Clinical trial NCT01926886
Conditions: Breast Cancer
Sponsor: Hoffmann-La Roche
Start date: 2013-11-19; Completion date: 2017-07-19
Enrollment: 102 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This single arm, multicenter study will evaluate the safety of assisted subcutaneous administration of trastuzumab in participants with HER2+ eBC. Participants who have completed the first 6 cycles of intravenous (IV) trastuzumab as part of the (neo)adjuvant treatment will be eligible to receive a further 12 cycles of trastuzumab in this study. Participants will receive IV trastuzumab at initial loading dose of 8 milligrams per kilogram (mg/kg) body weight (BW) for three-weekly (q3w) regimen and then recommended maintenance dose of 6 mg/kg BW q3w for the first 3 cycles (cycles 7-9) in hospital followed by subcutaneous (SC) administration of trastuzumab at a fixed dose of 600 mg q3w for next 3 cycles (Cycles 10-12) at hospital and SC administration of trastuzumab at a fixed dose of 600 mg q3w at home for the next 6 cycles (Cycles 13-18).

Detailed description:

Arms: arm 1: Participants with HER2+ eBC who completed the first 6 cycles of trastuzumab IV infusion as part of the (neo) adjuvant treatment will be included to continue to receive 12 cycles of trastuzumab to complete a total of 18 cycles of trastuzumab. Participants will receive trastuzumab IV infusion at initial loading dose of 8 mg/kg BW for q3w regimen as a part of neo adjuvant treatment before entering in the study and then recommended maintenance dose of 6 mg/kg BW q3w for the first 3 cycles (cycles 7-9) in hospital followed by SC administration of trastuzumab at a fixed dose of 600 mg q3w for next 3 cycles (Cycles 10-12) at hospital and SC administration of trastuzumab at a fixed dose of 600 mg q3w at home for the next 6 cycles (Cycles 13-18) (Each cycle=21 days). arm 2: Health Care Professionals (HCPs) included for polling purposes. HCPs were not enrolled in the study.
Interventions: intervention 1: Trastuzumab
Intervention descriptions: intervention 1: Trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w; Trastuzumab 600 mg q3w SC injection will be administered as per the schedule specified in the arm.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
A SINGLE ARM MULTI-CENTER STUDY INVESTIGATING THE AT 
HOME ADMINISTRATION OF TRASTUZUMAB SUBCUTANEOUS 
VIAL FOR THE TREATMENT OF PATIENTS WITH                    
HER2-POSITIVE EARLY BREAST CANCER 
NCT Number: 
NCT01926886 
Document Date: 
PROTOCOL 
Version 3: 21 October 2015 
STATISTICAL ANALYSIS PLAN 
Final Version: 11 December 2015 
 
 




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TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM ..................................................................... 8 
PROTOCOL SYNOPSIS ...................................................................................... 9 
1. 
BACKGROUND ........................................................................................... 20 
1.1 
Background on Breast Cancer – Treatment 
Options for Early Breast Cancer ............................................ 20 
1.2 
Background on Study Treatments.......................................... 20 
1.2.1 
Human Epidermal Growth Factor Receptor 2 
(HER2) 
20 
1.2.2 
Trastuzumab (rhuMAb HER2, Herceptin®) ............................ 21 
1.2.2.1 Trastuzumab IV .................................................................... 22 
1.2.2.2 Pharmacokinetics of Trastuzumab IV ................................... 22 
1.2.2.3 Efficacy of Trastuzumab IV in Early Breast 
Cancer (Adjuvant Setting) ................................................................... 23 
1.2.2.4 Safety of Trastuzumab IV ..................................................... 24 
1.2.2.5 Trastuzumab SC ................................................................... 26 
1.2.2.6 Non-clinical Studies with Trastuzumab SC ........................... 28 
1.2.2.7 Clinical Studies with Trastuzumab SC .................................. 28 
1.3 
Study Rationale and Benefit–Risk Assessment ..................... 32 
1.3.1 
Rationale for Test Product Dosage ........................................ 32 
1.3.2 
Rationale for Patients with eBC ............................................. 33 
1.3.3 
Benefits of SC Administration of Trastuzumab ...................... 34 
2. 
OBJECTIVES .............................................................................................. 35 
2.1 
Primary Objective ................................................................... 35 
2.2 
Secondary Objectives ............................................................ 36 
3. 
STUDY DESIGN ......................................................................................... 36 
3.1 
Description of Study ............................................................... 36 
3.1.1 
Patient population .................................................................. 37 
3.1.2 
Steering Committee ............................................................... 37 
3.2 
Length of Study ...................................................................... 37 
3.3 
Safety Follow-up .................................................................... 37 


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3.4 
End of Study .......................................................................... 37 
3.5 
Overall Number of Patients .................................................... 37 
3.6 
Patient Enrolment .................................................................. 37 
3.7 
Countries/Centers .................................................................. 37 
3.8 
Rationale for Study Design .................................................... 38 
3.8.1 
Rationale for Pooling Strategy ............................................... 38 
3.8.2 
Rationale for Test Product Regimen ...................................... 39 
3.9 
Outcome Measures ................................................................ 40 
3.9.1 
Safety Outcome Measures .................................................... 40 
3.9.2 
Patient-Reported Outcome Measures .................................... 40 
3.9.3 
HCP-REPORTED OUTCOME MEASURES .......................... 41 
3.9.4 
OTHER .................................................................................. 41 
4. 
MATERIALS AND METHODS..................................................................... 41 
4.1 
Patients .................................................................................. 41 
4.2 
Inclusion Criteria .................................................................... 42 
4.3 
Exclusion Criteria ................................................................... 42 
4.4 
Study Treatment .................................................................... 44 
4.4.1 
Formulation, Packaging, and Handling .................................. 44 
4.4.1.1 Trastuzumab IV .................................................................... 44 
4.4.1.2 Trastuzumab SC ................................................................... 45 
4.4.2 
Dosage, Administration, and Compliance .............................. 45 
4.4.3 
Investigational Medicinal Product Accountability ................... 46 
4.4.3.1 Assessment of Compliance .................................................. 47 
4.4.3.2 Destruction of the IMPs ........................................................ 47 
4.4.4 
Post-Trial Access to Trastuzumab SC ................................... 48 
4.5 
Concomitant Therapy ............................................................. 48 
4.5.1 
Permitted Therapy ................................................................. 48 
4.5.2 
Prohibited Therapy ................................................................. 48 
4.6 
Study Assessments ............................................................... 49 
4.6.1 
Description of Study Assessments ......................................... 49 
4.6.1.1 Mandatory Procedure for Enrolment ..................................... 49 
4.6.1.2 Clinical Assessments During Treatment Period .................... 50 


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4.6.1.3 Clinical Assessments at the Safety Follow-up 
visit 
54 
4.6.1.4 Clinical Assessments in Follow-up visits .............................. 54 
4.6.1.5 Follow-Up Assessments ....................................................... 54 
4.6.1.6 Assessments at Unplanned Visits ........................................ 54 
4.7 
Patient, Study, and Site Discontinuation ................................ 55 
4.7.1 
Patient Discontinuation .......................................................... 55 
4.7.1.1 Discontinuation from Study Drug .......................................... 55 
4.7.1.2 Withdrawal from Study ......................................................... 55 
4.7.2 
Study and Site Discontinuation .............................................. 55 
5. 
ASSESSMENT OF SAFETY ....................................................................... 56 
5.1 
Safety Plan ............................................................................ 56 
5.1.1 
General Safety Assessments ................................................. 56 
5.1.2 
Cardiac Safety Assessments ................................................. 57 
5.1.2.1 LVEF Assessment ................................................................ 57 
5.1.3 
Management of Specific AEs ................................................. 57 
5.1.3.1 Infusion-Associated Symptoms and Allergic 
Reactions ............................................................................................ 58 
5.1.4 
Management of Specific Adverse Events .............................. 58 
5.1.4.1 Dose Modifications, Interruptions and Delays for 
Trastuzumab ....................................................................................... 58 
5.2 
Safety Parameters and Definitions......................................... 59 
5.2.1 
Adverse Events ...................................................................... 60 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)......................................................................................... 60 
5.2.3 
Pregnancy and Contraception ............................................... 61 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................. 61 
5.3.1 
Adverse Event Reporting Period ............................................ 62 
5.3.2 
Table 3 Eliciting Adverse Event Information .......................... 62 
5.3.3 
Assessment of Severity of Adverse Events ........................... 62 
5.3.4 
Assessment of Causality of Adverse Events .......................... 63 
5.3.5 
Procedures for Recording Adverse Events ............................ 64 
5.3.5.1 Diagnosis versus Signs and Symptoms ............................... 64 


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5.3.5.2 Adverse Events Occurring Secondary to Other 
Events 64 
5.3.5.3 Persistent or Recurrent Adverse Events ............................... 65 
5.3.5.4 Abnormal Laboratory Values ................................................ 65 
5.3.5.5 Abnormal Vital Sign Values .................................................. 66 
5.3.5.6 Abnormal Liver Function Tests ............................................. 66 
5.3.5.7 Deaths .................................................................................. 67 
5.3.5.8 Preexisting Medical Conditions ............................................. 67 
Worsening of the Underlying Condition .............................................. 67 
5.3.5.9 Hospitalization or Prolonged Hospitalization......................... 67 
5.3.5.10 Overdoses .......................................................................... 68 
5.3.5.11 Patient-Reported Outcome Data ........................................ 68 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 68 
5.4.1 
Emergency Medical Contacts ................................................ 69 
5.4.2 
Reporting Requirements for Serious Adverse 
Events 
69 
5.4.3 
Reporting Requirements for Pregnancies .............................. 70 
5.4.3.1 Pregnancies in Female Patients ........................................... 70 
5.4.3.2 Pregnancies in Female Partners of Male Patients ................ 70 
5.4.3.3 Abortions .............................................................................. 71 
5.4.3.4 Congenital Anomalies/Birth Defects ..................................... 71 
5.4.4 
Reporting Requirements for Cardiac Events      
related to CHF .......................................................................................... 71 
5.5 
Follow-Up of Patients after Adverse Events ........................... 71 
5.5.1 
Investigator Follow-Up ........................................................... 71 
5.5.2 
Sponsor Follow-Up ................................................................ 72 
5.6 
Post-Study Adverse Events ................................................... 72 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ................................................................. 73 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 73 
6.1 
Determination of Sample Size ............................................... 74 
6.2 
Summaries of Conduct of Study ............................................ 74 


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6.3 
Summaries of BASELINE CHARACTERISTICS.................... 74 
6.4 
Safety Analyses ..................................................................... 74 
6.5 
Patient Reported Outcome Analysis ...................................... 76 
7. 
DATA COLLECTION AND MANAGEMENT ................................................ 76 
7.1 
Data Quality Assurance ......................................................... 76 
7.2 
Electronic Case Report Forms ............................................... 77 
7.3 
Patient-Reported Outcome Data ............................................ 78 
7.4 
Source Data Documentation .................................................. 78 
7.5 
Use of Computerized Systems............................................... 79 
7.6 
Retention of Records ............................................................. 79 
8. 
ETHICAL CONSIDERATIONS .................................................................... 79 
8.1 
Compliance with Laws and Regulations ................................ 79 
8.2 
Informed Consent .................................................................. 79 
8.3 
Institutional Review Board or Ethics Committee .................... 80 
8.4 
Confidentiality ........................................................................ 80 
8.5 
Financial Disclosure ............................................................... 81 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ...................................................................................... 81 
9.1 
Study Documentation ............................................................. 81 
9.2 
Site Inspections...................................................................... 81 
9.3 
Administrative Structure ......................................................... 81 
9.4 
Publication of Data and Protection of Trade 
Secrets ................................................................................... 81 
9.5 
Protocol Amendments ............................................................ 82 
10. REFERENCES ............................................................................................ 83 
 
 
 
 
 
 


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LIST OF APPENDICES 
1. Table of Assessments 
2. LVEF Algorithm 
3. NYHA Classification 
4. MDASI 
5. HCPEX 
6. PSQ1 & PSQ2 
7. PEX-P1 & PEX-P2 
 


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PROTOCOL ACCEPTANCE FORM 
TITLE: 
A SINGLE ARM MULTI-CENTER STUDY 
INVESTIGATING THE AT HOME 
ADMINISTRATION OF TRASTUZUMAB 
SUBCUTANEOUS VIAL FOR THE TREATMENT 
OF PATIENTS WITH HER2-POSITIVE EARLY 
BREAST CANCER. 
PROTOCOL NUMBER: 
ML28794 
VERSION NUMBER: 
3.0 
EUDRACT NUMBER: 
2013-000123-13 
 
 
TEST PRODUCT: 
Trastuzumab SC (RO 45-2317) 
MEDICAL MONITOR: 
 
SPONSOR: 
N.V. Roche S.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 to the contact provided below. Please retain 
the original for your study files. 
{Name}  
{Address} 
 
 


 
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PROTOCOL SYNOPSIS 
TITLE: 
A SINGLE ARM MULTI-CENTER STUDY INVESTIGATING THE 
AT HOME ADMINISTRATION  OF TRASTUZUMAB 
SUBCUTANEOUS VIAL FOR THE TREATMENT OF PATIENTS 
WITH HER2-POSITIVE EARLY BREAST CANCER. 
PROTOCOL NUMBER: 
ML28794 
 
EUDRACT NUMBER: 
2013-000123-13 
 
 
TEST PRODUCT: 
Trastuzumab SC (RO 45-2317) 
PHASE: 
IIIb 
INDICATION: 
HER2-positive early breast cancer. 
SPONSOR: 
N.V. Roche S.A. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Objectives 
 
Primary Objective 
The primary objective of this study is to assess the overall safety and tolerability of subcutaneous 
(SC) trastuzumab with assisted administration using a conventional syringe and needle (vial 
formulation, hereafter referred to as trastuzumab SC vial) when administered at home for the 
treatment of patients with HER2-positive (HER2+) early breast cancer (eBC). 
 
Secondary Objectives 
To describe: 
• 
The evolution of individual patient experience across treatment periods: 
• 
Patient experience with trastuzumab IV administered in the hospital. 
• 
Patient experience with trastuzumab SC vial administered in the hospital. 
• 
Patient experience with trastuzumab SC vial administered at home. 
• 
Patient reporting of symptoms. 
• 
Patient reporting on the quality of care provided in the hospital and at home. 
• 
HCP overall satisfaction and perceived time savings with trastuzumab SC vial 
formulation administered in the hospital. 
• 
Disease-free survival (DFS). 
 
Study Design 
Description of Study 
Single arm multicenter study planned to enroll 100 patients with HER2+ eBC as part of a global 
prospective, non-randomized, open label phase IIIb study. 
 
Patients with HER2+ eBC who completed the first 6 cycles of trastuzumab IV as part of the 
(neo)adjuvant treatment can be included to continue to receive 12 cycles of trastuzumab to 
complete a total of 18 cycles of trastuzumab. 
 
The study will assess the safety and tolerability of trastuzumab SC vial when administered at 
home. 
In total, patients will receive 12 cycles of trastuzumab in the study to complete a total of 18 
cycles trastuzumab. 
The 12 cycles of trastuzumab will be administered according to following schedule: 
 
 
Trastuzumab IV will be administered in the hospital by a HCP for the first 3 cycles 
(Trastuzumab cycle 7 to 9 defined as treatment period 1) 
 
Trastuzumab SC vial will be administered in the hospital by a HCP for the next 3 cycles 
(Trastuzumab cycle 10 to 12 defined as treatment period 2) 
 
Trastuzumab SC vial will be administered at home by a  HCP for the following 6 cycles 
(Trastuzumab cycles 13 to 18 defined as treatment period 3) 
Appendix 1, schedule of assessments. 
 


 
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Number of Patients 
This study will include 100 patients in total. 
 
Target Population  
 
Patients must meet the following criteria for study entry: 
Inclusion Criteria: 
1. Female and male patients aged ≥ 18 years 
2. Signed informed consent prior to any study specific procedure 
3. Able and willing to comply with protocol 
4. Eastern Cooperative Oncology Group (ECOG) performance status 0–1 
5. Hormonal therapy will be allowed as per institutional guidelines 
6. Left ventricular ejection fraction (LVEF) of ≥ 50% measured by echocardiography 
(ECHO) or multiple gated acquisition (MUGA) scan prior to first dose of trastuzumab SC, 
or, for those who were receiving trastuzumab when beginning the study, documented 
results within an acceptable limit from a cardiac assessment within 3 months prior to 
enrolment 
7. HER2-positive disease immunohistochemistry (IHC)3+ or in situ hybridization (ISH) 
positive, in line with local reimbursement criteria and determined in a local laboratory 
that is experienced/certified in HER2-expression testing using an accurate and validated 
assay 
8. Histologically confirmed non-metastatic primary invasive adenocarcinoma of the breast 
9. No evidence of residual, locally recurrent or metastatic disease after completion of 
surgery and chemotherapy, (neo-adjuvant or adjuvant). Available patient data supporting 
continuation of trastuzumab, no restaging required. 
10. Use of concurrent curative radiotherapy will be permitted 
11. Patients have completed the first 6 cycles of trastuzumab IV as part of the (neo)adjuvant 
treatment  
 
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 who have 
been disease-free for at least 5 years, are eligible 
2. Patients with severe dyspnea at rest or requiring supplementary oxygen therapy 
3. Patients with other 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) 


 
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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 dose of study drug 
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, or a history of 
severe allergic or immunological reactions, e.g. difficult to control asthma 
10. Patients assessed by the investigator to be unable or unwilling to comply 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) 
Hemoglobin < 10 g/dL 
12. Impaired hepatic function (as indicated by any of the following): 
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 
 
 
Length of Study  
The local study is estimated to last approximately 4 years from enrollment of the first patient up 
to 1 year of recruitment,  8 months of study treatment, and 2 years of drug free follow-up.  
 
Treatment Duration 
Patients with HER2+ eBC who completed the first 6 cycles of trastuzumab IV as part of the 
(neo)adjuvant treatment can be included to continue to receive 12 cycles of trastuzumab to 
complete a total of 18 cycles of trastuzumab, unless intolerable toxicity or investigator-assessed 
disease progression occurs, or the patient withdraws consent. 
The first 3 cycles trastuzumab in the study will be administered intravenously in the hospital. The 
next 3 cycles trastuzumab will be administered subcutaneously with a handheld syringe by a 
trained HCP in the hospital and the last 6 cycles trastuzumab will be administered 
subcutaneously with a handheld syringe by a trained HCP at the patients home. 
 


 
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Safety Follow-up 
All patients will be followed up until investigator-assessed disease progression occurs, 
withdrawn consent, loss to follow-up, death or up to 24 months after the patient has received 
his/her last study treatment, whichever occurs first. 
 
End of Study 
Last Patient Last Visit (LPLV) in the follow-up period. 
 
Centers 
This is a multicenter study.  In total 23 centers will participate. 
 
Safety Outcome Measures 
Primary objective is safety and tolerability as a function of collected AEs. 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). 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 
o 
Cardiac AEs 
o 
CHF (according to NCI CTCAE version 4.0 and New York Heart Association [NYHA] 
Classification) 
o 
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: 
o 
Exposure to study medication 
o 
Duration of treatment, follow-up, and safety observation 
o 
ECOG 
o 
Concomitant medications 
o 
Laboratory data, vital signs and physical examination  
o 
Premature withdrawals and major protocol violations 
 
 
 
 
 
 
 


 
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Patient-Reported Outcome Measures 
 
 
Patient experience with the treatment provided during the in-hospital part of the study: 
Patients will be asked to complete a questionnaire (PSQ1, appendix 6) related to the 
quality of care provided during trastuzumab administration in the hospital prior to the first 
dose trastuzumab SC vial  administered at home = prior to cycle13. 
 
 
Patient experience with the treatment provided during the at home part of the study: 
Patients will be asked to complete a questionnaire (PSQ2, appendix 6) related to the 
quality of care provided during trastuzumab SC vial administration at home prior to the 
fifth dose trastuzumab SC vial administered at home = prior to cycle 17. 
 
 
Patient reporting of symptoms using the MD Anderson Symptom Inventory (MDASI, 
appendix 4): Patients will be asked to rate the severity of 13 core items on a scale from 
0 to 10. Patients will be asked to complete the MDASI 4 times: Prior to the first dose 
trastuzumab IV = prior to cycle 7, prior to the first dose trastuzumab SC vial = prior to 
cycle 10, prior to the first dose trastuzumab SC vial administered at home = prior to 
cycle 13 and prior to the fourth dose trastuzumab SC vial administered at home = prior 
to cycle 16. 
 
HCP-Reported Outcome Measures 
 
 
HCP overall satisfaction and perceived time savings with trastuzumab SC vial in the 
hospital will be assessed by a Health Care Professional Questionnaire (HCPEX-1, 
appendix 5): The HCPEX-1 questionnaire will be completed by a HCP administering 
trastuzumab IV and SC vial in the hospital after at least 3 patients completed the in 
hospital part of the study ( 3 patients must have completed treatment period 1 and 2). 
 
Other outcome Measures 
 
Patients will be interviewed by a HCP to assess: 
 
Patient experience with trastuzumab IV and SC vial administered in the hospital. 
Patients will be interviewed by a HCP to complete the PEX-P1 (appendix 7) prior to the 
third dose trastuzumab SC = prior to cycle 12. 
 
 
Patient experience with trastuzumab SC vial administered at home. 
Patients will be interviewed by a HCP to complete the PEX-P2 (appendix 7) at the safety 
follow-up visit, following 4 weeks after the last trastuzumab SC vial administration at 
home.  
 
 
Investigational Medicinal Products 
Test Product 
Both trastuzumab IV and SC are regarded as investigational medicinal product in this study. 
 
Trastuzumab SC  


 
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Trastuzumab SC will be administered subcutaneously with a fixed dose of 600 mg (irrespective 
of body weight) throughout the study treatment phase q3w for 9 cycles. Concurrent curative 
radiotherapy or anti-hormone therapy will be allowed as per institutional guidelines. 
In this local study, trastuzumab SC will be supplied as a vial for manual administration via hand-
held syringe, 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 administered by HCP. 
 
Trastuzumab IV. 
As a three-weekly regimen the recommended initial loading dose of trastuzumab IV is 8 mg/kg 
body weight. The recommended maintenance dose of trastuzumab IV at three-weekly intervals 
is 6 mg/kg body weight, beginning three weeks after the loading dose. 
Trastuzumab IV loading dose should be administered as a 90-minute intravenous infusion. Do 
not administer as an intravenous push or bolus. Herceptin intravenous infusion should be 
administered by a health-care provider prepared to manage anaphylaxis and an emergency kit 
should be available. Patients should be observed for at least six hours after the start of the first 
infusion and for two hours after the start of the subsequent infusions for symptoms like fever and 
chills or other infusion-related symptoms. Interruption or slowing the rate of the infusion may help  
control such symptoms. The infusion may be resumed when symptoms abate.  
If the initial loading dose was well tolerated, the subsequent doses can be administered as a 30-
minute infusion. 
 
Comparator 
Not applicable. 
 
 
Procedures (summary) 
The complete schedule of assessment is provided in Appendix 1 of the protocol. 
 
Statistical Methods 
The primary safety population will be defined as all enrolled patients who received at least one 
dose of trastuzumab IV study medication.  
The secondary safety population will be defined as all enrolled patients who received at least 
one dose of trastuzumab SC 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. All baseline 
summaries and efficacy analyses will be based on the ITT population. 
 
Study Analysis Methods 
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. Overall safety follow-up 24 months subsequently to the first safety follow-up visit. 
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. 


 
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Summaries will include the incidence of AEs and SAEs, AEs leading to premature 
discontinuation of study treatment, and specific cardiac AEs and SAEs. 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 safety parameters include summaries of LVEF, 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 analysis 
The secondary analyses of patients’ experience, patient reporting of symptoms and health care 
professional experience and overall satisfaction 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)  
Details will be described in the statistical analysis plan that will be finalized before data base 
lock. 
 
Determination of Study Sample Size 
One hundred subjects are foreseen to be enrolled to assess the overall safety and tolerability of 
trastuzumab SC vial when administered at home. This sample size was not based on a formal 
calculation but mainly driven by feasibility and a reasonable width of a 95% confidence interval 
for the rate of AEs and SAEs. Based on an expected rate of AEs of 97% (23) and 100 subjects, a 
95% confidence interval of 91% to 99% would be obtained. For an expected rate of SAEs of 21% 
(ref. 23) and 100 subjects, a 95% confidence interval ranging from 13% to 29% would be 
obtained. 
  


 
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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 
Hb 
hemoglobin 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor receptor 2 
HIV 
immunodeficiency virus 
HCP 
health care professional 


 
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HR 
hazard ratio 
ICH 
International Conference on Harmonization 
IHC 
immunohistochemistry 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IRB 
iDMC 
Institutional Review Board 
Internal Data Monitoring Committee 
IRR 
infusion-related reaction 
ISH 
in situ hybridization 
ITT 
intent-to-treat 
IV 
intravenous 
LVEF 
left ventricular ejection fraction 
LPLV 
last patient, last visit 
mBC 
metastatic breast cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
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 
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 
 
 


 
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SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOC 
system-organ class 
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 – TREATMENT 
OPTIONS FOR EARLY 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.  
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 disease 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 for 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 and neoadjuvant treatment of eBC (Untch 2010). The use of trastuzumab 
in the adjuvant setting is 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 improved the outcome for eBC patients with HER2-positive disease. 
 
1.2 
BACKGROUND ON STUDY TREATMENTS  
1.2.1 
HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 (HER2) 
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). There is clear evidence that increased expression and activity of 
HER2 induces cell transformation and tumorigenesis. In BC, unlike a variety of other epithelial 


 
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malignancies, HER2 gene amplification is 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). In current practice, most investigators report that the 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 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, compared to 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) 
and eBC (approved in 2005) 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 both the adjuvant 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 


 
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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 clinically relevant 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). 
Currently, the marketed formulation of trastuzumab is for intravenous administration (trastuzumab 
IV, Herceptin®). The majority of available clinical data have been obtained with trastuzumab IV. 
For the regulatory status and approved indications in specific countries, please refer to local 
prescribing information. 
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 18 cycles q3w. 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 
Pharmacokinetics 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 


 
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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)  
 
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 


 
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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 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 
Safety of Trastuzumab IV  
1.2.2.4.1 
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 


 
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incidence of symptomatic heart failure events was 2.0% in trastuzumab-treated patients 
compared with 0.45% in the chemotherapy-alone arm, and that and the majority (86%) of these 
patients recovered with appropriate treatment (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). 
1.2.2.4.2 
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 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 


 
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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. 
1.2.2.5 
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, such as in the adjuvant setting. 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 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 
1.2.2.7.1) and BO22227, HannaH studies (Section 1.2.2.7.2). 


 
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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.  
1.2.2.5.1 
Recombinant human hyaluronidase (rHuPH20) 
1.2.2.5.1.1 
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.  
1.2.2.5.1.2 
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.  
 
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 


 
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site reactions, consisting of erythema, pain, edema, induration or pruritus (communication 
Halozyme Therapeutics Inc. on preliminary study results) 
 
 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.  
1.2.2.6 
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.  
1.2.2.7 
Clinical Studies with Trastuzumab SC 
Trastuzumab SC (formulated with rHuPH20) has been reported in one completed clinical trial 
(BP22023, CP2) (Wynne et al. 2010) and one ongoing clinical trial in eBC (BO22227, HannaH) 
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  
 
See the Herceptin Investigator's Brochure for details on clinical studies. 
1.2.2.7.1 
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.  


 
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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. 
1.2.2.7.2 
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 


 
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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). 
1.2.2.7.3 
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 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). 
1.2.2.7.4 
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 


 
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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. 
  
1.3 
STUDY RATIONALE AND BENEFIT–RISK 
ASSESSMENT 
Trastuzumab SC is a new route of administration. It has demonstrated similar PK and efficacy in 
pCR in the treatment of HER2-positive eBC in the neoadjuvant setting as compared to 
trastuzumab IV. No new safety signals were identified. 
Roche is conducting a global phase IIIb Umbrella study to assess the safety and tolerability of 
trastuzumab solution injected subcutaneously (vial) in patients with HER2-positive eBC. 
This sudy is conducted under this umbrella and will there for contribute safety data to a global 
database for a pooled analysis.  
In this Umbrella study, the safety and tolerability of trastuzumab SC will be explored in a wider 
patient population to gain better understanding of the safety profile of trastuzumab SC in the 
treatment of HER2-positive eBC patients, whilst addressing additional local/regional scientific 
questions and investigations in patient sub-populations.  
In this local study, the safety and tolerability of trastuzumab SC will be explored further to gain 
better understanding of the safety profile of trastuzumab SC in the treatment of HER2-positive 
eBC when administered at home. 
Today, patients receive 18 cycles of trastuzuamb IV every 3 weeks as part of the adjuvant 
treatment. The administration of trastuzumab subcutaneous formulation at home could represent 
a more convenient option for patients and health care professionals in the future. 
1.3.1 
RATIONALE FOR TEST PRODUCT DOSAGE 
 
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 trastuzumab serum trough 
concentrations (Ctrough) that are non-inferior to those obtained with q3w trastuzumab IV 


 
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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 1.2.2.7.1) 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 WITH EBC 
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. 
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 18 cycles.  
Trastuzumab is a standard component of adjuvant treatment in patients with HER2-positive eBC 
It is fact that patients have to attend clinics q3w ubntil 18 infusions of trastuzumab IV are 
completed. 


 
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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 adjuvant setting, i.e. assisted 
administration using a conventional syringe (vial formulation) and self-administration using a SID. 
The observed incidence of CHF-related SAEs 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.  
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 1.2.2.7.2 for details). Efficacy is hence expected to be comparable to that 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 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).  
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 


 
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completion of chemotherapy. 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 (Single Injection Device) versus with the 
conventional syringe and needle. 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). 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 
1.2.2.7.4) 
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 
will give patients greater independence which is believed 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 this study is to assess the overall safety and tolerability of subcutaneous 
(SC) trastuzumab with assisted administration using a conventional syringe and needle (vial 
formulation, hereafter referred to as trastuzumab SC vial) when administered at home for the 
treatment of patients with HER2-positive (HER2+) early breast cancer (eBC). 


 
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2.2 
SECONDARY OBJECTIVES 
To describe: 
• 
The evolution of individual patient experience across treatment periods: 
• 
Patient experience with trastuzumab IV administered in the hospital. 
• 
Patient experience with trastuzumab SC vial administered in the hospital. 
• 
Patient experience with trastuzumab SC vial administered at home. 
• 
Patient reporting of symptoms. 
• 
Patient reporting on the quality of care provided during treatment in the hospital 
and at home.  
• 
HCP overall satisfaction and perceived time savings with trastuzumab SC vial 
administered in the hospital. 
• 
Disease-free survival (DFS) 
 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
The study is a Phase IIIb, open-label, multinational, multicenter, study to assess the safety and 
tolerability of trastuzumab subcutaneous formulation when administered at home for the 
treatment of patients with HER2-positive eBC. Safety data will be collected and transferred to a 
global database for a pooled analysis.  
This study specifically investigates the administration of trastuzumab subcutaneous vial 
administered at home by a HCP. Collecting information on how patients experience being treated 
at home is an important aspect of this study. The evolution of individual patient experience across 
treatment periods will be evaluated. This study incorporates patient reported outcomes for 
experience and satisfaction with the treatment provided. 
Patients with HER2+ eBC who completed  the first 6 cycles of trastuzumab IV as part of the 
(neo)adjuvant treatment can be included to continue to receive 12 cycles of trastuzumab to 
complete a total of 18 cycles of adjuvant trastuzumab. 
 
The 12 cycles of trastuzumab will be administered according to following schedule: 
 
 
Trastuzumab IV will be administered in the hospital by a HCP for the first 3 cycles 
(Trastuzumab Cycle 7 to 9 defined as treatment period 1) 
 
Trastuzumab SC vial will be administered in the hospital by a HCP for the next 3 cycles 
(Trastuzumab Cycle 10 to 12 defined as treatment period 2) 
 
Trastuzumab SC vial will be administered at home by a  HCP for the following 6 cycles 
(Trastuzumab Cycle 13 to 18 defined as treatment period 3) 
 
The study is expected to include approximately 100 patients.  


 
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The study is estimated to last approximately 4 years. Patient enrolment will be staggered 
according to local study timelines and is expected to take up to 1 year. Patients will be treated in 
the study for a period of 8 months with a follow-up of 24 months. 
Schedules of assessments for patients are provided in Appendix 1. 
3.2 
PATIENT POPULATION 
 
Patients with HER2-positive early breast cancer who were eligible for a (neo)adjuvant treatment 
with trastuzumab, eg. clinical stage I (T1, N0, M0) to IIIC (any T, N3, M0) and completed  the first 
6 cycles of trastuzumab IV as part of the (neo)adjuvant treatment can be included to continue to 
receive 12 cycles of adjuvant trastuzumab to complete a total of 18 cycles. 
3.3 
INTERNAL DATA MONITORING COMMITTEE 
Adequate monitoring and scientific oversight will be ensured by the country medical monitor and 
the medical monitor of the data management company. Both roles ensure an adequate 
monitoring of the safety of the patients.   
3.4 
LENGTH OF STUDY  
The study is estimated to last approximately 4 years from enrollment of the first patient into study 
(up to 1 year of recruitment 8 months of study treatment, and 2 years of follow-up).  
3.5 
SAFETY FOLLOW-UP 
All patients will be followed up until investigator-assessed disease progression occurs, withdrawn 
consent, loss to follow-up, death or up to 24 months after the patient has received his/her last 
study treatment, whichever occurs first. 
3.6 
END OF STUDY 
Last patient last visit (LPLV) in the follow-up period.  
3.7 
OVERALL NUMBER OF PATIENTS 
The study is expected to include approximately 100 patients.  
3.8 
PATIENT ENROLMENT 
100 patients with HER2+ eBC who completed the first 6 cycles trastuzumab IV as part of a 
(neo)adjuvant treatment, will be enrolled over a period of 12 months in 23 sites in 2 countries 
(Belgium and Israel). 
 
3.9 
COUNTRIES/CENTERS 
The study will be performed in  2 countries (Belgium and Israel) with approximately 23 sites.  
 


 
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3.10 
RATIONALE FOR STUDY DESIGN 
Trastuzumab SC is a new administration route that has demonstrated efficacy and tolerability in 
the treatment of HER2-positive eBC (see Section 1.2.2). In this study, the safety and tolerability of 
trastuzumab SC will be explored further to gain better understanding of the safety profile of 
trastuzumab SC in the treatment of HER2-positive eBC when administered at home. 
The administration of trastuzumab subcutaneous formulation at home could represent a more 
convenient option for patients and health care professionals in the future. 
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. 
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.  
If safety and compliance are provided, the at home administration of trastuzumab subcutaneous 
formulation might represent a more convenient treatment option for patients in the future.  
 
3.10.1 
RATIONALE FOR POOLING STRATEGY 
This study is part of a multi-center, international global umbrella study. 
The data from this study and other 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. Data will 
be further explored using the following subgroups of interest: 
 
eBC neo-adjuvant 
 
eBC adjuvant 
 
mBC first line 
 
mBC second and later line 


 
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 
mBC long responders 
 
trastuzumab SC monotherapy 
 
trastuzumab SC combination therapy 
3.10.2 
RATIONALE FOR TEST PRODUCT REGIMEN 
Trastuzumab IV and trastuzumab SC are regarded as investigational medicinal products (IMPs).  
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; Goldhirsch 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 treatment parameters, the 
efficacy of trastuzumab SC is expected to be similar to that observed in trastuzumab IV trials. 
Patients have completed the first 6 cycles trastuzumab IV as part of their normal care, before 
being enrolled in this study. All eligible patients will receive the following 12 cycles trastuzumab  
in the study. 
Trastuzumab IV will be administered for the first 3 cycles in this study unless intolerable toxicity 
or investigator-assessed disease progression occurs, or the patient withdraws consent. 
Trastuzumab IV will be administered as a three-weekly regimen. The recommended initial 
loading dose of trastuzumab IV is 8 mg/kg body weight. The recommended maintenance dose of 
trastuzumab IV at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the 
loading dose. 
Trastuzumab IV loading dose should be administered as a 90-minute intravenous infusion. Do 
not administer as an intravenous push or bolus. Patients should be observed for at least six hours 
after the start of the first infusion and for two hours after the start of the subsequent infusions for 
symptoms like fever and chills or other infusion-related symptoms.Interruption or slowing the rate 
of the infusion may help  control such symptoms. The infusion may be resumed when symptoms 
abate. If the initial loading dose was well tolerated, the subsequent doses can be administered as 
a 30-minute infusion. 
 
All eligible patients will receive the next 6 cycles trastuzumab subcutaneously. A fixed dose of 
600 mg trastuzumab SC throughout the study, administered q3w (irrespective of body weight) for 
6 cycles , unless intolerable toxicity or investigator-assessed disease progression occurs, or the 
patient withdraws consent. Known advantages of the use of a 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 trastuzumab SC was selected with the aim of achieving trastuzumab serum 
trough concentrations (Ctrough) that are non-inferior to those obtained with trastuzumab IV 
administration. Importantly, this dose is consistent with the findings of the BP22023 (CP2) trial 
and identical to that evaluated in the recently reported BO22227 (HannaH) study.  
 
 


 
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3.11 
OUTCOME MEASURES  
3.11.1 
SAFETY OUTCOME MEASURES 
The safety outcome measures for this study are as follows: 
The primary objective is safety and tolerability as a function of collected Aes. 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. 
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 
o Cardiac AEs 
o CHF (according to NCI CTCAE version 4.0 and New York Heart Association [NYHA] 
Classification) 
o LVEF over time. In the event of an asymptomatic decline in LVEF, an algorithm 
(Appendix 2) will be used to determine whether to continue trastuzumab treatment 
 
Secondary safety assessments will include the following: 
o Exposure to study medication 
o Duration of treatment, follow-up, and safety observation 
o ECOG 
o Concomitant medications 
o Laboratory data, vital signs and physical examination  
o Premature withdrawals and major protocol violations 
 
3.11.2 
PATIENT-REPORTED OUTCOME MEASURES 
 


 
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 
Patient experience with the treatment provided during the in-hospital part of the study: 
Patients will be asked to complete a questionnaire (PSQ1 - Appendix 6) related to the 
quality of care provided during trastuzumab administration in the hospital prior to the first 
dose trastuzumab SC vial  administered at home = prior to cycle 13. 
 
 
Patient experience with the treatment provided during the at home part of the study: 
Patients will be asked to complete a questionnaire (PSQ2 - Appendix 6) related to the 
quality of care provided during trastuzumab SC vial administration at home prior to the 
fifth dose trastuzumab SC vial administered at home = prior to cycle 17. 
 
 
Patient reporting of symptoms using the MD Anderson Symptom Inventory (MDASI, 
appendix 4):Patients will be asked to rate the severity of 13 core items on a scale from 0 
to 10. Patients will be asked to complete the MDASI 4 times: Prior to the first dose 
trastuzumab IV = prior to cycle 7, prior to the first dose trastuzumab SC vial = prior to 
cycle 10, prior to the first dose trastuzumab SC vial administered at home = prior to cycle 
13 and prior to the fourth dose trastuzumab SC vial administered at home = prior to cycle 
16. 
 
3.11.3 
HCP-REPORTED OUTCOME MEASURES  
 
HCP overall satisfaction and perceived time savings with trastuzumab SC vial in the 
hospital will be assessed by a Health Care Professional Questionnaire (HCPEX-1): The 
HCPEX-1 questionnaire will be completed by a HCP administering trastuzumab IV and 
SC vial in the hospital after at least 3 patients completed the in hospital part of the study 
( 3 patients must have completed treatment period 1 and 2). 
3.11.4 
OTHER 
Patients will be interviewed by a HCP to assess: 
 
Patient experience with trastuzumab IV and SC vial administered in the hospital. 
Patients will be interviewed by a HCP to complete the PEX-P1 (appendix 7) prior to the 
third dose trastuzumab SC = prior to cycle 12. 
 
 
Patient experience with trastuzumab SC vial administered at home. 
Patients will be interviewed by a HCP to complete the PEX-P2 (appendix 7) at the safety 
follow-up visit, following 4 weeks after the last trastuzumab SC vial administration at 
home.  
 
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
The study population will include patients with eBC with Eastern Cooperative Oncology Group 
(ECOG) performance status 0–1 (Oken et al. 1983). This can include patients with concomitant 


 
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hormonal therapy and prior anti-HER2 therapy. 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 5.2.3 for 
further details. 
Patients must meet the following criteria for study entry: 
1. 
Female and male patients aged ≥ 18 years 
2. 
Signed informed consent prior to any study specific procedure 
3. 
Able and willing to comply with protocol 
4. 
ECOG performance status 0–1 
5. 
Hormonal therapy will be allowed as per institutional guidelines 
6. 
Left ventricular ejection fraction (LVEF) of ≥ 50% measured by echocardiography 
(ECHO) or multiple gated acquisition (MUGA) scan prior to first dose of trastuzumab, or, 
for those who were receiving trastuzumab when beginning the study, documented 
results within an acceptable limit from a cardiac assessment within 3 months prior to 
enrolment 
7. 
HER2-positive disease IHC3+ or ISH positive as determined in a local laboratory that is 
experienced/certified in HER2-expression testing using an accurate and validated 
assay 
8. 
Histologically confirmed non-metastatic primary invasive adenocarcinoma of the breast 
9. 
No evidence of residual, locally recurrent or metastatic disease after completion of 
surgery and chemotherapy (neo-adjuvant or adjuvant). Available patient data 
supporting continuation of trastuzumab, no restaging required 
10. Use of concurrent curative radiotherapy will be permitted 
11. Patients completed the first 6 cycles of trastuzumab IV as part of the (neo)adjuvant 
treatment 
 
4.3 
EXCLUSION CRITERIA  
Patients who meet any of the following criteria will be excluded from study entry: 
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 who 
have been disease-free for at least 5 years, are eligible 
2. 
Patients with severe dyspnea at rest or requiring supplementary oxygen therapy 
3. 
Patients with other concurrent serious diseases that may interfere with planned 
treatment, including severe pulmonary conditions/illness 


 
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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 dose of study drug 
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®, or the adhesive of the subcutaneous device, or a history of severe allergic 
or immunological reactions, e.g. difficult to control asthma 
10. Patients assessed by the Investigator to be unable or unwilling to comply 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 x 109/L) 
b) 
Platelets < 100,000 / mm3 (< 100 x 109/L) 
c) 
Hemoglobin < 10 g/dL 
12. Impaired hepatic function (as indicated by any of the following): 
a) 
Serum total bilirubin > 1.5 x upper limit of normal (ULN) 
b) 
Alanine amino transferase (ALT) and/or aspartate amino transferase (AST) > 2.5 x 
ULN 
c) 
Alkaline phosphatase (ALP) > 2.5 x ULN 
13. Inadequate renal function, as indicated by serum creatinine > 1.5 x ULN 
 


 
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4.4 
STUDY TREATMENT  
Trastuzumab SC vial and trastuzumab IV are regarded as IMP in this study.  
4.4.1 
FORMULATION, PACKAGING, AND HANDLING 
The study drugs will be manufactured by the Sponsor. Study drug packaging will be overseen by 
the Sponsor clinical trial supplies department and bear a label with the identification required by 
local law, the protocol number, drug identification and dosage. 
The packaging and labeling of the study medication will be in accordance with Sponsor standards 
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 temperature conditions, and report any 
deviations or product complaints to the Monitor upon discovery. 
4.4.1.1 
Trastuzumab IV 
Herceptin 150 mg powder for concentrate for solution for infusion. One 15 ml clear glass type I 
vial with butyl rubber stopper laminated with a fluoro-resin film containing 150 mg of trastuzumab. 
Appropriate aseptic technique should be used. Each vial of Herceptin is reconstituted with 7.2 ml 
of water for injections (not supplied). Use of other reconstitution solvents should be avoided.  
After reconstitution with water for injections the reconstituted solution is physically and chemically 
stable for 48 hours at 2°C – 8°C. Any remaining reconstituted solution should be discarded.  
Solutions of Herceptin for infusion are physically and chemically stable in polyvinylchloride, 
polyethylene or polypropylene bags containing sodium chloride 9 mg/ml (0.9%) solution for 
injection for 24 hours at temperatures not exceeding 30°C.  
From a microbiological point of view, the reconstituted solution and Herceptin infusion solution 
should be used immediately. The product is not intended to be stored after reconstitution and 
dilution unless this has taken place under controlled and validated aseptic conditions. If not used 
immediately, in-use storage times and conditions are the responsibility of the user. 
Vials of trastuzumab SC should be stored at 2°C to 8°C in appropriate facilities at the institution.  
Trastuzumab for intravenous administration will be supplied by Roche. Packaging of trastuzumab 
for intravenous use will be overseen by the Roche Clinical Trial Supplies department.  
For further details, see the trastuzumab IV local prescribing information. 
 


 
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4.4.1.2 
Trastuzumab SC 
The drug product in the vials for manual injection contains 120 mg/mL trastuzumab. The drug 
product 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-trehalose 
dihydrate (bulking agent), methionine (stabilizer), and polysorbate 20 (stabilizer/emulsifier) in 
water for injection (WFI) at a pH of 5.5 ± 0.5. Vials of trastuzumab SC should be stored at 2°C to 
8°C in appropriate facilities at the institution.  
 
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 is considered an integral medicinal product and 
therefore as a single IMP for this study.  
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.  
For further details, see the trastuzumab Investigator’s Brochure or local prescribing information. 
4.4.2 
DOSAGE, ADMINISTRATION, AND COMPLIANCE 
The trastuzumab regimen in this daughter protocol will only include mono therapy, for the 
treatment of HER2+ eBC. Patients will receive 12 cycles of trastuzumab to complete a total of 18 
cycles of trastuzumab therapy. 
Trastuzumab IV will be administered intravenously q3w for the first 3 cycles. 
Trastuzumab IV will be administered intravenously in the hospital. 
The recommended initial loading dose is 8 mg/kg body weight. 
The recommended maintenance dose of Herceptin at three-weekly intervals is 6 mg/kg body 
weight, beginning three weeks after the loading dose. 
If the patient misses a dose of trastuzumab IV by one week or less, then the usual maintenance 
dose (three-weekly regimen: 6 mg/kg) should be given as soon as possible. Do not wait until the 
next planned cycle. Subsequent maintenance doses (three-weekly regimen: 6 mg/kg 
respectively) should then be given according to the previous schedule.  
If the patient misses a dose of trastuzumab IV by more than one week, a re-loading dose should 
be given over approximately 90 minutes (three-weekly regimen: 8 mg/kg). Subsequent Herceptin 
maintenance doses (three-weekly regimen 6 mg/kg respectively) should then be given (three-
weekly regimen every 3 weeks) from that point. 
 
Trastuzumab SC vial will be administered subcutaneously with a fixed dose of 600 mg 
(irrespective of body weight) q3w for the next 9 cycles.  
Concurrent curative radiotherapy or anti-hormone therapy will be allowed as per institutional 
guidelines. 


 
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Trastuzumab SC will be supplied as a vial for manual administration via hand-held syringe and 
will be subcutaneously injected slowly over a period of up to 5 minutes by a trained HCP. 
 
Vial: ready to use solution (600 mg trastuzumab/5mL and rHuPH20 10000 units/5 mL) for 
manual administration using a hand-held syringe. 
The recommended dose  for trastuzumab SC is 600mg/5ml given every 3 weeks. The fixed dose 
should not be adjusted to the patient’s body weight and there is no need for a loading dose on the 
first administration. 
Vials of trastuzumab SC should be stored at 2°C to 8°C in appropriate facilities at the institution. 
Once removed from the refrigerator, trastuzumab SC must be administered within 6 hours and 
should not be kept above 25°C. 
At all times during this study the trastuzumab SC vials will be stored in appropriate facilities at the 
institution (hospital pharmacy). 
Trastuzumab SC vial is supplied as a ready-to-use solution and does not need to be reconstituted 
nor diluted.  
It is not necessary to prepare trastuzumab SC in a sterile environment, this can be done in the 
administration room. 
During the at home period of the study,  trastuzumab SC will be administered at home by trained 
HCP.  
The HCP administering trastuzumab SC vial at home will pick up the unopened trastuzumab SC 
vial at the pharmacy of the institution. During transport the storage conditions as described above 
are to be respected.  
Empty trastuzumab SC vials need to be returned to the hospital pharmacy on the next pick-up.  
If a patient misses a dose of trastuzumab SC, it tis recommended that the next dose of 
600mg/5ml be administered as soon as possible. Subsequent doses should be given according 
to the normal schedule. 
Guidelines for dosage modification and treatment interruption or discontinuation are provided in 
Section 5.1.4.  
 
4.4.3 
INVESTIGATIONAL MEDICINAL PRODUCT ACCOUNTABILITY 
All IMP required for completion of this study will be provided by the Sponsor. 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.  


 
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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.  
4.4.3.1 
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.  
 
4.4.3.2 
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 
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 


 
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4.4.4 
POST-TRIAL ACCESS TO TRASTUZUMAB SC 
Roche does not intend to provide trastuzumab SC (or IV) or other study interventions to patients 
after conclusion of the study or any earlier patient withdrawal. Subsequent treatment will be at the 
investigator’s discretion and according to local practice.  
4.5 
CONCOMITANT THERAPY 
 
4.5.1 
PERMITTED THERAPY  
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, 
herbal/homeopathic remedies, nutritional supplements) used by a patient from 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 side effects of trastuzumab, may be 
used at the discretion of the investigator. Concomitant medication and treatment should be 
prescribed according to the investigator’s judgment and following the local labels for trastuzumab. 
Concomitant medication 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  
 
Hormonal therapy for patients with hormone receptor positive disease (according to local 
clinical practice) 
 
Bisphosphonates may be given according to their product license and routine clinical 
practice, at the investigator’s discretion, to treat documented osteoporosis 
 
Palliative surgical procedures. Any diagnostic, therapeutic or surgical procedure performed 
during the study period should be recorded including the dates, description of the 
procedure(s), and any clinical findings 
 
Palliative radiotherapy (if indicated) 
4.5.2 
PROHIBITED THERAPY 
The following therapies are prohibited: 
 
Concurrent treatment with other systemic HER2-directed immunotherapy 
 
Concurrent investigational agents or anthracyclines 
 


 
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4.6 
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 regard to the 
protocol’s inclusion and 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’s inclusion and exclusion criteria is to be completed by the Investigator. 
An Eligibility Screening Failure Log must be maintained by the Investigator. 
4.6.1 
DESCRIPTION OF STUDY ASSESSMENTS  
4.6.1.1 
Mandatory Procedure for Enrolment  
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. 
The socio-demographic/baseline characteristic data listed below will be captured, where available. 
For the schedule of mandatory clinical assessments, please refer to appendix 1.  
4.6.1.1.1 
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. 
4.6.1.1.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, BC disease history (including 
ER/PgR status, prior anti-cancer treatments, 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 current concomitant treatments for eBC, as well 
as the route and dose, will be collected when available. 
Demographic data will include date of birth, gender, and self-reported ethnic origin. 
4.6.1.1.3 
HER2 Status 
To be eligible for the study, patients with eBC must have confirmed HER2-positivity defined as 
one of the following and in line with local reibursement criteria if applicable: 
 
A score of 3+ by IHC 


 
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 
Gene amplification positive by ISH performed by a validated and approved test in a certified 
and experienced center 
4.6.1.1.4 
Vital signs and physical examination 
Assessment of 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. 
4.6.1.1.5 
Pregnancy test 
A serum pregnancy test in women of childbearing potential will be performed within 7 days prior 
to the first dose of study treatment. Any positive urine pregnancy test needs to be confirmed by 
serum pregnancy test. 
4.6.1.1.6 
Past and current concomitant treatments  
All concomitant medications and prior treatments for eBC 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. 
4.6.1.1.7 
ECOG performance status 
To be eligible for the study, patients should have ECOG PS 0–1 according to the ECOG PS 
Scale (Oken et al. 1982). 
4.6.1.1.8 
Baseline safety data  
Baseline safety data will be collected as described in Section 4.6.1.2. Baseline safety data 
include: AEs and SAEs (as described in Section 4.6.1.2.3), cardiac safety (standard 12-lead ECG 
and LVEF assessments as described in Section 4.6.1.2.3, hematology and biochemistry (as 
described in Section 4.6.1.2.4) and concomitant medication. 
4.6.1.2 
Clinical Assessments During Treatment Period 
4.6.1.2.1 
Timing of Assessments during Treatment 
Please see appendix 1 for the schedule of assessments performed during the treatment period. 


 
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4.6.1.2.2 
Tumor and response evaluations: Breast cancer follow-up 
DFS is a secondary efficacy endpoint for patients with eBC 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 BC 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 uncertainty, disease relapse should be confirmed by histological or 
cytological examination of a 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, efforts should be made to obtain an autopsy report. 
4.6.1.2.2 
ECOG performance status 
Performance status will be evaluated using the ECOG Performance Status Scale (Oken et al. 
1982).  
4.6.1.2.3 
Safety clinical assessments  
The following clinical safety assessments and procedures will be performed. For the schedule of 
mandatory safety assessments please refer to Appendix 1. For full details of safety assessments 
please refer to Section 5.1. 
4.6.1.2.3.1 
Adverse events 
The National Cancer Institute (NCI) Common Terminology Criteria 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 and any Cardiac Event related to CHF occurring during the study will be 
reported to the Sponsor within 24 hours of the investigator becoming aware of them. 
For other instructions on documenting and handling AEs please refer to Appendix 1  and Section 
5.3. 
4.6.1.2.3.2 
Vital signs and physical examination 
These assessments will be performed as described in Section 4.6.1.1.2 for enrolment of patients. 
4.6.1.2.3.3 
Electrocardiograms 
A standard 12-lead ECG needs to be performed as specified in Appendix 1, Schedule of 
Assessments. 
4.6.1.2.3.4 
LVEF 
LVEF assessments should be performed by either ECHO or MUGA scan within 3 months prior to 
the first trastuzumab SC administration to be eligible for participation in the study: the same 
imaging technique should be used per patient throughout the study. ECHO should be the method 


 
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of choice for these assessments. LVEF assessment should be performed as per institutional 
practice. 
Symptomatic left ventricular dysfunction (congestive heart failure [CHF]) 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 monitored according to standard medical practice. 
The incidence of CHF will also be recorded throughout the study. 
4.6.1.2.3.5 
Concomitant medication 
All concomitant medications must be reported in the eCRF starting at the Screening visit. These 
include:  
 
Date and extent 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 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) 
4.6.1.2.4 
Laboratory assessments  
Normal ranges for the study laboratory parameters must be supplied to the Sponsor before the 
study starts (Appendix 1). 
The following laboratory assessments and procedures will be performed in patients with eBC. For 
the schedule of mandatory laboratory assessments in patients with eBC please refer to Appendix 
1. HER2 status determination is described in Section 4.6.1.1.3. 
 
4.6.1.2.4.1 
Hematology and biochemistry 
Hematology tests include: Hb, WBC and differential, ANC, and platelet count. 
Biochemistry tests include: creatinine, urea (BUN), SGPT (ALT), SGOT (AST), total bilirubin, ALP, 
albumin, sodium, potassium, and calcium. 


 
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All hematology and blood chemistry laboratory tests will be completed at local laboratories. 
Additional hematology and biochemistry tests may be performed as per institutional practice, but 
these data will not be collected. 
4.6.1.2.4.2 
Pregnancy test 
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. 
4.6.1.2.5 
Other Assessments During Treatment Period 
4.6.1.2.5.1 
Patient Reported Outcomes 
4.6.1.2.5.1.1 Patient reporting of symptoms 
 
Patient reporting of symptoms using the MD Anderson Symptom Inventory (MDASI, 
appendix 4):Patients will be asked to rate the severity of 13 core items on a scale from 0 
to 10. Patients will be asked to complete the MDASI 4 times: Prior to the first dose 
trastuzumab IV = prior to cycle 7, prior to the first dose trastuzumab SC vial = prior to 
cycle 10, prior to the first dose trastuzumab SC vial administered at home = prior to 
cycle 13 and prior to the fourth dose trastuzumab SC vial administered at home = prior 
to cycle 16. 
 
4.6.1.2.5.1.2 Patient reporting of experience and overall satisfaction 
 
Patient experience with the treatment provided during the in-hospital part of the study: 
Patients will be asked to complete a questionnaire (PSQ1, appendix 6) related to the 
quality of care provided during trastuzumab administration in the hospital prior to the first 
dose trastuzumab SC vial  administered at home = prior to cycle 13. 
 
 
Patient experience with the treatment provided during the at home part of the study: 
Patients will be asked to complete a questionnaire (PSQ2, appendix 6) related to the 
quality of care provided during trastuzumab SC vial administration at home prior to the 
fifth dose trastuzumab SC vial administered at home =  prior to cycle 17. 
 
 
 
4.6.1.2.5.2 
HCP reported Outcomes 
 
HCP overall satisfaction and perceived time savings with trastuzumab SC vial in the 
hospital will be assessed by a Health Care Professional Questionnaire (HCPEX-1, 
appendix 5): The HCPEX-1 questionnaire will be completed by a HCP administering 
trastuzumab IV and SC vial in the hospital after at least 3 patients completed the in 
hospital part of the study ( 3 patients must have completed treatment period 1 and 2). 
 


 
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4.6.1.3.5.3  Other  
Patients will be interviewed by a HCP to assess: 
 
Patient experience with trastuzumab IV and SC vial administered in the hospital. 
Patients will be interviewed by a HCP to complete the PEX-P1 (appendix 7) prior to the 
third dose trastuzumab SC = prior to cycle 12. 
 
 
Patient experience with trastuzumab SC vial administered at home. Patients will be 
interviewed by a HCP to complete the PEX-P2 (appendix 7) at the safety follow-up visit, 
following 4 weeks after the last trastuzumab SC vial administration at home. 
4.6.1.3 
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 (see Section 4.6.1.2) except that no treatment drug will 
be administered.  
Please see Appendix 1 for the schedule of assessments performed at the safety follow-up visit. 
4.6.1.4 
Clinical Assessments in Follow-up visits 
Cardiac assessments at 6, 12, 18 and 24 months 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 followed as outlined in Sections 5.5 and 5.6. 
Please see Appendix 1 or the schedule of assessments performed in the follow-up visits.  
After the follow-up visit, patients will continue follow-up as recommended in routine clinical 
practice (every 6 months to evaluate disease progression and cardiac function) for a maximum of 
24 months following treatment cessation or until disease progression, whichever occurs first. 
Please see Appendix 1  for the schedule of assessments performed in the follow-up visits. 
 
 
4.6.1.5 
Follow-Up Assessments 
After the safety follow-up visit, AEs should be followed as outlined in Sections 5.5 and 5.6. 
Please see Appendix 1  for the schedule of follow-up assessments. 
4.6.1.6 
Assessments at Unplanned Visits 
Please see Appendix 1 for assessments that are required to be performed in case of an 
unplanned visit. 


 
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4.7 
PATIENT, STUDY, AND SITE DISCONTINUATION 
4.7.1 
PATIENT DISCONTINUATION 
The Investigator has the right to discontinue a patient from study drug or withdraw a patient from 
the study at any time. In addition, patients have the right to voluntarily discontinue study drug or 
withdraw from the study at any time for any reason. Reasons for discontinuation of study drug or 
withdrawal from the study may include, but are not limited to, the following: 
 
Patient withdrawal of consent at any time 
 
Any medical condition that the Investigator or Sponsor determines may jeopardize the 
patient’s safety if he or she continues in the study 
 
Investigator or Sponsor determines it is in the best interest of the patient 
 
Patient non-compliance, specifically defined as non-compliance with the study procedures, 
the schedule of assessments or protocol-defined timelines 
4.7.1.1 
Discontinuation from Study Drug 
Patients must discontinue study drug if they experience 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. 
Patients who discontinue study drug prematurely will be asked to return to the clinic for a safety 
follow-up visit (see Section 5.6) and may undergo follow-up assessments (see Section 4.6.1.4). 
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. 
4.7.1.2 
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. 
4.7.2 
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. 


 
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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 
Trastuzumab IV will be administered intravenously.  
The recommended maintenance dose of Herceptin at three-weekly intervals is 6 mg/kg body 
weight, beginning three weeks after the loading dose. 
Trastuzumab SC vial will be administered subcutaneously at a fixed does 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 
Assessments). 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 3 cycles. 
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 haematological and 
biochemical parameters) will be graded according to National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 (see Appendix 3). Changes in 
concomitant medication will be recorded at each study visit. 
Trastuzumab will be given as specified in Section 4.4.2. 


 
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Before starting a new treatment cycle, toxicity must have resolved as specified in the following 
sections. 
Trastuzumab 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. 
5.1.2 
CARDIAC SAFETY ASSESSMENTS 
Cardiac function will be evaluated regularly throughout the study, by measuring LVEF using 
echocardiography, MUGA scan or MRI (method selected according to local practice), ECG, and 
assessment of cardiac signs and symptoms.  
Cardiac safety assessments will be performed at screening, approximately 3-monthly during 
trastuzumab treatment with the results available prior to trastuzumab administration, at the Safety 
Follow-up visit (LVEF assessment may occur prior to the day of the Safety Follow-up visit if 
clinically indicated) and then at 6, 12, 18 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 3 months prior to first trastuzumab 
IV administration. To be eligible for participation in this study, patients must have a baseline LVEF 
≥ 50%. The method of assessment (ECHO, MUGA, or MRI) 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. LVEF assessment results must be available before/on the day of the next 
scheduled trastuzumab administration, and, should a reduction in LVEF be noticed compared to 
screening, 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 Appendix 1 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 3). 
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 screening and to a LVEF < 50% for eBC 
patients may require temporary or permanent cessation of trastuzumab in accordance with the 


 
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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; see Section 4.6.1.2.2. 
5.1.3.1 Infusion-Associated Symptoms and Allergic Reactions 
 
Administration of monoclonal antibodies, including trastuzumab, may cause infusion-associated 
symptoms such as fever, chills, hypotension, shortness of breath, skin rashes, headache, 
nausea, vomiting, or allergic reactions. Patients with extensive pulmonary disease, e.g., 
lymphangitis, multiple metastases, recurrent pleural effusions, and those with preexisting 
pulmonary compromise who are treated with trastuzumab, may be at increased risk of serious 
infusion-associated symptoms. Therefore, careful consideration must be made before enrolling 
patients with chronic lung disease into the study. 
Study treatment will be administered in a setting with emergency equipment and staff that is 
trained to monitor for and respond to medical emergencies. Patients who experience an NCI-
CTCAE version 4.0 Grade 4 allergic reaction, acute respiratory distress syndrome (ARDS), or 
bronchospasm will be discontinued from study treatment. 
Patients who experience infusion-associated symptoms may be managed by: 
 
Slowing or stopping the trastuzumab infusion 
 
Supportive 
care 
with 
oxygen, 
beta-agonists, 
antihistamines, 
antipyretics, 
or 
corticosteroids as appropriate at the Investigator's discretion 
Premedication with corticosteroids, antihistamines, and antipyretics may be used before 
subsequent trastuzumab infusions at the Investigator’s discretion. 
If infusion-associated symptoms occur, patients will be monitored until complete resolution of 
signs and symptoms.  
 
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 
Continue trastuzumab SC therapy 


 
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Toxicity related to trastuzumab study 
treatment 
Action  
pertaining to trastuzumab SC*  
 
(excluding cardiac) toxicity 
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 < 50% 
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 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.  
 
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 


 
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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) 
 
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 IInvestigator's judgment (e.g., may jeopardize the patient or 
may require medical/surgical intervention to prevent one of the outcomes listed above) 
 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an AE 
(rated as mild, moderate, or severe, or according to NCI CTCAE criteria; see Section 5.3.3); the 


 
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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 
In patients of childbearing potential and women < 1 year after the onset of menopause, 
appropriate contraceptive measures are mandatory during study treatment (examples: barrier 
method [condoms, diaphragm]; intra-uterine devices; surgical methods, or abstinence). 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 Clinical Trial Pregnancy Reporting Form, [gcp_for000023]. 
The Investigator should 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 is 
required (i.e., use of two forms of contraception as stated above) during the study and for at least  
7 months following the last dose of study treatment when a highly effective form of contraception 
is not appropriate. 
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).  


 
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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 AEs/SAEs, regardless of relationship to study drug, will be 
reported until study closure. The investigator does not need to actively monitor subjects for 
adverse events once the trial has ended. However, if becoming aware of any serious adverse 
events and non-serious adverse events of special interest occurring to a subject, the investigator 
should report those to the sponsor (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.  
5.3.2 
TABLE 3 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 4 will be used for assessing severity for AEs that are not specifically listed in the NCI 
CTCAE. 


 
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Table 4 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  
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 CAUSALITY OF ADVERSE EVENTS 
Investigators should use their knowledge of the patient, the circumstances surrounding the event, 
and an evaluation of any potential alternative causes to determine whether or not an 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 


 
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 
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 
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. 


 
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 
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 (as defined in Section 4.5.1.7.1) 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. 
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 


 
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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 
 
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 as an AE 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). 


 
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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 iDMC 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 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. 
For eBC, 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”). 
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”). 
5.3.5.9 
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 study drug administration)}  
 
Hospitalization for a preexisting condition, provided that all of the following criteria are met: 
 
The hospitalization was planned prior to the study or was scheduled during the study 
when elective surgery became necessary because of the expected normal progression 
of the disease 
 
The patient has not suffered an AE 
 
Hospitalization due solely to progression of the underlying cancer 
5.3.5.10 
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). 
5.3.5.11 
Patient-Reported Outcome Data 
AE reports will not be derived from PRO data. However, if any patient responses suggestive of a 
possible AE are identified during site review of the PRO questionnaires, site staff will alert the 
Investigator, who will determine if the criteria for an AE have been met and will document the 
outcome of this assessment in the patient's medical record per site practice. If the event meets 
the criteria for an AE, it will be reported on the Adverse Event eCRF. 
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 
 
Cardiac Events related to CHF including abnormality test finding such as LVEF drop 
 
Pregnancies 
 
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 


 
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 
Change in the event’s outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting 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 
To ensure the safety of study patients, an Emergency Call Center Help Desk will access 
the Roche Medical Emergency List, escalate emergency medical calls, provide medical 
translation service (if necessary), connect the investigator with a Roche Medical Monitor, 
and track all calls. The Emergency Call Center Help Desk will be available 24 hours per 
day, 7 days per week. 
The telephone number for the Help Desk is 00 32 2 525 82 11. 
5.4.2 
REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS 
For reports of SAEs, Investigators should record all case details that can be gathered within 24 
hours on the Adverse Event eCRF and submit the report via the electronic data capture (EDC) 
system. A report will be generated and sent to Roche Safety Risk Management by the EDC 
system. 


 
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In the event that the EDC system is unavailable, a paper Serious Adverse Event/Non-Serious 
Adverse Event of Special Interest CRF and Fax Coversheet should be completed and faxed to 
Roche Safety Risk Management or its designee within 24 hours after learning of the event, using 
the fax numbers provided to Investigators (see "Protocol Administrative and Contact Information 
& List of Investigators"). Once the EDC system is available, all information will need to be entered 
and submitted via the EDC system.  
 
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 1 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 
Pregnancy Report eCRF should be completed by the Investigator within 24 hours after learning of 
the pregnancy and submitted via the EDC system. A pregnancy report will automatically be 
generated and sent to Roche Safety Risk Management. Pregnancy should not be recorded on 
the Adverse Event eCRF. 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. 
In the event that the EDC system is unavailable, a Pregnancy Report worksheet and Pregnancy 
Fax Coversheet should be completed and faxed to Roche Safety Risk Management or its 
designee within 24 hours after learning of the pregnancy, using the fax numbers provided to 
Investigators (see "Protocol Administrative and Contact Information & List of Investigators"). 
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 Pregnancy Report eCRF should be completed by the Investigator within 24 
hours after learning of the pregnancy and submitted via the EDC system. 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 eCRF 
with additional information on the 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. 
In the event that the EDC system is unavailable, follow reporting instructions provided in Section 
5.4.3.1. 


 
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5.4.3.3 
Abortions 
Any spontaneous abortion should be classified as an SAE (as the Sponsor considers 
spontaneous abortions to be medically significant events), recorded on the Adverse Event eCRF, 
and reported to the Sponsor 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 an SAE, recorded on the Adverse Event 
eCRF, and reported to the Sponsor within 24 hours after learning of the event (see Section 5.4.2). 
5.4.4 
REPORTING REQUIREMENTS FOR CARDIAC EVENTS      
RELATED TO CHF  
The Investigator must report all cardiac events related to CHF (serious & non-serious) to the 
Sponsor within 24 hours after learning of the event, regardless of relationship to study drug. 
 
 
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. 
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  


 
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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.  
Cardiac AEs and SAEs: Follow until one of the following occurs:  
 
Resolved or improved to baseline state  
 
Investigator confirms that no further improvement can be expected  
 
Death 
 
Clinical or safety data will no longer be collected, or final database closure.  
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 once the study has 
ended. 
The Sponsor should also be notified if the Investigator becomes aware of the development of 
cancer or a congenital anomaly/birth defect in a subsequently conceived offspring of a patient 
that participated in this study. 
The Investigator should report these events to Roche Safety Risk Management on the Adverse 
Event eCRF. If the Adverse Event eCRF is no longer available, the Investigator should report 


 
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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. 
 
A descriptive analysis of the safety parameters will be performed.  
 
In addition, patient experience and overall satisfaction, patient reporting of symptoms and 
health care professional experience and satisfaction will be analyzed descriptively. 
Details will be described in the statistical analysis plan that will be finalized before data base lock. 
No formal hypothesis will be tested nonetheless, statistical tests will be applied and p-values 
calculated to explore specific aspects of the study material 
Local safety 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.  
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). 
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 
 
discrete data will be summarized using frequency counts and percentages 
 


 
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6.1 
DETERMINATION OF SAMPLE SIZE 
 
One hundred subjects are foreseen to be enrolled to assess the overall safety and tolerability of 
trastuzumab SC vial when administered at home. This sample size was not based on a formal 
calculation but mainly driven by feasibility and a reasonable width of a 95% confidence interval 
for the rate of AEs and SAEs. Based on an expected rate of AEs of 97% (23) and 100 subjects, a 
95% confidence interval of 91% to 99% would be obtained. For an expected rate of SAEs of 21% 
(23) and 100 subjects, a 95% confidence interval ranging from 13% to 29% would be obtained 
(confidence intervals calculated using Clopper-Pearson methodology). 
 
 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
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: 
 
Noncompliance with inclusion criteria 
 
Noncompliance with exclusion criteria 
 
Noncompliance 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 population. 
Summaries will include: 
 
Demography (age, gender) 
 
HER2 determination 
 
Medical History (including BC Disease History) 
 
Pregnancy Test Results 
 
Prior Medications 
 
6.4 
SAFETY ANALYSES 
Safety endpoints of this study are: 
 
Adverse Events (AEs) 
 
Serious Adverse Events (SAEs) 


 
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 
LVEF 
 
Exposure to study medication 
 
Duration of treatment 
 
Duration of follow-up 
 
Vital Signs, weight, height and ECOG 
 
Concomitant Medications 
 
Hematology and Serum Chemistry 
All safety summaries will be based on the safety population.  
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 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. AEs and SAEs starting in-hospital and in the home setting will be reported separately 
and combined  


 
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Cardiac monitoring (12-lead ECG and LVEF) will be summarized by cycle including change from 
baseline summaries where appropriate. 
Exposure to study treatment (trastuzumab) 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. 
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 analyses for safety reporting and presentation of safety and efficacy results. These annual 
reporting events will start 1 year after first patient’s first visit and end when the last patient has 
finished follow-up. 
 
6.5 
PATIENT REPORTED OUTCOME ANALYSIS 
The questionnaires that assess patient overall satisfaction and experience with the administration 
of trastuzumab SC vial in the hospital and at home will be analyzed descriptively by presenting 
frequencies and percentages for the different questions. 
Patient reporting of symptoms using the MDASI will be analyzed descriptively at each time point 
the questionnaire was assessed and for each item separately using descriptive statistics like 
mean, standard deviation, median, interquartiles range and minimum and maximum values. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
Data management will be performed by a CRO. 


 
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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.  
The overall procedures for quality assurance of clinical study data are described in the Roche 
Standard Operational Procedures 
Accurate and reliable data collection will be assured by verification and cross–check of the 
eCRFs against the investigator’s records by the study monitor (source document verification and 
critical variables checks).  
A comprehensive validation check program utilizing front-end checks in the eCRF will verify the 
data. Discrepancies and queries will be generated accordingly in the eCRF for online resolution 
by the investigator at the site.  
 
The eCRF data will be reviewed on an ongoing basis for medical and scientific plausibility 
according to the Study Management Team Data Review Plan as described in the Data Quality 
Plan.  
Roche will perform oversight of the data management of this study, including approval of the 
CRO’s 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’s audit trail. System 
backups for data stored at the CRO and records retention for the study data will be consistent 
with the CRO’s standard procedures. 
Roche will ensure the quality of safety and efficacy data to be transferred to the global database. 
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. 


 
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7.3 
PATIENT-REPORTED OUTCOME DATA 
PRO data will be collected on paper. During the in hospital part of the study the questionnaires 
will be provided to the patient by the study nurse or other study-related personnel. During the at 
home period the patient will receive a patient diary in which all planned visit dates will be marked. 
This diary will also contain all questionnaires to be completed by the patient while he or she is 
been treated at home. 
Patients will complete the questionnaires at defined time points during the study. The nurse 
administering trastuzumab subcutaneous vial at home, will remind the patient of the timing for 
each questionnaires to be completed. The completed questionnaires will be handed by the 
patient to the site at the first visit following the date of completion of the respective questionnaire. 
The study site personnel will transfer the PRO data into the eCRF. 
Once the study is complete, the PRO data, audit trail, and trial and system documentation will be 
archived. The Investigator will receive patient data for the site in both human- and machine-
readable formats on an archival-quality compact disc that must be kept with the study records as 
source data. Acknowledgement of receipt of the compact disc is required. In addition, the 
Sponsor will receive all patient data in a machine-readable format on a compact disc. 
7.4 
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 7.6. 
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. 


 
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7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve as the 
source document if the system has been validated in accordance with health authority 
requirements pertaining to computerized systems used in clinical research. An acceptable 
computerized data collection system allows preservation of the original entry of data. If original 
data are modified, the system should maintain a viewable audit trail that shows the original data 
as well as the reason for the change, name of the person making the change, and date of the 
change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of IMP, 
including eCRFs, ePRO 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’s sample Informed Consent Form (and ancillary sample Informed Consent Forms such as 
a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will be provided to each 
site. If applicable, it will be provided in a certified translation of the local language. The Sponsor 
or its designee must review and approve any proposed deviations from Roche's sample Informed 
Consent Forms or any alternate consent forms proposed by the site (collectively, the “Consent 
Forms”) before IRB/EC submission. The final IRB/EC-approved Consent Forms must be provided 
to 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 


 
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each patient shall document the informed consent process and that written informed consent was 
obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures or when 
new information becomes available that may affect the willingness of the patient to participate. 
The final revised IRB/EC-approved Consent Forms must be provided to the Sponsor for health 
authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and IRB/EC 
policy) during their participation in the study. For any updated or revised Consent Forms, the case 
history or clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained using the updated/revised Consent Forms for continued 
participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s legally 
authorized representative. All signed and dated Consent Forms must remain in each patient’s 
study file or in the site file and must be available for verification by study monitors at any time. 
 
8.3 
INSTITUTIONAL 
REVIEW 
BOARD 
OR 
ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, and 
relevant supporting information must be submitted to the EC by the Principal Investigator and 
reviewed and approved by the EC before the study is initiated. In addition, any patient recruitment 
materials must be approved by the EC.  
The Principal Investigator is responsible for providing written summaries of the status of the study 
to the EC annually or more frequently in accordance with the requirements, policies, and 
procedures established by the EC. Investigators are also responsible for promptly informing the 
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 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 EC, and archived in the site’s study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the study 
through assignment of a unique patient identification number. This means that patient names are 
not included in data sets that are transmitted to any the Sponsor location. 
Patient medical information obtained by this study is confidential and may only be disclosed to 
third parties as permitted by the Informed Consent Form (or separate authorization for use and 


 
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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 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 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 ECs to 
inspect facilities and records relevant to this study. 
9.3 
ADMINISTRATIVE STRUCTURE 
The study will have an internal Data Monitoring Committee.  
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. 


 
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The Sponsor will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter trials only in their entirety and not as individual center data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. Any formal publication of the study in which 
contribution of 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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46. Russell SD, Blackwell KL, Lawrence J, et al. Independent adjudication of symptomatic heart 
failure with the use of doxorubicin and cyclophosphamide followed by trastuzumab adjuvant 
therapy: a combined review of cardiac data from the National Surgical Adjuvant breast and 
Bowel Project B-31 and the North Central Cancer Treatment Group N9831 clinical trials. J 
Clin Oncol. 2010; 28:3416-21. 
47. Sant M, Allemani C, Capocaccia R, et al. Stage at diagnosis is a key explanation of 
differences in breast cancer survival across Europe. Int J Cancer 2003; 106: 416-22. 
48. Schechter AL, Stern DF, Vaidyanathan L, et al. The neu oncogene: An erb-B-related gene 
encoding a 185,000-Mr tumour antigen. Nature 1984; 312:513-6. 
49. Sjögren S, Inganäs M, Lindgren A, et al. Prognostic and predictive value of c-erbB-2 
overexpression in primary breast cancer, alone and in combination with other prognostic 
markers. J Clin Oncol 1998 Feb;16(2):462-9. 
50. Slamon DJ, Clark GM, Wong SG et al. Human breast cancer: correlation of relapse and 
survival with amplification of the HER-2/neu oncogene, Science 1987; 235:177-82 
51. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in 
human breast and ovarian cancer. Science 1989; 244:707-12Slamon DJ, Leyland-Jones B, 
Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER-2 for 
metastatic breast cancer. N Engl J Med 2001; 344:783−92. 
52. Slamon D, Eiermann W, Robert N, et al. BCIRG-006 Phase III trial comparing AC→T with 
AC→TH and with TCH in the adjuvant treatment of HER2-amplified early breast cancer 
patients: third planned efficacy analysis. San Antonio Breast Cancer Symposium 2009 
abstract 62.  
53. Slamon D, Eiermann W, Robert N, et al. (Breast Cancer International Research Group). 
Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011; 365:1273-83. 
54. Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant 
chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007; 
369:29-36.  
55. Spielmann M, Roche H, Delozier T, et al. Trastuzumab for patients with axillary-node-
positive breast cancer: results of the FNCLCC-PACS 04 trial. J Clin Oncol 2009; 27:6129-34. 
56. Sundaresan S, Penuel E, Sliwkowski MX. The biology of human epidermal growth factor 
receptor 2. Curr Oncol Rep. 1999; 1:16-22. 
57. Tan-Chiu E, Yothers G, Romond E, et al. Assessment of cardiac dysfunction in a 
randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with 
or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor 
receptor 2-overexpressing breast cancer: NSABP B-31. J. Clin. Oncol 2005; 23:7811-9. 
58. Untch M. Targeted Therapy for Early and Locally Advanced Breast Cancer. Breast Care 
(Basel) 2010; 5:144-52. 


 
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59. Verma S, Lavasani S, Mackey J, et al. Optimizing the management of HER2-positive early 
breast cancer: the clinical reality. Curr Oncol 2010; 17:20-33. 
60. Vogel C, Cobleigh M, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent 
in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002; 
20:719-26. 
61. Wynne C, Harvey V, Schwabe C, Waaka D, McIntyre C, Bittner B. The development of a 
formulation of trastuzumab for subcutaneous administration. European Society for Medical 
Oncology Congress 2010 (Abs 218PD). 
62. Wynne CJ, Wakka DS, Ellis-Pegler RB, et al. Comparative pharmacokinetics of trastuzumab 
subcutaneous formulation administered using a proprietary single-use injection device, or 
manually using a syringe. European Society for Medical Oncology Congress 2012 (Abs 
submitted). 
63. Yarden Y, Sliwkowski M. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 
2:127-37


 
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Appendix 1  
Schedule of Assessments 
 
 
Screeni
ng 
Baselin
e 
Treatment period 
(cycles trastuzumab) 
Safety FU 
Visit (o) 
Follow-up visits 
(Treatment cycle ) 
Day -28 
to 1 
Day -7 to 
1 
Period 1 – 
Hospital  
[Trastuzumab IV] 
(Cycle 7-9) 
All visits within 
+/-  3 days of 
scheduled 
treatment day 
Period 2 – 
Hospital  
[Trastuzumab SC] 
( Cycle 10-12) 
All visits within 
+/-  3 days of 
scheduled 
treatment day 
Period 3 – Home 
 [Trastuzumab SC]  
(Cycle 13-18) 
 
4 weeks after last 
study treatment 
+7 days 
Continuing for up to 24 
months after treatment 
cessation 
+/-  15 days 
(Cycle  
13-15) 
All visits 
within 
+/- 3 
days of 
schedu-
led treat-
ment 
day 
(Cycle  
16-18) 
All 
visits 
within 
+/- 
3 
days of 
sche-
duled 
treat-
ment 


 
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day 
Explain study and 
obtain 
signed 
informed consent (a) 
x 
 
 
 
 
 
 
 
Demographics 
and 
medical history (b,c) 
x 
 
 
 
 
 
 
 
Review 
inclusion/exclusion 
criteria 
x 
 
 
 
 
 
 
 
Vital 
signs 
and 
physical assessment 
(d) 
x 
 
X 
X 
X 
X 
X 
X 
X X X X X X x 
 
Weight, height (e) 
x 
 
X 
X 
X 
X 
X 
X 
X X X X X X x 
 
ECOG performance 
status (v) 
x 
 
X(v) 
x(v) 
X(v) 
 
X 
 
Cardiac monitoring: 
12-lead ECG (f) 
LVEF (f) 
Signs/symptoms (f) 
 
X 
X* 
X 
 
Cardiac 
safety 
assessments 
will 
be 
performed 
approximately 3-monthly during treatment period. 
    
 
X 
X 
X 
Cardiac assessments at 
6, 12, 18 and 24 months 
following 
treatment 
cessation 
Pregnancy test (g) 
 
X 
 
 
 
 
 
 


 
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Hematology 
and 
biochemistry (h) 
x 
 
X(h) 
X(h) 
(If 
not 
done 
during 
first part 
of 
treatme
nt 
period) 
X (h) 
X (h)  
(If not done during 
first 
part 
of 
treatment period) 
X 
 
Routine 
breast 
cancer follow-up (i) 
Assessments as per institutional practice or ASCO adjuvant follow-up guidelines 2006 to be reported 6-monthly (i) 
AEs and SAEs (j) 
x 
X 
X 
X 
X 
X 
X 
X 
Past and  Current 
Concomitant 
medications (k) 
x 
X 
X 
X 
X 
X 
X 
X 
Trastuzumab IV (l) 
 
 
x 
 
 
 
 
 
Trastuzumab SC (m) 
 
 
 
X 
X 
X 
 
 
PRO MDASI (p) 
 
 
X 
X 
X 
X 
 
 
PRO PSQ1 (q) 
 
 
 
 
X 
 
 
 
PRO PSQ2 (r) 
 
 
 
 
 
X 
 
 
HCPEX-1 (s) 
 
 
 
X 
 
 
 
 


 
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PEX-P1 (t) 
 
 
 
X 
 
 
 
 
PEX-P2 (u) 
 
 
 
 
 
 
X 
 
 
 
 
 
Treatment period 1: The first 3 administrations of trastuzumab will be performed intravenously at 6mg/kg in the hospital (cycle 7 to 9). 
 
Treatment period 2: The next 3 administrations of trastuzumab will be performed subcutaneously in the hospital. Trastuzumab SC vial 
will be administered by a HCP at a fixed dose of 600 mg, into the thigh over a period of up to 5 minutes, using conventional handheld 
syringes (cycle 10 to 12).  
 
Treatment period 3: The next 6 administrations of trastuzumab will be performed subcutaneously at home. Trastuzumab SC vial will be 
administered by a HCP at a fixed dose of 600 mg, into the thigh over a period of up to 5 minutes, using conventional handheld syringes 
(cycle 13 to 18).  
 
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] Vital signs and physical assessment including pulse, blood pressure, and body temperature 
[e] Weight is measured for 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 
[f] LVEF assessments by either ECHO or MUGA scan: the same imaging technique should be used per patient throughout the study. *The 
screening LVEF assessment should be performed within 3 months prior to the first trastuzumab IV administration. To be eligible for participation in 
this study, patients must have a baseline LVEF ≥ 50% for eBC patients. Cardiac safety assessments will be performed within 3 months prior to the 


 
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first trastuzumab SC vial administration and approximately 3-monthly during further trastuzumab SC vial treatment at the Safety Follow-up visit 
(LVEF assessment may occur prior to the day of the Safety Follow-up visit if clinically indicated) and then at 6, 12, 18 and 24 months after treatment 
cessation and immediately in case of cardiac failure. 
[g] 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 study treatment. 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 
[h] Patients will undergo 4 lab evaluations: one at screening, one during hospital treatment period, one during at home treatment period and one 
during first safety follow-up visit. Choice of cycle within treatment period is upon discretion of the investigator.  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, albumin, sodium, potassium and calcium. Additional hematology and biochemistry tests may be performed as 
per institutional practice, but these data will not be collected 
[i] 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)[j] After informed consent, but prior to initiation of study treatment, only SAEs caused by a protocol-mandated intervention will be collected. 
All treatment-emergent AEs occurring until 4 weeks after the last SC administration of trastuzumab will be recorded in the eCRF, irrespective of the 
type of event and drug-event relationship. From 4 weeks to 6 months after the last study drug administration, related AEs, related/unrelated SAEs 
and cardiac AEs should be reported, except for pregnancy that needs to be reported to 7 months after the last study drug administration. From 6 
months after the last study drug administration until the end of the follow-up period only related AEs/SAEs and cardiac AEs should be reported. 
NCI-CTCAE version 4 should be used for AE coding 
[k] All concomitant medication will be recorded between the Screening and the Safety Follow-up visits. Thereafter, only anti-cancer treatments given 
to treat a recurrence will be reported 
[l] Trastuzumab IV is administered intravenously at 6mg/kg for the subsequent doses, every 3 weeks for the first 3 cycles (cycle 7 to 9)[m] 
Trastuzumab is administered subcutaneously at a fixed dose of 600 mg, 3-weekly for a total of 9 cycels (cycle 10-18) (regardless of body weight) 
[o] Patients will undergo a Safety Follow-up visit 4 weeks after their last dose of study treatment 
(p) Patient reporting of symptoms using the MD Anderson Symptom Inventory (MDASI, appendix 4):Patients will be asked to rate the severity of 13 
core items on a scale from 0 to 10. Patients will be asked to complete the MDASI 4 times: Prior to the first dose trastuzumab IV = prior to cycle 7, 
prior to the first dose trastuzumab SC vial = prior to cycle 10, prior to the first dose trastuzumab SC vial administered at home = prior to cycle 13 
and prior to the fourth dose trastuzumab SC vial administered at home = prior to cycle 16.  


 
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(q) Patient experience with the treatment provided during the in-hospital part of the study: Patients will be asked to complete a questionnaire (PSQ1, 
appendix 6) related to the quality of care provided during trastuzumab administration in the hospital prior to the first dose trastuzumab SC vial  
administered at home = prior to cycle13.(r) Patient experience with the treatment provided during the at home part of the study: Patients will be 
asked to complete a questionnaire (PSQ2, appendix 6) related to the quality of care provided during trastuzumab SC vial administration at home 
prior to the fifth dose trastuzumab SC vial administered at home = prior to cycle 17. 
(s) HCP overall satisfaction and perceived time savings with trastuzumab SC vial in the hospital will be assessed by a Health Care Professional 
Questionnaire (HCPEX-1, appendix 5): The HCPEX-1 questionnaire will be completed by a HCP administering trastuzumab IV and SC vial in the 
hospital after at least 3 patients completed the in hospital part of the study ( 3 patients must have completed treatment period 1 and 2) 
(t) Patient experience with trastuzumab IV and SC vial administered in the hospital. 
Patients will be interviewed by a HCP to complete the PEX-P1 (appendix 7) prior to the third dose trastuzumab SC = prior to cycle 12. 
(u) Patient experience with trastuzumab SC vial administered at home. Patients will be interviewed by a HCP to complete the PEX-P2 (appendix 7) 
at the safety follow-up visit, following 4 weeks after the last trastuzumab SC vial administration at home. 
(v) Patients will undergo 5 ECOG measurements: one at screening , one per treatment period and one during first safety follow-up visit. Choice of 
cycle within treatment period is upon discretion of the investigator.  
 
 
 




 
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Appendix 3  
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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Appendix 5 
HCPEX 
 
HCPEX-1  
  
Healthcare Professionals’ Experiences towards Either IV or SC Herceptin (VIAL) in Breast Cancer    
   
(HCP Questionnaire)   
   
At least 3 patients at your center have now finished the “in hospital” part of the trial. Your own 
experiences and opinions about the different methods are an important part of the study.   
Your confidentiality will be respected and none of the information we receive will be used in a  
way that could identify you.   
 
 
Date:  Day      /     Month     /    Year 
 
 
Site Number: 
 
                          Staff  Initials: 
 
  
  
1. What is your specialty?   
 
   oncologist   gynaecologist   oncologist/specialist chemo nurse    other   
  
If other please specify   
 
 
 
 
Now some questions about the subcutaneous (SC) Herceptin administration:   
  
 
2. Did you personally administer the SC Herceptin in the study?   
  
  always   sometimes   never   
  
If never who did administer the SC Herceptin in the study?  
  
  another oncologist   another gynaecologist   another oncologist/specialist chemo nurse    other   
  
If other please specify   
 
 
 
 
3. How many minutes preparation time was required for Herceptin SC vial in the pharmacy?   
  
 <5           6 -10             11-15       16-20     >20           not sure  
  


 
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4. How many minutes in total did it usually take to administer the Herceptin subcutaneously using the hand 
held syringe?   
  
 <3         <5       6 -15       16-30     31-60      61-90    >90      not sure  
  
  
5. How long do you think the SC sessions usually lasted from patients’ arrival until departure?    
  
< 2 hours     > 2 but < 3 hours         >3 but <4hours       > 4 hours  
  
  
6. How reliable was using the hand held syringe to give Herceptin subcutaneously?   
  
 not at all        fairly           very  
  
If not at all reliable please give details why:   
  
  
 
 
7. Overall how easy did you/your staff find giving Herceptin subcutaneously using the hand held syringe?   
  
 not at all     fairly        very  
  
If not at all easy please give details why   
  
  
  
  
Now some questions about the IV Herceptin administration:  
  
  
8. Which IV method did most of your patients have for their Herceptin treatment during the study?   
  
 cannula           Venous Access Device (VAD)         
not sure  
  
If VAD which type was this (tick all that apply):-    
 Hickman     Groshong     PICC       Port-a-Cath       other         not sure  
  
  
9. Did you personally administer the IV Herceptin in this study?   
  
 always          sometimes           never 
If never, who did administer the IV Herceptin in the study?   
  
 another oncologist     another gynaecologist      another oncologist/specialist   
chemo nurse      other       not sure  
  
  
If other please specify   
  
 
  
  
10. Did you personally cannulate the patients having Herceptin in the study?   
  
 always         sometimes            never  


 
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If never who did cannulate patients in the study?   
  
  another oncologist   another gynaecologist   another oncologist/specialist chemo nurse    other     
not sure  
  
If other please specify   
  
  
 
  
11. How many minutes preparation time do you think the Herceptin IV required in the pharmacy?   
  
  <5            6 -10            11-15        16-20        >20         not sure  
  
  
12. If a patient needed cannulation how many minutes do you think this usually took?   
  
  <5            6 -10            11-15        16-20        >20         not sure  
  
  
13. How many minutes in total do you think connecting the Herceptin infusion and administering it IV usually 
took?   
  
  <3          <5             6 -15              16-30  
  31-60 
  61-90   >90     not sure  
  
  
14. How long do you think the IV Herceptin sessions usually lasted from patients’ arrival until departure?      
  

< 2 hours  
  > 2 but < 3 hours 
  >3 but <4hours  
  > 4 hours   
  
15. How anxious do you think the IV Herceptin treatment made patients feel?   
  

  not at all 
  fairly  
  very  
  
  
16. How reliable do you think the IV Herceptin administration was overall?   
  

  not at all 
  fairly  
  very  
  
If not at all reliable please give details why    
  
  
  
 
17. Overall how easy did you/your staff find IV Herceptin administration   
  

  not at all 
  fairly  
  very  
  
  
 
 
 
 
 
 
 
 
 


 
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Now consider using these different methods of Herceptin administration in normal practice outside 
the study setting:  
   
Overall which method of administration would:  
18. be quickest from start of preparation to finish of administration (excluding observation period)?   
  
  IV                       SC (handheld syringe)                  no difference  
  
  
19. require less resource use for preparation and administration, for example nursing time, facility costs, 
equipment etc?   
  
  IV                       SC (handheld syringe)                  no difference  
  
  
  
   
Thank you very much for your time   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix 6 
 
PSQ1 & PSQ2 
 
 
PSQ-1 
 
 
Date : 
 
Site Number :  
 
 
 
 
 
Patient Study Number:  
 
Each question is about your experience during the in hospital part of the study  
If a question does not apply to you, please use the ”Not applicable” option.  
 
About the clinicians  
 
1a Did the clinicians talk to you in a way 
that was easy to understand? 
 
1b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important  
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2a Do you have confidence in the 
clinicians’ professional competence? 
 
2b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important  
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3a To what degree do you perceive that 
the clinicians cared about you? 
 
3b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important  
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4a Did you perceive the clinicians to be 
interested in your description of your 
situation? 
 
4b How important was this to you? 


 
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Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important  
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5a Did you get enough time to talk and 
interact with the clinicians? 
 
5b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important  
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
About the other staff 
 
By the “other staff” we mean: the nursing staff 
 
6a Did the nurses talk to you in a way 
that was easy to understand? 
 
6b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important 
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7a Do you have confidence in the nurses’ 
professional skills? 
 
7b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important 
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8a To what degree do you perceive that 
the nurses cared about you? 
 
8b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important 
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Trastuzumab—F. Hoffmann-La Roche Ltd. 
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9a Did you perceive the nurses to be 
interested in your description of your 
situation? 
 
9b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important 
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10a Did you get enough time to talk and 
interact with the nurses? 
 
10b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important 
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other questions 
11a Did you have to wait before you were 
admitted for services at the institution? 
 
11b How important was this to you? 
No 
Yes, but 
not long 
Yes, quite 
long 
Yes, much 
long 
 
Not 
important 
A little 
important 
Important 
Very 
important 
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12a Did you get the impression that the 
hospital equipment was in good order? 
 
12b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important 
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13a Did you get the impression that the 
hospital was otherwise in good order? 
 
13b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important 
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14a   Overall, was the help and treatment 
you received at the institution satisfactory? 
 
14b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important 
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Trastuzumab—F. Hoffmann-La Roche Ltd. 
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105 
PSQ-2 
 
Date : 
 
Site Number :  
 
 
 
 
 
Patient Study Number:  
 
Each question is about your experience during the at home part of the study  
If a question does not apply to you, please use the ”Not applicable” option.  
 
About the clinicians  
 
1a Did the clinicians talk to you in a way 
that was easy to understand? 
 
1b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important  
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2a Do you have confidence in the 
clinicians’ professional competence? 
 
2b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important  
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3a To what degree do you perceive that 
the clinicians cared about you? 
 
3b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important  
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4a Did you perceive the clinicians to be 
interested in your description of your 
situation? 
 
4b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important  
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Trastuzumab—F. Hoffmann-La Roche Ltd. 
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106 
5a Did you get enough time to talk and 
interact with the clinicians? 
 
5b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important  
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
About the other staff 
 
By the “other staff” we mean: the nursing staff 
 
6a Did the nurses talk to you in a way 
that was easy to understand? 
 
6b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important 
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7a Do you have confidence in the nurses’ 
professional skills? 
 
7b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important 
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8a To what degree do you perceive that 
the nurses cared about you? 
 
8b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important 
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9a Did you perceive the nurses to be 
interested in your description of your 
situation? 
 
9b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important 
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Trastuzumab—F. Hoffmann-La Roche Ltd. 
Protocol ML28794, Version 3, 21 October 2015 
107 
10a Did you get enough time to talk and 
interact with the nurses? 
 
10b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important 
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other questions 
 
11a Did you get the impression that the 
nurses’ equipment was in good order? 
 
11b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important  
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12a Overall, was the help and treatment 
you received at home satisfactory? 
 
12b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important  
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13a Overall, what benefit have you had 
from the care at home? 
 
13b How important was this to you? 
Not 
at 
all 
To a 
small 
extent 
To a 
moderate 
extent 
To a 
large 
extent 
To a 
very 
large 
extent 
Not 
applicable 
 
Not 
important 
A little 
important 
Important 
Very 
important  
Of utmost 
importance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Trastuzumab—F. Hoffmann-La Roche Ltd. 
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108 
Appendix 7 
PEX-P1 & PEX-2 
 
PEX – P1 
 
Patient Experience with Herceptin IV and SC (vial) administered in the hospital 
 
 
Date: 
 
 
 
 
 
 
Site Number:  
 
 
 
 
Patient Study Number: 
  
You have now received the drug Herceptin in 2 different ways in the hospital and I’d like to ask you a 
few questions about your experiences. There aren’t any right or wrong answers. The interview 
should only take about 25 minutes. If you feel uncomfortable at any time please ask me to stop. 
None of the information will be used outside of the study in a way that could identify you.  
 
 
First some general questions about the place where you had your study treatment  
 
1. Where did you have your Herceptin study treatment?     
 
   hospital chemotherapy department  other chemotherapy clinic  doctor’s office    other  
 
2. Was this the same place as for your chemotherapy treatment?  
 
 yes       no   
 
 
3. How long did it take you to travel there?  
 
   <1 hour   1-2 hours   >2 hrs 
  
4. How easy was it travelling there?  
 
   not at all     fairly     very  
 
5. Did someone always have to take you there by car or public transport?  
 
   always      sometimes       never  
 
6. Was the cost of travelling there a problem for you?  
 
   not at all     fairly     very  
 
7. So taking all these things above into consideration was travelling for Herceptin treatment overall a 
problem for you?  
 
   yes      no   
 
 
So that’s the travelling now some questions about the place where you had your study treatment    
 
8. How helpful were the nursing and medical staff who gave you your study treatment  
 
  not at all     fairly   very  
  
9. How pleasant overall was the place where you had your study treatment?  


 
Trastuzumab—F. Hoffmann-La Roche Ltd. 
Protocol ML28794, Version 3, 21 October 2015 
109 
 
   not at all     fairly   very  
  
 
Now I’ll ask you about the 3 Herceptin study treatments which were given intravenously (Interviewer 
some explanation about different types of IV maybe needed please use your descriptions, photos 
and diagrams to help)   
10. How was your IV Herceptin given?  
 
    cannula/needle   Venous Access Device(VAD)   both  
  
11. If VAD  was this :-   Hickman   PICC    Port-a-Cath    other  
 
  
Note to interviewer: If patient had VAD only then go to Q 15. If both methods of IV given (VAD and 
cannula) for any reason please ask Qs 12 to 25.   
  
12. Did the hospital staff ever have any difficulty inserting the cannula (needle)?  
 
   very often   sometimes   never  
  
13. How many minutes did insertion of the cannula usually take?  
 
   <5            6 -10         11-15    16-20   >20  
  
14. How painful was this usually?  
 
   not at all     fairly   very  
 
 
Note to interviewer if patient only ever had cannulation for IV go to Q 17  
 
15. How many minutes did connection to the access port/line usually take?  
 
   <5            6 -10              11-15    16-20   >20  
  
 
16. How painful was this usually?  
 
   not at all     fairly   very  
  
17. How long did the IV sessions usually last from arrival until departure?     
 
   <2 hours   >2 but <3 hours   >3 but <4 hours   >4hours  
  
18. How anxious did having the IV treatment make you feel?  
 
   not at all      fairly    very  
  
19. In general how would you describe these IV Herceptin study sessions?  
 
   very unpleasant   somewhat unpleasant   acceptable  
 
 
Now I’d like to ask you about the 3 Herceptin study treatments which were given subcutaneously in 
the hospital   
  
20. Did the medical or nursing staff ever have any difficulty giving the Herceptin injection subcutaneously?  
 


 
Trastuzumab—F. Hoffmann-La Roche Ltd. 
Protocol ML28794, Version 3, 21 October 2015 
110 
   very often   sometimes   never  
  
21. How many minutes did it usually take?  
 
   <5            6 -10              11-15    16-20   >20  
  
22. How painful was this usually?  
 
   not at all     fairly   very  
  
23. How long did the SC sessions usually last from arrival in the hospital until departure ?    
 
   <2 hours   >2 but <3 hours   >3 but <4 hours   >4hours  
  
24. How anxious did having the SC treatment make you feel?  
 
   not at all      fairly    very  
  
25. In general how would you describe these SC treatment sessions in the hospital?  
 
   very unpleasant   fairly unpleasant   acceptable  
 
 
Thank you very much for your time and help with this study. I hope that the rest of your treatment 
goes well.  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Trastuzumab—F. Hoffmann-La Roche Ltd. 
Protocol ML28794, Version 3, 21 October 2015 
111 
PEX – P2 
 
Patient experience with the at home administration of Herceptin subcutaneous vial  
 
 
Date: 
 
 
 
 
 
 
Site Number:   
 
 
 
Patient Study Number: 
 
 
 
We would like to ask you some questions about your experiences with the at home administration of 
Herceptin subcutaneous vial. There aren’t any right or wrong answers. The interview should only 
take about 5 minutes. If you feel uncomfortable at any time please ask me to stop. None of the 
information will be used outside of the study in a way that could identify you.  
 
 
1. Did the nursing staff ever have any difficulty giving the Herceptin injection subcutaneously?  
 
   very often   sometimes   never  
  
2. How many minutes did the injection (it) usually take?  
 
   <5            6 -10              11-15    16-20   >20  
  
3. How painful was this usually?  
 
   not at all     fairly   very  
  
4. How long did the SC sessions usually last from arrival until departure of the nurse ?    
 
   <2 hours   >2 but <3 hours   >3 but <4 hours   >4hours  
  
5. How anxious did having the SC treatment make you feel?  
 
   not at all      fairly    very  
  
6. In general how would you describe these SC treatment sessions at home?  
 
   very unpleasant   fairly unpleasant   acceptable  
  
 
Thank you very much for your time and help with this study. I hope that the rest of your treatment 
goes well.  
  
 


 
Herceptin SC ML28794 
 
Statistical Analysis Plan 
 
Final Version 
Page 1 of 29 
 
Statistical Analysis Plan 
 
 
NV Roche S.A. 
 
 
 
Herceptin SC ML28794 
 
Test Product: Trastuzumab SC (RO 45-2317) 
 
A SINGLE ARM MULTI-CENTER STUDY INVESTIGATING 
THE AT HOME ADMINISTRATION OF TRASTUZUMAB 
SUBCUTANEOUS VIAL FOR THE TREATMENT OF 
PATIENTS WITH HER2-POSITIVE EARLY BREAST 
CANCER.  
 
 
 
Author(s): 
 
 
Document Status:  Final Version  
                    11st  December 2015 
                    
Previous Versions: 
 
 
 
 
 
 
 
 
 
STATEMENT OF CONFIDENTIALITY  
The information contained in this document, especially unpublished data, is the property of NV Roche SA. (or 
under its control), and therefore provided to you in confidence for review by you and/or your staff. It is understood 
that this information will not be disclosed to others without written authorization from Roche. 


 
Herceptin SC ML28794 
 
Statistical Analysis Plan 
 
Final Version 
Page 2 of 29 
  
APPROVAL SIGNATURES 
 
Sponsor: 
 
Name: 
 
Title:  
  
 
 
 
 
 
 
 
 
Signature 
Date 
 
 
 
 
Name: 
 
 
Title: 
 
 
 
 
 
 
 
 
Signature 
Date 
 
 
 
 
CRO: 
 
 
 
Name: 
 
 
Title:  
 
 
 
 
 
 
 
 
 
 
Signature 
Date 
 
 
Name: 
  
Title:  
  
 
 
 
 
 
 
 
 
 
Signature 
Date 


 
Herceptin SC ML28794 
 
Statistical Analysis Plan 
 
Final Version 
Page 3 of 29 
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* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*   Provide person’s initial and last name. 
** Update the Last Revision Dates on the cover page and the header. 
 


 
Herceptin SC ML28794 
 
Statistical Analysis Plan 
 
Final Version 
Page 4 of 29 
Contents 
ABBREVIATIONS ................................................................................................................... 6 
1 
INTRODUCTION ................................................................................................. 8 
2 
STUDY OBJECTIVES ......................................................................................... 8 
2.1 
PRIMARY OBJECTIVE ................................................................................................ 8 
2.2 
SECONDARY OBJECTIVE ........................................................................................... 8 
3 
STUDY DESIGN ................................................................................................... 8 
3.1 
OVERVIEW OF STUDY DESIGN .................................................................................. 8 
3.1.1 Patients with eBC .................................................................................................... 9 
3.2 
SCHEDULE OF ASSESSMENTS .................................................................................... 9 
3.3 
SAMPLE SIZE .......................................................................................................... 15 
3.4 
STUDY ENDPOINTS ................................................................................................. 15 
3.5 
STUDY VISITS ......................................................................................................... 16 
3.6 
RANDOMIZATION .................................................................................................... 16 
4 
STUDY ANALYSIS POPULATIONS ............................................................... 16 
4.1 
INTENT TO TREAT (ITT) POPULATION ..................................................................... 17 
4.2 
SAFETY POPULATION .............................................................................................. 17 
4.3 
WITHDRAWN PATIENTS .......................................................................................... 17 
4.4 
BLINDING ............................................................................................................... 17 
5 
STATISTICAL METHODOLOGY .................................................................. 17 
5.1 
DATA QUALITY ASSURANCE .................................................................................. 17 
5.2 
DATA TRANSFER AND PREPARATION ...................................................................... 17 
5.3 
SUBGROUPS ............................................................................................................ 18 
5.4 
INTERIM ANALYSIS ................................................................................................. 18 
5.5 
DISPOSITION OF PATIENTS ...................................................................................... 18 
5.6 
BASELINE AND DEMOGRAPHIC CHARACTERISTICS ................................................. 19 
5.7 
SAFETY ANALYSIS .................................................................................................. 19 
5.7.1 Adverse events ....................................................................................................... 19 
5.7.2 LVEF ...................................................................................................................... 21 
5.7.3 Previous and Concomitant Treatments ................................................................. 21 
5.7.4 Laboratory findings ............................................................................................... 21 
5.7.5 Vital Signs .............................................................................................................. 22 
5.7.6 ECG ....................................................................................................................... 22 
5.7.7 Weight .................................................................................................................... 22 
5.7.8 Physical Examination ............................................................................................ 22 
5.7.9 Pregnancy Tests ..................................................................................................... 22 
5.7.10 ECOG Performance Status .................................................................................... 23 
5.8 
EFFICACY ANALYSIS .............................................................................................. 23 
5.8.1 Disease-free Survival ............................................................................................. 23 
5.9 
EXPOSURE .............................................................................................................. 23 
5.9.1 Extent of Exposure to Trastuzumab SC ................................................................. 23 
5.9.2 Extent of Exposure to Trastuzumab IV .................................................................. 24 
5.9.3 Extent of exposure to other non-study drug medications ...................................... 24 
5.10 
PATIENT-REPORTED OUTCOME ANALYSIS ............................................................. 24 
5.11 
HCP REPORTED OUTCOME ANALYSIS .................................................................... 25 


 
Herceptin SC ML28794 
 
Statistical Analysis Plan 
 
Final Version 
Page 5 of 29 
5.12 
OTHER OUTCOME MEASURES .................................................................................. 26 
5.13 
CENTRE EFFECTS .................................................................................................... 26 
5.14 
PROTOCOL VIOLATIONS.......................................................................................... 26 
5.15 
MISSING VALUES – MISSING VISITS ....................................................................... 26 
5.16 
DEVIATIONS FROM SAP .......................................................................................... 27 
5.17 
REFERENCES ........................................................................................................... 28 
APPENDIX 1 
ADMINISTRATION ASSOCIATED REACTIONS .............................. 29 
 


 
Herceptin SC ML28794 
 
Statistical Analysis Plan 
 
Final Version 
Page 6 of 29 
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 
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 
(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 
IRR 
infusion-related reaction 
ISH 
in situ hybridization 
ITT 
intent-to-treat 


 
Herceptin SC ML28794 
 
Statistical Analysis Plan 
 
Final Version 
Page 7 of 29 
IV 
intravenous 
LVEF 
left ventricular ejection fraction 
LPLV 
last patient, last visit 
mBC 
metastatic breast cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
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 
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 
SEM 
Standard Error of the Mean 
SID 
single-use injection device 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOC 
system-organ class 
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 ML28794. This SAP includes all details for the analysis and reporting (tables, 
listings and graphs) of the data collected as part of this protocol.   
 
2 Study Objectives 
2.1 
Primary Objective 
The primary objective of this study is to assess the overall safety and tolerability of 
subcutaneous (SC) trastuzumab with assisted administration using a conventional syringe and 
needle (vial formulation, hereafter referred to as trastuzumab SC vial) when administered at 
home for the treatment of patients with HER2-positive (HER2+) early breast cancer (eBC). 
2.2 
Secondary Objective 
The secondary objectives for this study are to describe: 
 The evolution of individual patient experience across treatment periods: 
o Patient experience with trastuzumab IV administered in the hospital.  
o Patient experience with trastuzumab SC vial administered in the hospital.  
o Patient experience with trastuzumab SC vial administered at home. 
 Patient reporting of symptoms.  
 Patient reporting on the quality of care provided in the hospital and at home.  
 HCP overall satisfaction and perceived time savings with trastuzumab SC vial 
formulation administered in the hospital.  
 Disease-free survival (DFS).  
 
3 
Study Design 
3.1 
Overview of Study Design 
The study is a Phase IIIb, open-label, multinational, multicenter, study to assess the overall 
safety and tolerability of trastuzumab subcutaneous formulation when administered at home 
for the treatment of patients with HER2-positive eBC. Safety data will be collected and 
transferred to a global database for a pooled analysis.  
This study specifically investigates the administration of trastuzumab subcutaneous vial 
administered at home by a HCP. Collecting information on how patients experience being 
treated at home is an important aspect of this study. This study incorporates patient reported 
outcomes for experience and satisfaction with the treatment provided. 


 
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Patients with HER2+ eBC who completed the first 6 cycles of trastuzumab IV as part of the 
(neo)adjuvant treatment can be included to continue to receive 12 cycles of trastuzumab to 
complete a total of 18 cycles of adjuvant trastuzumab.  
 
The 12 cycles of trastuzumab will be administered according to following schedule:  
 Trastuzumab IV will be administered in the hospital by a HCP for the first 3 cycles 
(Trastuzumab cycle 7 to 9 defined as treatment period 1)  
 Trastuzumab SC vial will be administered in the hospital by a HCP for the next 3 
cycles (Trastuzumab cycle 10 to 12 defined as treatment period 2)  
 Trastuzumab SC vial will be administered at home by a HCP for the following 6 
cycles (Trastuzumab cycles 13 to 18 defined as treatment period 3)  
The study is expected to include approximately 100 patients in 23 centres in Belgium and 
Israel.  
 
3.1.1 
Patients with eBC 
Patients with HER2-positive early breast cancer who were eligible for a (neo)adjuvant 
treatment with trastuzumab, eg. clinical stage I (T1, N0, M0) to IIIC (any T, N3, M0) and 
completed the first 6 cycles of trastuzumab IV as part of the (neo)adjuvant treatment can be 
included to continue to receive 12 cycles of adjuvant trastuzumab to complete a total of 18 
cycles. 
3.2 
Schedule of Assessments 
Figure 1: Schedule of Assessments 


 
 
Screening 
Baseline 
Treatment period 
(cycles trastuzumab) 
Safety FU 
Visit (o) 
Follow-up visits 
(Treatment cycle ) 
Day -28 to 1 
Day -7 to 
1 
Period 1 – 
Hospital  
[Trastuzumab IV] 
(Cycle 7-9) 
All visits within 
+/-  3 days of 
scheduled 
treatment day 
Period 2 – Hospital  
[Trastuzumab SC] 
( Cycle 10-12) 
All visits within +/-  
3 days of 
scheduled 
treatment day 
Period 3 – Home 
 [Trastuzumab SC]  
(Cycle 13-18) 
 
4 weeks after last 
study treatment 
+7 days 
Continuing for up to 24 
months 
after 
treatment 
cessation 
+/-  15 days 
(Cycle  
13-15) 
All 
visits 
within 
+/- 3 
days of 
schedu-
led 
treat-
ment 
day 
(Cycle  
16-18) 
All visits 
within +/- 
3 days of 
sche-
duled 
treat-
ment day 
Explain study and 
obtain 
signed 
informed consent (a) 
X 
 
 
 
 
 
 
 
Demographics 
and 
medical history (b,c) 
X 
 
 
 
 
 
 
 


 
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Review 
inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
Vital 
signs 
and 
physical assessment 
(d) 
X 
 
X 
X 
X 
X 
X 
X 
X X X X 
X X x 
 
Weight, height (e) 
X 
 
X 
X 
X 
X 
X 
X 
X X X X 
X X x 
 
ECOG performance 
status (v) 
X 
 
X(v) 
x(v) 
X(v) 
 
X 
 
Cardiac monitoring: 
12-lead ECG (f) 
LVEF (f) 
Signs/symptoms (f) 
 
X 
X* 
X 
 
Cardiac safety assessments will be performed approximately 
3-monthly during treatment period. 
    
 
X 
X 
X 
Cardiac assessments at 6, 
12, 18 and 24 months 
following 
treatment 
cessation 
Pregnancy test (g) 
 
X 
 
 
 
 
 
 
Hematology 
and 
biochemistry (h) 
X 
 
X(h) 
X(h) 
(If 
not 
done 
during 
first part 
of 
treatme
nt 
period) 
X (h) 
X (h)  
(If 
not 
done 
during first part of 
treatment period) 
X 
 


 
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Routine breast cancer 
follow-up (i) 
Assessments as per institutional practice or ASCO adjuvant follow-up guidelines 2006 to be reported 6-monthly (i) 
AEs and SAEs (j) 
X 
X 
X 
X 
X 
X 
X 
X 
Past and  Current 
Concomitant 
medications (k) 
X 
X 
X 
X 
X 
X 
X 
X 
Trastuzumab IV (l) 
 
 
x 
 
 
 
 
 
Trastuzumab SC (m) 
 
 
 
X 
X 
X 
 
 
PRO MDASI (p) 
 
 
X 
X 
X 
X 
 
 
PRO PSQ1 (q) 
 
 
 
 
X 
 
 
 
PRO PSQ2 (r) 
 
 
 
 
 
X 
 
 
HCPEX-1 (s) 
 
 
 
X 
 
 
 
 
PEX-P1 (t) 
 
 
 
X 
 
 
 
 
PEX-P2 (u) 
 
 
 
 
 
 
X 
 
Treatment period 1: The first 3 administrations of trastuzumab will be performed intravenously at 6mg/kg in the hospital (cycle 7 to 9). 
Treatment period 2: The next 3 administrations of trastuzumab will be performed subcutaneously in the hospital. Trastuzumab SC vial will be administered by a 
HCP at a fixed dose of 600 mg, into the thigh over a period of up to 5 minutes, using conventional handheld syringes (cycle 10 to 12).  
Treatment period 3: The next 6 administrations of trastuzumab will be performed subcutaneously at home. Trastuzumab SC vial will be administered by a HCP at 
a fixed dose of 600 mg, into the thigh over a period of up to 5 minutes, using conventional handheld syringes (cycle 13 to 18).  


 
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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] Vital signs and physical assessment including pulse, blood pressure, and body temperature 
[e] Weight is measured for 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 
[f] LVEF assessments by either ECHO or MUGA scan: the same imaging technique should be used per patient throughout the study. *The screening LVEF 
assessment should be performed within 3 months prior to the first trastuzumab IV administration. To be eligible for participation in this study, patients must have a 
baseline LVEF ≥ 50% for eBC patients. Cardiac safety assessments will be performed within 3 months prior to the first trastuzumab SC vial administration and 
approximately 3-monthly during further trastuzumab SC vial treatment at the Safety Follow-up visit (LVEF assessment may occur prior to the day of the Safety 
Follow-up visit if clinically indicated) and then at 6, 12, 18 and 24 months after treatment cessation and immediately in case of cardiac failure. 
[g] 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 study treatment. Additional pregnancy testing should be 
completed as clinically indicated for the duration of study treatment and until at least 6 months 7 months after the last dose of study treatment. Any positive urine 
pregnancy test needs to be confirmed by serum pregnancy test 
[h] Patients will undergo 4 lab evaluations: one at screening, one during hospital treatment period, one during at home treatment period and one during 
first safety follow-up visit. Choice of cycle within treatment period is upon discretion of the investigator.  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, albumin, sodium, potassium and calcium. Additional hematology and biochemistry tests may be performed as per institutional practice, but 
these data will not be collected 
[i] 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)[j] After informed consent, but prior to 
initiation of study treatment, only SAEs caused by a protocol-mandated intervention will be collected. All treatment-emergent AEs occurring until 4 weeks after 
the last SC administration of trastuzumab will be recorded in the eCRF, irrespective of the type of event and drug-event relationship. From 4 weeks to 6 months 
after the last study drug administration, related AEs, related/unrelated SAEs and cardiac AEs should be reported, except for pregnancy that needs to be 


 
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reported to 6 months 7 months after the last study drug administration. From 6 months after the last study drug administration until the end of the follow-up 
period only related AEs/SAEs and cardiac AEs should be reported. NCI-CTCAE version 4 should be used for AE coding 
[k] All concomitant medication will be recorded between the Screening and the Safety Follow-up visits. Thereafter, only anti-cancer treatments given to treat a 
recurrence will be reported 
[l] Trastuzumab IV is administered intravenously at 6mg/kg for the subsequent doses, every 3 weeks for the first 3 cycles (cycle 7 to 9)[m] Trastuzumab is 
administered subcutaneously at a fixed dose of 600 mg, 3-weekly for a total of 9 cycels (cycle 10-18) (regardless of body weight) 
[o] Patients will undergo a Safety Follow-up visit 4 weeks after their last dose of study treatment 
(p) Patient reporting of symptoms using the MD Anderson Symptom Inventory (MDASI, appendix 4):Patients will be asked to rate the severity of 13 core items 
on a scale from 0 to 10. Patients will be asked to complete the MDASI 4 times: Prior to the first dose trastuzumab IV = prior to cycle 7, prior to the first dose 
trastuzumab SC vial = prior to cycle 10, prior to the first dose trastuzumab SC vial administered at home = prior to cycle 13 and prior to the fourth dose 
trastuzumab SC vial administered at home = prior to cycle 16.  
(q) Patient experience with the treatment provided during the in-hospital part of the study: Patients will be asked to complete a questionnaire (PSQ1, appendix 6) 
related to the quality of care provided during trastuzumab administration in the hospital prior to the first dose trastuzumab SC vial  administered at home = prior to 
cycle13. 
(r) Patient experience with the treatment provided during the at home part of the study: Patients will be asked to complete a questionnaire (PSQ2, appendix 6) 
related to the quality of care provided during trastuzumab SC vial administration at home prior to the fifth dose trastuzumab SC vial administered at home = prior 
to cycle 17. 
(s) HCP overall satisfaction and perceived time savings with trastuzumab SC vial in the hospital will be assessed by a Health Care Professional 
Questionnaire (HCPEX-1, appendix 5): The HCPEX-1 questionnaire will be completed by a HCP administering trastuzumab IV and SC vial in the 
hospital after at least 3 patients completed the in hospital part of the study ( 3 patients must have completed treatment period 1 and 2) 
(t) Patient experience with trastuzumab IV and SC vial administered in the hospital. 
Patients will be interviewed by a HCP to complete the PEX-P1 (appendix 7) prior to the third dose trastuzumab SC = prior to cycle 12. 
(u) Patient experience with trastuzumab SC vial administered at home. Patients will be interviewed by a HCP to complete the PEX-P2 (appendix 7) 
at the safety follow-up visit, following 4 weeks after the last trastuzumab SC vial administration at home. 
(v) Patients will undergo 5 ECOG measurements: one at screening, one per treatment period and one during first safety follow-up visit. 
Choice of cycle within treatment period is upon discretion of the investigator.  


 
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3.3 
Sample Size 
One hundred subjects are foreseen to be enrolled to assess the overall safety and tolerability of 
trastuzumab SC vial when administered at home. This sample size was not based on a formal 
calculation but mainly driven by feasibility and a reasonable width of a 95% confidence 
interval for the rate of AEs and SAEs. Based on an expected rate of AEs of 97% and 100 
subjects, a 95% confidence interval of 91% to 99% would be obtained. For an expected rate 
of SAEs of 21% and 100 subjects, a 95% confidence interval ranging from 13% to 29% 
would be obtained (confidence intervals calculated using Clopper-Pearson methodology). 
3.4 
Study Endpoints 
 Primary Endpoint: 
Endpoints relating to primary objective: 
 Incidence and severity (by NCI CTCAE version 4.0) of AEs and SAEs; 
 Incidence of AEs / SAEs leading to premature discontinuation of study treatment; 
 Cardiac Safety Endpoints: 
o Incidence of Cardiac AEs / SAEs ; 
o Incidence of CHF by severity (NCI CTCAE version 4 and New York Heart; 
Association [NYHA] Classification); 
o LVEF over time and Changes from baseline. 
 
 Secondary Endpoints: 
 Safety: 
o Exposure to study medication; 
o Duration of treatment, follow-up and safety observation; 
o ECOG performance status; 
o Concomitant medications; 
o Changes in laboratory values over time; 
o Changes in vital signs over time; 
o Physical examination; 
o ECG (normal/abnormal) over time; 
o Weight and percent change from baseline in weight over time; 
o Premature withdrawals and major protocol violations. 
 Efficacy 
o Disease Free Survival (eBC patients). 
 PRO  
o Patient experience with the treatment provided during the in-hospital part of 
the study evaluated with PSQ1 questionnaire completed by the patient prior  to 
the first dose of trastuzumab SC at home (prior to cycle 13); 
o Patient experience with the treatment provided during the at home part of the 
study, evaluated with PSQ2 questionnaire, completed by the patient prior  to 
the fifth dose of trastuzumab SC at home (prior to cycle 17); 
o Patient reporting symptoms using the MD Anderson Symptom Inventory 
(MDASI) questionnaire. 


 
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 HCP-Reported outcome   
o HCP overall satisfaction and perceived time savings with trastuzumab SC vial 
in the hospital using questionnaire HCPEX-1. 
 Other outcome   
o Patient experience with trastuzumab IV and SC vial administered in the 
hospital evaluated with PEX-P1 questionnaire, completed by the HCP when 
interviewing the patient prior to the third dose trastuzumab SC; 
o Patient experience with trastuzumab SC vial administered at home, evaluated 
with PEX-P2 questionnaire, completed by the HCP when interviewing the 
patient at the safety follow-up visit. 
3.5 
Study Visits 
For each patient, the day of first infusion of study medication trastuzumab IV that is to say 
day 1 of cycle 7 will be considered as study day 1.  
All efficacy and safety data will be listed as recorded on the CRF, sorted by site identifier, 
patient identifier, cycle identifier and timepoint (if needed). 
For a number of endpoints, when summarised or analysed by subgroup, data may be required 
to be assigned to individual treatment cycles.  If the data in question was not collected on 
cycle-specific eCRF pages (e.g. adverse events), the following procedure is defined: 
Administration of trastuzumab will be day one of each cycle.  This cycle will continue 
until the day prior to the subsequent dose of trastuzumab or the day of the safety 
follow-up visit, whichever occurs first. 
Assessments such as AEs and concomitant medications that occur on or after the dose 
of trastuzumab in cycle ‘x’ but prior to the subsequent dose of trastuzumab in cycle 
‘x+1’ will be assigned to cycle ‘x’.   
Such methodology is essential for the display of data ‘by treatment cycle’.  Such displays will 
be necessary for a number of the subgroups where data from different cycles belongs to 
different subgroups.  
3.6 
Randomization 
This study is a single arm multicentre, non-randomized study. 
Disease free survival will be assessed using all data from the first study drug administration 
(i.e. Day 1 of Cycle 7) to study end. 
 
4 Study Analysis Populations 
There will be two 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. 


 
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4.1 
Intent to treat (ITT) Population 
The ITT population will consist of all enrolled patients who were scheduled to receive study 
medication except patients considered as screen failure and patients who will be considered as 
not to be retained into the efficacy analysis (e.g. violation of eligibility criteria that may have 
an impact on efficacy analysis).The ITT population will be the primary efficacy population. 
4.2 
Safety Population 
The safety population will consist of all enrolled patients who received at least one dose of 
study medication (trastuzumab SC or trastuzumab IV) except patients with protocol 
deviations being able to have an impact or bias on the safety measurement. 
 The Safety population will be the primary population used for safety analysis and summaries. 
4.3 
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. 
4.4 
Blinding 
Not applicable.  This study is open label. 
 
5 Statistical Methodology 
5.1 
Data Quality Assurance 
Data will be transcribed by the site from the paper source documents to the eCRF.  The eCRF 
will integrate comprehensive validation checks that will be performed directly at the site to 
assure appropriate data quality.  Part of the data (ie. core data), extracted from the eCRF and 
mapped to a standard file structure, will be transferred to the Global Medical Affairs to form 
part of the Global Umbrella analysis: limited programmed checks in the Roche global 
database will be used to verify the data and discrepancy reports will be generated accordingly.  
These will be transferred electronically to the affiliate for resolution. 
5.2 
Data Transfer and Preparation 
Part of the data from this study (ie. core data) will be transferred on a monthly basis to the 
Global Umbrella database by the Data-management department.  The files being transferred 
will be comma delimited (csv format) and will be structured according to the data transfer 
specifications (an annotated version of the core eCRF).  Each file will contain all the core data 
from this study (up to the database lock for Analyse 1 and in its entirety for Analysis 2).  
Thus, old csv files will not need to be referenced as new data is transferred.   


 
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In addition to forming the global database, data received by global from these csv files such as 
AEs, Conmeds and Medical History will be sent for coding internally at Roche with preferred 
terms and other coded items being returned to the local database.    
5.3 
Subgroups 
Safety and efficacy endpoints may be reported in subgroups defined below: 
 Treatment administration (IV, SC hospital, SC at home), 
 Country (Belgium, Israel). 
5.4 
Interim Analysis 
The analysis will be conducted into sequence: 
A primary analysis (Analysis 1) will be conducted 4 weeks after end of study treatment (first 
safety follow-up visit), this analysis will be based on primary and all secondary endpoints. 
A safety follow-up analysis (Analysis 2) will be conducted 24 months after treatment 
cessation. This analysis will be based on safety follow-up as well as the DFS analysis.    
5.5 
Disposition of Patients 
The following characteristics will be summarised for all patients: 
 Number and percentage of screened patients; 
 Number and percentage of screen failure with reasons; 
 Number and percentage of patients having received at least one cycle of study 
treatment; 
 Number of patients that were withdrawn before receiving any study treatment with 
reason of withdrawal; 
 Number of patients failing one or more eligibility criteria but staying in the study; 
 Number of patients failing one or more eligibility criteria omitted from the efficacy 
analysis because of possible interference with outcome. 
The following characteristics will be summarised for both ITT and Safety populations: 
 Number and percentage of patients completing treatment (Yes, No); 
 Number and percentage patients completing 4 week safety follow-up visit (Yes, No); 
 Reasons for discontinuation of treatment and 4weeks safety follow-up. 
The same tables will be presented by country (Belgium, Israel). 
 


 
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5.6 
Baseline and Demographic Characteristics 
All baseline and demographic characteristics will be summarised for both the safety and ITT 
populations.  Included will be: 
 age 
 gender 
 race 
 weight 
 baseline pregnancy test result will be summarised for females of child bearing 
potential 
 history of breast cancer specifying: 
o Time since diagnosis : (Date of informed consent  - Date of diagnosis) / 360.25 
o Tumor grade 
o Nodal involvement 
 previous cancer treatment 
 treatment category (eB / eBC adjuvant) 
 medical history 
 previous treatments (other than for breast cancer) 
 concomitant anti-cancer treatment (such as hormonal therapy, etc) 
 ECG 
 HER2 results 
 Hormonal receptor status 
A same analysis will be conducted for both ITT and safety populations, distinguishing 
country. 
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.  Age will be presented and summarised as an integer only. 
Medical history will be coded using MedDRA (version 18.0) and summarised by System 
Organ Class and Preferred Term. 
5.7 
Safety Analysis 
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 and CHF will additionally be graded using the NYHA class (I, II, III or IV). 
5.7.1 
Adverse events 
Incidence of AEs will be presented for the entire study duration.  Additionally, selected tables 
will be presented by treatment administration periods (IV, SC in hospital, SC at home). 
Only post study start AEs (starting on the day of or after first administration of study drug) 
will be included in the summary tables. Where an AE start 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. 


 
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For summaries by ‘treatment administration’ subgroup (eg. IV at hospital, SC at hospital, SC 
at home), 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 days 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. 
Endpoints related to adverse events, serious adverse events and administration associated 
reactions will be summarised by presenting the number and percentage of patients having any 
event along with a 95% Clopper Pearson confidence interval.  The proportions of patients 
experiencing the following will be summarised: 
 Any adverse event 
 Any serious adverse event 
 Any adverse event by CTC grade (1, 2, 3, 4) 
 Any serious adverse event by CTC grade (1, 2, 3, 4) 
 Any CHF by NYHA class (I, II, III, IV) 
 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 
These proportions of patients will also be described by country separately. 
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: 
 Overall 
 Occurrences of Emergent AEs >= 5% 
 Related AEs only  
 By maximum intensity (CTC grade) 
 By maximum class (NYHA classification) [for CHF and cardiac AEs only]. 
 
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. 


 
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Time to onset (days) will be summarised for cardiac and CHF AEs (overall) using descriptive 
statistics.  Time to onset will be calculated as (start date of AE – date of first treatment in the 
relevant treatment period) + 1.   
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. 
5.7.2 
LVEF 
LVEF percentage will be summarised over time (including change from baseline) using 
descriptive statistics.  Categorical findings will also be summarised over time. 
Baseline was defined at screening visit. 
Mean values (+/-SEM)  values will be presented graphically with line graphs over time. 
Only the latest LVEF data within a visit will be used in the summary tables. 
5.7.3 
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 
therapeutic area and preferred drug name. All medications other than study drugs 
(trastuzumab SC and trastuzumab IV) will be summarised in this fashion.  Further summaries 
of specific medications given for breast cancer are defined in the exposure section (5.9.3).  
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.  If it 
is unclear which subgroup to which it should be assigned, the medication will be assigned to 
all relevant subgroups.  
Before any statistical analyses, all the medications will be coded with INN-Drug Dictionary 
(ongoing version). 
5.7.4 
Laboratory findings 
Results from the following laboratory parameters will be summarised for the Overall group of 
patients:  
Haematology:  
Haemoglobin, white blood cell (WBC) count and differential, and absolute neutrophil count 
(ANC) and platelet count. 
Biochemistry:  
Creatinine, Blood urea nitrogen (BUN), aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT), total bilirubin, alkaline phosphatase, albumin, sodium, potassium, 
calcium. 


 
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Changes in haematology and biochemistry laboratory values from baseline to each visit will 
be summarised. 
Baseline will be defined at screening visit. 
Shift tables for the haematology and biochemistry laboratory parameters comparing out-of 
ranges values at baseline versus out-of ranges values at each visit will be presented. The same 
shift tables presenting NCS / CS values at baseline versus NCS/CS values at each visit will 
also be done. 
For blood differentials, results given in absolute value will be analysed separately than results 
expressed in percents. 
Notes: 
All results outside predefined normal ranges will be flagged in the data listings. 
Only the most recent set of laboratory results within a visit will be used in the summary 
tables. 
5.7.5 
Vital Signs 
Vital signs (systolic and diastolic blood pressure, temperature and pulse) will be summarised 
over time (including change from baseline) using descriptive statistics. For systolic and 
diastolic blood pressure, statistics on pre and post administration measurements will be 
distinguished and differences between post and pre administrations measurements will also be 
described. 
Baseline will be defined at baseline visit or at screening visit (if done within 7 days before 
first study drug administration), when missing assessment at baseline visit. 
5.7.6 
ECG 
Number and percentage of patients with abnormal clinically significant ECG (12-Lead) will 
be described over time. 
5.7.7 
Weight 
Weight and also percent change from baseline will be summarised over time. Baseline for 
weight will be defined at baseline visit or at screening visit (if done within 7 days before first 
study drug administration), when missing assessment at baseline visit. 
 
5.7.8 
Physical Examination  
Abnormal results at each visit will be listed. Number and percentage of patients with 
abnormal physical examinations will be described over time. 
5.7.9 
Pregnancy Tests 
Pregnancy test results throughout the study will be listed only.  Baseline results are 
summarised as part of demography and baseline characteristics.  


 
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5.7.10 
ECOG Performance Status 
ECOG performance status (Grade 0 - Grade 4) will be summarised by visit, presenting the 
number and percentage of patients in each category. 
5.8 
Efficacy Analysis 
5.8.1 
Disease-free Survival  
DFS is defined as time from first study drug administration (i.e. Day 1 of Cycle 7) to local, 
regional or distant recurrence, contralateral breast cancer 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 (last cycle or last follow-up visit or date of last contact). Time will be 
calculated in months as follows: 
DFS = (date of event – date of first study drug administration + 1) / 30.4375 
For the primary analysis, the DFS should be analysed  up to the time period including the 4 
weeks safety follow-up visit. For patients who completed this period, the date of Safety 
follow-up should be taken. For early withdrawal patients, the date of premature 
discontinuation should be taken (date of withdrawal of study treatment period or date of 
withdrawal of the safety follow-up period). 
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.  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. 
5.9 
Exposure 
Exposure will be summarised as set out in the following sections using the safety and ITT 
populations. 
5.9.1 
Extent of Exposure to Trastuzumab SC 
Exposure to trastuzumab SC will summarised overall and also within each of the study drug 
related subgroups listed in section 5.3. 
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 percentage of missed doses, duration of injection, dose injected, percentage of 
injections delayed (by reason), vial site of injection, location for injection (home / hospital) 
and administrator (HCP). 


 
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5.9.2 
Extent of Exposure to Trastuzumab IV 
The total number of cycles received will be summarised both by descriptive statistics and 
frequency counts.  Trastuzumab IV will be counted as being taken within a cycle if any dose 
administered during that cycle. 
Trastuzumab IV administration details will be summarised by cycle and overall and will 
include dosage, percentage of missed doses, duration of infusion, percentage of dose infused 
(planned vs. actual), percentage of infusions delayed (by reason). 
5.9.3 
Extent of exposure to other non-study drug medications 
Exposure to other treatments given for eBC other than trastuzumab SC, trastuzumab IV will 
be summarised overall. 
The following medications are collected for the study period rather than by cycle: 
 hormone therapy 
 radiotherapy 
 chemotherapy 
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. 
This analysis will also be done by country (Belgium, Israel). 
 
5.10 
Patient-Reported Outcome Analysis 
All patient-reported outcome endpoints will be analysed using the ITT population. They 
concerned Patient Satisfaction Questionnaires (PSQ1 and PSQ2 questionnaires) and MDASI 
questionnaire. 
a) PSQ1 and PSQ2 questionnaires: 
 Patient experience with the treatment provided during the in-hospital part of the study 
will be evaluated with PSQ1 questionnaire completed by the patient prior to the first 
dose of trastuzumab SC at home (prior to cycle 13). PSQ1 is quality of care 
questionnaire containing 28 questions categorised on the opinion of patients about the 
clinicians, opinion of patient about the other staff  and other questions. 
 Patient experience with the treatment provided during the at-home part of the study 
will be evaluated with PSQ2 questionnaire completed by the patient prior to the fifth 
dose of trastuzumab SC at home (prior to cycle 17). PSQ2 is quality of care 
questionnaire containing 26 questions categorised on the opinion of patients about the 
clinicians, opinion of patient about the other staff  and other questions. 
Number and percentage of patients for each question/answer’s modality of PSQ1 and 
PSQ2 questionnaires will be described. The same analysis will be done by country 
(Belgium, Israel). 


 
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Questions regarding opinion of the patients about the clinicians and about the other staff 
are the same in the both questionnaires. So in order to make a comparison between the 2 
questionnaires, bar charts presenting the percentage of patients in each question/answer’s 
modality for both PSQ1 and PSQ2 in a same graph will be done for these 2 categories 
(opinion about the clinician, about the other staff) separately. Regarding the 3rd category 
‘Other questions’, the percentage of patients in each question/answer’s modality will be 
presented in a similar graph but presenting the both questionnaires results, separately. 
These graphs will also be done distinguishing country. 
 
b) MDASI questionnaire 
Patient reporting symptoms was evaluated using the MD Anderson Symptom Inventory 
(MDASI) questionnaire. With this questionnaire, patients will be asked to rate the severity 
of 13 core items on a scale from 0 to 10 on the 4 following visits: 
 Prior to the first dose trastuzumab IV i.e. prior to cycle 7,  
 Prior to the first dose trastuzumab SC vial i.e. prior to cycle 10,  
 Prior to the first dose trastuzumab SC vial administered at home i.e. 
prior to cycle 13 , 
 Prior to the fourth dose trastuzumab SC vial administered at home 
i.e. prior to cycle 16. 
Each scale rating will be analysed as continuous items with number of patients, number of 
missing answers, mean, standard deviation, median, Q1 and Q3 and also minimum and 
maximum at each visit, separately. 
Bar charts summarising the mean (+/- SEM) evolution of each core item over time could be 
added, if relevant. 
The same analysis will be conducted by country (Belgium, Israel). 
 
5.11 
HCP Reported Outcome Analysis 
HCP overall satisfaction and perceived time savings with trastuzumab SC vial in the hospital 
will be assessed by a Health Care Professional Questionnaire (HCPEX-1). The HCPEX-1 
questionnaire will be completed by a HCP administering trastuzumab IV and SC vial in the 
hospital after at least 3 patients completed the in hospital part of the study (3 patients must 
have completed treatment period 1 and 2). The questionnaire contains 19 items that will be 
summarized by using descriptive statistics (number of HCP and percentage for categorical 
items,  number of HCP, number of missing answers, mean, standard deviation, median, Q1 
and Q3 and also minimum and maximum for continuous items). 
 
 


 
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5.12 
Other outcome measures 
Patients will be interviewed by a HCP to assess:  
 Patient experience with trastuzumab IV and SC vial administered in the hospital; 
 Patient experience with trastuzumab SC vial administered at home. 
This interview will be done by using the PEX-P1 and PEX-P2 questionnaires as follows: 
  Patients will be interviewed by a HCP to complete the PEX-P1 prior to the third dose 
trastuzumab SC i.e. prior to cycle 12 in order to evaluate the patient experience with 
trastuzumab IV and SC vial administered in the hospital. PEX-P1 questionnaire 
contains 25 items. 
 Patients will be interviewed by a HCP to complete the PEX-P2  at the safety follow-up 
visit, following 4 weeks after the last trastuzumab SC vial administration at home in 
order to evaluate the patient experience with trastuzumab SC vial administered at 
home. PEX-P2 questionnaire contains 6 items. 
The both questionnaires will be summarized separately by using descriptive statistics (number 
of patients and percentage for categorical items,  number of patients, number of missing 
answers, mean, standard deviation, median, Q1 and Q3 and also minimum and maximum for 
continuous items). 
 
The same analysis will be conducted by country (Belgium, Israel). 
 
5.13 
Centre effects 
Not applicable. 
5.14 
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 
Full details of these criteria will be finalised prior to the primary analysis time point. 
5.15 
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. 


 
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5.16 
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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5.17 
References 
None. 
 
 


 
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Appendix 1 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):