Clinical trial NCT03556358
Conditions: Breast Cancer Breast Neoplasms HER2-positive Breast Cancer Stage II Breast Cancer Stage IIIA Breast Cancer
Keywords: trastuzumab Herceptin
Sponsor: Tanvex BioPharma USA, Inc.
Start date: 2018-06-28; Completion date: 2021-02-04
Enrollment: 809 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase III, double-blind, randomized, multicenter study to compare the efficacy and to evaluate the safety and immunogenicity of TX05 (trastuzumab) with Herceptin® in subjects with HER2 positive early breast cancer.

Detailed description:

Arms: arm 1: • Intravenous (IV) epirubicin, 75 mg/m\^2 and cyclophosphamide 600 mg/m2 every 3 weeks for 4 cycles

Followed by:

• IV TX05 8 mg/kg loading dose then 6 mg/kg and paclitaxel 175 mg/m2 every 3 weeks for 4 cycles arm 2: • Intravenous (IV) epirubicin, 75 mg/m\^2 and cyclophosphamide 600 mg/m2 every 3 weeks for 4 cycles

Followed by:

• IV Herceptin 8 mg/kg loading dose then 6 mg/kg and paclitaxel 175 mg/m2 every 3 weeks for 4 cycles
Interventions: intervention 1: TX05 (trastuzumab) intervention 2: Herceptin® intervention 3: Paclitaxel intervention 4: Epirubicin intervention 5: Cyclophosphamide
Intervention descriptions: intervention 1: 8 mg/kg, 90 min IV infusion (Cycle 5), followed by 6 mg/kg, 60 min IV infusion (Cycles 6 - 8) intervention 2: 8 mg/kg, 90 min IV infusion (Cycle 5), followed by 6 mg/kg, 60 min IV infusion (Cycles 6 - 8) intervention 3: 175 mg/m\^2, 60 min IV infusion, every 3 weeks (Cycles 5-8) intervention 4: 75 mg/m\^2, IV bolus infusion, every 3 weeks (Cycles 1-4) intervention 5: 600 mg/m\^2, 30 min IV infusion, every 3 weeks (Cycles 1-4)

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
A randomized, double-blind, parallel group, Phase III trial to compare the efficacy, safety, and 
immunogenicity of TX05 with Herceptin® in subjects with HER2 positive early breast cancer 
NCT03556358 
Document Date: 30 November 2017 
 


Tanvex Biologics Corp. 
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1 
TITLE PAGE 
CLINICAL STUDY PROTOCOL 
A randomized, double-blind, parallel group, Phase III trial to compare the efficacy, 
safety, and immunogenicity of TX05 with Herceptin® in subjects with HER2 positive 
early breast cancer 
 
 
Protocol No.:  TX05-03 Amendment 1 
IND No.:  116582 
EudraCT No.:  2017-004190-13 
Test Product: 
TX05 (Trastuzumab) 
Indication: 
Breast Cancer 
Sponsor: 
Tanvex Biologics Corp. 
Development Phase: 
III 
Sponsor Signatory: 
 
Date of the Protocol: 
30 November 2017 
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 randomized, double-blind, parallel group, Phase III trial to 
compare the efficacy, safety, and immunogenicity of TX05 with Herceptin® in subjects 
with HER2 positive early breast cancer 
 
PROTOCOL NUMBER:  TX05-03 
 
 
 
 
 
Signature 
 
 


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INVESTIGATOR SIGNATURE PAGE 
 
PROTOCOL TITLE:  A randomized, double-blind, parallel group, Phase III trial to 
compare the efficacy, safety, and immunogenicity of TX05 with Herceptin® in subjects 
with HER2 positive early breast cancer 
 
PROTOCOL NUMBER:  TX05-03 
 
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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Page 5 of 79 
 
3 
GENERAL INFORMATION 
A randomized, double-blind, parallel group, Phase III trial to compare the efficacy, 
safety, and immunogenicity of TX05 with Herceptin® in subjects with HER2 positive 
early breast cancer 
Protocol No.: 
TX05-03 
Date of the Protocol: 
30 November 2017 
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 randomized, double-blind, parallel group, Phase III trial to compare the efficacy, safety, and immunogenicity 
of TX05 with Herceptin® in subjects with HER2 positive early breast cancer 
Study Center(s): 
It is planned that approximately 209 centers will be initiated for this study in 19 countries. 
Publication(s): 
None. 
Planned Study Period: 
October 2017 to August 2019 
Development Phase: 
Phase III 
Objectives: 
Primary Objective: 
To demonstrate the therapeutic equivalence of TX05 (proposed biosimilar trastuzumab) to Herceptin 
(trastuzumab) based on the pathologic complete response (pCR) rate following neoadjuvant chemotherapy, 
defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected 
breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy 
(ypT0/Tis ypN0), in subjects with human epidermal growth factor receptor positive (HER2+) invasive early 
breast cancer (EBC). 
Secondary Objective: 
To compare objective response rate (ORR) between the 2 treatment arms; immunogenicity, safety, and 
tolerability will also be assessed. 
Methodology: 
This is a randomized, double-blinded, parallel group, equivalence, multicenter Phase III study.  The study will 
consist of a Screening period (Days -28 to 0), and 8 cycles of neoadjuvant treatment (Week 0 [Day 1] to 
Week 24), followed by surgery (3 to 7 weeks from the 1st day of the last cycle/last dose of study drug).  
Post-surgery, subjects may be eligible to enroll in a separate (extension) protocol to receive single agent 
adjuvant treatment with trastuzumab (Herceptin or TX05) for up to 10 treatment cycles. 
800 subjects with HER2+ EBC will be randomized (1:1) to receive up to 8 cycles of neoadjuvant chemotherapy 
as follows:  
• 
Intravenous (IV) epirubicin, 75 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks for 4 cycles  
Followed by either: 
• 
IV TX05 8 mg/kg loading dose then 6 mg/kg and paclitaxel 175 mg/m2 every 3 weeks for 4 cycles. 
OR  
• 
IV Herceptin 8 mg/kg loading dose then 6 mg/kg and paclitaxel 175 mg/m2 every 3 weeks for 4 cycles.  
Tumor status will be evaluated at Screening.  Radiographic assessments (computed tomography [CT] scan of 
chest or magnetic resonance imaging of chest [only if CT scan cannot be performed] and bilateral 
mammography or ultrasound) obtained per the subject’s standard of care (SOC) prior to randomization do not 
need to be repeated and are acceptable to use as baseline evaluations, as long as the following criteria are met: 
• 
Obtained within 6 weeks before randomization.  
• 
Were performed using the method requirements outlined in Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 (see Appendix 4), and 
• 
Are the same technique/modality that will be used to follow identified lesions throughout the trial and at the 
End of Treatment/Early Termination (EOT/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 
Subjects will attend study visits every 3 weeks (± 3 days).  Study procedures include physical examination, vital 
signs, weight, Eastern Cooperative Oncology Group (ECOG) performance status, clinical laboratory tests, 
adverse events (AEs), and concomitant medication. 
Cardiac safety will be assessed at Screening, Cycle 5 (Week 12) (prior to administration of study drug), and at 
the EOT/ET Visit using 12-lead electrocardiogram (ECG) and echocardiography or multi-gated acquisition 
(MUGA) 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 prior to initiation of infusion at Cycle 5 (Week 12), prior to infusion at Cycle 7 (Week 18), and the 
EOT/ET Visit. 
Pharmacokinetic samples for assessment of trough serum concentration (Ctrough) will be taken from 100 subjects 
in each treatment arm (200 total) prior to initiation of infusion at Cycle 5 (Week 12), Cycle 6 (Week 15), 
Cycle 7 (Week 18), Cycle 8 (Week 21), and the EOT/ET Visit. 
Subjects completing neoadjuvant treatment (and those prematurely discontinuing neoadjuvant treatment at any 
time) will attend an EOT/ET Visit, 3 weeks after last administration of study drug (Week 24).  Subjects will 
undergo a definitive surgical resection of their primary tumor, as part of their SOC, i.e., lumpectomy or 
mastectomy with sentinel node (SN) biopsy or axillary lymph node dissection (ALND).  Surgical resection will 
be performed within 3 to 7 weeks from the 1st day of the last cycle/last dose of study drug. 
The primary efficacy endpoint, pCR, is the proportion of subjects in each treatment arm who achieve pCR 
(ypT0/Tis ypN0).  Pathology of the tumor sample and pathologic response will be assessed locally and reviewed 
centrally by a qualified pathologist.  Assessments will be compliant with FDA guidance and sites will be 
provided with training for site pathologists.  Surgeons will follow the standard local process for performing the 
biopsy. 
Number of Subjects: 
It is planned that 800 subjects will be enrolled to ensure completion of 740 subjects. 
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. Histologically confirmed HER2 overexpressing invasive primary operable Stage II/IIIa breast cancer by 
American Joint Committee on Cancer 7th Edition staging criteria.  Tumor tissue sample must be available 
for central analysis. 
4. Planned surgical resection of breast tumor (lumpectomy or mastectomy, and SN biopsy or ALND). 
5. Planned neoadjuvant chemotherapy. 
6. HER2 overexpression as assessed by: 
- 
Gene amplification by fluorescent in-situ hybridization (FISH), chromogenic in-situ hybridization 
(CISH), or dual in-situ hybridization (DISH) (as defined by the manufacturer’s kit instruction); OR 
- 
Overexpression by immunohistochemistry (IHC) categorized as IHC 3+; OR 
- 
Overexpression by immunohistochemistry categorized as IHC2+ with FISH, CISH, or DISH 
confirmation. 
Central review will be performed retrospectively for subjects who were determined to be HER2 positive by 
use of either an approved assay listed in Appendix 1 or two different analytical test methods that were not 
considered Sponsor approved.  The results from non-approved IHC and in-situ hybridization analytical tests 
must be unequivocal (i.e., IHC result must be categorized as IHC3+). 
If a subject’s tumor HER2 status cannot be determined by using an approved assay (see Appendix 1) or two 
different HER2 assays performed locally, a tissue sample can be sent to the central laboratory early in 


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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 
Screening for evaluation; results of the assessment will be returned to the investigator for inclusion in 
subjects’ source documents. 
7. Ipsilateral, measurable tumor longest diameter > 2 cm. 
8. Known estrogen receptor (ER) and progesterone receptor (PR) hormone status prior to randomization.  If 
ER/PR status is not available locally, testing may be performed by central laboratory during Screening. 
9. ECOG performance status of 0 or 1. 
10. Adequate bone marrow, hepatic, and renal functions as evidenced by the following: 
- 
Absolute neutrophils count ≥ 1,500/µL 
- 
Hemoglobin ≥ 9 g/dL 
- 
Platelet count ≥ 100,000/µL 
- 
Creatinine clearance ≥ 40 mL/min 
- 
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) 
- 
Aspartate 
aminotransferase 
(serum 
glutamic 
oxaloacetic 
transaminase) 
and 
alanine 
 
aminotransferase (serum glutamic pyruvic transaminase) ≤ 2.5 x ULN 
- 
Alkaline phosphatase ≤ 5 x ULN 
11. LVEF ≥ 50% or within the normal level of the institution, as assessed by echocardiography or MUGA scan. 
12. Able to comply with the study protocol. 
13. Female subjects of childbearing potential must have a negative serum pregnancy test within 1 week 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 
6 months after last administration of study drug. 
Exclusion Criteria 
Subjects meeting any of the following criteria must not be enrolled in the study: 
1. Participation in any interventional clinical study or having taken any investigational therapy during the 
2 month period immediately preceding administration of the first dose of study drug. 
2. Bilateral breast cancer. 
3. Inflammatory breast cancer. 
4. Metastases. 
5. Previous chemotherapy, biologic therapy, radiation, or surgery for any active malignancy, including breast 
cancer. 
6. Subjects with one or more of the following conditions: 
- 
Cardiac insufficiency (New York Heart Association III or IV); myocardial infarction, 
coronary/peripheral artery bypass graft, congestive heart failure, cerebrovascular accident, unstable 
angina pectoris, uncontrolled arrhythmia, or pulmonary embolus within the previous 12 months prior to 
the first administration of study drug. 
- 
Clinically significant active infection. 
- 
Poorly controlled diabetes mellitus. 
- 
Uncontrolled hypertension (blood pressure > 150/100 mmHg despite optimal medical therapy). 
- 
Major surgery, significant traumatic injury, or radiation therapy within 4 weeks of first administration 
of study drug. 
- 
Grade 3 hemorrhage within 4 weeks of first administration of study drug. 
7. Pre-existing clinically significant (≥ Grade 2) peripheral neuropathy. 
8. History of malignancy within the last 5 years, except adequately excised squamous or basal cell carcinoma 
of the skin, cervical carcinoma in situ, and superficial bladder cancer. 
9. Severe dyspnea at rest requiring supplementary oxygen therapy. 


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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 
10. Known positive status for human immunodeficiency virus. 
11. Known acute or chronic-active infection with hepatitis B surface antigen or hepatitis C virus. 
12. 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. 
13. Lactating or pregnant female. 
14. 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 6 months after the last administration of study drug.  
Subjects must agree to not breast-feed while receiving study drug. 
15. Subject has known sensitivity to any of the products to be administered during the study, including 
mammalian cell derived drug products, trastuzumab, murine proteins, or to any of the excipients. 
16. Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range 
despite optimal medical therapy. 
17. Subject likely to not be available to complete all protocol required study visits or procedures. 
Test Product, Dose, and Mode of Administration: 
IV TX05 8 mg/kg loading dose then 6 mg/kg and paclitaxel 175 mg/m2 every 3 weeks for 4 cycles. 
Treatment with TX05 will be preceded by IV epirubicin, 75 mg/m2 and cyclophosphamide 600 mg/m2 every 
3 weeks for 4 cycles. 
Reference Therapy, Dose, and Duration of Administration: 
IV Herceptin 8 mg/kg loading dose then 6 mg/kg and paclitaxel 175 mg/m2 every 3 weeks for 4 cycles.  
Treatment with Herceptin will be preceded by IV epirubicin, 75 mg/m2 and cyclophosphamide 600 mg/m2 every 
3 weeks for 4 cycles. 
Duration of Treatment: 
The study will consist of a Screening period (Days -28 to 0) and a double-blind neoadjuvant treatment period 
(Week 0 [Day 1] to Week 21), an EOT/ET Visit at Week 24, followed by surgery (3 to 7 weeks from the 1st day 
of the last cycle/last dose of study drug). 
Criteria for Evaluation: 
Efficacy Endpoints: 
Primary efficacy endpoint: the proportion of subjects in each treatment arm who, based on the central 
pathological review, achieve pCR, defined as the absence of residual invasive cancer on hematoxylin and eosin 
evaluation of the complete resected breast specimen and all sampled regional lymph nodes following 
completion of neoadjuvant systemic therapy (ypT0/Tis ypN0).  Pathology of the tumor sample and pathologic 
response will be assessed locally and reviewed centrally by a qualified pathologist.  The primary efficacy 
analysis will be based on the central pathological review. 
Secondary efficacy endpoint: ORR, according to RECIST version 1.1 (see Appendix 4), as assessed by the 
investigator. 
Immunogenicity Assessments: 
• 
Incidence of ADA. 
• 
Incidence of Nab. 
Safety Assessments: 
• 
Treatment-emergent AE (TEAE) and serious AE (SAE). 
• 
Death 
• 
Clinical laboratory parameters 


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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 
• 
Vital signs 
• 
12-Lead ECG cardiac ejection fraction 
• 
Physical examination 
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 modified intent-to-treat (mITT) population will include all subjects who are randomized into the study and 
receive at least 1 dose of TX05 or Herceptin.  The mITT population will be used for sensitivity analysis of the 
primary efficacy endpoint and for primary analysis of secondary efficacy endpoints. 
The per protocol (PP) population will include all subjects who meet all of the following criteria: 
• 
mITT population. 
• 
No major protocol deviations that impact the efficacy endpoints. 
• 
An adequate tumor sample by definitive surgical resection of their primary tumor.  
The PP population will be used as the primary analysis for the primary efficacy endpoint. 
The safety population will include all subjects who are randomized into the study and have received at least one 
dose of study drug.  The safety population will be used for safety and immunogenicity endpoints. 
Two one-sided hypothesis tests will be performed in the study for pCR in order to show that TX05 is equivalent 
to Herceptin: 
 
TEST 1: H0a: θ1 / θ2 > 1.325  vs. H1a: θ1 / θ2 < 1.325 
 
TEST 2: H0b: θ1 / θ2 < 0.755  vs. H1b: θ1 / θ2 > 0.755 
Where θ1 is the proportion of pCR for subjects randomized to TX05 group, θ2 is the proportion of pCR for 
subjects randomized to Herceptin.  Equivalence will be concluded if the 95% confidence interval of the risk 
ratio is completely contained within the pre-defined interval [0.755, 1.325]. 
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 ............................................................................................ 11 
5.1 
List of Tables .................................................................................................. 14 
5.2 
List of Figures................................................................................................. 14 
5.3 
List of Appendices and Supplements ............................................................. 14 
6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................ 15 
7 
INTRODUCTION ....................................................................................................... 17 
7.1 
Background..................................................................................................... 17 
7.2 
Nonclinical Studies ......................................................................................... 18 
7.2.1 
Nonclinical Pharmacology ......................................................................... 18 
7.2.2 
Pharmacokinetics ....................................................................................... 18 
7.2.3 
Toxicology ................................................................................................. 19 
7.2.4 
Summary and Nonclinical Safety Assessment .......................................... 19 
7.3 
Clinical Studies ............................................................................................... 20 
7.3.1 
Pharmacokinetics ....................................................................................... 20 
7.3.2 
Safety ......................................................................................................... 21 
7.4 
Rationale ......................................................................................................... 21 
8 
STUDY OBJECTIVES ............................................................................................... 23 
8.1 
Primary Objective ........................................................................................... 23 
8.2 
Secondary Objective ....................................................................................... 23 
9 
INVESTIGATIONAL PLAN ...................................................................................... 24 
9.1 
Overall Study Design and Plan....................................................................... 24 
9.1.1 
Schedule of Assessments ........................................................................... 26 
9.1.2 
Study Assessments ..................................................................................... 31 
9.1.2.1 
Screening Period -28 days .......................................................... 31 
9.1.2.2 
Randomization............................................................................ 31 
9.1.2.3 
Treatment Period: Epirubicin + Cyclophosphamide: Cycle 1 
(Week 0) to Cycle 4 (Week 9) .................................................... 32 
9.1.2.4 
Treatment Period: TX05/Herceptin + Paclitaxel: Cycle 5 
(Week 12) to Cycle 8 (Week 21) ................................................ 33 
9.1.2.5 
End of Treatment/Early Termination Visit (Week 24) - Prior 
to Surgery ................................................................................... 34 
9.1.2.6 
Surgery (Week 24 to 28 - 3 to 7 weeks from the 1st day of 
the last cycle/last dose of study drug)......................................... 34 
9.2 
Discussion of Study Design............................................................................ 35 


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9.2.1 
Risk/Benefit and Ethical Assessment ........................................................ 35 
9.3 
Selection of Study Population ........................................................................ 37 
9.3.1 
Inclusion Criteria ....................................................................................... 37 
9.3.2 
Exclusion Criteria ...................................................................................... 38 
9.3.3 
Withdrawal of Subjects .............................................................................. 39 
9.3.4 
Lost to Follow-Up ...................................................................................... 40 
9.3.5 
Early Termination ...................................................................................... 40 
9.3.6 
Missed Dose ............................................................................................... 40 
10 
TREATMENT OF SUBJECTS ................................................................................... 42 
10.1 
Identity of Study Treatment(s) ....................................................................... 42 
10.1.1 
Administration of Study Treatment(s) ....................................................... 42 
10.2 
Treatment Regimen Adjustments ................................................................... 42 
10.3 
Study Treatment Packaging and Labeling ...................................................... 43 
10.3.1 
Storage ....................................................................................................... 43 
10.4 
Blinding and Randomization of Study Treatment(s)...................................... 43 
10.4.1 
Procedure for Breaking the Randomization Code ..................................... 43 
10.5 
Subject Compliance ........................................................................................ 44 
10.6 
Study Treatment Accountability ..................................................................... 44 
10.7 
Concomitant Therapy ..................................................................................... 44 
11 
ASSESSMENTS ......................................................................................................... 46 
11.1 
Endpoints ........................................................................................................ 46 
11.1.1 
Primary Endpoint: ...................................................................................... 46 
11.1.2 
Secondary Endpoint: .................................................................................. 46 
11.1.3 
Immunogenicity Assessments: .................................................................. 46 
11.2 
Disease Assessment ........................................................................................ 46 
11.3 
Definitive Surgical Resection ......................................................................... 47 
11.4 
Objective Response Rate ................................................................................ 47 
11.5 
Tumor HER2, Progesterone Receptor and Estrogen Receptor Testing ......... 48 
11.6 
Echocardiogram/MUGA ................................................................................ 48 
11.7 
Pharmacokinetic Sampling ............................................................................. 48 
11.8 
Immunogenicity Sampling ............................................................................. 49 
11.9 
Laboratory Assessments ................................................................................. 49 
11.10 
Electrocardiogram Assessments ..................................................................... 50 
11.11 
Physical Examination ..................................................................................... 50 
11.12 
Vital Signs ...................................................................................................... 51 
12 
SAFETY MONITORING AND REPORTING .......................................................... 52 
12.1 
Adverse Events ............................................................................................... 52 
12.1.1 
Definitions ................................................................................................. 52 
12.1.1.1 Recording of Adverse Events ..................................................... 52 
12.1.2 
Abnormal Laboratory Values/Vital Signs/Electrocardiograms ................. 54 


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12.1.3 
Deaths ........................................................................................................ 55 
12.1.4 
Overdose .................................................................................................... 55 
12.1.5 
Pregnancy .................................................................................................. 55 
12.1.6 
Reporting of Serious Adverse Events ........................................................ 55 
13 
STATISTICAL EVALUATION ................................................................................. 57 
13.1 
Sample Size and Power .................................................................................. 57 
13.2 
Analysis Populations ...................................................................................... 58 
13.2.1 
Modified Intent to Treat Population .......................................................... 58 
13.2.2 
Per Protocol Population ............................................................................. 58 
13.2.3 
Safety Population ....................................................................................... 58 
13.3 
Statistical Methods ......................................................................................... 58 
13.3.1 
General Principles ...................................................................................... 58 
13.3.2 
Missing Data .............................................................................................. 58 
13.3.3 
Demographic and Baseline Characteristics ............................................... 59 
13.3.4 
Subject Disposition .................................................................................... 59 
13.3.5 
Efficacy Analysis ....................................................................................... 59 
13.3.5.1 Analysis of Primary Endpoint .................................................... 59 
13.3.5.2 Analysis of Secondary Endpoint ................................................ 59 
13.3.6 
Immunogenicity Assessment ..................................................................... 60 
13.3.7 
Safety Analysis .......................................................................................... 60 
13.3.8 
Interim Analysis ......................................................................................... 60 
14 
DIRECT ACCESS TO SOURCE DATA/NOTES ..................................................... 61 
15 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 62 
15.1 
Conduct of the Study ...................................................................................... 62 
15.2 
Study Monitoring............................................................................................ 62 
16 
ETHICS ....................................................................................................................... 63 
16.1 
Independent Ethics Committee/Institutional Review Board .......................... 63 
16.2 
Written Informed Consent .............................................................................. 63 
17 
DATA HANDLING AND RECORD KEEPING ....................................................... 64 
17.1 
Case Report Forms/Source Data Handling..................................................... 64 
17.2 
Retention of Essential Documents .................................................................. 64 
18 
FINANCING AND INSURANCE .............................................................................. 65 
19 
PUBLICATION POLICY ........................................................................................... 66 
20 
REFERENCE LIST ..................................................................................................... 67 
21 
APPENDICES ............................................................................................................. 70 
 


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5.1 
List of Tables 
Table 9–1 
Schedule of Assessments ................................................................................... 27 
Table 9–2 
Schedule of Blood Sampling .............................................................................. 30 
Table 11–1 
Hematology and Clinical Chemistry Assessments............................................. 50 
Table 12–1 
Classification of AE Relationship to Investigational Product ............................ 54 
Table 13–1 
Rates of pCSR from Neoadjuvant Herceptin Studies ........................................ 57 
 
5.2 
List of Figures 
Figure 9–1 
Study Design Flow Diagram .............................................................................. 26 
 
5.3 
List of Appendices and Supplements 
Appendix 1 
Approved HER2 Assays 
Appendix 2 
ECOG Performance Status 
Appendix 3 
Estimated Creatinine Clearance Using the Cockcroft-Gault formula 
Appendix 4 
RECIST version 1.1 Guidelines 
Appendix 5 
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 
ALND 
Axillary lymph node dissection 
ANC 
Absolute neutrophil counts 
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 
BSA 
Body surface area 
CI 
Confidence interval 
CISH 
Chromogenic in-situ hybridization 
Cmax 
Maximum concentration 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Trough serum concentration 
DISH 
Dual in-situ hybridization 
EBC 
Early breast cancer 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
EOT 
End of Treatment 
ER 
Estrogen receptor 
ET 
Early termination 
EU 
European Union 
FDA 
Food and Drug Administration 
FISH 
Fluorescent in-situ hybridization 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HER 
Human epidermal growth factor receptor 
HIV 
Human immunodeficiency virus 
ICH 
International Council for Harmonization 
IEC 
Independent ethics committee 
IgG1 
Immunoglobulin G1 


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IHC 
Immunohistochemistry 
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 
mITT 
Modified intent-to-treat 
MRI 
Magnetic resonance imaging 
MUGA 
Multi-gated acquisition 
Nab 
Neutralizing antibodies 
NCCN 
National Comprehensive Cancer Network 
NOAH 
Neoadjuvant Herceptin 
ORR 
Objective response rate 
pCR 
Pathologic complete response 
PK 
Pharmacokinetic 
PP 
Per protocol 
PR 
Progesterone receptor 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SN 
Sentinel node 
SOC 
Standard of care 
SOP 
Standard operating procedure 
SST 
Serum separator tube 
t1/2 
Terminal half-life 
TEAE 
Treatment-emergent adverse event 
TK 
Toxicokinetic 
Tmax 
Time to maximum concentration 
TNFα 
Tumor necrosis factor alpha 
ULN 
Upper limit of normal 
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 the 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 level 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.  


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Study results and adverse events (AEs) associated with the use of trastuzumab are described 
in the Herceptin package insert. 
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 samples 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 (t1/2), 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 


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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 
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 labelled 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% dose/g 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 


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pharmacology studies demonstrated the biosimilarity of TX05 to US-licensed Herceptin, with 
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, in-life, 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 


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completed 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. 
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.  


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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. 
A randomized, double-blind, parallel group, trial in subjects with HER2 positive EBC will be 
conducted to demonstrate that TX05 has similar efficacy, safety, and immunogenicity to 
Herceptin.  Subjects who complete this study may be eligible to enroll in a separate 
(extension) protocol designed to further assess and characterize the safety 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 
8.1 
Primary Objective 
To demonstrate the therapeutic equivalence of TX05 (proposed biosimilar trastuzumab) to 
Herceptin (trastuzumab) based on the pathologic complete response (pCR) rate following 
neoadjuvant chemotherapy, defined as the absence of residual invasive cancer on 
hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled 
regional 
lymph 
nodes 
following 
completion 
of 
neoadjuvant 
systemic 
therapy 
(ypT0/Tis ypN0), in subjects with HER2 positive (HER2+) invasive EBC. 
8.2 
Secondary Objective 
To compare objective response rate (ORR) between the 2 arms; immunogenicity, safety, and 
tolerability will also be assessed. 


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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a randomized, double-blinded, parallel group, equivalence, multicenter Phase III 
study.  The study will consist of a Screening period (Days -28 to 0), and 8 cycles of 
neoadjuvant treatment (Week 0 [Day 1] to Week 21), followed by surgery (3 to 7 weeks from 
the 1st day of the last cycle/last dose of study drug).  Post-surgery, subjects may be eligible to 
enroll in a separate (extension) protocol to receive adjuvant treatment with trastuzumab 
(Herceptin or TX05) for up to 10 treatment cycles. 
800 subjects with HER2+ EBC will be randomized (1:1) to receive up to 8 cycles of 
neoadjuvant chemotherapy as follows:  
• IV epirubicin, 75 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks for 4 cycles  
Followed by either: 
• IV TX05 8 mg/kg loading dose then 6 mg/kg and paclitaxel 175 mg/m2 every 3 weeks for 
4 cycles. 
OR 
• IV Herceptin 8 mg/kg loading dose then 6 mg/kg and paclitaxel 175 mg/m2 every 
3 weeks for 4 cycles.  
Tumor status will be evaluated at Screening.  Radiographic assessments (computed 
tomography [CT] scan of chest or magnetic resonance imaging [MRI] of chest [only if CT 
scan cannot be performed] and bilateral mammography or ultrasound) obtained per the 
subject’s standard of care (SOC) prior to randomization do not need to be repeated and are 
acceptable to use as baseline evaluations, as long as the following criteria are met: 
• Obtained within 6 weeks before randomization.  
• Were performed using the method requirements outlined in Response Evaluation Criteria 
in Solid Tumors (RECIST) version 1.1 (see Appendix 4), and  
• Are the same technique/modality that will be used to follow identified lesions throughout 
the trial and at the End of Treatment/Early Termination (EOT/ET) Visit. 
Subjects will attend study visits every 3 weeks (± 3 days).  Study procedures include physical 
examination, vital signs, weight, Eastern Cooperative Oncology Group (ECOG) performance 
status, clinical laboratory tests, AEs, and concomitant medication. 
Cardiac safety will be assessed at Screening, Cycle 5 (Week 12) (prior to administration of 
study drug), and at the EOT/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 
prior to initiation of infusion at Cycle 5 (Week 12), prior to infusion at Cycle 7 (Week 18), 
and the EOT/ET Visit. 


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Pharmacokinetic samples for assessment of trough serum concentration (Ctrough) will be taken 
from 100 subjects in each treatment arm (200 total) prior to initiation of infusion at Cycle 5 
(Week 12), Cycle 6 (Week 15), Cycle 7 (Week 18), Cycle 8 (Week 21), and the EOT/ET 
Visit. 
Subjects completing neoadjuvant treatment (and those prematurely discontinuing neoadjuvant 
treatment at any time) will attend an EOT/ET Visit, 3 weeks after last administration of study 
drug (Week 24 or earlier if subject prematurely discontinued).  Subjects will undergo a 
definitive surgical resection of their primary tumor, as part of their SOC, i.e., lumpectomy or 
mastectomy with sentinel node (SN) biopsy or axillary lymph node dissection (ALND).  
Surgical resection will be performed within 3 to 7 weeks from the 1st day of the last 
cycle/last dose of study drug. 
The primary efficacy endpoint, pCR, is the proportion of subjects in each treatment arm who 
achieve pCR (ypT0/Tis ypN0).  Pathology of the tumor sample and pathologic response will 
be assessed locally and reviewed centrally by a qualified pathologist.  Assessments will be 
compliant with FDA guidance15 and sites will be provided with training for site pathologists, 
providing detailed instructions for the pathologists’ awareness.  Surgeons will follow the 
standard local process for performing the biopsy.  Full instructions for the preparation, 
handling, and shipping of the pathology samples will be included in the central laboratory 
manual. 
 


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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 
(-28 days)1 
Randomization1 
Neoadjuvant Cycle (week) 
EOT/ET2  
Surgery3 
Epirubicin + 
Cyclophosphamide 
Trastuzumab + Paclitaxel 
1 (0) 
2 (3) 
3 (6) 
4 (9) 
5 (12) 
6 (15) 
7 (18) 
8 (21) 
Week 24 
Visit Window (days) 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
 
Informed consent4 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical & surgical history 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination5 
X 
 
 
 
 
 
 
 
 
X 
 
Weight and BSA6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy test8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
Histologically confirmed 
invasive breast cancer 
X 
 
 
 
 
 
 
 
 
 
 
HER2 expression9 
X 
 
 
 
 
 
 
 
 
 
 
ER & PR Testing10 
X 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Viral disease screen12 
X 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
X 
 
 
 
 
X 
 
 
 
X 
 
LVEF (echocardiography 
or MUGA) 
X 
 
 
 
 
X 
 
 
 
X 
 


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Study Procedure 
Screening 
(-28 days)1 
Randomizat
ion1 
Neoadjuvant Cycle (week) 
EOT/ET2  
Surgery3 
Epirubicin + 
Cyclophosphamide 
Trastuzumab + Paclitaxel 
1 (0) 
2 (3) 
3 (6) 
4 (9) 
5 (12) 
6 (15) 
7 (18) 
8 (21) 
Week 24 
Study drug administration13 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Immunogenicity sampling14 
 
 
 
 
 
X 
 
X 
 
X 
 
PK sampling15 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Tumor assessment16 
X 
 
 
 
 
 
 
 
 
X 
 
AE assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Subject compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Definitive surgical 
resection17 
 
 
 
 
 
 
 
 
 
 
X 
AE: Adverse Event; BSA: Body Surface Area; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EOT/ET: End of Treatment/Early Termination; ER: 
Estrogen Receptor; HER: Human epidermal growth factor receptor; LVEF: Left ventricular ejection fraction; MUGA: Multi-gated acquisition; PK: pharmacokinetic; PR: 
Progesterone Receptor. 
1. All Screening procedures, laboratory results, and repeat laboratory results must be completed and reviewed within the screening period prior to randomization.  
Randomization of eligible subjects is preferred no more than 4 business days before administration of first dose of study drug. 
2. All subjects completing neoadjuvant treatment (and those prematurely discontinuing neoadjuvant treatment at any time) will attend an EOT/ET Visit 3 weeks after last 
administration of study drug.  The allowable window for the EOT/ET Visit is ± 7 days. 
3. Subjects will undergo a definitive surgical resection of their primary tumor, as part of their standard of care (SOC), 3 to 7 weeks from the 1st day of the last cycle/last 
dose of study drug. 
4. Informed consent must be obtained prior to undergoing any study-specific procedure and may occur prior to the 28-day Screening period. 
5. Complete physical examinations will be conducted at Screening and at the EOT/ET Visit.  All other evaluations will be at the discretion of the investigator.  Height will 
be recorded at Screening only. 
6. Weight and BSA will be recorded at Screening and Day 1 of each cycle and as clinically indicated.  The weight from Day 1 of Cycles 5, 6, 7, and 8 should be used to 
calculate the dosage of trastuzumab to be administered.  The BSA from Day 1 of each cycle should be used to calculate the dosage of chemotherapy to be administered. 
7. Temperature, blood pressure, pulse rate, and respiratory rate will be recorded at each timepoint.  


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8. Subjects of childbearing potential will have a blood serum pregnancy test at Screening.  A urine pregnancy test will also be performed prior to each treatment cycle to 
exclude potential pregnancy. 
9. HER2-positive tumor status for study eligibility will be based on the test performed by the local laboratory at the time of diagnosis or as determined by the central 
laboratory where not known locally.  HER2 status that was determined locally will be confirmed by the central laboratory.  Tumor tissue sample must be available for 
central analysis. 
10. Only for subjects with unknown ER and/or PR status. 
11. Clinical laboratory tests (hematology, clinical chemistry, and urinalysis) will be performed by local laboratories. 
12. Hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), and/or human immunodeficiency virus (HIV) to be conducted by local laboratory only in countries where 
regulations mandate testing or if warranted by known subject history. 
13. Subjects will receive 8 cycles of neoadjuvant chemotherapy: Cycles 1-4: epirubicin 75 mg/m2 by IV bolus infusion and cyclophosphamide 600 mg/m2 by 30-minute IV 
infusion, on Day 1 of the treatment cycle and thereafter every 3 weeks until Cycle 4.  Cycles 5 to 8: TX05 or Herceptin 8 mg/kg body weight by 90-minute IV infusion 
and paclitaxel 175 mg/m2 administered over 60 minutes by IV infusion followed by TX05 of Herceptin 6 mg/kg body weight by 60-minute IV infusion and paclitaxel 
175 mg/m2 administered over 60 minutes by IV infusion, on Day 1 of the treatment cycle and thereafter every 3 weeks until Cycle 8. 
14. Serum samples for detection of anti-drug antibodies (ADA) and neutralizing antibodies (Nab) will be collected prior to initiation of infusion at Cycle 5 (Week 12), prior 
to infusions at Cycle 7 (Week 18), and the EOT/ET Visit.  For those subjects who terminate the study early before Cycle 5, there is no need to take the EOT/ET ADA 
sample. 
15. For 100 subjects in each of the 2 treatment arms (200 subjects total), PK samples will be taken prior to initiation of infusion at Cycle 5 (Week 12), Cycle 6 (Week 15), 
Cycle 7 (Week 18), Cycle 8 (Week 21), and the EOT/ET Visit.  PK samples will be taken for assessment of trough serum concentration (Ctrough). 
16. Computed tomography (CT) scan of chest or magnetic resonance imaging (MRI) of chest (only if CT scan cannot be performed) and bilateral mammography or 
ultrasound of the breast required at Screening for all subjects, within 6 weeks prior to randomization.  Unilateral repeat mammography or ultrasound of the breast must 
be performed at the EOT/ET Visit and as clinically indicated.  Radiographic assessments obtained per the subject’s SOC prior to randomization do not need to be 
repeated if (1) they were obtained within 6 weeks prior to randomization, (2) they were performed using the method requirements outlined in Response Evaluation 
Criteria in Solid Tumors (RECIST version 1.1) (3) the same imaging technique should be used throughout the study for the subject, and (4) appropriate documentation 
indicating that these radiographic tumor assessments were performed as SOC is available in the subject’s source notes.  Final disease assessment at the EOT/ET Visit 
will include repeat CT scan of chest or MRI of chest (only if CT scan cannot be performed) and unilateral mammography or ultrasound of breast. Assessments are not to 
be scheduled based on the scheduled calendar date of the EOT/ET Visit.  
17. Subjects will undergo a definitive surgical resection of their primary tumor, as part of their SOC, i.e., lumpectomy or mastectomy with sentinel node (SN) biopsy or 
axillary lymph node dissection (ALND).  Surgical resection will be performed within 3 to 7 weeks from the 1st day of the last cycle/last dose of study drug.  Pathology of 
the tumor sample and pathologic response will be assessed locally and reviewed centrally by a qualified pathologist. 
 


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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) 
EOT/ET 
Visit 
Hematology 
4 mL 
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 
4.5 mL 
Pharmacokinetics 
(100 subjects per 
treatment arm) 
 
 
 
 
 
7 mL 
7 mL 
7 mL 
7 mL 
7 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 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 -28 days 
Subjects are to undergo a Screening Visit 28 days prior to the planned first day of study 
treatment.  Screening assessments are as follows: 
• Obtain written informed consent 
• Record demographic information 
• Record medical and surgical history 
• Perform physical examination (including height at Screening only) 
• Record weight and body surface area (BSA) 
• Record vital signs (temperature, blood pressure, pulse rate, and respiratory rate) 
• Perform pregnancy test (for subjects of childbearing potential) (within 1 week of first 
administration of study drug) 
• Assess ECOG performance status 
• Assess eligibility criteria 
• Confirm histologically invasive breast cancer 
• Confirm HER2 status based on local laboratory test performed at the time of diagnosis.  If 
HER2 status is unknown it must be taken using approved test (see Appendix 1) or two 
different analytical test methods that were not considered Sponsor approved.  Central 
laboratory testing may be used to determine HER2 status if test is not available locally.  
Confirm tumor tissue sample is available for central laboratory. 
• Perform estrogen receptor (ER) and progesterone receptor (PR) testing if not already 
known and documented 
• Perform clinical laboratory tests (hematology, clinical chemistry, urinalysis) 
• Perform viral disease screen (Hepatitis B surface antigen [HBsAg], hepatitis C virus 
[HCV], and/or Human Immunodeficiency Virus [HIV] only in countries where 
regulations mandate testing or if warranted by known subject history) 
• Perform 12-lead ECG 
• Assess LVEF (echocardiography or MUGA) 
• Perform tumor assessment 
9.1.2.2 
Randomization 
Randomization will occur after the Screening Visit and prior to the treatment period. 


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9.1.2.3 
Treatment Period: Epirubicin + Cyclophosphamide: Cycle 1 (Week 0) to 
Cycle 4 (Week 9) 
Cycle 1 (Week 0) 
• Record weight and BSA 
• Record vital signs (temperature, blood pressure, pulse rate, and respiratory rate) 
• Perform pregnancy test (for subjects of childbearing potential) 
• Assess ECOG performance status 
• Perform clinical laboratory tests (hematology, clinical chemistry, urinalysis) 
• Study drug administration 
• Record AEs 
• Assess subject compliance 
• Record concomitant medications 
Cycle 2 (Week 3), Cycle 3 (Week 6), and Cycle 4 (Week 9) 
• Record weight and BSA 
• Record vital signs (temperature, blood pressure, pulse rate, and respiratory rate) 
• Perform pregnancy test (for subjects of childbearing potential) 
• Assess ECOG performance status 
• Perform clinical laboratory tests (hematology, clinical chemistry, urinalysis) 
• Study drug administration 
• Record AEs 
• Assess subject compliance 
• Record concomitant medications 


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9.1.2.4 
Treatment Period: TX05/Herceptin + Paclitaxel: Cycle 5 (Week 12) to 
Cycle 8 (Week 21) 
Cycle 5 (Week 12) 
• Record weight and BSA 
• Record vital signs (temperature, blood pressure, pulse rate, and respiratory rate) 
• Perform pregnancy test (for subjects of childbearing potential) 
• Assess ECOG performance status 
• Perform clinical laboratory tests (hematology, clinical chemistry, urinalysis) 
• Perform 12-lead ECG 
• Assess LVEF (echocardiography or MUGA) 
• Perform immunogenicity sampling 
• Perform PK sampling (prior to initiation of infusion in 100 subjects per treatment arm) 
• Study drug administration 
• Record AEs 
• Assess subject compliance 
• Record concomitant medications 
Cycle 6 (Week 15), Cycle 7 (Week 18), and Cycle 8 (Week 21) 
• Record weight and BSA 
• Record vital signs (temperature, blood pressure, pulse rate, and respiratory rate) 
• Perform pregnancy test (for subjects of childbearing potential) 
• Assess ECOG performance status 
• Perform clinical laboratory tests (hematology, clinical chemistry, urinalysis) 
• Perform immunogenicity sampling (Cycle 7 [Week 18] only) 
• Perform PK sampling (prior to initiation of infusion in 100 subjects per treatment arm) 
• Study drug administration 
• Record AEs 
• Assess subject compliance 
• Record concomitant medications 


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9.1.2.5 
End of Treatment/Early Termination Visit (Week 24) - Prior to Surgery 
• Perform physical examination 
• Record vital signs (temperature, blood pressure, pulse rate, and respiratory rate) 
• Assess ECOG performance status 
• Perform clinical laboratory tests (hematology, clinical chemistry, urinalysis) 
• Perform 12-lead ECG 
• Assess LVEF (echocardiography or MUGA) 
• Perform tumor assessment 
• Perform immunogenicity sampling 
• Perform PK sampling (in 100 subjects per treatment arm) 
• Record AEs 
• Record concomitant medications 
9.1.2.6 
Surgery (Week 24 to 28 - 3 to 7 weeks from the 1st day of the last cycle/last 
dose of study drug) 
• Definitive surgical resection/obtain tumor sample 


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9.2 
Discussion of Study Design 
The hypothesis tested in this clinical study is that TX05 has sufficient similarity of PK, 
safety, efficacy, and immunogenicity to Herceptin to support market approval and availability 
to subjects for whom 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. 
As noted above, 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 candidates16,17,18.  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.  This will be formally assessed in a 3-way 
PK bridging study that will be conducted in parallel to the study described herein in order to 
demonstrate the PK and safety similarities between TX05, US and EU-licensed Herceptin. 
Trastuzumab given every 3 weeks (8 mg/kg loading dose, 6 mg/kg maintenance dose) is per 
the US Herceptin label for EBC19.  The US Herceptin label does not include an indication in 
the neoadjuvant breast cancer setting, however, it is widely used in clinical practice and 
neoadjuvant trastuzumab treatment is recommended by the National Comprehensive Cancer 
Network (NCCN) guideline on breast cancer (Version 2 2017)20. 
For this intended biosimilar, TX05, HER2 positive EBC potentially amenable to surgery 
provides a sensitive and uniform population of subjects.  For this population of EBC, 
pathological complete response, pCR, following neoadjuvant treatment has been shown to 
correlate with progression-free survival and overall survival.  There is precedence for use of 
and this endpoint in both the US and EU as the primary endpoint for biosimilar equivalence 
studies for trastuzumab. 
The most frequently published pCR definition (absence of invasive neoplastic cells in the 
breast and lymph nodes) and FDA guidance to industry15 will be used in this study consistent 
with previous studies investigating trastuzumab given concurrently with taxanes and 
anthracyclines in the neoadjuvant setting21. 
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).  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.   


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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 and that are unknown at this time. 


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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. Histologically confirmed HER2 overexpressing invasive primary operable Stage II/IIIa 
breast cancer by American Joint Committee on Cancer 7th Edition staging criteria.  Tumor 
tissue sample must be available for central analysis. 
4. Planned surgical resection of breast tumor (lumpectomy or mastectomy, and SN biopsy or 
ALND). 
5. Planned neoadjuvant chemotherapy. 
6. HER2 overexpression as assessed by: 
- 
Gene amplification by fluorescent in-situ hybridization (FISH), chromogenic in-situ 
hybridization (CISH), or dual in-situ hybridization (DISH) (as defined by the 
manufacturer’s kit instruction); OR  
- 
Overexpression by immunohistochemistry (IHC) categorized as IHC 3+; OR 
- 
Overexpression by immunohistochemistry categorized as IHC2+ with FISH, CISH, or 
DISH confirmation. 
• Central review will be performed retrospectively for subjects who were determined to be 
HER2 positive by use of either an approved assay listed in Appendix 1 or two different 
analytical test methods that were not considered Sponsor approved.  The results from 
non-approved IHC and in-situ hybridization analytical tests must be unequivocal (i.e., 
IHC result must be categorized as IHC3+). 
• If a subject’s tumor HER2 status cannot be determined by using an approved assay (see 
Appendix 1), or two different HER2 assays performed locally, a tissue sample can be sent 
to the central laboratory early in Screening for evaluation; results of the assessment will 
be returned to the investigator for inclusion in subjects’ source documents.  
7. Ipsilateral, measurable tumor longest diameter > 2 cm. 
8. Known ER and PR hormone status prior to randomization.  If ER/PR status is not 
available locally, testing may be performed by central laboratory during Screening. 
9. ECOG performance status of 0 or 1 (see Appendix 2). 
10. Adequate bone marrow, hepatic, and renal functions as evidenced by the following: 
- 
Absolute neutrophils count ≥ 1,500/µL 
- 
Hemoglobin ≥ 9 g/dL 
- 
Platelet count ≥ 100,000/µL 


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- 
Creatinine clearance ≥ 40 mL/min (see Appendix 3) 
- 
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) 
- 
Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) and alanine 
 
aminotransferase (serum glutamic pyruvic transaminase) ≤ 2.5 x ULN 
- 
Alkaline phosphatases ≤ 5 x ULN 
11. LVEF ≥ 50% or within the normal level of the institution, as assessed by 
echocardiography or MUGA scan. 
12. Able to comply with the study protocol. 
13. Female subjects of childbearing potential must have a negative serum pregnancy test 
within 1 week 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 6 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. Participation in any interventional clinical study or having taken any investigational 
therapy during the 2 month period immediately preceding administration of the first dose 
of study drug. 
2. Bilateral breast cancer. 
3. Inflammatory breast cancer. 
4. Metastases. 
5. Previous chemotherapy, biologic therapy, radiation, or surgery for any active malignancy, 
including breast cancer. 
6. Subjects with one or more of the following conditions: 
- 
Cardiac insufficiency (New York Heart Association III or IV); myocardial infarction, 
coronary/peripheral artery bypass graft, congestive heart failure, cerebrovascular 
accident, unstable angina pectoris, uncontrolled arrhythmia, or pulmonary embolus 
within the previous 12 months prior to the first administration of study drug. 
- 
Clinically significant active infection. 
- 
Poorly controlled diabetes mellitus. 
- 
Uncontrolled hypertension (blood pressure > 150/100 mmHg despite optimal medical 
therapy). 
- 
Major surgery, significant traumatic injury, or radiation therapy within 4 weeks of 
first administration of study drug. 
- 
Grade 3 hemorrhage within 4 weeks of first administration of study drug. 


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7. Pre-existing clinically significant (≥ Grade 2) peripheral neuropathy. 
8. History of malignancy within the last 5 years, except adequately excised squamous or 
basal cell carcinoma of the skin, cervical carcinoma in situ, and superficial bladder 
cancer. 
9. Severe dyspnea at rest requiring supplementary oxygen therapy. 
10. Known positive status for HIV. 
11. Known acute or chronic-active infection with HBsAg or HCV. 
12. 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. 
13. Lactating or pregnant female. 
14. 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 6 months after the last administration of study drug.  Subjects 
must agree to not breast-feed while receiving study drug. 
15. Subject has known sensitivity to any of the products to be administered during the study, 
including mammalian cell derived drug products, trastuzumab, murine proteins, or to any 
of the excipients. 
16. Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the 
normal range despite optimal medical therapy. 
17. Subject likely to not be available to complete all protocol required study visits or 
procedures. 
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) EOT procedures should be 
performed. 
If it is necessary to discontinue the study drug earlier than planned, subjects should continue 
to be followed per protocol to capture safety and efficacy assessments for the duration of the 
study period. 
Subjects who withdraw from the study prior to the EOT/ET Visit should complete the 
procedures scheduled for that visit.   


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Subjects who discontinue the study 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.  Study drug discontinuation due to AEs considered 
not related to study drug will be followed until resolution. 
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. 
• 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 
maintenance dose (6 mg/kg) should be administered as soon as possible.  Do not wait until 
the next planned cycle.  Subsequent maintenance doses should be administered 21 days later 
according to 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 


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possible.  Subsequent TX05/Herceptin maintenance 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 420 mg of TX05, sufficient to deliver 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 Ig-based drug products. 
Subjects will receive up to 8 cycles of neoadjuvant chemotherapy as follows: 
Cycles 1 to 4:  
• Epirubicin 75 mg/m2 by IV bolus infusion and cyclophosphamide 600 mg/m2 by 
30-minute IV infusion, on Day 1 of Cycle 1 and thereafter every 3 weeks until Cycle 4. 
Followed by: 
TX 05 Cycles 5 to 8:  
• TX05 8 mg/kg body weight by 90-minute IV infusion and paclitaxel 175 mg/m2 
administered over 60 minutes by IV infusion (Cycle 5). 
• TX05 6 mg/kg body weight by 60-minute IV infusion and paclitaxel 175 mg/m2 
administered over 60 minutes by IV infusion, on Day 1 of the treatment cycle (Cycles 6 
to 8). 
OR 
Herceptin Cycles 5 to 8: 
• Herceptin 8 mg/kg body weight by 90-minute IV infusion and paclitaxel 175 mg/m2 
administered over 60 minutes by IV infusion (Cycle 5).  
• Herceptin 6 mg/kg body weight by 60-minute IV infusion and paclitaxel 175 mg/m2 
administered over 60 minutes by IV infusion, on Day 1 of the treatment cycle (Cycles 6 
to 8). 
Specific instructions on dose preparation and administration are provided in the separate 
dosage and administration instructions. 
10.2 
Treatment Regimen Adjustments 
Chemotherapy regimens should be administered according to the local label. 
Dose modification guidelines are provided in Appendix 5. 
In the event of toxicity attributed to trastuzumab, treatment should be either temporarily or 
permanently discontinued, as below.  Following a temporary discontinuation, treatment may 


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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.  The central 
pathology readers for pCR will also be blinded to study treatment.  A computer 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.  Subjects will be 
randomized after the Screening Visit and prior to the treatment period.  Randomization of 
eligible subjects is preferred no more than 4 business days before administration of first dose 
of study drug.  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. 


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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.  All randomization codes must be returned to the Sponsor at 
the end of the study. 
10.7 
Concomitant Therapy 
Concomitant medications administered for any reason must be locally-approved and 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. 
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 other than definitive 
surgery for the targeted tumor lesion post neoadjuvant therapy is discouraged unless 


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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 EOT/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 
Primary Endpoint: 
The primary efficacy endpoint is the proportion of subjects in each treatment arm who 
achieve pCR, defined as the absence of residual invasive cancer on hematoxylin and eosin 
evaluation of the complete resected breast specimen and all sampled regional lymph nodes 
following completion of neoadjuvant systemic therapy (ypT0/Tis ypN0).  Pathology of the 
tumor sample and pathologic response will be assessed locally and reviewed centrally by a 
qualified pathologist.  The primary efficacy analysis will be based on the central pathological 
review. 
11.1.2 
Secondary Endpoint: 
ORR, defined as the percentage of subjects having Complete or Partial Response at the 
EOT/ET Visit, according to RECIST version 1.1 (see Appendix 4), as assessed by the 
investigator. 
11.1.3 
Immunogenicity Assessments: 
• Incidence of ADA. 
• Incidence of Nab. 
11.2 
Disease Assessment 
CT scan of chest or MRI of chest (only if CT scan cannot be performed) and bilateral 
mammography or ultrasound of the breast is required at Screening for all subjects.  Unilateral 
repeat mammography or ultrasound of the breast must be performed at the EOT/ET Visit and 
as clinically indicated.  Radiographic assessments obtained per the subject’s SOC prior to 
randomization do not need to be repeated if: 
1. They were obtained within 6 weeks prior to randomization. 
2. They were performed using the method requirements outlined in RECIST version 1.1 
(see Appendix 4). 
3. The same imaging technique should be used throughout the study for the subject. 
4. Appropriate documentation indicating that these radiographic tumor assessments were 
performed as SOC is available in the subject’s source notes.  
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 of all other aspects of the chest. 


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Final disease assessment at the EOT/ET Visit will include repeat CT scan of chest or MRI of 
chest (only if CT scan cannot be performed) and unilateral mammography or ultrasound of 
breast.  Assessments are not to be scheduled based on the scheduled calendar date of the 
EOT/ET Visit. 
11.3 
Definitive Surgical Resection 
Subjects will undergo a definitive surgical resection of their primary tumor, as part of their 
SOC, i.e., lumpectomy or mastectomy with SN biopsy or ALND.  Surgical resection will be 
performed within 3 to 7 weeks from the 1st day of the last cycle/last dose of study drug.  
Pathology of the tumor sample and pathologic response will be assessed locally and reviewed 
centrally by a qualified pathologist, and data will be documented by the investigator in the 
source documentation and in the eCRF.  Sites will follow standard operating procedures 
(SOPs) for collection and handling of pathology specimens to be compliant with FDA 
guidance15.  Sites will be provided with training for surgeons and site pathologists.  Surgeons 
will follow the instructions provided to ensure localization of the tumor bed, postoperative 
specimen radiographs to verify excision and use of colored sutures or other approaches to 
orient the specimen.  Full instructions for the preparation, handling, and shipping of the 
pathology samples will be included in the central laboratory manual. 
Pathological assessment requires adequate sampling of the correct area of the breast and 
should follow the guidelines provided, including: 
• Correlate area to sample with clinical and imaging findings (pretreatment tumor size and 
location). 
• Identify clip, if present/tumor bed. 
• Document the (largest) cross section(s) of pretreatment area of involvement with a map of 
the tissue blocks (a minimum of 1 block prepared per centimeter of pretreatment tumor 
size, or at least 10 blocks in total, whichever is greater, with 3 to 5 mm slices).  Areas of 
concern identified by either the radiologist’s interpretation of the specimen radiograph(s) 
or the pathologist’s assessment of the gross specimen(s) should be subjected to more 
extensive sectioning.  Given that tumors may shrink concentrically or irregularly, subjects 
with no evidence of residual disease identified on initial evaluation should have additional 
blocks examined to ensure that no residual disease has been overlooked, and in particular, 
that no positive margins have been missed that may be surgically improved.  All 
surgically removed lymph nodes must be entirely submitted for histologic evaluation, 
sectioned at 2-mm intervals. 
The percentage of subjects in each treatment group who have pCR will be determined, using 
the resulting data from the assessments of the tumors following surgery after treatment 
completion and according to FDA guidance15. 
11.4 
Objective Response Rate 
Radiographic assessments of the tumor will be performed within 6 weeks prior to 
randomization and at the EOT/ET Visit.  An ORR status will be determined at the EOT/ET 
Visit using the RECIST version 1.1 guidelines (see Appendix 4). 


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11.5 
Tumor HER2, Progesterone Receptor and Estrogen Receptor Testing 
Tumor HER2 status and the PR and ER status will be assessed at Screening.  Tumor tissue 
blocks or slides will be assessed by the local laboratory as outlined in the Laboratory Manual.  
Tissue samples for HER2 status and eligibility must be available and sent to the central 
laboratory for concordance testing. 
Central review will be performed retrospectively for subjects who were determined to be 
HER2 positive by use of either an approved assay listed in Appendix 1 or two different 
analytical test methods that were not considered Sponsor approved.  
If a subject’s tumor HER2 status cannot be determined by using an approved assay (see 
Appendix 1 [or two different HER2 assays performed locally]), due to lack of site availability 
or ability to perform such testing, a tissue sample can be sent to the central laboratory early in 
Screening for potential eligibility evaluation; results of the assessment will be returned to the 
investigator for inclusion in subjects’ source documents. 
Concordance testing results will not be shared with the sites or filed in site files.  If sites use 
local testing for inclusion of a subject and the central lab HER2 result is discrepant, the 
subject will not be included in the PP population at the time of analysis. 
If PR and ER hormone status can’t be assessed locally at Screening, testing may be 
performed by the central laboratory.  These results will be sent back to the site and should be 
filed in the subject’s medical record. 
11.6 
Echocardiogram/MUGA 
Assessment of LVEF using an echocardiogram or MUGA scan will be performed at 
Screening and prior to dosing at Cycle 5 (Week 12) and the EOT/ET Visit.  The modality 
used for individual subjects should be consistent throughout the study. 
11.7 
Pharmacokinetic Sampling 
Pharmacokinetic samples will be taken from 100 subjects in each treatment arm (200 total) 
prior to initiation of infusion at Cycle 5 (Week 12), Cycle 6 (Week 15), Cycle 7 (Week 18), 
Cycle 8 (Week 21), and the EOT/ET Visit.  Sites will be notified which subjects will be 
included in this PK sampling.  PK sampling is not to be done unless the subject is selected 
and the same subjects will be used for all PK assessments timepoints.  The PK samples will 
be taken for assessment of Ctrough. 
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).  A serum 
separator tube (SST) 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 


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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, one for PK analysis and the other one for 
back-up shipment/PK 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. 
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 5 (Week 12), prior to infusion of study drug at Cycle 7 (Week 18), and 
the EOT/ET Visit.  For those subjects who terminate the study early before Cycle 5, there is 
no need to take the EOT/ET ADA sample.   
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.  An SST 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. 
11.9 
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. 


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Table 11–1 
Hematology and Clinical Chemistry Assessments 
Hematology 
Clinical Chemistry 
Hemoglobin 
Alanine Aminotransferase 
Platelets 
Aspartate Aminotransferase 
White Blood Cells 
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.   
Viral disease screening: HBsAg, HbcAb, HCV, and HIV testing to demonstrate eligibility is 
required only in countries where regulations mandate testing or if warranted by known 
subject history. 
All tests will be performed by local laboratories. 
11.10 
Electrocardiogram Assessments 
12-lead ECGs will be performed at Screening, prior to dosing at Cycle 5 (Week 12), and at 
the EOT/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 history.  Should a clinically significant abnormality be reported during the 
treatment period, it will be recorded as an AE. 
11.11 
Physical Examination 
Complete physical examinations will be conducted at Screening and at the EOT/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 and BSA will be recorded at Screening 
and Day 1 of each cycle, and as clinically indicated.  The weight from Day 1 of Cycles 5, 6, 
7, and 8 should be used to calculate the dosage of trastuzumab to be administered.  The BSA 


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collected from Day 1 of each cycle should be used to calculate the dosage of chemotherapy to 
be administered.  BSA should be calculated using the DuBois formula as follows: 
BSA = 0.007184 x (weight [kg]0.425 x height [m]0.725) 
11.12 
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. 
 


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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 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 study should be considered an AE. 
SAEs will be recorded from Screening, while AEs will be recorded from Day 1 (Week 0) of 
Cycle 1 of study treatment. 
All ongoing AEs should be followed up for 30 days after the last administration of study 
drug, with the exception of any ongoing study drug-related AEs, which should be followed 
until resolution, unless in the investigator's opinion, the AE is unlikely to resolve due to the 
subject's underlying disease.  Any new SAEs occurring up to 30 days after the last 
administration of study drug, or until enrollment in the extension study, should be reported 
according to Section 12.1.6. 
At any time after the EOT/ET Visit, if an investigator learns of an SAE that can be 
reasonably related to study drug, he/she should promptly notify the Sponsor. 


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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. 
• The laboratory/vital signs abnormality causes the subject to modify the dose of study 
treatment. 


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• The investigator believes that the abnormality should be reported as an AE. 
• If an abnormal laboratory value or vital sign is associated with clinical signs and 
symptoms, the sign or symptom should be reported as an AE and the associated 
laboratory result or vital sign should be considered additional information that must be 
collected on the relevant eCRF. 
12.1.3 
Deaths 
Should a death occur within the study period or within 30 days after the last administration of 
study drug an AE form and an SAE form should be completed, detailing the AE that resulted 
in the death (NB, death is an outcome, not an event).  The SAE must be reported within 
24 hours of awareness of the event by any site staff or study team member.  The report should 
contain a comment regarding the co-involvement of progression of disease, if appropriate, 
and should assign main and contributory causes of death. 
12.1.4 
Overdose 
Treatment of study drug overdose (chemotherapy and trastuzumab) is at the discretion of the 
investigator. 
12.1.5 
Pregnancy 
Subjects of childbearing potential will have a blood serum pregnancy test at Screening.  A 
urine pregnancy test will also be performed prior to each treatment cycle to exclude potential 
pregnancy. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study drug may 
have interfered with the effectiveness of a contraceptive medication.  However, the outcome 
of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or congenital 
abnormality) must be followed up and documented even after the subject has been withdrawn 
from the study. 
All reports of congenital abnormalities/birth defects are SAEs.  Spontaneous miscarriages 
should also be reported and handled as SAEs.  Elective abortions without complications 
should not be handled as AEs.  All outcomes of pregnancy must be reported to the Sponsor 
on a pregnancy outcomes report form. 
12.1.6 
Reporting of Serious Adverse Events 
Investigators and other site personnel must inform appropriate 
 representatives of any 
SAE that occurs (whether or not attributable to the study drug) in the course of the study 
within one day (i.e., immediately but no later than the end of the next business day) of when 
he or she becomes aware of it. 
All SAE reports must be faxed to the following number within 24 hours: 
 DRUG SAFETY (Pharmacovigilance Department) 


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Europe and Asia Pacific 
 
 
 
  
E-mail: 
Americas 
 
 
 
 
E-mail: 
 
The 
 representative will work with the investigator to compile all the necessary 
information and ensure that the appropriate Sponsor representative receives a report within 
one day (24 hours) for all fatal and life-threatening cases and within 5 days for all other 
SAEs. 
Follow-up information on SAEs must also be reported by the investigator within the same 
time frames. 
If a non-serious AE becomes serious, this and other relevant follow-up information must also 
be provided to 
 within one day as described above.  For a non-serious AE that becomes 
serious but which is not fatal or life-threatening a report should be received within 5 days. 
The following variables will be recorded for each AE:  verbatim/AE description, time and 
date for AE start and stop, maximum intensity, seriousness, causality rating, whether or not 
the AE caused the subject to discontinue, and the outcome. 
All SAEs have to be reported, whether or not considered causally related to the 
investigational product or to the study procedure(s).  All SAEs will be recorded in the eCRF.  
The investigator is responsible for informing the independent ethics committee (IEC) of the 
SAE as per local requirements.  The investigator should report to 
 who will forward 
the report to the appropriate Sponsor representative. 


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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 primary endpoint definition and/or its analysis will 
also be reflected in a protocol amendment. 
13.1 
Sample Size and Power 
The primary efficacy endpoint is the proportion of subjects in each treatment arm who, 
achieve 
pCR. 
 
For 
the 
calculation 
of 
the 
equivalence 
margin, 
neoadjuvant 
Herceptin22,23,24,25,26 studies of ‘trastuzumab + chemotherapy (anthracyclines and/or taxanes-
based)’ vs ‘chemotherapy (anthracyclines and/or taxanes-based) alone’ were considered.  
pCR rates were reported for 4 studies with HER2-positive subjects in early or locally 
advanced breast cancer.  The rate of pCR for each study is provided in the table below. 
Table 13–1 
Rates of pCSR from Neoadjuvant Herceptin Studies 
Name 
Trastuzumab + Chemotherapy 
(T + C) 
Chemotherapy Alone 
(C) 
NOAH (MO16432) 22,23 
(n =115) 
46 (40.0%) 
(n=116) 
24 (20.7%) 
Buzdar24 
(n=23) 
15 (65.2%) 
(n=19) 
5 (26.3%) 
Pierga25 
(n=62) 
16 (25.8%) 
(n=58) 
11 (19.0%) 
ABCSG-2426 
(n=44) 
17 (38.6%) 
(n=49) 
13 (26.5%) 
Combined risk ratio of pCRa 
95% CI (T+C:C) 
1.755b 
[1.317, 2.337] 
C: Chemotherapy; CI: Confidence Interval; NOAH: NeOAdjuvant Herceptin; T: Trastuzumab. 
a. 
Using the inverse variance-weighed method 
b. Chi square test was used to test for homogeneity at 0.05 level (Q=1.817, p=0.611). 
Based on the results of meta-analysis, the combined risk ratio for trastzumab + chemotherapy 
over chemotherapy alone is estimated to be 1.755.  The equivalence margin is determined as 
[0.755, 1.325] to protect 50% of the effect size based on a log scale (upper equivalence limit 
is exp[0.5×ln(1.755)=1.325]). 
With 370 subjects per treatment group, there is 85% probability that the observed two-sided 
95% CI of the risk ratio of TX05 + chemotherapy to Herceptin + chemotherapy will lie 
within [0.755, 1.325] assuming a 5% type 1 error rate, a pCR rate of 44.6% in both treatment 
groups, and that the actual risk ratio is 1.00.  Allowing for 7.5% losses to follow-up, at least 
400 subjects per arm, 800 in total, will be randomized. 


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13.2 
Analysis Populations 
13.2.1 
Modified Intent to Treat Population 
The modified intent-to-treat (mITT) population will include all subjects who are randomized 
into the study and receive at least 1 dose of TX05 or Herceptin.  The mITT population will be 
used for sensitivity analysis of the primary efficacy endpoint and for primary analysis of 
secondary efficacy endpoints. 
13.2.2 
Per Protocol Population 
The per protocol (PP) population will include all subjects who meet all of the following 
criteria: 
• Randomized and receive at least one dose of study drug, either TX05 or Herceptin. 
• No major protocol deviations that impact the efficacy endpoints. 
• An adequate tumor sample by definitive surgical resection of their primary tumor.  
The PP population will be used as the primary analysis for the primary efficacy endpoint. 
13.2.3 
Safety Population 
The safety population will include all subjects who are randomized into the study and have 
received at least one dose of study drug (TX05 or Herceptin).  The safety population will be 
used for safety and immunogenicity endpoints. 
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 “as randomized” for 
efficacy analyses, but “as treated” for all other analyses.  For these other analyses, if there are 
any cases where subjects received both drugs, they will be assigned to the treatment initially 
given. 
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 in each analysis set 
• Subjects completing the study/withdrawing early (including withdrawal reason) 
• Subject allocation by site 
13.3.5 
Efficacy Analysis 
13.3.5.1 
Analysis of Primary Endpoint 
The primary efficacy endpoint is the proportion of subjects in each treatment arm who, based 
on the central pathological review, achieve pCR, assessed by central reading, defined as the 
absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete 
resected breast specimen and all sampled regional lymph nodes following completion of 
neoadjuvant systemic therapy (ypT0/Tis ypN0).   Subjects who are included in the analysis 
population but do not have efficacy assessments will be assessed as non-responders in the 
mITT population. 
Two one-sided hypothesis tests will be performed in the study for pCR in order to show that 
TX05 is equivalent to Herceptin: 
TEST 1: H0a: θ1 / θ2 > 1.325  vs. H1a: θ1 / θ2 < 1.325 
TEST 2: H0b: θ1 / θ2 < 0.755  vs. H1b: θ1 / θ2 > 0.755 
Where θ1 is the proportion of pCR for subjects randomized to TX05 group, θ2 is the 
proportion of pCR for subjects randomized to Herceptin.  Justification of equivalence margin 
[0.755, 1.325] is described in the Section 13.1.  
Equivalence will be concluded if the 95% CI of the risk ratio is completely contained within 
the pre-defined interval [0.755, 1.325].  
This endpoint will be analyzed with the PP population.  Detailed analysis will be described in 
the SAP. 
13.3.5.2 
Analysis of Secondary Endpoint 
Secondary endpoints include the following: 


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• ORR, defined as the percentage of subjects having Complete or Partial Response at the 
EOT/ET Visit, according to RECIST version 1.1 (see Appendix 4), as assessed by the 
investigator. 
Frequency and percentage of subjects who meet the pCR and ORR criteria will be reported.  
Risk Ratio and its 95% CI will be estimated.  Analysis will be performed with the mITT 
population and sensitive analysis will be performed with the PP population.  Detailed analysis 
will be described in the SAP. 
13.3.6 
Immunogenicity Assessment 
Immunogenicity data (ADA and Nab) will be summarized and analyzed descriptively for 
each scheduled protocol assessment time-point. 
13.3.7 
Safety Analysis 
The safety parameters will include the following: 
• TEAE and SAE 
• Death 
• Clinical laboratory parameters 
• Vital signs 
• 12-Lead ECG cardiac ejection fraction 
• 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.  TEAEs observed during 
Cycle 1 to 4 and TEAEs observed from Day 1 of Cycle 5 will be summarized separately by 
treatment group.  Drug related TEAEs and SAEs will be also summarized by treatment 
group. 
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. 
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 SOPs 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 
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. 
13. 
Barok M, Isola J, Palyi-Krekk Z, et al. Trastuzumab causes antibody-dependent 
cellular cytotoxicity-mediated growth inhibition of submacroscopic JIMT-1 breast 


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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. 
FDA Guidance for Industry: Pathological Complete Response in Neoadjuvant 
Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support 
Accelerated Approval (October 2014)  
https://www.fda.gov/downloads/drugs/guidances/ucm305501.pdf 
16. 
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. 
17. 
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. 
18. 
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. 
19. 
Herceptin US Package Information October 2010. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/103792s5256lbl.pdf. 
20. 
National Comprehensive Cancer Network (NCCN) guideline on breast cancer 
(Version 2 2017) 
https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf 
21. 
Ismael G, Hegg R, Muehlbauer S, et al. Subcutaneous Versus Intravenous 
Administration of (Neo)Adjuvant Trastuzumab in Patients with HER2-Positive, 
Clinical Stage I–III Breast Cancer (HannaH Study): A Phase 3, Open-Label, 
Multi-centre, Randomised Trial. Lancet Oncol 2012;13(9):869–78. 
22. 
Herceptin®: European Public Assessment Report – Product Information 19/04/2017.  
23. 
Gianni L, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant 
trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive 
locally advanced breast cancer (the NOAH trial): a randomised controlled superiority 
trial with a parallel HER2-negative cohort. Lancet 2010;375(9712): 377-384. 
24. 
Buzdar AU, et al. Significantly higher pathologic complete remission rate after 
neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: 
results of a randomized trial in human epidermal growth factor receptor 2–positive 
operable breast cancer. J Clin Oncol 2005;23(16):3676-3685. 
25. 
Pierga JY(1), Delaloge S, Espié M, et al. A multicenter randomized phase II study of 
sequential epirubicin/cyclophosphamide followed by docetaxel with or without 
celecoxib or trastuzumab according to HER2 status, as primary chemotherapy for 


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localized invasive breast cancer patients. Breast Cancer Res Treat 2010 
Jul;122(2):429-37. 
26. 
Steger GG(1), Greil R, Lang A, et al; Austrian Breast and Colorectal Study Group 
(ABCSG). Epirubicin and docetaxel with or without capecitabine as neoadjuvant 
treatment for early breast cancer: final results of a randomized phase III study 
(ABCSG-24). Ann Oncol 2014 Feb;25(2):366-71. 
 


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21 
APPENDICES 
Appendix 1 
Approved HER2 Assays 
HER2 results based on 1 of the following commercial kit assays are acceptable (for the 
purposes of study entry).  Of note, additional HER2 assays approved by the FDA not listed 
below are also considered acceptable for the purposes of study entry. 
IHC Approved 
Assay 
FISH Approved 
Assay 
CISH Approved 
Assay 
DISH Approved 
Assay 
HercepTest™ (Dako) 
Pathvysion HER2 
DNA Probe Kit 
(Abbott Molecular) 
SPOT-Light® HER2 
CISH™ Kit 
(Invitrogen 
Corporation) 
INFORM HER2 
Dual ISH DNA 
Probe Cocktail Assay 
(Ventana) 
Pathway™ Her2 
(Ventana)a 
INFORM HER2/neu 
Probe (Ventana) 
HER2 CISH 
PharmDx™ Kit 
(Dako) 
 
Bond™ Oracle™ 
HER2 IHC System 
(Leica Biosystems) 
Dakocytomation 
HER2 FISH 
PharmDx™ Kit 
(Dako) 
 
 
PATHWAY 
HER2/neu 
(Ventana)b 
 
 
 
a. PATHWAY™ Her2 (clone CB11) is a mouse monoclonal antibody intended for 
laboratory use for the semi-quantitative detection of c-erbB-2 antigen in sections of 
formalin fixed, paraffin embedded normal and neoplastic tissue on a Ventana automated 
immunohistochemistry slide staining device. 
b. PATHWAY HER-2/neu (clone 4B5) is rabbit monoclonal antibody intended for the 
semi-quantitative detection of HER2 antigent in sections of formalin-fixed, 
paraffin-embedded normal and neoplastic tissue.  Created to run on a Ventana automated 
immunohistochemistry slide staining device, it is indicated as an aid in the assessment of 
breast cancer subjects for whom Herceptin treatment is considered. 
 
 


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Appendix 2 
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 selfcare but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% 
of waking hours. 
4 
Completely disabled.  Cannot carry on any selfcare. Totally confined to 
bed or chair. 
5 
Dead. 


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Appendix 3 
Estimated Creatinine Clearance Using the Cockcroft-Gault formula 
CCr={((140–age) x weight)/(72 x SCr)}x 0.85 (if female) 
Where CCr = creatinine clearance and SCr = serum creatinine (in mg/dL). 


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Appendix 4 
RECIST version 1.1 Guidelines 
Adapted from Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation 
criteria in solid tumours: Revised RECIST guideline (version 1.1). European Journal of 
Cancer  2009;45(2):228–47. 
 
CATEGORIZING LESIONS AT BASELINE 
Measurable Lesions 
• Lesions that can be accurately measured in at least one dimension. 
• Lesions with longest diameter at least 10 mm or greater when assessed by CT or MRI 
(slice thickness 5-8 mm), measured in the axial plane. If the slice thickness is greater than 
5 mm (including any inter-slice gap), the longest diameter must be at least twice the slice 
thickness. 
• Lesions with longest diameter at least 20 mm when assessed by Chest X-ray, only if the 
tumor is clearly outlined by well-aerated lung. 
• Malignant lymph nodes with a short axis (defined as the largest measurement 
perpendicular to the longest diameter of the lesion) 15 mm or greater when assessed by 
CT or MRI. 
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for 
all other lesions. 
Non-measurable disease 
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as 
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, superficial lesions, and abdominal masses 
identified by physical exam that are not measurable by reproducible imaging techniques. 
• Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of measurability 
at baseline. 
• Previous local treatment: A previously irradiated lesion (or lesion subjected to other local 
treatment) is non-measurable unless it has progressed since completion of treatment. 
Normal sites 
• Cystic lesions: Simple cysts should not be considered as malignant lesions and should not 
be recorded either as target or non-target disease.  Cystic lesions thought to represent 
cystic metastases can be measurable lesions, if they meet the specific definition above.  If 
non-cystic lesions are also present, these are preferred as target lesions. 
• Normal nodes: Nodes with short axis <10 mm are considered normal and should not be 
recorded or followed either as measurable or non-measurable disease. 


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Tumor Assessments 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within the window of time specified in Table 9–1 prior to treatment and all 
disease must be documented appropriately.  If the baseline assessment is inadequate, 
subsequent statuses generally should be indeterminate. 
The determination of whether lesions are measurable is performed only at baseline.  
“Measurable” at baseline means eligible for selection as target lesions, and thus for 
quantitative assessment throughout the study.  Once selected as a target lesion, a lesion 
remains target throughout the study. 
Target lesions 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  Target 
lesions should be selected on the basis of size (longest lesions) and suitability for accurate 
repeated measurements.  Record the longest diameter for each lesion, except in the case of 
pathological lymph nodes for which the short axis should be recorded.  The sum of the 
diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions at 
baseline will be the basis for comparison to look for partial response at later assessments. 
• If 2 target lesions coalesce the longest diameter measurement of the coalesced mass is 
used. If a large target lesion splits, the sum of the parts is used. 
• Measurements for target lesions that become small should continue to be recorded. If a 
target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be recorded. 
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement should 
still be recorded. 
Non-target disease 
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT 
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a 
single item on the case report form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’). 
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If not, subsequent objective statuses may 
be indeterminate. 


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Target disease 
• Complete Response (CR): Complete disappearance of all target lesions with the exception 
of nodal disease.  All target nodes must decrease to normal size (short axis < 10 mm).  All 
target lesions must be assessed. 
• Partial Response (PR): Greater than or equal to 30% decrease under baseline of the sum 
of diameters of all target measurable lesions.  The short diameter is used in the sum for 
target nodes, while the longest diameter is used in the sum for all other target lesions.  All 
target lesions must be assessed. 
• Stable: Does not qualify for CR, PR or Progression.  All target lesions must be assessed.  
Stable can follow PR only in the rare case that the sum increases by less than 20% from 
the nadir, but enough that a previously documented 30% decrease no longer holds. 
• Objective Progression (PD): 20% increase in the sum of diameters of target measurable 
lesions above the smallest sum observed (over baseline if no decrease in the sum is 
observed during therapy) with a minimum absolute increase of 5 mm. 
• Objective Response Rate (ORR) defined as the percentage of subjects having Complete 
or Partial Response at EOT/ET, based on radiographic assessments of the tumor. 
• Indeterminate. Progression has not been documented, and 
o one or more target lesions have not been assessed, 
o or assessment methods used were inconsistent with those used at baseline and 
impaired assessment, 
o or one or more target lesions cannot be measured accurately (e.g. poorly visible 
unless due to being too small to measure), 
o or one or more target lesions were excised or irradiated and have not reappeared 
or increased. 
Non-target disease 
• CR: Disappearance of all non-target lesions and normalization of tumor marker levels.  
All lymph nodes must be ‘normal’ in size (<10 mm short axis). 
• Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level above 
the normal limits. 
• PD: Unequivocal progression of pre-existing lesions. Generally the overall tumor burden 
must increase sufficiently to merit discontinuation of therapy.  In the presence of stable 
disease (SD) or PR in target disease, progression due to unequivocal increase in 
non-target disease should be rare. 
• Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at baseline. 


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New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD. If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  If 
repeat assessments confirm the lesion, then progression should be recorded on the date of the 
initial assessment.  A lesion identified in an area not previously scanned will be considered a 
new lesion. 
Supplemental Investigations 
• If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with biopsy 
or fine needle aspirate.  If no disease is identified, objective status is CR. 
• If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status. 
Subjective progression 
Subjects requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment eCRFs.  This should be 
indicated on the EOT/ET eCRF as off treatment due to Global Deterioration of Health Status. 
Every effort should be made to document objective progression even after discontinuation of 
treatment. 
 
 


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Appendix 5 
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 
 
Epirubicin Dose Modifications 
Epirubicin hydrochloride injection dosage adjustments for hematologic and non-hematologic 
toxicities within a cycle of treatment, is based on nadir platelet counts <50,000/mm3, absolute 
neutrophil counts (ANC) <250/mm3, neutropenic fever, or Grades 3/4 nonhematologic 
toxicity.  Reduce Epirubicin hydrochloride injection Day 1 dose in subsequent cycles to 75% 
of the Day 1 dose given in the current cycle.  Delay Day 1 chemotherapy in subsequent 
courses of treatment until platelet counts are ≥100,000/mm3, ANC ≥1500/mm3, and 
nonhematologic toxicities have recovered to ≤ Grade 1. 
 


Tanvex Biologics Corp. 
CONFIDENTIAL 
30 November 2017 
Protocol TX05-03 Amendment 1 
 
 
 
Final 
 
Page 78 of 79 
 
Paclitaxel Dose Modifications 
 
Paclitaxel Dose Adjustment Guidelines 
Grade 2 neuropathy 
• 
Reduce paclitaxel by 1 dose level. 
• 
Trastuzumab should continue at the same dose level. 
Grade ≥3 neuropathy 
• 
Hold paclitaxel until event resolves or returns to 
baseline.  
• 
Decrease paclitaxel dose by 1 dose level. 
• 
Trastuzumab should continue at the same dose level. 
Grade 3 or 4 acute hypersensitivity despite 
adequate premedication 
• 
Discontinue paclitaxel and consider trastuzumab 
monotherapy. 
ANC <1000/mm3 (1.0 × 109/L), or platelet 
<75,000/mm3 (75 × 109/L) on day of scheduled 
paclitaxel treatment 
• 
Hold paclitaxel until ANC ≥1000/mm3 (1.0 × 109/L), 
and platelet ≥75,000/mm3 (75 × 109/L). 
• 
Consider treatment with growth factor (eg, G-CSF) 
according to local guidelines. 
• 
If event reoccurs, reduce paclitaxel by 1 dose level. 
• 
Trastuzumab should continue at the same dose level. 
Grade 4 neutropenia lasting ≥7 days 
Grade 4 febrile neutropenia 
Grade 3 or 4 documented infection with 
neutropenia (ANC <1000/mm3 [1.0 × 109/L]) 
• 
Hold paclitaxel until ANC ≥1000/mm3 (1.0 × 109/L). 
• 
Reduce paclitaxel by 1 dose level. 
• 
Consider treatment with growth factor (eg, G-CSF) 
according to local guidelines. 
• 
Trastuzumab should continue at the same dose level. 
• 
If event reoccurs, reduce paclitaxel to the next lower 
dose level or discontinue paclitaxel at the 
investigator’s discretion. 
Grade 4 thrombocytopenia 
• 
Hold paclitaxel until platelet ≥75,000/mm3 
(75 × 109/L). 
• 
Reduce paclitaxel by 1 dose level. 
• 
Trastuzumab should continue at the same dose level. 
• 
If the event reoccurs, reduce paclitaxel to the next 
lower dose level or discontinue paclitaxel at the 
investigator’s discretion. 
For potential cases of drug-induced liver injury 
• 
Hold paclitaxel. 
• 
Contact the Sponsor immediately to discuss next 
steps, including evaluation of alternative causes. 
• 
This must be reported as an SAE.  Refer to the AE 
section for additional information on potential 
drug-induced liver injury. 
Other Grade 3 or 4 non-hematologic toxicity 
including nausea and/or vomiting despite 
optimal medical therapy, and fatigue/asthenia 
lasting more than 3 days 
• 
Hold paclitaxel until recovery to ≤ Grade 1 or 
baseline.  
• 
Paclitaxel dose adjustment and/or paclitaxel or 
trastuzumab discontinuation should be performed 
according to the investigator’s medical judgment. 


Tanvex Biologics Corp. 
CONFIDENTIAL 
30 November 2017 
Protocol TX05-03 Amendment 1 
 
 
 
Final 
 
Page 79 of 79 
 
Cyclophosphamide Dose Modifications 
Cyclophosphamide Dose Adjustment Guidelines 
Hematological 
Toxicity 
Delay 1 week if neutrophils <1.0 x 109/L and/or platelets <100 x 109/L.  
20% dose reduction should be considered if myelosuppression results in delay of 
subsequent courses 
Renal Impairment 
Creatinine Clearance (mL/min) 
Cyclophosphamide Dose 
> 21 
100% 
10 to 20 
75% 
< 10 
50% 
Hepatic 
Impairment 
Bilirubin 
ALT/ Alkaline 
Phosphatase 
Cyclophosphamide Dose 
1.5 to 3 x ULN 
2.5 to 5 x ULN 
100% 
3 to 5 x ULN 
5 to 10 x ULN 
100% 
.> 5 x ULN 
.> 10 x ULN 
Consider dose reduction / use alternative 
regimen* 
* Cyclophosphamide is not recommended in patients if bilirubin > 1.5 x ULN or 
AST/ALT >2 to 3xULN, but exposure to active metabolites may not be increased and 
therefore a dose reduction may not be necessary. Consultant decision. 
NCI Common 
Toxicity Criteria 
Toxicity 
Definition 
Dose Adjustment 
Febrile neutropenia 
ANC < 0.5 x 109/L plus fever 
requiring IV antibiotics +/- 
hospitalization 
20% reduction  
Other toxicities 
Grade III/IV toxicity (except 
alopecia) 
Continue with 20% dose 
reduction of suspected causative 
agent(s) provided toxicity has 
resolved to Grade I or less.  If 
further toxicity occurs, an 
additional reduction may be made 
after discussion with consultant 
Defer treatment for any grade III/IV non-haematological toxicity (excluding alopecia). 
If a delay of more than 3 weeks is required for recovery, or more than 
2 dose reductions are necessary, the patient should discontinue treatment. 
 

SAP_001.pdf: 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
A randomized, double-blind, parallel group, Phase III trial to compare the efficacy, safety, and 
immunogenicity of TX05 with Herceptin® in subjects with HER2 positive early breast cancer 
NCT03556358 
Document Date: 04 Feb 2021 


Protocol Title: 
A randomized, double-blind, parallel group, Phase III trial to compare 
the efficacy, safety, and immunogenicity of TX05 with Herceptin® in 
subjects with HER2 positive early breast cancer 
Protocol Number: 
TX05-03 Amendment 1 
Protocol Version, Date 
Final, 30 Nov 2017 
ID:  
3903/0002 
Document Version, Date: 
Final 3.0, 4FEB2021  
Prepared by:  
 
On behalf of: 
Tanvex Biologics Corp. 
 
Confidentiality statement: 
 
The information provided in this document is strictly confidential.  
 
The recipients of the SAP must not disclose the confidential information 
contained within this document or any related information to other persons 
without the permission of the sponsor. 
 
In addition, the recipients of the SAP must keep this confidential document in a 
controlled environment which prevents unauthorized access to the document. 
 
 
DocUUID : 88b281fc-eae4-4bc1-84bb-02bc43ef148d
Page 2 of 48


 
 
CSR 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: TX05-03 
Version: Final 3.0, Date: 12Jun2020 
                                                                          Page 2 of 47
 
SIGNATURE PAGE FROM 
 
 
Prepared 
 by:  
 
 
  
 
Date  
(DD MMM YYYY) 
 
 
Reviewed 
 by:  
 
 
 
 
 
 
 
Date  
(DD MMM YYYY) 
 
 
 
 
DocUUID : 88b281fc-eae4-4bc1-84bb-02bc43ef148d
Page 3 of 48


 
 
CSR 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: TX05-03 
Version: Final 3.0, Date: 12Jun2020 
                                                                          Page 3 of 47
 
 
SIGNATURE PAGE FROM TANVEX 
 
Approved at Tanvex Biologics Corp. by: 
 
 
 
 
 
 
 
 
 
Date  
(DD MMM YYYY) 
 
 
 
 
DocUUID : 88b281fc-eae4-4bc1-84bb-02bc43ef148d
Page 4 of 48


 
 
CSR 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: TX05-03 
Version: Final 3.0, Date: 12Jun2020 
                                                                          Page 4 of 47
 
REVISION HISTORY 
 
Version/Date 
Version 
name 
Section 
Changes implemented 
Version 1.0/  
27-Jul-2018 
Initial 
approve
d version 
N/A 
N/A 
Version 2.0/  
02-Sep-2019 
Final 
Version 
2.0 
8.5.1 
Treatment 
duration 
Removed 
duration 
of 
Epirubicin/Cyclophosphamide/Paclitaxel
. 
Version 2.0/ 
02-Sep-2019 
Final 
Version 
2.0 
8.8.3 
Clinical 
laboratory evaluations 
8.8.5 
Physical 
examinations 
8.8.6 
12-lead 
Electrocardiograms 
8.8.7.3 ECOG 
Removed all shift tables from baseline of 
cycle 1. 
Version 2.0/ 
05-Sep-2019 
Final 
Version 
2.0 
8.8.7.5 LVEF 
Added shift table from baseline of cycle 
5. 
Version 2.0/  
16-Oct-2019 
Final 
Version 
2.0 
LIST 
OF 
ABBREVIATIONS 
Updated ‘NaB’ to ‘Nab’. 
Version 2.0/  
16-Oct-2019 
Final 
Version 
2.0 
3.1 General study design 
Updated ‘up to 10 treatment cycles’ to ‘up 
to 13 treatment cycles’. 
Version 2.0/ 
16-Oct-2019 
Final 
Version 
2.0 
3.3 Study treatments and 
assessments 
Removed “bacteriostatic”. 
Version 2.0/  
16-Oct-2019 
Final 
Version 
2.0 
5 Sample size and power 
 
Updated typo: 
- pCSR’ to ‘pCR’ in Table 5.1. 
- trastzumab to trastuzumab. 
Version 2.0/  
16-Oct-2019 
Final 
Version 
2.0 
7.1 Derived Variables 
Separated baseline and change from 
baseline; 
- Baseline:‘Baseline of cycle 1’/ 
‘Baseline of cycle 5’ 
- Change from baseline: ‘Change from 
cycle 1 baseline’/ ‘Change from cycle 5 
baseline’.. 
Version 2.0/  
16-Oct-2019 
Final 
Version 
2.0 
7.2.2.2 Missing Causality 
and Severity for Adverse 
Events 
Separated Causality imputation rule of 
AE is missing for cycle 1-4 and cycle 5-
8. 
Version 2.0/ 
16-Oct-2019 
Final 
Version 
2.0 
8.8.1 
Adverse events 
1. Specified cycle for AE tables. 
2. Added AE tables for related to study 
drug. 
DocUUID : 88b281fc-eae4-4bc1-84bb-02bc43ef148d
Page 5 of 48


 
 
CSR 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: TX05-03 
Version: Final 3.0, Date: 12Jun2020 
                                                                          Page 5 of 47
 
 
3. Updated ‘epirubicin and 
cyclophosphamide’ to ‘ epirubicin and/or 
cyclophosphamide’.   
Version 3.0/ 
19-Nov-2019 
Final 
Version 
3.0 
8.8.7.5 LVEF 
LVEF, add category ‘Hyperdynamic’ for 
value greater than 70%. 
Version 3.0/ 
16-Apr-2020 
Final 
Version 
3.0 
7.2.2.1 Partial Dates for 
Adverse Events 
Updated imputation rule of AE start date. 
Version 3.0/ 
16-Apr-2020 
Final 
Version 
3.0 
8.8.1 
Adverse events 
Updated definition for ‘TEAEs for Cycles 
1-4’ and ‘TEAEs for Cycle 5-8’. 
Version 3.0/ 
12-Jun-2020 
Final 
Version 
3.0 
6.4 Per Protocol 
Population 
Added to clarify protocol deviation 
criteria for PP set. 
Version 
3.0/4FEB202
1 
Final 
Version 
3.0 
6.4 Per Protocol 
Population 
Updated to clarify that those delay >8 
weeks due to COVID 19 will not be 
excluded and those indetermined PCR 
will be excluded. 
DocUUID : 88b281fc-eae4-4bc1-84bb-02bc43ef148d
Page 6 of 48


 
CSR 
Statistical Analysis Plan (SAP) 
 
 
Statistical Analysis Plan 
Protocol Number: TX05-03 
Version: Final 3.0, Date: 4FEB2021
                                                                     Page 6 of 47
 
TABLE OF CONTENTS 
 
SIGNATURE PAGE FROM 
 ...................................................................................... 2 
SIGNATURE PAGE FROM TANVEX ............................................................................... 3 
REVISION HISTORY .......................................................................................................... 4 
TABLE OF CONTENTS ...................................................................................................... 6 
LIST OF ABBREVIATIONS ............................................................................................... 8 
1 INTRODUCTION ......................................................................................................... 10 
2 STUDY OBJECTIVES ................................................................................................. 11 
2.1 Primary objective(s) ............................................................................................. 11 
2.2 Secondary objective(s) ......................................................................................... 11 
3 STUDY DESIGN .......................................................................................................... 12 
3.1 General study design ............................................................................................ 12 
3.2 Randomization and blinding ................................................................................. 13 
3.3 Study treatments and assessments ........................................................................ 13 
Table 3.3.1:  Schedule of Study Assessments ............................................................... 15 
Table 3.3.2: Schedule of Blood Sampling ..................................................................... 18 
4 STUDY ENDPOINTS ................................................................................................... 19 
4.1 Primary efficacy endpoint(s) ................................................................................ 19 
4.2 Secondary efficacy endpoint(s) ............................................................................ 19 
4.3 Immunogenicity Assessments .............................................................................. 19 
4.4 Safety endpoint(s) ................................................................................................. 19 
5 SAMPLE SIZE AND POWER ..................................................................................... 20 
6 ANALYSIS POPULATIONS ....................................................................................... 21 
6.1 Enrolled population .............................................................................................. 21 
6.2 All randomized population ................................................................................... 21 
6.3 Modified Intent to Treat Population ..................................................................... 21 
6.4 Per Protocol Population ........................................................................................ 21 
6.5 Safety Population .................................................................................................. 22 
7 Statistical Considerations and analysis .......................................................................... 23 
7.1 Derived Variables ................................................................................................. 23 
7.2 Handling of missing data and outliers .................................................................. 24 
7.2.1 Missing data analysis methods ................................................................. 24 
7.2.2 Handling of missing or incomplete dates ................................................. 24 
7.2.2.1 Partial Dates for Adverse Events .............................................................. 24 
7.2.2.2 Missing Causality and Severity for Adverse Events ................................ 26 
7.2.2.3 Missing or partial dates for concomitant medication ............................... 26 
8 STATISTICAL METHODS.......................................................................................... 28 
8.1 General statistical conventions ............................................................................. 28 
8.2 Subject disposition ................................................................................................ 28 
8.3 Protocol deviations ............................................................................................... 29 
8.4 Demographics and baseline characteristics .......................................................... 29 
8.4.1 Demographics ........................................................................................... 29 
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Statistical Analysis Plan 
Protocol Number: TX05-03 
Version: Final 3.0, Date: 4FEB2021
                                                                     Page 7 of 47
 
8.4.2 Baseline and disease characteristics ......................................................... 29 
8.4.3 Medical history ......................................................................................... 29 
8.4.4 Prior and concomitant medications and surgeries/procedures ................. 29 
8.5 Extent of exposure ................................................................................................ 30 
8.5.1 Treatment duration ................................................................................... 30 
8.5.2 Cumulative Dose ...................................................................................... 31 
8.5.3 Relative Dose Intensity ............................................................................. 31 
8.6 Efficacy analyses .................................................................................................. 32 
8.6.1 Analysis methods ...................................................................................... 32 
8.6.1.1 Multiplicity ............................................................................................... 32 
8.6.1.2 Treatment by center interaction analysis (multi-center study) ................. 32 
8.6.2 Analysis of primary efficacy endpoint(s) ................................................. 32 
8.6.3 Analysis of secondary efficacy endpoint(s).............................................. 33 
8.7 Immunogenicity analyses ..................................................................................... 33 
8.8 Safety analyses ..................................................................................................... 34 
8.8.1 Adverse events .......................................................................................... 34 
8.8.2 Death ......................................................................................................... 35 
8.8.3 Clinical laboratory evaluations ................................................................. 35 
8.8.4 Vital signs ................................................................................................. 36 
8.8.5 Physical examinations .............................................................................. 36 
8.8.6 12-lead Electrocardiograms ...................................................................... 36 
8.8.7 Other safety assessments .......................................................................... 36 
8.9 Interim analysis .................................................................................................... 37 
9 CHANGES TO PLANNED ANALYSIS FROM STUDY PROTOCOL ..................... 38 
10 REFERENCES .............................................................................................................. 39 
11 APPENDICES ............................................................................................................... 40 
Appendix 1 
Dose Modification Guidelines ............................................. 40 
Appendix 2  
RECIST version 1.1 Guidelines .......................................... 44 
 
 
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Statistical Analysis Plan (SAP) 
 
 
Statistical Analysis Plan 
Protocol Number: TX05-03 
Version: Final 3.0, Date: 4FEB2021
                                                                     Page 8 of 47
 
LIST OF ABBREVIATIONS 
 
Abbreviation 
or 
special term 
Explanation 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
BMI 
Body mass index 
BSA 
Body surface area 
CI 
Confidence interval 
CRF 
Case report form 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of Treatment 
ER 
Estrogen receptor 
ET 
Early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HER 
Human epidermal growth factor receptor 
HIV 
Human immunodeficiency virus 
ICH 
International Council for Harmonization 
IV 
Intravenous 
IWRS 
Interactive web response system 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
MRI 
Magnetic resonance imaging 
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Statistical Analysis Plan 
Protocol Number: TX05-03 
Version: Final 3.0, Date: 4FEB2021
                                                                     Page 9 of 47
 
Nab 
Neutralizing antibodies 
NCS 
Not Clinically Significant 
NOAH 
Neoadjuvant Herceptin 
ORR 
Objective response rate 
pCR 
Pathologic complete response 
PK 
Pharmacokinetic 
PP 
Per protocol 
PR 
Progesterone receptor 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
Risk Ratio 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
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CSR 
Statistical Analysis Plan (SAP) 
 
 
Statistical Analysis Plan 
Protocol Number: TX05-03 
Version: Final 3.0, Date: 4FEB2021
                                                                     Page 10 of 47
 
1 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide detailed descriptions of the statistical 
methods, data derivations and data displays for study protocol TX05-03 Final “A randomized, 
double-blind, parallel group, Phase III trial to compare the efficacy, safety, and immunogenicity of 
TX05 with Herceptin® in subjects with HER2 positive early breast cancer” dated 30Nov2017 and 
decision log ID #21 of “Action-Decision Log Tanvex TX05-03_03May2018” for CSR analysis. The 
table of contents and templates for the TFLs will be produced in a separate document. 
Any deviations from this SAP will be described and justified in the Clinical Study Report (CSR). 
The preparation of this SAP has been in accordance with FDA regulations (CFR, Sections 312.50 
and 312.56) and with ICH GCP (CPMP 135/95). 
All data analyses and generation of TFLs will be performed using SAS 9.4® or higher. 
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Statistical Analysis Plan 
Protocol Number: TX05-03 
Version: Final 3.0, Date: 4FEB2021
                                                                     Page 11 of 47
 
2 
STUDY OBJECTIVES 
2.1 
Primary objective(s) 
The primary objective of this study is to demonstrate the therapeutic equivalence of TX05 (proposed 
biosimilar trastuzumab) to Herceptin (trastuzumab) based on the pathologic complete response 
(pCR) rate following neoadjuvant chemotherapy, defined as the absence of residual invasive cancer 
on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled 
regional lymph nodes following completion of neoadjuvant systemic therapy (ypT0/Tis ypN0), in 
subjects with HER2 positive (HER2+) invasive EBC. 
2.2 
Secondary objective(s) 
The secondary objective of this study is to compare objective response rate (ORR) between the 2 
arms; immunogenicity, safety, and tolerability will also be assessed. 
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Statistical Analysis Plan 
Protocol Number: TX05-03 
Version: Final 3.0, Date: 4FEB2021
                                                                     Page 12 of 47
 
3 
STUDY DESIGN 
3.1 
General study design 
This is a randomized, double-blinded, parallel group, equivalence, multicenter Phase III study. The 
study will consist of a Screening period (Days -28 to 0), and 8 cycles of neoadjuvant treatment (Week 
0 [Day 1] to Week 21), followed by surgery (3 to 7 weeks from the 1st day of the last cycle/last dose 
of study drug). Post-surgery, subjects may be eligible to enroll in a separate (extension) protocol to 
receive adjuvant treatment with trastuzumab (Herceptin or TX05) for up to 13 treatment cycles.  
800 subjects with HER2+ EBC will be randomized (1:1) to receive up to 8 cycles of neoadjuvant 
chemotherapy as follows: 
x 
IV epirubicin, 75 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks for 4 cycles 
Followed by either: 
x 
IV TX05 8 mg/kg loading dose then 6 mg/kg and paclitaxel 175 mg/m2 every 3 weeks for 4 
cycles. 
OR 
x 
IV Herceptin 8 mg/kg loading dose then 6 mg/kg and paclitaxel 175 mg/m2 every 3 weeks 
for 4 cycles. 
Figure 3.1: Study Design Flow Diagram 
 
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Protocol Number: TX05-03 
Version: Final 3.0, Date: 4FEB2021
                                                                     Page 13 of 47
 
3.2 
Randomization and blinding 
Both randomization and blinding techniques will be used in this study to minimize bias. This is a 
double-blinded study and randomized treatment assignments will be blinded to the subject, 
investigator/study staff and Sponsor’s study team conducting the study. The central pathology 
readers for pCR will also be blinded to study treatment. A computer 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. Subjects will be randomized after the Screening Visit and 
prior to the treatment period. The randomization will be stratified by ‘Hormone Receptor (HR) 
Status’ and ‘Tumor Stage’, including: Strata 1: HR Positive and Tumor Stage II; Strata 2: HR Positive 
and Tumor Stage IIIa; Strata 3: HR Negative and Tumor Stage II; Strata 4: HR Negative and Tumor 
Stage IIIa with 1: 1 ratio. Randomization of eligible subjects is preferred no more than 4 business 
days before administration of first dose of study drug. At the initiation of the study, all sites will be 
instructed on how to use IWRS for breaking the blind, if necessary. 
3.3 
Study treatments and assessments 
TX05 drug product is a sterile, preservative-free, lyophilized product in a 50 mL glass vial. Each vial 
contains 420 mg of TX05, sufficient to deliver 420 mg. After reconstitution with 20 mL of 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 Ig-based drug products. 
Subjects will receive up to 8 cycles of neoadjuvant chemotherapy as follows: 
Cycles 1 to 4:  
x 
Epirubicin 75 mg/m2 by IV bolus infusion and cyclophosphamide 600 mg/m2 by 30-minute IV 
infusion, on Day 1 of Cycle 1 and thereafter every 3 weeks until Cycle 4. 
Followed by: 
TX 05 Cycles 5 to 8:  
x 
TX05 8 mg/kg body weight by 90-minute IV infusion and paclitaxel 175 mg/m2 administered 
over 60 minutes by IV infusion (Cycle 5). 
x 
TX05 6 mg/kg body weight by 60-minute IV infusion and paclitaxel 175 mg/m2 administered 
over 60 minutes by IV infusion, on Day 1 of the treatment cycle (Cycles 6 to 8). 
OR 
Herceptin Cycles 5 to 8: 
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Protocol Number: TX05-03 
Version: Final 3.0, Date: 4FEB2021
                                                                     Page 14 of 47
 
x 
Herceptin 8 mg/kg body weight by 90-minute IV infusion and paclitaxel 175 mg/m2 administered 
over 60 minutes by IV infusion (Cycle 5).  
x 
Herceptin 6 mg/kg body weight by 60-minute IV infusion and paclitaxel 175 mg/m2 administered 
over 60 minutes by IV infusion, on Day 1 of the treatment cycle (Cycles 6 to 8). 
A detailed description of procedures and assessments to be conducted during this study is 
summarized in the schedule of study assessments in Table 3.3.1 and schedule of blood sampling in 
Table 3.3.2 below. 
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Protocol Number: TX05-03 
Version: Final 3.0, Date: 4FEB2021
                                                                     Page 15 of 47
 
Table 3.3.1:  Schedule of Study Assessments 
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Statistical Analysis Plan 
Protocol Number: TX05-03 
Version: Final 3.0, Date: 4FEB2021
                                                                     Page 16 of 47
 
Study Procedure 
Screening 
(-28 
days)1 
Randomization1 
Neoadjuvant Cycle (week) 
EOT/ET2  
Surgery3 
Epirubicin + 
Cyclophosphamide 
Trastuzumab + 
Paclitaxel 
1 
(0) 
2 
(3) 
3 
(6) 
4 
(9) 
5 
(12
) 
6 
(15
) 
7 
(18
) 
8 
(21
) 
Week 24 
Visit Window 
(days) 
 
± 3 
± 
3 
± 
3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
 
Informed consent4 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical & surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
Physical 
examination5 
X 
 
 
 
 
 
 
 
 
X 
 
Weight and BSA6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy test8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG 
performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
Histologically 
confirmed invasive 
breast cancer 
X 
 
 
 
 
 
 
 
 
 
 
HER2 expression9 
X 
 
 
 
 
 
 
 
 
 
 
ER & PR Testing10 
X 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory 
tests11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Viral disease 
screen12 
X 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
X 
 
 
 
 
X 
 
 
 
X 
 
LVEF 
(echocardiography 
or MUGA) 
X 
 
 
 
 
X 
 
 
 
X 
 
Study drug 
administration13 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Immunogenicity 
sampling14 
 
 
 
 
 
X 
 
X 
 
X 
 
PK sampling15 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Tumor 
assessment16 
X 
 
 
 
 
 
 
 
 
X 
 
AE assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Statistical Analysis Plan 
Protocol Number: TX05-03 
Version: Final 3.0, Date: 4FEB2021
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Subject compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant 
medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Definitive surgical 
resection17 
 
 
 
 
 
 
 
 
 
 
X 
AE: Adverse Event; BSA: Body Surface Area; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; 
EOT/ET: End of Treatment/Early Termination; ER: Estrogen Receptor; HER: Human epidermal growth factor receptor; 
LVEF: Left ventricular ejection fraction; MUGA: Multi-gated acquisition; PK: pharmacokinetic; PR: Progesterone 
Receptor. 
1. 
All Screening procedures, laboratory results, and repeat laboratory results must be completed and reviewed within the 
screening period prior to randomization.  Randomization of eligible subjects is preferred no more than 4 business days 
before administration of first dose of study drug. 
2. 
All subjects completing neoadjuvant treatment (and those prematurely discontinuing neoadjuvant treatment at any 
time) will attend an EOT/ET Visit 3 weeks after last administration of study drug.  The allowable window for the 
EOT/ET Visit is ± 7 days. 
3. 
Subjects will undergo a definitive surgical resection of their primary tumor 3 to 7 weeks from the 1st day of the last 
cycle/last dose of study drug. 
4. 
Informed consent must be obtained prior to undergoing any study-specific procedure and may occur prior to the 28-
day Screening period. 
5. 
Complete physical examinations will be conducted at Screening and at the EOT/ET Visit.  All other evaluations will 
be at the discretion of the investigator.  Height will be recorded at Screening only. 
6. 
Weight and BSA will be recorded at Screening and Day 1 of each cycle and as clinically indicated.  The weight from 
Day 1 of Cycles 5, 6, 7, and 8 should be used to calculate the dosage of trastuzumab to be administered.  The BSA 
from Day 1 of each cycle should be used to calculate the dosage of chemotherapy to be administered. 
7. 
Temperature, blood pressure, pulse rate, and respiratory rate will be recorded at each timepoint.  
8. 
Subjects of childbearing potential will have a blood serum pregnancy test at Screening.  A urine pregnancy test will 
also be performed prior to each treatment cycle to exclude potential pregnancy. 
9. 
HER2-positive tumor status for study eligibility will be based on the test performed by the local laboratory at the time 
of diagnosis or as determined by the central laboratory where not known locally.  HER2 status that was determined 
locally will be confirmed by the central laboratory.  Tumor tissue sample must be available for central analysis. 
10. Only for subjects with unknown ER and/or PR status. 
11. Clinical laboratory tests (hematology, clinical chemistry, and urinalysis) will be performed by local laboratories. 
12. Hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), and/or human immunodeficiency virus (HIV) to be 
conducted by local laboratory only in countries where regulations mandate testing or if warranted by known subject 
history. 
13. Subjects will receive 8 cycles of neoadjuvant chemotherapy: Cycles 1-4: epirubicin 75 mg/m2 by IV bolus infusion 
and cyclophosphamide 600 mg/m2 by 30-minute IV infusion, on Day 1 of the treatment cycle and thereafter every 3 
weeks until Cycle 4.  Cycles 5 to 8: TX05 or Herceptin 8 mg/kg body weight by 90-minute IV infusion and paclitaxel 
175 mg/m2 administered over 60 minutes by IV infusion followed by TX05 of Herceptin 6 mg/kg body weight by 60-
minute IV infusion and paclitaxel 175 mg/m2 administered over 60 minutes by IV infusion, on Day 1 of the treatment 
cycle and thereafter every 3 weeks until Cycle 8. 
14. Serum samples for detection of anti-drug antibodies (ADA) and neutralizing antibodies (Nab) will be collected prior 
to initiation of infusion at Cycle 5 (Week 12), prior to infusions at Cycle 7 (Week 18), and the EOT/ET Visit.  For 
those subjects who terminate the study early before Cycle 5, there is no need to take the EOT/ET ADA sample. 
15. For 100 subjects in each of the 2 treatment arms (200 subjects total), PK samples will be taken prior to initiation of 
infusion at Cycle 5 (Week 12), Cycle 6 (Week 15), Cycle 7 (Week 18), Cycle 8 (Week 21), and the EOT/ET Visit.  
PK samples will be taken for assessment of trough serum concentration (Ctrough). 
16. Computed tomography (CT) scan of chest or magnetic resonance imaging (MRI) of chest (only if CT scan cannot be 
performed) and bilateral mammography or ultrasound of the breast required at Screening for all subjects, within 6 
weeks prior to randomization.  Unilateral repeat mammography or ultrasound of the breast must be performed at the 
EOT/ET Visit and as clinically indicated.  Radiographic assessments obtained per the subject’s standard of care (SOC) 
prior to randomization do not need to be repeated if (1) they were obtained within 6 weeks prior to randomization, (2) 
they were performed using the method requirements outlined in Response Evaluation Criteria in Solid Tumors 
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Protocol Number: TX05-03 
Version: Final 3.0, Date: 4FEB2021
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(RECIST version 1.1) (3) the same imaging technique should be used throughout the study for the subject, and (4) 
appropriate documentation indicating that these radiographic tumor assessments were performed as SOC is available 
in the subject’s source notes.  Final disease assessment at the EOT/ET Visit will include repeat CT scan of chest or 
MRI of chest (only if CT scan cannot be performed) and unilateral mammography or ultrasound of breast. Assessments 
are not to be scheduled based on the scheduled calendar date of the EOT/ET Visit.  
17. Subjects will undergo a definitive surgical resection of their primary tumor 3 to 7 weeks from the 1st day of the last 
cycle/last dose of study drug, i.e. lumpectomy or mastectomy with sentinel node (SN) biopsy or axillary lymph node 
dissection (ALND).  Pathology of the tumor sample and pathologic response will be assessed locally and reviewed 
centrally by a qualified pathologist. 
 
Table 3.3.2: Schedule of Blood Sampling 
Assessment 
Screenin
g 
Cycle 
1  
(Wee
k 0) 
Cycle 
2 
(Wee
k 3) 
Cycle 
3 
(Wee
k 6) 
Cycle 
4 
(Wee
k 9) 
Cycle 
5 
(Wee
k 12) 
Cycle 
6 
(Wee
k 15) 
Cycle 
7 
(Wee
k 18) 
Cycle 
8 
(Wee
k 21) 
EOT/
ET 
Visit 
Hematology 
4 mL 
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 
4.5 
mL 
Pharmacokinetics 
(100 subjects per 
treatment arm) 
 
 
 
 
 
7 mL 
7 mL 
7 mL 
7 mL 
7 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 
SOC, at the investigator's discretion for the purpose of planning treatment administration, dose modification (Appendix 1), 
following AEs, or as clinically indicated. 
 
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Protocol Number: TX05-03 
Version: Final 3.0, Date: 4FEB2021
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4 
STUDY ENDPOINTS 
4.1 
Primary efficacy endpoint(s) 
The primary efficacy endpoint is the proportion of subjects in each treatment arm who achieve pCR, 
defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the 
complete resected breast specimen and all sampled regional lymph nodes following completion of 
neoadjuvant systemic therapy (ypT0/Tis ypN0). Pathology of the tumor sample and pathologic 
response will be assessed locally and reviewed centrally by a qualified pathologist. The primary 
efficacy analysis will be based on the central pathological review.  
4.2 
Secondary efficacy endpoint(s) 
ORR, defined as the percentage of subjects having Complete or Partial Response at the EOT/ET 
Visit, according to RECIST version 1.1 (see Appendix 2), as assessed by the investigator. 
4.3 
Immunogenicity Assessments  
x 
Incidence of ADA. 
x 
Incidence of Nab. 
4.4 
Safety endpoint(s) 
x 
Treatment-emergent AE (TEAE) and serious AE (SAE). 
x 
Death 
x 
Clinical laboratory parameters  
x 
Vital signs 
x 
12-Lead ECG cardiac ejection fraction 
x 
Physical examination 
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Protocol Number: TX05-03 
Version: Final 3.0, Date: 4FEB2021
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5 
SAMPLE SIZE AND POWER 
The primary efficacy endpoint is the proportion of subjects in each treatment arm who, achieve pCR. 
For the calculation of the equivalence margin, neoadjuvant Herceptin1, 2, 3, 4, 5 studies of ‘trastuzumab 
+ chemotherapy (anthracyclines and/or taxanes based)’ vs ‘chemotherapy (anthracyclines and/or 
taxanes-based) alone’ were considered. pCR rates were reported for 4 studies with HER2-positive 
subjects in early or locally advanced breast cancer. The rate of pCR for each study is provided in the 
table below. 
Table 5.1: Rates of pCR from Neoadjuvant Herceptin Studies 
Name 
Trastuzumab + 
Chemotherapy 
(T + C) 
Chemotherapy Alone 
(C) 
NOAH (MO16432) 1,2 
(n =115) 
46 (40.0%) 
(n=116) 
24 (20.7%) 
Buzdar3  
(n=23) 
15 (65.2%) 
(n=19) 
5 (26.3%) 
Pierga4  
(n=62) 
16 (25.8%) 
(n=58) 
11 (19.0%) 
ABCSG-245 
(n=44) 
17 (38.6%) 
(n=49) 
13 (26.5%) 
Combined risk ratio of pCRa 
95% CI (T+C:C) 
1.755b 
[1.317, 2.337] 
C: Chemotherapy; CI: Confidence Interval; NOAH: NeOAdjuvant Herceptin; T: Trastuzumab. 
a. 
Using the inverse variance-weighed method 
b. 
Chi square test was used to test for homogeneity at 0.05 level (Q=1.817, p=0.611). 
Based on the results of meta-analysis, the combined risk ratio for trastuzumab + chemotherapy over 
chemotherapy alone is estimated to be 1.755. The equivalence margin is determined as [0.755, 1.325] 
to protect 50% of the effect size based on a log scale (upper equivalence limit is 
exp[0.5×ln(1.755)=1.325]). 
With 370 subjects per treatment group, there is 85% probability that the observed two-sided 95% CI 
of the risk ratio of TX05 + chemotherapy to Herceptin + chemotherapy will lie within [0.755, 1.325] 
assuming a 5% type 1 error rate, a pCR rate of 44.6% in both treatment groups, and that the actual 
risk ratio is 1.00. Allowing for 7.5% losses to follow-up, at least 400 subjects per arm, 800 in total, 
will be randomized 
 
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Protocol Number: TX05-03 
Version: Final 3.0, Date: 4FEB2021
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6 
ANALYSIS POPULATIONS 
6.1 
Enrolled population 
The enrolled population will include the subjects who have signed-off the informed consent form 
and performed any assessment at the screening visit. 
6.2 
All randomized population 
The all randomized population will include the subjects who are randomized into the study regardless 
taking the study drug. It will be used for the data listings unless specified otherwise. 
6.3 
Modified Intent to Treat Population 
The modified intent-to-treat (mITT) population will include all subjects who are randomized into the 
study and receive at least 1 dose of TX05 or Herceptin. A sensitivity analysis of the primary efficacy 
variable and the primary analysis of the secondary efficacy endpoint will be performed using the 
mITT population.  
6.4 
Per Protocol Population 
The per protocol (PP) population will include all subjects who meet all of the following criteria: 
x 
Randomized and receive at least one dose of study drug, either TX05 or Herceptin. 
x 
No major protocol deviations that impact the efficacy endpoints. The following major 
protocol deviations are considered to exclude from Per Protocol Population. 
- 
Not meet the following HER2 results. 
o A central HER2 result of Positive. 
o A local HER2 result of Positive and no central HER2 result.” 
- 
Failed to complete 8 cycles of treatment. 
- 
Surgery performed > 8 weeks from last dose not based on COVID-19 delays. (Those 
delay due to COVID-19 will not be excluded.) 
- 
Tumor size < 2 cm or not measurable. 
- 
Invasive breast carcinoma not histologically confirmed. 
- 
Presence of metastatic disease, bilateral lesions or inflammatory breast cancer. 
- 
Not evaluable (cannot be assessed or indetermined) for pCR assessment as reported by 
central lab. 
- 
Subjects that receive incorrect IP/comparator (only TX05 or Herceptin) assigned to 
subject (for example subject is assigned to TX05-03 arm and receives Herceptin) 
A central/local HER2 test results and a central pCR assessment deviations will be checked in 
captured datasets. Other above protocol deviations will be described in Protocol Deviation Criteria 
Form (CTM002-SOP-T01). 
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x 
An adequate tumor sample by definitive surgical resection of their primary tumor.  
The primary efficacy analysis will be carried out using the PP population. 
6.5 
Safety Population 
The safety population will include all subjects who are randomized into the study and have received 
at least one dose of study drug (TX05 or Herceptin). The safety population will be used for safety 
and immunogenicity endpoints.  
 
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Version: Final 3.0, Date: 4FEB2021
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o If month and year of onset date are the same as month and year of the first 
dose date in Cycle 5, impute AE start day as day of first dose date in Cycle 5  
o Else impute AE start day as 1 
When only day and month are missing: 
If it is the end date of an AE, December 31st of the year will be used. 
   For start date of an AE: 
x 
If the year of the AE onset date is prior to the year of the first dose date in Cycle 1, 
impute AE start month and day as January 1st  
Otherwise, 
x 
If AE stop date is prior to first dose of Cycle 1, impute the AE start month and day as 
January 1st 
x 
If the AE stop date is on or after first dose of Cycle 1 but before first dose of Cycle 5:  
o 
If the year of onset date is the same as the year of the first dose date in Cycle 1,  
impute the AE start month and day as the month and day of the first dose date in 
Cycle 1. 
o 
Else impute AE start month and day as January 1st  
x 
If the AE stop date is on or after first dose of Cycle 5 or AE stop date is completely 
missing:  
x 
For AEs occurred in Cycle 1 - 4 or ongoing AE re-entered into Cycle 5: 
o If the year of onset date is the same as the year of the first dose date in Cycle 1, 
impute the AE start month and day as the month and day of the first dose date 
in Cycle 1 
o Else impute AE start month and day as January 1st  
x 
For new AE (not ongoing AE carried from Cycle 1 - 4) entered into Cycle 5: 
o If the year of onset date is the same as the year of the first dose date in Cycle 5, 
impute the AE start month and day as the month and day of the first dose date 
in Cycle 5 
o Else impute AE start month and day as January 1st  
If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site with 
no imputation.  For this type of AE, if it has partial AE stop date, compare the AE stop date 
to the first dose date in Cycle 1 and Cycle 5. If the AE stop date is before the first dose date 
of Cycle 1 then the AE should be considered as a pre-treatment AE. If the AE stop date is 
on or after the first dose date in Cycle 1 but before the first dose date of Cycle 5, the AE 
will be considered TEAE for Cycle 1- 4. Otherwise, if the AE stop date is on or after the 
first dose date in Cycle 5 or is an ongoing AE, the AE will be considered as TEAE for Cycle 
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5 - 8; if the AE stop date is on or after the first dose date in Cycle 5 and the given AE is new 
event (not ongoing AE carried from Cycle 1- 4), the AE will be considered as TEAE for 
Cycle 5 - 8 only. 
For records with partial AE start date, the imputed AE start date will be used in the treatment 
emergent AE determination.  
7.2.2.2 Missing Causality and Severity for Adverse Events 
When the causality of the AE is missing: 
 
If the causality of AEs is missing, causality will not be imputed for AEs prior to the first 
dose of Cycle 1 
 
If the causality of AEs is missing during Cycle 1 – Cycle 4, Causality will be imputed as 
“Possibly related” to Epirubicin/Cyclophosphamide for AEs which occurred started after the 
first dose of Cycle 1 for Epirubicin/Cyclophosphamide before the first dose of Cycle 5. 
 
If the causality of AE is missing after the first dose of Cycle 5 for TX05/Herceptin/Paclitaxel, 
Causality will be imputed as “Possibly related” to TX05/Herceptin/Paclitaxel for AEs which 
occurred started after the first dose of Cycle 5 for TX05/Herceptin/Paclitaxel. 
When the severity of AEs is missing: 
 
Prior to study treatment: severity will not be imputed. 
 
During study treatment: missing severity will be imputed as severe. 
7.2.2.3 Missing or partial dates for concomitant medication 
When only day is missing: 
x 
If it is the start date of the medication prior to the first dose of Cycle 1, the first day of the 
month will be used. 
x 
If it is the start date of the medication and the new record (not ongoing medication from 
Cycle 1 - 4): 
o If month and year is equal to the month and year of the first dose of Cycle 
1, then the day of the first dose in Cycle 1 will be used; 
o Else the first day of the month will be used. 
x 
If it is the end date of the medication, then the last day of the month will be used. 
When day and month are missing: 
x 
If it is the start date of the medication prior to the first dose of Cycle 1, January 1st of the 
year will be used. 
x 
If it is the start date of the medication and the new record (not ongoing medication from 
Cycle 1 - 4): 
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o If year is equal to the year of first dose in Cycle 5, then the day and month 
of the first dose in Cycle 5 will be used;  
o Else January 1st of the year will be used, 
x 
If it is the end date of the medication, then December 31st of the year will be used. 
If Year of medication start date is missing, no imputation will be done. 
 
 
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Version: Final 3.0, Date: 4FEB2021
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8 
STATISTICAL METHODS 
8.1 
General statistical conventions 
All statistical procedures will be completed using SAS version 9.4 or higher. 
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 “as randomized” for efficacy analyses, 
but “as treated” for all other analyses. For these other analyses, if there are any cases where subjects 
received both drugs, they will be assigned to the treatment initially given. 
Given the design of the study, there are two types of baseline, defined as follows: 
Baseline of cycle 1 (whole study): the last non-missing assessment with a collection date prior 
to the first dose date of epirubicin or cyclophosphamide.  
Baseline of cycle 5 (TX05/Herceptin): the last non-missing assessment with a collection date 
prior to the first dose date of TX05/Herceptin and paclitaxel. 
Those two types of baseline will be analyzed separately. For change from baseline regarding the test 
values, baseline of cycle 1 will be used for test values collected during cycle 1 – cycle 8, baseline of 
cycle 5 will be used for test values collected during cycle 5 – cycle 8.   
8.2 
Subject disposition 
Subject disposition information will be summarized by treatment group and overall. The data 
summary will contain the following information: 
x 
Number of subjects screened 
x 
Number of subjects randomized 
x 
Number of subjects treated 
x 
Number and percent of subjects receiving study drug (TX05 or Herceptin) 
x 
Number and percent of subjects in each analysis set (mITT, PP, safety) 
x 
Number and percent of subjects completing the study/withdrawing early (including 
withdrawal reason) 
A listing will be prepared to present data concerning subject disposition.  
Subject allocation by site will be summarized. 
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8.3 
Protocol deviations 
The number of patients excluded from the PP analysis set and reasons for exclusion will be 
summarized by treatment group and overall. 
Population membership details will be listed, including reason for exclusion from each population. 
Subjects with study protocol deviations will be summarized by type of violation (major or non- 
major) and listed by treatment and site.  
A listing will include the inclusion/exclusion criteria violated at Screening and at Baseline Visits, as 
well as other protocol deviations identified based on data recorded on the CRF. 
8.4 
Demographics and baseline characteristics 
8.4.1 Demographics 
Demographic and baseline characteristics will be analysed in a descriptive fashion and results will 
be presented overall and by treatment group. 
Sex, race, and ethnicity as categorical variables will be summarized using frequency count and 
percentages. 
Age, height, weight and BSA as continuous demographic variables will be summarized by 
descriptive statistics. 
Demographics will be listed for all randomized subjects.  
8.4.2 Baseline and disease characteristics 
The categorical baseline characteristics such as estrogen receptor (ER) status, progesterone receptor 
(PR) status, hormone receptor (HR) status, tumor stage, ECOG performance status, Baseline Overall 
Interpretation of ECG, Viral disease (HBsAg, HBcAb, HCV, and HIV), breast cancer diagnosis 
(stage at initial diagnosis, stage at screening, histopathological classification at screening, HER2 
status based on local determination and central review separately) will be summarized using 
frequency counts and percentage by treatment group. Baseline is defined as baseline of cycle 1. 
Baseline characteristics will be listed for all randomized subjects.  
8.4.3 Medical history 
A summary of medical history will be presented by system organ class (SOC) and preferred terms 
(PTs) using Medical Dictionary for Regulatory Affairs® (MedDRA). Medical history will be listed 
by subject. 
8.4.4 Prior and concomitant medications and surgeries/procedures 
If the start date of a medication (including the imputed start date if applicable) is prior to first dose 
date of Cycle 1 or if the start date of the medication is missing, then the medication will be classified 
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as a prior medication.  
Concomitant medication is classified as follows: 
x 
For the concomitant medication for Cycle 1 - 4, if start data of a medication (including the 
imputed end date, if applicable)  is missing or on or before the first dose date of Cycle 5 and 
the end date of a medication (including the imputed end date, if applicable) is on or after the 
first dose date of Cycle 1, or if the end date of the medication is missing; 
x 
For the concomitant medication for Cycle 5 - 8, if the start date of medication is missing or 
on or before the first dose date of Cycle 5 and end date of medication is missing or on or 
after the first dose date of Cycle 5.  
Prior and concomitant medications, coded using the most recent version of the WHO Drug 
Dictionary, will be summarized by treatment group and overall. The numbers of subjects using 
concomitant medications will be categorized by drug classification (Anatomical Therapeutic 
Chemical1) and PT. Concomitant medications will be listed.  
Concomitant Surgeries / Procedures will be listed appropriately. 
Breast tumor surgery will be summarized by treatment group and overall. The data summary will 
contain the following information: 
x 
Number and percent of subjects performed surgery 
x 
Number and percent of subjects did not perform surgery (including the reason) 
x 
Breast surgery (Lumpectomy, Mastectomy and Other) 
x 
Axilla surgery (Sentinel node resection, Axillary lymph node dissection and Other) 
x 
Surgery outcome (Unresected, Resected, Partially resected and Not found) 
x 
Pathological response (Complete pathological response, Partial pathological response 
and No pathological response) 
Surgery will be listed for all randomized subjects. 
8.5 
Extent of exposure 
The extent of exposure will be characterized according to the number of subjects exposed, the 
duration of exposure, and the dose to which they were exposed.  
Treatment exposure will be presented for Epirubicin, Cyclophosphamide, TX05/Herceptin and 
Paclitaxel separately using the safety population and will be listed appropriately. 
8.5.1 Treatment duration 
Descriptive statistics will be provided by treatment for the following:  
x 
Number of cycles of Epirubicin  
x 
Number of cycles of Cyclophosphamide  
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x 
Number of cycles of TX05/Herceptin  
x 
Number of cycles of Paclitaxel  
x 
Duration of TX05/Herceptin exposure (weeks) 
Durations (weeks) are defined as the following, 
x 
Duration of TX05/Herceptin exposure  (weeks) = (Last date of administration of 
TX05/Herceptin  – First date of Administration of TX05/Herceptin+ 21)/7 
8.5.2 Cumulative Dose 
Cumulative dose is defined as the total dose given during the study treatment exposure and will be 
summarized for each of the study treatments. For patients who do not receive any drug, the 
cumulative dose will be set to zero 
x 
Total Epirubicin dose administered (mg and mg/m2) 
x 
Total Cyclophosphamide dose administered (mg and mg/m2) 
x 
Total TX05/Herceptin dose administered (mg and mg/kg) 
x 
Total Paclitaxel dose administered (mg and mg/m2) 
8.5.3 Relative Dose Intensity 
Relative dose intensity is defined as following, 
x 
Relative Dose Intensity of Epirubicin = ([total Epirubicin dose administered in mg/m2]/ 
[planned total Epirubicin dose])*100 
x 
Relative Dose Intensity of Cyclophosphamide = ([total Cyclophosphamide dose 
administered in mg/m2]/ [planned total Cyclophosphamide dose])*100 
x 
Relative Dose Intensity of TX05/Herceptin = ([total TX05/Herceptin dose administered in 
mg/kg]/ [planned total TX05/Herceptin dose])*100 
x 
Relative Dose Intensity of Paclitaxel= ([total Paclitaxel dose administered in mg/m2]/ 
[planned total Paclitaxel dose])*100 
where planned total dose is the prescribed starting dose * number of cycles of Epirubicin (mg/m2), 
Cyclophosphamide (mg/m2), TX05/Herceptin (mg/kg) or Paclitaxel (mg/m2) respectively. 
In addition, number and percentage will be provided for the subjects with relative dose intensity <50, 
50-<70, 70-<90, 90-<110 and t110.   
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8.6 
Efficacy analyses 
8.6.1 Analysis methods 
The analyses of the primary and secondary endpoints will be performed using the mITT population 
and the PP population.  
8.6.1.1 Multiplicity 
Not applicable. 
8.6.1.2 Treatment by center interaction analysis (multi-center study) 
Not applicable. 
8.6.2 Analysis of primary efficacy endpoint(s) 
The primary efficacy endpoint is the proportion of subjects in each treatment arm who, based on the 
central pathological review, achieve pCR, assessed by central reading, defined as the absence of 
residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast 
specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic 
therapy (ypT0/Tis ypN0).  
Two one-sided hypothesis tests will be performed in the study for pCR in order to show that TX05 
is equivalent to Herceptin: 
TEST 1: H0a: θ1 / θ2 > 1.325 vs. H1a: θ1 / θ2 < 1.325 
TEST 2: H0b: θ1 / θ2 < 0.755 vs. H1b: θ1 / θ2 > 0.755 
Where θ1 is the proportion of pCR for subjects randomized to TX05 group, θ2 is the proportion of 
pCR for subjects randomized to Herceptin. Justification of equivalence margin [0.755, 1.325] is 
described in the Section 5. Equivalence will be concluded if the 95% CI of the risk ratio is completely 
contained within the pre-defined interval [0.755, 1.325]. 
Frequency and percentage of subjects who meet the pCR criteria will be summarized in each 
treatment group.  The primary analysis for pCR by central pathological review will be performed 
using the PP population. RR and its 95% CI will be provided and estimated. Asymptotic method will 
be applied to compute the confidence interval using standard normal percentile. To assess the 
robustness of the primary efficacy analysis, the primary efficacy variable will be evaluated in a 
sensitivity analysis using the mITT population. Subjects who are included in the mITT population, 
but do not have efficacy assessments will be assessed as non-responders. 
Sensitivity analyses using log-binomial regression will be performed using subjects from the mITT 
and PP populations6. Treatment group and the stratification factors (‘Hormone Receptor (HR) Status’ 
and ‘Tumor Stage’) will be included as factors and pCR by central pathological review result will be 
the response variable.  The 95% confidence interval of the RR will be computed. In case of failure 
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of convergence using log-binomial regression model, modified poisson regression will be applied 
instead, if convergence of poisson regression model is not met, the stratified mantel-haenszel chi-
square statistic will be performed alternately. Stratification factors (‘Hormone Receptor (HR) Status’ 
and ‘Tumor Stage’) will be included as the controlled categorical factors. 
An additional sensitivity analysis using the tipping point approach will be performed with the mITT 
population as performed by the FDA for the CT-P13 biosimilar study7. Tipping point analysis is one 
of the multiple imputation methods under the missing not at random assumption. Tipping point 
analysis will be used to explore the sensitivity of statistical results by shifting the response rate in 
subjects who have been withdrawn. The nominal list of imputing the pCR rate will be determined 
based on the data such as considering pCR rate of completers and withdrawer of each treatment 
groups. The subjects with missing pCR will be imputed either responder or non-responder based on 
the listed pCR rate. 1000 complete datasets will be generated and CIs will be constructed for every 
nominal pCR rate accordingly. It is repeated by listed pCR rates. 
Listings will be produced for both investigator assessment and central review. 
8.6.3 Analysis of secondary efficacy endpoint(s) 
The secondary efficacy endpoint is: 
x 
ORR, defined as the percentage of subjects having Complete or Partial Response at the 
EOT/ET Visit, according to RECIST version 1.1 (see Appendix 2), as assessed by the 
investigator. 
ORR and the individual rates for CR, PR, SD, PD will be summarized descriptively using the 
frequency count and the percentage of subjects in each treatment group. The RR and its 95% CI will 
be estimated for ORR in the same way as for the primary efficacy variable. The primary efficacy 
analysis for the secondary efficacy endpoint will be carried out using the mITT population. A 
sensitivity analysis will be performed using the PP population. 
Listings will be produced for tumor assessment. 
8.7 
Immunogenicity analyses 
Immunogenicity data (ADA and Nab) will be summarized and analysed descriptively for each 
scheduled protocol assessment time-point. A shift table from baseline (baseline of cycle 5) to each 
scheduled protocol assessment time-point as well as overall will be provided by treatment group. 
Overall positive response is defined as negative at baseline and positive at least one positive at 
subsequent time point. The analysis will be performed with the safety population. 
Immunogenicity data (ADA and Nab) will be listed.  
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8.8 
Safety analyses 
The safety parameters will include the following: 
x 
TEAE and SAE 
x 
Death 
x 
Clinical laboratory parameters  
x 
Vital signs 
x 
12-Lead ECG  
x 
Physical examination  
These analyses will be performed using the safety population. 
8.8.1 Adverse events 
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, Severity of 
TEAEs will be graded according to CTCAE, by treatment group and overall.  
Treatment-emergent AEs are defined as AEs occurring during or after the initial dose of drug in 
related Cycle. Adverse events documented prior to the initial dose cannot be classified as TEAEs 
unless there is a worsening in severity during or after the initial dose of study drug. Given the design 
of the study and the way AEs are collected, there are two types of TEAEs, defined as follows: 
TEAEs for Cycles 1 - 4: AEs newly occurring on or after the first dose of epirubicin or 
cyclophosphamide and before the first dose of the TX05/Herceptin or Paclitaxel, or events newly  
occurring on or after the first dose of epirubicin or cyclophosphamide and within the last dose of 
epirubicin or cyclophosphamide in subjects that discontinue early from the study. Or worsening 
in severity on or after Day 1 of Cycle 1 and before Day 1 of Cycle 5. Or worsening in severity 
on or after Day 1 of Cycle 1 and within the last dose of epirubicin or cyclophosphamide in 
subjects that discontinue early from the study.  
TEAEs for Cycles 5 - 8: AEs newly occurring on or after the first dose of TX05/Herceptin or 
Paclitaxel, or worsening in severity during or after Day1 of Cycle 5.  
The overall incidence of TEAEs with all causalities will be summarized by treatment group and 
overall. The number and percent subjects will be reported in each of the categories: TEAEs, study 
drug related TEAE, TEAEs leading to study drug withdrawal, TEAEs leading to death, serious 
TEAEs, study drug related serious TEAE serious TEAEs leading to study drug withdrawal, and 
serious TEAEs leading to death.  
Summary tables for overview TEAEs, TEAEs leading to study drug withdrawal, TEAEs leading to 
death, serious TEAEs leading to study drug withdrawal, and serious TEAEs leading to death will be 
provided for Cycle 1 - 4 for all randomized subjects, and Cycle 5 - 8 for all safety subjects. 
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Summary tables for TEAEs by system organ class and preferred term, TEAEs by maximum severity, 
serious TEAEs by system organ class and preferred term will be provided for Cycle 5 - 8 for all 
safety subjects. 
Summary tables for TEAEs related to study drug (TX05/Herceptin) by system organ class and 
preferred term, TEAEs related to study drug (TX05/Herceptin) leading to study drug withdrawal, 
TEAEs related to study drug (TX05/Herceptin) leading to death, TEAEs related to study drug 
(TX05/Herceptin) by maximum severity, serious TEAEs related to study drug (TX05/Herceptin) by 
system organ class and preferred term, serious TEAEs related to study drug (TX05/Herceptin) 
leading to study drug withdrawal, serious TEAEs related to study drug (TX05/Herceptin) leading to 
death, serious TEAEs related to study drug (TX05/Herceptin) by maximum severity. 
In summaries by SOC and PT, adverse events will be sorted by decreasing frequency within each 
SOC and PT according to the alphabetically order of total. In summaries by PT, AEs will be sorted 
by decreasing frequency according to the alphabetically order of alphabetically order of total. 
Where a subject has the same adverse event, based on preferred terminology, reported multiple times 
in the treatment period, the subject will only be counted once at the preferred terminology level in 
adverse event frequency tables. 
Where a subject has multiple adverse events within the same system organ class in the treatment 
period, the subject will only be counted once at the system organ class level in adverse event 
frequency tables. 
When reporting adverse events by severity, in addition to providing a summary table based on the 
event selection criteria detailed above, summary table will also be provided, only the most severe 
occurrence will be included in the incidence. 
All AEs will be listed. Additional listings will include AEs reported as reasons for 
discontinuation/death, and serious AEs.  
8.8.2 Death 
Listings will be produced for death with primary cause. 
8.8.3 Clinical laboratory evaluations 
Clinical safety laboratory data will be presented by treatment group and overall for each scheduled 
visit. For laboratory tests with quantitative values, descriptive statistics (number of subjects, mean, 
median, SD, min, and max) of the observed values and changes from baseline (baseline of cycle 1) 
at each scheduled visit will be reported. Change from baseline (baseline of cycle 5) laboratory data 
will be presented by treatment group and overall from cycle 5 for each scheduled visit.  For laboratory 
tests with categorical values, the number and percent of subjects in each category will be summarized 
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by treatment group at each scheduled visit. Shift tables from baseline (baseline of cycle 5) for values 
outside the normal ranges will be presented as appropriate.   
Listings will be produced for all laboratory parameters. 
8.8.4 Vital signs 
Observed values and changes from baseline (baseline of cycle 1) for vital sign measurements 
(temperature, blood pressure, pulse rate, and respiratory rate) will be summarized by treatment group 
and overall for each scheduled visit. Change from baseline (baseline of cycle 5) vital sign data will 
be presented by treatment group and overall from cycle 5 for each scheduled visit. 
A listing will be produced for all vital signs. 
8.8.5 Physical examinations 
All physical examination data and abnormalities (Normal, Abnormal-NCS, Abnormal-CS and Not 
Examined) will be summarized by treatment group and overall for each scheduled visit (including 
pre-treatment and post-treatment results).  
A listing will be produced for all physical examination data. 
8.8.6 12-lead Electrocardiograms 
Observed values and changes from baseline (baseline of cycle 1) of continuous 12-lead ECG 
measurements (Heart Rate (beats/min), QRS Duration (msec), PR Interval (msec), QT Interval 
(msec), QTc Interval Unspecified (msec)) will be summarized by treatment group and overall for 
each scheduled protocol assessment visit. 
Shift tables from baseline (baseline of cycle 5) to end of treatment visit of normal vs. abnormal (NCS, 
CS) assessments will be provided by treatment group and overall. 
Clinically notable abnormalities with thresholds of:  
QTcF value > 450 msec, > 480 msec and > 500 msec, change of from baseline > 30 msec, > 60 
msec and > 90 msec;  
PR interval<120 msec or >210 msec, QRS complex >110 msec  
will be summarized by treatment group at each scheduled visit using descriptive statistics. 
A listing will be produced for all ECG measurements. 
8.8.7 Other safety assessments 
8.8.7.1 Pharmacokinetics 
The analysis of the PK will be described in a separate analysis plan if needed.. 
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8.8.7.2 Weight and BSA 
Observed values and changes from baseline (baseline of cycle 1) for weight and BSA will be 
summarized by treatment group and overall for each scheduled visit. Change from baseline (baseline 
of cycle 5) data will be summarized by treatment group and overall from cycle 5 for each scheduled 
visit. 
A listing will be produced for all weight, BSA and BMI. 
8.8.7.3 ECOG 
All ECOG data will be summarized by treatment group and overall for each scheduled visit 
(including pre-treatment and post-treatment results). Shift table from baseline (baseline of cycle 5) 
to each post-baseline scheduled visit will be provided by treatment group and overall.  
A listing will be produced for all ECOG data. 
8.8.7.4 Pregnancy 
Pregnancy test results will be listed. 
8.8.7.5 LVEF 
Visit values and changes from baseline (baseline of cycle 1) for LVEF will be summarized by 
treatment group and overall for each scheduled protocol assessment visit. Change from baseline 
(baseline of cycle 5) data will be summarized by treatment group and overall from cycle 5 for each 
scheduled visit. 
In addition, LVEF quantitative values will be classified into the following 4 categories:  
Hyperdynamic: LVEF greater than 70%  
Normal: LVEF from 50% to 70% with midpoint 60% 
Mild dysfunction = LVEF from 40% to 49% with midpoint 45% 
Moderate dysfunction = LVEF from 30% to 39% with midpoint 35% 
Severe dysfunction = LVEF less than 30%  
Shift tables from baseline (baseline of cycle 5) to end of treatment visit of LVEF quantitative values 
will be provided by treatment group and overall. 
A listing will be produced for all LVEF. 
8.9 
Interim analysis 
Not applicable. 
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9 
CHANGES TO PLANNED ANALYSIS FROM STUDY 
PROTOCOL 
Not applicable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10 
REFERENCES 
1. 
Herceptin®: European Public Assessment Report – Product Information 19/04/2017.  
2. 
Gianni L, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant 
trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally 
advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a 
parallel HER2-negative cohort. Lancet 2010;375(9712): 377-384. 
3. 
Buzdar AU, et al. Significantly higher pathologic complete remission rate after neoadjuvant 
therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized 
trial in human epidermal growth factor receptor 2–positive operable breast cancer. J Clin 
Oncol 2005;23(16):3676-3685. 
4. 
Pierga JY(1), Delaloge S, Espié M, et al. A multicenter randomized phase II study of 
sequential epirubicin/cyclophosphamide followed by docetaxel with or without celecoxib or 
trastuzumab according to HER2 status, as primary chemotherapy for localized invasive 
breast cancer patients. Breast Cancer Res Treat 2010 Jul;122(2):429-37. 
5. 
Steger GG(1), Greil R, Lang A, et al; Austrian Breast and Colorectal Study Group (ABCSG). 
Epirubicin and docetaxel with or without capecitabine as neoadjuvant treatment for early 
breast cancer: final results of a randomized phase III study (ABCSG-24). Ann Oncol 2014 
Feb;25(2):366-71. 
6. 
Jiming Fang. Using SAS® Procedures FREQ, GENMOD, LOGISTIC, and PHREG to 
Estimate Adjusted Relative Risks – A Case Study. Statistics and Data Analysis; SAS Global 
Forum 2011; 345-2011. 
7. 
FDA 
Statistical 
Review 
and 
Evaluation 
of 
CT-P13. 
Available 
at 
https://www.accessdata fda.gov/drugsatfda_docs/nda/2016/125544Orig1s000StatR.pdf. 
Accessed Mar 07, 2018 
 
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11 
APPENDICES 
Appendix 1 
Dose Modification Guidelines 
Trastuzumab Dose Modifications 
Trastuzumab Dose Adjustment Guidelines 
Infusion Reaction 
x 
Mild or moderate: decrease rate of infusion 
x 
Dyspnea or clinically significant hypotension: 
interrupt infusion, administer appropriate 
medical therapy, which may include 
epinephrine, corticosteroids, 
diphenhydramine, bronchodilators, or 
oxygen; monitor until complete resolution 
x 
Severe or life-threatening: consider 
permanent discontinuation 
Decline of LVEF  
Asymptomatic absolute decline ı
16% from baseline  
OR  
Absolute decline ı10% from 
baseline and below the institutional 
limit of normal 
x 
Initiate monthly monitoring of LVEF and 
consider cardiac support 
x 
Hold trastuzumab for at least 4 weeks 
x 
Dosing may resume if within 4-8 weeks the 
LVEF returns to normal limits and the 
absolute decrease from baseline is İ15%. 
x 
Permanently discontinue trastuzumab 
x 
If persistent (>8 weeks) LVEF decline  
x 
If suspension of trastuzumab dosing on 
more than 3 occasions for cardiomyopathy 
Symptomatic cardiac failure 
x 
Hold trastuzumab, monitor LVEF and seek 
cardiology input 
 
Epirubicin Dose Modifications 
Epirubicin hydrochloride injection dosage adjustments for hematologic and non-hematologic 
toxicities within a cycle of treatment, is based on nadir platelet counts <50,000/mm3, absolute 
neutrophil counts (ANC) <250/mm3, neutropenic fever, or Grades 3/4 nonhematologic toxicity.  
Reduce Epirubicin hydrochloride injection Day 1 dose in subsequent cycles to 75% of the Day 1 
dose given in the current cycle.  Delay Day 1 chemotherapy in subsequent courses of treatment until 
platelet counts are ≥100,000/mm3, ANC ≥1500/mm3, and nonhematologic toxicities have recovered 
to ≤ Grade 1. 
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Paclitaxel Dose Modifications 
Paclitaxel Dose Adjustment Guidelines 
Grade 2 neuropathy 
x 
Reduce paclitaxel by 1 dose level. 
x 
Trastuzumab should continue at the same dose 
level. 
Grade ≥3 neuropathy 
x 
Hold paclitaxel until event resolves or returns to 
baseline.  
x 
Decrease paclitaxel dose by 1 dose level. 
x 
Trastuzumab should continue at the same dose 
level. 
Grade 3 or 4 acute hypersensitivity 
despite adequate premedication 
x 
Discontinue paclitaxel and consider trastuzumab 
monotherapy. 
ANC <1000/mm3 (1.0 × 109/L), or 
platelet <75,000/mm3 (75 × 109/L) on 
day of scheduled paclitaxel treatment 
x 
Hold paclitaxel until ANC ı1000/mm3 (1.0 × 
109/L), and platelet ı75,000/mm3 (75 × 109/L). 
x 
Consider treatment with growth factor 
(eg, G-CSF) according to local guidelines. 
x 
If event reoccurs, reduce paclitaxel by 1 dose 
level. 
x 
Trastuzumab should continue at the same dose 
level. 
Grade 4 neutropenia lasting ı7 days 
Grade 4 febrile neutropenia 
Grade 3 or 4 documented infection with 
neutropenia (ANC <1000/mm3 [1.0 × 
109/L]) 
x 
Hold paclitaxel until ANC ı1000/mm3 (1.0 × 
109/L). 
x 
Reduce paclitaxel by 1 dose level. 
x 
Consider treatment with growth factor (eg, 
G-CSF) according to local guidelines. 
x 
Trastuzumab should continue at the same dose 
level. 
x 
If event reoccurs, reduce paclitaxel to the next 
lower dose level or discontinue paclitaxel at the 
investigator’s discretion. 
Grade 4 thrombocytopenia 
x 
Hold paclitaxel until platelet ı75,000/mm3 
(75 × 109/L). 
x 
Reduce paclitaxel by 1 dose level. 
x 
Trastuzumab should continue at the same dose 
level. 
x 
If the event reoccurs, reduce paclitaxel to the next 
lower dose level or discontinue paclitaxel at the 
investigator’s discretion. 
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Paclitaxel Dose Adjustment Guidelines 
For potential cases of drug-induced 
liver injury 
x 
Hold paclitaxel. 
x 
Contact the Sponsor immediately to discuss next 
steps, including evaluation of alternative causes. 
x 
This must be reported as an SAE.  Refer to the 
AE section for additional information on 
potential drug-induced liver injury. 
Other Grade 3 or 4 non-hematologic 
toxicity including nausea and/or 
vomiting despite optimal medical 
therapy, and fatigue/asthenia lasting 
more than 3 days 
x 
Hold paclitaxel until recovery to Grade 1 or 
baseline.  
x 
Paclitaxel dose adjustment and/or paclitaxel or 
trastuzumab discontinuation should be performed 
according to the investigator’s medical judgment. 
 
 
 
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Cyclophosphamide Dose Modifications 
Cyclophosphamide Dose Adjustment Guidelines 
Hematological 
Toxicity 
Delay 1 week if neutrophils <1.0 x 109/L and/or platelets <100 x 109/L.  
20% dose reduction should be considered if myelosuppression results in 
delay of subsequent courses 
Renal 
Impairment 
Creatinine Clearance (mL/min) 
Cyclophosphamide Dose 
> 21 
100% 
10 to 20 
75% 
< 10 
50% 
Hepatic 
Impairment 
Bilirubin 
ALT/ Alkaline 
Phosphatase 
Cyclophosphamide Dose 
1.5 to 3 x ULN 
2.5 to 5 x ULN 
100% 
3 to 5 x ULN 
5 to 10 x ULN 
100% 
.> 5 x ULN 
.> 10 x ULN 
Consider dose reduction / use 
alternative regimen* 
* Cyclophosphamide is not recommended in patients if bilirubin > 1.5 x 
ULN or AST/ALT >2 to 3xULN, but exposure to active metabolites may 
not be increased and therefore a dose reduction may not be necessary. 
Consultant decision. 
NCI Common 
Toxicity 
Criteria 
Toxicity 
Definition 
Dose Adjustment 
Febrile 
neutropenia 
ANC < 0.5 x 109/L plus 
fever requiring IV 
antibiotics +/- 
hospitalization 
20% reduction  
Other toxicities Grade III/IV toxicity (except 
alopecia) 
Continue with 20% dose 
reduction of suspected 
causative agent(s) provided 
toxicity has resolved to 
Grade I or less.  If further 
toxicity occurs, an additional 
reduction may be made after 
discussion with consultant 
Defer treatment for any grade III/IV non-haematological toxicity (excluding 
alopecia). 
If a delay of more than 3 weeks is required for recovery, or more than 
2 dose reductions are necessary, the patient should discontinue treatment. 
 
 
 
 
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Appendix 2  RECIST version 1.1 Guidelines 
Adapted from Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in 
solid tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer  
2009;45(2):228–47. 
CATEGORIZING LESIONS AT BASELINE 
Measurable Lesions 
x 
Lesions that can be accurately measured in at least one dimension. 
x 
Lesions with longest diameter at least 10 mm or greater when assessed by CT or MRI (slice 
thickness 5-8 mm), measured in the axial plane. If the slice thickness is greater than 5 mm 
(including any inter-slice gap), the longest diameter must be at least twice the slice thickness. 
x 
Lesions with longest diameter at least 20 mm when assessed by Chest X-ray, only if the tumor 
is clearly outlined by well-aerated lung. 
x 
Malignant lymph nodes with a short axis (defined as the largest measurement perpendicular to 
the longest diameter of the lesion) 15 mm or greater when assessed by CT or MRI. 
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for all other 
lesions. 
Non-measurable disease 
Non-measurable disease includes lesions too small to be considered measurable (including nodes 
with short axis between 10 and 14.9 mm) and truly non-measurable disease such as pleural or 
pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, lymphangitic 
involvement of skin or lung, superficial lesions, and abdominal masses identified by physical exam 
that are not measurable by reproducible imaging techniques. 
x 
Bone disease: Bone disease is non-measurable with the exception of soft tissue components that 
can be evaluated by CT or MRI and meet the definition of measurability at baseline. 
x 
Previous local treatment: A previously irradiated lesion (or lesion subjected to other local 
treatment) is non-measurable unless it has progressed since completion of treatment. 
Normal sites 
x 
Cystic lesions: Simple cysts should not be considered as malignant lesions and should not be 
recorded either as target or non-target disease.  Cystic lesions thought to represent cystic 
metastases can be measurable lesions, if they meet the specific definition above.  If non-cystic 
lesions are also present, these are preferred as target lesions. 
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x 
Normal nodes: Nodes with short axis <10 mm are considered normal and should not be recorded 
or followed either as measurable or non-measurable disease. 
Tumor Assessments 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as close as 
possible prior to study start.  For an adequate baseline assessment, all required scans must be done 
within the window of time specified in Table 3.3.1 prior to treatment and all disease must be 
documented appropriately.  If the baseline assessment is inadequate, subsequent statuses generally 
should be indeterminate. 
The determination of whether lesions are measurable is performed only at baseline.  “Measurable” 
at baseline means eligible for selection as target lesions, and thus for quantitative assessment 
throughout the study.  Once selected as a target lesion, a lesion remains target throughout the study. 
Target lesions 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, representative of 
all involved organs, should be identified as target lesions at baseline.  Target lesions should be 
selected on the basis of size (longest lesions) and suitability for accurate repeated measurements.  
Record the longest diameter for each lesion, except in the case of pathological lymph nodes for which 
the short axis should be recorded.  The sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions at baseline will be the basis for comparison to look for 
partial response at later assessments. 
x 
If 2 target lesions coalesce the longest diameter measurement of the coalesced mass is used. If a 
large target lesion splits, the sum of the parts is used. 
x 
Measurements for target lesions that become small should continue to be recorded. If a target 
lesion becomes too small to measure, 0 mm should be recorded if the lesion is considered to have 
disappeared; otherwise a default value of 5 mm should be recorded. 
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement should still be 
recorded. 
Non-target disease 
All non-measurable disease is non-target.  All measurable lesions not identified as target lesions are 
also included as non-target disease.  Measurements are not required but rather assessments will be 
expressed as ABSENT, INDETERMINATE, PRESENT/NOT INCREASED, INCREASED.  
Multiple non-target lesions in one organ may be recorded as a single item on the case report form 
(e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION 
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Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If not, subsequent objective statuses may be 
indeterminate. 
Target disease 
x 
Complete Response (CR): Complete disappearance of all target lesions with the exception of 
nodal disease.  All target nodes must decrease to normal size (short axis < 10 mm).  All target 
lesions must be assessed. 
x 
Partial Response (PR): Greater than or equal to 30% decrease under baseline of the sum of 
diameters of all target measurable lesions.  The short diameter is used in the sum for target nodes, 
while the longest diameter is used in the sum for all other target lesions.  All target lesions must 
be assessed. 
x 
Stable: Does not qualify for CR, PR or Progression.  All target lesions must be assessed.  Stable 
can follow PR only in the rare case that the sum increases by less than 20% from the nadir, but 
enough that a previously documented 30% decrease no longer holds. 
x 
Objective Progression (PD): 20% increase in the sum of diameters of target measurable lesions 
above the smallest sum observed (over baseline if no decrease in the sum is observed during 
therapy) with a minimum absolute increase of 5 mm. 
x 
Objective Response Rate (ORR) defined as the percentage of subjects having Complete or Partial 
Response at EOT/ET, based on radiographic assessments of the tumor. 
x 
Indeterminate. Progression has not been documented, and 
o one or more target lesions have not been assessed, 
o or assessment methods used were inconsistent with those used at baseline and impaired 
assessment, 
o or one or more target lesions cannot be measured accurately (e.g. poorly visible unless 
due to being too small to measure), 
o or one or more target lesions were excised or irradiated and have not reappeared or 
increased. 
Non-target disease 
x 
CR: Disappearance of all non-target lesions and normalization of tumor marker levels.  All lymph 
nodes must be ‘normal’ in size (<10 mm short axis). 
x 
Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level above the 
normal limits. 
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x 
PD: Unequivocal progression of pre-existing lesions. Generally the overall tumor burden must 
increase sufficiently to merit discontinuation of therapy.  In the presence of stable disease (SD) 
or PR in target disease, progression due to unequivocal increase in non-target disease should be 
rare. 
x 
Indeterminate: Progression has not been determined and one or more non-target sites were not 
assessed or assessment methods were inconsistent with those used at baseline. 
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD. If a new lesion is equivocal, 
for example due to its small size, continued assessment will clarify the etiology.  If repeat assessments 
confirm the lesion, then progression should be recorded on the date of the initial assessment.  A lesion 
identified in an area not previously scanned will be considered a new lesion. 
Supplemental Investigations 
x 
If CR determination depends on a residual lesion that decreased in size but did not disappear 
completely, it is recommended the residual lesion be investigated with biopsy or fine needle 
aspirate.  If no disease is identified, objective status is CR. 
x 
If progression determination depends on a lesion with an increase possibly due to necrosis, the 
lesion may be investigated with biopsy or fine needle aspirate to clarify status. 
Subjective progression 
Subjects requiring discontinuation of treatment without objective evidence of disease progression 
should not be reported as PD on tumor assessment eCRFs.  This should be indicated on the EOT/ET 
eCRF as off treatment due to Global Deterioration of Health Status. Every effort should be made to 
document objective progression even after discontinuation of treatment. 
 
 
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