An Indian Multicentric Open Label Prospective Phase IV Study to Evaluate Safety and Efficacy of Trastuzumab in Her2 Positive, Node Positive or High Risk Node Negative Breast Cancer as Part of a Treatment Regimen Consisting of Doxorubicin, Cyclophosphamide, With Either Docetaxel or Paclitaxel (AC-TH) or Docetaxel and Carboplatin (TCH)
Phase: PHASE4
Conditions: Breast Cancer
Sponsor: Hoffmann-La Roche

 
Official Title: An Indian Multicentric Open Label Prospective Phase IV Study to 
Evaluate Safety and Efficacy of Trastuzumab in Her2 Positive, Node 
Positive or High Risk Node Negative Breast Cancer as Part of a 
Treatment Regimen Consisting of Doxorubicin, Cyclophosphamide, 
With Either Docetaxel or Paclitaxel (AC-TH) or Docetaxel and 
Carboplatin (TCH) 
NCT Number: NCT02419742 
Document Date: Protocol Version 1: 29-July-2013 
 
 
 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
 
TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ................................................................................................ 7 
1. 
BACKGROUND ................................................................................................... 27 
1.1 
Background on Breast cancer ......................................................... 27 
1.2 
Background on Trastuzumab .......................................................... 29 
1.2.1 
Trastuzumab IV .............................................................................. 29 
1.2.2 
Efficacy of trastuzumab in Early Breast Cancer 
(Adjuvant setting) .......................................................................... 30 
1.2.3 
Safety of Trastuzumab IV ............................................................... 32 
1.3 
Study Rationale and Benefit–Risk Assessment ............................... 34 
2. 
OBJECTIVES ....................................................................................................... 35 
2.1 
Primary Objectives ......................................................................... 35 
2.2 
Secondary Objectives ..................................................................... 35 
3. 
STUDY DESIGN .................................................................................................. 36 
3.1 
Description of Study ....................................................................... 36 
3.2 
Procedures (Summary) ................................................................... 37 
3.2.1 
During screening and baseline phase following assessments will be 
carried to evaluate the subject eligibility: ....................................... 37 
3.2.2 
Administration of treatment regimen: ............................................. 38 
3.2.3 
During treatment period .................................................................. 40 
3.2.4 
Follow-up Phase ............................................................................. 40 
3.3 
End of Study .................................................................................. 40 
3.4 
Rationale for Study Design ............................................................. 41 
3.4.1 
Rationale for Test Product Dosage .................................................. 41 
3.4.2 
Rationale for Patient Population ..................................................... 41 
3.5 
Outcome Measures ......................................................................... 42 
3.5.1 
Efficacy Outcome Measures ........................................................... 42 
3.5.2 
Safety Outcome Measures .............................................................. 42 
4. 
MATERIALS AND METHODS ........................................................................... 43 
4.1 
Patients ........................................................................................... 43 
4.1.1 
Inclusion Criteria ............................................................................ 43 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
4.1.2 
Exclusion Criteria ........................................................................... 43 
4.2 
Method of Treatment  Assignment .................................................. 44 
4.3 
Study Treatment ............................................................................. 45 
4.3.1 
Formulation, Packaging, and Handling ........................................... 45 
4.3.2 
Dosage, Administration, and Compliance ....................................... 46 
4.3.3 
Investigational Medicinal Product Accountability ........................... 53 
4.3.4 
Post-Trial Access to Trastuzumab................................................... 53 
4.4 
Concomitant Therapy ..................................................................... 54 
4.4.1 
Permitted Therapy .......................................................................... 54 
4.4.2 
Prohibited Therapy ......................................................................... 54 
4.5 
Study Assessments ......................................................................... 54 
4.5.1 
Description of Study Assessments .................................................. 54 
4.5.2 
Timing of Study Assessments ......................................................... 59 
4.6 
Patient, Study, and Site Discontinuation ......................................... 61 
4.6.1 
Patient Discontinuation................................................................... 61 
4.6.2 
Study and Site Discontinuation ....................................................... 63 
5. 
ASSESSMENT OF SAFETY ................................................................................ 63 
5.1 
Safety Plan ..................................................................................... 63 
5.1.1 
Management of Specific Adverse Events ........................................ 66 
5.2 
Safety Parameters and Definitions .................................................. 66 
5.2.1 
Adverse Events............................................................................... 67 
5.2.2 
Serious Adverse Events (Immediately Reportable to 
the Sponsor) ................................................................................... 67 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) ....................................... 68 
5.2.4 
Selected Adverse Events................................................................. 68 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ........................................................................... 69 
5.3.1 
Adverse Event Reporting Period ..................................................... 69 
5.3.2 
Eliciting Adverse Event Information .............................................. 69 
5.3.3 
Assessment of Severity of Adverse Events ..................................... 70 
5.3.4 
Assessment of Causality of Adverse Events .................................... 71 
5.3.5 
Procedures for Recording Adverse Events ...................................... 71 

 
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5.4 
Immediate Reporting Requirements from Investigator 
to Sponsor ...................................................................................... 77 
5.4.1 
Emergency Medical Contacts ......................................................... 77 
5.4.2 
Reporting Requirements for Serious Adverse Events 
and Non-Serious Adverse Events of Special Interest ...................... 78 
5.4.3 
Reporting Requirements for Pregnancies ........................................ 78 
5.5 
Follow-Up of Patients after Adverse Events ................................... 79 
5.6 
Post-Study Adverse Events ............................................................. 80 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and Ethics 
Committees .................................................................................... 81 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ........................... 81 
6.1 
Determination Of Sample Size ....................................................... 81 
6.2 
Summaries of Conduct of Study ..................................................... 82 
6.3 
Efficacy Analyses ........................................................................... 82 
6.4 
Safety Analyses .............................................................................. 83 
6.5 
Interim Analyses ............................................................................ 84 
7. 
DATA COLLECTION AND MANAGEMENT .................................................... 84 
7.1 
Data Quality Assurance .................................................................. 84 
7.2 
Electronic Case Report Forms ........................................................ 84 
7.3 
Source Data Documentation ........................................................... 85 
7.4 
Use of Computerized Systems ........................................................ 85 
7.5 
Retention of Records ...................................................................... 86 
8. 
ETHICAL CONSIDERATIONS ........................................................................... 86 
8.1 
Compliance with Laws and Regulations ......................................... 86 
8.2 
Informed Consent ........................................................................... 86 
8.3 
Institutional Review Board or Ethics Committee ............................ 87 
8.4 
Confidentiality ............................................................................... 88 
8.5 
Financial Disclosure ....................................................................... 88 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION............................................................................................. 89 
9.1 
Study Documentation ..................................................................... 89 
9.2 
Monitoring ..................................................................................... 89 

 
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9.3 
Site Inspections .............................................................................. 89 
9.4 
Administrative Structure ................................................................. 89 
9.5 
Publication of Data and Protection of Trade Secrets ....................... 89 
9.6 
Protocol Amendments .................................................................... 90 
10. REFERENCES ...................................................................................................... 90 
 
 
LIST OF TABLES 
 
Table - 1 Guidelines for Managing Specific Adverse Events .......................................... 66 
 
Table 2 -  Adverse Event Severity Grading Scale ........................................................... 70 
 
 
LIST OF APPENDICES 
 
APPENDIX 1 - SCHEDULE OF ASSESSMENTS (AC-TH PROTOCOL)………………...…………….19 
APPENDIX 2 - SCHEDULE OF ASSESSMENTS (TCH PROTOCOL)…….……...…………………….22 
APPENDIX 3 - ECOG PERFORMANCE STATUS…………………………….……...……………….…95 
APPENDIX 4 - HER2 TESTING AND ALGORITHM IN BREAST CANCER……………..……….….96 
APPENDIX 5 - SALIENT FEATURES FROM BREAST CANCER ASSESSMENT ASCO          
ADJUVANT FOLLOW UP GUIDELINES 2006……………………………….…..….97 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
PROTOCOL ACCEPTANCE FORM 
 
STUDY TITLE             :  AN 
INDIAN 
MULTICENTRIC 
OPEN 
LABEL 
PROSPECTIVE PHASE IV STUDY TO EVALUATE 
SAFETY AND EFFICACY OF TRASTUZUMAB IN 
HER2 POSITIVE, NODE POSITIVE OR HIGH RISK 
NODE NEGATIVE BREAST CANCER AS PART OF A 
TREATMENT 
REGIMEN 
CONSISTING 
OF 
DOXORUBICIN, 
CYCLOPHOSPHAMIDE, 
WITH 
EITHER DOCETAXEL OR PACLITAXEL(AC→TH) 
OR DOCETAXEL AND CARBOPLATIN (TCH) 
 
PROTOCOL 
NUMBER                      :   ML28714 
 
VERSION NUMBER  :    1.0 
 
EUDRACT NUMBER:    NA 
 
IND NUMBER             :    NA 
 
TEST PRODUCT        :   Trastuzumab (Ro 45-2317)  
  Made for F. Hoffmann-La Roche Ltd 
 
MEDICALMONITOR:    Dr.
 
SPONSOR                     : Roche Products (India) Pvt. Ltd. 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
____________________________________ 
Principal Investigator’s Name (Print) 
 
____________________________________                      ________________ 
Principal Investigator’s Signature   
 
 
 
 
 
     Date 
 
Please return a copy of the form as instructed by your local study monitor.  
 
Please retain the original for your study files. 
 
 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
PROTOCOL SYNOPSIS 
TITLE: 
AN 
INDIAN 
MULTICENTRIC 
OPEN 
LABEL 
PROSPECTIVE PHASE IV STUDY TO EVALUATE 
SAFETY AND EFFICACY OF TRASTUZUMAB IN HER2 
POSITIVE, NODE POSITIVE OR HIGH RISK NODE 
NEGATIVE BREAST CANCER AS PART OF A 
TREATMENT 
REGIMEN 
CONSISTING 
OF 
DOXORUBICIN, 
CYCLOPHOSPHAMIDE, 
WITH 
EITHER DOCETAXEL OR PACLITAXEL (AC→TH) OR 
DOCETAXEL AND CARBOPLATIN (TCH) 
PROTOCOL 
NUMBER: 
ML28714 
VERSION NUMBER: 1.0 
EUDRACT 
NUMBER: 
NA 
IND NUMBER: 
NA 
TEST PRODUCT: 
Trastuzumab  
PHASE: 
IV Post marketing study 
INDICATION: 
HER2 positive early breast cancer  
SPONSOR: 
Roche Products India Pvt. Ltd. 
The View, 2nd floor, 165, Dr Annie Besant Road, Worli, 
Mumbai-400018, India 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
Objectives: 
 
Primary Objectives:  
 
The primary objective for this study is as follows: 
 
• To evaluate the safety of Trastuzumab for the treatment of HER2-positive node 
positive or high risk node negative breast cancer patients with regimen consisting of 
doxorubicin and cyclophosphamide followed by either paclitaxel or docetaxel 
(AC→TH) or a regimen consisting of docetaxel and carboplatin (TCH) in Indian 
population. 
 
Secondary Objectives: 
 
The secondary objectives for this study are as follows: 
 
• To determine the disease free survival (DFS)  
• To determine the overall survival (OS) 
 
Study Design: 
 
Description of Study 
 
This is a prospective, phase IV, multi-center, single arm, open-label, interventional 
study in patients with HER2-positive node positive or high risk node negative breast 
cancer. A total of approximately 109 patients will be enrolled at approximately 10 sites 
across India. Patients eligible as per the inclusion and exclusion criteria will be treated 
with either AC→TH or TCH treatment regimens. 
 
The choice of the Trastuzumab treatment regimen (either AC→TH or TCH) will be 
based on investigators’ discretion referring the local prescribing document of 
Trastuzumab. 
 
AC→TH regimen:  
 
• Every 3 weeks for 4 cycles, patients in the AC→TH regimen will be receiving 60 
mg/m2 doxorubicin as a  5 to15 minute I.V. bolus injection followed by 600 
mg/m2 cyclophosphamide as a 5 to 60 minute I.V. bolus injection. 
• On Day 1 of Cycle 5, 4-mg/kg Trastuzumab loading dose will be administered as 
a 90 minute I.V. infusion as a weekly regimen OR 8-mg/kg Trastuzumab loading 
dose will be administered as a 90-minute I.V. infusion as a 3 weekly regimen at 
Investigator’s discretion.  
• If weekly regimen of Trastuzumab is selected, on Day 8 of Cycle 5, 2 mg/kg 
Trastuzumab will be administered as a 30-minute I.V. infusion and 2mg/ kg 
every week as a weekly regimen will be given OR beginning on Day 1 of Cycle 
6, Trastuzumab 6 mg/kg will be administered as a 30-minute I.V. infusion every 
3 weeks as a 3 weekly regimen for four cycles.  

 
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• Docetaxel 100 mg/m2 or Paclitaxel 175 mg/m2 (at investigator’s discretion) will 
be administered as a 1 hour I.V. infusion every 3 weeks for four cycles, 
beginning on Day 1 of Cycle 5 and continued for up to Cycle 8. 
• Three weeks after the last treatment with docetaxel/paclitaxel (i.e., on Day 1 of 
Cycle 9), 6 mg/kg Trastuzumab will be administered as a 30-minute I.V. infusion 
every 3 weeks. Trastuzumab treatment will be continued up to cycle 22 
(completing a total 52 week trastuzumab therapy). 
 
TCH regimen: 
 
• Trastuzumab will be given intravenously at a dose of 4 mg/kg loading dose  
administered as a 90 minute I.V. infusion followed by 2 mg/kg administered as a 
30 minute I.V. infusion weekly as a weekly regimen or 8-mg/kg Trastuzumab 
loading dose administered as a 90 minute I.V. infusion followed by 6 mg/kg 
administered as a 30 minute I.V. infusion 3 weekly as a 3 weekly regimen during 
chemotherapy from cycle 1 to 6 at Investigator’s discretion.  
 
• Every 3 weeks for six cycles, patients in the TCH regimen will be receiving 75 
mg/m2 docetaxel as a 60-minute I.V. bolus injection followed by AUC 6 x (GFR 
+ 25) carboplatin as a 30 to 60 minute I.V. bolus injection. 
 
• After completion of chemotherapy, Trastuzumab will be administered at a dose 
of 6 mg/kg every 3 weeks up to cycle 18 (completing total 52 week trastuzumab 
therapy) 
 
The patient will be followed up for duration of 12 months from the last dose  of 
Trastuzumab. All adverse events occurring during treatment and this follow up period 
will be captured. 
 
Number of Patients 
 
A total of approximately 109 patients will be enrolled at approximately 10 sites across 
India. 
 
Target Population 
 
Patients must meet the following criteria for study entry: 
 
Inclusion criteria: 
 
• Able and willing to give written informed consent and comply with the 
requirements of the study protocol 
• Adult female patients, ≥18 years of age 
• Histologically confirmed early invasive HER2 positive, node positive or high risk 
node negative breast cancer with no evidence of residual, locally recurrent or 
metastatic disease and defined as clinical stage I to IIIA that is eligible for adjuvant 
treatment with Trastuzumab 

 
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• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 
• HER2 over-expression/amplification defined as either IHC3+, or IHC2+ and FISH-
positive as determined in a central laboratory. 
• At time of starting Trastuzumab therapy, Left ventricular ejection fraction (LVEF) 
measured by echocardiography.  
• Screening left ventricular ejection fraction (LVEF) ≥ 55% 
• Adequate bone marrow, renal, and hepatic function  
• Agreement to use an adequate, non-hormonal means of contraception by women of 
childbearing potential. 
 
Exclusion Criteria: 
 
Patients who meet any of the following criteria will be excluded from study entry: 
 
• Any contraindication to Trastuzumab 
• Previous adjuvant breast cancer treatment with an approved or investigational 
anti-HER2 agent 
• History of other malignancy, except for curatively treated carcinoma in situ of the 
cervix or basal cell carcinoma and patients with other curatively treated 
malignancies who have been disease-free for at least 5 years 
• Past history of ductal carcinoma in situ and/or lobular carcinoma that has been 
treated with any systemic therapy or with radiation therapy to the ipsilateral breast 
where the invasive cancer subsequently develops 
• Locally advanced (stage IIIB and IIIC) and Metastatic disease (stage IV) 
• Clinically relevant cardiovascular disorder or disease 
• Uncontrolled hypertension, or history of hypertensive crisis or hypertensive 
encephalopathy 
• History of severe allergic or immunological reactions, e.g. difficult to control 
asthma 
• Pregnant or lactating women 
 
Length of Study 
 
The study is estimated to last approximately 4 years, based on an expected 18-month 
recruitment, 12 months of study treatment and 12 months of follow-up after the 
treatment. 
 
End of Study 
 
End of study is defined as the last patient last visit in the follow-up period. The study 
will end when all patients have been followed for at least 12 months after their last 
study treatment, or if withdrawal from the study, lost to follow up or death. The final 
analysis of OS and DFS will be conducted and updated safety parameters will be 
summarized at this stage. 
 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
Efficacy Outcome Measures 
 
The efficacy outcome measures for this study are as follows: 
 
• Disease free survival rate (DFS) and Overall Survival rate (OS). 
 
As per institutional practice or American Society of Clinical Oncology (ASCO) 
adjuvant follow-up guidelines 2006, Breast cancer assessments for DFS and OS are to 
be reported for every 6 months. 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
 
• All Adverse Event (AE) and Serious Adverse Event (SAE) as well as laboratory 
abnormalities will be recorded and graded according to the NCI-CTCAE version 
4.0.  
 
• Cardiac function will be evaluated by measuring LVEF by echocardiography. 
Symptomatic left ventricular dysfunction (congestive heart failure [CHF]) will be 
graded according to the New York Heart Association functional classification.  
 
• AEs and SAEs related to Trastuzumab will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 15.1 or greater. 
 
• Patients will undergo a Safety Follow-up, 4 weeks after their last dose of study 
treatment. 
 
• Cardiac function will be evaluated by measuring LVEF by echocardiography. 
Symptomatic left ventricular dysfunction (congestive heart failure [CHF]) will be 
graded according to the New York Heart Association functional classification.  
 
• AEs and SAEs also will be summarized using number and percentage by System 
Organ Class and Preferred Term. Summaries will be presented for all adverse 
events and adverse events related to study drug. 
 
• Adverse events will also be summarized by toxicity grade, outcome, seriousness 
and action taken to the study medication. 
 
 
 
 
 
 
 
 
 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
 
Investigational Medicinal Products 
 
Not Applicable as the test product is licensed for use in the study disease and will be 
used in the same form and dose as approved. 
 
Test Product 
 
Trastuzumab- Trastuzumab is a humanized IgG1 kappa monoclonal antibody that 
selectively binds with high affinity to the extracellular domain of the human epidermal 
growth factor receptor 2 protein (HER2).  
 
Test drug administration: Trastuzumab will be administered as weekly or 3 weekly 
regimens at the investigator’s discretion. 
 
Weekly regimen: 
 
Initial dose of 4 mg/kg as an intravenous infusion over 90 minutes followed by 
subsequent dose of 2 mg/kg as an intravenous infusion over 30 minutes every week. 
 
Three weekly regimen:  
 
Initial dose of 8 mg/kg as an intravenous infusion over 90 minutes followed by 
subsequent dose of 6 mg/kg as an intravenous infusion over 30 minutes every three 
weeks.  
 
Non-Investigational Medicinal Products 
 
Anthracycline based therapy (AC→TH protocol)  
 
Doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks for 4 
cycles, followed by docetaxel (100 mg/m2 every 3 weeks for 4 cycles) or paclitaxel 
(175 mg/m2 every 3 weeks for 4 cycles). Trastuzumab is started concurrently with 
docetaxel or paclitaxel and continued to complete 52 weeks therapy. Dose and 
frequency of administration of taxanes is at investigator’s discretion. 
 
Non-anthracycline based therapy (TCH protocol)  
 
Docetaxel (75 mg/m2) and carboplatin (AUC, 6 mg/ml/min x (GFR + 25)) every 3 week 
for 6 cycles will be given along with adjuvant therapy of Trastuzumab to complete 52 
weeks therapy. 
 
All the chemotherapeutic agents will administered as per the local prescribing 
information. 
 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
 
Comparator 
 
There is no comparator as it is a single arm interventional trial. 
 
Statistical Methods 
 
Descriptive statistics will be calculated in the analysis for all safety, efficacy and 
laboratory parameters at defined courses, specified in the study schedule assessment. 
 
Safety Analysis 
 
• Safety measurements include adverse events, laboratory tests (hematology and 
biochemistry), vital signs, electrocardiograms, physical examinations, and 
toxicity evaluations.  
 
• Toxicities will be evaluated at each course of therapy using the NCI-CTCAE 
version 4.0 or a non-CTC grading scale for toxicities that are not covered by the 
NCI CTC. 
 
• Adverse Event (AE) and Serious Adverse Event (SAE) related to Trastuzumab 
will be summarized by using number and percentage (Incidence of AEs and 
SAEs). AEs and SAEs related to Trastuzumab will be coded using MedDRA, 
version 15.1 or greater. 
 
• AEs and SAEs also will be summarized using number and percentage by System 
Organ Class and Preferred Term. Summaries will be presented for all adverse 
events and adverse events related to study drug. Adverse events will also be 
summarized by toxicity grade, outcome, seriousness and action taken to the study 
medication. 
 
• All the Laboratory evaluations (hematology & biochemistry) will be considered 
at baseline and completion/early termination visits. Change from Baseline will be 
calculated for all the available hematology and biochemistry parameters as 
specified in the CRF pages.  
 
• ECOG performance status will be collected at baseline and every 4 Cycles during 
treatment period. Counts and percentages will be reported in the results. 
 
• Patient data will be analyzed for evidence of cumulative toxicity with repeated 
courses of therapy. Summary of ECG status will be evaluated at all visits. Counts 
and percentages will be reported in the results.  
 
• HER-2 testing will be collected at Baseline/Screening.  
 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
• LVEF will be collected for every 3 months or and percentage change from 
baseline will be reported for every 3 months. 
 
Efficacy analysis 
 
• Efficacy measurements include Disease free survival and Overall survival.  
 
• DFS is defined as time from the date of first study treatment to the date of local, 
regional or distant recurrence, contra-lateral breast cancer or death due to any 
cause.  
 
• OS is defined as time from the date of first study treatment until date of death, 
regardless of the cause of death. 
 
• These variables will be summarized by the Kaplan Meier method, and KM plots 
will be provided. 
 
Determination of Sample Size   
 
A total of approximately 109 subjects will be required to conduct a phase IV study to 
evaluate safety and efficacy of Trastuzumab in HER2 positive node positive or high risk 
node negative breast cancer by assuming level of significance 5%, incidence of adverse 
event 65.9%, precision 10% and dropout rate 20%. 
 
Justification for Sample size 
 
Incidence of adverse event in AC→TH group with Grade 3 or 4 hematologic events 
such as neutropenia, leucopenia, febrile neutropenia, neutropenic infection, anemia, 
thrombocytopenia, leukemia were 71.5%, 60.3 %, 10.9%, 11.9%, 3.1%, 2.1% and 0.1% 
respectively. In TCH group incidence of adverse event with Grade 3 or 4 hematologic 
events such as neutropenia, leucopenia, febrile neutropenia, neutropenic infection, 
anemia, thrombocytopenia, leukemia were 65.9%, 48.2 %, 9.6 %, 11.2%, 5.8%, 6.1% 
and 0.1% respectively.1  
 
While considering the 71.5%, the highest incidence of adverse event in AC→TH group, 
sample size of 99 patients will be required. Similarly, by considering the highest 
incidence of adverse event 65.9% in TCH group, sample size of 109 patients will be 
required. Also considered the incidence of 68.7% (i.e. mean of 71.5% and 65.9%), 104 
patients will be required. The above three calculations, assumed a 5% level of 
significance, 10% precision and 20% dropout rate. Considering all the above calculation, 
it is suggested that approximately 109 patients will be required for the proposed study. 
 
 
 
 
 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
Interim Analyses  
No Interim Analysis Planned for this study. 
 
Procedures (Summary) 
 
During screening and baseline phase following assessments will be carried to 
evaluate the subject eligibility: 
 
Informed consent, allocation of subject number, demographics, physical examination, 
vital signs, inclusion and exclusion criteria, relevant medical history, previous and 
concomitant medication details, confirmation of early breast cancer disease by histology, 
radiography (mammogram), (tumor size < 5 cm and < 4 positive lymph nodes), CT/MRI, 
Eastern Cooperative Oncology Group (ECOG) performance status, electrocardiogram 
(ECG), measurement of LVEF by echocardiography, haematology and biochemistry 
assessment.  
 
HER2-positive status on fixed tissue blocks from the primary tumor assessed by IHC 
(immuno histochemistry) and/or FISH (fluorescence insitu hybridisation) according to 
institutional criteria.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
 
Administration of treatment regimen: 
 
The choice of the Trastuzumab treatment regimen (either AC→TH or TCH) will be 
based on investigators’ discretion. 
 
Order of administration in AC→TH protocol : Post AC therapy, Trastuzumab first 
followed by docetaxel/paclitaxel. 
 
Drug 
Dose 
Administration Guideline 
Cycles* 1-4  
Doxorubicin 
60 mg/m2 
Administered as I.V. bolus 
over 5 to15 min. 
Cyclophosphamide 
 
600 mg/m2  
 
Administered I.V. over 5 to 
60 min. (use non-PVC 
equipment). 
Cycles 5-8   
Trastuzumab  
4 mg/kg (Loading dose) 
followed by 2 mg/kg 
(Maintenance dose) 
every week 
or 8 mg/kg (Loading 
dose), followed by 6 
mg/kg (Maintenance 
dose) every 3 weeks 
• Loading dose: I.V. in 250 mL 
NS over 90 min. Observe for 
90 minutes post infusion 
• Maintenance dose: I.V. in 
250 mL NS over 30 min on 
all the doses, observe for 30 
minutes post infusion. 
Taxane 
 
Docetaxel (100 mg/m2)  
or  
Paclitaxel (175 mg/m2) 
Administered I.V. in 250 mL 
NS over 1 hour (use non-
PVC equipment). 
Cycles 9 to 22 
Trastuzumab  
6 mg/kg (Maintenance 
dose) every 3 week 
 
I.V. in 250 mL NS over 30 
min on the all doses, observe 
for 30 minutes post infusion.  
*Cycle: 21 days 
 
 
 
 
 
 
 
 
 
 
 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
 
 
Order of administration in TCH protocol: Trastuzumab first, docetaxel second, 
carboplatin third. 
 
Drug  
Dose  
 Administration Guideline  
Cycle* 1-6 
Trastuzumab 
4 mg/kg (Loading dose) 
followed by 2 mg/kg 
(Maintenance dose) every 
week 
or 
8 mg/kg (Loading dose), 
followed by 6 mg/kg 
(Maintenance dose) every 
3 week 
 
• Loading dose: I.V. in 250 mL 
NS over 90 min. Observe for 1 
hour post-infusion  
 
• Maintenance dose: I.V. in 250 
mL NS over 30 min on the all 
doses, observe for 30 minutes 
post infusion. 
Docetaxel  
 
75 mg/m2  
 
Administered I.V. in 250 mL 
NS over 1 hour (use non-PVC 
equipment). 
Carboplatin  
 
Dose = AUC 6 x (GFR + 
25)  
Administered I.V. in 500 mL 
D5W over 30 to 60 min 
 Cycle 7 to 18 
Trastuzumab  
6 mg/kg (Maintenance 
dose) every 3 weeks 
• I.V. in 250 mL NS over 30 min 
on the all doses, observe for 30 
minutes post infusion.  
 
*Cycle: 21 days 
 
As per institutional practice or American Society of Clinical Oncology (ASCO) 
adjuvant follow-up guidelines 2006, Breast cancer assessments for DFS and OS 
are to be reported for every 6 months. 
 
American Society of Clinical Oncology (ASCO) 2006 Guideline for Breast Cancer 
Follow-up in the adjuvant setting (Khatcheressian et al. 2006). In brief: 
 
• History/physical examination - every 3 to 6 months for the first 3 years after primary 
therapy; every 6 to 12 months for years 4 and 5; then annually. 
• Mammography - first post-treatment mammogram 1 year after the initial 
mammogram that leads to diagnosis, but no earlier than 6 months after definitive 
radiation therapy. Subsequent mammograms should be obtained as indicated for 
surveillance of abnormalities. 
 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
• 
Pelvic examination - regular gynecologic follow-up is recommended for all women. 
Patients who receive tamoxifen should be advised to report any vaginal bleeding to 
their physicians. 
 
The following are not recommended for routine surveillance: Routine blood tests (full 
blood counts and liver function tests), imaging studies (chest x-ray, bone scans, liver 
ultrasound, CT scans, FDG-PET scans, and breast MRI) and tumor marker assessments 
(CA 15-3, CA 27.29, and CEA). 
 
However, bone scan, liver imaging, and brain CT scan will be performed if clinically 
indicated. 
 
During treatment period 
 
• Safety parameters will be assessed for every cycle.  
 
• Vital signs, physical examination and treatment compliance will be performed 
for every cycle and subject safety will be evaluated. 
 
• LVEF and ECG will be assessed for every 3 months (4 cycles) to evaluate 
cardiac safety of the patients. 
 
• ECOG will be assessed for every 3 months (4 cycles) to evaluate performance 
status of the patients. 
 
• Hematology and biochemistry assessments will also be performed during the 
study if clinically indicated. 
 
• Routine breast cancer follow up is done at cycle 9 and 17. History/physical 
examination, mammography and pelvic examination will be carried out. 
 
Follow-up Phase: 
 
Thereafter during follow up period of one year, cardiac assessments at 6 and 12 months 
following treatment cessation will be done. Survival follow-up can be performed by 
regular telephonic calls and/or clinic visits every 6 months. 
Please see Appendix 1 and 2 for schedule of assessments. 
 

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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
Appendix 1- Schedule of Assessments (AC→TH protocol) 
 
Screeni
ng and 
baseline 
Treatment Period (Cycle/Week) 
Unpla
nned 
Visit a 
Comple
tion/Ear
ly 
Termin
ation 
Visit b 
Follow
-Up c 
Week 
–2 to –1  1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 53 56 59 62 65 
 
 
 
Cycle 
 
1 2 3 4 
5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion & Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General medical 
history and baseline 
conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs d 
X 
x x x x 
x x x x x x 
x 
x x x x 
x 
x x x 
x 
x x 
x 
x 
x 
Weight 
X 
x x x x 
x x x x x x 
x 
x x x x 
x 
x x x 
x 
x x 
x 
x 
x 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
e 
X 
x x x x 
x x x x x x 
x 
x x x x 
x 
x x x 
x 
x x 
x 
x 
x 
Hematology f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Histology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiography 
(mammogram) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
CT/MRI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Biochemistry g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
LVEF(measured by 
Echocardiography) 
X 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
x 
x 
12 Lead ECG 
X 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
x 
x 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
HER2 testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
X 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
x 
x 
Chemotherapy h 
 
x x x x 
x x x x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trastuzumab 
administration i 
 
 
 
 
 
x x x x x x 
x 
x x x x 
x 
x x x 
x 
x x 
 
 
 
Routine Breast 
Cancer follow up j 
X 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
Treatment compliance 
 
x x x x 
x x x x x x 
x 
x x x x 
x 
x x x 
x 
x x 
x 
x 
 
Concomitant 
medications 
X 
x x x x 
x x x x x x 
x 
x x x x 
x 
x x x 
x 
x x 
x 
x 
 
Adverse events 
X 
x x x x 
x x x x x x 
x 
x x x x 
x 
x x x 
x 
x x 
x 
x 
x 
Survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 

 
Trastuzumab—Roche Products (India) Pvt. Ltd                                                 Page 21 of 98 
Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
eCRF = electronic Case Report Form. 
Notes: All assessments should be performed within 3 days of the scheduled visit, unless otherwise specified. On treatment days, all 
assessments should be performed prior to dosing, unless otherwise specified. 
a Visit not specified by the protocol. 
b Patients who complete the study or discontinue from the study early will be asked to return to the clinic 4 weeks after the last dose of study 
drug for a follow-up visit. 
c Follow-up information will be collected via telephone calls and/or clinic visits every 6 months until death, loss to follow-up, or study 
termination by the Sponsor. 
d Respiratory rate, pulse rate, temperature, systolic and diastolic blood pressure, before and after trastuzumab infusion. 
e Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF. New or worsening abnormalities 
should be recorded on the Adverse Event eCRF. 
f Includes hemoglobin, hematocrit, platelet count, RBC count, WBC count, absolute differential count (neutrophils, eosinophils, lymphocytes, 
monocytes, basophils, other cells). Hematology assessment will also be performed during the study, if clinically indicated. 
g Includes sodium, potassium, chloride, bicarbonate, fasting glucose, BUN or urea, creatinine, calcium, total and direct bilirubin, total protein, 
albumin, ALT, AST, alkaline phosphatase, phosphorus, magnesium, LDH, creatine phosphokinase, uric acid. Biochemistry assessment will 
also be performed during the study, if clinically indicated. 
h Doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks for 4 cycles (Cycles 1 to 4), followed by docetaxel (100 mg/m2) 
or paclitaxel (175 mg/m2 every 3 weeks for 4 cycles (Cycles 5 to 8). 
i The selection of the dosage regimen from cycle 5 to 8 (weekly or 3 weekly) at investigators’ discretion. After completion of chemotherapy, 
Trastuzumab will be administered every 3 weeks from cycle 9 to cycle 22 (so as  to complete total of 52 week Trastuzumab therapy). 
j History/physical examination, mammography and pelvic examination will be carried out during the routine breast cancer follow-up. 
 
 
 

 
Trastuzumab—Roche Products (India) Pvt. Ltd                                                 Page 22 of 98 
Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
Appendix 2 - Schedule of Assessments (TCH protocol) 
 
Screenin
g and 
baseline 
Treatment Period (Cycle/Week) 
Unplanne
d Visit a 
Completio
n/Early 
Terminati
on Visit b 
Follow-Up 
c 
Week 
–2 to –1  1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 53 
 
 
 
Cycle 
 
1 2 3 4 
5 
6 7 8 9 10 11 12 13 14 15 16 17 18 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion & 
Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General medical 
history and baseline 
conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs d 
X 
x x x x 
x 
x x x x x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Weight 
X 
x x x x 
x 
x x x x x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
e 
X 
x x x x 
x 
x x x x x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Hematology f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Histology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiography 
(mamogram) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
CT/MRI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Biochemistry g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
LVEF (measured by 
Echocardiography) 
X 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
x 
x 
12 Lead ECG 
X 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
x 
x 
HER2 testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
X 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
x 
x 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
Chemotherapy h 
 
x x x x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trastuzumab 
administration i 
 
x x x x 
x 
x x x x x x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Routine Breast 
Cancer follow up j 
X 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
x 
 
Treatment 
compliance 
 
x x x x 
x 
x x x x x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Concomitant 
medications 
X 
x x x x 
x 
x x x x x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Adverse events 
X 
x x x x 
x 
x x x x x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 

 
Trastuzumab—Roche Products (India) Pvt. Ltd                                                 Page 24 of 98 
Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
eCRF = electronic Case Report Form. 
Notes:  All assessments should be performed within 3 days of the scheduled visit, unless otherwise specified.  On treatment days, all 
assessments should be performed prior to dosing, unless otherwise specified. 
a Visit not specified by the protocol. 
b Patients who complete the study or discontinue from the study early will be asked to return to the clinic 4 weeks after the last dose of 
study drug for a follow-up visit. 
c Follow-up information will be collected via telephone calls and/or clinic visits every 6 months until death, loss to follow-up, or study 
termination by the Sponsor. 
d Respiratory rate, pulse rate, temperature, systolic and diastolic blood pressure, before and after trastuzumab infusion. 
e Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  New or worsening 
abnormalities should be recorded on the Adverse Event eCRF. 
f Includes hemoglobin, hematocrit, platelet count, RBC count, WBC count, absolute differential count (neutrophils, eosinophils, 
lymphocytes, monocytes, basophils, other cells). Hematology assessment will also be performed during the study, if clinically indicated. 
g Includes sodium, potassium, chloride, bicarbonate, fasting glucose, BUN or urea, creatinine, calcium, total and direct bilirubin, 
total protein, albumin, ALT, AST, alkaline phosphatase, phosphorus, magnesium, LDH, creatine phosphokinase, uric acid. Biochemistry 
assessment will also be performed during the study, if clinically indicated. 
h Docetaxel (75 mg/m2) and carboplatin (AUC, 6 mg/ml/min x (GFR + 25)) every 3 week for 6 cycles. 
i The selection of the dosage regimen from cycle 1 to 6 (weekly or 3 weekly) at investigators’ discretion. After completion of 
chemotherapy, Trastuzumab will be administered every 3 weeks from cycle 7 to cycle 18 (so as to complete 52 week Trastuzumab 
therapy). 
j History/physical examination, mammography and pelvic examination will be carried out during the routine breast cancer follow-up. 
 
 

Trastuzumab—Roche Products (India) Pvt. Ltd                                   Page 25 of 98 
Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
 
Definition 
AC→TH 
 
Regimen consisting of Doxorubicin and 
Cyclophosphamide followed by either Paclitaxel or 
Docetaxel 
ADCC 
 
Antibody-Dependent Cell-Mediated Cytotoxicity 
AE 
 
Adverse Event 
AGC 
 
Advanced Gastric Cancer 
ALT 
 
Alanine aminotransferase 
ASCO 
 
American Society of Clinical Oncology 
AST 
 
Aspartate aminotransferase 
BWFI 
 
Bacteriostatic Water For Injection 
CHF 
 
Congestive Heart Failure 
CHO 
 
Chinese Hamster Ovary 
CISH 
 
Chromogenic in situ Hybridization 
CRF 
 
Case Report Form 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
CMF 
 
Cyclophosphamide plus Methotrexate plus Fluorouracil 
DCIS 
 
Ductal Carcinoma in situ 
DFS 
 
Disease Free Survival 
DR 
 
Duration of Response 
EC 
 
Ethics Committee 
ECG 
 
Electrocardiogram 
ECOG 
 
Eastern Cooperative Oncology Group 
eCRF 
 
electronic Case Report Form 
EGFR 
 
Epidermal Growth Factor Receptor 
EFS 
 
Event-Free Survival 
FDA 
 
Food and Drug Administration 
FISH 
 
Fluorescence in situ Hybridization 
HER2 
 
Human Epidermal growth factor Receptor 2 

 
Trastuzumab—Roche Products (India) Pvt. Ltd                                                 Page 26 of 98 
Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
HERA 
 
Herceptin Adjuvant Trial 
HIPAA 
 
Health Insurance Portability and Accountability Act 
HR 
 
Hazard Ratio 
ICH 
 
International Conference on Harmonisation 
ICMR 
 
Indian Council of Medical Research 
IHC 
 
Immuno Histo Chemistry 
IMP 
 
Investigational Medicinal Product 
IND 
 
Investigational New Drug (application) 
IRB 
 
Institutional Review Board 
IxRS 
 
Interactive Voice and Web Response System 
LPLV 
 
Last patient, Last visit 
LVEF 
 
Left Ventricular Ejection Fraction. 
MBC 
 
Metastatic Breast Cancer 
mEDC 
 
MakroCare Electronic Data Capture 
NCI 
 
National Cancer Institute 
NSCLC 
 
Non-Small Cell Lung Cancer 
OS 
 
Overall Survival 
ORR 
 
Objective Tumor Response Rate 
PBCR 
 
Population-Based Cancer Registries 
pCR 
 
pathological Complete Response 
PD 
 
Pharmacodynamic 
PK 
 
Pharmacokinetic 
SAE 
 
Serious Adverse Event 
SWFI 
 
Sterile Water For Injection 
TCH 
 
Regimen consisting of Docetaxel and Carboplatin 
TTP 
 
Time to disease Progression 
UICC 
 
International Union Against Cancer 
ULN 
 
Upper Limit of Normal 
VEGF 
 
Vascular Endothelial Growth Factor 

 
Trastuzumab—Roche Products (India) Pvt. Ltd                                                 Page 27 of 98 
Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
 
1. 
BACKGROUND 
1.1 BACKGROUND ON BREAST CANCER  
 
Breast cancer (BC) is the most common cancer in women (23% of all cancers), 
with a global prevalence of more than 1 million patients and an annual mortality 
rate of approximately 450,000 deaths (American Cancer Society). Breast cancer 
has a widely variable incidence between countries and regions. The developed 
countries with a small proportion of the world population account for almost 50% 
of breast cancers diagnosed worldwide.2 The lowest breast cancer incidence is 
reported from Far Eastern and South-East Asian countries.3,4 In the developing 
countries of Asia, the health care burden on account of breast cancer has been 
steadily mounting. It is expected that in the coming decades, these countries 
would account for majority of new breast cancer patients diagnosed globally. 
Over 100,000 new breast cancer patients are estimated to be diagnosed annually 
in India.5 As per the Indian Council of Medical Research (ICMR)- population-
based cancer registries (PBCR) data, breast cancer is the commonest cancer 
among women in urban registries of Delhi, Mumbai, Ahmedabad, Calcutta, and 
Trivandrum where it constitutes > 30% of all cancers in females. In the rural 
PBCR of Barshi, breast cancer is the second commonest cancer in women after 
cancer of the uterine cervix.6 In Europe and North America, most breast cancers 
are diagnosed when the cancer is still confined to the breast, with or without loco-
regional lymph node spread, and can be treated with curative intent. In Europe, 
around 79% are potentially operable (stage T1-3/N0/+M0), 7% are locally 
advanced (T4/Nx/M0), and 6% are metastatic (M1) at diagnosis.7,8  
 
According to a study conducted in four major cities (Mumbai, Trivandrum, 
Chennai and Lucknow) of India, the percentage incidence in various stages of 
Early Breast cancer was, stage I - 7.8%, 4.4%, 1% and 4%; stage II – 57.4%, 
42.3%, 23% and 33%; stage III – 28.9%, 40.5%, 52% and 47%).9 In another study 
done in a large cohort of patients managed over a long time period at a New Delhi 
hospital, it was noted that the percentage incidence of stage III-a (27%) 
predominated, followed by II-b (16%) and stage I (1.4%).10 The etiology of breast 
cancer is unclear, although it is likely that hormonal and genetic factors play a 
role.11 The incidence of breast cancer increases with age, doubling every year up 
until menopause.12 Risk factors include early age of first menarche, later age of 
first full term pregnancy, late menopause and a family history of breast cancer.13  
 
 
 
 
 
 
 
 
 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
 
1.1.1 Role of Human Epidermal Growth Factor Receptors (HER2) status 
The human epidermal growth factor receptor 2 (HER2, HER2/neu, c-erbB-2) 
gene, first discovered in 1984,14 is localized to chromosome 17q and encodes a 
transmembrane tyrosine kinase receptor protein that is a member of the epidermal 
growth factor receptor (EGRF), or HER, family.15 This HER family of four 
receptors mediates the growth, differentiation and survival of cells.16,17,18 The 
evidence that increased expression and activity of HER2 induces cell 
transformation and tumorigenesis is overwhelming. In BC, unlike a variety of 
other epithelial malignancies, HER2 gene amplification is uniformly associated 
with HER2 (p185neu) protein overexpression.  
 
HER2 gene amplification and/or protein overexpression has been associated with 
aggressive tumor behaviour, including increased cell proliferation, cell motility, 
tumor invasiveness, progressive regional and distant metastases, accelerated 
angiogenesis, and reduced apoptosis and poor prognosis.15,19,20,21,22,23 A review of 
107 studies involving 39,730 BC patients found that in the majority (88%) of the 
studies, either HER2 gene amplification or HER2 (p185neu) protein 
overexpression predicted BC outcome by either univariate or multivariate 
analysis.17 The frequency of HER2-positivity in these studies ranged from 9% to 
74% (mean 22.2%). However, in current practice, most investigators report that 
the true HER2-positive rate is in the range of 15%–20%.17,24 The major slide-
based 
HER2 testing 
approaches 
include 
immunohistochemistry 
(IHC), 
fluorescence in situ hybridization, and chromogenic in situ hybridization. 
Her2/neu positivity was present in 27.10 % of cases in a study done in south 
Indian population25 and 29% of HER2+ subtype in another study.26 Studies have 
shown that women whose tumors exhibit either amplification of the HER2 gene 
or overexpression of its encoded protein have a more aggressive form of BC that 
is associated with significantly shortened disease-free and overall survival (OS) 
compared with women whose tumors do not over express HER2.27  
 
1.1.1.1 Treatment Options For early Breast Cancer 
Breast cancer prognosis and treatment options are generally based on AJCC 
staging/ TNM classification. Surgery is the main modality of local treatment for 
early breast cancer (eBC) and (with or without radiotherapy) can control loco-
regional disease in the majority of patients. However, a significant percentage of 
patients relapse after loco-regional treatment and develop metastases. Systemic 
chemotherapy or endocrine therapy in hormone receptor-positive patients reduce 
the risk of relapse and are given either prior to surgery (neoadjuvant therapy) or 
following surgery (adjuvant therapy). In recent decades, the use of adjuvant 
systemic therapies in eBC has increased extensively and has most likely 
contributed to the substantial decline in BC mortality observed in the U.S. and in 
some European countries.28,29,30 
 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
In the last few years, there has been accelerated progress in the treatment of eBC, 
with the introduction of taxanes and aromatase inhibitors, and, most impressively, 
trastuzumab (a humanized anti-ERBB2 monoclonal antibody) to the adjuvant 
portfolio.29 Cytotoxic chemotherapy, endocrine therapy, radiotherapy, and 
molecular targeted therapies currently represent the backbone of modern systemic 
BC treatment. Several targeted drugs with different molecular pathways have 
received approval for metastatic breast cancer (mBC), but trastuzumab is the only 
such therapy that is currently approved for adjuvant treatment of eBC.31 The use 
of trastuzumab in the adjuvant setting is also supported by international treatment 
guidelines for women with HER2 positive BC.32,33 The introduction of 
trastuzumab last decade has particularly improved the outcome for eBC patients 
with HER2-positive disease. 
 
1.2 BACKGROUND ON TRASTUZUMAB  
1.2.1 Trastuzumab IV 
Trastuzumab is produced by a genetically engineered Chinese hamster ovary 
(CHO) cell line grown in large scale, which secretes Trastuzumab into the culture 
medium. 
The 
antibody 
is 
then 
purified 
extensively 
using 
standard 
chromatographic and filtration methods. 
 
Trastuzumab for intravenous (IV) administration is supplied commercially as a 
lyophilized preparation in either single-use (150 mg) or multi-dose (440 mg) vials. 
It is formulated in histidine/histidine-HCl, α,α-trehalose dihydrate, and 
polysorbate 20. Following reconstitution in either sterile water for injection 
(SWFI) or bacteriostatic water for injection (BWFI), it is further diluted in 250 
mL 0.9% sodium chloride solution for administration. 
 
The addition of trastuzumab to standard chemotherapy increases time to 
progressive disease or the length of progression-free survival (PFS), and improves 
survival when given with chemotherapy to women with HER2-positive BC.29,34 
Clinical benefits are greatest in patients with tumors strongly overexpressing 
HER2, graded 3+ by IHC, and/or with HER2 gene amplification (see 
Trastuzumab Summary of Product Characteristics, 2012). 
 
Trastuzumab is well tolerated both as a single agent and in combination with 
standard chemotherapy.34,35 The most significant adverse event (AE) observed in 
patients who received trastuzumab was cardiac dysfunction, reflected by 
asymptomatic decreases in LVEF and, less frequently, by clinically symptomatic 
congestive heart failure (CHF). Risk factors for cardiac failure in the setting of 
trastuzumab treatment include co administration with anthracycline-based 
chemotherapy, increasing age, declining LVEF during treatment to below the 
lower limit of normal, and the use of anti hypertensive medications.36  

 
Trastuzumab—Roche Products (India) Pvt. Ltd                                                 Page 30 of 98 
Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
The efficacy and safety of trastuzumab IV have been well characterized. 
Trastuzumab IV is administered to eBC patients for a total duration of one year. 
Adjuvant trastuzumab IV may be given as monotherapy, starting after completion 
of adjuvant chemotherapy, or in combination with the taxane component of 
adjuvant chemotherapy (followed by trastuzumab monotherapy). 
 
1.2.1.1 Clinical Pharmacokinetics of Trastuzumab 
In a study of Early Breast Cancer (HERA/BO16348), using a loading dose of 8 
mg/kg followed by a maintenance dose of 6 mg/kg q3W, a t1/2 of 16.2 days was 
observed (range 11.0-22.8 days).37 Steady-state concentrations were achieved by 
Week 37, with mean trough and peak concentrations of 63 µg/mL and 216 µg/mL, 
respectively. A population PK (PPK) analysis of data from the single-agent trials 
(H0407g, H0551g, and H0649g) showed that the mean t1/2 of Trastuzumab is 
28.5 days (95% confidence interval [CI] 25.5-32.8 days).38 These data are 
supported by a later PPK analysis in 194 patients using data from four Phase I and 
II trials (BO15935, WO16229, BO15899 and M77004) in which the typical 
population PK parameter values reported were clearance (CL) = 0.226 L/day and 
volume of distribution of the central compartment (Vc) = 3.17 L,39 which 
supported the 3-weekly dosing regimen. An update to this PPK analysis which 
added data from 71 patients in the intensive loading dose regimen (MO16892), 
confirmed the primary PK parameter values as CL = 0.241 L/day, Vc = 3.02 L 
and terminal half-life of about 3 weeks.40 
 
When Trastuzumab was administered in combination with: paclitaxel, docetaxel, 
paclitaxel plus doxorubicin, cisplatin and either capecitabine or 5-fluorouracil, 
Trastuzumab did not alter the plasma concentrations of the chemotherapeutic 
agents or the metabolites that were analyzed. In addition, Trastuzumab serum 
concentrations were not altered by the chemotherapeutic agents that were given in 
combination with it for the treatment of breast cancer patients. 
 
1.2.2 Efficacy of trastuzumab in Early Breast Cancer (Adjuvant setting) 
 
Six phase III multi-centre randomized controlled trials investigated the efficacy 
and safety of adjuvant trastuzumab IV in combination with or after standard 
adjuvant chemotherapy in the treatment of early breast cancer:  
• Herceptin Adjuvant (HERA, BO16348) trial.41,30,42  
• North Central Cancer Treatment Group trial (NCCTG) N9831 trial.29,43,44,45 
• National Surgical Adjuvant Breast and Bowel Project (NSABP) trial            
B-31.46,44,45 
• Breast Cancer International Research Group (BCIRG-006) study.1,47  
• Protocol Adjuvant dans le Cancer du Sein (PACS04) trial.48  
• Finland Herceptin (FinHer) trial.49  
Together, these trials accrued more than 15,000 women with node-positive or 
high-risk node-negative BC and used a variety of cytotoxic agents in various 
combinations, doses, and orders of administration. Four of these trials (HERA, 
N9831, B31 and BCIRG-006) are considered pivotal. 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
 
In the HERA study, trastuzumab treatment was started following completion of an 
approved neoadjuvant or adjuvant chemotherapeutic regimen (and radiotherapy as 
indicated) and continued for one or two years. In studies B31, N9831 and 
BCIRG-006, trastuzumab started after completion of four cycles of 
doxorubicin/cyclophosphamide and was administered for one year, either 
concurrently with four cycles of taxane chemotherapy (B31, N9831), or 
concurrently with six cycles of a non-anthracycline-containing taxane-based 
regimen (BCIRG-006), or after completion of chemotherapy.  
 
The Breast Cancer International Research Group 006 (BCIRG-006) conducted a 
randomized trial on 3222 women with HER2-positive, invasive, high-risk, node-
negative or node-positive adenocarcinoma (stage T1, T2, or T3) from 41 countries 
to receive a standard adjuvant anthracycline–taxane chemotherapy regimen, the 
same regimen plus trastuzumab, or a new non-anthracycline, trastuzumab-based 
regimen.   
 
All four pivotal randomized controlled trials (HERA, N9831, B31 and BCIRG-
006) demonstrated significantly improved DFS, and three (HERA, B31 and 
BCIRG-006) demonstrated significantly improved OS. The DFS benefits were 
observed regardless of age, nodal status, hormonal status, or tumor size in all 
trials.1,47,50 Importantly, the most recent follow-up data from the HERA trial29 and 
the combined analysis of the NCCTG N9831 and NASBP B-31 trials47 both 
demonstrate consistent DFS and OS advantages of adjuvant trastuzumab over a 
median follow-up of 8 years. Further, the significant benefits in DFS and OS were 
maintained over a median follow-up of approximately 5½ years in the BCIRG-
006 study,1 which is the longest follow-up reported to date. The long-term clinical 
benefits of one-year trastuzumab treatment clearly continue to outweigh the risks 
of adverse effects47 and the regimen is considered standard of care with support 
from all major treatment guidelines.32,33  
 
Of the four pivotal randomized trials, the N9831 study was the only one to 
directly compare the concurrent and sequential use of trastuzumab. This study 
identified a strong trend for a 25% reduction in the risk of an outcome event when 
trastuzumab is started concurrently as compared to sequentially after paclitaxel.45 
Therefore, based on a positive risk/benefit ratio, the authors recommended that 
trastuzumab be incorporated in a concurrent fashion when administered with 
paclitaxel,45 which also resulted in the approval of the concurrent use of 
trastuzumab and chemotherapy.  
 
For further details, refer to the current Herceptin (Ro 45-2317, Trastuzumab) IB. 
 
 
 
 
 

 
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1.2.3 Safety of Trastuzumab IV  
1.2.3.1 Cardiac Safety of Trastuzumab IV  
The most clinically relevant AE associated with trastuzumab IV is left ventricular 
cardiac dysfunction (e.g. CHF). In patients with HER2-positive eBC enrolled in 
pivotal clinical trials, trastuzumab treatment for 1 year (administered concurrently 
or sequentially with chemotherapy) appeared to be associated with a decrease in 
LVEF, an increase in the incidence of CHF (where specified, this was severe 
[New York Heart Association or NYHA] class III or IV or grade 3 or 4 or 
symptomatic CHF) and discontinuation of treatment as a result of cardiac Aes.51 
Cardiac toxicity described as NYHA class III/IV CHF occurred in 0%–0.9% of 
patients in the control arms and in 0%–3.8% of patients in the trastuzumab-
containing arms of the four pivotal trials (HERA, N9831, B31 and BCIRG-006). 
However, the cardiotoxicity observed with concurrent or sequential trastuzumab 
treatment appeared to be mostly reversible following trastuzumab discontinuation, 
and no significant increase in cardiac death was reported.51   
 
An overview of cardiac safety data from selected trials of trastuzumab in 
combination with a taxane after anthracyclines for HER2-overexpressing eBC 
shows rates of symptomatic or severe CHF of < 4% and asymptomatic declines in 
left ventricular ejection fractions of > 10 points in ≤ 30% of patients. However, 
inter-study comparisons of chemotherapy-induced cardiac dysfunction are 
difficult because of the use of different definitions of cardiac dysfunction and 
different parameters for assessing cardiac safety.52 These levels were considered 
below safety cut-off points set by the individual studies’ independent data 
monitoring committees.53  
 
The NeoALTTO trial recorded no major cardiac dysfunction, with only one 
patient having a left ventricular ejection fraction of less than 50% and a decrease 
of more than 10% from baseline in trastuzumab group.54  
 
The NSABP B-31 trial determined the 5-year cumulative cardiac event rate 
(NYHA class III or IV CHF or cardiac death) to be 3.8% in patients randomly 
assigned to trastuzumab versus 0.9% in patients who received chemotherapy 
alone.55,56 In the NCCTG N9831 trial, the incidence of CHF was 0% in the 
chemotherapy-alone arm, 2.2% in patients who received sequential chemotherapy 
and trastuzumab, and 3.3% in patients who received concurrent chemotherapy and 
trastuzumab. An independent adjudication of the cardiac events occurring in 
studies B-31 and N9831 determined that the incidence of symptomatic heart 
failure events was 2.0% in trastuzumab-treated patients compared with 0.45% in 
the chemotherapy-alone arm, and that and the majority (86%) of these patients 
recovered with appropriate treatment.56   
 
 
 
 

 
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The long-term incidence of cardiac AEs in patients with eBC who were treated 
with trastuzumab IV for 1 year after completion of neoadjuvant or adjuvant 
chemotherapy was also evaluated in the HERA trial. Of the 1,698 patients 
randomly assigned to observation and 1,703 randomly assigned to 1 year of 
trastuzumab treatment, 94% had been treated with anthracyclines. The incidence 
of discontinuation of trastuzumab because of cardiac disorders was low (5.1%). 
At a median follow-up of 3.6 years, the incidence of cardiac end points remained 
low, though it was higher in the trastuzumab group than in the observation group 
(severe CHF, 0.8% vs. 0.0%, respectively; confirmed significant LVEF decreases, 
3.6% vs. 0.6%, respectively). In the trastuzumab group, 59 of 73 patients with a 
cardiac end point reached acute recovery.57  
 
1.2.3.2 Post-marketing Safety Summary of Trastuzumab IV 
It is estimated that over one million patients have been treated with trastuzumab 
IV as of October 2011 (Roche, Data on file). 
 
The most common (occurring in ≥1 out of 10 treated patients) adverse reactions 
are infusion-associated symptoms such as fever and chills, usually following the 
first infusion of trastuzumab IV. These symptoms are usually mild to moderate in 
severity and occur infrequently with subsequent trastuzumab IV infusions in up to 
40% of patients. Other very common (≥1/10 patients) adverse reactions include 
febrile neutropenia, tremor, dizziness, headache, blood pressure changes (increase 
or decrease), irregular heartbeat, palpitation, cardiac flutter, decreased ejection 
fraction, dyspnea, wheezing, diarrhea, vomiting, nausea, lip swelling, abdominal 
pain, erythema, rash, swelling of the face, arthralgia, muscle tightness, myalgia, 
asthenia, chest pain, fatigue, influenza-like symptoms, infusion-related reaction, 
and pain.  
 
Some adverse reactions to trastuzumab IV infusion can be serious and include 
dyspnea, hypotension, elevated blood pressure, wheezing, bronchospasm, 
tachycardia, reduced oxygen saturation, and respiratory distress. In the post-
marketing setting, very rare (<1/10,000) occurrences of severe infusion reactions 
leading to a fatal outcome have been associated with the use of trastuzumab IV.  

 
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Severe pulmonary events leading to death have been reported with the use of 
trastuzumab IV in the post-marketing setting (4 out of 10,000 treated patients). 
Signs, symptoms, and clinical findings included interstitial lung disease including 
pulmonary 
infiltrates, 
acute respiratory 
distress 
syndrome, 
pneumonia, 
pneumonitis, pleural effusion, respiratory distress, acute pulmonary edema, and 
pulmonary insufficiency. These events may or may not occur as sequelae of 
infusion reactions. Patients with symptomatic intrinsic lung disease or with 
extensive tumor involvement of the lungs, resulting in dyspnea at rest, may be at 
greater risk of severe reactions. Other risk factors associated with interstitial lung 
disease include prior or concomitant therapy with other anti-neoplastic therapies 
such as taxanes, gemcitabine, vinorelbine and radiation therapy.  
 
In addition, severe hypersensitivity reactions have been infrequently reported in 
patients treated with trastuzumab IV (the exact incidence of these events is 
unknown). Signs and symptoms include anaphylaxis, urticaria, bronchospasm, 
angioedema, and/or hypotension. In some cases, the reactions have been fatal. 
Symptom onset generally occurred during an infusion, but onset after the 
completion of an infusion has also been reported. Reactions were most commonly 
reported in association with the initial infusion.  
 
The immunogenicity of trastuzumab IV has been investigated in clinical studies 
that included 903 MBC patients. Human anti–human antibodies to trastuzumab 
were detected in one patient, who had no allergic manifestations.  
 
More detailed information on the full safety profile of trastuzumab IV is found in 
the Herceptin (Ro 45-2317, Trastuzumab) IB. 
 
1.3 
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT 
The human epidermal growth factor 2 (HER2) receptors are an example of 
tyrosine kinase receptors that, when overexpressed through gene amplification, 
facilitate malignant tumorigenesis.19,20,58 Overexpression of HER2 is observed in 
approximately one-fifth of tumors taken from patients with breast cancer. 
Therefore, a strategy to antagonize the abnormal function of overexpressed HER2 
was developed to improve the course of patients with HER2 overexpressing 
cancer. 
 
 
Trastuzumab, a humanized monoclonal antibody against HER2 receptors 
indicated for the treatment of patients with HER2-positive MBC (first approved in 
1998) and EBC (approved in 2005). Since its initial approval in 1998, 
trastuzumab has become standard of care for patients with HER2-positive breast 
cancer and is widely used for its approved indications in both the adjuvant and 
metastatic settings.15,59,33  
 

 
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In India, based on BCIRG 006 trial, trastuzumab is approved for adjuvant 
treatment of HER2 over-expressing node positive or high risk node negative 
breast cancer  as part of a treatment regimen consisting of doxorubicin, 
cyclophosphamide, and either paclitaxel or docetaxel or with docetaxel and 
carboplatin. The current study is postmarketing requirement study to gain 
understanding of safety of trastuzumab in Indian patients.  The efficacy and safety 
of intravenous (IV) trastuzumab have been well characterized. The benefit to risk 
ratio of adjuvant trastuzumab in the current study is therefore expected to be 
favourable. 
 
2. 
OBJECTIVES 
 
2.1 PRIMARY OBJECTIVES 
The primary objective for this study is as follows: 
 
• 
To evaluate the safety of Trastuzumab for the treatment of HER2-positive 
node positive or high risk node negative breast cancer patients with regimen 
consisting of doxorubicin and cyclophosphamide followed by either 
paclitaxel or docetaxel (AC→TH) or a regimen consisting of docetaxel and 
carboplatin (TCH) in Indian population. 
 
2.2 SECONDARY OBJECTIVES 
 
The secondary objectives for this study are as follows: 
• 
To determine the disease free survival (DFS). 
• 
To determine the overall survival (OS). 
 
 

 
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3. 
STUDY DESIGN 
3.1 DESCRIPTION OF STUDY 
 
This is a prospective, phase IV, multi-center, single arm, open-label, 
interventional study in patients with HER2-positive node positive or high risk 
node negative breast cancer. A total of approximately 109 patients will be 
enrolled at approximately 10 sites across India. Patients eligible as per the 
inclusion and exclusion criteria will be treated with either AC→TH or TCH 
treatment regimens. 
 
The choice of the Trastuzumab treatment regimen (either AC→TH or TCH) will 
be based on investigator’s discretion referring the local prescribing document of 
Trastuzumab. 
 
AC→TH regimen:  
 
• Every 3 weeks for 4 cycles, patients in the AC→TH regimen will be 
receiving 60 mg/m2 doxorubicin as a  5 to15 minute I.V. bolus injection 
followed by 600 mg/m2 cyclophosphamide as a 5 to 60 minute I.V. bolus 
injection. 
 
• On Day 1 of Cycle 5, 4-mg/kg Trastuzumab loading dose will be 
administered as a 90 minute I.V. infusion as a weekly regimen OR 8-mg/kg 
Trastuzumab loading dose will be administered as a 90-minute I.V. infusion 
as a 3 weekly regimen at Investigator’s discretion.  
 
• If weekly regimen of Trastuzumab is selected, on Day 8 of Cycle 5, 2 mg/kg 
Trastuzumab will be administered as a 30-minute I.V. infusion and 2mg/ kg 
every week as a weekly regimen will be given OR beginning on Day 1 of 
Cycle 6, Trastuzumab 6 mg/kg will be administered as a 30-minute I.V. 
infusion every 3 weeks as a 3 weekly regimen for four cycles.  
 
• Docetaxel 100 mg/m2 or Paclitaxel 175 mg/m2 (at investigator’s discretion) 
will be administered as a 1 hour I.V. infusion every 3 weeks for four cycles, 
beginning on Day 1 of Cycle 5 and continued for up to Cycle 8. 
 
• Three weeks after the last treatment with docetaxel/paclitaxel (i.e., on Day 1 
of Cycle 9), 6 mg/kg Trastuzumab will be administered as a 30-minute I.V. 
infusion every 3 weeks. Trastuzumab treatment will be continued up to cycle 
22 (completing a total 52 week trastuzumab therapy). 
 
TCH regimen: 
 
• Trastuzumab will be given intravenously at a dose of 4 mg/kg loading dose  
administered as a 90 minute I.V. infusion followed by 2 mg/kg administered 
as a 30 minute I.V. infusion weekly as a weekly regimen or 8-mg/kg 
Trastuzumab loading dose administered as a 90 minute I.V. infusion followed 
by 6 mg/kg administered as a 30 minute I.V. infusion 3 weekly as a 3 weekly 
regimen during chemotherapy from cycle 1 to 6 at Investigator’s discretion.  
 

 
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• Every 3 weeks for six cycles, patients in the TCH regimen will be receiving 
75 mg/m2 docetaxel as a 60-minute I.V. bolus injection followed by AUC 6 x 
(GFR + 25) carboplatin as a 30 to 60 minute I.V. bolus injection. 
 
• After completion of chemotherapy, Trastuzumab will be administered at a 
dose of 6 mg/kg every 3 weeks up to cycle 18 (completing total 52 week 
trastuzumab therapy) 
 
Patients will be followed up for duration of 12 months from the date of last 
dose of Trastuzumab. All adverse events occurring during treatment and this 
follow up period will be captured. 
 
3.2 PROCEDURES (SUMMARY) 
 
3.2.1 During screening and baseline phase following assessments will be carried 
to evaluate the subject eligibility: 
 
Informed consent, allocation of subject number, demographics, physical 
examination, vital signs, inclusion and exclusion criteria, relevant medical history, 
previous and concomitant medication details, conformation of early breast cancer 
disease by histology, radiography (mammogram) (tumor size < 5 cm and < 4 
positive lymph nodes), CT/MRI,  Eastern Cooperative Oncology Group (ECOG) 
performance status, electrocardiogram (ECG), measurement of LVEF by 
echocardiography, haematology and biochemistry assessment.  
 
HER2-positive status on fixed tissue blocks from the primary tumor assessed by 
IHC (immuno histochemistry) and/or FISH (fluorescence insitu hybridisation) 
according to institutional criteria will be performed at central laboratory. 
 
 

 
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3.2.2 Administration of treatment regimen: 
 
The choice of the Trastuzumab treatment regimen (either AC→TH or TCH) will 
be based on investigators’ discretion. 
 
Order of administration in AC→TH protocol: Post AC therapy, Trastuzumab 
first followed by docetaxel/paclitaxel. 
 
Drug  
Dose  
 Administration Guideline  
Cycles* 1-4  
Doxorubicin 
60 mg/m2 
Administered as I.V. bolus 
over 5 to15 min. 
Cyclophosphamide 
 
600 mg/m2  
 
Administered I.V. over 5 to 
60 min. (use non-PVC 
equipment).  
Cycles 5-8   
Trastuzumab  
4 mg/kg (Loading 
dose) followed by 2 
mg/kg (Maintenance 
dose) every week 
or 8 mg/kg (Loading 
dose), followed by 6 
mg/kg (Maintenance 
dose) every 3 weeks 
 
• Loading dose: I.V. in 250 mL 
NS over 90 min. Observe for 
90 minutes post infusion.  
• Maintenance dose: I.V. in 
250 mL NS over 30 min on 
all the doses, observe for 30 
minutes post infusion 
Taxane 
 
Docetaxel (100 
mg/m2 ) 
or  
Paclitaxel (175 
mg/m2) 
Administered I.V. in 250 mL 
NS over 1 hour (use non-
PVC equipment). 
Cycles 9 to 22 
Trastuzumab  
6 mg/kg 
(Maintenance dose) 
every 3 week 
 
I.V. in 250 mL NS over 30 
min on the all doses, observe 
for 30 minutes post infusion.  
*Cycle: 21 days 
 
 
 
 
 
 
 
 

 
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Order of administration in TCH protocol: Trastuzumab first, docetaxel 
second, carboplatin third. 
 
Drug  
Dose  
 Administration Guideline  
Cycle* 1-6 
Trastuzumab 
4 mg/kg (Loading 
dose) followed by 2 
mg/kg (Maintenance 
dose) every week 
OR 8 mg/kg 
(Loading dose), 
followed by 6 mg/kg 
(Maintenance dose) 
every 3 week 
 
• Loading dose: I.V. in 250 
mL NS over 90 min. Observe 
for 1 hour post-infusion  
 
• Maintenance dose: I.V. in 
250 mL NS over 30 min on 
the all doses, observe for 30 
minutes post infusion 
 
Docetaxel  
 
75 mg/m2  
 
Administered I.V. in 250 mL 
NS over 1 hour (use non-
PVC equipment). 
Carboplatin  
 
Dose = AUC 6 x 
(GFR + 25)  
Administered I.V. in 500 mL 
D5W over 30 to 60 min 
 Cycle 7 to 18 
Trastuzumab  
6 mg/kg 
(Maintenance dose) 
every 3 weeks 
I.V. in 250 mL NS over 30 
min on the all doses, observe 
for 30 minutes post infusion.  
*Cycle: 21 days 
 
As per institutional practice or American Society of Clinical Oncology (ASCO) 
adjuvant follow-up guidelines 2006, Breast cancer assessments for DFS and OS are to 
be reported for every 6 months. 
 
 
American Society of Clinical Oncology (ASCO) 2006 Guideline for Breast 
Cancer Follow-up in the adjuvant setting (Khatcheressian et al. 2006). In brief: 
• History/physical examination - every 3 to 6 months for the first 3 years after 
primary therapy; every 6 to 12 months for years 4 and 5; then annually. 
• Mammography - first post-treatment mammogram 1 year after the initial 
mammogram that leads to diagnosis, but no earlier than 6 months after 
definitive radiation therapy. Subsequent mammograms should be obtained as 
indicated for surveillance of abnormalities. 
• Pelvic examination - regular gynecologic follow-up is recommended for all 
women. Patients who receive tamoxifen should be advised to report any 
vaginal bleeding to their physicians. 
 

 
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The following are not recommended for routine surveillance: Routine blood tests 
(full blood counts and liver function tests), imaging studies (chest x-ray, bone 
scans, liver ultrasound, CT scans, FDG-PET scans, and breast MRI), tumor 
marker assessments (CA 15-3, CA 27.29, and CEA). 
 
However, bone scan, liver imaging, and brain CT scan will be performed if 
clinically indicated. 
 
3.2.3 During treatment period 
 
• Safety parameters will be assessed for every cycle.  
• Vital signs, physical examination and treatment compliance will be performed 
for every cycle and subject safety will be evaluated. 
• LVEF and ECG will be assessed for every 3 months (4 cycles) to evaluate 
cardiac safety of the patients. 
• ECOG will be assessed for every 3 months (4 cycles) to evaluate performance 
status of the patients. 
• Hematology and biochemistry assessments will also be performed during the 
study if clinically indicated. 
• Routine breast cancer follow up is done at cycle 9 and 17. History/physical 
examination, mammography and pelvic examination will be carried out. 
 
3.2.4 Follow-up Phase 
 
During follow up period of one year, Cardiac assessments at 6 and 12 months 
following treatment cessation. Survival follow-up can be performed by 
telephonic calls and/or clinic visits every 6 months. 
 
3.3 END OF STUDY 
 
The study is estimated to last approximately 4 years, based on an expected 18-
month recruitment, 12 months of study treatment and 12 months of follow-up 
after the treatment.  
 
End of study is defined as the last patient last visit in the follow-up period. 
 
The study will end when all patients have been followed for at least 12 months 
after their last study treatment, or if withdrawal from the study, loss to follow up 
or death. The final analysis of OS and DFS will be conducted and updated safety 
parameters will be summarized at this stage. 
 
 
 
 

 
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3.4 RATIONALE FOR STUDY DESIGN 
Four pivotal randomized controlled trials demonstrated significantly improved 
DFS, and three (HERA, B31 and BCIRG-006) demonstrated significantly 
improved OS. NCCTG 9831 study compared the concurrent and sequential use 
of trastuzumab in treatment of HER2+ ve early breast cancer. This study 
identified a strong trend for a 25% reduction in the risk of an outcome event 
when trastuzumab is started concurrently as compared to sequentially after 
paclitaxel.45 Therefore, based on a positive risk/benefit ratio, the authors 
recommended that trastuzumab be incorporated in a concurrent fashion when 
administered with paclitaxel,45 which also resulted in the approval of the 
concurrent use of trastuzumab with chemotherapy. Further, BCIRG-006 study 
supported the concurrent use of trastuzumab and additionally explored efficacy 
and safety of non-anthracycline based regimen of trastuzumab. In India, based on 
BCIRG 006, trastuzumab is approved for adjuvant treatment of HER2 over-
expressing node positive or high risk node negative breast cancer as part of a 
treatment regimen consisting of doxorubicin, cyclophosphamide, and either 
paclitaxel or docetaxel (anthracycline based regimen) or with docetaxel and 
carboplatin(non-anthracycline based regimen). In current phase IV study, use of 
anthracycline or non-anthracycline regimen of trastuzumab or choice of taxane 
will be at the discretion of the investigator. It is designed to get safety of 
concurrent use of trastuzumab in the adjuvant setting in Indian HER2+ve breast 
cancer patients. 
 
3.4.1 Rationale for Test Product Dosage 
BCIRG006, NSABP B31, NCCTG N9831 studies support the therapeutic 
efficacy and safety of Trastuzumab in the treatment of early stage breast cancer. 
The study defined and approved dosage regiment will be used. Either weekly or 
3 weekly dosing of trastuzumab will be used at the discretion of the investigator. 
In weekly regimen, 4 mg/kg (Loading dose) followed by 2 mg/kg (Maintenance 
dose) every week or in 3 weekly regimen 8 mg/kg (Loading dose), followed by 6 
mg/kg (Maintenance dose) trastuzumab will be given every 3 week. 
 
3.4.2 Rationale for Patient Population 
 
Similar to the pivotal studies of trastuzumab in adjuvant setting, in this study, 
adult patients with histologically confirmed early invasive HER2 positive, node 
positive or high risk node negative breast cancer with no evidence of residual, 
locally recurrent or metastatic disease and defined as clinical stage I to IIIA that 
is eligible for adjuvant treatment with Trastuzumab will be enrolled. The 
performance status of these patients on Eastern Cooperative Oncology Group 
(ECOG) should be from 0 to 2 and HER2 over-expression/amplification for these 
patients should be defined as either IHC3+, or IHC2+ and FISH-positive as 
determined in a central laboratory. Screening left ventricular ejection fraction 
(LVEF) should be ≥ 55%. 
 

 
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As Bazell summarises: “No company had ever tested a breast-cancer drug in the 
newly diagnosed population because doctors did not want to use an unproved 
therapy on patients in the early, more treatable stages of disease” (1998: 137).60  
 
3.5 OUTCOME MEASURES  
 
3.5.1 Efficacy Outcome Measures 
 
The efficacy outcome measures for this study are as follows: 
 
• Disease free survival rate (DFS) and Overall Survival rate (OS). 
 
As per institutional practice or American Society of Clinical Oncology (ASCO) 
adjuvant follow-up guidelines 2006, Breast cancer assessments for DFS and OS 
are to be reported for every 6 months. 
 
3.5.2 Safety Outcome Measures 
 
The safety outcome measures for this study are as follows: 
• All Adverse Event (AE) and Serious Adverse Event (SAE) as well as 
laboratory abnormalities will be recorded and graded according to the NCI-
CTCAE version 4.0.  
 
• Cardiac 
function 
will 
be 
evaluated 
by 
measuring 
LVEF 
by 
echocardiography. 
 
• Symptomatic left ventricular dysfunction (congestive heart failure [CHF]) 
will be graded according to the New York Heart Association functional 
classification.  
 
• AEs and SAEs related to Trastuzumab will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 15.1 or greater. 
 
• Patients will undergo a Safety Follow-up, 4 weeks after their last dose of 
study treatment. 
 
• AEs and SAEs also will be summarized using number and percentage by 
System Organ Class and Preferred Term. Summaries will be presented for 
all adverse events and adverse events related to study drug. 
 
• Adverse events will also be summarized by toxicity grade, outcome, 
seriousness and action taken to the study medication. 
 
 

 
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4. 
MATERIALS AND METHODS  
4.1 PATIENTS 
Adult female patients with early invasive HER2 positive, node positive or 
high risk node negative breast cancer. 
 
4.1.1 Inclusion Criteria 
 
Patients must meet the following criteria for study entry: 
• Able and willing to give written informed consent and comply with the 
requirements of the study protocol. 
 
• Adult female patients, ≥18 years of age 
 
• Histologically  confirmed early invasive HER2 positive, node positive or 
high risk node negative breast cancer with no evidence of residual, locally 
recurrent or metastatic disease and defined as clinical stage I to IIIA that is 
eligible for adjuvant treatment with Trastuzumab 
 
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 
 
• HER2 over-expression/amplification defined as either IHC3+, or IHC2+ and 
FISH-positive as determined in a central laboratory 
 
• At time of starting Trastuzumab therapy, Left ventricular ejection fraction 
(LVEF) measured by echocardiography 
 
• Screening left ventricular ejection fraction (LVEF) ≥ 55% 
 
• Adequate bone marrow, renal, and hepatic function  
 
• Agreement to use an adequate, non-hormonal means of contraception by 
women of childbearing potential 
 
4.1.2 Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
• Any contraindication to Trastuzumab 
 
• Previous adjuvant breast cancer treatment with an approved or 
investigational anti-HER2 agent 
 
• History of other malignancy, except for curatively treated carcinoma in situ 
of the cervix or basal cell carcinoma and patients with other curatively 
treated malignancies who have been disease-free for at least 5 years 

 
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• Past history of ductal carcinoma in situ and/or lobular carcinoma that has 
been treated with any systemic therapy or with radiation therapy to the 
ipsilateral breast where the invasive cancer subsequently develops 
 
• Locally advanced (stage IIIB and IIIC) and Metastatic disease (stage IV) 
 
• Clinically relevant cardiovascular disorder or disease 
 
• Uncontrolled hypertension, or history of hypertensive crisis or hypertensive 
encephalopathy 
 
• History of severe allergic or immunological reactions, e.g. difficult to 
control asthma 
 
• Pregnant or lactating women 
 
4.2 METHOD OF TREATMENT  ASSIGNMENT  
 
Patients eligible as per the inclusion and exclusion criteria will be treated with 
either AC→TH or TCH treatment regimens. 
The choice of the Trastuzumab treatment regimen (either AC→TH or TCH) will 
be based on investigators’ discretion referring the local prescribing document of 
Trastuzumab. 
 
AC→TH regimen:  
 
• Every 3 weeks for 4 cycles, patients in the AC→TH regimen will be 
receiving 60 mg/m2 doxorubicin as a  5 to15 minute I.V. bolus injection 
followed by 600 mg/m2 cyclophosphamide as a 5 to 60 minute I.V. bolus 
injection. 
 
• On Day 1 of Cycle 5, 4-mg/kg Trastuzumab loading dose will be 
administered as a 90 minute I.V. infusion as a weekly regimen OR 8-mg/kg 
Trastuzumab loading dose will be administered as a 90-minute I.V. infusion 
as a 3 weekly regimen at Investigator’s discretion.  
 
• If weekly regimen of Trastuzumab is selected, on Day 8 of Cycle 5, 2 mg/kg 
Trastuzumab will be administered as a 30-minute I.V. infusion and 2mg/ kg 
every week as a weekly regimen will be given OR beginning on Day 1 of 
Cycle 6, Trastuzumab 6 mg/kg will be administered as a 30-minute I.V. 
infusion every 3 weeks as a 3 weekly regimen for four cycles.  
 
• Docetaxel 100 mg/m2 or Paclitaxel 175 mg/m2 (at investigator’s discretion) 
will be administered as a 1 hour I.V. infusion every 3 weeks for four cycles, 
beginning on Day 1 of Cycle 5 and continued for up to Cycle 8. 
 

 
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• Three weeks after the last treatment with docetaxel/paclitaxel (i.e., on Day 1 
of Cycle 9), 6 mg/kg Trastuzumab will be administered as a 30-minute I.V. 
infusion every 3 weeks. Trastuzumab treatment will be continued up to cycle 
22 (completing a total 52 week trastuzumab therapy). 
 
TCH regimen: 
 
• Trastuzumab will be given intravenously at a dose of 4 mg/kg loading dose  
administered as a 90 minute I.V. infusion followed by 2 mg/kg administered 
as a 30 minute I.V. infusion weekly as a weekly regimen or 8-mg/kg 
Trastuzumab loading dose administered as a 90 minute I.V. infusion followed 
by 6 mg/kg administered as a 30 minute I.V. infusion 3 weekly as a 3 weekly 
regimen during chemotherapy from cycle 1 to 6 at Investigator’s discretion.  
 
• Every 3 weeks for six cycles, patients in the TCH regimen will be receiving 
75 mg/m2 docetaxel as a 60-minute I.V. bolus injection followed by AUC 6 x 
(GFR + 25) carboplatin as a 30 to 60 minute I.V. bolus injection. 
 
• After completion of chemotherapy, Trastuzumab will be administered at a 
dose of 6 mg/kg every 3 weeks up to cycle 18 (completing total 52 week 
trastuzumab therapy) 
 
The patient will be followed up for duration of 12 months from the last dose  
of Trastuzumab. All adverse events occurring during treatment and this 
follow up    period will be captured. 
 
4.3 STUDY TREATMENT  
4.3.1 Formulation, Packaging, and Handling 
4.3.1.1 Trastuzumab 
 
Trastuzumab is produced by a genetically engineered Chinese hamster ovary 
(CHO) cell line grown in large scale, which secretes Trastuzumab into the culture 
medium. 
The 
antibody 
is 
then 
purified 
extensively 
using 
standard 
chromatographic and filtration methods. 
 
Trastuzumab for intravenous (IV) administration is supplied commercially as a 
lyophilized preparation in multi-dose (440 mg) vials. It is formulated in 
histidine/histidine-HCl, α,α-trehalose dihydrate, and polysorbate 20. Following 
reconstitution in either sterile water for injection (SWFI) or bacteriostatic water 
for injection (BWFI), it is further diluted in 250 mL 0.9% sodium chloride 
solution for administration. 
 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
Vials of trastuzumab are shipped with cool packs at a temperature ranging from 
2°C to 8°C (36°F to 46°F), and must be placed in a refrigerator (same temperature 
range) immediately upon receipt to ensure optimal retention of physical and 
biochemical integrity. Temperature logs must be maintained (in accordance with 
local pharmacy practice) on the refrigerator to ensure proper storage conditions. 
Do not use beyond the expiry date stamped on the vial. DO NOT FREEZE. 
Trastuzumab may be sensitive to shear-induced stress (e.g. agitation or rapid 
expulsion from a syringe). DO NOT SHAKE. Vigorous handling of solutions of 
trastuzumab results in aggregation of the protein and may create cloudy solutions.  
 
4.3.2 Dosage, Administration, and Compliance 
 
HER2 testing is mandatory prior to initiation of Trastuzumab therapy. 
 
Trastuzumab should be administrated as intravenous infusion. 
 
Should not be administered as an intravenous push or bolus. 
 
Weekly schedule: 
 
AC→TH regimen:  
 
Patients in the AC→TH regimen will be receiving 60 mg/m2 doxorubicin as a 5 to 
15 minute I.V. bolus injection followed by 600 mg/m2 cyclophosphamide as a 5 
to 60 minute I.V. bolus injection, every 3 weeks for 4 cycles. Docetaxel 100 
mg/m2 or Paclitaxel 175 mg/m2 (at investigator’s discretion) will be administered 
as a 1-hour I.V. infusion every 3 weeks for four cycles, beginning on Day 1 of 
Cycle 5 and continued for up to Cycle 8. 
 
TCH regimen: 
 
Patients in the TCH regimen will be receiving 75 mg/m2 docetaxel as a 60-minute 
I.V. bolus injection followed by AUC 6 x (GFR + 25) carboplatin as a 30 to 60 
minute I.V. bolus injection, every 3 weeks for six cycles. 
 
Loading dose: The recommended initial loading dose is 4 mg/kg body weight. 
Trastuzumab administered as a 90 minute intravenous infusion. Patients should be 
observed for fever and chills or other infusion-associated symptoms. Interruption 
of the infusion may help control such symptoms. The infusion may be resumed 
when symptoms abate. 
 
Subsequent doses: The recommended weekly dose of Trastuzumab is 2 mg/kg 
body weight. If the prior dose was well tolerated, the dose can be administered as 
a 30 minute infusion. Patients should be observed for fever and chills or other 
infusion-associated symptoms. 
 

 
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Alternative 3-weekly schedule: 
 
AC→TH regimen:  
 
Patients in the AC→TH regimen will be receiving 60 mg/m2 doxorubicin as a 5 
to 15 minute I.V. bolus injection followed by 600 mg/m2 cyclophosphamide as a 
5 to 60 minute I.V. bolus injection, every 3 weeks for 4 cycles. Docetaxel 100 
mg/m2 or Paclitaxel 175 mg/m2 (at investigators discretion) will be administered 
as a 1-hour I.V. infusion every 3 weeks for four cycles, beginning on Day 1 of 
Cycle 5 and continued for up to Cycle 8. 
 
TCH regimen: 
 
Patients in the TCH regimen will be receiving 75 mg/m2 docetaxel as a 60 
minute I.V. bolus injection followed by AUC 6 x (GFR + 25) carboplatin as a 30 
to 60 minute I.V. bolus injection, every 3 weeks for six cycles.  
 
Initial loading dose of 8 mg/kg body weight administered as infusions over 
approximately 90 minutes, followed by 6 mg/kg body weight 3 weeks later as 
infusions over 30 minutes and then 6 mg/kg repeated at three weekly intervals as 
infusions over 30 minutes. If the prior dose was well tolerated, the dose can be 
administered as a 30 minute infusion. 
 
Patients with early breast cancer should be treated with Trastuzumab for a total of 
52 week, but not exceeding 52 week.  
 
Dose reduction/ modification for toxicities 
 
There are no dose adjustments of trastuzumab foreseen for toxicity. If a patient 
cannot tolerate trastuzumab infusions, trastuzumab treatment will be stopped 
completely. Trastuzumab treatment need not be delayed for some toxicities that 
necessitate a delay in chemotherapy. 
 
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. 
 
If the patient misses a dose of Trastuzumab by one week or less, then the usual 
maintenance dose of Trastuzumab (6 mg/kg in 3weekly regimen or 2 mg/kg in 
weekly regimen) should be given as soon as possible (do not wait until the next 
planned cycle). Carry on the maintenance doses according to the original 
schedule.  
 
If the patient misses a dose of trastuzumab by more than one week, treatment 
should be restarted as if she were a new patient. The treatment should be re-
started as soon as possible (don’t wait until the next planned cycle) with a 

 
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loading dose of  8 mg/kg in 3weekly regimen or 4mg/kg in weekly regimen. 
Subsequent maintenance trastuzumab doses of trastuzumab should be given 6 
mg/kg every 3 weekly or 2 mg/kg weekly from that point as per the selected 
schedule of administration. 
 
To keep trastuzumab in synchrony with concurrent chemotherapy, and to 
maintain trastuzumab dose intensity, the maintenance trastuzumab dose 6mg/kg 
should be given at the scheduled time, even though the chemotherapy dose is 
delayed. When the chemotherapy is next given (after resolution of toxicity), 
trastuzumab maintenance 6mg/kg dose should also be given. Subsequent 
trastuzumab doses are given in synchrony with concurrent chemotherapy, every 3 
weeks. Note that this means that trastuzumab doses of 6 mg/kg may occasionally 
be given only one week after the previous trastuzumab dose. 
 
The specific instructions to reduce or hold the dose of chemotherapy should be 
followed. For instructions refer to the manufacturer’s prescribing information or 
follow the routine center/institution practice. 
 
Carboplatin 
 
Intermittent courses of Carboplatin in combination with cyclophosphamide 
should not be repeated until the neutrophil count is at least 2,000 and the platelet 
count is at least 100,000.61  
 
Doxorubicin 
 
When possible, to reduce the risk of developing cardiotoxicity in patients 
receiving Doxorubicin after stopping treatment with other cardiotoxic agents, 
especially those with long half-lives such as trastuzumab, Doxorubicin-based 
therapy should be delayed until the other agents have cleared from the 
circulation. On intravenous administration of Doxorubicin, extravasation may 
occur with or without an accompanying burning or stinging sensation, even if 
blood returns well on aspiration of the infusion needle. If any signs or symptoms 
of extravasation have occurred, the injection or infusion should be immediately 
terminated and restarted in another vein. If extravasation is suspected, 
intermittent application of ice to the site for 15 min. q.i.d. × 3 days may be 
useful. The benefit of local administration of drugs has not been clearly 
established. Because of the progressive nature of extravasation reactions, close 
observation and plastic surgery consultation are recommended. Blistering, 
ulceration and/or persistent pain are indications for wide excision surgery, 
followed by split-thickness skin grafting. 
 
The most commonly used dose schedule when used as a single agent is 60 to 75 
mg/m2 as a single intravenous injection administered at 21 day intervals. The 
lower dosage should be given to patients with inadequate marrow reserves due to 
old age, or prior therapy, or neoplastic marrow infiltration. 

 
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Local erythematous streaking along the vein as well as facial flushing may be 
indicative of too rapid an administration. A burning or stinging sensation may be 
indicative of perivenous infiltration and, if this occurs, the infusion should be 
immediately terminated and restarted in another vein. Perivenous infiltration may 
occur painlessly.62 
 
Cyclophosphamide 
 
Dosages must be adjusted in accord with evidence of antitumor activity and/or 
leukopenia. The total leukocyte count is a good, objective guide for regulating 
dosage. Transient decreases in the total white blood cell count to 2000 cells/mm3 
(following short courses) or more persistent reduction to 3000 cells/mm3 (with 
continuing therapy) are tolerated without serious risk of infection if there is no 
marked granulocytopenia.63 
 
Paclitaxel 
 
All patients should be premedicated prior to Paclitaxel administration in order to 
prevent severe hypersensitivity reactions. Such premedication may consist of 
dexamethasone 20 mg PO administered approximately 12 and 6 hours before 
Paclitaxel, diphenhydramine (or its equivalent) 50 mg I.V. 30 to 60 minutes prior 
to Paclitaxel, and cimetidine (300 mg) or ranitidine (50 mg) I.V. 30 to 60 minutes 
before Paclitaxel. 
 
For patients with solid tumors (ovary, breast and NSCLC), courses of Paclitaxel 
should not be repeated until the neutrophil count is at least 1,500 cells/mm3 and 
the platelet count is at least 100,000 cells/mm3. Patients who experience severe 
neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe 
peripheral neuropathy during Paclitaxel Injection, USP therapy should have 
dosage reduced by 20% for subsequent courses of Paclitaxel. The incidence of 
neurotoxicity and the severity of neutropenia increase with dose.64  
 
Docetaxel 
 
Patients who are dosed initially at 100 mg/m2 and who experience either febrile 
neutropenia, neutrophils <500 cells/mm3 for more than 1 week, or severe or 
cumulative cutaneous reactions during Docetaxel Injection therapy should have 
the dosage adjusted from 100 mg/m2 to 75 mg/m2. If the patient continues to 
experience these reactions, the dosage should either be decreased from 75 mg/m2 
to 55 mg/m2 or the treatment should be discontinued. Conversely, patients who 
are dosed initially at 60 mg/m2 and who do not experience febrile neutropenia, 
neutrophils <500 cells/mm3 for more than 1 week, severe or cumulative cutaneous 
reactions, or severe peripheral neuropathy during Docetaxel Injection therapy may 
tolerate higher doses. Patients who develop ≥grade 3 peripheral neuropathy 
should have Docetaxel Injection treatment discontinued entirely. 

 
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Combination Therapy with Docetaxel Injection in the Adjuvant Treatment of 
Breast Cancer Docetaxel Injection in combination with doxorubicin and 
cyclophosphamide should be administered when the neutrophil count is ≥1,500 
cells/mm3. Patients who experience febrile neutropenia should receive G-CSF in 
all subsequent cycles. Patients who continue to experience this reaction should 
remain on G-CSF and have their Docetaxel Injection dose reduced to 60 mg/ m2. 
Patients who experience grade 3 or 4 stomatitis should have their Docetaxel 
Injection dose decreased to 60 mg/ m2. Patients who experience severe or 
cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms 
during Docetaxel Injection therapy should have their dosage of Docetaxel 
Injection reduced from 75 to 60 mg/ m2. If the patient continues to experience 
these reactions at 60 mg/ m2, treatment should be discontinued.65 
 
Administration 
 
Trastuzumab 
 
Trastuzumab should be carefully handled during reconstitution. Causing 
excessive foaming during reconstitution or shaking the reconstituted trastuzumab 
may result in problems with the amount of trastuzumab that can be withdrawn 
from the vial. Use appropriate aseptic technique when performing the following 
reconstitution steps: Using a sterile syringe, slowly inject the 20 mL of diluent 
into the vial containing the lyophilized cake of Trastuzumab. The stream of 
diluent should be directed into the lyophilized cake. Swirl the vial gently to aid 
reconstitution. DO NOT SHAKE. Slight foaming of the product may be present 
upon reconstitution. Allow the vial to stand undisturbed for approximately 5 
minutes. Parenteral drug products should be inspected visually for particulate 
matter and discoloration prior to administration, whenever solution and container 
permit. Inspect visually for particulates and discoloration. The solution should be 
free of visible particulates, clear to slightly opalescent and colorless to pale 
yellow. Use of other reconstitution solvents is not allowed. The reconstituted 
solution contains 21 mg/mL trastuzumab and will be added to 250 mL of 0.9% 
Sodium Chloride Injection. The product is not intended to be stored after 
reconstitution and dilution unless this has taken place under aseptic conditions. 
Once the infusion is prepared it should be administered immediately. 
Reconstituted solutions made with solvent (bacteriostatic water for injection) for 
the 440 mg vial of trastuzumab is stable for 28 days when stored refrigerated at 
2°C-8°C. Any remaining reconstituted solution should be discarded after 28 days. 
Do not freeze the reconstituted solution. The reconstituted solution contains 
preservative and is therefore suitable for multiple use. Trastuzumab should be 
carefully handled during reconstitution. Causing excessive foaming during 
reconstitution or shaking the reconstituted trastuzumab may result in problems 
with the amount of trastuzumab that can be withdrawn from the vial. 
Determine the volume of the solution required based on a dose (mg 
trastuzumab/kg body weight,) 

 
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Volume (mL) =              
Body weight (kg) × dose (mg/kg) 
            21 (mg/mL, concentration of reconstituted solution) 
 
The appropriate amount of solution should be withdrawn from the vial and added 
to an infusion bag containing 250 ml of 0.9% sodium chloride solution. Do not 
use with glucose-containing solutions since it causes aggregation of the protein. 
The bag should be gently inverted to mix the solution in order to avoid foaming. 
Parenteral solutions should be inspected visually for particulates and discoloration 
prior to administration. The product is not to be stored after dilution unless this 
has taken place under aseptic conditions. Once the infusion is prepared it should 
be administered immediately. If diluted aseptically the infusion may be stored for 
a maximum of 24 hours (at 2-8 °C). No incompatibilities between trastuzumab 
and polyvinylchloride or polyethylene bags have been observed. Trastuzumab can 
be administered in an outpatient setting. It should not be administered as an i.v. 
push or bolus. Patients should be observed for at least six hours after the start of 
the first dose of trastuzumab (i.e. 4.5 hours from the end of the infusion). The 
observation period may be shortened to 2 hours after the start of the infusion (i.e. 
1.5 hours from the end of the infusion) based on investigators discretion. 
Emergency equipment must be available. On very rare occasions, patients have 
experienced the onset of infusion symptoms or pulmonary symptoms more than 
six hours after the start of the trastuzumab infusion. 
 
Patients should be warned of the possibility of such a late onset and should be 
instructed to contact their physician if these symptoms occur. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
 
 
Chemotherapy 
 
For chemotherapy drugs refer to the manufacturer’s prescribing information or 
follow the routine center/institution practice, at discretion of Investigator. 
 
Order of administration in AC→TH protocol: Post AC therapy, 
Trastuzumab first followed by docetaxel/paclitaxel 
 
Drug 
Dose 
Cycles* 1-4  
Doxorubicin 
60 mg/m2 
Cyclophosphamide 
600 mg/m2 
Cycles 5-8   
Trastuzumab  
4 mg/kg (Loading dose) followed by 2 mg/kg 
(Maintenance dose) every week 
OR 8 mg/kg (Loading dose), followed by 6 
mg/kg (Maintenance dose) every 3 week 
Taxane 
 
Docetaxel (100 mg/m2)  
or  
Paclitaxel (175 mg/m2) 
Cycles 9 to 22 
Trastuzumab  
6 mg/kg (Maintenance dose) every 3 week 
*Cycle: 21 days 
 
Order of administration in TCH protocol: Trastuzumab first, docetaxel 
second, carboplatin third. 
 
Drug 
Dose 
Cycle* 1-6 
Trastuzumab 
4 mg/kg (Loading dose) followed by 2 mg/kg 
(Maintenance dose) every week 
OR 8 mg/kg (Loading dose), followed by 6 
mg/kg (Maintenance dose) every 3 week 
Docetaxel  
 
75 mg/m2  
 
Carboplatin  
 
Dose = AUC 6 x (GFR + 25)  
 Cycle 7 to 18 
Trastuzumab  
6 mg/kg (Maintenance dose) 
*Cycle: 21 days 
 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
 
 
 
Compliance: 
 
Accountability and patient compliance will be assessed by measuring duration of 
drug administration as well as maintaining adequate drug dispensing records. 
Investigator is required to maintain adequate records of the disposition of the 
study medications, including dates, the quantity of drug received and to whom it 
was dispensed (patient -by- patient accounting), and accounts of any drug 
accidentally or deliberately destroyed. 
 
Records for receipt, storage, use, and disposition will be maintained by the study 
site. A drug-dispensing log will be kept current for each patient and should 
contain the identification of each patient and the date and quantity of drug 
dispensed. 
 
All records regarding disposition of the test product will be available for 
inspection by the clinical trial monitor. All supplies, including partially used or 
empty containers and the dispensing logs, must be returned to the Roche Monitor 
or designee at the end of the study. 
 
4.3.3 Investigational Medicinal Product Accountability 
 
The test product Trastuzumab will be provided by the sponsor and the non-
investigational medicinal products required for completion of this study, 
purchased by the patients will be reimbursed by the sponsor as per the bills.  
 
The test product will either be disposed of at the study site according to the study 
site’s institutional standard operating procedure or returned to the Sponsor with 
the appropriate documentation. The site's method of test product destruction must 
be agreed upon by the Sponsor. The site must obtain written authorization from 
the Sponsor before any test product is destroyed, and test product destruction 
must be documented on the appropriate form. 
 
Accurate records of all test products received at, dispensed from, returned to, and 
disposed of by the study site should be recorded on the Drug Inventory Log. 
 
 
 
4.3.4 Post-Trial Access to Trastuzumab  
 
Not Applicable. 
 
 
 

 
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4.4 CONCOMITANT THERAPY 
 
4.4.1 Permitted Therapy  
 
Concomitant therapy includes any medication (e.g. prescription drugs, over the 
counter drugs, herbal/homeopathic remedies, nutritional supplements) used by a 
patient from 30 days prior to screening to the study completion/early termination 
visit. All concomitant medications should be reported to the investigator and 
recorded in the Concomitant medications section of the eCRF. 
 
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use. 
 
4.4.2 Prohibited Therapy 
 
Doxorubicin taken along with Trastuzumab causes cardiotoxicity, hence it should 
not be administered along with Trastuzumab. 
 
Patients who are experiencing dyspnoea at rest due to complications of advanced 
malignancy and comorbidities may be at increased risk of a fatal infusion 
reaction. Therefore, these patients should not be treated with Trastuzumab.  
 
Trastuzumab is contraindicated in patients with known hypersensitivity to 
Trastuzumab or to any other component of the product. No formal drug 
interaction studies have been performed with Trastuzumab in humans. Clinically 
significant interactions with the concomitant medication used in clinical trials 
have not been observed. 
 
4.5 STUDY ASSESSMENTS  
 
4.5.1 Description of Study Assessments 
 
The study comprises of three phases, screening phase, treatment phase and 
follow-up phase. 
 
Screening phase: 
 
During screening and baseline phase patients will undergo an evaluation to 
determine eligibility to participate in this study. The screening evaluation will 
include subject eligibility, demographic data, physical examination, vital signs, 
inclusion and exclusion criteria, relevant medical history, previous and 
concomitant medication details, conformation of early breast cancer disease by 
histology, radiography (mammogram) ((tumor size < 5 cm and < 4 positive lymph 

 
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nodes), CT/MRI, Eastern Cooperative Oncology Group (ECOG) performance 
status, electrocardiogram (ECG), measurement of LVEF by echocardiography, 
haematology and biochemistry assessment.  
 
HER2-positive status on fixed tissue blocks from the primary tumor assessed by 
IHC (immuno histochemistry) and/or FISH (fluorescence insitu hybridization). 
Sample for this test will be sent to the central laboratory for analysis. 
 
Choice of treatment regimen: 
 
The choice of the Trastuzumab treatment regimen (either AC→TH or TCH) will 
be based on investigators’ discretion. 
Order of administration in AC→TH protocol : Post AC therapy, Trastuzumab first 
followed by docetaxel/paclitaxel. 
 
 
Drug 
Dose 
Administration Guideline 
Cycles* 1-4  
Doxorubicin 
60 mg/m2 
Administered as I.V. bolus 
over 5 to 15 min. 
Cyclophosphamide 
 
600 mg/m2  
 
Administered I.V. over 5 to 
60 min. (use non-PVC 
equipment).  
Cycles 5-8   
Trastuzumab  
4 mg/kg (Loading 
dose) followed by 2 
mg/kg (Maintenance 
dose) every week 
or 8 mg/kg (Loading 
dose), followed by 6 
mg/kg (Maintenance 
dose) every 3 weeks 
 
• Loading dose: I.V. in 250 
mL NS over 90 min. 
Observe for 90 minutes 
post infusion.  
• Maintenance dose: I.V. in 
250 mL NS over 30 min on 
all the doses, observe for 30 
minutes post infusion 
Taxane 
 
Docetaxel (100 
mg/m2) 
            or  
Paclitaxel (175 
mg/m2) 
Administered I.V. in 250 
mL NS over 1 hour (use 
non-PVC equipment). 
Cycles 9 to 22 
Trastuzumab  
6 mg/kg 
(Maintenance dose) 
every 3 week 
 
I.V. in 250 mL NS over 30 
min on the all doses, 
observe for 30 minutes post 
infusion.  
 
*Cycle: 21 days 

 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
 
 
 
Order of administration in TCH protocol: Trastuzumab first, docetaxel 
second, carboplatin third. 
 
Drug 
Dose 
Administration Guideline 
Cycle* 1-6 
Trastuzumab 
4 mg/kg (Loading 
dose) followed by 2 
mg/kg (Maintenance 
dose) every week 
OR 8 mg/kg 
(Loading dose), 
followed by 6 mg/kg 
(Maintenance dose) 
every 3 week 
• Loading dose: I.V. in 250 
mL NS over 90 min. 
Observe for 1 hour post-
infusion 
• Maintenance dose: I.V. in 
250 mL NS over 30 min on 
the all doses, observe for 30 
minutes post infusion 
Docetaxel 
 
75 mg/m2 
 
Administered I.V. in 250 
mL NS over 1 hour (use 
non-PVC equipment). 
Carboplatin 
 
Dose = AUC 6 x 
(GFR + 25) 
Administered I.V. in 500 
mL D5W over 30 to 60 min 
Cycle 7 to 18 
Trastuzumab 
6 mg/kg 
(Maintenance dose) 
every 3 weeks 
I.V. in 250 mL NS over 30 
min on the all doses, 
observe for 30 minutes post 
infusion. 
 
*Cycle: 21 days 
 
As per institutional practice or American Society of Clinical Oncology (ASCO) 
adjuvant follow-up guidelines 2006, Breast cancer assessments for DFS and OS 
are to be reported for every 6 months. 
 
American Society of Clinical Oncology (ASCO) 2006 Guideline for Breast 
Cancer Follow-up in the adjuvant setting (Khatcheressian et al. 2006). In brief: 
 
• 
History/physical examination - every 3 to 6 months for the first 3 years after 
primary therapy; every 6 to 12 months for years 4 and 5; then annually. 
• 
Mammography - first post-treatment mammogram 1 year after the initial 
mammogram that leads to diagnosis, but no earlier than 6 months after 
definitive radiation therapy. Subsequent mammograms should be obtained 
as indicated for surveillance of abnormalities. 

 
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• 
Pelvic examination - regular gynecologic follow-up is recommended for all 
women. Patients who receive tamoxifen should be advised to report any 
vaginal bleeding to their physicians. 
 
The following are not recommended for routine surveillance: Routine blood tests 
(full blood counts and liver function tests), imaging studies (chest x-ray, bone 
scans, liver ultrasound, CT scans, FDG-PET scans, and breast MRI), tumor 
marker assessments (CA 15-3, CA 27.29, and CEA).  
 
However, bone scan, liver imaging, and brain CT scan will be performed if 
clinically indicated. 
 
During treatment period 
 
• 
Safety parameters will be assessed for every cycle.  
• 
Vital signs, physical examination and treatment compliance will be 
performed for every cycle and subject safety will be evaluated. 
• 
LVEF and ECG will be assessed for every 3 months (4 cycles) to evaluate 
cardiac safety of the patients. 
• 
ECOG will be assessed for every 3 months (4 cycles) to evaluate 
performance status of the patients. 
• 
Hematology and biochemistry assessments will also be performed during the 
study if clinically indicated. 
 
Follow-up Phase: 
 
Thereafter during follow up period of one year, Cardiac assessments at 6 and 12 
months following treatment cessation. Survival follow-up can be performed by 
regular telephonic calls and/or clinic visits every 6 months. 
 
4.5.1.1 Medical History and Demographic Data 
 
A complete medical history including clinically significant diseases, surgeries, 
cancer history (including prior cancer therapies and procedures), reproductive 
status, smoking history, use of alcohol and drugs of abuse, and all medications 
(e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic 
remedies, nutritional supplements) used by the patient within 2 weeks prior to 
screening will be recorded on the eCRF. Demographic data will include age, sex, 
and self-reported race/ethnicity. 
 
4.5.1.2 Physical Examinations 
 
A complete physical examination will be performed at each visit on relevant 
body systems and data will be recorded in the eCRF. Any abnormality identified 
at baseline should be recorded in the eCRF. 
 

 
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At subsequent visits, changes from baseline abnormalities should be recorded in 
patient notes. New or worsened clinically significant abnormalities should be 
recorded as adverse events. 
 
 
4.5.1.3 Vital Signs  
 
As per routine clinical practice, available vital signs including measurements of 
respiratory rate, pulse rate, systolic and diastolic blood pressure, and 
temperature will be measured before and after trastuzumab infusion, and 
recorded on the eCRF. New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event Form. 
 
4.5.1.4 Tumor and Response Evaluations  
 
Available data on tumor and treatment outcome from the medical records and 
patient interviews on medical history and disease characteristics (which are 
routinely performed in accordance with current guidelines and local standard of 
care) will be documented in the eCRF. The data available according to the 
response assessment will be captured in the eCRF. 
 
The investigator will continue to assess patients according to routine clinical 
practice at their discretion. Additional treatment outcome data may be collected 
for patients who continue to visit the doctor as per local standard of care till the 
end of study. 
 
4.5.1.5 Laboratory Assessments  
 
The laboratory assessments including hematology and biochemistry will be 
performed at screening visit from all the enrolled patients. Samples for these 
tests will be sent to the study site's local laboratory for analysis: 
 
Hematology and Biochemistry need not be repeated at baseline if not clinically 
indicated. 
The laboratory tests to be performed are listed below: 
 
• 
Hematology (WBC count, RBC count, hemoglobin, hematocrit, platelet 
count, absolute differential count [neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells). 
 
• 
Biochemistry (sodium, potassium, chloride, bicarbonate, fasting glucose, 
BUN or urea, creatinine, total protein, albumin, phosphorus, magnesium, 
calcium, total and direct bilirubin, alkaline phosphatase, ALT, AST, 
creatine phosphokinase, uric acid, LDH). 
 

 
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HER2-positive status on fixed tissue blocks from the primary tumor assessed by 
IHC (immuno histochemistry) and/or FISH (fluorescence insitu hybridisation) 
according to institutional criteria will be performed at central laboratory. Please 
see Appendix 4 for algorithm on HER2 testing. 
 
Laboratory test results will be recorded on the laboratory results pages of the 
Case Report Form. Laboratory test value abnormalities as such should not be 
reported on the AE page of the eCRF as adverse events, unless there is an 
associated clinical condition for which the patient is given treatment or 
concomitant treatment altered, it is considered to be a serious adverse event, 
leads to a change in study medication (e.g. dose modification/ interruption) or 
the patient is permanently discontinued from study drug because of the 
abnormal test value. 
 
4.5.1.6 12 Lead ECG 
 
ECGs will be performed at baseline, cycle 5, cycle 9, cycle 13, cycle 17, cycle 
21(only for AC-TH Regimen), termination visit and during follow-up. 
 
ECGs for each patient should be obtained from the same machine whenever 
possible. To minimize variability, it is important that patients be in a resting 
position for ≥ 10 minutes prior to each ECG evaluation. Body position should be 
consistently maintained for each ECG evaluation to prevent changes in heart 
rate. Environmental distractions (e. g: television, radio, conversation) should be 
avoided during the pre-ECG resting period and during ECG recording.  
 
For safety monitoring purposes, the investigator or designee must review, sign, 
and date all ECG tracings. Paper copies will be kept as part of the patient's 
permanent study file at the site.  
 
4.5.2 Timing of Study Assessments 
 
4.5.2.1 Screening and Pretreatment Assessments 
 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent 
Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.   
 
Screening tests and evaluations will be performed within 2 weeks prior to cycle 
1, unless otherwise specified.  Results of standard-of-care tests or examinations 
performed prior to obtaining informed consent and within 2 weeks prior to cycle 
1 may be used; such tests do not need to be repeated for screening. All screening 
evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before randomization. The investigator will maintain a 

 
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screening log to record details of all patients screened and to confirm eligibility 
or record reasons for screening failure, as applicable. 
 
Pretreatment tests and evaluations will be performed within 2 weeks prior to 
cycle 1after confirmation of other eligibility criteria, unless otherwise specified. 
 
Please see Appendix 1 and 2 for the schedule of screening and pretreatment 
assessments. 
 
4.5.2.2 Assessments during Treatment 
 
All assessments must be performed on the day of the specified visit, unless a 
time window is specified in the schedule of assessments (see Appendix 1 and 2). 
Assessments scheduled on the day of study treatment administration should be 
performed prior to administration of study treatment, unless otherwise noted in 
the schedule of assessments. 
All the enrolled patients will be required to visit the study site during week -2 to 
-1(baseline), study cycles 1 to 22 (1 cycle=21 days) for AC→TH regimen and 
cycles 1 to 18 for TCH regimen. Unscheduled clinical evaluations may occur at 
anytime if deemed appropriate by the Investigator. 
 
• 
Safety parameters will be assessed for every cycle.  
• 
Vital signs before and after study drug administration, physical 
examination and treatment compliance will be performed for every cycle 
and subject safety will be evaluated. 
• 
LVEF and ECG will be assessed for every 3 months (4 cycles) to evaluate 
cardiac safety of the patients. 
• 
ECOG will be assessed for every 3 months (4 cycles) to evaluate 
performance status of the patients. 
• 
Hematology and biochemistry assessments will also be performed during 
the study if clinically indicated. 
 
Please see Appendix 1 and 2 for the schedule of assessments performed during 
the treatment period. 
 
4.5.2.3 Assessments at Study Completion/Early Termination Visit 
 
Patients who complete the study or discontinue from the study early will be 
asked to return to the clinic 4 weeks after the last dose of study drug. The visit at 
which response assessment shows recurrent disease may be used as the study 
completion/early termination visit. 
 
Please see Appendix 1 and 2 for the schedule of assessments performed at the 
study completion/early termination visit. 
 
4.5.2.4 Follow-up Assessments 

 
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During follow up period of one year, Cardiac (LVEF and ECG) assessments at 6 
and 12 months following treatment cessation are done. Survival follow-up can 
be performed by regular telephonic calls and/or clinic visits every 6 months. 
 
Please see Appendix 1 and 2 for the schedule of follow-up assessments. 
 
4.5.2.5 Assessments at Unplanned Visits 
 
Please see Appendix 1 and 2 for assessments that are required to be performed 
in case of an unplanned visit. 
 
4.6 PATIENT, STUDY, AND SITE DISCONTINUATION 
 
4.6.1 Patient Discontinuation 
 
The investigator has the right to discontinue a patient from study drug or 
withdraw a patient from the study at any time.  In addition, patients have the 
right to voluntarily discontinue study drug or withdraw from the study at any 
time for any reason.  Reasons for discontinuation of study drug or withdrawal 
from the study may include, but are not limited to, the following: 
 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may 
jeopardize the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
 
4.6.1.1 Discontinuation from Study Drug 
 
Patients must discontinue study drug if they experience any of the following: 
 
• 
Pregnancy (unless the potential benefit for the mother outweighs the 
potential risk to the fetus). 
 
• 
If patients have a continued decrease in left ventricular function, but remain 
asymptomatic, the physician should consider discontinuing therapy if no 
clinical benefit of Trastuzumab therapy has been seen. 
 
• 
If LVEF has not improved, or declined further, discontinuation of 
Trastuzumab should be strongly considered, unless the benefits for the 
individual patient are deemed to outweigh the risks. 
 
• 
Discontinuation of Trastuzumab therapy should be strongly considered in 
patients who develop clinically significant heart failure unless the benefits 
for an individual patient are deemed to outweigh the risks. 
 

 
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LVEF 45–49 
Hold trastuzumab 
Repeat LVEF in 3 weeks 
≥ 10 EF points from baseline 
Hold trastuzumab 
Repeat LVEF in 3 weeks 
< 10 EF 
points from 
baseline 
LVEF  ≤ 44 or 
LVEF 45–49 
and ≥10 points 
from baseline 
LVEF 45–49 and < 
10 points from 
baseline or LVEF > 
49 
LVEF ≤ 44 or 
LVEF 45–49 
and ≥10 points 
from baseline 
 
Continue 
trastuzumab 
LVEF 45–49 < 10 
points from 
baseline or 
LVEF > 49 
Stop 
trastuzumab 
Resume trastuzumab 
Stop 
trastuzumab 
Resume 
trastuzumab 
LVEF ≤44 
LVEF < 50 
Continue 
trastuzumab 
LVEF ≥50 
Patients who discontinue study drug prematurely will be asked to return to the 
clinic for a study completion/early termination visit and may undergo follow-up 
assessments. The primary reason for premature study drug discontinuation 
should be documented on the appropriate eCRF. Patients who discontinue study 
drug prematurely will not be replaced. 
 
Algorithm for knowing how to prevent, monitor, and manage cardiac events in 
patients undergoing cytotoxic chemotherapy using trastuzumab based on the 
changes in LVEF66 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.6.1.2 Withdrawal from Study 
 
Every effort should be made to obtain information on patients who withdraw 
from the study. The primary reason for withdrawal from the study should be 
documented on the appropriate eCRF. Patients will not be followed for any 
reason after consent has been withdrawn. Patients who withdraw from the study 
will not be replaced. 

 
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4.6.2 Study and Site Discontinuation 
 
The Sponsor has the right to terminate this study at any time. Reasons for 
terminating the study may include, but are not limited to, unsatisfactory patient 
enrollment. 
 
The Sponsor will notify the investigator if the study is placed on hold, or if the 
Sponsor decides to discontinue the study.   
 
The Sponsor has the right to replace a site at any time.  Reasons for replacing a 
site may include, but are not limited to, the following: 
 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the GCP guidelines and regulations 
 
5. 
ASSESSMENT OF SAFETY  
 
5.1 SAFETY PLAN 
 
Trastuzumab therapy should only be initiated under supervision of a physician 
experienced in the treatment of cancer patients.  
 
The council of International organizations of Medical sciences (CIOMS) 
working group has recommended as the use of the development core safety 
information (DCSI) as the summary of identified safety issues for an 
investigational product or drug.66 The Developmental Core Safety Information 
(DCSI) provides a concise summary of any contraindications, warnings and 
precautions, provisional adverse drug reactions (ADRs) and other significant 
safety information regarding the use of Trastuzumab. 
 
1) Infusion Reactions 
 
Serious adverse reactions to Trastuzumab infusion including dyspnoea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation 
and respiratory distress have been reported infrequently. The Trastuzumab 
infusion should be discontinued and the patient monitored until resolution of any 
observed symptoms. Serious reactions have been treated successfully with 
supportive therapy such as oxygen, beta-agonists and corticosteroids. In rare 
cases, these reactions are associated with a clinical course culminating in a fatal 
outcome.  
Patients who are experiencing dyspnoea at rest due to complications of 
advanced malignancy or comorbidities may be at increased risk of a fatal 

 
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infusion reaction. Therefore, these patients should be treated with extreme 
caution and the risk versus the benefit considered for each patient. 
 
2) Pulmonary Adverse Events 
 
Severe pulmonary events have been reported rarely with the use of Trastuzumab 
in the post-marketing setting. These rare events have occasionally resulted in 
fatal outcome. In addition, rare cases of pulmonary infiltrates, acute respiratory 
distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory 
distress, acute pulmonary edema and respiratory insufficiency have been 
reported. These events may occur as part of an infusion-related reaction or with 
a delayed onset. Patients with symptomatic intrinsic lung disease or with 
extensive tumor involvement of the lungs, resulting in dyspnoea at rest, may be 
at greater risk of severe reactions. 
 
3) Cardiovascular Adverse Events 
 
Heart failure (New York Heart Association [NYHA] class II-IV) has been 
observed in patients receiving Trastuzumab therapy alone or in combination 
with paclitaxel following anthracycline (doxorubicin or epirubicin)–containing 
chemotherapy. This may be moderate to severe and has been associated with 
death.  
 
 
Caution should be exercised in treating patients with symptomatic heart failure, 
a history of hypertension, or documented coronary artery disease. Candidates for 
treatment with Trastuzumab, especially those with prior anthracycline and 
cyclophosphamide (AC) exposure, should undergo baseline cardiac assessment 
including history and physical examination, ECG and echocardiogram. A 
careful risk-benefit assessment should be made before deciding to treat with 
Trastuzumab. 
In Early Breast Cancer, the following patients were excluded from the HERA 
trial, therefore there are no data about the benefit : risk balance, and 
consequently treatment cannot be recommended in such patients: 
 
• 
History of documented congestive heart failure 
• 
High-risk uncontrolled arrhythmias 
• 
Angina pectoris requiring medication 
• 
Clinically significant valvular disease 
• 
Evidence of transmural infarction on ECG 
• 
Poorly controlled hypertension 
 
Cardiac function should be further monitored during treatment (e.g. every three 
months). Monitoring may help to identify patients who develop cardiac 
dysfunction. Patients who develop asymptomatic cardiac dysfunction may 
benefit from more frequent monitoring (e.g. every 6-8 weeks). If patients have a 

 
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continued decrease in left ventricular function, but remain asymptomatic, the 
physician should consider discontinuing therapy if no clinical benefit of 
Trastuzumab therapy has been seen. 
 
If LVEF drops 10 ejection points from baseline and to below 50%, Trastuzumab 
should be withheld and a repeat LVEF assessment performed within 
approximately 3 weeks. If LVEF has not improved, or declined further, 
discontinuation of Trastuzumab should be strongly considered, unless the 
benefits for the individual patient are deemed to outweigh the risks. 
 
If symptomatic cardiac failure develops during Trastuzumab therapy, it should 
be treated with the standard medications for this purpose. Discontinuation of 
Trastuzumab therapy should be strongly considered in patients who develop 
clinically significant heart failure unless the benefits for an individual patient are 
deemed to outweigh the risks. 
 
The safety of continuation or resumption of Trastuzumab in patients who 
experience cardiotoxicity has not been prospectively studied. However, most 
patients who developed heart failure in the pivotal trials improved with standard 
medical treatment. This included diuretics, cardiac glycosides, and/or 
angiotensin-converting enzyme inhibitors. The majority of patients with cardiac 
symptoms and evidence of a clinical benefit of Trastuzumab treatment continued 
on weekly therapy with Trastuzumab without additional clinical cardiac events. 
 
4) Interstitial lung disease 
 
Risk factors associated with interstitial lung disease include prior or concomitant 
therapy with other anti-neoplastic therapies known to be associated with it such 
as taxanes, gemcitabine, vinorelbine and radiation therapy. 
 
5) Benzyl Alcohol Sensitivity 
 
Benzyl alcohol, used as a preservative in bacteriostatic water for injection in the 
440 mg multidose vial, has been associated with toxicity in neonates and 
children up to 3 years old. When administering Trastuzumab to a patient with a 
known sensitivity to benzyl alcohol, Trastuzumab should be reconstituted with 
water for injection, and only one dose per Trastuzumab vial should be used. Any 
unused portion must be discarded. Sterile water for injection, used to 
reconstitute the 150 mg single dose vial, does not contain benzyl alcohol. 
 
6) Pregnancy/Nursing Mothers 
 
Trastuzumab should be avoided during pregnancy unless the potential benefit 
for the mother outweighs the potential risk to the fetus. In the post-marketing 
setting, some associated with fatal pulmonary hypoplasia of the fetus, cases of 
oligohydramnios have been reported in pregnant women receiving Trastuzumab. 

 
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Women of childbearing potential should be advised to use effective 
contraception during treatment with Trastuzumab and for at least 6 months after 
treatment has concluded. Women who become pregnant should be advised of 
the possibility of harm to the fetus. If a pregnant woman is treated with 
Trastuzumab, close monitoring by a multidisciplinary team is desirable. It is not 
known whether Trastuzumab can affect reproductive capacity. Animal 
reproduction studies revealed no evidence of impaired fertility or harm to the 
fetus. 
 
7) Potential for Drug-Drug Interactions 
 
There has been no formal drug interaction studies performed with Trastuzumab 
in humans. Clinically significant interactions with the concomitant medication 
used in clinical trials have not been observed. 
 
5.1.1 Management of Specific Adverse Events 
 
Table - 1 Guidelines for Managing Specific Adverse Events 
 
Event 
Action to Be Taken 
Infusion Reactions • During the first infusion with Trastuzumab, chills 
and/or fever are observed commonly in patients. 
• Other signs and/or symptoms may include nausea, 
vomiting, pain, rigors, headache, cough, dizziness, 
rash, asthenia, and hypertension. 
• These symptoms are usually mild to moderate in 
severity, and occur infrequently with subsequent 
Trastuzumab infusions. 
• These symptoms can be treated with an 
analgesic/antipyretic such as meperidine or 
paracetamol, or an antihistamine such as 
diphenhydramine 
 
 
5.2 SAFETY PARAMETERS AND DEFINITIONS 
 
Safety assessments will consist of monitoring and recording adverse events, 
including serious adverse events and non-serious adverse events of special 
interest; measurement of protocol-specified safety laboratory assessments; 
measurement of protocol-specified vital signs; and other protocol-specified tests 
that are deemed critical to the safety evaluation of the study. 
 
All the Adverse Event (AE) and Serious Adverse Events (SAEs) will be 
captured appropriately. 
 
 

 
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5.2.1 Adverse Events 
 
According to the ICH guideline for Good Clinical Practice, an adverse event is 
any untoward medical occurrence in a clinical investigation subject administered 
a pharmaceutical product, regardless of causal attribution. An adverse event can 
therefore be any of the following: 
 
• 
Any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal 
product. 
 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition). 
 
• 
Recurrence of an intermittent medical condition (e.g., headache) not 
present at baseline. 
 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, 
X-ray) that is associated with symptoms or leads to a change in study 
treatment or concomitant treatment or discontinuation from study drug. 
 
• 
Adverse events that are related to a protocol-mandated intervention, 
including those that occur prior to assignment of study treatment 
(e.g., screening invasive procedures such as biopsies). 
 
5.2.2 Serious Adverse Events (Immediately Reportable to the Sponsor) 
 
A serious adverse event is any adverse event that meets any of the following 
criteria: 
 
• 
Fatal (i.e., the adverse event actually causes or leads to death). 
• 
Life threatening (i.e., the adverse event, in the view of the investigator, 
places the patient at immediate risk of death). 
• 
This does not include any adverse event that had it occurred in a more 
severe form or was allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization.  
• 
Results in persistent or significant disability/incapacity (i.e., the adverse 
event results in substantial disruption of the patient’s ability to conduct 
normal life functions). 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to study drug. 

 
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• 
Significant medical event in the investigator's judgment (e.g., may 
jeopardize the patient or may require medical/surgical intervention to 
prevent one of the outcomes listed above). 
 
The terms “severe” and “serious” are not synonymous. Severity refers to the 
intensity of an adverse event (rated as mild, moderate, or severe, or according to 
NCI CTCAE criteria; see Section 5.3.3); the event itself may be of relatively 
minor medical significance (such as severe headache without any further 
findings). 
 
Severity and seriousness need to be independently assessed for each adverse 
event recorded on the eCRF. 
 
Serious adverse events are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event). 
 
5.2.3 Non-Serious Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
 
Immediate reporting to the Sponsor is already well defined for serious adverse 
events. Non-serious adverse events of special interest also require immediate 
reporting to the Sponsor for real-time monitoring. Non-serious adverse events of 
special interest are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours) Adverse events of special interest for 
this study include the following: 
 
• 
Cases of an elevated ALT or AST in combination with either an elevated 
bilirubin or clinical jaundice.  
 
Investigators must report as an adverse event the occurrence of either of the 
follow: 
 
• 
Suspected transmission of an infectious agent by the study drug. 
• 
Cardiac failure congestive. 
 
5.2.4 Selected Adverse Events 
 
Selected adverse events do not require immediate reporting and should not be 
confused with non-serious adverse events of special interest which require 
reporting to the Sponsor immediately (i.e., no more than 24 hours) after learning 
of an event. 
 
 
 
 
 

 
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Additional data will be collected for the following selected adverse events in 
guided questionnaire : 
 
• 
Cardiac AEs 
• 
Hemolytic Anemia 
• 
Infusion related reactions 
• 
Interstitial Lung Disease 
• 
Thyroid dysfunction 
 
 
5.3 METHODS AND TIMING FOR CAPTURING AND ASSESSING SAFETY 
PARAMETERS 
 
The investigator is responsible for ensuring that all adverse events (see Section 
5.2.1 for definition) are recorded on the Adverse Event eCRF and reported to the 
Sponsor. 
For each adverse event recorded on the Adverse Event eCRF, the investigator 
will make an assessment of seriousness, severity, and causality.   
 
5.3.1 Adverse Event Reporting Period 
 
Investigators will seek information on adverse events at each patient contact. All 
adverse events, whether reported by the patient or noted by study personnel, will 
be recorded in the patient’s medical record and on the Adverse Event eCRF. 
 
After informed consent has been obtained but prior to initiation of study 
drug, only serious adverse events caused by a protocol-mandated intervention 
should be reported (e.g., serious adverse events related to invasive procedures 
such as biopsies). 
 
After initiation of study drug, all adverse events, regardless of relationship to 
study drug will be reported after the last dose of study drug. After the end of the 
follow-up period and after study closure, all SAEs and non-serious AESIs 
(regardless of causality) occurring to a subject should be reported to the sponsor 
if the investigator becomes aware of them. The investigator is not required to 
actively monitor patients after the study has ended. 
 
5.3.2 Eliciting Adverse Event Information 
 
A consistent methodology of non-directive questioning should be adopted for 
eliciting adverse event information at all patient evaluation time points.  
Examples of non-directive questions include the following: 
 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?”  

 
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5.3.3 Assessment of Severity of Adverse Events 
 
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used 
for assessing adverse event severity. Table below will be used for assessing 
severity for adverse events that are not specifically listed in the NCI CTCAE. 
 
Table 2 -  Adverse Event Severity Grading Scale  
 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; 
clinical or diagnostic observations only; or 
intervention not indicated 
2 
Moderate; minimal, local, or non-invasive 
intervention indicated; or limiting age 
appropriate instrumental activities of daily 
living a 
3 
Severe or medically significant, but not 
immediately life threatening; hospitalization 
or prolongation of hospitalization indicated; 
disabling; or limiting self care activities of 
daily living b,c 
4 
Life-threatening consequences or urgent 
intervention indicated d  
5 
Death related to adverse event d 
 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse 
Events. 
 
Note: 
Based 
on 
the 
NCI 
CTCAE 
(v4.0), 
which 
can 
be 
found 
at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE 4.03 2010-06-
14 QuickReference 8.5x11.pdf 
 
a 
Instrumental activities of daily living refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc. 
b 
Examples of self-care activities of daily living include bathing, dressing and 
undressing, feeding one's self, using the toilet, and taking medications, as performed 
by patients who are not bedridden. 
c 
If an event is assessed as a "significant medical event," it must be reported as a 
serious adverse event. 
d 
Grade 4 and 5 events must be reported as serious adverse events  
 
 
 
 

 
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5.3.4 Assessment of Causality of Adverse Events 
 
Investigators should use their knowledge of the patient, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether or not an adverse event is considered to be related to the 
study drug, indicating "yes" or "no" accordingly.  The following guidance 
should be taken into consideration: 
 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where 
applicable) 
• 
Known association of the event with the study drug or with similar 
treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications 
known to increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated 
with the occurrence of the event 
 
5.3.5 Procedures for Recording Adverse Events 
 
Investigators should use correct medical terminology/concepts when recording 
adverse events on the Adverse Event eCRF.  Avoid colloquialisms and 
abbreviations. 
Only one adverse event term should be recorded in the event field on the 
Adverse Event eCRF. 
 
5.3.5.1 Diagnosis versus Signs and Symptoms 
 
Infusion-Related Reactions  
 
Adverse events that occur during or within 24 hours after study drug infusion 
should be captured as individual signs and symptoms rather than a diagnosis of 
allergic reaction or infusion reaction. 
 
Other Adverse Events 
 
For adverse events other than infusion-related reactions, a diagnosis (if known) 
should be recorded on the Adverse Event eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, 
asterixis, and elevated transaminases). However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or 
syndrome at the time of reporting, each individual event should be recorded on 

 
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the Adverse Event eCRF.  If a diagnosis is subsequently established, all 
previously reported adverse events based on signs and symptoms should be 
nullified and replaced by one adverse event report based on the single diagnosis, 
with a starting date that corresponds to the starting date of the first symptom of 
the eventual diagnosis. 
 
5.3.5.2 Adverse Events Occurring Secondary to Other Events 
 
In general, adverse events occurring secondary to other events (e.g., cascade 
events or clinical sequelae) should be identified by their primary cause, with the 
exception of severe or serious secondary events. However, medically significant 
adverse events occurring secondary to an initiating event that are separated in 
time should be recorded as independent events on the Adverse Event eCRF. For 
example: 
 
• 
If vomiting results in mild dehydration with no additional treatment in a 
healthy adult, only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported 
separately on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events 
should be reported separately on the eCRF. 
• 
If dizziness leads to a fall and subsequent fracture, all three events should 
be reported separately on the eCRF. 
• 
If neutropenia is accompanied by a mild, non-serious infection, only 
neutropenia should be reported on the eCRF. 
• 
If neutropenia is accompanied by a severe or serious infection, both events 
should be reported separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if 
it is unclear as to whether the events are associated. 
 
Recurrence of breast cancer should not be reported as an AE since this is clearly 
consistent with progression/relapse of the underlying disease. Hospitalization 
due solely to the relapse of underlying malignancy should NOT be reported as 
an SAE. Clinical symptoms of relapse may be reported as AEs if the symptom 
cannot be determined as exclusively due to the relapse of the underlying 
malignancy, or does not fit the expected pattern of relapse for the disease under 
study. If there is any uncertainty about an adverse event being due only to the 
disease under study, it should be reported as an AE or SAE. 
 
 
 
 

 
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5.3.5.3 Persistent or Recurrent Adverse Events 
 
A persistent adverse event is one that extends continuously, without resolution, 
between patient evaluation time points. Such events should only be recorded 
once on the Adverse Event eCRF. The initial severity of the event should be 
recorded, and the severity should be updated to reflect the most extreme severity 
any time the event worsens.  If the event becomes serious, the Adverse Event 
eCRF should be updated to reflect this. 
 
A recurrent adverse event is one that resolves between patient evaluation time 
points and subsequently recurs.  Each recurrence of an adverse event should be 
recorded separately on the Adverse Event eCRF. 
 
5.3.5.4 Abnormal Laboratory Values 
 
Not every laboratory abnormality qualifies as an adverse event. A laboratory 
test result should be reported as an adverse event if it meets any of the following 
criteria: 
 
• 
Accompanied by clinical symptoms. 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation). 
• 
Results in a medical intervention (e.g., potassium supplementation for 
hypokalemia) or a change in concomitant therapy. 
• 
Clinically significant in the investigator’s judgment.  
 
It is the investigator’s responsibility to review all laboratory findings. Medical 
and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an adverse event. 
 
If a clinically significant laboratory abnormality is a sign of a disease or 
syndrome (e.g., alkaline phosphatase and bilirubin 5 times the upper limit 
of normal [ULN] associated with cholecystitis), only the diagnosis 
(i.e., cholecystitis) should be recorded on the Adverse Event eCRF. 
 
If a clinically significant laboratory abnormality is not a sign of a disease or 
syndrome, the abnormality itself should be recorded on the Adverse Event 
eCRF, along with a descriptor indicating if the test result is above or below the 
normal range (e.g., "elevated potassium," as opposed to "abnormal potassium").  
If the laboratory abnormality can be characterized by a precise clinical term per 
standard definitions, the clinical term should be recorded as the adverse event.  
For example, an elevated serum potassium level of 7.0 mEq/L should be 
recorded as “hyperkalemia.” 
 

 
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Observations of the same clinically significant laboratory abnormality from visit 
to visit should not be repeatedly recorded on the Adverse Event eCRF, unless 
the etiology changes.  The initial severity of the event should be recorded, and 
the severity or seriousness should be updated any time the event worsens. 
 
5.3.5.5 Abnormal Vital Sign Values 
 
Not every vital sign abnormality qualifies as an adverse event. A vital sign 
result should be reported as an adverse event if it meets any of the following 
criteria: 
 
• 
Accompanied by clinical symptoms. 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation). 
• 
Results in a medical intervention or a change in concomitant therapy. 
• 
Clinically significant in the investigator’s judgment. 
 
It is the investigator’s responsibility to review all vital sign findings. Medical 
and scientific judgment should be exercised in deciding whether an isolated 
vital sign abnormality should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or 
syndrome (e.g., high blood pressure), only the diagnosis (i.e., hypertension) 
should be recorded on the Adverse Event eCRF. 
 
Observations of the same clinically significant vital sign abnormality from visit 
to visit should not be repeatedly recorded on the Adverse Event eCRF, unless 
the etiology changes.  The initial severity of the event should be recorded, and 
the severity or seriousness should be updated any time the event worsens. 
 
5.3.5.6 Abnormal Liver Function Tests 
 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either 
an elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of 
cholestasis or other causes of hyperbilirubinemia is considered to be an 
indicator of severe liver injury.  Therefore, investigators must report as an 
adverse event the occurrence of either of the following: 
 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total 
bilirubin > 2 × ULN. 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical 
jaundice. 
• 
The most appropriate diagnosis or (if a diagnosis cannot be established) the 
abnormal laboratory values should be recorded on the Adverse Event eCRF 
and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event), either as a serious adverse event or a non-serious 
adverse event of special interest. 

 
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5.3.5.7 Deaths 
 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period that are attributed by the 
investigator solely to progression of Early Breast Cancer should be recorded 
only on the Study Completion/Early Discontinuation eCRF. All other on-study 
deaths, regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor. 
 
Death should be considered an outcome and not a distinct event. The event or 
condition that caused or contributed to the fatal outcome should be recorded as 
the single medical concept on the Adverse Event eCRF. Generally, only one 
such event should be reported. The term “sudden death” should only be used 
for the occurrence of an abrupt and unexpected death due to presumed cardiac 
causes in a patient with or without preexisting heart disease, within 1 hour of the 
onset of acute symptoms or, in the case of an unwitnessed death, within 
24 hours after the patient was last seen alive and stable.  If the cause of death is 
unknown and cannot be ascertained at the time of reporting, “unexplained 
death” should be recorded on the Adverse Event eCRF.  If the cause of death 
later becomes available (e.g., after autopsy), “unexplained death” should be 
replaced by the established cause of death. 
 
 
During post-study survival follow-up, deaths attributed to progression of Early 
Breast Cancer should be recorded only on the Survival eCRF or Study 
Completion/Early Discontinuation eCRF.  
 
5.3.5.8 Preexisting Medical Conditions 
 
A preexisting medical condition is one that is present at the screening visit for 
this study.  Such conditions should be recorded on the General Medical History 
and Baseline Conditions eCRF. 
 
A preexisting medical condition should be recorded as an adverse event only if 
the frequency, severity, or character of the condition worsens during the study.  
When recording such events on the Adverse Event eCRF, it is important to 
convey the concept that the preexisting condition has changed by including 
applicable descriptors (e.g., “more frequent headaches”). 
 
 
 
 
 
 
 

 
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5.3.5.9 Lack of Efficacy or Worsening of Early Breast Cancer 
 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events. These data will be 
captured as efficacy assessment data only. In most cases, the expected pattern of 
progression will be based on RECIST criteria. In rare cases, the determination 
of clinical progression will be based on symptomatic deterioration. However, 
every effort should be made to document progression using objective criteria. If 
there is any uncertainty as to whether an event is due to disease progression, it 
should be reported as an adverse event. 
 
5.3.5.10 Hospitalization or Prolonged Hospitalization 
 
Any adverse event that results in hospitalization or prolonged hospitalization 
should be documented and reported as a serious adverse event (per the 
definition of serious adverse event), except as outlined below.   
 
The following hospitalization scenarios are not considered to be serious adverse 
events: 
 
• 
Hospitalization for respite care. 
• 
Planned hospitalization required by the protocol (e.g., for study drug 
administration). 
• 
Hospitalization for a preexisting condition, provided that all of the 
following criteria are met. 
 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected normal 
progression of the disease. 
 
The patient has not suffered an adverse event. 
 
5.3.5.11 Overdoses 
 
Study drug overdose is the accidental or intentional use of the drug in an 
amount higher than the dose being studied.  An overdose or incorrect 
administration of study drug is not an adverse event unless it results in untoward 
medical effects.   
 
Any study drug overdose or incorrect administration of study drug should be 
noted on the Study Drug Administration eCRF.  
 

 
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All adverse events associated with an overdose or incorrect administration of 
study drug should be recorded on the Adverse Event eCRF. If the associated 
adverse event fulfills serious criteria, the event should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event). 
 
5.4 IMMEDIATE REPORTING REQUIREMENTS FROM INVESTIGATOR 
TO SPONSOR 
 
Certain events require immediate reporting to allow the Sponsor to take 
appropriate measures to address potential new risks in a clinical trial. The 
investigator must report such events to the Sponsor immediately; under no 
circumstances should reporting take place more than 24 hours after the 
investigator learns of the event. The following is a list of events that the 
investigator must report to the Sponsor within 24 hours after learning of the event, 
regardless of relationship to study drug: 
 
• 
Serious adverse events. 
• 
Non-serious adverse events of special interest. 
• 
Pregnancies. 
 
The investigator must report new significant follow-up information for these 
events to the Sponsor immediately (i.e., no more than 24 hours after becoming 
aware of the information). New significant information includes the following: 
 
• 
New signs or symptoms or a change in the diagnosis. 
• 
Significant new diagnostic test results. 
• 
Change in causality based on new information. 
• 
Change in the event’s outcome, including recovery. 
• 
Additional narrative information on the clinical course of the event. 
 
Investigators must also comply with local requirements for reporting serious 
adverse events to the local health authority and IRB/EC. 
 
5.4.1 Emergency Medical Contacts 
 
Medical Monitor (Roche Medical Responsible) Contact Information: 
  
Primary Contact 
 
Medical Monitor: Dr.
 
Telephone No.: +91-22-24941414 
Mobile Telephone No.: 
 
 
 
 

 
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5.4.3.2 Abortions 
 
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers spontaneous abortions to be medically significant events), 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event).   
 
5.4.3.3 Congenital Anomalies/Birth Defects 
 
Any congenital anomaly/birth defect in a child born to a female patient should 
be classified as a serious adverse event, recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event). 
 
5.5 FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
 
5.5.1.1 Investigator Follow-Up 
 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the 
patient is lost to follow up, or the patient withdraws consent. Every effort should 
be made to follow all serious adverse events considered to be related to study 
drug or trial-related procedures until a final outcome can be reported. 
 
During the study period, resolution of adverse events (with dates) should be 
documented on the Adverse Event eCRF and in the patient’s medical record to 
facilitate source data verification. If, after follow-up, return to baseline status or 
stabilization cannot be established, an explanation should be recorded on the 
Adverse Event eCRF.  
 
All pregnancies reported during the study should be followed until pregnancy 
outcome.   
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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5.5.1.2 Sponsor Follow-Up 
 
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, 
electronic mail, and/or a monitoring visit to obtain additional case details and 
outcome information (e.g., from hospital discharge summaries, consultant 
reports, autopsy reports) in order to perform an independent medical assessment 
of the reported case. 
 
5.6 POST-STUDY ADVERSE EVENTS 
 
At the safety follow-up visit, the Investigator should instruct each patient to report 
to the Investigator any subsequent adverse events. 
  
After study closure, the Sponsor should be notified if the investigator becomes 
aware of any death, serious adverse event, or other adverse event of special 
interest occurring at any time after a patient has discontinued study participation 
regardless of the relationship to the study drug. The investigator is not required to 
actively monitor patients after the study has ended. 
  
The Sponsor should also be notified if the Investigator becomes aware of the 
development of cancer or a congenital anomaly/birth defect in a subsequently 
conceived offspring of a patient that participated in this study. 
  
The investigator should report these events to Roche Safety Risk Management on 
the Adverse Event eCRF. If the Adverse Event eCRF is no longer available, the 
investigator should report the event directly to Roche Safety Risk Management 
via telephone (see "Protocol Administrative and Contact Information & List of 
Investigators"). 
 
During post-study survival follow-up, deaths attributed to progression of early 
breast cancer should be recorded only on the Survival eCRF or Study 
Completion/Early Discontinuation eCRF. 
 
 
 
 
 
 
 
 
 
 
 
 

 
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5.7 EXPEDITED 
REPORTING 
TO 
HEALTH 
AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND ETHICS 
COMMITTEES 
 
The Sponsor will promptly evaluate all serious adverse events and non-serious 
adverse events of special interest against cumulative product experience to 
identify and expeditiously communicate possible new safety findings to 
investigators, IRBs, ECs, and applicable health authorities based on applicable 
legislation. 
 
To determine reporting requirements for single adverse event cases, the Sponsor 
will assess the expectedness of these events using the following reference 
documents: 
• Local prescribing information for Trastuzumab 
• Trastuzumab Core Data Sheet  
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
 
Reporting requirements will also be based on the investigator's assessment of 
causality and seriousness, with allowance for upgrading by the Sponsor as needed. 
 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
 
6.1  DETERMINATION OF SAMPLE SIZE 
 
A total of approximately 109 subjects will be required to conduct a phase IV 
study to evaluate safety and efficacy of Trastuzumab in HER2 positive node 
positive or high risk node negative breast cancer by assuming level of significance 
5%, incidence of adverse event 65.9%, precision 10% and dropout rate 20%. 
 
Incidence of adverse event in AC-TH group with Grade 3 or 4 hematologic events 
such as neutropenia, leucopenia, febrile neutropenia, neutropenic infection, 
anemia, thrombocytopenia, leukemia were 71.5%, 60.3 %, 10.9%, 11.9%, 3.1%, 
2.1% and 0.1% respectively. In TCH group incidence of adverse event with Grade 
3 or 4 hematologic events such as neutropenia, leucopenia, febrile neutropenia, 
neutropenic infection, anemia, thrombocytopenia, leukemia were 65.9%, 48.2 %, 
9.6 %, 11.2%, 5.8%, 6.1% and 0.1% respectively.  
 

 
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While considering the 71.5%, the highest incidence of adverse event in AC-TH 
group, sample of size 99 patients will be required. Similarly, by considering the 
highest incidence of adverse event 65.9% in TCH group, sample of size 109 
patients will be required. Also considered the incidence of 68.7% (i.e. mean of 
71.5% and 65.9%), 104 patients will be required. The above three calculations, 
assumed a 5% level of significance, 10% precision and 20% dropout rate. 
Considering all the above calculation, it is suggested that approximately 109 
patients will be required for the proposed study. 
 
6.2 SUMMARIES OF CONDUCT OF STUDY 
 
The demographic characteristics will be summarized for all the patients enrolled 
into the study. All baseline & demographic data and general medical history will 
be summarized at screening visit. Descriptive statistics such as number of non-
missing observations (n), mean, median, Standard Deviation (SD), 1st Quartile 
(Q1), 3rd Quartile (Q3), minimum and maximum will be estimated for continuous 
variables (e.g. Age, Height .etc) and frequency counts and percentages will be 
employed for categorical variables (e.g. Gender, Race.etc). All statistical tests will 
be done at 5 % significance level and p ≤ 0.05 indicate the significance. Two – 
sided 95% confidence interval (CI) will be constructed, wherever appropriate. 
 
6.3 EFFICACY ANALYSES 
 
The secondary objectives include Disease free survival and Overall survival. DFS 
is defined as time from the date of first study treatment to the date of local, 
regional or distant recurrence, contra-lateral breast cancer or death due to any 
cause. OS is defined as time from the date of first study treatment until date of 
death, regardless of the cause of death. 
 
The median Disease free survival time and median overall survival time with 95% 
confidence interval will be estimated using Kaplan Meier method and KM plots 
will also be provided. Log rank test will be used to compare the median survival 
time between subjects with ECOG PS 0 and ECOG PS 1-2 at baseline for DFS 
and OS. 
 
 
 

 
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6.4 SAFETY ANALYSES 
 
Safety measurements include adverse events, laboratory tests (hematology and 
biochemistry), vital signs, electrocardiograms, physical examinations, and toxicity 
evaluations. Toxicities will be evaluated at each course of therapy using the NCI-
CTCAE version 4.0 or a non-CTC grading scale for toxicities that are not covered 
by the NCI CTC. 
 
Adverse Events (AEs) and Serious Adverse Events (SAEs) related to 
Trastuzumab will be summarized by using number and percentage (Incidence of 
AEs and SAEs). AEs and SAEs related to Trastuzumab will be coded using 
MedDRA, version 15.1 or greater. AEs and SAEs also will be summarized using 
number and percentage by System Organ Class and Preferred Term. Summaries 
will be presented for all adverse events and adverse events related to study drug. 
Adverse events will also be summarized by toxicity grade, outcome, seriousness 
and action taken to the study medication. 
 
All the Laboratory evaluations (hematology & biochemistry) will be considered at 
baseline and completion/early termination visits. Descriptive statistics such as n, 
mean, median, standard deviation (SD), Q1,Q3, minimum (Min), and maximum 
(Max) will be provided for all. Change from Baseline will be calculated for all the 
available hematology and biochemistry parameters as specified in the eCRF pages. 
Mean change from baseline will be compared using paired t test or Wilcoxon 
signed-rank test  based on normality assumption. 
 
ECOG performance status will be collected at baseline and every 4 Cycles during 
treatment period. Counts and percentages will be reported in the results. 
Generalized McNemar’s test will be used to compare the ECOG PS between 
baseline and follow-up visits. 
 
Patient data will be analyzed for evidence of cumulative toxicity with repeated 
courses of therapy. Summary of ECG status will be evaluated at all visits. Counts 
and percentages will be reported in the results.  
 
 
HER-2 testing will be collected at Baseline/Screening. This will be summarized 
using number and percentage. 
 
LVEF will be collected for every 3 months or and percentage change from 
baseline will be reported for every 3 months. Mean change from baseline will be 
compared using paired t test or Wilcoxon signed-rank test based on normality 
assumption. All statistical tests will be done at 5 % significance level and p ≤ 0.05 
indicate the significance. 
 

 
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6.5 INTERIM ANALYSES 
 
No Interim Analysis Planned for this study. 
 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 DATA QUALITY ASSURANCE 
 
The overall procedures for quality assurance of clinical study data are described in 
the Roche Standard Operational Procedures. 
 
a) Data collection 
 
Source data entered manually will be collected via mEDC using eCRFs. Sites will 
be responsible for data entry into the mEDC system. In the event of discrepant 
data, the clarification from the sites will be requested, which the sites will resolve 
electronically in the mEDC system. If a subject withdraws from the study, the 
reason must be noted on the eCRF. All missing data should also be accounted for 
in the eCRF. The investigator should ensure the accuracy, completeness and 
timeliness of the data reported to the sponsor. A comprehensive validation check 
program will verify the data and discrepancy reports will be generated 
accordingly for resolution by the investigator. 
 
b) Data management 
 
Data cleaning activity will be performed by the data management team. For any 
missing/incorrect/ uncertain data in the eCRF, the data management team will 
raise a query. The investigator is requested to provide the necessary justification.  
 
c) Assignment of preferred terms 
 
For classification purposes, preferred terms will be assigned by the sponsor to the 
original terms entered on the eCRF, using the current version of MedDRA 
(Medical dictionary for regulatory activities) for AEs and diseases. 
 
7.2 ELECTRONIC CASE REPORT FORMS  
 
Sites will receive training and will have access to eCRF filling instructions.  
eCRFs will be submitted electronically to the CRO and should be handled in 
accordance with instructions from the Sponsor/CRO. 
 
All eCRFs should be completed by designated, trained site staff. eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. At 
the end of the study, the investigator will receive patient data for his or her site in 
a readable format on a compact disc that must be kept with the study records.  
 Acknowledgement of receipt of the compact disc is required. 

 
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7.3 SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
 
Source documents (paper or electronic) are those in which patient data are 
recorded and documented for the first time.  They include, but are not limited to, 
hospital records, clinical and office charts, laboratory notes, memoranda, patient-
reported outcomes, evaluation checklists, pharmacy dispensing records, recorded 
data from automated instruments, copies of transcriptions that are certified after 
verification as being accurate and complete, microfiche, photographic negatives, 
microfilm or magnetic media, X-rays, patient files, and records kept at pharmacies, 
laboratories, and medico-technical departments involved in a clinical trial. 
 
Before study initiation, the types of source documents that are to be generated will 
be clearly defined in the Trial Monitoring Plan. This includes any protocol data to 
be entered directly into the eCRFs (i.e., no prior written or electronic record of the 
data) and considered source data. 
 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained 
per the policy for retention of records. 
 
To facilitate source data verification, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The investigational 
site must also allow inspection by applicable health authorities. 
 
7.4 USE OF COMPUTERIZED SYSTEMS 
 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), 
the electronic record can serve as the source document if the system has been 
validated in accordance with health authority requirements pertaining to 
computerized systems used in clinical research.  An acceptable computerized data 
collection system allows preservation of the original entry of data. If original data 
are modified, the system should maintain a viewable audit trail that shows the 
original data as well as the reason for the change, name of the person making the 
change, and date of the change. 
 
 
 

 
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7.5 RETENTION OF RECORDS 
 
Records and documents pertaining to the conduct of this study and the distribution 
of IMP, including eCRFs, Informed Consent Forms, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for at 
least 15 years after completion or discontinuation of the study, or for the length of 
time required by relevant national or local health authorities, whichever is longer. 
After that period of time, the documents may be destroyed, subject to local 
regulations.   
 
No records may be disposed of without the written approval of the Sponsor.  
Written notification should be provided to the Sponsor prior to transferring any 
records to another party or moving them to another location. 
 
8. 
ETHICAL CONSIDERATIONS 
 
8.1 COMPLIANCE WITH LAWS AND REGULATIONS 
 
The investigator will ensure that this study is conducted in full conformance with 
the principles of the “Declaration of Helsinki” and or with the laws and 
regulations of India (Schedule-Y), whichever affords the greater protection to the 
individual. The study must fully adhere to the principles outlined in “Guideline 
for Good Clinical Practice” ICH Tripartite Guideline or with local law if it affords 
greater protection to the patient.  
 
8.2 INFORMED CONSENT 
 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed 
Consent Forms such as a Child’s Assent or Caregiver's Informed Consent Form, 
if applicable) will be provided to each site. If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must 
review and approve any proposed deviations from the Sponsor's sample Informed 
Consent Forms or any alternate consent forms proposed by the site (collectively, 
the “Consent Forms”) before IRB/EC submission.  The final IRB/EC approved 
Consent Forms must be provided to the Sponsor for health authority submission 
purposes according to local requirements. 
 
 
 
 
 

 
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The Consent Forms must be signed and dated by the patient or the patient’s 
legally authorized representative before his or her participation in the study.  The 
case history or clinical records for each patient shall document the informed 
consent process and that written informed consent was obtained prior to 
participation in the study. 
 
The Consent Forms should be revised whenever there are changes to study 
procedures or when new information becomes available that may affect the 
willingness of the patient to participate.  The final revised IRB/EC-approved 
Consent Forms must be provided to the Sponsor for health authority submission 
purposes. 
 
Patients must be re-consented to the most current version of the Consent Forms 
(or to a significant new information/findings addendum in accordance with 
applicable laws and IRB/EC policy) during their participation in the study.  For 
any updated or revised Consent Forms, the case history or clinical records for 
each patient shall document the informed consent process and that written 
informed consent was obtained using the updated/revised Consent Forms for 
continued participation in the study. 
 
A copy of each signed Consent Form must be provided to the patient or the 
patient’s legally authorized representative.  All signed and dated Consent Forms 
must remain in each patient’s study file or in the site file and must be available for 
verification by study monitors at any time. 
 
8.3 INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
 
It is the responsibility of the Ethics Committee/ Institutional Review Board to 
have the EC/ IRB registered duly with the DCGI (vide gazette G. S. R. 72(E) 
before granting the approvals. 
 
This protocol, the Informed Consent Forms, any information to be given to the 
patient, and relevant supporting information must be submitted to the IRB/EC by 
the Principal Investigator and reviewed and approved by the IRB/EC before the 
study is initiated.  In addition, any patient recruitment materials must be approved 
by the IRB/EC.  
 
The Principal Investigator is responsible for providing written summaries of the 
status of the study to the IRB/EC annually or more frequently in accordance with 
the requirements, policies, and procedures established by the IRB/EC.  
Investigators are also responsible for promptly informing the IRB/EC of any 
protocol amendments (see Section 9.6). 
 

 
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In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events 
to the local health authority and IRB/EC.  Investigators may receive written IND 
safety reports or other safety-related communications from the Sponsor.  
Investigators are responsible for ensuring that such reports are reviewed and 
processed in accordance with health authority requirements and the policies and 
procedures established by their IRB/EC, and archived in the site’s study file.  
 
8.4 CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled 
in the study through assignment of a unique patient identification number. This 
means that patient names are not included in data sets that are transmitted to any 
Sponsor location. 
 
Patient medical information obtained by this study is confidential and may only 
be disclosed to third parties as permitted by the Informed Consent Form 
(or separate authorization for use and disclosure of personal health information) 
signed by the patient, unless permitted or required by law. 
 
Medical information may be given to a patient’s personal physician or other 
appropriate medical personnel responsible for the patient’s welfare, for treatment 
purposes. 
 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, 
Sponsor monitors, representatives, and collaborators, and the IRB/EC for each 
study site, as appropriate. 
 
8.5 FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit 
complete and accurate financial certification or disclosure statements to the 
appropriate health authorities.  Investigators are responsible for providing 
information on financial interests during the course of the study and for 1 year 
after completion of the study i.e. LPLV. 
 
 
 
 
 

 
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9. 
STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION 
 
9.1 STUDY DOCUMENTATION 
 
The investigator must maintain adequate and accurate records to enable the 
conduct of the study to be fully documented, including but not limited to the 
protocol, protocol amendments, Informed Consent Forms, and documentation of 
IRB/EC and governmental approval.  In addition, at the end of the study, the 
investigator will receive the patient data, which includes an audit trail containing 
a complete record of all changes to data. 
 
9.2 MONITORING 
 
On-site monitoring will be performed before, during, and after the study. The 
monitor will ensure that the study is conducted, recorded and reported in 
accordance with the protocol, SOPs, GCP, and the applicable regulatory 
requirements. The monitor will check the accuracy and completeness of the eCRF 
entries, source documents, and other study-related records against each other. The 
investigator will provide direct access to source data/documents for study-related 
monitoring. 
 
The monitor will follow written SOPs as well as procedures that are specified 
by Sponsor for monitoring of this study. 
 
9.3 SITE INSPECTIONS 
 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator 
will permit national and 
local 
health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRBs/ECs to inspect facilities and 
records relevant to this study. 
 
9.4 ADMINISTRATIVE STRUCTURE 
The study will be conducted by the sponsor. Data Management and Statistical 
services will be provided by a contract research organization (CRO). Assessment 
of laboratory test results will be performed locally. 
 
9.5 PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
The results of this study may be published or presented at scientific meetings.  If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the Sponsor prior to submission. This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies 
that may not yet be available to the investigator. 
 

 
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The Sponsor will comply with the requirements for publication of study results.  
In accordance with standard editorial and ethical practice, the Sponsor will 
generally support publication of multicenter trials only in their entirety and not as 
individual center data.  In this case, a coordinating investigator will be designated 
by mutual agreement. 
 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. Any formal 
publication of the study in which contribution of Sponsor personnel exceeded that 
of conventional monitoring will be considered as a joint publication by the 
investigator and the appropriate Sponsor personnel. 
 
Any inventions and resulting patents, improvements, and/or know-how 
originating from the use of data from this study will become and remain the 
exclusive and unburdened property of the Sponsor, except where agreed 
otherwise. 
 
9.6 PROTOCOL AMENDMENTS 
 
Any protocol amendments will be prepared by the Sponsor. Protocol amendments 
will be submitted to the IRB/EC and to regulatory authorities in accordance with 
local regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact 
information). 
 
10. 
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Appendix 3 - ECOG Performance Status* 
 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance 
without restriction 
1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, e.g., light 
house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out 
any work activities. Up and about more than 50% of waking 
hours 
3 
Capable of only limited selfcare, confined to bed or chair more 
than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally 
confined to bed or chair 
5 
Dead 
 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, 
J., Davis, T.E., McFadden, E.T.,Carbone, P.P.: Toxicity And Response Criteria  
Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.

 
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Appendix 5 - Salient features from Breast cancer assessment ASCO adjuvant  
follow up guidelines 2006 
Mode of Surveillance 
Summary of Recommendations 
Recommended breast cancer 
surveillance 
 
History/physical examination 
Every 3 to 6 months for the first 3 years after primary 
therapy; every 6 to 12 months for years 4 and 5; then 
annually 
Patient 
education 
regarding 
symptoms of recurrence 
Physicians 
should 
counsel 
patients 
about 
the 
symptoms of recurrence including new lumps, bone 
pain, chest pain, abdominal pain, dyspnea or persistent 
headaches; helpful websites for patient education 
include www.plwc.org and www.cancer.org 
Referral for genetic counseling 
Criteria include: Ashkenazi Jewish heritage; history of 
ovarian cancer at any age in the patient or any first- or 
second-degree relatives; any first-degree relative with 
a history of breast cancer diagnosed before the age of 
50 years; two or more first- or second degree relatives 
diagnosed with breast cancer at any age; patient or 
relative with diagnosis of bilateral breast cancer; and 
history of breast cancer in a male relative 
Breast self-examination 
All women should be counseled to perform monthly 
breast self-examination  
Mammography 
First post-treatment mammogram 1 year after the 
initial mammogram that leads to diagnosis but no 
earlier than 6 months after definitive radiation therapy; 
subsequent mammograms should be obtained as 
indicated for surveillance of abnormalities 
Coordination of care 
Continuity of care for breast cancer patients is 
encouraged and should be performed by a physician 
experienced in the surveillance of cancer patients and 
in breast examination, including the examination of 
irradiated breasts; if follow-up is transferred to a PCP, 
the PCP and the patient should be informed of the 
long-term options regarding adjuvant hormonal 
therapy for the particular patient; this may necessitate 
rereferral for oncology assessment at an interval 
consistent with guidelines for adjuvant hormonal 
therapy 
Pelvic examination 
Regular gynecologic follow-up is recommended for all 
women; patients who receive tamoxifen should be 
advised to report any vaginal bleeding to their 
physicians 
Breast 
cancer 
surveillance 
testing: not recommended 
 
Routine blood tests 
CBCs and liver function tests are not recommended 

 
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Imaging studies 
Chest x-ray, bone scans, liver ultrasound, computed 
tomography scans, FDG-PET scans, 
and breast MRI are not recommended  
Tumor markers 
CA 15-3, CA 27.29, and carcinoembryonic antigen are 
not recommended 
FDG-PET 
FDG-PET scanning is not recommended for routine 
breast cancer surveillance 
Breast MRI 
Breast MRI is not recommended for routine breast 
cancer surveillance 
Abbreviations; PCP, primary care physician; FDG-PET, _18F_fluorodeoxyglucose–
positron emission tomography; MRI, magnetic resonance imaging. 
 
Source: Khatcheressian JL, Wolff AC, Smith TJ, et al. American Society of Clinical 
Oncology 2006 update of the breast cancer follow-up and management guidelines in the 
adjuvant setting. J Clin Oncol. 2006 Nov 1;24(31):5091-7.