumab and US-licensed Avastin in healthy male 
subjects. 
Study Population 
18-55 yrs.  healthy male volunteers 
Sample Size 
Assuming a CV of 20% (Knight et al., 2016) in male healthy subjects 
and 1.05 for the geometric mean ratio (TRS003/ China-approved 
bevacizumab/US-licensed Avastin®/) of AUC0-inf, the study with 29 
evaluable subjects per arm will have 95% power to demonstrate the 
PK similarity between TRS003, China-approved bevacizumab, and 
US-licensed Avastin (90% confidence interval [CI] of geometric 
mean ratio within 80-125%). Assuming a 15% drop out rate 
(including non-evaluable subjects) and a 95% power, approximately 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  11 | 50 
 
114 subjects (38 per arm) will be randomized in 1:1:1 ratio to ensure
adequate power to demonstrate PK similarity using 3 pairwise 
comparisons. 
Number of Study 
Centers Planned 
Approximately 1-3 study sites located in the United States.  
Additional sites may be added if necessary. 
Study Design 
This is a 12-week, randomized, double-blind, single-dose PK study. 
Approximately 114 healthy male subjects (screening occurred within 
28 days prior to dosing) will be randomized 1:1:1 to either TRS003,
China-approved bevacizumab, and US-licensed Avastin groups. 
Study drug will be dispensed as a single 3 mg/kg dose for
intravenous infusion within 90 minutes. PK and immunogenicity 
samples will be collected and safety will be assessed. 
Pharmacokinetic (PK) 
and Immunogenicity 
evaluations 
For details for PK and immunogenicity sample collections refer to 
Schedule of Activities. If a sample is positive in the screening assay, 
a confirmatory assay will be conducted. If a confirmatory assay is 
positive, the titer and the neutralization activity will be tested.  
Teruisi is conducting the assay validation for PK and anti-drug 
antibo
 
Safety Evaluations 
Safety will be assessed by periodic physical examination findings, 
vital signs, clinical laboratory tests, 12-lead ECGs, and AEs.   
Statistical Analysis 
Safety population consists of all subjects who received the 
investigational product.  
PK population consists of all subjects who have evaluable 
concentration-time data.  
Descriptive statistics of PK parameters (geometric mean, CV%, 
arithmetic mean, median, SD, minimum and maximum) will be 
provided.  
The primary assessment of PK similarity will be based upon a 90% 
CI for the ratio of the geometric means (TRS003, China-approved 
bevacizumab and US-licensed Avastin) for AUC0-inf on PK analysis 
set. If the 90% CI of the ratio of the geometric means for AUC0-inf is 
within the range of 80-125%, then PK similarity will be concluded. 
Secondary PK parameters such as but not limited to Cmax, AUClast
will be analyzed using the same statistical approach. A 
nonparametric approach, for example, Wilcoxon signed-rank test, 
will be taken to evaluate parameters such as t1/2. Exploratory 
analyses may be performed for other PK parameters as deemed 
appropriate. 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  12 | 50 
 
All AEs will be listed and summarized using descriptive 
methodology. The incidence of AEs for each treatment will be 
presented by severity and association with the study drugs. Clinical 
laboratory parameters, vital signs, and ECG parameters will be listed 
and summarized using descriptive statistics. The number and 
percentage of subjects testing positive for ADAs will be summarized 
by treatment and time point. 
 
 
 
 

P a g e  13 | 50 
 
Table 1 
Schedule of Activities 
Protocol   Activity 
 
 
Clinical Research Unit (CRU) 
Confinement 
Outpatient Visits 
 
Screen 
-D28 
to  
 D2 
- 
D1 
Pre-
dose 
D1 
0h 
Infusion 
0h 
Post 
EOI 
0.5 
hour* 
Post 
EOI 
4h 
±10 
min 
8h 
±10 
min 
24h 
D2 
±1h 
48h 
D3 
±4h  
96h 
D5 
±8h 
168h 
D8 
±8 h 
336h 
D15 
±1 
day 
672h 
D29 
±2 
days 
1008h 
D43 
±2 
days 
1344h 
D57 
±2 
days 
1680h 
D71 
±2 
days 
2016h D85 
(EOS) 
±2 days 
Signed Informed Consent 
(ICF)1 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria  
× 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics2 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight3 
× 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
× 
Medical History 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
× 
Physical Examination 
× 
× 
 
 
 
 
 
 
× 
 
 
 
 
× 
 
× 
 
× 
Current 
Medications/OTC/supplements 
× 
× 
 
 
 
 
 
 
 
 
 
 
 
× 
 
× 
 
× 
Vital Signs4 
× 
× 
 
× 
x 
× 
x 
x 
× 
× 
 
× 
 
× 
 
× 
 
× 
12 Lead Electrocardiogram 
(ECG)5 
× 
 
 
 
 
× 
 
 
 
 
 
 
 
 
 
 
 
× 
Alcohol breath test 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events (AE) 
× 
                                             Ongoing 
Laboratory Tests 
Hematology & Serum 
Chemistry6 
× 
× 
 
 
 
 
 
 
× 
 
 
× 
 
× 
 
× 
 
× 
Coagulation Tests7 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening for HIV, HBV, 
HCV8 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001  
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  14 | 50 
 
Protocol   Activity 
 
 
Clinical Research Unit (CRU) Confinement 
Outpatient Visits 
 
Screen 
-D28 
to  
 D2 
- 
D1 
Pre-
dose 
0h 
Infusion 
0h 
Post 
EOI 
0.5 
hour 
Post 
EOI 
4h 
±10 
min 
8h 
±10 
min 
24h 
D2 
±1h 
48h 
D3 
±4h  
96h 
D5 
±8h 
168h 
D8 
±8 h 
336h 
D15 
±1 
day 
672h 
D29 
±2 
days 
1008h 
D43 
±2 
days 
1344h 
D57 
±2 
days 
1680h 
D71 
±2 
days 
2016h D85 
(EOS) 
±2 days 
Urinalysis (U/A)9 
× 
 
 
 
 
 
 
 
× 
 
 
× 
 
× 
 
× 
 
× 
Urine drug screen 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of 
TRS003//China approved 
bevacizumab or US -Licensed 
Avastin 
 
 
 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics (PK)10 
 
 
× 
 
x 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Anti-Drug Antibodies (ADA) 11 
 
 
× 
 
 
 
 
 
 
 
 
 
× 
× 
 
× 
 
× 
EOS=End of Study; EOI=End of Infusion; HIV = human immunodeficiency virus; HBV = hepatitis B virus; HCV = hepatitis C virus; D=Day 
*0.5 h post EOI is 2 h post the start of infusion if the infusion starts at 0 and ends at 90 min 
1. 
Written consent must be obtained prior to performing any protocol specific procedure. 
2. 
Age, height, gender, ethnicity, and race at screening where possible 
3. 
Body weight will be measured at screening and -D1 and D85.  
4. 
Vital signs include temperature, pulse, respiratory rate, and blood pressure. Vital signs will be assessed at supine position at screening and on the visits at the 
clinical research unit. Vital sign will be performed within 30 minutes prior to the infusion. Additionally, vital signs will be taken before every PK sampling. 
5. 
ECGs (single ECG only) will be collected at screening, within 30 minutes post EOI, and as clinically indicated, and at EOS. The subjects should take supine 
position. 
6. 
Hematology includes Complete blood count (CBC) (hematocrit (HCT), hemoglobin, red blood cells (RBC), Red Cell Distribution Width (RDW), Mean 
Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular Hemoglobin Concentration (MCHC), platelets, white blood cells (WBC) 
with absolute differential counts of neutrophils, lymphocytes, monocytes, eosinophils, and basophils).  Serum Chemistry ALT, AST, ALP, K+, Na+, Cl-, Ca2+, 
TBIL, blood urea nitrogen (BUN) or urea, creatinine, uric acid, glucose (non-fasted), albumin. Assessments will be performed on screen, within 72 hours prior to 
dosing (if the labs are 
3weeks old), and on D2, D8, D29, D57 and D85. 
7. 
 INR/PT and aPTT: Assessments will be performed on screening. 
8. 
HIV screening (Antigen/antibody test), HCV antibodies, hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), total hepatitis B core antibody 
(anti-HBc), IgM antibody to hepatitis B core antigen (IgM anti-HBc).  
9. 
Dipstick is acceptable. Assessments will be performed on screening and on D2, D8, D29, D57 and D85.  
10. PK samples will be collected at pre-dose, 0 h (at EOI), 0.5h, 4h, 8h, 24h (Day 2), 48h (Day 3), 96h (Day 5), 168h (Day 8), 336h (Day 15), 672h (Day 29), 1008h 
(Day 43), 1344h (Day 57), 1680h (Day 71), and 2016h (Day 85) hours post EOI  

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001  
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  15 | 50 
 
11. Blood samples for ADA analyses will be collected at pre-dose, 336h (Day15), 672h (Day 29), 1344h (Day 57) and 2016h (Day 85) hours after EOI. 
 
 
 
Table 2 
Approximate Blood Volumes (mL) Sampled During the Study  
Protocol   Activity 
 
 
Clinical Research Unit (CRU) Confinement 
Outpatient Visits 
 
Screen 
-D28 
to  
 D2 
- 
D1 
 
Pre-
dose 
0h 
Infusion 
0h 
Post 
EOI 
0.5 
hour* 
Post 
EOI 
4h 
±10 
min 
8h 
±10 
min 
24h 
D2 
±1h 
48h 
D3 
±4h  
96h 
D5 
±8h 
168h 
D8 
±8 h 
336h 
D15 
±1 
day 
672h 
D29 
±2 
days 
1008h 
D43 
±2 
days 
1344h 
D57 
±2 
days 
1680h 
D71 
±2 
days 
2016h 
D85 
(EOS) 
±2 days 
Initial Screening Labs (mL) 
12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology & Serum 
Chemistry (safety labs) (mL) 
 
101 
 
 
 
 
 
 
10 
 
 
10 
 
10 
 
10 
 
10 
Pharmacokinetics (PK) (mL) 
 
 
6 
 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
Anti-Drug Antibodies (ADA) 
(mL) 
 
 
8 
 
 
 
 
 
 
 
 
 
8 
8 
 
8 
 
8 
Total Amount per visit (mL) 
12 
10 
14 
 
6 
6 
6 
6 
16 
6 
6 
16 
14 
24 
6 
24 
6 
24 
 
 
1. 
Hematology includes Complete blood count (CBC) (hematocrit (HCT), hemoglobin, red blood cells (RBC), Red Cell Distribution Width (RDW), Mean 
Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular Hemoglobin Concentration (MCHC), platelets, white blood cells (WBC) 
with absolute differential counts of neutrophils, lymphocytes, monocytes, eosinophils, and basophils).  Serum Chemistry ALT, AST, ALP, K+, Na+, Cl-, Ca2+, 
TBIL, blood urea nitrogen (BUN) or urea, creatinine, uric acid, glucose (non-fasted), albumin. Assessments will be performed within 72 hours prior to dosing (if 
the labs are 
3weeks old). 

P a g e  16 | 50 
 
1 
INTRODUCTION 
1.1 
BACKGROUND 
Angiogenesis is a rate-limiting step in multiple pathological processes and is also one of the 
hallmarks of cancer growth and development. Therefore, angiogenesis has emerged as a valid 
therapeutic target in the field of oncology. As the tumor grows, tumor initiates the process called 
stimulating the production of angiogenic factors, especially human vascular endothelial growth 
factor (VEGF) (Hanahan & Folkman, 1996). Activation of angiogenic factors induces 
neovascularization, which is an important step for tumor progression and   metastasis (Hanahan 
et al., 1996; Menakuru et al., 2008). VEGF blockade has demonstrated to have direct antitumor 
affect in human and animal cancer tumor cells by cutting the vascular supply and inhibiting 
endothelial proliferation. Several VEGF family members, VEGF-A through VEGF-E and 
placental growth factor (PIGF), have been identified in the human genome, among which most 
pro-angiogenic activity is mediated by VEGF-A (Zondor and Medina 2004). At least 9 pro-
angiogenic VEGF isoforms are generated as a result of alternative splicing from a single gene, 
and VEGF165, VEGF121 and VEGF121b are the most abundant isoforms of VEGF (Ferrara et al, 
2004). 
Bevacizumab (AVASTIN®) is a recombinant humanized monoclonal antibody developed by 
Genentech used to inhibit VEGF that recognizes all isoforms of VEGF-A and thus inhibiting its 
biologic activity (Genentech Inc.2015). Bevacizumab became first angiogenesis inhibitor 
approved by FDA on February 26, 2004 for oncology use in the USA.  Bevacizumab is approved 
for the treatment of multiple types of advanced/metastatic solid tumors including metastatic 
colorectal cancer (mCRC); First-line non-squamous non-small cell lung cancer (NSCLC); 
recurrent glioblastoma (GB); metastatic renal cell carcinoma (mRCC); persistent, recurrent, or 
metastatic carcinoma of the cervix; recurrent epithelial ovarian, fallopian tube or primary 
peritoneal cancer. 
TRS003 is developed as a proposed biosimilar product to the US-licensed reference product 
(RP), Avastin® (bevacizumab). Similar to US-licensed RP, TRS003 is a recombinant humanized 
monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  17 | 50 
 
endothelial growth factor type A (VEGF-A). Through the neutralization of VEGF, angiogenesis 
required for the growth and persistence of solid tumors and their metastases is inhibited.   
The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of 
health reform (Affordable Care Act) that was signed into law on March 23, 2010. The BPCI Act 
-
, RP). This 
abbreviated licensure pathway under section 351(k) of the PHS Act permits reliance on certain 
existing scientific knowledge about the safety and effectiveness of the reference product, and 
enables a biosimilar biological product to be licensed based on less than a full complement of 
product specific nonclinical and clinical data. 
describe that 
 withstanding minor 
differences in clinically inact
differences between the biological product and the reference product in terms of the safety, 
The analytical and nonclinical similarity assessments, as 
well as a pharmacokinetic similarity study performed were intended to evaluate analytical 
similarity and functional activity of TRS003, US-licensed RP and China-approved bevacizumab 
side-by-side to support the extrapolation to all of the US-licensed RP indications for which 
Teruisi is seeking licensure for TRS003.  
 
1.2 
RATIONAL OF THE STUDY 
Teruisi has been successful in applying platform technology in a number of its programs for 
manufacturing monoclonal antibodies to facilitate process development and scale up.  TRS003 cell 
line was developed by Destiny and vials of PCB were provided to Teruisi in 2015 for IND-enabling 
CMC development.  Cell culture development platform comprises 3 phases including (1) media & 
feed screening performed in the shake flask, (2) process optimization taken place in the 3-L 
Bioreactor, process parameters such as seeding density, feed strategy, temperature, pH, DO, 
agitation speed, and sparge rate etc. are defined; key performance parameters such as productivity, 
growth and metabolite profile, and product quality (PQ) by Process Analytical Technology (PAT) 
are evaluated, and (3) scale up to the 200-L.  Recovery process development employs a 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  18 | 50 
 
standardized 3-column platform, consisting of MabSelect SuRe on Protein A Affinity, cation 
exchange in a bind and elute (B/E) mode, and anion exchange in a flow through mode.  In addition, 
two orthogonal viral clearance steps, including a low-pH inactivation step and viral filtration step 
are included in the process to maximize product safety. A number of analytical assays have been 
developed to evaluate the product quality and safety. So far, four Drug Substance and four Drug 
Product lots have been manufacturing at 200 L scale for preclinical and clinical studies. The 
analytical 3-way similarity assessment results showed that TRS003 is similar to US-licensed 
Avastin and China-approved bevacizumab.  A series of nonclinical studies have been conducted 
to evaluate and compare the pharmacological, pharmacokinetics and toxicological properties of 
the TRS003 and US-licensed RP, and China-approved bevacizumab. Comparable profiles of 
among TRS003, US-licensed RP, and China- approved bevacizumab have been observed in 
binding affinity, specificity and activity of Fab and Fc regions, in anti-tumor efficacy using 
xenograft models, and in PK and safety studies using cynomolgus monkeys. 
 
1.3 
PRECLINICAL STUDIES 
Bevacizumab, the active ingredient of US-licensed Avastin®, is a recombinant humanized 
monoclonal immunoglobulin G1 subtype (IgG1) antibody targeting human vascular endothelial 
growth factor type A (VEGF-A). Bevacizumab binds with high affinity and selectivity to all 
known isoforms of soluble VEGF. The mechanism of action for bevacizumab across indications 
is neutralizing the biologic activity of VEGF protein through steric blockade of binding to its 
receptors VEGFR-1 (Flt-1) and VEGFR2 (KDR) on the surface of endothelial cells. Activation 
of VEGF receptors results in transduction signals that elicit mitogenic and pro-survival activity 
in vascular endothelial cells. Blockade of the VEGF/VEGFRs signaling pathway inhibits VEGF 
mediated angiogenesis, including that associated with tumor growth. VEGFR expression is very 
low or undetectable in most normal tissues (with the exception of renal glomeruli) but is 
significantly up-regulated in the vasculature of many solid tumors. The neutralization of VEGF 
by bevacizumab provides a relatively specific inhibition of tumor angiogenesis and thereby 
inhibition of tumor growth and metastasis.  
TRS003 is a biological similar product for US-licensed Avastin® (bevacizumab). It has identical 
amino acid sequence as Avastin®. Following the FDA recommended stepwise approach, 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  19 | 50 
 
comprehensive analytical similarity assessments were conducted and all the available in vitro 
data support that TRS003 has similar physicochemical primary structure, higher order structure, 
biological functions and Fc characteristics with the US-licensed Avastin® and China-approved 
bevacizumab. Additional nonclinical development studies have been conducted to evaluate and 
compare the dose-responsive pharmacological properties of the TRS003 and US- license Avastin 
and China-approved bevacizumab.  
Functional testing focused on the mechanism of action, therefore, multiple assays interrogating 
Fab-mediated activities were conducted, including binding and neutralization of VEGF in 
HUVEC cell proliferation assay. The results from these assays confirmed that TRS003, US- 
license Avastin and China-approved bevacizumab have similar functional activities.   
Fc functionality was included in the testing plan to assess Fc-binding activities and the structural 
integrity of the Fc domain. These induced comparative binding to multiple Fc receptors and the 
complement molecule C1q as well as lack of Fc-mediated effector function ADCC and CDC. 
There is no contribution of Fc receptor binding to the pharmacological activity and efficacy 
profile of TRS003, US- license Avastin and China-approved bevacizumab .  
The PK study following a single intravenous (IV) administration of 1, 3 and 10 mg/kg of two lots 
of TRS003, one lot of US-licensed RP and one lot of China-approved bevacizumab were 
conducted in naïve Sprague-Dawley (SD) rats. Intravenous administration was chosen because it 
is the intended clinical administration route. SD rat is not a pharmacological relevant species; 
however, it is a sensitive test system to assess the primary and higher order structures (such as 
glycan structure of the antibody), as well as the structural integrity of the molecules. In addition, 
it can be used to detect potential off-target toxicity. In this study, no test article related adverse 
clinical effects were observed. All anti-VEGF antibodies were well tolerated. No difference was 
observed in serum concentration-time curves of the four lots of antibodies. This study 
demonstrated similar PK parameters after dosing of both TRS003,US-licensed RP and China-
approved bevacizumab, confirming that similar exposures were achieved in SD rats after 
treatment with either TRS003, US-licensed and China- approved bevacizumab.  
In summary, the analytical, pharmacological and PK similarity assessment results form the basis 
for the conclusion that TRS003 is similar to US-licensed RP and China-approved bevacizumab 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  20 | 50 
 
and that TRS003 is expected to have similar clinical performance in all indications approved for 
US-licensed RP Refer to 
 for details).  
 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  21 | 50 
 
2 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
 To assess pharmacokinetic (PK) similarity between TRS003, China-approved 
bevacizumab and US-licensed Avastin, as measured by AUC0-inf in healthy male subjects 
after a single 3 mg/kg dose. 
 
2.2 
SECONDARY OBJECTIVE 
 To assess other PK parameters such as but not limited to Cmax, AUClast following a single 
dose of TRS003, China-approved bevacizumab and US-licensed Avastin in healthy male 
subjects. 
 To determine the incidence of immunogenicity against TRS003, China-approved 
bevacizumab, and US-licensed Avastin in healthy male subjects. 
 To evaluate the safety of TRS003, China-approved bevacizumab and US-licensed 
Avastin in healthy male subjects. 
 
 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  22 | 50 
 
3 
STUDY POPULATION AND SUBJECT ENROLLMENT 
3.1 
ELIGIBILITY CRITERIA 
3.1.1 Inclusion Criteria: 
1. Healthy, male subjects, 18-55 years old with no significant medical history, and in good 
health as determined by detailed medical history, full physical examination, vital signs, 
12-lead electrocardiogram (ECG), urinalysis and laboratory tests at screening. 
2. Body mass index of 17.5-30.5 kg/m2 and body weight of 50-95 kg.  
3. Protocol-specified hematology, coagulation, blood chemistry and urinalysis within the 
laboratory normal range at screening, unless deemed not clinically significant by the 
Investigator. 
4. Subjects must have adequate organ function according to the following laboratory values:  
a. Bone marrow function (absolute neutrophil count 1500/mm3 and platelet count 
100,000/mm3) 
b. Adequate liver function [alanine aminotransferase (ALT) 3 × upper limit normal 
(ULN) and alkaline phosphatase 2 × ULN, total bilirubin 1.5 mg/dL] 
c. Adequate renal function creatinine clearance 60 mL/min based on Cockcroft-
Gault equation. 
5. Subjects must agree to use an acceptable form of birth control throughout the study and 
for at least 18 weeks after the study is over. 
 
3.1.2 Exclusion Criteria: 
1. Subjects unable to give voluntary informed consent. 
2. Evidence or history of clinically significant disease, cancer other than adequately treated 
basal cell or squamous cell carcinoma of the skin. 
3. Subjects on anticoagulant drugs, anemic or with known bleeding diatheses. 
4. Subjects with a history of severe, uncontrolled hypertension, heart disease, 
cerebrovascular incidents, gastrointestinal bleeding, hemoptysis, frequent epistaxis or 
gingival bleeding. 
5. History clinically significant orthostatic hypotension, fainting spells, vasovagal syncope. 
6. Uncontrolled severe hypertension (140/90 mm Hg). 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  23 | 50 
 
7. Previous treatment with an anti-VEGF antibody or any other antibody or protein targeting 
the VEGF receptor. 
8. Use of any prescription, investigational drugs, herbal supplements or nonprescription 
drugs within 1 month or 5 half-lives (whichever is longer) prior to the first dose, or 
dietary supplements within 1 week prior to the first dose. If needed, 
paracetamol/acetaminophen may be used, but must be documented in the Concomitant 
medications/Significant non-drug therapies page of the CRF. 
9. Serious unhealed wound, cutaneous ulcer or bone fracture at the time of screening.  
10. Major surgery or major dental procedure or significant traumatic injury within 2 months 
prior to screening, or any planned surgery or procedure within 3 months after 
investigational treatment administration. Subjects must have recovered from all acute 
surgery- or trauma-related complications. 
11. Subject
and family history of recent or recurrent thromboembolism or other 
clotting and coagulation disorders. 
12. Donated blood over 400 mL within 3 months.  
13. History of relevant and clinically significant intra-abdominal inflammation, 
gastrointestinal perforation or gall bladder perforation. 
14. History of severe allergic or anaphylactic reaction to a therapeutic drug or severe 
seasonal allergies.   
15. Recent (within the last three [3] years) and/or recurrent history of acute or chronic 
bronchospastic disease (including asthma and chronic obstructive pulmonary disease, 
treated or not treated). 
16. A positive hepatitis B, hepatitis C or HIV tests at screening indicative of a current or past 
infection. 
17. Current use of tobacco or nicotine-containing products. Concomitant treatment was given 
only if Investigator believes strictly necessary and should be documented. 
18. Current use of any biologic drugs. 
 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  24 | 50 
 
3.2 
LIFESTYLE CONSIDERATIONS 
3.2.1 Meals and Dietary Restrictions 
Subjects will receive a standard diet whilst resident in the clinical center. 
3.2.2 Alcohol 
Refrain from intake of alcoholic beverages from 48 hours prior to study treatment administration 
until Day 8 postdose. After Day 8, subjects are discouraged from consuming alcohol until the 
completion of the study, but may consume no more than 1 unit of alcohol per day. 
3.2.3 Activity 
Subjects will abstain from strenuous exercise for 24 hours before each blood collection for 
clinical laboratory tests. Subjects may participate in light recreational activities during the study 
(eg, watching television, reading). 
Subjects should refrain from strenuous exercise for 48 hours before the Day -1 and admission to 
the clinical center and throughout the study. 
Subjects will be advised not to donate blood or plasma donation for at least 3 months after the 
last dose administration. 
 
3.3 
OVERALL STUDY DESIGN  
Study Schema 
From dosing until End of Study (EOS)-12 weeks 
PK & ADA Sampling 
Screening
28 days
ICF, H&P, Labs, Evaluate 
Subjects for 
Eligibility Criteria See Schedule 
of Activities
Randomization
TRS003
Single dose of 3 mg/kg 
IV infusion for 90 min
China-approved bevacizumab
Single dose of 3 mg/kg 
IV infusion for 90 min
US-Liscensed Avastin
Single dose of 3 mg/kg 
IV infusion for 90 min

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  25 | 50 
 
Safety labs, H&P see Schedule of Activities 
This is a 12-week, randomized, double-blind, single-dose PK study. Approximately 114 healthy 
male subjects (screening occurred within 28 days prior to dosing) will be randomized 1:1:1 to 
either TRS003, China-approved bevacizumab or US-licensed Avastin groups. Study drug will be 
dispensed as a single 3 mg/kg dose IV infusion within 90 minutes. PK and immunogenicity 
samples will be collected and safety will be assessed. 
 
3.4 
DOSE SELECTION RATIONAL 
Based on PK of bevacizumab, healthy subjects provide more homogenous population with less 
PK variability compared to those of cancer patient population. Due to the potential risk of 
ovarian failure, male healthy subjects are selected for the proposed PK similarity study.  
The approved therapeutic dose of Avastin are between 5 and 15 mg/kg given Q2W or Q3W. The 
3 mg/kg was chosen based on the PK linearity of bevacizumab at dose of 1-20 mg/kg and the 
high analytical sensitivity for the determination of bevacizumab concentrations at lower dose 
ranges. A dose of 3 mg/kg of study drug is not expected to pose a significant risk to healthy 
subjects. 
The 90-minute IV infusion is consistent with US-licensed Avastin prescribing information.  
 
3.5 
SCREENING VISIT 
Potential subject will be scheduled for a screening visit.  Screening procedures will take place on 
the Clinical Research Center.   
Prior to participation in the study, all volunteers will have a routine history and physical along 
with screening blood tests weight, height and vitals obtained at the screening visit.  In this 
proposed application, all subjects will have a baseline 12 lead ECG to exclude cardiovascular 
disease before entering the study.  
ensure subjects safety during the treatment (Refer to Table 1 for details).   
After all the screening results are obtained eligibility criteria will be reviewed and a complete 
clinical evaluation will be performed. All screening assessments will occur within 28 days prior 
to the study drug admission.  

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  26 | 50 
 
specifically for this study, it needs not be repeated after signed ICF has been obtained.  However, 
the assessments must fulfill the study requirements and should be performed within the specified 
timeframe prior to the study drug administration. If hematology and serum chemistry labs were 
3 weeks as indicated in Schedule of Activities the laboratory evaluations need to be 
repeated within 72 hours prior dosing. Retesting of abnormal screening values that lead to 
exclusion are allowed only once during the Screening Phase (to reassess eligibility). The last 
result obtained prior to dosing with study drug will be used to determine eligibility.  
drug administration. 
During the study period, AEs will be evaluated with each outpatient visit. The recent medical 
history assessment will include recent medication changes including over the counter 
medications or supplements. 
 
3.6 
RANDOMIZATION AND BLINDING 
Subjects in each clinical site will be 1:1:1 randomized prior to dosing using a computer-
generated randomization schedule to receive either TRS003, US-licensed Avastin or China-
approved bevacizumab.  
Both the principal investigator and subject will be blinded as to whether a subject is receiving 
TRS003, US-licensed Avastin or China-approved bevacizumab.  A designated person in the 
Investigational Pharmacy will dispense the appropriate drug accordingly.  
Each vial administered to subjects will have a unique code, and quick unblinding will be 
performed by Investigational Drug Pharmacy, the principal investigator, or the sponsor should a 
medical emergency arise for a participant.  Upon completion of the study participation, all 
subjects will be unblinded. 
 
3.7 
CONFINEMENT PERIOD 
This is randomized, double-blind, single-dose, three-arm, parallel-group, phase 1 study to 
compare pharmacokinetic and safety of TRS003 to China-approved bevacizumab and US-
licensed Avastin, when administered intravenously to healthy male subjects. If safety labs are  

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  27 | 50 
 
 3 weeks, safety laboratory   assessments should be repeated within 72 hours (-Day1) before the 
drug administration. Additionally, vital signs, medication history, physical exam will be done on 
-Day1 and eligibility will be re-evaluated after the repeat laboratory assessments results are 
received. Subject will visit the clinical research site in the Day-1 admission and will stay at the 
unit 24 hour after the drug administration. Dose should be calculated based on the most recent 
weight.  
All drug administrations will be performed in the clinical center under the supervision of 
appropriately trained staff. Subjects will stay at the clinical unit for at least 24 hours after dosing 
for PK and safety assessment. After 24 hours subject will be followed until the Day 85 (12 
Weeks) as an outpatient (Refer to the Table 1 and Table 2). 
3.8 
DURATION OF TREATMENT 
The duration of this study will be 16 weeks (28-day screening period and 12-week post-dose 
assessment). Subjects will be followed until the Day 85 (12 Weeks) following the single dose of 
the study drug (Refer to the Table 1). 
 
3.9 
OUTPATIENT VISITS 
For outpatient visits and procedures see Schedule of Activities (Table 1 and Table 2). On days  
3, 5, 8, 15, 29, 43, 57, 71, 85 days after the study drug administration, subjects will return to 
undergo the assessments outlined in the Schedule of Activities. Subjects will receive physical 
examination, will be evaluated for vital signs and AEs. Additionally, during these visits blood 
samples will be obtained for safety labs, PK and ADA samples (Refer to Table 1 and Table 2)  
 
3.10 END OF STUDY (EOS) VISIT 
At the EOS safety labs and assessments are evaluated (Refer to Table 1 and Table 2).  
 
 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  28 | 50 
 
4 
STUDY DRUG AND TREATMENT ALLOCATIONS 
4.1 
TREATMENT COMPLIANCE 
The site will maintain accurate dosage preparation records and should ensure that all 
pertinent/required information on the preparation and administration of the dose is captured.  
The details of drug administration will be recorded in the CRF. Upon termination of the study, or 
at the request of the sponsor, the pharmacist must return the study drugs to Sponsor, unless it is 
destroyed at the site as agreed upon by both the sponsor and the site. 
 
4.2 
STUDY DRUG DESCRIPTION, STORAGE AND HANDLING 
TRS003 developed as a proposed biosimilar of bevacizumab (Avastin®, Genentech), TRS003 is 
a recombinant humanized IgG  monoclonal antibody (mAb) targeting vascular endothelial 
growth factor (VEGF), a critical angiogenic factor involved in both physiological and 
pathological conditions. There are several isoforms of VEGF that are encoded by a single gene. 
The isoforms include placental growth factor and VEGF-A through VEGF-E. Most pro-
angiogenic activity is mediated by VEGF-A.  Like bevacizumab, TRS003 molecule binds 
VEGF-A and prevents VEGF-A from binding to its cell surface receptor VEGFR2, ultimately 
resulting in an inhibition of angiogenesis.  
TRS003 is composed of two identical heavy chains of 49,713 Da each, and two identical light 
chains of 23,447 Da each. The predominant glycan moiety of TRS003 is N-linked typical core 
fucosylated biantennary glycan with 0, 1 or 2 terminal galactose residues attached to each heavy 
chain at Asn-303 in the Fc region. The average size of the N-linked oligosaccharide moiety is 
approximately 1,500 Da per heavy chain. 
The TRS003 drug substance is formulated at 25 mg/mL in 5.8 mg/mL sodium phosphate 
(monobasic, monoh
-
trehalose dihydrate, 0.4 mg/mL polysorbate 20, pH 6.2. The formulated TRS003 drug substance 
(DS) and TRS03 drug product (DP; 100 mg/vial) is a clear to opalescent, colorless to slightly 
brown liquid that is essentially free of visible particles. 
The TRS003 drug product is a sterile solution for intravenous infusion consisting of 4 mL of 
TRS003 drug substance that is filled into single-use Type I glass vials capped with butyl stopper.  

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  29 | 50 
 
US licensed AVASTIN vials [100 mg (NDC 50242-060-01) and 400 mg (NDC 50242-061-01)] 
shake. Avastin is a clear to slightly opalescent, colorless to pale brown solution in single-dose 
vials. 
original carton until time of use. No incompatibilities between Avastin and polyvinylchloride or 
polyolefin bags have been observed.  
China-approved bevacizumab is supplied in 100 mg and 400 mg preservative-free, single-use 
vials to deliver 4 mL or 16 mL of Bevacizumab (25 mg/mL). 
-
trehalose dihydrate, sodium phosphate (monobasic, monohydrate), sodium phosphate (dibasic, 
anhydrous), polysorbate 20, and Water for Injection. Bevacizumab Injection for intravenous use 
is a sterile, clear to slightly opalescent, colorless to pale brown solution, with pH of 5.9~6.3. 
 
4.3 
DRUG ADMINISTRATION 
Use appropriate aseptic technique. Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration, whenever solution and container 
permit. 
Withdraw necessary amount of TRS003/China--approved bevacizumab or US licensed Avastin 
and dilute in a total volume of 100 mL of 0.9% Sodium Chloride Injection, USP. Discard any 
unused portion left in a vial, as the product contains no preservatives. 
DO NOT ADMINISTER OR MIX WITH DEXTROSE SOLUTION. 
Do not administer as an intravenous push or bolus. Administer only as an intravenous (IV) 
infusion within 90 minutes the dose of 3 mg/kg. 
TRS003/ China-approved bevacizumab/US-licensed Avastin administration should be completed 
within 4 hours at room temperature after dilution or within 8 hours at 2-8
 after dilution. This 
ensures sufficient time for healthcare professionals to conduct the drug preparation and 
administration. 
 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  30 | 50 
 
4.4 
SPECIAL PRECAUTIONS AND CLINICAL INTERVENTIONS 
Participants will receive only a single dose of 3mg/kg of TRS003, China-approved bevacizumab 
or US-licensed Avastin, thus it is unlikely that this treatment will cause any major AEs 
characteristic for bevacizumab. 
 
4.4.1 Infusion Reactions 
All therapeutic monoclonal antibodies (mAbs) used for cancer treatment have the potential to 
cause infusion reactions.  Symptoms vary with a wide spectrum of severity, ranging from mild 
fever and chills to life-threatening anaphylaxis with bronchospasm, and hypotension. Typically, 
infusion reactions to monoclonal antibodies develop within 30-120 minutes after the initiation of 
drug infusion, although symptoms may not show up until 24 hours. The majority of reactions 
occur after the first or second exposure to drug, although it can also occur during subsequent 
treatments. Infusion reactions (e.g., hypertension, hypertensive crisis, wheezing, oxygen 
desaturation) and hypersensitivity [including anaphylactic/anaphylactoid reactions], chest pain, 
rigors, headache, diaphoresis) may occur with the first infusion (uncommon). Stop infusion in 
patients experiencing severe infusion reactions and administer appropriate therapy.  
To date there is no data that suggest that routine premedication or reinstitution of therapy in 
patients with previous severe infusion reactions prevents these infusion reactions. However, 
premedication can help to reduce the severity of infusion reaction but anaphylaxis cannot be 
prevented by premedication. Thus, following supplies and equipment needs to be readily in any 
area where chemotherapy is administered: IV fluids, epinephrine, antihistamines, oxygen, 
aerosolized bronchodilators, intubation and tracheostomy equipment, and a defibrillator. 
Infusion reactions are classified according to NCI CTCAE Grading.  
 
 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  31 | 50 
 
Table 3 
Management of Infusion-Related Reactions/Hypersensitivity Reactions (NCI 
CTCAE Grade) 
Grade 1 
Mild transient reaction; 
infusion interruption NOT 
indicated; intervention NOT 
indicated
 
Monitor subject closely until recovery from symptoms, Consider 
premedication with 50 mg diphenhydramine or 650 mg acetaminophen at 
least 30 minutes before additional study drug administration 
Grade 2 
Cessation of infusion or 
therapy is indicated. 
Responds promptly to 
symptomatic treatment. 
 
Stop infusion; start IV saline infusion; IV 50 mg diphenhydramine or 650
mg acetaminophen; depending on symptoms, consider corticosteroids and 
bronchodilator therapy; remain at bedside and monitor subject until recovery 
from symptoms 
 
Restart infusion at 50% of initial rate: if no further complications ensue after 
30 minutes, the rate may be increased to 100% of the original infusion rate; 
monitor subject closely.  
 
Prophylactic medication indicated for less than or equal to 24 hours 
 
Symptoms recur: stop and discontinue further treatment at that visit; 
administer diphenhydramine 50 mg IV, and remain at bedside and monitor 
the subject until resolution of symptoms. The amount of study drug infused 
must be recorded on the eCRF. 
Grade 3-4  
Prolonged recurrence of 
symptoms,  
hospitalization indicated for 
other clinical sequelae, 
maybe life threatening and 
hospitalization may require. 
Should discontinuation from 
treatment  
 
Stop infusion; start IV saline infusion; recommend bronchodilators, 
epinephrine 0.2 to 1 mg of a 1: 1,000 solution for subcutaneous 
administration or 0.1 to 0.25 mg of a 1: 10,000 solution injected slowly for 
IV 
administration, 
and/or 
diphenhydramine 
50 
mg 
IV 
with 
methylprednisolone 100 mg IV (or equivalent), as needed. 
 
Subject should be monitored until the investigator is comfortable that the 
symptoms will not recur. Investigators should follow their institutional 
guidelines for the treatment of anaphylaxis. In the case of late-occurring 
hypersensitivity symptoms (for example, appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment 
may be given (e.g., oral antihistamine, or corticosteroids). 
 
4.4.2 Extravasation 
In the event of extravasation, infusion should be stopped immediately and the investigator needs 
to be consulted immediately. Treatment of extravasation should follow local standard of care. 
 
4.5 
WARNINGS AND PRECAUTIONS OF BEVACIZUMAB 
GI fistula and intraabdominal abscess formation have been observed to be higher incidence in 
patients receiving Avastin products during metastatic CRC and ovarian cancer. Avastin treated 
cervical cancer patients also had higher incidence of gastrointestinal-vaginal fistulas, who may 
also develop bowel obstruction and require surgical intervention.  

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  32 | 50 
 
Most Common non-GI fistulas associated with Avastin were tracheoesophageal, bronchopleural, 
biliary, vaginal, renal and bladder fistulas occurring within the 6 months of Avastin treatment. 
Avastin impairs the wound healing in animal models, thus administration of Avastin should be 
avoided at least 28 days before and after surgery. 
Arterial and venous thromboembolic effects were also associated with Avastin use. Avastin 
should not be administered to subjects with a >Grade 3 arteria and venous thromboembolic 
(ATE/VTE). 
Avastin also increases ovarian failure incidence is premenopausal females.  
Additionally, Avastin can also affect following system organ class (SOC): cardiovascular 
(hypertension/hypotension, venous thromboembolism, peripheral edema, arterial thrombosis), 
CNS (headaches, fatigue, dizziness, peripheral sensory neuropathy, anxiety, myasthenia gravis), 
endocrine and metabolic (ovarian failure, hyperglycemia, hypomagnesemia, weight loss, 
hyponatremia, hypocalcemia, hypoalbuminemia), dermatologic (exfoliative dermatitis, 
xeroderma, alopecia) 
(Refer to Avastin label for details about warnings and precautions) 
 
4.6 
CONTRAINDICATIONS 
Hypersensitivity to bevacizumab, any component of the formulation, Chinese hamster ovary cell 
products or other recombinant human or humanized antibodies. 
 
4.7 
PROTOCOL THERAPY AND OFF STUDY CRITERIA  
Participation in this research study is completely voluntary. Subjects are free to withdraw from 
this study at any time by informing the PI or one of the co-investigators.  If a subject, for 
whatever reason, no longer meets the inclusion or exclusion criteria, they will be notified and 
withdrawn from the study.  Furthermore, if the volunteer is noncompliant they will be withdrawn 
from the study and another matched volunteer will be recruited to take their place.    
Additionally, prior to removal from study, effort must be made to have all subjects complete at 
least 1 outpatient visit that involves safety labs. 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  33 | 50 
 
 
4.7.1 Criteria for removal from protocol therapy: 
 Completion of protocol therapy 
 Participant requests to be withdrawn from the study 
 Investigator discretion 
 Lost to follow-up or noncompliance 
 AEs or safety concerns by Investigator or Sponsor 
 
4.7.2 Off Study Criteria 
Once a subject is taken off study, no further data can be collected.   
 Completed study D85-oupatient visit 
 Participant requests to be withdrawn from study 
 Subject during outpatient visit period 
 Death or serious side effects 
 Screen failure 
 
4.7.3 Subject Replacement 
Subjects who do not receive the full dose of study drug, or who withdraw from the study or with 
significant protocol violations may be replaced at the discretion of the investigator after 
informing the Sponsor.  
 
4.8 
STUDY CLOSURE 
The investigator may terminate the study at any time in the interest of subject welfare. The 
sponsor may terminate the study prematurely at any time. Reasons for the closure of an 
investigational site or termination of a study may include:  
 
The Investigator fails to comply with the protocol or ICH/GCP guidelines  
 
Safety concerns  
 
Inadequate recruitment of subjects by the investigator  
 
Completion of the study 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  34 | 50 
 
If the clinical study is prematurely terminated or suspended, the sponsor or CRO representative 
will inform the investigator and the regulatory authorities of the termination/ suspension and the 
reasons for the termination/suspension as appropriate. The investigator should promptly notify 
the IEC/IRB of the termination or suspension and provide reasons. The sponsor reserves the right 
to close the investigational site or terminate the study in its entirety at any time, for reasonable 
cause.  
Premature termination of the study by either PI or sponsor will be governed under the terms of 
the contract between both parties. 
 
 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  35 | 50 
 
5 
STUDY ASSESTMENTS AND EVALUATIONS 
5.1 
BLOOD SAMPLES FOR PK EVALUATIONS 
Blood samples will be collected from all subjects to determine the serum concentration of 
TRS003/China-approved bevacizumab and US- licensed Avastin using a validated immunoassay 
for PK analyses. PK samples will be collected at multiple timepoints throughout the study (Refer 
to Table 1).  
Approximately 6 ml blood will be collected at each of the following time points. Serum will be 
separated and stored for bioanalysis of TRS003//China-approved bevacizumab and US-licensed 
Avastin concentration with a validated assay.  
 
5.2 
BLOOD SAMPLES FOR IMMUNOGENICITY EVALUATIONS  
Immunogenicity samples will be collected at multiple timepoints throughout the study after the 
end of infusion (Refer to Table 1). If a sample is positive in the screening assay, a confirmatory 
assay will be conducted. If a confirmatory assay is positive, the titer and the neutralization 
activity will be tested.  
Teruisi is conducting the assay validation for PK and anti-drug antibody (ADA) assays according 
 
Approximately 8 ml blood will be collected and serum will be separated and stored for bioanalysis 
of anti-TRS003 antibodies with validated assays. The incidence of antibodies against TRS003 will 
be summarized for all subjects who received investigational drug.  
 
5.3 
SAFETY ASSESSMENTS 
Safety will be assessed by periodic physical examination findings, vital signs, clinical laboratory 
tests, 12-lead ECGs, and AEs (Refer to Table 1).  All AEs will be listed and summarized using 
descriptive methodology. The incidence of AEs for each treatment will be presented by severity 
and association with the study drug. Clinical laboratory parameters, vital signs, and ECG 
parameters will be listed and summarized using descriptive statistics. The number and 
percentage of subjects testing positive for ADAs will be summarized by treatment and time 
point. 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  36 | 50 
 
 
5.4 
CONFLICT OF INTEREST 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial. 
 
 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  37 | 50 
 
6 
DATA COLLECTION AND MANAGEMENT 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
Hardcopies of the study visit worksheets will be used as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case 
report form (eCRF) derived from source documents should be consistent with the data recorded 
on the source documents. All source documents should be completed in a legible manner to 
ensure accurate interpretation of data.   
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into EDC system, a 21 CFR Part 11-
compliant data capture system. The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source documents. 
Only individuals who have received training on the EDC are allowed to make eCRF entries, 
corrections, and alterations. Training must be documented and a log of all EDC users and their 
rights within the system must be maintained. The data management team will raise queries in the 
EDC system to resolve discrepancies. The Investigator must verify that all data entries in the 
eCRFs are accurate and correct. 
Any outstanding entries must be completed immediately upon notice. No blank sections should 
be left on CRF and explanations has to be recorded for all missing data. All source documents 
should be retained. All essential documents should only contain subject coded identifiers and no 
personal identifying information should be transmitted. 
 
6.1 
STUDY RECORD RETENTIONS 
After completion of the study and when all collected data are validated, the database will be 
locked, pursuant to the prior approval by the Sponsor (or its designee). Final data will be 
extracted from the EDC system and delivered in the form of SAS® datasets. A Portable 
Document Format (PDF) copy of the eCRF will be produced for each study subject and included 
in the final delivery.  

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  38 | 50 
 
All data obtained during the conduct of the protocol will be kept in secure network drives or in 
approved alternative sites that comply with sponsors/CROs security standards. Each Subject will 
have identifiers that will be kept at the study sites.  
If clinical site/sponsor becomes aware of loss or destruction of data due to a major breach 
occurrence that has jeopardized subject confidentiality and trial data, the IRB will be notified.  
Study 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 until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be 
destroyed without the written consent of the sponsor, if applicable. It is the responsibility of the 
sponsor to inform the investigator when these documents no longer need to be retained.  
 
6.2 
PROTOCOL DEVIATIONS 
A protocol deviation is any noncompliance with the clinical trial protocol, study manuals, or ICH 
GCP requirements. The noncompliance may be either on the part of the participant, the investigator, 
or the study site staff. As a result of deviations, corrective actions are to be developed by the site 
and implemented promptly.  
These practices are consistent with ICH GCP:  
 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
 
5.1 Quality Assurance and Quality Control, section 5.1.1  
 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 5 working days of identification of the protocol deviation, or within 5 working 
days of the scheduled protocol-required activity.  All deviations must be addressed in study 
source documents and if applicable, in eCRFs and study reports, in coordination with the sponsor 
or their designated CRO.  Protocol deviations must be sent to the reviewing IRB per their 
policies. The site investigator is responsible for knowing and adhering to the requirements of the 
reviewing IRB. 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  39 | 50 
 
6.3 
PUBLICATION AND DATA SHARING 
Both the use of data and the publication policy are detailed within the clinical study agreement.  
Intellectual property rights (and related matters) generated by the Investigator and others 
performing the clinical study will be subject to the terms of a clinical study agreement that will be 
agreed between the Institution and the Sponsor or their designee.   
 
 
 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  40 | 50 
 
7 
HUMAN SUBJECT PROTECTION AND REGULATORY OVERSIGHT 
7.1 
INFORMED CONSENT PROCESSES AND DOCUMENTATION 
In obtaining and documenting informed consent, the investigator must comply with applicable 
regulatory requirements (e.g., 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56) and should 
written approval for the protocol and the written ICFs and any other written information to be 
provided to the participants. Participants will be asked to read and review IRB-approved ICFs 
and other written information.  ICF should include detailed description of study procedures, risk 
an 
Subject Protection Services.  Additionally, investigator will explain the research study to the 
arise. Investigator should explain their rights as research participants, study procedures, risk and 
benefits, anticipated adverse effects.  Participants will have the opportunity to carefully review 
the written consent form and ask questions prior to signing. ICF should be signed prior to any 
interventions for the study. Participants must be informed that participation is voluntary and that 
they may withdraw from the study at any time, without prejudice. Participant will be given a 
copy of the signed consent form and the original consent form will be kept as a permanent 
record.  
 
7.2 
CONFIDENTIALITY AND PRIVACY 
led and a number is used as the identifier instead of the 
subject
co-investigators will have the list of study subject  
names as they correlate with the study number.  Only some of the research staff involved with 
the study will have access to data. This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor 
 
 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  41 | 50 
 
8 
SAFETY REPORTING 
8.1 
DEFINITIONS 
An adverse (AE) event is defined as any reaction, side effect, or untoward event that occurs 
during the course of the clinical trial whether or not the event is considered related to the 
treatment or clinically significant.  
For this clinical trial, AEs will include any events reported by the subject, any new medical 
conditions, symptoms, any new abnormal findings on physical examination or laboratory 
evaluation. Additionally, any worsening of a pre-existing condition or abnormality will also be 
considered as an AE. 
All AEs must be recorded on eCRF. All AEs must be followed return to baseline or stabilizes. 
Serious adverse events (SAE): 
A serious adverse event is defined as any adverse experience that meets any of the following 
criteria:  
 
Results in death;  
 
Is life-threatening  
 
Requires hospitalization or prolongation of existing hospitalization. Additionally, 
complications occurring during hospitalization are also considered AEs.  
 
Results in persistent or significant disability or incapacity (This definition is not intended 
to include experiences of relatively minor medical significance such as uncomplicated headache, 
nausea, vomiting, diarrhea, influenza, or accidental trauma (e.g., sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial disruption.);  
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  
Adverse Reaction  
Any AE caused by a drug. 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  42 | 50 
 
8.2 
CAUSALITY OF AES 
Causality assessment has become a common routine procedure in pharmacovigilance. Causality 
assessments can decrease disagreement between assessors, classify relationship likelihood and 
improvement of scientific evaluation. 
 
Limitations of causality assessment are following:  
 
It can NOT assess accurate quantitative measurement of relationship likelihood 
 
It can NOT distinguish valid from invalid cases 
 
It can NOT prove the connection between drug and event 
 
It can NOT quantify the contribution of a drug to the development of an adverse event 
All adverse events (AEs) must have their relationship to study intervention assessed by the 
clinician who examines and evaluates the participant based on temporal relationship and his/her 
clinical judgment. The degree of certainty about causality will be graded using the 2 categories 
below. In a clinical trial, the study product must always be suspect. 
Related:  The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
Not Related:  There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
Protocol Deviation  
Any change, divergence, or departure from the IRB-approved research protocol.   
Non-compliance 
The failure to comply with applicable Human Research Protections Program policies, IRB 
requirements, or regulatory requirements for the protection of human research subjects. 
Unanticipated Problem 
Any incident, experience, or outcome that: 
 
Is unexpected in terms of nature, severity, or frequency in relation to  

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  43 | 50 
 
(a) the research risks that are described in the IRB-approved research protocol and informed 
 
(b) the characteristics of the subject population being studied; AND 
 
Is related or possibly related to participation in the research; AND 
 
Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.3 
CATEGORIZATION OF AES 
All AEs and clinically significant laboratory abnormalities will be graded according to Common 
Terminology Criteria for AEs, Version 4.03 dated 14 June 2010. For any term that is not 
specifically listed on the CTCAE scale, intensity will be assigned a grade of 1 through 5 using 
the following CTCAE guidelines: 
Grade 1: Mild; asymptomatic or mild symptoms, clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting age- 
appropriate instrumental activities of daily living. 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE. 
 
8.4 
REPORTING OF SAES AND SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS 
(SUSARS) 
Any SAE, including death resulting from any cause, which occurs to any subject participating in 
this study must be reported by investigator to the sponsor within 24 hours (and IRB as required) 
of first becoming aware of the SAE. The study sponsor will be responsible for notifying the FDA 
of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in 
no case later than 7 calendar days after the sponsor's initial receipt of the information.  In 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  44 | 50 
 
addition, the sponsor must notify FDA and all participating investigators in an IND safety report 
of potential serious risks, from clinical trials or any other source, as soon as possible, but in no 
case later than 15 calendar days after the sponsor determines that the information qualifies for 
reporting 
SAEs will be collected by the investigator from day 1 through 85 days after the last dose of study 
medication.  SAEs that occur within 85 days following the drug administration, must also be 
reported within the same timeframe. Any SAE that is judged by the investigator to be related to 
the study medication must be reported regardless of the amount of time since the drug 
administration. Follow-up information collected for any initial report of an SAE must also be 
reported to the sponsor (or its designee) within 24 hours of receipt by the investigator. All SAEs 
will be followed until resolution, stabilization of condition, or until follow-up is no longer 
possible. To fully understand the nature of any SAE, obtaining follow-up information is 
important. Whenever possible, relevant medical records such as discharge summaries, medical 
consultations, and clinical laboratory reports should be obtained.  
 
8.5 
IRB REPORTING  
The investigators will report to the IRB the following according to the requirements of reviewing 
IRB: 
 
All SAEs  
 
Non-compliance to GCP or protocol deviations as required by IRB 
IND Safety Reports and any unexpected incidences or problems during the trial may be also 
reportable to the IRB as per IRB requirement. 
 
8.6 
QUALITY ASSURANCE AND QUALITY CONTROL 
Quality control (QC) procedures will be implemented to assure that any missing data will be 
communicated with sites for clarification and resolution.  

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  45 | 50 
 
Standard Operating Procedures (SOPs) should be available to monitors. Monitors will verify that 
all the clinical trial procedures are conducted, documented and reported in compliance with the 
protocol, ICH, GCP, GLP, GMP and other applicable regulatory requirements.  
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities. 
 
8.7 
CLINICAL MONITORING PLAN  
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
ICH GCP, and with applicable regulatory requirement(s).  
Details of clinical site monitoring will be documented in a separate Study Monitoring Plan 
(SMP). The SMP describes in detail who will conduct the monitoring, at what frequency 
monitoring will be done, at what level of detail monitoring will be performed, and the 
distribution of monitoring reports. In general monitoring visits would include pre-study visits (to 
qualify the site and investigators), study initiation visit, interim visits at appropriate frequency 
based on recruitment speed and need to clean data for dose-escalation decisions, and study 
closeout visits after database lock.  
Independent audits may be conducted by the sponsor to ensure monitoring practices are 
performed consistently across all participating sites and that monitors are following the SMP. 
Monitors are qualified by training and experience to monitor the progress of clinical trials. 
Personnel monitoring this study will not be affiliated in any way with the trial conduct 
A monitor(s)/sponsor representative(s) will meet with the investigator and his/her staff prior to 
the entrance of the first subject to review study procedures and methods of recording study data. 
After enrollment of the first subject, a monitor(s)/sponsor representative(s) will be assigned to 
periodically monitor each investigator site for study progress and to verify that standards of 
Good Clinical Practice (GCP) and/or ICH guidelines were followed.  

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  46 | 50 
 
The investigator is expected to prepare for the monitor visit, ensuring that all source documents, 
completed CRFs, signed consent forms and other study related documents are readily available 
for review.  
As a sponsor for clinical trials, FDA regulations require the Investigators to facilitate monitoring 
process. Monitors will evaluate adherence to the protocol, regulations, SOPs, human subject 
protection, study data, specifically data that could affect the interpretation of primary study 
endpoints. This is done through independent verification of study data with source 
documentation focusing on: 
 
Informed consent process 
 
Eligibility confirmation 
 
Drug administration and accountability 
 
Adverse events monitoring 
 
Response assessment. 
 
 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  47 | 50 
 
9 
STATISTICAL CONSIDERATIONS 
9.1 
GENERAL STATISTICAL CONSIDERATIONS 
Descriptive statistics will be utilized for all safety, efficacy, immunogenicity, and 
pharmacokinetic parameters. Data will be summarized using descriptive statistics (number of 
subjects, mean, median, standard deviation, minimum, and maximum) for continuous variables 
and using frequencies and percentages for discrete variables. All data collected will be presented 
in subject listings.  
 
9.2 
PHARMACOKINETIC ANALYSIS 
Serum drug concentration-time data will be analyzed by standard non-compartmental methods. 
The PK parameters will include maximum drug concentration (Cmax) and AUClast, clearance 
(CL), terminal half-life (t1/2), and volume distribution at steady state (Vss). Descriptive statistics 
of PK parameters (geometric mean, CV%, arithmetic mean, median, SD, minimum and 
maximum) will be provided.  
The primary assessment of 3-way PK similarity (3 pairwise comparison) will be based upon a 
90% confidence interval (CI) for the ratio of the geometric means (TRS003 versus China-
approved bevacizumab, TRS003 versus US-licensed Avastin, and US-licensed Avastin versus 
China-approved bevacizumab) for AUC0-inf on the PK analysis set. If the 90% CI of the ratio of 
the geometric means for AUC0-inf is within the range of 80-125%, then PK similarity will be 
concluded. If there are multiple study sites, the significance of clinical sites will also be tested 
and may be included into the final statistical model.  
Secondary PK parameters such as but not limited to Cmax, AUClast will be analyzed using the 
same statistical approach. A nonparametric approach, for example, Wilcoxon signed-rank test, 
will be taken to evaluate parameters such as t1/2. Exploratory analyses may be performed for 
other PK parameters as deemed appropriate. 
 
9.3 
IMMUNOGENICITY ANALYSIS 
All samples will first be analyzed for ADAs in a screening assay. Study samples with results 
below the screening cut-off will be reported as negative for ADAs. In the event of a positive 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  48 | 50 
 
result in the screening assay, samples will be analyzed in the confirmatory assay. The incidence 
of ADA will be summarized for all subjects who received at least one administration of 
investigational drugs. Impact of ADAs on PK and safety of investigational drug will be 
evaluated, if applicable.    
 
9.4 
DETERMINATION OF SAMPLE SIZE
Assuming a CV of 20% (Knight et al., 2016) in male healthy subjects and 1.05 for the geometric 
mean ratio  of AUC0-inf, the study with 29 evaluable subjects per arm will have 95% power to 
demonstrate the PK similarity between TRS003/China approved bevacizumab and US-licensed 
Avastin (90% CI of geometric mean ratio within 80-125%). Assuming a 15% drop out rate 
(including non-evaluable subjects) and a 95% power, approximately 114 subjects (38 per arm) 
will be randomized in 1:1:1 ratio. 
Note: 80%, 85%, 90%, and 95% power corresponding to a sample size of 18/arm, 20/arm, 
23/arm, and 29/arm, respectively. 
 
9.5 
POPULATION ANALYSIS 
9.5.1 Safety Population Analysis 
Safety population consists of all subjects who received the investigational product.  
 
9.5.2 PK Population Analysis 
PK population consists of all subjects who have evaluable concentration-time data.  
 
9.6 
SAFETY ANALYSIS 
Any subject receiving investigational drug will be included in the summaries and listings of 
safety data. Safety and tolerability profile will be characterized by following criteria: 
 Relationship of study therapy and laboratory abnormalities. 
Adverse events will be classified using the MedDRA classification system. The severity of the 
toxicities will be graded according to the NCI CTCAE version 4.03. 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  49 | 50 
 
Safety will be assessed by periodic physical examination findings, vital signs, clinical laboratory 
tests, 12-lead ECGs, and AEs (Refer to Table 1).  All AEs will be listed and summarized using 
descriptive methodology. The incidence of AEs for each treatment will be presented by severity 
and association with the study drugs. Clinical laboratory parameters, vital signs, and ECG 
parameters will be listed and summarized using descriptive statistics. The number and 
percentage of subjects testing positive for ADAs will be summarized by treatment and time 
point. 
9.7 
TABULATION OF INDIVIDUAL PARTICIPATION DATA 
Data tabulations will summarize the following subject numbers: 
 
Enrolled 
 
Investigational drug treatment dose received 
 
Evaluable for safety  
 
Protocol violations 
 
Protocol completions 
 
Withdraw from study due to: 
 
Withdrew consent 
 
Lost to Follow-up 
 
 

    
Sponsor:    Zhejiang Teruisi Pharmaceutical Inc.  
 
 
 Protocol Number: TRS00301001 
 
 
 
 
 
 
 
                                     
 
Version 1.0 
 
P a g e  50 | 50 
 
10 REFERENCES  
1. Ferrara, N. (2004). Vascular endothelial growth factor: basic science and clinical 
progress. Endocrine reviews, 25(4), 581-611. 
2. Genentech Inc (2015) Avastin® (bevacizumab) prescribing information. 
http://www.gene.com/download/pdf/avastin_prescribing.pdf. Accessed 20 May 2015 
3. Hanahan D1, Christofori G, Naik P, Arbeit J. Transgenic mouse models of tumour 
angiogenesis: the angiogenic switch, its molecular controls, and prospects for preclinical 
therapeutic models. Eur J Cancer. 1996 Dec;32A(14):2386-93. 
4. Hanahan D1, Folkman J. Patterns and emerging mechanisms of the angiogenic switch 
during tumorigenesis. Cell. 1996 Aug 9;86(3):353-64. 
5. Knight B, Rassam D, Liao S, Ewesuedo R. A phase I pharmacokinetics study 
comparing PF-06439535 (a potential biosimilar) with bevacizumab in healthy male 
volunteers. Cancer Chemother Pharmacol. 2016 Apr;77(4):839-46. doi: 
10.1007/s00280-016-3001-2.  
6. Menakuru SR1, Brown NJ, Staton CA, Reed MW. Angiogenesis in pre-malignant 
conditions. Br J Cancer. 2008 Dec 16;99(12):1961-6. doi: 10.1038/sj.bjc.6604733. Epub 
2008 Oct 21. 
7. Zondor, S. D., & Medina, P. J. (2004). Bevacizumab: an angiogenesis inhibitor with 
efficacy in colorectal and other malignancies. Annals of Pharmacotherapy, 38(7-8), 
1258-1264.