Conditions: Breast Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 110
Healthy volunteers: no

Brief summary:
This is a prospective, Phase IV, multi-center, single arm, open-label, interventional study to evaluate the safety of trastuzumab for the treatment of human epidermal growth factor receptor 2 protein (HER2)-positive node positive or high risk node negative breast cancer participants with regimen consisting of doxorubicin and cyclophosphamide followed by either paclitaxel or docetaxel (AC-TH Regimen) or a regimen consisting of docetaxel and carboplatin (TCH Regimen) in Indian population.

Detailed description:

Arms:
arm 1: Participants will receive trastuzumab as a part of either AC-TH or TCH treatment regimen. The choice of the regimen will be based on investigator's discretion referring the local prescribing document of trastuzumab. AC-TH consists of doxorubicin and cyclophosphamide followed by either paclitaxel or docetaxel. TCH consists of docetaxel and carboplatin. Trastuzumab will be common in both treatment regimens and could be administered weekly or every 3 weeks, as per investigator discretion. Each cycle will be of 3 weeks.

Interventions: intervention 1: Carboplatin intervention 2: Cyclophosphamide intervention 3: Docetaxel intervention 4: Doxorubicin intervention 5: Paclitaxel intervention 6: Trastuzumab
Intervention descriptions: intervention 1: TCH regimen: Carboplatin dose = Target Area Under Curve (AUC) (6 milligrams\*milliliter/minute \[mg\*mL/min\]) multiplied by (Glomerular Filtration Rate \[GFR\] + 25). Carboplatin will be administered as IV bolus every 3 weeks for 6 cycles (Cycles 1 to 6). intervention 2: AC-TH regimen: Cyclophosphamide 600 mg/m\^2 IV bolus every 3 weeks for 4 cycles (Cycles 1 to 4). intervention 3: AC-TH regimen: Docetaxel 100 mg/m\^2 IV infusion every 3 weeks for 4 cycles (Cycles 5 to 8). TCH regimen: Docetaxel 75 mg/m\^2 IV bolus every 3 weeks for 6 cycles (Cycles 1 to 6). intervention 4: Participants will receive Doxorubicin 60 mg/m\^2 administered as I.V. bolus injection over 5 to 15 minute every 3 weeks for 4 cycles for AC-TH regimen. intervention 5: AC-TH regimen: Paclitaxel 175 mg/m\^2 IV infusion every 3 weeks for 4 cycles (Cycles 5 to 8). intervention 6: AC-TH regimen: For weekly administration, 4 milligrams per kilograms (mg/kg) loading dose on Day 1 of Cycle 5, followed by 2 mg/kg on Day 8 of Cycle 5 and 2 mg/kg every week for 4 cycles (up to Cycle 8). For 3 weekly administration, 8 mg/kg loading dose on Day 1 of Cycle 5, followed by 6 mg/kg every 3 for 4 cycles (up to Cycle 8). From Day 1 of Cycle 9, 6 mg/kg will be administered every 3 weeks up to Cycle 22. TCH regimen: For weekly administration, 4 mg/kg loading dose followed by 2 mg/kg weekly from Cycles 1 to Cycle 6. For 3 weekly administration, 8 mg/kg loading dose followed 6 mg/kg every 3 weeks from Cycles 1 to 6. From Cycle 7, 6 mg/kg every 3 weeks up to Cycle 18. All administrations will be intravenous (IV) infusion.

Protocol document:
Prot_000.pdf: 
 
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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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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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 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 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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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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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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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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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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• 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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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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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. 
 


Trastuzumab—Roche Products (India) Pvt. Ltd                                   Page 19 of 98 
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 


 
Trastuzumab—Roche Products (India) Pvt. Ltd                                                 Page 20 of 98 
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 


 
Trastuzumab—Roche Products (India) Pvt. Ltd                                                 Page 23 of 98 
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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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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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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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
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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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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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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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
 
 
 
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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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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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
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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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
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. 
REFERENCES 
 
1. 
Slamon D, Eiermann W, Robert N et al; Breast Cancer International 
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2. 
Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol. 
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3. 
National Cancer Registry Program: Ten year consolidated report of the 
Hospital Based Cancer Registries, 1984–1993, an assessment of the burden 
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4. 
Agarwal G, Pradeep PV, Aggarwal V et al: Spectrum of breast cancer in 
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5. 
Nandakumar A, Anantha N, Venugopal TC et al: Survival in breast cancer: a 
population-based study in Bangalore, India. Int J Cancer 1995;60:593–6. 


 
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6. 
National Cancer Registry Programme: Consolidated report of the population 
based cancer registries 1990–1996. Indian Council of Medical Research, 
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7. 
Sant M, Allemani C, Capocaccia R, et al. Stage at diagnosis is a key 
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8. 
Verma S, Lavasani S, Mackey J, et al. Optimizing the management of HER2-
positive early breast cancer: the clinical reality. Curr Oncol 2010 
Aug;17(4):20-33. 
9. 
Agarwal G and Ramakant P. Breast Cancer Care in India: The Current 
Scenario and the Challenges for the Future. Breast Care (Basel). 2008 March; 
3(1): 21–27 
10.  Saxena S, Rekhi B, Bansal A, Bagga A, Chintamani, Murthy NS. Clinico-
morphological patterns of breast cancer including family history in a New 
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11. Iselius L, Slack J, Littler M et al. Genetic epidemiology of breast cancer in 
Britain. Ann Hum Genet 1991;55(Pt 2):151-9. 
12. Clinical evidence: a compendium of the best available evidence for effective 
health care: issue 3. London: BMJ Publishing Group, 2000. 
13. Chappuis PO, Rosenblatt J, Foulkes WD. The influence of familial and 
hereditary factors on the prognosis of breast cancer (Review). Annals of 
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14. Schechter AL, Stern DF, Vaidyanathan L, et al. The neu oncogene: An erb-
B-related gene encoding a 185,000-Mr tumor antigen. Nature 1984; 312:513-
6. 
15. Ross JS, Slodkowska EA, Symmans WF, et al. The HER-2 receptor and 
breast cancer: ten years of targeted anti-HER-2 therapy and personalized 
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16. Sundaresan S, Penuel E, Sliwkowski MX. The biology of human epidermal 
growth factor receptor 2. Curr Oncol Rep. 1999; 1:16-22. 
17. Yarden Y, Sliwkowski M. Untangling the ErbB signalling network. Nat Rev 
Mol Cell Biol 2001; 2:127-37. 
18. Gschwind A, Fischer OM, Ullrich A. The discovery of receptor tyrosine 
kinases: targets for cancer therapy. Nat Rev Cancer 2004; 4:361-70. 
19. Slamon DJ, Clark GM, Wong SG et al. Human breast cancer: correlation of 
relapse and survival with amplification of the HER-2/neu oncogene, Science 
1987; 235:177-82. 
20. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-
oncogene in human breast and ovarian cancer. Science 1989; 244:707-12. 
21. Sjögren S, Inganäs M, Lindgren A, et al. Prognostic and predictive value of 
c-erbB-2 overexpression in primary breast cancer, alone and in combination 
with other prognostic markers. J Clin Oncol 1998 Feb;16(2):462-9. 
22. Moasser MM. The oncogene HER2: Its signaling and transforming functions 
and its role in human cancer pathogenesis. Oncogene 2007; 26:6469-87. 


 
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23. Ménard S, Fortis S, Castiglioni F, et al. HER2 as a prognostic factor in breast 
cancer. Oncology. 2001; 61 Suppl 2:67-72. 
24. Lund MJ, Butler EN, Hair BY, et al. Age/race differences in HER2 testing 
and in incidence rates for breast cancer triple subtypes: a population-based 
study and first report. Cancer 2010; 116:2549-59. 
25. Dawood S, Broglio K, Buzdar AU, Hortobagyi GN, Giordano SH. Prognosis 
of women with metastatic breast cancer by HER2 status and trastuzumab 
treatment: an institutional-based review. J Clin Oncol. 2010; 28:92-8. 
26. Ambroise M, Ghosh M, Mallikarjuna VS, Kurian A. Immunohistochemical 
profile of breast cancer patients at a tertiary care hospital in South India. 
Asian Pac J Cancer Prev. 2011;12(3):625-9. 
27. Munjal K, Ambaye A, Evans MF, Mitchell J, Nandedkar S, Cooper K. 
Immunohistochemical analysis of ER, PR, Her2 and CK5/6 in infiltrative 
breast carcinomas in Indian patients. Asian Pac J Cancer Prev. 
2009;10(5):773-8. 
28. Verma S, Lavasani S, Mackey J, et al. Optimizing the management of HER2-
positive early breast cancer: the clinical reality. Curr Oncol 2010; 17:20-33. 
29. Goldhirsch A, Piccart-Gebhart MJ, Procter M,et al.. HERA TRIAL: 2 years 
versus 1 year of trastuzumab after adjuvant chemotherapy in women with 
HER2-positive early breast cancer at 8 years of median follow up. Cancer 
Res; 72(24 Suppl.) December 2012 Page 103s-104s. 
30. Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after 
adjuvant chemotherapy in HER2-positive breast cancer: a randomised 
controlled trial. Lancet 2007; 369:29-36. 
31. Untch M. Targeted Therapy for Early and Locally Advanced Breast Cancer. 
Breast Care (Basel) 2010; 5:144-52. 
32. National Comprehensive Cancer Network. NCCN clinical practice guidelines 
in oncology: Breast cancer, Version 2.2012 [online]. Available from URL: 
http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf [Accessed 
2012 July 18] 
33. Aebi S, Davidson T, Gruber G, Cardoso F; ESMO Guidelines Working 
Group. Primary breast cancer: ESMO Clinical Practice Guidelines for 
diagnosis, treatment and follow-up. Ann Oncol. 2011; 22 Suppl 6:vi12-24. 
34. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a 
monoclonal antibody against HER2 for metastatic breast cancer that 
overexpresses HER2. N Engl J Med 2001;344:783-92 
35. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the 
efficacy and safety of humanized anti-HER2 monoclonal antibody in women 
who have HER2-overexpressing metastatic breast cancer that has progressed 
after chemotherapy for metastatic disease. J Clin Oncol. 1999; 17:2639-48. 
36. Tan-Chiu E, Yothers G, Romond E, et al. Assessment of cardiac dysfunction 
in a randomized trial comparing doxorubicin and cyclophosphamide 
followed by paclitaxel, with or without trastuzumab as adjuvant therapy in 
node-positive, human epidermal growth factor receptor 2-overexpressing 
breast cancer: NSABP B-31. J. Clin. Oncol 2005; 23:7811-9. 


 
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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
37. Clinical Study Report: HERA (BO16348) Interim Analysis: A randomized 
multi-centre comparison of 1 year Herceptin treatment versus observation 
only in women with HER2-positive primary breast cancer who have 
completed adjuvant therapy. Roche Report 1019820, Jan 2006. 
38. 
Population pharmacokinetics of Trastuzumab 
following weekly dosing of Herceptin: covariate analysis. South San 
Francisco (CA): Genentech; 2001 Report No. 01-329-1451. 
39. 
Population pharmacokinetics and covariates analysis 
using data from Herceptin phase II/III studies BO15935, WO16229, 
BO15899 and M77004. Roche Report 1018264, March 2005. 
40. 
Population pharmacokinetic analysis of combined 
phase II/III studies: BO15899, BO15935, WO16229, M77004, and 
MO16982. Roche Report 1034069, June 2009. 
41. Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. Trastuzumab after 
adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 
353:1659-72. 
42. Gianni L, Dafni U, Gelber RD, et al. Treatment with trastuzumab for 1 year 
after adjuvant chemotherapy in patients with HER2-positive early breast 
cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 
2011; 12:236-44. 
43. Perez EA, Romond EH, Suman VJ et al. Updated results of the combined 
analysis of NCCTG N9831 and NSABP B-31. Adjuvant chemotherapy with 
or without trastuzumab (H) in patients with HER2-positive breast cancer. 
Proc ASCO 2007, abstract 512.  
44. Perez EA, Suman VJ, Davidson NE, et al. Results of chemotherapy alone, 
with sequential or concurrent addition of 52 weeks of trastuzumab in the 
NCCTG N9831 HER2-positive adjuvant breast cancer trial. San Antonio 
Breast Cancer Symposium 2009 abstract 80.  
45. Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab 
plus adjuvant chemotherapy for operable human epidermal growth factor 
receptor 2-positive breast cancer: Joint Analysis of Data From NCCTG 
N9831 and NSABP B-31. J Clin Oncol 2011; 29:3366-73. 
46. Colozza M, de Azambuja E, Cardoso F, et al. Breast cancer: achievements in 
adjuvant systemic therapies in the pre-genomic era. Oncologist 2006; 11:111-
25. 
47. Romond E, Suman VJ, Jeong J-H, et al. Trastuzumab plus adjuvant 
chemotherapy for HER2-positive breast cancer: Final planned joint analysis 
of overall survival (OS) from NSABP B-31 and NCCTG N9831. Cancer Res; 
72(24 Suppl.) December 2012 Page 105s. 
48. Spielmann M, Roche H, Delozier T, et al. Trastuzumab for patients with 
axillary-node-positive breast cancer: results of the FNCLCC-PACS 04 trial. J 
Clin Oncol 2009; 27:6129-34. 
49. Joensuu H, Bono P, Kataja V, et al. Fluorouracil, epirubicin, and 
cyclophosphamide with either docetaxel or vinorelbine, with or without 
trastuzumab, as adjuvant treatments of breast cancer: final results of the 
FinHer Trial. J Clin Oncol 2009 27:5685-92. 


 
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50. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with 
Trastuzumab followed by adjuvant Trastuzumab versus neoadjuvant 
chemotherapy alone, in patients with HER2-positive locally advanced breast 
cancer (the NOAH trial): a randomised controlled superiority trial with a 
parallel HER2-negative cohort. Lancet. 2010; 375: 377-384. 
51. Garnock-Jones KP, Keating GM, Scott LJ. Trastuzumab: A review of its use 
as adjuvant treatment in human epidermal growth factor receptor 2 (HER2)-
positive early breast cancer. Drugs. 2010; 70:215-39. 
52. Ewer MS, O'Shaughnessy JA. Cardiac toxicity of trastuzumab-related 
regimens in HER2-overexpressing breast cancer. Clin Breast Cancer. 2007; 
7:600-7. 
53. Jahanzeb M. Adjuvant trastuzumab therapy for HER2-positive breast cancer. 
Clin Breast Cancer 2008; 8:324-33. 
54. Baselga J, Bradbury I, Eidtmann H, et al. inib with trastuzumab for HER2-
positive early breast cancer (NeoALTTO): a randomised, open-label, 
multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. 
55. Rastogi P, Jeong J, Geyer CE. Five year update of cardiac dysfunction on 
NSABP 
B-31, 
a 
randomized 
trial 
of 
sequential 
doxorubicin/cyclophosphamide (AC)→paclitaxel (T) vs. AC→T with 
trastuzumab(H). ASCO Annual Meeting 2007 abstract LBA513. 
56. Russell SD, Blackwell KL, Lawrence J, et al. Independent adjudication of 
symptomatic heart failure with the use of doxorubicin and cyclophosphamide 
followed by trastuzumab adjuvant therapy: a combined review of cardiac 
data from the National Surgical Adjuvant breast and Bowel Project B-31 and 
the North Central Cancer Treatment Group N9831 clinical trials. J Clin 
Oncol. 2010; 28:3416-21. 
57. Procter M, Suter TM, de Azambuja E, et al. Longer-term assessment of 
trastuzumab-related cardiac adverse events in the Herceptin Adjuvant 
(HERA) trial. J Clin Oncol 2010; 28:3422-8. 
58. Hynes NE. Amplification and overexpression of the erbB 2 gene in human 
tumors: its involvement in tumor development, significance as a prognostic 
factor, and potential as a target for cancer therapy. Sem Cancer Biol. 1993; 
4:19–26. 
59. Gnant M, Harbeck N, Thomssen C. St. Gallen 2011: Summary of the 
Consensus Discussion. Breast Care (Basel). 2011;6(2):136-141. 
60. Bazell (1998) Her-2: The making of Herceptin, a revolutionary treatment for 
breast cancer is published in the UK by Random House. 
61. Available from URL:http://www.drugs.com/pro/carboplatin.html (accessed 
on 21 Jan 2013) 
62. Available from URL:http://www.drugs.com/pro/doxorubicin.html (accessed 
on 21 Jan 2013). 
63. Available from URL: http://www.drugs.com/pro/cyclophosphamide.html 
(accessed on 21 Jan 2013). 
64. Available from URL: http://www.drugs.com/pro/paclitaxel.html (accessed on 
21 Jan 2013). 


 
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65. Available from URL: http://www.drugs.com/pro/docetaxel.html (accessed on 
21 Jan 2013). 
66. Jones AL, Barlow M, Barrett-Lee PJ et al. Management of cardiac health in 
trastuzumab-treated patients with breast cancer: updated United Kingdom 
National Cancer Research Institute recommendations for monitoring. Br J 
Cancer. 2009 Mar 10;100(5):684-92. 
 
 
 
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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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
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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Protocol ML28714, Version – 1.0 (Jul 29, 2013) 
 
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. 
 

SAP_001.pdf: 
 
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: SAP Version 2: 18-June-2021 
 
 
 


 
 
18 Jun 2021 
Confidential and Proprietary to Roche Products (India) Pvt. Ltd. 
Statistical Analysis Plan (ML28714) 
 
 
Page 1 of 178 
 
 
     STATISTICAL ANALYSIS PLAN 
 
 
PROTOCOL 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 NO.  
: 
ML28714 
STUDY DRUG 
 
:  
Trastuzumab (Ro 45-2317) 
VERSION NUMBER 
:  
Version 2.0 
IND NUMBER 
 
: 
4517 
EUDRACT Number 
: 
NA 
SPONSOR 
 
: 
Roche Products (India) Pvt. Ltd. 
PLAN PREPARED BY 
: 
 
 
 
Dr.
 
DATE FINAL 
 
: 
18 Jun 2021 
DATE AMENDED  
: 
NA 


 
 
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Confidential and Proprietary to Roche Products (India) Pvt. Ltd. 
Statistical Analysis Plan (ML28714) 
 
 
Page 2 of 178 
 
Sponsor Signature 
 
I hereby declare that I have reviewed the statistical analysis plan and agree to its form and content.  In addition, 
I confirm that the outlined statistical analysis plan contains all relevant information for the data analysis to be 
performed in the Protocol No. - ML28714 study by the Biostatistics Department. 
 
 
 
Represented by: 
___________________________________________ 
    _______________ 
 
  Date 
 
 
 
 
Represented by: 
___________________________________________ 
_______________ 
 
Date 
 
 
 
 
 
 
                                                    
 
 
 
 
 






 
 
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Confidential and Proprietary to Roche Products (India) Pvt. Ltd. 
Statistical Analysis Plan (ML28714) 
 
 
Page 5 of 178 
 
STATISTICAL ANALYSIS PLAN AMENDMENT 
RATIONALE 
 
 
 
 
  


 
 
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Statistical Analysis Plan (ML28714) 
 
 
Page 6 of 178 
 
TABLE OF CONTENT 
1.0 
BACKGROUND .................................................................................................................................... 13 
2.0 
STUDY DESIGN .................................................................................................................................... 13 
2.1 
Protocol Synopsis ............................................................................................................... 14 
2.2 
Study Objectives and Endpoints ......................................................................................... 14 
2.2.1 
Study Objectives ................................................................................................................. 14 
2.2.1.1 
Primary Objectives ............................................................................................................. 14 
2.2.1.2 
Secondary Objectives ......................................................................................................... 15 
2.2.2 
Study Outcome Measures ................................................................................................... 15 
2.2.2.1 
Efficacy Outcome Measures ............................................................................................... 15 
2.2.2.2 
Safety Outcome Measures .................................................................................................. 15 
2.3 
Determination of Sample Size ............................................................................................ 16 
2.4 
Analysis Timing ................................................................................................................. 16 
3.0 
STUDY CONDUCT ............................................................................................................................... 16 
4.0 
STATISTICAL METHODS ................................................................................................................. 16 
4.1 
Analysis Population ............................................................................................................ 17 
4.1.1 
Intent–to-Treat (ITT) population ........................................................................................ 17 
4.1.2 
Safety population ................................................................................................................ 17 
4.2 
Analysis of Study Conduct ................................................................................................. 17 
4.2.1 
Demographics and Baseline Characteristics ....................................................................... 17 
4.3 
Efficacy and Safety Analyses ............................................................................................. 17 
4.3.1 
Efficacy Analyses ............................................................................................................... 17 
4.3.2 
Safety Analyses .................................................................................................................. 18 
4.4 
Missing Data....................................................................................................................... 18 
4.5 
Interim Analyses ................................................................................................................. 18 
4.6 
Additional Analyses ........................................................................................................... 18 
4.7 
Data Listings....................................................................................................................... 18 
4.8  
Plots and Figures ................................................................................................................ 19 
5.0 
REFERENCES ....................................................................................................................................... 19 
14.1 
Demographics and Baseline Characteristics ................................................................................ 29 
14.1.1 
Patient Disposition .......................................................................................................................... 29 
Table 14.1.1.1 
Summary of Inclusion/Exclusion Criteria- Enrolled Population 
(N=XXX) ........................................................................................ 29 
Table 14.1.1.2 
Summary of Patient Disposition- Enrolled Population (N=XXX) .......... 30 
Table 14.1.1.3 
Summary of Patient Disposition by Site- Enrolled Population 
(N=XXX) ........................................................................................ 31 


 
 
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Page 7 of 178 
 
Table 14.1.1.4 
Summary of Subject Follow-up Rate at each Visit- Enrolled 
Population (N=XXX) ........................................................................ 32 
14.1.2 
Demographic and Baseline Characteristics .................................................................................. 33 
Table 14.1.2.1 
Summary of Patient Demographics at Screening- ITT Population 
(N=XXX) ........................................................................................ 33 
Table 14.1.2.2 
Summary of Medical History at Screening- ITT Population 
(N=XXX) ........................................................................................ 34 
Table 14.1.2.3 
Summary of Cancer History and Reproductive Status at 
Screening- ITT Population (N=XXX)................................................. 35 
Table 14.1.2.4 
Summary of Smoking, Alcoholic and Drug Abuse History at 
Screening- ITT Population (N=XXX)................................................. 37 
Table 14.1.2.5 
Summary of Prior Cancer Surgery at Screening- ITT Population 
(N=XXX) ........................................................................................ 39 
Table 14.1.2.6 
Summary of Histology and Mammogram at Screening- ITT 
Population (N=XXX) ........................................................................ 40 
Table 14.1.2.7 
Summary of Prior Concomitant Medication at Screening- ITT 
Population (N=XXX) ........................................................................ 41 
Table 14.1.2.8 
Summary of Vital Signs at Screening- ITT Population (N=XXX) ......... 42 
Table 14.1.2.9 
Summary of Physical Examination at Screening- ITT Population 
(N=XXX) ........................................................................................ 45 
Table 14.1.2.10 
Summary of Investigations done at Screening- ITT Population 
(N=XXX) ........................................................................................ 48 
Table 14.1.2.11 
Summary of Routine Breast Cancer Follow Up at Screening- ITT 
Population (N=XXX) ........................................................................ 50 
14.2 
Efficacy Analysis ............................................................................................................................. 52 
Table 14.2.1.1 
Summary of Disease Free Survival at End of Study- ITT 
Population (N=XXX) ........................................................................ 52 
Table 14.2.1.2 
Summary of Disease Free Survival by K-M Analysis- ITT 
Population (N=XXX) ........................................................................ 53 
Table 14.2.1.3 
Summary of Median Survival Time between ECOG sub-groups 
for Disease Free Survival- ITT Population (N=XXX) .......................... 54 
Table 14.2.1.4 
Summary of Overall Survival at Each Visit - ITT Population 
(N=XXX) ........................................................................................ 55 
Table 14.2.1.5 
Summary of Overall Survival by K-M Analysis- ITT Population 
(N=XXX) ........................................................................................ 56 
Table 14.2.1.6 
Summary of Overall Survival by K-M Analysis for Disease 
Status .............................................................................................. 56 
Table 14.2.1.7 
Summary of Median Survival Time between ECOG sub-groups 
for Overall Survival- ITT Population (N=XXX) .................................. 57 
14.3  
Safety Analysis ................................................................................................................................ 58 
14.3.1 
Adverse Events ................................................................................................................................ 58 
Table 14.3.1.1 
Overall Summary of Adverse Events- Safety Population 
(N=XXX) ........................................................................................ 58 
Table 14.3.1.2 
Overall Summary of Treatment Emergent Adverse Events -
Safety Population (N=XXX) ............................................................. 60 
Table 14.3.1.3 
Overall Summary of Non-Treatment Emergent Adverse Events-
Safety Population (N=XXX) ............................................................. 62 


 
 
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Table 14.3.1.4 
Summary of Adverse Events (including subjects reporting SAEs) 
by MedDRA System Organ Class and Preferred Term-Safety 
Population (N=XXX) ........................................................................ 64 
Table 14.3.1.5 
Summary of Adverse Events (excluding subjects reporting 
SAEs) by MedDRA System Organ Class and Preferred Term-
Safety Population (N=XXX) ............................................................. 65 
Table 14.3.1.6 
Summary of Adverse Events by MedDRA System Organ Class 
and Preferred Term by Intensity-Safety Population (N=XXX) .............. 66 
Table 14.3.1.7 
Summary of Adverse Events by MedDRA System Organ Class 
and Preferred Term by Action Taken-Safety Population 
(N=XXX) ........................................................................................ 68 
Table 14.3.1.8 
Summary of Adverse Events by MedDRA System Organ Class 
and Preferred Term by Event Outcome-Safety Population 
(N=XXX) ........................................................................................ 69 
14.3.2 
Serious Adverse Events .................................................................................................................. 71 
Table 14.3.2.1 
Overall Summary of Serious Adverse Events -Safety Population 
(N=XXX) ........................................................................................ 71 
Table 14.3.2.2 
Summary of Serious Adverse Events by MedDRA System Organ 
Class and Preferred Term -Safety Population (N=XXX) ...................... 73 
14.3.3 
Concomitant Medication ................................................................................................................ 74 
Table 14.3.3.1 
Summary of Concomitant Medication Assessment -Safety 
Population (N=XXX) ........................................................................ 74 
14.3.4 
Vital Signs ....................................................................................................................................... 75 
Table 14.3.4.1  
Summary of Weight at all visits -Safety Population (N=XXX) ............. 75 
Table 14.3.4.2  
Summary of Vital Signs at different Cycles before administration 
of Trastuzumab-Safety Population (N=XXX) ..................................... 76 
Table 14.3.4.3  
Summary of Vital Signs at different Cycles (for Prior and Post 
Loading Dose) -Safety Population (N=XXX) ...................................... 78 
Table 14.3.4.4  
Summary of Vital Signs at different Cycles (for Prior and Post 
Maintenance Dose) -Safety Population (N=XXX) ............................... 80 
Table 14.3.4.5 
Summary of Vital Signs at different Cycles (for Prior and Post 
Administration) -Safety Population (N=XXX) .................................... 83 
Table 14.3.4.6  
Summary of Vital Signs at End of Study-Safety Population 
(N=XXX) ........................................................................................ 85 
14.3.5  
Physical Examination ..................................................................................................................... 88 
Table 14.3.5.1 
Summary of Physical Examination at all visits-Safety Population 
(N=XXX) ........................................................................................ 88 
14.3.6  
Laboratory Assessments ................................................................................................................ 89 
Table 14.3.6.1 
Summary of Hematology-Safety Population (N=XXX) ....................... 89 
Table 14.3.6.1.1  
Summary of WBC Count of Hematology-Safety Population 
(N=XXX) ........................................................................................ 89 
Table 14.3.6.1.2 
Summary of RBC Count of Hematology-Safety Population 
(N=XXX) ........................................................................................ 90 
Table 14.3.6.1.3 
Summary of Hemoglobin of Hematology-Safety Population 
(N=XXX) ........................................................................................ 90 
Table 14.3.6.1.4 
Summary of Hematocrit of Hematology-Safety Population 
(N=XXX) ........................................................................................ 90 


 
 
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Table 14.3.6.1.5 
Summary of Platelet Count of Hematology-Safety Population 
(N=XXX) ........................................................................................ 90 
Table 14.3.6.1.6 
Summary of Neutrophils of Hematology-Safety Population 
(N=XXX) ........................................................................................ 90 
Table 14.3.6.1.7 
Summary of Eosinophils of Hematology-Safety Population 
(N=XXX) ........................................................................................ 90 
Table 14.3.6.1.8 
Summary of Basophils of Hematology-Safety Population 
(N=XXX) ........................................................................................ 90 
Table 14.3.6.1.9 
Summary of Monocytes of Hematology-Safety Population 
(N=XXX) ........................................................................................ 90 
Table 14.3.6.1.10 
Summary of Lymphocytes of Hematology-Safety Population 
(N=XXX) ........................................................................................ 90 
Table 14.3.6.1.11 
Summary of Other cells of Hematology-Safety Population 
(N=XXX) ........................................................................................ 90 
Table 14.3.6.1.12  
Shift table for Parameters of Hematology-Safety Population 
(N=XXX) ........................................................................................ 91 
Table 14.3.6.2 
Summary of Biochemistry-Safety Population (N=XXX) ...................... 92 
Table 14.3.6.2.1  
Summary of Sodium of Biochemistry-Safety Population 
(N=XXX) ........................................................................................ 92 
Table 14.3.6.2.2 
Summary of Potassium of Biochemistry-Safety Population 
(N=XXX) ........................................................................................ 93 
Table 14.3.6.2.3 
Summary of Calcium of Biochemistry -Safety Population 
(N=XXX) ........................................................................................ 93 
Table 14.3.6.2.4 
Summary of Chloride of Biochemistry-Safety Population 
(N=XXX) ........................................................................................ 93 
Table 14.3.6.2.5 
Summary of Bicarbonate of Biochemistry-Safety Population 
(N=XXX) ........................................................................................ 93 
Table 14.3.6.2.6 
Summary of Fasting Glucose of Biochemistry-Safety Population 
(N=XXX) ........................................................................................ 93 
Table 14.3.6.2.7 
Summary of BUN/ Urea of Biochemistry-Safety Population 
(N=XXX) ........................................................................................ 93 
Table 14.3.6.2.8 
Summary of Creatinine of Biochemistry-Safety Population 
(N=XXX) ........................................................................................ 93 
Table 14.3.6.2.9 
Summary of Total Protein of Biochemistry-Safety Population 
(N=XXX) ........................................................................................ 93 
Table 14.3.6.2.10 
Summary of Albumin of Biochemistry-Safety Population 
(N=XXX) ........................................................................................ 93 
Table 14.3.6.2.11 
Summary of Phosphorus of Biochemistry-Safety Population 
(N=XXX) ........................................................................................ 93 
Table 14.3.6.2.12 
Summary of Magnesium of Biochemistry-Safety Population 
(N=XXX) ........................................................................................ 93 
Table 14.3.6.2.13 
Summary of Total Bilirubin of Biochemistry-Safety Population 
(N=XXX) ........................................................................................ 93 
Table 14.3.6.2.14 
Summary of Direct Bilirubin of Biochemistry-Safety Population 
(N=XXX) ........................................................................................ 94 
Table 14.3.6.2.15 
Summary of Alkaline Phosphatase of Biochemistry-Safety 
Population (N=XXX) ........................................................................ 94 


 
 
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Table 14.3.6.2.16 
Summary of Creatinine Phosphokinase of Biochemistry-Safety 
Population (N=XXX) ........................................................................ 94 
Table 14.3.6.2.17 
Summary of ALT of Biochemistry-Safety Population (N=XXX) .......... 94 
Table 14.3.6.2.18 
Summary of AST of Biochemistry-Safety Population (N=XXX) .......... 94 
Table 14.3.6.2.19 
Summary of Uric Acid of Biochemistry-Safety Population 
(N=XXX) ........................................................................................ 94 
Table 14.3.6.2.20 
Summary of LDH of Biochemistry-Safety Population (N=XXX) .......... 94 
Table 14.3.6.2.21  
Shift table for Parameters of Biochemistry-Safety Population 
(N=XXX) ........................................................................................ 95 
Table 14.3.6.3 
Summary of LVEF-Safety Population (N=XXX) ................................ 96 
Table 14.3.6.4 
Summary of 12 Lead Electrocardiogram-Safety Population 
(N=XXX) ........................................................................................ 98 
Table 14.3.6.5 
Summary of ECOG-Safety Population (N=XXX) ............................... 99 
Table 14.3.6.5.1 
Summary of ECOG PS-Safety Population (N=XXX) ......................... 100 
Table 14.3.6.6 
Summary of Routine Breast Cancer Follow Up-Safety 
Population (N=XXX) ...................................................................... 101 
Table 14.3.6.7 
Summary of CT/MRI and Mammogram at Study Completion 
and Follow-up-Safety Population (N=XXX) ..................................... 104 
Table 14.3.7 
Summary of Drug Administration-Safety Population (N=XXX) ......... 106 
Table 14.3.7.1 
Summary of Drug Administration in AC→TH Regimen -Safety 
Population (N=XXX) ...................................................................... 106 
Table 14.3.7.1.1 
Summary of Chemotherapy- Doxorubicin Administration in 
AC→TH Regimen-Safety Population (N=XXX) ............................... 106 
Table 14.3.7.1.2 
Summary of Chemotherapy- Cyclophosphamide Administration-
Safety Population (N=XXX) ........................................................... 108 
Table 14.3.7.1.3 
Summary of Chemotherapy- Docetaxel/ Paclitaxel 
Administration-Safety Population (N=XXX) .................................... 110 
Table 14.3.7.1.4 
Summary of Trastuzumab Administration (weekly total dose=8 
mg/kg) in AC→TH Regimen-Safety Population (N=XXX) ................ 112 
Table 14.3.7.1.5 
Summary of Trastuzumab Administration (weekly total dose=6 
mg/kg) in AC→TH Regimen-Safety Population (N=XXX) ................ 116 
Table 14.3.7.1.6 
Summary of Trastuzumab Administration in AC→TH Regimen-
Safety Population (N=XXX) ........................................................... 120 
Table 14.3.7.2 
Summary of Drug Administration in TCH Regimen-Safety 
Population (N=XXX) ...................................................................... 122 
Table 14.3.7.2.1 
Summary of Chemotherapy- Docetaxel Administration in TCH 
Regimen-Safety Population (N=XXX) ............................................. 122 
Table 14.3.7.2.2 
Summary of Chemotherapy- Carboplatin Administration in TCH 
Regimen-Safety Population (N=XXX) ............................................. 124 
Table 14.3.7.2.3 
Summary of Trastuzumab Administration (weekly-total 
dose=8mg/kg) in TCH Regimen-Safety Population (N=XXX) ........... 126 
Table 14.3.7.2.4 
Summary of Trastuzumab Administration (weekly-total 
dose=6mg/kg) in TCH Regimen-Safety Population (N=XXX) ........... 130 
Table 14.3.7.2.5 
Summary of Trastuzumab Administration in TCH Regimen-
Safety Population (N=XXX) ........................................................... 134 
1.2 
Figures ........................................................................................................................................... 138 
14.2.1 
Figures for Efficacy Analysis ....................................................................................................... 139 


 
 
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Figure 14.2.1.1 
K-M Plot for Disease Free Survival by Treatment-ITT 
Population (N=XXX) ...................................................................... 139 
Figure 14.2.1.2 
K-M Plot for Overall Survival by Regimen-ITT Population 
(N=XXX) ...................................................................................... 140 
Figure 14.2.1.3 
K-M Plot for Overall Survival by Disease Status-ITT Population 
(N=XXX) ...................................................................................... 140 
Figure 14.2.1.4 
Line Diagram for LVEF over a period of time-Safety Population 
(N=XXX) ...................................................................................... 141 
Figure 14.2.1.5 
Multiple Bar Diagram for ECOG over a period of time-Safety 
Population (N=XXX) ...................................................................... 142 
1.3 
LISTINGS ..................................................................................................................................... 143 
16.2 
Patient Data Listings .................................................................................................................... 143 
Listing 16.2.1 
Listing of Patient Discontinuation-ITT Population (N=XXX) ............. 143 
Listing 16.2.2.1 
Listing of Protocol Deviation -ITT Population (N=XXX) .................. 144 
Listing 16.2.2.2 
Listing of Analysis Population Sets-ITT Population (N=XXX) ........... 145 
Listing 16.2.3 
Listing of Patients who fail to meet Inclusion/Exclusion Criteria-
ITT Population (N=XXX) ............................................................... 146 
16.2.4 
Listing of Demographics .............................................................................................................. 147 
Listing 16.2.4.1 
Listing of Patient Demographics -ITT Population (N=XXX) .............. 147 
Listing 16.2.4.2 
Listing of Medical History at Screening -ITT Population 
(N=XXX) ...................................................................................... 148 
Listing 16.2.4.3 
Listing of Cancer History at Screening -ITT Population 
(N=XXX) ...................................................................................... 149 
Listing 16.2.4.4 
Listing of Reproductive Status at Screening -ITT Population 
(N=XXX) ...................................................................................... 150 
Listing 16.2.4.5 
Listing of Smoking, Alcoholic & Drug Abuse History at 
Screening -ITT Population (N=XXX)............................................... 151 
Listing 16.2.4.6 
Listing of Prior Cancer Therapy & Prior Cancer Surgery at 
Screening -ITT Population (N=XXX)............................................... 152 
Listing 16.2.4.7 
Listing of Histology and HER2 testing test at screening -ITT 
Population (N=XXX) ...................................................................... 153 
16.2.6 
Listing for Efficacy ....................................................................................................................... 154 
Listing 16.2.6.1 
Listing of Survival Assessment -ITT Population (N=XXX) ................ 154 
16.2.7 
Listing for Adverse Event ............................................................................................................ 155 
Listing 16.2.7.1 
Listing of Adverse Event -Safety Population (N=XXX) ..................... 155 
16.2.8 
Lab Test Evaluations .................................................................................................................... 156 
Listing 16.2.8.1 
Listing of Hematology -Safety Population (N=XXX) ........................ 156 
Listing 16.2.8.2 
Listing of Biochemistry -Safety Population (N=XXX) ....................... 157 
Listing 16.2.8.3 
Listing of 12 Lead ECG, LVEF and ECOG -Safety Population 
(N=XXX) ...................................................................................... 158 
Listing 16.2.8.4 
Listing of Mammogram and CT/MRI -Safety Population 
(N=XXX) ...................................................................................... 159 
16.4 
Individual subject data listings .................................................................................................... 160 
Listing 16.4.1 
Listing of Vital Signs -Safety Population (N=XXX) .......................... 160 
Listing 16.4.1.1 
Listing of Vital Signs -Safety Population (N=XXX) .......................... 160 


 
 
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Listing 16.4.1.2 
Listing of Vital Signs during different Loading, Maintenance and 
Administration Dose-Safety Population (N=XXX) ............................ 161 
Listing 16.4.2 
Listing of Physical Examination -Safety Population (N=XXX) ........... 162 
Listing 16.4.3.1 
Listing of Routine Breast Cancer Follow Up -Safety Population 
(N=XXX) ...................................................................................... 163 
Listing 16.4.3.2 
Listing of Other Investigations -Safety Population (N=XXX) ............. 164 
Listing 16.4.4 
Listing of Cycle Delay, Reminder and Treatment Compliance -
Safety Population (N=XXX) ........................................................... 165 
Listing 16.4.5 
Listing of Study Drug Administration -Safety Population 
(N=XXX) ...................................................................................... 166 
Listing 16.4.5.1 
Listing of Chemotherapy- Doxorubicin Administration for 
AC→TH Regimen -Safety Population (N=XXX) .............................. 166 
Listing 16.4.5.2 
Listing of Chemotherapy- Cyclophosphamide Administration for 
AC→TH Regimen -Safety Population (N=XXX) .............................. 167 
Listing 16.4.5.3 
Listing of Chemotherapy- Docetaxel/ Paclitaxel Administration 
for AC→TH Regimen -Safety Population (N=XXX) ......................... 168 
Listing 16.4.5.4 
Listing of Chemotherapy- Docetaxel Administration for TCH 
Regimen -Safety Population (N=XXX) ............................................ 169 
Listing 16.4.5.5 
Listing of Chemotherapy- Carboplatin Administration for TCH 
Regimen -Safety Population (N=XXX) ............................................ 170 
Listing 16.4.5.6 
Listing of Trastuzumab Administration for Both Regimen -
Safety Population (N=XXX) ........................................................... 171 
Listing 16.4.5.6.1 
Listing of Trastuzumab Administration (8mg/kg weekly/3-
weekly) for Both Regimen-Safety Population (N=XXX).................... 171 
Listing 16.4.5.6.2 
Listing of Trastuzumab Administration (6mg/kg weekly/3-
weekly) for Both Regimen -Safety Population (N=XXX) ................... 174 
Listing 16.4.5.6.3 
Listing of Trastuzumab Administration (6mg/kg) for Both 
Regimen -Safety Population (N=XXX) ............................................ 177 
Listing 16.4.6 
Listing of Concomitant Medication -Safety Population (N=XXX) ...... 178 
 


 
 
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1.0 
BACKGROUND 
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. 
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. Clinical benefits are greatest in patients with tumors strongly 
overexpressing HER2, graded 3+ by IHC, and/or with HER2 gene amplification. 
Previously many studies of Phase III were done using single-agent and in combination with standard 
chemotherapy, such as Herceptin Adjuvant (HERA, BO16348) trial, North Central Cancer Treatment 
Group trial (NCCTG) N9831 trial, National Surgical Adjuvant Breast and Bowel Project (NSABP) 
trial B-31, Breast Cancer International Research Group (BCIRG-006) study, Protocol Adjuvant dans 
le Cancer du Sein (PACS04) trial, Finland Herceptin (FinHer) trial etc. 
It is estimated that over one million patients have been treated with trastuzumab IV as of October 
2011 (Roche, Data on file). 
2.0 
STUDY DESIGN  
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 60mg/m2 
doxorubicin as a 5 to15 minute I.V. bolus injection followed by 600mg/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). 
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. 
There are two types of medicinal products in this study investigational medicinal product and non-
investigational medicine. 
Investigational Medicinal Products 
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 regimens: 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. 
2.1 
Protocol Synopsis 
The protocol number is ML28714 titled as “An Indian Multi-centric 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).” and the Version is 1.0 amended on 29 July 2013. 
2.2 
Study Objectives and Endpoints 
2.2.1 Study Objectives 
2.2.1.1 Primary Objectives 
The primary objective for this study is as follows:- 


 
 
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• 
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.  
2.2.1.2 Secondary Objectives 
The secondary objectives for this study are as follows:- 
• 
To determine the disease free survival (DFS) 
• 
To determine the overall survival (OS) 
 
2.2.2 Study Outcome Measures 
2.2.2.1 Efficacy Outcome Measures 
The efficacy outcome measures for this study are as follows: 
• Disease free survival rate (DFS) and Overall Survival rate (OS) 
 
2.2.2.2 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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2.3 
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. 
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. 
2.4 
Analysis Timing 
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, 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. 
3.0 
STUDY CONDUCT 
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. 
Safety will be carefully evaluated, and the type of data collected and the frequency with which patients 
are monitored will ensure safety of the patients. 
The study team will periodically review patient eligibility and CRF data to ensure that the study is 
compliant with Good Clinical Practice. 
4.0 
STATISTICAL METHODS 
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 indicates the significance. Two-sided 95% confidence interval (CI) will be 
constructed, wherever appropriate.  


 
 
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All baseline summaries and efficacy analyses will be based on the intent-to-treat (ITT) population. This 
will be defined as all enrolled patients. All safety summaries and analysis will be based on the safety 
population, defined as all enrolled patients who receive at least one dose of study medication. 
Disease free survival (DFS) and Overall survival (OS) will be analyzed by the Kaplan-Meier (KM) 
approach. 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. 
Efficacy variables will be summarized for the intent-to-treat (ITT) population. 
4.1 
Analysis Population 
4.1.1 Intent–to-Treat (ITT) population 
Intent-to-Treat (ITT) population is defined as all the patients who are enrolled in the study. 
4.1.2 Safety population 
Safety population will include all those patients who have received at least one dose of study 
medication. 
4.2 
Analysis of Study Conduct 
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 analysis for different parameters is described below: 
4.2.1 Demographics and Baseline Characteristics 
Subject demographics include Age, Sex and Race. 
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 indicates the significance. Two – sided 95% confidence interval (CI) will be constructed, 
wherever appropriate.  
Medical/Surgical History includes clinically significant diseases, surgeries, cancer history, reproductive 
status, smoking, alcoholic and drug abuse history, prior cancer therapy, prior cancer surgery will be 
summarized by frequency counts and percentages. 
All demography and baseline characteristics (collected at either the screening or baseline) will be 
summarized using the ITT population. 
4.3 
Efficacy and Safety Analyses 
4.3.1 Efficacy Analyses 
The efficacy outcomes include Disease free survival rate and Overall survival rate. 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. 


 
 
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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. 
4.3.2 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 NCICTCAE 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 Cochrane Q 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≤0.05indicate the significance.  
4.4 
Missing Data 
No statistical imputation method will be applied for any missing values.  
4.5 
Interim Analyses 
An Interim Analysis was done for safety once all enrolled patients have received at least one dose of 
the IP.
4.6 
Additional Analyses  
If any additional statistical analyses required during the final analysis, appropriate methods will be 
used, and any changes, including the rationale for use, will be documented via Statistical Analysis Plan 
amendment. Any deviations from the planned analyses or prospective amendments to the statistical 
analysis plan will be documented in the Clinical Study Report (CSR). 
4.7 
Data Listings 
All CRF data, as well as any outcomes derived from the data, will be summarised in detailed data 
listings. Patient data listings will be presented for all patients enrolled into the study. 


 
 
 
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4.8  
Plots and Figures 
The plots and graphs will be presented to illustrate the analysis of safety and efficacy.  
• 
A K-M plot of survival probability versus time will be generated to see the overall survival 
profile of the patients in each regimen and for overall also.  
• 
A K-M plot of DFS probability versus time will be generated to see the DFS profile of the 
patients in each regimen and for overall also. 
• 
A multiple bar chart will be generated to understand the ECOG performance status at each 
visit.   
• 
A graph of  LVEF  over a period of time for all patients (Including mean and median)  
5.0 
REFERENCES 
1. ICH E3: Structure and content of Clinical Study Reports, November 1995, Committee for Proprietary 
Medicinal Products. 
2. ICH E9: Statistical Principles for Clinical Trials, September 1998, Committee for Proprietary 
Medicinal Products. 
 
 


 
 
 
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APPENDIX 1 
PROTOCOL SYNOPSIS 
 


 
 
 
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APPENDIX 2 
SCHEDULE OF ASSESSMENTS 
 


 
 
 
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14.1 
Demographics and Baseline Characteristics 
14.1.1 
Patient Disposition 
Table 14.1.1.1 
Summary of Inclusion/Exclusion Criteria- Enrolled Population (N=XXX)  
Inclusion/Exclusion Criteria, n (%)[1] 
Overall 
(N=XX) 
 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Number of Subjects Screened 
XXX 
 
 
 
Number of Subjects Enrolled [1] 
XX (XX.X %) 
 
XX (XX.X %) 
XX (XX.X %) 
Number of Subjects Enrolled meeting all Inclusion Criteria  
XX (XX.X %) 
 
XX (XX.X %) 
XX (XX.X %) 
Number of Subjects meeting at least one exclusion criteria 
XX (XX.X %) 
 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Source: Listing 16.2.3 
 
Note: [1] Percentage will be calculated by taking respective column header count as denominator. 
 
 
General Note:  
➢ Subjects who are meeting inclusion and exclusion criteria will be considered for eligibility analysis.  
➢ Subjects who are eligible will be considered to enroll into the study.  


 
 
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Table 14.1.1.2 
Summary of Patient Disposition- Enrolled Population (N=XXX) 
 
Patient Disposition, n (%) [1] 
Overall 
(N=XX) 
Trastuzumab with AC→TH 
Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Population 
 
 
 
   ITT Population 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
   Safety Population 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Patients  who completed the  protocol 
 
 
 
   Yes 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
   No 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Reason for discontinuation  
 
 
 
   Adverse Event 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
   Disease progression 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
   Death 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
   Insufficient therapeutic response 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
   Lost to follow Up 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
   Withdrew Consent 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
   Investigator’s decision 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
   Other 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Source Data: Listing 16.2.1, 16.2.2.1 and 16.2.2.2 
Note: 
[1] Percentages will be calculated using respective column header group count as denominator. 


 
 
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Table 14.1.1.3 
Summary of Patient Disposition by Site- Enrolled Population (N=XXX) 
Site, n (%) [1] 
Overall 
(N=XX) 
Trastuzumab with AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH Regimen 
(n=XX) 
Site 1  
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Site 2 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Site 3 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Site 4 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Site 5 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
…… 
…… 
…… 
…… 
Site n 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Source Data: Listing 16.2.1 
Note: 
[1] Percentages will be calculated using corresponding column header group count as denominator. 


 
 
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Table 14.1.1.4 
Summary of Subject Follow-up Rate at each Visit- Enrolled Population (N=XXX) 
Visit, n (%)[1] 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH Regimen 
(n=XX) 
Screening and Baseline 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Cycle 1 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Cycle 2 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Cycle 3 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Cycle 4 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Cycle 5 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Cycle 6 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
…… 
…… 
…… 
…… 
Source Data: Listing 16.2.1 
Note: 
 [1] Percentages will be calculated using respective column header group count as denominator. 


 
 
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14.1.2 
Demographic and Baseline Characteristics 
Table 14.1.2.1 
Summary of Patient Demographics at Screening- ITT Population (N=XXX) 
Demographics 
Statistics / Category, n(%)[1] 
Overall 
(N=XX) 
Trastuzumab with AC→TH 
Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Age (years) [2] 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q3 
XX.X 
XX.X 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [3] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Sex 
 
 
 
 
 
Male 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Female 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Missing [3] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Race 
 
 
 
 
 
Indian 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Others 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Missing [3] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Source Data: Listing 16.2.4.1 
Note:  
[1]Percentages will be calculated using respective column header group count as denominator. 
[2]If Date of Birth date is given then to calculate the Age by following formula: Age = {[Date of Informed Consent signed (Screening Date) – Date of Birth +1] /365.25 
[3]If a particular parameter measurement is not captured, it will be displayed under ‘Missing’ category. 


 
 
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Table 14.1.2.2 
Summary of Medical History at Screening- ITT Population (N=XXX) 
System Organ Class/Preferred Term, n (%) [1] 
Overall 
(N=XX) 
Trastuzumab with AC→TH 
Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
 
 
 
 
System Organ Class 1  
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Preferred Term 1 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Preferred Term 2 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
…………… 
…………… 
…………… 
…………… 
System Organ Class 2  
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Preferred Term 1  
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Preferred Term 2  
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
…………… 
……………… 
……………… 
……………… 
 
 
 
 
Source Data: Listing 16.2.4.2 
Note:  
[1]Percentage will be calculated by taking respective column header group count as denominator. 
General Note: 
➢ Medical Conditions will be coded using MedDRA version 21.1 or later 


 
 
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Table 14.1.2.3 
Summary of Cancer History and Reproductive Status at Screening- ITT Population (N=XXX) 
 
History 
 
Statistics/Category, n (%)[1] 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with 
TCH Regimen 
(n=XX) 
Cancer History 
 
 
 
 
Stage of Cancer(During Diagnosis) 
 
 
 
 
 
Stage IA 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Stage IB 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Stage IIA 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Stage IIB 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Stage IIIA 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Stage IIIB 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Stage IV 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Current Stage of Cancer 
 
 
 
 
 
Stage IA 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Stage IB 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Stage IIA 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Stage IIB 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Stage IIIA 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Stage IIIB 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Stage IV 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Reproductive Status 
 
 
 
 
Reproductive Status 
 
 
 
 
 
Post-menopausal 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Surgically Sterile 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Uses contraception 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Other 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Menopausal age (years) 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q3 
XX.X 
XX.X 
XX.X 


 
 
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Range(Min:Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
No. of Live Births 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q3 
XX.X 
XX.X 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Source Data: Listing 16.2.4.3, Listing 16.2.4.4 
Note: 
[1] Percentages will be calculated using corresponding column header group count as denominator. 
[2]If a particular parameter measurement is not captured, it will be displayed under ‘Missing’ category. 


 
 
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Table 14.1.2.4 
Summary of Smoking, Alcoholic and Drug Abuse History at Screening- ITT Population (N=XXX) 
 
History 
 
Statistics/Category, n (%)[1] 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Smoking Status 
 
 
 
 
 
Smoker 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Former Smoker 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Never Smoked 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
If “Smoking status” is Smoker, 
 
 
 
 
Average no. of Cigarettes per day [3] 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q3 
XX.X 
XX.X 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Chew Tobacco 
 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
If “Yes”, 
 
 
 
 
Average quantity (g/day)[4] 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q3 
XX.X 
XX.X 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 


 
 
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Alcoholic Status 
 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
If “Yes”, 
 
 
 
 
Alcohol Taken [5] 
 
 
 
 
 
Occasional 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Light 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Moderate 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Heavy 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Drug Abuse Status 
 
 
 
 
 
Positive 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Negative 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Source Data: Listing 16.2.4.5 
Note: 
[1] Percentages will be calculated using corresponding column header group count as denominator. 
[2] If a particular parameter measurement is not captured, it will be displayed under ‘Missing’ category. 
[3] Percentages will be calculated using count “Smoker” of “Smoking status” as denominator.  
[4] Percentages will be calculated using count “Yes” of “Chew Tobacco” as denominator.  
[5] Percentages will be calculated using count “Yes” of “Alcoholic Status” as denominator. 


 
 
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Table 14.1.2.5 
Summary of Prior Cancer Surgery at Screening- ITT Population (N=XXX)  
System Organ Class/Preferred Term, n (%) [1] 
Overall 
(N=XX) 
Trastuzumab with AC→TH 
Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
 
 
 
 
System Organ Class 1  
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Preferred Term 1 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Preferred Term 2 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
…………… 
…………… 
…………… 
…………… 
System Organ Class 2  
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Preferred Term 1  
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Preferred Term 2  
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
…………… 
……………… 
……………… 
……………… 
 
 
 
 
Source Data: Listing 16.2.7 
Note:  
[1]Percentage will be calculated by taking respective column header group count as denominator. 
General Note: 
➢ Prior Cancer Surgery will be coded using MedDRA version 21.1 or later. 


 
 
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Table 14.1.2.6 
Summary of Histology and Mammogram at Screening- ITT Population (N=XXX) 
 
History 
 
Statistics/Category, n (%)[1] 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Histology 
 
 
 
 
Biopsy performed 
 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
If “Yes” , Result 
 
 
 
 
Grade [2] 
 
 
 
 
 
Grade 1 (low grade) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Grade 2(intermediate grade) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Grade 3 (high grade) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Mammogram 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Findings 
 
 
 
 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Source Data: Listing 16.2.4.7, Listing 16.2.8.4 
Note: 
[1] Percentages will be calculated using corresponding column header group count as denominator. 
[2] Percentages will be calculated using count “Yes” of “Biopsy performed” as denominator. 


 
 
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Table 14.1.2.7 
Summary of Prior Medication at Screening- ITT Population (N=XXX) 
 
Therapeutic Class, Generic 
name, n (%) [1],[2] 
Overall 
(N=XX) 
Trastuzumab with AC→TH 
Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Count of Ongoing [3] 
Therapeutic  Class 1 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Generic Name 1 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Generic Name 2 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Generic Name 3 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
…… 
…… 
…… 
…… 
 
 
 
 
 
Source Data: Listing 16.4.6 
Note:  
[1] Percentages of Therapeutic class will be calculated from respective column header group count as denominator in percentage calculation. 
[2] Percentages of Generic Name will be calculated from Respective Class counts. 
[3] Percentages of Count of Ongoing will be calculated from respective generic name counts. 


 
 
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Table 14.1.2.8 
Summary of Vital Signs at Screening- ITT Population (N=XXX) 
 
Vital Signs [1] 
 
Statistics/Category, n (%) 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Respiratory Rate (breathes/min) 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Pulse Rate (Beats/min) 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Blood Pressure (mmHg) 
 
 
 
 
Systolic 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Diastolic 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 


 
 
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Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Temperature (°C) 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Weight (kgs.) 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Height (cms.) 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Source Data: Listing 16.4.1 


 
 
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Note: 
[1] Percentages will be calculated using corresponding column header group count as denominator. 
[2] If a particular parameter measurement is not captured, it will be displayed under ‘Missing’ category. 


 
 
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Table 14.1.2.9 
Summary of Physical Examination at Screening- ITT Population (N=XXX) 
 
System/Result/Significance [1] 
 
Statistics/Category, n (%) 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Heart 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Clinical Significance [2] 
 
 
 
 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Lungs 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Clinical Significance [2] 
 
 
 
 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Abdomen 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Clinical Significance [2] 
 
 
 
 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Neurological 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Clinical Significance [2] 
 
 
 
 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Head 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 


 
 
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Clinical Significance [2] 
 
 
 
 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Ears, nose and throat 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Clinical Significance [2] 
 
 
 
 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Neck 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Clinical Significance [2] 
 
 
 
 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Extremities 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Clinical Significance [2] 
 
 
 
 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Lymph nodes 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Clinical Significance [2] 
 
 
 
 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Skin 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Clinical Significance [2] 
 
 
 
 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 


 
 
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Musculoskeletal 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Clinical Significance [2] 
 
 
 
 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Others 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Clinical Significance [2] 
 
 
 
 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Source Data: Listing 16.4.2 
Note: 
[1] Percentages will be calculated using corresponding column header group count as denominator. 
[2] Percentages will be calculated using count “Done” of “Body System” as denominator. 


 
 
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Table 14.1.2.10 Summary of Investigations done at Screening- ITT Population (N=XXX) 
Investigations [1] 
Statistics/Category, n (%) 
Overall 
(N=XX) 
Trastuzumab with AC→TH 
Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
12 Lead Electrocardiogram 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Clinical Significance [2] 
 
 
 
 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
LVEF 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Value (%) 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Clinical Significance [2] 
 
 
 
 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
HER2 Testing 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Method [2] 
 
 
 
 
 
IHC 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
FISH 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 


 
 
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Both 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
If IHC [3] 
 
 
 
 
Observation 
0 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
+1 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
+2 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
+3 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
If FISH [3] 
 
 
 
 
Observation 
Positive 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Negative 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Brain CT/MRI 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Clinical Significance [2] 
 
 
 
 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Bone Scan 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Clinical Significance [2] 
 
 
 
 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Liver Imaging 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Clinical Significance [2] 
 
 
 
 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Source Data: Listing 16.2.4.7, Listing 16.2.8.3, Listing 16.2.8.4 
Note: 
[1] Percentages will be calculated using corresponding column header group count as denominator. 
[2] Percentages for clinical significance (CS/NCS) will be calculated using count “Done” of “Investigations” as denominator. 
[3] Percentages for HER2 testing will be calculated using count “Done” as denominator. 


 
 
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Table 14.1.2.11 Summary of Routine Breast Cancer Follow Up at Screening- ITT Population (N=XXX) 
Breast Cancer History[1] 
Statistics/Category, n (%) 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Familial History 
 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Physical Examination 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Presence of symptoms 
 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
If Yes, then symptoms [2] 
 
 
 
 
 
New lumps 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Bone pain 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Chest pain 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Dyspnea 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Abdominal pain 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Persistent headaches 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Others 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Mammography 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
If Done, Results of 
Mammogram [3] 
 
 
 
 
 
Normal 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Abnormal 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Pelvic Examination 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 


 
 
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Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
If Done, Results of Pelvic 
Examination [4] 
 
 
 
 
 
Normal 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Abnormal 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Source Data: Listing 16.4.3.1 
Note: 
[1] Percentages will be calculated using corresponding column header group count as denominator. 
[2] Percentages will be calculated using count “Yes” of “Presence of symptoms” as denominator. 
[3] Percentages will be calculated using count “Done” of “Mammography” as denominator. 
[4] Percentages will be calculated using count “Done” of “Pelvic Examination” as denominator. 


 
 
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14.2 Efficacy Analysis 
Table 14.2.1.1 
Summary of Disease Free Survival at End of Study- ITT Population (N=XXX) 
Visits 
Category, n (%) [1] 
Overall 
(N=XX) 
Trastuzumab with AC→TH 
Regimen 
(n=XX) 
Trastuzumab with 
TCH Regimen 
(n=XX) 
End of Study 
 
 
 
 
 
 
 
 
 
Disease Free Patients 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Source Data: Listing 16.2.6.1 
Note: 
[1] Percentage will be calculated taking “n” count as denominator.  
[2] “n” denotes the number of subjects who would have completed “X visits” in study from the date of randomization 
. 


 
 
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Table 14.2.1.2 
Summary on  Disease Progression by K-M Analysis- ITT Population (N=XXX) 
Category, n (%) [1] 
Overall 
(N=XX) 
Trastuzumab with AC→TH 
Regimen 
(n=XX) 
Trastuzumab with TCH Regimen 
(n=XX) 
Number (%) of Patients who achieved Disease Progression 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Number (%) of censored Patients 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Median duration of Disease Progression (95 % CI) [2] 
XX.X (XX.XX : XX.XX) 
XX.X (XX.XX : XX.XX) 
XX.X (XX.XX : XX.XX) 
Source Data: Listing 16.2.6.1 
Note: 
[1] Percentage will be calculated taking respective column header group count as denominator. 
[2] The median duration of Disease Progression will be estimated by Kaplan-Meier method and also 95 % confidence interval will be calculated for the median duration of 
Disease Progression. 
 
General Note: 
➢ Events: It will be the documented Disease Progression. 
➢ Censoring: Subjects for whom disease progression is not observed during study period, drop outs and lost-to-follow up subjects will be censored at the time of last 
follow-up visit. 
 
 


 
 
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Table 14.2.1.3 
Summary of Median Survival Time between ECOG sub-groups for Disease Free Survival- ITT Population (N=XXX)  
 
Category, n (%) 
 
Overall 
(N=XX) 
 
 
Trastuzumab with AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH Regimen 
(n=XX) 
 
ECOG PS 0 
 
ECOG PS 1-2  ECOG PS 0 
 
ECOG PS 1-2 ECOG PS 0 
 
ECOG PS 1-2  
Median duration of Overall Survival [1] 
XX.X 
 
XX.X 
 
XX.X 
 
XX.X 
XX.X 
 
XX.X 
 
p-value (Using Log-rank Test)[2] 
 
0.XXXX 
 
 
 
0.XXXX 
 
 
0.XXXX 
 
 
Source Data: Listing 16.2.6.1 
Note: 
[1] The median duration of overall survival will be estimated by Kaplan-Meier method. 
[2] The Log-rank Test will be used to compare the median survival time between the subjects with ECOG PS 0 and ECOG PS 1-2 at Baseline. 
General Note: 
➢ Events will be the documented  Disease Free. 
➢ Censoring: Subjects without occurrence of death during study period, drop outs and lost-to-follow up subjects will be censored at the time of last follow-up visit. 
 
Programming Note: 
➢ The duration will be considered as difference between first drug administrations to date of documented death of any patient. 


 
 
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Table 14.2.1.4 
Summary of Overall Survival at Each Visit - ITT Population (N=XXX) 
Visits 
Category, n (%) [1] 
Overall 
(N=XX) 
Trastuzumab with AC→TH 
Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
End of Study 
 
 
 
 
 
 
 
 
 
Alive Patients 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Source Data: Listing 16.2.6.1 
Note: 
[1] “n” denotes the number of subjects who would have completed X months in study from the date of randomization 
[2] Percentage will be calculated taking respective “n” count as denominator. 


 
 
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Table 14.2.1.5 
Summary of Overall Survival by K-M Analysis-ITTPopulation (N=XXX) 
Category, n (%) [1] 
Overall 
(N=XX) 
Trastuzumab with AC→TH 
Regimen 
(n=XX) 
Trastuzumab with TCH Regimen 
(n=XX) 
Number (%) of Patients who died 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Number (%) of censored Patients 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Median duration of Overall Survival (90 % CI) [2] 
XX.X (XX.XX : XX.XX) 
XX.X (XX.XX : XX.XX) 
XX.X (XX.XX : XX.XX) 
Source Data: Listing 16.2.1 
Note: 
[1] Percentage will be calculated taking respective column header group count as denominator. 
[2] The median duration of overall survival will be estimated by Kaplan-Meier method and also 95% confidence interval will be calculated for the median duration of overall 
survival. 
 
General Note: 
➢ Events: It  will be the documented Death. 
➢ Censoring: Subjects who are alive during study period, drop outs and lost-to-follow up subjects will be censored at the time of last follow-up visit. 
Programming Note: 
➢ The duration will be considered as difference between first drug administrations to date of documented death of any patient. 
➢ The probability of survival at any visit will be derived by the “OUTSURV =” option of PROC LIFETEST. The probability from Survival Distribution Function in 
dataset derived by “OUTSURV =” option will be represented at each specified time point. 
➢ Same mock-up will be used to generate the table for Aggressive vs. Non-aggressive by specifying “Disease Status” as STRATA in PROC LIFETEST with change in 
table number and table title as: 
 
Table 14.2.1.6 
Summary of Overall Survival by K-M Analysis for Disease Status  


 
 
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Table 14.2.1.7 
Summary of Median Survival Time between ECOG sub-groups for Overall Survival- ITT Population (N=XXX)  
 
Category, n (%) 
 
Overall 
(N=XX) 
 
 
Trastuzumab with AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH Regimen 
(n=XX) 
 
ECOG PS 0 
 
ECOG PS 1-2  ECOG PS 0 
 
ECOG PS 1-2 ECOG PS 0 
 
ECOG PS 1-2  
Median duration of Overall Survival [1] 
XX.X 
 
XX.X 
 
XX.X 
 
XX.X 
XX.X 
 
XX.X 
 
p-value (Using Log-rank Test)[2] 
 
0.XXXX 
 
 
 
0.XXXX 
 
 
0.XXXX 
 
 
Source Data: Listing 16.2.6.1 
Note: 
[1] The median duration of overall survival will be estimated by Kaplan-Meier method. 
[2] The Log-rank Test will be used to compare the median survival time between the subjects with ECOG PS 0 and ECOG PS 1-2 at Baseline. 
General Note: 
➢ Events will be the documented death of the patient due to any cause. 
➢ Censoring: Subjects without occurrence of death during study period, dropouts and lost-to-follow up subjects will be censored at the time of last follow-up visit. 
 
Programming Note: 
➢ The duration will be considered as difference between first drug administrations to date of documented death of any patient. 


 
 
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14.3 Safety Analysis 
14.3.1 
Adverse Events 
Table 14.3.1.1 
Overall Summary of Adverse Events- Safety Population (N=XXX) 
Events 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Total Number of AEs Reported 
XX 
XX 
XX 
 
 
 
 
Subjects Reporting Any AEs [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Subjects Reporting 1 AE 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Subjects Reporting >1 AE 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Subjects Reporting No AEs [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Number of AEs with Intensity (NCI -CTCAE v4.0): [2] 
 
 
 
Grade 0 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Grade 1 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Grade 2 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Grade 3 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Grade 4 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Grade 5 
 
 
 
 
 
 
 
Number of AEs with Relationship to study drug:[2] 
 
 
 
Related 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Not Related 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Number of AEs by Action taken:[2] 
 
 
 
Dose modification 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Stop Therapy 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Dose delay 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
No action 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 


 
 
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Number of AEs by Event Outcome:[2] 
 
 
 
Resolved 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Resolved-with Sequelae 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Ongoing 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Death 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Unknown 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Subjects Reporting AEs Leading to Discontinuation [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Subjects Reporting Serious AEs [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Subjects Reporting Death 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Source Data: Listing 16.2.7.1 
Note: 
[1] Percentage will be calculated by taking respective column header group count as denominator. 
[2] Percentage will be calculated by taking count of ‘Total Number of AEs Reported’ in corresponding treatment group as denominator. 
General Note: 
➢ Adverse events will be coded using MedDRA version 22.1 or later. 
➢ AEs: Adverse Events 


 
 
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Table 14.3.1.2 
Overall Summary of Treatment Emergent Adverse Events -Safety Population (N=XXX) 
Events 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Total Number of TEAEs Reported 
XX  
XX  
XX  
 
 
 
 
Subjects Reporting Any TEAEs [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Subjects Reporting 1 TEAE 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Subjects Reporting >1 TEAE 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Subjects Reporting No TEAEs [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Number of TEAEs with Intensity (NCI -CTCAE v4.0): [2] 
 
 
 
 
Grade 1 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Grade 2 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Grade 3 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Grade 4 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Grade 5 
 
 
 
 
 
 
 
Number of TEAEs with Relationship to study drug:[2] 
 
 
 
 
Related 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Not Related 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Number of TEAEs by Action taken:[2] 
 
 
 
No action taken 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Infusion Slow Down 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Infusion Interrupted 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Appropriate Medical Therapies Administered 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Number of TEAEs by Event Outcome:[2] 
 
 
 
 
Resolved No-Sequelae 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 


 
 
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Resolved-with Sequelae 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Unresolved 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Death 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Subjects Reporting TEAEs Leading to Withdraw [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Subjects Reporting Serious TEAEs [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Subjects Reporting Death 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Source Data: Listing 16.2.7 
Note: 
[1] Percentage will be calculated by taking respective column header group count as denominator. 
[2] Percentage will be calculated by taking count of ‘Total Number of TEAEs Reported’ in corresponding treatment group as denominator. 
General Note: 
➢ Adverse events will be coded using MedDRA version 22.1 or later. 
➢ TEAEs: Treatment Emergent Adverse Events 


 
 
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Table 14.3.1.3 
Overall Summary of Non-Treatment Emergent Adverse Events-Safety Population (N=XXX)  
Events 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Total Number of non-TEAEs Reported 
XX  
XX  
XX  
 
 
 
 
Subjects Reporting Any non-TEAEs [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Subjects Reporting 1 non-TEAE 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Subjects Reporting >1 non-TEAE 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Subjects Reporting No non-TEAEs [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Number of non-TEAEs with Intensity (NCI -CTCAE v4.0): [2] 
 
 
 
 
Grade 1 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Grade 2 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Grade 3 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Grade 4 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Grade 5 
 
 
 
 
 
 
 
Number of non-TEAEs with Relationship to study drug:[2] 
 
 
 
 
Related 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Not Related 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Number of non-TEAEs by Action taken:[2] 
 
 
 
No action taken 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Infusion Slow Down 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Infusion Interrupted 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Appropriate Medical Therapies Administered 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Number of non-TEAEs by Event Outcome:[2] 
 
 
 
 
Resolved No-Sequelae 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 


 
 
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Resolved-with Sequelae 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Unresolved 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Death 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Subjects Reporting non-TEAEs Leading to Withdraw [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Subjects Reporting Serious non-TEAEs [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Subjects Reporting Death 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Source Data: Listing 16.2.7 
Note: 
[1] Percentage will be calculated by taking respective column header group count as denominator. 
[2] Percentage will be calculated by taking count of ‘Total Number of non TEAEs Reported’ in corresponding treatment group as denominator. 
 
General Note: 
➢ Non Treatment Emergent Adverse events will be coded using MedDRA version 22.1 or later. 
➢ Non TEAEs: Non Treatment Emergent Adverse events 


 
 
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Table 14.3.1.4 
Summary of Adverse Events (including subjects reporting SAEs) by MedDRA System Organ Class and Preferred Term-Safety Population 
(N=XXX)  
System Organ Class/Preferred Term, n (%) [1] 
Overall 
(N=XX) 
Trastuzumab with AC→TH 
Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Total number of subjects with at least one Adverse 
Events(including subjects reporting SAEs) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Total number of Adverse Events 
XX 
XX 
XX 
 
 
 
 
System Organ Class 1  
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Preferred Term 1 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Preferred Term 2 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
…………… 
…………… 
…………… 
…………… 
System Organ Class 2  
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Preferred Term 1  
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Preferred Term 2  
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
…………… 
……………… 
……………… 
……………… 
 
 
 
 
Source Data: Listing 16.2.7 
Note:  
[1] Percentage will be calculated by taking respective column header group count as denominator. 
General Note: 
➢ Adverse events will be coded using MedDRA version 22.1 or later. 
➢ All Adverse events are presented as: number of subjects (percent of subjects) [number of events]. 
➢ Subjects may have reported more than one event per system organ class or preferred term. Subjects will be only counted once for each system organ class or preferred 
term. 


 
 
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Table 14.3.1.5 
Summary of Adverse Events (excluding subjects reporting SAEs) by MedDRA System Organ Class and Preferred Term-Safety Population 
(N=XXX)  
System Organ Class/Preferred Term, n (%) [1] 
Overall 
(N=XX) 
Trastuzumab with AC→TH 
Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Total number of subjects with at least one Adverse 
Events(excluding subjects reporting SAEs) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Total number of Adverse Events 
XX 
XX 
XX 
 
 
 
 
System Organ Class 1  
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Preferred Term 1 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Preferred Term 2 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
…………… 
…………… 
…………… 
…………… 
System Organ Class 2  
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Preferred Term 1  
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Preferred Term 2  
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
…………… 
……………… 
……………… 
……………… 
 
 
 
 
Source Data: Listing 16.2.7 
Note:  
[1] Percentage will be calculated by taking respective column header group count as denominator. 
 
General Note: 
➢ Adverse events will be coded using MedDRA version 22.1 or later 
➢ All Adverse events are presented as: number of subjects (percent of subjects) [number of events]. 
➢ Subjects may have reported more than one event per system organ class or preferred term. Subjects will be only counted once for each system organ class or preferred 
term. 


 
 
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Table 14.3.1.6 
Summary of Adverse Events by MedDRA System Organ Class and Preferred Term by Intensity-Safety Population (N=XXX) 
 
System Organ Class/Preferred Term, n (%) [1] 
Intensity 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Total number of subjects with 
at least one Adverse Events (Including subjects 
reporting SAEs) 
 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Total number of Adverse Events 
 
XX 
XX 
XX 
 
 
 
 
 
System Organ Class 1 
 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Preferred Term 1 
 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Grade 1 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Grade 2 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Grade 3 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Grade 4 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Grade 5 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
 
 
 
 
Preferred Term 2 
 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Grade 1 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Grade 2 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Grade 3 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Grade 4 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Grade 5 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
…………… 
……………… 
……………… 
……………… 
……………… 
 
 
 
 
 
Source Data: Listing 16.2.7.1 
Note:  
[1] Percentage will be calculated by taking respective column header group count as denominator. 
General Note: 
➢ Adverse events will be coded using MedDRA version 22.1 or later 
➢ All Adverse events are presented as: number of subjects (percent of subjects) [number of events]. 


 
 
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➢ Subjects may have reported more than one event per system organ class or preferred term. Subjects will be only counted once for each system organ class or preferred 
term. 
 


 
 
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Table 14.3.1.7 
Summary of Adverse Events by MedDRA System Organ Class and Preferred Term by Action Taken-Safety Population (N=XXX) 
System Organ Class/Preferred Term, n 
(%) [1] 
Action Taken 
Overall 
(N=XX) 
Trastuzumab with AC→TH 
Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Total number of subjects with  
at least one Adverse Events (including 
subjects with SAEs) 
 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Total number of Adverse Events 
 
XX 
XX 
XX 
 
 
 
 
 
System Organ Class 1  
 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Preferred Term 1 
 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Dose modification 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Stop Therapy 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Dose delay 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
No action 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
 
 
 
 
Preferred Term 2 
 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Dose modification 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Stop Therapy 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Dose delay 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
No action 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
…………… 
……………… 
……………… 
……………… 
……………… 
 
 
 
 
 
Source Data: Listing 16.2.7.1 
Note:  
[1] Percentage will be calculated by taking respective column header group count as denominator. 
General Note: 
➢ Adverse events will be coded using MedDRA version 22.1 or later 
➢ All Adverse events are presented as: number of subjects (percent of subjects) [number of events]. 
➢ Subjects may have reported more than one event per system organ class or preferred term. Subjects will be only counted once for each system organ class or preferred 
term. 


 
 
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Table 14.3.1.8 
Summary of Adverse Events by MedDRA System Organ Class and Preferred Term by Event Outcome-Safety Population (N=XXX)  
System Organ Class/Preferred Term, n (%) 
[1] 
Event Outcome 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Total number of subjects with  
at least one Adverse Events (including subjects 
reporting SAEs) 
 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Total number of Adverse Events 
 
XX 
XX 
XX 
 
 
 
 
 
System Organ Class 1  
 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Preferred Term 1 
 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Resolved 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Resolved-with Sequelae 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Ongoing 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Death 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Unknown 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
 
 
 
 
Preferred Term 2 
 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Resolved 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Resolved-with Sequelae 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Ongoing 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Death 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Unknown 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
…………… 
……………… 
……………… 
……………… 
……………… 
 
 
 
 
 
Source Data: Listing 16.2.7.1 
Note:  
[1] Percentage will be calculated by taking respective column header group count as denominator. 
General Note: 
➢ Adverse events will be coded using MedDRA version 22.1 or later 
➢ All Adverse events are presented as: number of subjects (percent of subjects) [number of events]. 


 
 
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➢ Subjects may have reported more than one event per system organ class or preferred term. Subjects will be only counted once for each system organ class or preferred 
term. 
 
 
 
 
 
 
 
 
. 
 


 
 
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14.3.2 
Serious Adverse Events 
Table 14.3.2.1 
Overall Summary of Serious Adverse Events -Safety Population (N=XXX) 
Events 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Total Number of SAEs Reported 
XX 
XX 
XX 
 
 
 
 
Subjects Reporting Any SAEs [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Subjects Reporting 1 SAE 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Subjects Reporting >1 SAE 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Subjects Reporting No SAEs [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Number of SAEs with Intensity (NCI -CTCAE v4.0): [2] 
 
 
 
Grade 1 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Grade 2 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Grade 3 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Grade 4 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Grade 5 
 
 
 
 
 
 
 
Number of SAEs with Relationship to study drug:[2] 
 
 
 
Related 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Not Related 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Number of SAEs by Action taken:[2] 
 
 
 
Dose modification 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Stop Therapy or discontinuation of treatment 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Dose delay 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
No action 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 


 
 
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Number of SAEs by Event Outcome:[2] 
 
 
 
Resolved 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Resolved-with Sequelae 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Ongoing 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Death 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Unknown 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Subjects Reporting SAEs Leading to Discontinuation [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Subjects Reporting Serious SAEs [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Subjects Reporting Death 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Source Data: Listing 16.2.7.1 
Note: 
[1] Percentage will be calculated by taking respective column header group count as denominator. 
[2] Percentage will be calculated by taking count of ‘Total Number of SAEs Reported’ in corresponding treatment group as denominator. 
General Note: 
➢ Serious Adverse events will be coded using MedDRA version 22.1 or later. 
➢ SAEs: Serious Adverse Events 


 
 
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Table 14.3.2.2 
Summary of Serious Adverse Events by MedDRA System Organ Class and Preferred Term -Safety Population (N=XXX) 
System Organ Class/Preferred Term, n (%) [1] 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Total number of subjects with at  
least one serious adverse event  
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Total number of serious adverse events 
XX 
XX 
XX 
 
 
 
 
System Organ Class 1  
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Preferred Term 1 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Preferred Term 2 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
…………… 
…………… 
…………… 
…………… 
System Organ Class 2  
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Preferred Term 1  
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
Preferred Term 2  
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
XX (XX.X %) [XX] 
 
…………… 
…………… 
…………… 
…………… 
 
 
 
 
Source Data: Listing 16.2.7.1 
Note:  
[1] Percentage will be calculated by taking respective column header group count as denominator. 
General Note: 
➢ Serious Adverse events will be coded using MedDRA version 22.1 or later 
➢ All Serious Adverse events are presented as: number of subjects (percent of subjects) [number of events]. 
➢ Subjects might have reported more than one event per system organ class or preferred term. Subjects will be only counted once for each system organ class or preferred 
term. 


 
 
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14.3.3 
Concomitant Medication 
Table 14.3.3.1 
Summary of Concomitant Medication Assessment -Safety Population (N=XXX) 
 
Therapeutic Class, n (%) 
[1] 
Generic name, n (%) 
[2] 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Count of Ongoing [3] 
Therapeutic  Class 1 
 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
Generic Name 1 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Generic Name 2 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Generic Name 3 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
…… 
…… 
…… 
…… 
…… 
 
 
 
 
 
 
Source Data: Listing 16.4.6 
Note:  
[1] Percentages of Therapeutic class will be calculated from respective column header group count as denominator in percentage calculation. 
[2] Percentages of Generic Name will be calculated from Respective Class counts. 
[3] Percentages of Count of Ongoing will be calculated from respective generic name counts. 
 




 
 
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Table 14.3.4.2  Summary of Vital Signs at different Cycles before administration of Trastuzumab-Safety Population (N=XXX) 
Vital Signs 
Statistics 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
 
 
 
 
 
Cycle 1 
 
 
 
 
Respiratory Rate(Breaths/minute) 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Pulse rate (Beats/minute) 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Blood Pressure(mm Hg) 
 
 
 
 
Systolic 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 




 
 
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Table 14.3.4.3  Summary of Vital Signs at different Cycles (for Prior and Post Loading Dose) -Safety Population (N=XXX) 
Vital Signs 
Statistics 
Overall 
  (N=XX) 
Trastuzumab with AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH Regimen 
(n=XX) 
 
 
Prior Loading 
Dose 
Post Loading 
Dose 
Prior Loading Dose 
Post Loading 
Dose 
Prior Loading 
Dose 
Post Loading 
Dose 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle X 
 
 
 
 
 
 
 
 
 
Respiratory 
Rate(Breaths/minute) 
 
 
 
 
 
 
 
 
n 
XX 
XX 
XX 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Range(Min: 
Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
 
 
 
 
 
Pulse rate (Beats/minute) 
 
 
 
 
 
 
 
 
 
 
n 
XX 
XX 
XX 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Range(Min: 
Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
 
 
 
 
 
Blood Pressure(mmHg) 
 
 
 
 
 
 
 
Systolic 
 
 
 
 
 
 
 
 
n 
XX 
XX 
XX 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 




 
 
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Table 14.3.4.4  Summary of Vital Signs at different Cycles (for Prior and Post Maintenance Dose) -Safety Population (N=XXX) 
Vital Signs 
Statistics 
Overall 
  (N=XX) 
Trastuzumab with AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH Regimen 
(n=XX) 
 
 
Prior 
Maintenance 
Dose 
Post 
Maintenance 
Dose 
Prior Maintenance 
Dose 
Post 
Maintenance 
Dose 
Prior Maintenance 
Dose 
Post 
Maintenance 
Dose 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle X 
 
 
 
 
 
 
 
 
 
Weekly Basis 
 
 
 
 
 
 
 
 
 
Day 1 
 
 
 
 
 
 
 
 
 
Respiratory 
Rate(Breaths/minute) 
 
 
 
 
 
 
 
 
n 
XX 
XX 
XX 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Range(Min: 
Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
 
 
 
 
 
Pulse rate 
(Beats/minute) 
 
 
 
 
 
 
 
 
 
 
n 
XX 
XX 
XX 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Range(Min: 
Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
 
 
 
 
 


 
 
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Blood Pressure(mmHg) 
 
 
 
 
 
 
 
Systolic 
 
 
 
 
 
 
 
 
n 
XX 
XX 
XX 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Range(Min: 
Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
 
 
 
 
 
Diastolic 
 
 
 
 
 
 
 
 
n 
XX 
XX 
XX 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Range(Min: 
Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
 
 
 
Temperature (°C) 
 
 
 
 
 
 
 
 
n 
XX 
XX 
XX 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Range(Min: 
Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
… 
… 
… 
… 
… 
… 
… 
… 
Source Data: Listing 16.4.1.2 
Note: 
[1] If a particular parameter measurement is not captured, will be displayed under ‘Missing’ category 




 
 
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Table 14.3.4.5 
Summary of Vital Signs at different Cycles (for Prior and Post Administration) -Safety Population (N=XXX) 
Vital Signs 
Statistics 
Overall 
(N=XX) 
Trastuzumab with AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH Regimen 
(n=XX) 
Prior 
Administration 
Post 
Administration 
Prior 
Administration 
Post 
Administration 
Prior 
Administration 
Post 
Administration 
 
 
 
 
 
 
 
 
Cycle X 
 
 
 
 
 
 
 
Respiratory 
Rate(Breaths/minute) 
 
 
 
 
 
 
 
 
n 
XX 
XX 
XX 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Range(Min: 
Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
 
 
 
Pulse rate 
(Beats/minute) 
 
 
 
 
 
 
 
 
n 
XX 
XX 
XX 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Range(Min: 
Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
 
 
 
Blood Pressure(mmHg) 
 
 
 
 
 
 
 
Systolic 
 
 
 
 
 
 
 
 
n 
XX 
XX 
XX 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 




 
 
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Table 14.3.4.6  Summary of Vital Signs at End of Study-Safety Population (N=XXX) 
Vital Signs 
Statistics 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
 
 
 
 
 
Study Completion/Early Termination Visit 
 
 
 
 
 
 
 
 
 
Respiratory Rate(Breaths/minute) 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Pulse rate (Beats/minute) 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Blood Pressure(mmHg) 
 
 
 
 
Systolic 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 


 
 
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Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Diastolic 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Temperature (°C) 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Weight (kgs.) 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [1] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
… 
… 
… 
… 
… 
Source Data: Listing 16.4.1.1 
Note: 
[1] If a particular parameter measurement is not captured, will be displayed under ‘Missing’ category 






 
 
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14.3.6 Laboratory Assessments  
Table 14.3.6.1 
Summary of Hematology-Safety Population (N=XXX) 
Table 14.3.6.1.1  Summary of WBC Count of Hematology-Safety Population (N=XXX) 
Visits/Statistics/Category, n 
(%) [1] 
 
 
Baseline 
Change from Baseline 
 
Overall 
(N=XX) 
 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with 
TCH Regimen 
(n=XX) 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with 
TCH Regimen 
(n=XX) 
 
Done 
X (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
- 
- 
- 
Baseline 
 
 
 
 
 
 
 
 
 
n 
XX 
XX 
XX 
- 
- 
- 
Mean 
XX.X 
XX.X 
XX.X 
- 
- 
- 
SD 
XX.XX 
XX.XX 
XX.XX 
- 
- 
- 
Median 
XX.X 
XX.X 
XX.X 
- 
- 
- 
Q1 
XX.X 
XX.X 
XX.X 
- 
- 
- 
Q2 
XX.X 
XX.X 
XX.X 
- 
- 
- 
Range(Min: Max) 
XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
- 
- 
- 
Missing [3] 
XX (XX.X 
%) 
XX (XX.X %) 
XX (XX.X %) 
- 
- 
- 
 
 
 
 
 
 
 
Significance [2] 
 
 
 
 
 
 
CS 
X (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
- 
- 
- 
NCS 
X (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
Done 
X (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
X (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Cycle1 
 
 
 
 
 
 
 
 
 
n 
XX 
XX 
XX 
XX 
XX 
XX 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
Q1 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
Q2 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
Range(Min: Max) 
XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
Missing [3] 
XX (XX.X%) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X%) 
XX (XX.X %) 
XX (XX.X %) 




 
 
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Table 14.3.6.1.12  
Shift table for Parameters of Hematology-Safety Population (N=XXX) 
Parameters/Statistics/Catego
ry, n (%) [1] 
 
 
Overall 
(N=XX) 
 
 
 
Trastuzumab with AC→TH Regimen 
(n=XX) 
 
 
Trastuzumab with TCH Regimen 
(n=XX) 
Baseline 
End of 
Study 
 
Baseline 
End of Study 
Baseline 
End of Study 
 
 
 
CS 
NCS 
 
CS 
NCS 
 
CS 
NCS 
 
 
WBC Count 
 
 
 
 
 
 
 
 
 
CS 
XX(XX.X
%) 
XX(XX.X
%) 
XX(XX.X
%) 
XX(XX.X%
) 
XX(XX.X
%) 
XX(XX.X
%) 
XX(XX.X%
) 
XX(XX.X
%) 
XX(XX.X
%) 
 
 
NCS 
XX(XX.X
%) 
XX(XX.X
%) 
XX(XX.X
%) 
XX(XX.X%
) 
XX(XX.X
%) 
XX(XX.X
%) 
XX(XX.X%
) 
XX(XX.X
%) 
XX(XX.X
%) 
 
 
 
 
 
 
 
 
 
 
 
 
RBC Count 
 
 
 
 
 
 
 
 
 
CS 
XX(XX.X
%) 
XX(XX.X
%) 
XX(XX.X
%) 
XX(XX.X%
) 
XX(XX.X
%) 
XX(XX.X
%) 
XX(XX.X%
) 
XX(XX.X
%) 
XX(XX.X
%) 
 
 
NCS 
XX(XX.X
%) 
XX(XX.X
%) 
XX(XX.X
%) 
XX(XX.X%
) 
XX(XX.X
%) 
XX(XX.X
%) 
XX(XX.X%
) 
XX(XX.X
%) 
XX(XX.X
%) 
 
 
 
 
 
 
 
 
 
 
 
 
…… 
…… 
…… 
…… 
…… 
…… 
…… 
…… 
…… 
…… 
Source Data: Listing 16.2.8.1 
Note: 
[1] Percentage will be calculated by using CS and NCS count at Baseline as denominator. 
 
 
 
 
Programming Note: 
➢ The same shift table will include the analysis for other Hematology parameters: Hemoglobin, Hematocrit, Platelet Count, Neutrophils, Eosinophils, Basophils, 
Monocytes, Lymphocytes and other cells. 


 
 
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Table 14.3.6.2 
Summary of Biochemistry-Safety Population (N=XXX) 
Table 14.3.6.2.1  Summary of Sodium of Biochemistry-Safety Population (N=XXX)  
Visits/Statistics/Category, n (%) [1] 
 
Baseline 
 
 
Change from 
baseline 
 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with 
TCH Regimen 
(n=XX) 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with 
TCH Regimen 
(n=XX) 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
- 
- 
- 
Baseline 
 
 
 
 
 
 
n 
XX 
XX 
XX 
- 
- 
- 
Mean 
XX.X 
XX.X 
XX.X 
- 
- 
- 
SD 
XX.XX 
XX.XX 
XX.XX 
- 
- 
- 
Median 
XX.X 
XX.X 
XX.X 
- 
- 
- 
Q1 
XX.X 
XX.X 
XX.X 
- 
- 
- 
Q2 
XX.X 
XX.X 
XX.X 
- 
- 
- 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
- 
- 
- 
Missing [3] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
- 
- 
- 
 
 
 
 
 
 
 
Significance [2] 
 
 
 
 
 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
- 
- 
- 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
- 
- 
- 
 
 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Cycle1 
 
 
 
 
 
 
n 
XX 
XX 
XX 
XX 
XX 
XX 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
Q1 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
Q2 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
Missing [3] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
 
 
p-value [4] 
0.XXXX 
0.XXXX 
0.XXXX 
- 
- 
- 
 
 
 
 
 
 
 
Significance [2] 
 
 
 
 
 
 




 
 
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Table 14.3.6.2.14Summary of Direct Bilirubin of Biochemistry-Safety Population (N=XXX)  
Table 14.3.6.2.15Summary of Alkaline Phosphatase of Biochemistry-Safety Population (N=XXX)  
Table 14.3.6.2.16Summary of Creatinine Phosphokinase of Biochemistry-Safety Population (N=XXX)  
Table 14.3.6.2.17Summary of ALT of Biochemistry-Safety Population (N=XXX)  
Table 14.3.6.2.18Summary of AST of Biochemistry-Safety Population (N=XXX)  
Table 14.3.6.2.19Summary of Uric Acid of Biochemistry-Safety Population (N=XXX)  
Table 14.3.6.2.20Summary of LDH of Biochemistry-Safety Population (N=XXX)  




 
 
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Table 14.3.6.3 
Summary of LVEF-Safety Population (N=XXX) 
Visits/Statistics/Category, n 
(%) [1] 
Baseline 
                           Change from Baseline 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with 
TCH Regimen 
(n=XX) 
 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with 
TCH Regimen 
(n=XX) 
Done 
X (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
- 
- 
- 
Baseline 
 
 
 
 
 
 
 
n 
XX 
XX 
XX 
- 
- 
- 
Mean 
XX.X 
XX.X 
XX.X 
- 
- 
- 
SD 
XX.XX 
XX.XX 
XX.XX 
- 
- 
- 
Median 
XX.X 
XX.X 
XX.X 
- 
- 
- 
Q1 
XX.X 
XX.X 
XX.X 
- 
- 
- 
Q2 
XX.X 
XX.X 
XX.X 
- 
- 
- 
Range(Min: Max) 
XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
- 
- 
- 
Missing [3] 
XX (XX.X 
%) 
XX (XX.X %) 
XX (XX.X %) 
- 
- 
- 
 
 
 
 
 
 
 
Significance [2] 
 
 
 
 
 
 
CS 
X (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
- 
- 
- 
NCS 
X (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
- 
- 
- 
 
 
 
 
 
 
 
 
Done 
X (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
X (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Cycle5 
 
 
 
 
 
 
 
n 
XX 
XX 
XX 
XX 
XX 
XX 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
Q1 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
Q2 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
Range(Min: Max) 
XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
Missing [3] 
XX (XX.X 
%) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X 
%) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
 
 
p-value [4] 
0.XXXX 
0.XXXX 
0.XXXX 
- 
- 
- 
 
 
 
 
 
 
 










 
 
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Table 14.3.6.6 
Summary of Routine Breast Cancer Follow Up-Safety Population (N=XXX) 
 
Examination [1] 
 
Statistics/Category, n (%), [1] 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with 
TCH Regimen 
(n=XX) 
Cycle 9 
 
 
 
 
Physical Examination 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Occurrence of any symptoms 
 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Any recurrence of prior symptoms 
 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
If Yes, Specify [2] 
 
 
 
 
 
New Lumps 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Bone Pain 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Chest Pain 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Dyspnea 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Abdominal pain 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Persistent headaches 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Others 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Location of recurrence [2] 
 
 
 
 
 
Local 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Regional 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Distant 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Contra-lateral breast cancer 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Mammography 
 
 
 
 


 
 
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 Page 102 of178 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Results of Mammogram 
 
 
 
 
 
Normal 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Abnormal 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Pelvic Examination 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Results of Pelvic Examination 
 
 
 
 
 
Normal 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Abnormal 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Brain CT/MRI 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Findings 
 
 
 
 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Bone Scan 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Findings 
 
 
 
 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Liver Imaging 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Findings 
 
 
 
 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 




 
 
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 Page 104 of178 
 
Table 14.3.6.7 
Summary of CT/MRI and Mammogram at Study Completion and Follow-up-Safety Population (N=XXX) 
 
Test 
 
Statistics/Category, n (%), [1] 
Overall 
(N=XX) 
Trastuzumab with 
AC→TH Regimen 
(n=XX) 
Trastuzumab with 
TCH Regimen 
(n=XX) 
Study Completion/ Early Termination 
 
 
 
 
CT/MRI 
 
 
 
 
Size of Lesion 1 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Size of Lesion 2 
 
 
 
 
 
n 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Mammogram 
 
 
 
 
 
Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
Finding 
 
 
 
 
 
CS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
NCS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 




 
 
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 Page 106 of178 
Table 14.3.7 
Summary of Drug Administration-Safety Population (N=XXX) 
Table 14.3.7.1 
Summary of Drug Administration in AC→TH Regimen -Safety Population (N=XXX) 
Table 14.3.7.1.1 Summary of Chemotherapy- Doxorubicin Administration in AC→TH Regimen-Safety Population (N=XXX)  
 
Administration  
 
Statistics/Category, n (%)[1] 
Overall 
(N=XX) 
Trastuzumab with AC→TH 
Regimen 
(n=XX) 
Cycle 1 
 
 
 
Doxorubicin administered 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Dose of 60 mg/m² Doxorubicin administered 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Administration of Doxorubicin delayed 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
…… 
…… 
…… 
…… 
Source Data: Listing 16.4.5.1 
Note: 
[1] Percentages will be calculated using corresponding column header group count as denominator. 
[2] If a particular parameter measurement is not captured, will be displayed under ‘Missing’ category 








 
 
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Table 14.3.7.1.3 Summary of Chemotherapy- Docetaxel/ Paclitaxel Administration-Safety Population (N=XXX) 
 
Administration  
 
Statistics/Category, n (%)[1] 
Overall 
(N=XX) 
Trastuzumab with AC→TH 
Regimen 
(n=XX) 
Cycle X 
 
 
 
Drug administered to the patient 
 
 
 
 
Docetaxel 
XX (XX.X %) 
XX (XX.X %) 
 
Paclitaxel 
XX (XX.X %) 
XX (XX.X %) 
 
None 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Dose of 100 mg/m² Docetaxel administered on Day 1 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Dose of 175 mg/m² Paclitaxel administered on Day 1 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Administration for the above mentioned drug 
delayed 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Administration of Cyclophosphamide delayed 
 
 
 




 
 
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 Page 112 of178 
 
Table 14.3.7.1.4 Summary of Trastuzumab Administration (weekly total dose=8 mg/kg) in AC→TH Regimen-Safety Population (N=XXX)  
 
Administration  
 
Statistics/Category, n (%)[1] 
Overall 
(N=XX) 
Trastuzumab with AC→TH 
Regimen 
(n=XX) 
Cycle 5 
 
 
 
Schedule of Trastuzumab administration 
 
 
 
 
Weekly 
XX (XX.X %) 
XX (XX.X %) 
 
3-Weekly 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
If Weekly, then [3] 
 
 
 
Total loading dose of 4 mg/kg administered to 
the patient on Day 1 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Observation 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 


 
 
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Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 113 of178 
Patients who were administered Trastuzumab 
(2 mg/kg) on Day 8 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Observation 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Patients who were administered Trastuzumab 
(2 mg/kg) on Day 15 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 


 
 
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Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 114 of178 
 
 
 
 
Duration of Observation 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
If 3-Weekly, then [4] 
 
 
 
Total loading dose of 8 mg/kg administered to 
the patient on Day 1 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Observation 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
……. 
……. 
……. 
……. 


 
 
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Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 115 of178 
Source Data: Listing 16.4.5.6a 
Note: 
[1] Percentages will be calculated using corresponding column header group count as denominator. 
[2] If a particular parameter measurement is not captured, will be displayed under ‘Missing’ category. 
[3] Percentages will be calculated using “Weekly” count of “Schedule of Trastuzumab administration” as denominator. 
[4] Percentages will be calculated using “3-Weekly” count of “Schedule of Trastuzumab administration” as denominator. 


 
 
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Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 116 of178 
 
Table 14.3.7.1.5 Summary of Trastuzumab Administration (weekly total dose=6 mg/kg) in AC→TH Regimen-Safety Population (N=XXX)  
 
Administration  
 
Statistics/Category, n (%)[1] 
Overall 
(N=XX) 
Trastuzumab with AC→TH 
Regimen 
(n=XX) 
Cycle X 
 
 
 
Schedule of Trastuzumab administration 
 
 
 
 
Weekly 
XX (XX.X %) 
XX (XX.X %) 
 
3-Weekly 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
If Weekly, then [3] 
 
 
 
Total loading dose of 2 mg/kg administered to 
the patient on Day 1 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Observation 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 


 
 
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Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 117 of178 
Patients who were administered Trastuzumab 
(2 mg/kg) on Day 8 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Observation 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Patients who were administered Trastuzumab 
(2 mg/kg) on Day 15 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 


 
 
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Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 118 of178 
 
 
 
 
Duration of Observation 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
If 3-Weekly, then [4] 
 
 
 
Total loading dose of 6 mg/kg administered to 
the patient on Day 1 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Observation 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
……. 
……. 
……. 
……. 




 
 
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Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 120 of178 
 
Table 14.3.7.1.6 Summary of Trastuzumab Administration in AC→TH Regimen-Safety Population (N=XXX)  
 
Administration  
 
Statistics/Category, n (%)[1] 
Overall 
(N=XX) 
Trastuzumab with AC→TH 
Regimen 
(n=XX) 
Cycle X 
 
 
 
Dose of 6 mg/kg Trastuzumab administered on Day 1 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Observation 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
……. 
……. 
……. 
……. 
Source Data: Listing 16.4.5.6c 
Note: 
[1] Percentages will be calculated using corresponding column header group count as denominator. 
[2] If a particular parameter measurement is not captured, will be displayed under ‘Missing’ category. 
 




 
 
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Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 122 of178 
 
Table 14.3.7.2 
Summary of Drug Administration in TCH Regimen-Safety Population (N=XXX)  
Table 14.3.7.2.1 Summary of Chemotherapy- Docetaxel Administration in TCH Regimen-Safety Population (N=XXX)  
 
Administration  
 
Statistics/Category, n (%)[1] 
Overall 
(N=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Cycle X 
 
 
 
Docetaxel administered 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Dose of 75 mg/m² Docetaxel administered 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Administration of Docetaxel delayed 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
…… 
…… 
…… 
…… 
Source Data: Listing 16.4.5.4 
Note: 
[1] Percentages will be calculated using corresponding column header group count as denominator. 
[2] If a particular parameter measurement is not captured, will be displayed under ‘Missing’ category 




 
 
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Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 124 of178 
 
Table 14.3.7.2.2 Summary of Chemotherapy- Carboplatin Administration in TCH Regimen-Safety Population (N=XXX)  
 
Administration  
 
Statistics/Category, n (%)[1] 
Overall 
(N=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Cycle X 
 
 
 
Docetaxel administered on Day1 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Total Dose of Carboplatin (mg) 
 
 
 
 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
GFR (ml/min) 
 
 
 
 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 




 
 
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Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 126 of178 
 
Table 14.3.7.2.3 Summary of Trastuzumab Administration (weekly-total dose=8mg/kg) in TCH Regimen-Safety Population (N=XXX)  
 
Administration  
 
Statistics/Category, n (%)[1] 
Overall 
(N=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Cycle X 
 
 
 
Schedule of Trastuzumab administration 
 
 
 
 
Weekly 
XX (XX.X %) 
XX (XX.X %) 
 
3-Weekly 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
If Weekly, then [3] 
 
 
 
Total loading dose of 4 mg/kg administered to 
the patient on Day 1 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Observation 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 


 
 
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Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 127 of178 
Patient take Trastuzumab (2 mg/kg) on Day 8 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Observation 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Patient take Trastuzumab (2 mg/kg) on Day 15 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Observation 
n 
XX 
XX 


 
 
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Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 128 of178 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
If 3-Weekly, then [4] 
 
 
 
Total loading dose of 8 mg/kg administered to 
the patient on Day 1 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Observation 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
……. 
……. 
……. 
……. 
Source Data: Listing 16.4.5.6a 
Note: 


 
 
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Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 129 of178 
[1] Percentages will be calculated using corresponding column header group count as denominator. 
[2] If a particular parameter measurement is not captured, will be displayed under ‘Missing’ category. 
[3] Percentages will be calculated using “Weekly” count of “Schedule of Trastuzumab administration” as denominator. 
[4] Percentages will be calculated using “3-Weekly” count of “Schedule of Trastuzumab administration” as denominator. 


 
 
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Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 130 of178 
 
Table 14.3.7.2.4 Summary of Trastuzumab Administration (weekly-total dose=6mg/kg) in TCH Regimen-Safety Population (N=XXX)  
 
Administration  
 
Statistics/Category, n (%)[1] 
Overall 
(N=XX) 
Trastuzumab with TCH 
Regimen 
(n=XX) 
Cycle X 
 
 
 
Schedule of Trastuzumab administration 
 
 
 
 
Weekly 
XX (XX.X %) 
XX (XX.X %) 
 
3-Weekly 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
If Weekly, then [3] 
 
 
 
Total loading dose of 2 mg/kg administered to 
the patient on Day 1 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Observation 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 


 
 
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Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 131 of178 
Patient take Trastuzumab (2 mg/kg) on Day 8 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Observation 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Patient take Trastuzumab (2 mg/kg) on Day 15 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Observation 
n 
XX 
XX 


 
 
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Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 132 of178 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
If 3-Weekly, then [4] 
 
 
 
Total loading dose of 6 mg/kg administered to 
the patient on Day 1 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Observation 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
……. 
……. 
……. 
……. 
Source Data: Listing 16.4.5.6b 
Note: 




 
 
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Table 14.3.7.2.5 Summary of Trastuzumab Administration in TCH Regimen-Safety Population (N=XXX) 
 
Administration  
 
Statistics/Category, n (%)[1] 
Overall 
(N=XX) 
Trastuzumab with AC→TH 
Regimen 
(n=XX) 
Cycle X 
 
 
 
Dose of 6 mg/kg Trastuzumab administered on Day 1 
 
 
 
 
Yes 
XX (XX.X %) 
XX (XX.X %) 
 
No 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Administration 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
Duration of Observation 
n 
XX 
XX 
 
Mean 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
 
Q1 
XX.X 
XX.X 
 
Q2 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [2] 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
……. 
……. 
……. 
……. 
Source Data: Listing 16.4.5.6c 
Note: 
[1] Percentages will be calculated using corresponding column header group count as denominator. 
[2] If a particular parameter measurement is not captured, will be displayed under ‘Missing’ category. 
 




 
 
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Table 14.3.7.2.6a 
Summary of exposure to Doxorubicin and cyclophosphamide in patients treated with ACTH regimen-ITT     Population(N=XXX) 
 
Category, n (%) 
 
No. of cycles received 
Treated patients (%) 
AC* 
 
 
 
1(Cycle 1) 
XX (XX.X %) 
 
2(Cycle 2) 
XX (XX.X %) 
 
3(Cycle 3) 
XX (XX.X %) 
 
4(Cycle 4) 
XX (XX.X %) 
Source Data: Listing 16.4.5.1 & Listing 16.4.5.2 
Note: 
[1] Percentages will be calculated by taking the subject in AC-TH regimen Count as denominator. 
General Note: 
* Subject in AC-TH Regimen recieved AC treatment between the Cycle 1 to Cycle 4. 


 
 
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Table 14.3.7.2.6b 
 Summary of exposure to taxanes and trastuzumab in patients treated with AC-TH regimen(3-Weekly) (N=XXX) 
 
Category, n (%) 
 
No. of cycles received 
Treated patients (%) 
TH* 
 
 
 
5(Cycle 5) 
XX (XX.X %) 
 
6(Cycle 6) 
XX (XX.X %) 
 
7(Cycle 7) 
XX (XX.X %) 
 
8(Cycle 8) 
XX (XX.X %) 
 
……… 
 
 
……… 
 
 
 
 
Source Data: Listing 16.4.5.6.1 ,Listing 16.4.5.6.2 ,Listing 16.4.5.6.2a , Listing 16.4.5.6.3 
[1] Percentages will be calculated by taking the subject in AC-TH regimen from ITT Population count as denominator. 
General Note: 
* Subject in AC-TH Regimen received study medication (TH) in 3-weekly basis between the Cycle 9 to Cycle 22 and some subjects takes study medication (TH) in 3- 
weekly basis between cycle 5 to cycle 8. 
Programming Note: The same table will also include the analysis for the cycle9, cycle10, cycle11, cycle12, cycle13, cycle14, cycle15, cycle16, cycle17, cycle18, cycle19, 
cycle20, cycle21 and cycle22. 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Table 14.3.7.2.6c: Summary of exposure to taxanes and trastuzumab in patients treated with AC-TH regimen(Weekly) (N=XXX) 
 
Category, n (%) 
 
No. of cycles received 
Day of Receive 
Treated patients 
(%) 
TH* 
 
 
 
 
Treatment Cycle 5 
Day-1 
XX (XX.X %) 
 
Treatment Cycle 5 
Day-8 
XX (XX.X %) 
 
Treatment Cycle 5 
Day-15 
XX (XX.X %) 
 
……. 
 
XX (XX.X %) 
 
……… 
 
 
 
……… 
 
 
 
 
 
 
Source Data:Listing 16.4.5.3 & Listing 16.4.5.6.1a 
Note: 
[1] Percentages will be calculated by taking the subject in AC-TH regimen from ITT Population count as denominator. 
General Note: 
* Subject in AC-TH Regimen received study medication (TH) in weekly basis between the Cycle 9 to Cycle 22. 
 
Programming Note: The same table will also include the analysis for the cycle6, cycle7, cycle8. 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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1.2 
Figures 
14.2.1 
Figures for Efficacy Analysis 
Figure 14.2.1.1 K-M Plot for Disease Free Survival by Treatment-ITT Population (N=XXX)  
K-M Plot 
A step diagram of K-M analysis for AC→TH Regimen, TCH Regimen and Overall will be generated where X-axis will represent 
Time (Days) and Y-axis will represent Disease Free survival probability for AC→TH Regimen, TCH Regimen and Overall. 
Source Data: Table 14.2.2.2 


 
 
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Figure 14.2.1.2 K-M Plot for Overall Survival by Regimen-ITT Population (N=XXX)   
K-M Plot 
A step diagram of K-M analysis for AC→TH Regimen, TCH Regimen and Overall will be generated where X-axis will represent 
Time (Days) and Y-axis will represent overall survival probability for AC→TH Regimen, TCH Regimen and Overall. 
Source Data: Table 14.2.1.2 
 
 
 
 
 
 
Source Data: Table 14.2.1.3 
➢ Same analysis figure will be prepared for the Efficacy Population with an appropriate change in title: 
Figure 14.2.1.3 K-M Plot for Overall Survival by Disease Status-ITT Population (N=XXX)   


 
 
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Figure 14.2.1.4 Line Diagram for LVEF over a period of time-Safety Population (N=XXX)   
Line Diagram for Mean for both 
AC→TH Regimen, TCH Regimen and 
Overall 
Two line diagram for LVEF will be generated where X-axis will represent Time (Days) and Y-axis will represent Mean for both 
AC→TH Regimen, TCH Regimen and Overall. 
Source Data: Table 14.3.6.7 


 
 
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Figure 14.2.1.5 Multiple Bar Diagram for ECOG over a period of time-Safety Population (N=XXX)   
Multiple Bar Diagram for ECOG for 
both AC→TH Regimen, TCH Regimen 
and Overall 
Multiple Bar diagram for ECOG will be generated where X-axis will represent ECOG status at different Time (only Baseline and 
Study Completion Visit) and Y-axis will represent Count and Frequency for both AC→TH Regimen, TCH Regimen and Overall. 
Source Data: Table 14.3.6.5 


 
 
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1.3 
LISTINGS 
16.2 
Patient Data Listings 
Listing 16.2.1 
Listing of Patient Discontinuation-ITT Population (N=XXX) 
Site No./ Subject 
ID 
Age/Sex 
The patient completed the 
protocol 
If No, Date of last administration of 
study regimen 
The primary reason for 
discontinuation 
If other reason, 
specify 
NN/XXX 
NN/XXX 
Yes/No 
DDMMMYYYY 
XXXX 
XXXX 
NN/XXX 
NN/XXX 
Yes/No 
DDMMMYYYY 
XXXX 
XXXX 
NN/XXX 
NN/XXX 
Yes/No 
DDMMMYYYY 
XXXX 
XXXX 
… 
… 
… 
… 
… 
… 
 


 
 
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Listing 16.2.2.1 Listing of Protocol Deviation -ITT Population (N=XXX) 
Site No./ Subject ID 
Age/ Sex 
Date 
Reason of Deviation 
Comments 
NN/XXX 
NN/XXX 
DDMMMYYYY 
XXXXXXX 
XXX 
NN/XXX 
NN/XXX 
DDMMMYYYY 
XXXXXXX 
XXX 
NN/XXX 
NN/XXX 
DDMMMYYYY 
XXXXXXX 
XXX 
… 
… 
… 
… 
… 
 


 
 
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Listing 16.2.2.2 Listing of Analysis Population Sets-ITT Population (N=XXX) 
Site No./ Subject ID 
Age/Sex 
ITT Population 
Safety Population 
NN/XXX 
NN/XXX 
Yes/No 
Yes/No 
NN/XXX 
NN/XXX 
Yes/No 
Yes/No 
NN/XXX 
NN/XXX 
Yes/No 
Yes/No 
… 
… 
… 
… 
 


 
 
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Listing 16.2.3 
Listing of Patients who fail to meet Inclusion/Exclusion Criteria 
 
Site No./ 
Subject 
ID 
Age/Sex 
Patient signed the 
Informed Consent 
Date of 
Informed Consent 
All Inclusion criteria met 
If No, Inclusion 
Criteria Number(s) 
Any Exclusion 
criteria met 
If yes, Exclusion 
criteria 
number(s) 
NN/XXX 
NN/XXX 
Yes/No 
DDMMMYYYY 
Yes/No/NA 
NN 
NN 
NN 
NN/XXX 
NN/XXX 
Yes/No 
DDMMMYYYY 
Yes/No/NA 
NN 
NN 
NN 
NN/XXX 
NN/XXX 
Yes/No 
DDMMMYYYY 
Yes/No/NA 
NN 
NN 
NN 
… 
… 
… 
… 
… 
… 
… 
… 
 
 


 
 
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16.2.4 
Listing of Demographics 
Listing 16.2.4.1 Listing of Patient Demographics -ITT Population (N=XXX) 
 
Site No./ Subject ID 
Age 
Sex 
Date of Birth 
Race 
Treatment 
 
NN/XXX 
NN 
Male/Female 
DDMMMYYYY 
XXX 
XXX 
 
NN/XXX 
NN 
Male/Female 
DDMMMYYYY 
XXX 
XXX 
 
NN/XXX 
NN 
Male/Female 
DDMMMYYYY 
XXX 
XXX 
 
… 
… 
… 
… 
… 
… 
 
 


 
 
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Listing 16.2.4.2 Listing of Medical History at Screening -ITT Population (N=XXX) 
 
Site No./ Subject ID 
Age/Sex 
Medical 
Conditions 
Start date 
Stop Date 
Ongoing 
Currently Being 
Treated 
NN/XXX 
NN/XXX 
XXX 
DDMMMYYYY 
DDMMMYYYY 
XXX 
Yes/No 
NN/XXX 
NN/XXX 
XXX 
DDMMMYYYY 
DDMMMYYYY 
XXX 
Yes/No 
NN/XXX 
NN/XXX 
XXX 
DDMMMYYYY 
DDMMMYYYY 
XXX 
Yes/No 
… 
… 
… 
… 
… 
… 
… 
 


 
 
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Listing 16.2.4.3 Listing of Cancer History at Screening -ITT Population (N=XXX) 
 
Site No./ Subject ID 
Age/Sex 
Primary 
Diagnosis 
Date of Diagnosis 
Method of 
Diagnosis 
Stage of Cancer 
(during diagnosis) 
Current stage of 
Cancer 
NN/XXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
Yes/No 
NN/XXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
Yes/No 
NN/XXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
Yes/No 
… 
… 
… 
… 
… 
… 
… 
 


 
 
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Listing 16.2.4.4 Listing of Reproductive Status at Screening -ITT Population (N=XXX) 
 
Site No./ Subject ID 
Age/Sex 
Reproductive Status 
Menopausal age 
No. of Live births 
Breast Feeding History 
NN/XXX 
NN/XXX 
XXX 
NN 
NN 
XXX 
NN/XXX 
NN/XXX 
XXX 
NN 
NN 
XXX 
NN/XXX 
NN/XXX 
XXX 
NN 
NN 
XXX 
… 
… 
… 
… 
… 
… 
 


 
 
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Listing 16.2.4.5 Listing of Smoking, Alcoholic & Drug Abuse History at Screening -ITT Population (N=XXX) 
 
Site No./ 
Subject ID 
Age/Sex 
Smokin
g Status 
If Smoking Status is 
Smoker, Average no. of 
Cigarettes per day 
Chew 
tobacco 
If Yes, the 
average 
quantity 
Alcoholic 
Status 
If “Alcoholic 
Status” is Yes 
Drug abuse 
Status 
Positive/Negative 
If “drug abuse 
Status” is 
positive, specify 
NN/XXX 
NN/XX
X 
XXX 
NN 
Yes/No 
NN 
XXX 
XXX 
XXX 
XXX 
NN/XXX 
NN/XX
X 
XXX 
NN 
Yes/No 
NN 
XXX 
XXX 
XXX 
XXX 
NN/XXX 
NN/XX
X 
XXX 
NN 
Yes/No 
NN 
XXX 
XXX 
XXX 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
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Listing 16.2.4.6 Listing of Prior Cancer Therapy & Prior Cancer Surgery at Screening -ITT Population (N=XXX) 
 
Site No./ 
Subject ID 
Age/Sex 
Prior Cancer Therapy 
Prior Cancer Surgery 
Treatm
ent 
agent 
Start date 
Stop Date 
Reason for 
stopping 
Therapy type 
Site/ Organ 
System 
Type of 
Procedure 
Date of Surgery 
NN/XXX 
NN/XX
X 
XXX 
DDMMMYY
YY 
DDMMMYYYY 
XXX 
XXX 
XXX 
XXX 
DDMMMYYYY 
NN/XXX 
NN/XX
X 
XXX 
DDMMMYY
YY 
DDMMMYYYY 
XXX 
XXX 
XXX 
XXX 
DDMMMYYYY 
NN/XXX 
NN/XX
X 
XXX 
DDMMMYY
YY 
DDMMMYYYY 
XXX 
XXX 
XXX 
XXX 
DDMMMYYYY 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
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Listing 16.2.4.7 Listing of Histology and HER2 testing test at screening -ITT Population (N=XXX) 
 
Site No./ 
Subject 
ID 
Age/Sex 
Histology 
HER2 Testing 
Biopsy 
Performed 
Date of Biopsy 
Biopsy 
Result 
Grade 
Not Done 
Date of sample 
collection 
Method 
Used 
If IHC, 
observation 
If FISH, 
observation 
NN/XXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
XXX 
NN/XXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
XXX 
NN/XXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 


 
 
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16.2.6 
Listing for Efficacy  
Listing 16.2.6.1 Listing of Survival Assessment -ITT Population (N=XXX) 
Site 
No./ 
Subject 
ID 
Age/Se
x 
Visi
tna
me 
Reg
ime
n 
Sur
viva
l 
Stat
us 
Specify the 
date for the 
selected 
status 
If Died, 
cause of 
death 
Recurr
ence of 
any 
prior 
sympto
ms 
If 
“Yes”
, 
specif
y 
Therapy
/ 
medicati
on used 
Any new 
therapy/ 
medication 
have been 
introduced 
If “Yes”, 
specify the 
details 
Date of 
initiation 
Has the 
follow up 
discontinu
ed 
If 
“Yes”, 
specify 
the 
reason 
NN/XX
X 
NN/XX
X 
XX
X 
XX
X 
XX
X 
DDMMMY
YYY 
XXX 
Yes/No 
XXX 
XXX 
Yes/No 
XXX 
DDMMMY
YYY 
Yes/No 
XXX 
NN/XX
X 
NN/XX
X 
XX
X 
XX
X 
XX
X 
DDMMMY
YYY 
XXX 
Yes/No 
XXX 
XXX 
Yes/No 
XXX 
DDMMMY
YYY 
Yes/No 
XXX 
NN/XX
X 
NN/XX
X 
XX
X 
XX
X 
XX
X 
DDMMMY
YYY 
XXX 
Yes/No 
XXX 
XXX 
Yes/No 
XXX 
DDMMMY
YYY 
Yes/No 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
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16.2.7 
Listing for Adverse Event  
Listing 16.2.7.1 Listing of Adverse Event -Safety Population (N=XXX) 
Site 
No./ 
Subje
ct ID 
Age/Se
x 
Visi
ts 
Regime
n 
Patient 
experie
nced 
any AE 
SO
C 
Prefe
rred 
Term 
Eve
nt 
Date of 
Onset 
Date of 
Resolution 
Ongoin
g 
Grad
e of 
Seve
rity 
Causali
ty 
Actio
n 
taken 
with 
study 
medic
ation 
Ou
tco
me 
Has the 
patient 
taken 
any 
medica
tion to 
treat 
the AE 
Is the 
reporte
d event 
serious 
NN/X
XX 
NN/XX
X 
XX
X 
XXX 
Yes/No 
XX
X 
XXX 
XX
X 
DDMMMY
YYY 
DDMMMY
YYY 
Yes/No 
XXX 
Yes/No 
XXX 
XX
X 
Yes/No 
Yes/No 
NN/X
XX 
NN/XX
X 
XX
X 
XXX 
Yes/No 
XX
X 
XXX 
XX
X 
DDMMMY
YYY 
DDMMMY
YYY 
Yes/No 
XXX 
Yes/No 
XXX 
XX
X 
Yes/No 
Yes/No 
NN/X
XX 
NN/XX
X 
XX
X 
XXX 
Yes/No 
XX
X 
XXX 
XX
X 
DDMMMY
YYY 
DDMMMY
YYY 
Yes/No 
XXX 
Yes/No 
XXX 
XX
X 
Yes/No 
Yes/No 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
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16.2.8 
Lab Test Evaluations 
Listing 16.2.8.1 Listing of Hematology -Safety Population (N=XXX) 
 
Site No./ 
Subject ID 
Age/Sex 
Visit 
Regime
n 
Lab 
Test 
Not Done 
Values 
Unit 
Significance 
If Clinically Significant, 
specify details 
NN/XXX 
NN/XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
NN 
CS/NCS 
NN 
NN/XXX 
NN/XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
NN 
CS/NCS 
NN 
NN/XXX 
NN/XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
NN 
CS/NCS 
NN 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
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Listing 16.2.8.2 Listing of Biochemistry -Safety Population (N=XXX) 
Site No./ 
Subject ID 
Age/Sex 
Visit 
Regime
n 
Lab 
Test 
Not Done 
Values 
Unit 
Significance 
If Clinically Significant, 
specify details 
NN/XXX 
NN/XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
NN 
CS/NCS 
NN 
NN/XXX 
NN/XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
NN 
CS/NCS 
NN 
NN/XXX 
NN/XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
NN 
CS/NCS 
NN 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
  


 
 
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Listing 16.2.8.3 Listing of 12 Lead ECG, LVEF and ECOG -Safety Population (N=XXX) 
 
Site No./ 
Subject 
ID 
Age/Sex 
Visit 
Regi
men 
12 Lead ECG 
LVEF 
ECOG Performance 
Status 
Not 
Done 
Date of 
assessment 
Signifi
cance 
If CS, 
please 
specify 
Not 
Done 
Date of 
assessment 
Significanc
e 
If CS, 
please 
specify 
Date of 
Assessment 
ECO
G 
Scor
e 
NN/XXX 
NN/XX
X 
XXX 
XXX 
XXX 
DDMMMYY
YY 
XXX 
XXX 
XXX 
DDMMMYY
YY 
XXX 
XXX 
DDMMMYY
YY 
NN 
NN/XXX 
NN/XX
X 
XXX 
XXX 
XXX 
DDMMMYY
YY 
XXX 
XXX 
XXX 
DDMMMYY
YY 
XXX 
XXX 
DDMMMYY
YY 
NN 
NN/XXX 
NN/XX
X 
XXX 
XXX 
XXX 
DDMMMYY
YY 
XXX 
XXX 
XXX 
DDMMMYY
YY 
XXX 
XXX 
DDMMMYY
YY 
NN 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 


 
 
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Listing 16.2.8.4 Listing of Mammogram and CT/MRI -Safety Population (N=XXX) 
Site No./ 
Subject 
ID 
Age/Sex 
Visit 
Regimen 
Mammogram 
CT/MRI 
Date when 
Mammography 
done 
Findings 
CS/NCS 
If CS, specify 
Site of 
Lesion 
Location 
Method of 
Assessment 
Date of 
Assessment 
Size 
(mm) 
NN/XXX 
NN/XXX 
XXX 
XXX 
DDMMMYYYY 
XXX 
DDMMMYYYY 
XXX 
XXX 
XXX 
DDMMMYYYY 
NN 
NN/XXX 
NN/XXX 
XXX 
XXX 
DDMMMYYYY 
XXX 
DDMMMYYYY 
XXX 
XXX 
XXX 
DDMMMYYYY 
NN 
NN/XXX 
NN/XXX 
XXX 
XXX 
DDMMMYYYY 
XXX 
DDMMMYYYY 
XXX 
XXX 
XXX 
DDMMMYYYY 
NN 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 






 
 
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Listing 16.4.2 
Listing of Physical Examination -Safety Population (N=XXX) 
 
Site No./ 
Subject ID 
Age/Sex 
Visit 
Regimen 
Not 
Done 
Date of Examination 
Body 
System/Site 
Not Done 
 
If Clinically 
Significant, 
specify details 
Significance 
NN/XXX 
NN/XXX 
XXX 
XXX 
XXX 
DDMMMYYYY 
NN 
NN 
CS/NCS 
XXX 
NN/XXX 
NN/XXX 
XXX 
XXX 
XXX 
DDMMMYYYY 
NN 
NN 
CS/NCS 
XXX 
NN/XXX 
NN/XXX 
XXX 
XXX 
XXX 
DDMMMYYYY 
NN 
NN 
CS/NCS 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
  


 
 
18 Jun 2021 
Confidential and Proprietary to JSS Medical Research India Limited 
 
 
Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 163 of178 
 
Listing 16.4.3.1 Listing of Routine Breast Cancer Follow Up -Safety Population (N=XXX) 
 
Site 
No./ 
Subje
ct ID 
Age/S
ex 
Vis
it 
Regim
en 
Date of 
assessment 
Familial 
History 
Physical Examination 
Mammography 
Any 
Famil
ial 
Histo
ry 
If 
yes, 
pleas
e 
speci
fy 
Done/
Not 
Done 
 
If Done, 
Done/
Not 
Done 
If 
not 
done
, 
speci
fy 
reas
on 
Results of 
Mammog
ram 
If 
Abnor
mal, 
specify 
Occurre
nce of 
any new 
sympto
ms 
If 
Yes, 
speci
fy 
Recurre
nce of 
prior 
sympto
ms 
If 
yes, 
speci
fy 
Locatio
n of 
recurre
nce 
NN/X
XX 
NN/X
XX 
XX
X 
XXX 
DDMMMY
YYY 
XXX 
XXX 
XXX 
 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
NN/X
XX 
NN/X
XX 
XX
X 
XXX 
DDMMMY
YYY 
XXX 
XXX 
XXX 
 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
NN/X
XX 
NN/X
XX 
XX
X 
XXX 
DDMMMY
YYY 
XXX 
XXX 
XXX 
 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 


 
 
18 Jun 2021 
Confidential and Proprietary to JSS Medical Research India Limited 
 
 
Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 164 of178 
 
Listing 16.4.3.2 Listing of Other Investigations -Safety Population (N=XXX) 
 
Site No./ 
Subject 
ID 
Age/Sex 
Visit 
Regi
men 
Pelvic Examination 
Brain CT/MRI 
Bone Scan 
Liver Imaging 
Done
/ Not 
Done 
If not 
done, 
specif
y 
Resu
lt of 
Pelvi
c 
Exa
mina
tion 
If 
Abnor
mal, 
specif
y 
Date of 
Assessment 
Fin
ding
s 
If 
CS, 
spec
ify 
Date of 
Assessment 
Fin
ding
s 
If 
CS, 
spec
ify 
Date of 
Assessment 
Findi
ngs 
If CS, 
specify 
NN/XX
X 
NN/XX
X 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
DDMMMYY
YY 
XX
X 
XX
X 
DDMMMY
YYY 
XX
X 
XX
X 
DDMMMY
YYY 
XXX 
XXX 
NN/XX
X 
NN/XX
X 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
DDMMMYY
YY 
XX
X 
XX
X 
DDMMMY
YYY 
XX
X 
XX
X 
DDMMMY
YYY 
XXX 
XXX 
NN/XX
X 
NN/XX
X 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
DDMMMYY
YY 
XX
X 
XX
X 
DDMMMY
YYY 
XX
X 
XX
X 
DDMMMY
YYY 
XXX 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 


 
 
18 Jun 2021 
Confidential and Proprietary to JSS Medical Research India Limited 
 
 
Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 165 of178 
 
Listing 16.4.4 
Listing of Cycle Delay, Reminder and Treatment Compliance -Safety Population (N=XXX) 
Site No./ 
Subject 
ID 
Age/Sex 
Visit 
Regi
men 
Cycle Delay 
Reminder 
Treatment 
Compliance 
Has the 
cycle 
delayed 
If Yes, 
Specif
y 
Reaso
n 
Patient experienced 
any change in 
previous AE or new 
AE since last visit 
Patient experienced any change in 
previous concomitant medications 
or new concomitant medications 
since last visit 
Patient 
experienced any 
unplanned visit 
since last visit 
Is the patient 
compliant to the 
protocol specific 
procedures 
NN/XXX 
NN/XX
X 
XXX 
XXX 
Yes/No 
XXX 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
NN/XXX 
NN/XX
X 
XXX 
XXX 
Yes/No 
XXX 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
NN/XXX 
NN/XX
X 
XXX 
XXX 
Yes/No 
XXX 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 


 
 
18 Jun 2021 
Confidential and Proprietary to JSS Medical Research India Limited 
 
 
Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 166 of178 
 
Listing 16.4.5 
Listing of Study Drug Administration -Safety Population (N=XXX) 
Listing 16.4.5.1 Listing of Chemotherapy- Doxorubicin Administration for AC→TH Regimen -Safety Population (N=XXX) 
Site No./ 
Subject ID 
Age/Sex 
Visit 
Has Doxorubicin 
administered to 
the patient 
Was the dose of 60 
mg/m² Doxorubicin 
administered to the 
patient 
If No, 
please 
Specify 
Date of 
Administrati
on 
Start 
time 
Stop 
Time 
Is the administration 
of Doxorubicin 
delayed 
If Yes, 
specify 
NN/XXX 
NN/XXX 
XXX 
Yes/No 
Yes/No 
XXX 
DDMMMYY
YY 
NN:N
N 
NN:NN 
Yes/No 
XXX 
NN/XXX 
NN/XXX 
XXX 
Yes/No 
Yes/No 
XXX 
DDMMMYY
YY 
NN:N
N 
NN:NN 
Yes/No 
XXX 
NN/XXX 
NN/XXX 
XXX 
Yes/No 
Yes/No 
XXX 
DDMMMYY
YY 
NN:N
N 
NN:NN 
Yes/No 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
18 Jun 2021 
Confidential and Proprietary to JSS Medical Research India Limited 
 
 
Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 167 of178 
 
Listing 16.4.5.2 Listing of Chemotherapy- Cyclophosphamide Administration for AC→TH Regimen -Safety Population (N=XXX) 
Site No./ 
Subject ID 
Age/Sex 
Visit 
Has 
Cyclophosphamide 
administered to 
the patient 
Was the dose of 600 
mg/m² 
Cyclophosphamide 
administered to the 
patient 
If No, 
please 
Specify 
Date of 
Administrati
on 
Start 
time 
Stop 
Time 
Is the administration 
of 
Cyclophosphamide 
delayed 
If Yes, 
specify 
NN/XXX 
NN/XXX 
XXX 
Yes/No 
Yes/No 
XXX 
DDMMMYY
YY 
NN:N
N 
NN:NN 
Yes/No 
XXX 
NN/XXX 
NN/XXX 
XXX 
Yes/No 
Yes/No 
XXX 
DDMMMYY
YY 
NN:N
N 
NN:NN 
Yes/No 
XXX 
NN/XXX 
NN/XXX 
XXX 
Yes/No 
Yes/No 
XXX 
DDMMMYY
YY 
NN:N
N 
NN:NN 
Yes/No 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
18 Jun 2021 
Confidential and Proprietary to JSS Medical Research India Limited 
 
 
Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 168 of178 
 
Listing 16.4.5.3 Listing of Chemotherapy- Docetaxel/ Paclitaxel Administration for AC→TH Regimen -Safety Population (N=XXX) 
Site No./ 
Subject ID 
Age/Sex 
Visit 
Drug 
administ
ered to 
the 
patient 
If “Docetaxel”, was 
the dose of 100 
mg/m² administered 
to the patient on Day 
1 
If 
“No”, 
specif
y 
If “Paclitaxel”, was the 
dose of 175 mg/m² 
administered to the 
patient on Day 1 
If No, 
Specif
y 
Date of 
Administratio
n 
Start 
time 
Stop 
Time 
If none of the 
drug 
administered, 
please specify 
the reason 
NN/XXX 
NN/XX
X 
XXX 
XXX 
Yes/No 
XXX 
Yes/No 
XXX 
DDMMMYYY
Y 
NN:NN 
NN:NN 
XXX 
NN/XXX 
NN/XX
X 
XXX 
XXX 
Yes/No 
XXX 
Yes/No 
XXX 
DDMMMYYY
Y 
NN:NN 
NN:NN 
XXX 
NN/XXX 
NN/XX
X 
XXX 
XXX 
Yes/No 
XXX 
Yes/No 
XXX 
DDMMMYYY
Y 
NN:NN 
NN:NN 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
18 Jun 2021 
Confidential and Proprietary to JSS Medical Research India Limited 
 
 
Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 169 of178 
 
Listing 16.4.5.4 Listing of Chemotherapy- Docetaxel Administration for TCH Regimen -Safety Population (N=XXX) 
Site No./ 
Subject ID 
Age/Sex 
Visit 
Has Docetaxel 
administered to 
the patient 
Was the dose of 75 
mg/m² Docetaxel 
administered to the 
patient 
If No, 
please 
Specify 
Date of 
Administrati
on 
Start 
time 
Stop 
Time 
Is the administration 
of Docetaxel delayed 
If Yes, 
specify 
NN/XXX 
NN/XXX 
XXX 
Yes/No 
Yes/No 
XXX 
DDMMMYY
YY 
NN:N
N 
NN:NN 
Yes/No 
XXX 
NN/XXX 
NN/XXX 
XXX 
Yes/No 
Yes/No 
XXX 
DDMMMYY
YY 
NN:N
N 
NN:NN 
Yes/No 
XXX 
NN/XXX 
NN/XXX 
XXX 
Yes/No 
Yes/No 
XXX 
DDMMMYY
YY 
NN:N
N 
NN:NN 
Yes/No 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
18 Jun 2021 
Confidential and Proprietary to JSS Medical Research India Limited 
 
 
Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 170 of178 
 
Listing 16.4.5.5 Listing of Chemotherapy- Carboplatin Administration for TCH Regimen -Safety Population (N=XXX) 
Site No./ 
Subject ID 
Age/Sex 
Visit 
Has 
Carboplatin 
administered 
on Day 1 
Total Dose of 
Carboplatin 
GFR 
(ml/min) 
If No, 
please 
Specify 
Date of 
Administratio
n 
Start 
time 
Stop 
Time 
Is the 
administration of 
Carboplatin 
delayed 
If Yes, 
specify 
NN/XXX 
NN/XX
X 
XXX 
Yes/No 
NN 
NN 
XXX 
DDMMMYYY
Y 
NN:NN 
NN:NN 
Yes/No 
XXX 
NN/XXX 
NN/XX
X 
XXX 
Yes/No 
NN 
NN 
XXX 
DDMMMYYY
Y 
NN:NN 
NN:NN 
Yes/No 
XXX 
NN/XXX 
NN/XX
X 
XXX 
Yes/No 
NN 
NN 
XXX 
DDMMMYYY
Y 
NN:NN 
NN:NN 
Yes/No 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
18 Jun 2021 
Confidential and Proprietary to JSS Medical Research India Limited 
 
 
Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 171 of178 
 
Listing 16.4.5.6 Listing of Trastuzumab Administration for Both Regimen -Safety Population (N=XXX) 
Listing 16.4.5.6.1 
Listing of Trastuzumab Administration (8mg/kg /3-weekly) for Both Regimen-Safety Population (N=XXX) 
Site No./ 
Subject ID 
Age/Sex Visit 
Regimen 
Schedule of 
Trastuzumab 
administratio
n 
(Weekly/ 3-
Weekly) 
Was total 
loading 
dose of 8 
mg/kg 
administe
red to the 
patient 
on Day 1 
If No, 
please 
Specify 
Date of 
Administrati
on 
Start 
time 
Stop 
Time 
Observation Start 
Time 
Observ
ation 
Stop 
Time 
If any 
AE 
occurre
d, 
please 
NN/XXX 
NN/XX
X 
XXX 
XXX 
XXX 
Yes/No 
XXX 
DDMMMYY
YY 
NN:NN 
NN:NN 
NN:NN 
NN:NN 
XXX 
NN/XXX 
NN/XX
X 
XXX 
XXX 
XXX 
Yes/No 
XXX 
DDMMMYY
YY 
NN:NN 
NN:NN 
NN:NN 
NN:NN 
XXX 
NN/XXX 
NN/XX
X 
XXX 
XXX 
XXX 
Yes/No 
XXX 
DDMMMYY
YY 
NN:NN 
NN:NN 
NN:NN 
NN:NN 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 16.4.5.6.1a  Listing of Trastuzumab Administration (8mg/kg weekly) for Both Regimen-Safety Population(N=XXX) 


 
 
18 Jun 2021 
Confidential and Proprietary to JSS Medical Research India Limited 
 
 
Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 172 of178 
Site 
No./ 
Subject 
ID 
Age/Sex Visi
t 
Regime
n 
Schedule of 
Trastuzumab 
administration(Week
ly) 
Day of 
Administrati
on 
Was total 
loading 
dose of 4 
mg/kg/2 
mg/kg /2 
mg/kg 
administere
d to the 
patient on 
Day 1/8/15 
If No, 
please 
Specif
y 
Date of 
Administratio
n 
Start 
time 
Stop 
Time 
Observatio
n Start 
Time 
Observatio
n Stop 
Time 
If any 
AE 
occurre
d, please 
NN/XX
X 
NN/XX
X 
XX
X 
XXX 
XXX 
NN 
Yes/No 
XXX 
DDMMMYYY
Y 
NN:N
N 
NN:N
N 
NN:NN 
NN:NN 
XXX 
NN/XX
X 
NN/XX
X 
XX
X 
XXX 
XXX 
NN 
Yes/No 
XXX 
DDMMMYYY
Y 
NN:N
N 
NN:N
N 
NN:NN 
NN:NN 
XXX 
NN/XX
X 
NN/XX
X 
XX
X 
XXX 
XXX 
NN 
Yes/No 
NN 
XXX 
DDMMMYYY
Y 
NN:N
N 
NN:N
N 
NN:NN 
NN:NN 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 


 
 
18 Jun 2021 
Confidential and Proprietary to JSS Medical Research India Limited 
 
 
Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 173 of178 
 
 


 
 
18 Jun 2021 
Confidential and Proprietary to JSS Medical Research India Limited 
 
 
Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 174 of178 
 
Listing 16.4.5.6.2 
Listing of Trastuzumab Administration (6mg/kg /3-weekly) for Both Regimen -Safety Population (N=XXX) 
Site No./ 
Subject ID 
Age/Sex Visit 
Regimen 
Schedule of 
Trastuzumab 
administratio
n 
(3-Weekly) 
Was total 
loading 
dose of 6 
mg/kg 
administe
red to the 
patient 
on Day 1 
If No, 
please 
Specify 
Date of 
Administrati
on 
Start 
time 
Stop 
Time 
Observation Start 
Time 
Observ
ation 
Stop 
Time 
If any 
AE 
occurre
d, 
please 
NN/XXX 
NN/XX
X 
XXX 
XXX 
XXX 
Yes/No 
XXX 
DDMMMYY
YY 
NN:NN 
NN:NN 
NN:NN 
NN:NN 
XXX 
NN/XXX 
NN/XX
X 
XXX 
XXX 
XXX 
Yes/No 
XXX 
DDMMMYY
YY 
NN:NN 
NN:NN 
NN:NN 
NN:NN 
XXX 
NN/XXX 
NN/XX
X 
XXX 
XXX 
XXX 
Yes/No 
XXX 
DDMMMYY
YY 
NN:NN 
NN:NN 
NN:NN 
NN:NN 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
18 Jun 2021 
Confidential and Proprietary to JSS Medical Research India Limited 
 
 
Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 175 of178 
 
 
 


 
 
18 Jun 2021 
Confidential and Proprietary to JSS Medical Research India Limited 
 
 
Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 176 of178 
Listing 16.4.5.6.2a  Listing of Trastuzumab Administration (6mg/kg weekly) for Both Regimen-Safety Population(N=XXX) 
Site 
No./ 
Subject 
ID 
Age/Sex Visi
t 
Regime
n 
Schedule of 
Trastuzumab 
administration(Week
ly) 
Was total 
loading 
dose of 6 
mg/kg/2 
mg/kg 
administer
ed to the 
patient on 
Day 1/8/15 
If No, 
please 
Specif
y 
Date of 
Administratio
n 
Day of 
Administrati
on 
 
Start 
time 
Stop 
Time 
Observati
on Start 
Time 
Observati
on Stop 
Time 
If any 
AE 
occurre
d, 
please 
NN/XX
X 
NN/XX
X 
XX
X 
XXX 
XXX 
Yes/No 
XXX 
DDMMMYY
YY 
NN 
 NN:N
N 
NN:N
N 
NN:NN 
NN:NN 
XXX 
NN/XX
X 
NN/XX
X 
XX
X 
XXX 
XXX 
Yes/No 
XXX 
DDMMMYY
YY 
NN 
 NN:N
N 
NN:N
N 
NN:NN 
NN:NN 
XXX 
NN/XX
X 
NN/XX
X 
XX
X 
XXX 
XXX 
Yes/No 
NN 
XXX 
DDMMMYY
YY 
NN 
 NN:N
N 
NN:N
N 
NN:NN 
NN:NN 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
18 Jun 2021 
Confidential and Proprietary to JSS Medical Research India Limited 
 
 
Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 177 of178 
Listing 16.4.5.6.3 
Listing of Trastuzumab Administration (6mg/kg) for Both Regimen -Safety Population (N=XXX) 
Site No./ 
Subject 
ID 
Age/Sex 
Visit 
Regi
men 
Was total loading dose of 6 
mg/kg administered to the 
patient on Day 1 
If No, 
specify 
Date of 
administrati
on 
Start 
Time 
Stop Time 
Observatio
n Start 
Time 
Observati
on Stop 
Time 
If any AE 
occurred, 
please 
specify 
NN/XXX 
NN/XXX 
XXX 
XXX 
Yes/No 
XXX 
DDMMMYY
YY 
NN:NN 
NN:NN 
NN:NN 
NN:NN 
XXX 
NN/XXX 
NN/XXX 
XXX 
XXX 
Yes/No 
XXX 
DDMMMYY
YY 
NN:NN 
NN:NN 
NN:NN 
NN:NN 
XXX 
NN/XXX 
NN/XXX 
XXX 
XXX 
Yes/No 
XXX 
DDMMMYY
YY 
NN:NN 
NN:NN 
NN:NN 
NN:NN 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 


 
 
18 Jun 2021 
Confidential and Proprietary to JSS Medical Research India Limited 
 
 
Statistical Analysis Plan (ML28714) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page 178 of178 
 
Listing 16.4.6 
Listing of Prior and Concomitant Medication -Safety Population (N=XXX) 
Site No./ Subject 
ID 
Age/Sex 
Medication 
Indication 
Start Date 
Stop Date 
Ongoing 
Daily 
Dose 
Units 
Route 
Frequency 
NN/XXX 
NN/XXX 
XXX 
XXX 
DDMMMYY
YY 
DDMMMYY
YY 
XXX 
NN 
XXX 
XXX 
NN 
NN/XXX 
NN/XXX 
XXX 
XXX 
DDMMMYY
YY 
DDMMMYY
YY 
XXX 
NN 
XXX 
XXX 
NN 
NN/XXX 
NN/XXX 
XXX 
XXX 
DDMMMYY
YY 
DDMMMYY
YY 
XXX 
NN 
XXX 
XXX 
NN 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
…