Clinical trial NCT01940497
Conditions: Breast Cancer
Sponsor: Hoffmann-La Roche
Start date: 2013-11-15; Completion date: 2018-03-27
Enrollment: 240 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This non-randomized, multicenter, open-label study will assess the safety and efficacy of subcutaneously administered trastuzumab in participants with early and locally advanced HER2-positive breast cancer in two sequential cohorts. First 120 participants will be treated with subcutaneous (SC) trastuzumab 600 milligrams (mg) vial (Cohort A) and the subsequent 120 participants will be treated with SC trastuzumab prefilled single use injection device (SID) (Cohort B). Participants from each cohort will receive neoadjuvant or adjuvant chemotherapy consisting of doxorubicin every 3 weeks (q3w) (1 cycle) for 4 cycles followed by paclitaxel weekly or docetaxel every 3 weeks (q3w) in combination with SC trastuzumab (600 mg) q3w for 4 cycles and a further 14 cycles of SC trastuzumab (600 mg) q3w alone. All participants will be followed up for 24 months after the last participant has received the last dose of study treatment, or earlier in case of withdrawal from the study, loss to follow-up or death.

Detailed description:

Arms: arm 1: Participants will receive trastuzumab 600 mg SC using a vial q3w (1 cycle) for 1 year (4 cycles in combination with adjuvant or neoadjuvant chemotherapy \[consisting of doxorubicin, paclitaxel or docetaxel\] and 14 cycles administered alone). arm 2: Participants will receive trastuzumab 600 mg SC using SID q3w (1 cycle) for 1 year (4 cycles in combination with adjuvant or neoadjuvant chemotherapy \[consisting of doxorubicin, paclitaxel or docetaxel\] and 14 cycles administered alone).
Interventions: intervention 1: Doxorubicin intervention 2: Docetaxel intervention 3: Paclitaxel intervention 4: Trastuzumab
Intervention descriptions: intervention 1: Participants will receive doxorubicin in doses according to the locally-approved regimen q3w (1 cycle), for 4 cycles prior to initiation of trastuzumab treatment. intervention 2: Participants will receive docetaxel in doses according to the locally-approved regimen q3w for 12 weeks, in combination with trastuzumab. intervention 3: Participants will receive paclitaxel in doses according to the locally-approved regimen weekly for 12 weeks, in combination with trastuzumab. intervention 4: Participants will receive trastuzumab 600 mg SC (vial or SID) q3w for 18 cycles.

Protocol documents:
Prot_000.pdf: 
Official Title: 
NATIONAL PHASE IIIB PROSPECTIVE ,  TWO-COHORT  NON-
RANDOMIZED,  MULTI-CENTRE,  OPEN  LABEL  STUDY  TO  
ASSESS THE SAFETY  OF  SUBCUTANEOUS  TRASTUZUMAB 
AND  MOLECUAR BIOMARKERS  IN PATIENTS  WITH EARLY 
AND LOCALLY ADVANCED HER2-POSITIVE  BREAST CANCER 
NCT Number: 
NCT01940497 
Document Date: 
PROTOCOL 
Version 2: 27 May 2014 




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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................... 2 
LIST OF TABLES ............................................................................................................................. 8 
LIST OF APPENDICES..................................................................................................................... 8 
PROTOCOL ACCEPTANCE FORM ................................................................................................... 9 
PROTOCOL SYNOPSIS ................................................................................................................. 10 
Primary Objective ...................................................................................................................... 10 
Study Design .............................................................................................................................. 11 
Description of the Study ............................................................................................................ 11 
Inclusion Criteria: ....................................................................................................................... 13 
Exclusion Criteria ....................................................................................................................... 14 
Length of Study .......................................................................................................................... 15 
Treatment Duration ................................................................................................................... 15 
Safety Follow-up ........................................................................................................................ 15 
End of Study ............................................................................................................................... 15 
Safety Outcome Measures ......................................................................................................... 15 
Efficacy Outcome Measures ....................................................................................................... 16 
Investigational Medicinal Products ............................................................................................ 17 
Trastuzumab SC (vial and SID) will be considered as an Investigational Medicinal Product (IMP) 
in this study. .............................................................................................................................. 17 
SID: a ready-to-use automated injection device containing 600 mg/5 ml trastuzumab .............. 17 
Comparator ................................................................................................................................ 18 
Non-Investigational Medicinal Products .................................................................................... 18 
Statistical Methods .................................................................................................................... 18 
Primary Analysis ........................................................................................................................ 19 
Secondary Analysis .................................................................................................................... 19 
Exploratory Analysis .................................................................................................................. 20 


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Interim Analyses ........................................................................................................................ 20 
Determination of Study Sample Size .......................................................................................... 20 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................................................. 22 
1. 
Background ....................................................................................................................... 25 
1.1 
Background on Breast Cancer ............................................................................................ 25 
1.1.1 
TREATMENT OPTIONS FOR eBC ........................................................................... 25 
1.2 
Background on Study Treatments ...................................................................................... 26 
1.2.1 
HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR (HER) ................................... 26 
1.2.2 
TRASTUZUMAB (Rhumab HER2, HERCEPTIN®) .................................................... 27 
1.2.2.1 
Trastuzumab IV ................................................................................................ 28 
1.2.2.2 
Pharmacokinectics of Trastuzumab IV ............................................................ 28 
1.2.2.3 
Efficacy of Trastuzumab IV In Early Breast Cancer (Adjuvant Setting) ............ 28 
1.2.2.4 Efficacy of Trastuzumab IV in Early and Locally Advanced Breast Cancer 
(Neoadjuvant Setting) ........................................................................................................ 30 
1.2.2.5 
   Safety of Trastuzumab IV........................................................................... 31 
1.2.2.5.1 
Cardiac Safety of Trastuzumab IV ............................................................... 31 
1.2.2.5.2 
Post-Marketing Safety Summary of Trastuzumab IV .................................. 32 
1.2.2.6 
Trastuzumab SC ............................................................................................... 33 
1.2.2.6.1 
RECOMBINANT HUMAN HYALURONIDASE (rHuPH20) ............................... 34 
1.2.2.6.1.1 
NON CLINICAL STUDIES WITH rHuPH20
 
34 
1.2.2.6.1.2 
Clinical Studies with rHuPH20
 
34 
1.2.2.7 
Non Clinical Studies with Trastuzumab SC ...................................................... 36 
1.2.2.8 
Clinical Studies With Trastuzumab SC ............................................................. 36 
1.2.2.8.1 
 Study BP22023 .......................................................................................... 38 
1.2.2.8.2 
 Study BO22227 ......................................................................................... 39 
1.2.2.8.3 
 Study BO25532 ......................................................................................... 39 
1.2.2.8.4 
 Ongoing Studies ........................................................................................ 40 
1.3 
Study Rationale and Benefit–Risk Assessment ................................................................... 41 
1.3.1.1 
Trastuzumab SC ............................................................................................... 41 
2. 
OBJECTIVES ....................................................................................................................... 45 
2.1 
Primary Objective ............................................................................................................... 45 
2.2 
SECONDARY OBJECTIVES .................................................................................................... 45 
2.3 
Exploratory Objectives ........................................................................................................ 46 
3. 
STUDY DESIGN .................................................................................................................. 46 
3.1 
DESCRIPTION OF STUDY ..................................................................................................... 46 
3.1.1 
ADDITIONAL CHARACTERISTICS OF STUDY DESIGN ............................................. 47 
3.1.2 
LOCAL STEERING COMMITTEE ............................................................................. 48 
3.2 
Length of Study ................................................................................................................... 48 
3.2.1 
Treatment duration ....................................................................................................... 49 
3.3 
Safety follow-up .................................................................................................................. 49 


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3.4 
END OF STUDY .................................................................................................................... 49 
The end of study is defined as last patient last visit ( LPLV) in the follow-up period. ................... 49 
3.5 
NUMBER OF PATIENTS ....................................................................................................... 49 
3.6 
CENTERS ............................................................................................................................. 49 
3.7 
RATIONALE for study design ............................................................................................... 49 
3.7.3 
RATIONALE FOR TEST PRODUCT REGIMEN .......................................................... 50 
3.7.4 
RATIONALE FOR SID ............................................................................................. 50 
3.7.5  
 RATIONALE FOR ASSESSMENT OF BIOMARKERS .......................................................... 51 
3.8 
OUTCOME MEASURES ........................................................................................................ 52 
3.8.1 
EFFICACY OUTCOME MEASURES .......................................................................... 52 
3.8.2 
SAFETY OUTCOME MEASURES ............................................................................. 53 
3.8.3 
PHYSICIAN/PATIENT-SATISFACTION OUTCOME MEASURES ................................ 53 
3.8.4 
EXPLORATORY OUTCOME MEASURES ................................................................. 54 
4. 
MATERIALS AND METHODS .............................................................................................. 54 
4.1 
TARGET POPULATION ......................................................................................................... 54 
4.2 
INCLUSION CRITERIA ........................................................................................................... 55 
4.3 
EXCLUSION CRITERIA .......................................................................................................... 56 
4.4 
STUDY TREATMENT ............................................................................................................ 57 
4.5 
TRASTUZUMAB SC DOSES AND ADMINISTRATION ............................................................. 57 
4.6 
CHEMOTHERAPY DOSES AND ADMINISTRATION ............................................................... 58 
4.7 
NEOADJUVANT CHEMOTHERAPY RECOMANDATIONS ...................................................... 58 
4.8 
SYSTEMIC TREATMENT AFTER ADJUVANT-NEOADJUVANT chemoTHERAPY ..................... 59 
4.9 
STUDY TREATMENT - IMP ................................................................................................... 59 
4.9.1 
TRASTUZUMAB SC ................................................................................................ 59 
4.9.1.1 
FORMULATION, PACKAGING AND HANDLING ................................................ 60 
4.9.1.2 
INVESTIGATIONAL MEDICINAL PRODUCT ACCOUNTABILITY .......................... 61 
4.9.1.3 
ASSESSMENT OF COMPLIANCE ....................................................................... 61 
4.9.1.4 
DESTRUCTION OF THE IMPs ............................................................................ 61 
4.9.1.5 
 POST-TRIAL ACCESS TO TRASTUZUMAB SC ........................................................ 62 
4.10 
CONCOMITANT THERAPY .............................................................................................. 62 
4.10.1 
  PERMITTED THERAPIES .................................................................................... 62 
4.10.2 
PROHIBITED THERAPIES ....................................................................................... 63 
4.11 
STUDY ASSESSMENTS .................................................................................................... 63 
4.11.1 
 DESCRIPTION OF STUDY ASSESSMENT ............................................................... 63 
4.11.1.1 
MANDATORY PROCEDURE FOR PATIENTS ENROLLMENT .......................... 63 
4.11.1.1.1 
TIMING OF SCREENING AND PRETREATMENT ASSESSMENTS .................. 66 
4.11.1.1.2 
MEDICAL HISTORY AND DEMOGRAPHIC DATA ......................................... 66 
4.11.1.1.3 
HER 2 STATUS ............................................................................................ 66 
4.11.1.1.4 
VITAL SIGNS AND PHYSICAL EXAMINATION .............................................. 67 
4.11.1.1.5 
PREGNANCY TEST ...................................................................................... 67 
4.11.1.1.6 
PAST AND CURRENT CONCOMITANT TREATMENTS ................................. 67 
4.11.1.1.7 
BASELINE EBC DATA .................................................................................. 67 
4.11.1.1.8 
ECOG PERFORMANCE STATUS .................................................................. 68 


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4.11.1.1.9 
MANDATORY SAMPLES FOR STUDY INCLUSION ....................................... 68 
4.11.1.1.10 
OPTIONAL DONATION OF REMAINING MATERIALS AND CONSENT ....... 68 
4.11.1.1.11 
BASELINE SAFETY DATA ........................................................................... 69 
4.12 
CLINICAL ASSESSMENT DURING TREATMENT PERIOD ......................................... 69 
4.13 
CLINICAL ASSESSMENTS AT THE SAFETY FOLLOW UP    VISIT .......................... 72 
4.14 
CLINICAL ASSESSMENTS IN FOLLOW UP VISITS.................................................... 72 
4.17 
PATIENT AND HCP SATISFACTION OUTCOMES ............................................... 73 
4.18 
PATIENT, STUDY, AND SITE DISCONTINUATION ............................................................ 73 
4.18.1     Patient Discontinuation ....................................................................................... 73 
4.18.1.1 
DISCONTINUATION FROM STUDY DRUG ......................................................... 73 
4.18.1.2 
WITHDRAWAL FROM STUDY ........................................................................... 74 
4.18.2 
STUDY AND SITE DISCONTINUATION ................................................................... 74 
5. 
assessment of safety ......................................................................................................... 74 
5.1 
SAFETY PLAN ....................................................................................................................... 74 
5.1.1 
GENERAL SAFETY ASSESSMENTS .......................................................................... 75 
5.1.2 
CARDIAC SAFETY ASSESSMENTS .......................................................................... 75 
5.1.2.1 
LVEF ASSESSMENT ........................................................................................... 76 
5.1.3 
MANAGEMENT OF SPECIFIC AEs .......................................................................... 76 
5.1.4 
MANAGEMENT OF SPECIFIC ADVERSE EVENTS ................................................... 77 
5.1.4.1 
DOSE MODIFICATIONS, INTERRUPTIONS AND DELAYS FOR TRASTUZUMAB .. 77 
5.2 
SAFETY PARAMETERS AND DEFINITIONS ........................................................................... 78 
5.2.1 
ADVERSE EVENTS ................................................................................................. 78 
5.2.2 
SERIOUS ADVERSE EVENTS (IMMEDIATELY REPORTABLE TO THE SPONSOR) ..... 79 
5.2.3 
PREGNANCY AND CONTRACEPTION .................................................................... 79 
5.3 
Methods and Timing for Capturing and Assessing Safety Parameters ............................... 80 
5.3.1 
ADVERSE EVENT REPORTING PERIOD .................................................................. 80 
5.3.2 
ELICITING ADVERSE EVENT INFORMATION .......................................................... 81 
5.3.3 
ASSESSMENT OF SEVERITY OF ADVERSE EVENTS................................................. 81 
5.3.4 
ASSESSMENT OF CASUALITY OF ADVERSE EVENTS .............................................. 82 
5.3.5 
PROCEDURES FOR RECORDING ADVERSE EVENTS ............................................... 82 
5.3.5.1 
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS ................................................... 82 
5.3.5.2 
ADVERSE EVENTS OCCURRING SECONDARY TO OTHER EVENTS .................... 83 
5.3.5.3 
PERSISTENT OR RECURRENT ADVERSE EVENTS .............................................. 83 
5.3.5.4 
ABNORMAL LABORATORY VALUES ................................................................. 84 
5.3.5.5 
ABNORMAL VITAL SIGN VALUES ..................................................................... 84 
5.3.5.6 
ABNORMAL LIVER FUNCTION TESTS ............................................................... 85 
5.3.5.7 
DEATHS ............................................................................................................ 85 
5.3.5.8 
PREEXISTING MEDICAL CONDITIONS .............................................................. 86 
5.3.5.9 
LACK OF EFFICACY OR WORSENING OF THE UNDERLYING CONDITION ......... 86 
5.3.5.10 
HOSPITALIZATION OR PROLONGED HOSPITALIZATION .................................. 86 
5.3.5.11 
OVERDOSES ..................................................................................................... 87 
5.4 
Immediate Reporting Requirements from Investigator to Sponsor .................................... 87 
5.4.1 
EMERGENCY MEDICAL CONTACTS ....................................................................... 88 
MEDICAL MONITOR (ROCHE MEDICAL RESPONSIBLE) CONTACT INFORMATION .......... 88 
5.4.2 
REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS ............................ 89 
5.4.3 
REPORTING REQUIREMENTS FOR PREGNANCIES ................................................ 89 
5.4.3.1 
 PREGNANCIES IN FEMALE PATIENTS ............................................................. 89 
5.4.3.2 
PREGNANCIES IN FEMALE PARTNERS OF MALE PATIENTS .............................. 89 
5.4.3.3 
ABORTIONS ...................................................................................................... 90 


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5.4.3.4 
CONGENITAL ANOMALIES/BIRTH DEFECTS ..................................................... 90 
5.4.4 
REPORTING REQUIREMENTS FOR MEDICAL DEVICE COMPLAINTS ..................... 90 
5.5 
Follow-Up of Patients after Adverse Events ....................................................................... 90 
5.5.1 
INVESTIGATOR FOLLOW-UP ................................................................................. 90 
5.5.2 
SPONSOR FOLLOW-UP ......................................................................................... 91 
5.6 
Post-Study Adverse Events.................................................................................................. 91 
5.7 
Expedited Reporting to Health Authorities, Investigators, Institutional Review Boards, and 
Ethics Committees ........................................................................................................................ 92 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................................................... 92 
6.1 
DETERMINATION OF SAMPLE SIZE ..................................................................................... 93 
6.2 
Summaries of Conduct of Study .......................................................................................... 93 
6.3 
Summaries of BASELINE CHARACTERISTICS ........................................................................ 94 
6.4 
Efficacy Analyses ................................................................................................................ 95 
6.5 
SAFETY ANALYSES ............................................................................................................... 95 
6.6 
Patient-SATISFACTION Outcome Analyses ......................................................................... 97 
6.7 
HCP-SATISFACTION Outcome Analyses .............................................................................. 97 
6.8 
Exploratory Analyses .......................................................................................................... 98 
6.9 
Interim Analyses ................................................................................................................. 99 
7. 
DATA COLLECTION AND MANAGEMENT ........................................................................... 99 
7.1 
Data Quality Assurance ...................................................................................................... 99 
7.2 
Electronic Case Report Forms ........................................................................................... 100 
7.3 
Source Data Documentation ............................................................................................ 100 
7.4 
Use of Computerized Systems........................................................................................... 100 
7.5 
Retention of Records ........................................................................................................ 101 
8. 
ETHICAL CONSIDERATIONS ............................................................................................. 101 
8.1 
Compliance with Laws and Regulations ........................................................................... 101 
8.2 
Informed Consent ............................................................................................................. 101 
8.3 
Institutional Review Board or Ethics Committee .............................................................. 102 
8.4 
Confidentiality .................................................................................................................. 102 
8.5 
Financial DiSClosure.......................................................................................................... 103 
9. 
STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION ................................. 103 
9.1 
STUDY DOCUMENTATION ................................................................................................ 103 
9.2 
SITE INSPECTIONS ............................................................................................................. 103 
9.3 
ADMINISTRATIVE STRUCTURE .......................................................................................... 103 
9.4 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS ....................................... 104 


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9.5 
PROTOCOL AMENDMENTS ............................................................................................... 104 
10. 
REFERENCES .................................................................................................................... 105 
 


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LIST OF TABLES 
 
Table 1 Overview of the Clinical Development Program of SC Trastuzumab  
 
36 
Table 2 Action to be taken in case of trastuzumab-related toxicity  
 
 
 
75 
Table 3 Assessment of AE Severity  
 
 
 
 
 
 
 
 
 
79 
Table 4 Clopper-Pearson 95% Confidence Intervals for the incidence of different LVEF 
Grade 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
91 
 
LIST OF APPENDICES 
 
APPENDIX 1  
Schedule of assessment 
 
 
 
 
 
 
 
   109 
APPENDIX 2  
Algorithm for continuation and discontinuation of trastuzumab SC 
based on LVEF assessment in asymptomatic patients 
 
 
 
 
 
   116 
APPENDIX 3  
The conventional doses of the selected regimens chemotherapy 
agents 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   117 
APPENDIX 4  
NYHA Classification and Left Ventricular Systolic dysfunction NCI-
CTCAE version 4.0 Grading  
 
 
 
 
 
 
 
 
 
 
   118 
APPENDIX 5  
Single use injection device (SID) Satisfaction Questionnaire 
   119 
 
LIST OF FIGURES 
Figure 1  
 
Study design  
 
 
 
 
 
 
 
 
 
   45 


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PROTOCOL ACCEPTANCE FORM 
TITLE: 
NATIONAL PHASE IIIB PROSPECTIVE, TWO-
COHORT NON-RANDOMIZED, MULTI-CENTRE, 
OPEN LABEL STUDY TO ASSESS THE SAFETY 
OF SUBCUTANEOUS  TRASTUZUMAB AND 
MOLECULAR BIOMARKERS IN PATIENTS WITH 
EARLY 
AND LOCALLY 
ADVANCED HER2-
POSITIVE BREAST CANCER   
PROTOCOL NUMBER: 
ML28879 
VERSION NUMBER: 
2.0 
EUDRACT NUMBER: 
2013-001161-16 
IND NUMBER: 
Not Applicable 
TEST PRODUCT: 
Trastuzumab SC (RO 45-2317) 
MEDICAL MONITOR: 
Dr. 
 
STATISTICIAN: 
Dr, 
 
PRINCIPAL 
INVESTIGATOR: 
Dr. 
 
SPONSOR: 
Roche S.p.A 
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: 
NATIONAL PHASE IIIB PROSPECTIVE, TWO-COHORT NON-
RANDOMIZED, MULTI-CENTRE, OPEN LABEL STUDY TO 
ASSESS THE SAFETY OF SUBCUTANEOUS TRASTUZUMAB 
AND  MOLECULAR BIOMARKERS IN  PATIENTS WITH 
EARLY AND LOCALLY ADVANCED HER2-POSITIVE BREAST 
CANCER  
PROTOCOL NUMBER: 
ML28879 
EUDRACT NUMBER: 
2013-001161-16 
IND NUMBER: 
Not Applicable 
TEST PRODUCT: 
Trastuzumab SC (RO 45-2317) 
PHASE: 
IIIb 
INDICATION: 
Early and locally  advanced breast cancer  
SPONSOR: 
Roche S.p.A 
 
This study is a part (Daughter study) of Global (Umbrella) Study. An open-
label, multinational, multicenter phase IIIB study with subcutaneous 
administration of trastuzumab in patients with HER2 positive early breast 
cancer or metastatic breast cancer. 
Objectives 
Primary Objective 
The primary objective of the study is to assess the safety and tolerability of 
trastuzumab solution injected subcutaneously (vial or single-use injection 
device [SID]) in patients with HER2-positive early breast cancer (eBC) or 
locally advanced breast cancer (LABC) 
Secondary Objectives 
The secondary objectives for this study are the following: 
 Exposure to study medication 
  Duration of treatment, follow-up, and safety observation 
  Efficacy: 
 
disease-free survival ( DFS), overall survival (OS)  


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 
In the Neo-adjuvant setting activity of two sequential drug regimens, 
Anthracycline-containing 
regimen 
followed 
by 
concomitant 
administration of Taxane and Trastuzumab SC, assessed as the 
incidence of pathological Complete Response in breast and nodes 
(pCR; ypT0-is ypN0) 
 Patient Satisfaction using SID (single use injection device) 
 HCP satisfaction  
Explorative Secondary Objective 
The exploratory secondary objective of the local study is 
the assessment of 
PI3K mutation in tumor tissues and in circulating free DNA (cfDNA) in blood.  
These assessments will be performed: 
 
to evaluate the agreement between the PI3K mutation assessment in 
tumor tissue (gold standard) and in circulating free DNA (experimental) 
 
to correlate the baseline mutation status (in tumor tissue and cfDNA) 
with clinical outcome (pathological response to treatment in the 
neoadjuvant arm)  
 
to correlate the pharmacodynamic change of the cfDNA before and 
after treatment with clinical outcome. 
 
Local safety and efficacy data will be transferred to a global Umbrella 
database and will be pooled for analysis. These data will also be analyzed in 
subgroups according to study design, patient population, and other relevant 
factors.  
  
Study Design 
Description of the Study 
This is a prospective, two-cohort, non-randomized, multicenter, open-label  
study to assess the safety and tolerability of trastuzumab solution injected 
subcutaneously (vial or single-use injection device [SID]) in approximately 240 
patients with HER2-positive eBC or LABC who are eligible for anti-HER2 
therapy.  
The patients will be enrolled in two sequential cohorts. 
The first 120 patients will be treated with trastuzumab SC 600 mg/5ml vial 
(Cohort A) and the subsequent 120 patients will be treated with trastuzumab 
SC 600 mg/5ml prefilled single use injection device - SID ( Cohort B).  
In each cohort (A and B), patients will be allocated to adjuvant or neoadjuvant 
treatment, with pragmatic selection according to conventional clinical criteria 
and physician choice: 
 
Group 1 = Adjuvant chemotherapy + trastuzumab SC 
 
Group 2= Neoadjuvant chemotherapy + trastuzumab SC 


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In both groups the planned treatment will require sequential chemotherapy 
regimens  containing 4 cycles of Anthracyclines followed by 4 cycles of 
Taxanes based chemotherapy administered in combination with trastuzumab 
SC followed by trastuzumab alone. 
The following additional criteria must be satisfied: 
Concomitant trastuzumab SC 600mg administered subcutaneously using either 
a handheld syringe or SID, starting after Anthracyclines comprehensive 
sequences.  
The therapy should include a total of 18 cycles/1 year of trastuzumab SC. 
Doxorubicin cumulative doses ≤ 300 mg/m2 or equivalent for Epirubicin. 
Chemotherapy treatment duration, either in the Adjuvant or in the neoadjuvant 
group, of 8 total cycles. 
The whole neoadjuvant chemotherapy must be given before surgery. 
Surgery after neoadjuvant chemotherapy + trastuzumab SC should include 
conventional surgical procedures on the breast and on the axilla. SNB (Sentinel 
lymph node biopsy) is consented in patients with clinically negative axillary 
status at starting treatment. 
Postoperative 
RT 
and/or 
hormonal 
treatment 
can 
be 
administered 
concomitantly with trastuzumab SC as adjuvant treatment after chemotherapy, 
when indicated.  
With the purpose of fertility preservation, for adjuvant patients only, LH-RH 
analogous administration is allowed without any limitation.  
 
The following sequential chemotherapy regimens are allowed, for the Adjuvant 
and Neadjuvant subsets: 
 
 
 
AC/EC, 4 cycles (cycles A1 to A4)  →  weekly Paclitaxel,  
 12 wks 
 
AC/EC, 4 cycles (cycles A1 to A4) → Docetaxel, 4 cycles 
 
FAC/FEC, 4 cycles (cycles A1 to A4) 
→  weekly 
Paclitaxel, 
  
 
12 wks 
 
FAC/FEC, 4 cycles (cycles A1 to A4) →  
Docetaxel, 4 cycles. 
 
Adjuvant chemotherapy should start within 10 weeks from definite surgery. 
Primary chemotherapy with Anthracyclines should start as soon as possible 
after study inclusion and no later than 5 working days. 
Tissues samples from diagnostic core biopsy and from surgical specimens, as 
well as blood samples at the planned time points should be collected as 
reported in Appendix 1. 


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The centralization of biological materials (tissues and blood) is a definite 
prerequisite for the study for the evaluation of PI3K mutations, as well the 
centralized re-evaluation of HER2 positivity on tissues. The results of HER2 
positivity performed centrally will not be required prior to the enrollment into the 
study. 
Safety and efficacy data (DFS and OS) collected in this local study will be 
transferred to a global Umbrella database for a pooled analysis.  
The schedules of mandatory clinical assessments for patients with eBC and for 
patients with LABC are provided in Appendix 1. 
 
Number of Patients 
This study will recruit 240 total patients (eBC and LABC).  
Target Population  
Patients must meet the following criteria for study entry: 
Inclusion Criteria: 
To be eligible for the study, a patient must fulfill each of the following criteria: 
1. 
Female and male patients aged ≥ 18 years 
2. 
Signed informed consent before any specific study procedure 
3. 
Able and willing to comply with protocol 
4. 
Eastern Cooperative Oncology Group (ECOG) performance status 0–1 
5. 
HER2-positive disease immunohistochemistry (IHC) 3+ or in situ hybridization 
(ISH) positive, as determined in a local laboratory that is experienced/certified in 
HER2-expression testing using an accurate and validated assay 
6. 
Histologically confirmed non-metastatic primary invasive adenocarcinoma of 
the breast. Stage of disease: T1-4, N0-3, M0.  
pT1a-b and pTmic may be included in the presence of at least one of the following 
unfavorable prognostic factors: 
 
clinical( concomitant axillary involvement)  
and/or  
 
biological (negative hormonal receptor status and/or high tumor grade and/or 
young age and/or lymph/vascular invasion and/or high Ki-67)  
7. 
Left ventricular ejection fraction (LVEF) of ≥ 55% measured by 
echocardiography (ECHO) or multiple gated acquisition (MUGA) scan prior to 
 
first dose of trastuzumab SC 
8. 
Availability of formalin–fixed paraffin-embedded (FFPE) tissue block or partial 
block from diagnostic core biopsy (only neoadjuvant patients) and from surgical 
specimens (both adjuvant and neoadjuvant patients), with representative invasive 
part of the tumor for additional biomarker analysis  
9. 
Intact skin at site of SC injection on the thigh 


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Exclusion Criteria  
1. 
History of other malignancy which could affect compliance with the protocol or 
interpretation of results. Patients with curatively treated carcinoma in situ of the 
cervix or basal cell carcinoma, and patients with other curatively treated 
malignancies, other than breast cancer, who have been disease-free for at least 5 
years, are eligible 
2.  
Severe dyspnea at rest or requiring supplementary oxygen therapy 
3. 
Concurrent serious diseases that may interfere with planned treatment, 
including severe pulmonary conditions/illness 
4. 
Serious cardiac illness or medical conditions that would preclude the use of 
trastuzumab, specifically: history of documented congestive heart failure (CHF), 
high-risk uncontrolled arrhythmias, angina pectoris requiring medication, 
 
clinically significant valvular disease, evidence of transmural infarction on 
electrocardiogram (ECG), diagnosed poorly controlled hypertension 
5. 
Known infection with human immunodeficiency virus (HIV), active hepatitis B 
virus (HBV) or hepatitis C virus (HCV) 
6. 
Pregnant or lactating women. Positive serum pregnancy test in women of 
childbearing potential, premenopausal or less than 12 months of amenorrhea 
post-menopause, within 7 days prior to the first administration of the protocol 
required chemotherapy treatment 
7. 
Women of childbearing potential, premenopausal or less than 12 months of 
amenorrhea post-menopause (unless surgically sterile), and male patients with 
partners of childbearing potential who are unable or unwilling to use adequate 
contraceptive measures during study treatment. In this study, menopause is 
defined as a minimum of 12 consecutive months of amenorrhea during which time 
no other biological or physiological cause had been identified as a potential cause 
of this state. Examples of adequate contraceptive measures are intrauterine 
device, barrier method (condoms, diaphragm) also in conjunction with spermicidal 
jelly, or total abstinence. Oral, injectable, or implant hormonal contraceptives are 
not acceptable 
8. 
Concurrent enrolment in another clinical trial using an investigational anti-
cancer treatment, including hormonal therapy, bisphosphonate therapy and 
immunotherapy, within 28 days prior to the first dose of study treatment 
9. 
Known hypersensitivity to trastuzumab, murine proteins, to any of the 
excipients of Herceptin® including hyaluronidase, or the adhesive of  the  SC 
device (for cohort B), or a history of severe allergic or immunological reactions, 
e.g. difficulty to control asthma 
10. 
No compliance or adherence with the requirements of the protocol 
11. Inadequate bone marrow function (as indicated by any of the  following):  
a) Absolute neutrophil count (ANC) < 1,500 / mm3 (< 1.5 × 109/L) 
b) Platelets < 100,000 / mm3 (< 100 × 109/L) 
c) 
Hemoglobin < 10 g/dL 
12. Impaired hepatic function (as indicated by any of the following):  


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a) Serum total bilirubin > 1.5 × upper limit of normal (ULN) 
b) Alanine amino transferase (ALT) and/or aspartate amino transferase  
(AST) > 2.5 × ULN 
c) 
Alkaline phosphatase (ALP) > 2.5 × ULN 
13. Inadequate renal function, as indicated by serum creatinine > 1.5 × ULN 
14. Hormonal treatment concomitant with chemotherapy (allowed in adjuvant 
phase with adjuvant Trastuzumab SC.) 
15. 
Pre-existing motor or sensory neuropathy of Grade >1 
16. 
Sincronous bilateral invasive breast cancer 
Length of Study  
The study is estimated to last 5 years from the enrollment of the first patient (18 
months of recruitment 15 months of study treatment and 2 years of follow-up) 
Treatment Duration  
eBC and LABC patients will be treated with trastuzumab for a total of 18 cycles/1 
year, unless intolerable toxicity or investigator-assessed disease progression 
occurs or the patient withdraws consent. 
Safety Follow-up  
All patients will be followed up for 24 months after the last patient has received 
his/her last study treatment, or earlier, if one of the following is documented: 
withdrawal from the study, loss to follow-up or death. 
End of Study 
Last patient last visit (LPLV) in the follow-up period  
Centers 
A total of 60 oncological centers in Italy will be selected 
Safety Outcome Measures 
Adverse event (AE) collection will be the primary endpoint for this study. 
Summaries to be produced will include: 
 
Incidence and severity by NCI CTCAE version 4.0 of AEs and serious 
adverse events (SAEs) 
 
AEs leading to premature discontinuation of study treatment  
 
Cardiac safety 
 
Cardiac AEs 
 CHF (according to NCI CTCAE version 4.0 and New York Heart Association 
[NYHA] Classification) 
 LVEF over time. In the event of an asymptomatic decline in LVEF, an 
algorithm (Appendix 2 in the protocol) will be used to determine whether to 
continue trastuzumab SC treatment 
 Secondary safety assessments will include the following: 
 Exposure to study medication 


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 Duration of treatment, follow-up, and safety observation 
 ECOG 
 Concomitant medications 
 Laboratory data, vital signs and physical examination  
 Premature withdrawals and major protocol violations 
The primary analysis will be for all patients in the Safety population.  
Efficacy Outcome Measures 
The efficacy outcome measures of this study will be to collect data for 
subcutaneous administration of trastuzumab in the treatment of HER2-
positive eBC and LABC: 
 DFS 
 OS 
Diagnosis of breast cancer relapse will be made based on routine clinical, 
radiological and laboratory criteria. In case of uncertainly, disease 
progression should be confirmed by histological or cytological examination of 
a suspicious lesion, if possible. 
In the Neo-adjuvant setting, the activity of two sequential drug regimens, 
Anthracycline-containing regimen followed by concomitant administration of 
Taxane and Trastuzumab SC, will be assessed as: 
 the incidence of pathological Complete Response in breast and nodes (pCR) 
(ypT0-is ypN0). Residual in situ disease (ypTis) is considered as pCR. 
Physician/Patient-Satisfaction Outcome Measures 
Patient Satisfaction will be assessed by Patient Satisfaction Questionnaire 
only in Cohort B (use of Trastuzumab SC SID). 
In Cohort B, a questionnaire will be completed by patients able to use SID, who  
completed a minimum of 14 administrations of trastuzumanb SC using SID ( at 
least 10 self- administered).  
Health Care Professional (HCP) satisfaction will be assessed by a Health Care 
Professional Questionnaire (HCPQ). A questionnaire will be completed by both 
the Investigator and a study nurse at each site when at least 4 patients from 
their site have received at least 5 cycles of adjuvant study treatment. (For sites 
that recruit <4 patients, the investigator and a study nurse will each complete 
an HCPQ when the last patient at their site has received at least 5 cycles of 
adjuvant study treatment). 
 
Translational study 


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The assessment of PI3K mutations will be performed at baseline in tumor 
tissues (core biopsy and tumor block for neoadjuvant patients; tumor block for 
adjuvant patients) and both at baseline (before starting anthracycline 
treatment) pre- and post- SC trastuzumab-chemotherapy combination in blood 
derived circulating free DNA (cfDNA). 
A comparison between PI3K mutation assessment in tumor tissue collected at 
baseline (core biopsy and tumor block for neoadjuvant patients; tumor block 
for adjuvant patients) (gold standard assessment) and the assessment of PI3K 
mutation in cfDNA (experimental assessment) will be performed.  
Sensitivity, specificity, positive and negative predictive value and overall 
agreement for the experimental assessment will be calculated. 
Correlative studies will be performed according to the following clinical 
outcome: 
 the achievement of pathological complete response (pCR) of invasive tumor 
in breast and axilla (in situ residual disease allowed). Patients progressed 
under treatment or for which surgery will not be feasible at the end of 
treatment will be considered as not having achieved a pCR. The association 
between clinical outcomes (pCR) and the baseline assessment of the PI3K 
mutation status as defined in tumor samples or cfDNA, will be performed.  
The pharmacodynamic changes of the PI3K mutation assessment in cfDNA by 
comparing the baseline and after treatment evaluation will be defined. 
Moreover a correlation between these pharmacodynamic changes and clinical 
outcome (pCR) will be performed.   
Investigational Medicinal Products 
Trastuzumab SC (vial and SID) will be considered as an Investigational 
Medicinal Product (IMP) in this study. 
Trastuzumab SC will be administered subcutaneously with a fixed dose of 
600 mg (irrespective of body weight) throughout the study treatment q3wks 
for 1 year. Concurrent complementary radiotherapy and adjuvant hormonal 
therapy will be allowed as per institutional guidelines. 
Trastuzumab SC will be supplied as a vial for manual administration via hand-
held syringe (Cohort A) or SID (Cohort B). With either method, trastuzumab 
will be subcutaneously injected slowly over a period of up to 5 minutes. 
Vial: ready to use solution (600 mg trastuzumab/5 ml) for manual 
administration using a hand-held syringe 
SID: a ready-to-use automated injection device containing 600 mg/5 ml 
trastuzumab 
Administration using a hand-held syringe must be performed by HCP. SID 
might be administered in the hospital by HCP or self-administration. For self-
administration, patients must have been trained by HCP. Once adequately 
trained, patients should be asked to self-administer the drug under the 
supervision of the HCP. 


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Comparator 
Not applicable. 
Non-Investigational Medicinal Products 
Chemotherapy regimen inclusive of Anthracyclines and Taxanes for 8 cycles, 
considered as non investigational Medicinal Product, (adjuvant and 
neoadjuvant) will be administered in accordance with the local prescribing 
information. Doses will be calculated for all drugs according to the patient’s 
body surface area (BSA). In calculating BSA, actual weights should be used. 
The following combination therapies may be used with trastuzumab SC 
according to local approved regimen: 
 AC/EC, 4 cycles   
→ weekly Paclitaxel, 12 wks 
 AC/EC, 4 cycles   
→ Docetaxel, 4 cycles 
 FAC/FEC, 4 cycles  → weekly Paclitaxel, 12 wks 
 FAC/FEC, 4 cycles  → Docetaxel, 4 cycles 
Chemotherapy should be administered following trastuzumab SC injection, 
and as per local Product Information and the investigator’s discretion. 
Hormonal therapy and complementary radiotherapy can be administered 
concurrently, as adjuvant after chemotherapy , according to local guidelines. 
Procedures (summary) 
The complete schedule of assessment is provided in Appendix 1 of the 
protocol. 
Collected tumor tissues and blood samples in both subsets will be centrally 
analyzed at the end of treatment of the last included patient.  
The analysis of PI3K mutation on tissues and on serum cfDNA, as well the 
centralized re-evaluation of HER2-positivity on tissues will be performed for 
care of the laboratories of 
 
. 
The results of HER 2 positivity performed centrally will not be required prior to 
the enrollment into the study. 
Moreover, the patients will be proposed to donate the remnants of biological 
samples for future biomarker researches, to the 
. The 
biological samples will be stored in the 
 
 
 
 
 
 
 
, under the 
supervision and responsibility of the 
. 
Statistical Methods 
The Safety population will be defined as all enrolled patients who received at 
least one dose of study medication. All summaries of safety data will be based 
on the Safety population. 
The Intent-to-Treat (ITT) population will be defined as all enrolled patients.  
The modified-Intent-to-Treat (m-ITT) population will be defined as all enrolled 


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patients satisfying inclusion and exclusion criteria for eligibility.  All baseline 
summaries will be based on the ITT , while efficacy analyses will be based on 
the m-ITT population. 
Primary Analysis 
The primary analysis of the safety endpoints will be undertaken once all 
patients have completed the study (treatment phase and safety follow-up (4 
weeks after their last dose of study treatment)).  
The incidence of AEs and SAEs will be summarized according to the primary 
system-organ class (SOC) and within each SOC, by the Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term. 
Analysis will focus on incidence of AEs and SAEs, AEs leading to premature 
discontinuation of study treatment, specific cardiac AEs and SAEs and 
summaries of LVEF. Summaries will include frequency counts and 
percentages. For certain AEs (or groups of AEs), e.g. cardiac AEs, 95% 
confidence intervals (calculated using Clopper-Pearson methodology) for 
incidences will be provided. 
Secondary Analysis 
Secondary safety parameters include exposure to study medication, duration 
of treatment and follow-up, vital signs, weight, height, ECOG, concomitant 
medications, laboratory parameters, premature withdrawals, and major 
protocol violations. 
Secondary efficacy endpoint for Neo-adjuvant setting will be pCR.  
According to the literature data, the expected rate of pCR will be about 35-40%. 
(Gianni L, 2008). Response rate will be presented as proportion with relative 
95% confidence intervals. 
Secondary efficacy endpoints for eBC and LABC are also DFS and OS. 
DFS is defined as the time from baseline visit until first documented disease or 
death, whichever comes first. Patients who have no disease and have not died 
or who are lost to follow-up at the time of analysis will be censored at the date 
of the last tumor assessment where no disease was documented or the last 
date of follow-up for disease, whichever is last. Patients without post baseline 
tumor assessments will be censored at the time of their baseline visit unless 
death occurs prior to their first scheduled tumor assessment. 
OS is defined as the time from baseline visit until death from any cause. 
Patients still alive at the time of analysis and patients who are lost to follow-up 
will be censored at their last time known to be alive. 
The OS and DFS experience will be estimated using Kaplan-Meier 
methodology and summarized using, the 25 h and 75th percentiles, the median 
and a 95% confidence interval for the median. The plot of Kaplan-Meier 
estimates for the single treatment group will be presented. 


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Data derived from the questionnaires regarding patients’ satisfaction and HCP 
satisfaction will be also presented as proportion with relative 95% confidence 
intervals. 
Exploratory Analysis 
For the analysis of translational study, the association of PI3K mutation status 
at baseline and pCR (neoadjuvant arm) will be assessed by means of a 
univariate and multivariate logistic regression analysis, where the odds of pCR 
will be modeled as function of the marker and adjusted by baseline factors 
relative to tumor and patients characteristics. The association between the 
pharmacodynamic change of the assessment for the PI3K mutation status in 
cfDNA pre- and post- treatment and pCR will be performed as described above. 
The cut-off value for statistical significance will be set =0.05 two tails. 
The analysis of efficacy secondary end points will be conducted 
according to local and to central HER2 evaluation, while the translational 
evaluations will be conducted only on the central HER2 positive cases. 
All analyses will be described on the overall population of interest and broken 
down by relevant characteristics of patients and disease, where deemed 
appropriate. 
Interim Analyses 
The primary analysis will be undertaken once all patients have completed the 
study (treatment phase and 28-days safety follow-up visit). In addition to this 
primary analysis there will be annual interim analysis for safety reporting and 
presentation of safety and efficacy results. These annual reporting events will 
start 1 year after first visit and end when the last patient has finished follow-up 
 
Determination of Study Sample Size 
The study focuses on a sample of patients eligible for adjuvant and 
neoadjuvant chemotherapy+ trastuzumab SC. 
Patients will receive treatment according to the following schema, which is 
usually adopted in clinical practice. 
 Neoadjuvant:  
CT x 4 cycles (Cycles A1 to A4)→CT+Trastuzumab SC 
x 4 cycles (Cycles 1 to 4)→ Surgery → Trastuzumab  SC x 14 cycles 
(Cycles 5 to 18)  
 Adjuvant: 
Surgery → CT x 4 cycles (Cycles A1 to 
A4)→CT+Trastuzumab SC x 4 cycles (Cycles 1 to 4) →  Trastuzumab 
SC x 14 cycles (Cycles 5 to 18) 
Since the chemotherapy amount of treatment is expected to be the same in the 
two groups, it is reasonable to expect the same incidence of side effects.  


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For the purpose of the estimation of the sample size, the LVEF rate has been 
chosen as the safety endpoint of primary interest. The tables provide the 
resultant confidence intervals for various sample sizes and various event rates, 
according to the assumptions derived by NOAH study (Gianni et al, Lancet 
2010). Assuming an observed LVEF Grade≥ 1 rate of 25%, a LVEF Grade≥2 of 
4% and a LVEF Grade≥3 of 2% a sample size of 240 will produce a 95% 
confidence interval deemed sufficiently precise to draw valid conclusions 
around the event rate. Safety results within each treatment group will be useful 
for descriptive purpose. The estimation of the confidence intervals will be 
performed using SAS based on Clopper-Pearson methodology. 
 
Clopper-Pearson 95% Confidence Intervals for the incidence of different LVEF Grade 
 
LVEF Grade: estimated incidence 
Number of Patients 
≥3:    2% 
≥2:    4% 
≥1:    25% 
50 
0.1% - 10.6% 
0.5% - 13.7% 
14.6% - 40.3% 
190 
0.6% -   5.3% 
1.8% -   8.1% 
19.3% - 32.1% 
240 
0.7% -   4.8% 
2.0% -   7.5% 
19.7% - 31.0% 
 
 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase  
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the serum concentration-time curve 
BC 
breast cancer 
BUN 
blood urea nitrogen 
CHF 
congestive heart failure 
CI 
confidence interval 
Cmax 
maximum concentration 
CNS 
central nervous system 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
common terminology criteria for adverse events 
DCIS 
ductal carcinoma in situ 
DLT 
dose-limiting toxicity 
DoR 
duration of response 
eBC 
early breast cancer 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiography 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EEA 
European economic area 
EGRF 
epidermal growth factor receptor 
EU 
European Union 
FDA 
Food and Drug Administration 


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Hb 
Hemoglobin 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor receptor 2 
HIV 
immunodeficiency virus 
HCP 
health care professional 
HR 
hazard ratio 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRR 
infusion-related reaction 
ISH 
in situ hybridization 
ITT 
intent-to-treat 
IV 
LABC 
Intravenous 
Locally Advanced Early Breast Cancer 
LVEF 
left ventricular ejection fraction 
LPLV 
last patient, last visit 
mBC 
metastatic breast cancer 
MedDRA 
MR 
Medical Dictionary for Regulatory Activities 
Medical Responsible 
MRI 
magnetic resonance imaging 
m-ITT 
modified intent-to-treat 
MUGA 
multiple-gated acquisition 
NCI 
National Cancer Institute 
NYHA 
New York Heart Association 
ORR 
overall response rate 
OS 
overall survival 


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pCR 
pathological complete response 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression free survival 
PK 
Pharmacokinetic 
PR 
partial response 
PRO 
patient-reported outcome 
q3w 
every 3 weeks 
Qw 
Weekly 
RECIST 
response evaluation criteria for solid tumors 
rHuPH20 
recombinant humanized hyaluronidase 
SAE 
serious adverse event 
SC 
Subcutaneous 
SD 
standard deviation 
SID 
single-use injection device 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOC 
STIAMP 
system-organ class 
Suspected Transmission of Infectious Agents via a 
Medicinal Product 
ULN 
WBC 
upper limit of normal 
white blood cells 
WHO 
World Health Organization 
 
 
 
 
 


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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). In Europe 
and the USA, most BCs 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 
T1-3N0/+M0), 7% are locally advanced (T4NxM0), and 6% are metastatic (M1) 
at diagnosis (Sant et al. 2003). However, BC remains a major cause of death in 
women aged between 35 and 59 years.  
1.1.1 
TREATMENT OPTIONS FOR EBC  
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 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 (Verma et al. 2010; Colozza et al. 2006, Ferlay et al. 2007).  
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 to the adjuvant portfolio (Colozza et al. 2006). 
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 or neoadjuvant 
treatment of eBC (Untch 2010). The use of trastuzumab in the adjuvant setting 
is also supported by international treatment guidelines for women with 
HER2-positive BC (NCCN 2012; Gnant et al. 2011; Aebi et al. 2011). The 
introduction of trastuzumab last decade has particularly improved the outcome 
for eBC patients with HER2-positive disease. 


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1.2 
BACKGROUND ON STUDY TREATMENTS  
1.2.1 
HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 
(HER) 
The human epidermal growth factor receptor 2 (HER2, HER2/neu, c-erbB-2) 
gene, first discovered in 1984 (Schechter et al. 1984), 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 (Ross et al. 2009). This HER family of four receptors mediates the 
growth, differentiation and survival of cells (Sundaresan et al. 1999; Yarden 
and Sliwkowski 2001; Gschwind et al. 2004). 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 (Ross et 
al. 2009; Slamon et al. 1987; Slamon et al. 1989; Sjögren et al. 1998; Moasser 
2007; Ménard et al. 2001). 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 (Ross et al. 2009). 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% (Ross et al. 2009; Lund et al. 2010). 
The 
major 
slide-based 
HER2 
testing 
approaches 
include 
immunohistochemistry 
(IHC), 
fluorescence 
in 
situ 
hybridization, 
and 
chromogenic in situ hybridization.  
HER2 amplified BCs comprise a specific disease subset with a unique 
molecular portrait and biologic characteristics that distinguish them from other 
types of BCs (Moasser 2007; Crowe et al. 2006). 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 (Dawood et al. 
2010). 
Evidence indicates that dysregulation of ligands and receptors of the HER 
family are important in the pathogenesis of cancer. HER receptors normally 
exist as inactive monomers. Activation of HER receptors occurs following 
ligand binding, leading to receptor dimerization and cell signaling through the 
PI3-kinase/AKT pathway for promotion of tumor cell survival and through the 
mitogen-activated 
protein 
kinase 
pathway 
for 
cellular 
proliferation. 
Overexpression of HER2 in BC has been correlated with high histological 


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grade, increased mitotic activity, p53 mutation, negative estrogen receptor (ER) 
status, absence of bcl2, and absence of lobular architecture. Despite 
associations 
with 
other 
known 
negative 
prognostic 
factors, 
HER2 
overexpression has been independently associated with poorer disease-free 
survival (DFS) and OS compared with tumors that do not overexpress HER2 
(Pauletti et al. 2000, Ménard et al. 2001). Approximately 65% of BCs are ER-
positive and progesterone receptor-positive (American Cancer Society).  
Until the advent of HER2-targeted agents, patients who had HER2-positive 
eBC faced a markedly poorer prognosis, including reduced relapse-free and 
OS, than patients with HER2-negative eBC (Ménard et al. 2001; Ross et al. 
1998). 
1.2.2 
TRASTUZUMAB (RHUMAB HER2, HERCEPTIN®) 
Trastuzumab is a humanized monoclonal antibody directed against the 
extracellular domain of HER2. It is indicated for the treatment of patients with 
HER2-positive mBC (first approved in 1998), eBC (approved in 2005), LABC 
(approved in 2011) and HER2-positive metastatic gastric cancer (approved in 
2010). Since its initial approval in 1998, trastuzumab has become standard of 
care for patients with HER2-positive BC and is widely used for its approved 
indications in the adjuvant, neoadjuvant and metastatic settings (Ross et al. 
2009; NCCN 2012; Gnant et al. 2011; Aebi et al. 2011).  
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 (Romond et al. 2005; Slamon et al. 2001). Clinical benefits are greatest in 
patients with tumors strongly overexpressing HER2, graded 3+ by IHC, and/or 
with HER2 gene amplification (see Herceptin® Summary of Product 
Characteristics, 2006). 
A randomized Phase II study evaluated trastuzumab and docetaxel vs. 
docetaxel alone as a first-line treatment for HER2-positive mBC. The addition 
of trastuzumab to 100 mg/m2 docetaxel for at least six cycles resulted in 
superior clinical efficacy with improved overall response rates (ORR), time to 
progressive disease, time to treatment failure, and duration of response (Marty 
et al. 2005). 
Trastuzumab is well tolerated both as a single agent and in combination with 
standard chemotherapy (Cobleigh et al. 1998; Slamon et al. 2001). 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 (Tan-Chiu et al. 2005). 


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Currently, the marketed formulation of trastuzumab is for intravenous 
administration (trastuzumab IV, Herceptin®). All available clinical data have 
been obtained with trastuzumab IV. 
1.2.2.1 
Trastuzumab IV  
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). 
At the time of writing, adjuvant trastuzumab IV monotherapy is widely approved, 
and concurrent administration in combination with adjuvant chemotherapy is 
also approved or expected to be approved in many countries. Trastuzumab IV 
may be given weekly (q1w) or 3-weekly (q3w) to patients with mBC but in the 
adjuvant setting, when given as monotherapy, it is generally given q3w.  
For the regulatory status and approved indications in specific countries, please 
refer to the current Herceptin (Ro 45-2317, Trastuzumab) Investigator’s 
Brochure (IB) and local prescribing information. 
1.2.2.2 
Pharmacokinectics of Trastuzumab IV  
Based on a population pharmacokinetic (PK) analysis of data primarily from the 
mBC setting (Herceptin Report No. 1018264) the predicted median AUC (over 
a period of 3 weeks at steady-state) for the q1w and q3w regimens were 1677 
and 1793 mg*day/L, respectively, and the corresponding median Cmin values 
were 64.9 and 47.3 mg/L, respectively. A two-compartment model satisfactorily 
described the data. The typical trastuzumab IV PK parameters were as follows: 
clearance (CL) of 0.026 L/day and a volume of distribution of the central 
compartment (Vc) of 3.17 L (which corresponds to human plasma volume, 
which is the Vc characteristic of IgG immunoglobulins). The equilibrium half-life 
is about 26 days which is similar to that of endogenous IgG1 immunoglobulin 
(23 days) which constitutes the backbone of trastuzumab IV. 
Refer to the Herceptin (Ro 45-2317, Trastuzumab) IB for further details 
regarding the pharmacokinetics of trastuzumab IV. 
1.2.2.3 
Efficacy of Trastuzumab IV 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 (Piccart-Gebhart et al. 2005; 
Smith et al. 2007; Gianni et al. 2011)  
 
North Central Cancer Treatment Group trial (NCCTG) N9831 trial 
(Romond et al. 2005; Perez et al. 2007; Perez et al. 2009; Perez et al. 
2011)  


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 
National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 
(Romond et al. 2005; Perez et al. 2007; Perez et al. 2009; Perez et al. 
2011)  
 
Breast Cancer International Research Group (BCIRG-006) study (Slamon 
et al. 2009, Slamon et al. 2011)  
 
Protocol Adjuvant dans le Cancer du Sein (PACS04) trial (Spielmann et al. 
2009)  
 
Finland Herceptin (FinHer) trial (Joensuu et al. 2009).  
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.  
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.  
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 tumour size in all 
trials (Gianni et al, 2011; Slamon et al. 2011; Perez et al. 2011). Importantly, 
the most recent follow-up data from the HERA trial (Gianni et al. 2011) and the 
combined analysis of the NCCTG N9831 and NASBP B-31 trials (Perez et al. 
2011) both demonstrate consistent DFS and OS advantages of adjuvant 
trastuzumab over a median follow-up of 4 years. Further, the significant 
benefits in DFS and OS were maintained over a median follow-up of 
approximately 5 ½ years in the BCIRG-006 study (Slamon et al. 2011), 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 
effects (Perez et al. 2011) and the regimen is considered standard of care with 
support from all major treatment guidelines (NCCN 2012; Gnant et al. 2011; 
Aebi et al. 2011).  
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 (Perez et al. 2009). Therefore, based on a positive risk/benefit ratio, 
the authors recommended that trastuzumab be incorporated in a concurrent 
fashion when administered with paclitaxel (Perez et al. 2009), which also 


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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. 
1.2.2.4 Efficacy of Trastuzumab IV in Early and Locally Advanced Breast 
Cancer (Neoadjuvant Setting) 
Neoadjuvant chemotherapy is a defined treatment strategy for breast cancer, 
even though clinical trials in unselected patient populations have shown no 
difference in long term results between neoadjuvant and adjuvant 
chemotherapy. In these trials the effects of neoadjuvant chemotherapy were 
reported in terms of pathological complete response (pCR), or complete loco-
regional eradication of invasive disease at the pathological post-surgical 
evaluation. This condition is considered as an indicator of the response to 
systemic treatment of micrometastases and it is regarded as a surrogate 
marker of better long-term survival. 
Starting from the pivotal MDACC trial (Buzdar et al, 2007), the addition of 
trastuzumab to conventional neoadjuvant chemotherapy regimens for patients, 
homogenously selected for the presence of HER2-positive disease, resulted in 
higher pCR in comparison with the control arm of chemotherapy alone.The 
likelihood of pCR in this studies varied from 31.7 to 66.7 %, with a few 
eterogeneity among the adopted evaluation criteria.   
One of the most important studies is NOAH trial, where 228 HER-2-positive BC 
patients were randomly assigned to receive a neoadjuvant chemotherapy 
regimen consisting of doxorubicin, paclitaxel, cyclophosphamide, methotrexate 
and fluorouracil with or without trastuzumab given concurrently. Patients further 
received adjuvant trastuzumab for a total of 1 year. A parallel cohort of 99 
patients with HER-2-negative disease was included and treated with the same 
chemotherapy regimen. In HER2-positive subset, pCR (ypT0-is ypN0) was 
significantly increased in the combination arm, 38%, in comparison with the 
chemotherapy alone arm, 20%. In addition to the advantage in the likelihood of 
pCR, the population of trastuzumab-treated patients showed a substantial 
improvement of event-free survival at 3 years, with a hazard ratio of 0.59 (95% 
CI: 0.38–0.90). Only two patients (2%) developed symptomatic cardiac failure 
that responded to treatment, and no cardiac deaths were reported (Gianni L et 
al, 2008).  
The German GeparQuattro study also evaluated neoadjuvant trastuzumab. 
This randomized phase 3 trial assessed the incorporation of capecitabine in an 
anthracycline/taxane-based regimen and the concurrent use of trastuzumab 
with these chemotherapy regimens in HER-2-overexpressing patients. Of 1509 
patients included, 445 patients had HER-2-positive BC and received 
trastuzumab (6 mg/kg) every 3 weeks concomitant with all chemotherapy 
cycles. pCR rate was higher in HER-2-positive disease compared with the 
HER-2-negative group (31.7% versus 15.7%). In the subgroup of patients that 
did not respond to epirubicin/cyclophosphamide, the pCR rate was also higher 


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in HER-2-positive versus HER-2-negative tumours (16.7% versus 3.3%). 
Grade 3 and 4 neutropenia as well as conjunctivitis were seen in the 
trastuzumab-treated group, but there were no cardiac safety concerns (von 
Minckwitz et al, 2010). 
These trials prompted to the conventional incorporation of trastuzumab into the 
neoadjuvant regimens for women with HER2-positive disease. 
1.2.2.5   
 
Safety of Trastuzumab IV 
1.2.2.5.1 
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 described in Section 1.2.2.3, 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 (Garnock-Jones et 
al. 2010). 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 (Garnock-Jones et al. 2010).  
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 (Ewer and O’Shaughnessy 
2007). These levels were considered below safety cut-off points set by the 
individual studies’ independent data monitoring committees (Jahanzeb et al. 
2008).  
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 (Rastogi et al. 2007, Russell et al. 2010). 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 (Perez et al. 2008). 
An independent adjudication of the cardiac events occurring in studies B-31 
and N9831 determined that the incidence of symptomatic heart failure events 


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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 (Russell et al. 2010).  
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 
(Procter et al. 2010). 
1.2.2.5.2 
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.  
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 tumour involvement of the lungs, resulting in dyspnea at rest, may be 


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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. 
1.2.2.6 
Trastuzumab SC 
Trastuzumab for subcutaneous (SC) administration has been developed by F. 
Hoffmann-La Roche Ltd to address the known limitations of IV administration 
(e.g. infusion-related reactions, long administration times, requirement for 
hospital facilities, treatment barrier for patients with poor venous access, 
continued use of port-a-cath systems). Administration of trastuzumab SC takes 
significantly less time (up to 5 minutes) compared to IV infusion (30 to 90 
minutes) and this is expected to improve treatment convenience and 
compliance. These attributes are particularly important for patients treated over 
prolonged periods of time. In clinical studies conducted to date, administration 
of trastuzumab SC is associated with a reduced frequency and intensity of 
administration-related reactions. Such reduction in adverse effects of 
administration has also been observed with another monoclonal antibody, 
alemtuzumab (MabCampath®) (Lundin et al. 2002). Treatment fatigue has been 
reported to lead to premature treatment cessation in a small proportion of 
patients treated with chemotherapy (Coates et al. 1983).  
In the HannaH study (a Phase III randomized, open-label, international study of 
the SC formulation of trastuzumab in HER2-positive eBC patients), the safety 
profile of trastuzumab SC was comparable to that of trastuzumab IV (Jackisch 
et al. 2012). Subcutaneous injection of trastuzumab SC formulation was 
generally well tolerated with a low incidence of injection site reactions (grades 1 
and 2). These findings support the potential of trastuzumab SC to provide 
improved convenience for patients compared to the existing IV formulation 
(Pivot et al. 2012). In addition, SC administration also offers the potential for 
administration of trastuzumab outside a hospital/outpatient clinic setting in the 
future, further improving convenience and compliance.  
The feasibility and patient acceptability of subcutaneous administration of any 
drug is dependent on the volume that must be administered. A key excipient in 


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the subcutaneous formulation is the enzyme hyaluronidase, which enables 
larger volumes to be administered without a decrease in patient acceptability. 
Animal-derived hyaluronidase has been available commercially for over 60 
years and is used primarily as a permeation enhancer to increase the 
dispersion and absorption of other co-administered drugs. Hyaluronidase 
transiently hydrolyses hyaluronan, a matrix component of the subcutaneous 
matrix. The hydrolysis leads to decreased viscosity of the subcutaneous matrix 
and, thus, to an improved delivery of subcutaneous administered drugs to the 
systemic circulation. The decreased viscosity is also expected to facilitate 
subcutaneous administration of larger volumes of fluid.  
For information on the subcutaneous formulation please refer to the BP22023, 
CP2 (Section 1.2.2.6.2.2.1) and BO22227, HannaH studies (Section 
1.2.2.6.2.3). 
More recently, preparations of recombinant humanized hyaluronidase 
(rHuPH20) have become available. rHuPH20 has a higher purity and is 
associated with improved efficacy and tolerability compared with the animal-
derived enzyme. In the United States, one recombinant humanized 
hyaluronidase (Hylenex® [Hylenex: Full Prescribing Information]) is licensed to 
facilitate the absorption and dispersion of drugs when given subcutaneous at 
doses between 50 IU and 300 IU (Frost et al. 2007). The rHuPH20 used in this 
study is generated from a second generation of the Hylenex® process (Gen 2 
process) with an improved yield and purity.  
1.2.2.6.1 
RECOMBINANT HUMAN HYALURONIDASE (rHuPH20) 
1.2.2.6.1.1 
NON CLINICAL STUDIES WITH rHuPH20 
After IV administration in the dose range 0.3 to 30 mg/kg, rHuPH20 
demonstrated nonlinear PK, rapid clearance and a half-life of around 5 minutes 
at the lowest dose tested. The bioavailability of rHuPH20 following 
subcutaneous administration was extremely low (not determinable at low doses, 
6% to 8% in the dose range 3 to 30 mg/kg). Treatment of various species with 
rHuPH20 (IV or SC) was generally well tolerated and no major abnormalities 
were noted in any toxicology studies. 
For details on non-clinical studies with rHuPH20 please refer to the Herceptin® 
Investigator’s Brochure.  
1.2.2.6.1.2 
Clinical Studies with rHuPH20 
The safety and efficacy of hyaluronidase products have been widely 
established. 
The 
most 
significant 
safety 
risk 
identified 
is 
hypersensitivity/allergenicity, which is thought to be related to the lack of purity 
of the animal-derived preparations (Frost et al. 2007, Harris 2003). The purity 
and hence the safety risks of hyaluronidase preparations have further been 
enhanced by the development of the humanized recombinant enzyme 
rHuPH20. Clinical data are available from four studies with rHuPH20.  


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 In an allergic sensitivity study (R04-0851), 100 healthy volunteers were 
injected intradermally with 0.1 mL (15 U) of rHuPH20 and saline control. 
The most common side effects were generally mild redness, bruising, 
swelling, discomfort and itching. No AEs were serious and none were 
judged to be related to study treatment 
 A proof-of-concept dose escalation study (HZ2-06-02) with adalimumab 
and rHuPH20 in 15 patients with rheumatoid arthritis evaluated the 
effects of rHuPH20 on the PK, safety and tolerability of adalimumab. A 
single co-administration of adalimumab with rHuPH20 increased 
adalimumab exposure by a weighted average of 13% compared to 
adalimumab alone. The injection was well tolerated with only mild and 
moderate AEs 
 HZ2-07-01 was a double-blinded, within-subject-controlled, two way 
cross-over study comparing the time to inject (flow rate), safety and 
tolerability of a subcutaneous administered 10% (2,000 mg in 20 mL) 
solution of immunoglobulin G (diluted Carimune NF) with and without 
rHuPH20 in 30 healthy volunteers. There was a statistically non-
significant trend towards a decrease in time to inject and an increase in 
flow rate in the presence of rHuPH20 relative to the control group. The 
most common AEs were injection site reactions, consisting of erythema, 
pain, edema, induration or pruritus (communication Halozyme 
Therapeutics Inc. on preliminary study results) 
 HZ2-07-02 investigated the subcutaneous injection of different rHuPH20 
concentrations in a viscous solution of IgG and adalimumab in healthy 
volunteers using different volumes of injection (2, 8 and 16 mL). The 
maximum total enzyme dose administered in this study was 96,000 U. 
The injections were well tolerated with no serious adverse events 
(SAEs) reported. All injection site reactions such as erythema, pain and 
induration were mild (98%) or moderate (2%) in severity. There was a 
trend to lower mean time to inject in subjects who received rHuPH20 
compared to those who received injections without rHuPH20, as well as 
a trend towards an increase in the exposure to adalimumab in the 
presence of rHuPH20. Pain increased across all volume cohorts after 
injection, with no clear difference between the presence and absence of 
rHuPH20. The highest total rHuPH20 dose administered in the clinical 
studies was 96,000 U and this was well tolerated by healthy volunteers. 
Overall, the results of these studies have shown that rHuPH20 is generally well 
tolerated, with no SAEs reported. AEs were mild or moderate in severity and 
most were injection site reactions. The highest total rHuPH20 dose 
administered in the clinical studies was 96,000 U and this was well tolerated by 
healthy volunteers. 
For detailed information on the clinical trials conducted with rHuPH20, please 
refer to the Herceptin® Investigator’s Brochure.  


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1.2.2.7 
Non Clinical Studies with Trastuzumab SC 
An overview of completed non-clinical pharmacology, PK, and toxicology 
studies for trastuzumab subcutaneous is provided in the Herceptin® 
Investigator’s Brochure. Overall, these studies showed that rHuPH20 enabled 
more rapid absorption of trastuzumab SC, and that subcutaneous 
administration of trastuzumab formulated with rHuPH20 was well tolerated 
locally and systemically.  
1.2.2.8 
Clinical Studies With Trastuzumab SC 
Trastuzumab SC (formulated with rHuPH20) has been reported in two 
completed clinical trials (BP22023, CP2 and BO22227, HannaH) (Wynne et al. 
2010; Ismael et al, 2012) using conventional syringe and hypodermic needle 
for administration. In addition, the recently completed study (BO25532, CP3) 
demonstrated comparable exposure between subcutaneous administration with 
the single-use injection device (SID) versus with the conventional syringe and 
needle (Wynne et al. 2012). A patient preference and health care professional 
(HCP) satisfaction study (MO22982, PrefHer) comparing trastuzumab 
subcutaneous administration using SID or hand-held syringe with conventional 
administration of trastuzumab IV administration is currently ongoing. A Phase 
III prospective study (MO28048, SafeHer) to assess the safety of trastuzumab 
SC (manual administration via hand-held syringe or SID) as adjuvant therapy in 
patients with operable HER2-positive EBC has been recently initiated. 
An overview of the clinical development of Trastuzumab SC is presented in 
Table 1. As shown a pharmacokinetics study is completed and several phase II 
and III studies are ongoing. 


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Table 1 Overview of the Clinical Development Program of SC 
Trastuzumab 
Studies  
Status 
Design 
Primary Objective 
Trastuzumab SC (vial)  
Phase Ib Dose-
finding Study 
(BP22023, CP2)  
Completed 
Dose-finding/dose 
confirmation study  
OL, PG, single dose, 
MC  
Select the dose of 
trastuzumab SC which results 
in comparable exposure to 
that achieved from an IV 
dose of trastuzumab  
Phase III Clinical 
Study (BO22227, 
HannaH)  
Completed 
PK, efficacy and 
safety study in the 
neoadjuvant/adjuvant 
setting  
OL, PG, randomized, 
multiple-dose, MC  
Non-inferiority of pre-surgery 
trastuzumab Ctrough and pCR  
Phase I Device 
Qualification Study 
(BO25532, CP3)  
Completed 
PK bridging to 
injection device  
OL, PG, randomized, 
single dose, MC  
PK comparability of 
trastuzumab SC dosing via a 
SID or via hand-held needle 
and syringe used in previous 
clinical studies.  
Additional Studies  
Phase II Patient 
Preference Study 
(MO22982, 
PrefHER)  
Ongoing  
Patient preference 
and HCP satisfaction 
study  
Randomized, MC, 
cross-over study and 
PK study 
To evaluate patient 
preference for trastuzumab 
SC administration using a 
SID/ hand-held needle and 
syringe or trastuzumab IV  
Phase III Safety 
Study [MO28048, 
SafeHer] 
Ongoing 
Safety Study  
Non-randomized two-
cohort, MC, OL 
To evaluate the safety of 
assisted- and self-
administered  
trastuzumab SC as adjuvant 
therapy  
HCP: Health Care Professional; MC: Multi-centre; OL: Open-label; pCR: pathological 
complete response; PG: Parallel group; PK: pharmacokinetic; SID: single use injection 
device  
 


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See the Herceptin Investigator's Brochure for details on clinical studies. 
1.2.2.8.1 
 
Study BP22023 
Study BP22023 (CP2, Wynne et al. 2010) was a dose-finding study of 
trastuzumab SC, conducted in healthy male volunteers and patients with 
HER2-positive EBC. Part 1 of the study was designed to select a trastuzumab 
SC dose (formulated with rHuPH20) that resulted in comparable exposure and 
trough levels at least as high as those achieved with trastuzumab IV at dose of 
6 mg/kg. Part 2 of the study was designed to confirm the subcutaneous dose 
selected from part 1. Twenty-four healthy male subjects and 42 female patients 
with HER2-positive eBC received single doses of either IV or trastuzumab SC.  
In Part 1, a total of 86 AEs were observed in 27 subjects/patients. Of these, 
71% were considered to be mild, 28% moderate and there was one SAE (an 
infusion-related reaction [IRR]).  
In Cohort 1, in which male healthy volunteers received trastuzumab IV at 
6 mg/kg, the most commonly observed AEs were headache (3 AEs), 
musculoskeletal pain (2), diarrhea (2), abdominal pain (2) and IRR (2).  
In Cohort 2, in which female patients received trastuzumab IV at 6 mg/kg, the 
most commonly observed AE was headache which occurred in 2 patients. 
In Cohorts 3 to 5, in which male subjects received trastuzumab SC at 6, 8 and 
10 mg/kg, there was no apparent dose-related increase in AEs and 
subcutaneous administration was generally well tolerated. The most commonly 
observed AEs were headache (4 events; 3 mild, 1 moderate), upper respiratory 
tract infection (4 events; all mild) and influenza-like illness (3 events; 2 
moderate, 1 mild).  
In Part 2, a total of 181 AEs were observed in 39 female patients. Of these, 
72.5% were considered to be mild, 25.5% moderate and there were four (2%) 
severe AEs.  
In Cohorts A and B, there was no apparent dose-related increase in AEs and 
subcutaneous administration was generally well tolerated. The most commonly 
observed AEs in these patients were headache (27 events; 18 mild, 8 
moderate, 1 severe), diarrhea (8 events; 6 mild, 2 moderate), lethargy (6 
events; 4 mild, 2 moderate) and injection site erythema (6 events; all mild). 
As this was the first study during which subjects/patients received trastuzumab 
SC, special consideration was given to the local tolerability related to drug 
administration. In subjects/patients who received trastuzumab SC, there were 
18 AEs that were classified as administration site conditions. All but two of 
these AEs were mild in severity. There were two instances of moderate 
injection site pain. 
No deaths or serious AEs (SAEs) occurred in this study. 


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1.2.2.8.2 
 
Study BO22227 
Study BO22227 (HannaH) compared the PK profile, efficacy, and safety of the 
subcutaneous and IV formulations in patients with HER2-positive eBC. The 
HannaH study was a phase III, randomized, international, open-label, trial in 
the (neo)adjuvant setting. 
Patients with HER2-positive, operable, locally advanced or inflammatory BC 
were randomly assigned to eight cycles of neoadjuvant chemotherapy 
administered concurrently with trastuzumab every 3 weeks either IV (8 mg/kg 
loading dose, 6 mg/kg maintenance dose) or subcutaneous (fixed dose of 600 
mg); 1:1 ratio. Chemotherapy consisted of four cycles of docetaxel (75 mg/m²) 
followed by four cycles of fluorouracil (500 mg/m²), epirubicin (75 mg/m²), and 
cyclophosphamide (500 mg/m²), every 3 weeks. After surgery, patients 
continued trastuzumab to complete 1 year of treatment. Co-primary endpoints 
were serum trough concentration (Ctrough) at predose cycle 8 before surgery 
(non-inferiority margin for the ratio between groups of 0.80) and pathological 
complete response (pCR; non-inferiority margin for the difference between 
groups of –12·5%), analyzed in the per-protocol population. This study is 
registered with ClinicalTrials.gov, number NCT00950300. Finding: 299 patients 
were randomly assigned to receive intravenous trastuzumab and 297 to 
receive trastuzumab SC. The geometric mean pre-surgery Ctrough was 51.8 
μg/mL (coefficient of variation 52.5%) in the IV group and 69.0 μg/mL (55.8%) 
in the subcutaneous group. The geometric mean ratio of Ctrough subcutaneous 
to Ctrough IV was 1.33 (90% CI 1.24–1.44). 107 (40.7%) of 263 patients in the IV 
group and 118 (45.4%) of 260 in the subcutaneous group achieved a pCR. The 
difference between groups in pCR was 4.7% (95% CI –4.0 to 13.4). Thus 
trastuzumab SC was non-inferior to trastuzumab IV for both co-primary 
endpoints. The incidence of grade 3–5 adverse events was similar between 
groups. The most common of these adverse events were neutropenia (99 
[33.2%] of 298 patients in the IV group vs 86 [29·0%] of 297 in the 
subcutaneous group), leucopenia (17 [5.7%] vs 12 [4.0%]), and febrile 
neutropenia (10 [3.4%] vs 17 [5.7%]). However, more patients had SAE in the 
subcutaneous group (62 [21%] of 297 patients) than in the IV group (37 [12%] 
of 298); the difference was mainly attributable to infections and infestations (24 
[8.1%] in the subcutaneous group vs 13 [4.4%] in the IV group). Four AEs led 
to death (one in the intravenous group and three in the subcutaneous group), 
all of which occurred during the neoadjuvant phase. Of these, two—both in the 
subcutaneous group—were deemed to be treatment related. Trastuzumab SC, 
administered over about 5 min, has a PK profile and efficacy non-inferior to 
standard IV administration, with a similar safety profile to trastuzumab IV, and 
therefore offers a valid treatment alternative. No new safety signals were 
identified with trastuzumab SC (Ismael et al. 2012). 
1.2.2.8.3 
 
Study BO25532 
Study BO25532 (CP3) was a randomized, open-label, parallel, 2-arm, multi-
centre Phase I study to investigate the comparability of PK of trastuzumab 


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administered subcutaneously using either the SID or a conventional syringe 
and hypodermic needle. The study also assessed the performance of the SID 
and evaluated the immunogenicity of trastuzumab and rHuPH20. 
Enrolment was completed in September 2011, with a total of 119 healthy male 
subjects randomized 1:1 to receive a single 600 mg subcutaneous injection by 
either administration method. The primary objective of the study was met, with 
the results for both co-primary PK endpoints within the standard bioequivalence 
range of [0.8, 1.25], meeting the pre-specified criteria for comparability. 
Sensitivity analyses of the co-primary endpoints that included non-dose 
normalized or non-body-weight adjusted calculations were in line with the 
primary analysis.  
Trastuzumab was well tolerated after single-dose administration by both 
methods and no apparent differences related to the injection method were 
observed (Wynne et al. 2012). 
1.2.2.8.4 
 
Ongoing Studies 
STUDY MO22982 
MO22982 (PrefHer) is a Phase II international, randomized, open-label, two-
cohort, two-arm crossover study to evaluate patient’s preference and HCP 
satisfaction with subcutaneous versus IV administration of trastuzumab in 
HER2-positive EBC, following surgery and completion of chemotherapy 
(neoadjuvant or adjuvant). As (neo)adjuvant treatment may also include 
trastuzumab, randomized patients are stratified by de novo vs. non de novo 
trastuzumab. Patients in Arm A receive trastuzumab SC (4 cycles) followed by 
trastuzumab IV (4 cycles). Patients randomized to Arm B receive trastuzumab 
IV (4 cycles) followed by trastuzumab SC (4 cycles). Patients enrolled into 
Cohort 1 receive trastuzumab SC administered via a SID, and patients enrolled 
into Cohort 2 receive trastuzumab SC administered from a vial with a hand-
held syringe. An estimated 200 patients will be randomized to obtain at least 
160 evaluable patients in each cohort, giving a total of approximately 
400 patients to obtain 320 evaluable patients. The enrollment of Cohort 1 
patients is complete, enrollment of Cohort 2 patients is ongoing. 
STUDY MO28048 
MO28048 (SafeHer) is a Phase III, prospective, two-cohort, non-randomized, 
multicenter, multinational, open label study to assess the safety of assisted- 
and self-administered trastuzumab SC as adjuvant therapy in patients with 
operable HER2-positive eBC. Approximately 2,500 patients with HER2-positive 
eBC whose tumor has been excised will be enrolled into the study. The trial is 
ongoing and will be conducted at approximately 500 centers in approximately 
60 countries. 
1.2.2.9 
Subcutaneous Single-Use Injection Device (SID) 
The SID is a single-use device for the subcutaneous administration/injection of 
medicinal products such as trastuzumab. The medicinal product to be injected 


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is contained in an integral non-removable cartridge and the entire content of 
the cartridge is delivered to the patient in a single injection through a needle 
that retracts when the injection is complete. The administration rate is fixed 
(approximately 1.5 mL/min) and the dosage delivered is pre-set and controlled 
at the product manufacturing stage. The device deploys a mechanism to retract 
the needle when the injection is completed, preventing handling injuries. The 
trastuzumab SID will administer trastuzumab (600 mg) (formulated with 
10,000U of rHuPH20). The device will be applied to the patient’s thigh and 
activated by study staff. Information on the preparation for use of the SID is 
provided in a separate leaflet. 
Trastuzumab SC (SID) is supplied in a SID. The cartridge included in the SID 
contains a nominal content 120 mg/mL of trastuzumab mixed with 2,000 U/mL 
rHuPH20) in 5mL. Information on the preparation for use of the SID is provided 
in a separate leaflet.  
Trastuzumab SC for manual injection will be supplied in a vial containing a 
ready to use solution with a nominal content of 120 mg/mL of trastuzumab 
mixed with 2,000 U/mL rHuPH20 in 5mL and must not be diluted prior to 
administration. The solution is injected using a hand-held syringe fitted with a 
27 gauge needle. Further information on the preparation and administration is 
provided as a separate leaflet.  
1.3 
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT 
Trastuzumab SC is a new administration route that has demonstrated similar 
PK and efficacy in pCR in the treatment of HER2-positive eBC in the 
neoadjuvant setting, during which no new safety signals were identified. 
This study is a Phase IIIb, open-label, multicenter study to assess the safety 
and tolerability of trastuzumab solution injected subcutaneously (vial or SID) in 
patients with HER2-positive eBC. In addition efficacy parameters (disease free 
survival and overall survival), exposure to study medication, duration of 
treatment, follow-up and safety follow-up will be analysed. This study is a part 
(Daughter study) of global umbrella study. Safety and efficacy data will be 
collected in local (Daughter) study and transferred to a global database for a 
pooled analysis. This study will be run in order to gain a better understanding of 
the safety profil of trastuzumab SC. 
1.3.1  
RATIONALE FOR TEST PRODUCT DOSAGE 
1.3.1.1 
Trastuzumab SC 
Trastuzumab SC will be given q3w at a fixed dose of 600 mg. Use of a fixed 
dose for all patients and all cycles greatly simplifies dosing, reduces the 
potential for error, and reduces wastage. Fixed doses have been used for other 
therapeutic monoclonal antibodies, particularly in chronic conditions, such as 
rheumatoid arthritis (e.g. adalimumab). The fixed dose of trastuzumab for 
subcutaneous administration was selected with the aim of achieving 


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trastuzumab serum trough concentrations (Ctrough) that are non-inferior to 
those obtained with q3w trastuzumab IV administration. The fixed (600 mg) 
dose of trastuzumab used in this study was calculated based on PK modelling 
of preliminary data from the BP22023 study (see section 1.2.2.8.1) which 
showed that 600 mg doses of trastuzumab SC were able to achieve serum 
Ctrough levels at least as high as those achieved with standard weight-
adjusted trastuzumab IV dosing. Trastuzumab exhibits linear pharmacokinetics 
in the clinical dose range, which is an indication that target receptors are 
saturated. 
Therefore, 
achieving 
Ctrough 
levels 
with 
subcutaneous 
administration that are at least as high as with the IV dosing, indicates that 
efficacy should be comparable. Patients with lower body weight may be 
exposed to higher Ctrough levels than if they were dosed on a weight-adjusted 
basis. However, studies in which higher than standard (or more frequent) 
doses of trastuzumab were given (Clinical Study Report 1026709; Vogel et al. 
2002) and reports of patients accidentally overdosed with trastuzumab IV, do 
not indicate any detrimental effect on patient safety. Moreover, based on data 
from the BP22023 study, the predicted maximal concentrations following eight 
q3w cycles of 600 mg are expected to be below the Ctrough of trastuzumab IV 
observed in the MO16982 study (range 199-375 mg/L). In study MO16982 
patients were initially dosed with 6 mg/kg weekly and no increase in AEs was 
observed (Clinical Study Report 1026709). More recently, results of the 
HannaH study (BO22227) have been released. The study met its two co-
primary endpoints, i.e. observed trastuzumab Ctrough after 7 cycles and the 
primary efficacy variable of pathological complete response, thereby 
demonstrating comparable bioavailability and efficacy of the subcutaneous and 
IV formulations of trastuzumab. The fixed dose of 600 mg of trastuzumab SC 
will be administered with a fixed dose of 10,000 U of rHuPH20 (2,000 U/ml). 
The dose of rHuPH20 was selected based on non-clinical PK studies with a 
number of antibodies, including trastuzumab. These studies showed a trend for 
increasing dispersion and absorption with increasing concentrations of 
rHuPH20 (Clinical Study Report 1029906; Halozyme Study Report). Of note, a 
higher amount of rHuPH20 (6,000 U/ml) did not improve the absorption of 
trastuzumab as compared to a formulation containing 2,000 U/ml rHuPH20. 
The selected rHuPH20 concentration was further verified in clinical studies for 
satisfactory absorption parameters. Non-clinical and clinical data demonstrate 
that the selected amount of rHuPH20 contained in the trastuzumab SC 
formulation is well-tolerated. 
1.3.2  
RATIONALE FOR PATIENTS  
Surgery is the main modality of local treatment for BC (with or without 
radiotherapy) and can control loco-regional disease in the majority of patients. 
Systemic chemotherapy (or endocrine therapy in hormone receptor-positive 
patients) reduces the risk of relapse and is given either prior to surgery 
(neoadjuvant therapy) or following surgery (adjuvant therapy) or both. Cytotoxic 
chemotherapy, endocrine therapy, radiotherapy, and molecular targeted 
therapies currently represent the backbone of modern systemic BC treatment. 


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Patients with HER2-positive eBC frequently require extensive treatment lasting 
months or years. Many require surgery, adjuvant chemotherapy (usually given 
IV for 4-6 months) and/or hormonal therapy, and radiotherapy (often given daily 
for 4-6 weeks), as well as trastuzumab. Adjuvant trastuzumab is given IV q1w 
or q3w for a total of one year. This necessitates regular clinic visits and, when 
started after completion of adjuvant chemotherapy and adjuvant radiotherapy if 
indicated, it greatly extends the period of time over which the patient is obliged 
to attend the hospital or clinic which can cause inconvenience and increased 
costs to patients. Even when started concurrently with the taxane component of 
chemotherapy (Herceptin license permitting), trastuzumab monotherapy still 
continues for several months after completion of other systemic therapy.  
Trastuzumab infusions are given over 30 to 90 minutes (or longer if there are 
infusion-related symptoms). Subcutaneous administration of trastuzumab is 
quicker (lasting up to 5 minutes) and this alone could improve convenience for 
patients (and clinic staff).  
Furthermore, subcutaneous administration does not require IV access (which 
can be problematic in some patients after completion of chemotherapy) and, 
based on the findings of the BP22023 study (Wynne et al. 2010) and previous 
observations with subcutaneous alemtuzumab administration (Lundin et al. 
2002), may reduce the incidence of infusion-related symptoms. Use of a SID 
may also enable self-administration of trastuzumab in the future. This could 
potentially further improve convenience for patients and compliance with 
therapy.  
The most clinically relevant AE associated with trastuzumab IV is left 
ventricular cardiac dysfunction or CHF. Cardiac toxicity, as measured by the 
rate of NYHA class III/IV CHF was the most significant AE, occurring in 0%–
3.8% of patients in the trastuzumab-containing arms of six randomized 
adjuvant trials. The current study is designed to investigate the safety and 
tolerability of two subcutaneous administration methods for trastuzumab in the 
(Neo)-adjuvant setting, i.e. assisted administration using a conventional syringe 
(vial formulation) and self-administration using a SID. The observed LVEF rate 
served as basis for the determining the sample size for the current trial. Patient 
satisfaction with self-administration using a SID is assessed as part of the 
secondary objectives of the study.  
Trastuzumab is now a standard component of adjuvant treatment in patients 
with HER2-positive eBC. The trastuzumab SC dose selected for this study is 
consistent with the findings of the BP22023 (CP2) trial and identical to that 
evaluated in the recently completed BO22227 (HannaH) study (see Section 
1.2.2.8.1f or details). Efficacy is hence expected to be comparable to that 
observed in trastuzumab IV trials. Safety data from the BP22023 and BO22227 
studies show that trastuzumab SC is well tolerated, with no safety signals 
detected compared to trastuzumab IV in the BO22227 study. The benefit to risk 
ratio of adjuvant trastuzumab SC in the current trial is therefore expected to be 


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favorable. Further, the convenience of subcutaneous administration of 
trastuzumab will give patients greater independence which is expected to 
increase compliance. 
Several targeted drugs with different molecular pathways have achieved 
approval for mBC, but trastuzumab is the only such therapy that is currently 
approved for adjuvant or neoadjuvant treatment of eBC (Untch 2010). The use 
of trastuzumab in the adjuvant setting is also supported by international 
treatment guidelines for women with HER2-positive BC (NCCN 2012; 
Goldhirsch et al. 2011; Aebi et al. 2011). The introduction of trastuzumab at the 
end of 1990s has particularly improved the outcome for eBC patients with 
HER2-positive disease (Colozza et al. 2006). 
1.3.3  
BENEFITS OF SC ADMINISTRATION OF TRASTUZUMAB 
The current marketed formulation of trastuzumab is for IV administration. 
Trastuzumab infusions are given over 30 to 90 minutes (or longer if there are 
infusion-related symptoms). The administration of trastuzumab necessitates 
regular clinic visits and when started after completion of adjuvant 
chemotherapy (and adjuvant radiotherapy, if indicated), greatly extends the 
period of time over which the patient is obliged to attend the hospital or clinic, 
at great inconvenience and cost. Even when started concurrently with the 
taxane 
component 
of 
chemotherapy 
(Herceptin® 
license 
permitting), 
trastuzumab monotherapy still continues for several months after completion of 
other systemic therapy. Subcutaneous administration of trastuzumab is quicker 
(lasting approximately 5 minutes) and this alone could improve convenience for 
patients (and clinic staff). Furthermore, subcutaneous administration does not 
require IV access, which can be problematic in some patients after completion 
of chemotherapy. Use of a pre-loaded SID should also reduce preparation time 
for pharmacy or clinic staff and might, in the future, enable administration 
outside a hospital/outpatient clinic setting. This SID could potentially further 
improve convenience for patients and compliance with therapy. The patient SID 
Satisfaction Questionnaire, developed for use in Study MO28048, will be used 
in the current study to collect data on patient satisfaction, comfort level and 
convenience of trastuzumab administrations using the SID. It is expected that 
with the switch from IV to subcutaneous administration route, HCP time would 
be saved. Time gained could be invested in other patient care activities, or 
increase the number of patients that could be treated at a site. Further it is 
expected that the amount of medical supplies and resources required would be 
reduced. 
Trastuzumab SC (formulated with rHuPH20) has been evaluated in three 
completed clinical trial: BP22023 (CP2), BO22227 (HannaH) a clinical trial 
using conventional syringes and hypodermic needles for administration and a 
PK study BO25532 (CP3) to demonstrate comparable exposure between 
subcutaneous administration with the SID versus with the conventional syringe 
and needle. Trastuzumab was well tolerated after single-dose administration by 


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both methods and no apparent differences related to the injection method were 
observed (Wynne et al. 2012). Two clinical trial with trastuzumab SC are 
ongoing in patients with eBC: MO22982 (PrefHer) will evaluate patient’s 
preference and HCP satisfaction, and MO28048 (SafeHer) will assess the 
safety of assisted- and self-administered trastuzumab SC (see Section 
1.2.2.8.4) 
As mentioned earlier, trastuzumab is now a standard component of adjuvant 
treatment in patients with HER2-positive eBC, and is supported by all major 
treatment guidelines. The long-term benefits trastuzumab IV treatments have 
been demonstrated. The dosing of trastuzumab SC in this study has been 
chosen to achieve serum trough levels at least as high as those achieved by 
the IV formulation.  
Efficacy of trastuzumab SC is hence expected to be comparable to IV. 
Trastuzumab IV has an established safety profile, supported by a clinical 
database comprised of approximately 14,000 female patients with HER2-
positive eBC (in addition to patients with HER2-positive MBC). Safety data from 
the BP22023 and BO22227 studies show that trastuzumab SC is well tolerated, 
with no new safety signals detected compared to trastuzumab IV in the 
BO22227 study. The benefit to risk ratio of trastuzumab SC administration in 
this trial is therefore expected to be favorable. The main advantage of 
trastuzumab SC is the reduced administration time (approximately 5 minutes) 
compared to the IV infusions. The convenience of subcutaneous administration 
of trastuzumab using a single-use pre filled device (SID) will give patients 
greater independence which is believed to increase compliance and to lead to 
an improved quality of life. 
Beside 
improving 
patients 
convenience 
and 
comfort, 
subcutaneous 
administration of trastuzumab may also optimize medical resource utilization by 
reducing administration time, requiring no dedicated infusion staff and no need 
for infusion bag preparation.  
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of the study is to assess the safety and tolerability of 
trastuzumab solution injected subcutaneously (vial or single-use injection 
device [SID]) in patients with HER2-positive early breast cancer (EBC) or 
locally advanced breast cancer (LABC). 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives for this study are the following: 
 
Exposure to study medication 
 
 Duration of treatment, follow-up, and safety observation 


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 
 Efficacy: 
 
overall survival (OS), disease-free survival (DFS)   
 
In the Neo-adjuvant setting activity of two sequential drug regimens, 
Anthracycline-containing 
regimen 
followed 
by 
concomitant 
administration of Taxane and Trastuzumab SC, assessed as the 
incidence of pathological Complete Response in breast and nodes 
(pCR; ypT0-is ypN0) 
 
Patient Satisfaction using SID (single use injection device) 
 
HCP satisfaction  
2.3 
EXPLORATORY OBJECTIVES 
The exploratory secondary objective of the local study is the assessment of 
PI3K mutation in tumor tissues and in circulating free DNA (cfDNA) in blood. 
These assessments will be performed:  
 to  evaluate the agreement between the PI3K mutation assessment in 
tumor tissue (gold standard) and in circulating free DNA (experimental) 
 to correlate the baseline mutation status (in tumor tissue and cfDNA) with 
clinical outcome: pathological response to treatment (neoadjuvant arm)  
 to correlate the pharmacodynamic change of the cfDNA before and after 
treatment with clinical outcome. 
3. 
STUDY DESIGN 
Figure 1: Overview of dosing Schedule 
 
 
 
 
 
 
 
 
 
 
3.1 
DESCRIPTION OF STUDY 
This is a prospective, two-cohort, non-randomized, multicenter, open-label study 
to assess the safety and tolerability of trastuzumab solution injected 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 


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subcutaneously (vial or single-use injection device [SID]) in approximately 240 
patients with HER2-positive eBC or LABC who are eligible for anti-HER2 therapy.  
The first 120 patients will be treated with trastuzumab SC 600 mg/5ml vial (Cohort 
A) and the subsequent 120 patients will be treated with trastuzumab SC 600 
mg/5ml prefilled single use injection device - SID ( Cohort B).  
The patients will be enrolled in two sequential cohorts. 
In each cohort (A and B), patients will be allocated to adjuvant or neoadjuvant 
treatment, with pragmatic selection according to conventional clinical criteria and 
physician choice: 
 
 Group 1= Adjuvant chemotherapy + trastuzumab SC 
 Group 2 = Neoadjuvant chemotherapy + trastuzumab SC 
 
In both groups the planned treatment will require sequential chemotherapy 
regimens comprehensive of Anthracyclines and Taxanes, starting with 
Anthracycline-containing sequence. 
The following drug regimens are allowed: 
 
AC/EC, 4 cycles (Cycles A1 to A4) → weekly Paclitaxel, 12 wks + 
trastuzumab 600 mg SC every 3 weeks, 4 cycles (Cycles 1 to 4) → 
trastuzumab 600 mg SC every 3 weeks, 14 cycles (Cycles 5 to 18) 
 
AC/EC, 4 cycles (Cycles A1 to A4) → Docetaxel, 4 cycles+ trastuzumab 
600 mg SC every 3 weeks, 4 cycles (Cycles 1 to 4) → trastuzumab 600 
mg SC every 3 weeks, 14 cycles (Cycles 5 to 18) 
 
FAC/FEC, 4 cycles (Cycles A1 to A4) → weekly Paclitaxel, 12 wks + 
trastuzumab 600 mg SC every 3 weeks, 4 cycles (Cycles 1 to 4) → 
trastuzumab 600 mg SC every 3 weeks, 14 cycles (Cycles 5 to 18) 
 
FAC/FEC, 4 cycles (Cycles A1 to A4)→ Docetaxel, 4 cycles + trastuzumab 
600 mg SC every 3 weeks, 4 cycles (Cycles 1 to 4) → trastuzumab 600 
mg SC every 3 weeks, 14 cycles (Cycles 5 to 18) 
The regimen selection is based on the physician preference and convenience. 
The conventional doses of the selected regimens are detailed in the Appendix 3. 
3.1.1 
ADDITIONAL CHARACTERISTICS OF STUDY DESIGN 
Concomitant trastuzumab SC, 600mg administered subcutaneously using either a 
handheld syringe or SID, starting after the Anthracyclines comprehensive 
sequences.  
The therapy should include a total of 18 cycles/1 year of trastuzumab SC. 
Doxorubicin cumulative doses ≤ 300 mg/m2 or equivalent for Epirubicin. 
Chemoterapy treatment duration, either in the adjuvant and in the neoadjuvant 
group, of 8 total cycles. 


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The whole neoadjuvant chemotherapy must be given before surgery. 
Surgery after neoadjuvant chemotherapy + trastuzumab SC should include 
conventional surgical procedures on the breast and on the axilla. SNB (Sentinel 
lymph node biopsy) is consented in patients with clinically negative axillary status 
at starting treatment. Surgery after neoadjuvant chemotherapy should be 
performed 3-4 weeks after the last chemotherapy cycle, or until toxicity, 
specifically bone marrow toxicity recovery. 
Postoperative RT and/or hormonal treatment can be administered concomitantly 
with trastuzumab SC as adjuvant treatment after chemotherapy, when indicated. 
Adjuvant chemotherapy should start within 10 weeks from definite surgery. 
Primary chemotherapy should start as soon as possible after study inclusion and 
no later than 5 working days. 
Tissues samples from diagnostic core biopsy and from surgical specimens, as far 
as blood samples at the planned time points should be collected as reported in the 
Appendix 1. 
The centralization of biological materials (tissues and blood) is a definite 
prerequisite for the study for the evaluation of PI3K mutations, as well the 
centralized re-evaluation of HER2 positivity on tissues. The results of HER2 
positivity performed centrally will not be required prior to the enrollment into the 
study. 
Safety and efficacy data (DFS and OS) collected in this local study will be 
transferred to a global Umbrella database for a pooled analysis.  
The schedules of mandatory clinical assessments for patients with eBC and for 
patients with LABC are provided in Appendix 1. 
3.1.2 
LOCAL STEERING COMMITTEE 
A local Steering Committee will be established to provide scientific oversight and 
to ensure that the risk-benefit assessment is maintained during the duration of the 
trial. The Steering Committee will be made up of Investigators and Roche (the 
Sponsor) representatives and meet at the regular intervals. A separate Steering 
Committee charter will outline the committee’s composition and members’ roles, 
responsibilities and the frequency of meeting. 
3.2 
LENGTH OF STUDY 
The study is estimated to last 5 years from the enrollment of the first patient (18 
months of recruitment, 15 months of study treatment (3 months of chemotherapy 
with anthracyclines + 12 months of trastustuzumab in combination with Taxane 
based chemotherapy) and 2 years of follow-up. 


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3.2.1 
TREATMENT DURATION 
Patients with eBC will be treated with trastuzumab SC for 1 year, unless 
intolerable toxicity or investigator-assessed disease progression occurs, or the 
patient withdraws consent. 
3.3 
SAFETY FOLLOW-UP 
All patients will be followed up for 24 months after the last patient has received 
his/her last study treatment, or earlier, if one of the following is documented: 
withdrawal from the study, loss to follow-up or death. 
3.4 
END OF STUDY 
The end of study is defined as last patient last visit ( LPLV) in the follow-up period.  
3.5 
NUMBER OF PATIENTS 
This local (Daughter) study will recruit 240 patients (eBC and LABC) in total.  
3.6 
CENTERS 
The study will be performed in approximately 60 oncological centers in Italy. 
3.7 
RATIONALE FOR STUDY DESIGN 
Trastuzumab SC is a new administration route that has demonstrated similar PK 
and efficacy in pCR in the treatment of HER2-positive eBC and LABC in the 
neoadjuvant setting, during which no new safety signals were identified (Ismael G, 
Lancet Oncol, 2012). 
This is a Phase IIIb, open-label, multinational, multicenter study to assess the 
safety and tolerability of trastuzumab solution injected subcutaneously (vial or SID) 
in patients with HER2-positive EBC or LABC. Safety and efficacy data collected in 
this local (Daughter) study will be transferred to a global database for a pooled 
analysis.  
In this study, the safety and tolerability of trastuzumab SC will be explored, to gain 
better understanding of the safety profile of trastuzumab SC in the treatment of 
HER2-positive eBC and LABC patients, whilst addressing more additional 
scientific questions and investigations. 
 
3.7.1 
RATIONALE FOR PATIENT POPULATION 
Measurement of HER2 overexpression is a standard of care in determining 
eligibility for trastuzumab therapy (see the Herceptin Package Insert). 
Measurement of HER2 gene amplification has traditionally been performed using 
IHC measurement. HER2 gene amplification determined by in situ hybridization 
(ISH) has also proven to be a reliable method for demonstrating HER2-positive 


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status (Press et al. 2005). Patients whose tumors are positive for HER2 
overexpression represent the patient population eligible for study enrollment. 
In the current study eBC and LABC patients with HER2 positive tumors will be 
included. 
For more details on rationale for patients with eBC please see Section 1.3.2. 
3.7.2 
RATIONALE FOR POOLING STRATEGY 
The data from local studies conducted in various countries will be pooled due to 
similar designs, endpoints and data structure. A large global database of safety 
and efficacy data will be created, whilst ensuring these data are collected in a 
standard, high-quality manner.  
Safety and efficacy data will be pooled, summarized and analyzed where 
appropriate.  
3.7.3 
RATIONALE FOR TEST PRODUCT REGIMEN 
The trastuzumab regimen will depend on the patient population and could include 
mono-or combination therapy. 
All eligible patients will receive a fixed dose of 600 mg trastuzumab SC throughout 
the study, administered q3w (irrespective of body weight) for 1year, unless 
intolerable toxicity or investigator-assessed disease progression occurs, or the 
patient withdraws consent. Know advantages of the use of the fixed dose for all 
patients and all cycles include a greatly simplified dosing, reduced potential for 
error, and reduced wastage. The fixed dose of 600 mg of trastuzumab for 
subcutaneous administration was selected with the aim of achieving trastuzumab 
serum trough concentrations (Ctrough) that are non-inferior to those obtained with 
q3w trastuzumab IV administration. Importantly, this dose is consistent with the 
findings of the BP22023 study (CP2) and identical to that evaluated in the recently 
reported BO 22227 (HannaH) study. 
The regimen consisting of 1 year trastuzumab treatment administered 3–weekly is 
considered standard of care in patients with eBC, as supported by all major 
treatment guidelines (NCCN 2011; Goldhirsh et al. 2011; Aebi et al 2011). This 1-
year treatment duration is consistent with the current label for trastuzumab IV. 
Based on the comparability of the treatment parameters, the efficacy of 
trastuzumab SC is expected to be similar to that observed in trastuzumab IV trials. 
3.7.4 
RATIONALE FOR SID 
Trastuzumab may be supplied as vial or SID. The SID is a single-use injection 
device for the subcutaneous administration of medicinal products such as 
trastuzumab SC. At the press of a button, the syringe needle is automatically 
inserted and the drug is delivered. Upon completion of injection, the needle 
retracts to prevent handling injuries and visual indication is provided to confirm 
that the full dose has been delivered. The administration rate is fixed 


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(approximately 1 mL/min, resulting in a 5-minute injection time) and the dosage 
delivered is pre-set and controlled at the product manufacturing stage, i.e. 600 mg 
of trastuzumab formulated with 10,000U of rHuPH20. These attributes ensures a 
standardized, consistent administration of the medicinal product. The current 
study is designed to investigate the safety and tolerability of two subcutaneous 
administration methods for trastuzumab, i.e. assisted administration using a 
conventional syringe ( vial formulation) and self-administration using a SID. Use of 
the preloaded SID should  reduce preparation time for pharmacy, for clinical staff 
and might, in the future, enable administration outside a Hospital/ Out patient 
clinic setting. Use of a SID may also enable self-administration of trastuzumab in 
the future. This could potentially further improve convenience for patients and 
compliance with therapy  
3.7.5   
RATIONALE FOR ASSESSMENT OF BIOMARKERS 
HER2 potently activates PI3K via heterodimerization with HER3, and trastuzumab 
down regulates the ligand-independent HER2 dimerization and growth factor 
signaling cascades downstream of HER2, including the PI3K/AKT/mTOR pathway 
(Yakes 2002; Nagata, 2004; Junttila, 2009; Mohisin 2005).  
Among preclinical models of resistance to trastuzumab, two of the major 
mechanistic hypothesis behind trastuzumab refractory disease have been 
changes in the HER2 molecule itself  and the activation of the PI3K/AKT pathway. 
Hyperactivation of the PI3K/AKT/mTOR pathway has been described through 
several different molecular lesions: loss of the PTEN tumor suppressor, increase 
of this signal through the activation of HER2-related receptors, such as HER3, or 
non-HER receptors, such as insulin-like growth factor I receptors (Lu 2001; 
Sergina 2007), and mutational activation of PIK3CA (Berns 2007).  
The gene encoding one of the PI3K catalytic subunits, p110α (PIK3CA), has been 
found to be mutated in about 25% of breast cancers. In particular this mutations 
have been detected in 13-30% of HER2-positive diseases. Most of the reported 
mutations (≥80%) are localized to three hotspots in exons 9 (E542 e E545) and 20 
(H1047) of the PIK3CA gene. Exon 20 mutations predominate in breast cancer, in 
contrast to colorectal cancer where exon 9 mutations predominate (Samuels 
2004). 
Data from in vitro and in vivo studies suggest that mutations in the PIK3CA gene 
confer resistance to trastuzumab and that in HER2-overexpressing cancer cells 
the inhibition of both HER2 and mTOR pathways is required for the optimal 
antitumor effect of anti HER2 agents (Miller, 2009;  Yao, 2009; Junttila, 2009; 
Garcia Garcia, 2012). HER2+ breast cancer cell lines are highly sensitive to PI3K 
and mTOR inhibitors before and after acquiring resistance to trastuzumab or 
lapatinib, suggesting that these drug-resistant cells remain PI3K-dependent. 
An increased frequency of changes that activate PI3K/AKT signaling, including in 
particular PI3KCA mutation, have been reported in trastuzumab-resistant 
metastatic breast cancer (Chandarlapaty 2012). Retrospective analyses in cohorts 
of patients with HER2+ metastatic breast cancer (Esteva, 2010; Wang, 2011; 


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Razis,  2011) have shown that tumors harboring PIK3CA mutations and/or 
decreased levels of PTEN have a poor outcome following treatment with 
trastuzumab compared to HER2+ tumors with a 'wild-type' PI3K pathway. Morever, 
a neoadjuvant study in patients with HER2+ breast cancer showed that both 
alterations (PIK3CA mutations and PTEN loss) were associated with a statistically 
lower pathological complete response rate to trastuzumab with chemotherapy 
(Dave 2011). To confirm the concurrent importance of these two signals, a few 
clinical studies suggest that combined targeting of HER2 and the PI3K pathway 
may be superior to HER2-directed therapy alone (Morrow 2011;  Andrè 2010; 
Jerusalem 2011). 
Somatic mutations in the PI3K pathway may than identify cancers with aberrant 
activation of, and potential dependence on, this signaling pathway providing a 
biomarker to identify patients unlikely to respond to trastuzumab-based therapy. 
This hypotesis is however derived from retrospective series and needs to be 
prospectively 
confirmed 
in 
patients 
with 
HER2-positive 
breast 
cancer, 
homogenous for stage of disease. 
Availability of biomarkers that predict responses to cancer therapy is instrumental 
to the rational use of cancer drugs, even though translational studies based on 
tissue evaluation often suffer because of obvious methodological limitations. 
Circulating free DNA (cfDNA) has been shown to be present both in circulating 
tumor cells in blood and as fragments in the plasma of metastatic cancer patients. 
cfDNA profiles may reflect DNA status in corresponding breast cancer tissues, but 
results from clinical studies prospectively and specifically addressing these issues 
are lacking. (van der Auwera, 2009; Board 2010). Minimally invasive blood 
analyses of cell-free nucleic acid potentially allow repetitive real-time monitoring of 
events associated with treatment response and relapse and will, therefore, gain 
clinical utility in the determination of prognosis and treatment efficacy. A recent 
trial investigated the potential utility of circulating free DNA (cfDNA) as a source 
for PIK3CA mutation detection in patients with breast cancer. In the metastatic 
group, where a PIK3CA mutation was present in tumour, the 'pick up' in plasma-
derived cfDNA was 80%, even though no PIK3CA mutations were detected in 
matched cfDNA for early breast cancer cases. (Board, 2010). 
These data represents the rational for the sequential and concomitant evaluation 
of PI3KCA mutation in tissue and in plasmatic cfDNA in breast cancer patients 
receiving SC trastuzumab in combination with chemotherapy, either in the 
neadjuvant and in the adjuvant setting. 
3.8 
OUTCOME MEASURES  
3.8.1 
EFFICACY OUTCOME MEASURES 
The efficacy outcome measures of this study will be to collect data for 
subcutaneous administration of trastuzumab in the treatment of HER 2-positive 
eBC and LABC: 
 
DFS 


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 
OS 
Diagnosis of breast cancer relapse will be made based on routine clinical, 
radiological and laboratory criteria. In case of uncertainly, disease progression 
should be confirmed by histological or cytological examination of a suspicious 
lesion, if possible. 
In the Neo-adjuvant setting, the activity of two sequential drug regimens, 
Anthracycline-containing regimen followed by concomitant administration of 
Taxane and Trastuzumab SC, will be assessed as: 
 
the incidence of pathological Complete Response in breast and 
nodes (pCR) (ypT0-is ypN0). Residual in situ disease (ypTis) is 
considered as pCR. 
Laboratory data, vital signs and physical examination data may be summarized. 
3.8.2 
SAFETY OUTCOME MEASURES 
The safety outcome measures for this study are as follows: 
AEs collection will be the primary endpoint in this study. Summaries will include: 
 
Incidence and severity by NCI CTCAE version 4.0 of AEs and SAEs 
 
AEs leading to premature discontinuation of study treatment 
 
Cardiac safety 
 
● 
Cardiac AEs 
 
● 
CHF (according to NCI CTCAE version 4.0 and New York Heart  
 
 
Association [NYHA] Classification) 
● 
LVEF over time. In the event of an asymptomatic decline in LVEF, 
an  algorithm (Appendix 2 in the protocol) will be used to determine 
whether to continue trastuzumab treatment 
 
Secondary safety assessments will include the following: 
 ● 
Exposure to study medication 
 ● 
Duration of treatment, follow-up, and safety observation 
 ● 
ECOG 
 ● 
Concomitant medications 
 ● 
Laboratory data, vital signs and physical examination  
 ● 
Premature withdrawals and major protocol violations 
The primary analysis will be for all patients. In addition, clinically relevant safety 
parameters will be analyzed in patient subgroups (eBC neo-adjuvant versus eBC 
adjuvant, trastuzumab SC monotherapy versus combination with taxanes, etc). 
3.8.3 
PHYSICIAN/PATIENT-SATISFACTION OUTCOME MEASURES 
Patient Satisfaction will be assessed by Patient Satisfaction Questionnaire only 
in Cohort B (use of Trastuzumab SC SID). 


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In Cohort B, a questionnaire will be completed by patients able to use SID, who 
completed a minimum of 14 administrations of trastuzumanb SC using SID (at 
least 10 self- administered).  
Health Care Professional (HCP) satisfaction will be assessed by a Health Care 
Professional Questionnaire (HCPQ). A questionnaire will be completed by both 
the Investigator and a study nurse at each site when at least 4 patients from their 
site have received at least 5 cycles of adjuvant study treatment. (For those sites 
that recruit <4 patients the investigator and a study nurse will each complete an 
HCPQ when last patient at their site has received at least 5 cycles of adjuvant 
study treatment). 
3.8.4 
EXPLORATORY OUTCOME MEASURES 
The focus on translational study is the evaluation of PI3KCA mutations at the most 
frequent sites (Exon 9, E545K and E542K, and Exon 20, H1047R) in the tumoral 
bed togheter with its correlation with the presence of the same mutation in the 
cfDNA.  
Evaluation of PI3KCA mutation in tumor tissues and in blood will be tested in all 
patients enrolled at the following time points:  
 
Plasma samples will be drawn at baseline (after eligibility is 
confirmed, just before the first dose of anthracycline), on treatment 
pre-Cycle 5 (after first sequence comprehensive of Anthracycline) 
and on treatment pre-Cycle 9 (after second sequence comprehensive 
of Taxane and trastuzumab SC).  
 
Tissue samples will be obtained from pretreatment primary tumor 
(biopsy material, neoadjuvant group) and from surgical specimens 
(adjuvant and neoadjuvant groups) 
The analysis of PI3K mutation on tissues and on serum cfDNA, as well the 
centralized re-evaluation of HER2 positivity on tissues, will be performed for care 
of 
 
. 
The results of HER2 positivity performed centrally will not be required prior to the 
enrollment into the study. 
 
The details of biological samples collection are detailed in the Laboratory Manual. 
 
4. 
MATERIALS AND METHODS 
4.1 
TARGET POPULATION 
The target population for this study will include patients presenting for the first time 
with early or locally advanced HER2-positive breast cancer who have not received 
any previous treatment for invasive malignancy.  


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The definition of locally advanced breast cancer (LABC) for this study is the 
following: presence of skin infiltration, irrespective of tumor dimension and/or 
axillary status (clinical stage T4 N0-3), or extensive axillary involvement, 
irrespective of tumor dimension or skin infiltration (T1-4, N2-3).  
Diagnosis of invasive breast cancer must have been confirmed through a core 
biopsy. 
Furthermore, patients must have given their informed consent and must not meet 
any of the exclusion criteria detailed in Section 4.3. 
4.2 
INCLUSION CRITERIA 
Patients and partners must agree to use a barrier method of contraception during 
the treatment period and for at least 7 months after the last dose of study drug. 
Please see Section 5.4.3 for further details. 
To be eligible for the study, a patient must fulfill each of the following criteria: 
1. 
Female and male patients aged ≥ 18 years 
2. 
Signed informed consent before any specific study procedure 
3. 
Able and willing to comply with protocol 
4. 
Eastern Cooperative Oncology Group (ECOG) performance status 0–1 
5. 
HER2-positive disease immunohistochemistry (IHC)3+ or in situ 
hybridization (ISH) positive, as determined in a local laboratory that is 
experienced/certified in HER2-expression testing using an accurate and 
validated assay 
6. 
Histologically confirmed non-metastatic primary invasive adenocarcinoma 
of the breast. Stage of disease: T1-4, N0-3, M0.  
T1a-b and pTmic may be included in the presence of at least one of the 
following unfavorable prognostic factors: 
 
clinical( concomitant axillary involvement)  
and/or  
 
biological (negative hormonal receptor status and/or high tumor 
grade and/or young age and/or lymph/vascular invasion and/or 
high Ki-67)  
7. 
Left ventricular ejection fraction (LVEF) of ≥ 55% measured by 
echocardiography (ECHO) or multiple gated acquisition (MUGA) scan 
prior to  first dose of trastuzumab SC 
8. 
Availability of formalin–fixed paraffin-embedded (FFPE) tissue block or 
partial block from diagnostic core biopsy (only neoadjuvant patients) and 
from surgical specimens (both adjuvant and neoadjuvant patients), with 
representative invasive part of the tumor for additional biomarker analysis  
9. 
Intact skin at site of SC injection on the thigh 


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4.3 
EXCLUSION CRITERIA 
1. 
History of other malignancy which could affect compliance with the 
protocol or interpretation of results Patients with curatively treated 
carcinoma in situ of the cervix or basal cell carcinoma, and patients with 
other curatively treated malignancies, other than breast cancer, who have 
been disease-free for at least 5 years, are eligible 
2.  Severe dyspnea at rest or requiring supplementary oxygen therapy 
3. 
Concurrent serious diseases that may interfere with planned treatment, 
including severe pulmonary conditions/illness 
4. 
Serious cardiac illness or medical conditions that would preclude the use 
of trastuzumab, specifically: history of documented congestive heart failure 
(CHF), high-risk uncontrolled arrhythmias, angina pectoris requiring 
medication,  clinically significant valvular disease, evidence of transmural 
infarction on electrocardiogram (ECG), diagnosed poorly controlled 
hypertension 
5. 
Known infection with human immunodeficiency virus (HIV), active hepatitis 
B virus (HBV) or hepatitis C virus (HCV) 
6. 
Pregnant or lactating women. Positive serum pregnancy test in women of 
childbearing potential, premenopausal or less than 12 months of 
amenorrhea post-menopause, within 7 days prior to first administration of 
the protocol required chemotherapy treatment.  
7. 
Women of childbearing potential, premenopausal or less than 12 months 
of amenorrhea post-menopause (unless surgically sterile), and male 
patients with partners of childbearing potential who are unable or unwilling 
to use adequate contraceptive measures during study treatment. In this 
study, menopause is defined as a minimum of 12 consecutive months of 
amenorrhea during which time no other biological or physiological cause 
had been identified as a potential cause of this state. Examples of 
adequate contraceptive measures are intrauterine device, barrier method 
(condoms, diaphragm) also in conjunction with spermicidal jelly, or total 
abstinence. Oral, injectable, or implant hormonal contraceptives are not 
acceptable 
8. 
Concurrent enrolment in another clinical trial using an investigational anti-
cancer treatment, including hormonal therapy, bisphosphonate therapy 
and immunotherapy, within 28 days prior to the first dose of study 
treatment 
9. 
Known hypersensitivity to trastuzumab, murine proteins, to any of the 
excipients of Herceptin® including hyaluronidase, or the adhesive of 
 the  SC device (for cohort B), or a history of severe allergic or 
immunological reactions, e.g. difficulty to control asthma 
10. No compliance or adherence with the requirements of the protocol 
11. Inadequate bone marrow function (as indicated by any of the  following):  
d) Absolute neutrophil count (ANC) < 1,500 / mm3 (< 1.5 × 109/L) 


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e) Platelets < 100,000 / mm3 (< 100 × 109/L) 
f) Hemoglobin < 10 g/dL 
12. Impaired hepatic function (as indicated by any of the following):  
d) Serum total bilirubin > 1.5 × upper limit of normal (ULN) 
e) Alanine amino transferase (ALT) and/or aspartate amino transferase  
(AST) > 2.5 × ULN 
f) Alkaline phosphatase (ALP) > 2.5 × ULN 
13. Inadequate renal function, as indicated by serum creatinine > 1.5 × ULN 
14. Hormonal treatment concomitant with chemotherapy (allowed in adjuvant 
phase with adjuvant Trastuzumab SC.) 
15. Pre-existing motor or sensory neuropathy of Grade >1 
16. Sincronous bilateral invasive breast cancer 
4.4 
STUDY TREATMENT  
Patients in each cohort (A and B) will be allocated to one of the two treatment 
Groups, 1 (adjuvant) or 2 (neoadjuvant), according to pragmatic selection, taking 
into account the conventional clinical criteria, the physician choice and patient 
convenience. 
4.5 
TRASTUZUMAB SC DOSES AND ADMINISTRATION 
Trastuzumab will be administered subcutaneously with a fixed dose of 600 mg 
(irrespective of body weight) throughout the treatment phase q3w for 1 year 
(Cycles 1 to 18). 
Trastuzumab administration may be delayed to assess or treat AEs such as 
cardiac AEs, myelosuppression, or other events, as detailed in Table 2.  
No dose adjustment is needed in case of delayed administration of trastuzumab 
SC as a fixed (600 mg) dose of trastuzumab is given for all subcutaneous cycles 
in this study. 
Dose reductions are not permitted for toxicity. Patients who experience injection-
related symptoms may be pre-medicated with paracetamol and antihistamines for 
subsequent injections.  
Trastuzumab will be supplied as a vial for manual administration via hand-held 
syringe or SID. With either method, trastuzumab will be subcutaneously injected 
slowly over a period of up to 5 minutes. 
 
Vial: ready to use solution (600 mg trastuzumab/5mL and rHuPH20 10000 
units/5 mL) for manual administration using a hand-held syringe 
 
SID: a ready-to-use automated injection device containing 600 mg/5mL 
trastuzumab and rHuPH20 10000 units/5 mL 
 
Vial must be administered by HCP.  
SID might be administered at the hospital by HCP or by self- administration. The 
first injection will be administered by a trained HCP (physician or nurse). During 


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the first assisted administration, patients will receive a copy of the Instructions for 
Use supplied with the SID and personal instructions from a HCP on how to self-
administer the study drug. After at least one assisted trastuzumab SC injection 
using the SID, patients assessed by the investigator as competent to self-
administer the study drug using the SID will be allowed to self-administer the 
remaining trastuzumab SC doses under the direct supervision of a HCP. Patients 
not deemed competent to self-administer the study drug will have all their 
trastuzumab SC doses administered by a trained HCP (physician or nurse). 
In the event of a device failure, the complaint must be reported to the Sponsor as 
described in 5.4.4 .The device must also be returned via courier to the Sponsor for 
assessment. Supplemental dosing requirements for the patient will be assessed 
by the Investigator as per the instructions provided.  
Patients in Cohort B should receive treatment with the device as per protocol; 
however, if a patient refuses treatment, she/he will revert to manual SC 
administration of trastuzumab for all remaining cycles to complete at least 18 
cycles in total as part of the study. 
No dose modification of trastuzumab SC will be allowed in any case. 
4.6 
CHEMOTHERAPY DOSES AND ADMINISTRATION  
Chemotherapy doses will be calculated for all drugs according to the body surface 
(BSA). In calculating BSA, actual weights should be used. No downward 
adjustments to “ideal” body weight are allowed and the limit of 2.2 m2 should be 
used in the few patients who should have a larger calculation of BSA. 
Doses of chemotherapy should be modified according to the conventional criteria, 
by considering side effects intensity and frequency. 
Before starting a new treatment cycle, toxicity must have resolved, as specified in 
the following sections. 
Chemotherapy should be administered following trastuzumab SC injection, and as 
per local Product Information and the investigator’s discretion. 
Taxane based Chemotherapy and trastuzumab SC are to be given on the same 
day in a three weekly regimen. Administration of taxane or trastuzumab SC may 
need to deviate from the planned Schedule e.g. due to adverse event. If the delay 
in dosing for either drug is foreseen to be 7 days or less, then chemotherapy and 
trastuzumab should be given together on the same day. In case the dosing delay 
is more than 7 days, chemotherapy and trastuzumab administration may be 
uncoupled and given on different days as clinically indicated. However, 
chemotherapy and trastuzumab should be brought back to a common 
administration Schedule as soon as possible. 
4.7 
NEOADJUVANT CHEMOTHERAPY RECOMANDATIONS 
Before each treatment cycle, tumor dimensions (largest perpendicular diameters) 
will be carefully assessed by physical examination. 


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In the absence of disease progression the chemotherapy program must be 
continued as planned. 
Patients with evidence of local tumor progression (increase of ≥25% in the product 
of the two largest diameters) will be admitted for surgery as appropriate.  
Surgery should be performed within 3-4 weeks from the last dose, according to 
procedures defined by the local surgeon, who should take into account tumor size 
and site, breast volume, focality and patient’s attitude. 
Whenever possible, conservative surgery is preferred. 
Sentinel node biopsy (SNB) is considered an acceptable procedure only for 
patients judged to have an axillary negative nodal status (clinically and/or 
echographically and/or cytologically detected) before starting neoadjuvant 
chemotherapy. 
Lymph node axillary dissection should be performed preferentially up to the third 
level. Dissection of the first two levels could be considered. Nodal sampling and 
the dissection of the first level only cannot be accepted.  
All the patients submitted to conservative surgery will receive post-operative 
irradiation, according to standard procedures. 
Patients included into the neoadjuvant group must continue trastuzumab SC 
treatment at the Scheduled interval even in the peri-operative period (± 1 week).  
4.8 
SYSTEMIC TREATMENT AFTER ADJUVANT-NEOADJUVANT 
CHEMOTHERAPY 
Hormonal therapy in patients with ER and/or PgR-positive disease will be allowed 
only after adjuvant chemotherapy and therefore rest on the decision of the 
Participating Center. 
All the selected adjuvant hormonal therapies can be given concurrently with 
trastuzumab SC.  
With the purpose of fertility preservation, for adjuvant patients only, LH-RH 
analogous administration is allowed without any limitation.  
 
4.9 
STUDY TREATMENT - IMP 
Trastuzumab SC is the investigational medical product (IMP) in this study, 
according to local approval status and guidelines, supplied as vials and SID 
formulations. 
4.9.1 
TRASTUZUMAB SC 
The IMP in the SID and in the vials for manual injection, contains 120 mg/mL 
trastuzumab. The IMP contains 2000 units/mL rHuPH20 (manufactured in a 
Chinese hamster ovary [CHO] cell line) acting as a permeation enhancer, 
histidine/histidine-HCl(buffer), alpha, alpha-trehalosedihydrate (bulking agent), 
methionine (stabilizer), and polysorbate 20 (stabilizer/emulsifier) in water for 


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injection (WFI) at a pH of 5.5 ± 0.5. Trastuzumab SC will be provided in the 
following presentations.  
 
Ro 045-2317/F06 - Device formulation: Trastuzumab 600 mg/5 mL plus 
rHuPH20 10000 units/5 mL prefilled SID. Details for equilibration of the device 
to room temperature can be found in the separate instruction leaflet. 
 
Ro 045.2317/F07 – Vial for manual subcutaneous injection formulation: 
Trastuzumab 600 mg/5 mL plus rHuPH20 10000 units/5 mL vial.  
According to the Medical Device Directive, the drug/device combination 
isconsidered an integral medicinal product and therefore as a single IMP for this 
study.  
The recommended storage conditions are 2-8°C, protected from light. Batch-
specific details and information on shelf-life are given in the packaging label. The 
drug product must not be diluted and should be used according to the instruction 
leaflet provided separately. 
Trastuzumab will be administered subcutaneously with a fixed dose of 600 mg 
(irrespective of body weight) throughout the treatment phase q3w for 1 year. 
Trastuzumab will be supplied as a vial for manual administration via hand-held 
syringe for the first 120 patients (Cohort A) or SID, for the following 120 (Cohort B). 
With either method, trastuzumab will be subcutaneously injected slowly over a 
period of up to 5 minutes. 
Trastuzumab for subcutaneous administration will be supplied by Roche. 
Packaging of trastuzumab for subcutaneous use will be overseen by the Roche 
Clinical Trial Supplies department. Each IMP unit will bear a label with the 
identification required by local law, the protocol number, drug identification and 
dosage. The packaging and labelling of trastuzumab SC will be in accordance 
with Roche standard and local regulations.  
 
Guidelines for treatment interruption or discontinuation are reported in Table 2 . 
4.9.1.1 
FORMULATION, PACKAGING AND HANDLING 
The study drug will be manufactured and supplied by the Sponsor. Packaging of 
trastuzumab for subcutaneous use will be overseen by the Roche Clinical Trial 
Supplies department. Each IMP unit will bear a label with the identification 
required by local law, the protocol number, drug identification and dosage. 
The packaging and labelling of trastuzumab SC (vials and SID) will be in 
accordance with Roche standard and local regulations. 
The study drug must be stored according to the details on the Product Information. 
The drug label indicates the storage temperature. 
Upon arrival of investigational products at the site, site personnel should check 
them for damage and verify proper identity, quantity, integrity of seals and 


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temperature conditions, and report any deviations or product complaints to the 
Monitor upon discovery. 
For further details, see the trastuzumab Investigator’s Brochure or local 
prescribing information. 
4.9.1.2 
INVESTIGATIONAL 
MEDICINAL 
PRODUCT 
ACCOUNTABILITY 
The investigational site will acknowledge receipt of IMP, using the IxRS to confirm 
the shipment condition and content. Any damaged shipments will be replaced.  
The Investigator is responsible for the control of the drugs under investigation. 
Adequate records for the receipt (e.g. Drug Receipt Record) and disposition (e.g. 
Drug Dispensing Log) of the IMP must be maintained. Accountability and patient 
compliance will be assessed by maintaining adequate “drug dispensing” and 
return records.  
Accurate records must be kept for each IMP provided by the sponsor. These 
records must contain the following information:  
 
Documentation of IMP shipments received from the sponsor (date received, 
quantity and batch number)  
 
Disposition of unused IMP not dispensed to a patient  
 
A Drug Dispensing Log must be kept current and should contain the following 
information:  
 
Identification of the patient to whom the IMP was dispensed;  
 
The date(s), quantity and batch number of the IMP dispensed to the 
patient.  
4.9.1.3 
ASSESSMENT OF COMPLIANCE  
The Investigator is responsible for ensuring that the study drug is administered in 
compliance with the protocol. Delegation of this task must be approved by the 
investigator and clearly documented. Patient compliance will be assessed by 
maintaining adequate study drug dispensing records. All records and drug supplies 
must be available for inspection by the Roche Study Monitor at every monitoring 
visit.  
Copies of the dispensing & inventory logs will be retrieved by the Monitor at study 
end.  
4.9.1.4 
DESTRUCTION OF THE IMPs  
Used and unused IMP will be kept at the site (or designated pharmacy, depending 
on local practice) for accountability and destruction. Local or institutional 
regulations may require immediate destruction of used IMPs for safety reasons 
e.g., cytotoxicity. In these cases, it may be acceptable for the investigational site 
staff to destroy the dispensed IMP before inspection by the Monitor, provided that 
source document verification is performed on the remaining inventory and 


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reconciled against the documentation of quantity shipped, dispensed, returned 
and destroyed. Written authorization must be obtained from the Sponsor at study 
start up before destruction of unused trastuzumab SC can take place at a site.  
Written documentation of destruction must contain the following:  
 
Identity (batch numbers and patient numbers) of the IMP(s) destroyed  
 
Quantity of the IMP(s) destroyed  
 
Date of destruction (date discarded in designated hazardous container for 
destruction)  
 
Method of destruction (the site must provide the Sponsor with documentation 
of their institutional policy and procedures for handling and disposing of 
hazardous drugs)  
 
Name and signature of responsible person who discarded the IMP in a 
hazardous container for destruction 
4.9.1.5  
POST-TRIAL ACCESS TO TRASTUZUMAB SC 
Roche does not intend to provide trastuzumab SC to patients after conclusion 
of the study or any earlier patient withdrawal.  
4.10 
CONCOMITANT THERAPY 
4.10.1 
  PERMITTED THERAPIES 
Concomitant therapy includes any medication (e.g., prescription drugs, 
over-the-counter 
drugs, 
herbal/homeopathic 
remedies, 
nutritional 
supplements) used by a patient from screening to the safety follow-up visit. 
Thereafter only medication applicable for long term reporting must be 
reported, including breast cancer treatments, anticancer treatment given to 
treat a recurrence, medication related to the treatment of SAEs that are 
applicable for long-term reporting. All concomitant medications should be 
reported to the investigator and recorded on the Concomitant Medications 
electronic Case Report Form (eCRF). All protocol-allowed medications taken 
by the patient for concomitant disease(s) should be continued as necessary 
during the study and be recorded on the eCRF. 
Any medication which is necessary for the management of patients 
( antiemetic, hematopoietic growth factors, transfusions etc.) must be used at 
the discretion of the investigator and will be reported in the case report form 
(CRF). 
Concomitant medication permitted may include: 
 
Paracetamol 
(acetaminophen) 
or 
other 
analgesics, 
and 
diphenhydramine, chlorpheniramine, or other antihistamines used 
according to local clinical practice for the prevention and treatment of 
IRR associated with trastuzumab  


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 
Complementary radiotherapy concurrent with trastuzumab SC is 
consented, provided that in the Adjuvant setting it must be postponed 
at the end of chemotherapy. 
 
Adjuvant hormonal treatment after chemotherapy must be given 
concomitantly with trastuzumab SC, when indicated. 
 
With the purpose of fertility preservation, for adjuvant patients only, 
LH-RH analogous administration is allowed without any limitation  
 
Biphosphonates may be given at the investigator’s discretion, to treat 
documented osteoporosis 
 
Maintenance therapy for patients with chronic conditions, such as 
hypothyroidism, hypertension, diabetes, etc. 
4.10.2 
PROHIBITED THERAPIES 
The following treatment are not permitted: 
 
Concurrent treatment with other systemic HER2-directed immunotherapy 
 
Concurrent investigational agents of any type  
 
Hormonal treatment concomitant with neoadjuvant chemotherapy (even with 
the purpose of fertility preservation).  
 
Other chemotherapy regimens than those specified at paragraph 3.1. 
4.11 
STUDY ASSESSMENTS 
All patients must provide written informed consent before any study-specific 
assessments or procedures are performed.  
Prior to enrolment in the study, the Investigator will assess each patient with 
regards to the protocol inclusion exclusion criteria to determine his/her eligibility 
for the study. Patients must fulfill all the entry criteria for participation in the study. 
An Eligibility Screening Form documenting the Investigator’s assessment of each 
patient with regard to the protocol inclusion and exclusion criteria is to be 
completed by the Investigator. 
An Eligibility Screening Failure Log must be maintained by the Investigator. 
4.11.1  
DESCRIPTION OF STUDY ASSESSMENT 
4.11.1.1 
MANDATORY 
PROCEDURE 
FOR 
PATIENTS 
ENROLLMENT 
Once a patient has fulfilled the entry criteria, he/she will be assigned a study 
number in a consecutive order at each center. Each center will also have a center 
number assigned by the sponsor. 
A patient Enrollment and Identification Code list must be maintained by the 
Investigator. 


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All the investigation procedures must be performed within 4 weeks prior to first 
chemotherapy administration with the exception of the baseline breast cancer 
evaluation with the following timelines: 
Neoadiuvant Group. 
 
Screening radiological examinations to exclude metastatic disease do not 
need to be repeated if completed within 8 weeks prior to the first 
chemotherapy administration . 
 
Bilateral Mammography do not need to be repeated if completed within 6 
weeks prior to the first chemotherapy administration. 
 
Adiuvant Group. 
 
Screening radiological examinations to exclude metastatic disease do not 
need to be repeated if completed within 8 weeks prior to the first 
chemotherapy administration  
 
Bilateral Mammography do not need to be repeated if completed within 6 
months prior to the first chemotherapy administration 
 
For the schedule of mandatory clinical assessment please refer to Appendix 1. 
NEOADJUVANT GROUP 
Complete history and physical examination with the measure of breast nodule will 
be performed at baseline. The neoplastic nodule must be marked with a 
cutaneous tatoo or a clip located under echographic guidance.  
Bilateral mammography, with the measurement of tumor size, focality, presence 
and extension of microcacifications is required. Any additional conventional 
methods employed as per local medical practice, such as ultrasound, and Breast 
MRI are complementary, optional, imaging.  
Diagnostic core biopsy of primary tumor is mandatory. It is recommended to use a 
14-gauge needle by means of an automated device fired 3-4 times into the lesion 
to collect sufficient amount of tissue for confirmation of the presence of invasive 
malignant carcinoma, testing prognostic and predictive indicators and collect 
tumor specimens. 
Histological examination must include: 
 
Pathological diagnosis of invasive subtype and histological subtype 
 
Hormonal receptor status (ER and PgR) 
 
HER2 positivity defined as IHC 3+ or ISH positivity for HER2 cases 
scored as IHC 2+ as assessed in a local laboratory  
 
Kinetic indeces (Ki67/Mib) 
 
Tumor grade 
Radiological examinations to exclude metastatic dissemination, (at least: chest X-
ray, liver ultrasound, bone scan) must be performed. Alternative imaging 
procedures (TAC, PET) are consented according to the local guidelines.  


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A twelve lead ECG and evaluation of LVEF by multigated scintigraphic scan 
(MUGA) or echography will be performed. 
LVEF assessments should be performed by either ECHO or MUGA scan: the 
same imaging technique should be used per patient throughout the study. ECHO 
should be the method of choice for these assessments. LVEF assessment should 
be performed as per institutional practice. 
Laboratory tests providing measurement of: 
 
Hematology: hemoglobin, white blood cells and differential, absolute 
neutrophil count (ANC), platelets count. 
 
Biochemistry: serum creatinine, urea (BUN), total serum bilirubin, 
alkaline  phosphatase, ALT, AST, sodium, calcium, potassium, 
glycaemia, albumin. 
Pregnancy test for pre and perimenopausal women 
ADJUVANT GROUP 
Complete history and physical examination with the measure of breast nodule will 
be registered at baseline.  
Bilateral mammography, with the measurement of tumor size, focality, presence 
and extension of microcacifications. Breast echography and Breast MRI are 
complementary, optional imaging. 
Histological diagnosis must include: 
 
Pathological diagnosis of invasive subtype and histological subtype 
 
Hormonal receptor status (ER and PgR) 
 
HER2 positivity disease defined as IHC 3+ or ISH positivity as 
determined in a local laboratory 
 
Kinetic indeces (Ki67/Mib) 
 
Tumor grade 
 
Pathological disease extension evaluation after surgery must include: 
 
Tumor size and focality 
 
Nodal status and total examined nodes 
 
Margin status for conservatively-treated women 
 
Report of the eventual skin/ muscle infiltration 
Radiological examination to exclude metastatic dissemination, (at least: chest X-
ray, liver ultrasound, bone scan) must be performed. Alternative imaging 
procedures (TAC, PET) are consented according to the local guidelines  
A twelve lead ECG and evaluation of LVEF by multigated scintigraphic scan or 
echography 
 
Laboratory tests providing measurement of: 


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 
Hematology: hemoglobin, white blood cells and differential, absolute 
neutrophil count (ANC), platelets count. 
 
Biochemistry: serum creatinine, urea (BUN), total serum bilirubin, 
alkaline  phosphatase, ALT, AST, sodium, calcium, potassium, 
glycaemia, albumin. 
Pregnancy test for pre and perimenopausal women. 
Once a patient has fulfilled the entry criteria, he/she will be assigned a study 
number in a consecutive order at each center. Each center will also have a center 
number assigned by the sponsor. 
A patient Enrollment and Identification Code List must be maintained by the 
Investigator. 
4.11.1.1.1 
TIMING 
OF 
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.  
Please see Appendix 1 for the schedule of screening and pretreatment 
assessments. 
4.11.1.1.2 
MEDICAL HISTORY AND DEMOGRAPHIC DATA 
Medical history includes clinically significant diseases, surgeries, BC disease 
history (including ER/PgR status, current medications and symptoms), and all 
medications (e.g., prescription drugs, over-the-counter drugs, herbal/homeopathic 
remedies, nutritional supplements) used by the patient starting from the screening 
visit. The year of start and end date (when applicable) of the past and concomitant 
treatments, as well the route and dose, will be collected when available. 
Demographic data will include date of birth, gender, and self-reported ethnic origin 
if permitted by local regulations.  
4.11.1.1.3 
HER 2 STATUS 
To be eligible for the study, patients with eBC or LABC must have confirmed 
HER2- positivity as determined in a local laboratory, defined as one of the 
following: 
o A score of 3+ by ICH 
o Gene amplification positive by ISH performed by a validated and 
approved test in a certified and experienced center. 
The re-evaluation of HER2-positivity will be centralized at 
, 
. 


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The results of HER2-positivity performed centrally will not be required prior to the 
enrollment into the study. 
 
4.11.1.1.4 
VITAL SIGNS AND PHYSICAL EXAMINATION 
Vital signs assessment includes pulse, blood pressure, body weight, height, and 
body temperature. Vital signs measurements will be taken while the patient is in a 
seated position. Height is only measured at Screening. 
A general physical exam (including a general neurological exam, as clinically 
indicated) will be performed. Physical examinations will be performed according to 
local practice; however, particular attention should be given to the cardiovascular 
system.  
Any abnormality identified at Screening should be recorded on the General 
Medical History and Baseline Conditions eCRF. At subsequent visits, new or 
worsened abnormalities should be recorded as AEs on the Adverse Event eCRF. 
4.11.1.1.5 
PREGNANCY TEST 
A serum pregnancy test in women of childbearing potential will be performed 
within 7 days prior to the first dose of anthracycline. Urine pregnancy testing for 
should be repeated every 3 months for the duration of study treatment and until at 
least 7 months after the last dose of study treatment. Any positive urine pregnancy 
test needs to be confirmed by serum pregnancy test. 
4.11.1.1.6 
PAST AND CURRENT CONCOMITANT TREATMENTS  
All concomitant medications and prior treatments for BC must be reported in the 
eCRF starting at the Screening visit.  
The year of start and end date (when applicable) of the past and current 
concomitant treatments for eBC, as well as the route and dose, will be collected 
when available. 
4.11.1.1.7 
BASELINE EBC DATA  
Baseline eBC data will be collected as described in Section 4.12 
Diagnosis of BC relapse will be made based on routine clinical, radiological and 
laboratory criteria. In case of uncertainty, disease relapse should be confirmed by 
histological or cytological examination of a suspicious lesion, if possible. 


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4.11.1.1.8 
ECOG PERFORMANCE STATUS 
To be eligible for the study, patients with eBC or LABC should have ECOG PS 0–
1 according to the ECOG PS Scale (Oken et al. 1982). 
4.11.1.1.9  
MANDATORY SAMPLES FOR STUDY INCLUSION 
Tumor samples in the form of formalin-fixed paraffin-embedded tumor block or 
partial block (16 slides) and blood samples are required for study enrollment.  
Tissue samples must be obtained from:  
 
Pretreatment - primary tumor biopsy material (neoadjuvant group)  
 
surgical specimens (adjuvant and neoadjuvant groups)  
Blood samples must be obtained for all patients at three different time points:  
 
at baseline (after eligibility is confirmed, before first cycle of anthracycline – 
pre-Cycle A1 ) 
 
after first sequence comprehensive of Anthracycline (Cycles A1 -A4), 
before starting trastuzumab SC in combination with taxanes (pre-Cycle1)  
 
after second sequence comprehensive of Taxane and trastuzumab SC, 
(pre-Cycle 5) 
The modalities of tissue and blood handling and collection are detailed in the 
specific Laboratotory Manual. 
Timing of sample collection is reported in the Appendix 1.  
During the study (at timepoint decided by the Sponsor), tissues and blood 
samples must be sent to the central laboratories to perform the analysis of the 
exploratory biomarkers as well the re-evaluation of HER 2 positivity. The 
confirmation of Her2-positivity is required to be sure that the correlation of 
translational analysis and pCR  will be performed on the correct HER2-positive 
population.   
4.11.1.1.10 
OPTIONAL 
DONATION 
OF 
REMAINING 
MATERIALS AND CONSENT 
The patients will be proposed to donate the remnants of biological samples for 
future biomarker researches, to the 
. The biological 
samples will be stored in the 
 
 
 
 
 
, under the supervision and 
responsibility of the 
. 
Specimens for future biomarker research will be collected for patients who give 
specific consent to participate in this optional research to increase knowledge and 
understanding of disease biology. 
A specific Informed Consent Form will be provided and the investigator will 
document in the e-CRF whether or not the patient has given consent to donate the 
sample. 


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4.11.1.1.11 
BASELINE SAFETY DATA 
Baseline safety data will be collected as described in section 4.12. Baseline safety 
data include: AEs and SAEs, cardiac safety (standard 12-lead ECG and LVEF 
assessments, hematology and biochemistry and concomitant medication. 
4.12 
CLINICAL ASSESSMENT DURING TREATMENT PERIOD 
All patients will be closely monitored for safety and tolerability during all cycles of 
therapy. 
Patients should be assessed for toxicity prior to each dose. 
4.12.1  
TIMING OF ASSESSMENT DURING TREATMENT 
Please see Appendix 1 for the Schedule of assessments performed during the 
treatment period. 
Scheduled study visits are based on a 21-day cycle. All visits must occur within ± 
5 business days from the Scheduled date. 
4.12.2  
EFFICACY CLINICAL ASSESSMENT  
Clinical efficacy assessments and procedures described below will be performed. 
For the schedule of mandatory efficacy assessments please refer to Appendix1 
4.12.3  
TUMOR AND RESPONSE EVALUATIONS: BREAST 
CANCER FOLLOW-UP 
pCR is the secondary efficacy endpoint for Neo-adjuvant patients in this study. 
Mammography, with the measurement of residual tumor size, focality,  presence 
and extension of microcacifications must be repeated for patients included into the 
neoadjuvant group at the end of treatment, i.e before surgery. For this Group, the 
intermediate mammography after Anthracycline-containing sequence is optional, 
but it is recommended. Ultrasound or MRI are optional. 
DFS is a secondary efficacy endpoint for patients with eBC and LABC in this 
study. DFS is defined as time from the date of first treatment to the date of local, 
regional or distant recurrence, contralateral BC or death due to any cause. 
Diagnosis of relapse will be made based on routine clinical, radiological and 
laboratory criteria as described in Appendix 1. Acceptable methods of 
confirmation of recurrence include radiology, CT scan, brain scan, ultrasound or 
cytology, as per local practice. In case of uncertainly, disease relapse should be 
confirmed by histological or cytological examination of suspicious lesion, if 
possible. 
In case of a suspicious recurrence that leads to death quite quickly without having 
the possibility to confirm relapse of disease, effort should be made to obtain an 
autopsy report. 
 
4.12.4   ECOG PERFORMANCE STATUS 


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Performance Status will be evaluated using the ECOG performance Status Scale 
(Oken et al. 1982). 
 
4.12.5   
SAFETY CLINICAL ASSESSMENTS  
The following clinical safety assessments and procedures will be performed. For 
the schedule of safety mandatory assessments please refer to Appendix 1. For full 
details of safety assessments please refer to section 5.1 
 
4.12.5.1 
ADVERSE EVENTS 
The National Cancer Institute (NCI) Common terminology for Adverse Events 
(CTCAE) version 4.0 will be used to evaluate the clinical safety of the treatment in 
this study. In addition, symptomatic left ventricular dysfunction will be graded 
according to NYHA classification. 
In addition, SAEs occurring during the study will be reported to the Sponsor 
within 24 hours of the investigator becoming aware of them. 
For other instruction on documenting and handling AEs please refer to Appendix 1 
and Section 5.3 
 
4.12.5.2 
VITAL SIGN AND PHYSICAL EXAMINATION 
At each cycle, vital signs assessment includes pulse, blood pressure, body weight, 
height, and body temperature. Vital signs measurements will be taken while the 
patient is in a seated position. Starting from Cycle 1 blood pressure should be 
measured pre- and post- trastuzumab administration. 
A general physical exam (including a general neurological exam, as clinically 
indicated) will be performed. Physical examinations will be performed according to 
local practice; however, particular attention should be given to the cardiovascular 
system.  
New or worsened abnormalities should be recorded as AEs on the Adverse Event 
eCRF. 
 
4.12.5.3 
 
ELECTROCARDIOGRAMS 
A standard 12-lead ECG needs to be performed as specified in Appendix 1, 
Schedule of Assessment 
 
4.12.3.5.4  
LVEF 
LVEF assessments should be performed by ECHO or MUGA Scan within 28 days 
prior to the first trastuzumab SC administration to be eligible for participation in the 
study and during treatment with trastuzumab SC at Cycles 1, 5, 9, 13 and 17, at 
safety follow up visit and every 6 months later: the same imaging technique 
should be used per patient throughout the study. ECHO should be the method of 


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choice for these assessments. LVEF assessment should be performed as per 
institutional practice 
Symptomatic left ventricular dysfunction (congestive heart failure) will be graded 
according to NCI-CTCAE version 4.0 and the New York Heart Association 
functional classification. Any patient who develops clinical signs and symptoms 
suggesting CHF, with the diagnosis confirmed by a suggestive chest X-ray and a 
drop in LVEF by ECHO or MUGA will be discontinued from the study medication. 
CHF should be treated and monitor according to standard medical practice. The 
incidence of CHF will also be recorded through the study 
 
4.12.5.5 
 
CONCOMITANT MEDICATION 
All concomitant medication must be reported in the eCRF starting at the 
Screening visit. These include: 
 
Date and extend of primary surgery 
 
Any loco-regional radiation therapy ( extent or volume and total dose) 
 
Any hormonal therapy and/or surgical and radiation-induced ovarian 
ablation and drug induced ovarian suppression (type, drug name, dose 
and schedule, anticipated duration of therapy) 
 
Bisphosphonate therapy 
 
Any additional medication that is necessary for the management of the 
patient may be used at the discretion of the investigator 
All concomitant medications are to be reported until the Safety Follow-up visit. 
Thereafter, only medication applicable for long-term reporting must be reported, 
including: 
 
Breast cancer treatment (e.g., hormonal therapy) 
 
Anti-cancer treatments given to treat a recurrence 
 
Medications related to the treatment of SAEs that are applicable for long-
term reporting (e.g.,treatment of heart failure) 
 
4.12.6   
LABORATORY ASSESSMENT 
Local laboratory assessments scheduled at day 1 of all cycles must be performed 
within 72 hours prior to study treatment administration. Normal ranges for the 
study laboratory parameters must be supplied to the Sponsor before the study 
starts. 
For the schedule of mandatory laboratory assessments please refere to Appendix 
1. 
 
4.12.6.1 
HEMATOLOGY AND BIOCHEMISTRY  
Hematology test including hemoglobin, white blood cells and differential, ANC, 
platelets count have to be performed at every cycle during chemotherapy, every 4 


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cycles during administration of trastuzumab SC alone and 4 weeks after last study 
treatment. 
Biochemistry test including serum creatinine, urea (BUN), total bilirubin, alkaline 
phosphatase, ALT, AST, sodium, calcium, potassium, glycaemia albumin have to 
be performed at every cycle during chemotherapy, every 4 cycles during 
administration of trastuzumab SC alone and 4 weeks after last study treatment. 
All hematology and blood chemistry laboratory tests will be completed at local 
laboratories. 
4.12.6.2 
PREGNANCY TEST    
Urine pregnancy testing should be completed as clinically indicated for the 
duration of study treatment every 3 months (cycle 1, cycle 5, cycle 9, cycle 13, 
cycle 17). Additional pregnancy testing should be completed as clinically indicated 
for the duration of the study and until at least 7 months after the last dose of study 
treatment. Any positive urine pregnancy test needs to be confirmed by serum 
pregnancy test.  
4.13 
CLINICAL ASSESSMENTS AT THE SAFETY FOLLOW UP  
 
 
VISIT 
Patients who complete the treatment or discontinue from the study early will be 
asked to return to the clinic 28 days after the last dose of study drug for a safety 
follow-up visit. 
The clinical assessments to be performed at the safety follow-up visit are identical 
to the assessments during the treatment period except that no treatment drug will 
be administered. 
Please see Appendix1 for the schedule of assessments performed at the safety 
follow-up visit. 
4.14 CLINICAL ASSESSMENTS IN FOLLOW UP VISITS 
All patients must be followed for 24 months after the last patient has received 
his/her last study treatment, according to the Schedule of assessments as 
outlined in the Appendix 1. 
Cardiac assessment at 6, 12, 18 and 24 months ( ± 2  weeks) following treatment 
cessation will be performed. At these visits, concomitant medication will be 
recorded, routine breast cancer follow-up will be performed. After the safety 
follow-up visit, AEs should be collected as outlined in section 5.5 and 5.6. 
Please see Appendix1 for the schedule of assessments performed in the follow-up 
visit. 
Conventional clinical and instrumental tests for breast cancer follow up are based 
on standard guidelines and local policies and they are not considered as study 
procedures. 
After the follow-up visits, patients will be switched to standard treatment, 
according to Investigator’s choice and continue follow-up as recommended in 


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routine clinical practice (every 6 months to evaluate disease progression and 
cardiac function).  
 
4.15 
FOLLOW-UP ASSESSMENTS 
After the safety follow-up visit, AEs should be reported as outlined in section 5.5 
and 5.6. 
Please see Appendix1 for the schedule of Follow-up assessments.  
 
4.16 
ASSESSMENTS OF UNPLANNED VISITS 
Assessment other than those specified in Appendix 1, Schedule of Assessment, 
may be performed, as clinically indicated and need to be adequately documented. 
4.17 
PATIENT AND HCP SATISFACTION OUTCOMES 
Patient Satisfaction will be assessed by Patient Satisfaction Questionnaire 
(Appendix 5) in Cohort B only. 
In Cohort B, a questionnaire will be completed by patients able to use SID, who         
completed a minimum of 14 administrations of trastuzumanb SC using SID (at   
least 10 self- administered).  
Health Care Professional (HCP) satisfaction will be assessed by a Health Care 
Professional Questionnaire (HCPQ). A questionnaire will be completed by both 
the investigator and a study nurse at each site when at least 4 patients from their 
site have received at least 5 cycles of adjuvant study treatment. (For those sites 
that recruit <4 patients the Investigator and a study nurse will each complete an 
HCPQ when last patient at their site has received at least 5 cycles of adjuvant 
study treatment). 
4.18 
PATIENT, STUDY, AND SITE DISCONTINUATION 
4.18.1     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.  
4.18.1.1 
DISCONTINUATION FROM STUDY DRUG 
Patients must discontinue study drug if any of the following: 
 
Changes in LVEF (see Appendix 2) 
 
Pregnancy: a patient must be instructed to stop taking the test “drug” and 
immediately inform the Investigator if she becomes pregnant during the study. 
Other reasons for drug discontinuation are: 
 
Patient withdrawal of consent at any time 


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 
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 
 
Patient non-compliance, specifically defined as non-compliance with the study 
procedures, the Schedule of assessments or protocol-defined timelines 
Patients who discontinue study drug prematurely will be asked to return to the 
clinic for a safety follow-up visit (see Section 4.13) and has to undergo follow-up 
assessments (see Section 4.14). 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. 
4.18.1.2 
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. 
4.18.2 
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 the following: 
 
The incidence or severity of AEs in this or other studies indicates a potential 
health hazard to patients. 
 
Patient enrollment is unsatisfactory. 
The Sponsor will notify the Investigator if the study is placed on hold, or if the 
Sponsor decides to discontinue the study or development program.  
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 International Conference on Harmonization (ICH) 
guideline for Good Clinical Practice 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
During the combination treatment, if any of the individual study medications must 
be delayed for 1 day or more, the trastuzumab should be delayed according to 


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details reported insection 4.6. Trastuzumab will be administered subcutaneously 
at a fixed dose of 600 mg regardless of body weight.  
5.1.1 
GENERAL SAFETY ASSESSMENTS 
Patients will be assessed by prior medical history, vital signs (including blood 
pressure, heart rate, temperature), weight and height (Screening only), physical 
examination, AEs and concomitant medications. A complete medical history 
(including demographic profile and prior treatments for cancer) will be 
documented at Screening. 
A general physical exam (including general neurological exam, as clinically 
indicated) will be performed at screening, every cycle during trastuzumab SC 
treatment, at the post-treatment safety follow-up visit and subsequently according 
to the ASCO 2006 Guideline for Breast Cancer Follow-up in the adjuvant setting 
(Khatcheressian et al. 2006) during the follow-up period (see Appendix 1, 
Schedule of assessment). During physical examination, particular attention should 
be given to the cardiovascular system.  
Apart from physical exams, subcutaneous injection sites will be checked at every 
visit and blood pressure will be measured before and after trastuzumab SC 
administration every cycle, as specified in Appendix 1, Schedule of Assessments. 
AEs will be monitored and documented continuously during study (at each 3-
weekly treatment visit and during the post-treatment follow-up, as detailed in 
Section 5.3.1). Serious adverse events (SAEs) will also be monitored, 
documented and reported; refer to Sections 5.4.2 and 5.5 for details on SAE 
reporting and follow-up requirements, respectively. All AEs and SAEs (including 
patients’ symptoms and signs of toxicity and clinically significant hematological 
and biochemical parameters) will be graded according to National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
Changes in concomitant medication will be recorded at each study visit. 
Trastuzumab will be given as specified in Section 4.5 
Before starting a new treatment cycle, toxicity must have resolved as specified in 
the following sections. 
Trastuzumab SC administration may be delayed to assess or treat AEs such as 
cardiac AEs, myelosuppression, or other events. No dose reduction will be 
allowed for trastuzumab SC administration. 
5.1.2 
CARDIAC SAFETY ASSESSMENTS 
Cardiac function will be evaluated regularly throughout the study, by measuring 
LVEF using echocardiography or MUGA Scan (method selected according to local 
practice), ECG, and assessment of cardiac signs and symptoms.  
For eBC patients and LABC, cardiac safety assessments will be performed at 
Screening, approximately 3-monthly during trastuzumab SC treatment (at Cycle 1, 
Cycle 5, Cycle 9, Cycle 13 and Cycle 17; with the results available prior to 
trastuzumab administration), at the Safety Follow-up visit (LVEF assessment may 


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occur prior to the day of the Safety Follow-up visit if clinically indicated) and then 
at 6, 12 and 24 months after treatment cessation and immediately as per Section 
5.1.3 in case of cardiac failure; see Appendix 1, Schedule of Assessments. 
5.1.2.1 
LVEF ASSESSMENT 
The Screening LVEF assessment should be performed within 28 days, prior to the 
first Anthracycline containing regimens administration. To be eligible for 
participation in this study, patients must have a baseline LVEF ≥ 55%.The method 
of assessment (ECHO or MUGA,) is at the Investigator’s discretion; however, to 
the extent possible, the same imaging technique is to be used for each patient 
throughout the study. The LVEF assessment will be repeted prior to the first 
trastuzumab SC administration (C1) and subsequently every tree cycles. The 
results must be available before/on the day of the next Scheduled trastuzumab 
administration, and, should a reduction in LVEF be noticed compared to the pre-
trastuzumab treatment start (C1), a decision to give or hold that dose must be 
made based on the algorithm provided in Appendix 2. In addition, any patient who 
develops clinical signs or symptoms suspicious of cardiac failure at any time 
during the study should undergo an LVEF assessment immediately.  
Of note, if MUGA Scans are chosen, Investigators must be aware that there may 
be local guidelines which govern how many MUGA Scans (or the amount of 
irradiation) a patient is allowed to have in a year, and must ensure that patients 
are able to adhere to the cardiac assessment Schedule as outlined in Appendix1. 
In case additional LVEF assessments become necessary for the medical 
management of a patient, the Investigator may use echocardiography instead of a 
MUGA scan to remain within the locally accepted amount of irradiation.  
Symptomatic left ventricular dysfunction (congestive heart failure) will be graded 
according to NCI-CTCAE version 4.0 and the New York Heart Association (NYHA) 
functional classification (see Appendix 4). 
5.1.3 
MANAGEMENT OF SPECIFIC AES 
Cardiac safety will be monitored throughout the study, as described in Section 
5.1.2. In addition to the Scheduled assessments, any patient who develops clinical 
signs or symptoms suspicious of cardiac failure at any time during the study 
should undergo an LVEF assessment immediately. Patients whose LVEF falls ≥ 
10 percentage points from the value recorded before starting trastuzumab 
treatment (C1) and to a LVEF< 55% may require temporary or permanent 
cessation 
of 
trastuzumab 
in 
accordance 
with 
the 
treatment 
continuation/discontinuation algorithm shown in APPENDIX 2. A repeat LVEF 
assessment should be performed approximately 3 weeks later. If the LVEF has 
not improved or has declined further, trastuzumab should be discontinued. All 
such patients should be referred for assessment by a cardiologist and followed up. 
Trastuzumab should also be discontinued in any patient who develops clinically 
significant heart failure. 


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5.1.4 
MANAGEMENT OF SPECIFIC ADVERSE EVENTS 
5.1.4.1 
DOSE MODIFICATIONS, INTERRUPTIONS AND DELAYS 
FOR TRASTUZUMAB 
Administration of trastuzumab SC may be delayed to assess or treat AEs, as 
detailed in Table 2.  
Table 2 Action to be Taken in Case of Trastuzumab-Related Toxicity 
 
Toxicity related to trastuzumab study 
treatment 
Action  
pertaining to trastuzumab SC*  
 
1. 
Non-hematological, grade 1 or 2 
(excluding cardiac) toxicity 
Continue trastuzumab SC therapy 
2. 
Non-hematological, grade 3 or 4 
(excluding cardiac) toxicity and 
toxicity resolved within a maximum of 
5 weeks calculated from last planned 
administration 
Hold trastuzumab SC therapy until recovery to 
grade ≤ 2.  
 
3. 
Non-hematological, grade 3 or 4 
(excluding cardiac), toxicity NOT 
resolved to grade <2 or disappeared 
within a maximum of 5 weeks 
calculated from last planned 
administration 
Discontinue trastuzumab SC permanently.  
4. 
Recurrence of non-hematological 
grade 3 or 4 (excluding cardiac) 
toxicity upon re-challenge  
Discontinue trastuzumab SC permanently.  
5. 
Cardiac toxicity: asymptomatic drop 
in LVEF ≥ 10 percentage points from 
Screening and to a LVEF <55%  
Trastuzumab SC therapy to be held, 
continued or resumed according to the 
algorithm depicted in appendix 2.  
6. 
Cardiac toxicity: symptomatic CHF 
Discontinue trastuzumab SC permanently. 
7. 
Cardiac toxicity: other than significant 
asymptomatic LVEF drop or CHF 
Actions must follow rules 1 to 3 for non-
hematological toxicities 
8. 
Hematological toxicity  
Trastuzumab needs not to be withheld for 
hematological toxicity 
* Concurrent anti-cancer/endocrine therapy (as applicable) may continue at the 
Investigator’s discretion. 
 
If the patient misses a dose of trastuzumab SC, then the usual maintenance dose 
should be given as soon as possible, with subsequent maintenance doses given 
q3w. No dose adjustment is needed in case of delayed administration of 


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trastuzumab SC as a fixed (600 mg) dose of trastuzumab is given for all 
subcutaneous cycles in this study. 
Dose reductions are not permitted for toxicity. Patients who experience infusion-
related or injection-related symptoms may be pre-medicated with paracetamol and 
antihistamines for subsequent infusions/injections.  
In the event of a device failure, the complaint must be reported to the Sponsor as 
described in 5.4.4. The device must also be returned via courier to the Sponsor for 
assessment. Supplemental dosing requirements for the patient will be assessed 
by the Investigator as per the instructions provided.  
Patients should receive treatment with the device as per protocol; however, if a 
patient refuses the patient will revert to trastuzumab SC vial for all remaining 
cycles to complete at least 18 cycles in total as part of the study. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, including SAEs; 
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. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
ADVERSE EVENTS 
According to the ICH guideline for Good Clinical Practice, an AE is any untoward 
medical 
occurrence 
in 
a 
clinical 
investigation 
subject 
administered a 
pharmaceutical product, regardless of causal attribution. An AE 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), except as described 
in Section 5.3.5.9 
 
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 
 
AEs 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) 


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5.2.2 
SERIOUS ADVERSE EVENTS (IMMEDIATELY REPORTABLE 
TO THE SPONSOR) 
An SAE is any AE that meets any of the following criteria: 
 
Fatal (i.e., the AE actually causes or leads to death) 
 
Life threatening (i.e., the AE, in the view of the Investigator, places the patient 
at immediate risk of death) 
This refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event which hypothetically 
might have caused death if it was more severe 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10) 
 
Results in persistent or significant disability/incapacity (i.e., the AE 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 
 
Significant medical event in the Investigators’ 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 AE (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 AE 
recorded on the eCRF. 
Serious AEs are required to be reported by the Investigator to the Sponsor within 
24 hours after learning of the event (see Section 5.4.2 for reporting instructions). 
 
5.2.3 
PREGNANCY AND CONTRACEPTION 
For patients of childbearing potential and women < 1 year after the onset of 
menopause, appropriate contraceptive measures are mandatory during study 
treatment. Examples of adequate contraceptive measures are intrauterine device, 
barrier method (condoms, diaphragm) also in conjunction with spermicidal jelly, or 
total abstinence. Oral, injectable, or implant hormonal contraceptives are not 
acceptable. 
Based on PK considerations, contraceptive measures are recommended for at 
least 7 months following the last dose of trastuzumab. 
A patient must be instructed to stop taking the test “drug” and immediately inform 
the Investigator if she becomes pregnant during the study. The Investigator should 
report all pregnancies within 24 hours to the Sponsor, using the paper Clinical 
Trial Pregnancy Reporting Form, [gcp_for000023]. The Investigator should 


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counsel the patient, discuss the risks of continuing with the pregnancy, and the 
possible effects on the fetus. Monitoring of the patient should continue until 
conclusion of the pregnancy.  
Pregnancies occurring up to 7 months after the completion of trastuzumab must 
also be reported to the Investigator. 
For male patients with a female partner of childbearing potential, cooperation of 
female partner in accepting the contraceptive methods listed above is required  
during the study and for at least 7 months following the last dose of study 
treatment.  
Due to potential dual risk of embryo-fetal toxicity (such as oligohydramnios) 
resulting from systemic exposure to rHuPH20 and trastuzumab, the need for strict 
adherence to the guidance on contraceptive usage should be reinforced. Should a 
woman become pregnant during the active treatment phase of a subcutaneous 
trastuzumab trial her participation should be ended. Should a woman choose to 
continue with both the pregnancy and trastuzumab treatment, a multi-disciplinary 
team should closely follow her. There is no evidence to suggest that male 
exposure to rHuPH20 poses a risk to the developing foetus. 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The Investigator is responsible for ensuring that all AEs (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor 
in accordance with instructions provided in this section and in Sections 5.45.6. 
The Investigator is also responsible for reporting medical device complaints (see 
Section 5.4.4). 
For each AE recorded on the Adverse Event eCRF, the Investigator will make an 
assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1 
ADVERSE EVENT REPORTING PERIOD 
Investigators will seek information on AEs at each patient contact. All AEs, 
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 SAEs caused by a protocol-mandated intervention should be reported (e.g., 
SAEs related to invasive procedures such as biopsies). 
After initiation of study drug, all SAEs/AEs, regardless of relationship to study 
drug, will be reported until study closure. After this period, the Investigator should 
report any deaths and serious adverse events. The Investigator is not required to 
actively monitor patients after the study has ended (see Section 5.6).  
Symptomatic congestive heart failure must be reported irrespective of causal 
relationship during the full course of the study, even if the patient starts a new 
anticancer regimen.  


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5.3.2 
ELICITING ADVERSE EVENT INFORMATION 
A consistent methodology of non-directive questioning should be adopted for 
eliciting AE information at all patient evaluation timepoints. 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?”  
5.3.3 
ASSESSMENT OF SEVERITY OF ADVERSE EVENTS 
The AE severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing AE severity. Table 3 will be used for assessing severity for AEs that are 
not specifically listed in the NCI CTCAE. 
Table 3 Assessment of AE Severity 
CTC Grade  
Equivalent To:  
Definition  
Grade 1  
Mild  
Mild; asymptomatic or mild 
symptoms; 
clinical 
or 
diagnostic observations only; 
or intervention not indicated  
Grade 2  
Moderate  
Moderate; minimal, local, or 
non-invasive 
intervention 
indicated; or limiting age-
appropriate 
instrumental 
activities of daily living a  
Grade 3  
Severe  
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  
Grade 4  
Life threatening  
Life-threatening 
consequences 
or 
urgent 
intervention indicated d  
Grade 5  
Death  
Death related to adverse 
event d  


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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 (see 
Section 5.4.2 for reporting instructions), per the definition of SAE in Section 5.2.2.  
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for reporting instructions), 
per the definition of serious adverse event in Section 5.2.2.  
 
5.3.4 
ASSESSMENT OF CASUALITY 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 AE 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 
 
For patients receiving combination therapy, causality will be assessed individually 
for each protocol-mandated therapy. 
5.3.5 
PROCEDURES FOR RECORDING ADVERSE EVENTS 
Investigators should use correct medical terminology/concepts when recording 
AEs on the Adverse Event eCRF. Avoid colloquialisms and abbreviations. 
Only one AE term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS 
For all AEs 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 the Adverse Event eCRF. If a diagnosis is subsequently 
established, all previously reported AEs based on signs and symptoms should be 


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nullified and replaced by one AE 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, AEs 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 AEs 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 AEs 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. 
5.3.5.3 
PERSISTENT OR RECURRENT ADVERSE EVENTS 
A persistent AE is one that extends continuously, without resolution, between 
patient evaluation timepoints. 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. 


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A recurrent AE is one that resolves between patient evaluation timepoints and 
subsequently recurs. Each recurrence of an AE should be recorded separately on 
the Adverse Event eCRF. 
5.3.5.4 
ABNORMAL LABORATORY VALUES 
Not every laboratory abnormality qualifies as an AE. A laboratory test result 
should be reported as an AE 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 AE. 
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 AE. For example, 
an elevated serum potassium level of 7.0 mEq/L should be recorded as 
“hyperkalemia.” 
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 AE. A vital sign result should be 
reported as an AE 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 


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 
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 AE. 
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 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 
(see Section 5.3.5.1) and reported to the Sponsor within 24 hours after learning of 
the event, either as an SAE or a non-serious AE of special interest (see Section 
5.4.2). 
5.3.5.7 
DEATHS 
Deaths that occur before study closure regardless of relationship to study drug, 
must be recorded on the Adverse Event eCRF (as an outcome) and immediately 
reported to the Sponsor (see Section 5.4.2). This includes death attributed to 
progression of BC. For deaths occurring after this period, please refer to Section 
5.6. 
A local Steering committee will monitor the frequency of deaths from all causes.  
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 


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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 eBC 
should be recorded only on the Survival 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 AE 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”). 
5.3.5.9 
LACK OF EFFICACY OR WORSENING OF THE UNDERLYING 
CONDITION 
Medical occurrences or symptoms of deterioration that are anticipated as part of 
the patient’s underlying BC should be recorded as an adverse event if judged by 
the Investigator to have unexpectedly worsened in severity or frequency or 
changed in nature at any time during the study. When recording an unanticipated 
worsening of BC on the Adverse Event eCRF, it is important to convey the 
concept that the condition has changed by including applicable descriptors (e.g., 
“accelerated BC”). 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as AEs. These data will be captured as 
efficacy assessment data only 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 AE. 
5.3.5.10 
HOSPITALIZATION OR PROLONGED HOSPITALIZATION 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE (per the definition of SAE in Section 5.2.2), 
except as outlined below.  
The following hospitalization scenarios are not considered to be SAEs: 
 
Hospitalization for respite care 


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 
Planned hospitalization required by the protocol (e.g., for study drug 
administration or insertion of access device for chemotherapy 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 AE 
 
Hospitalization due solely to progression of the underlying cancer 
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 AE 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.  
All AEs associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF. If the associated AE fulfills 
serious criteria, the event should be reported to the Sponsor within 24 hours after 
learning of the event (see Section 5.4.2). 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
The Investigator must report the following events to the Sponsor within 24 hours 
after learning of the event, regardless of relationship to study drug: 
 
SAEs 
 
Pregnancies 
 
Device complaints  
 
Suspected Transmission of Infectious Agents via a Medicinal Product 
(STIAMP) 
 
The Investigator must report new significant follow-up information for these events 
to the Sponsor within 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 
 


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Investigators must also comply with local requirements for reporting SAEs to the 
local health authority and IRB/EC. 
All SAEs regardless of the relationship to the study drug or the time elapsed from 
the last study drug administration even if the study has been closed, MUST be 
collected and reported. All participating Investigators and the respective 
independent Ethics Committees (ECs) will be notified of all Suspected 
Unexpected Serious Adverse Reactions (SUSARs) that are reported during the 
study. An AE only qualifies as a SUSAR when all of the following conditions are 
met:  
 
The event is serious (SAE);  
 
The event is deemed related to the study drug, according to the criteria 
provided in Section 5.3.4. (Note: any suspicion of a causal relationship should 
lead to an assessment of ‘related’);  
 
When assessed against the known safety profile of trastuzumab SC (as 
described in the IB), the event is considered unexpected (not foreseen in the 
IB).  
When all patients at a particular site are off treatment as defined by the protocol:  
 
Individual SUSAR reports originating in that particular trial will be forwarded to 
all participating Investigators and the IECs associated with their sites, on an 
expedited basis;  
 
Individual SUSARs considered to be a significant safety issue and/or which 
result in Roche recommending a change to the Informed Consent Form (ICF), 
will be reported in an expedited manner to all Investigators and reviewing 
IECs;  
 
SUSAR reports originating from other trials using the same IMP will be 
provided as six-monthly SUSAR Reports (SSRs) to all Investigators and IECs 
where long-term follow-up studies are carried out.  
5.4.1 
EMERGENCY MEDICAL CONTACTS 
MEDICAL 
MONITOR 
(ROCHE 
MEDICAL 
RESPONSIBLE) 
CONTACT 
INFORMATION  
 
The Investigators involved in the study will receive a toll-free number for an 
Emergency Medical Call Centre to be used for study related medical 
emergencies.  This number is intended to be used for emergencies outside the 
normal working hours or when the regular medical contact for the study cannot be 
reached.  
The Call Centre is manned 24 hours a day/7 days per week/52 weeks per year by 
an outside vendor, who will access the appointed Medical Responsible (MR) for 
each ongoing study directly from a Roche portal (GCP Resource Center, 24-hr 
Medical 
Emergency 
Physicians 
Contact, 


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http://gcpcenter.roche.com/synergy/portal/view/pdq-spi/gcpcenter/34-
64711453/).  
The people at the Call Centre are not medically trained and will not provide any 
medical information; rather, they will contact the Medical Responsible (Duty 
Doctor) at 
, and connect them to the investigator.  
For each study, several MR are appointed providing a robust escalation matrix.   
5.4.2 
REPORTING REQUIREMENTS FOR SERIOUS ADVERSE 
EVENTS  
For reports of SAEs, Investigators should report to Roche all case details that can 
be gathered, within 24 hours after learning, completing the paper SAE Reporting 
Form and faxing it to the SAE Responsible, using the fax numbers reported into 
the SAE Cover Sheet which is to be faxed along with SAE report form. 
All information concerning the SAEs should also be reported into e-CRF. 
5.4.3 
REPORTING REQUIREMENTS FOR PREGNANCIES 
5.4.3.1 
 PREGNANCIES IN FEMALE PATIENTS 
For women of childbearing potential (defined as pre-menopausal, less than one 
year after the onset of menopause or not surgically sterilized), appropriate 
contraceptive measures are mandatory during study treatment (see Section 5.2.3). 
Based on PK considerations, contraceptive measures are recommended for at 
least 7 months following the last dose of trastuzumab. 
Female patients of childbearing potential will be instructed to immediately inform 
the Investigator if they become pregnant during the study or within 7 months after 
the last dose of study drug. A paper Pregnancy Report Form should be completed 
and faxed to SAE Responsible within 24 hours after learning, using the fax 
numbers reported into the Pregnancy Cover Sheet which is to be faxed along with 
SAE report form. The Investigator should discontinue study drug and counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the fetus. 
Monitoring of the patient should continue until conclusion of the pregnancy. 
5.4.3.2 
PREGNANCIES IN FEMALE PARTNERS OF MALE PATIENTS 
Male patients will be instructed through the Informed Consent Form to 
immediately inform the Investigator if their partner becomes pregnant during the 
study or within 7 months after the last dose of study drug. A paper Pregnancy 
Report worksheet should be completed and faxed to SAE Responsible within 24 
hours after learning, using the fax numbers reported into the Pregnancy Cover 
Sheet which is to be faxed along with SAE report form. Attempts should be made 
to collect and report details of the course and outcome of any pregnancy in the 
partner of a male patient exposed to study drug. The pregnant partner will need to 
sign an Authorization for Use and Disclosure of Pregnancy Health Information to 
allow for follow-up on her pregnancy. Once the authorization has been signed, the 
Investigator will update the Pregnancy Report with additional information on the 


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course and outcome of the pregnancy. An Investigator who is contacted by the 
male patient or his pregnant partner may provide information on the risks of the 
pregnancy and the possible effects on the fetus, to support an informed decision 
in cooperation with the treating physician and/or obstetrician. 
5.4.3.3 
ABORTIONS 
Any spontaneous abortion should be classified as a SAE (as the Sponsor 
considers spontaneous abortions to be medically significant events), recorded on 
the paper SAE Reporting Form, and reported to the SAE Responsible within 24 
hours after learning of the event (see Section 5.4.2).  
5.4.3.4 
CONGENITAL ANOMALIES/BIRTH DEFECTS 
Any congenital anomaly/birth defect in a child born to a female patient or female 
partner of a male patient exposed to study drug should be classified as a SAE, 
recorded on the paper SAE Reporting Form, and reported to the SAE Responsible 
within 24 hours after learning of the event (see Section 5.4.2). 
5.4.4 
REPORTING 
REQUIREMENTS 
FOR 
MEDICAL 
DEVICE 
COMPLAINTS 
The Investigator must report all medical device complaints to the SAE 
Responsible. The Investigator should document as much information as possible 
on an e-mail to be sent to the SAE responsible, including the product batch 
number and expiration date. If the medical device complaint results in an adverse 
event, the paper Medical Device (MD) Complaint Form must be completed and 
reported to SAE Responsible within 24 hours after learning of the event. The 
adverse event must be reported on the Adverse Event eCRF. If the event is 
serious, beside the e-mail a SAE form should be faxed to Safety Responsible 
within 24 hours after learning of the event, as outlined in Section 5.4.2. 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
INVESTIGATOR FOLLOW-UP 
 
The Investigator should follow each AE 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 SAEs until a final outcome can be reported. 
During the study period, resolution of AEs (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. If the EDC system is not available at the time of pregnancy outcome, 
follow reporting instructions provided in Section 5.4.3.1. 


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After the 28 day period following the last dose of trastuzumab in an individual 
patient, AE follow-up will continue as follows:  
RELATED AEs AND SAEs will be followed until one of the following occurs:  
 
Resolved or improved to baseline state  
 
Investigator confirms that no further improvement can be expected  
 
Start of a new anti-cancer regimen  
 
Death  
UNRELATED SEVERE OR LIFE THREATENING AEs AND SAEs will be 
followed until one of the following occurs:  
 
Resolved or improved to baseline state  
 
Severity improved to Grade 2  
 
Investigator confirms that no further improvement can be expected  
 
Start of new anti-cancer regimen  
 
Death  
UNRELATED GRADE 1 OR GRADE 2 AEs will be followed until 4 weeks after 
the last dose of study drug in an individual patient.  
The final outcome of each adverse event must be recorded on the eCRF.  
FOLLOW-UP OF ABNORMAL LABORATORY TEST VALUES  
In the event of medically significant unexplained abnormal laboratory test values, 
the tests should be repeated and followed up until they have returned to the 
normal range or baseline state and/or an adequate explanation of the abnormality 
is found. If a clear explanation is established it should be recorded on the eCRF. 
5.5.2 
SPONSOR FOLLOW-UP 
For SAEs 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. The Sponsor should be 
notified if the Investigator becomes aware of any death or serious adverse event 
occurring at any time, after a patient has discontinued study participation, even 
after study closure, regardless of relationship to treatment of 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. 


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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 these events, indefinitely, directly to Roche Safety Risk 
Management via telephone (see "Protocol Administrative and Contact Information 
& List of Investigators"). 
5.7 
EXPEDITED 
REPORTING 
TO 
HEALTH 
AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
To determine reporting requirements for single adverse event cases, the Sponsor 
will assess the expectedness of these events using the following reference 
documents: 
 
Trastuzumab Investigator's Brochure 
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 
 
The following is an outline of the statistical methodology that will be used to report 
and analyze this study. A more detailed description will be provided in a separate 
statistical analysis plan (SAP) that may include additional exploratory analysis not 
explicitly mentioned in the following sections. 
Local safety and efficacy data will be transferred to a global database and will be 
pooled for analysis. These data will also be analyzed in subgroups according to 
study design, patient population, and other relevant factors.The Intent-to-Treat 
(ITT) population will be defined as all enrolled patients.  The modified-
Intent-to-Treat (m-ITT) population will be defined as all enrolled patients 
satisfying inclusion and exclusion criteria for eligibility.  All baseline 
summaries will be based on the ITT , while efficacy analyses will be based 
on the m-ITT population. 
All safety summaries will be based on the safety population, defined as all 
recruited patients who receive at least one dose of study medication (trastuzumab 
SC) 
Where it is stated that data will be summarized, unless alternative methods are 
given, the following will apply: 
 
continuous data will be summarized using: mean, median, range, standard 
deviation and standard error 


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 
discrete data will be summarized using frequency counts and percentages 
6.1 
DETERMINATION OF SAMPLE SIZE 
The study focuses on a sample of patients eligible for adjuvant and neoadjuvant 
chemotherapy + trastuzumab SC. 
Patients will receive treatment according to the following schema, which are 
usually adopted in clinical practice. 
A)    Neoadjuvant:  
CT x 4 cycles→ CT+Trastuzumab SC x 4 cycles → Surgery 
→ Trastuzumab SC x 14 cycles 
B)    Adjuvant: 
Surgery → CT x 4 cycles→CT+Trastuzumab SC x 4 cycles →  
Trastuzumab SC x 14 cycles 
Since the chemotherapy amount of treatment is expected to be the same in the 
two groups, it is reasonable to expect the same incidence of side effects.  
For the purpose of the estimation of the sample size, the LVEF rate has been 
chosen as the safety endpoint of primary interest. The tables provide the resultant 
confidence intervals for various sample sizes and various event rates, according 
to the assumptions derived by NOAH study (ref.) Assuming an observed LVEF 
Grade≥ 1 rate of 25%, a LVEF Grade≥2 of 4% and a LVEF Grade≥3 of 2% a 
sample size of 240 will produce a 95% confidence interval deemed sufficiently 
precise to draw valid conclusions around the event rate. Safety results within each 
treatment group will be useful for descriptive purpose. The estimation of the 
confidence intervals will be performed using SAS based on Clopper-Pearson 
methodology. 
 
Table 4 
Clopper-Pearson 95% Confidence Intervals for the incidence of 
different LVEF Grade 
 
LVEF Grade: Estimated Indicence 
Number of Patients 
≥3:    2% 
≥2:    4% 
≥1:    25% 
50 
0.1% - 10.6% 
0.5% - 13.7% 
14.6% - 40.3% 
190 
0.6% -   5.3% 
1.8% -   8.1% 
19.3% - 32.1% 
240 
0.7% -   4.8% 
2.0% -   7.5% 
19.7% - 31.0% 
 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
This is a phase III prospective, two-cohort, non-randomized, multi-centre, national, 
open label study. Eligible patients with HER2-positive eBC and LABC will be 
allocated to one of two cohorts:  


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 
Cohort A (approximately 120 patients) will receive trastuzumab SC by 
assisted administration using a conventional syringe. 
 
Cohort B (approximately 120 patients) will receive trastuzumab SC, first 
assisted, then self-administered using a SID. 
Patients in both cohorts will receive a total of 18 cycles of trastuzumab SC, unless 
disease recurrence, unacceptable toxicity or patient withdrawal necessitates 
earlier treatment cessation. During adjuvant / neoadjuvant therapy, patients will be 
assessed for safety and efficacy, as detailed in Appendix 1. 
Safety endpoints are the primary objectives in this study.  
Secondary efficacy endpoints include pCR (only neoadjuvant Group), DFS, OS, 
patients’ satisfaction with trastuzumab SC administration using the SID (Cohort B 
patients who went on to self-administration only) and HCP satisfaction.   
The primary analysis of safety endpoints, the analysis of efficacy (pCR) and the 
analysis of efficacy ( DFS, OS) will take place when all patients have received 18 
cycles of trastuzumab SC and have completed the post-treatment Safety Follow-
up assessments. The final analysis  with the summaries for safety parameters will 
be performed when the last patient has been followed up for at least 24 months 
after her/his last study treatment, or earlier, if one of the following is documented 
for all treated patients: withdrawal of consent, loss to follow up or death. This is 
expected to take place approximately 5 years after the enrolment of the first 
patient, based on an expected 18-month recruitment period per cohort, 15 months 
of study treatment and 2 years of follow- up after the last study treatment of the 
last patient. There will be no adjustments for multiplicity of endpoints or within-
subgroups comparisons.  
A Clinical Study Report (CSR) will be written at the time of the primary endpoint 
analysis, and distributed to Health Authorities in keeping with the applicable 
regulatory requirements. All subsequent data analyses will be reflected in an 
addendum to the CSR.  
In order to assess the conduct of the study, major protocol violations will be 
summarized and listed. Such violations will be defined prior to the first reporting 
event but will include at least the following: 
Non compliance with inclusion criteria 
 
Non compliance with exclusion criteria 
 
Non compliance with study treatment 
 
Use of disallowed concomitant medication 
6.3 
SUMMARIES OF BASELINE CHARACTERISTICS 
All demography and baseline disease characteristics (collected at either the 
Screening 
or 
Baseline 
visits) 
will 
be 
summarized 
using 
the 
ITT 
populationSummaries will include: 
 
Demography (age, gender,weight) 
 
HER2 determination 


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 
Medical History (including BC Disease History) 
 
Pregnancy Test Results 
 
Prior Medications 
 
6.4 
EFFICACY ANALYSES 
The efficacy endpoints will be analysed using the m-ITT population. 
The secondary efficacy endpoint for neo-adjuvant setting will be pCR in breast 
and in nodes (ypT0 is ypN0). Residual in situ disease (ypTis) is considered as 
pCR.  According to the literature data, the expected rate of pCR will be about 35-
40%. (Gianni L, 2008). 
The response rate will be presented as proportion with relative confidence 
intervals.  
As far as the other efficacy endpoint is concerned ,OS is defined as the time 
from baseline visit until death from any cause. Patients still alive at the time of 
analysis and patients who are lost to follow-up will be censored at their last time 
known to be alive. 
DFS is defined as the time from baseline visit until first documented disease or 
death, whichever comes first. Patients who have no disease and have not died or 
who are lost to follow-up at the time of analysis will be censored at the date of the 
last tumor assessment where no disease was documented or the last date of 
follow-up for disease, whichever is last. Patients without post baseline tumor 
assessments will be censored at the time of their baseline visit unless death 
occurs prior to their first scheduled tumor assessment. 
The analysis of OS and DFS will be estimated using Kaplan-Meier methodology 
and summarized using the 25th and 75th percentiles, the median survival and a 
95% confidence interval for the median. The plot of Kaplan-Meier estimates for 
the single treatment group will be presented. 
6.5 
SAFETY ANALYSES 
AEs collection will be the primary endpoint in this study. Summaries to be 
produced will include: 
 
Incidence and severity by NCI CTCAE version 4.0 of AEs and SAEs 
 
AEs leading to premature discontinuation of study treatment 
 
Cardiac safety 
 
● 
Cardiac AEs 
 
● 
CHF (according to NCI CTCAE version 4.0 and New York Heart  
 
 
Association [NYHA] Classification) 


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● 
LVEF over time. In the event of an asymptomatic decline in LVEF, 
an  algorithm (Appendix 2 in the protocol) will be used to determine 
whether to continue trastuzumab treatment 
 
Secondary safety assessments will include the following: 
 ● 
Exposure to study medication 
 ● 
Duration of treatment, follow-up, and safety observation 
 ● 
ECOG 
 ● 
Concomitant medications 
 ● 
Laboratory data, vital signs and physical examination  
 ● 
Premature withdrawals and major protocol violations 
The safety summaries will be based on the safety population defined as all 
enrolled patients who received at least one dose of study medication.  
AEs will be coded centrally by the Sponsor using the latest MedDRA dictionary 
and summarized by body system and preferred term. 
Summaries will include frequency counts and percentages. For certain AEs (or 
groups of AEs) of interest, e.g. Cardiac AEs, 95% confidence intervals for 
incidences will be provided. Confidence intervals will be calculated using Clopper-
Pearson methodology. 
Summaries will include: 
 
The incidence of AEs and SAEs  
o overall  
o by severity using NCI CTCAE version 4.0 
o by relationship to study drug 
 
The incidence of AEs leading to premature discontinuation of study 
treatment 
o overall  
o by severity using NCI CTCAE version 4.0 
o by relationship to study drug 
 
The incidence of specific Cardiac AEs and SAEs 
o  overall 
o by severity using NCI CTCAE version 4.0 
o by relationship to study drug 
These adverse event summaries will be based on treatment emergent adverse 
events (those events starting on or after first study drug and within 28 days after 


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last study drug). Similar summaries for the safety follow-up period (starting after 
28 days after last study drug and continuing to study end) will be produced. AEs 
and SAEs occurring prior to first study drug will be listed only. 
Cardiac monitoring (12-lead ECG and LVEF) will be summarized by cycle 
including change from baseline summaries where appropriate. 
Exposure to study treatment will be summarized overall and by cycle. Summary 
measures will include: 
 
days on drug 
 
total daily dose 
 
cumulative dose 
Duration of the treatment period will be summarized in both days and cycles.  
Duration of safety follow-up will be summarized in days. 
Vital signs will be summarized by cycle including change from baseline as 
appropriate. 
Concomitant medications will be coded centrally by the Sponsor using the latest 
INN (International Nonproprietary Name) dictionary and summarized during the 
treatment phase by super class term and preferred term. 
Anti-cancer treatments given to treat a recurrence will also be summarized during 
safety follow-up.  
Hematology and serum chemistry results will be summarized by cycle including 
change from baseline as appropriate. For laboratory parameters where CTC 
grading is available, shift tables and change from baseline to worst on-treatment 
value will be produced. 
6.6 
PATIENT-SATISFACTION OUTCOME ANALYSES 
Patient’s Satisfaction with trastuzumab SC administration using the SID will be 
evaluated for patients who went on self-administration only. 
Data derived from the questionnaires regarding patients satisfaction will be 
presented as proportion with relative 95% confidence intervals. 
6.7 
HCP-SATISFACTION OUTCOME ANALYSES 
The ‘HCP satisfaction with SC trastuzumab’ will be assessed by the following 
questions on the HCPQ:  
I. “All things considered, do you think neo/adjuvant Herceptin SC administration 
is a valid option considering the patients advantages? 


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II. “All things considered, do you think neo/ adjuvant Herceptin SC 
administration 
is 
a 
valid 
option 
considering 
the 
department 
organization/simplification? 
 
At each site, the investigator and a study nurse will complete a HCPQ after 4 
patients have received at least 5 cycles of adjuvant study treatment. (For those 
sites that recruit <4 patients the investigator and a study nurse will each complete 
an HCPQ when last patient at their site has received at least 5 cycles of adjuvant 
study treatment). 
Data derived from the questionnaires regarding HCP satisfaction will be presented 
as proportion with relative 95% confidence intervals. 
6.8 
EXPLORATORY ANALYSES 
For the analysis of translational study, the association of PI3K mutation status at 
baseline and pCR (neoadjuvant arm) will be assessed by means of a univariate 
and multivariate logistic regression analysis, where the odds of pCR will be 
modeled as function of the marker and adjusted by baseline factors relative to 
tumor and patients characteristics. 
The association between the pharmacodynamic change of the assessment for the 
PI3K mutation status in cfDNA pre and post treatment and pCR will be performed 
as described below. The cut-off value for statistical significance will be set =0.05 
two tails. 
A comparison between PI3K mutation assessment in tumor tissue collected at 
baseline (core biopsy and tumor blocks in the neoadjuvant and adjuvant arm 
respectively) (gold standard assessment) and the assessment of PI3K mutation 
in cfDNA (experimental assessment) will be performed and consistency will be 
assessed by k statistic. 
Sensitivity, specificity, positive and negative predictive value and overall 
agreement for the experimental assessment will be calculated. 
Correlative studies will be performed according to the following clinical outcome: 
 the achievement of pathological complete response (pCR) of invasive tumor in 
breast and axilla (is situ residual disease allowed). Patients progressed under 
treatment or for which surgery will not be feasible at the end of treatment will be 
considered as not having achieved a pCR. 
● the association between clinical outcomes (pCR) and the baseline assessment 
of the PI3K mutation status as defined in tumor samples or cfDNA will be 
performed.  
● the pharmacodynamic changes of the PI3K mutation assessment in cfDNA by 
comparing the pharmacodynamic changes and clinical outcome (pCR) will be 
performed. 


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The analysis of efficacy secondary end points will be conducted according both to 
local and to central HER2 evaluation, while the translational evaluations will be 
conducted only on the central HER2 positive cases. 
All analyses will be described on the overall population of interest and broken 
down by relevant characteristics of patients and disease, where deemed 
appropriate. 
 
6.9 
INTERIM ANALYSES 
The primary analysis will be undertaken once all patients have completed the 
study (treatment phase and 28-days safety follow-up visit). In addition to this 
primary analysis there will be annual interim analysis for safety reporting and 
presentation of safety and efficacy results. These annual reporting events will start 
1 year after first visit and end when the last patient has finished follow-up. 
 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
Data management will be performed by a CRO. 
The Sponsor will supply eCRF specifications for this study. A contract research 
organization (CRO) will be responsible for data management of this study, 
including quality checking of the data. Data entered manually will be collected via 
EDC using eCRFs. Sites will be responsible for data entry into the EDC system. In 
the event of discrepant data, the CRO will request data clarification from the sites, 
which the sites will resolve electronically in the EDC system. 
The CRO will produce a Data Quality Plan that describes the quality checking to 
be performed on the data. Central laboratory data will be sent directly to the CRO, 
using the CRO standard procedures to handle and process the electronic transfer 
of these data. 
Roche will perform oversight of the data management of this study, including 
approval of the CRO data management plans and specifications. Data will be 
periodically transferred electronically from the CRO to Roche, and Roche’s 
standard procedures will be used to handle and process the electronic transfer of 
these data.  
eCRFs and correction documentation will be maintained in the EDC system audit 
trail. System backups for data stored at the CRO and records retention for the 
study data will be consistent with the CRO standard procedures.  
Roche will ensure the quality of safety and efficacy data to be transferred to the 
global database. 


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7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed using a Sponsor-designated EDC system. Sites will 
receive training and a have access to a manual for appropriate eCRF completion. 
eCRFs will be submitted electronically to Roche and should be handled in 
accordance with instructions from the Sponsor. 
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.  
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 described in Section 7.5 
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 


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original data as well as the reason for the change, name of the person making the 
change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution 
of IMP, including eCRFs, questionnaire data, 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 
This study will be conducted in full conformance with the ICH E6 guideline for 
Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws 
and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the individual. The study will comply with the 
requirements of the ICH E2A guideline (Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting). Studies conducted in the 
United States or under a U.S. Investigational New Drug (IND) application will 
comply with U.S. FDA regulations and applicable local, state, and federal laws. 
Studies conducted in the EU/EEA will comply with the EU Clinical Trial Directive 
(2001/20/EC). 
8.2 
INFORMED CONSENT 
Roche 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 Roche 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 Roche for health authority submission 
purposes according to local requirements. 
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 


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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 
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 9.5). 
In addition to the requirements for reporting all AEs to the Sponsor, Investigators 
must comply with requirements for reporting SAEs 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 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 
the Sponsor location. 


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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, 
the 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. 
 
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 
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, The Sponsor monitors, 
representatives, and collaborators, and the IRBs/ECs to inspect facilities and 
records relevant to this study. 
9.3 
ADMINISTRATIVE STRUCTURE 
The study will have a local Steering Committee.  
IxRS and eCRF will be conducted by a contract research organization (CRO) 
together with the Sponsor.  


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Assessment of laboratory test results will be performed locally.  
9.4 
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. 
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 the Sponsor personnel exceeded 
that of conventional monitoring will be considered as a joint publication by the 
Investigator and the appropriate the 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. 
9.5 
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). 


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APPENDIX 1 
Schedule of Assessments  
NEOADJUVANT PATIENTS 
  
Screening 
Baseline 
Pre-Surgery Treatment Period 
Surgery 
Post-Surgery Treatment Period 
Safety  
Follow-up 
Follow-up visits 
Day 
-28 to 1 
-7 to 1 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 4 weeks after 
last study 
treatment 
 
Continuing for 24 months after 
safety follow (months 
6,12,18,24)  
(Treatment Cycle #) 
  
  
A1 
A2, 
A3 
A4 
1 
2, 3, 
4 
  
5 
6, 7, 
8 
9 
10, 11, 
12 
13 
14, 15, 
16 
17 
18 
 
 
Explain study and obtain 
signed Informed 
Consent [a] 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
Demographics and 
medical history [b, c] 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
HER2 determination [d] 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
Review inclusion/ 
exclusion criteria 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
Baseline Breast Cancer 
evaluation [e] 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs, physical 
examination [f], weight, 
and height [g] 
x 
x 
x 
x 
x 
x 
x 
  
X 
x 
x 
x 
x 
x 
x 
x 
  
  
ECOG performance 
status 
x 
  
x 
  
  
x 
  
  
x 
  
x 
  
x 
  
x 
 
x 
x 
Cardiac monitoring [h, p] 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
12-lead ECG 
x 
  
 
  
  
x 
  
  
X 
  
x 
  
x 
  
x 
 
x 
x 
LVEF 
x 
  
 
  
  
x 
  
  
X 
  
x 
  
x 
  
x 
 
x 
x 
Signs/symptoms 
 
 
 
x 
  
 
  
  
x 
  
  
X 
  
x 
  
x 
  
x 
 
x 
x 
Anthracycline 
containing 
regimens 
Starting 
trastuzumab 
(+ taxanes) 
Trastuzumab ± RT ± hormonal therapy 




 
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Trastuzumab—Roche S.p.A. 
Protocol ML28879, Version 2.0 dated 27.05.2014 
ADJUVANT PATIENTS 
 
Screening 
Baseline 
Treatment Period 
Safety  
Follow-up 
Follow-up visits 
Weeks 
Days -28 to -
1 
Days -7 to 
-1 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 weeks after 
last study 
treatment  
Continuing for 24 months 
after safety follow (months 
6,12,18,24) 
(Treatment Cycle #) 
  
  
A1 
A2, 
A3 
A4 
1 
2, 3, 4 
5 
6, 7, 8 
9 
10, 11, 
12 
13 
14, 15, 
26 
 
17 
18  
Explain study and 
obtain signed Informed 
Consent [a] 
x 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
Demographics and 
medical history [b, c] 
x 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
HER2 determination [d] 
x 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
Baseline Breast Cancer 
evaluation [e] 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion/ 
exclusion criteria 
x 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
Vital signs, physical 
examination [f], weight, 
and height [g] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
 
 
x 
x 
  
  
ECOG performance 
status 
x 
  
x 
  
  
x 
  
x 
  
X 
  
x 
  
x 
 
x 
x 
Anthracycline 
containing 
regimens 
Starting 
trastuzumab 
(+ taxanes) 
Trastuzumab ± RT ± hormonal therapy 
 
 




 
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Trastuzumab—Roche S.p.A. 
Protocol ML28879, Version 2.0 dated 27.05.2014 
 
AE = adverse event, ASCO = American Society of Clinical Oncology, ECG = electrocardiogram, ECOG = Eastern Cooperative Oncology Group, 
LPLV = last patient last visit, LVEF = left ventricular ejection fraction, PK = pharmacokinetic, SAE = serious adverse event, SC = subcutaneous 
First dose of drug = study cycle 1, Day 1. A treatment period is approximately 3 months in duration, i.e. 4 treatment cycles. Assessments can also 
be performed more frequently if clinically indicated.  
 
Notes 
[a] Written Informed Consent must be obtained before any study-specific assessments or procedures are performed  
[b] Demographic data including date of birth, gender, and self-reported ethnic origin where permitted by local regulations 
[c] Breast cancer disease history, including ER/PgR status, prior anticancer treatments, current medications and symptoms 
[d] HER2-positivity is defined as immunohistochemistry (IHC)3+ or gene amplification by in situ hybridization (ISH) 
[e] Baseline breast cancer evaluation to be completed within 4 weeks before protocol related chemotherapy treatment start, with the following 
exceptions: Screening radiological examinations to exclude metastatic disease (chest X-ray, liver ultrasound, bone scan) do not need to be 
repeated if completed within 8 weeks prior to the first chemotherapy administration; Bilateral Mammography do not need to be repeated if 
completed within 6 weeks prior to the first chemotherapy administration. 
[f] Vital signs and physical examination including pulse, blood pressure, and body temperature are measured at Screening, at every treatment cycle, 
and at the Safety Follow-up visit 
[g] Weight is measured at baseline, at every treatment cycle, at the Safety Follow-up visit, and at each visit during follow-up period. Height is only 
measured at Screening 
[h] LVEF assessments by either ECHO or MUGA Scan: the same imaging technique should be used per patient throughout the study. 
Echocardiography should be the method of choice for these assessments. LVEF assessment is mandatory at Screening. During treatment, a 
3-monthly assessment should be performed or as per institutional practice and immediately as per Section 5.1.3 in case of cardiac failure 
[i] Applicable to women of childbearing potential (premenopausal or less than 12 months of amenorrhea post-menopause, and who have not 
undergone surgical sterilization); a serum pregnancy test needs to be completed within 7 days prior to the first dose of first administration of the 
protocol required chemotherapy treatment. Testing should be repetaed every 3 months for the duration of study treatment and until at least 7 
months after the last dose of study treatment . Any positive urine pregnancy test needs to be confirmed by serum pregnancy test. Additional 
pregnancy testing should be completed as clinically indicated for the duration of study treatment and until at least 7 months after the last dose of 
study treatment. Any positive urine pregnancy test needs to be confirmed by serum pregnancy test. 
[j] Hematology: hemoglobin, white blood cells (WBC) and differential, absolute neutrophil count (ANC), platelet count. Biochemistry: creatinine, urea 
(BUN), SGPT (ALT), SGOT (AST), total bilirubin, alkaline phosphatase, glycaemia, albumin, sodium, potassium and calcium. Additional 
hematology and biochemistry tests may be performed as per institutional practice, but these data will not be collected 


 
 
Pag. 116 of 121 
Trastuzumab—Roche S.p.A. 
Protocol ML28879, Version 2.0 dated 27.05.2014 
 
[k] 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.  
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) 
In neoadjuvant setting mammogram and ultrasound have to be performed at Screening and before surgery. After first sequence comprehensive of 
Anthracycline (4 cycles, on day 1 of first cycle of subsequent sequence) the mammogram is optional. 
[l] After informed consent, but prior to initiation of study treatment, only SAEs caused by a protocol-mandated intervention will be collected. Before 
study closure, all AEs/SAEs will be reported regardless of the study drug relationship. After study closure, all SAEs will be reported indefinitely 
regardless relationship to the drug. NCI-CTCAE version 4 should be used for AE coding. All SAEs, and AEs that are not resolved after the end of 
study, should be followed-up until resolution. See section 5.3.1 for AEs reporting period. 
[m] All concomitant medications and prior treatments for BC must be reported in the eCRF starting at the Screening visit. The year of start and end 
date (when applicable) of the past and current concomitant treatments for BC, as well as the route and dose, will be collected when available. All 
concomitant medication will be recorded between the Screening and the Safety Follow-up visits. Thereafter, only medication applicable for long-
term reporting must be reported, including: breast cancer treatments (e.g., hormonal therapy), anti-cancer treatments given to treat a recurrence, 
medications related to the treatment of SAEs that are applicable for long-term reporting (e.g., treatment of heart failure) 
[n] Trastuzumab is administered subcutaneously at a fixed dose of 600 mg, 3-weekly for a total of at least 18 cycles/1 year (regardless of body 
weight) starting after first chemotherapy sequence based on anthracycline ( 4 cycles).  
[o] Pathological Response assessment to be performed using the resected tumor according to guidelines provided 
[p] Approximately 3-monthly (every 4 cycles) refers to pre-study treatment administration at: Cycle 5 (after 4 cycles of anthracycline based 
chemotherapy), Cycle 9 (after 4 cycles of taxane based chemotherapy plus trastuzumab SC), Cycles 13, 17 and 21 and at safety follow-up visit (4 
weeks after last study treatment). Cardiac assessments at follow-up visits have to be performed at 6, 12, 18 and 24 months following treatment 
cessation. 
[q] Patients will undergo a Safety Follow-up visit 4 weeks after their last dose of study treatment 
 
* Local Blood samples will be obtained at the following time points: 
Adjuvant:  


 
 
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Trastuzumab—Roche S.p.A. 
Protocol ML28879, Version 2.0 dated 27.05.2014 
 
1. basal (Day 1-7);  
2. after first sequence comprehensive of Anthracycline containing regimens(on Day 1 of first cycle of Taxane + trastuzumab SC 
administration)  
3. end of chemotherapy treatment (on Day 1 of C 5 before starting administration of Trastuzumab alone) 
Neoadjuvant:  
1 
basal (Day 1-7);  
2 
after first sequence comprehensive of Anthracycline containing regimens (on Day 1 of first cycle of Taxane + trastuzumab SC 
 
administration)  
3 
end of chemotherapy treatment (8 cycles, on Day 1 of first cycle of subsequent sequence) 
 
 
* *Local: Tissue samples will be obtained at the following points: 
Neoadjuvant:  
 
basal (Day 1-7);  
 
at surgery 
Adjuvant: 
 
at surgery 
 




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Trastuzumab—Roche S.p.A. 
Protocol ML28879, Version 2.0 dated 27.05.2014 
 
 
Appendix 3  
The conventional doses of the selected regimens Chemotherapy 
Agents 
 
EC:  
Epirubicin 90 mg/m2 
 
 
Cyclophosphamide, 600 mg/m2 
 
AC:  
Doxorubicin, 60 mg/m2 
Cyclophosphamide, 600 mg/m2 
 
Docetaxel, 100 mg/m2 1 hour infusion every 3 weeks 
Docetaxel, 75 mg/m2 1 hour infusion every 3 weeks 
 
Paclitaxel, 80 mg/m2 1 hour infusion every one week 
 
FAC:   Fluorouracil, 600 mg/m2 
 
 
Doxorubicin, 60 mg/m2 
 
 
Cyclophosphamide, 600 mg/m2 
 
 
Iv bolus every 3 weeks 
 
FEC: 
Fluorouracil, 600 mg/m2 
 
 
Epirubicin, 90 mg/m2 
 
 
Cyclophosphamide, 600 mg/m2 
 
 
IV bolus every 3 weeks 
 
 


 
 
 
 
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Trastuzumab—Roche S.p.A. 
Protocol ML28879, Version 2.0 dated 27.05.2014 
 
Appendix4  
NYHA Classification and Left Ventricular Systolic Dysfunction 
NCI CTCAE version 4.0 Grading 
Class I 
Patients with cardiac disease but without resulting limitations of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea or angina pain. 
Class II 
Patients with cardiac disease resulting in slight limitations of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea or anginal pain. 
Class III 
Patients with cardiac disease resulting in marked limitations of physical 
activity. They are comfortable at rest. Less than ordinary physical activity 
causes fatigue, palpitation, dyspnea or anginal pain 
Class IV 
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of cardiac insufficiency or of the 
angina syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased. 
Oxford textbook of internal medicine. Vol 2, pp 2228. Oxford University Press. 1997 
 
 


 
 
 
 
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Trastuzumab—Roche S.p.A. 
Protocol ML28879, Version 2.0 dated 27.05.2014 
 
APPENDIX 5 
Single-use Injection Device (SID) Satisfaction Questionnaire 
Studio ML 28879   
 
The SID Satisfaction Questionnaire has to be completed by patients in Cohort B who 
completed a minimum of 14 administrations of trastuzumanb SC using SID,  at least 10 
self- administered  
 
Site number:    __________________ 
 
Date: ______________________ 
 
Patient number: _________________ 
 
Please rate your level of agreement or disagreement with each the following statements, by placing an 
“X” in the appropriate box (one answer for each statement): 
1 Following the first injection given by the physician/nurse and training on how to use the SID, I 
felt comfortable injecting the study drug by myself. 
 
1 Strongly Disagree       2 Disagree       3 Unsure       4 Agree       5 Strongly 
agree 
2 The SID was convenient and easy to use. 
 
1 Strongly Disagree       2 Disagree       3 Unsure       4 Agree       5 Strongly 
agree 
3 I am confident giving myself an injection in the thigh with the SID. 
1 Strongly Disagree       2 Disagree       3 Unsure       4 Agree       5 Strongly agree 
4 Taking all things into account, I find self-administration using the SID satisfactory. 
1 Strongly Disagree       2 Disagree       3 Unsure       4 Agree       5 Strongly 
agree 
5 
If given the opportunity, I would choose to continue self-injecting the study drug using the SID 
at home. 
1 Strongly Disagree       2 Disagree       3 Unsure       4 Agree       5 Strongly agree 

SAP_001.pdf: 
 
Official Title: 
NATIONAL PHASE IIIB PROSPECTIVE ,  TWO-COHORT  NON-
RANDOMIZED,  MULTI-CENTRE,  OPEN  LABEL  STUDY  TO  
ASSESS THE SAFETY  OF  SUBCUTANEOUS  TRASTUZUMAB 
AND  MOLECUAR BIOMARKERS  IN PATIENTS  WITH EARLY 
AND LOCALLY ADVANCED HER2-POSITIVE  BREAST CANCER 
NCT Number: 
NCT01940497 
Document Date: 
STATISTICAL ANALYSIS PLAN 
Version 1: 6 October 2016 
Version 2: 30 July 2018 
 
 
 
 






Herceptin SC ML28879  
 
Statistical Analysis Plan 
 
Version 2.0, 30th July 2018  
 
Page 3 of 35 
Change Log for Changes Made after Approval 
Revision 
Date** 
Section(s) 
Modified 
Brief Description of 
Revision(s) or Reason(s) for 
Revision 
Modifications Reviewed 
and Approved by* 
30JUL2018
Paragraph 
5.5.7, 
Tables14.5.4.3 
and 14.5.4.4 
Comparison between 
Investigator’s assessment of 
normality of LVEF(%) and 
normality assessment as per 
protocol was introduced due 
to Sponsor’s request. 
 
 
Table 14.3.5.9 Split into Table 14.3.5.9.1 and 
14.3.5.9.2 
 
 
Table 14.5.5 
Added a graph to display 
LVEF (%) over time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*   Provide person’s initial and last name. 
** Update the Last Revision Dates on the cover page and the header. 
 


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Page 4 of 35 
Contents 
ABBREVIATIONS ................................................................................................................... 6 
1 
INTRODUCTION ................................................................................................. 8 
2 
STUDY OBJECTIVES ......................................................................................... 8 
2.1 
PRIMARY OBJECTIVE ................................................................................................ 8 
2.2 
SECONDARY OBJECTIVES ......................................................................................... 8 
3 
STUDY DESIGN ................................................................................................... 9 
3.1 
PRIMARY OBJECTIVE ................................................................................................ 9 
3.2 
OVERVIEW OF STUDY DESIGN .................................................................................. 9 
3.3 
SCHEDULE OF ASSESSMENTS .................................................................................. 11 
3.3.1 Adjuvant patients schedule of Assessments ........................................................... 11 
3.3.2 Neoadjuvant patients schedule of Assessments ..................................................... 13 
3.4 
SAMPLE SIZE .......................................................................................................... 17 
3.5 
STUDY ENDPOINTS ................................................................................................. 17 
3.6 
STUDY VISITS ......................................................................................................... 18 
3.7 
RANDOMIZATION .................................................................................................... 19 
4 
STUDY ANALYSIS POPULATIONS ............................................................... 19 
4.1.1 Intent to treat Population (ITT) ............................................................................. 19 
4.1.2 Modified Intent to treat Population (m-ITT) ......................................................... 19 
4.1.3 Safety Population (SAF) ........................................................................................ 19 
4.1.4 Explorative Population (EXP) ............................................................................... 19 
4.1.5 Patient Satisfaction Questionnaire Population (PSQ) .......................................... 19 
4.1.6 Health Care Professional Questionnaire Population (HCPQ) ............................. 19 
4.2 
WITHDRAWN PATIENTS .......................................................................................... 20 
4.3 
BLINDING ............................................................................................................... 20 
5 
STATISTICAL METHODOLOGY .................................................................. 20 
5.1 
DATA QUALITY ASSURANCE .................................................................................. 20 
5.2 
SUBGROUPS ............................................................................................................ 20 
5.3 
ANALYSIS TIMING .................................................................................................. 21 
5.4 
BASELINE AND DEMOGRAPHIC CHARACTERISTICS ................................................. 21 
5.5 
SAFETY ANALYSIS .................................................................................................. 22 
5.5.1 Adverse events ....................................................................................................... 22 
5.5.2 Previous and Concomitant Treatments ................................................................. 25 
5.5.3 Laboratory findings ............................................................................................... 25 
5.5.4 Vital Signs .............................................................................................................. 26 
5.5.5 Pregnancy Tests ..................................................................................................... 26 
5.5.6 ECG ....................................................................................................................... 26 
5.5.7 LVEF ...................................................................................................................... 26 
5.5.8 ECOG Performance Status .................................................................................... 26 
5.5.9 Physical Examination ............................................................................................ 27 
5.6 
EFFICACY ANALYSIS .............................................................................................. 27 
5.6.1 Overall Survival ..................................................................................................... 27 
5.6.2 Disease-free Survival ............................................................................................. 27 
5.6.3 Pathological Complete Response (pCR) ............................................................... 27 
5.6.4 Patients (using SID) and  HCP satisfaction derived from questionaries .............. 28 


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5.7 
EXPLORATIVE ANALYSIS ........................................................................................ 28 
5.8 
DISPOSITION OF PATIENTS ...................................................................................... 28 
5.9 
EXPOSURE .............................................................................................................. 29 
5.9.1 Extent of Exposure to Trastuzumab SC ................................................................. 29 
5.9.2 Extent of exposure to other non-study drug medications ...................................... 29 
5.10 
SURVIVAL FOLLOW-UP ........................................................................................... 30 
5.11 
PROTOCOL VIOLATIONS.......................................................................................... 30 
5.12 
MISSING VALUES – MISSING VISITS ....................................................................... 31 
5.13 
DEVIATIONS FROM SAP .......................................................................................... 31 
6 
TABLES AND LISTINGS .................................................................................. 32 
6.1 
TABLE FORMAT ...................................................................................................... 32 
6.2 
CONVENTIONS ........................................................................................................ 32 
6.3 
REFERENCES ........................................................................................................... 32 
APPENDIX 1  ALGORITHM FOR CONTINUATION AND  DISCONTINUATION OF 
TRASTUZUMAB SC OR IV BASED ON LVEF ASSESSMENT IN ASYMPTOMATIC 
PATIENTS .............................................................................................................................. 33 
APPENDIX 2 
ADMINISTRATION ASSOCIATED REACTIONS .............................. 34 
APPENDIX 3 .......................................................................................................................... 35 
LABORATORY SPECIFIC DERIVATIONS ..................................................................... 35 
 


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Abbreviations 
 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase  
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the serum concentration-time curve 
BC 
breast cancer 
BSA 
Body Surface Area 
BUN 
blood urea nitrogen 
CHF 
congestive heart failure 
CI 
confidence interval 
Cmax 
maximum concentration 
CNS 
central nervous system 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
common terminology criteria for adverse events 
DCIS 
ductal carcinoma in situ 
DBP 
Diastolic Blood Pressure 
DFS 
disease free survival 
DLT 
dose-limiting toxicity 
DoR 
duration of response 
eBC 
early breast cancer 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECHO 
echocardiography 
ECOG 
Eastern Cooperative Oncology Group 
(e)CRF 
(electronic) Case Report Form 
EDC 
electronic data capture 
EEA 
European economic area 
EGRF 
epidermal growth factor receptor 
EU 
European Union 
FDA 
Food and Drug Administration 
Hb 
haemoglobin 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor receptor 2 
HIV 
immunodeficiency virus 
HCP 
health care professional 
HR 
hazard ratio 
ICH 
International Conference on Harmonization 
IHC 
immunohistochemistry 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
INR 
international normalised ratio 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 


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IRR 
infusion-related reaction 
ISH 
in situ hybridization 
ITT 
intent-to-treat 
IV 
intravenous 
LABC 
locally advanced breast cancer 
LVEF 
left ventricular ejection fraction 
LPLV 
last patient, last visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
m-ITT 
modified intent-to-treat 
MRI 
magnetic resonance imaging 
MUGA 
multiple gated acquisition 
NCI 
National Cancer Institute 
NYHA 
New York Heart Association 
ORR 
overall response rate 
OS 
overall survival 
pCR 
pathological complete response 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression free survival 
PK 
pharmacokinetic 
PPAS 
per-protocol population analysis set 
PR 
partial response 
PRO 
patient-reported outcome 
q3w 
every 3 weeks 
qw 
weekly 
RECIST 
response evaluation criteria for solid tumours 
rHuPH20 
recombinant humanised hyaluronidase 
SAE 
serious adverse event 
SC 
subcutaneous 
SD 
standard deviation 
SID 
single-use injection device 
SBP 
Systolic Blood Pressure 
SI 
standard international 
SOC 
system-organ class 
TEAE 
treatment emergent adverse event 
TESAE 
treatment emergent serious adverse event 
ULN 
upper limit of normal 
WBC 
white blood cells 
WHO 
World Health Organization 
 
 
 
 
 


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1 Introduction 
This document describes the statistical methods to be used during the analyses and reporting of 
study ML28879. This SAP includes all details for the analysis and reporting (tables, listings 
and graphs) of the data collected as part of this protocol.   
This Statistical Analysis Plan is based on the protocol version Final 2.0, dated 27 May 2014. 
 
2 Study Objectives 
2.1 
Primary Objective 
The primary objective of the study is to assess the safety and tolerability of trastuzumab solution 
injected subcutaneously (vial or single-use injection device [SID]) in patients with HER2-
positive early breast cancer (eBC) or locally advanced breast cancer (LABC). 
 
2.2 
Secondary Objectives 
The secondary safety objectives for this study are to assess: 
o Exposure to study medication 
o Duration of treatment and  follow-up 
o ECOG 
o Vital sign, physical examination and laboratory parameters 
o Concomitant medication  
o Premature withdrawals and major protocols violation 
 
The secondary efficacy endpoint will be: 
o Disease Free Survival (DFS) 
o Overall Survival  (OS) 
o For neo-adjuvant setting, incidence of pathological Complete Response (pCR) in breast 
and in nodes (ypT0-is ypN0) 
o Patient Satisfaction using SID (single use injection device) 
o HCP satisfaction  
 
Furthermore, will be implemented an Explorative Analysis on the central HER2 positive 
cases to evaluate the association of PI3K mutation status in tumor tissues and in circulating 
free DNA (cfDNA) in blood. We performed the following assessment: 
o Agreement evaluation at baseline and at Cycle 5 between PI3K mutation assessment in 
tumor tissue (gold standard) and in circulating free DNA (experimental) 
o Association between the baseline mutation status with pCR in neo-adjuvant arm 


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o Association between pharmacodynamics change (baseline, Cycle 1, Cycle 5) of the 
cfDNA before and after treatment with clinical outcomes 
A sensitivity analysis will be performed on the HER2 positive cases confirmed by the 
Central Laboratory (IHC=3+ or FISH=Amplified). 
 
 
3 Study Design 
3.1 
Primary Objective 
The primary objective of this study is to assess the safety and tolerability of trastuzumab 
solution injected subcutaneously in patients with HER2-positive eBC or LABC.  
 
The primary analysis of safety endpoints, the analysis of efficacy (pCR) and the analysis of 
efficacy ( DFS, OS) will take place when all patients have received 18 cycles of trastuzumab 
SC and have completed the post-treatment Safety Follow-up assessments. The final analysis 
with the summaries for safety parameters will be performed when the last patient has been 
followed up for at least 24 months after her/his last study treatment, or earlier, if one of the 
following is documented for all treated patients: withdrawal of consent, loss to follow up or 
death. This is expected to take place approximately 5 years after the enrolment of the first 
patient, based on an expected 18-month recruitment period per cohort, 15 months of study 
treatment and 2 years of follow- up after the last study treatment of the last patient. There 
will be no adjustments for multiplicity of endpoints or within-subgroups comparisons. 
A Clinical Study Report (CSR) will be written at the time of the primary endpoint analysis, 
and distributed to Health Authorities in keeping with the applicable regulatory 
requirements. All subsequent data analyses will be reflected in an addendum to the CSR. 
 
 
3.2 
Overview of Study Design 
This study is a part (Daughter study) of Global (Umbrella) Study. 
This is a prospective, two-cohort, non-randomized, multicenter, open-label  study to assess 
the safety and tolerability of trastuzumab solution injected subcutaneously (vial or single-
use injection device [SID]) in approximately 240 patients with HER2-positive eBC or LABC 
who are eligible for anti-HER2 therapy.  
The patients will be enrolled in two sequential cohorts. 
The first 120 patients will be treated with trastuzumab SC 600 mg/5ml vial (Cohort A) and 
the subsequent 120 patients will be treated with trastuzumab SC 600 mg/5ml prefilled single 
use injection device - SID ( Cohort B).  
In each cohort (A and B), patients will be allocated to adjuvant or neoadjuvant treatment, 
with pragmatic selection according to conventional clinical criteria and physician choice: 
 Group 1 = Adjuvant chemotherapy + trastuzumab SC 
 Group 2= Neoadjuvant chemotherapy + trastuzumab SC 


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In both groups the planned treatment will require sequential chemotherapy regimens  
containing 4 cycles of Anthracyclines followed by 4 cycles of Taxanes based chemotherapy 
administered in combination with trastuzumab SC followed by trastuzumab alone. 
 
Here below the detailed schemas: 
Adjuvant Schema 
Surgery → CT x 4 cycles (Cycles A1 to A4)→CT + Trastuzumab SC x 4 cycles (Cycles 1 to 
4) →  Trastuzumab SC x 14 cycles (Cycles 5 to 18) 
Neoadjuvant Schema 
CT x 4 cycles (Cycles A1 to A4)→CT + Trastuzumab SC x 4 cycles (Cycles 1 to 4)→ Surgery 
→ Trastuzumab  SC x 14 cycles (Cycles 5 to 18) 










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[e] Baseline breast cancer evaluation to be completed within 4 weeks before protocol related chemotherapy treatment start, with the following 
exceptions: Screening radiological examinations to exclude metastatic disease (chest X-ray, liver ultrasound, bone scan) do not need to be 
repeated if completed within 8 weeks prior to the first chemotherapy administration; Bilateral Mammography do not need to be repeated if 
completed within 6 weeks prior to the first chemotherapy administration. 
[f] Vital signs and physical examination including pulse, blood pressure, and body temperature are measured at Screening, at every treatment cycle, 
and at the Safety Follow-up visit 
[g] Weight is measured at baseline, at every treatment cycle, at the Safety Follow-up visit, and at each visit during follow-up period. Height is only 
measured at Screening 
[h] LVEF assessments by either ECHO or MUGA Scan: the same imaging technique should be used per patient throughout the study. 
Echocardiography should be the method of choice for these assessments. LVEF assessment is mandatory at Screening. During treatment, a 
3-monthly assessment should be performed or as per institutional practice and immediately as per Section 5.1.3 in case of cardiac failure 
[i] Applicable to women of childbearing potential (premenopausal or less than 12 months of amenorrhea post-menopause, and who have not 
undergone surgical sterilization); a serum pregnancy test needs to be completed within 7 days prior to the first dose of first administration of the 
protocol required chemotherapy treatment. Testing should be repeated every 3 months for the duration of study treatment and until at least 7 
months after the last dose of study treatment . Any positive urine pregnancy test needs to be confirmed by serum pregnancy test. Additional 
pregnancy testing should be completed as clinically indicated for the duration of study treatment and until at least 7 months after the last dose of 
study treatment. Any positive urine pregnancy test needs to be confirmed by serum pregnancy test. 
[j] Hematology: hemoglobin, white blood cells (WBC) and differential, absolute neutrophil count (ANC), platelet count. Biochemistry: creatinine, urea 
(BUN), SGPT (ALT), SGOT (AST), total bilirubin, alkaline phosphatase, glycaemia, albumin, sodium, potassium and calcium. Additional 
hematology and biochemistry tests may be performed as per institutional practice, but these data will not be collected 
 [k] 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. 
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) 
In neoadjuvant setting mammogram and ultrasound have to be performed at Screening and before surgery. After first sequence comprehensive of 
Anthracycline (4 cycles, on day 1 of first cycle of subsequent sequence) the mammogram is optional. 
[l] After informed consent, but prior to initiation of study treatment, only SAEs caused by a protocol-mandated intervention will be collected. Before 
study closure, all AEs/SAEs will be reported regardless of the study drug relationship. After study closure, all SAEs will be reported indefinitely 
regardless relationship to the drug. NCI-CTCAE version 4 should be used for AE coding. All SAEs, and AEs that are not resolved after the end of 
study, should be followed-up until resolution. See section 5.3.1 for AEs reporting period. 
[m] All concomitant medications and prior treatments for BC must be reported in the eCRF starting at the Screening visit. The year of start and end 
date (when applicable) of the past and current concomitant treatments for BC, as well as the route and dose, will be collected when available. All 
concomitant medication will be recorded between the Screening and the Safety Follow-up visits. Thereafter, only medication applicable for long-term 


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reporting must be reported, including: breast cancer treatments (e.g., hormonal therapy), anti-cancer treatments given to treat a recurrence, 
medications related to the treatment of SAEs that are applicable for long-term reporting (e.g., treatment of heart failure) 
[n] Trastuzumab is administered subcutaneously at a fixed dose of 600 mg, 3-weekly for a total of at least 18 cycles/1 year (regardless of body 
weight) starting after first chemotherapy sequence based on anthracycline ( 4 cycles). 
[o] Pathological Response assessment to be performed using the resected tumor according to guidelines provided 
[p] Approximately 3-monthly (every 4 cycles) refers to pre-study treatment administration at: Cycle 5 (after 4 cycles of anthracycline based 
chemotherapy), Cycle 9 (after 4 cycles of taxane based chemotherapy plus trastuzumab SC), Cycles 13, 17 and 21 and at safety follow-up visit (4 
weeks after last study treatment). Cardiac assessments at follow-up visits have to be performed at 6, 12, 18 and 24 months following treatment 
cessation. 
[q] Patients will undergo a Safety Follow-up visit 4 weeks after their last dose of study treatment 
* Local Blood samples will be obtained at the following time points: 
Adjuvant: 
 
1. basal (Day 1-7); 
2. after first sequence comprehensive of Anthracycline containing regimens(on Day 1 of first cycle of Taxane + trastuzumab SC 
administration) 
3. end of chemotherapy treatment (on Day 1 of C 5 before starting administration of Trastuzumab alone) 
Neoadjuvant: 
1 basal (Day 1-7); 
2 after first sequence comprehensive of Anthracycline containing regimens (on Day 1 of first cycle of Taxane + trastuzumab SC 
administration) 
3 end of chemotherapy treatment (8 cycles, on Day 1 of first cycle of subsequent sequence) 
* *Local: Tissue samples will be obtained at the following points: 
Neoadjuvant: 
basal (Day 1-7); 
at surgery 
Adjuvant: 
at surgery 
 


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3.4 
Sample Size 
The estimation of sample size is based on the LVEF rate that is a safety endpoint of primary 
interest. 
The tables provide below shows the resultant confidence intervals for various sample sizes and 
various event rates, according to the assumptions derived by previous studies. Assuming an 
observed LVEF Grade≥ 1 rate of 25%, a LVEF Grade≥2 of 4% and a LVEF Grade≥3 of 2% a 
sample size of 240 will produce a 95% confidence interval deemed sufficiently precise to draw 
valid conclusions around the event rate. Safety results within each treatment group will be 
useful for descriptive purpose. The estimation of the confidence intervals will be performed 
using SAS based on Clopper-Pearson methodology. 
Table 1 
Clopper-Pearson 95% Confidence Intervals for the incidence of different LVEF 
Grade 
 
LVEF Grade: Estimated Incidence 
Number of Patients
≥3:    2%
≥2:    4%
≥1:    25%
50
0.1% - 10.6%
0.5% - 13.7%
14.6% - 40.3%
190
0.6% -   5.3%
1.8% -   8.1%
19.3% - 32.1%
240
0.7% -   4.8%
2.0% -   7.5%
19.7% - 31.0%
 
3.5 
Study Endpoints 
 Primary Safety Endpoints include: 
o Incidence and severity by NCI CTCAE version 4.0 of AEs and serious adverse events     
(SAEs); 
o Incidence of AEs leading to premature discontinuation of study treatment;  
o Cardiac safety 
o Incidence of Cardiac AEs (detected by MedDRA system organ class: Cardiac 
Disorders); 
o Incidence of CHF (according to NCI CTCAE version 4.0 and New York Heart 
Association [NYHA] Classification); 
o Change of LVEF over time. In the event of an asymptomatic decline in LVEF, 
an algorithm (see appendix 1 in this SAP) will be used to determine whether to 
continue trastuzumab SC treatment; 
 
 Secondary Safety Endpoints include: 
o Exposure to study medication (overall and by cycle) 
o Duration of treatment period (days and cycles) 
o Duration of safety follow-up (days) 
o ECOG 
o Concomitant medication 
o Vital sign, physical examination and laboratory parameters 


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o Premature withdrawals and major protocols violation 
 
 Secondary Efficacy Endpoints include: 
o DFS and OS 
o incidence of pathological Complete Response in breast and nodes (pCR) (ypT0-is 
ypN0). Residual in situ disease (ypTis) is considered as pCR (for the neo-adjuvant 
setting the activity of two sequential drug regimens). 
o Patients (using SID) and  HCP satisfaction derived from questionaries 
 
 Secondary Explorative Endpoints include: 
 for the E542K, E545K, H1047R gene expressions 
o frequency and percentage of the gene mutation in tumor tissue (baseline and Cycle 
5) and in circulating free DNA (baseline, Cycle 1 and Cycle 5); 
o evaluation the agreement between the PI3K mutation assessment in tumor tissue 
and in circulating free DNA at baseline and at Cycle 5; 
 for the most frequent gene expression 
o correlation, using univariate and multiple generalized linear model, of baseline 
mutation status (in tumor tissue and cfDNA) with clinical outcome (pathological 
response to treatment in the neoadjuvant arm). 
o correlation, using univariate and multiple generalized linear model, of 
pharmacodynamic change of the cfDNA before and after treatment with clinical 
outcome, 
 
3.6 
Study Visits 
For each patient, the day of first Anthracycline administration will be considered study day 1.  
 
Each assessment will be assigned a study day calculated as follows: 
 If the date of assessment < date of study day 1 then  
o study day = (date of assessment – date of study day 1) 
 If the date of assessment ≥ date of study day 1 then  
o study day = (date of assessment – date of study day 1) +1  
In the same way reported above it is defined the day of first Trastuzumab SC administration,  
considered as study treatment day 1. 
Each assessment will be assigned a study day calculated as follows: 
 If the date of assessment < date of study treatment 1 then  
o treatment day = (date of assessment – date of treatment day 1) 
 If the date of assessment ≥ date of study day 1 then  
o treatment day = (date of assessment – date of treatment day 1) +1  
All efficacy and safety data will be listed as recorded on the CRF, sorted by site identifier, 
patient identifier, cycle identifier/study day/treatment day. 


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3.7 
Randomization 
Not applicable for this protocol. This is a non-randomized study. 
 
4 Study Analysis Populations 
Agreement and authorization of subjects included/excluded from each analysis set will be 
conducted prior to the database lock of the study. 
There will be four populations defined for the study analyses. Other analysis populations may 
be defined based on more restrictive criteria, such as fulfilment of eligibility criteria or a 
minimum duration of the observation period. Such populations will be defined prior to the 
primary reporting event. 
4.1.1 Intent to treat Population (ITT) 
The intent-to-treat (ITT) population will contains all enrolled patients. 
All baseline summaries will be based on the ITT. 
  
4.1.2 Modified Intent to treat Population (m-ITT) 
The modified-Intent-to-Treat (m-ITT) population will be defined as all enrolled patients 
satisfying inclusion and exclusion criteria for eligibility. All efficacy analyses will be based on 
the m-ITT population. 
 
4.1.3 Safety Population (SAF) 
The safety population will consist of all enrolled patients who received at least one dose of any 
study medication (trastuzumab). The Safety population will be the primary population used for 
safety analysis and summaries. 
 
4.1.4 Explorative Population (EXP) 
The explorative population will consist of all enrolled patients belongs to neo-adjuvant setting 
who meet al inclusion and exclusion criteria for eligibility and received at least one dose of 
study medication (trastuzumab). The Explorative population will be the primary population 
used for the analysis of the translational study (explorative analysis). 
 
4.1.5 Patient Satisfaction Questionnaire Population (PSQ) 
The Patient Satisfaction Questionnaire Population will consist of all enrolled patients belongs 
to Cohort B (use of Trastuzumab SC SID), who will be able to use SID, who will complete a 
minimum of 14 administrations of trastuzumanb SC using SID (at least 10 self- administered). 
 
4.1.6 Health Care Professional Questionnaire Population (HCPQ) 
The Health Care Professional Questionnaire Population will consist of all Investigators and 
study nurses that will complete the questionnaire at each site when at least 4 patients from 
their site have received at least 5 cycles of adjuvant study treatment. For that recruit <4 


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patients, the investigators and a study nurses will each complete an HCPQ when the last 
patient at their site has received at least 5 cycles of study treatment. 
 
4.2 
Withdrawn Patients 
Patients have the right to withdraw from the study at any time for any reason.  Those who 
withdraw from the study will not be replaced. 
 
4.3 
Blinding 
Not applicable. This study is open label. 
 
5 Statistical Methodology 
5.1 
Data Quality Assurance 
The data for this study will originate from a number of individual local studies and, once 
combined, will be stored in a global database in the form of SAS datasets. Data from this study 
will be transcribed by the site from the paper source documents to the eCRF (IDAS database). 
From the eCRF the data will be entered into database and from there, the pre-specified core 
data will be transferred to the central global Umbrella database. A comprehensive validation 
check has to be performed at the site to assure appropriate data quality.   
 
5.2 
Subgroups 
Results, including demographic, patient characteristics, safety and efficacy, may be reported 
for individual subgroups, in addition to the analysis populations described above. Possible 
subgroups are listed below. The first list is defined at the patient level where each patient is 
either in or out of each subgroup. The second list is defined at the cycle level where patients 
can contribute to such a subgroup for one cycle but may not for a subsequent cycle. 
Patient level subgroups (defined at time of enrolment): 
 neo-adjuvant 
 adjuvant 
Cycle level subgroups: 
 trastuzumab SC monotherapy 
 trastuzumab SC combination therapy 
 trastuzumab SC administered using vial 
 trastuzumab SC administered using SID 
The incidence of AEs, SAEs, AEs leading to premature discontinuation, specific cardiac AEs 
and SAEs will be analysed by taking into account the following subgroup: 


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 severity 
 relation to study drug 
 
There will be no adjustment  for multiplicity of endpoints or within subgroup comparisons. 
 
The decision on the subgroups and endpoints to be analysed will be made prior to the time of 
analysis based on considerations such as the number of patients in subgroups of interest. 
 
5.3 
Analysis Timing 
The following analyses have been/will be performed for this study: 
 
 Interim Analysis performed by the Global group and presented in Copenhagen at 
ESMO Congress. 
Title of presented abstract is: 210P - An open-label, multinational, multicentre, phase 
IIIB umbrella study of subcutaneous trastuzumab with or without chemotherapy or 
pertuzumab in patients with HER2-positive early or metastatic breast cancer 
(UmbHER1):  
Interim safety results from early breast cancer studies) patients enrolled by 27th 
November 2015 were included (719 of patients globally involved - 228 patients from 
ML28879) 
All patient visits (treatment, unscheduled, end of study, withdrawal, follow up, AE, 
concomitant medications) that took place up to 27th November 2015 were included 
into the Interim Analysis. 
 
 Primary Analysis 
The primary analysis will be undertaken once all patients have completed the study 
(treatment phase and 28-days safety follow-up visit). A selection of tables, figures and 
listings will be presented for the primary analysis. 
 
 Final Analysis 
All final, planned analyses identified in this SAP will be performed following Sponsor 
Authorization of this Statistical Analysis Plan, Database Lock and Sponsor Authorization 
of Analysis Sets. 
 
5.4 
Baseline and Demographic Characteristics 
Baseline, is defined as the last scheduled non-missing measurement taken prior to the first 
administration of any study drug. 


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All screening/baseline and demographic characteristics will be listed and/or summarised for the 
ITT population. Included will be: 
 date of birth 
 sex 
 race 
 ethnicity 
 female reproductive status 
 inclusion/exclusion criteria 
 medical history and breast cancer history (including Stage/Pathological Stage TNM, 
Histological examination/subtype, Diagnostic Procedures) 
 HER2 evaluation (Immunohistochemistry (IHC), In situ hybridization (ISH)) 
 physical examination 
 vital signs (including: height, weight, body mass index (BMI), body surface area (BSA), 
systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse rate, temperature) 
 ECOG 
 radiological examination 
 cardiac monitoring (12-lead ECG and LVEF examination) 
 physical examination 
 laboratory examination (haematology and biochemistry) 
 baseline pregnancy test result will be summarised for females of child bearing potential 
In general, continuous data will be summarized using: number of cases, mean, standard 
deviation, median, and range. Whereas, discrete data will be summarized using frequency 
counts and percentages. 
Age will be calculated as the integer: ((date of consent – date of birth) / 365.25).  If day of birth 
is missing it will be replaced with the 1st of the month; if the month is missing it will be replaced 
with January.   
Medical history will be coded using MedDRA (the latest available version) and summarised by 
body system and preferred term. 
 
5.5 
Safety Analysis 
Safety is the primary endpoint of this protocol. All safety variables will be presented for the 
safety population. 
All AEs and laboratory variables will be assessed according to the National Cancer Institute 
Common Terminology Criteria for AEs (NCI CTC-AE) version 4.0 grading system.  Cardiac 
AEs will additionally be graded using the NYHA class (I, II, III or IV). 
5.5.1 Adverse events 
Incidence of AEs will be presented for the entire study duration. Additionally, selected tables 
will be presented by subgroups as specified in section 5.2. 
Both Treatment Emergent Adverse Events (TEAE - starting on the day of or after first 
administration of study drug (trastuzumab) and within 28 days after last study drug) and AE for 
the safety follow-up period (starting after last study drug and continuing to study end) will be 


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included in the summary tables. The general rule is that where an AE starts date is partially or 
fully missing, and it is unclear as to whether the AE started after the start of the study, it will 
be assumed to be on-study. 
AEs and SAEs occurring prior to the first drug administration will be listed only. 
For summaries by subgroup, an AE will be assigned to a specific study drug administration 
subgroup if it occurred on or after the first dose by that administration method and prior to the 
first (subsequent) date of a treatment by another administration method. If there is no 
subsequent treatment by another route then a 35 day cut off will be applied. Where an AE start 
date is partially or fully missing, and it is unclear to which subgroup the AE should be assigned, 
the AE will be assigned to all relevant subgroups. 
Tables of nonserious adverse events (excluding any SAEs), organized by SOC, then preferred 
term, that occurred at a frequency of ≥ 5% in any treatment group, will be presented for TEAE 
and Related TEAE, with the following details: 
• Total number of patients experiencing at least 1 nonserious AE by treatment group/arm, 
applying the 5% threshold; 
• Number of PATIENTS with each nonserious AE preferred term by treatment group/arm. 
 
Endpoints related to adverse events (incidence and severity), serious adverse events (incidence 
and severity), incidence of TEAEs/AEs that leading to premature discontinuation of study 
treatment, incidence of Cardiac TEAEs/AEs (detected by MedDRA system organ class: 
Cardiac Disorders), incidence of CHF (according to NCI CTCAE version 4.0 and New York 
Heart Association [NYHA] Classification) and Change of LVEF over time will be summarised 
by presenting the number and percentage of patients having any event. The proportions of 
patients experiencing the following will be summarised: 
 
 Any adverse event 
 Any serious adverse event 
 Grade 3+ CHF 
 Any administration associated reaction [defined in Appendix 2 
Administration 
Associated Reactions2] 
 Any adverse event by CTC grade (1, 2, 3, 4) 
 Any serious adverse event by CTC grade (1, 2, 3, 4) 
 Cardiac adverse events 
 Cardiac serious adverse events 
 Any cardiac adverse event by NYHA class (I, II, III, IV) 
 Any serious cardiac adverse event by NYHA class (I, II, III, IV) 
 Adverse events leading to discontinuation 
 Serious adverse events leading to discontinuation 
Summary tables by system organ class (SOC) and preferred term of the number and percentage 
of patients having events will be presented using the following displays: 
o overall 
o related AEs only  
o by maximum intensity (CTC grade) 


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o by maximum class (NYHA classification) [for cardiac adverse events only] 
o by anthracycline/taxane/trastuzumab administration [for Grade 3+ and of suspected 
cardiac origin AEs only] 
o within/more than 28 days prior to the first trastuzumab administration [of suspected 
cardiac origin AEs only] 
o by planned chemotherapy regimen [for Grade 3+ and of suspected cardiac origin AEs 
only] 
The above outputs will be repeated for: 
o all AEs 
o Grade 3+ AEs (table by CTC grade not required) 
o all SAEs  
o Grade 3+ SAEs (table by CTC grade not required) 
o all Administration Associated Reactions 
o AEs of suspected cardiac origin (intensity summaries repeated for NYHA Class) 
o AEs symptomatic of left ventricular systolic dysfunction (intensity summaries repeated 
for NYHA Class) 
o AEs resulting in LVEF decrease (intensity summaries repeated for NYHA Class) 
o SAEs of suspected cardiac origin (intensity summaries repeated for NYHA Class) 
o SAEs symptomatic of left ventricular systolic dysfunction (intensity summaries 
repeated for NYHA Class) 
o SAEs resulting in LVEF decrease (intensity summaries repeated for NYHA Class) 
o AEs leading to study drug discontinuation  
o AEs leading to study drug dose modification  
o AEs leading to chemotherapy discontinuation  
o AEs leading to chemotherapy dose modification  
o AEs leading to death 
  
Within a single summary table, patients with more than one occurrence of the same adverse 
event in a particular system organ class/preferred term will be counted only once in the total of 
those experiencing adverse events in that particular system organ class/preferred term. 
Adverse events will also be summarised by relationship and by maximum CTC grade, where 
each patient’s maximum CTC grade will be used in the summary. If a patient experiences the 
same adverse event at more than one CTC grade level, or with more than one relationship to 
study drug, the most severe rating or the stronger causal relationship to study drug will be given 
precedence. Any missing CTC grade, causality, or outcome will not be imputed but classed as 
unknown. 
Related refers to those events that there is a reasonable suspected causal relationship to the 
study drug, or with an unknown relationship. 
Adverse events will be coded using MedDRA (the latest available version) and all other 
information collected will be listed as appropriate. 
Deaths 
A summary of deaths will be presented, tabulating the number and percentage of patients by 
primary cause of death and relationship to study drug. An AE and SAE summary of events with 
an outcome of death will be presented. 


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Length of Time on Study 
Length of time on study is defined as time from first study drugs dose (should be expected 
Anthracycline for both arms) to patient's last assessment. 
Length of Study = (date of last assessment – date of first dose + 1) / 30.4375 
[where 30.4375 = average number of days per month = 365.25/12] 
Kaplan-Meier (KM) estimates of the median time to event and the corresponding two-sided 
95% confidence interval will be presented along with the estimates for the 25th and 75th 
percentiles and the associated ranges (minimum, maximum). The survivor function will be 
displayed graphically using a Kaplan-Meier curve. 
5.5.2 Previous and Concomitant Treatments 
Summaries of prior and concomitant medications will be presented for the safety population.  
Prior medications are those that stopped before exposure to study drug; concomitant 
medications are those taken during the study, including those started before but ongoing at first 
dose of study drug. 
The incidence of prior medications and of concomitant medications will be presented by 
preferred drug name. All medications other than study drugs will be summarised in this fashion.  
Prior medications and of concomitant medications will be also presented for those patients with 
abnormality finding in ECG or LVEF at screening. 
Where medication start or end dates are partially or fully missing, and it is unclear as to whether 
the medication is prior or concomitant, it will be assumed that it is concomitant.   
Previous and Concomitant Treatments will be presented for the ITT population and coded using 
WHO-DRL dictionary (the latest available version). Previous and Concomitant Treatments will 
be summarized by primary therapeutic subgroup (3rd level ATC code) and generic name. 
5.5.3 Laboratory findings 
Results from the following laboratory parameters will be summarised for the safety population:  
Haematology:  
Haemoglobin, white blood cell (WBC) count and differential, and absolute neutrophil count 
(ANC) and platelet count. 
Biochemistry:  
Creatinine, blood urea nitrogen (BUN), urea, aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT), total bilirubin, glucose, alkaline phosphatase (ALP), albumin, sodium, 
potassium, calcium. 
The following summaries will be provided for laboratory data: 
 
 Actual and change from baseline by visit (for quantitative measurements); 
 Shift from baseline according to normal range criteria (for quantitative measurements 
and categorical measurements) according to the following classification: within normal 
range, below the normal range and above the normal range (Low/Normal/High) 
Notes: 


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The data will be presented in the SI units (Appendix 3). 
 
5.5.4 Vital Signs 
Vital signs and physical parameters will be summarised over time (including change from 
baseline) using descriptive statistics. 
The following Vital Signs/physical parameters measurements will be reported for this study: 
  Systolic Blood Pressure (mmHg) 
  Diastolic Blood Pressure (mmHg) 
  Heart Rate (bpm)  
  Weight (kg) 
  Height (cm) – only at screening/baseline 
  BSA (m2) – calculated on the basis of Du Bois Du Bois formula as  (weight 0.425 x height 
0.725) x 0.007184 
The following summaries will be provided for vital signs data: 
 
 Actual and change from baseline by visit (for quantitative measurements) 
5.5.5 Pregnancy Tests 
Pregnancy test results throughout the study will be listed only. Baseline results are summarised 
as part of demography and baseline characteristics. 
5.5.6 ECG 
Abnormal results at each visit will be listed only. 
5.5.7 LVEF 
LVEF percentage will be summarised over time (including change from baseline) using 
descriptive statistics. Categorical findings will also be summarised over time. 
A comparison between Investigator’s assessment of normality on LVEF percentage and 
assessment definition as per protocol will be performed over time.  
As per protocol, LVEF percentage is assessed as “abnormal” if: 
- 
LVEF (%) ≤ 44% 
OR 
- 
LVEF (%) between 45% and 49% with a baseline change of more than 10%. 
If LVEF(%) is greater than or equal to 50%, normality is assessed.  
Mean values will be presented graphically with line graphs over time. 
5.5.8 ECOG Performance Status 
ECOG performance status (Grade 0 - Grade 5) will be summarised by visit by presenting the 
number and percentage of patients in each category. 


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5.5.9 Physical Examination 
Abnormal results at each visit will be listed only. 
 
5.6 
Efficacy Analysis 
The efficacy outcome measures of this study will be to collect data for subcutaneous 
administration of trastuzumab in the treatment of HER2-positive eBC and LABC. The efficacy 
analysis will be performed on the m-ITT population and will be presented by cohort (Cohort 
A: Trastuzumab SC 600 mg/5ml VIALS; Cohort B: Trastuzumab SC 600 mg/5ml SID) and 
groups (Group 1: Adjuvant chemotherapy and trastuzumab SC; Group 2: Neoadjuvant 
chemotherapy and trastuzumab SC.). No formal hypothesis testing, to evaluate the difference 
between cohorts/groups, is planned. 
5.6.1 Overall Survival 
Overall Survival (OS) is defined as time from first study drugs dose (should be expected 
Anthracycline for both arms) to death from any cause. Patients who have not died will be 
censored on the date they were last known to be alive. Time will be calculated in months as 
follows: 
OS = (date of death – date of first dose + 1) / 30.4375 
[where 30.4375 = average number of days per month = 365.25/12] 
Kaplan-Meier (KM) estimates of the median time to event and the corresponding two-sided 
95% confidence interval will be presented along with the estimates for the 25th and 75th 
percentiles and the associated ranges (minimum, maximum). The survivor function will be 
displayed graphically using a Kaplan-Meier curve. 
A life-table of the number and percentage of patients who died and those at risk in 3-monthly 
time periods will also be presented. 
5.6.2 Disease-free Survival  
Disease free Survival (DFS) is defined as time from first study drugs dose (should be expected 
Anthracycline for both arms) to local, regional or distant recurrence or death from any cause 
(whichever occurs first). Patients who have neither had a recurrence nor died will be censored 
on the date of their last visit.  Time will be calculated in months as follows: 
DFS = (date of recurrence/death – date of first dose + 1) / 30.4375 
Kaplan-Meier (KM) estimates of the median time to event and the corresponding two-sided 
95% confidence interval will be presented along with the estimates for the 25th and 75th 
percentiles and the associated ranges (minimum, maximum).  The survivor function will be 
displayed graphically using a Kaplan-Meier curve. 
A life-table presenting the number and percentage of patients in each category (local recurrence, 
regional recurrence, distant recurrence, contralateral breast cancer, second non-breast 
malignancy and death) and the number at risk in 3-monthly time periods will also be presented. 
5.6.3 Pathological Complete Response (pCR) 
The incidence of pCR in breast and nodes (ypT0-is ypN0), in Neoadjuvant group only,  will be 
presented as proportion with relative 95% confidence interval. 


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5.6.4 Patients (using SID) and  HCP satisfaction derived from questionaries 
Patient Satisfaction will be assessed by Patient Satisfaction Questionnaire only in Cohort B 
(use of Trastuzumab SC SID) and Health Care Professional (HCP) satisfaction will be 
assessed by a Health Care Professional Questionnaire (HCPQ).  
 
Answers will be summarized using frequency counts and percentages. Open questions will 
not be summarized. 
 
 
5.7 
Explorative Analysis 
For the explorative analysis, the association of PI3K mutation status at baseline and pCR (only 
for the neoadjuvant arm) will be assessed by means of a univariate and multiple generalized 
linear model, with binomial link function, where the odds of pCR will be modelled as function 
of the marker and adjusted by baseline factors relative to tumor and patients characteristics. 
The best model will be selected by means of stepwise procedure. The cut-off value for 
statistical significance will be set =0.05 two tails. 
 
Also, the association between the pharmacodynamics change of the of the PI3K mutation 
assessment in cfDNA, pre and post treatment, and pCR will be performed as described above. 
 
An association between PI3K mutation assessment in tumor tissue collected at baseline  (gold 
standard) and in cfDNA (experimental) will be performed by means of the Pearson 
Correlation. 
 
Incidence of pathological complete response (pCR) of invasive tumor in breast and axilla. 
Patients progressed under treatment or for which surgery will not be feasible at the end of 
treatment will be considered as not having achieved a pCR. 
 
The data will also be analysed in subgroups defined, according to study design, patient 
population, and other relevant factors.  
 
5.8 
Disposition of Patients 
The following will be summarised for the safety, ITT and m-ITT populations: 
 number and percentage in each analysis population 
 number and percentage completing treatment (Yes, No) 
 number and percentage completing follow-up (Yes, No) 
 reasons for discontinuation of treatment and follow-up  
The number and percentage of screen failures overall and by reason for failure will be presented 
 


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5.9 
Exposure 
Exposure will be summarised as set out in the following sections using the safety  population. 
5.9.1 Extent of Exposure to Trastuzumab SC 
Exposure to trastuzumab SC will be summarised overall and also within each of the study drug 
related subgroups listed in section 5.2. 
The total number of cycles received will be summarised both by descriptive statistics and 
frequency counts. Trastuzumab SC will be counted as being taken within a cycle if any dose 
administered during that cycle. 
Trastuzumab SC administration details will be summarised by cycle and overall and will 
include, duration of injection, dose injected, percentage of injections delayed (by reason), vial 
/SID, and administrator (self / HCP, only over time). 
Summary statistics, overall and by cycle for the Actual Total Dose Delivered (mg), Dose 
Intensity (mg/kg/week), and Relative Dose Intensity (%) will be presented and calculated as 
follow: 
Actual Total Dose Delivered (mg) = sum over all cycles of actual dose received (mg). 
Dose Intensity: DI (mg/kg/week) = [Actual Total Dose Delivered (unit/kg)/Duration of 
exposure (week)]. 
Planned Dose Intensity: PDI (mg/kg/week) = [Sum of planned doses (mg/kg)/Duration of 
exposure (week)]. Planned dose intensity (PDI) will be the assigned dose per week planned to 
be given to patients as per protocol. 
Relative Dose intensity: RDI (%) = [DI (mg/kg/week) / PDI (mg/kg/week)] x 100 
 
5.9.2 Extent of exposure to other non-study drug medications 
Exposure to other treatments given for eBC other than trastuzumab SC will be summarised 
overall. 
The following medications will be summarised with the total n for each being defined as the 
number of patients receiving at least one dose of the medication in question: 
 doxorubicin 
 epirubicin  
 cyclophosphamide 
 fluorouracil  
 docetaxel 
For these medications the total number of cycles received will be summarised both by 
descriptive statistics and frequency counts. Dose and delays will be summarised by cycle and 
overall. The following medications are collected for the study period rather than by cycle: 
 hormone therapy 
 radiotherapy 
 chemotherapy  


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Daily dose of hormone therapy will be summarised by treatment. Total dose of radiotherapy 
will be summarised overall and by site. Total dose per cycle of chemotherapy will be 
summarised by treatment. 
  
Other non-study drug medications will be will be presented for the ITT population and coded 
using WHO-DRL dictionary (the latest available version). These medications will be 
summarized by primary therapeutic subgroup (3rd level ATC code) and generic name. 
 
5.10 
Survival Follow-up 
The length of time patients were on study (last visit date – informed consent date + 1) will be 
summarised overall using ITT population. 
In additional a reverse Kaplan Meier curve will be constructed using the overall survival data 
where deaths will be censored and the original censored observations will count as events.  This 
will give a good indication of median follow-up. 
 
5.11 
Protocol Violations 
Patients who meet any of the following criteria will be summarised, listed and presented in the 
study report: 
 non-compliance with inclusion criteria 
 non-compliance with exclusion criteria 
 non-compliance with study medication 
 use of disallowed concomitant medication 
The following treatment are not permitted: 
 Concurrent treatment with other systemic HER2-directed immunotherapy 
 Concurrent investigational agents of any type 
 Hormonal treatment concomitant with neoadjuvant chemotherapy (even with the 
purpose of fertility preservation). 
 Other chemotherapy regimens than those specified at paragraph 3.1 of the Protocol. 
 
Full details of these criteria will be finalised prior to the primary analysis time point. 
 


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5.12 
Missing Values – Missing Visits 
Missing, unused and spurious data will be dealt with as such. There is no intention to implement 
any procedure for replacing missing data. 
 
5.13 
Deviations from SAP 
Any deviations from the original statistical plan will be described and justified in the final 
clinical study report. 
 


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6 Tables and Listings 
6.1 
Table Format 
All output will be produced using SAS version 9.4 or a later version. 
In the top left portion of each table/listing, a table/listing number followed by the title of the 
table/listing will be presented.  After the title line, optional sub-title or population information 
can be presented. Horizontal lines will appear before and after the column heading of the 
table/listing.  Footnotes will be put under the main body of text at the bottom of the page also 
separated by a page-wide horizontal line.  
The last row(s) of footnotes will contain the following information: 
 SAS program name  
 the date and time of creation of table/listing  
A landscape layout is proposed for both table and listing presentations. 
In listings every effort will be made to contain a patient’s data to a single page.  In the case that 
a patient’s record has to be continued to the next page, an appropriate identification (e.g., the 
patient ID number) must be presented at the beginning of that page. 
 
6.2 
Conventions 
Unless otherwise specified, in summary tables of continuous variables, the minimum and 
maximum values will be displayed to the same number of decimal places as the raw data, the 
mean and median will be presented to one extra decimal place compared to the raw data, and 
the standard deviation will be displayed to two extra decimal places compared to the raw data. 
Wherever possible data will be decimal aligned. 
Unless otherwise specified frequency tabulations will be presented by number and percentage, 
where the percentage is presented in brackets to 1 decimal place. 
Summaries will generally be based on non-missing data with the number of patients with 
missing data also presented.  To this end, the number of patients contributing to the summaries 
plus the number with missing data should add to the top-line ‘N’ for the table.   
P-values, if applicable, will be presented to 4 decimal places.  If the p-value is less than 0.0001 
then it will be presented as <.0001. If the rounded result is a value of 1.000, it will be displayed 
as >.9999.  Any date information in the listing will use the date9. format, for example, 
07MAY2002.  In the listing, a unit associated with a variable will be presented only once within 
parentheses either below or next to that variable in the heading portion.  
Listings should be sorted by treatment group, patient and visit.   
 
6.3 
References 
None. 


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APPENDIX 1  Algorithm for continuation and  
discontinuation of trastuzumab 
SC or IV based on LVEF 
assessment 
in 
asymptomatic 
patients 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2 Administration Associated Reactions 
Defined using Standardised MedDRA Query (SMQ20000021w).  The following preferred 
terms are defined as Administration Associated Reactions (note that this list may be updated 
with future MedDRA releases): 
 
 
 
 
 


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Appendix 3  
Laboratory Specific Derivations 
 
To convert from the conventional unit to the SI unit, multiply by the conversion factor:  
 
Parameter 
Conventional 
Unit 
Conversion 
Factor 
SI Unit 
Hematology 
Hemoglobin  
g/dL 
10 
g/L 
WBC count 
x 103/µL 
1 
x 109/L 
Neutrophils  
x 103/µL 
1 
x 109/L 
Eosinophils 
x 103/µL 
1 
x 109/L 
Lymphocytes 
x 103/µL 
1 
x 109/L 
Monocytes 
x 103/µL 
1 
x 109/L 
Basophils 
x 103/µL 
1 
x 109/L 
Other cells 
tbd 
tbd 
tbd 
Platelets count 
x 103/µL 
1 
x 109/L 
Biochemistry 
 
 
 
Creatinine 
mg/dL 
76.25 
µmol/L 
Glucose 
mg/dL 
0.0555 
mmol/L 
Albumin 
g/dL 
10 
g/L 
BUN 
mg/dL 
0.357 
mmol/L 
Urea 
mg/dL 
0.357 
mmol/L 
ALP 
U/L 
1 
U/L 
ALT 
U/L 
1 
U/L 
AST 
U/L 
1 
U/L 
Sodium 
mEq/L 
1 
mmol/L 
Calcium 
mg/dL 
0.25 
mmol/L 
Potassium 
mEq/L 
1 
mmol/L 
 


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APPROVAL SIGNATURES 
Study 
Name: 
 
Biostatistician: 
Title: 
 
 
 
.. . 
Signature 
' 
Date 
Reviewer: 
Name: 
 
Title: 
 
 
Signature 
Date 
Approved by: 
Name: 
 
Title: 
 - Italy 
. 
 
Signature 
Date 
Approved by: 
Name: 
 
Title: 
 - Italy 
Signature 
Date 
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