A Double-blinded Extension Study to Provide Adjuvant Treatment With Single Agent Herceptin® or TX05 and Assess Continued Safety and Immunogenicity in Subjects With HER2-positive Early Breast Cancer Following Neoadjuvant Treatment and Surgical Resection in Protocol TX05-03
Phase: PHASE3
Conditions: HER2-positive Breast Cancer, Early-stage Breast Cancer, Breast Cancer, Breast Neoplasms, Stage II Breast Cancer, Stage IIIA Breast Cancer
Sponsor: Tanvex BioPharma USA, Inc.

 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
A double-blinded extension study to provide adjuvant treatment with single agent Herceptin® or 
TX05 and assess continued safety and immunogenicity in subjects with HER2-positive early 
breast cancer following neoadjuvant treatment and surgical resection in Protocol TX05-03 
 
NCT04109391 
 
Document Date: 13 December 2018 

 
Tanvex Biologics Corp. 
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13 December 2018 
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1 
TITLE PAGE 
CLINICAL STUDY PROTOCOL 
A double-blinded extension study to provide adjuvant treatment with single agent 
Herceptin® or TX05 and assess continued safety and immunogenicity in subjects with 
HER2-positive early breast cancer following neoadjuvant treatment and surgical 
resection in Protocol TX05-03 
 
 
Protocol No.:  TX05-03E 
IND No.:  116582 
EudraCT No.:  2018‐000236‐97 
Test Product: 
TX05 (Trastuzumab) 
Indication: 
Breast Cancer 
Sponsor: 
Tanvex Biologics Corp. 
Development Phase: 
III 
Sponsor Signatory: 
 
Date of the Protocol: 
13 December 2018 
Version of the Protocol: 
Final 
 
 
The confidential information in this document is provided to you as an investigator, potential 
investigator, or consultant for review by you, your staff and applicable Independent Ethics 
Committee (IEC) and/or Institutional Review Board (IRB).  It is understood that the 
information will not be disclosed to others without written authorization from Tanvex 
Biologics Corp. except to the extent necessary to obtain informed consent from those persons 
to whom the drug may be administered. 
 
 

 
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CLINICAL RESEARCH ORGANIZATION SIGNATURE PAGE 
 
PROTOCOL TITLE:  A double-blinded extension study to provide adjuvant treatment 
with single agent Herceptin® or TX05 and assess continued safety and immunogenicity in 
subjects with HER2-positive early breast cancer following neoadjuvant treatment and 
surgical resection in Protocol TX05-03 
 
PROTOCOL NUMBER:  TX05-03E 
 
 
 
 
 
 
 
 
 
Name and Job Title 
 
 
 
 
 
Date (day/month/year) 
 
 
 
Signature 
 
 

 
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INVESTIGATOR SIGNATURE PAGE 
 
PROTOCOL TITLE:  A double-blinded extension study to provide adjuvant treatment 
with single agent Herceptin® or TX05 and assess continued safety and immunogenicity in 
subjects with HER2-positive early breast cancer following neoadjuvant treatment and 
surgical resection in Protocol TX05-03 
 
PROTOCOL NUMBER:  TX05-03E 
 
I agree to conduct the study outlined above in accordance with the terms and conditions of the 
protocol, International Council for Harmonization (ICH) guidelines on Good Clinical Practice 
(GCP) and with applicable regulatory requirements.  All information pertaining to the study 
shall be treated in a confidential manner. 
 
 
 
 
 
 
 
Name and Job Title 
 
 
 
 
 
Date (day/month/year) 
Signature 
 
 
 

 
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13 December 2018 
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3 
GENERAL INFORMATION 
A double-blinded extension study to provide adjuvant treatment with single agent 
Herceptin® or TX05 and assess continued safety and immunogenicity in subjects with 
HER2-positive early breast cancer following neoadjuvant treatment and surgical 
resection in Protocol TX05-03 
Protocol No.: 
TX05-03E 
Date of the Protocol: 
13 December 2018 
Date and Number of Amendment(s): 
1 
Sponsor: 
Tanvex Biologics Corp. 
 
33F, No. 99, Sec 1 
 
Xintai 5th Street 
 
Xizhi District 
 
New Taipei City 221 
 
Taiwan 
Clinical Research Organization: 
 
 
 
 
 
 
 
Sponsor Signatory: 
 
 
 
 
 
 
 
 
 
 

 
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4 
STUDY SYNOPSIS 
Name of Sponsor/Company: 
Tanvex Biologics Corp. 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
TX05 
Name of Active Ingredient: 
Trastuzumab 
Title of Study: 
A double-blinded extension study to provide adjuvant treatment with single agent Herceptin® or TX05 and 
assess continued safety and immunogenicity in subjects with HER2-positive early breast cancer following 
neoadjuvant treatment and surgical resection in Protocol TX05-03 
Study Center(s): 
This study will only recruit subjects from clinical sites that participated in Study TX05-03. 
Publication(s): 
None. 
Planned Study Period: 
October 2018 to June 2020 
Development Phase: 
Phase III 
Objectives: 
• 
To collect safety, tolerability, and immunogenicity data for single agent Herceptin or TX05 in the adjuvant 
setting in subjects with early human epidermal growth factor receptor (HER2)-positive breast cancer who 
completed neoadjuvant treatment and primary resection in Protocol TX05-03. 
• 
To collect safety, tolerability, and immunogenicity data following a single transition from neoadjuvant 
Herceptin to adjuvant TX05 in this population. 
• 
To collect disease-free survival (DFS) and overall survival (OS) data in this population. 
Methodology: 
This is an extension study for subjects who were treated in the prior TX05/Herceptin neoadjuvant study 
(Protocol TX05-03) and successfully underwent surgical resection.  Eligible subjects will receive adjuvant 
treatment with single agent Herceptin or TX05 for up to 13 treatment cycles.  The study will consist of a 
Screening period (Days -14 to 0) at least 4 weeks post-surgery to confirm eligibility to continue Herceptin or 
TX05 treatment, and an adjuvant treatment period (Week 0 [Day 1] to Week 36).  All subjects completing the 
study will attend the End of Study (EOS) Visit at Week 45 (± 7 days).  Those discontinuing the study at any 
time will attend an Early Termination (ET) Visit 9 weeks (± 7 days) after the last administration of study drug. 
Subjects fulfilling the eligibility criteria for this extension study will receive intravenous (IV) Herceptin or 
TX05 (8 mg/kg loading dose then 6 mg/kg) every 3 weeks for 13 cycles, as follows: (1) subjects originally 
assigned to TX05 in the neoadjuvant study will receive TX05; and (2) subjects originally assigned to Herceptin 
in the neoadjuvant study will be randomized (1:1) to receive either Herceptin or TX05. 
Subjects will attend study visits every 3 weeks until Week 36 (± 3 days).  Study procedures include physical 
examination, vital signs, weight, Eastern Cooperative Oncology Group performance status, clinical laboratory 
tests, recording of adverse events (AEs), and concomitant medication. 
Clinical assessments will be performed before administration of study drug.  Clinical laboratory tests will be 
performed at Screening, Week 0, and then at every other study visit until the EOS/ET Visit.  Tumor assessments 
will be performed at Screening and EOS/ET Visit by means of a computed tomography (CT) scan or magnetic 
resonance imaging (only if CT scan cannot be performed) of the chest, abdomen, and pelvis.  
Cardiac safety will be assessed at Screening and Cycle 6 (Week 15) prior to administration of study drug and 
at the EOS/ET Visit using 12-lead electrocardiogram (ECG) and echocardiography or multi-gated acquisition 
scan to evaluate the left ventricular ejection fraction (LVEF). 
Samples for the evaluation of anti-drug antibodies (ADA), including neutralizing antibodies (Nab) will be 
obtained before the administration of Cycle 1 (Week 0) and Cycle 6 (Week 15), and at the EOS/ET Visit. 

 
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Name of Sponsor/Company: 
Tanvex Biologics Corp. 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
TX05 
Name of Active Ingredient: 
Trastuzumab 
Once subjects complete adjuvant treatment with single agent Herceptin or TX05 they may move on to other 
therapies as recommended by their treating physician.  Subjects who prematurely discontinue adjuvant 
treatment with single agent Herceptin or TX05 may move on to other therapies as recommended by their 
treating physician, even if they consent to remain in the study. 
Number of Subjects: 
It is estimated that a minimum of 330 subjects will be enrolled into the double-blind extension study. This 
estimate is based on 740 subjects completing the neoadjuvant study and approximately 45% of these being 
eligible to continue treatment in this extension study. 
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria 
Subjects eligible for enrollment in the study must meet all of the following criteria: 
1. Signed written informed consent. 
2. Females ≥ 18 years of age. 
3. Completed neoadjuvant treatment (regardless of treatment arm) in the TX05/ Herceptin neoadjuvant study 
and the investigator believes the subject requires continued access to single agent trastuzumab in order to 
continue deriving clinical benefit. 
4. Successfully undergone surgical resection of their primary tumor with no evidence of residual disease (as 
determined by local assessment) and no other adjuvant therapy, other than trastuzumab, is planned.  
However, subjects will be allowed to receive hormonal therapy if they have hormone receptor positive 
tumors.  Subjects will also be allowed to receive adjuvant radiation therapy, if required by their treating 
physician. 
5. Able to comply with the study protocol. 
6. Female subjects of childbearing potential must have a negative serum pregnancy test within 14 days of 
first administration of study drug and agree to use effective contraception (hormonal contraceptive, 
intrauterine device, diaphragm with spermicide, or condom with spermicide) throughout the study period 
and for 7 months after last administration of study drug. 
Exclusion Criteria 
Subjects meeting any of the following criteria must not be enrolled in the study: 
1. Breast cancer metastases or residual disease post operatively (as determined by local assessment). 
2. History or presence of a medical condition or disease that in the investigator's opinion would place the 
subject at an unacceptable risk for study participation. 
3. Lactating or pregnant female. 
4. Women of childbearing potential who do not consent to use highly effective methods of birth control (e.g. 
true abstinence [periodic abstinence {e.g. calendar ovulation, symptothermal, post-ovulation methods} 
and withdrawal are not acceptable methods of contraception], sterilization, or other non-hormonal forms 
of contraception) during treatment and for at least 7 months after the last administration of study 
drug.  Subjects must agree to not breast-feed while receiving study drug. 
5. Any condition that in the opinion of the Investigator represents an obstacle for study conduct and/or 
represents a potential unacceptable risk for subjects. 
Test Product, Dose, and Mode of Administration: 
IV TX05 8 mg/kg loading dose then 6 mg/kg every 3 weeks for 13 cycles. 
Reference Therapy, Dose, and Duration of Administration: 
IV Herceptin 8 mg/kg loading dose then 6 mg/kg every 3 weeks for 13 cycles.  

 
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13 December 2018 
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Name of Sponsor/Company: 
Tanvex Biologics Corp. 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
TX05 
Name of Active Ingredient: 
Trastuzumab 
Duration of Treatment: 
The study will consist of a Screening period (Days -14 to 0) and a double-blinded adjuvant treatment period 
(Week 0 [Day 1] to Week 36) and an EOS/ET Visit 9 weeks (± 7 days) after the last administration of study 
drug. 
Criteria for Evaluation: 
Safety Assessments: 
• 
Treatment-emergent AEs and serious AEs. 
• 
Death. 
• 
Clinical laboratory parameters. 
• 
Vital signs. 
• 
12-Lead ECG. 
• 
LVEF. 
• 
Physical examination. 
Immunogenicity Endpoints: 
• 
Incidence of ADA. 
• 
Incidence of Nab.  
Efficacy Endpoints: 
• 
DFS, defined as the time from randomization in the neoadjuvant study (Protocol TX05-03) to the 
documentation of a first failure, where a failure is the recurrence of breast cancer or a diagnosis of a second 
primary cancer. 
• 
OS, defined as the time from randomization in the neoadjuvant study (Protocol TX05-03) until death from 
any cause. 
Statistical Methods: 
In general, continuous variables will be summarized using the following standard descriptive summary 
statistics: number of observations, arithmetic mean, standard deviation, minimum, median, and maximum.  
Categorical variables will be displayed by means of frequency tables including percentages. 
The safety population will include all subjects who are randomized into this extension study and have received 
at least one dose of study drug.  The safety population will be used for all analyses. 
The time to event endpoints (DFS and OS) will be summarized using Kaplan-Meier survival curves.  The 
Kaplan-Meier survival estimates, together with the number of subjects, percentage of subjects to experience 
the event, and the number and percentage of subjects censored will be summarized in a table by treatment 
group. 
No interim analysis is planned. 
 

 
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5 
TABLE OF CONTENTS 
1 
TITLE PAGE ......................................................................................................... 1 
2 
SIGNATURE PAGES ........................................................................................... 2 
3 
GENERAL INFORMATION ................................................................................ 5 
4 
STUDY SYNOPSIS .............................................................................................. 6 
5 
TABLE OF CONTENTS ...................................................................................... 9 
5.1 
List of Tables .......................................................................................... 12 
5.2 
List of Figures ........................................................................................ 12 
5.3 
List of Appendices and Supplements ..................................................... 12 
6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................ 13 
7 
INTRODUCTION ............................................................................................... 15 
7.1 
Background ............................................................................................ 15 
7.2 
Nonclinical Studies ................................................................................. 16 
7.2.1 
Nonclinical Pharmacology ................................................................. 16 
7.2.2 
Pharmacokinetics ............................................................................... 16 
7.2.3 
Toxicology ......................................................................................... 17 
7.2.4 
Summary and Nonclinical Safety Assessment .................................. 17 
7.3 
Clinical Studies ....................................................................................... 18 
7.3.1 
Pharmacokinetics ............................................................................... 18 
7.3.2 
Safety ................................................................................................. 19 
7.4 
Rationale ................................................................................................. 19 
8 
STUDY OBJECTIVES ....................................................................................... 21 
9 
INVESTIGATIONAL PLAN .............................................................................. 22 
9.1 
Overall Study Design and Plan............................................................... 22 
9.1.1 
Schedule of Assessments ................................................................... 23 
9.1.2 
Study Assessments ............................................................................. 28 
9.1.2.1 
Screening Period -14 days .................................................. 28 
9.1.2.2 
Treatment Period: TX05/Herceptin: Cycle 1 (Week 0) to 
Cycle 13 (Week 36) ............................................................ 28 
9.1.2.3 
End of Study Visit (Week 45)/Early Termination Visit ..... 29 
9.2 
Discussion of Study Design ................................................................... 29 
9.2.1 
Risk/Benefit and Ethical Assessment ................................................ 30 
9.3 
Selection of Study Population ................................................................ 30 
9.3.1 
Inclusion Criteria ............................................................................... 30 
9.3.2 
Exclusion Criteria .............................................................................. 31 
9.3.3 
Withdrawal of Subjects ...................................................................... 31 
9.3.4 
Lost to Follow-Up .............................................................................. 32 
9.3.5 
Early Termination .............................................................................. 33 

 
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9.3.6 
Missed Dose ....................................................................................... 33 
10 
TREATMENT OF SUBJECTS ........................................................................... 34 
10.1 
Identity of Study Treatment(s) ............................................................... 34 
10.1.1 
Administration of Study Treatment(s) ............................................... 34 
10.2 
Treatment Regimen Adjustments ........................................................... 34 
10.3 
Study Treatment Packaging and Labeling .............................................. 34 
10.3.1 
Storage ............................................................................................... 34 
10.4 
Blinding and Randomization of Study Treatment(s).............................. 34 
10.4.1 
Procedure for Breaking the Randomization Code ............................. 35 
10.5 
Subject Compliance ................................................................................ 35 
10.6 
Study Treatment Accountability ............................................................ 35 
10.7 
Concomitant Therapy ............................................................................. 36 
11 
ASSESSMENTS ................................................................................................. 37 
11.1 
Endpoints ................................................................................................ 37 
11.1.1 
Safety Endpoints: ............................................................................... 37 
11.1.2 
Immunogenicity Endpoints: ............................................................... 37 
11.1.3 
Efficacy Endpoints ............................................................................. 37 
11.2 
Tumor Assessment ................................................................................. 37 
11.3 
Echocardiogram/MUGA ........................................................................ 38 
11.4 
Laboratory Assessments ......................................................................... 38 
11.5 
Electrocardiogram Assessments ............................................................. 38 
11.6 
Physical Examination ............................................................................. 39 
11.7 
Vital Signs .............................................................................................. 39 
11.8 
Immunogenicity Sampling ..................................................................... 39 
12 
SAFETY MONITORING AND REPORTING .................................................. 40 
12.1 
Adverse Events ....................................................................................... 40 
12.1.1 
Definitions ......................................................................................... 40 
12.1.1.1 Recording of Adverse Events ............................................. 40 
12.1.2 
Abnormal Laboratory Values/Vital Signs/Electrocardiograms ......... 42 
12.1.3 
Deaths ................................................................................................ 43 
12.1.4 
Overdose ............................................................................................ 43 
12.1.5 
Pregnancy .......................................................................................... 43 
12.1.6 
Reporting of Serious Adverse Events ................................................ 43 
13 
STATISTICAL EVALUATION ......................................................................... 45 
13.1 
Sample Size and Power .......................................................................... 45 
13.2 
Analysis Populations .............................................................................. 45 
13.2.1 
Safety Population ............................................................................... 45 
13.3 
Statistical Methods ................................................................................. 45 
13.3.1 
General Principles .............................................................................. 45 

 
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13.3.2 
Missing Data ...................................................................................... 45 
13.3.3 
Demographic and Baseline Characteristics ....................................... 46 
13.3.4 
Subject Disposition ............................................................................ 46 
13.3.5 
Safety Analysis .................................................................................. 46 
13.3.6 
Immunogenicity Assessment ............................................................. 47 
13.3.7 
Efficacy Analysis ............................................................................... 47 
13.3.8 
Interim Analysis ................................................................................. 47 
14 
DIRECT ACCESS TO SOURCE DATA/NOTES ............................................. 48 
15 
QUALITY CONTROL AND QUALITY ASSURANCE .................................. 49 
15.1 
Conduct of the Study .............................................................................. 49 
15.2 
Study Monitoring ................................................................................... 49 
16 
ETHICS ............................................................................................................... 50 
16.1 
Independent Ethics Committee/Institutional Review Board .................. 50 
16.2 
Written Informed Consent ...................................................................... 50 
17 
DATA HANDLING AND RECORD KEEPING ............................................... 51 
17.1 
Case Report Forms/Source Data Handling............................................. 51 
17.2 
Retention of Essential Documents .......................................................... 51 
18 
FINANCING AND INSURANCE ...................................................................... 52 
19 
PUBLICATION POLICY ................................................................................... 53 
20 
REFERENCE LIST ............................................................................................. 54 
21 
APPENDICES ..................................................................................................... 56 
 

 
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5.1 
List of Tables 
Table 9–1 
Schedule of Assessments ........................................................................... 24 
Table 9–2 
Schedule of Blood Sampling ...................................................................... 27 
Table 11–1 
Hematology and Clinical Chemistry Assessments..................................... 38 
Table 12–1 
Classification of AE Relationship to Investigational Product .................... 42 
 
5.2 
List of Figures 
Figure 9–1 
Study Design Flow Diagram ...................................................................... 23 
 
5.3 
List of Appendices and Supplements 
Appendix 1 
ECOG Performance Status 
Appendix 2 
Dose Modification Guidelines 
 

 
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6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
Anti-drug antibodies 
ADCC 
Antibody-dependent cellular cytotoxicity 
AE 
Adverse event 
AUC0-∞ 
Area under the plasma concentration-time curve 0 to infinity 
AUC0-24 
Area under the plasma concentration-time curve 0 to 24 hours 
AUC0-t 
Area under the plasma concentration-time curve 0 to last measured 
concentration 
CI 
Confidence interval 
Cmax 
Maximum concentration 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DFS 
Disease-free survival 
EBC 
Early breast cancer 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
EOS 
End of Study 
ET 
Early Termination 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HER 
Human epidermal growth factor receptor 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IgG1 
Immunoglobulin G1 
IRB 
Institutional Review Board 
IV 
Intravenous 
IWRS 
Interactive web response system 
LLOQ 
Lower limit of quantitation 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MUGA 
Multi-gated acquisition 
Nab 
Neutralizing antibodies 
OS 
Overall survival 

 
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PK 
Pharmacokinetic 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
Standard of care 
TEAE 
Treatment-emergent adverse event 
TK 
Toxicokinetic 
Tmax 
Time to maximum concentration 
TNFα 
Tumor necrosis factor alpha 
US 
United States 
VEGF 
Vascular endothelial growth factor 

 
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7 
INTRODUCTION 
7.1 
Background 
Human epidermal growth factor receptor (HER2) belongs to a family of growth factor tyrosine 
kinase receptors which include endothelial growth factor receptor, HER1, HER3, and HER4 
receptors1.  By forming hetero-homo-dimers with members of the family, they play a critical 
role in mediating cell growth, differentiation, and survival.  The HER2 (or c-erbB2) proto-
oncogene encodes a transmembrane receptor protein of 185 kDa, which is structurally related 
to HER1.  HER2 protein overexpression is observed in 25%–30% of primary breast cancers.  
In a subset of breast cancers, a high level of HER2 is detected that is 10 to 100 times greater 
than that found in the normal breast epithelium2,3.  Even a moderate overexpression leads to a 
constitutively activated HER2 receptor by associating with itself, thus enhancing its tyrosine 
kinase activities.  Tyrosine kinase activity promotes an increased proliferation rate, resistance 
to tumor necrosis factor alpha (TNFα), decreased expression of adhesion molecules, and 
increased vascular endothelial growth factor (VEGF) secretion3,4. 
Trastuzumab (Herceptin®) is a humanized monoclonal antibody that recognizes an 
extracellular epitope (amino acids 529-627), a region very close to the transmembrane region 
of HER25.  A major mechanism by which trastuzumab exerts its activity is through binding to 
HER2.  Herceptin-bound HER2 will not hetero/homodimerize, which in turn, will 
down-regulate the receptor activity and subsequently lead to the inhibition of the signal 
transduction pathway6.  Trastuzumab has been shown, both in vitro and in animals to inhibit 
the growth of human tumor cells that overexpress HER27,8,9.  In in vitro studies, a treatment of 
trastuzumab reduces cellular resistance to TNFα10, restores adhesion molecules11, and reduces 
VEGF production12.  In addition to the inhibition of receptor-mediated functions, trastuzumab 
has a strong antibody-dependent cellular cytotoxicity (ADCC) against HER2-overexpressing 
cells.  This component of trastuzumab-dependent ADCC is an important factor in the 
specificity of trastuzumab activity since HER2-overexpressing tumor cells would likely be 
preferentially targeted for ADCC rather than tissues with normal levels of HER213,14.  
Herceptin was approved for marketing in the United States (US) by the Food and Drug 
Administration (FDA) in 1998 and in the European Union (EU) in 2000.  A comprehensive 
program of nonclinical pharmacology and toxicology studies were completed to support its 
safe clinical use.  It is indicated for the treatment of HER2-overexpressing breast cancer and 
HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma in the 
FDA label and for HER2 positive metastatic breast cancer, HER2 positive early breast cancer 
(EBC) and HER2 positive metastatic adenocarcinoma of the stomach or gastroesophageal 
junction in the European Medicines Agency (EMA) label.  A series of clinical studies, 
including pharmacokinetic (PK) and safety/efficacy studies support the approved indications, 
including the treatment of HER2-overexpressing breast cancer and the treatment of 
HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.  Study 
results and adverse events (AEs) associated with the use of trastuzumab are described in the 
Herceptin package insert. 

 
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TX05 is being developed as a proposed biosimilar product to the approved trastuzumab 
(Herceptin).  It is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that 
selectively binds to the extracellular domain of HER2 (ErbB2/HER2p185).  TX05 is a highly 
purified protein that contains a 1328 amino acid humanized monoclonal IgG1 antibody.  TX05 
has an identical amino acid sequence and similar physicochemical and in vitro functional 
properties to trastuzumab. 
7.2 
Nonclinical Studies 
7.2.1 
Nonclinical Pharmacology 
The Sponsor has performed a detailed analytical and functional characterization and 
comparison of TX05 and US-licensed Herceptin.  Physicochemical characterization showed 
identical primary sequence, and similar physicochemical characteristics in terms of size, 
charge, glycan profiles, and other parameters.  In vitro biological characterization focused on 
the biological activities that are most relevant to the in vivo function of trastuzumab also 
showed a great degree of similarity between TX05 and Herceptin.  Importantly, recent 
characterization data support that certain manufacturing improvements that were implemented 
after the initial clinical PK study of TX05 have further improved the similarity of TX05 to 
Herceptin with respect to levels of afucosylated glycans and associated biologic activity 
(FcγRIIIA binding and ADCC activity) (Section 7.3.1). 
7.2.2 
Pharmacokinetics 
The PK of TX05 in comparison to US-licensed Herceptin have been evaluated in 
Sprague-Dawley rats and in Cynomolgus monkeys. 
In Sprague-Dawley rats, TX05, Herceptin (25 mg/kg), or vehicle control was administered by 
a single intravenous (IV) bolus injection into the tail vein.  Plasma concentrations of TX05 and 
Herceptin were quantifiable over the 14-day sampling period.  All pre-dose concentrations and 
control sample concentrations were below the lower limit of quantitation ([LLOQ] 
0.100 μg/mL).  As expected for IV bolus dosing, peak TX05 or Herceptin concentrations were 
reached at the first sampling timepoint of 10 minutes for both dose groups.  Concentration 
profiles for both compounds followed a slow decline resulting in an indeterminate terminal 
elimination phase, consequently terminal half-life, volume of distribution, and clearance were 
not reported.  TX05 and Herceptin exposure were similar, with a calculated TX05-to-Herceptin 
ratio of 1.08 for area under the plasma concentration-time curve 0 to 24 hours (AUC0-24).  There 
were no anti-drug antibodies (ADA)-related effects on the overall exposure of TX05 or 
Herceptin in the dosed groups given that all samples from the dosed groups were either 
screened or confirmed negative for ADA. 
In female Cynomolgus monkeys (4 per group), 2 to 5 years of age, TX05 or Herceptin 
(25 mg/kg) was administered by a single IV bolus injection.  PK parameters were generated 
from TX05 and Herceptin individual concentrations in plasma from Day 1.  Plasma 
concentrations of TX05 and Herceptin were quantifiable over the 28-day sampling period.  All 
pre-dose concentrations were below the LLOQ.  Peak concentrations were observed at 

 
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2.5 hours after the start of infusion for TX05 and at 2 hours after the start of infusion for 
Herceptin.  The exposure between TX05 and Herceptin was considered to be similar, and the 
differences in the toxicokinetic (TK) parameters were within the standard deviations 
calculated. 
No distribution studies of TX05 have been performed.  However, in the European summary 
basis of approval for Herceptin, it was noted that the distribution and fate of radiolabeled (125I) 
trastuzumab were compared with those of similarly labeled human IgG1 in tumor-bearing 
beige-nude athymic mice (Herceptin European public assessment report).  Through tissue and 
blood analysis, and whole blood autoradiography, it was shown that the disposition of the 
specific (trastuzumab) and non-specific IgG1 antibodies were similar in blood and non-tumor 
tissues.  However uptake of radioactivity was localized in tumor tissue for 125I-labeled 
trastuzumab and not for IgG1, and was shown to be saturable.  Peak tumor uptake occurred 24 
to 48 hours after administration and ranged from 22 to 66% of the dose per gram of tissue. 
7.2.3 
Toxicology 
A single dose comparative study with a single administration of TX05 and US-licensed 
Herceptin assessing PK, immunogenicity, and systemic tolerability has been completed in 
Sprague-Dawley rats.  Dose selection for the toxicology study was based upon consideration 
of the clinically relevant dose with the formulated material and providing toxicology data for 
comparison to US-licensed Herceptin.  TX05, US-licensed Herceptin (25 mg/kg) or vehicle 
control were administered to the appropriate animals by IV (slow bolus) injection to the tail 
vein once on Day 1.  Evaluations included in-life procedures (mortality, morbidity, clinical 
observation, body weight, and food consumption), laboratory evaluations, evaluation of ADA 
and complete necropsy evaluation of toxicology groups at termination.  
All animals survived to scheduled necropsy.  There were no related TX05- or Herceptin-related 
clinical observations during the study.  All animals were normal throughout the study period.  
One Herceptin-dosed TK animal was noted with labored breathing, pale ear, and red periorbital 
skin on Day 1 after the 10-minute post-dose blood collection.  These clinical signs were 
attributed to the animal struggling during the sample collection and were considered stress-
related.   
There was no detection of anti-TX05 or anti-Herceptin antibodies during the study.  There were 
no changes in any parameters considered related to either TX05 or Herceptin administration, 
including in-life, clinical pathology, gross pathology, organ weights, and histopathology 
assessments. 
7.2.4 
Summary and Nonclinical Safety Assessment 
Physicochemical characterization of TX05 as well as the side-by-side comparison with 
Herceptin, has shown identical primary sequence of the 2 proteins, and similar 
physicochemical characteristics in terms of size, charge, and glycan profiles.  The in vitro 
pharmacology studies demonstrated the biosimilarity of TX05 to US-licensed Herceptin, with 

 
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respect to several key biologic activities, including binding to the target receptor and inhibition 
of growth of HER2 expressing cells. 
In vivo studies further support the biosimilarity of TX05 and Herceptin by demonstration of 
similarity in PK of TX05 and Herceptin in Sprague-Dawley rats by similarity of exposure 
following a single dose of 25 mg/kg of TX05 or Herceptin, with a calculated TX05/Herceptin 
ratio of 1.08 for AUC0-24; and in Cynomolgus monkeys, by exposure and clearance following 
a single dose of 25 mg/kg of TX05 or Herceptin, with a ratio between AUC0-24 of TX05 to 
Herceptin of 1.21. 
Good tolerability of TX05 and Herceptin in Sprague-Dawley rats was demonstrated following 
a single dose of 25 mg/kg of TX05 or Herceptin, with no changes in any parameters related to 
TX05 or Herceptin, including laboratory parameters, clinical pathology, gross pathology, organ 
weights, and histopathology.  Similarly, good tolerability of a single dose of 25 mg/kg of TX05 
or Herceptin was seen in Cynomolgus monkeys, with no clinical signs associated with either 
test article.  
7.3 
Clinical Studies 
7.3.1 
Pharmacokinetics 
A Phase 1 PK study of TX05 and Herceptin in 70 healthy adult male subjects has been 
completed and demonstrated PK similarity of TX05 in comparison to the reference product, 
US-licensed Herceptin.  Secondary study objectives were to compare the safety and tolerability 
of TX05 and the reference product and to assess the incidence of ADA.  The primary endpoint 
of this PK study was the area under the plasma concentration-time curve 0 to infinity (AUC0-
∞).  PK similarity was claimed if the 90% confidence interval (CI) of the ratio of means of the 
log-transformed AUC0-∞ was entirely within the limits of (80.00%, 125.00%).  Other PK 
endpoints included area under the plasma concentration-time curve 0 to last measured 
concentration (AUC0-t) and maximum concentration (Cmax). 
Values of time to maximum concentration (Tmax) ranged between 1.50 and 6.00 hours for both 
TX05 and Herceptin.  Mean AUC0-t/∞ values were 96.53% and 98.55% for the test and reference 
formulation, respectively.  It is considered that the sampling schedule covered the 
concentration-time curve long enough to provide a reliable estimate of the extent of exposure. 
The PK and statistical results indicate that the test/reference ratio of means of log-transformed 
AUC0-∞ was 93.32% (90% CI 86.79 - 100.34%), for log-transformed AUC0-t was 91.20% (90% 
CI 84.58 - 98.34%), and for log-transformed Cmax was 96.12% (90% CI 90.68 - 101.88%).  The 
point estimates and their 90% CIs were all contained within the range of 80.00% to 125.00% 
demonstrating the PK similarity of TX05 to US-licensed Herceptin. 
As noted above, some manufacturing improvements were introduced for TX05 following this 
initial PK study.  As the pre-change TX05 and Herceptin were shown to be PK equivalent in 
the initial PK study despite some minor differences, it is not anticipated that the improvements 
in post-change TX05 (Section 7.2.1), which have made it even more similar to Herceptin, 
would negatively impact the PK or safety profile similarity demonstrated in the completed 

 
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study.  Additionally, a reduction in the level of Man5 in the post-change TX05, which could 
theoretically slightly reduce its clearance, may be expected to bring the AUC ratio of post-
change TX05 and Herceptin even closer to 1.  Therefore, post-change TX05 is expected to 
show a very similar PK to Herceptin as well as to the pre-change TX05. 
7.3.2 
Safety 
In the PK study, both drugs were generally safe and well tolerated by study subjects.  There 
were no discernible patterns in treatment-emergent AEs (TEAEs), laboratory, or 
electrocardiogram (ECG) parameters, and no treatment-emergent serious AEs (SAEs) were 
reported over the course of the study.  Subjects in both treatment groups experienced TEAEs 
with a low frequency, of which, the most common were headache, upper respiratory tract 
infection, and nasal congestion.  Other TEAEs included nausea, drug screen positive, myalgia, 
and vomiting.  
The severity of all TEAEs was mild to moderate.  No severe or life-threatening TEAEs were 
reported in this study.  The TEAEs reported as possibly, probably, or definitely related to study 
drug in both treatment groups were generally consistent with those previously reported to be 
associated with Herceptin (Herceptin package insert).  Thirteen TEAEs were considered 
definitely related to study drug, including chills, injection site extravasation, neutrophil count 
decrease, nausea, headache, muscular weakness, myalgia, and ocular hyperemia.  These 
TEAEs were reported by 3 subjects in TX05 group and 4 subjects in Herceptin group.  All 
these TEAEs resolved by the end of the study.  One subject was discontinued from the study 
following observation of chills, headache, and muscle weakness following initiation of a 
Herceptin infusion. 
The assessment of anti-trastuzumab antibody at different timepoints revealed positive screen 
assay results in both Herceptin and TX05 groups prior to and/or after drug exposure.  Following 
specificity assay/final results, only one subject in the TX05 group tested positive for anti-
trastuzumab antibody at baseline; post-dose values were negative.  No other subject tested 
positive for anti-trastuzumab antibody following the confirmatory assays in this study. 
Further details are provided in the Investigator Brochure. 
7.4 
Rationale 
TX05 is being developed as a potential biosimilar to Herceptin.  A biosimilar medicine is a 
medicine that is similar to a biological medicine that has already been authorized (the biological 
reference medicine).  Biosimilarity between the biosimilar and the biological reference 
medicine has to be established in a stepwise approach at all levels: quality, nonclinical, and 
clinical.  The demonstration of biosimilarity is based on the concept of totality of the evidence, 
in which all structural, functional, nonclinical, and clinical data are evaluated to show high 
similarity to the reference product.  As part of this stepwise approach, a clinical human study 
must be conducted in a sensitive and homogeneous subject population to demonstrate similar 
efficacy and safety compared to the reference product. 

 
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The studies detailed above in Section 7.2 and 7.3 have demonstrated similarity between TX05 
and the reference product, Herceptin, and as well as the systemic tolerability of TX05.  The 
results from these studies, as well as comparability studies of TX05 before and following 
manufacturing improvements, were considered to be sufficient to support further clinical 
development of TX05. 
This is an extension study for subjects treated in the prior TX05/Herceptin neoadjuvant study 
(Protocol TX05-03).  Subjects who completed the TX05-03 study may be eligible to enroll in 
this separate protocol designed to further assess and characterize the safety, immunogenicity, 
and efficacy of TX05 and Herceptin as single agents. 
This study will be conducted in compliance with the protocol and with the International 
Council for Harmonization (ICH) guidelines on Good Clinical Practice (GCP). 

 
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8 
STUDY OBJECTIVES 
• To collect safety, tolerability, and immunogenicity data for single agent Herceptin or TX05 
in the adjuvant setting in subjects with early HER2-positive breast cancer who completed 
neoadjuvant treatment and primary resection in Protocol TX05-03. 
• To collect safety, tolerability, and immunogenicity data following a single transition from 
neoadjuvant Herceptin to adjuvant TX05 in this population. 
• To collect disease-free survival (DFS) and overall survival (OS) data in this population. 

 
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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is an extension study for subjects treated in the prior TX05/Herceptin neoadjuvant study 
(Protocol TX05-03) and successfully underwent surgical resection.  Eligible subjects will 
receive adjuvant treatment with single agent Herceptin or TX05 for up to 13 treatment cycles.  
The study will consist of a Screening period (Days -14 to 0) at least 4 weeks post-surgery to 
confirm eligibility to continue Herceptin or TX05 treatment, and an adjuvant treatment period 
(Week 0 [Day 1] to Week 36).  All subjects completing the study will attend the End of Study 
(EOS) Visit at Week 45 (± 7 days). Those discontinuing the study at any time will attend an 
Early Termination (ET) Visit 9 weeks (± 7 days) after the last administration of study drug.  
Subjects fulfilling the eligibility criteria for this extension study will receive IV Herceptin or 
TX05 (8 mg/kg loading dose then 6 mg/kg) every 3 weeks for 13 cycles, as follows: (1) subjects 
originally assigned to TX05 in the neoadjuvant study will receive TX05; and (2) subjects 
originally assigned to Herceptin in the neoadjuvant study will be randomized (1:1) to receive 
either Herceptin or TX05. 
Subjects will attend study visits every 3 weeks until Week 36 (± 3 days).  Study procedures 
include physical examination, vital signs, weight, Eastern Cooperative Oncology Group 
(ECOG) performance status, clinical laboratory tests, recording of AEs, and concomitant 
medication. 
Clinical assessments will be performed before administration of study drug.  Clinical laboratory 
tests will be performed at Screening, Week 0, and then at every other study visit until the 
EOS/ET Visit.  Tumor assessments will be performed at Screening and EOS/ET Visit by means 
of a computed tomography (CT) scan or magnetic resonance imaging ([MRI] only if CT scan 
cannot be performed) of the chest, abdomen, and pelvis.  
Cardiac safety will be assessed at Screening and Cycle 6 (Week 15) prior to administration of 
study drug and at the EOS/ET Visit using 12-lead ECG and echocardiography or multi-gated 
acquisition (MUGA) scan to evaluate the left ventricular ejection fraction (LVEF). 
Samples for the evaluation of ADA, including neutralizing antibodies (Nab) will be obtained 
before the administration of Cycle 1 (Week 0) and Cycle 6 (Week 15), and at the EOS/ET Visit. 
Once subjects complete adjuvant treatment with single agent Herceptin or TX05 they may 
move on to other therapies as recommended by their treating physician.  Subjects who 
prematurely discontinue adjuvant treatment with single agent Herceptin or TX05 may move on 
to other therapies as recommended by their treating physician, even if they consent to remain 
in the study. 

 
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Figure 9–1 
Study Design Flow Diagram 
 
9.1.1 
Schedule of Assessments 
The schedule of assessments is presented in Table 9–1. 

 
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Table 9–1 
Schedule of Assessments 
Study Procedure 
Screening 
(- 14 days) 
Adjuvant Cycle (week) 
EOS/ET1 
Week 45 
TX05 
1 
(0) 
2 
(3) 
3 
(6) 
4 
(9) 
5 
(12) 
6 
(15) 
7 
(18) 
8 
(21) 
9 
(24) 
10 
(27) 
11 
(30) 
12 
(33) 
13 
(36) 
 
Visit Window (days) 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Weight4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory tests7 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
12-Lead ECG 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
LVEF (echocardiography or MUGA)8  
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration9 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Immunogenicity sampling10 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Tumor assessment11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
AE assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

 
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Study Procedure 
Screening 
(- 14 days) 
Adjuvant Cycle (week) 
EOS/ET1 
Week 45 
TX05 
1 
(0) 
2 
(3) 
3 
(6) 
4 
(9) 
5 
(12) 
6 
(15) 
7 
(18) 
8 
(21) 
9 
(24) 
10 
(27) 
11 
(30) 
12 
(33) 
13 
(36) 
 
Subject compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADA: anti-drug antibodies; AE: adverse event; CT: computed tomography; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EOS/ET: End of 
Study/Early Termination; IV: intravenous; LVEF: left ventricular ejection fraction; MRI: magnetic resonance imaging; MUGA: multi-gated acquisition; Nab: neutralizing 
antibodies. 
1. All subjects completing adjuvant treatment will attend the EOS/ET Visit 9 weeks (± 7 days) after the last administration of study drug.  Subjects that withdraw from 
treatment due to disease progression, but consent to stay in the study, will attend the ET visit 9 weeks (± 7 days) after the last administration of study drug and thereafter 
continue to be followed up by telephone for overall survival status every 6 weeks until Week 45 (± 7 days).  Subjects that withdraw from treatment for any other reason 
than disease progression, and consent to remain in study, will continue to attend the scheduled study visits including the EOS visit.  In the event that such a subject 
subsequently experiences disease progression, he/she will attend the ET visit 9 weeks (± 7 days) after the last administration of study drug if this has not already occurred, 
and thereafter be followed-up by telephone for overall survival status every 6 weeks until Week 45 (± 7 days).  Subjects completely discontinuing from study will attend 
the ET visit 9 weeks (± 7 days) after the last administration of study drug and no further data will be collected. 
2. Informed consent must be obtained prior to undergoing any study-specific procedure and may occur prior to the 14-day Screening period. 
3. Complete physical examinations will be conducted at Screening and at the EOS/ET Visit.  All other evaluations will be at the discretion of the investigator.  Height will be 
recorded at Screening only. 
4. Weight will be recorded at Screening and Day 1 of each cycle and as clinically indicated.  The weight from Day 1 of each cycle should be used to calculate the dosage of 
study drug to be administered. 
5. Temperature, blood pressure, pulse rate, and respiratory rate will be recorded at each timepoint. 
6. Subjects of childbearing potential will have a blood serum pregnancy test at Screening and at the EOS/ET Visit. A urine pregnancy test will also be performed prior to 
each treatment cycle to exclude potential pregnancy. 
7. Clinical laboratory tests (hematology, clinical chemistry, and urinalysis) will be performed by local laboratories.  Clinical laboratory tests can be performed at other visits 
at the discretion of the investigator. 
8. LVEF (echocardiography or MUGA) should be assessed as clinically indicated during the adjuvant treatment period. 
9. Subjects will receive up to 13 cycles of adjuvant chemotherapy: Herceptin or TX05 8 mg/kg body weight will be administered by 60-minute IV infusion, on Day 1 of 
treatment Cycle 1 and thereafter 6 mg/kg body weight every 3 weeks until Cycle 13. 

 
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10. Serum samples for detection of ADA and Nab will be collected before the administration of study drug at Cycle 1 (Week 0) and Cycle 6 (Week 15), and at the EOS/ET 
Visit. 
11. CT scan or MRI, only if CT scan cannot be performed, of chest, abdomen, and pelvis. 
 

 
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The schedule of blood samples that will be drawn for each subject is presented in Table 9–2. 
Table 9–2 
Schedule of Blood Sampling 
Assessment 
Screening 
Cycle 
1  
(Week 
0) 
Cycle 
2 
(Week 
3) 
Cycle 
3 
(Week 
6) 
Cycle 
4 
(Week 
9) 
Cycle 
5 
(Week 
12) 
Cycle 
6 
(Week 
15) 
Cycle 
7 
(Week 
18) 
Cycle 
8 
(Week 
21) 
Cycle 
9 
(Week 
24) 
Cycle 
10 
(Week 
27) 
Cycle 
11 
(Week 
24) 
Cycle 
12 
(Week 
24) 
Cycle 
13 
(Week 
24) 
EOS/ET 
Visit 
Hematology 
4 mL 
4 mL 
 
4 mL 
 
4 mL 
 
4 mL 
 
4 mL 
 
4 mL 
 
4 mL 
4 mL 
Clinical 
Chemistry 
4.5 mL 
4.5 
mL 
 
4.5 
mL 
 
4.5 
mL 
 
4.5 
mL 
 
4.5 
mL 
 
4.5 
mL 
 
4.5 
mL 
4.5 mL 
Immunogenicity 
 
7 mL 
 
 
 
 
7 mL 
 
 
 
 
 
 
 
7 mL 
Additional blood tests may be performed for viral disease screen and pregnancy testing (if required at Screening) and per standard of care (SOC), 
at the investigator's discretion for the purpose of planning treatment administration, dose modification, following AEs, or as clinically indicated. 
 

 
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9.1.2 
Study Assessments 
9.1.2.1 
Screening Period -14 days 
Subjects are to undergo a Screening Visit 14 days prior to the planned first day of study 
treatment.  Screening assessments are as follows: 
• Assess eligibility criteria 
• Obtain written informed consent 
• Record medical and surgical history 
• Perform physical examination (including height at Screening only) 
• Record weight 
• Record vital signs (temperature, blood pressure, pulse rate, and respiratory rate) 
• Perform pregnancy test (for subjects of childbearing potential) (within 14 days of first 
administration of study drug) 
• Assess ECOG performance status (Appendix 1) 
• Perform clinical laboratory tests (hematology, clinical chemistry, urinalysis) 
• Perform 12-lead ECG 
• Assess LVEF (echocardiography or MUGA) 
• Perform tumor assessment 
9.1.2.2 
Treatment Period: TX05/Herceptin: Cycle 1 (Week 0) to Cycle 13 (Week 36) 
Cycle 1 (Week 0) 
• Randomization (subjects originally assigned to Herceptin in the TX05-03 study will be 
randomized [1:1] to receive either Herceptin or TX05; subjects originally assigned to TX05 
in the TX05-03 study will continue to receive TX05) 
• Record weight 
• Record vital signs (temperature, blood pressure, pulse rate, and respiratory rate) 
• Perform pregnancy test (for subjects of childbearing potential) 
• Assess ECOG performance status (Appendix 1) 
• Perform clinical laboratory tests (hematology, clinical chemistry, urinalysis) 
• Study drug administration 
• Perform immunogenicity sampling 
• Record AEs 
• Assess subject compliance 
• Record concomitant medications 

 
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Cycle 2 (Week 3) to Cycle 13 (Week 36) 
• Record weight 
• Record vital signs (temperature, blood pressure, pulse rate, and respiratory rate) 
• Perform pregnancy test (for subjects of childbearing potential) 
• Assess ECOG performance status (Appendix 1) 
• Perform clinical laboratory tests ([hematology, clinical chemistry, urinalysis] Cycle 3, 
Cycle 5, Cycle 7, Cycle 9, Cycle 11, and Cycle 13 only) 
• Perform 12-lead ECG (Cycle 6 only) 
• Assess LVEF ([Cycle 6 only] echocardiography or MUGA) 
• Study drug administration 
• Perform immunogenicity sampling (Cycle 6 only) 
• Record AEs 
• Assess subject compliance 
• Record concomitant medications 
9.1.2.3 
End of Study Visit (Week 45)/Early Termination Visit  
• Perform physical examination 
• Record vital signs (temperature, blood pressure, pulse rate, and respiratory rate) 
• Perform pregnancy test (for subjects of childbearing potential) 
• Perform clinical laboratory tests (hematology, clinical chemistry, urinalysis) 
• Perform 12-lead ECG 
• Assess LVEF (echocardiography or MUGA) 
• Perform immunogenicity sampling 
• Perform tumor assessment 
• Record AEs 
• Record concomitant medications 
9.2 
Discussion of Study Design 
This study will evaluate the similarity in long-term safety, efficacy, and immunogenicity of 
TX05 compared to Herceptin in subjects for whom adjuvant trastuzumab treatment is indicated. 
To develop a biosimilar, the PK, efficacy, and safety profiles of the proposed biosimilar must 
be similar to the marketed product.  In order to support global development of TX05 as a 
biosimilar, one comparator arm is included in this study.  The comparator to be used in this 
clinical study is EU-licensed Herceptin. 

 
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TX05 has been shown to be similar to US-licensed Herceptin with respect to in vitro 
physicochemical and functional characterization, and in vivo PK and safety profile in animals 
and in healthy human subjects.  The PK and safety/tolerability profile similarity of EU- and 
US-licensed Herceptin has been demonstrated in published PK studies of trastuzumab 
biosimilar candidates15,16,17.  Due to the demonstrated PK similarity of TX05 and US-licensed 
Herceptin, it is considered that these studies indirectly support the anticipated PK similarity of 
TX05 with EU-licensed Herceptin, and thus the use of EU-licensed Herceptin as a comparator 
for the proposed study. 
The efficacy endpoints assessed in this study (DFS and OS) are commonly used endpoints in 
oncology trials with OS traditionally regarded as the ultimate measure of 
treatment benefit. 
Trastuzumab given every 3 weeks (8 mg/kg loading dose then 6 mg/kg dose) is per the US 
Herceptin label for EBC18.  For this intended biosimilar, TX05, subjects with HER2-positive 
EBC following neoadjuvant treatment and surgical resection provides a sensitive and uniform 
population of subjects. 
9.2.1 
Risk/Benefit and Ethical Assessment 
There is a substantial body of data related to the safety and efficacy of Herceptin in subjects 
with breast or gastric cancer (FDA and EMA Herceptin prescribing information).  Prior to the 
TX05-03 study, no studies of TX05 have been conducted in subjects with EBC.  However, as 
mentioned, there is substantial nonclinical and clinical pharmacological and PK data showing 
the biosimilarity of TX05 to US-based Herceptin.   
In general, the risks and discomforts anticipated to be associated with TX05 in subjects with 
breast cancer are those that are known for Herceptin and may include  fever, nausea, vomiting, 
infusion reactions, diarrhea, infections, increased cough, headache, fatigue, shortness of breath, 
rash, neutropenia (low white blood cells), anemia (low red blood cells), and muscle aches.  
Serious side effects that have been documented with Herceptin include cardiomyopathy, 
serious infusion reactions, embryo-fetal toxicity, pulmonary toxicity, and exacerbation of 
chemotherapy-induced neutropenia as noted in the prescribing information for Herceptin.  
Please refer to Herceptin prescribing information for more detail.  There may be additional 
risks or side effects that are related to TX05 that are unknown at this time. 
9.3 
Selection of Study Population 
9.3.1 
Inclusion Criteria 
Subjects eligible for enrollment in the study must meet all of the following criteria: 
1. Signed written informed consent. 
2. Females ≥ 18 years of age. 
3. Completed neoadjuvant treatment (regardless of treatment arm) in the TX05/ Herceptin 
neoadjuvant study and the investigator believes the subject requires continued access to 
single agent trastuzumab in order to continue deriving clinical benefit. 

 
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4. Successfully undergone surgical resection of their primary tumor with no evidence of 
residual disease (as determined by local assessment) and no other adjuvant therapy, other 
than trastuzumab, is planned.  However, subjects will be allowed to receive hormonal 
therapy if they have hormone receptor positive tumors.  Subjects will also be allowed to 
receive adjuvant radiation therapy, if required by their treating physician. 
5. Able to comply with the study protocol. 
6. Female subjects of childbearing potential must have a negative serum pregnancy test within 
14 days of first administration of study drug and agree to use effective contraception 
(hormonal contraceptive, intrauterine device, diaphragm with spermicide, or condom with 
spermicide) throughout the study period and for 7 months after last administration of study 
drug. 
9.3.2 
Exclusion Criteria 
Subjects meeting any of the following criteria must not be enrolled in the study: 
1. Breast cancer metastases or residual disease post operatively (as determined by local 
assessment). 
2. History or presence of a medical condition or disease that in the investigator's opinion 
would place the subject at an unacceptable risk for study participation. 
3. Lactating or pregnant female. 
4. Women of childbearing potential who do not consent to use highly effective methods of 
birth control (e.g. true abstinence [periodic abstinence {e.g. calendar ovulation, 
symptothermal, post-ovulation methods} and withdrawal are not acceptable methods of 
contraception], sterilization, or other non-hormonal forms of contraception) during 
treatment and for at least 7 months after the last administration of study drug.  Subjects 
must agree to not breast-feed while receiving study drug. 
5. Any condition that in the opinion of the Investigator represents an obstacle for study 
conduct and/or represents a potential unacceptable risk for subjects. 
9.3.3 
Withdrawal of Subjects 
A subject may withdraw from the study at any time at her own request, or may be withdrawn 
at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons without compromising the subject’s medical care. 
If a subject is off treatment for greater than 4 weeks due to any reason (for example toxicity, 
other AE/SAE, non-compliance, lost to follow-up) then she should be discontinued from study 
treatment.  If possible (i.e. subject is not lost to follow-up) EOS procedures should be 
performed. 
If it is necessary to discontinue the study drug earlier than planned then: 
• Subjects that withdraw from treatment due to disease progression, but consent to stay in the 
study, will attend the ET visit 9 weeks (± 7 days) after the last administration of study drug 

 
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and thereafter continue to be followed up by telephone for overall survival status every 6 
weeks until Week 45 (± 7 days).  Subjects that withdraw from treatment for any other 
reason than disease progression, and consent to remain in study, will continue to attend the 
scheduled study visits including the EOS visit.  In the event that such a subject subsequently 
experiences disease progression, he/she will attend the ET visit 9 weeks (± 7 days) after the 
last administration of study drug if this has not already occurred, and thereafter be followed-
up by telephone for overall survival status every 6 weeks until Week 45 (± 7 days). 
• Subjects completely discontinuing from study will attend the ET visit 9 weeks (± 7 days) 
after the last administration of study drug and no further data will be collected. 
Subjects who discontinue treatment due to an AE considered related to study drug should be 
followed until the event is resolved, considered stable, or the investigator determines the event 
is no longer clinically significant. 
Subjects that withdraw from treatment, but consent to stay in the study, may move on to other 
therapies as recommended by their treating physician. 
Subjects who withdraw from treatment for any reason or completely withdraw from the study 
for any reason prior to the EOS Visit should complete the procedures scheduled for that visit 
(ET Visit) 9 weeks (± 7 days) after the last administration of study drug.   
If the subject withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a subject withdraws from the study, she may request destruction of any samples that have 
been taken and not yet tested, and the investigator must document this in the site study records. 
The reasons for study drug discontinuation and/or subject withdrawal from the study must be 
recorded in the subject’s medical record and electronic case report form (eCRF). 
9.3.4 
Lost to Follow-Up 
A subject will be considered lost to follow-up if she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the site.  
The following actions must be taken if a subject fails to return to the site for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in the 
study. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the subject (where possible, 3 telephone calls and, if necessary, 
a certified letter to the subject’s last known mailing address or local equivalent methods).  
These contact attempts should be documented in the subject’s medical record. 

 
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• Should the subject continue to be unreachable, she will be considered to be lost to 
follow-up. 
9.3.5 
Early Termination 
This study may be terminated at any time by the Sponsor for any reason, including if serious 
side effects should occur, if the investigator does not adhere to the protocol or if, in the 
Sponsor's judgment, there are no further benefits to be achieved from the study.  In this event, 
the Sponsor will inform the study investigators, institutions, and all regulatory authorities. 
9.3.6 
Missed Dose 
If the subject has missed a dose of TX05/Herceptin by 1 week or less, then the usual dose 
(6 mg/kg) should be administered as soon as possible.  Do not wait until the next planned cycle.  
Subsequent doses should be administered 21 days later according to the three-weekly schedule. 
If the subject has missed a dose of TX05/Herceptin by more than 1 week, a re-loading dose of 
TX05/Herceptin should be administered over approximately 90 minutes (8 mg/kg) as soon as 
possible.  Subsequent TX05/Herceptin doses (6 mg/kg) should be administered 21 days later 
according to the three-weekly schedule. 

 
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10 
TREATMENT OF SUBJECTS 
10.1 
Identity of Study Treatment(s) 
10.1.1 
Administration of Study Treatment(s) 
TX05 drug product is a sterile, preservative-free, lyophilized product in a 50 mL glass vial.  
Each vial contains 150 mg or 420 mg of TX05, sufficient to deliver 150 mg or 420 mg.  After 
reconstitution with 20 mL of bacteriostatic water for injection, the product formulation is 
21 mg/mL TX05, 4.2 mM histidine/histidine hydrochloride, 50.4 mM trehalose, and 0.007% 
(w/v) polysorbate 20, pH 6.0.  The formulation of the TX05 drug product is identical in 
composition to Herceptin.  The selected components are well-known antibody stabilizers and 
the target pH is similar to other formulations of immunoglobulin-based drug products. 
Subjects will receive up to 13 cycles of adjuvant chemotherapy.  TX05 or Herceptin 8 mg/kg 
body weight will be administered by 60-minute IV infusion on Day 1 of treatment Cycle 1 and 
thereafter 6 mg/kg body weight every 3 weeks until Cycle 13. 
Specific instructions on dose preparation and administration are provided in the separate 
dosage and administration instructions. 
10.2 
Treatment Regimen Adjustments 
Dose modification guidelines are provided in Appendix 2. 
In the event of toxicity attributed to trastuzumab, treatment should be either temporarily or 
permanently discontinued, as below.  Following a temporary discontinuation, treatment may 
resume with the administration of a loading dose of trastuzumab in accordance with local SOC. 
• Decrease the rate of infusion for mild or moderate infusion reactions. 
• Interrupt the infusion in subjects with dyspnea or clinically significant hypotension. 
• Discontinue the infusion for severe or life-threatening infusion reactions. 
10.3 
Study Treatment Packaging and Labeling 
The labels of the study drug will be in the local language and comply with the legal 
requirements of each country.  All blank spaces should be completed by site staff prior to 
dispensing to subjects. 
10.3.1 
Storage 
The study drug may be prepared up to 24 hours prior to dose administration, where it is stored 
refrigerated (2ºC to 8ºC/36ºF to 46ºF) or up to 8 hours where it is stored below 30ºC (86ºF), 
and protected from light.  Study drug should be removed from refrigerator and allowed to 
acclimate to room temperature over approximately 15 minutes prior to infusion. 
10.4 
Blinding and Randomization of Study Treatment(s) 
Both randomization and blinding techniques will be used in this study to minimize bias.  This 
is a double-blinded study and so randomized treatment assignments will be blinded to the 
subject, investigator/study staff and Sponsor’s study team conducting the study.  A computer 

 
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generated randomization schema will be centrally available via interactive web response 
system (IWRS) to all sites that meet the requirements for participation in the study.  In order 
to maintain the study blind, all eligible subjects will be randomized within the IWRS for this 
extension study.  Subjects originally assigned to TX05 in the neoadjuvant study protocol TX05-
03 will continue to receive TX05 in this extension study.  Subjects originally assigned to 
Herceptin in the neoadjuvant study will be randomized (1:1) before the administration of study 
drug at Cycle 1 (Week 0) to receive either Herceptin or TX05.  At the initiation of the study, 
all sites will be instructed on how to use IWRS for breaking the blind, if necessary. 
10.4.1 
Procedure for Breaking the Randomization Code 
Blinding should only be broken in emergency situations for reasons of individual subject safety 
when knowledge of the study drug assignment is required for medical management.  Whenever 
possible, the investigator or sub-investigator can consult with a member of the study team prior 
to breaking the blind; however, should a situation arise where unblinding is required, the 
investigator at that site may perform immediate unblinding without the need for 
communication with the Sponsor.  At all other times, treatment and randomization information 
will be kept confidential and will not be released to the investigator/site staff until the 
conclusion of the study. 
If the blind for a subject has been broken, the reason must be fully documented in source 
documents and entered on the eCRF.  Any AE or SAE associated with breaking the blind must 
be recorded and reported as specified in this protocol. 
10.5 
Subject Compliance 
Study treatment will be administered under the supervision of the investigator/site staff.  
Compliance will be monitored by site staff by using the source documents and the eCRFs.  The 
site study pharmacist is responsible for drug preparation, the maintenance of accurate and 
complete dispensing and accountability forms showing the receipt and dispensation of study 
drug.  The pharmacist will also be responsible for performing accountability and reconciliation 
of the study drug, and documentation of background therapy administered, including tracking 
the number of vials used and manufacturer’s lot numbers. 
10.6 
Study Treatment Accountability 
Each vial dispensed must be recorded in the Study Drug Accountability Log. 
Records shall be maintained of the delivery of study treatment(s) to the study center(s), the 
inventory at the study center(s), the use of each subject and the return to the Sponsor. 
These records shall include dates, quantities, batch numbers, expiry dates, and the unique code 
numbers assigned to the study drug and to the study subjects. 
The investigator shall be responsible for ensuring that the records adequately document that 
the subjects were provided the doses specified in the protocol and that all study drug received 
from the Sponsor is reconciled. 

 
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10.7 
Concomitant Therapy 
Concomitant medications administered for any reason must be locally-approved and with doses 
used and regimens that are considered SOC for the treated indication. 
Medications and (non-drug treatments) will be monitored continuously by the investigator.  
Treatment for co-morbidities, disease signs and symptoms, and TEAEs should be provided as 
necessary in the judgment of the investigator.  Supportive care may include premedication with 
antiemetics to limit treatment-related nausea and vomiting.  Subjects may receive prophylaxis 
of treatment-induced diarrhea.  Anti-inflammatory or narcotic analgesics may be offered as 
needed. 
Prophylactic use of hematopoietic growth factors to support neutrophil or platelet counts 
according to local SOC is permitted during this study.  Subjects who enter the study on stable 
doses of erythropoietin or darbepoietin may continue this treatment, and subjects may start 
either drug during the study at the discretion of the investigator.  Subjects with neutropenic 
fever or infection should be treated promptly and may receive therapeutic colony-stimulating 
factors if appropriate.  Packed red blood cell and platelet transfusions may be administered as 
clinically indicated. 
Subjects will be allowed to receive hormonal therapy during adjuvant treatment with single 
agent Herceptin or TX05 if they have hormone receptor positive tumors. 
It is not anticipated that subjects who have undergone surgical resection of their primary tumor 
with no evidence of residual disease would require radiation therapy, but if required by their 
treating physician, subjects can receive adjuvant radiation therapy during TX05 or Herceptin 
therapy. 
All concomitant medications and treatments should be recorded in the subject’s source 
documents and entered into the eCRF, available during study monitor visits, and included in 
SAE reports. 
Surgery during study participation to manage breast cancer lesions is discouraged unless 
medically necessary in the judgment of the investigator.  In this case, the subject will be 
discontinued from the study prior to the surgical procedure.  In such cases, the EOS/ET Visit 
should be completed. 
No other investigational drug may be used during treatment on this protocol, and concurrent 
participation in another clinical study is not allowed. 

 
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11 
ASSESSMENTS 
11.1 
Endpoints 
11.1.1 
Safety Endpoints: 
• TEAEs and SAEs. 
• Death. 
• Clinical laboratory parameters. 
• Vital signs. 
• 12-lead ECG.  
• LVEF. 
• Physical examination. 
11.1.2 
Immunogenicity Endpoints: 
• Incidence of ADA. 
• Incidence of Nab. 
11.1.3 
Efficacy Endpoints 
• DFS, defined as the time from randomization in the neoadjuvant study (Protocol TX05-03) 
to the documentation of a first failure, where a failure is the recurrence of breast cancer or 
a diagnosis of a second primary cancer. 
• OS, defined as the time from randomization in the neoadjuvant study (Protocol TX05-03) 
until death from any cause. 
11.2 
Tumor Assessment 
A CT scan or MRI (only if CT scan cannot be performed) of the chest, abdomen, and pelvis is 
required at Screening for all subjects.   
The CT scans should be performed with contrast agents unless contraindicated for medical 
reasons.  If IV contrast is medically contraindicated, the imaging modality to be used to follow 
the disease (either CT without contrast or MRI) should be the modality which best evaluates 
the disease, and the choice should be determined by the investigator in conjunction with the 
local radiologist.  Depending on the adequacy for evaluation of disease, a combination of CT 
without contrast should most often be used.  CT without contrast is preferred for evaluation of 
lesions in lung parenchyma.  MRI is not adequate for evaluation of lung parenchyma but should 
also be performed to evaluate all other aspects of the chest. 
Final tumor assessment at the EOS/ET Visit will include repeat CT scan or MRI (only if CT 
scan cannot be performed) of the chest, abdomen, and pelvis.  Assessments are not to be 
scheduled based on the scheduled calendar date of the EOS/ET Visit. 

 
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11.3 
Echocardiogram/MUGA 
Assessment of LVEF using an echocardiogram or MUGA scan will be performed at Screening, 
prior to dosing at Cycle 6 (Week 15), at the EOS/ET Visit, and as clinically indicated during 
the adjuvant treatment period.  The modality used for individual subjects should be consistent 
throughout the study. 
11.4 
Laboratory Assessments 
Hematology and clinical chemistry tests will include the parameters presented in Table 11–1. 
Hematology and clinical chemistry samples will be drawn at the timepoints described in 
Table 9–1.  A total of 4 mL for hematology samples and 4.5 mL for clinical chemistry samples 
will be drawn (see Table 9–2).  Additional blood tests may be performed per SOC, at the 
investigator's discretion for the purpose of planning treatment administration, dose 
modification, following AEs, or as clinically indicated. 
Table 11–1 
Hematology and Clinical Chemistry Assessments 
Hematology 
Clinical Chemistry 
Hemoglobin 
Alanine Aminotransferase 
Platelets 
Aspartate Aminotransferase 
Complete blood count with differential 
Alkaline Phosphatase 
Absolute Neutrophil Count 
Sodium 
 
Potassium 
 
Total Calcium 
 
Total Bilirubin 
 
Blood Urea Nitrogen or Urea 
 
Creatinine 
 
Albumin 
Urinalysis, including pH, erythrocyte, leukocyte, glucose, and protein will be conducted at the 
same visits at which blood laboratory tests are performed.   
All tests will be performed by local laboratories. 
11.5 
Electrocardiogram Assessments 
12-lead ECGs will be performed at Screening, prior to dosing at Cycle 6 (Week 15), and at the 
EOS/ET Visit.  12-lead ECGs will be obtained after the subject has been resting semi-supine 
for at least 10 minutes prior to times indicated.  All ECGs should be recorded with the subject 
in the same physical position.  A standardized ECG machine should be used, and the subject 
should be examined using the same machine throughout the study if possible. 
An assessment of normal or abnormal will be recorded and if the ECG is considered abnormal, 
the abnormality will be documented on the eCRF.  In cases where a clinical significant 
abnormality is found at baseline (Screening), this should be recorded in the subject’s medical 

 
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history.  Should a clinically significant abnormality be reported during the treatment period, it 
will be recorded as an AE. 
11.6 
Physical Examination 
Complete physical examinations will be conducted at Screening and at the EOS/ET Visit, 
including general appearance, skin, eyes, ear/nose/throat, head and neck, heart, chest and lungs, 
abdomen, extremities, lymph nodes, musculoskeletal, neurological, and other body systems if 
applicable for describing the status of their health.  All other evaluations will be at the discretion 
of the investigator. 
Height will be recorded at Screening only.  Weight will be recorded at Screening and Day 1 of 
each cycle, and as clinically indicated.  The weight from Day 1 of Cycles 1 to 13 should be 
used to calculate the dosage of trastuzumab to be administered. 
11.7 
Vital Signs 
Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) will be performed at 
all timepoints.  All tests will be obtained in the sitting position after the subject has rested for 
10 minutes.  The date and time of the assessment should be recorded on the subject’s eCRF. 
11.8 
Immunogenicity Sampling 
Serum samples for detection of ADA and Nab will be collected prior to initiation of infusion 
of study drug at Cycle 1 (Week 0), Cycle 6 (Week 15), and at the EOS/ET Visit.   
Whole blood samples (7 mL) will be collected (see Table 9–2) to provide approximately 3 mL 
of serum for drug concentration measurement at each timepoint.  Blood samples will be 
collected into appropriately labeled glass tubes containing no additive (a silicone coated plastic 
tube is acceptable if non-additive glass red top tube is not available) at times specified above.  
A serum separator tube should not be used. 
Blood samples will be allowed to clot at room temperature for at least 20 minutes for a complete 
clot.  The clotted samples will be placed into an ice bath for approximately 10 minutes prior to 
the centrifugation.  Serum will be separated from the whole blood within approximately 40 
minutes of collection.  The specimen should be centrifuged at 1500 x g for approximately 10 
minutes in an ambient centrifuge (a refrigerated centrifuge is acceptable if available) to harvest 
the serum.  After centrifugation, the upper serum layer is carefully transferred with a disposable 
pipette and split into 2 labeled screw capped plastic storage tubes (each with approximately 1.5 
mL of serum for ADA and Nab analysis respectively).  The same plastic storage tubes will be 
frozen and thawed for each assay.  The sample should be re-centrifuged immediately if red 
blood cells are inadvertently drawn into the serum.  Serum samples will be frozen in an upright 
position at approximately -70°C (-20°C is acceptable if -70°C is not available at the site) within 
90 minutes of sample collection.  The shipment address and assay laboratory contact 
information will be provided to the investigator prior to or during the initiation of the study. 

 
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12 
SAFETY MONITORING AND REPORTING 
12.1 
Adverse Events 
12.1.1 
Definitions 
The definitions for AEs and SAEs are given below.  It is of the utmost importance that all staff 
involved in the study are familiar with the content of this section.  The principal investigator is 
responsible for ensuring this. 
Adverse Event 
An AE is defined as any untoward medical occurrence in a subject, or clinical investigation 
subject administered a pharmaceutical product, and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign, 
symptom, or disease temporally associated with the use of a medicinal (investigation) product, 
whether or not related to the medicinal (investigational) product. 
Serious Adverse Event 
An SAE is defined as, but is not limited to, one that: 
• Results in death 
• Is life-threatening 
• Requires in-patient hospitalization or prolongs existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience, when based on 
appropriate medical judgment, they may jeopardize the subject or the subject may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
12.1.1.1 
Recording of Adverse Events 
For the purposes of this study, any detrimental change in the subject's condition, after signing 
the informed consent form and up to completion of the EOS Visit should be considered an AE. 
Ongoing drug-related AEs and SAEs from the neoadjuvant study (Protocol TX05-03) and any 
SAEs that occurred after completion of the neoadjuvant study will be recorded at Screening in 
the subject’s medical history, while AEs occurring in this extension study will be recorded 
from Day 1 (Week 0) of Cycle 1 of study treatment. 
All ongoing AEs in this extension study should be followed up until the EOS/ET Visit, with 
the exception of any ongoing study drug-related AEs, which should be followed until the event 
is resolved, considered stable, or the investigator determines the AE is no longer clinically 
significant. 

 
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At any time after the EOS/ET Visit, if an investigator learns of an SAE that can be reasonably 
related to study drug, he/she should promptly notify the Sponsor. 
The investigator will assess the intensity of AEs based on the Common Terminology Criteria 
for Adverse Events (CTCAE) v4.03: 
• Mild (asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated) 
• Moderate (minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living) 
• Severe (hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living) 
• Life-threatening (urgent intervention indicated) 
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Section 12.1.1. 
An AE of severe intensity need not necessarily be considered serious.  For example, nausea 
that persists for several hours may be considered severe nausea, but not an SAE.  On the other 
hand, a stroke that results in only a limited degree of disability may be considered a mild stroke 
but would be an SAE. 
The investigator will use his/her clinical judgment to determine the degree of likelihood that 
the study product (TX05 or Herceptin) was responsible for the reported AE/SAE.  Alternative 
causes, such as natural history of the underlying diseases, concomitant therapy, other risk 
factors, and the temporal relationship of the event to the study product, will be considered and 
investigated.  The investigator should consult the Investigator’s Brochure in the determination 
of his/her assessment. 
The standard nomenclature for defining the causal relationship between an AE and the study 
product is listed in the following table (Table 12–1). 

 
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Table 12–1 
Classification of AE Relationship to Investigational Product 
Unrelated 
No temporal association to study product. 
An alternate etiology has been established. 
The event does not follow the known pattern of 
response to study product. 
The event does not reappear or worsen with 
re-challenge. 
Probably not related/remote 
No temporal association to study product. 
Event could readily be produced by clinical state, 
environmental or other interventions. 
The event does not follow the known pattern of 
response to study product. 
The event does not reappear or worsen with 
re-challenge. 
Possibly related 
Reasonable temporal relationship to study product. 
The event is not readily produced by clinical state, 
environmental, or other interventions. 
The event follows a known pattern of response to the 
study product or as yet unknown pattern of response. 
Probably related 
There is a reasonable temporal association with the 
study product. 
The event is not readily produced by clinical state, 
environmental, or other interventions. 
The event follows a known pattern of response to the 
study product. 
The event decreases with de-challenge. 
Definitely related 
There is a reasonable temporal relationship to the 
study product. 
The event is not readily produced by clinical state, 
environmental, or other interventions. 
The event follows a known pattern of response to the 
study product. 
The event decreases with de-challenge and recurs 
with re-challenge. 
For an AE to be a suspected drug-related event, there should be at least a reasonable possibility 
of a causal relationship between the study drug and the AE. 
12.1.2 
Abnormal Laboratory Values/Vital Signs/Electrocardiograms 
Laboratory/vital signs/ECG abnormalities should be reported as AEs if any one of the 
following criteria is met: 
• Any criterion for an SAE is fulfilled. 
• The laboratory/vital signs abnormality causes the subject to discontinue from the study 
treatment. 
• The laboratory/vital signs abnormality causes the subject to interrupt the study treatment. 

 
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13 
STATISTICAL EVALUATION 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be maintained during the 
study.  This document may reflect modification to the plans outlined in the protocol; however, 
any major modifications of the endpoint definitions and/or analyses will also be reflected in a 
protocol amendment. 
13.1 
Sample Size and Power 
It is estimated that a minimum of 330 subjects will be enrolled into this double-blinded 
extension study.  This estimate is based on 740 subjects completing the neoadjuvant study 
(TX05-03) and approximately 45% of these being eligible to continue treatment in this 
extension study. 
13.2 
Analysis Populations 
13.2.1 
Safety Population 
The safety population will include all subjects who are enrolled into this extension study and 
have received at least one dose of study drug (TX05 or Herceptin) in the adjuvant treatment 
phase.  The safety population will be used for all analyses. 
13.3 
Statistical Methods 
13.3.1 
General Principles 
All individual data as well as results of statistical analyses, whether explicitly discussed in the 
following sections or not, will be presented in individual subject data listings and statistical 
summary tables. 
In general, continuous variables will be summarized using the following standard descriptive 
summary statistics: number of observations, arithmetic mean, standard deviation, minimum, 
median, and maximum.  Categorical variables will be displayed by means of frequency tables 
including percentages.  Subjects will be assigned to treatment groups (TX05 only, Herceptin 
only, and Herceptin/TX05 transition) for all analyses.  If there are any cases where subjects 
received both drugs in the adjuvant setting (TX05-03), they will be assigned to the treatment 
initially given in this extension study. 
A SAP will be prepared and finalized before study data are unblinded. 
The statistical analysis will be performed using the SAS version 9.4 or higher. 
13.3.2 
Missing Data 
Partial dates of start or stop date of AEs will be imputed in an appropriately conservative way; 
detailed methods will be described in the SAP. 
Other missing values will not be imputed, unless otherwise specified. 

 
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13.3.3 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be analyzed in a descriptive fashion and results 
will be presented overall and by treatment group. 
13.3.4 
Subject Disposition 
The following will be summarized (overall and by treatment group where applicable): 
• Subjects screened 
• Subjects randomized 
• Subjects treated 
• Subjects receiving study drug (TX05 or Herceptin) 
• Subjects completing the study/withdrawing early (including withdrawal reason) 
• Subject allocation by site 
13.3.5 
Safety Analysis 
The safety parameters will include the following: 
• TEAE and SAE 
• Death 
• Clinical laboratory parameters 
• Vital signs 
• 12-Lead ECG 
• LVEF 
• Physical examination 
TEAEs will be described using descriptive statistics, and coded according to the Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class and MedDRA preferred 
term, graded according to CTCAE, by treatment group and overall.  Drug-related TEAEs and 
SAEs will be also summarized by treatment group (TX05 only, Herceptin only, and 
Herceptin/TX05 transition). 
Clinical safety laboratory data: clinical safety laboratory data will be presented by treatment 
group and overall.  For each visit, the actual result and the change from baseline will be 
presented.  Shift tables for values outside the normal ranges will be presented as appropriate. 
Otherwise, safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.  For continuous measurements (laboratory and vital signs 
data), change from baseline will be additionally summarized by treatment and visit.  Subject 
listings will be produced for all safety parameters. 
The safety analysis will be carried with the safety population and will be analyzed according 
to the treatment they actually received.  Detailed analysis will be described in the SAP. 

 
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13.3.6 
Immunogenicity Assessment 
Immunogenicity data (ADA and Nab) will be summarized and analyzed descriptively for each 
scheduled protocol assessment timepoint. 
13.3.7 
Efficacy Analysis 
Efficacy will be assessed using the time to event endpoints DFS and OS.  DFS is defined as 
the time from randomization in the neoadjuvant study (Protocol TX05-03) to the 
documentation of a first failure, where a failure is the recurrence of breast cancer or a diagnosis 
of a second primary cancer. 
OS is defined as the time from randomization in the neoadjuvant study (Protocol TX05-03) 
until death from any cause. 
DFS and OS will be summarized using Kaplan-Meier survival curves.  The Kaplan-Meier 
survival estimates, together with the number of subjects, percentage of subjects to experience 
the event, and the number and percentage of subjects censored will be summarized in a table 
by treatment group. 
13.3.8 
Interim Analysis 
There will be no interim analysis. 

 
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14 
DIRECT ACCESS TO SOURCE DATA/NOTES 
The investigator/institution shall provide direct access to source data/documents for 
study-related monitoring, audits, IEC/Institutional Review Board (IRB) review and regulatory 
inspection. 

 
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15 
QUALITY CONTROL AND QUALITY ASSURANCE 
15.1 
Conduct of the Study 
The Sponsor or designee shall implement and maintain quality control and quality assurance 
procedures with written standard operating procedures to ensure that the study is conducted 
and data are generated, documented and reported in compliance with the protocol, ICH GCP, 
and applicable regulatory requirements. 
This study shall be conducted in accordance with the provisions of the Declaration of Helsinki 
(October 1996) and all revisions thereof, and in accordance with FDA regulations (CFR, 
Sections 312.50 and 312.56) and with ICH GCP (CPMP 135/95). 
15.2 
Study Monitoring 
The study will be monitored to ensure that it is conducted and documented according to the 
protocol, GCP, and all applicable regulatory requirements.  On site visits will be made at 
appropriate times during the period of the study.  Monitors must have direct access to source 
documentation in order to check the consistency of the data recorded in the eCRFs. 
The investigator shall permit the monitor to review study data as frequently as deemed 
necessary to ensure that data are being recorded in an adequate manner and that protocol 
adherence is satisfactory. 

 
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16 
ETHICS 
16.1 
Independent Ethics Committee/Institutional Review Board 
Prior to the start of the study, the investigator is responsible for ensuring that the protocol and 
consent form have been reviewed and approved by a relevant IEC/IRB.  The IEC/IRB shall be 
appropriately constituted and perform its functions in accordance with FDA, ICH GCP, and 
local requirements as applicable. 
The investigator may not deviate from the protocol without a formal protocol amendment 
having been established and approved by an appropriate IEC/IRB, except when necessary to 
eliminate immediate hazards to the subject or when the change(s) involve(s) only logistical or 
administrative aspects of the study.  Any deviations may result in the subject having to be 
withdrawn from the study and render that subject non-evaluable. 
The IEC/IRB shall approve all protocol amendments (except for logistical or administrative 
changes), written informed consent documents and document updates, subject recruitment 
procedures (e.g. advertisements), written information to be provided to the subjects, 
Investigator's Brochure, available safety information, information about payment and 
compensation available to subjects, the investigator's curriculum vitae and/or other evidence 
of qualifications and any other documents requested by the IEC/IRB and Regulatory Authority 
(Competent Authority) as applicable. 
16.2 
Written Informed Consent 
All parties will ensure protection of subject personal data and will not include subject names 
on any Sponsor forms, reports, publications, or in any other disclosures, except where required 
by laws. 
The nature and purpose of the study shall be fully explained to each subject (or their legally 
responsible guardian). 
Written informed consent must be obtained from each subject (or guardian) prior to any study 
procedures being performed.  The investigator will keep the original signed copies of all 
consent forms in his/her files and will provide a duplicate copy to the subject. 
The informed consent document used during the informed consent process must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements reviewed by 
the Sponsor or designee, approved by the IRB/IEC before use, and available for inspection.  A 
copy of the letter indicating IEC/IRB approval must be provided to the Sponsor or designee 
prior to the study initiations. 

 
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17 
DATA HANDLING AND RECORD KEEPING 
17.1 
Case Report Forms/Source Data Handling 
Clinical data will be entered on eCRFs for transmission to the Sponsor or designee.  Data on 
eCRFs transmitted via the web based data system must correspond to and be supported by 
source documentation maintained at the study center.  All study forms and records transmitted 
to the Sponsor or designee must carry only coded identifiers such that personally identifying 
information is not transmitted.  The primary method of data transmittal is via the secure, 
internet-based electronic data capture (EDC) system maintained by the Sponsor or designee.  
Access to the EDC system is available to authorized users via the study’s internet website, 
where an assigned username and password are required for access.  The EDC system is in 
compliance with applicable data protection guidelines and regulations. The eCRFs will be 
considered complete when all missing and/or incorrect data have been resolved. 
Source documents are considered to be all information in original records and certified copies 
of original records of clinical findings, observations, data or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. 
17.2 
Retention of Essential Documents 
All records relating to the conduct of this study are to be retained by the investigator according 
to ICH, local regulations, or as specified in the clinical study agreement, whichever is longer.  
Prior to transfer or destruction of these records, the Sponsor must be notified in writing and 
given the opportunity to further store such records.  The investigator will allow representatives 
of Sponsor or Sponsor’s designee (and of the applicable regulatory authorities) to inspect all 
study records, eCRFs, and corresponding portions of the study subjects’ office and/or hospital 
medical records at regular intervals across the study.  These inspections are for the purpose of 
verifying the adherence to the protocol, the completeness and accuracy of the data being filled 
in the eCRF, and compliance with applicable regulations. 
The Sponsor and the investigator agree that the study subject medical records will be 
maintained in a confidential manner.  The clinical study report will not identify any subject by 
name. 

 
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18 
FINANCING AND INSURANCE 
Financial aspects of the study are addressed in a separate clinical study agreement.  The 
principal investigator is required to have adequate current insurance to cover claims for 
negligence and/or malpractice.  The Sponsor will provide insurance coverage for the clinical 
study as required by national regulations. 

 
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19 
PUBLICATION POLICY 
The Sponsor shall retain the ownership of all data.  When the study is complete the Sponsor 
shall arrange the analysis and tabulation of data.  A clinical study report shall then be prepared, 
which may be used for publication, presentation at scientific meetings, or submission to 
regulatory authorities.  All proposed publications based on this study must be subject to the 
Sponsor's approval requirements. 

 
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20 
REFERENCE LIST 
1. 
Olayioye MA, Neve RM, Lane HA, et al. The ErbB signaling network: receptor hetero-
dimerization in development and Cancer. EMBO J 2000;19(13):3159-67. 
2. 
Moasser MM. The Oncogene HER2: its signaling and transforming functions and its 
role in human cancer pathogenesis. Oncogene 2007;26(45):6469-87. 
3. 
Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER2/neu proto-oncogene in 
human breast and ovarian cancer. Science 1989;244(4905):707-12. 
4. 
Lonardo F, Di Marco E, King CR, et al. The normal erbB-2 product is an atypical 
receptor-like tyrosine kinase with constitutive activity in the absence of ligand. New 
Biologist 1990;2(11):992-1003. 
5. 
Fendly BM, Winget M, Hudziak RM, et al. Characterization of murine monoclonal 
antibodies reactive to either the human epidermal growth factor receptor orHER2/neu 
gene product. Cancer Res 1990;50(5):1550-8. 
6. 
Wehrman TS, Raab WJ, Casipit CL, et al. A system for quantifying dynamic protein 
interactions defines a role for Herceptin in modulating ErbB2 interactions. Proc Nati 
Acad Sci 2006;103(50):19063-8. 
7. 
Hudziak RM, Lewis GD, Winget M, et al. p185HER2 monoclonal antibody has 
antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor 
necrosis factor. Mol Cell Biol 1989;9(3):1165-72. 
8. 
Lewis GD, Figari I, Fendly B, et al. Differential responses of human tumor cell lines to 
anti-p185HER2 monoclonal antibodies. Cancer Immunol Immunother 1993;37(4):255-
63. 
9. 
Baselga J, Norton L, Albanell J, et al. Recombinant humanized Anti-HER2 Antibody 
(HerceptinTM) enhances the antitumor activity of paclitaxel and doxorubicin against 
HER2/neu 
overexpressing 
human 
breast 
cancer 
xenografts. 
Cancer 
Res 
1998;58(13):2825-31. 
10. 
Cuello M, Ettenberg SA, Clark AS, et al. Down-regulation of the ErbB-2 receptor by 
Trastuzumab (Herceptin) enhances Tumor necrosis factor-related apoptosis-inducing 
ligand-mediated apoptosis in breast and ovarian cancer cell lines that overexpress ErbB-
2. Cancer Res 2001;61(12):4892-900. 
11. 
Lesniak D, Xu Y, Deschenes J, et al. β1-Integrin Circumvents the Antiproliferative 
Effects of Trastuzumab in Human Epidermal Growth Factor Receptor-2–Positive 
Breast Cancer. Cancer Res 2009;69(22):8620-8. 
12. 
Izumi Y, Xu L, Tomaso E, et al. Tumour biology: Herceptin acts as an anti-angiogenic 
cocktail. Nature 2002;416(6878):279-80. 

 
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13. 
Barok M, Isola J, Palyi-Krekk Z, et al. Trastuzumab causes antibody-dependent cellular 
cytotoxicity-mediated growth inhibition of submacroscopic JIMT-1 breast cancer 
xenografts despite intrinsic drug resistance. Mol Cancer Ther 2007;6(7):2065-72. 
14. 
Musolino A, Naldi N, Bortesi B, et al. Immunoglobulin G fragment C receptor 
polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with 
HER-2/neu-positive metastatic breast cancer. J Clin Oncol 2008;26(11):1789-96. 
15. 
Hanes V, Chow V, Zhang N, et al. A Randomized, Single-Blind, Single-Dose Study 
Evaluating the Pharmacokinetic Equivalence of Proposed Biosimilar ABP 980 and 
Trastuzumab in Healthy Male Subjects. Cancer Chemother Pharmacol 2017;79(5):881-
888. 
16. 
Pivot X, Curtit E, Jung Lee Y, et al. A Randomized Phase I Pharmacokinetic Study 
Comparing Biosimilar Candidate SB3 and Trastuzumab in Healthy Male Subjects. Clin 
Ther 2016;38(7):1665-1673. 
17. 
Yin D, Barker KB, Li R, et al. A randomized phase 1 pharmacokinetic trial comparing 
the potential biosimilar PF-05280014 with trastuzumab in healthy volunteers 
(REFLECTIONS B327-01). Br J Clin Pharmacol 2014;78(6):1281-90. 
18. 
Herceptin US Package Information October 2010. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/103792s5256lbl.pdf. 
 

 
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APPENDICES 
Appendix 1 
ECOG Performance Status 
Grade 
ECOG Definition 
0 
Fully active, able to carry on all pre-disease activities without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g. light house work or 
office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care. Totally confined 
to bed or chair. 
5 
Dead. 

 
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Appendix 2 
Dose Modification Guidelines 
Trastuzumab Dose Modifications 
Trastuzumab Dose Adjustment Guidelines 
Infusion Reaction 
• 
Mild or moderate: decrease rate of infusion 
• 
Dyspnea or clinically significant hypotension: 
interrupt infusion, administer appropriate medical 
therapy, which may include epinephrine, 
corticosteroids, diphenhydramine, bronchodilators, 
or oxygen; monitor until complete resolution 
• 
Severe or life-threatening: consider permanent 
discontinuation 
Decline of LVEF  
Asymptomatic absolute decline ≥16% 
from baseline  
OR  
Absolute decline ≥10% from baseline 
and below the institutional limit of 
normal 
• 
Initiate monthly monitoring of LVEF and consider 
cardiac support 
• 
Hold trastuzumab for at least 4 weeks 
• 
Dosing may resume if within 4-8 weeks the LVEF 
returns to normal limits and the absolute decrease 
from baseline is ≤15%. 
• 
Permanently discontinue trastuzumab 
• 
If persistent (>8 weeks) LVEF decline  
• 
If suspension of trastuzumab dosing on more 
than 3 occasions for cardiomyopathy 
Symptomatic cardiac failure 
• 
Hold trastuzumab, monitor LVEF and seek 
cardiology input