Clinical trial NCT01566721
Conditions: Breast Neoplasms
Sponsor: Hoffmann-La Roche
Start date: 2012-05-17; Completion date: 2020-02-19
Enrollment: 2577 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This multicenter, two-cohort, non-randomized, open-label study will evaluate the safety and tolerability of assisted and self-administered SC Herceptin as adjuvant therapy in participants with early HER2-positive breast cancer following tumor excision. Participants will receive Herceptin 600 milligrams (mg) SC every 3 weeks for 18 cycles, either by an assisted administration using a conventional syringe and needle/vial formulation (Cohort A) or with assisted and self-administration using a single-use injection device (SID) in selected participants (Cohort B).

Detailed description:

Arms: arm 1: Participants will receive SC Herceptin by an assisted administration using a conventional syringe and needle/vial formulation. arm 2: Participants will receive SC Herceptin with assisted and/or self-administered use of an SID. The first administration will be performed by a trained healthcare professional. If well tolerated and the participant is willing and judged competent to perform self-administration, subsequent administration of SC Herceptin may be performed by the participant.
Interventions: intervention 1: Herceptin
Intervention descriptions: intervention 1: Herceptin will be given as 600 mg SC (into thigh) on Day 1 of each 3-week cycle for up to 18 cycles.

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
 
A PHASE III PROSPECTIVE, TWO-COHORT NON-RANDOMIZED, 
MULTICENTER, MULTINATIONAL, OPEN-LABEL STUDY TO 
ASSESS THE SAFETY OF ASSISTED- AND SELF-ADMINISTERED 
SUBCUTANEOUS TRASTUZUMAB AS THERAPY IN PATIENTS 
WITH OPERABLE HER2-POSITIVE EARLY BREAST CANCER 
[SafeHer Study] 
NCT Number: NCT01566721 
Document Date: Protocol Version 4: 11-November-2016 
 
 
 


Title
11-Nov-2016 20:30:25
Date and Time (UTC)
Company Signatory
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, 
especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its 
control) and therefore is provided to you in confidence as an investigator, potential investigator, or 
consultant, for review by you, your staff, and an applicable Ethics Committee or Institutional 
Review Board.  It is understood that this information will not be disclosed to others without written 
authorization from Roche except to the extent necessary to obtain informed consent from persons 
to whom the drug may be administered. 
Trastuzumab—F. Hoffmann-La Roche Ltd 
Protocol MO28048, Version 4 
PROTOCOL 
TITLE: 
A PHASE III PROSPECTIVE, TWO-COHORT 
NON-RANDOMIZED, MULTICENTER, MULTINATIONAL, 
OPEN-LABEL STUDY TO ASSESS THE SAFETY OF 
ASSISTED- AND SELF-ADMINISTERED 
SUBCUTANEOUS TRASTUZUMAB AS THERAPY IN 
PATIENTS WITH OPERABLE HER2-POSITIVE EARLY 
BREAST CANCER [SafeHer Study] 
PROTOCOL NUMBER: 
MO28048 
VERSION NUMBER: 
4  
EUDRACT NUMBER: 
2011-005328-17 
IND NUMBER: 
Not applicable 
TEST PRODUCT: 
Trastuzumab SC (RO 45-2317) 
MEDICAL MONITOR: 
 Ph.D.  
SPONSOR: 
F. Hoffmann-La Roche Ltd
DATE FINAL: 
Version 1:  30 November 2011 
DATES AMENDED: 
Version 2:  19 November 2012 
Version 3:  18 March 2013 
Version 4:  See electronic date stamp below. 


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PROTOCOL AMENDMENT, VERSION 4: 
RATIONALE 
Changes to the protocol, along with a rationale for each change, are summarized below: 
• 
The protocol title page was updated to align with current Sponsor practices.  The 
Medical Monitor and the primary and secondary contacts for the study were 
updated. 
• 
The guidelines for additional follow-up of patients beyond the Safety Follow-up visit 
(performed 4 weeks after the last dose of study treatment) were revised to include 
“or investigator’s routine practice” for consistency in Section 3.1, Section 4.5.1.3, 
Section 4.5.1.8, Section 4.5.2.2, and Section 5.1.1 and the Schedule of 
Assessments in Appendix 1.  
• 
The concomitant medications monitored after the Safety Follow-up visit were 
clarified in Section 3.4.2, Section 4.4, Section 4.5.2.4, and the Schedule of 
Assessments in Appendix 1 to include breast cancer treatments (e.g., endocrine 
therapy), anti-cancer treatments given to treat breast cancer recurrence, and 
medications related to the treatment of serious adverse events (SAEs) for 
consistency and clarity. 
• 
As noted in the Note to File (dated 30 September 2016), an inconsistency was 
noted in the following sections of Protocol MO28040, Version 3:  Section 4.5.2.4, 
Section 5.3.1, and Appendix 1, Footnote (l).  Changes were made to maintain 
consistency between Section 4.5.2.4 and Section 5.3.1. 
• 
The term “Study Completion/Early Discontinuation eCRF” was updated to “Death 
eCRF page” in Section 5.3.5.7 to maintain consistency between the protocol and the 
eCRF. 
• 
The Herceptin (RO 45-2317, Trastuzumab) Investigator’s Brochure was clarified as 
the primary reference safety information for determining the expectedness of 
adverse events in Section 5.7. 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


 
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PROTOCOL AMENDMENT, VERSION 4: 
SUMMARY OF CHANGES 
GLOBAL CHANGES 
The Medical Monitor has been changed to 
, Ph.D. 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.2.2.3.2:  Study BO22227 (HannaH) 
Study BO22227 wasis a Phase III, randomized, open-label, multicenter trial involving 
596 female patients with HER2-positive early breast cancer in which the 
pharmacokinetics, efficacy, and safety of trastuzumab SC were compared with IV 
trastuzumab.  Co-primary endpoints are serum Ctrough pre-surgery and pathological 
complete response (pCR). 
SECTION 2.3:  EXPLORATORY OBJECTIVES  
Two aAdditional, exploratory objectives will be investigated in a subset of patients 
(Cohort B) at selected study sites: 
SECTION 3.1:  DESCRIPTION OF STUDY 
Patients will undergo a Safety Follow-up visit 4 weeks after their last dose of study 
treatment, with further follow-up according to the American Society of Clinical Oncology 
(ASCO) 2006 Guideline for Breast Cancer Follow-up in the adjuvant setting 
(Khatcheressian et al. 2006) or investigator’s routine practice.  All patients will be 
followed-up for cancer recurrence and survival until study end.  The duration of follow-up 
will be at least 5 years after their last study treatment, unless one of the following occurs 
first:  withdrawal of consent, loss to follow-up, or death.  After disease progression, 
patients will be managed as per local practice and followed for survival only. 
SECTION 3.4.2:  Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
All concomitant medication will be recorded between the Screening and the Safety 
Follow-up visits.  Thereafter, only medication applicable for long term reporting will 
be recorded including breast cancer treatments (e.g., endocrine therapy), 
anti-cancer treatments given to treat a recurrence, and medications related to the 
treatment of SAEs that are applicable for long term reporting (e.g., treatment of 
heart failure) will be recorded. 
 
SECTION 4.4:  CONCOMITANT THERAPY 
All concomitant medications are to be reported until the Safety Follow-up visit.  
Thereafter, only medication applicable for long-term reportingthe following medications 
must be reported, including: 
• 
Breast cancer treatments (e.g., hormonal therapy) 
• 
Anti-cancer treatments given to treat a recurrence 


 
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• 
Medications related to the treatment of serious AEsthat are applicable for long term 
reporting (e.g., treatment of heart failure). 
 
SECTION 4.5.1.3:  Physical Examinations 
A general physical exam (including a general neurological exam, as clinically indicated) 
will be performed at screening, approximately 3-monthly during trastuzumab SC 
treatment (at Week 13/Cycle 5, Week 25/Cycle 9, Week 37/Cycle 13, and 
Week 52/Cycle 18), 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) or investigator’s routine practice.  Physical 
examinations will be performed according to local practice; however, particular attention 
should be given to the cardiovascular system. 
SECTION 4.5.1.8:  Breast Cancer Evaluations and Follow-Up 
Patients will be assessed for residual disease (as per institutional practice) not more 
than 4 weeks before the first dose of study drug.  Screening radiologic examinations to 
exclude metastatic disease should include a bilateral mammogram or breast MRI, and 
chest X-ray (CXR) or breast ultrasound.  Should a previously taken chest CT or PET 
scan be available, then these results can also be used for eligibility assessment.  These 
imaging tests do not need to be repeated if completed within 12 months prior to the first 
study treatment.  In addition, bone scan and liver imaging should be performed if 
clinically indicated.  During study treatment and the post-treatment follow-up period, 
patients will be followed for disease recurrence according to the investigator’s routine 
practice or the American Society of Clinical Oncology (ASCO) 2006 Guideline for Breast 
Cancer Follow-up (Khatcheressian et al. 2006) or investigator’s routine practice (see 
Appendix 1, Schedule of Assessments). 
SECTION 4.5.2.4:  Post-treatment Follow-up Visits (minimum 5 years) 
All patients will be followed-up for cancer recurrence and survival till study end (i.e., until 
all patients have had a minimum 5-year follow-up) yearly or at higher frequency based 
on the site standard of care.  The duration of follow-up will be at least 5 years after the 
last study treatment or until withdrawal from the study, lost to follow-up, or death, 
whichever occurs first.  During this post-treatment follow-up period, patients will undergo 
the following assessments: 
• 
Breast cancer follow-up according to the ASCO 2006 Guideline for Breast Cancer 
Follow-up (Khatcheressian et al. 2006) and reporting every 6 months or as per 
institutional standard practices (see Section 4.5.1.8 for details) 
• 
Blood samples for immunogenicity and PK analyses will be collected from a subset 
of Cohort B patients (at selected sites only) 6 months after their last study 
treatment. 
• 
Patients’ weight must also recorded 6 months after their last study treatment if 
participating to immunogenicity and PK testing. 
• 
Pregnancy test as clinically indicated up to 67 months after last study treatment 


 
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• 
AE follow-up:  After initiation of study drug, all AEs/SAEs (except unrelated non-
cardiac AEs in the follow-up period), regardless of relationship to study drug, will be 
reported until study closure.  The investigator does not need to actively monitor 
subjects for AEs 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). 
• 
Concomitant medications:  Only medication applicable for long term reporting 
mustbreast cancer treatments (e.g., endocrine therapy), anti-cancer treatments 
given to treat a recurrence, and medications related to the treatment of SAEs will 
be reportedrecorded; refer to Section 4.4 for details. 
• 
Cardiac safety assessments will be performed at 6, 12, and 24 months and at yearly 
intervals until 5 years after treatment cessation (see Section 5.1.1.2 for details); 
• 
Survival:  After disease progression, patients will be managed as per local practice 
and followed for survival only. 
 
After study treatment completion (or early discontinuation), AEs should be followed as 
outlined in Section 5.5 and Section 5.6. 
Please see Appendix 1 for the schedule of follow-up assessments. 
SECTION 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, 
adverse events, 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, approximately 3-monthly (every 4 cycles) 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) or investigator’s routine practice during the 5-year 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, SC injection sites will be checked at every visit, and blood pressure will be 
measured before and after trastuzumab SC administration every 4 cycles, as specified in 
Appendix 1, Schedule of Assessments. 
SECTION 5.3.1:  Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported 


 
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(e.g., serious adverse events related to invasive procedures such as biopsies).  All other 
adverse events will be recorded as medical history. 
After initiation of study drug, all AEs/SAEs (except unrelated non-cardiac AEs in the 
follow-up period), regardless of relationship to study drug, will be reported until study 
closure.  The investigator does not need to actively monitor subjects for AEs 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). 
Any injection-site reactions are considered to be related AEs/SAEs and should be 
reported accordingly. 
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. 
SECTION 5.3.5.7:  Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur prior to study 
closure that are attributed by the investigator solely to progression of EBC should be 
recorded only on the Study Completion/Early Discontinuation Death eCRF page.  All 
other on-study deaths, regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  
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 pre-existing heart disease, within 1 hour of the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should 
be replaced by the established cause of death. 
During study survival follow-up, deaths attributed to progression of EBC should be 
recorded only on the Survival eCRF or Study Completion/Early Discontinuation Death 
eCRF page. 


 
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SECTION 5.4.1:  Emergency Medical Contacts 
Medical Monitor (Roche Medical Responsible) Contact Information  
Primary Contact 
Medical Monitor: 
 M.D. 
Address: 
F. Hoffmann La Roche Ltd. 
 
 
 
4070 Basel, Switzerland 
Telephone No.: 
 
Mobile Telephone No.: 
 
 
Secondary Contact 
Medical Monitor: 
Dr. 
 M.D., PhD 
Address: 
  
 
 Belgium 
Telephone No.: 
  + 650 225-1000 
MobileOffice Telephone No.:
 
To ensure the safety of study patients, an Emergency Medical Call Centre 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 Medical Call Centre Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk and 
Medical Monitor contact information will be distributed to all investigators (see "Protocol 
Administrative and Contact Information & List of Investigators"). 
SECTION 5.4.3.1:  Pregnancies in Female Patients 
For women of childbearing potential (defined as premenopausal, less than 1 year after 
the onset of menopause or not surgically sterilized), appropriate contraceptive measures 
are mandatory during study treatment (see Section 4.5.1.7.3).  Based on 
pharmacokinetic 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 67 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 the study drug and counsel the patient, discussing the 


 
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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").  As soon as the EDC system is operating, the 
Pregnancy Report eCRF will be completed. 
SECTION 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 
67 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. 
SECTION 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 adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.  
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 


 
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The Investigator must report new significant follow-up information for these events to the 
Sponsor within 24 hours after becoming aware of the information.  New significant 
information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event (including 
outcome of a reported pregnancy, as applicable) 
 
In an individual patient, AE follow-up will continue as follows: 
Related or cardiac AEs and SAEs will be followed until one of the following occurs: 
• 
Resolved or improved to baseline state 
• 
Relationship is reassessed as unrelated 
• 
Investigator confirms that no further improvement can be expected  
• 
Start of a new anti-cancer regimen  
• 
Death 
 
Unrelated non-cardiac AEs severe or life threatening (Grade 3 or Grade 4) and 
SAEs (any grade) 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 non-cardiac AEs (Grade 1 or Grade 2) will be followed until 4 weeks after 
the last dose of study drug in an individual patient.  
The final outcome of each adverse event must be recorded on the eCRF. 
Follow-up of Abnormal Laboratory Test Values 
In the event of medically significant unexplained abnormal laboratory test values, the 
tests should be repeated and followed up until they have returned to the normal range or 
baseline state and/or an adequate explanation of the abnormality is found.  If a clear 
explanation is established it should be recorded on the eCRF. 


 
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SECTION 5.6:  POST-STUDY ADVERSE EVENTS 
At the safetyfinal follow-up visit of the study, 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 related to study drug, occurring at any time, after a patient has discontinued study 
participation, even after study closure, regardless of relationship to treatment of study 
drug.  The investigator is not required to actively monitor patients after the study has 
ended. 
The Sponsor should also be notified if the Investigator becomes aware of the 
development of cancer or a congenital anomaly/birth defect in a subsequently conceived 
offspring of a patient that participated in this study. 
The Investigator should report these events to Roche Safety Risk Management on the 
Adverse Event eCRF.  If the Adverse Event eCRF is no longer available, the Investigator 
should report these events, indefinitely, directly to Roche Safety Risk Management via 
telephone (see "Protocol Administrative and Contact Information & List of Investigators"). 
SECTION 5.7:  EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, 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 document(s): 
• 
Herceptin (RO 45-2317, Trastuzumab) IB  
• 
Local prescribing information for Herceptin  
• 
Herceptin Core Data Sheet 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
SECTION 6.5.1:  Secondary Efficacy Variables 
Secondary efficacy endpoints include disease-free survival (DFS) and overall survival 
(OS) and will be assessed in both cohorts.  
• 
DFS is defined as the time from the date of first treatment to the date of local, 
regional, or distant recurrence; contralateral invasive breast cancer (including 
second primary non breast cancer or contralateral or ipsilateral ductal carcinoma in 
situ [DCIS]); or death due to any cause.  
• 
OS is defined as time from the date of first treatment until date of death, regardless 
of the cause of death.  
 


 
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DFS and OS will be analyzed as a time-to-event variable for the ITT population (see 
Section 6.5.2).  
In addition, patients’ satisfaction with trastuzumab SC administration using the SID will 
be evaluated for Cohort B patients who went on to self-administration only. 
SECTION 6.5.2:  Analyses of Efficacy Endpoints 
The efficacy endpoints, DFS and OS, will be analyzed as a time-to-event variable for the 
ITT and PP populations and for each cohort.  Estimates and corresponding 95% 
confidence intervals for the survivor function for the time-to-event variable will be 
obtained by using the KM approach.  A frequency table will be also provided for the type 
of DFS event (e.g., local, regional, or distant recurrence; contralateral breast cancer; or 
death). 
A preliminary analysis of efficacy (DFS and OS) will take place when all patients have 
received 18 cycles of trastuzumab SC and have completed the post-treatment Safety 
Follow-up assessments.  The final analysis of OS and DFS will take place when the last 
patient has been followed up for at least 5-years after her/his last study treatment, or 
earlier, if one of the following is documented for all treated patients:  withdrawal of 
consent, loss to follow-up, or death.  This is expected to take place approximately 
8 years after the enrollment of the first patient, based on an expected 18-month 
recruitment period per cohort, 12 months of study treatment, and 5 years of follow-up 
after the last study treatment  
Patients’ satisfaction with trastuzumab SC administration using the SID (Cohort B 
patients who went on to self-administration only) will be summarized by frequency tables 
and presented graphically. 
APPENDIX 1:  Schedule of Assessments 
The Schedule of Assessments has been revised to reflect the changes to the protocol. 
 


 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 19 
PROTOCOL SYNOPSIS .................................................................................... 20 
1. 
BACKGROUND .......................................................................................... 31 
1.1 
Background on Breast Cancer............................................... 31 
1.1.1 
Epidemiology......................................................................... 31 
1.1.2 
The Role of HER2-Receptor Status....................................... 31 
1.1.3 
Treatment of Early Breast Cancer ......................................... 32 
1.2 
Background on Trastuzumab................................................. 32 
1.2.1 
Intravenous Trastuzumab (Herceptin®) ................................. 32 
1.2.1.1 
Pharmacokinetics of Trastuzumab IV .................................... 33 
1.2.1.2 
Efficacy of Trastuzumab IV in Early Breast 
Cancer (Adjuvant Setting)...................................................... 33 
1.2.1.3 
Safety of Trastuzumab IV ...................................................... 36 
1.2.2 
Trastuzumab SC.................................................................... 39 
1.2.2.1 
Recombinant Human Hyaluronidase (rHuPH20) ................... 40 
1.2.2.2 
Nonclinical Studies with Trastuzumab SC ............................. 42 
1.2.2.3 
Clinical Studies with Trastuzumab SC................................... 43 
1.2.3 
Subcutaneous Single-Use Injection Device (SID).................. 54 
1.3 
Study Rationale and Benefit-Risk Assessment...................... 55 
2. 
OBJECTIVES.............................................................................................. 56 
2.1 
Primary Objective .................................................................. 56 
2.2 
Secondary Objectives............................................................ 56 
2.3 
Exploratory Objectives........................................................... 57 
3. 
STUDY DESIGN ......................................................................................... 57 
3.1 
Description of Study .............................................................. 57 
3.1.1 
Overview................................................................................ 60 
3.1.2 
Steering Committee............................................................... 61 
3.2 
End of Study.......................................................................... 61 
3.3 
Rationale for Study Design.................................................... 61 
3.3.1 
Rationale for Test Product Dosage........................................ 62 


 
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3.3.2 
Rationale for the Patient Population ...................................... 63 
3.3.3 
Rationale for Control Group................................................... 64 
3.3.4 
Rationale for Immunogenicity and 
Pharmacokinetic Assessments.............................................. 64 
3.3.5 
Rationale for Observation Time Assessments....................... 64 
3.4 
Outcome Measures ............................................................... 65 
3.4.1 
Efficacy Outcome Measures.................................................. 65 
3.4.2 
Safety Outcome Measures .................................................... 65 
3.4.3 
Patient-Reported Outcome Measures ................................... 66 
3.4.4 
Exploratory Outcome Measures ............................................ 66 
4. 
MATERIALS AND METHODS .................................................................... 67 
4.1 
Patients.................................................................................. 67 
4.1.1 
Inclusion Criteria.................................................................... 67 
4.1.2 
Exclusion Criteria................................................................... 68 
4.2 
Method of Treatment Assignment and Blinding..................... 70 
4.3 
Study Treatment.................................................................... 70 
4.3.1 
Formulation, Packaging, and Handling.................................. 70 
4.3.2 
Dosage, Administration, and Compliance.............................. 71 
4.3.2.1 
Preparation and Administration of Trastuzumab 
for SC Injection...................................................................... 71 
4.3.2.2 
Dose and Schedule of Trastuzumab SC................................ 73 
4.3.2.3 
Dose Modifications, Interruptions, and Delays....................... 73 
4.3.3 
Name of Additional Required Medication............................... 75 
4.3.4 
Investigational Medicinal Product Accountability ................... 75 
4.3.4.1 
Assessment of Compliance ................................................... 75 
4.3.4.2 
Destruction of the IMPs ......................................................... 75 
4.3.5 
Post-Trial Access to Trastuzumab......................................... 76 
4.4 
Concomitant Therapy ............................................................ 76 
4.4.1 
Permitted Therapy ................................................................. 76 
4.4.2 
Prohibited Therapy ................................................................ 77 
4.5 
Study Assessments ............................................................... 78 
4.5.1 
Description of Study Assessments ........................................ 78 
4.5.1.1 
Medical History and Demographic Data ................................ 78 


 
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4.5.1.2 
Vital Signs.............................................................................. 78 
4.5.1.3 
Physical Examinations........................................................... 78 
4.5.1.4 
Electrocardiograms................................................................ 78 
4.5.1.5 
Performance status ............................................................... 78 
4.5.1.6 
Other Clinical Safety Assessments........................................ 78 
4.5.1.7 
Laboratory Assessments ....................................................... 79 
4.5.1.8 
Breast Cancer Evaluations and Follow-Up ............................ 81 
4.5.1.9 
Treatment Satisfaction with the SID ...................................... 83 
4.5.1.10 
Pharmacoeconomic Assessments and Medical 
Care Utilization ...................................................................... 83 
4.5.2 
Timing of Study Assessments ............................................... 83 
4.5.2.1 
Screening and Pre-treatment Assessments .......................... 83 
4.5.2.2 
Assessments during Treatment............................................. 85 
4.5.2.3 
Assessments at Treatment Completion/Early 
Termination:  Safety Follow-Up Visit...................................... 86 
4.5.2.4 
Post-treatment Follow-up Visits (Minimum 5 
years)..................................................................................... 86 
4.5.2.5 
Assessments at Unplanned Visits ......................................... 87 
4.6 
Patient, Study, and Site Discontinuation................................ 87 
4.6.1 
Patient Discontinuation.......................................................... 87 
4.6.1.1 
Discontinuation from Study Drug........................................... 88 
4.6.1.2 
Withdrawal from Study........................................................... 88 
4.6.2 
Study and Site Discontinuation.............................................. 89 
5. 
ASSESSMENT OF SAFETY....................................................................... 89 
5.1 
Safety Plan ............................................................................ 89 
5.1.1 
General Safety Assessments ................................................ 89 
5.1.1.1 
Observation Time Assessment.............................................. 90 
5.1.1.2 
Cardiac Safety Assessments................................................. 90 
5.1.1.3 
LVEF Assessment ................................................................. 90 
5.1.2 
Management of Specific Adverse Events .............................. 91 
5.2 
Safety Parameters and Definitions ........................................ 91 
5.2.1 
Adverse Events ..................................................................... 92 
5.2.1.1 
Laboratory Test Abnormalities............................................... 92 


 
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5.2.2 
Serious Adverse Events (Immediately Reportable 
to Roche)............................................................................... 93 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 93 
5.3.1 
Adverse Event Reporting Period ........................................... 94 
5.3.2 
Eliciting Adverse Event Information ....................................... 94 
5.3.3 
Assessment of Severity of Adverse Events ........................... 94 
5.3.4 
Assessment of Causality of Adverse Events ......................... 95 
5.3.5 
Procedures for Recording Adverse Events............................ 96 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 96 
5.3.5.2 
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 96 
5.3.5.3 
Persistent or Recurrent Adverse Events................................ 97 
5.3.5.4 
Abnormal Laboratory Values ................................................. 97 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 98 
5.3.5.6 
Abnormal Liver Function Tests.............................................. 98 
5.3.5.7 
Deaths ................................................................................... 99 
5.3.5.8 
Pre-existing Medical Conditions ............................................ 99 
5.3.5.9 
Lack of Efficacy or Worsening of the Underlying 
Condition ............................................................................... 99 
5.3.5.10 
Hospitalization or Prolonged Hospitalization........................ 100 
5.3.5.11 
Overdoses ........................................................................... 100 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 101 
5.4.1 
Emergency Medical Contacts.............................................. 101 
5.4.2 
Reporting Requirements for Serious Adverse 
Events.................................................................................. 102 
5.4.3 
Reporting Requirements for Pregnancies............................ 103 
5.4.3.1 
Pregnancies in Female Patients.......................................... 103 
5.4.3.2 
Pregnancies in Female Partners of Male Patients............... 103 
5.4.3.3 
Abortions ............................................................................. 104 
5.4.3.4 
Congenital Anomalies/Birth Defects .................................... 104 
5.4.4 
Reporting Requirements for Medical Device 
Complaints........................................................................... 104 
5.5 
Follow-Up of Patients after Adverse Events ........................ 105 


 
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5.5.1 
Investigator Follow-Up......................................................... 105 
5.5.2 
Sponsor Follow-Up .............................................................. 106 
5.6 
Post-Study Adverse Events................................................. 106 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, and Ethics Committees ................................. 107 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 107 
6.1 
Determination of Sample Size ............................................. 107 
6.2 
Summaries of Conduct of Study.......................................... 109 
6.3 
Summaries of Treatment Group Comparability ................... 110 
6.4 
Safety Analyses................................................................... 110 
6.4.1 
Primary Safety Endpoint...................................................... 110 
6.5 
Efficacy Analyses ................................................................ 111 
6.5.1 
Secondary Efficacy Variables.............................................. 111 
6.5.2 
Analyses of Efficacy Endpoints............................................ 111 
6.5.3 
Other Analyses.................................................................... 112 
6.6 
Analysis Populations ........................................................... 112 
6.7 
Pharmacokinetic Analyses................................................... 113 
6.8 
Patient–Reported Outcome Analyses.................................. 113 
6.9 
Exploratory Analyses........................................................... 113 
6.9.1 
Immunogenicity ................................................................... 113 
6.9.2 
Observation Time ................................................................ 113 
6.9.3 
Subgroup Analyses ............................................................. 113 
6.10 
Interim Safety Analyses....................................................... 114 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 114 
7.1 
Data Quality Assurance....................................................... 114 
7.2 
Electronic Case Report Forms............................................. 115 
7.3 
Source Data Documentation................................................ 115 
7.4 
Use of Computerized Systems ............................................ 116 
7.5 
Retention of Records........................................................... 116 
8. 
ETHICAL CONSIDERATIONS.................................................................. 117 
8.1 
Compliance with Laws and Regulations .............................. 117 
8.2 
Informed Consent ................................................................ 117 


 
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8.3 
Ethics Committee ................................................................ 118 
8.4 
Confidentiality...................................................................... 118 
8.5 
Financial Disclosure ............................................................ 118 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 119 
9.1 
Study Documentation .......................................................... 119 
9.2 
Site Inspections ................................................................... 119 
9.3 
Administrative Structure....................................................... 119 
9.4 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 119 
9.5 
Protocol Amendments ......................................................... 120 
10. REFERENCES ......................................................................................... 121 
 
 
LIST OF TABLES 
Table 1 
Efficacy of Trastuzumab IV in the Adjuvant EBC Setting ............ 35 
Table 2 
Cardiac Safety of Trastuzumab IV in the Adjuvant Setting ......... 37 
Table 3 
Overview of Completed Nonclinical Pharmacology, PK, and 
Toxicology Studies with Trastuzumab SC (Formulated with 
rHuPH20).................................................................................... 42 
Table 4 
Overview of the Clinical Development Program of 
Trastuzumab SC......................................................................... 44 
Table 5 
Summary of Treatment Cohorts and Adverse Events, 
Study BP22023........................................................................... 45 
Table 6 
Mean (CV%) Trastuzumab Serum Pharmacokinetic 
Parameters, Following Trastuzumab IV and SC 
Administration, Study BP22023 .................................................. 48 
Table 7 
Predicted Ctrough (μg/mL) at Pre-dose Cycle 8 ......................... 49 
Table 8 
Management of Trastuzumab-Related Toxicity........................... 74 
Table 9 
Assessment of AE Severity......................................................... 95 
Table 10 
Clopper-Pearson 95% Confidence Intervals for the Observed 
CHF-Related SAE Incidence..................................................... 108 
 


 
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LIST OF FIGURES 
Figure 1 
Mean (±SD) Trastuzumab Concentration-Time Profile by 
Cohort ......................................................................................... 47 
Figure 2 
Distribution or Simulated Median Ctrough Levels at Cycles 1 
and 8 with a Dose of 600 mg Trastuzumab SC........................... 51 
Figure 3 
Distribution of Simulated Median AUCtau Levels at Cycles 1 
and 8 with a Dose of 600 mg Trastuzumab SC........................... 52 
Figure 4 
Study Design............................................................................... 60 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments......................................................... 127 
Appendix 2 
ECOG Performance Status Scale............................................. 131 
Appendix 3 
New York Heart Association (NYHA) Functional 
Classification System for Heart Failure ..................................... 132 
Appendix 4 
Algorithm for Continuation and Discontinuation of 
Trastuzumab SC Based on LVEF Assessment in 
Asymptomatic Patients ............................................................. 133 
Appendix 5 
Common Terminology Criteria for Adverse Events................... 134 
Appendix 6 
Single-Use Injection Device (SID) Satisfaction Questionnaire .. 135 
Appendix 7 
Single-Use Injection Device (SID) Observers Usability 
Questionnaire............................................................................ 136 


   
Trastuzumab⎯F. Hoffmann-La Roche Ltd 
19/Protocol MO28048, Version 4 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE III PROSPECTIVE, TWO-COHORT 
NON-RANDOMIZED, MULTICENTER, MULTINATIONAL, 
OPEN-LABEL STUDY TO ASSESS THE SAFETY OF 
ASSISTED- AND SELF-ADMINISTERED 
SUBCUTANEOUS TRASTUZUMAB AS THERAPY IN 
PATIENTS WITH OPERABLE HER2-POSITIVE EARLY 
BREAST CANCER [SafeHer Study] 
PROTOCOL NUMBER: 
MO28048 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2011-005328-17 
IND NUMBER: 
Not applicable 
TEST PRODUCT: 
Trastuzumab SC (RO 45-2317) 
MEDICAL MONITOR: 
, Ph.D 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy to 
your local study monitor. 
 


   
Trastuzumab⎯F. Hoffmann-La Roche Ltd 
20/Protocol MO28048, Version 4 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III PROSPECTIVE, TWO-COHORT NON-RANDOMIZED, 
MULTICENTER, MULTINATIONAL, OPEN-LABEL STUDY TO 
ASSESS THE SAFETY OF ASSISTED- AND SELF-
ADMINISTERED SUBCUTANEOUS TRASTUZUMAB AS 
THERAPY IN PATIENTS WITH OPERABLE HER2-POSITIVE 
EARLY BREAST CANCER [SAFEHER STUDY] 
PROTOCOL NUMBER: 
MO28048 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2011-005328-17 
IND NUMBER: 
Not applicable 
TEST PRODUCT: 
Trastuzumab SC (RO 45-2317) 
PHASE: 
Phase III 
INDICATION: 
HER2-positive early breast cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives and Endpoints 
Primary Objective 
The primary objective of this study is to assess the overall safety and tolerability of trastuzumab 
subcutaneous (SC) in HER2-positive early breast cancer (EBC) patients with assisted 
administration using a conventional syringe and needle (vial formulation) or with assisted- and 
self-administration using a single-use injection device (SID) in selected patients. 
Secondary Objectives 
Secondary objectives include the evaluation of the following parameters: 
• 
Efficacy (both cohorts): 
• 
Disease-free survival (DFS) 
• 
Overall survival (OS) 
• 
Patient satisfaction with trastuzumab SC administration using the SID (patients in Cohort B 
who went on to self-administration of the study drug). 
 
Exploratory Objectives 
Additional, exploratory objectives will be investigated in a subset of patients (Cohort B) at 
selected study sites: 
• 
To assess the immunogenicity of trastuzumab and recombinant human hyaluronidase 
(rHuPH20)  
• 
To examine and characterize tolerability of the trastuzumab SC over a 6 hour time period 
after the start of the first administration and over a 2 hour time period after the start of 
subsequent trastuzumab administrations (only in patients using the SID Cohort B]) 
• 
Monitoring of SID usability in a subgroup of 48 patients in Cohort B 
 


   
Trastuzumab⎯F. Hoffmann-La Roche Ltd 
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In addition, in some countries and sites, Medical Care Utilization (MCU, e.g. time and motion) 
and/or pharmacoeconomic substudies will be conducted.  Details of the substudies will be 
described in separate protocols. 
Study Design 
This is a Phase III, prospective, two-cohort, non-randomized, multicenter, multinational, 
open-label study in approximately 2500 patients with HER2-positive EBC who are eligible for 
anti-HER2 therapy. 
Eligible patients will be allocated to Cohort A or B at the investigator’s discretion depending 
upon availability of the cohorts for recruitment: 
• 
Cohort A (approximately 1,800 patients): trastuzumab SC 600 mg assisted administration 
into the thigh over a period of approximately 5 minutes using conventional handheld 
syringes with hypodermic needles for a total of 18 cycles (3-weekly); 
• 
Cohort B (approximately 700 patients): trastuzumab SC at a fixed dose of 600 mg 
presented in a SID.  The first administration will be assisted (performed by a HCP).  If well 
tolerated and if the patient is willing and judged competent by the HCP to do so, 
subsequent administrations may be self-administered into the thigh over a period of 
approximately 5 minutes using the SID for a total of up to 18 cycles (3-weekly).  
• 
Patients will remain at the study site to be observed for a period of 6 hours after their first 
trastuzumab administration and 2 hours thereafter for subsequent trastuzumab 
administrations.  Patients may be required to remain onsite for an extended period of time if 
considered clinically necessary by the Investigator.  
 
Description of Study 
All potential study patients must provide signed written informed consent (approved by the 
relevant independent Ethics Committee [EC]) before undergoing any study-specific procedure.  
Results of the screening assessments must be available, and patients must meet all eligibility 
criteria prior to enrollment into the study.  
During trastuzumab SC therapy, patients will be assessed for safety and efficacy.  
In addition to efficacy and safety assessments, select sites will also perform immunogenicity 
testing to determine whether HAHAs against trastuzumab or rHuPH20 develop in patients 
receiving trastuzumab SC using the SID. 
Patients will undergo a Safety Follow-up visit 4 weeks after their last dose of study treatment, 
with further follow-up according to the American Society of Clinical Oncology 2006 Guideline for 
Breast Cancer Follow-up in the adjuvant setting or investigator’s routine practice.  All patients 
will be followed-up for cancer recurrence and survival until study end.  The duration of follow-up 
will be at least 5 years after their last study treatment, unless one of the following occurs first:  
withdrawal of consent, loss to follow-up, or death.  After disease progression, patients will be 
managed as per local practice and followed for survival only. 
In some countries and sites, MCU (e.g., time and motion) and/or pharmacoeconomic substudies 
will be conducted.  Details of the substudies will be described in separate protocols. 
Number of Patients 
Approximately 2500 patients will be enrolled into the study.  The trial will be conducted at 
approximately 520 centers in approximately 60 countries. 
Target Population 
The study will recruit adult consenting patients with newly diagnosed HER2-positive (IHC 3+ or 
HER2-positive in situ hybridization [ISH]) early breast cancer who are eligible for treatment with 
trastuzumab (e.g., clinical Stage I [T1, N0, M0] to IIIC [any T, N3, M0]).  Patients treated without 
neoadjuvant or adjuvant chemotherapy, such as patients with low-risk node-negative tumors 
≤ 1.0 cm, elderly patients (> 65 years of age), or patients who refuse chemotherapy, will also be 
eligible to participate in the study, but their enrollment will be limited to approximately ≤ 10% of 
the total study population. 


   
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Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. 
Signed written informed consent approved by the reviewing independent Ethics Committee 
(EC) 
2. 
Female or male aged 18 years or above 
3. 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
4. 
Histologically confirmed early invasive HER2-positive carcinoma of the breast with no 
evidence of residual, locally recurrent, or metastatic disease and defined as clinical Stage I 
(T1, N0, M0) to IIIC (any T, N3, M0) that is eligible for treatment with trastuzumab 
Note:  Patients treated without neoadjuvant or adjuvant chemotherapy, such as patients with 
low-risk node-negative tumors ≤ 1.0 cm, elderly patients (> 65 years of age), or patients with 
HER2-positive EBC but denying chemotherapy, will also be eligible to participate in the 
study, but their enrollment will be limited to approximately ≤ 10% of the total study 
population.  
5. 
HER2-positive EBC, defined as IHC 3+ or positive in situ hybridization (ISH testing) by 
validated and approved methods within a certified laboratory 
6. 
Screening left ventricular ejection fraction (LVEF) ≥ 55% as measured by echocardiography, 
multi-gated acquisition (MUGA) scan, or Magnetic Resonance Imaging (MRI) per local 
practice 
7. 
Agreement to use an adequate, nonhormonal means of contraception by women of 
childbearing potential (defined as premenopausal and not surgically sterilized or < 1 year 
after the onset of menopause) and by male participants with partners of childbearing 
potential only.  Examples of adequate contraceptive measures are an intrauterine device, a 
barrier method (condoms or diaphragm) in conjunction with spermicidal jelly, or total 
abstinence.  Oral, injectable, or implant hormonal contraceptives are not acceptable for 
females participating in the study. 
8. 
Intact skin at site of SC injection on the thigh 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Cancer-Related Criteria 
1. 
Previous neoadjuvant or adjuvant breast cancer treatment with an approved or 
investigational anti-HER2 agent  
2. 
History of other malignancy which could affect compliance with the protocol or interpretation 
of results (including previous invasive ipsilateral or contralateral breast cancer).  Patients 
with curatively-treated carcinoma in situ of the cervix or basal cell carcinoma and patients 
with other curatively-treated malignancies other than breast cancer who have been 
disease-free for at least 5 years are eligible. 


   
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3. 
Past history of ductal carcinoma in situ (DCIS) within the last 5 years that has been treated 
with any systemic therapy OR with radiation therapy to the ipsilateral breast where invasive 
cancer subsequently develops.  Patients who had their DCIS treated with surgery only are 
allowed to enter the study. 
4. 
Metastatic disease 
 
Hematological, Biochemical, and Organ Function 
5. 
Inadequate bone marrow function (as indicated by any of the following):  
• 
Total white blood cell count (WBC) < 2500/mm3 (< 2.5 × 109/L) 
• 
Neutrophil count < 1500/mm3 (< 1.5 × 109/L) 
• 
Platelets < 100,000/mm3 (< 100 × 109/L) 
• 
Hemoglobin < 10 g/dL 
6. 
Impaired hepatic function (as indicated by any of the following): 
• 
Serum total bilirubin > 1.5 × upper limit of normal (ULN) 
• 
Alanine amino transferase (ALT) > 2.5 × ULN 
• 
Aspartate amino transferase (AST) > 2.5 × ULN  
• 
Alkaline phosphatase (ALP) > 2.5 × ULN  
7. 
Impaired renal function, as indicated by serum creatinine > 1.5 × ULN 
 
Other Study Drug-Related Exclusion Criteria 
8. 
Serious cardiac illness or medical conditions including but not confined to: 
• 
History of documented heart failure or systolic dysfunction (LVEF < 50%) 
• 
High-risk uncontrolled arrhythmias such as atrial tachycardia with a heart rate > 100/min 
at rest, significant ventricular arrhythmia (ventricular tachycardia), or higher-grade 
atrioventricular (AV) block (second-degree AV block Type 2 [Mobitz 2] or third-degree 
AV block) 
• 
Angina pectoris requiring anti-anginal medication 
• 
Clinically significant valvular heart disease 
• 
Evidence of transmural infarction on electrocardiogram (ECG) 
• 
Poorly controlled or uncontrolled hypertension (blood pressure consistently over 
140/90 mmHg, despite treatment) or history of hypertensive crisis or hypertensive 
encephalopathy 
9. 
Other concurrent serious diseases that may interfere with planned treatment including 
severe pulmonary conditions/illness 
10. Prior maximum cumulative dose of doxorubicin > 360 mg/m2 or maximum cumulative dose 
of epirubicin > 720 mg/m2 or equivalent 
11. Known hypersensitivity to trastuzumab, murine proteins, or excipients, or a general 
hypersensitivity to adhesives (Cohort B only) 
12. History of severe allergic or immunological reactions, for example, difficult to control asthma. 
 


   
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General Exclusion Criteria 
13. Pregnancy or lactation 
14. Unable or unwilling to comply with the requirements of the protocol, as assessed by the 
investigator 
15. Concurrent enrollment 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 
16. Major surgical procedure or significant traumatic injury within 14 days prior to the first dose 
of study treatment or anticipated need for major surgery during the course of study treatment 
except for breast cancer surgery for patient receiving study drug in the neoadjuvant setting.  
Patients must be free of any clinically significant sequelae of prior surgery before they can 
receive their first dose of study treatment. 
17. More than 12 weeks between the end of the last chemotherapy cycle and the first dose of 
study treatment, in case these treatments are initiated sequentially.  This criterion does not 
apply to patients who are starting trastuzumab SC without previous or concurrent 
chemotherapy or concurrently with chemotherapy. 
18. Current peripheral neuropathy of Grade 3 or greater per the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0 
 
No exceptions or waivers will be granted for the above listed inclusion and exclusion criteria. 
Length of Study 
The study is estimated to last approximately 8 years, based on an expected 18-month 
recruitment period per cohort, 12 months of study treatment and 5 years of follow-up after the 
last study treatment.  
To allow for the enrolment of 1800 patients in Cohort A (compared to 700 in Cohort B), 
recruitment for Cohort A may be initiated earlier than recruitment for Cohort B. 
End of Study 
End of study is defined as the last patient last visit in the follow-up period.  The study will end 
when all patients have been followed for approximately 5 years after their last study treatment, 
or earlier, if one of the following is documented for all treated patients:  withdrawal of consent, 
loss to follow-up, or death.  The final analysis of OS and DFS and updated summaries for safety 
parameters will be performed at this stage. 
Safety Outcome Measures 
All clinical adverse events (AEs) and serious adverse events (SAEs), as well as abnormal 
laboratory values, will be recorded and graded according to the NCI-CTCAE version 4.0. 
Cardiac function will be evaluated by measuring LVEF (using echocardiography, Multi Gated 
Acquisition (MUGA) scan or Magnetic Resonance Imaging [MRI]) and ECG.  Symptomatic left 
ventricular dysfunction (CHF) will be graded according to NCI-CTCAE, version 4.0 and the 
NYHA functional classification. 
Patients will undergo a Safety Follow-up visit 4 weeks after their last dose of study treatment 
with further follow-up according to the American Society of Clinical Oncology (ASCO) 2006 
Guideline for Breast Cancer Follow-up in the adjuvant setting or investigator’s routine practice.  
All concomitant medication will be recorded between the Screening and the Safety Follow-up 
visits.  Thereafter, breast cancer treatments (e.g., endocrine therapy), anti-cancer treatments 
given to treat a recurrence, and medications related to the treatment of SAEs will be recorded. 
Efficacy Outcome Measures 
DFS is defined as time from the date of first treatment to the date of local, regional, or distant 
recurrence; contralateral breast cancer; or death due to any cause.  


   
Trastuzumab⎯F. Hoffmann-La Roche Ltd 
25/Protocol MO28048, Version 4 
OS is defined as time from the date of first treatment until date of death, regardless of the cause 
of death.  
Patients in Cohort B, who went on to self-administration of the study drug will be asked to rate 
their overall satisfaction with trastuzumab SC administrations using the SID by completing a 
5-item SID satisfaction questionnaire.  The questionnaire will be completed after the 4th cycle 
and at the Safety Follow-up visit (or at least 1 day after the last trastuzumab SC injection), after 
a minimum of 2 successful self-administrations of the study drug.  
Exploratory Outcome Measures 
Immunogenicity of trastuzumab and rHuPH20 will be tested in a subset of patients enrolled in 
Cohort B at select sites.  Serum samples (for anti-trastuzumab antibody analysis) and plasma 
samples (for anti-rHuPH20 antibody analysis) will be drawn at baseline (after eligibility is 
confirmed, i.e., just before the first study treatment), on-treatment (pre-Cycle 9 dose, Week 25), 
and at least 6 months after the end of treatment for testing in a central laboratory. 
The exploratory MCU and/or pharmacoeconomic parameters will be described in separate 
substudy protocols. 
In addition to the study assessments, all clinical AEs that occur during the observation period 
will be collected for all patients in Cohort B (within 6 hours after start of the first trastuzumab 
administration or within 2 hours (within 6 hours after start of the first trastuzumab administration 
or within 2 hours after start of following trastuzumab administrations).  Data collected during the 
observation period will include:  Frequency, incidence, and grade of AEs; onset and resolution 
times of AEs (dd:mm:yyyy:hh:mm); outcome of AEs; and details of treatments provided 
following AEs during the observation period. 
Information on the usability of the SID will be collected via SID monitoring questionnaire, will be 
provided to the first 48 patients enrolled in Cohort B who were judged able and were willing to 
self-administer remaining doses from the SID under direct observation of the HCP.  The SID 
Device Observation is to be completed by HCPs.  
Investigational Medicinal Products 
The investigational medicinal product for this study is trastuzumab SC 600 mg, supplied as a 
vial and SID formulations. 
Patients in both cohorts will receive a fixed dose of 600 mg trastuzumab SC throughout the 
study, administered 3-weekly for a total of 18 cycles, unless disease recurrence, unacceptable 
toxicity, or patient withdrawal necessitates earlier treatment cessation. 
Trastuzumab SC treatment may be initiated: 
• 
After completion of neoadjuvant or adjuvant chemotherapy (sequentially) 
• 
In combination with neoadjuvant or adjuvant paclitaxel or docetaxel chemotherapy 
(concurrently) 
• 
or without adjuvant chemotherapy 
• 
or in combination with neoadjuvant chemotherapy followed by trastuzumab therapy for 
locally advanced (including inflammatory) disease or tumors > 2 cm in diameter 
 
For patients receiving trastuzumab SC with concurrent chemotherapy, trastuzumab SC must be 
administered first, followed by the administration of chemotherapy.  Hormonal therapy and 
radiotherapy (if applicable) may be given concomitantly with trastuzumab SC, as per local 
guidelines. 
All study treatment administrations will occur in a hospital setting as follows: 
• 
Cohort A: Trastuzumab SC 600 mg will be injected subcutaneously by an HCP into the 
thigh over a period of approximately 5 minutes using a handheld syringe with a gauge 25 or 
27 hypodermic needle. 
• 
Cohort B: Trastuzumab SC 600 mg will be injected subcutaneously into the thigh over a 
period of approximately 5 minutes using the SID.  The first administration will be assisted 
(performed by a HCP [physician or nurse]), and then following administrations may be 
self-administered into the thigh (if the patient is willing and judged competent by the HCP) 
over a period of approximately 5 minutes using the SID. 


   
Trastuzumab⎯F. Hoffmann-La Roche Ltd 
26/Protocol MO28048, Version 4 
 
Non-Investigational Medicinal Products 
Not applicable. 
Statistical Methods 
Primary Analysis 
Safety endpoints are the primary objectives in this study and will include:  all AEs, Grade 
≥ 3 AEs, SAEs, AEs leading to premature discontinuation of study treatment, AEs causing 
interruption of trastuzumab SC, cardiac AEs, CHF-related SAEs, premature withdrawals from 
study and study medication, exposure to treatment, laboratory parameters, LVEF, vital signs, 
ECG, weight, and ECOG performance status.  
The primary analyses of the safety endpoints will consist of summary results with 95% 
confidence intervals and descriptions.  They will be performed for the safety population (SP) 
defined as all enrolled patients who received at least one dose of study medication.  There will 
be two safety populations, one for each cohort (SP1 for Cohort A and SP2 for Cohort B).  The 
safety endpoints will be summarized for each cohort and overall.  
The primary analysis of the safety endpoints will take place when all patients have received 
18 cycles of trastuzumab SC and have completed the Safety Follow-up assessments (4 weeks 
after their last dose of study treatment).  The primary analysis of safety endpoints will take place 
when all patients have received 18 cycles of trastuzumab SC and have completed the post-
treatment Safety Follow-up assessments.  Updated summaries for safety parameters will be 
prepared when the last patient has been followed up for at least 5 years after her/his last study 
treatment, or earlier, if one of the following is documented for all treated patients:  withdrawal of 
consent, loss to follow-up, or death.  All safety summaries and analyses will be performed for 
Cohort A and for Cohort B.  There is no formal statistical hypothesis comparing Cohort A and 
Cohort B, and there will be no adjustments for multiplicity of endpoint comparisons.  The safety 
summaries and analyses will be summarized for each cohort and overall. 
Secondary and Exploratory Analyses 
Secondary efficacy endpoints include DFS, OS (both cohorts) and patients’ satisfaction with 
trastuzumab SC administration using the SID (Cohort B patients who went on to self-
administration only).  Secondary efficacy endpoints will be analyzed for the Intent-to-Treat (ITT) 
population (defined as all patients enrolled in the study) and the Per-Protocol population 
(defined as all patients in the ITT population who have received at least one dose of study 
medication and did not have major protocol violations).  Protocol violations necessitating 
exclusion from the Per-Protocol population will be described in the Statistical Analysis Plan 
(SAP). 
A preliminary analysis of DFS and OS will be undertaken at the time of the primary safety 
analysis, i.e. when all patients (Cohort A and Cohort B) have received 18 cycles of 
trastuzumab SC and have completed the Safety Follow-up assessments (4 weeks after their 
last dose of study treatment).  The final analysis of OS and DFS will take place when the last 
patient has been followed up for approximately 5 years after her/his last study treatment, or 
earlier, if one of the following is documented for all treated patients: withdrawal of consent, loss 
to follow-up or death.  This is expected to take place approximately 8 years after the enrolment 
of the first patient, based on an expected 18-month recruitment period per cohort, 12 months of 
study treatment and approximately 5 years of follow- up after the last study treatment. 
Patients’ satisfaction with trastuzumab SC administration using the SID (Cohort B) patients 
who went on to self-administration only) will be summarized by frequency tables and presented 
graphically. 
Exploratory study analyses of the immunogenicity of trastuzumab and rHuPH20 will be 
performed in a subset of patients enrolled in Cohort B at select sites, based on samples 
collected at baseline (just before the first study treatment), on-treatment (pre-Cycle 9 dose, 
Week 25) and at least 6 months after the end of treatment.  The percentage of patients who 
develop anti-trastuzumab or anti-rHuPH20 antibodies or both will be presented.  Serum 
trastuzumab concentration data will be used in the assessment of anti-trastuzumab antibodies. 
Exploratory study analyses for all clinical AEs that occur during the observation period will be 
evaluated, analyzed and presented and further exploratory analysis will be performed for all 


   
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patients in Cohort B (within 6 hours after start of the first trastuzumab administration or within 
2 hours after start of following trastuzumab administrations).  Details of the analysis will be 
documented in the Statistical Analysis Plan (SAP) and will include the following: 
• 
Analysis of frequency, incidence and grading of AEs during the observation period 
• 
Analysis of time from last preceding administration of study drug to onset time of AE 
occurrence (dd:mm:yyyy:hh:mm) during the observation period 
• 
Analysis of time to resolution (dd:mm:yyyy:hh:mm) and outcome of AEs observed during 
the observation period 
• 
Analysis of treatments provided following AEs during the observation period 
 
Exploratory analyses on the usability of the SID summarizing the parameters collected via SID 
monitoring questionnaire will be provided to the first 48 patients enrolled in Cohort B who were 
judged able, and were willing to self-administer remaining doses from the SID under direct 
observation of the HCP.  The SID Device Observation is to be completed by HCPs.  
Determination of Sample Size 
A sample size of approximately 2500 patients is planned for this study with approximately 
1800 patients enrolled in Cohort A and approximately 700 patients enrolled in Cohort B.  
There is no formal statistical hypothesis, hence all safety (primary) endpoints results will be 
presented by 95% confidence intervals and descriptively explained. 
For the purpose of the estimation of sample size, the incidence/proportion of congestive heart 
failure (CHF)-related SAEs was chosen as a safety endpoint of primary interest.  Based on an 
observed CHF-related SAE incidence rate of 4% and a sample size of 1800 patients in 
Cohort A, the upper limit of the 95% confidence interval for the incidence rate will be 5.0%.  For 
Cohort B, the same CHF-related SAE incidence rate and a sample size of 700 patients will give 
an upper limit of the 95% CI of 5.7%.  The estimation of the sample size is produced by the SAS 
program and nQuery Version 6. 
In Cohort B only, exploratory analyses on the usability of the SID summarizing the parameters 
collected via SID monitoring questionnaire will be provided to the first 48 patients enrolled who 
were judged able, and were willing to self-administer remaining doses from the SID under direct 
observation of the HCP.  A sample size of 48 patients using the SID for 17 cycles to 
self-administer a dose without assistance equates to sample of n = 816 dosing events.  If 
0 events occur in this sample of trials it can be stated with 99% confident it will be <1% in the 
true population.  The Adjusted Wald Approximate lower-limit of one-sided confidence interval for 
binomial distributed proportions statistical model has been used. 
Refer to the protocol and the SAP for further details. 
Interim Safety Analyses  
Three interim safety analyses are planned for the study, when approximately 500, 1000, and 
2500 patients have received at least one trastuzumab SC injection. 


   
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT (SGPT) 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST (SGOT) 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration−time curve 
BCIRG 
Breast Cancer International Research Group  
BUN 
Blood urea nitrogen 
CEA 
Carcinoembryonic Antigen 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CISH 
Chromogenic in situ hybridization  
CL 
Clearance 
Cmax 
Maximum plasma concentration 
Cmin 
Minimum plasma concentration 
CMF 
Cyclophosphamide methotraxate fluoricil 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case Report Form[s] 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CT 
Computerized tomography 
Ctrough 
Trough plasma concentration 
CV% 
Coefficient of variation 
CXR 
Chest X-Ray 
DCIS 
Ductal carcinoma in situ 
DFS 
Disease-free survival 
DISH 
Dual inform in situ hybridization 
EBC 
Early breast cancer 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report form 
EDC 
Electronic data capture 


   
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EEA 
European Economic Area 
EFS 
Event-free survival 
EU 
European Union 
FDG-PET 
Fluorodeoxyglucose-positron emission tomography 
FISH 
Fluorescence in situ hybridization 
GCP 
Good Clinical Practice 
HAHA 
Human anti–human antibodies 
HCP 
Health Care Professional 
HER2 
Human epidermal growth factor receptor-2 
HR 
Hazard ratio 
HV 
Healthy volunteers 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
ICF 
Informed Consent form 
ICMJE 
International Committee of Medical Journal Editors 
IgG 
Immunoglobulin G 
IHC 
Immunohistochemistry 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug 
INN 
International Non-proprietary Name 
IRR 
Infusion-related reaction 
ISH 
In situ hybridization 
ITT 
Intent-to-treat 
IU 
International Units 
IV 
Intravenous(ly) 
KM 
Kaplan-Meyer (analysis method) 
LVEF 
Left ventricular ejection fraction 
LVSD 
Left Ventricular Systolic Dysfunction 
MBC 
Metastatic breast cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Image 
MUGA 
Multiple gated acquisition 
NCCN 
National Comprehensive Cancer Network 
NCCTG 
North Central Cancer Treatment Group  
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for 
Adverse Events 
NSABP 
National Surgical Adjuvant Breast Project 
NYHA 
New York Heart Association 


   
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OS 
Overall survival 
PD 
Progressive disease or Pharmacodynamic 
PS 
Performance Status 
PK 
Pharmacokinetic(s) 
PPK 
Population Pharmacokinetic(s) 
p.o. 
Per os (oral administration) 
q1w 
Every week 
Q3W 
Every 3 weeks 
rHuPH20 
Recombinant humanized hyaluronidase 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SD 
Standard Deviation 
SID 
Single-use injection device 
SISH 
Automated silver enhanced in situ hybridization 
SmPC 
Summary of Product Characteristics 
SSR 
Six-monthly SUSAR report 
SUSAR 
Suspected unexpected serious adverse reactions 
TCH 
Taxol, Carboplatin and Herceptin 
T1/2 
Half-life  
TNM 
Primary tumor/regional lymph nodes/distant metastasis 
Tmax 
Time to maximum plasma concentration  
ULN 
Upper limit of normal 
US  
United States  
Vc 
Volume of distribution of the central compartment 
WBC 
White blood count 
WFI 
Water for injection 
 


   
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1. 
BACKGROUND  
1.1 
BACKGROUND ON BREAST CANCER 
1.1.1 
Epidemiology 
Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer 
death in women worldwide, with an estimated 1.4 million new breast cancer cases and 
458,000 deaths in 2008 (Jemal et al. 2010).  More than half of all cases occur in 
industrialized countries.  It is estimated that about 361,000 women (27.3% of cancers in 
women) are diagnosed (Parkin et al. 2005), and around 131,900 die annually of breast 
cancer in Europe, with breast cancer remaining the major cause of death in women aged 
between 35 and 59 (Ferlay et al. 2007).  In the United States, the number of newly 
diagnosed breast cancer cases was estimated to be 209,000 (13.7% of all cancers and 
28.0% of cancers in women), and the number of breast cancer-related deaths estimated 
to be 40,200 (7.1% of all cancer deaths and 14.7% of cancer deaths in women) in the 
year 2010 (Jemal et al. 2010; Kris et al. 2010).  In Europe and North America, most 
breast cancers are diagnosed when the cancer is still confined to the breast, with or 
without loco-regional lymph node spread, and can be treated with curative intent.  In 
Europe, around 79% are potentially operable (stage T1-3/N0/+M0), 7% are locally 
advanced (T4/Nx/M0), and 6% are metastatic (M1) at diagnosis (Sant et al. 2003; 
Verma et al. 2010). 
1.1.2 
The Role of HER2-Receptor Status 
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, or HER, family (Ross et al. 2009).  This HER family of 
four receptors mediates the growth, differentiation and survival of cells 
(Yarden and Sliwkowski 2001; Gschwind et al. 2004).  The evidence that increased 
expression and activity of HER2 induces cell transformation and tumorigenesis is 
overwhelming.  In breast cancer, unlike a variety of other epithelial malignancies, HER2 
gene amplification is uniformly associated with HER2 (p185neu) protein overexpression.  
HER2 gene amplification and/or protein overexpression has been associated with 
aggressive tumor behavior, 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 breast cancer patients found that in the majority (88%) of 
the studies, either HER2 gene amplification or HER2 (p185neu) protein overexpression 
predicted breast cancer outcome by either univariate or multivariate analysis 
(Ross et al. 2009).  The frequency of HER2-positivity in these studies ranged from 9% to 
74% (mean 22.2%).  However, in current practice, most investigators report that the true 
HER2-positive rate is in the range of 15%−20% (Ross et al. 2009; Lund et al. 2010).  


   
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The major slide-based HER2 testing approaches include immunohistochemistry (IHC), 
fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH), 
automated silver enhanced in situ hybridization (SISH), and dual inform in situ 
hybridization (DISH) (all in situ techniques). 
HER2-amplified breast cancers comprise a specific disease subset with a unique 
molecular portrait and biologic characteristics that distinguish them from other types of 
breast cancers (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 breast cancer 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).  
1.1.3 
Treatment of Early Breast Cancer 
Surgery is the main modality of local treatment for breast cancer (with or without 
radiotherapy) and can control loco-regional disease in the majority of patients.  However, 
a significant percentage of patients relapse after loco-regional treatment and develop 
metastases.  Systemic chemotherapy (or endocrine therapy in hormone 
receptor-positive patients) reduces the risk of relapse and is given either prior to surgery 
(neoadjuvant therapy) or following surgery (adjuvant therapy).  In recent decades, the 
use of adjuvant systemic therapies for early breast cancer (EBC) has increased 
extensively and has most likely contributed to the substantial decline in breast cancer 
mortality observed in the U.S. and in some European countries (Verma et al. 2010; 
Colozza et al. 2006; Autier et al. 2010).  
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 breast cancer treatment.  Several targeted drugs with 
different molecular pathways have achieved approval for metastatic breast cancer 
(MBC), but trastuzumab is the only such therapy that is currently approved for adjuvant 
or neoadjuvant treatment of EBC (Untch 2010).  The use of trastuzumab in the adjuvant 
setting is also supported by international treatment guidelines for women with 
HER2-positive breast cancer (NCCN 2010; Gnant et al. 2011; Aebi et al. 2011).  The 
introduction of trastuzumab at the end of 1990s has particularly improved the outcome 
for early breast cancer patients with HER2-positive disease. 
1.2 
BACKGROUND ON TRASTUZUMAB 
1.2.1 
Intravenous Trastuzumab (Herceptin®) 
Trastuzumab (Herceptin®) 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 


   
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HER2-positive metastatic gastric cancer (approved in 2010).  The efficacy and safety of 
intravenous (IV) trastuzumab have been well characterized.  Since its initial approval in 
1998, trastuzumab has become standard of care for patients with HER2-positive breast 
cancer and is widely used for its approved indications in both the adjuvant and 
metastatic settings (Ross et al. 2009; NCCN 2010; Gnant et al. 2011; Aebi et al. 2011).  
Intravenous trastuzumab is administered to EBC patients for a total duration of one year.  
Adjuvant trastuzumab IV may be given as monotherapy, starting after completion of 
adjuvant chemotherapy, or in combination with the taxane component of adjuvant 
chemotherapy (followed by trastuzumab monotherapy).  At the time of writing, adjuvant 
trastuzumab IV monotherapy is widely approved, and concurrent administration in 
combination with adjuvant chemotherapy is also approved or expected to be approved in 
many countries.  Intravenous trastuzumab 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.  
1.2.1.1 
Pharmacokinetics of Trastuzumab IV 
Based on a population pharmacokinetic (PK) analysis of data primarily from the 
metastatic breast cancer setting (Clinical Study Report 1018264), the predicted median 
AUC (over a period of 3 weeks at steady-state) for the q1w and Q3W regimens were 
1677 and 1793 mg • day/L, respectively, and the corresponding median Cmin values were 
64.9 and 47.3 mg/L, respectively.  A two-compartment model satisfactorily described the 
data.  The typical trastuzumab IV PK parameters were as follows:  clearance (CL) of 
0.026 L/day and a volume of distribution of the central compartment (Vc) of 3.17 L 
(which corresponds to human plasma volume, which is the Vc characteristic of IgG 
immunoglobulins).  The equilibrium half-life is about 26 days, which is similar to that of 
endogenous IgG1 immunoglobulin (23 days) which constitutes the backbone of 
trastuzumab IV. 
Refer to the Herceptin (RO 45-2317, Trastuzumab) IB for further details regarding the 
pharmacokinetics of trastuzumab IV. 
1.2.1.2 
Efficacy of Trastuzumab IV in Early Breast Cancer (Adjuvant 
Setting) 
Six Phase III, multicenter, 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) 


   
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• 
North Central Cancer Treatment Group trial (NCCTG) N9831 trial 
(Romand 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 
(Romand 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 breast cancer 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 
(see Table 1). 
All four pivotal randomized controlled trials (HERA, N9831, B31, and BCIRG-006) 
demonstrated significantly improved disease-free survival (DFS), and three (HERA, B31 
and BCIRG-006) demonstrated significantly improved overall survival (OS; see Table 1).  
The DFS benefits were observed regardless of age, nodal status, hormonal status, or 
tumor size in all trials (Gianni et al. 2011; Slamon et al. 2011; Perez et al. 2011).  
Importantly, the most recent follow-up data from the HERA trial (Gianni et al. 2011) and 
the combined analysis of the NCCTG N9831 and NASBP B-31 trials (Perez et al. 2011) 
both demonstrate consistent DFS and OS advantages of adjuvant trastuzumab over a 
median follow-up of 4 years.  Further, the significant benefits in DFS and OS were 
maintained over a median follow-up of approximately 5 ½ years in the BCIRG-006 study 
(Slamon et al. 2011), which is the longest follow-up reported to date.  The long-term 
clinical benefits of 1-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 2010; 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).  


   
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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. 
Table 1 
Efficacy of Trastuzumab IV in the Adjuvant EBC Setting 
Study 
Median 
FU (mo) 
Interventio
ns 
No. of 
Patients a 
DFS 
OS 
SEQUENTIAL TRASTUZUMAB 
CT ± RT→O
BS 
1698 
2-yr DFS: 81% 
4-yr DFS: 72% 
2-yr OS: 95%
4-yr OS: 88% 
CT ± RT→T 
(× 1 yr) 
1703 
2-yr DFS: 87% 
HR 0.64, 
p < 0.0001 
4-yr DFS: 79% 
HR 0.76, 
p < 0.0001 
2-yr OS: 97%
HR 0.66, 
p = 0.012 
4-yr OS: 89%
HR 0.85, 
p = 0.11 
HERA (Piccart-
Gebhart et al. 
2005; Gianni et al. 
2011) 
N = 5090 
48 
CT ± RT→T 
(× 2 yrs) 
1701 
NR 
NR 
AC→P 
1087 
5-yr DFS: 72% 
NR 
AC→P→T 
1097 b 
5-yr DFS: 80% 
HR 0.70, 
p = 0.0005 
HR 0.86, 
p = 0.281 
NCCTG N9831 
(Perez et al. 2009) 
N = 3505 
(1097 sequential) 
66 
AC→P + 
T→T 
949 
5-yr DFS: 84% 
HR 0.75, 
p = 0.019 
NR 
CONCURRENT TRASTUZUMAB 
AC→P 
1046 
4-yr DFS: 72% 
NR 
NSABP B-31 
(Perez et al. 2011) 
N = 2101 
47 
AC→P + T 
1055 
4-yr DFS: 85% 
NR 
AC→P 
1679 
3-yr DFS: 75% 
4-yr DFS: 74% 
3-yr OS: 92%
4-yr OS: 86% 
B-31 + N9831 
(Romond et al. 
2005; Perez et al. 
2007; Perez et al. 
2011) 
N = 3351 c 
47 
AC→P + T 
1672 
3-yr DFS: 87% 
4-yr DFS: 86% 
HR 0.51, 
95%CI: 
0.44−0.59 
3-yr OS: 94%
4-yr OS: 93%
HR 0.59, 
95%CI: 
0.48−0.73 


   
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Table 1 
Efficacy of Trastuzumab IV in the Adjuvant EBC Setting (cont.) 
 
Study 
Median 
FU (mo) 
Interventio
ns 
No. of 
Patients a 
DFS 
OS 
AC→P 
1679 
3-yr DFS: 75% 
4-yr DFS: 74% 
3-yr OS: 92%
4-yr OS: 86% 
B-31 + N9831 
(Romond et al. 
2005; Perez et al. 
2007; Perez et al. 
2011) 
N = 3351 c 
47 
AC→P + T 
1672 
3-yr DFS: 87% 
4-yr DFS: 86% 
HR 0.51, 
95%CI: 
0.44−0.59 
3-yr OS: 94%
4-yr OS: 93%
HR 0.59, 
95%CI: 
0.48−0.73 
AC→D 
1073 
5-yr DFS: 75% 
5-yr OS: 87% 
AC→D + T 
(× 1 yr) 
1074 
5-yr DFS: 84% 
HR 0.64, 
p < 0.001 
5-yr OS: 92%
HR 0.63, 
p < 0.001 
BCIRG-006 
(Slamon et al. 
2009; Slamon et al. 
2011) 
N = 3222 
65 
D + Carbo + 
T (× 1 yr) 
1075 
5-yr DFS: 81% 
HR 0.75, 
p = 0.04 
5-yr OS: 91%
HR 0.77, 
p = 0.04 
AC = doxorubicin plus cyclophosphamide; Carbo = carboplatin; CEF = cyclophosphamide, 
epirubicin and fluorouracil; CI = confidence interval; CT = chemotherapy; D = docetaxel; 
DFS = disease-free survival; FU = follow-up; HR = hazard ratio; NSS = not statistically significant; 
OBS = observation; OS = overall survival; P = paclitaxel; RT = radiotherapy; T = trastuzumab. 
a Number of patients denotes patients included in the efficacy analyses. 
b Joint analysis of the NSABP B-31 and NCCTG N9831 trials. 
c Excluded from the joint analysis by Romond et al. (Perez et al. 2007). 
 
1.2.1.3 
Safety of Trastuzumab IV  
1.2.1.3.1 
Cardiac Safety of Trastuzumab IV 
The most clinically relevant adverse event (AE) associated with trastuzumab IV is left 
ventricular cardiac dysfunction (congestive heart failure or CHF).  In patients with 
HER2-positive EBC enrolled in pivotal clinical trials described in Section 1.2.1.2, 
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 adverse events (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 (see Table 2).  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 


   
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symptomatic or severe CHF of < 4% and asymptomatic declines in left ventricular 
ejection fractions of > 10 percentage points in ≤ 30% of patients.  However, interstudy 
comparisons of chemotherapy-induced cardiac dysfunction are difficult because of the 
use of different definitions of cardiac dysfunction and different parameters for assessing 
cardiac safety (Ewer and O’Shaughnessy 2007).  These levels were considered below 
safety cut-off points set by the individual studies’ independent data monitoring 
committees (Jahanzeb et al. 2008).  
The NSABP B-31 trial determined the 5-year cumulative cardiac event rate (NYHA 
Class III or IV CHF or cardiac death) to be 3.8% in patients randomly assigned to 
trastuzumab versus 0.9% in patients who received chemotherapy alone 
(Rastogi et al. 2007; Russell et al. 2010).  In the NCCTG N9831 trial, the incidence of 
CHF was 0% in the chemotherapy-alone arm, 2.2% in patients who received sequential 
chemotherapy and trastuzumab, and 3.3% in patients who received concurrent 
chemotherapy and trastuzumab (Perez et al. 2008).  An independent adjudication of the 
cardiac events occurring in Studies B-31 and N9831 determined that the incidence of 
symptomatic heart failure events 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 1698 patients randomly assigned to 
observation and 1703 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 endpoints 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 endpoint reached acute recovery 
(Procter et al. 2010). 
Table 2 
Cardiac Safety of Trastuzumab IV in the Adjuvant Setting 
Study 
Interventions 
No. of 
Pts a 
LVEF↓ from 
BL, % of pts 
Symptomatic HF, 
% of pts 
SEQUENTIAL TRASTUZUMAB 
CT ± RT→OBS 
1698 
Signif: 0.5% 
0.1% (NYHA Class 
III/IV: 0) 
CT ± RT→T × 1 yr 
1703 
Signif: 3% 
2% (NYHA Class 
III/IV: 0.6%) 
HERA (Piccart-
Gebhart et al. 2005; 
Gianni et al. 2011; 
Procter et al. 2010) 
N = 5090 
CT ± RT→T × 2 yrs 
1701 
NR 
NR 


   
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Table 2 
Cardiac Safety of Trastuzumab IV in the Adjuvant Setting (cont.)  
AC→P 
1087 
NR 
NR 
NCCTG N9831 
(Perez et al. 2009)  
N = 3133 
AC→P→T 
1097 
NR 
Gr 3/4 or SCD: 2.8% 
CONCURRENT TRASTUZUMAB 
AC→P 
872 
NR 
NYHA Class III/IV or 
SCD at 5 yrs: 0.9% 
NSABP B-31 
(Perez et al. 2007; 
Tan-Chiu et al. 
2005; Romond 
2005; Rastogi et al. 
2007) 
N = 2043 
AC→P + T 
864 
NR 
NYHA Class III/IV or 
SCD at 5 yrs: 3.8% 
AC→P 
1087 
NR 
NR 
NCCTG N9831 
(Perez et al. 2009)  
N = 3133 
AC→P + T→T 
949 
NR 
Gr3/4 or SCD: 3.3% 
AC→D 
1073 
↓ > 10%: 11% 
Gr3/4: 0.7% 
AC→D + T (× 1 yr) 
1074 
↓ > 10%:19% 
Gr3/4: 2.0% 
BCIRG-006 
(Slamon et al. 2009; 
Slamon et al. 2011)  
N = 3222 
D + Carbo + T (× 1 yr)
1075 
↓ > 10%: 9% 
Gr3/4: 0.4% 
AC = doxorubicin plus cyclophosphamide; BL = baseline; CEF = cyclophosphamide, epirubicin 
and fluorouracil; CT = chemotherapy; D = docetaxel; FU = follow-up; Gr = Grade (NCI-CTCAE); 
NR = not reported; NYHA = New York Heart Association (functional class); OBS = observation; 
P = paclitaxel; RT = radiotherapy; SCD = sudden cardiac death; Signif = significant drop in LVEF 
(symptomatic or asymptomatic); T = trastuzumab; yr = year. 
Note:  The assessments and definitions differed among the studies; therefore the data provided 
are not suitable for comparisons between trials. 
a Number of patients denotes patients included in the analyses. 
 
1.2.1.3.2 
Post-marketing Safety Summary of Trastuzumab IV 
It is estimated that over 1 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 of 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 


   
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oxygen saturation, and respiratory distress.  In the post-marketing setting, very rare 
(< 1 of 10,000 patients) 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 tumor involvement of the lungs 
resulting in dyspnea at rest may be at greater risk of severe reactions.  Other risk factors 
associated with interstitial lung disease include prior or concomitant therapy with other 
anti-neoplastic therapies such as taxanes, gemcitabine, vinorelbine, and radiation 
therapy. 
In addition, severe hypersensitivity reactions have been infrequently reported in patients 
treated with trastuzumab IV (the exact incidence of these events is unknown).  Signs 
and symptoms include anaphylaxis, urticaria, bronchospasm, angioedema, and/or 
hypotension.  In some cases, the reactions have been fatal.  Symptom onset generally 
occurred during an infusion, but onset after the completion of an infusion has also been 
reported.  Reactions were most commonly reported in association with the initial 
infusion. 
The immunogenicity of trastuzumab IV has been investigated in clinical studies that 
included 903 MBC patients.  Human anti–human antibodies (HAHA) to trastuzumab 
were detected in 1 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 
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).  
Subcutaneous administration of trastuzumab takes significantly less time (up to 
5 minutes) compared to IV infusion (30−90 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.  
Subcutaneous administration offers the potential for self-administration of trastuzumab, 
which is expected to further improve treatment convenience and compliance. 


   
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40/Protocol MO28048, Version 4 
1.2.2.1 
Recombinant human hyaluronidase (rHuPH20) 
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 SC 
formulation is the enzyme hyaluronidase, which enables larger volumes to be 
administered without reduced tolerability and 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 component 
of the subcutaneous matrix, leading to reduced viscosity of the extracellular matrix of the 
hypodermis and, thus, to an improved delivery of SC administered drugs to the systemic 
circulation.  The decreased viscosity is also expected to facilitate SC administration of 
larger volumes of fluid.  
More recently, recombinant human hyaluronidase (rHuPH20) has been developed and 
approved to improve dispersion and absorption of co-administered drugs.  This 
recombinant human molecule has a higher purity and is associated with improved 
efficacy and tolerability compared with the animal-derived enzyme.  In the US, one 
recombinant humanized hyaluronidase, Hylenex® (Hylenex® Prescribing 
Information 2005), is licensed to facilitate the absorption and dispersion of drugs when 
given SC at doses between 50 IU and 300 IU (Frost 2007).  The rHuPH20 used in the 
current study is produced from a second generation of the Hylenex® process, with an 
improved yield and purity.  It has been combined with trastuzumab to allow safe and 
comfortable subcutaneous injection of volumes ≥ 3 mL. 
1.2.2.1.1 
Nonclinical Studies with rHuPH20 
After IV administration in the dose range 0.3−30 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 SC administration was extremely low 
(not determinable at low doses, 6%−8% in the dose range 3−30 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 further details on nonclinical studies with rHuPH20 refer to the Herceptin 
(RO 45-2317, Trastuzumab) IB. 
1.2.2.1.2 
Clinical Studies with rHuPH20 
Mammalian hyaluronidase preparations differing in source species and manufacturing 
processes have been the subject of multiple investigations and regulatory approvals in 
Europe, the US, and Asia.  It is estimated that these products have been administered to 
tens of millions of patients in the US.  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 2007; Harris 2003).  Humanized recombinant 


   
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41/Protocol MO28048, Version 4 
hyaluronidase preparations are associated with an improved purity and corresponding 
decreased safety risk.  
Clinical data are available from four studies with rHuPH20.  
• 
In an allergic sensitivity study (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 (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.  
• 
Study HZ2-07-01 was a double-blind, within-subject-controlled, two-way cross-over 
trial comparing the time to inject (flow rate), safety, and tolerability of a SC 
administered 10% (2000 mg in 20 mL) solution of immunoglobulin G (diluted 
Carimune® NF) with and without rHuPH20 in 30 healthy volunteers.  There was a 
statistically nonsignificant trend towards a decrease in time to inject and an increase 
in flow rate in the presence of rHuPH20 relative to the control group.  The most 
common AEs were injection-site reactions consisting of erythema, pain, edema, 
induration, or pruritus (communication with Halozyme Therapeutics Inc. on 
preliminary study results). 
• 
Study HZ2-07-02 investigated the SC 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 these clinical studies was 96,000 U in 
Study HZ2-07-02, and this was well tolerated by healthy volunteers.  
For further information on the clinical trials conducted with rHuPH20, refer to the 
Herceptin (RO 45-2317, Trastuzumab) IB.  


   
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1.2.2.2 
Nonclinical Studies with Trastuzumab SC 
An overview of completed nonclinical pharmacology, PK, and toxicology studies of 
trastuzumab SC is provided in Table 3.  Overall, these studies showed that rHuPH20 
enabled more rapid absorption of trastuzumab SC, and that SC administration of 
trastuzumab formulated with rHuPH20 was well tolerated locally and systemically.  
For further information, refer to the Herceptin (RO 45-2317, Trastuzumab) IB. 
Table 3 
Overview of Completed Nonclinical Pharmacology, PK, and 
Toxicology Studies with Trastuzumab SC (Formulated with 
rHuPH20) 
Study Type 
Objective 
Species 
Key findings 
Pharmacology 
In vivo efficacy in 
mouse xenograft 
model 
Comparison of 
trastuzumab SC with 
trastuzumab IV 
Mouse 
Comparable efficacy 
providing similar trough 
levels achieved 
Pharmacokinetics 
PK (non GLP) 
Assessment of 
trastuzumab SC PK in 
preparation for 
efficacy/pharmacology 
study (above) 
Mouse 
Bioavailability of 
trastuzumab SC estimated 
at 83.4% 
PK/dose finding  
Optimization of 
trastuzumab SC 
formulation for clinical 
studies 
Mini-pig 
More rapid absorption of 
trastuzumab SC 
formulated with rHuPH20 
than without rHuPH20 
PK assessment 
Assessment of 
trastuzumab SC PK in 
preparation for 13 
week repeat dose 
toxicity study 
Cynomolgus 
monkey 
Maximum serum 
trastuzumab levels 
achieved 24 hours after 
trastuzumab SC (PK 
comparable to mini-pig) 
AUC = area under the curve; GLP = Good Laboratory Practices; IV = intravenous; 
PK = pharmacokinetic; rHUPH20 = recombinant humanized hyaluronidase; SC = subcutaneous.


   
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43/Protocol MO28048, Version 4 
Table 3 
Overview of Completed Nonclinical Pharmacology, PK, and 
Toxicology Studies with Trastuzumab SC (Formulated with 
rHuPH20) (cont.) 
 
Study Type 
Objective 
Species 
Key findings 
Toxicology 
Local tolerance  
Clinical symptoms and 
injection site reactions 
following single dose 
trastuzumab SC 
Rabbit 
No signs of systemic 
toxicity.  No macroscopic 
or microscopic findings 
attributable to treatment 
13 week repeat dose 
toxicity 
High dose toxicity, 
clinical symptoms, and 
injection site reactions 
Cynomolgus 
monkey 
Trastuzumab exposure 
(AUC) comparable to that 
achieved at highest doses 
in nonclinical IV safety 
program.  No adverse 
findings for any of the 
parameters evaluated.  
Low immunogenicity 
(anti-trastuzumab 
antibodies found in 1 of 
4 recovery animals) 
AUC = area under the curve; GLP = Good Laboratory Practices; IV = intravenous; 
PK = pharmacokinetic; rHUPH20 = recombinant humanized hyaluronidase; SC = subcutaneous. 
 
1.2.2.3 
Clinical Studies with Trastuzumab SC 
Subcutaneous trastuzumab (formulated with rHuPH20) has been studied in one 
completed clinical trial (BP22023, CP2) and one ongoing clinical trial (BO22227, 
HannaH) using conventional syringes and hypodermic needles for administration.  In 
addition, a PK study (BO25532, CP3) now completed in healthy volunteers has 
demonstrated comparable exposure between SC administration with the single-use 
injection device (SID) versus with the conventional syringe and needle.  Lastly, a patient 
satisfaction and health care professional (HCP) preference study (MO22982, PrefHer) 
comparing trastuzumab SC administration using SID and vial with trastuzumab IV 
administration is ongoing in parallel with the current study. 


   
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44/Protocol MO28048, Version 4 
Table 4 
Overview of the Clinical Development Program of Trastuzumab 
SC 
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) 
Ongoing 
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) 
Ongoing 
PK bridging to 
injection device 
OL, PG, randomized, 
single-dose, MC 
Pharmacokinetic 
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 
To evaluate patient 
preference for trastuzumab 
SC administration using a 
SID or vial versus 
trastuzumab IV 
HCP = health care professional; MC = multicenter; OL = open-label; pCR = pathological complete 
response; PG = parallel-group; PK = pharmacokinetic; SID = single-use injection device. 
 
1.2.2.3.1 
Study BP22023 (CP2) 
Study BP22023 (Wynne et al. 2013) included two parts:  trastuzumab SC dose finding in 
healthy male subjects and subsequent dose confirmation in female HER2‑positive 
breast cancer patients.  Twenty-four healthy male subjects and 46 female subjects with 
HER2-positive EBC received single doses of either trastuzumab IV or trastuzumab SC, 
as outlined in Table 5.  The dose of rHuPH20 received depended on the volume 
administered, which depended on the body weight-based dose of trastuzumab.  The 
concentration of trastuzumab in the SC formulation was 120 mg/mL.  The concentration 
of rHuPH20 was 2000 U/mL.  


   
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45/Protocol MO28048, Version 4 
Table 5 
Summary of Treatment Cohorts and Adverse Events, 
Study BP22023 
AEs 
Cohort 
Route of 
administration
Subjects 
Dose 
(mg/kg)
Subjects 
n (%) 
Events 
n 
[Gr1/Gr2/Gr3]
Part 1 (Dose finding) 
All Subjects 
 
 
 
27 (90) 
86 [61/24/1] 
1 
IV 
6 healthy males 
6 
5 
26 [19/6/1] 
2 
IV 
6 HER2-positive 
EBC females 
6 
6 
24 [17/7/0] 
3 
SC 
6 healthy males 
6 
5 
12 [9/3/0] 
4 
SC 
6 healthy males 
10 
5 
11 [8/3/0] 
5 
SC 
6 healthy males 
8 
6 
13 [8/5/0] 
Part 2 (Dose confirmation) 
All subjects 
 
 
 
39 (98) 
181 [131/46/4]
A 
SC 
20 HER2-positive 
EBC females 
8 
19 
87 [61/23/3] 
B 
SC 
20 HER2-positive 
EBC females 
12 
20 
94 [70/23/1] 
EBC = early breast cancer; IV = intravenous; mod = moderate; SC = subcutaneous; sev = severe. 
 
Safety Data from Study BP22023 
The BP22023 protocol allowed healthy volunteers and patients to receive premedication 
(e.g., paracetamol and/or phenergan) prior to the administration of trastuzumab SC, at 
the discretion of the investigator, for prophylaxis of infusion-related reactions (IRRs). 
In Part 1, a total of 86 AEs were observed in 27 out of 30 subjects.  Of these, 71% were 
considered to be Grade 1 intensity, and 28% were Grade 2 intensity (Table 5).  Two 
IRRs were observed in Cohort 1.  One event was assessed as Grade 2 intensity, the 
other as Grade 3 intensity.  Premedication to lower the risk of IRR was given to 
2 subjects in Cohorts 1 and 3, respectively, and to one subject of Cohort 4.  Neither of 
the healthy male volunteers experiencing an IRR in Cohort 1 had received any 
premedication before being administered trastuzumab IV.  The number of subjects 
reporting AEs was similar in all the cohorts in Part 1, but there were fewer events 
reported in the SC cohorts.  In Cohorts 3−5, in which male subjects received 
trastuzumab SC at 6, 8, and 10 mg/kg; there was no apparent dose-related increase in 
frequency or severity of AEs, and the SC administration was generally well tolerated. 
In Part 2, a total of 181 AEs were observed in 39 out of 40 female patients.  Of these, 
72.5% were considered to be Grade 1 intensity, 25.5% were Grade 2 intensity, and there 


   
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46/Protocol MO28048, Version 4 
were 4 (2%) Grade 3 AEs (Table 5).  In Cohorts A and B, there was no apparent 
dose-related increase in the frequency or intensity of AEs observed, and the SC 
administration was generally well tolerated. 
As this was the first study during which subjects received trastuzumab SC, special 
consideration was given to the local tolerability related to drug administration.  In 
subjects who received trastuzumab SC, there were 18 AEs that were classified as 
administration site conditions.  A total of 16 (89%) AEs were of mild intensity and 
included erythema (7), discoloration (5), injection-site swelling (2), injection-site 
discomfort (1), and injection-site reaction (1).  There were two instances of moderate 
injection-site pain.  There were no changes in laboratory parameters, vital signs or ECG 
parameters that constituted an AE. 
Pharmacokinetic Data from Study BP22023 
Comparable trastuzumab PK was observed in Part 1 between female patients and 
healthy male volunteers receiving 6 mg/kg IV, with a mean Cmax of 185 μg/mL compared 
with 150 μg/mL and a mean AUCinf of 1800 μg • day/mL compared with 
1610 μg • day/mL in female patients and healthy male volunteers, respectively 
(Figure 1).  
Mean maximum serum concentrations (Cmax) of trastuzumab increased proportionally 
with increasing doses of trastuzumab SC, 66.8, 82.0, and 102 μg/mL for 6, 8, and 
10 mg/kg trastuzumab SC, respectively.  Mean AUC0-inf also increased over the range of 
SC doses administered, 1350, 1960, and 2500 day • µg/mL for 6, 8, and 10 mg/kg 
trastuzumab SC, respectively (Table 6).   
Following preliminary PK analysis of trastuzumab serum samples in all subjects in Part 1 
(Cohorts 1 to 5), 20 patients were administered a single dose of 8 mg/kg 
trastuzumab SC (Cohort A), as this was the trastuzumab SC dose level expected to 
achieve a comparable exposure to the approved maintenance dose of 6 mg/kg 
trastuzumab IV.  In Cohort B, patients were administered a single dose of 12 mg/kg 
trastuzumab SC to assess PK characteristics and safety, as well as to support modelling 
and simulation.  The absolute bioavailability based on AUC0-inf ranged between 83.9% 
and 93.2% in healthy male volunteers and 87.1% and 98.6% in female patients. 
The available data suggested dose proportionality in Cmax and AUC0-inf over the range of 
trastuzumab SC doses administered (6−12 mg/kg) both in Part 1 and Part 2. 


   
Trastuzumab⎯F. Hoffmann-La Roche Ltd 
47/Protocol MO28048, Version 4 
Figure 1 Mean (±SD) Trastuzumab Concentration-Time Profile by Cohort 
 
EBC = early breast cancer; IV = intravenous; SC = subcutaneous; SD = standard deviation. 
1: 6 mg/kg IV, healthy subjects 
2: 6 mg/kg IV, EBC subjects 
3: 6 mg/kg SC, healthy subjects  
4: 10 mg/kg SC, healthy subjects 
5: 8 mg/kg SC, healthy subjects  
A: 8 mg/kg SC, EBC subjects 
B: 12 mg/kg SC, EBC subjects 
 


   
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Table 6 
Mean (CV%) Trastuzumab Serum Pharmacokinetic Parameters, 
Following Trastuzumab IV and SC Administration, Study 
BP22023 
Cohort 
Route of 
Administration 
Subjects 
(n) 
Dose 
(mg/kg)
Cmax 
(μg/mL)
tmax 
(hour) a 
AUCinf 
(day/μg/mL) 
t1/2 
(hour)
CDay22 
(μg/mL)
1 
IV 
H (6) 
6 
150 
(9.57) 
1.65 (1.6−24.0)
1610 (18.9) 
254 
(12.7)
25.6 
(47.1) 
2 
IV 
EBC (6) 
6 
185 
(23.2) 
3.00 
(1.55−24.0) 
1800 (13.9) 
244 
(28.4)
27.5 
(27.1) 
3 
SC 
H (6) 
6 
66.8 
(17.1) 
156.00 
(95.95−216.10)
1350 (23.7) 
227 
(24.7)
31.6 
(38.1) 
5 
SC 
H (6) 
8 
82.0 
(13.8) 
96.00 
(96.00−215.98)
1960 (12.4) 
236 
(18.6)
39.4 
(13.9) 
4 
SC 
H (6) 
10 
102 
(16.8) 
132.12 
(96.00−216.00)
2500 (20.6) 
240 
(14.3)
51.4 
(30.8) 
A 
SC 
EBC (20)
8 
88.4 
(37.7) 
97.13 
(47.93−216.60)
2090 (30.6) 
241 
(19.9)
37.8 
(27.5) 
B 
SC 
EBC (20)
12 
151 
(38.7) 
96.05 
(24.53−241.40)
3550 (27.7) 
270 
(29.6)
60.8 
(36.2) 
AUC = area under the curve; Cmax = maximum serum concentration; EBC = early breast cancer; 
H = Healthy; IV = Intravenous; SC = Subcutaneous; tmax = time to achieve maximum serum 
concentration; t1/2 = elimination half-life. 
Note:  Values represent means (standard deviation), unless otherwise indicated. 
a Median (min−max). 
 
Plasma concentrations of rHuPH20 were assessed in all subjects who received 
trastuzumab SC at predose and 0.5 h, 1 h, and 24 h postdose.  Plasma rHuPH20 
concentrations were below the limit of quantification for all sampling points in all 
subjects, indicating that the use of the enzyme as a permeation enhancer for 
trastuzumab does not result in quantifiable systemic exposure to the enzyme. 
Immunogenicity Results from Study BP22023 
Blood samples were taken at screening, Days 15, 85 and follow-up (5 months postdose) 
to allow for testing of antibodies to either trastuzumab or rHuPH20. 
Nine of 58 (15.5%) subjects who had been administered trastuzumab SC were deemed 
positive for antibodies to rHuPH20 after confirmatory assay analysis.  Five of these 
subjects had a positive confirmatory assay at all timepoints including screening, one 
subject was positive at screening, Day 15 and follow up and negative at Day 85, one 
subject was positive at screening, Day 15 and Day 85 but negative at follow up, another 
one was positive at Day 85 but negative at follow-up; and the remaining subject was 
positive at Day 85 and follow-up.  All samples were negative in the neutralizing antibody 
assay. 


   
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A total of 263 samples were assayed in 58 subjects for the occurrence of 
anti-trastuzumab antibodies.  Eleven samples in 8 of 58 (14%) subjects receiving 
trastuzumab SC were positive for antibodies to trastuzumab after the confirmatory 
assay.  All samples from the screening visits were negative for anti-trastuzumab 
antibodies.  In 6 subjects out of the 8 above, the follow-up sample was negative after 
one positive sample.  No anti-trastuzumab antibodies were detected in subjects 
receiving trastuzumab IV.  Neutralizing antibody tests for trastuzumab were not 
performed, as the assay was not available at the time.  Samples have been discarded in 
the interim.  Likewise, results from titering assays are not available. 
The presence of a positive confirmatory assay for trastuzumab or rHuPH20 was not 
associated with a difference in safety or trastuzumab PK profile.  This also held true for 
the 3 patients who developed anti-drug antibodies (ADA) to both proteins. 
Pharmacokinetic Modelling of Fixed Trastuzumab SC Dose Selection 
In the dose-finding Study BP22023, subjects received trastuzumab SC on a body 
weight-adjusted basis.  Preliminary trastuzumab IV and SC PK data from this study were 
integrated into a PK model, and simulations were then used to predict Ctrough and AUC 
for various trastuzumab SC doses based on 100 simulations of 130 subjects, which 
provided a 5 to 95th% tile range for the 5th% tile, median, and 95% tile concentration 
values.  The simulations were based on a normal distribution of body weight, with a 
mean of 68 kg and standard deviation of 11 kg.  The simulations indicated that a flat and 
a weight-based dosing strategy would result in a comparable range of exposure with a 
relationship to body weight that is inverse, and a fixed dose of 600 mg would result in 
Ctrough values that are at least as high as with the 3-weekly (Q3W) IV regimen (8 mg/kg 
loading dose followed by 6 mg/kg maintenance dose).  For example, as shown in 
Table 7, the IV upper bound of the confidence interval (CI) of the median Ctrough is 
63 μg/mL and is comparable to the SC lower bound of the CI of the median Ctrough 
predicted at 67 μg/mL.  
Table 7 
Predicted Ctrough (μg/mL) at Pre-dose Cycle 8 
Ctrough at Predose Cycle 8 (μg/mL) 
 
5th% tile 
P5 [P5-P95] 
Median 
[P5-P95] 
95th% tile 
P95 [P5-P95] 
Q3W IV regimen (8/6 mg/kg) 
23 [16-32] 
46 [37-63] 
84 [67-109] 
SC regimen 600 mg 
38 [28-49] 
79 [67-95] 
143 [120-174] 
P5 = 5th percentile; P95 = 95th percentile; Q3W = 3-weekly. 
 
Figure 2 illustrates the distribution of predicted median Ctrough and predicted 5th 
percentile of Ctrough, respectively, at Cycles 1 and 8, comparing the IV loading and 
maintenance doses of 8 mg/kg and 6 mg/kg, and a fixed SC dose of 600 mg.  For both 


   
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cycles, with the selected fixed dose of 600 mg, median Ctrough values were predicted to 
be higher than those achieved with the IV doses. 
Figure 3 illustrates the distribution of predicted median AUCtau and predicted 5th 
percentile of AUCtau, respectively, at Cycles 1 and 8, comparing the IV loading and 
maintenance doses of 8 mg/kg and 6 mg/kg and the fixed SC dose of 600 mg.  For 
Cycle 8, with the selected fixed dose of 600 mg, median AUCtau values were predicted to 
be higher than those achieved with the IV 6 mg/kg maintenance dose.  For Cycle 1, 
median AUCtau values were predicted to be lower than those achieved with the IV 
8 mg/kg loading dose.  It was predicted that with a 600 mg fixed dose of trastuzumab 
SC, a cumulative AUC comparable to the Q3W IV regimen would be reached during 
Cycle 3. 
The predicted Cmax values after SC administration (95th percentile) also did not exceed 
the maximum exposure previously measured for the IV regimen in the HERA trial 
(Clinical Study Report 1019820).  Therefore, no unexpected safety issues related to 
trastuzumab exposure were anticipated with a 600 mg fixed dose of trastuzumab SC.  
Based on these data, a fixed dose of 600 mg was selected as an appropriate dose for 
further studies using trastuzumab SC. 


   
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Figure 2 Distribution or Simulated Median Ctrough Levels at Cycles 1 and 8 with a Dose of 600 mg Trastuzumab SC 
 
Ctrough = trough plasma concentration; IV = intravenous; P5 = 5th percentile; SC = subcutaneous. 


   
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Figure 3 Distribution of Simulated Median AUCtau Levels at Cycles 1 and 8 with a Dose of 600 mg Trastuzumab 
SC 
 
AUC = area under the plasma concentration-time curve; IV = intravenous; P5 = 5th percentile; SC = subcutaneous.


   
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1.2.2.3.2 
Study BO22227 (HannaH) 
The findings of Study BP22023 indicating that trastuzumab SC has a tendency toward 
fewer administration-related reactions compared to trastuzumab IV were further 
investigated in the Phase III clinical efficacy bridging Study BO22227 (HannaH).  
Study BO22227 is a Phase III, randomized, open-label, multicenter trial involving 
596 female patients with HER2-positive early breast cancer in which the 
pharmacokinetics, efficacy, and safety of trastuzumab SC were compared with IV 
trastuzumab.  Co-primary endpoints are serum Ctrough pre-surgery and pathological 
complete response (pCR).  
In this study, patients with operable or locally advanced disease were randomized to 
eight cycles of either trastuzumab IV or trastuzumab SC given concurrently with 
chemotherapy.  Patients randomized to trastuzumab IV received the standard 3-weekly 
regimen (8 mg/kg loading followed by 6 mg/kg every 3 weeks), and patients randomized 
to trastuzumab SC received a fixed dose of 600 mg of trastuzumab (formulated with 
rHuPH20 2000 IU/mL to give a fixed dose of 10,000 U) every 3 weeks by conventional 
SC injection using a syringe and needle.  After surgery, patients received a further 
10 cycles of trastuzumab IV or SC as per randomization to complete 1 year of treatment.  
Study BO22227 met its co-primary endpoints, which were the trastuzumab concentration 
in the blood (serum concentrations) and efficacy. 
Results of the study indicated that trastuzumab SC demonstrated comparable efficacy to 
trastuzumab IV within the planned boundaries for non-inferiority with regard to the pCR 
and the concentration in the blood (Ctrough).  No new safety signals were identified with 
trastuzumab SC, and AEs were consistent with trastuzumab IV, with the most common 
AEs being infections and abnormal blood counts (anemia and low white blood cell 
count).  The overall safety profile and tolerability in both arms was consistent with that 
expected from combination treatment with anthracycline, taxane, and trastuzumab.  No 
new or unexpected safety findings were observed.  The proportion of patients reporting 
an AE of any grade during neoadjuvant/adjuvant treatment and treatment-free follow-up 
was 93.9% (280 of 298 patients) in the trastuzumab IV arm compared with 97.3% 
(289 of 297 patients) in the trastuzumab SC arm.  The most frequently occurring AEs 
were alopecia (62.8% in trastuzumab IV vs. 62.6% in trastuzumab SC), nausea (48.7% 
vs. 48.5%), neutropenia (46.3% vs. 44.1%), diarrhea (36.6% vs. 33.7%), asthenia 
(25.2% vs. 24.6), fatigue (26.5% vs. 22.6%), and vomiting (23.2% in each arm).  Most 
AEs were Grade 1 or 2 in intensity.  The incidence of Grade ≥ 3 events (severe) was 
52% (155 of 298 patients) in the trastuzumab IV arm versus 51.9% (154 of 297 patients) 
in the trastuzumab SC arm.  Full assessment of the data is publicly available 
(Ismael et al. 2012). 
1.2.2.3.3 
Study BO25532 (CP3) 
Study BO25532 was a randomized, open-label, parallel, 2-arm, multicenter Phase I 
study to investigate the comparability of PK of trastuzumab administered subcutaneously 


   
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using either the SID or a conventional syringe with a hypodermic needle.  The study also 
assessed the performance of the SID and evaluated the immunogenicity of trastuzumab 
and rHuPH20. 
Enrollment was completed in September 2011, with a total of 119 healthy male subjects 
randomized 1:1 to receive a single 600 mg SC 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 nondose 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 
there were no apparent differences related to the injection method (Wynne et al. 2012). 
1.2.2.3.4 
Study MO22982 (PrefHer) 
This is a Phase II international, randomized, open-label, two-cohort, two-arm crossover 
study to evaluate patient’s preference and HCP satisfaction with SC versus IV 
administration of trastuzumab in HER2-positive EBC following surgery and completion of 
chemotherapy (neoadjuvant or adjuvant).  Approximately 200 patients will be 
randomized 1:1 in each cohort to receive either trastuzumab treatment.  In Cohort 1, half 
of the patients will receive trastuzumab SC (600 mg fixed dose; 4 cycles) via a single 
use injection device (SID) followed by trastuzumab IV (8 mg/kg loading dose required 
only if Cycle 1 of study treatment is the initial dose of trastuzumab, otherwise 6 mg/kg 
Q3W; 4 cycles) or to trastuzumab IV followed by trastuzumab SC.  All patients will then 
continue to receive the remaining trastuzumab IV to complete 18 cycles of trastuzumab 
administration.  In Cohort 2, half of the patients will receive trastuzumab SC (600 mg 
fixed dose; 4 cycles) administered from a vial with a hand-held syringe followed by 
trastuzumab IV (8 mg/kg loading dose required only if Cycle 1 of study treatment is the 
initial dose of trastuzumab, otherwise 6 mg/kg Q3W; 4 cycles) or to trastuzumab IV 
followed by trastuzumab SC.  All patients will then continue to receive the remaining 
trastuzumab SC to complete 18 cycles of trastuzumab administration.  The primary 
endpoint is the proportion of subjects indicating an overall preference for either the SC or 
the IV route of administration.  Efficacy endpoints include EFS.  Immunogenicity of 
trastuzumab and rHuPH20 will also be evaluated. 
1.2.3 
Subcutaneous Single-Use Injection Device (SID) 
The SID is a single-use device for the subcutaneous administration of medicinal 
products such as trastuzumab SC.  The medicinal product to be injected is contained in 
an integral non-removable cartridge.  The entire content of the cartridge is delivered to 
the patient in a single injection through a needle that retracts when the injection is 
complete and if prematurely removed from the body to prevent needle stick injuries in 
handling.  The administration rate is fixed (approximately 1 mL/min, resulting in an 
approximate 5-minute injection time), and the dosage delivered is preset and controlled 


   
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at the product manufacturing stage (i.e., 600 mg of trastuzumab formulated with 
10,000 U of rHuPH20).  The medicinal product is administered through intact skin into 
the patient’s upper thigh.  
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT  
Patients with HER2-positive early breast cancer frequently require extensive treatment 
lasting months or years.  Many require surgery, adjuvant chemotherapy (usually given IV 
for 4−6 months) and/or hormonal therapy, and radiotherapy (often given daily for 
4−6 weeks), as well as trastuzumab.  Adjuvant trastuzumab is given IV q1w or Q3W for 
a total of one year.  This necessitates regular clinic visits, and, when started after 
completion of adjuvant chemotherapy and adjuvant radiotherapy if indicated, it greatly 
extends the period of time over which the patient is obliged to attend the hospital or 
clinic, which can cause inconvenience and increased costs to patients.  Even when 
started concurrently with the taxane component of chemotherapy (Herceptin license 
permitting), trastuzumab monotherapy still continues for several months after completion 
of other systemic therapy. 
Trastuzumab infusions are given over 30−90 minutes (or longer if there are 
infusion-related symptoms).  SC administration of trastuzumab is quicker (lasting up to 
5 minutes), and this alone could improve convenience for patients (and clinic staff).  
Furthermore, SC administration does not require IV access (which can be problematic in 
some patients after completion of chemotherapy).  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 (see Section 1.2.1.2).  
The current study is designed to investigate the safety and tolerability of two SC 
administration methods for trastuzumab in the (neo-)adjuvant setting, i.e. assisted 
administration using a conventional syringe (vial formulation) and self-administration 
using a SID.  The observed 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.  
Trastuzumab is now a standard component of (neo)-adjuvant treatment in patients with 
HER2-positive EBC.  The trastuzumab SC dose selected for this study is consistent with 
the findings of the BP22023 (CP2) trial and identical to that evaluated in the BO22227 
(HannaH) study (see Section 1.2.2 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 


   
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to risk ratio of adjuvant trastuzumab SC in the current trial is therefore expected to be 
favorable.  Further, the convenience of SC administration of trastuzumab will give 
patients greater independence, which is expected to increase compliance. 
One of the exploratory objectives of the study is to collect additional safety data over a 
specified observation time (according to trastuzumab EU SmPc) following trastuzumab 
administrations in patients using the SID (Cohort B).  
It will be assessed whether the prolonged observation time of the patients following 
trastuzumab SC administration (during the pre-specified time as per SmPC) is required 
for patients’ safety.  It is anticipated there may be a higher possibility of AEs following 
the first administration of trastuzumab; therefore, the patient will be required to remain at 
site for 6 hours after start of the first trastuzumab administration.  For all subsequent 
trastuzumab applications, patients will be required to remain onsite for 2 hours after start 
of drug administration.  However, the patient may be required to remain onsite for an 
extended period of time if considered clinically necessary by the investigator.  During this 
time, detailed information of AEs and associated treatment will be recorded and 
analyzed relative to the last preceding administration of trastuzumab.  
Therefore, in Cohort B, in addition to onset and resolution dates and times of AEs, 
detailed information about premedications prior to trastuzumab administration will be 
collected.  Also, in addition to the date, the onset and resolution time of the treatment of 
AEs occurring during the observation time will be investigated.  At the discretion of the 
investigator, patients will have the opportunity to self-administer trastuzumab via the 
SID; therefore, the SID performance under self-administration conditions will be 
monitored.  
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of the study is to assess the overall safety and tolerability of 
trastuzumab SC in HER2-positive EBC patients with assisted administration using a 
conventional syringe and needle (vial formulation) or with assisted- and 
self-administration using a SID in selected patients. 
2.2 
SECONDARY OBJECTIVES 
Secondary objectives include the evaluation of the following parameters: 
• 
Efficacy (both cohorts): 
• 
DFS (Disease-free survival) 
• 
OS (Overall survival) 
• 
Patient satisfaction with trastuzumab SC administration using the SID (patients in 
Cohort B who went on to self-administration of the study drug). 
 


   
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2.3 
EXPLORATORY OBJECTIVES  
Additional, exploratory objectives will be investigated in a subset of patients (Cohort B) 
at selected study sites: 
1. 
To assess the immunogenicity of trastuzumab and recombinant human 
hyaluronidase (rHuPH20) 
2. 
To examine and characterize tolerability of the trastuzumab SC over a 6-hour time 
period after the start of the first administration and over a 2-hour time period after 
the start of subsequent trastuzumab administrations (only in patients using the SID 
[Cohort B]) 
3. 
Monitoring of SID usability in a subgroup of 48 patients in Cohort B 
 
In addition, in some countries and sites, medical care utilization (MCU; e.g., time and 
motion) and/or pharmacoeconomic substudies will be conducted.  Details of the 
substudies will be described in separate protocols. 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY  
This is a Phase III, prospective, two-cohort, non-randomized, multicenter, multinational, 
open-label study in approximately 2500 patients with HER2-positive EBC who are 
eligible for anti-HER2 therapy.  A planned total of approximately 2500 evaluable patients 
will be enrolled into the study.  The trial will be conducted at approximately 520 centers 
in approximately 60 countries.  
All potential study patients must provide signed written informed consent (approved by 
the relevant independent ethics committee [EC]) before undergoing any study-specific 
procedure.  Results of the screening assessments must be available, and patients must 
meet all eligibility criteria prior to enrollment into the study.  
Eligible patients will be allocated to Cohort A or B at the investigator’s discretion 
depending upon availability of the cohorts for recruitment: 
• 
Cohort A (approximately 1800 patients):  trastuzumab SC 600 mg assisted 
administration into the thigh over a period of approximately 5 minutes using 
conventional handheld syringes with hypodermic needles 
• 
Cohort B (approximately 700 patients):  trastuzumab SC at a fixed dose of 600 mg 
presented in a SID.  The first administration will be assisted (performed by a HCP).  
If well tolerated and if the patient is willing and judged competent by the HCP to do 
so, subsequent administrations may be self-administered into the thigh over a 
period of approximately 5 minutes using the SID for a total of up to 18 cycles 
(3-weekly).  
Patients will remain at the study site to be observed for a period of 6 hours after 
their first trastuzumab administration and 2 hours thereafter for subsequent 


   
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trastuzumab administrations.  Patients may be required to remain onsite for an 
extended period of time if considered clinically necessary by the investigator. 
 
To allow for the enrollment of 1800 patients in Cohort A (compared to 700 patients in 
Cohort B), recruitment for Cohort A may be initiated earlier than recruitment for 
Cohort B. 
The study design is shown in Figure 4. 
Patients in both cohorts will receive a fixed dose of 600 mg trastuzumab SC throughout 
the study, administered 3-weekly for a total of 18 cycles, unless disease recurrence, 
unacceptable toxicity, or patient withdrawal necessitates earlier treatment cessation.  All 
study treatment administrations in both cohorts will occur in a hospital setting.  
Trastuzumab SC treatment may be initiated: 
• 
After completion of neoadjuvant or adjuvant chemotherapy (sequentially) 
• 
In combination with neoadjuvant or adjuvant paclitaxel or docetaxel chemotherapy 
(concurrently) 
• 
or without adjuvant chemotherapy 
• 
or in combination with neoadjuvant chemotherapy followed by trastuzumab therapy 
for locally advanced (including inflammatory) disease or tumors > 2 cm in diameter 
 
For patients receiving trastuzumab SC with concurrent chemotherapy, trastuzumab SC 
must be administered first, followed by the administration of chemotherapy as per 
standard site procedures.  The observation time starts with the start of trastuzumab SC 
administration. 
The enrollment of patients treated without neoadjuvant or adjuvant chemotherapy, such 
as: 
• 
Patients with low risk node negative tumors ≤ 1.0 cm 
• 
Elderly patients (> 65 years of age)  
• 
or patients who refuse chemotherapy will be limited to ≤ 10% of the total study 
population)  
 
Hormonal therapy and radiotherapy (if applicable) may be given concomitantly with 
trastuzumab SC, as per local guidelines. 
Patients will be assessed for safety and efficacy, as detailed in Appendix 1, Schedule of 
Assessments.  In addition to efficacy and safety assessments, select sites will also 
perform immunogenicity testing to determine whether HAHAs against trastuzumab or 
rHuPH20 develop in patients receiving trastuzumab SC using the SID.  Since the 
evaluation of anti-trastuzumab assay results requires corresponding serum trastuzumab 
concentrations, the anti-trastuzumab analyses will be coupled with PK assessments.  


   
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Patients in either study arm who cannot tolerate trastuzumab SC will come off study and 
further treated at the investigator’s discretion.  
Patients will undergo a Safety Follow-up visit 4 weeks after their last dose of study 
treatment, with further follow-up according to the American Society of Clinical Oncology 
(ASCO) 2006 Guideline for Breast Cancer Follow-up in the adjuvant setting 
(Khatcheressian et al. 2006) or investigator’s routine practice.  All patients will be 
followed-up for cancer recurrence and survival until study end.  The duration of follow-up 
will be at least 5 years after their last study treatment, unless one of the following occurs 
first:  withdrawal of consent, loss to follow-up, or death.  After disease progression, 
patients will be managed as per local practice and followed for survival only.  
In some countries and sites, MCU (e.g., time and motion) and/or pharmacoeconomic 
substudies will be conducted.  Details of the substudies will be described in separate 
protocols. 
The primary analysis of safety endpoints and a preliminary analysis of efficacy (DFS and 
OS) will take place when all patients have received 18 cycles of trastuzumab SC and 
have completed the post-treatment Safety Follow-up assessments.  The final analysis of 
OS and DFS and updated summaries for safety parameters will be performed when the 
last patient has been followed up for at least 5 years after her/his last study treatment, or 
earlier, if one of the following is documented for all treated patients:  withdrawal of 
consent, loss to follow-up, or death.  This is expected to take place approximately 
8 years after the enrollment of the first patient, based on an expected 18-month 
recruitment period per cohort, 12 months of study treatment, and 5 years of follow-up 
after the last study treatment.  The study design is shown in Figure 4 and the Schedule 
of Assessments in Appendix 1.  


   
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3.1.1 
Overview  
Figure 4 Study Design 
 
EBC = early breast cancer; HCP = healthcare provider; HER2 = human epidermal growth factor receptor-2; SC = subcutaneous; SID = single-use 
injection device. 
Notes:  Participating investigators must opt for one route of administration per patient.  For enrollment to Cohort B, patients need to be willing to 
self-administer the study drug based on the instructions for use supplied with the SID and personal instructions provided by an HCP during the 
first assisted administration.  All trastuzumab SC administrations will occur in a hospital setting.  Patients in both cohorts will receive trastuzumab 
SC 3-weekly, for a total of 18 cycles, unless disease recurrence, unacceptable toxicity or patient withdrawal necessitates early cessation of 
treatment.  If trastuzumab SC is initiated in the neoadjuvant phase, surgery should be programmed after the dosing at Cycle 8, without 
interruption of trastuzumab treatment. 
a Cohort A:  Trastuzumab SC 600 mg will be injected by an HCP into the thigh over a period of approximately 5 minutes using a conventional 
handheld syringe with a gauge 25 or 27 hypodermic needle. 
b Cohort B:  Trastuzumab SC 600 mg will be injected into the thigh over a period of approximately 5 minutes using the SID.  The first injection will 
be administered by a trained HCP (physician or nurse).  Patients assessed by the investigator as competent to self-administer the study drug 
using the SID and are willing to will be allowed to self-administer the remaining trastuzumab SC doses under the direct supervision of a HCP.  
Patients not deemed competent to self-administer the study drug, or are not willing will have all their trastuzumab SC doses administered by a 
trained HCP (physician or nurse). 


   
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3.1.2 
Steering Committee 
A Steering Committee is established to provide scientific oversight and to ensure that the 
risk-benefit assessment is maintained during the total duration of the trial.  
Responsibilities of the Steering Committee include recommendation to the Sponsor of 
any protocol amendments, monitoring of accrual, compliance and safety during the 
conduct of the trial, and reviewing the results of three interim safety analyses when 
approximately 500, 1000, and 2500 patients have received at least one trastuzumab SC 
injection.  Upon study completion, the Steering Committee will provide its interpretation 
of the results to the Sponsor, including their proposal for publications.  Timing and type 
of publications generated by the SafeHer study will be defined in conjunction with the 
Sponsor.  
The SafeHer Steering Committee is made up of investigators and Roche representatives 
and meets at regular intervals.  The committee is composed of up to 10 members, 
including the Chairperson.  The Chairperson of the Steering Committee is responsible 
for scheduling and conducting the meetings.  Decisions of the Steering Committee are 
based on a majority vote.  
Refer to the SafeHer Steering Committee Charter for further details. 
3.2 
END OF STUDY 
End of study is defined as the last patient last visit in the follow-up period.  The study will 
end when all patients have been followed for approximately 5 years after their last study 
treatment, or earlier, if one of the following is documented for all treated patients:  
withdrawal of consent, loss to follow-up, or death.  The final analysis of OS and DFS and 
updated summaries for safety parameters will be performed at this stage.  
The study is estimated to last approximately 8 years. 
3.3 
RATIONALE FOR STUDY DESIGN 
This Phase III prospective, two-cohort non-randomized, multicenter, multinational, 
open-label study will assess the overall safety and tolerability of two SC administration 
methods of trastuzumab (assisted administration using a conventional needle and 
syringe and self-administration using a SID) in HER2-positive EBC patients.  The safety 
and tolerability of the two SC administration methods will be evaluated over a standard 
treatment period of 18 cycles (administered every 3 weeks).  With this comprehensive 
approach, any potential problems associated with multiple administrations 
(e.g., positioning the SID to avoid previous sites of administration) will also be assessed.  
Patients will be allocated to Cohort A or B at the investigator’s discretion.  For 
enrollment into Cohort B, patients need to be willing to self-administer the study drug 
from the SID based on personal instructions/training provided by an HCP during the first 
assisted administration in addition to a quick reference guide and an instructional 


   
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animation describing the injection device handling and use, including how to respond if 
the SID loses sufficient contact with the body.  
Administration by the SID could enable self-administration of trastuzumab in the future.  
The SID satisfaction questionnaire used in this study and the device usability monitoring 
questionnaire has been developed specifically for this purpose. 
3.3.1 
Rationale for Test Product Dosage 
Subcutaneous trastuzumab will be given Q3W at a fixed dose of 600 mg in both cohorts.  
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 SC administration was 
selected with the aim of achieving trastuzumab serum trough concentrations (Ctrough) that 
are non-inferior to those obtained with Q3W trastuzumab IV administration.  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 1.2.2.3.1), 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 SC 
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 Cmax 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 
SC 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 (2000 U/mL).  The dose of rHuPH20 was selected based on 
nonclinical 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 09520).  Of note, a higher amount of rHuPH20 (6000 U/mL) did not improve the 


   
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absorption of trastuzumab as compared to a formulation containing 2000 U/mL 
rHuPH20.  The selected rHuPH20 concentration was further verified in clinical studies 
for satisfactory absorption parameters.  Nonclinical and clinical data demonstrate that 
the selected amount of rHuPH20 contained in the trastuzumab SC formulation is well 
tolerated. 
3.3.2 
Rationale for the Patient Population 
Adjuvant systemic therapies for early breast cancer have contributed to the substantial 
decline in breast cancer mortality in the past couple of decades (Verma et al. 2010; 
Colozza et al. 2006).  The introduction of trastuzumab has particularly improved the 
outcome for early breast cancer patients with HER2-positive disease.  Since its initial 
approval in 1998, trastuzumab has become standard of care for patients with 
HER2-positive breast cancer and is widely used for its approved indications in both the 
adjuvant and metastatic settings (Ross et al. 2009; NCCN 2010; Gnant et al. 2011; 
Aebi et al. 2011). 
HER2 positivity, defined as the over-expression or amplification of HER2, is a 
prerequisite for the use of trastuzumab.  Recent reports indicate that approximately 
15%−20% of breast cancers are HER2-positive (Ross et al. 2009; Lund et al. 2010).  
Patients with HER2-positive early breast cancer frequently require extensive treatment 
lasting months or years.  Many require surgery, adjuvant chemotherapy (usually given 
intravenously for 4−6 months) and/or hormonal therapy (given for 5−7 years), and 
radiotherapy (often given daily for 4−6 weeks), as well as trastuzumab.  Adjuvant 
trastuzumab is given IV every week or every three weeks for a total of one year. 
Although trastuzumab in combination with chemotherapy is now standard of care for 
patients with HER2-positive EBC larger than 1 cm, its role in the management of small 
(≤ 1 cm) HER2-positive tumors has not been established.  There are two main reasons 
for this gap:  first of all, most small breast cancers have a good prognosis and adjuvant 
chemotherapy is not routinely recommended for their management.  In addition, due to 
this perceived good prognosis, patients with small (< 1 cm, T1a,b) node-negative (N0) 
HER2-positive cancers were largely excluded from the pivotal adjuvant trastuzumab 
trials (Constantinidou and Smith 2011).  However, recent data from several retrospective 
analyses suggest that small HER2-positive cancers might have a worse clinical outcome 
than previously estimated, and that more active adjuvant treatment including anti-HER2 
therapy may be warranted in these cases (Amar et al. 2010; Tanaka et al. 2011; 
Constantinidou and Smith 2011).  Subset analysis of one trastuzumab trial (HERA) 
demonstrated that patients with 1−2 cm cancers derived at least as much clinical benefit 
from 1 year of adjuvant trastuzumab with chemotherapy as the overall cohort 
(Piccart et al. 2005; Smith et al. 2007; Untch et al. 2008), and 2 retrospective studies 
have confirmed the same observation (McArthur et al. 2009; Rodrigues et al. 2010).  
These findings raise a key, but currently unanswered, clinical question of whether 
patients with small HER2-positive cancers should be offered adjuvant trastuzumab and 


   
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chemotherapy (Banerjee and Smith 2010; Constantinidou and Smith 2011).  The 
importance of this issue is underscored by the steady increase in the number of women 
being diagnosed with T1a,bN0 primary tumors, which is largely due to the introduction of 
mammography screening programs and increased breast cancer awareness 
(Banerjee and Smith 2010; Fracheboud et al. 2004). 
In addition to patients with small HER2-positive tumors, there are other relevant 
subpopulations with HER2-positive EBC who do not receive adjuvant chemotherapy.  
These include elderly patients and patients refuse chemotherapy due to the associated 
toxicities.  Elderly patients with hormone-sensitive HER2-positive EBC may show benefit 
from endocrine treatment in combination with trastuzumab only 
(Constantinidou and Smith 2011).  
In the current study, patients with HER2-positive EBC treated without neoadjuvant or 
adjuvant chemotherapy (such as patients with low-risk node-negative tumors ≤ 1.0 cm, 
elderly patients [> 65 years of age], or patients who refuse chemotherapy) will comprise 
approximately 10% of the overall study population.  Importantly, a prospectively planned 
subgroup analysis is expected to produce relevant data on the efficacy and safety of 
trastuzumab SC in this important subset of patients. 
3.3.3 
Rationale for Control Group 
Not applicable; no formal statistical comparison of Cohort A and Cohort B is planned. 
3.3.4 
Rationale for Immunogenicity and Pharmacokinetic 
Assessments 
With the introduction of a SC administration route, there is a potential that the previously 
observed very low incidence of HAHA formation (1 of 903 patients in previous clinical 
trials) could be increased.  Based on published studies comparing IV and SC 
administration of protein drugs, there were either no significant increases in the 
incidence of HAHA following SC administration, or, in cases where increased 
immunogenicity was observed, the magnitude of the increase was small, i.e. less than 
2-fold (Hale et al. 2004; Srinivas et al. 1997). 
Immunogenicity testing is included in this study to determine whether HAHAs against 
trastuzumab or rHuPH20 develop, and whether these affect the safety and/or efficacy of 
trastuzumab SC.  Samples for immunogenicity testing will be collected from a subset of 
patients enrolled in Cohort B at select sites (see Section 3.4.4). 
3.3.5 
Rationale for Observation Time Assessments 
One of the exploratory objectives of the study is to collect additional safety data over a 
specified observation time (according to trastuzumab EU SmPC) following trastuzumab 
administrations in patients using the SID (Cohort B).  


   
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It will be assessed whether the prolonged observation time of the patients following 
trastuzumab SC administration (during the pre-specified time as per SmPC) is required 
for patients’ safety.  It is anticipated there may be a higher possibility of AEs following 
the first administration of trastuzumab.  Therefore, the patient will be required to remain 
at site for 6 hours after start of the first trastuzumab administration.  For all subsequent 
trastuzumab applications, patients will be required to remain onsite for 2 hours after start 
of drug administration.  However, the patient may be required to remain onsite for an 
extended period of time if considered clinically necessary by the investigator.  During this 
time, detailed information on AEs and associated treatment will be recorded and 
analyzed relative to the last preceding administration of trastuzumab.  
Therefore, in Cohort B, in addition to onset and resolution dates and times of AEs, 
detailed information about premedications prior to trastuzumab administration will be 
collected.  Also, in addition to the date, the onset and resolution time of the treatment of 
AEs occurring during the observation time will be investigated.  At the discretion of the 
investigator, patients will have the opportunity to self-administer trastuzumab via the 
SID; therefore, the SID performance under self-administration conditions will be 
monitored.  
3.4 
OUTCOME MEASURES 
3.4.1 
Efficacy Outcome Measures 
The efficacy outcome measures will be analyzed as secondary endpoints in this study 
and are defined as follows: 
• 
DFS:  time from the date of first treatment to the date of local, regional or distant 
recurrence, contralateral breast cancer or death due to any cause.  The DFS rate at 
2 years and yearly up to 5 years will also be presented.  
• 
OS:  time from the date of first treatment until date of death, regardless of the cause 
of death.  The OS rate at 2 years and yearly up to 5 years will also be presented. 
 
Patients in Cohort B, who went on to self-administration of the study drug will be asked 
to rate their overall satisfaction with trastuzumab SC administrations using the SID by 
completing a 5-item SID satisfaction questionnaire.  The questionnaire will be completed 
after the 4th cycle and at the Safety Follow-up visit (or at least 1 day after the last 
trastuzumab SC injection), after a minimum of 2 successful self-administrations of the 
study drug.  
The SID satisfaction questionnaire was created specifically for this trial (see 
Appendix 6). 
3.4.2 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
All clinical adverse events (AEs) and serious adverse events (SAEs), as well as 
abnormal laboratory values, will be recorded and graded according to the National 


   
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Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), 
version 4.0. 
• 
Cardiac function will be evaluated by measuring left ventricular ejection fraction 
(LVEF) (using echocardiography, Multi Gated Acquisition (MUGA) scan or Magnetic 
Resonance Imaging [MRI]) and ECG.  Symptomatic left ventricular dysfunction 
(CHF) will be graded according to NCI-CTCAE, version 4.0 and the NYHA functional 
classification. 
• 
All concomitant medication will be recorded between the Screening and the Safety 
Follow-up visits.  Thereafter, breast cancer treatments (e.g., endocrine therapy), 
anti-cancer treatments given to treat a recurrence, and medications related to the 
treatment of SAEs will be recorded. 
 
3.4.3 
Patient-Reported Outcome Measures 
Not applicable. 
3.4.4 
Exploratory Outcome Measures 
Immunogenicity of trastuzumab and rHuPH20 will be tested in a subset of patients 
enrolled in Cohort B at select sites.  Serum samples (for anti-trastuzumab antibody 
analysis) and plasma samples (for anti-rHuPH20 antibody analysis) will be drawn at 
baseline (after eligibility is confirmed, i.e., just before the first study treatment), 
on-treatment (pre-Cycle 9 dose, Week 25), and at least 6 months after the end of 
treatment for testing in a central laboratory.  
In addition to the study assessments described in Appendix 1, all clinical AEs that occur 
during the observation period will be collected for all patients in Cohort B (within 6 hours 
after start of the first trastuzumab administration or within 2 hours after start of following 
trastuzumab administrations).  Data collected during the observation period will include:  
frequency, incidence, and grade of AEs; onset and resolution times of AEs 
(dd:mm:yyyy:hh:mm); outcome of AE; and details of treatments provided following AEs 
during the observation period. 
Information on the usability of the SID will be collected via SID monitoring questionnaire 
(Appendix 7), will be provided to the first 48 patients enrolled in Cohort B who were 
judged able and were willing to self-administer remaining doses from the SID under 
direct observation of the HCP.  The SID Device Observation is to be completed by 
HCPs.  
The exploratory MCU and/or pharmacoeconomic parameters will be described in 
separate substudy protocols. 


   
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4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
The study will recruit adult consenting patients with newly diagnosed HER2-positive (IHC 
3+ or HER2-positive in situ hybridization [ISH]) early breast cancer who are eligible for 
treatment with trastuzumab (e.g., clinical Stage I [T1, N0, M0] to IIIC [any T, N3, M0]).  
Patients treated without neoadjuvant or adjuvant chemotherapy, such as patients with 
low-risk node-negative tumors ≤ 1.0 cm, elderly patients (> 65 years of age), or patients 
who refuse chemotherapy, will also be eligible to participate in the study, but their 
enrollment will be limited to approximately ≤ 10% of the total study population. 
Under no circumstances are patients who enroll in this study permitted to be re-enrolled 
to the same study for a second course of treatment. 
4.1.1 
Inclusion Criteria 
Patients must meet ALL of the following criteria to be eligible for participation in this 
study according to the timing specified in the schedule of assessment: 
1. 
Signed written informed consent approved by the reviewing independent Ethics 
Committee (EC) 
2. 
Female or male aged 18 years or above 
3. 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
4. 
Histologically confirmed early invasive HER2-positive carcinoma of the breast with 
no evidence of residual, locally recurrent, or metastatic disease and defined as 
clinical Stage I (T1, N0, M0) to IIIC (any T, N3, M0) that is eligible for treatment with 
trastuzumab 
Note:  Patients treated without neoadjuvant or adjuvant chemotherapy, such as 
patients with low-risk node-negative tumors ≤ 1.0 cm, elderly patients (> 65 years of 
age), or patients with HER2-positive EBC but denying chemotherapy, will also be 
eligible to participate in the study, but their enrollment will be limited to 
approximately ≤ 10% of the total study population.  
5. 
HER2-positive EBC, defined as IHC 3+ or positive in situ hybridization (ISH testing) 
by validated and approved methods within a certified laboratory 
6. 
Screening left ventricular ejection fraction (LVEF) ≥ 55% as measured by 
echocardiography, multi-gated acquisition (MUGA) scan, or Magnetic Resonance 
Imaging (MRI) per local practice 
7. 
Agreement to use an adequate, nonhormonal means of contraception by women of 
childbearing potential (defined as premenopausal and not surgically sterilized or 
< 1 year after the onset of menopause) and by male participants with partners of 
childbearing potential only.  Examples of adequate contraceptive measures are an 
intrauterine device, a barrier method (condoms or diaphragm) in conjunction with 
spermicidal jelly, or total abstinence.  Oral, injectable, or implant hormonal 
contraceptives are not acceptable for females participating in the study. 


   
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8. 
Intact skin at site of SC injection on the thigh 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will not be eligible for participation in this 
study: 
Cancer-related Criteria: 
1. 
Previous neoadjuvant or adjuvant breast cancer treatment with an approved or 
investigational anti-HER2 agent  
2. 
History of other malignancy which could affect compliance with the protocol or 
interpretation of results (including previous invasive ipsilateral or contralateral breast 
cancer).  Patients with curatively-treated carcinoma in situ of the cervix or basal cell 
carcinoma and patients with other curatively-treated malignancies other than breast 
cancer who have been disease-free for at least 5 years are eligible. 
3. 
Past history of ductal carcinoma in situ (DCIS) within the last 5 years that has been 
treated with any systemic therapy OR with radiation therapy to the ipsilateral breast 
where invasive cancer subsequently develops.  Patients who had their DCIS treated 
with surgery only are allowed to enter the study. 
4. 
Metastatic disease 
 
Hematological, Biochemical, and Organ Function: 
5. 
Inadequate bone marrow function (as indicated by any of the following):  
• 
Total white blood cell count (WBC) < 2500/mm3 (< 2.5 × 109/L) 
• 
Neutrophil count < 1500/mm3 (< 1.5 × 109/L) 
• 
Platelets < 100,000/mm3 (< 100 × 109/L) 
• 
Hemoglobin < 10 g/dL 
6. 
Impaired hepatic function (as indicated by any of the following): 
• 
Serum total bilirubin > 1.5 × upper limit of normal (ULN) 
• 
Alanine amino transferase (ALT) > 2.5 × ULN 
• 
Aspartate amino transferase (AST) > 2.5 × ULN  
• 
Alkaline phosphatase (ALP) > 2.5 × ULN  
7. 
Impaired renal function, as indicated by serum creatinine > 1.5 × ULN 
 
Other Study Drug-related Exclusion Criteria: 
8. 
Serious cardiac illness or medical conditions including but not confined to: 
• 
History of documented heart failure or systolic dysfunction (LVEF < 50%) 
• 
High-risk uncontrolled arrhythmias such as atrial tachycardia with a heart rate 
> 100/min at rest, significant ventricular arrhythmia (ventricular tachycardia), or 
higher-grade atrioventricular (AV) block (second-degree AV block Type 2 
[Mobitz 2] or third-degree AV block) 


   
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• 
Angina pectoris requiring anti-anginal medication 
• 
Clinically significant valvular heart disease 
• 
Evidence of transmural infarction on electrocardiogram (ECG) 
• 
Poorly controlled or uncontrolled hypertension (blood pressure consistently over 
140/90 mmHg, despite treatment) or history of hypertensive crisis or 
hypertensive encephalopathy 
9. 
Other concurrent serious diseases that may interfere with planned treatment 
including severe pulmonary conditions/illness 
10. Prior maximum cumulative dose of doxorubicin > 360 mg/m2 or maximum 
cumulative dose of epirubicin > 720 mg/m2 or equivalent 
11. Known hypersensitivity to trastuzumab, murine proteins, or excipients, or a general 
hypersensitivity to adhesives (Cohort B only) 
12. History of severe allergic or immunological reactions, for example, difficult to control 
asthma. 
 
General Exclusion Criteria: 
13. Pregnancy or lactation 
14. Unable or unwilling to comply with the requirements of the protocol, as assessed by 
the investigator 
15. Concurrent enrollment 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 
16. Major surgical procedure or significant traumatic injury within 14 days prior to the 
first dose of study treatment or anticipated need for major surgery during the course 
of study treatment except for breast cancer surgery for patient receiving study drug 
in the neoadjuvant setting.  Patients must be free of any clinically significant 
sequelae of prior surgery before they can receive their first dose of study treatment. 
17. More than 12 weeks between the end of the last chemotherapy cycle and the first 
dose of study treatment, in case these treatments are initiated sequentially.  This 
criterion does not apply to patients who are starting trastuzumab SC without 
previous or concurrent chemotherapy or concurrently with chemotherapy. 
18. Current peripheral neuropathy of Grade 3 or greater per the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), 
version 4.0 
 
No exceptions or waivers will be granted for the above listed inclusion and exclusion 
criteria. 


   
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4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
It is anticipated that approximately 2500 patients will be recruited into the study.  Eligible 
patients with HER2-positive EBC will be allocated to one of the two following cohorts at 
the investigator’s discretion:  
• 
Cohort A (approximately 1800 patients):  trastuzumab SC 600 mg via assisted 
administration into the thigh over a period of approximately 5 minutes using 
handheld syringes with hypodermic needles 
• 
Cohort B (approximately 700 patients):  trastuzumab SC 600 mg, first assisted, 
then self-administered into the thigh over a period of approximately 5 minutes using 
the SID.  For enrollment into Cohort B, patients need to be willing to self-administer 
the study drug from the SID based on personal instructions/training provided by an 
HCP during the first assisted administration in addition to a quick reference guide 
and an instructional animation describing the injection device handling and use, 
including how to respond if the SID loses sufficient contact with the body.  
 
4.3 
STUDY TREATMENT 
4.3.1 
Formulation, Packaging, and Handling 
The investigational medicinal product (IMP) for this study is trastuzumab SC 600 mg 
supplied as vial and SID formulations:  
• 
Cohort A:  RO 045.2317/F07, manual SC injection formulation:  trastuzumab SC 
600 mg/5 mL vial 
• 
Cohort B:  RO 045-2317/F06, device formulation:  trastuzumab SC 600 mg/5 mL 
prefilled, single-use injection device 
 
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. 
The drug product in the vials for manual injection (Cohort A) and in the SID (Cohort B) 
contains 120 mg/mL trastuzumab and 2000 U/mL rHuPH20 (manufactured in a Chinese 
hamster ovary 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 ± 0.3.  
The recommended storage conditions are 2−8°C protected from light for both 
trastuzumab SC formulations.  Batch-specific details and information on shelf-life are 
given in the packaging label. 
Trastuzumab for SC administration will be supplied by Roche.  Packaging of 
trastuzumab for SC 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.  


   
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For further details, refer to the Herceptin (RO 45-2317, Trastuzumab) IB. 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Preparation and Administration of Trastuzumab for SC 
Injection 
Cohort A:  Trastuzumab SC for manual injection will be supplied in a vial containing a 
ready-to-use solution with a nominal content of 600 mg of trastuzumab.  The solution is 
injected using a conventional handheld syringe fitted with a hypodermic needle.  Further 
information on the preparation and administration is provided as a separate instruction 
leaflet. 
Cohort B:  Trastuzumab SC is supplied in a SID.  The cartridge included in the device 
contains a nominal content 600 mg of trastuzumab.  Information on the preparation and 
use of the SID is provided in the quick reference guide supplied with the SID. 
The drug product must not be diluted and should be used according to the instructional 
leaflet provided separately.  The solution should not be administered at 2−8°C.  Details 
for equilibration of the device to room temperature can be found in the quick reference 
guide supplied with the SID. 
The total time that trastuzumab SC (for manual injection and in a SID) is stable outside 
the fridge is 6 hours.  Trastuzumab should be allowed to equilibrate prior to injection.  
The drug may be returned to the fridge if necessary, but it must be allowed to reach 
room temperature prior to administration, and the total time out of the fridge prior to 
administration must not exceed 6 hours. 
Patients will be enrolled into one of two cohorts at the investigator’s discretion.  
All study treatment administrations will occur in a hospital setting as follows: 
• 
Cohort A:  Trastuzumab SC 600 mg will be injected subcutaneously by an HCP into 
the thigh over a period of approximately 5 minutes using a handheld syringe with a 
gauge 25 or 27 hypodermic needle. 
• 
Cohort B:  Trastuzumab SC 600 mg will be injected subcutaneously into the thigh 
over a period of approximately 5 minutes using the SID.  The first administration will 
be assisted (performed by a HCP [physician or nurse]), and then following 
administrations may be self-administered into the thigh (if the patient is willing and 
judged competent by the HCP) over a period of approximately 5 minutes using the 
SID.  During HCP-assisted administration, the HCP will assist the patient to use the 
SID to self-administer the dose.  The HCP should moderate the level of assistance 
provided with an assessment of the patient’s competence.  Competent subjects will 
be asked if they are willing to continue by self-administration of the study drug from 
the SID.  Willing patients will be allowed to self-administer the remaining 
trastuzumab SC doses under the direct supervision of a HCP.  Patients assessed as 
not competent or are not willing to self-administer the study drug from the SID will 
have all the remaining trastuzumab SC doses administered by the HCP. 


   
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Those patients judged competent by the investigator and willing to self-administer 
remaining doses with the SID will be provided with training from the HCP during the 
first assisted administration and will be provided with instructional materials (a quick 
reference guide and an instructional animation describing the injection device 
handling and use, including how to respond if the SID loses sufficient contact with 
the body).   
Patients will remain onsite to be observed for a period of 6 hours after start of their 
first trastuzumab administration and for 2 hours after the start of each subsequent 
trastuzumab administrations.  Patients may be required to remain onsite for an 
extended period of time if considered clinically necessary by the investigator 
(e.g., emergence of AEs). 
In addition to the study assessments described in Appendix 1, all clinical AEs that 
occur during the observation period, onset and resolution dates and times of AEs, 
the collection of detailed information about premedications prior to trastuzumab 
administration, and in addition to the date, the onset and resolution time of treatment 
of AEs occurring during the observation time will be collected. 
The SID satisfaction questionnaire will only be completed by patients who have 
successfully completed a minimum of 2 self-administrations of the study drug in 
Cohort B.  
For SID usability monitoring purposes, the first 48 patients enrolled in Cohort B will 
have their SID use monitored and recorded on the SID monitoring questionnaire by 
the trained HCP or investigator, intended to collect information about aspects of use 
related to usability of the device (see Appendix 7).  
 
In the event of a SID failure which results in incomplete administration (injection of a 
portion of the full dose) to the patient, the missed portion of the trastuzumab SC dose 
may be manually administered from a vial.  An instruction leaflet will be provided that will 
explain how to assess the amount needed to inject from a vial in the event of a SID 
failure.  Subsequent doses should be administered using the SID.  Device failures must 
also be reported to the Sponsor as a Medical Device Complaint (see Section 5.4.4).  The 
device must then be returned via courier to Roche for assessment.  In case of multiple 
(> 1) device failures at different treatment cycles, the patient will revert to manual SC 
administrations of trastuzumab (using a conventional hand-held SC syringe) for all 
remaining cycles in order to complete 18 cycles in total as part of the study. 
Any injection-related symptoms must have resolved before the patient is discharged, 
unless deemed clinically insignificant by the investigator.  Patients who experience 
injection-related symptoms may be premedicated with paracetamol and antihistamines 
for subsequent injections. 


   
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4.3.2.2 
Dose and Schedule of Trastuzumab SC 
Trastuzumab SC treatment may be initiated after completion of neoadjuvant or adjuvant 
chemotherapy (sequentially), in combination with neoadjuvant or adjuvant paclitaxel or 
docetaxel chemotherapy (concurrently), or without adjuvant chemotherapy.  In case of 
sequential treatment, the interval between the last dose of chemotherapy and the first 
dose of trastuzumab SC should not be longer than 12 weeks.  For patients receiving 
trastuzumab SC with adjuvant chemotherapy, trastuzumab SC must be administered 
first, followed by the administration of chemotherapy.  For patients receiving trastuzumab 
SC without neoadjuvant or adjuvant chemotherapy, the start of trastuzumab SC should 
be within a maximum of 3 months following surgery. 
Patients in both cohorts will receive a fixed dose of 600 mg trastuzumab SC throughout 
the study, administered 3-weekly for a total of 18 cycles, unless disease recurrence, 
unacceptable toxicity, or patient withdrawal necessitates earlier treatment cessation.  
Hormonal therapy and radiotherapy (if applicable) may be given concomitantly with 
trastuzumab SC, as per local guidelines. 
Recommended chemotherapy regimens with trastuzumab to be followed in the adjuvant 
setting are as stated in the pivotal trials (see Table 1:  sequential trastuzumab; HERA 
and NCCTG N9831:  and concurrent trastuzumab; NSABP B31, B31 + N9831 and 
BCIRG 006).  In the neoadjuvant-adjuvant setting, clinical Study MO16432 (NOAH), 
trastuzumab was administered concurrently with chemotherapy. 
For neoadjuvant treatment, the following will be applied:  
• 
In patients with early breast cancer eligible for neoadjuvant treatment, trastuzumab 
SC should only be used concurrently with low-dose anthracycline regimens 
(maximum cumulative doses:  doxorubicin 180 mg/m2 or epirubicin 360 mg/m2). 
• 
If patients have been treated concurrently with low-dose anthracyclines and 
trastuzumab in the neoadjuvant setting, no additional cytotoxic chemotherapy 
should be given after surgery. 
• 
After the neoadjuvant phase (8 cycles) of trastuzumab SC, patients will undergo 
surgery without interruption of trastuzumab treatment.  After surgery, patients will 
receive additional 10 cycles of SC trastuzumab to complete 1 year of treatment with 
trastuzumab.  
• 
Surgery should be planned after dosing at Cycle 8 without interruption of 
trastuzumab treatment. 
 
4.3.2.3 
Dose Modifications, Interruptions, and Delays 
Administration of trastuzumab SC may be delayed to assess or treat adverse events, as 
detailed in Table 8.  


   
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Table 8 
Management of Trastuzumab-Related Toxicity 
Toxicity Related to Study Treatment 
Action 
Hematological and non-hematological, 
Grade 1 or 2 (excluding cardiac) toxicity 
Continue with study treatment (all medication in the 
cycle)  
Hematological and non-hematological, 
Grade 3 or 4 (excluding cardiac) toxicity 
Hold study treatment (all medication in the cycle) until 
recovery to Grade ≤ 2.  Toxicity resolved to Grade ≤ 2 
within a maximum of 5 weeks calculated from last 
administration:  Resume study treatment.  Toxicity did 
NOT resolve to Grade ≤ 2 within a maximum of 
5 weeks calculated from last administration:  
Discontinue trastuzumab permanently.  Take patient 
off study drug.  Continue treatment as deemed 
suitable by local investigator. 
Recurrence of non-hematological, Grade 
3 or 4 (excluding cardiac) toxicity upon 
re-challenge 
Discontinue trastuzumab permanently.  Take patient 
off study drug.  Continue treatment as deemed 
suitable by local investigator. 
Cardiac toxicity (significant 
asymptomatic drop in LVEF 
(≥ 10 percentage points from baseline 
and to a LVEF < 50%) 
Study treatment (all medication in the cycle) to be 
held, continued or resumed according to the algorithm 
depicted in Appendix 5. 
Cardiac toxicity (symptomatic congestive 
heart failure) 
Trastuzumab to be discontinued permanently (patient 
to be taken off study) 
Cardiac toxicity (other than significant 
asymptomatic LVEF drop or CHF) 
Actions must follow rules 1 to 3.  For 
non-hematological toxicities 
Hematological toxicity:  Neutropenia 
< 1.5 × 109/L 
Hold study treatment (all medication in the cycle) until 
neutrophils ≥ 1.5 × 109/L. 
 
For toxicity related to concurrently administered chemotherapy, specific 
instructions/actions should be followed in the relevant SmPC.  In the case of 
chemotherapy-related hematological or non-hematological toxicity, the following action 
should be applied: 
• 
Grade 1 or 2, continue trastuzumab treatment 
• 
Grade 3 or 4, hold trastuzumab treatment until recovery to ≤ Grade 2 
 
If the patient misses a dose of trastuzumab SC, then the usual dose should be given as 
soon as possible, with subsequent doses given every 3 weeks.  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 SC cycles in this study. 
Dose reductions are not permitted for toxicity.  Patients who experience injection-related 
symptoms may be premedicated with paracetamol and antihistamines for subsequent 
infusions/injections.  


   
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4.3.3 
Name of Additional Required Medication 
Not applicable. 
4.3.4 
Investigational Medicinal Product Accountability 
The investigator is responsible for the control of the drugs under investigation.  Adequate 
records for the receipt (e.g., Drug Receipt Record) and disposition (e.g., Drug 
Dispensing Log) of the IMP must be maintained.  Accountability and patient compliance 
will be assessed by maintaining adequate drug dispensing and return records.  
Accurate records must be kept for each IMP provided by the Sponsor.  These records 
must contain the following information: 
• 
Documentation of IMP shipments received from the Sponsor (date received, 
quantity, and batch number) 
• 
Disposition of unused IMP not dispensed to a patient 
• 
A Drug Dispensing Log must be kept current and should contain the following 
information:  
Identification of the patient to whom the IMP was dispensed 
The date(s), quantity, and batch number of the IMP dispensed to the patient 
 
4.3.4.1 
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. 
4.3.4.2 
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 


   
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• 
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); it is recommended to burn the vials and SIDs at 1200°C. 
• 
Name and signature of responsible person who discarded the IMP in a hazardous 
container for destruction 
 
4.3.5 
Post-Trial Access to Trastuzumab 
Trastuzumab SC will only be provided to study patients for the protocol-defined 
18 cycles.  Subsequent treatment will be at the investigator’s discretion and according to 
local practice.  
4.4 
CONCOMITANT THERAPY 
All concomitant medications and prior treatments for breast cancer 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 the following medications must be reported: 
• 
Breast cancer treatments (e.g., hormonal therapy) 
• 
Anti-cancer treatments given to treat a recurrence 
• 
Medications related to the treatment of serious AEs 
 
4.4.1 
Permitted Therapy 
In this study, trastuzumab SC treatment may be initiated after completion of neoadjuvant 
or adjuvant chemotherapy (sequentially), in combination with neoadjuvant or adjuvant 
paclitaxel or docetaxel chemotherapy (concurrently), or without adjuvant chemotherapy, 
or in combination with neoadjuvant chemotherapy followed by trastuzumab therapy for 
locally advanced (including inflammatory disease or tumors > 2 cm in diameter).  The 
choice of adjuvant chemotherapy will be at the investigator’s discretion and according to 
standard of care for EBC. 


   
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Any medication which is necessary for the management of side effects of trastuzumab 
may be used at the discretion of the investigator.  Paracetamol (acetaminophen), 
antihistamines, and other supportive medication may be used according to local clinical 
practice for the treatment of reactions associated with trastuzumab SC administration, 
including pyrexia. 
Adjuvant tamoxifen (with or without a gonadotropin-releasing hormone agonist) or an 
aromatase inhibitor may be administered to patients with hormone receptor (estrogen 
and/or progesterone receptor) positive disease according to local practice.  Adjuvant 
hormonal therapy and adjuvant radiotherapy (if indicated) may be given concomitantly 
with trastuzumab SC.  
Patients may have started bisphosphonate therapy for a licensed indication before 
entering the study, and if so, this may continue.  Bisphosphonate therapy (oral and IV 
only) can also be initiated during the study for the treatment of documented 
osteoporosis.  If started during the trial, the patient must be assessed for evidence of 
progression first.  The use of bisphosphonates for prevention of bone metastases is not 
allowed unless they become licensed for this indication during the study. 
Other permitted concomitant therapies include: 
• 
Supportive care, including transfusions, which should be prescribed according to 
local guidelines and the Investigator’s clinical judgment 
• 
Anti-emetic regimens may be used at the discretion of the investigator. 
• 
Growth factors (i.e., G- or GM-CSF) may be used as clinically indicated according to 
institutional guidelines.  
• 
Maintenance therapy for patients with chronic conditions, such as hypothyroidism, 
hypertension, diabetes, etc. 
• 
Radiotherapy 
 
Subcutaneous injections (e.g., insulin or heparin) are allowed as long as they are 
administered at a different injection site from that of the study drug (i.e., other than the 
thigh). 
4.4.2 
Prohibited Therapy 
The following treatments are not permitted during trastuzumab SC treatment: 
• 
Concurrent treatment with other systemic HER2-directed immunotherapy 
• 
Concurrent investigational agents of any type 
• 
Concurrent treatment of anthracyclines with trastuzumab in the adjuvant setting 
 


   
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4.5 
STUDY ASSESSMENTS 
4.5.1 
Description of Study Assessments 
4.5.1.1 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), and all medications (e.g., prescription 
drugs, over-the-counter drugs, herbal/homeopathic remedies, and nutritional 
supplements) used by the patient starting from the Screening visit. 
Demographic data will include age, gender, and self-reported ethnic origin. 
4.5.1.2 
Vital Signs 
Vital signs include blood pressure, heart rate, and temperature measurements at 
screening and at the Safety Follow-up visit, as well as pre- and immediately post-
trastuzumab SC administration at Cycles 1, 5, 9, 13, and 18.  Vital signs measurements 
will be taken while the patient is in a seated position. 
4.5.1.3 
Physical Examinations 
A general physical exam (including a general neurological exam, as clinically indicated) 
will be performed at screening, approximately 3-monthly during trastuzumab SC 
treatment (at Week 13/Cycle 5, Week 25/Cycle 9, Week 37/Cycle 13, and 
Week 52/Cycle 18), 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) or investigator’s routine practice.  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. 
4.5.1.4 
Electrocardiograms 
A standard 12-lead ECG needs to be performed as specified in Section 5.1.2 and in 
Appendix 1, Schedule of Assessments. 
4.5.1.5 
Performance status 
Performance Status (PS) will be evaluated using the Eastern Cooperative Oncology 
Group (ECOG) PS Scale (see Appendix 2).  The assessment will be performed at 
screening, approximately 3-monthly (every 4 cycles) during study treatment, and at the 
post-treatment Safety Follow-up visit, as specified in Appendix 1, Schedule of 
Assessments. 
4.5.1.6 
Other Clinical Safety Assessments 
Refer to Section 5.1.2 for a description of cardiac safety assessments and Section 5.2.1 
for instructions on documenting and handling adverse events.  


   
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4.5.1.7 
Laboratory Assessments 
4.5.1.7.1 
HER2 Testing for Eligibility 
To be eligible for the study, patients must have confirmed HER2 overexpression (by 
IHC) or HER2 gene amplification (by validated and approved methods at the local 
laboratories) in the invasive part of the tumor, defined as one of the following: 
• 
A score of 3+ by IHC  
• 
A positive ISH result 
 
HER2 should be assessed in specialized local laboratories with an accurate and 
validated assay according to recommendations outlined in the SmPC for trastuzumab IV 
(Herceptin).  HER2 status needs to be assessed prior to the first dose of study drug, but 
otherwise, there is no time limit for when this is to be performed.  
4.5.1.7.2 
Safety Laboratory Assessments 
All hematology and blood chemistry laboratory tests will be completed at local 
laboratories.  Normal ranges for a study site’s local study laboratory parameters must be 
supplied to the Sponsor before the study starts.  
Blood samples for hematology and biochemistry are scheduled at screening, on Day 1 of 
Cycles 9 (Week 25) and 18 (Week 52) of study treatment, and at the Safety Follow-up 
visit.  Screening safety laboratory tests should be completed within 28 days prior to the 
first study treatment and should allow for an evaluation of all laboratory exclusion criteria 
as outlined in Section 4.1.2.  Screening values should be used to confirm eligibility. 
• 
Hematology tests include:  hemoglobin, WBC and differential, ANC, and platelet 
count.  
• 
Biochemistry tests include:  creatinine, urea/blood urea nitrogen (BUN), serum 
ALT/glutamic pyruvic transaminase (SGPT), AST/serum glutamic oxaloacetic 
transaminase (SGOT), total bilirubin, ALP, albumin, sodium, potassium, and 
calcium.  
 
For the purposes of this study, no additional samples are scheduled.  However, 
additional assessments may be performed as per institutional practice, as clinically 
indicated.  Results for samples other than those specified above (and listed in 
Appendix 1, Schedule of Assessments) will only be collected if associated with an AE. 
4.5.1.7.3 
Pregnancy Testing and Contraception 
Females of childbearing potential (defined as premenopausal and not surgically 
sterilized or less than 1 year after the onset of menopause) will undergo a serum 
pregnancy test within 7 days prior to the first dose of trastuzumab SC.  A positive 
pregnancy test at screening will lead to the exclusion of the patient.  Subsequent 
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 trastuzumab SC.  


   
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Women of childbearing potential and male participants with partners of childbearing 
potential must agree to use contraception during study treatment and for at least 
7 months post-study treatment.  Acceptable methods of contraception include: 
• 
Complete abstinence* (if consistent with the preferred and usual lifestyle of the 
patient).  Note:  periodic abstinence (e.g., calendar, ovulation, symptothermal 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
• 
Male sterilization* (with appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate; for female patients, the vasectomized male partner should 
be the sole partner. 
• 
Non-hormonal intrauterine device or intrauterine system  
• 
Barrier method: 
• 
Condom with spermicidal foam/gel/film/cream/suppository 
• 
Occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository 
*Considered highly-effective forms of contraception resulting in a low failure rate 
(i.e., less than 1% per year) 
 
The following birth control methods are not considered acceptable in this study: 
• 
Hormonal contraceptives (for females participating in the study) 
• 
Periodic abstinence (e.g., calendar, ovulation, symptothermal post-ovulation 
methods) and withdrawal 
• 
Single barrier methods (e.g., spermicides alone) 
 
4.5.1.7.4 
Immunogenicity and PK assessments (Subset of Cohort B) 
Immunogenicity of trastuzumab SC and recombinant human hyaluronidase (rHuPH20) 
will be tested in a subset of patients enrolled in Cohort B at select sites.  Sites 
interested in participating in the immunogenicity assessments will be selected and 
approved by Roche.  Serum samples (for anti-trastuzumab antibody analyses) and 
plasma samples (for anti-rHuPH20 antibody analysis) will be drawn at baseline (after 
eligibility is confirmed, i.e., just before the first study treatment), on-treatment (pre-Cycle 
9 dose, Week 25), and at least 6 months after the end of treatment.  Since the 
evaluation of anti-trastuzumab assay results requires corresponding serum trastuzumab 
concentrations, the anti-trastuzumab analyses will be coupled with PK assessments. 
The total blood loss for immunogenicity testing during the study is 18 mL.  At each of the 
three assessment timepoints, approximately 6 mL of blood will be required for the 
rHuPH20 antibody analysis and trastuzumab antibody analysis, including confirmation of 
the presence of trastuzumab and the titer in serum. 


   
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The date/time of immunogenicity and PK sampling must be carefully recorded in all 
cases.  On non-dosing days, the timing of sampling during the day will be at the 
investigator’s discretion.  Fasting is not a requirement for sampling. 
In the event of an injection-related reaction, the blood samples for immunogenicity 
testing must be drawn within 8 hours following the reaction (see Appendix 1, Schedule of 
Assessments).  
The serum and plasma samples (for anti-trastuzumab antibody and anti-rHuPH20 
antibody analyses, respectively) will be stored on dry ice until shipment in batches can 
be arranged to the designated central laboratory.  Details of sampling, handling, storage, 
and shipping are described in the study’s Sample Handling and Logistics Manual. 
A three-tiered analytical testing approach will be performed for HAHAs against both 
trastuzumab and rHuPH20.  Screening for the potential emergence of antibodies will use 
bridging immunoassays.  Any samples testing positive will be subsequently re-tested in 
a confirmatory assay.  Finally, confirmed positives will be tested for the presence of 
neutralizing antibodies.  
Samples will be kept for re-testing (if required) at the central laboratory and will be 
destroyed no later than 12 months after the Clinical Study Report (CSR) is finalized. 
4.5.1.8 
Breast Cancer Evaluations and Follow-Up 
Patients will be assessed for residual disease (as per institutional practice) not more 
than 4 weeks before the first dose of study drug.  Screening radiologic examinations to 
exclude metastatic disease should include a bilateral mammogram or breast MRI, and 
chest X-ray (CXR) or breast ultrasound.  Should a previously taken chest CT or PET 
scan be available, then these results can also be used for eligibility assessment.  These 
imaging tests do not need to be repeated if completed within 12 months prior to the first 
study treatment.  In addition, bone scan and liver imaging should be performed if 
clinically indicated.  During study treatment and the post-treatment follow-up period, 
patients will be followed for disease recurrence according to the American Society of 
Clinical Oncology (ASCO) 2006 Guideline for Breast Cancer Follow-up 
(Khatcheressian et al. 2006) or investigator’s routine practice (see Appendix 1, 
Schedule of Assessments).  In brief, the ASCO 2006 guidelines recommend: 
• 
History/physical examination:  every 3−6 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 led to diagnosis, but no earlier than 6 months after definitive 
radiation therapy.  Subsequent mammograms should be obtained as indicated for 
surveillance of abnormalities. 
• 
Pelvic examination:  regular gynecologic follow-up is recommended for all women.  
Patients who receive tamoxifen should be advised to report any vaginal bleeding to 
their physicians. 


   
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• 
Routine blood tests:  full blood counts and liver function tests are not recommended. 
• 
Imaging studies:  chest x-ray, bone scans, liver ultrasound, computerized 
tomography (CT) scans, fluorodeoxyglucose-positron emission tomography 
(FDG-PET) scans, and breast magnetic resonance imaging (MRI) are not 
recommended. 
• 
Tumor markers:  CA 15-3, CA 27.29, and CEA are not recommended. 
• 
Accordingly, assessments for recurrence/relapse will be primarily by physical 
examination and questioning the patient, with additional tests as clinically indicated 
and according to routine practice. 
4.5.1.8.1 
Assessment of Recurrence 
Disease-free survival (DFS) is a secondary endpoint in this study.  DFS is defined as 
time from the date of first treatment to the date of local, regional, or distant recurrence; 
contralateral breast cancer; or death due to any cause. 
The diagnosis of a first breast cancer recurrence or second primary cancer can be made 
only when clinical, radiological, and laboratory criteria are met.  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.  
Some patients may develop 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 in such patients. 
The earliest date of diagnosis of recurrent disease should be used and recorded.  This 
should be based on clinical, radiological, histological, or cytological evidence.  The 
recurrence of disease has to be backdated to the date of the first diagnosis of lesion 
(i.e., an objective finding), not to the date of occurrence of the first symptom. 
Recurrent disease includes:  local, regional, distant recurrence and contralateral breast 
cancer. 
a) Local recurrence:  In the ipsilateral breast after surgery: 
In case of conservative surgery (lumpectomy):  defined as evidence of tumor, 
except lobular carcinoma in situ, in the ipsilateral breast after mass excision.  
In case of mastectomy, local recurrence (other than ipsilateral breast after 
lumpectomy):  defined as evidence of tumor in any soft tissue or skin of the 
ipsilateral chest wall after mastectomy.  
b) Regional recurrence:  Defined as the development of tumor in the ipsilateral 
internal mammary and/or ipsilateral axillary lymph nodes, or extranodal soft tissue of 
the ipsilateral axilla.  Regional recurrence does not include supraclavicular lymph 
nodes or tumor in the opposite breast. 
c) Contralateral invasive breast cancer:  Defined as development of invasive lobular 
or invasive ductal cancer in the contralateral breast (Hudis et al. 2007). 


   
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d) Distant recurrence:  Defined as evidence of tumor in any area other than those 
described in subsections a) to c) above and the following: 
• 
Skin, subcutaneous tissue, and lymph nodes (other than local or regional) 
• 
Bone  
• 
Bone marrow 
• 
Lung  
• 
Liver 
• 
Central nervous system 
 
4.5.1.9 
Treatment Satisfaction with the SID 
Patients in Cohort B, who went on to self-administration of the study drug will be asked 
to rate their overall satisfaction with trastuzumab SC administrations using the SID by 
completing a five-item SID satisfaction questionnaire.  The questionnaire will be 
completed after the 4th cycle and at the Safety Follow-up visit (or at least 1 day after the 
last trastuzumab SC injection), after a minimum of 2 successful self-administrations of 
the study drug.  
The questionnaire includes five items (level of comfort with the self-administration after 
training by a physician/nurse, convenience and ease of use, confidence with the 
administrations, overall satisfaction, and feedback on whether the SID would be chosen 
in the future), which will be rated on a 5-point Likert scale (from 1 = strongly disagree to 
5 = strongly agree; see Appendix 6). 
Completion of the questionnaire should take about 5 minutes.  
For patients in Cohort B who discontinue study treatment prematurely for any reason, 
all efforts should be made to complete this questionnaire as part of the final assessment. 
4.5.1.10 
Pharmacoeconomic Assessments and Medical Care Utilization 
In some countries and sites, MCU (e.g., time and motion) and/or pharmacoeconomic 
substudies will be conducted.  Details of the substudies will be described in separate 
protocols. 
4.5.2 
Timing of Study Assessments 
4.5.2.1 
Screening and Pre-treatment 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.   
After consenting, patients will undergo the following screening procedures and 
assessments within 28 days prior to the first study treatment (denoted as Day 1), unless 


   
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otherwise specified or unless the procedure/assessment has already been conducted 
during this time period as part of the patient’s routine clinical care: 
• 
Demographics, complete medical history, and concomitant medications 
• 
HER2 determination (Note:  HER2 status needs to be assessed prior to the first 
dose of study drug, but otherwise there is no time limit for when this is to be 
performed.) 
• 
General physical examination (including neurological examination, if clinically 
indicated) 
• 
Measurement of vital signs (blood pressure, heart rate, and temperature), weight, 
and height 
• 
ECOG performance status 
• 
Cardiac assessments 
• 
Standard 12-lead ECG 
• 
LVEF is to be assessed within 14 days prior to the first study treatment if 
patients received anthracycline or 28 days prior to first study treatment for 
patients who received anthracycline-free regimens.  Assessment should be 
performed by echocardiography (ECHO), multigated acquisition (MUGA) scan, 
or MRI (Note:  ECHO is the preferred method). 
• 
Cardiac signs and symptoms 
• 
Clinical laboratory testing (hematology, serum biochemistry) with results available 
prior to enrollment into the study to confirm patient eligibility (to be done in the 
allowed screening period of 28 days). 
• 
Women of childbearing potential (defined as premenopausal, less than 1 year after 
the onset of menopause, or not surgically sterilized) will undergo a serum pregnancy 
test (β-HCG) within 7 days prior to the first dose of study treatment. 
• 
Cohort B (selected sites only):  Blood sample for immunogenicity testing (includes 
trastuzumab PK assessment) 
• 
Imaging scan to exclude residual/recurrent disease per Section 4.5.1.8 
(Note:  results of imaging scans performed prior to obtaining informed consent and 
within 12 months prior to Day 1 may be used, i.e., such tests do not need to be 
repeated for screening.)  
• 
Assessment of any SAEs caused by a protocol-mandated procedure 
 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment (also referred to as registration).  The investigator 
will maintain a screening log to record details of all patients screened and to confirm 
eligibility or document reasons for screening failure, as applicable.  Data of patients who 
fail screening will not be entered into the eCRF and the clinical trials database. 
Eligible patients will be allocated to either Cohort A or Cohort B at the investigator’s 
discretion.  For enrollment into Cohort B, patients need to be willing to self-administer 


   
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the study drug based on the instructions for use supplied with the SID and personal 
instructions provided by an HCP during the first assisted administration.  
Upon enrollment, patients will be assigned a unique study patient identification number.  
A Patient Enrollment List must be maintained by the investigator.  Enrollment and the 
start of study medication (Day 1) occur on the same day. 
Please see Appendix 1 for the schedule of screening and pretreatment assessments. 
4.5.2.2 
Assessments during Treatment 
All assessments must be performed on the day of the specified visit, unless a time 
window is specified in the schedule of assessments (see Appendix 1).  Assessments 
scheduled on the day of study treatment administration should be performed prior to 
administration of study treatment, unless otherwise noted in the schedule of 
assessments. 
The following assessments must be performed prior to the respective treatment visits, so 
that results are available prior to dosing:  hematology and biochemistry, LVEF, and 
routine breast cancer follow-up assessments. 
Patients will undergo the following assessments during the study treatment period:  
Assessments performed at each treatment visit: 
• 
Assessment of AEs (including SAEs) 
• 
Observation time for patients in Cohort B 
• 
SID monitoring for subgroup of patients in Cohort B 
• 
Treatment compliance 
• 
Concomitant medication 
• 
Survival follow-up 
 
Assessments performed at specified intervals: 
• 
Routine breast cancer follow-up, performed according to the ASCO 2006 Guideline 
for Breast Cancer Follow-up (Khatcheressian et al. 2006) or investigator’s routine 
practice and reported every 6 months or per institutional standard practices (see 
Section 4.5.1.8) 
• 
General physical examination (including neurological examination, if clinically 
indicated) will be performed on a 3-monthly basis (every 4 cycles). 
• 
Weight will be measured for all patients at screening.  For Cohort B patients 
participating to immunogenicity and PK testing at Cycle 9 (Week 25). 
• 
Vital signs measurement (blood pressure, heart rate, and temperature) pre- and 
immediately post-trastuzumab SC administration on a 3-monthly basis (every 
4 cycles; i.e., at Cycles 1, 5, 9, 13, and 18). 


   
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• 
Cardiac assessment (ECG, LVEF, and cardiac signs and symptoms) and evaluation 
of ECOG performance status performed on a 3-monthly basis (every 4 cycles); 
• 
Hematology and biochemistry at Cycles 9 (Week 25) and 18 (Week 52); 
• 
Blood samples for immunogenicity and PK testing (a subset of Cohort B patients at 
selected study sites) prior to Cycle 9 (Week 25) 
• 
SID satisfaction questionnaire after the 4th treatment cycle (Cohort B patients who 
have successfully completed a minimum of 2 self-administrations of the study drug) 
• 
Pregnancy test completed as clinically indicated 
 
Please see Appendix 1 for the schedule of assessments performed during the treatment 
period. 
4.5.2.3 
Assessments at Treatment Completion/Early Termination:  
Safety Follow-Up Visit 
Patients who complete the study treatment period (18 cycles of trastuzumab SC) or 
discontinue the study treatment early will be asked to return to the clinic 4 weeks after 
their last dose of trastuzumab SC for a Safety Follow-up visit.  The following 
assessments will be completed at the Safety Follow-up: 
• 
Physical exam (including neurological examination, if clinically indicated) 
• 
Vital signs (blood pressure, heart rate, and temperature), ECOG performance status 
• 
Assessment of AEs (including SAEs) and concomitant medication 
• 
Cardiac safety assessments, if clinically indicated (see Section 5.1.1.2 for details) 
• 
Clinical laboratory testing (hematology and serum biochemistry)  
• 
SID satisfaction questionnaire (Cohort B patients only who have successfully 
completed a minimum of 2 self-administrations of the study drug) at least 1 day after 
the last trastuzumab SC injection 
 
4.5.2.4 
Post-treatment Follow-up Visits (minimum 5 years) 
All patients will be followed-up for cancer recurrence and survival till study end (i.e., until 
all patients have had a minimum 5-year follow-up) yearly or at higher frequency based 
on the site standard of care.  The duration of follow-up will be at least 5 years after the 
last study treatment or until withdrawal from the study, lost to follow-up, or death, 
whichever occurs first.  During this post-treatment follow-up period, patients will undergo 
the following assessments: 
• 
Breast cancer follow-up according to the ASCO 2006 Guideline for Breast Cancer 
Follow-up (Khatcheressian et al. 2006) and reporting every 6 months or as per 
institutional standard practices (see Section 4.5.1.8 for details) 
• 
Blood samples for immunogenicity and PK analyses will be collected from a subset 
of Cohort B patients (at selected sites only) 6 months after their last study 
treatment. 


   
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• 
Patients’ weight must also recorded 6 months after their last study treatment if 
participating to immunogenicity and PK testing. 
• 
Pregnancy test as clinically indicated up to 7 months after last study treatment 
• 
AE follow-up:  After initiation of study drug, all AEs/SAEs (except unrelated non-
cardiac AEs in the follow-up period), regardless of relationship to study drug, will be 
reported until study closure.  The investigator does not need to actively monitor 
subjects for AEs 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). 
• 
Concomitant medications:  Only breast cancer treatments (e.g., endocrine therapy), 
anti-cancer treatments given to treat a recurrence, and medications related to the 
treatment of SAEs will be recorded; refer to Section 4.4 for details. 
• 
Cardiac safety assessments will be performed at 6, 12, and 24 months and at yearly 
intervals until 5 years after treatment cessation (see Section 5.1.1.2 for details); 
• 
Survival:  After disease progression, patients will be managed as per local practice 
and followed for survival only. 
 
After study treatment completion (or early discontinuation), AEs should be followed as 
outlined in Section 5.5 and Section 5.6. 
Please see Appendix 1 for the schedule of follow-up assessments. 
4.5.2.5 
Assessments at Unplanned Visits 
Assessments other than those specified in Appendix 1, Schedule of Assessments, may 
be performed as clinically indicated and need to be adequately documented.  
4.6 
PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
The investigator has the right to discontinue a patient from study drug or withdraw a 
patient from the study at any time.  In addition, patients have the right to voluntarily 
discontinue study drug or withdraw from the study at any time for any reason.  Patients 
should be informed of circumstances under which their participation may be terminated 
by the investigator or the study Sponsor without the patient’s consent and in case of 
such withdrawal, the reason(s) for withdrawal must be documented and explained to the 
patient. 
Patients have the right to withdraw from the study at any time for any reason.  Should a 
patient decide to withdraw, all efforts should be made to complete and report the 
observations prior to withdrawal as thoroughly as possible.  Patients will not be followed 
for any reason after consent has been withdrawn.   


   
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4.6.1.1 
Discontinuation from Study Drug 
Reasons for study drug discontinuation may include, but are not limited to the following: 
• 
Withdrawal of consent by the patient 
• 
Pregnancy 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if she or he continues receiving the study drug 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Intercurrent illness 
• 
AE(s) 
• 
Treatment failure 
• 
Protocol violation 
• 
Lack of compliance with the study and/or study procedures (e.g., dosing instructions 
or study visits) 
• 
Cure 
 
Patients refusing further study treatment should be asked if they can still be contacted 
for further information after treatment cessation.  The outcome of that discussion should 
be documented in both the medical records and in the eCRF. 
Patients who discontinue study treatment prematurely due to lack of tolerability will be 
clinically managed as per local practice and followed as outlined in the Schedule of 
Assessments, Appendix 1.  If the reason for treatment discontinuation is an AE, the 
principal specific event will be recorded in the eCRF.  
All prematurely withdrawn patients who have received at least one dose of trastuzumab 
should continue to be monitored for cardiac function as described in the Herceptin 
SmPC, within or outside the study, as appropriate. 
4.6.1.2 
Withdrawal from Study 
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Withdrawal of consent by the patient 
• 
Treatment failure 
• 
Protocol violation 
 
An excessive rate of withdrawals can render the study non-interpretable; therefore, 
unnecessary withdrawal of patients should be avoided, and all withdrawals should 
undergo a complete final evaluation at the time of termination, which should include 
documentation and an explanation of the reason for withdrawal. 
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 


   
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appropriate eCRF.  If lost to follow-up, the investigator should contact the patient or a 
responsible relative by telephone followed by registered mail or through a personal visit 
to establish as completely as possible the reason for the withdrawal. 
Enrolled patients who are prematurely discontinued from the study will not be replaced, 
irrespective of the reason for withdrawal.  
4.6.2 
Study and Site Discontinuation 
The Sponsor and study Steering Committee have the right to terminate the study at any 
time.  Should this be necessary, the required procedures will be implemented after 
review and consultation with the Steering Committee.  In terminating the study, Roche 
and the investigators will assure that adequate consideration is given to the protection of 
the patient’s interests.  The appropriate IEC and Regulatory Agencies will be informed 
accordingly. 
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: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Noncompliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
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, 
adverse events, 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, approximately 3-monthly (every 4 cycles) 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) or investigator’s routine practice during the 5-year 
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, SC injection sites will be checked at every visit, and blood 
pressure will be measured before and after trastuzumab SC administration every 4 
cycles, as specified in Appendix 1, Schedule of Assessments. 


   
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Adverse events 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 will also be monitored, documented, and 
reported; refer to Section 5.4.2 and Section 5.5 for details on SAE reporting and follow-
up requirements, respectively.  All AEs and SAEs (including patients’ symptoms and 
signs of toxicity and clinically significant hematological and biochemical parameters) will 
be graded according to National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.0 (see Appendix 5).  Changes in concomitant 
medication will be recorded at each study visit. 
5.1.1.1 
Observation Time Assessment 
In addition to the study assessments described in Appendix 1, all clinical AEs that occur 
during the observation period will be collected for all patients in Cohort B (within 6 hours 
after start of the first trastuzumab administration or within 2 hours after start of following 
trastuzumab administrations).  Data collected during the observation period will include:  
Frequency, incidence, and grade of AEs; onset and resolution times of AEs 
(dd:mm:yyyy:hh:mm); outcome of AEs; and details of treatments provided following AEs 
during the observation period. 
5.1.1.2 
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 SC treatment (at Week 13/Cycle 5, Week 25/Cycle 9, Week 
37/Cycle 13, and Week 52/Cycle 18; with the results available prior to trastuzumab 
administration) and then at 6, 12, and 24 months, and 3, 4, and 5 years after treatment 
cessation (see Appendix 1, Schedule of Assessments).  LVEF assessment should be 
performed at the Safety Follow-up visit (4 weeks after the end of treatment) only if 
clinically indicated. 
5.1.1.3 
LVEF Assessment 
The screening LVEF assessment should be performed within 14 days for prior 
anthracycline use or within 28 days prior to the first trastuzumab SC administration for 
anthracycline-free regimens, and the LVEF must be  ≥ 55% for the patient to be eligible 
for participation in this study.  The method of assessment (echocardiography, 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 4.  In addition, any patient who develops clinical signs or 
symptoms suspicious of cardiac failure at any time during the study should undergo an 


   
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LVEF assessment immediately.  If a patient has an LVEF result between 45%−49%, a 
drop of  ≥ 10% and is symptomatic, or is a patient for whom the study drug was 
permanently stopped due to a significant drop in LVEF, then a repeat LVEF should be 
performed as clinically indicated, with a minimum repeat LVEF within 3 weeks. 
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 (Appendix 5) and the New York Heart Association 
(NYHA) functional classification (Appendix 3). 
5.1.2 
Management of Specific Adverse Events 
Cardiac safety will be monitored throughout the study, as described in Section 5.1.1.2.  
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% may require temporary or permanent cessation of 
trastuzumab in accordance with the treatment continuation/discontinuation algorithm 
shown in Appendix 4.  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 4.3.3).  
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events; measurement of 
protocol-specified safety laboratory assessments; measurement of protocol-specified 
vital signs; and other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 


   
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5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.8 and 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 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.1.1 
Laboratory Test Abnormalities 
Local laboratories will be used for all safety laboratory tests.  Laboratory test reports 
should be included in the patient chart and made available for routine monitoring and 
source document verification. 
Any treatment-emergent abnormal laboratory result that is clinically significant should be 
recorded as a single diagnosis on the AE page in the eCRF.  Clinical significance is 
defined as meeting one or more of the following conditions: 
• 
Accompanied by clinical symptoms 
• 
Leading to a change in study medication (e.g., dose modification, interruption, or 
permanent discontinuation) 
• 
Requiring a change in concomitant therapy (e.g., addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy, or 
treatment) 
 
Laboratory test value abnormalities that are not considered clinically significant should 
not be recorded as AEs in the eCRF.  Laboratory test results obtained at timepoints 
other than those specified in Appendix 1 will only be recorded on the laboratory results 
e-form of the eCRF, if they are associated with an AE. 
Any laboratory result abnormality fulfilling the criteria for an SAE should be reported as 
such, in addition to being recorded as an AE in the eCRF. 


   
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5.2.2 
Serious Adverse Events (Immediately Reportable to Roche) 
A SAE is an experience that suggests a significant hazard, contraindication, side effect, 
or precaution.  It is any AE that at any dose fulfils at least one of the following criteria: 
• 
Fatal (i.e., the adverse event actually causes or leads to death) 
• 
Life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This 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 adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The term sudden death should be used only when the cause is of a cardiac origin as per 
standard definition.  The terms death and sudden death are clearly distinct and must not 
be used interchangeably. 
Please refer to Section 5.4 and Section 5.5 for details on how these events should be 
reported and followed up, respectively. 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe, or according to NCI-CTCAE 
criteria; see Section 5.3.3); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings).  Severity and 
seriousness need to be independently assessed for each adverse event recorded on the 
eCRF.  Serious adverse event s 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). 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.4 to Section 5.6.  


   
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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).   
The investigator is also responsible for reporting medical device complaints, regardless 
whether they are associated with adverse events or not (see Section 5.4.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported 
(e.g., serious adverse events related to invasive procedures such as biopsies).  All other 
adverse events will be recorded as medical history. 
After initiation of study drug, all AEs/SAEs (except unrelated non-cardiac AEs in the 
follow-up period), regardless of relationship to study drug, will be reported until study 
closure.  The investigator does not need to actively monitor subjects for AEs 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). 
Any injection-site reactions are considered to be related AEs/SAEs and should be 
reported accordingly. 
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 
Eliciting Adverse Event Information 
A consistent methodology of nondirective questioning should be adopted for eliciting 
adverse event information at all patient evaluation time points.  Examples of 
non-directive questions include the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?”  
 
5.3.3 
Assessment of Severity of Adverse Events 
The intensity of all adverse events will be graded according to the NCI-CTCAE, version 
4.0 on a five-point scale (Grade 1 to 5) and reported in detail on the eCRF.  
Table 9 will be used for assessing severity for AEs that are not specifically listed in the 
NCI-CTCAE. 


   
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Table 9 
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 adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
For patients receiving trastuzumab SC concurrently with adjuvant chemotherapy, 
causality will be assessed individually for each therapy. 


   
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5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct English medical terminology/concepts when recording 
AEs on the Adverse Event eCRF.  Colloquialisms and abbreviations should be avoided. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
For all adverse events, 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, 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 adverse events occurring 
secondary to an initiating event that are separated in time should be recorded as 
independent events on the Adverse Event eCRF.  
For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by a mild, nonserious infection, only neutropenia 
should be reported on the eCRF. 
• 
If neutropenia is accompanied by a severe or serious infection, both events should 
be reported separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 


   
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Recurrence of breast cancer (as defined in Section 4.5.1.8.1) 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 AE 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 adverse event 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 adverse event is one that resolves between patient evaluation time points 
and subsequently recurs.  Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
should be reported as an adverse event if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 times the upper limit of normal [ULN] 
associated with cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded 
on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 


   
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potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result should 
be reported as an adverse event if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either an elevated 
total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  
Therefore, investigators must report as an adverse event the occurrence of either of the 
following: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
 


   
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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, as a serious AE 
(see Section 5.4.2). 
5.3.5.7 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur prior to study 
closure that are attributed by the investigator solely to progression of EBC should be 
recorded only on the Death eCRF page.  All other on-study deaths, regardless of 
relationship to study drug, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 5.4.2).  
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 pre-existing heart disease, within 1 hour of the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should 
be replaced by the established cause of death. 
During study survival follow-up, deaths attributed to progression of EBC should be 
recorded only on the Death eCRF page. 
5.3.5.8 
Pre-existing Medical Conditions 
A pre-existing 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 pre-existing medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the pre-existing condition has changed by including applicable descriptors (e.g., 
“more frequent headaches”). 
5.3.5.9 
Lack of Efficacy or Worsening of the Underlying Condition 
Medical occurrences or symptoms of deterioration that are anticipated as part of the 
patient’s underlying breast cancer 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 
breast cancer on the Adverse Event eCRF, it is important to convey the concept that the 


   
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condition has changed by including applicable descriptors (e.g., “accelerated breast 
cancer”). 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  The determination of clinical progression 
will be based on objective evidence and/or symptomatic deterioration.  Every effort 
should be made to document progression using objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event. 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Section 5.2.2), except as outlined below.   
The following hospitalization scenarios are not considered to be serious adverse events: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study drug administration)  
• 
Hospitalization for a pre-existing condition, provided that all of the following criteria 
are met: 
• 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
• 
The patient has not suffered an adverse event 
• 
Hospitalization due solely to progression of the underlying cancer 
 
5.3.5.11 
Overdoses 
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied.  An overdose or incorrect administration of study drug is not 
an AE unless it results in untoward medical effects.   
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF.  
All adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF.  If the associated adverse event fulfils 
serious criteria, the event should be reported to the Sponsor within 24 hours after 
learning of the event (see Section 5.4.2). 


   
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5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
The investigator must report the following events to the Sponsor within 24 hours after 
becoming aware of the event, regardless of relationship to study drug: 
• 
SAEs (see definition in Section 5.2.2) 
• 
Pregnancies (for female study patients and female partners of male study patients) 
• 
Device complaints 
 
Investigators must also comply with local requirements for reporting SAEs to the local 
health authority and EC. 
Serious adverse events regardless of the relationship to the study drug MUST be 
collected and reported regardless of the time elapsed from the last study drug 
administration, even if the study has been closed.  All participating investigators and the 
respective independent Ethics Committees (ECs) will be notified of all Suspected 
Unexpected Serious Adverse Reactions (SUSARs) that are reported during the study.  
An AE only qualifies as a SUSAR when all of the following conditions are met: 
• 
The event is serious (SAE);  
• 
The event is deemed related to the study drug, according to the criteria provided in 
Section 5.3.4. (Note:  any suspicion of a causal relationship should lead to an 
assessment of ‘related’); 
• 
When assessed against the known safety profile of trastuzumab SC (as described in 
the IB), the event is considered unexpected (not foreseen in the IB).  
 
When all patients at a particular site are off treatment as defined by the protocol:  
• 
Individual SUSAR reports originating in that particular trial will be forwarded to all 
participating investigators and the IECs associated with their sites, on an expedited 
basis; 
• 
Individual SUSARs considered to be a significant safety issue and/or which result in 
Roche recommending a change to the Informed Consent Form (ICF), will be 
reported in an expedited manner to all investigators and reviewing IECs; 
• 
SUSAR reports originating from other trials using the same IMP will be provided as 
six-monthly SUSAR Reports (SSRs) to all investigators and IECs where long-term 
follow-up studies are carried out. 
 
5.4.1 
Emergency Medical Contacts 
Medical Monitor (Roche Medical Responsible) Contact Information  
Primary Contact 
Medical Monitor: 
 M.D. 
Telephone No.: 
 
Mobile Telephone No.: 
 
 


   
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Secondary Contact 
Medical Monitor: 
Dr. 
 M.D. 
Telephone No.: 
+ 650 225-1000 
Office Telephone No.:
 
To ensure the safety of study patients, an Emergency Medical Call Centre 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 Medical Call Centre Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk and 
Medical Monitor contact information will be distributed to all investigators (see "Protocol 
Administrative and Contact Information & List of Investigators").  
5.4.2 
Reporting Requirements for Serious Adverse Events  
For reports of serious adverse events, 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 or its designee by the EDC system. 
In the event that the EDC system is unavailable, a paper Serious Adverse Event 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.   
The investigator should report all complaints relating to the medical device used to 
administer the study treatment to Roche.  The investigator must document as much 
information as possible (based on the Medical Device Complaint Form) including the 
batch number and expiration date of the device and forward this to Roche Safety Risk 
Management or its designee within 24 hours of becoming aware of the complaint.  The 
investigator may also be requested to forward defective medical device samples to 
Roche.  
If the medical device complaint results in an AE, the information should be captured on 
the patient eCRF.  If the medical device complaint results in an SAE, the investigator 
should also complete an SAE Reporting Form and forward it to Roche Safety Risk 
Management within 24 hours of becoming aware of the event. 
According to Roche standard procedures, all AE reports/complaints from the use of 
investigational medicinal products (IMPs) that are associated with a Medical Device 
which is used to administer the IMP must be forwarded to Drug Safety and all AE 
reports/complaints associated with a Medical Device, and all Medical Device SAEs must 


   
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be forwarded to the Local Complaint Manager/relevant department for complaint 
management.  In addition, all medical device SAEs need to be reported within 24 hours 
to Roche Safety Risk Management or its designee. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
For women of childbearing potential (defined as premenopausal, less than 1 year after 
the onset of menopause or not surgically sterilized), appropriate contraceptive measures 
are mandatory during study treatment (see Section 4.5.1.7.3).  Based on 
pharmacokinetic 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 the 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").  As soon as the EDC system is operating, the 
Pregnancy Report eCRF will be completed. 
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 
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In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1. 
5.4.3.3 
Abortions 
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers spontaneous abortions to be medically significant events), recorded 
on the Adverse Event eCRF, and reported to the Sponsor within 24 hours after learning 
of the event (see Section 5.4.2).   
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient exposed to study drug should be classified as a serious adverse event, 
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 Medical Device Complaints 
The investigator must report all medical device complaints to Roche Safety Risk 
Management.  The investigator should document as much information as possible on 
the Medical Device Complaint Form, including the product batch number and expiration 
date and forward this to Roche Safety Risk Management within 24 hours of knowledge 
of the complaint.  The investigator may also be requested to forward defective medical 
device samples to Roche. 
If the medical device complaint results in an AE, the Medical Device Complaint eCRF 
must be completed and submitted through the EDC within 24 hours after learning of the 
event.  The AE must be reported on the Adverse Event eCRF.  If the medical device 
complaint results in an SAE, the investigator should also complete an SAE Reporting 
Form and forward it to Roche Safety Risk Management within 24 hours of knowledge, as 
outlined in Section 5.4.2. 
In the event of a device failure, the complaint must be reported to Roche Safety Risk 
Management.  The device must also be returned via courier to Roche for assessment.  
Supplemental dosing requirements for the patient will be assessed by the investigator as 
per the instructions provided.  In the case of a patient experiencing more than one 
device failure the patient will revert to SC trastuzumab for all remaining cycles to 
complete 18 cycles in total as part of the study. 
The investigator should report all complaints relating to the medical device used to 
administer the study treatment to Roche Safety Risk Management.  The investigator 
must document as much information as possible (based on the Medical Device 
Complaint Form [gcp_for000447]) including the batch number and expiration date and 
forward this to Roche Safety Risk Management within 24 hours of knowledge of the 
complaint.  The investigator may also be requested to forward defective medical device 
samples to Roche. 


   
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If the medical device complaint results in an AE, the information should be captured on 
the patient eCRF.  If the medical device complaint results in an SAE, the investigator 
should also complete an SAE Reporting Form [gcp_for004369] and forward it to Roche 
Safety Risk Management within 24 hours of knowledge. 
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 adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.  
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
The Investigator must report new significant follow-up information for these events to the 
Sponsor within 24 hours after becoming aware of the information.  New significant 
information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event (including 
outcome of a reported pregnancy, as applicable) 
 
In an individual patient, AE follow-up will continue as follows: 
Related or cardiac AEs and SAEs will be followed until one of the following occurs: 
• 
Resolved or improved to baseline state 
• 
Relationship is reassessed as unrelated 
• 
Investigator confirms that no further improvement can be expected  
• 
Start of a new anti-cancer regimen  
• 
Death 
 


   
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Unrelated non-cardiac AEs (Grade 3 or Grade 4) and SAEs (any grade) 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 non-cardiac AEs (Grade 1 or Grade 2) will be followed until 4 weeks after 
the last dose of study drug in an individual patient.  
The final outcome of each adverse event must be recorded on the eCRF. 
Follow-up of Abnormal Laboratory Test Values 
In the event of medically significant unexplained abnormal laboratory test values, the 
tests should be repeated and followed up until they have returned to the normal range or 
baseline state and/or an adequate explanation of the abnormality is found.  If a clear 
explanation is established it should be recorded on the eCRF.  
5.5.2 
Sponsor Follow-Up 
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information 
(e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
At the final follow-up visit of the study, 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 related 
to study drug, occurring at any time, after a patient has discontinued study participation, 
even after study closure.  The investigator is not required to actively monitor patients 
after the study has ended. 
The Sponsor should also be notified if the Investigator becomes aware of the 
development of cancer or a congenital anomaly/birth defect in a subsequently conceived 
offspring of a patient that participated in this study. 
The Investigator should report these events to Roche Safety Risk Management on the 
Adverse Event eCRF.  If the Adverse Event eCRF is no longer available, the Investigator 
should report these events, indefinitely, directly to Roche Safety Risk Management via 
telephone (see "Protocol Administrative and Contact Information & List of Investigators"). 


   
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5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, 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 document: 
• 
Herceptin (RO 45-2317, Trastuzumab) IB  
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
6.1 
DETERMINATION OF SAMPLE SIZE 
A sample size of approximately 2500 patients is planned for this study (approximately 
1800 patients in Cohort A and approximately 700 patients in Cohort B).  There is no 
formal statistical hypothesis; hence, all safety (primary) endpoints results will be 
presented by 95% confidence intervals and descriptively explained. 
For the purpose of the estimation of sample size, the incidence/proportion of congestive 
heart failure (CHF)-related SAEs was chosen as a safety endpoint of primary interest. 
Table 10 below includes 95% Clopper-Pearson confidence intervals for CHF-related 
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Table 10 Clopper-Pearson 95% Confidence Intervals for the Observed 
CHF-Related SAE Incidence 
Cohort A: 
Total number of patients:  1800 
 
Number of patients with CHF-related SAEs (incidence rate) 
95% Clopper Pearson CI 
18 (1%) 
0.1%−1.6% 
36 (2%) 
1.4%−2.8% 
72 (4%) 
3.1%−5.0% 
108 (6%) 
5.0%−7.2% 
144 (8%) 
6.8%−9.4% 
180 (10%) 
8.7%−11.5% 
Cohort B: 
Total number of patients:  700 
7 (1%) 
0.04%−2.1% 
14 (2%) 
1.1%−3.3% 
28 (4%) 
2.7%−5.7% 
42 (6%) 
4.4%−8.0% 
56 (8%) 
6.1%−10.3% 
70 (10%) 
7.9%−12.5% 
CI = Confidence Interval; CHF = congestive heart failure; SAE = serious adverse event. 
 
Therefore, based on an observed CHF-related SAE incidence rate of 4% 
(Romand et al. 2005; Ewer and O’Shaughnessy 2007) and a sample size of 
1800 patients in Cohort A, the upper limit of the 95% confidence interval (CI) for the 
incidence rate will be 5.0%.  For Cohort B, the same CHF-related SAE incidence rate 
and a sample size of 700 patients will give an upper limit of the 95% CI of 5.7%.  
The estimation of the sample size is produced by the SAS program and nQuery Version 
6. 
The split of the two cohorts in the current study was based on the availability of the 
device, which was planned to be due by the end of 2012.  The planned patient size was 
then further supported by the sample size calculation for the target event of CHF-related 
SAEs.  Based on an observed CHF-related SAE incidence rate of 4% (Romand et al. 
2005; Ewer and O’Shaughnessy 2007) and a sample size of 700 patients for Cohort B, 
the upper limit of the 95% CI for the incidence rate will be 5.7%.  CHF-related SAE 
events (N = 28) (4%) CI 2.7%−5.7%. 
In Cohort B only, exploratory analyses on the usability of the SID summarizing the 
parameters collected via SID monitoring questionnaire (Appendix 7) will be provided to 


   
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the first 48 patients enrolled who were judged able and were willing to self-administer 
remaining doses from the SID under direct observation of the HCP.  A sample size of 
48 patients using the SID for 17 cycles to self-administer a dose without assistance 
equates to sample of n = 816 dosing events.  If 0 events occur in this sample of trials, it 
can be stated with 99% confident it will be <1% in the true population.  The Adjusted 
Wald Approximate lower-limit of one-sided confidence interval for binomial distributed 
proportions statistical model has been used. 
Refer to the Statistical Analysis Plan (SAP) for further details. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
This is a Phase III prospective, two-cohort, non-randomized, multicenter, multinational, 
open-label study.  Eligible patients with HER2-positive EBC will be allocated to one of 
two cohorts at the investigators’ discretion:  
• 
Cohort A (approximately 1800 patients) will receive trastuzumab SC by assisted 
administration using a conventional syringe. 
• 
Cohort B (approximately 700 patients) will receive trastuzumab SC, first assisted, 
then self-administered (select patients) using a SID. 
 
Patients in both cohorts will receive a total of 18 cycles of trastuzumab SC, unless 
disease recurrence, unacceptable toxicity, or patient withdrawal necessitates earlier 
treatment cessation.  During adjuvant therapy, patients will be assessed for safety and 
efficacy, as detailed in Appendix 1. 
Safety endpoints are the primary objectives in this study.  Secondary efficacy endpoints 
include DFS, OS (both cohorts), and patient satisfaction with trastuzumab SC 
administration using the SID (Cohort B patients who went on to self-administration 
only).  In addition, immunogenicity of trastuzumab and rHuPH20 (with PK) will be 
analyzed in a subset of patients enrolled in Cohort B at select sites.  There is no formal 
statistical hypothesis for the comparison of Cohort A and Cohort B.  With the 
exceptions noted above, all summaries and analyses will be performed for Cohort A 
and for Cohort B. 
The primary analysis of safety endpoints and a preliminary analysis of efficacy (DFS, 
OS) will take place when all patients have received 18 cycles of trastuzumab SC and 
have completed the post-treatment Safety Follow-up assessments.  The final analysis of 
OS and DFS and updated summaries for safety parameters will be performed when the 
last patient has been followed up for at least 5 years after her/his last study treatment, or 
earlier, if one of the following is documented for all treated patients:  withdrawal of 
consent, loss to follow-up, or death.  This is expected to take place approximately 8 
years after the enrollment of the first patient, based on an expected 18-month 
recruitment period per cohort, 12 months of study treatment and 5 years of follow-up 


   
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after the last study treatment:  There will be no adjustments for multiplicity of endpoints 
or within-subgroups comparisons.  
Three interim safety analyses are planned for the study when approximately 500, 1000, 
and 2500 patients have received at least one trastuzumab SC injection.  More details 
are provided in the Section 3.1.2 of the protocol and in the Steering Committee Charter. 
A Clinical Study Report (CSR) will be written at the time of the primary endpoint analysis, 
and distributed to Health Authorities in keeping with the applicable regulatory 
requirements.  All subsequent data analyses will be reflected in an addendum to the 
CSR.  
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Not applicable; no formal statistical comparisons of the two cohorts are planned. 
6.4 
SAFETY ANALYSES 
6.4.1 
Primary Safety Endpoint 
Safety endpoints are the primary objectives in this study and will include:  all AEs, Grade 
≥ 3 AEs, SAEs, AEs leading to premature discontinuation of study treatment, AEs 
causing interruption of trastuzumab SC, cardiac AEs, CHF-related SAEs, premature 
withdrawals from study and study medication, exposure to treatment, laboratory 
parameters, LVEF, vital signs, ECG, weight, and ECOG performance status. 
The primary analysis of the safety endpoints will be performed for the safety population 
(SP) defined as all enrolled patients who received at least one dose of study medication.  
There will be two safety populations, one for each cohort (SP1 for Cohort A and SP2 for 
Cohort B).  The safety endpoints will be summarized for each cohort (SP1 and SP2) 
and overall (SP) as described below.  The primary analysis of safety endpoints will take 
place when all patients have received 18 cycles of trastuzumab SC and have completed 
the post-treatment Safety Follow-up assessments.  Updated summaries for safety 
parameters will be prepared when the last patient has been followed up for at least 5 
years after her/his last study treatment, or earlier, if one of the following is documented 
for all treated patients:  withdrawal of consent, loss to follow-up, or death.  
The analysis of AEs will focus on treatment-emergent adverse events (TEAEs) i.e, AEs 
occurring on the day of or after first administration of study drug.  Non-treatment 
emergent AEs (i.e., those occurring before commencement of study medication) will only 
be listed.  The incidence of AEs, AEs leading to premature discontinuation or interruption 
of study treatment, SAEs, Grade 3 and 4, and cardiac AEs will be summarized according 
to the primary system-organ class (SOC) and within each SOC by MedDRA preferred 
term.  The time to onset of the first episode of cardiac AEs will also be summarized 
using the Kaplan-Meier approach.  The incidence of deaths and cause of deaths will be 
listed and summarized by treatment cohort and overall. 


   
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LVEF will be summarized over time by means of mean, median, and range (mean and 
maximum) and will be presented graphically for each trastuzumab SC cohort and 
overall.  Vital signs, ECG, and weight will be summarized similar to LVEF. 
Safety laboratory parameters (hematology, biochemistry, as defined in 
Section 4.5.1.7.2), will be presented in shift tables according to NCI CTC grade at 
screening versus worst grade during trastuzumab treatment for each trastuzumab SC 
cohort and overall.  The summary of laboratory parameters will include means, standard 
deviation, minimum, and maximum values.  Select laboratory parameters may also be 
displayed graphically.  More details will be presented in the SAP. 
Exposure to study treatment (number of cycles administered) and duration of treatment 
exposure (calculated from date of first study treatment to the last treatment date) will be 
summarized.  
The number of patients who prematurely discontinue study treatment and the number of 
patients who withdrew from the study will be summarized, and reasons for withdrawal 
will be displayed. 
ECOG performance status will be summarized by frequency tables over time, and 
percentage of patients in different categories will be presented by bar charts at different 
timepoints. 
6.5 
EFFICACY ANALYSES 
6.5.1 
Secondary Efficacy Variables 
Secondary efficacy endpoints include disease-free survival (DFS) and overall survival 
(OS) and will be assessed in both cohorts.  
• 
DFS is defined as the time from the date of first treatment to the date of local, 
regional, or distant recurrence; contralateral invasive breast cancer (including 
contralateral or ipsilateral ductal carcinoma in situ [DCIS]); or death due to any 
cause.  
• 
OS is defined as time from the date of first treatment until date of death, regardless 
of the cause of death.  
 
DFS and OS will be analyzed as a time-to-event variable for the ITT population (see 
Section 6.5.2).  
In addition, patients’ satisfaction with trastuzumab SC administration using the SID will 
be evaluated for Cohort B patients who went on to self-administration only. 
6.5.2 
Analyses of Efficacy Endpoints 
The efficacy endpoints, DFS and OS, will be analyzed as a time-to-event variable for the 
ITT and PP populations and for each cohort.  Estimates and corresponding 95% 
confidence intervals for the survivor function for the time-to-event variable will be 


   
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obtained by using the KM approach.  A frequency table will be also provided for the type 
of DFS event (e.g., local, regional, or distant recurrence; contralateral breast cancer; or 
death). 
A preliminary analysis of efficacy (DFS and OS) will take place when all patients have 
received 18 cycles of trastuzumab SC and have completed the post-treatment Safety 
Follow-up assessments.  The final analysis of OS and DFS will take place when the last 
patient has been followed up for at least 5-years after her/his last study treatment, or 
earlier, if one of the following is documented for all treated patients:  withdrawal of 
consent, loss to follow-up, or death.  This is expected to take place approximately 
8 years after the enrollment of the first patient, based on an expected 18-month 
recruitment period per cohort, 12 months of study treatment, and 5 years of follow-up 
after the last study treatment  
Patients’ satisfaction with trastuzumab SC administration using the SID (Cohort B 
patients who went on to self-administration only) will be summarized by frequency tables 
and presented graphically. 
6.5.3 
Other Analyses 
Baseline characteristics will be summarized overall and for each treatment cohort.  The 
demographic profile, medical history, HER2-positivity, and serum pregnancy test at 
screening will be listed and summarized using appropriate descriptive statistics:  mean, 
standard, median, range (minimum and maximum), and 25th−75th quartiles for the 
continues variables and number/percentage of patients, medians, and ranges for the 
categorical variables. 
Concomitant medications will be summarized by class and preferred term for the ITT 
and safety populations.  Within each cohort, the number of cycles, as well as dosing 
information (e.g., dose interruptions, modifications, and delays), will be summarized by 
median and range.  
More details about the planned analyses will be presented in the SAP. 
6.6 
ANALYSIS POPULATIONS 
The Safety Population (SP) will include all enrolled patients who received at least one 
dose of study medication.  There will be two safety populations, one for each cohort 
(SP1 for Cohort A and SP2 for Cohort B). 
The intent to treat (ITT) population will include all patients enrolled in the study.  
The per-protocol population (PP) will include all ITT patients who have received at least 
one dose of study medication and did not have major protocol violations (which will be 
defined in the SAP). 


   
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6.7 
PHARMACOKINETIC ANALYSES 
Pharmacokinetic assessments will be limited to the confirmation of the presence and 
titer of trastuzumab in the serum of a subset of patients enrolled in Cohort B at select 
sites, who will also undergo immunogenicity testing (anti-trastuzumab assay; see 
Section 6.9.1).  
6.8 
PATIENT–REPORTED OUTCOME ANALYSES 
Not applicable. 
6.9 
EXPLORATORY ANALYSES 
6.9.1 
Immunogenicity 
Immunogenicity assessments will be summarized for a subset of patients enrolled in 
Cohort B at selected sites.  The percentage of patients who develop anti-human 
antibodies (HAHAs and ADAs) to trastuzumab SC or rHuPH20 or both will be presented.  
Serum trastuzumab concentration data will be used for the evaluation of the 
anti-trastuzumab assay. 
Details about analysis methods are provided in the Statistical Analysis Plan (SAP). 
6.9.2 
Observation Time  
Exploratory study analyses for all clinical AEs that occur during the observation period 
will be evaluated, analyzed, and presented, and further exploratory analysis will be 
performed for all patients in Cohort B (within 6 hours after start of the first trastuzumab 
administration or within 2 hours after start of following trastuzumab administrations).  
Details of the analysis will be documented in the Statistical Analysis Plan (SAP) and will 
include the following: 
• 
Analysis of frequency, incidence, and grade of AEs during the observation period 
• 
Analysis of time from last preceding administration of study drug to onset time of AE 
occurrence (dd:mm:yyyy:hh:mm) during the observation period 
• 
Analysis of time to resolution (dd:mm:yyyy:hh:mm) and outcome of AEs observed 
during the observation period 
• 
Analysis of treatments provided following AEs during the observation period 
 
Exploratory analyses on the usability of the SID summarizing the parameters collected 
via SID monitoring questionnaire (Appendix 7) will be provided to the first 48 patients 
enrolled in Cohort B who were judged able, and were willing to self-administer 
remaining doses from the SID under direct observation of the HCP.  The SID Device 
Observation is to be completed by HCPs.  
6.9.3 
Subgroup Analyses 
Selected safety and efficacy summaries will be repeated for the subgroup of patients 
treated without neoadjuvant or adjuvant chemotherapy, such as patients with low-risk, 


   
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node-negative tumors ≤ 1.0 cm, elderly patients (> 65 years of age), or patients who 
refuse chemotherapy.  Enrollment of patients treated without chemotherapy will be 
limited to ≤ 10% of the total study population.  Details of the planned subgroup analyses 
will be provided in the SAP.  
6.10 
INTERIM SAFETY ANALYSES 
Three interim safety analyses are planned when approximately 500, 1000, and 
2500 patients have received at least one trastuzumab SC injection. 
Details regarding the planned interim safety analyses will be provided in the Steering 
Committee Charter. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
A contract research organization (CRO) will be responsible for data management of this 
study, including quality checking of the data.  Roche will supply electronic eCRF 
specifications for the study.  The overall procedures for quality assurance of clinical 
study data are described in the Roche Standard Operational Procedures and/or those of 
the global Contract Research Organization (CRO) designee.  
Data entered manually will be collected via EDC using eCRFs.  Sites will be responsible 
for data entry into the EDC system.  The CRO will produce a Data Quality Plan that 
describes the quality checking to be performed on the data.  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.  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. 
The responsible monitors (CRO designee) will visit the investigators and will be allowed, 
on request, to inspect the study records, provided that patient confidentiality is 
maintained in accordance with local requirements.  It will be the monitor's responsibility 
to inspect the eCRFs at regular intervals throughout the study, to verify the adherence to 
the protocol and the completeness, consistency and accuracy of the data being entered 
on them.  The monitor must verify that the patient received the study drug as prescribed 
in the protocol.  The monitor should have access to laboratory test reports and other 
patient records needed to verify the entries on the eCRF.  The investigator (or deputy) 
agrees to cooperate with the monitor to ensure that any problems detected in the course 
of these monitoring visits are resolved. 
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 


   
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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.   
For classification purposes, preferred terms will be assigned by the Sponsor (or CRO 
designee) to the original terms entered on the eCRF, using the most up-to-date version 
of the Medical Dictionary for Regulatory Activities (MedDRA) terminology for adverse 
events and diseases and the International Non-proprietary Name (INN) Drug Terms and 
Procedures Dictionary for treatments and surgical and medical procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS 
A global CRO will handle eCRF development and review, eCRF online monitoring/data 
management, statistics, preparation of the final statistical report and clinical study report 
(CSR).  The CSR will be prepared when all patients have completed the Safety 
Follow-up visit (4 weeks after the last dose of study treatment).  An addendum to the 
CSR will be prepared when the last patient has completed 5 years of post-treatment 
follow-up.  
An eCRF must be completed for each enrolled (registered) patient.  If a patient 
withdraws from the study, the reason must be noted on the eCRF.  If a patient is 
withdrawn from the study because of a treatment-limiting AE, thorough efforts should be 
made to clearly document the outcome. 
eCRFs are to be completed using a Sponsor-designated EDC system.  Sites will receive 
training and have access to a manual for appropriate eCRF completion.  All eCRFs 
should be completed by designated, trained site staff, who will transcribe the collected 
patient data from paper source documents onto the eCRF.  In no case is the eCRF to be 
considered as source data for this trial.  eCRFs should be reviewed and electronically 
signed and dated by the investigator or an authorized designee.  eCRFs will be 
submitted electronically to Roche and should be handled in accordance with instructions 
from Roche. 
An audit trail will maintain a record of initial entries and changes made; reasons for 
change; time and date of entry; and user name of person authorizing entry or change.  
The data will be transferred directly to the clinical database. 
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 will be required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered by authorized site personnel from 
source documents into the eCRFs are accurate.  


   
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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 accuracy of data entered into the 
eCRFs must not be obliterated or destroyed and must be retained per the policy for 
retention of records described in Section 7.5. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and EC review.  The investigational site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research.  An acceptable computerized data collection system allows 
preservation of the original entry of data.  If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study, or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of 
time, the documents may be destroyed, subject to local regulations.   
No records may be disposed of without the written approval of Roche.  Written 
notification should be provided to Roche prior to transferring any records to another 
party or moving them to another location. 


   
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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 EU/EEA will comply with the EU Clinical 
Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
Roche’s sample Informed Consent Form will be provided to each site.  If applicable, it 
will be provided in a certified translation of the local language.  Roche 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 EC submission.  The final EC−approved Consent Forms must 
be provided to Roche for health authority submission purposes according to local 
requirements. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed 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 EC-approved Consent Forms must be provided to 
Roche 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 
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. 


   
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8.3 
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 adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and EC.  Investigators may receive written safety reports or other 
safety-related communications from Roche.  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 
Roche 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 Roche location. 
Patient medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the national and local health authorities, Roche 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. 


   
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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of 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 Roche or an authorized representative for inspection of 
study data, patients’ medical records, and eCRFs.  The investigator will permit national 
and local health authorities, Roche monitors, representatives, and collaborators; and the 
ECs to inspect facilities and records relevant to this study. 
9.3 
ADMINISTRATIVE STRUCTURE 
Please refer to the separate contact list for the contact information of the Sponsor and 
Global Roche Study Personnel. 
This information can be found at the local Roche affiliate office, and within the 
Investigator Site File.  
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 Roche 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. 
Roche will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, Roche 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 Roche personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Roche personnel. 


   
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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 Roche, except where agreed otherwise. 
9.5 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Investigators are 
responsible for promptly informing the EC of any amendments to the protocol. 
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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10. 
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Slamon D, Eiermann W, Robert N, et al. BCIRG-006 Phase III trial comparing AC→T 
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Trastuzumab⎯F. Hoffmann-La Roche Ltd 
127/Protocol MO28048, Version 4 
Appendix 1 
 
Schedule of Assessments 
 
Screening 
Study Treatment 
3-weekly (18 cycles) 
Safety Follow-
Up Visit q,r 
Follow-Up 
Visits k,r 
Study Week 
(Treatment Cycle #) 
Day -28 to 1 
Week 1 to 22 
Cycles  
1 to 8 r,u 
Week 25 
Cycle 9 r 
Week 28 to 49 
Cycles  
10 to 17 r 
Week 52 
Cycle 18 r 
4 weeks After 
Last Study 
Treatment 
(Minimum 
5 years After 
Last Study 
Treatment) 
Explain study and obtain 
signed Informed Consent a 
x 
 
 
 
 
 
 
Demographic profile b and 
medical history 
x 
 
 
 
 
 
 
HER2 Determination 
x 
 
 
 
 
 
 
Review inclusion/exclusion 
criteria 
x 
 
 
 
 
 
 
Physical Exam c 
x 
Approximately 3-monthly (every 4 cycles) p 
x 
x k 
Weight, height d 
x 
 
x d 
 
 
 
x d 
Vital Signs e 
x 
Approximately 3-monthly (every 4 cycles) e 
x 
 
ECOG performance status 
x 
Approximately 3-monthly (every 4 cycles) p 
x 
 
Cardiac monitoring 
 
12-lead ECG 
x 
LVEF f 
x f 
Signs/symptoms 
x 
Approximately 3-monthly (every 4 cycles) p 
x s 
Cardiac 
assessments at 
6, 12 and 
24 months, and 
at 3, 4 and 5 
years following 
treatment 
cessation 
Pregnancy test g 
x 
As clinically indicated 


 
 
 
 
Appendix 1 
Schedule of Assessments (cont.) 
 
Trastuzumab⎯F. Hoffmann-La Roche Ltd 
128/Protocol MO28048, Version 4 
 
Screening 
Study Treatment 
3-weekly (18 cycles) 
Safety Follow-
Up Visit q,r 
Follow-Up Visits 
k,r 
Study Week 
(Treatment Cycle #) 
Day -28 to 1 
Week 1 to 22 
Cycles  
1 to 8 r,u 
Week 25 
Cycle 9 r 
Week 28 to 49 
Cycles  
10 to 17 r 
Week 52 
Cycle 18 r 
4 weeks After 
Last Study 
Treatment 
(Minimum 5 years 
After Last Study 
Treatment) 
Blood samples for immunogenicity 
and PK testing h 
x [h] 
 
x [h] 
 
 
 
x 
(6 months after last 
study treatment) 
Hematology and biochemistry i 
x [t] 
 
x 
 
x 
x 
 
Imaging scan to exclude 
residual/recurrent disease j 
x 
 
 
 
Routine Breast-cancer follow-up k 
 
Assessments as per institutional practice or ASCO adjuvant follow-up guidelines 2006 to be reported 6-monthly k 
AEs and SAEs l 
x 
x 
x 
x 
x 
x 
x 
Concomitant medication m 
x 
x 
x 
x 
x 
x 
x m 
Trastuzumab SC n 
 
x 
x 
x 
x 
 
 
Exploratory Observation Time v 
 
x 
x 
x 
x 
 
 
SID monitoring questionnaire w 
 
x 
x 
x 
x 
 
 
Treatment compliance 
 
x 
x 
x 
x 
 
 
SID satisfaction questionnaire o 
 
After Cycle 4 o 
 
 
 
x 
 
Survival 
 
x 
x 
x 
x 
x 
x (at 12, 
24 months and at 
3, 4, and 5 years 
after last 
treatment) 
Note:  First dose of study drug = study Cycle 1, Day 1. 
a Written Informed Consent must be obtained before any study-specific assessments or procedures are performed. 


 
 
 
 
Appendix 1 
Schedule of Assessments (cont.) 
 
Trastuzumab⎯F. Hoffmann-La Roche Ltd 
129/Protocol MO28048, Version 4 
b Demographic data include date of birth, gender, and self-reported ethnic origin. 
c General physical exam may include neurological exam, as clinically indicated. 
d Weight is measured for all patients at screening.  For patient participating in PK sampling at Cycle 9 and 6 month after last study treatment.  Height is only 
measured at screening. 
e Vital signs include blood pressure, heart rate measurement and temperature at screening and Safety Follow-up visit, as well as pre- and immediately post-
trastuzumab SC administration at Cycles 1, 5, 9, 13, and 18. 
f LVEF has to be assessed within 14 days prior to the first study treatment for anthracycline regimens or 28 days prior to the first study treatment for 
anthracycline-free regimens, and 3-monthly thereafter by ECHO, MUGA, or MRI.  The same imaging technique needs to be used per patient throughout the study.  
A further LVEF assessment will be performed if patients are symptomatic at an LVEF between 45%−49% and a drop ≥ 10% as clinically indicated, but within 3 
weeks.  LVEF at the Safety Follow-up visit (4 weeks after the end of treatment) is not mandatory but will be performed if clinically indicated. 
g Applicable to women of childbearing potential; a serum pregnancy test needs to be completed within 7 days prior to the first study treatment.  Subsequent 
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 Subset of Cohort B selected sites only:  Blood samples (4 mL for PK and anti-trastuzumab analysis and 2 mL for rHuPH20 antibody analysis) should be taken at 
baseline (after eligibility is confirmed, i.e., just before the first study treatment) pre-Cycle 9 dose and 6 months after the last dose of study treatment. 
i Hematology:  hemoglobin, 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.  On Day 1 of Cycles 9 (Week 25) and 18 (Week 52), samples will be taken predose, and the results will be reviewed 
prior to dosing. 
j Screening radiologic examinations to exclude metastatic disease should include a bilateral mammogram or breast MRI and chest X-ray (CXR).  These imaging 
tests do not need to be repeated if completed within 12 months prior to the first study treatment.  In addition, bone scan, liver imaging, and brain CT scan should be 
performed if clinically indicated. 
k American Society of Clinical Oncology (ASCO) 2006 Guideline for Breast Cancer Follow-up in the adjuvant setting (Khatcheressian et al. 2006).  In brief: 
History/physical examination:  every 3−6 months for the first 3 years after primary therapy, every 6−12 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). 


 
 
 
 
Appendix 1 
Schedule of Assessments (cont.) 
 
Trastuzumab⎯F. Hoffmann-La Roche Ltd 
130/Protocol MO28048, Version 4 
l After informed consent, but prior to initiation of study medications, only SAEs caused by a protocol-mandated intervention will be collected.  All treatment-emergent 
AEs occurring until 4 weeks after the last administration of trastuzumab SC will be recorded in the eCRF, irrespective of the type of event and drug-event 
relationship.  From 4 weeks after the last study drug administration until the end of the follow-up period, related AEs, related/unrelated SAEs, and cardiac AEs 
should be reported. 
m All concomitant medication will be recorded between the Screening and the Safety Follow-up visits.  Thereafter, only breast cancer treatments (e.g., endocrine 
therapy), anti-cancer treatments given to treat a recurrence, and medications related to the treatment of SAEs will be recorded. 
n Trastuzumab SC is administered subcutaneously in the upper thigh at a fixed dose of 600 mg, 3-weekly for a total of 18 cycles. 
o After the 4th cycle  and at their final study visit (at least 1 day after the last trastuzumab SC injection), patients in Cohort B, who have successfully completed a 
minimum of 2 self-administrations of the study drug, will be asked to assess their satisfaction with the administration of trastuzumab SC using the SID by completing 
the 5-item SI satisfaction questionnaire. 
p Approximately 3-monthly (every 4 cycles) refers to pre-dosing at:  Week 13/Cycle 5, Week 25/Cycle 9, Week 37/Cycle 13, and Week 52/Cycle 18. 
q Patients will undergo a Safety Follow-up visit 4 weeks after their last dose of study treatment. 
r Visit windows of ± 3 days allowed for all visits (Cycles 1 to 18), ± 5 days at Safety Follow-up visit, and ± 15 days allowed for Follow-up visits. 
s An LVEF is only required at the Safety Follow-up visit if clinically indicated. 
t Screening laboratory values should be used to confirm eligibility. 
u For patients initiated on trastuzumab SC in neoadjuvant setting, surgery should be scheduled after dosing at Cycle 8.  Pathologist post-surgery tumor assessment 
should be recorded. 
v Cohort B only, observation time (6 hours post start of the first administration trastuzumab and 2 hours after the start of subsequent administrations) will include, in 
addition to onset and resolution dates and times of AEs, the collection of detailed information about premedications prior to trastuzumab administration and, in 
addition to the date, the onset and resolution time of treatment of AEs occurring during the observation time is investigated. 
w For SID monitoring purposes, the first 48 patients enrolled in Cohort B will have their SID use monitored and recorded on the SID monitoring questionnaire by the 
trained HCP or investigator intended to collect information about aspects of use related to usability of the device. 


 
Trastuzumab⎯F. Hoffmann-La Roche Ltd 
131/Protocol MO28048, Version 4 
Appendix 2 
 
ECOG Performance Status Scale 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light house work, office work). 
2 
Ambulatory and capable of all selfcare, but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or 
chair. 
5 
Dead 
Source:  Oken M et al. 1982. 
 
 


 
Trastuzumab⎯F. Hoffmann-La Roche Ltd 
132/Protocol MO28048, Version 4 
Appendix 3 
 
New York Heart Association (NYHA) Functional Classification 
System for Heart Failure 
 
Class 
Patient Symptoms 
Class I (Mild) 
No limitation of physical activity.  Ordinary physical activity does not 
cause undue fatigue, palpitation, or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity.  Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, or dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity.  Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort.  Symptoms 
of cardiac insufficiency at rest.  If any physical activity is undertaken, 
discomfort is increased. 
 
 


 
Trastuzumab⎯F. Hoffmann-La Roche Ltd 
133/Protocol MO28048, Version 4 
Appendix 4 
 
Algorithm for Continuation and Discontinuation of Trastuzumab 
SC Based on LVEF Assessment in Asymptomatic Patients 
 
 


 
Trastuzumab⎯F. Hoffmann-La Roche Ltd 
134/Protocol MO28048, Version 4 
Appendix 5 
 
Common Terminology Criteria for Adverse Events  
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 
Published:  May 28, 2009 (v4.03:  June 14, 2010) 
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 
National Institutes of Health, National Cancer Institute 
 
The CTCAE v4.0 manual can be found at the following URL:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
 


 
Trastuzumab⎯F. Hoffmann-La Roche Ltd 
135/Protocol MO28048, Version 4 
Appendix 6 
 
Single-Use Injection Device (SID) Satisfaction Questionnaire 
The SID satisfaction questionnaire is to be completed by patients in Cohort B who 
completed a minimum of 2 (preferably 3) self-administrations of the study drug. 
Please rate your level of agreement or disagreement with each the following statements, by 
placing an “X” in the appropriate box (one answer for each statement): 
1. Following the first injection given by the physician/nurse and training on how to 
use the SID, I felt comfortable injecting the study drug by myself. 
 
1 Strongly Disagree       2 Disagree       3 Unsure       4 Agree       5 Strongly agree 
2. The SID was convenient and easy to use. 
 
1 Strongly Disagree       2 Disagree       3 Unsure       4 Agree       5 Strongly agree 
3. I am confident giving myself an injection in the thigh with the SID. 
 
1 Strongly Disagree       2 Disagree       3 Unsure       4 Agree       5 Strongly agree 
4. Taking all things into account, I find self-administration using the SID satisfactory.
 
1 Strongly Disagree       2 Disagree       3 Unsure       4 Agree       5 Strongly agree 
5. If given the opportunity, I would choose to continue self-injecting the study drug 
using the SID in the future. 
 
1 Strongly Disagree       2 Disagree       3 Unsure       4 Agree       5 Strongly agree 
 
 
 
 


 
Trastuzumab⎯F. Hoffmann-La Roche Ltd 
136/Protocol MO28048, Version 4 
Appendix 7 
 
Single-Use Injection Device (SID) Observers Usability 
Questionnaire 
The SID Device Observation is to be completed by HCPs (physician or nurses) for 
48 patients selected in Cohort B who were judged able, and were willing to self-
administer remaining doses from the SID under direct observation of the HCP.  Patients 
participating in the usability questionnaire must self-administer with the SID and no 
assistance is to be provided unless it was not possible for a user to use the SID correctly 
(in which case assistance is permitted).  In this instance, the SID usability questionnaire 
must still be completed. 
Positioning of device; body site selection and prepare skin 
1. 
Does selection of body positioning of SID comply with 
instruction (semi-supine, anterior thigh)? 
(Circle the applicable answer) 
If NO please comment: 
_________________________________________________
_________________________________________________
______ 
[YES]         [NO] 
2. 
Which image below best describes the placement of the SID on the thigh of the 
patient? (Circle the applicable answer). 
[A]                                                              [B] 
 
[A] Across the Thigh 
 
[B] Along the thigh 


 
 
Appendix 7 
Single-Use Injection Device (SID) Observers 
Usability Questionnaire (cont.) 
Trastuzumab⎯F. Hoffmann-La Roche Ltd 
137/Protocol MO28048, Version 4 
3. 
Was the body site dry before attaching the SID? 
(Circle the applicable answer) 
[YES]         [NO] 
4. 
Was the SID stuck onto the skin with the adhesive pad 
removed? 
(Circle the applicable answer) 
 
If NO please comment: 
_________________________________________________
___________________________________________ 
[YES]         [NO] 
5. 
Was the full dose injected from the SID?   
Piston at end position of cartridge at the end of injection. 
(Circle the applicable answer) 
 
If NO please comment: 
_________________________________________________
_________________________________________ 
[YES]         [NO] 
6. 
Did the SID stop at any time during administration? This is 
indicated by the motor stopping and indicator light flashing 
alternating green and orange. 
(Circle the applicable answer) 
If YES please comment: 
______________________________________________________
______________________________________ 
[YES]         [NO] 
7. 
IF the SID did stop during the administration - 
Was the problem corrected to resume delivery?  
(To correct the SID was depressed onto the skin again within 
10 seconds and pressure maintained until the status light 
resumed slowly flashing orange and injection continued). 
[YES]         [NO] 
8. 
Following completion of the injection and removal of the SID 
from the body:  
Did the needle automatically retract into SID? 
[YES]         [NO] 
9. 
Was there residual liquid left at the injection site?   
[YES]         [NO] 
If Yes, please tick one of the options below: 
1 to 5 drops [      ] 
More than 5 drops 
[      ] 


 
 
Appendix 7 
Single-Use Injection Device (SID) Observers 
Usability Questionnaire (cont.) 
Trastuzumab⎯F. Hoffmann-La Roche Ltd 
138/Protocol MO28048, Version 4 
10. Was assistance given to a user at any time during the self-
administration? 
If YES please comment: 
_________________________________________________
_________________________________________________
_________________________________________________
_________________________________________________
_________________________________________________
_______________ 
[YES]         [NO] 
 

SAP_001.pdf: 
 
Official Title: 
 
A PHASE III PROSPECTIVE, TWO-COHORT NON-RANDOMIZED, 
MULTICENTER, MULTINATIONAL, OPEN-LABEL STUDY TO 
ASSESS THE SAFETY OF ASSISTED- AND SELF-ADMINISTERED 
SUBCUTANEOUS TRASTUZUMAB AS THERAPY IN PATIENTS 
WITH OPERABLE HER2-POSITIVE EARLY BREAST CANCER 
[SafeHer Study] 
NCT Number: NCT01566721 
Document Date: SAP Version 4: 20-February-2020