Clinical trial NCT03755141
Conditions: HER2-positive Breast Cancer Metastatic Breast Cancer
Sponsor: National Cancer Center, Korea
Start date: 2018-12-15; Completion date: 2022-06-30
Enrollment: 109 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Trastuzumab combined with chemotherapy has been approved as the first line therapy in HER2+ metastatic breast cancer. When patients experienced progression beyond trastuzumab containing therapy, T-DM1 is considered as the second line therapy followed by trastuzumab plus any other chemotherapeutic agents or lapatinib plus capecitabine.

A biosimilar drug is a biological product that is highly similar to a licensed biological product, with no clinically meaningful differences in terms of safety, purity, or potency. Several trastuzumab biosimilar products have been approved after efficacy and safety studies which were usually as the first line setting with taxane combined.

Even though trastuzumab biosimilar drugs demonstrated similarity of equivalence with trastuzumab in these studies, the efficacy of their second use beyond progression with other chemotherapeutic agents has not been tested yet. In addition, the investigators don't have any data regarding possible cross reactivity between trastuzumab and trastuzumab biosimilar drugs.

In this study, the investigators plan multicenter phase II clinical trial to test the efficacy, safety and immunogenicity of trastuzumab biosimilar, Herzuma® in combination with TPC in patients with HER2+ metastatic breast cancer who progressed after 2 or more HER-2 directed chemotherapy.

Detailed description:

Arms: arm 1: Herzuma + TPC
Interventions: intervention 1: Herzuma
Intervention descriptions: intervention 1: Herzuma + Treatment of Physician's Choice

Protocol documents:
Prot_SAP_000.pdf: 
Trastuzumab biosimilar + TPC protocol v.2 
 
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Open label, multicenter, prospective phase II study to investigate the efficacy and safety 
of Trastuzumab biosimilar (Herzuma®) plus treatment of physician’s choice (TPC) in 
Patients with HER-2 Positive Metastatic Breast Cancer Who Progressed after 2 or more 
HER-2 directed Chemotherapy 
 
 
 
Compound name: Trastuzumab biosimilar 
Phase: II 
Protocol version: 3.0 (2018-07-31) 
 
Principal investigator: In Hae Park MD, PhD 
 
 
 
 
 
 
 
 
 
Confidential  
This document contains confidential information belonging to K-MASTER. Except as otherwise agreed to in 
writing, by accepting or reviewing this document, you agree to hold this information in confidence and not copy 
or disclose it to others (except where required by applicable law) or use it for unauthorized purposes. In the 
event of any actual or suspected breach of this obligation, K-MASTER must be promptly notified. 
 


Trastuzumab biosimilar + TPC protocol v.2 
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
 
 
 
 
 
• 
I confirm agreement to conduct the study in compliance with the protocol. 
• 
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study. 
• 
I agree to ensure that all associates, colleagues and employees assisting in the 
conduct of the study are informed about their obligations. Mechanisms are in place 
to ensure that site staff receives the appropriate information throughout the study. 
 
 
 
 
 
 
 
 
Investigator Name: 
In Hae Park 
Investigator Address: 
Center for Breast Cancer, National Cancer Center, 
Goyang, Korea 
Investigator Phone Number: 
82-31-920-1680 
Investigator Fax Number: 
82-31-920-0858 
Investigator E-mail: 
parkih@ncc.re.kr 
Investigator Signature: 
Date: July 31, 2018 
 
 
 
 


Trastuzumab biosimilar + TPC protocol v.2 
 
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Table of contents 
Protocol summary ....................................................................................................................................................................... 7 
Study flow chart ........................................................................................................................................................................ 11 
1. 
INTRODUCTION .............................................................................................................................................................. 14 
1.1 HER2 amplified metastatic breast cancer.............................................................................................................. 14 
1.2 Trastuzumab biosimilar- Celltrion ............................................................................................................................. 14 
2.  STUDY DESIGN .................................................................................................................................................................. 15 
2.1 Overall design .................................................................................................................................................................... 15 
2.2 Patient enrollment ............................................................................................................................................................ 15 
2.3 Study objectives ................................................................................................................................................................ 16 
2.3.1 Primary objectives ............................................................................................................................................... 16 
2.3.2 Secondary objectives ......................................................................................................................................... 16 
2.3.3 Exploratory objectives ....................................................................................................................................... 16 
2.4 Endpoints .............................................................................................................................................................................. 16 
2.4.1 Primary endpoint ................................................................................................................................................. 16 
2.4.2 Secondary endpoints ......................................................................................................................................... 16 
2.4.3 Exploratory endpoints ....................................................................................................................................... 16 
3.  STUDY POPULATION ...................................................................................................................................................... 16 
3.1 Inclusion criteria ................................................................................................................................................................ 17 
3.2 Exclusion criteria................................................................................................................................................................ 17 
4. TREARMENT ........................................................................................................................................................................... 18 
4.1 Allocation to treatment.................................................................................................................................................. 18 
4.2 Treatment administration .............................................................................................................................................. 18 
4.2.1 Trastuzumab biosimlar, CT-P6 ........................................................................................................................ 18 


Trastuzumab biosimilar + TPC protocol v.2 
 
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4.2.1.1 Dosage, administration, and storage ............................................................................................. 18 
4.2.1.2 Dosage modification ............................................................................................................................. 19 
4.2.2 Treatment of physician’s choice (TPC) ........................................................................................................ 19 
4.2.3 Dose interruptions and delay ........................................................................................................................ 20 
4.3. Concomitant and excluded therapies .................................................................................................................... 20 
4.3.1 Concomitant therapy ......................................................................................................................................... 20 
4.3.2 Excluded therapy .................................................................................................................................................. 21 
4.4 Study assessments ........................................................................................................................................................... 21 
4.4.1 Screening and pretreatment assessments ............................................................................................... 21 
4.4.1.1 Medical history, concomitant medication, and demographic data ................................ 21 
4.4.1.2 Physical examination & vital sign ................................................................................................... 21 
4.4.1.3 Electrocardiogram, echocardiograms or multiple-gated acquisition scans (MUGA)22 
4.4.1.4 Tumor status .............................................................................................................................................. 22 
4.4.2 Assessments during treatment ...................................................................................................................... 22 
4.4.3 Study treatment discontinuation visit. ....................................................................................................... 22 
4.4.4 Follow-up assessment. ...................................................................................................................................... 22 
4.5 Patient discontinuation. ................................................................................................................................................. 22 
4.6 Statistical method ............................................................................................................................................................. 23 
4.6.1 Rationale for sample size ................................................................................................................................. 23 
4.6.2 Efficacy analysis .................................................................................................................................................... 23 
4.6.2.1 Progression free survival (PFS) .......................................................................................................... 23 
4.6.2.2 Overall survival (OS) .............................................................................................................................. 23 
4.6.2.3 Objective response rate (ORR) ......................................................................................................... 24 
4.6.3 Safety analysis ....................................................................................................................................................... 24 


Trastuzumab biosimilar + TPC protocol v.2 
 
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4.6.3.1 Study treatment exposure .................................................................................................................. 24 
4.6.3.2 Adverse events ......................................................................................................................................... 24 
4.6.4 Quality of life (QoL) analysis .......................................................................................................................... 24 
4.7 Assessment of safety ...................................................................................................................................................... 24 
4.7.1 Adverse event (AE) .............................................................................................................................................. 24 
4.7.2 Serious adverse event (SAE) ........................................................................................................................... 25 
4.7.3 Causality assessment .......................................................................................................................................... 26 
4.7.4 AE reporting period ............................................................................................................................................ 26 
5. QUALITY CONTROL AND QUALITY ASSURANCE ................................................................................................. 27 
6. DATA HANDLING AND RECORD KEEPING .............................................................................................................. 27 
6.1 Case Report Forms/Electronic Data Record ......................................................................................................... 27 
6.2 Record Retention .............................................................................................................................................................. 28 
7. ETHICS ...................................................................................................................................................................................... 28 
7.1 Institutional Review Board/Ethics Committee ..................................................................................................... 28 
7.2 Ethical Conduct of the Study ...................................................................................................................................... 29 
7.3 Subject Information and Consent ............................................................................................................................. 29 
7.4 Subject Recruitment ........................................................................................................................................................ 30 
7.5 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP .................................. 30 
8. DEFINITION OF END OF TRIAL ..................................................................................................................................... 30 
8.1. KCSG discontinuation criteria..................................................................................................................................... 30 
9. PUBLICATION OF STUDY RESULTS .............................................................................................................................. 30 
9.1 Communication of Results by K-MASTER ............................................................................................................. 31 
9.2 Publication by Investigators ........................................................................................................................................ 31 
10. REFERENCES ........................................................................................................................................................................ 31 


Trastuzumab biosimilar + TPC protocol v.2 
 
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Appendix 1. Abbreviations ................................................................................................................................................... 33 
Appendix 2. RECIST (Response Evaluation Criteria In Solid Tumors) version 1.1 Gudielines ............... 34 
Appendix 3. Quality of Life .................................................................................................................................................. 38 
 
 
 


Trastuzumab biosimilar + TPC protocol v.2 
 
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Protocol summary 
PROTOCOL SYNOPSIS 
Title 
Open label, multicenter, prospective phase II study to investigate the efficacy and safety of 
Trastuzumab biosimilar plus treatment of physician’s choice (TPC) in Patients with HER-2 
Positive Metastatic Breast Cancer Who Progressed after 2 or more HER-2 directed 
Chemotherapy 
Study duration 
Sep 2018 – Sep 2021 
(24 month enroll and additional 1-year follow-up) 
Study chair/ 
Institution 
In Hae Park, M.D., Ph.D 
National cancer center, Goyang, Korea 
Study Sub-
investigators  
Breast subcommittee, KCSG 
Study method 
Multicenter, Prospective, Single-arm, Phase II study 
Study 
hypothesis 
The combination of trastuzumab biosimilar plus TPC will provide a benefit in terms of 
progression free survival in patients with HER2-positive metastatic breast cancer who 
progressed after 2 or more HER-2 directed chemotherapy. 
Study 
Objectives 
1. Primary Objective 
⚫ Progression free survival (PFS): defined as the time from study entry until the first 
observation of disease progression according to the above schedule or death due to any 
cause. 
 
 
2. Secondary Objectives 
⚫ Objective response rate (ORR) defined as the percentage of patients experiencing 
confirmed complete response (CR) and partial response (PR) assessed by RECIST 
criteria v.1.1 
⚫ Overall survival (OS): defined as the time from study entry until death 
⚫ Safety 
⚫ Biomarker: Genetic aberrancies in tissue and plasma, Immune cell profile in tissue and 
PBMC, Ag-specific T cell frequencies before and after treatment, Th1 vs Th2 cytokine 
profile, HER2 CNV in cell free tumor DNA, antibody dependent cellular cytotoxicity 
(ADCC) 
⚫ QoL: measured by the European Organization for Research and Treatment Care Quality 
of Life Questionnaire 
 
Study 
Rationale 
 Trastuzumab combined with chemotherapy has been approved as the first line therapy in 
HER2+ metastatic breast cancer. When patients experienced progression beyond trastuzumab 
containing therapy, T-DM1 is considered as the second line therapy followed by trastuzumab 
plus any other chemotherapeutic agents or lapatinib plus capecitabine.  
A biosimilar drug is a biological product that is highly similar to a licensed biological product, 
with no clinically meaningful differences in terms of safety, purity, or potency. Several 


Trastuzumab biosimilar + TPC protocol v.2 
 
8 
 
trastuzumab biosimilar products have been approved after efficacy and safety studies which 
were usually as the first line setting with taxane combined.  
Even though trastuzumab biosimilar drugs demonstrated similarity of equivalence with 
trastuzumab in these studies, the efficacy of their second use beyond progression with other 
chemotherapeutic agents has not been tested yet. In addition, we don’t have any data regarding 
possible cross reactivity between trastuzumab and trastuzumab biosimilar drugs.  
In this study, we plan multicenter phase II clinical trial to test the efficacy, safety and 
immunogenicity of trastuzumab biosimilar in combination with TPC in patients with HER2+ 
metastatic breast cancer who progressed after 2 or more HER-2 directed chemotherapy. 
Subject 
Selection 
1. Eligibility criteria 
1) 
Patient is an adult, female ≥ 19 years old at the time of informed consent. 
2) 
Patient has histologically and/or cytologically confirmed diagnosis of HER2-positive 
breast cancer (HER-2/neu 3+ as defined by immunohistochemistry and/or HER-2/neu 
gene amplification as defined by fluorescence in situ hybridization). 
3) 
Metastatic or unresectable disease documented on diagnostic imaging studies. 
4) 
Prior 2 or more HER-2 directed therapy for metastatic disease is mandatory. 
5) 
Patient must have at least one measurable or evaluable lesion according to Response 
Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1) 
6) 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1 
7) 
Adequate bone marrow and organ function including: a) WBC ≥ 3500/ml; b) Platelets 
≥ 100,000/ul; c) Hemoglobin >9.0 g/dl; d) Total bilirubin ≤ 1.5x ULN; e) AST and 
ALT < 2.5 x ULN; f) Alkaline phosphatase <2.5x ULN; g) Creatinine ≤ 1.5x ULN or 
CCr >60 ml/min for patients with abnormal serum Cr level function. 
8) 
Life expectance longer than 3 months 
9) 
Patient has an adequate left ventricular ejection function of at least 50 % at baseline, as 
measured by echocardiography. 
10) Written informed consent 
 
2. Exclusion criteria 
1) 
Patient is pregnant or lactating, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin (hCG) laboratory test. 
2) 
Patient has symptomatic and unstable CNS metastases, except for treated brain 
metastases. Treated brain metastases are defined as having no evidence of progression 
or hemorrhage after treatment and no ongoing requirement for dexamethasone, as 
ascertained by clinical examination and brain imaging (MRI or CT) during the screening 
period. Anticonvulsants (stable dose) are allowed. 
3) 
Active and clinically significant bacterial, fungal or viral infection including hepatitis B 
(HBV), hepatitis C (HCV), known human immunodeficiency virus syndrome (HIV) or 
acquired immunodeficiency syndrome (AIDS)-related illness. Baseline viral assessment 
is not required in patients with no known infection. 
4) 
Major surgery within 4 weeks of first dose of investigational product or not fully 
recovered from any side effects of previous procedures. 
5) 
Any other malignancy within 3 years prior to first dose of investigational product except 
for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of 


Trastuzumab biosimilar + TPC protocol v.2 
 
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the cervix. 
6) 
QTc interval >480 msec (based on the mean value of the triplicate ECGs), family or 
personal history of long or short QT syndrome, Brugada syndrome or known history of 
QTc prolongation or Torsade de Pointes.  
7) 
Any of the following within 6 months of first dose of investigational product myocardial 
infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE v. 4.03 
Grade ≤2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, 
symptomatic congestive heart failure, cerebrovascular accident including transient 
ischemic attack, or symptomatic pulmonary embolism. 
8) 
History of symptomatic interstitial pneumonitis. 
9) 
Other severe acute or chronic medical or psychiatric condition, including recent (within 
the past year) or active suicidal ideation or behavior, or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study. 
 
Study 
Design 
& 
Treatment 
plan  
⚫ 
This study is a multicenter, prospective, single-arm, phase II study to evaluate the 
efficacy, safety and immunogenicity of trastuzumab biosimilar in combination with TPC 
in patients with HER2+ metastatic breast cancer who progressed after 2 or more HER-2
directed chemotherapy. 
 
⚫ 
Study drug information, dosage, and mode of administration 
- Trastuzumab biosimilar, Herzuma®, Celltrion, Inc. (Incheon, Republic of Korea): 
Intravenously administered on cycle 1 day 1 at a dose of 8mg/kg, then at a dose of 
6mg/kg every 3 weeks  
- Treatment of physician’s choice (TPC): gemcitabine, vinorelbine, eribulin, 
capecitabine, nab-paclitaxel ; treatment cycles will be 3 weeks and dosages will be 
determined by each investigator’s discretion.  
⚫ 
Treatment will occur until disease progression, unacceptable toxicity or patient 
withdrawal. 
⚫ 
Tumor measurement and evaluation are going to be performed at every 6 weekes till 
progression, then follow-up evaluation at every 18 weeks thereafter end of study. 
 
 
 
Statistical 
Consideration 
1. Sample size 


Trastuzumab biosimilar + TPC protocol v.2 
 
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The primary object of this study is to assess PFS in patients with HER-2 positive metastatic breast 
cancer who progressed after 2 or more HER-2 directed chemotherapy. 
One sided type I error rate 0.1, power 80%; 24 months of accrual period and 12 months of follow-
up. H0 = 2.8 months, H1=3.8 months. Then, a total of 108 patients will be needed in this trial. 
Considered 10% drop-out rate, we will enroll 119 patients. (ref. TH3RESA trial, Lancet Oncol 
2014;15:689-99) 
2. Efficacy analyses 
⚫ 
Primary endpoint : PFS 
- The PFS curve for single arm will be estimated using the Kaplan-Meier method.  
⚫ 
Secondary endpoint of ORR and OS :  
- ORR will be presented as a proportion and its corresponding 95% exact CI.  
- The OS curve for single arm will be estimated using the Kaplan-Meier method.  
3. Biomarker analyses 
⚫ 
Immune cell profiling and cytokine analysis using peripheral blood 
⚫ 
ADCC analysis  
⚫ 
CfDNA analysis : NGS, ddPCR  
⚫ 
Not all exploratory analyses will be included in the Clinical Study Report (CSR) unless 
they present meaningful findings or rare relevant to subject management. 
 
4. QoL analyses 
⚫ 
Baseline – after 3 Cycles – at the end of treatment date 
⚫ 
Measured by the European Organization for Research and Treatment Care Quality of 
Life Questionnaire (Korean version, EORTC QLQ-C30) 
Site of study 
This protocol is performed as an : 
      □Inpatient                  □Outpatient                      ■Both 
Where will study be conducted :  
■Multi-Center Arrangements: KCSG breast subcommittee member sites 
 


Trastuzumab biosimilar + TPC protocol v.2 
 
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Study flow chart  
 
The schedule of activities table provides an overview of the protocol visits and procedures. Refer to the STUDY 
PROCEDURES and ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment 
required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to 
conduct evaluations or assessments required to protect the well-being of the patient. 
Visit Identifier 
Baseline 
Cycle 1-2 
Cycle 3 and Beyond 
Follow up 
Protocol Activity 
Screen/ 
Baseline1 
Day 1 
Day 8 
Day 1 
(Day 8) 
Follow Up22 
Informed Consent2 
X 
 
 
 
 
 
Tumor History3 
X 
 
 
 
 
 
Medical History4 
X 
 
 
 
 
 
Signs and Symptoms5 
X 
X 
X 
X 
X 
 
Physical Examination6 
 
X 
X 
X 
X 
 
Weight/height 
 
X 
X 
X 
X 
 
Vital Signs7 
 
X 
X 
X 
X 
 
ECOG Performance Status8 
X 
X 
X 
X 
X 
 
Laboratory9 Assessments 
 
 
 
 
 
 
Hematology10 
X 
(X) 
X 
X 
 
 
 Blood Chemistry11 
X 
(X) 
 
X 
 
 
 Urinalysis12 
X 
 
 
 
 
 
 Coagulation13 
X 
 
 
 
 
 
 Pregnancy Test14 
X 
 
 
 
 
 
Triplicate ECG (12-lead)15 
X 
 
 
 
 
 
Echocardiography or MUGA 
scan16 
X 
 
 
X 
 
 
Adverse Events (AE)17 
X 
→ 
→ 
→ 
→ 
→ 
Concomitant Treatments18 
X 
→ 
→ 
→ 
→ 
 
Tumor Assessment19 
X 
 
 
X 
 
 
Whole Blood Biospecimen for 
PD analysis20 
 
X 
 
X 
 
 
Serum for Biomarker (BM) 
analysis21 
 
X 
 
X 
 
 
Plasma Biospecimen for 
Exploratory BM Assessments21 
 
X 
 
X 
 
 
QoL23 
 
X 
 
X 
 
 
FFPE tumor samples for K-
master panel analysis24 
X 
 
 
 
 
 
Abbreviations: ECG = electrocardiogram; → = ongoing/continuous event; AEs = adverse events; CT = computed tomography; MRI = 
magnetic resonance imaging; FFPE= Formalin-Fixed, Paraffin-Embedded; ( ) = Optional activity to be executed only if applicable. Please 
refer to the footnotes below for more details. 
Tests and procedures should be done on schedule, but occasional changes by ± 3 days (unless otherwise stated differently) are allowed for 
holidays, vacations and other administrative reasons.  
 
Footnotes 
1. 
Screening/Baseline Assessments: completed within 28 days of beginning investigational product unless otherwise specified as 
shown in the schedule of activities above.   
2. 
Informed Consent: obtained prior to undergoing any study specific procedures.  
3. 
Tumor History: collected within 28 days prior to first dose of study medication. Includes history of oncology disease including 
details of primary diagnosis and treatment history (systemic treatment, prior surgery and radiotherapy). When available primary diagnosis 
history should include known molecular characteristics of the patient’s tumor include mutations, amplifications, etc.  


Trastuzumab biosimilar + TPC protocol v.2 
 
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4. 
Medical History: collected within 28 days prior to first dose of study medication. Includes history of disease process other than 
oncology (active or resolved), and concomitant illnesses. Includes prior treatment including dosing and duration of administration as well as 
verification of concurrent medication.  
5. 
Signs & Symptoms: patients will be asked about any signs and symptoms experienced within the 14days of C1D1. During trial 
treatment any new or worsened conditions since baseline should be reported on the Adverse Event CRF.  
6. 
Physical examination: is a symptom directed exam conducted by a physician, trained physician’s assistant or nurse practitioner, 
as acceptable according to local regulation.  
7.        Vital signs: blood pressure and heart rate and should be recorded in the sitting position after approximately 5 minutes of rest.  
8. 
Performance status: ECOG scale to be assessed within 14 days prior to the first dose of investigational product, and as described 
in the table above.  
9. 
Laboratory Tests: 
⬧ 
Screening labs to be performed within 28 days of Cycle 1, Day 1 (C1D1). For subsequent cycles, pre-dose labs may also be drawn 
up to 24 hours in advance of scheduled dosing in order to obtain results prior to infusion.  
10. 
Hematology: No need to repeat on C1D1 if screening assessment performed within 28 days prior to C1D1.  
11. 
Blood Chemistry: No need to repeat on C1D1 if screening assessment performed within 28 days prior to C1D1  
12. 
Urinalysis: No need to repeat on C1D1 if screening assessment performed within 28 days prior to C1D1  
13. 
Coagulation Tests: No need to repeat on C1D1 if screening assessment performed within 28 days prior to C1D1. To be performed 
every per the schedule in the table above (± 3 day time window).  
14. 
Pregnancy Test: For female patients of childbearing potential, a pregnancy test, with sensitivity of at least 25mIU/mL, will be 
performed during screening period. Pregnancy test will also be repeated whenever potential pregnancy is suspected. Additional pregnancy 
tests may also be undertaken if requested by institutional review board/ethics committee (IRB/ECs) or if required by local regulations.   
15. 
ECG: Triplicate 12-lead ECG (per institutional practice) will be performed. Additional ECGs may be performed as clinically 
indicated.  
16. 
Echocardiography: an echocardiography or MUGA scan is required within 28 days of C1D1. Only subjects with LVEF of 50% 
or higher should be enrolled in the study. During study treatment period, echocardiography or MUGA scan is performed at Cycle 5 Day 1 (± 
7 days) and then every 24 weeks during active treatment period. 
17. 
Adverse Event (AE) Assessments: AEs should be documented and recorded at each visit using NCI CTCAE version 4.0.  
18. 
Concomitant Treatments: All concomitant medications and treatments should be recorded in the CRF including supportive care 
drugs, and the drugs used to treat adverse events or chronic diseases.  
19. 
Tumor Assessments:  
⬧ 
Baseline tumor assessments must be within 28 days of first dose.   
⬧ 
After C1D1, tumor assessments will be performed every 6 weeks ± 5 days while patient are receiving treatment. Tumor 
assessments will include all known or suspected disease sites. Imaging may include chest, abdomen and pelvis CT or MRI scans. 
Brain scans and bone scans will be performed at baseline if disease is suspected and on-study as appropriate to follow disease. 
Baseline CNS imaging is not required with the exception of symptomatic patients to rule out CNS metastases.   
⬧ 
Confirmation of response (CR/PR) is not required.  
⬧ 
Tumor assessment should be repeated at the end of study visit if more than 9 weeks have passed since the last evaluation.  
⬧ 
For those patients who discontinue for reasons other than disease progression, tumor assessments should be continued until 
progression of disease is documented.  
20. 
Whole blood biospecimens: will be collected pre dose on C1D1 and C3D1 to conduct pharmacodynamics assessments  
21. 
Serum/plasma biospecimens: Serum/plasma biospecimens will be collected on C1D1, on C3D1 and at end of treatment (EOT) 
visit for potential circulating nucleic acid analysis.  
22. 
Follow up: approximately 30 days (+/-10 days) after discontinuation of treatment patients will return to undergo review of 
concomitant medications, vital signs, and assessment for resolution of any treatment related toxicity. Patients continuing to experience toxicity 
at this point following discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the 


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clinical judgment of the investigator, that no further improvement is expected. In addition, patients will be followed up every 18 weeks until 
death, loss to follow-up, withdrawal of consent, or study termination for collecting survival data.  
23. 
Quality of life: Quarlity of life (QoL) will be checked at baseline, after C3, and on PD. This QoL will be measured by the European 
Organization for Research and Treatment Care Quality of Life Questionnaire (Korean version, EORTC QLQ-C30). 
24.        During screening period, tumor tissue (FFPE) should be obtained to perform CancerScan (K-master cancer panel). Tumor 
specimen from metastatic sites is preferred, though it is not limited to.  
 
 


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1. INTRODUCTION  
 
1.1 HER2 amplified metastatic breast cancer  
Breast cancer is the most common cancer worldwide in women. Human epidermal growth factor 
receptor 2 (HER2) is overexpressed in approximately 20% of breast cancers and several anti-HER2 
targeted therapy based treatments are considered as standard in this patient population. In addition to 
the first approved anti-HER2 therapy, trastuzumab, pertuzumab and T-DM1 are used as therapeutic 
options in HER2 positive metastatic breast cancer (MBC). The current consensus includes dual 
blockade (trastuzumab plus pertuzumab) with taxanes in the first line, followed by trastuzumab-
emtanxine (T-DM1) in the second line. Tyrosin kinase inhibitors, such as lapatinib or neratinib are 
also considered in case there is resistance to trastuzumab based therapy. Despite the remarkable 
progress in treatment of HER2 positive breast cancer, metastatic disease is still incurable in the 
majority of patients. Especially, those who progressed on anti-HER2 therapy at the first and second 
lines, their prognosis are dismal. Even after patients experienced disease progression on trastuzumab 
containing chemotherapy, sufficient data including guidelines such as NCCN and ABC3 
recommended continuing trastuzumab with any other chemotherapy agents including but not limited 
to vinorelbine, taxanes, capecitabine, eribuline, platinum, or gemcitabine. However, in our country 
anti-Her2 therapy, trastuzumab can only be used once in the metastatic setting since its use beyond 
progression is not approved and not reimbursed. In those cases, patients should be treated using just 
cytotoxic chemotherapy only.  
 
1.2 Trastuzumab biosimilar- Celltrion 
CT-P6 (CELLTRION, Incheon, Republic of Korea) is a biosimilar of reference trastuzumab, already 
approved in South Korea for the same indications as the reference product. CT-P6 has been found to be 
similar to reference trastuzumab in in vitro studies, including with respect to HER2 binding affinity, 
ADCC and anti-proliferation activity. CT-P6 also exhibited a similar profile to reference trastuzumab 
in in vivo toxicology studies. 
The PK similarity of CT-P6, and trastuzumab-US has been evaluated in a Phase 1, randomised, double-
blind, parallel-group study following a single intravenous (IV) administration of the study drugs to 70 
healthy male subjects. Pharmacokinetics, safety and immunogenicity were evaluated up to 10 weeks 
post-dose. Primary endpoints were area under the serum concentration–time curve (AUC) from time 0 
to infinity (AUC inf); AUC from time 0 to last quantifiable concentration (AUC last); and observed 
maximum serum concentration (Cmax). The pre-determined equivalence criterion was a 90% 
confidence interval of 80–125% for ratios of geometric least squares (LS) means. 
Equivalence of CT-P6 and reference trastuzumab was demonstrated. Ratios (CT-P6/reference 
trastuzumab) of geometric LS means (90% confidence interval) were: AUC inf 99.05 (93.00, 105.51); 
AUC last 99.30 (92.85, 106.20); Cmax 96.58 (90.93, 102.59). Safety profiles were similar; treatment-
emergent adverse events occurred in ten subjects (28.6%) in the CT-P6 group and 11 (31.4%) in the 


Trastuzumab biosimilar + TPC protocol v.2 
 
15 
 
reference trastuzumab group. No serious adverse events or deaths occurred. No subjects tested positive 
for anti-drug antibodies.  
These data add to the totality of evidence required to demonstrate biosimilarity. A phase III study of 
CT-P6 showed equivalent efficacy (pathologic complete remission rate) to reference trastuzumab and 
adverse events were similar in the neoadjuvant setting with HER2 positive early stage breast cancer 
patients. Even though many trastuzumab biosimilar including CT-P6 (trastuzumab-celltrion) 
demonstrated biological equivalence and comparable clinical efficacy to the reference drug, there was 
no further data regarding combination with other diverse cytotoxic chemotherapeutic drugs. More data 
of trastuzumab biosimilar with various combination partners would give an alternative and more cost-
effective treatment option in the clinical practice.   
 
 
2.  STUDY DESIGN 
 
2.1 Overall design 
This is a phase II multicenter, open-label one arm trial in patients with HER2-positive metastatic 
breast cancer who progressed after 2 or more HER-2 directed chemotherapy.  
 
    Figure 1. Study scheme 
 
2.2 Patient enrollment 
After written informed consent has been obtained and all screening procedures have been completed, 
eligibility has been established. For those patients who are eligible for enrollment, investigator should 
choose the chemotherapeutic regimen for TPC and record it on eCRF. The study site will obtain the 
patient identification number and treatment assignment from the system. 
 


Trastuzumab biosimilar + TPC protocol v.2 
 
16 
 
2.3 Study objectives 
   2.3.1 Primary objectives 
     - to determine PFS of trastuzumab biosimilar based therapy in patients with HER2 positive MBC 
who are resistant to two and more than two lines of anti-HER2 based treatment. 
   2.3.2 Secondary objectives 
     - to determine objective response rate (ORR) assessed by RECIST criteria v.1.1 
- to evaluate overall survival (OS) 
- to evaluate the safety profiles 
- to evaluate the QoL 
   2.3.3 Exploratory objectives 
- to evaluate potential biomarkers of outcomes such as clinical efficacy and safety  
 
2.4 Endpoints 
  2.4.1 Primary endpoint 
⚫ PFS defined as the time from study entry until the first observation of disease progression 
or death due to any cause. 
2.4.2 Secondary endpoints 
⚫ ORR defined as the percentage of patients experiencing confirmed complete response (CR) 
and partial response (PR) assessed by RECIST criteria v.1.1 
⚫ OS defined as the time from study entry until death or last follow-up date 
⚫ Safety including adverse events as characterized by type, frequency, severity (as graded by 
National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 
[NCI CTCAE v. 4.0]), timing, seriousness and relationship to study therapy and laboratory 
abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v. 
4.0) and timing. 
⚫ Quality of life (QoL) measured by the European Organization for Research and Treatment 
Care Quality of Life Questionnaire 
2.4.3 Exploratory endpoints 
    - Immune cell profile in PBMB, Th1 vs Th2 cytokine profile, NGS analysis using cfDNA, ADCC 
 
 
3.  STUDY POPULATION 


Trastuzumab biosimilar + TPC protocol v.2 
 
17 
 
 
Patients must meet all of the following inclusion/exclusion criteria to be eligible for enrollment into the 
study. Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study. 
 
3.1 Inclusion criteria 
1) Patient is an adult, female ≥ 19 years old at the time of informed consent. 
2) Patient has histologically and/or cytologically confirmed diagnosis of HER2-positive breast 
cancer (HER2/neu3+ as defined by immunohistochemistry and/or HER-2/neu gene 
amplification as defined by fluorescence in situ hybridization). 
3) Metastatic or unresectable disease documented on diagnostic imaging studies. 
4) Prior 2 or more HER-2 directed therapy for metastatic disease is mandatory. 
5) Patient must have at least one measurable or evaluable lesion according to Response 
Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1) 
6) Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1 
7) Adequate bone marrow and organ function including: a) WBC ≥ 3500/ml; b) Platelets ≥ 
100,000/ul; c) Hemoglobin >9.0 g/dL; d) Total bilirubin ≤ 1.5x ULN; e) AST and ALT < 2.5 
x ULN; f) Alkaline phosphatase <2.5x ULN; g) Creatinine ≤ 1.5x ULN or CCr >60 ml/min 
for patients with abnormal serum Cr level function. 
8) Patient has an adequate left ventricular ejection function of at least 50 % at baseline, as 
measured by echocardiography. 
9) Written informed consent 
 
3.2 Exclusion criteria  
1) Patient is pregnant or lactating, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive human chorionic 
gonadotropin (hCG) laboratory test. 
2) Patient has symptomatic and unstable CNS metastases, except for treated brain metastases. 
Treated brain metastases are defined as having no evidence of progression or hemorrhage after 
treatment and no ongoing requirement for dexamethasone, as ascertained by clinical 
examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants 
(stable dose) are allowed. 
3) Active and clinically significant bacterial, fungal or viral infection including hepatitis B (HBV), 
hepatitis C (HCV), known human immunodeficiency virus syndrome (HIV) or acquired 
immunodeficiency syndrome (AIDS)-related illness. Baseline viral assessment is not required 
in patients with no known infection. 
4) Major surgery within 4 weeks of first dose of investigational product or not fully recovered 
from any side effects of previous procedures. 
5) Any other malignancy within 3 years prior to first dose of investigational product except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix. 
6) QTc interval >480 msec (based on the mean value of the triplicate ECGs), family or personal 


Trastuzumab biosimilar + TPC protocol v.2 
 
18 
 
history of long or short QT syndrome, Brugada syndrome or known history of QTc 
prolongation or Torsade de Pointes.  
7) Any of the following within 6 months of first dose of investigational product myocardial 
infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE v. 4.03 
Grade ≤2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure, cerebrovascular accident including transient ischemic attack, or 
symptomatic pulmonary embolism. 
8) History of symptomatic interstitial pneumonitis. 
9) Other severe acute or chronic medical or psychiatric condition, including recent (within the 
past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase 
the risk associated with study participation or investigational product administration or may 
interfere with the interpretation of study results and, in the judgment of the investigator, would 
make the patient inappropriate for entry into this study. 
 
 
4. TREARMENT 
 
4.1 Allocation to treatment  
 For those patients who are eligible for enrollment, investigator should choose the 
chemotherapeutic regimen for TPC and record it on eCRF. The study site will obtain the patient 
identification number and treatment assignment from the system. 
 
4.2 Treatment administration  
  Trastuzumab biosimilar (CT-P6), Herzuma® will be supplied by KCSG. Study centers will receive 
trastuzumab prior to enrollment of the first patient. The clinical site pharmacy will prepare the study 
medication supply that is appropriate for the patient. The drug of TPC will not be supplied nor 
reimbursed by this trial. Instead, it will be selected and used as current national standard treatment 
guideline and be covered by National Insurance program.  
 
    4.2.1 Trastuzumab biosimlar, CT-P6 
    CT-P6, Herzuma® is available in its commercial package. It is supplied as a powder for IV 
infusion containing 150mg/dose vial and/or 420mg/dose vial trastuzumab.  
4.2.1.1 Dosage, administration, and storage 
Drug preparation and administration will be performed at the site by a physician, registered nurse 
or other qualified health care provider. Refer to the package insert for trastuzumab for instructions 
and steps necessary for preparation and administration. 
Trastuzumab requires a loading dose during the first cycle of treatment, if patient did not received 


Trastuzumab biosimilar + TPC protocol v.2 
 
19 
 
trastuzumab treatment within 8 weeks from the time of 1st study treatment. Doses of trastuzumab 
(8mg/kg at a loading dose, and then 6mg/kg at a maintenance dose) are given once every 3 weeks 
of the cycle. Trastuzumab loading dose should be administered as a 90-minute IV infusion. Do 
not administer as an IV push or bolus. If the initial loading dose was well tolerated, the subsequent 
doses can be administered as a 30-minute infusion.  
4.2.1.2 Dosage modification 
Dose adjustment for trastuzumab will be determined by the investigator’s discretion. Per the 
trastuzumab SPC, no reductions in the dose of trastumab were made during clinical trials. Patients 
may continue trastuzumab therapy during periods of reversible, chemotherapy-induced 
myelosuppression but they should be monitored carefully for complications of neutropenia during 
this time. In the event that trastuzumab is discontinued, the patient may continue to receive TPC 
based on the investigator’s discretion. For monitoring of LVEF, please refer to the algorithm in 
Figure. 
 
Figure 2. Algorithm for monitoring LVEF in study 
 
    4.2.2 Treatment of physician’s choice (TPC) 
In this trial, gemcitabine, vinorelbine, eribulin, nab-paclitaxel or capecitabine are allowed as 
combinational drugs with trastuzumab biosimilar. The proposed treatmend of physician’s choice 
will be documented prior to patient allocation.  
4.2.2.1 Dosage, administration, and storage 
Dose administration should be performed according to the drugs national prescribing 
duidelines. Refer to the appropriate package insert or national prescribing information as 
needed for details.  


Trastuzumab biosimilar + TPC protocol v.2 
 
20 
 
4.2.2.2 Dosage modification 
Dose modification should be performed according to the investigator’s discretion.  
    4.2.3 Dose interruptions and delay 
    Patients experiencing grade 3 or 4 treatment related toxicity or intolerable grade 2 toxicity despite 
supportive care should have their treatment interrupted and may not be restarted until the toxicity 
has recovered to grade ≤1 or tolerable grade 2. Appropriate follow up assessments should be done 
until adequate recovery as assessed by the investigator. If a treatment interruption continues 
beyond Day 21 of the current cycle, then the day treatment is restarted will be counted as Day 1 of 
the next cycle, and the previous cycle is extended accordingly.  
Treatment resumption for patients recovering from treatment related toxicity after >2 weeks of 
treatment interruption or cycle delay can be considered only if the patient is deemed to be deriving 
clinical benefit per the investigator’s medical judgment and needs to be agreed between the 
investigators. In the event of a treatment interruption for reasons other than treatment related 
toxicity (e.g., elective surgery) lasting >2 weeks, treatment resumption will be decided in 
consultation with the PI of this trial.  
Tumor assessments should be performed every 6 weeks (±5 days), regardless of cycle delays. 
If a dose of trastuzumab is missed/omitted by 1 cycle (3 weeks), then the usual maintenance dose 
should be administered as soon as possible. Then, subsequent maintenance doses should be 
administered every 21 days. If the patient requires omission of 2 and more than 2 trastuzumab 
maintenance doses for toxicity, the patient should be considered to be withdrawn from trastuzumab. 
In exceptional circumstances, a longer delay or omission of TPC may be permitted upon agreement 
between the investigators. In those cases, trastuzumab maintenance will be permitted if investigator 
believe clinical benefit of it to patients until study termination, disease progression or patient 
withdrawal.  
 
4.3. Concomitant and excluded therapies 
4.3.1 Concomitant therapy 
Concomitant therapy and premedication are defined as non-investigational medicinal products. 
Concomitant therapy includes any prescription medication, over –the – counter preparation, or herbal 
therapy bewteen the 14 days preceding enrollment and the study treatment discontinuation visit. 
Afterward, only anti-cancer therapies will be collected as part of the survival follow-up period.  
Premedication is allowed according to standard practice guidelines. Concomitant use of 
erythropoiesis-stimulating agents, G-CSF, or GM-CSF is allowed if clinically indicated in accordance 
with local prescribing guidelines. Palliative radiotherapy may be permitted to treat pre-existing painful 
bone metastases unless there is evidence of disease progression. Other medications considered 
necessary for the patient’s safety and well-being may be given at the discretion of the investigator. Use 
of biophosphonates is permitted for the control of bone pain and treatment of osteoporosis. If 


Trastuzumab biosimilar + TPC protocol v.2 
 
21 
 
bisphosphonates are required for the treatment of symptomatic malignancy associated hypercalcemia, 
tumor assessments should be performed to assess for potential disease progression.  
4.3.2 Excluded therapy 
 Use of the therapies described below is prohibited during the study prior to discontinuation of study 
treatment. Any therapies intended for the treatment of breast cancer other than trastuzumab and TPC 
including cytotoxic chemotherapy, immunotherapy, biologic or targeted agents are not allowed. Refer 
to the local prescribing guidelines for durg-drug interactions and excluded concomitant medications 
and precautions for the selected TPC.  
Radiotherapy for unequivocal disease progression is not permitted while on study treatment.  
 
4.4 Study assessments 
 All patients will be closely monitored for safety and tolerability during all cycles of therapy and at the 
study treatment discontinuation visit. Patients should be assessed for toxicity prior to each dose. Each 
cycle will be 21 days (3 weeks) in length. Study assessments are outlined in this section and the study 
flowchart.  
4.4.1 Screening and pretreatment assessments 
All screening evaluations must be completed and reviewed to confirm that patients meet all eligibility 
criteria. Written informed consent for participation in the study must be obtained before performing any 
study specific screening tests or evaluations. Screening tests will be performed within 28 days preceding 
the 1st treatment Day 1 of cycle 1.  
4.4.1.1 Medical history, concomitant medication, and demographic data 
Medical history, including clinically significant diseases, surgeries, cancer history (including prior 
cancer therapies and procedures), reproductive status, will be recorded at baseline.  
All medications used by the patient within 7 days prior to initiation of study treatment will be recorded.  
4.4.1.2 Physical examination & vital sign 
A complete physical examination will be performed at screening. Any abnormality identified at baseline 
should recorded on the eCRF.  
Limited, symptom-directed physical examination should be performed at post-baseline visits and as 
clinically indicated. Changes from baseline abnormalities should be recorded.  
Vital signs will include measurements of blood pressure, pulse rate, respiratory rate, and body 
temperature. At every clinic visit to receive study treatment, vital sign should be measured and if 
clinically indicated, during or after the infusion. Vital signs are not required to be entered into the eCRF 
unless abnormal and clinically significant.  


Trastuzumab biosimilar + TPC protocol v.2 
 
22 
 
4.4.1.3 Electrocardiogram, echocardiograms or multiple-gated acquisition scans (MUGA) 
A 12-lead ECG is required at screening and when clinically indicated. Any ECG abnormalities must be 
reviewed by the investigator and documented on the eCRF. 
LVEF will be assessed by echocardiography or MUGA scan at screening and before cycle 5 day 1. 
After then, echo (or MUGA) should be performed at every 24weeks. If circumstances allow, patients 
should be reassessed with the same technique used for baseline evaluation throughout the study.   
4.4.1.4 Baseline tumor status 
Disease status at baseline should be done with CT scan (chest CT, abdomen CT) and bone and recorded 
in the eCRF. If patients performed bone scan within 3 months, have no evidence of bone metastasis, or 
no symptom associated with progression of bone metastasis, bone scan could be skipped at the 
discretion of each investigator. If clinically indicated, other modalities such as MRI, or PET are allowed 
and any abnormal findings should be recorded into the eCRF. 
4.4.2 Assessments during treatment 
Visits are based on a 21-days cycle. All visits must occur within +/- 3 business days from the scheduled 
date, unless otherwise noted. All tumor assessments will be performed after every 6 weeks (+/- 5 days) 
of treatment. Assessments scheduled on the day of treatment administration should be performed prior 
to study treatment administration unless otherwise noted. If the timing of a protocol-mandated 
procedure coincides with a holiday and/or weekend, it should be performed on the nearest following 
date. In case that the treatment cycle exceeds more than 8, tumor assessments can be performed every 
9 weeks depending on physician’s discretion. 
Local laboratory assessments scheduled for day 1 of all cycles must be performed within 72 hours prior 
to study treatment administration unless otherwise specified.  
4.4.3 Study treatment discontinuation visit.  
Patients who discontinue study treatment will be aksed to return to the clinic approximately 30 days 
(+/-10 days) after the last study treatment administration for the study treatment discontinuation visit. 
Please, refer the study flow chart for assessment to be performed at this visit.  
4.4.4 Follow-up assessment.  
After the study treatment discontinuation visit, all participants will be followed for survival every 3 
months until death, loss to follow-up, withdrawal of consent, or study termination for collecting survival 
data.  
 
4.5 Patient discontinuation.  
Patients may withdraw from the study at any time at their own request, or they may be withdrawn at 
any time at the discretion of the investigator or sponsor for safety or behavioral reasons, or the inability 
of the patient to comply with the protocol required schedule of study visits or procedures at a given 
study site.  


Trastuzumab biosimilar + TPC protocol v.2 
 
23 
 
Reasons for discontinuation of may include: 
⬧ 
Objective disease progression according to RECISTv1.1;  
⬧ 
Global deterioration of health status requiring discontinuation;  
⬧ 
Unacceptable toxicity;  
⬧ 
Pregnancy;  
⬧ 
Lost to follow-up;  
⬧ 
Medication error without associated adverse event;  
⬧ 
Significant protocol violation;  
⬧ 
Patient refused further treatment;  
⬧ 
Significant patient noncompliance;  
⬧ 
Study terminated by Sponsor;  
⬧ 
Death. 
 
4.6 Statistical method 
4.6.1 Rationale for sample size  
This study is aiming to assess PFS of TPC plus trastuzumab biosimilar, CT-P6 in patients with HER-2 
positive metastatic breast cancer who progressed after 2 or more HER-2 directed chemotherapy.  
One sided type I error rate 0.1, power 80%; 24 months of accrual period and 12 months of follow-up. 
H0 = 2.8 months, H1=3.8 months. Then, a total of 108 patients will be needed in this trial. Considered 
10% drop-out rate, we will enroll 119 patients. (ref. TH3RESA trial, Lancet Oncol 2014;15:689-
99)4.6.2 Efficacy analysis 
4.6.2.1 Progression free survival (PFS) 
PFS is defined as the time from randomization to docutmented disease progression or death from any 
cause, whichever occurs first. Data for patients without disease progression or death will be censored 
at the time of the last tumor assessment date or, if no tumor assessment was performed after the baseline 
visit, at the time of allocation plus 1 day. Data from patients who are lost to follow-up will be censored 
at the last tumor assessment date that the patient was known to be progression free.  
Kaplan-Meier approach will be used to estimate median PFS and the corresponding confidential interval 
(CI). 
4.6.2.2 Overall survival (OS)  
Overall survival is defined as the time from the date of randomization to the date of death from any 
cause. Patients who are alive at data cutoff date will be censored at the last date they were known to be 
alive. Patients with no post-baseline information will be censored at the date of allocation plus 1 day.  


Trastuzumab biosimilar + TPC protocol v.2 
 
24 
 
Methods for OS analyses are similar to those described for the PFS endpoint.  
4.6.2.3 Objective response rate (ORR) 
Objective response is defined as a complete or partial response based on RECIST v 1.1. The ORR is 
the percentage of patients who are determined to have an objective response. For the ORR analysis, 
patients who do not have any record of post-baseline tumor assessment will be counted as non-
responders.  
4.6.3 Safety analysis 
Safety analyses will be performed on the treatment population who received any amount of study 
treatment.  
4.6.3.1 Study treatment exposure 
Treatment duration, number of cycles, dose intensity, and dose modification will be summarized with 
descriptive statistics.  
4.6.3.2 Adverse events 
All adverse events (AE), seriouse adverse events (SAE) occuring on and after the first dose of study 
treatment will be summarized by NCI-CTCAE grade. For events of varing severity, the highest grade 
will be used in the summaries.   
4.6.4 Quality of life (QoL) analysis 
The EORTC-QLQ-C30 data will be scored according to the EORTC- QLQ- C30 scording manual. 
Percentages of missing data will also be summarized at each timepoint. Assessment will be done at 3 
time points (baseline, after 3 cycles of treatment, and at the end of treatment date). Summary statistics 
of absolute scores of the QLQ-C30 scales and the changes from baseline will be summarized. Only 
patients with baseline assessment and at least one post-baseline assessment will be included in this 
analysis.  
 
4.7 Assessment of safety  
4.7.1 Adverse event (AE) 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associtated with the 
use of an investigational medicinal product or other protocol imposed intervention, regardless of 
attribution.  
This includes the following : 
⬧ 
AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with breast cancer that were not 
present prior to the AE reporting period. 
⬧ 
Complications that occur as a result of protocol-mandated interventions 


Trastuzumab biosimilar + TPC protocol v.2 
 
25 
 
⬧ 
AEs that occur prior to assignment of study treatment that are related to a protocol mandated 
intervention 
⬧ 
Preexisting medical conditions other than breast cancer judged by the investigator to have 
worsened in severity or frequency or change in character during the protocol specified AE 
reporting period. 
   4.7.2 Serious adverse event (SAE) 
    An SAE is any AE that is any of the following  
⬧ 
Fatal (i.e. the AE actually causes or leads to death) 
⬧ 
Life threatening (i.e. the AE, in the view of the investigator, places the patient at immedicate 
risk of death) 
⬧ 
Requires or prolongs inpatient hospitalization 
⬧ 
Results in persistent or significant disability/incapacity (i.e. the AE results in substantial 
disruption of the patient ability to conduct normal life functions) 
⬧ 
A congenital anomaly/birth defect in a neonate/infacnt born to a mother exposed to the 
investigational products  
⬧ 
Considered a significant medical event by the investigator (e.g. may jeopardize the patient or 
may require medical/surgical intervention to prevent one of the outcomes listed above) 
Hospitalization is defined as any initial admission (even less than 24hours) in a hospital or equivalent 
healthcare facility or any prolongation of an existing admission. Admission also includes transfer within 
the hospital to an acute/intensive care unit (e.g., from the psychiatric wing to a medical floor, medical 
floor to a coronary care unit, or neurological floor to a tuberculosis unit). An emergency room visit does 
not necessarily constitute a hospitalization; however, the event leading to the emergency room visit 
should be assessed for medical importance.  
Hospitalization does not include the following: 
⬧ 
Rehabilitation facilities;  
⬧ 
Hospice facilities; 
⬧ 
Respite care (e.g., caregiver relief);  
⬧ 
Skilled nursing facilities;  
⬧ 
Nursing homes;  
⬧ 
Same-day surgeries (as outpatient/same-day/ambulatory procedures). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE is not in 
itself an SAE. Examples include: 


Trastuzumab biosimilar + TPC protocol v.2 
 
26 
 
⬧ 
Admission for treatment of a preexisting condition not associated with the development of a  
new AE or with a worsening of the preexisting condition (e.g., for workup of persistent 
pretreatment laboratory abnormality); 
⬧ 
Social admission (e.g., patient has no place to sleep);  
⬧ 
Administrative admission (e.g., for yearly physical examination); 
⬧ 
Protocol-specified admission during a study (e.g., for a procedure required by the study 
protocol);  
⬧ 
Optional admission not associated with a precipitating clinical AE (e.g., for elective cosmetic 
surgery); 
⬧ 
Hospitalization for observation without a medical AE;  
⬧ 
Preplanned treatments or surgical procedures. These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient; 
⬧ 
Admission exclusively for the administration of blood products.  
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, the medical condition for which the procedure was performed should be 
reported if it meets the definition of an AE. For example, an acute appendicitis that begins during the 
AE reporting period should be reported as the AE, and the resulting appendectomy should be recorded 
as treatment of the AE. 
4.7.3 Causality assessment 
The investigator’s assessment of causality must be provided for all AEs (serious and non-serious); the 
investigator must record the causal relationship in the CRF, as appropriate, and report such an 
assessment in accordance with the SAE reporting requirements if applicable. An investigator’s causality 
assessment is the determination of whether there exists a reasonable possibility that the investigational 
product caused or contributed to an AE; generally the facts (evidence) or arguments to suggest a causal 
relationship should be provided. If the investigator does not know whether or not the investigational 
product caused the event, then the event will be handled as “related to investigational product” for 
reporting purposes. If the investigator's causality assessment is "unknown but not related to 
investigational product," this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as appropriate, and 
report such an assessment in accordance with the SAE reporting requirements, if applicable. 
4.7.4 AE reporting period 
After informed consent, but prior to initiation of study treatment, only SAEs caused by a protocol 
mandated intervention will be collected. After initiation of study treatment, all AEs and SAEs regardless 
of attribution will be collected until 30 days following the last administration of study treatment or study 
discontinuation, whichever is later.  


Trastuzumab biosimilar + TPC protocol v.2 
 
27 
 
The AE severity scale found in the NCI-CTCAE v 4.0 will be used for assessing AE severity  
 
 
5. QUALITY CONTROL AND QUALITY ASSURANCE 
 
Investigators will conduct periodic monitoring visits during study conduct to ensure that the protocol 
and Good Clinical Practices (GCPs) are being followed. The monitors may review source documents 
to confirm that the data recorded on CRFs are accurate. The investigator and institution will allow 
KCSG monitors/auditors or its agents and appropriate regulatory authorities direct access to source 
documents to perform this verification. This verification may also occur after study completion. 
During study conduct and/or after study completion, the study site may be subject to review by the 
institutional review board (IRB)/ethics committee (EC), and/or to quality assurance audits performed 
by KCSG and/or to inspection by appropriate regulatory authorities. 
The investigator(s) will notify KCSG immediately of any regulatory inspection notification in relation 
to the study. Furthermore, the investigator will cooperate with KCSG to prepare the study site for the 
inspection and will allow KCSG, whenever feasible, to be present during the inspection. The 
investigator will promptly provide copies of the inspection findings to KCSG. Before response 
submission to the regulatory authorities, the investigator will provide KCSG with an opportunity to 
review and comment on responses to any such findings. 
It is important that the investigator(s) and their relevant personnel are available during the monitoring 
visits and possible audits or inspections and that sufficient time is devoted to the process. 
 
 
6. DATA HANDLING AND RECORD KEEPING 
 
6.1 Case Report Forms/Electronic Data Record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or an 
electronic data record or both, depending on the data collection method used in this study. 
A CRF is required and should be completed for each included patient. The completed original CRFs 
are the sole property of KCSG and should not be made available in any form to third parties, except for 
authorized representatives of KCSG or appropriate regulatory authorities, without written permission 
from KCSG.  
The investigator has ultimate responsibility for the collection and reporting of all clinical, safety, and 
laboratory data entered on the CRFs and any other data collection forms (source documents) and 
ensuring that they are accurate, authentic/original, attributable, complete, consistent, legible, timely 


Trastuzumab biosimilar + TPC protocol v.2 
 
28 
 
(contemporaneous), enduring, and available when required. The CRFs must be signed by the 
investigator or by an authorized staff member to attest that the data contained on the CRFs are true. Any 
corrections to entries made in the CRFs or source documents must be dated, initialed, and explained (if 
necessary) and should not obscure the original entry.  
In most cases, the source documents are the hospital's or the physician's patient chart. In these cases, 
data collected on the CRFs must match the data in those charts.  
In some cases, the CRF, or part of the CRF, may also serve as source documents. In these cases, a 
document should be available at the investigative site as well as at KCSG and clearly identify those data 
that will be recorded in the CRF, and for which the CRF will stand as the source document. 
 
6.2 Record Retention 
To enable evaluations and/or audits from regulatory authorities or KCSG, the investigator agrees to 
keep records, including the identity of all participating patients (sufficient information to link records, 
e.g., CRFs and hospital records), all original signed informed consent documents, copies of all CRFs, 
safety reporting forms, source documents, and detailed records of treatment disposition, and adequate 
documentation of relevant correspondence (e.g., letters, meeting minutes, and telephone call reports). 
The records should be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.  
If the investigator becomes unable for any reason to continue to retain study records for the required 
period (e.g., retirement, relocation), KCSG should be prospectively notified. The study records must be 
transferred to a designee acceptable to KCSG, such as another investigator, another institution, or an 
independent third party arranged by KCSG. Investigator records must be kept for a minimum of 15years 
after completion or discontinuation of the study or for longer if required by applicable local regulations.  
The investigator must obtain KCSG's written permission before disposing of any records, even if 
retention requirements have been met. 
 
 
7. ETHICS 
 
7.1 Institutional Review Board/Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, protocol 
amendments, informed consent documents, and other relevant documents, e.g., recruitment 
advertisements, if applicable, from the IRB/EC. All correspondence with the IRB/EC should be retained 
in the investigator file.  Copies of IRB/EC approvals should be forwarded to KCSG.  


Trastuzumab biosimilar + TPC protocol v.2 
 
29 
 
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is where the 
change is necessary to eliminate apparent immediate hazards to the patients. In that event, the 
investigator must notify the IRB/EC and KCSG in writing immediately after the implementation. 
 
7.2 Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as well as the general 
principles set forth in the International Ethical Guidelines for Biomedical Research Involving Human 
Subjects (Council for International Organizations of Medical Sciences 2002), Guidelines for GCP 
(ICH1996), and the Declaration of Helsinki (World Medical Association1996 & 2008.  
In addition, the study will be conducted in accordance with the protocol, the ICH guideline on GCP, 
and applicable local regulatory requirements and laws. 
 
7.3 Subject Information and Consent 
All parties will ensure protection of patient personal data and will not include patient names or other 
identifiable data in any reports, publications, or other disclosures, except where required by law. 
When study data are compiled for transfer to KCSG and other authorized parties, patient names, 
addresses, and other identifiable data will be replaced by a numerical code based on a numbering system 
provided by KCSG in order to de-identify study patients. The study site will maintain a confidential list 
of patients who participated in the study, linking each patient’s numerical code to his or her actual 
identity. In case of data transfer, KCSG will maintain high standards of confidentiality and protection 
of patients’ personal data consistent with applicable privacy laws. 
The informed consent documents must be in compliance with ICH GCP, local regulatory requirements, 
and legal requirements, including applicable privacy laws. 
The informed consent documents used during the informed consent process must be reviewed and 
approved by the sponsor, approved by the IRB/EC before use, and available for inspection. 
The investigator must ensure that each study patient, or his or her legally acceptable representative, is 
fully informed about the nature and objectives of the study and possible risks associated with 
participation. 
Whenever consent is obtained from a patient’s legally acceptable representative the patient’s assent 
(affirmative agreement) must subsequently be obtained when the patient has the capacity to provide 
assent, as determined by the IRB/EC. If the investigator determines that a patient’s decisional capacity 
is so limited he/she cannot reasonably be consulted, then, as permitted by the IRB/EC and consistent 
with local regulatory and legal requirements, the patient’s assent may be waived with source 
documentation of the reason assent was not obtained. If the study patient does not provide his or her 
own consent, the source documents must record why the patient did not provide consent (e.g., minor, 
decisional impaired adult), how the investigator determined that the person signing the consent was the 
patient’s legally acceptable representative, the consent signer’s relationship to the study patient (e.g., 


Trastuzumab biosimilar + TPC protocol v.2 
 
30 
 
parent, spouse), and that the patient’s assent was obtained, or waived. If assent is obtained verbally it 
must be documented in the source documents. 
The investigator, or a person designated by the investigator, will obtain written informed consent from 
each patient or the patient’s legally acceptable representative before any study-specific activity is 
performed. The investigator will retain the original of each patient's signed consent/assent document. 
 
7.4 Subject Recruitment 
Advertisements approved by IRBs/ECs and investigator databases may be used as recruitment 
procedures.  
 
7.5 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (i.e, clinical hold) by an applicable competent 
authority in any area of the world, or if the investigator is aware of any new information that might 
influence the evaluation of the benefits and risks of the investigational product, KCSG should be 
informed immediately. 
In addition, the investigator will inform KCSG immediately of any urgent safety measures taken by the 
investigator to protect the study patients against any immediate hazard, and of any serious breaches of 
this protocol or of ICH GCP that the investigator becomes aware of. 
 
 
8. DEFINITION OF END OF TRIAL 
The end of the study will be at the 12 months after the last patient enrollment for purposes of closing 
out sites and informing the institutional review board/independent ethics committee (IRB/IEC).  
 
8.1. KCSG discontinuation criteria 
Premature termination of this study may occur because of a regulatory authority decision, change in 
opinion of the IRB/EC, or investigational product safety problems, or at the end of K-master program. 
If a study is prematurely terminated or discontinued, KCSG will promptly notify the investigator. After 
notification, the investigator must contact all participating patients and the hospital pharmacy (if 
applicable) promptly. As directed by KCSG, all study materials must be collected and all CRFs 
completed to the greatest extent possible. 
 
 
9. PUBLICATION OF STUDY RESULTS 


Trastuzumab biosimilar + TPC protocol v.2 
 
31 
 
 
9.1 Communication of Results by K-MASTER 
K-MASTER fulfills its commitment to publicly disclose clinical trial results through posting the results 
of studies on www.clinicaltrials.gov (ClinicalTrials.gov), CRIS (cris.nih.go.kr/cris/index.jsp), and/or 
www.KCSG.org, and other public registries in accordance with applicable local laws/regulations.   
In all cases, study results are reported by KCSG in an objective, accurate, balanced, and complete 
manner and are reported regardless of the outcome of the study.  
KCSG posts Public Disclosure Synopses (clinical study report synopses in which any data that could 
be used to identify individual patients has been removed) on CRIS (cris.nih.go.kr/cris/index.jsp) and 
www.clinicaltrials.gov. 
 
9.2 Publication by Investigators 
Drug supplier (Celltrion) support the exercise of academic freedom and has no objection to publication 
by principal investigator of the results of the study based on information collected or generated by 
principal investigator, whether or not the results are favorable to the study product. However, to ensure 
against inadvertent disclosure of confidential information or unprotected inventions, the investigator 
will provide drug suppliers an opportunity to review any proposed publication or other type of 
disclosure of the results of the study (collectively, “Publication”) before it is submitted or otherwise 
disclosed. 
If the study is part of a multicenter study, the investigator agrees that the first publication is to be a joint 
publication covering all study sites, and that any subsequent publications by the principal investigator 
will reference that primary publication.  
For all publications relating to the study, the K-MASTER will comply with KCSG ethical standards 
concerning publications and authorship. Publication of study results is also provided for K-MASTER 
and the investigators. 
 
 
10. REFERENCES 
1. Cardoso F, Costa A, Senkus E, et al. 3rd ESO-ESMO international consensus guidelines for advanced 
breast cancer (ABC3). Ann Oncol 2017, 28:16-33. 
2. Swain SM, Kim SB, Cortés J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive 
metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-
blind, placebo-controlled, phase 3 study. Lancet Oncol 2013; 14: 461–471. 
3. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. 
N Engl J Med 2012; 367: 1783–1791. 


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32 
 
4. Krop IE, Kim SB, González-Martín A, et al.  Trastuzumab emtansine versus treatment of physician's 
choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, 
phase 3 trial. Lancet Oncol 2014; 1: 689–699. 
5. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal 
growth factor receptor 2-positive advanced breast cancer: a German Breast Group 26/breast 
international group 03-05 study. J Clin Oncol 2009; 27: 1999–2006. 
6. Loibl S, Gianni L. HER2 positive breast cancer. Lancet 2016, 389;2415-2429. 
7. Francisco J. Esteva et al. A randomised trial comparing the pharmacokinetics and safety of the 
biosimilar CT-P6 with reference trastuzumab. Cancer Chemotherapy and Pharmacology 2018; 81(3): 
505-514. 
8. Stebbing J, Baranau Y, Baruash V, et al. CT-P6 compared with reference trastuzumab for HER2 
positive breast cancer: a randomized double-blind, active-controlled, phase 3 equivalence trial. Lancet 
Oncol 2017, 18:917-928.  
9. Esteva FJ, Saeki T, Kim H, et al. Efficacy and safety of the trastuzumab biosimilar candidate CT-P6. 
Future Oncol 2018, Feb 27.  
 


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Appendix 1. Abbreviations 
Abbreviation 
Term 
ADCC 
Antibody-dependent cellular cytotoxicity 
AE  
adverse event 
BC 
breast cancer 
CI  
confidence interval  
CR  
complete response  
CRF 
Case report form  
CT  
computed tomography  
CTCAE  
Common Terminology Criteria for Adverse Events  
EC  
Ethics Committee  
ECHO  
echocardiogram  
ECG 
Electrocardiogram  
ECOG  
Eastern Cooperative Oncology Group  
EOT 
End of treatment 
eCRF  
electronic Case Report Form  
FFPE  
formalin-fixed paraffin-embedded  
GCP  
Good Clinical Practice  
HBsAg 
Hepatitis B surface antigen B 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HER2  
human epidermal growth factor 2  
HIV 
Human immunodeficiency virus 
ICH  
International Conference on Harmonisation  
IHC  
immunohistochemistry  
IRB  
Institutional Review Board  
ITT  
intention-to-treat  
IV  
intravenous  
LPLV  
last patient last visit  
LVEF  
left ventricular ejection fraction  
MBC  
metastatic breast cancer  
MRI 
Magnetic resonance imaging 
MUGA  
multi-gated acquisition scan  
NCI 
National cancer institute 
NGS  
next-generation sequencing  
ORR  
objective response rate  
OS  
overall survival  
PD  
progressive disease  
PI3K 
Phosphoinositide 3 kinase 
PFS  
progression-free survival  
PK  
pharmacokinetic  
PO  
orally  
PR  
partial response  
RECIST  
Response Evaluation Criteria in Solid Tumors  
SAE 
Serious adverse events 
SD 
Stable disease 
ULN 
Upper limit of normal  
 
 
 


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Appendix 2. RECIST (Response Evaluation Criteria In Solid Tumors) version 1.1 
Guideline 
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1).  European Journal of Cancer 45 (2009) 228–247 
 
CATEGORIZING LESIONS AT BASELINE 
Measurable Lesions 
⬧ 
Lesions that can be accurately measured in at least one dimension.  
⬧ 
Lesions with longest diameter twice the slice thickness and at least 10mm or greater when assessed by 
CT or MRI (slice thickness 5-8mm).  
⬧ 
Lesions with longest diameter at least 20mm when assessed by Chest X-ray.  
⬧ 
Superficial lesions with longest diameter 10mm or greater when assessed by caliper.  
⬧ 
Malignant lymph nodes with the short axis 15mm or greater when assessed by CT. 
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for all other measurable 
lesions. 
Non-measurable disease 
Non-measurable disease includes lesions too small to be considered measurable (including nodes with short axis 
between 10 and 14.9mm) and truly non-measurable disease such as pleural or pericardial effusions, ascites, 
inflammatory breast disease, leptomeningeal disease, lymphangitic involvement of skin or lung, clinical lesions 
that cannot be accurately measured with calipers, 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 <10mm are considered normal and should not be recorded or 
followed either as measurable or non-measurable disease. 
Recording 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 28days prior to 
randomization and all disease must be documented appropriately. If baseline assessment is inadequate, subsequent 
statuses generally should be non-evaluable. 


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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 assessments performed on study.  
⬧ 
If two target lesions coalesce the 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 5mm should be recorded.  
NOTE: When nodal lesions decrease to <10mm (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 CR, Non-
CR/Non-PD, PD, Non-evaluable (NE). 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 a change needs to be made the case must be discussed with the radiologist to 
determine if substitution is possible. If not, subsequent objective statuses might be non-evaluable.  
Target Disease 
1. 
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 <10mm). All target lesions must be assessed.  
2. 
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.  
3. 
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.  
4. 
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 5mm.  
5. 
Non-evaluable (NE): Progression has not been documented, and  
⬧ 
One or more target measurable lesions have not been assessed; or  


Trastuzumab biosimilar + TPC protocol v.2 
 
36 
 
⬧ 
One or more target lesions cannot be measured accurately (e.g., poorly visible unless due to being too 
small to measure); or  
⬧ 
One or more target lesions were excised or irradiated.  
Non-target disease 
1. 
CR: Disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes 
must be ‘normal’ in size (<10mm short axis).  
2. 
Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level above the normal 
limits.  
3. 
PD: Unequivocal progression of pre-existing lesions. Generally the overall tumor burden must increase 
sufficiently to merit discontinuation of therapy. In the presence of SD or PR in target disease, progression due to 
unequivocal increase in non-target disease should be rare.  
4. 
NE: 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 
⬧ 
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 
Patients requiring discontinuation of treatment without objective evidence of disease progression should not be 
reported as PD on tumor assessment CRFs. This should be indicated on the end of treatment CRF as off treatment 
due to Global Deterioration of Health Status. Every effort should be made to document objective progression even 
after discontinuation of treatment. 
Table 1. Objective Response Status at each Evaluation 
Table 1. Objective Response Status at each Evaluation 
Target Lesions 
Non-target Disease 
New Lesions 
Objective status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE or Missing 
No 
PR 
PR 
Non-CR/Non-PD, NE or 
Missing 
No 
PR 
SD 
Non-CR/Non-PD, NE or 
No 
Stable 


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37 
 
Missing 
NE or Missing 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
If the protocol allows enrollment of patients with only non-target disease, the following table will be used: 
 
Table 2. Objective Response Status at each Evaluation for Patients with Non-Target Disease Only 
Table 2. Objective Response Status at each Evaluation for Patients with Non-Target Disease Only 
Non-target Disease 
New Lesions 
Objective status 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
NE 
No 
NE 
Unequivocal progression 
Yes or No 
PD 
Any 
Yes 
PD 
 
Best Overall Response 
The best overall response (BOR) is the best response recorded from the randomization until disease progression 
or death due to any cause. This is derived from the sequence of objective statuses.  Objective statuses are not 
considered after objective progression is documented or after start of the first anticancer treatment post 
discontinuation of protocol treatment. BOR for each patient will be derived as one of the following categories. 
⬧ 
Complete response (CR): At least one objective status of CR documented before progression.  
⬧ 
Partial response (PR): At least one objective status of PR documented before progression.  
⬧ 
Stable disease (SD): At least one objective status of stable documented at least 8weeks after 
randomization date and before progression but not qualifying as CR, PR.  
⬧ 
Progressive Disease (PD): Objective status of progression within 16weeks of randomization, not 
qualifying as CR, PR or SD.  
⬧ 
Non-evaluable (NE): Progression not documented within 16weeks after randomization and no other 
response category applies. 
 
 


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Appendix 3. Quality of Life 


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