Clinical trial NCT03674112
Conditions: HER2-Positive Early Breast Cancer
Sponsor: Hoffmann-La Roche
Start date: 2018-12-19; Completion date: 2022-10-12
Enrollment: 160 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a Phase II, randomized, multicentre, multinational, open-label, cross-over study in adult patients who have completed neoadjuvant chemotherapy with neoadjuvant pertuzumab and trastuzumab and have undergone surgical treatment of human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. The study will consist of two adjuvant treatment periods: a treatment cross-over period and a treatment continuation period. It will evaluate participant-reported preference for a subcutaneously administered fixed-dose combination formulation (FDC SC) of pertuzumab and trastuzumab compared with intravenously (IV) administered pertuzumab and trastuzumab formulations. The study will also evaluate participant-reported satisfaction with pertuzumab and trastuzumab FDC SC and health-related quality of life outcomes; healthcare professionals' perceptions of time/resource use and convenience of pertuzumab and trastuzumab FDC SC compared with pertuzumab and trastuzumab IV formulations; as well as the safety and efficacy of each study regimen.

Detailed description:

Arms: arm 1: In the Treatment Cross-Over Period of the study, participants randomized to Arm A first received pertuzumab IV and trastuzumab IV (P+H IV) administration for 3 treatment cycles followed by the pertuzumab and trastuzumab fixed-dose combination for subcutaneous administration (PH FDC SC) for 3 treatment cycles (1 cycle = 21 days). Following completion of this study period, participants chose one of the two study treatments to receive in the Treatment Continuation Period for the remaining anti-HER2 treatment cycles (18 planned cycles in total, including pre-study neoadjuvant treatment). After completing study treatment, participants entered the Follow-up Period wherein they were to be followed for 3 years from the date the last participant was randomized. arm 2: In the Treatment Cross-Over Period of the study, participants randomized to Arm B first received the pertuzumab and trastuzumab fixed-dose combination for subcutaneous administration (PH FDC SC) for 3 treatment cycles followed by pertuzumab intravenous (IV) and trastuzumab IV (P+H IV) administration for 3 treatment cycles (1 cycle = 21 days). Following completion of this study period, participants chose one of the two study treatments to receive in the Treatment Continuation Period for the remaining anti-HER2 treatment cycles (18 planned cycles in total, including pre-study neoadjuvant treatment). After completing study treatment, participants entered the Follow-up Period wherein they were to be followed for 3 years from the date the last participant was randomized.
Interventions: intervention 1: Pertuzumab and Trastuzumab Fixed-Dose Combination for Subcutaneous Administration (PH FDC SC) intervention 2: Pertuzumab IV intervention 3: Trastuzumab IV
Intervention descriptions: intervention 1: PH FDC SC will be administered subcutaneously (SC) at a fixed non-weight-based dose. A loading dose of 1200 mg pertuzumab and 600 mg trastuzumab is then followed by a maintenance dose of 600 mg pertuzumab and 600 mg trastuzumab once every 3 weeks (Q3W). intervention 2: Pertuzumab will be administered intravenously (IV) as a fixed non-weight-based dose of 840-mg IV loading dose and then 420-mg IV maintenance dose Q3W. intervention 3: Trastuzumab will be administered intravenously (IV) as an 8-mg/kg IV loading dose and then 6 mg/kg IV maintenance dose Q3W.

Protocol documents:
Prot_000.pdf: 
 
Official Title: A Randomized, Multicenter, Open-Label Cross-Over Study to 
Evaluate Patient Preference and Satisfaction of Subcutaneous 
Administration of the Fixed-Dose Combination of Pertuzumab and 
Trastuzumab in Patients With HER2-Positive Early Breast Cancer 
NCT Number: NCT03674112 
Document Date: Protocol Version 2: 14-December-2018 
 
 


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.
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab — F. Hoffmann-La Roche Ltd
Protocol MO40628, Version 2
PROTOCOL
TITLE:
A RANDOMIZED, MULTICENTER, OPEN-LABEL 
CROSS-OVER STUDY TO EVALUATE PATIENT 
PREFERENCE 
AND 
SATISFACTION 
OF 
SUBCUTANEOUS 
ADMINISTRATION 
OF 
THE 
FIXED-DOSE COMBINATION OF PERTUZUMAB 
AND TRASTUZUMAB IN PATIENTS WITH HER2-
POSITIVE EARLY BREAST CANCER
PROTOCOL NUMBER:
MO40628
VERSION NUMBER:
2
EUDRACT NUMBER:
2018-002153-30
IND NUMBER:
131009
TEST PRODUCT:
Fixed-dose combination of pertuzumab and trastuzumab 
for subcutaneous administration (RO7198574)
MEDICAL MONITOR:
Dr. 
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  24 July 2018
DATE AMENDED:
Version 2:  See electronic date stamp below
 
14-Dec-2018 13:59:04
z
Title
Approver's Name
Company Signatory
Date and Time (UTC)


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2 / Protocol MO40628, Version 2
PROTOCOL AMENDMENT, VERSION 2:
RATIONALE
Protocol MO40628 has been amended to correct minor errors and to provide clarification on 
several protocol details.  Changes to the protocol, along with a rationale for each change, 
are summarized below:
Sections Affected
Rationale for Change
4.1.1
Hormone receptor status was incorrectly referred to as 
“hormone receptor-positive status” in the inclusion criteria.  
This error has been corrected. 
4.5.11; Appendix 1 
(Schedule of 
Assessments)
Albumin has been added as part of blood chemistry at
Screening, for determination of patient eligibility.
5.2.4.3
Reporting conventions have been added for local infusion 
reactions.
6, 6.6, 9.4
An interim analysis will now be conducted to support a 
planned regulatory filing for FDC. The scope of this interim will 
be a subset of the analyses planned for the primary analysis.
Appendix 1 (Schedule of 
Assessments)
The timing of pregnancy tests during the Treatment Cross-
over and Treatment Continuation Periods has been clarified.  
It has been clarified that pregnancy testing is only required for 
women of childbearing potential. 
Appendix 1 (Schedule of 
Assessments)
The Schedule of Assessments has been revised to clarify that 
adverse events and concomitant medications are collected on 
an ongoing basis throughout the Treatment Cross-Over 
Period and the Treatment Continuation Period.
Appendix 1 (Schedule of 
Assessments)
It has been clarified that, for all protocol-mandated study 
visits, a time window of ± 3 days is allowed.
Appendix 1 (Schedule of 
Assessments)
It has been clarified that no specific investigations are 
required per protocol for Cycles 8-10 and Cycles 12-14 during 
the Treatment Continuation Period, although the investigator
may perform safety laboratory assessments or other tests per 
institutional practice. Information on treatment administration 
as well as any new or worsened clinically significant 
abnormalities will be collected.
Appendix 7
An error in the definition of Grade 4 left ventricular systolic 
dysfunction (LVSD) has been corrected.


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3 / Protocol MO40628, Version 2
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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4 / Protocol MO40628, Version 2
PROTOCOL AMENDMENT, VERSION 2:
SUMMARY OF CHANGES
PROTOCOL SYNOPSIS
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable.
PROTOCOL TITLE PAGE
VERSION NUMBER:
12
DATE FINAL:
See electronic date stamp below Version 1: 24 July 
2018
DATE AMENDED:
See electronic date stamp below
FOOTER
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab — F. Hoffmann-La Roche Ltd
Protocol MO40628, Version 12
PROTOCOL ACCEPTANCE FORM
VERSION NUMBER:
12
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
…
rHuPH20 
recombinant human PH20 hylauronidasehyaluronidase
4.1.1
Inclusion Criteria
…
Disease-specific criteria
…

Hormone receptor status of the primary tumour determined by local assessment. 
Hormone receptor positive status may be either positive (i.e. ER-positive and/or PgR-
positive) or negative (i.e. ER-negative and PgR-negative)




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6 / Protocol MO40628, Version 2
Committee. An interim analysis will be conducted to support a planned regulatory filing for FDC, 
which will consist of a subset of the analyses planned for the primary analysis. The results of this 
interim analysis will be evaluated by a Sponsor’s Internal Monitoring Committee. Further details 
will be specified in the Statistical Analysis Plan.
9.4
ADMINISTRATIVE STRUCTURE
…
If an interim safety analysis is conducted, the Sponsor’s Internal Data Monitoring Committee 
will evaluate the results.  The results of the interim analysis will be evaluated by a Sponsor’s 
Internal Monitoring Committee.




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8 / Protocol MO40628, Version 2
a.
Either pertuzumab and trastuzumab FDC SC or P+H IV will be selected by the patient for study treatment during the Treatment Continuation Period. 
During this period, pertuzumab and trastuzumab FDC SC or P+H IV will be administered for the number of 3-weekly cycles calculated based on the 
number of Perjeta and Herceptin cycles received as neoadjuvant treatment prior to study entry and P+H IV and pertuzumab and trastuzumab FDC SC 
cycles (six total cycles) received during the Treatment Cross-over Period. A total of 18 cycles of anti-HER2 treatment should be administered for EBC 
treatment unless disease recurrence, unacceptable toxicity or patient withdrawal from treatment necessitates early cessation of treatment. No specific 
investigations are required per protocol for Cycles 8-10 and Cycles 12-14 during the Treatment Continuation Period, although the PI may perform safety laboratory 
assessments or other tests per institutional practice (these results are not required to be reported in the eCRF). However, information on treatment administration will 
be collected, and new or worsened clinically significant abnormalities should be recorded as AEs on the Adverse Event eCRF.
…
n.
Haematology:  haemoglobin, total WBC, ANC / neutrophils, platelet count.  Limited biochemistry:  alkaline phosphatase; AST; ALT; LDH; total bilirubin;
creatinine. Albumin should be measured at Screening for determining patient eligibility. Bilirubin fractions (direct and indirect) must be included if total bilirubin 
is greater than ULN. During the treatment period, bloods for haematology / biochemistry may be taken within three days prior to study treatment 
administration.
o.
Pregnancy testing is only required for women of childbearing potential:  A woman of childbearing potential is defined as: post-menarchal, has not reached a 
post-menopausal state (post-menopausal defined as ≥12 continuous months of amenorrhea with no identified cause other than menopause), and has 
not undergone surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing potential may be adapted for alignment with local 
guidelines or requirements. For all women of childbearing potential, Ppregnancy tests must be performed via serum -human chorionic gonadotropin 
(HCG) at baseline within seven days prior to first study treatment administration. Urine pregnancy tests should be repeated during the Treatment Cross-
over and Treatment Continuation Periods within seven days prior to every three treatment cycles starting at Cycle 4, Cycle 7, Cycle 11 and Cycle 15 (or at 
last treatment cycle), (and as clinically indicated), with results available prior to study treatment administration, as well as at the End of Treatment Visit and 
at the Follow-up Visit until seven months after discontinuation of study treatment. Any positive urine pregnancy test must be confirmed with a serum 
-HCG test. 




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TABLE OF CONTENTS
1.
BACKGROUND .................................................................................................... 29
1.1
Background on HER2-Positive Early Breast Cancer............................ 29
1.2
Background on Study Medications....................................................... 30
1.2.1
Study Drug Nomenclature ................................................................... 30
1.2.2
Background on Perjeta ........................................................................ 30
1.2.3
Background on Herceptin .................................................................... 31
1.2.4
Background on Pertuzumab and Trastuzumab Fixed-Dose 
Combination for Subcutaneous Administration .................................... 31
1.3
Study Rationale and Benefit-Risk Assessment .................................... 33
1.3.1
Study Rationale ................................................................................... 33
1.3.2
Benefit-Risk Assessment..................................................................... 34
2.
OBJECTIVES AND ENDPOINTS ......................................................................... 34
2.1
Objectives............................................................................................ 35
2.1.1
Primary Objective ................................................................................ 35
2.1.2
Secondary Objectives.......................................................................... 35
2.1.2.1
Secondary Safety Objectives............................................................... 35
2.1.2.2
Secondary Efficacy Objective .............................................................. 36
3.
STUDY DESIGN................................................................................................... 36
3.1
Description of the Study....................................................................... 36
3.2
End of Study and Length of Study ....................................................... 39
3.3
Rationale for Study Design .................................................................. 40
3.3.1
Rationale for Perjeta IV, Herceptin IV, and Pertuzumab and 
Trastuzumab FDC SC Doses and Schedules ...................................... 40
3.3.2
Rationale for Patient Population .......................................................... 40
3.3.3
Rationale for Randomization Stratification Factors .............................. 40
3.3.4
Rationale for Randomized Cross-Over Design .................................... 41
3.3.5
Rationale for Patient Reported Outcome Assessments ....................... 41
4.
MATERIALS AND METHODS .............................................................................. 42
4.1
Patients ............................................................................................... 42
4.1.1
Inclusion Criteria.................................................................................. 42
4.1.2
Exclusion Criteria................................................................................. 44
4.2
Method of Treatment Assignment........................................................ 45
4.3
Study Treatment.................................................................................. 46
4.3.1
Study Treatment Formulation, Packaging, and Handling ..................... 46
4.3.1.1
Pertuzumab and Trastuzumab FDC SC............................................... 46
4.3.1.2
Perjeta IV............................................................................................. 46
4.3.1.3
Herceptin IV......................................................................................... 46
4.3.2
Study Treatment Dosage, Administration, and Compliance ................. 46
4.3.2.1
Pertuzumab and Trastuzumab FDC SC............................................... 47


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4.3.2.2
Perjeta IV............................................................................................. 47
4.3.2.3
Herceptin IV......................................................................................... 47
4.3.3
Investigational Medicinal Product Accountability.................................. 48
4.3.4
Continued Access to Pertuzumab and Trastuzumab FDC SC, 
Perjeta IV and Herceptin IV ................................................................. 48
4.4
Concomitant Therapy .......................................................................... 48
4.4.1
Permitted Therapy............................................................................... 49
4.4.2
Cautionary Therapy ............................................................................. 49
4.4.3
Prohibited Therapy .............................................................................. 50
4.5
Study Assessments ............................................................................. 50
4.5.1
Informed Consent Forms and Screening Log ...................................... 50
4.5.2
Medical History, Concomitant Medication, and Demographic 
Data..................................................................................................... 51
4.5.3
Pathology ............................................................................................ 51
4.5.4
Physical Examinations......................................................................... 51
4.5.5
Vital Signs ........................................................................................... 51
4.5.6
ECOG Performance Status.................................................................. 51
4.5.7
Clinical Breast Examination ................................................................. 52
4.5.8
Mammograms...................................................................................... 52
4.5.9
Diagnosis of Breast Cancer Recurrence or Second Primary 
Cancer................................................................................................. 52
4.5.10
Cardiac Function ................................................................................. 53
4.5.11
Laboratory Samples............................................................................. 53
4.5.12
Patient Reported Outcomes................................................................. 53
4.5.12.1
Patient Preference Questionnaire........................................................ 54
4.5.12.2
Therapy Administration Satisfaction Questionnaires............................ 54
4.5.12.3
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire (EORTC QLQ-C30) ................... 54
4.5.13
Healthcare Professional Reported Outcomes ...................................... 54
4.5.13.1
Healthcare Professional Questionnaire................................................ 54
4.6
Treatment, Patient, Study, and Site Discontinuation ............................ 54
4.6.1
Study Treatment Discontinuation......................................................... 54
4.6.2
Patient Discontinuation from Study...................................................... 55
4.6.3
Study Discontinuation.......................................................................... 55
4.6.4
Site Discontinuation............................................................................. 55
5.
ASSESSMENT OF SAFETY................................................................................. 56
5.1
Safety Plan.......................................................................................... 56
5.1.1
Risks Associated with Pertuzumab...................................................... 56
5.1.1.1
Hypersensitivity Reactions / Anaphylaxis and Administration-
Related Reactions ............................................................................... 56
5.1.1.2
Symptomatic Left Ventricular Systolic Dysfunction .............................. 57
5.1.1.3
Epidermal Growth Factor Receptor (HER1)-Related 
Toxicities ............................................................................................. 58
5.1.2
Risks Associated with Trastuzumab .................................................... 59


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5.1.2.1
Administration-Related Reactions, Allergic-Like Reactions, 
and Hypersensitivity............................................................................. 59
5.1.2.2
Pulmonary Events ............................................................................... 61
5.1.2.3
Symptomatic Left Ventricular Systolic Dysfunction .............................. 61
5.1.3
Reproductive Risks Associated with Pertuzumab and 
Trastuzumab ....................................................................................... 62
5.1.3.1
Breastfeeding ...................................................................................... 63
5.1.4
Management of Patients Who Experience Adverse Events ................. 63
5.1.4.1
Dose Modifications for Perjeta IV, Herceptin IV, and 
Pertuzumab and Trastuzumab FDC SC............................................... 63
5.1.4.2
Dose Delays and Treatment Interruption for Perjeta IV, 
Herceptin IV, and Pertuzumab and Trastuzumab FDC SC .................. 63
5.1.4.3
Management Guidelines...................................................................... 64
5.2
Safety Parameters and Definitions....................................................... 66
5.2.1
Adverse Events ................................................................................... 66
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor).............................................................................................. 66
5.2.3
Adverse Events of Special Interest (Immediately Reportable 
to the Sponsor).................................................................................... 67
5.2.4
Selected Adverse Events..................................................................... 67
5.2.4.1
Heart Failure........................................................................................ 67
5.2.4.2
Asymptomatic Declines in Left Ventricular Ejection Fraction................ 68
5.2.4.3
Administration-Related Reactions: Infusion-Related 
Reactions, Injection-Related Reactions, and Injection-Site 
Reactions and Infusion-Site Reactions.................................................... 68
5.3
Methods and Timing for Capturing and Assessing 
Safety Parameters............................................................................... 69
5.3.1
Adverse Event Reporting Period.......................................................... 69
5.3.2
Eliciting Adverse Event Information ..................................................... 70
5.3.3
Assessment of Severity of Adverse Events.......................................... 70
5.3.4
Assessment of Causality of Adverse Events........................................ 71
5.3.5
Procedures for Recording Adverse Events .......................................... 71
5.3.5.1
Diagnosis versus Signs and Symptoms............................................... 71
5.3.5.2
Adverse Events That Are Secondary to Other Events.......................... 72
5.3.5.3
Persistent or Recurrent Adverse Events .............................................. 72
5.3.5.4
Abnormal Laboratory Values ............................................................... 72
5.3.5.5
Abnormal Vital Sign Values ................................................................. 73
5.3.5.6
Abnormal Liver Function Tests ............................................................ 74
5.3.5.7
Deaths................................................................................................. 74
5.3.5.8
Pre-Existing Medical Conditions .......................................................... 74
5.3.5.9
Lack of Efficacy or Recurrence of Breast Cancer................................. 75
5.3.5.10
Hospitalization or Prolonged Hospitalization ........................................ 75
5.3.5.11
Patient Reported Outcome Data.......................................................... 75
5.4
Immediate Reporting Requirements from Investigator to 
Sponsor............................................................................................... 76


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5.4.1
Emergency Medical Call Centre .......................................................... 76
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest ...................................................... 76
5.4.2.1
Events That Occur Prior to Study Drug Initiation .................................. 76
5.4.2.2
Events That Occur after Study Drug Initiation...................................... 77
5.4.3
Reporting Requirements for Pregnancies ............................................ 77
5.4.3.1
Pregnancies in Female Patients .......................................................... 77
5.4.3.2
Pregnancies in Female Partners of Male Patients ............................... 78
5.4.3.3
Abortions ............................................................................................. 78
5.4.3.4
Congenital Anomalies / Birth Defects................................................... 78
5.4.4
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error .................................................................................. 78
5.5
Follow-Up of Patients after Adverse Events......................................... 79
5.5.1
Investigator Follow-Up......................................................................... 79
5.5.2
Sponsor Follow-Up .............................................................................. 80
5.6
Adverse Events That Occur after the Adverse Event 
Reporting Period.................................................................................. 80
5.7
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ........................... 80
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ................................. 81
6.1
Determination of Sample Size ............................................................. 81
6.2
Summaries of Conduct of Study .......................................................... 82
6.3
Summaries of Demographic and Baseline Characteristics................... 82
6.4
Primary Endpoint Analysis................................................................... 82
6.5
Secondary Endpoint Analyses ............................................................. 82
6.5.1
Safety Analyses................................................................................... 82
6.5.2
Efficacy Analyses ................................................................................ 84
6.6
Optional Interim Analyses.................................................................... 84
7.
DATA COLLECTION AND MANAGEMENT.......................................................... 85
7.1
Data Quality Assurance....................................................................... 85
7.2
Electronic Case Report Forms............................................................. 85
7.3
Source Data Documentation................................................................ 85
7.4
Use of Computerized Systems ............................................................ 86
7.5
Retention of Records........................................................................... 86
8.
ETHICAL CONSIDERATIONS.............................................................................. 86
8.1
Compliance with Laws and Regulations............................................... 86
8.2
Informed Consent................................................................................ 87
8.3
Institutional Review Board or Ethics Committee................................... 88
8.4
Confidentiality...................................................................................... 88
8.5
Financial Disclosure............................................................................. 89


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9.
STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION................ 89
9.1
Study Documentation .......................................................................... 89
9.2
Protocol Deviations.............................................................................. 89
9.3
Site Inspections ................................................................................... 89
9.4
Administrative Structure....................................................................... 89
9.5
Dissemination of Data and Protection of Trade Secrets....................... 90
9.6
Protocol Amendments ......................................................................... 90
10.
REFERENCES ..................................................................................................... 92
LIST OF TABLES
Table 1
Reporting Conventions for Left Ventricular Systolic 
Dysfunction / Congestive Heart Failure.................................................. 68
Table 2
Reporting Conventions for Administration-Related Reactions ................ 69
Table 3
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE ............................................................................. 70
Table 4
Causal Attribution Guidance .................................................................. 71
LIST OF FIGURES
Figure 1
Study Schema ....................................................................................... 37
Figure 2
Study Treatment Cycle Calculation ........................................................ 38
LIST OF APPENDICES
Appendix 1
Schedule of Activities............................................................................ 95
Appendix 2
Patient Reported Outcome Measures ................................................. 102
Appendix 3
Healthcare Professional Reported Outcome Measures....................... 110
Appendix 4
American Cancer Society / American Society of Clinical Oncology 
Breast Cancer Survivorship Care Guideline......................................... 123
Appendix 5
Eastern Cooperative Oncology Group Performance Status Scale....... 124
Appendix 6
Asymptomatic Decline in LVEF:  Algorithm for Continuation and 
Discontinuation of Study Treatment ..................................................... 125
Appendix 7
NYHA Functional Classification System for Heart Failure and LVSD 
NCI CTCAE V4.0 Grading.................................................................... 126


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15 / Protocol MO40628, Version 2
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A RANDOMIZED, MULTICENTER, OPEN-LABEL 
CROSS-OVER STUDY TO EVALUATE PATIENT 
PREFERENCE 
AND 
SATISFACTION 
OF 
SUBCUTANEOUS 
ADMINISTRATION 
OF 
THE 
FIXED-DOSE COMBINATION OF PERTUZUMAB 
AND TRASTUZUMAB IN PATIENTS WITH HER2-
POSITIVE EARLY BREAST CANCER
PROTOCOL NUMBER:
MO40628
VERSION NUMBER:
2
EUDRACT NUMBER:
2018-002153-30
IND NUMBER:
131009
TEST PRODUCT:
Fixed-dose combination of pertuzumab and trastuzumab 
for subcutaneous administration (RO7198574)
MEDICAL MONITOR:
Dr. 
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 of the 
signed form as instructed by your local study monitor.








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Study Design
Description of Study
This is a Phase II, randomized, multi-centre, multinational, open-label, cross-over study in adult 
patients who have completed neoadjuvant chemotherapy with neoadjuvant Perjeta and Herceptin and 
have undergone surgical treatment of HER2+ EBC. An overview of the study design is provided in the 
figure below.  A Schedule of Activities is provided in Appendix 1.
Study Schema
Abbreviations: IV: intravenous; P+H: Perjeta + Herceptin; FDC SC: subcutaneously 
administered fixed-dose combination of pertuzumab and trastuzumab; HCPQs: Healthcare 
Professional Questionnaires; PPQ: Patient Preference Questionnaire; SC subcutaneous; 
TASQ: Therapy Administration Satisfaction Questionnaire
Eligibility will be assessed within a 28-day screening period. Eligible patients will be enrolled and 
randomly allocated in a 1:1 ratio to treatment Arm A (P+H IV followed by pertuzumab and 
trastuzumab FDC SC) or treatment Arm B (FDC SC followed by P+H IV). Patients will be stratified 
according to neoadjuvant chemotherapy regimen (anthracyclines + taxanes vs. carboplatin + taxanes 
vs. taxanes only), neoadjuvant treatment response (pathologic complete response [pCR] vs. non-pCR)
and hormone receptor status (oestrogen receptor [ER]-positive and/or progesterone receptor [PgR]-
positive vs. ER-negative and PgR-negative). Study treatment will be initiated ≥2 weeks from breast 
cancer surgery but ≤9 weeks from the last administration of systemic neoadjuvant therapy and will be 
administered on Day 1 of each 3-week treatment cycle. No adjuvant chemotherapy is allowed after 
surgery, however, adjuvant hormone and/or radiation therapy are allowed.
Patients randomized to Arm A will receive P+H IV for three treatment cycles followed by pertuzumab 
and trastuzumab FDC SC for three treatment cycles. Patients randomized to Arm B will receive 
pertuzumab and trastuzumab FDC SC for three treatment cycles followed by P+H IV for three 
treatment cycles. This period of 3+3 cycles in both treatment arms constitutes the study Treatment 
Cross-over Period.
The 6 study treatment cycles of pertuzumab and trastuzumab FDC SC and P+H IV received during 
the Treatment Cross-over Period and P+H treatment cycles received in the neoadjuvant setting prior 
to study entry will be considered part of the total 18 anti-HER2 treatment cycles planned for all study 
patients. Following completion of the Treatment Cross-over Period, patients will enter the Treatment 
Continuation Period wherein they will receive the remaining anti-HER2 treatment cycles required to 
complete their 18 planned cycles unless disease recurrence, unacceptable toxicity or patient 
withdrawal from treatment necessitates early treatment cessation. Study treatment during this period 
will be either P+H IV or pertuzumab and trastuzumab FDC SC as selected by the patient at the end of 
the Treatment Cross-over Period. 


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Patients who, by the investigator’s assessment, cannot tolerate pertuzumab and trastuzumab FDC 
SC or P+H IV may be allowed to receive P+H IV or pertuzumab and trastuzumab FDC SC, 
respectively, for their remaining planned anti-HER2 treatment cycles. The investigator must obtain 
approval from the Medical Monitor to switch study treatment.
Patient preference will be assessed based on the Patient Preference Questionnaire (PPQ)
(administered following treatment administration on Day 1, Cycle 6 of the Treatment Cross-over 
Period). Treatment satisfaction will be assessed based on the Therapy Administration Satisfaction 
Questionnaire (TASQ) (administered following treatment administration on Day 1 of Cycles 3 and 6 of 
the Treatment Cross-over Period). 
Healthcare professionals will record their perception of 
time/resource use and convenience
of treatment administration completing the
Healthcare 
Professional Questionnaires (HCPQs). Perception of time use will be captured during the Treatment 
Cross-over Period and perception of convenience will be captured after administration of each 
patient’s treatment Cycle 6. Health-related quality of life will be assessed based on the European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-
C30 completed at baseline, Cycle 3, Cycle 6, and the end of study treatment visits as well as at 18 
months, 2 years, and 3 years from randomization. The study questionnaires are provided in 
Appendix 2 and Appendix 3.
Patients will be assessed for safety by regular evaluation of adverse events (AEs), vital signs, routine 
clinical laboratory tests (haematology, blood chemistry) and left ventricular ejection fraction (LVEF)
assessments; and by physical examinations. Adverse events will be reported and graded according to 
the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI 
CTCAE v4.0). Efficacy will be assessed based on investigator-evaluated disease status determined 
according to assessments conducted per institutional practice or according to the American Cancer 
Society / American Society of Clinical Oncology (ACS/ASCO) Breast Cancer Survivorship Care 
Guideline [Runowicz et al. 2016, see Appendix 4].
Patients will undergo an End of Treatment Visit approximately 28 days after completing study 
treatment and will enter the Follow-up Period wherein they will be followed for safety, disease status, 
survival and HRQoL (via the EORTC QLQ-C30) for three years from the date the last patient is 
randomized.
Patients who withdraw from the study following randomization will not be replaced. Patients can be 
screened for the study more than once.   
Number of Patients
Approximately 140 patients will be randomized in the study to obtain at least 126 evaluable patients. 
Target Population
The target population will consist of adult patients with HER2+ EBC who have received neoadjuvant 
Perjeta and Herceptin, and have completed neoadjuvant chemotherapy and subsequently undergone 
surgery for their breast cancer.  
Inclusion Criteria
Patients must meet the following criteria for study entry:
Disease-specific criteria

Female or male with histologically confirmed, HER2+ inflammatory, locally advanced or early-
stage breast cancer who have received neoadjuvant Perjeta + Herceptin and have completed 
neoadjuvant chemotherapy and subsequently undergone surgery for their breast cancer.
Note: The neoadjuvant chemotherapy regimen (including type and sequencing of selected agents) 
and the number of neoadjuvant Perjeta and Herceptin treatment cycles are at the discretion of the 
treating physician and patient. Subcutaneously administered Herceptin may have been used in 
the neoadjuvant setting. The use of any trastuzumab biosimilars in the neoadjuvant setting is not 
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
HER2+ breast cancer assessed at the local laboratory prior to initiation of neoadjuvant therapy. 
HER2+ status must be determined based on breast biopsy material obtained prior to neoadjuvant 
treatment and is defined as 3+ by immunohistochemistry (IHC) and/or positive by HER2 
amplification by in situ hybridization (ISH) with a ratio of ≥2 for the number of HER2 gene copies 
to the number of chromosome 17 copies

Hormone receptor status of the primary tumour determined by local assessment. Hormone 
receptor positive status may be either positive (i.e. ER-positive and/or PgR-positive) or negative 
(i.e. ER-negative and PgR-negative)

Completed all neoadjuvant chemotherapy and surgery. Adjuvant radiotherapy may be planned or 
ongoing at study entry and adjuvant hormone therapy is allowed during the study. Note that study 
treatment cannot be initiated within < 2 weeks of surgery but must be initiated ≤9 weeks from the 
last administration of systemic neoadjuvant therapy.

No evidence of residual, locally recurrent or metastatic disease after completion of surgery. 
Patients with clinical suspicion of metastases must undergo radiological assessments per 
institutional practice to rule out distant disease.

Wound healing after breast cancer surgery adequate per investigator’s assessment to allow 
initiation of study treatment within ≤9 weeks of last systemic neoadjuvant therapy

No adjuvant chemotherapy planned. Note that adjuvant hormonal treatment is allowed during the 
study.
General criteria

Signed Informed Consent Form

Age ≥18 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator’s judgment

Eastern Cooperative Oncology Group performance status 0 or 1

Intact skin at planned site of subcutaneous (SC) injections (thigh)

LVEF ≥55% measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA)
within 28 days of study randomization

No major surgical procedure unrelated to breast cancer within 28 days prior to randomization or 
anticipation of the need for major surgery during the course of study treatment

For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive measures, and agreement to refrain from donating eggs, as 
defined below:
Women must remain abstinent or use non-hormonal contraceptive methods with a failure rate of 
<1% per year, or 2 effective non-hormonal contraceptive methods during the study treatment 
periods and for 7 months after the last dose of study treatment. Women must refrain from 
donating eggs during this same period. 
A woman is considered to be of childbearing potential if she is post-menarchal, has not reached a 
post-menopausal state (post-menopausal defined as ≥ 12 continuous months of amenorrhea with 
no identified cause other than menopause), and has not undergone surgical sterilization (removal 
of ovaries and/or uterus). The definition of childbearing potential may be adapted for alignment 
with local guidelines or requirements.
Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization (with appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate) and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical 
trial and the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods 
of contraception.


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
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, 
and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must remain 
abstinent or use a condom during the study treatment periods and for seven months after the last 
dose of study treatment to avoid exposing the embryo. Men must refrain from donating sperm 
during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical 
trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods 
of preventing drug exposure. 

A negative serum pregnancy test must be available prior to randomization for women of 
childbearing potential (defined as post-menarchal, has not had ≥12 continuous months of 
amenorrhea with no identified cause other than menopause, and has not undergone surgical 
sterilization [removal of ovaries and/or uterus])
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Cancer-specific criteria

Stage IV (metastatic) breast cancer 

Current or prior history of active malignancy (other than current breast cancer) within the last five 
years. Appropriately treated non-melanoma skin cancer; in situ carcinomas, including cervix, 
colon, or skin; or Stage I uterine cancer within the last five years are allowed. 
A patient with previous invasive non-breast cancer is eligible provided he/she has been disease 
free for more than five years.

Previous systemic therapy (including chemotherapy, immunotherapy, HER2-targeted agents, 
endocrine therapy [selective oestrogen receptor modulators, aromatase inhibitors], and antitumor 
vaccines) for treatment or prevention of breast cancer, except neoadjuvant Perjeta, Herceptin and 
chemotherapy for current breast cancer
General criteria:

Investigational treatment within four weeks of enrolment 

Serious cardiac illness or medical conditions including, but not confined to, the following:
−
History of NCI CTCAE v4.0 Grade ≥ 3 symptomatic congestive heart failure (CHF) or New 
York Heart Association (NYHA) Class ≥ II
−
High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate ≥ 100/min at rest, 
significant ventricular arrhythmia [ventricular tachycardia], or higher-grade atrioventricular 
[AV]-block, such as second-degree AV-block Type 2 [Mobitz II] or third-degree AV-block)
−
Serious cardiac arrhythmia or severe conduction abnormality not controlled by adequate 
medication 
−
Angina pectoris requiring anti-angina medication
−
Clinically significant valvular heart disease
−
Evidence of transmural infarction on electrocardiogram (ECG)
−
Evidence of myocardial infarction within 12 months prior to randomization
−
Poorly controlled hypertension (e.g., systolic > 180 mmHg or diastolic > 100 mmHg)

History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural 
heart disease (e.g., severe left ventricular systolic dysfunction [LVSD], left ventricular 
hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic 


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testing), clinically significant electrolyte abnormalities (e.g., hypokalaemia, hypomagnesemia, 
hypocalcaemia), or family history of sudden unexplained death or long QT syndrome

Inadequate bone marrow function, defined by any of:
−
Absolute neutrophil count < 1.5 x 109/L
−
Platelet count < 100 x 109/L
−
Haemoglobin < 9 g/dL

Impaired liver function, defined by any of:
−
Serum (total) bilirubin > 1.25 x upper limit of normal (ULN). In case of Gilbert’s syndrome: a 
total bilirubin of 2 x ULN is permitted.
−
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 1.25 x ULN
−
Albumin < 25 g/L

Inadequate renal function with serum creatinine > 1.5 x ULN

Current severe, uncontrolled systemic disease that may interfere with planned treatment (e.g., 
clinically significant cardiovascular, pulmonary, or metabolic disease; wound-healing disorders)

Pregnant or breastfeeding, or intending to become pregnant during the study or within seven 
months after the last dose of study treatment. Women of childbearing potential must have a 
negative serum pregnancy test result within seven days prior to initiation of study treatment

Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator’s 
judgment, precludes the patient’s safe participation in, and completion of, the study

Known active liver disease, for example, active viral hepatitis infection (i.e., hepatitis B or hepatitis 
C), autoimmune hepatic disorders, or sclerosing cholangitis

Concurrent, serious, uncontrolled infections, or known infection with human immunodeficiency
virus (HIV)

Known hypersensitivity to any of the study drugs, excipients, and/or murine proteins

Current chronic daily treatment with corticosteroids (dose > 10 mg methylprednisolone or 
equivalent excluding inhaled steroids)
End of Study
The end of the study is defined the Last Patient, Last Visit (LPLV) which will occur three years after 
the last patient is randomized or the date at which the last data point required for the final statistical 
analysis or safety follow-up is received from the last patient, whichever occurs later.
In addition, the Sponsor may decide to terminate the study at any time.
Length of Study
The study is estimated to last approximately 4 years, based on a recruitment period of up to 10 
months and 3 years of follow-up after the last patient is randomized.
Investigational Medicinal Products
The investigational medicinal products (IMPs) for this study are pertuzumab and trastuzumab FDC 
SC, Perjeta IV, and Herceptin IV.
Test Product (Investigational Drug)
Pertuzumab and trastuzumab FDC SC is given as a fixed dose (i.e. non-weight based). Pertuzumab 
and trastuzumab FDC SC will be provided in a loading dose configuration and a maintenance dose 
configuration. The 15 mL loading dose consists of 1200 mg pertuzumab and 600 mg trastuzumab. 
The 10 mL maintenance dose consists of 600 mg pertuzumab and 600 mg trastuzumab. Patients who 
have had ≥ 6 weeks since their last neoadjuvant dose of Perjeta or Herceptin at study entry, or have 
had ≥6 weeks since their last study treatment during the study treatment periods, must receive a 
loading dose before continuing with maintenance doses for subsequent administrations. All 


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pertuzumab and trastuzumab FDC SC doses are administered by SC injection over 5 – 8 minutes at a 
rate of ≤ 2 mL/min with hand-held syringe to the thigh on Day 1 of each 3-week treatment cycle.
Patients should be monitored for 30 minutes after their first pertuzumab and trastuzumab FDC SC 
dose administration regardless of whether a loading dose is required. Patients should be monitored 
for 10 - 15 minutes following subsequent administrations. Patients can be observed for longer periods 
at the discretion of the investigator or if necessary, as per local requirements.
Comparator (Active Control)
Perjeta IV is administered at a dose of 840 mg (loading dose) or 420 mg (maintenance dose) on Day 
1 of each 3-week treatment cycle and should be administered before Herceptin IV. Patients who have 
had ≥ 6 weeks since their last neoadjuvant dose of Perjeta at study entry, or have had ≥6 weeks 
since their last study treatment during the study treatment periods, must receive a loading dose 
before continuing with maintenance doses for subsequent administrations. Perjeta IV loading dose (if 
required) will be administered as a 60-minute infusion (± 10 minutes), followed by an observation 
period of 60 minutes. If the loading dose infusion is well tolerated, subsequent maintenance doses 
can be administered over a period of 30 minutes (± 10 minutes) with an observation period of 30 
minutes. Patients can be observed for longer periods at the discretion of the investigator or if 
necessary, as per local requirements. The observation period should be completed prior to the 
subsequent Herceptin IV infusion.
Herceptin IV is administered at a dose of 8 mg/kg (loading dose) or 6 mg/kg (maintenance dose) on 
Day 1 of each 3-week treatment cycle. Patients who have had ≥ 6 weeks since their last neoadjuvant 
dose of Herceptin at study entry, or have had ≥ 6 weeks since their last study treatment during the 
study treatment periods, must receive a loading dose before continuing with maintenance doses for 
subsequent administrations. Herceptin IV loading dose (if required) will be administered as an infusion 
over approximately 90 (± 10) minutes after which the patient must be observed for 60 minutes. If the 
loading dose is well tolerated, subsequent maintenance doses can be administered as 30-minute 
infusions (± 10 minutes) followed by an observation period of 30 minutes. Patients can be observed 
for longer periods at the discretion of the investigator or if necessary, as per local requirements.
Non-Investigational Medicinal Products
Not applicable. 
Statistical Methods
Primary Analysis
The primary objective of this study is to evaluate patient preference for pertuzumab and trastuzumab 
FDC SC based on the proportion of patients indicating an overall preference for pertuzumab and 
trastuzumab FDC SC based on Question 1 of the PPQ. Question 1 of the PPQ is as follows: “All 
things considered, which method of administration did you prefer?”.
The primary endpoint will be analysed for the intent-to-treat (ITT) population and for the modified ITT 
(mITT) population. The mITT population will include all patients who received at least one dose by 
both SC and IV routes of administration during the Treatment Cross-over Period and subsequently 
answered at least Question 1 of the PPQ.  
A point estimate with associated 95% confidence interval (CI) for the proportion of patients who 
preferred pertuzumab and trastuzumab FDC SC will be calculated for the mITT and ITT populations.
Analysis of the primary study endpoint will take place when all patients have completed their last 
treatment administration during the Treatment Cross-over Period. 
Determination of Sample Size  
The binary primary endpoint (the proportion of patients who express a preference for pertuzumab and 
trastuzumab FDC SC) will be estimated with associated two-sided 95% CI.


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Assuming a rate of 70% of patients preferring pertuzumab and trastuzumab FDC SC and aiming at a 
distance from the estimated proportion to the CI limits of approximately ± 8%, a total of 126 patients 
are needed for the evaluation of preference. Hence, the observed rate of 70% of patients preferring 
pertuzumab and trastuzumab FDC SC could be estimated to be within 61.9% and 78.4% with a 
probability of 95%.
To allow for 10% of the patients not providing an evaluable preference assessment, approximately 
140 patients are targeted to be randomized into the study.
Optional Interim Analysis
An interim safety analysis may be conducted. The decision to perform an interim safety analysis will 
be based on ongoing review of safety data by the Medical Monitor. If conducted, the results of this 
interim analysis will be evaluated by a Sponsor’s Internal Data Monitoring Committee. An interim 
analysis will be conducted to support a planned regulatory filing for FDC, which will consist of a subset of the 
analyses planned for the primary analysis. The results of this interim analysis will be evaluated by a Sponsor’s 
Internal Monitoring Committee. Further details will be specified in the Statistical Analysis Plan.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ACE
angiotensin-converting enzyme
ACS/ASCO
American Cancer Society / American Society of Clinical Oncology Breast 
Cancer
ADA
anti-drug antibody
ADCC
antibody dependent cell-mediated cytotoxicity
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ARDS
acute respiratory distress syndrome
ARR
administration-related reactions
AST
aspartate aminotransferase
AUC
area under the curve
AV
atrioventricular
CHF
congestive heart failure
CI
confidence interval
CRO
contract research organization
Ctrough
serum trough concentration
DDFS
distant disease-free survival
EBC
early breast cancer
EC
Ethics Committee
ECD
extracellular domain
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EFS
event-free survival
EGFR
epidermal growth factor receptor
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire C30
ER
oestrogen receptor
EU
European Union
FDC SC
Fixed-dosed combination formulation for subcutaneous administration
HCG 
human chorionic gonadotropin 
HCP
healthcare professional
HCPQ
Healthcare Professional Questionnaire
HER2
human epidermal growth factor receptor 2
HER2+
HER2-positive


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HER
human epidermal growth factor receptor
Herceptin IV
Herceptin for IV administration
Herceptin SC
Herceptin for SC administration
HIPPA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HRQoL
health-related quality of life
ICH
International Council for Harmonisation
IDFS 
invasive disease-free survival 
Ig
immunoglobulin
IHC
immunohistochemistry
IV
intravenous(ly)
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
ISH
in situ hybridization
ISR
injection site reaction
ITT
intent-to-treat 
IUD
intrauterine device
IWRS
interactive web-based response system
LDH
lactate dehydrogenase
LPLV
last patient, last visit
LVEF
left ventricular ejection fraction
LVSD
left ventricular systolic dysfunction
MBC
metastatic breast cancer
MedDRA
Medical Dictionary for Regulatory Activities 
mITT
modified intent-to-treat 
MRI
magnetic resonance imaging
MUGA
multiple-gated acquisition scan
NCI CTCAE v4.0
National Cancer Institute Common Terminology Criteria for Adverse Events 
version 4.0 
NYHA
New York Heart Association
OS
overall survival
P+H IV 
Perjeta IV and Herceptin IV 
pCR
pathologic complete response
Perjeta IV
Perjeta for IV administration
PFS
progression–free survival
PgR
progesterone receptor
PK
pharmacokinetic(s)
PPQ
Patient Preference Questionnaire
PRO
patient reported outcome
QoL
quality of life


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rHuPH20 
recombinant human PH20 hylauronidasehyaluronidase
SAE
serious adverse event
SC
subcutaneous(ly)
SmPC
Summary of Product Characteristics
TASQ-IV
Therapy Administration Satisfaction Questionnaire – intravenous
TASQ-SC
Therapy Administration Satisfaction Questionnaire – subcutaneous 
ULN
upper limit of normal
U.S.
United States
WBC
white blood count


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1.
BACKGROUND
1.1
BACKGROUND ON HER2-POSITIVE EARLY BREAST CANCER
Among developed countries, breast cancer is the most common malignancy and was 
associated with 198 000 deaths in 2012 alone. Globally, its incidence is exceeded only by 
lung cancer [Ferlay et al. 2013]. 
Amplification or overexpression of the human epidermal growth factor receptor 2 (HER2) 
gene occurs in 20% to 30% of invasive breast cancers and has both prognostic and 
predictive implications [Slamon et al. 1987, Owens et al. 2004]. HER2 is a member of the 
family of human epidermal growth factor receptors (HER) that includes HER1 [also known as 
epidermal growth factor receptor (EGFR)], HER3, and HER4. Each HER receptor consists of
an extracellular ligand binding site, a transmembrane lipophilic segment, and an intracellular 
domain with tyrosine kinase catalytic activity. HER activation initiates a variety of intracellular 
signalling pathways
that are involved in cell proliferation, survival, differentiation, 
angiogenesis, and invasion. Low levels of HER2 are normally expressed on the surface of 
epithelial cells and are necessary for the normal development and repair of many tissues, 
including those of the breast, gastrointestinal tract, central nervous system and myocardium 
[Ozcelik et al. 2002, Vu and Claret 2012, Iqbal and Iqbal 2014]. When overexpressed in 
breast tumours, however, HER2 is associated with more aggressive disease characterized 
by shorter times to relapse and overall survival (OS) [Slamon et al. 1987, Carr et al. 2000].
HER2 activation occurs via autophosphorylation of receptor cytoplasmic domains through 
homo-dimerization or hetero-dimerization with other ligand-induced HER family members
wherein HER2 is the preferred HER family dimerization partner [Graus-Porta et al. 1997,
Moasser 2007]. Constitutive HER2 activation and downstream signalling can also occur by 
proteolytic cleavage of its extracellular domain (ECD), a process known as shedding, to 
produce a truncated internal domain [Molina et al. 2001]. 
The benefit of anti-HER2 treatment strategies for HER2-positive (HER2+) breast cancer was
first realized with the introduction of the anti-HER2 monoclonal antibody trastuzumab 
(Herceptin®) into clinical management in 2000 [Cobleigh et al. 1999, Slamon et al. 2001, 
Bonifazi et al. 2014]. The subsequent development of additional HER2-targeted agents,
including pertuzumab (Perjeta®; another HER2-specific monoclonal), trastuzumab 
emtansine (a trastuzumab-cytotoxic drug conjugate), and lapatinib and neratinib 
(HER2/HER1 tyrosine kinase inhibitors), has widened the range of available anti-HER2 
approaches including the possibility for dual HER2 blockade with Perjeta and Herceptin. 
Perjeta and Herceptin each bind to distinct epitopes on the HER2 ECD without competing 
with each other. As described in Sections 1.2.2 and 1.2.3, these molecules have 
complementary mechanisms for disrupting HER2 signalling. Dual HER2 blockade with 
Perjeta and Herceptin in HER2+ disease has been shown to improve pathologic complete 
response (pCR) in the neoadjuvant setting, invasive disease-free survival (IDFS) in the 
adjuvant setting, and progression-free survival (PFS) and OS in the metastatic setting, and 
has become standard of care in each of these indications [Swain et al. 2013, Gianni et al. 
2016, von Minckwitz et al. 2017, Cardoso et al. 2017, Curigliano et al. 2017, Gradisher et al. 
2018].


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While improving disease outcomes, the incorporation of intravenously administered (IV)
Perjeta and Herceptin IV (P+H IV) into HER2+ breast cancer care results in longer treatment 
administration schedules due to sequential administration of each monoclonal antibody in 
addition to IV chemotherapeutics. A recently reported metastatic breast cancer (MBC) study 
evaluated Herceptin IV and Perjeta IV combined for administration from a single infusion bag 
compared with Perjeta IV and Herceptin IV administered as sequential infusions. The study 
found the safety profile in the co-infused treatment group was consistent with the known 
toxicity profiles of each drug with no unexpected safety signals and no apparent alteration 
with co-mixing / co-infusion [Andersson et al. 2017]. 
More recently, Herceptin has been developed in a formulation for subcutaneous (SC) 
administration (see Section 1.2.3) that can be delivered in under 5 minutes versus the
30-60 minute infusions required for administration of the IV formulation. Herceptin SC has 
been shown to be preferred over Herceptin IV by HER2+ early breast cancer (EBC) patients 
in a randomized, cross-over study [Pivot et al. 2013]. Herceptin SC is currently approved in 
the EU for use in the neoadjuvant, adjuvant and metastatic HER2+ breast cancer settings
and is referenced for use with Perjeta IV in this jurisdiction. Initial data from a Phase IIIb 
single-arm safety study of combined treatment with Herceptin SC and Perjeta IV have shown 
a safety profile consistent with combined treatment with Herceptin and Perjeta IV 
formulations [Kummel et al. 2016]. As described in Section 1.2.4, pertuzumab formulated for 
SC administration and co-administration with Herceptin SC is undergoing development in 
this study and others.
1.2
BACKGROUND ON STUDY MEDICATIONS
1.2.1
Study Drug Nomenclature
Pertuzumab and trastuzumab are both monoclonal antibodies developed by Roche. 
Throughout the 
protocol, 
their 
international 
non-proprietary 
names 
(pertuzumab, 
trastuzumab) are used when describing their pharmacokinetic (PK) properties and when 
referring to the pertuzumab and trastuzumab fixed-dosed combination formulation for 
subcutaneous administration (FDC SC). 
Other versions of trastuzumab for IV administration may be available in some countries. To 
distinguish the source of trastuzumab that is an investigational medicinal product (IMP) in 
this study, as well as in Roche-sponsored clinical studies referenced in support of this study, 
the trade name (Herceptin) is used throughout the protocol when referring to the 
commercially available drug product (i.e. trastuzumab plus excipients). For consistency, the 
trade name (Perjeta) is also used when referring to the commercially available drug product 
(pertuzumab plus excipients) and IMP in this study.
1.2.2
Background on Perjeta
Perjeta is a recombinant, humanized immunoglobulin (Ig) G1 monoclonal that binds to the 
subdomain II of the HER2 ECD and sterically hinders HER2 dimerization [Franklin et al. 
2004]. Inhibition of homo-dimerization and ligand-activated hetero-dimerization precludes
activated intracellular signalling and downstream stimulation of HER-regulated pathways 
involved in tumorigenesis. In vitro studies have also shown that Perjeta can mediate 
antibody dependent cell-mediated cytotoxicity (ADCC).


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Perjeta and Herceptin each bind to distinct epitopes on the HER2 ECD without competing 
with each other. The molecules have complementary mechanisms for disrupting HER2
signalling (see Section 1.2.3) resulting in augmented in vitro and in vivo anti-proliferative 
activity when delivered in combination.
Perjeta is approved in the European Union (EU) and United States (U.S.) for IV 
administration (Perjeta IV) in combination with Herceptin and chemotherapy for the 
neoadjuvant and adjuvant (neo/adjuvant) HER2+ EBC at high risk of recurrence and in 
combination with Herceptin and docetaxel for the treatment of HER2+ MBC.
For further details of non-clinical and clinical studies with Perjeta, please refer to the Perjeta 
Investigator’s Brochure.
1.2.3
Background on Herceptin
Herceptin is a recombinant, humanized IgG1 monoclonal antibody with high affinity for the 
subdomain IV of the HER2 ECD. Herceptin binding has been shown to prevent access by 
proteases responsible for cleaving the ECD at the cell surface to produce the constitutively 
activated truncated form of HER2 [Molina et al. 2011]. In addition to inhibition of HER2 
shedding, Herceptin mediates ADCC on HER2-overexpressing cancer cells [Sliwkowski et al. 
1999]. 
The addition of Herceptin to standard chemotherapy in the treatment of HER2+ breast 
cancer improves pCR rates, disease-free survival and OS in the neoadjuvant and adjuvant 
settings; and PFS and OS in the metastatic setting [Slamon et al. 2001; Romond et al. 2005, 
Smith et al. 2007, Gianni et al. 2010, Cameron et al. 2017, Slamon et al. 2011]. Herceptin is 
indicated for the treatment of patients with HER2+ breast cancer in the neoadjuvant, 
adjuvant, and metastatic settings.
Herceptin can also be administered SC. Herceptin SC is approved in many countries as 
treatment for patients with HER2+ EBC and MBC.
For further details of non-clinical and clinical studies with Herceptin, please refer to the 
Herceptin Investigator’s Brochure.
1.2.4
Background on Pertuzumab and Trastuzumab Fixed-dose Combination 
for Subcutaneous Administration
Pertuzumab and trastuzumab FDC SC represents a combination of both anti-HER2 
monoclonal antibodies in a single drug product. A Phase III, randomized, multicentre, open-
label, two-arm study comparing the PK, efficacy, and safety of pertuzumab and trastuzumab 
FDC SC with P+H IV as neo/adjuvant treatment with chemotherapy (doxorubicin and 
cyclophosphamide followed by a taxane) for EBC is currently underway with 500 patients 
planned for enrolment (Roche Study WO40324).
As described in Section 1.2.2, Perjeta IV is approved for administration with Herceptin IV 
and Herceptin SC. Improvement in disease outcomes with combined P+H IV versus 
Herceptin alone has been shown in neoadjuvant and adjuvant studies in HER2+ EBC. In the 
randomized Phase II NEOSPHERE (Roche Study WO20697), patients receiving 
neoadjuvant Perjeta plus Herceptin and standard chemotherapies had a higher pCR rates 
(39.3%) over patients receiving neoadjuvant Perjeta IV or Herceptin IV with standard 


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chemotherapy (17.7% or 21.5%, respectively) [Gianni et al. 2012]. In the adjuvant setting, 
the Phase III APHINITY study (Roche Study BO25126) compared adjuvant P+H IV and 
standard chemotherapy to adjuvant placebo plus Herceptin IV and standard chemotherapy. 
The study found a statistically significant improvement in IDFS with a hazard ratio of 0.81 (95% 
confidence interval [CI], 0.66 to 1.00; p = 0.045) in favour of the Perjeta IV arm [von 
Minckwitz et al. 2017]. In each of these studies, combined treatment with Perjeta and 
Herceptin were found to be well tolerated. 
Herceptin for SC administration (Herceptin SC, see Section 1.2.3) has been shown to be as 
safe and effective as Herceptin for IV administration in a Phase III, randomized, open-label, 
non-inferiority study of neo/adjuvant treatment for HER2+ early EBC (Roche Study 
BO22227). In that study, Herceptin was administered every 3 weeks at a fixed dose of 600 
mg (SC arm) or at an 8 mg/kg loading dose followed by 6 mg/kg maintenance dose (IV arm).
Analyses of the co-primary endpoints (pCR and serum trough concentration [Ctrough]) found 
Herceptin SC non-inferior to Herceptin IV with respect to both PK profile and efficacy [Ismael 
et al. 2012]. Immunogenicity evaluations found 53 patients in Herceptin SC arm (n=297) had 
at least one anti-Herceptin anti-drug antibody (ADA) positive result post-baseline whereas 33 
patients in Herceptin IV arm (n=299) had at least one positive ADA result post-baseline. 
However, exploratory analyses suggested that the occurrence of anti-Herceptin ADAs had 
no clinical consequences with respect to PK, efficacy (patients with and without ADAs had 
similar pCR, OS, and event-free survival [EFS] rates), or safety. Analyses of EFS and OS 
conducted after median follow-ups of approximately 40 and 71 months supported the non-
inferiority of Herceptin SC. At 40 months, the unstratified hazard ratios for EFS and OS were 
0.95 (95% CI 0.69-1.30) and 0.76 (95% CI 0.44-1.32), respectively. At 71 months, the EFS 
and OS rates were 65% and 84% in both arms, respectively. During the study treatment 
period, the overall safety profile and tolerability in the IV and SC arms were consistent with 
that expected from combination treatment with chemotherapy and Herceptin. Safety findings 
in the follow-up analyses were also consistent with the known safety profile of Herceptin IV
[Jackisch et al. 2016, Herceptin Investigator’s Brochure, v18, 2017].
Patient reported preference for Herceptin SC (delivered via single-use injection device or 
handheld syringe and needle from a vial) over Herceptin IV was evaluated in a Phase II 
randomized, multi-centre, open-label, crossover study in over 480 patients with HER2+ EBC 
(Roche Study MO22982). The study found the majority (88.9%) of patients strongly preferred 
Herceptin SC over Herceptin IV. Results from questionnaires completed by healthcare 
professionals (HCPs) during the study indicated that HCPs were most satisfied with 
Herceptin SC administration compared with Herceptin IV administration. Healthcare 
professionals also reported notable time savings with Herceptin SC administration. Safety 
and efficacy (3-year EFS) were comparable among the study arms [Herceptin Investigator’s
Brochure, v18, 2017]. 
Pertuzumab formulated for SC administration is being tested in an ongoing open-label, two-
part, multicentre dose-finding / dose confirmation study (Roche Study BO30185). In part 1 of 
the study, two pertuzumab formulations were assessed in healthy male volunteers: 
pertuzumab given as a single-agent SC injection (for eventual use in co-administration with 
Herceptin SC single-agent injection) and pertuzumab formulated for SC administration co-
mixed with Herceptin SC in a single injection. Pertuzumab doses selected for evaluation with 


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SC administration in this study were based on IV-administered pertuzumab population PK 
modelling incorporating values of SC-administered trastuzumab PK parameters. In part 1 of 
Study BO30185, a 600 mg dose of pertuzumab SC was found to provide similar Ctrough and 
area under the curve  (AUC) as Perjeta IV delivered at a 420 mg dose. Part 2 of Study 
BO30185 includes confirmation of the 600 mg pertuzumab SC dose when administered with 
Herceptin SC co-mixed or as FDC in female EBC patients who have completed standard 
adjuvant treatment. Pertuzumab SC 600 mg (co-mixed and FDC) in EBC patients was 
confirmed to provide similar Ctrough and AUC to 420 mg Perjeta IV in healthy male volunteers
enrolled in study part 1. Dose proportionality through PK linearity is considered to confirm a 
pertuzumab 1200 mg SC loading dose [Perjeta Investigator’s Brochure, v17, 2018]. 
Study BO30185 safety data are available for the healthy volunteer cohorts in part 1 and for 
part 2 EBC cohorts receiving pertuzumab SC co-administered or co-mixed with Herceptin 
SC. The safety results are generally consistent with prior experience with combined 
treatment with P+H IV. Treatment in the final study cohort evaluating pertuzumab and 
trastuzumab FDC SC in EBC is ongoing [Perjeta Investigator’s Brochure, v17, 2018].
Herceptin SC, pertuzumab for SC administration, and pertuzumab and trastuzumab FDC SC 
are each formulated with 2000 U/mL human recombinant PH20 hyaluronidase (rHuPH20). 
The excipient acts as a permeation enhancer to allow SC administration of higher drug 
volumes. The concentration of rHuPH20 for these SC formulations was based on preclinical 
studies in mini-pigs (an animal model selected due to its similarities with human skin 
structure) and has been tested and found safe in clinical studies [Pivot et al. 2013, Rummel 
et al. 2017]. Human recombinant PH20 hyaluronidase included in formulations of human 
immunoglobulin, humanized monoclonals, and insulin has been found to induce only modest 
immunogenicity with no associated adverse events (AEs) [Rosengren et al. 2015]. 
Consistent with these findings, anti-rHuPH20 antibodies were detected in Study BO22227 of 
Herceptin SC, however, exploratory analyses suggest that their occurrence does not affect 
PK or safety [Herceptin Investigator’s Brochure, v18, 2017]. 
For further details of non-clinical and clinical studies with Herceptin SC, please refer to the 
Herceptin Investigator’s Brochure. For further details of non-clinical and clinical studies with 
Perjeta SC and pertuzumab and trastuzumab FDC SC, please refer to the Perjeta 
Investigator’s Brochure. 
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
1.3.1
Study Rationale
Treatment with P+H IV has been shown to be efficacious in both early and advanced 
metastatic HER2+ breast cancer and dual HER2 blockade with these agents has become 
standard of care in the neoadjuvant, adjuvant and metastatic settings (see Sections 1.1 and
1.2.4). Herceptin SC, which has been shown to have a similar safety profile and non-inferior
efficacy to Herceptin IV, can be administered more quickly and without requirement for IV 
access. The relative appeal of SC administration over IV administration and the reduction in 
time and resource use with SC administration have been reported by breast cancer patients 
and HCPs, respectively (see Section 1.2.4).


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Given the potential involvement of multiple treatment modalities including repeated IV 
administration of multiple systemic agents, standard therapy for EBC can be a complex and 
taxing experience for any patient. The requirements for individual drug preparation, 
sequential infusion periods and observation periods also result in greater use of limited 
medical resources. The development of an FDC SC formulation of pertuzumab and 
trastuzumab provides an opportunity to build on the improvements achieved by Herceptin 
SC by further reducing the burden associated with treatment for HER2+ breast cancer. By 
formally assessing, from the patients’ perspective, whether FDC SC administration of 
pertuzumab and trastuzumab is preferable to two separate, consecutive IV administrations, 
this study will provide patient experience data to supplement the results of the ongoing 
Roche Phase III WO20324 study comparing the PK, efficacy, and safety of these regimens.
This study will also document HCP reported perceptions of resource use with FDC SC 
administration to evaluate the impact of co-formulation and SC delivery on clinical resources. 
Study safety analyses will further characterize safety profiles of SC administration of co-
formulated pertuzumab and trastuzumab as well as the safety of switching from P+H IV to 
pertuzumab and trastuzumab FDC SC and vice versa. The measurement of secondary 
efficacy endpoints in this study will further investigate the potential effects of switching study 
treatments on disease outcomes. 
1.3.2
Benefit-Risk Assessment
As described in Section 1.2.4, the safety and efficacy of Herceptin SC has been shown to be 
consistent with Herceptin IV with no safety issues attributable to the route of administration 
or to formulation with rHuPH20. Pertuzumab dosing in the FDC SC formulation has been 
selected to provide similar PK as approved Perjeta IV dosing. No new safety issues have 
been seen in clinical evaluation of co-infused Perjeta IV and Herceptin IV preparations (see
Section 1.1). Ongoing clinical evaluation
of co-administered and co-formulated
SC 
preparations conducted by the Sponsor has also found no safety issues that would not be 
expected with sequential IV administrations (see Section 1.2.4).
This study is being conducted in HER2+ EBC patients for whom combined treatment with 
Perjeta IV and Herceptin is indicated. As summarized above, the benefit-risk of incorporating 
pertuzumab and trastuzumab FDC SC into study participants’ anti-HER2 regimen is based 
on the demonstrated non-inferiority of Herceptin SC PK profile and efficacy (as assessed by 
pCR rate) with respect to Herceptin IV, the equivalent bioavailability of pertuzumab SC and 
IV formulations and the consistency of safety profiles among IV, SC, and FDC SC 
formulations.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate patient reported preference for pertuzumab and trastuzumab FDC 
SC in HER2+ EBC. The study will also evaluate patient reported satisfaction with 
pertuzumab and trastuzumab FDC SC; HCP reported perception of time/resource use and 
convenience of pertuzumab and trastuzumab FDC SC and P+H IV; patient reported health-
related quality of life (HRQoL); the safety of each study regimen alone and within the context 
of the order in which they are administered; as well as efficacy in each treatment arm.


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2.1
OBJECTIVES
2.1.1
Primary Objective
The primary objective for this study is to evaluate patient preference for pertuzumab and 
trastuzumab FDC SC on the basis of the following endpoint:

Proportion of patients who preferred pertuzumab and trastuzumab FDC SC with 
treatment preference assessed via Question 1 of the Patient Preference Questionnaire 
(PPQ).
2.1.2
Secondary Objectives
Secondary objectives for this study are to evaluate:

Patient assessed satisfaction with pertuzumab and trastuzumab FDC SC and P+H IV 
based on patient responses to Question 1 of the Therapy Administration Satisfaction 
Questionnaire – subcutaneous (TASQ-SC) and TASQ – intravenous (TASQ-IV)

Patients’ choice of pertuzumab and trastuzumab FDC SC for the Treatment Continuation 
Period based on the proportion of patients who select pertuzumab and trastuzumab FDC 
SC for this study period

HCP
perception of time/resource use and convenience with pertuzumab and 
trastuzumab FDC SC based on HCP responses to the Healthcare Professional 
Questionnaires (HCPQs), by individual question

HRQoL with pertuzumab and trastuzumab FDC SC and P+H IV based on change in 
symptoms and function from baseline and over time as assessed by European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 
(EORTC QLQ-C30) scores, and mean and mean changes from baseline score in 
HRQoL by cycle as assessed by the Global Health Status / overall quality of life (QoL)
scale (items 29 and 30) of the EORTC QLQ-C30.
2.1.2.1
Secondary Safety Objectives
There are two secondary safety objectives for this study. The first is to evaluate the safety 
and tolerability of pertuzumab and trastuzumab FDC SC and P+H IV during the study 
Treatment Cross-over Period and the entire adjuvant treatment period (Treatment Cross-
over Period + Treatment Continuation Period) based on the following endpoints:

Incidence, nature and severity of all AEs, ≥ Grade 3 AEs, serious adverse events (SAEs)
and cardiac AEs (including left ventricular ejection fraction [LVEF] events) 

Incidence of premature withdrawal from study treatment 

Targeted vital signs and physical findings

Targeted clinical laboratory test results
The second safety objective for this study is to evaluate the safety of switching from 
pertuzumab and trastuzumab FDC SC to P+H IV and from P+H IV to pertuzumab and 
trastuzumab FDC SC based on:

Incidence, nature and severity of all AEs, ≥ Grade 3 AEs, SAEs and cardiac AEs 
(including LVEF events) during the study Treatment Cross-over Period by treatment arm.


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For all safety endpoints, AE severity will be determined according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0)
2.1.2.2
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the long-term efficacy of the 
pertuzumab and trastuzumab FDC SC and P+H IV based on the following endpoints:

Invasive disease-free survival, defined as the time from randomization to the first 
occurrence of one of the following events:
−
Ipsilateral invasive breast tumour recurrence (i.e., an invasive breast cancer involving 
the same breast parenchyma as the original primary lesion)
−
Ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast 
cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral 
breast)
−
Distant recurrence (i.e., evidence of breast cancer in any anatomic site other than the 
two above mentioned sites that has either been histologically confirmed or clinically 
diagnosed as recurrent invasive breast cancer)
−
Contralateral invasive breast cancer
−
Death attributable to any cause, including breast cancer, non-breast cancer, or 
unknown cause (but cause of death should be specified, if possible)
Note: Ipsilateral or contralateral in situ disease and second primary non-breast cancers 
(including in situ carcinomas and non-melanoma skin cancers) will not be counted as 
recurrence.

Invasive disease-free survival including second primary non-breast cancer, defined as 
IDFS with second primary non-breast invasive cancer (with the exception of non-
melanoma skin cancers and in situ carcinoma of any site) included as an event

Distant disease-free survival (DDFS), defined as the time from randomization to the date 
of distant breast cancer recurrence

OS, defined as the time from randomization to death from any cause.
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a Phase II, randomized, multi-centre, multinational, open-label, cross-over study in 
adult patients who have completed neoadjuvant chemotherapy with neoadjuvant Perjeta and 
Herceptin and have undergone surgical treatment of HER2+ EBC. An overview of the study 
design is provided in Figure 1. 


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Figure 1
Study Schema
Abbreviations: IV: intravenous; P+H: Perjeta + Herceptin; FDC SC: subcutaneously 
administered fixed-dose combination of pertuzumab and trastuzumab; HCPQ: Healthcare 
Professional Questionnaires; PPQ: Patient Preference Questionnaire; SC subcutaneous; 
TASQ: Therapy Administration Satisfaction Questionnaire
Eligibility will be assessed within a 28-day screening period. Eligible patients will be enrolled 
and randomly allocated in a 1:1 ratio to treatment Arm A (P+H IV followed by pertuzumab 
and trastuzumab FDC SC) or treatment Arm B (pertuzumab and trastuzumab FDC SC 
followed by P+H IV). Patients will be stratified according to neoadjuvant chemotherapy 
regimen (anthracyclines + taxanes vs. carboplatin + taxanes vs. taxanes only), neoadjuvant 
treatment response (pCR vs. non-pCR), and hormone receptor status (oestrogen receptor 
[ER]-positive and/or progesterone receptor [PgR]-positive vs. ER-negative and PgR-
negative). Study treatment will be initiated ≥ 2 weeks from breast cancer surgery but ≤ 9 
weeks from the last administration of systemic neoadjuvant therapy and will be administered 
on Day 1 of each 3-week treatment cycle. No adjuvant chemotherapy is allowed after 
surgery, however, adjuvant hormone and/or radiation therapy are allowed.
Patients randomized to Arm A will receive P+H IV for three treatment cycles followed by 
pertuzumab and trastuzumab FDC SC for three treatment cycles. Patients randomized to 
Arm B will receive pertuzumab and trastuzumab FDC SC for three treatment cycles followed 
by P+H IV for three treatment cycles. This period of 3+3 cycles in both treatment arms 
constitutes the study Treatment Cross-over Period.
The 6 study treatment cycles of pertuzumab and trastuzumab FDC SC and P+H IV received 
during the Treatment Cross-over Period and Perjeta and Herceptin treatment cycles 
received in the neoadjuvant setting prior to study entry will be considered part of the total 18 
anti-HER2 treatment cycles planned for all study patients. Following completion of the 
Treatment Cross-over Period, patients will enter the Treatment Continuation Period wherein 
they will receive the remaining anti-HER2 treatment cycles required to complete their 18 
planned cycles unless disease recurrence, unacceptable toxicity or patient withdrawal from 
treatment necessitates early treatment cessation. Study treatment during this period will be 
either P+H IV or pertuzumab and trastuzumab FDC SC as selected by the patient at the end 
of the Treatment Cross-over Period. See Figure 2 for examples of calculating the number of 


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study treatment cycles required during the Treatment Continuation Period. Patients will be 
followed for at least three years from randomization (the Follow-up Period) during which time 
they should be assessed at least every six months.
Figure 2
Study Treatment Cycle Calculation
OLD FIGURE
NEW FIGURE


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Patients who, by the investigator’s assessment, cannot tolerate pertuzumab and 
trastuzumab FDC SC or P+H IV may be allowed to receive P+H IV or pertuzumab and 
trastuzumab FDC SC, respectively, for their remaining planned anti-HER2 treatment cycles. 
The investigator must obtain approval from the Medical Monitor to switch study treatment. 
Patient preference will be assessed based on the PPQ (administered following treatment 
administration on Day 1, Cycle 6 of the Treatment Cross-over Period). Treatment 
satisfaction will be assessed based on the TASQ (administered following treatment 
administration on Day 1 of Cycles 3 and 6 of the Treatment Cross-over Period). Healthcare 
professionals will record their perception of time/resource use and convenience of treatment 
administration completing the HCPQs. Perception of time use will be captured during the 
Treatment Cross-over Period and perception of convenience will be captured after 
administration of each patient’s treatment Cycle 6. Health-related quality of life will be 
assessed based on EORTC QLQ-C30 completed at baseline, Cycle 3, Cycle 6, and the end 
of study treatment visits, as well as at 18 months, 2 years, and 3 years from randomization.
The study questionnaires are provided in Appendix 2 and Appendix 3.
Patients will be assessed for safety by regular evaluation of AEs, vital signs, routine clinical 
laboratory tests (haematology, blood chemistry) and LVEF assessments; and by physical 
examinations. Adverse events will be reported and graded according to the NCI CTCAE v4.0. 
Efficacy will be assessed based on investigator-evaluated disease status determined 
according to assessments conducted per institutional practice or according to the American 
Cancer Society / American Society of Clinical Oncology Breast Cancer (ACS/ASCO) Breast 
Cancer Survivorship Care Guideline [Runowicz et al. 2016, see Appendix 4].
Patients will undergo an End of Treatment Visit approximately 28 days after completing 
study treatment and will enter the Follow-up Period wherein they will be followed for disease 
status, survival and HRQoL (via the EORTC QLQ-C30) for 3 years from the date the last 
patient is randomized. The study Schedule of Activities is provided in Appendix 1.
Approximately 140 patients from approximately 42 study sites worldwide will be randomized 
in the study. Patients who withdraw from the study following randomization will not be 
replaced. Patients can be screened for the study more than once. 
3.2
END OF STUDY AND LENGTH OF STUDY
The end of the study is defined the Last Patient, Last Visit (LPLV) which will occur three 
years after the last patient is randomized or the date at which the last data point required for 
the final statistical analysis or safety follow-up is received from the last patient, whichever 
occurs later.
In addition, the Sponsor may decide to terminate the study at any time.
The study is estimated to last approximately 4 years, based on a recruitment period of up to 
10 months and 3 years of follow-up after the last patient is randomized.


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3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Perjeta IV, Herceptin IV, and Pertuzumab and Trastuzumab 
FDC SC Doses and Schedules
Perjeta IV and Herceptin IV loading and maintenance doses in the study are the approved 
doses for the treatment of EBC. 
Pertuzumab and trastuzumab FDC SC maintenance and loading doses in the study are 
based on the approved dose of Herceptin SC (600 mg Herceptin with no loading dose 
required), clinical studies of pertuzumab showing similar Ctrough and AUC with pertuzumab 
SC 600 mg and Perjeta IV 420 mg (Study BO30185), and dose proportionality of 
pertuzumab 1200 mg SC confirmed through PK linearity (see Section 1.2.4). 
Both the loading and maintenance doses of pertuzumab and trastuzumab FDC SC include 
2000 U/mL rHuPH20. The concentration of this excipient is the same as in the approved 
Herceptin SC formulation and has been tested in the aforementioned Study BO30185 (see 
Section 1.2.4).
The scheduling of all IMPs (every 3 weeks with loading doses required if ≥ 6 weeks since 
last administration of HER2-targeted therapy) are based on PK studies comparing IV and SC 
administrations of each molecule (Study BO22227, Study BO30185) and the approved 
scheduling for Perjeta IV, Herceptin IV and Herceptin SC.
3.3.2
Rationale for Patient Population
Early breast cancer patients who have received neoadjuvant Perjeta IV and Herceptin and 
have completed neoadjuvant chemotherapy and subsequently undergone surgery for their 
breast cancer were selected as the target population for this study since continued dual 
HER2+ blockade with Perjeta and Herceptin is standard of care in these patients. The 
completion of chemotherapy prior to study entry limits the influence of chemotherapy 
administrations and related toxicity on study endpoints. Patients will be allowed to receive 
adjuvant radiotherapy and/or hormone therapy during the study as these treatments will be 
indicated in some cases.
3.3.3
Rationale for Randomization Stratification Factors
To include as wide a population as possible while limiting imbalances that may affect study 
outcomes, randomization will be stratified. Since neoadjuvant treatment selections are 
associated with varying toxicities and disease outcomes, randomization will be stratified for 
neoadjuvant chemotherapy regimen (anthracyclines + taxanes vs. carboplatin + taxanes vs. 
taxanes only). 
Randomization will also be stratified for neoadjuvant treatment response (pCR vs. non-pCR)
and hormone receptor status (positive vs. negative) due to the associations of these factors 
with disease outcomes. Complete pathological response to neoadjuvant treatment has been 
shown to predict for improved disease outcomes in HER2+ EBC [Gianni et al. 2016]. 
Differences in treatment response with hormone receptor status have also been shown in 
HER2+ EBC trials of Herceptin and P+H IV [Cameron et al. 2017; Study BO25126 - see 
Perjeta Investigator’s Brochure 2018].


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3.3.4
Rationale for Randomized Cross-over Design
The primary objective of this study is to assess patient reported preference for pertuzumab 
and trastuzumab FDC SC. Patients will be randomized to receive either pertuzumab and 
trastuzumab FDC SC for three treatment cycles followed by P+H IV for three treatment 
cycles versus receiving P+H IV first, followed by pertuzumab and trastuzumab FDC SC. 
Patients in both treatment groups will then choose either IV or SC administered IMPs for 
their remaining HER2-targeted treatment cycles. 
Randomization accommodates potential treatment sequencing-related differences such as in 
the
nature and/or frequency of administration-related reactions (ARRs)
with either 
administration route (e.g. if ARRs to IV formulation occur more frequently following the
treatment break for surgery and/or with a loading dose) or in AEs attributable to switching 
administration routes. At the same time, the cross-over design provides exposure to both 
study regimens allowing each patient to act as their own control for patient reported 
outcomes (PROs) measured after study Cycle 3 and study Cycle 6. 
3.3.5
Rationale for Patient Reported Outcome Assessments
Early breast cancer is often asymptomatic, especially after tumour removal, thus it is 
important to assess treatment impact and tolerability to inform the benefit-risk ratio for a 
patient on adjuvant therapy. The PPQ used to assess the primary study endpoint has been 
developed in clinical trials assessing patient preference for SC administered monoclonal 
antibodies. An interview-based assessment was first developed to assess patient preference 
for Herceptin SC in a clinical trial of adjuvant Herceptin SC and IV in HER2+ EBC [Study 
MO22982, Pivot et al. 2013]. Interview questions were based on input from experienced 
clinicians, chemotherapy nurses and psychologists and were tested with patient volunteers 
prior to use in the study. The three interview questions identified as most informative in the 
Herceptin MO22982 study were then administered as the patient-completed PPQ in a 
subsequent lymphoma study evaluating preference for SC or IV administered rituximab 
[PrefMab study, Rummel et al. 2017]. Notably, PPQ endpoints collected in this study were 
considered adequate evidence for preference claims included in rituximab SC product 
labelling [Rituxan Hycela™ Package Insert 2017]. The TASQ questionnaires used in this 
study have been adapted from administration satisfaction questionnaires used in the 
aforementioned PrefMab study. 
Health-related quality of life evaluations in this study will contextualize a patient’s experience 
on trial, elucidating symptom and treatment burden between P+H IV and pertuzumab and 
trastuzumab FDC SC. Because treatment-related side effects have the potential to affect 
patient functioning and HRQoL, it is crucial to characterize not only the incidence of these 
side effects but also the associated trends and burden from the patient’s perspective, which 
would contribute to a more comprehensive understanding of treatment impact and tolerability. 
The EORTC QLQ-C30, is a well-known and commonly used questionnaire with strong 
demonstrated psychometric properties of both reliability and validity.


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4.
MATERIALS AND METHODS
4.1
PATIENTS
Adult patients with HER2+ EBC who have received neoadjuvant Perjeta and Herceptin, and 
have completed neoadjuvant chemotherapy and subsequently undergone surgery for their 
breast cancer will be enrolled in the study.  
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:
Disease-specific criteria

Female or male with histologically confirmed, HER2+ inflammatory, locally advanced or 
early-stage breast cancer who have received neoadjuvant Perjeta + Herceptin and have 
completed neoadjuvant chemotherapy and subsequently undergone surgery for their 
breast cancer.
Note: The neoadjuvant chemotherapy regimen (including type and sequencing of 
selected agents) and the number of neoadjuvant Perjeta and Herceptin treatment cycles 
are at the discretion of the treating physician and patient. Subcutaneously administered 
Herceptin may have been used in the neoadjuvant setting. The use of any trastuzumab 
biosimilars in the neoadjuvant setting is not allowed.

HER2+ breast cancer assessed at the local laboratory prior to initiation of neoadjuvant 
therapy. HER2+ status must be determined based on breast biopsy material obtained 
prior to neoadjuvant treatment and is defined as 3+ by immunohistochemistry (IHC) 
and/or positive by HER2 amplification by in situ hybridization (ISH) with a ratio of ≥ 2 for 
the number of HER2 gene copies to the number of chromosome 17 copies

Hormone receptor status of the primary tumour determined by local assessment. 
Hormone receptor positive status may be either positive (i.e. ER-positive and/or PgR-
positive) or negative (i.e. ER-negative and PgR-negative)

Completed all neoadjuvant chemotherapy and surgery. Adjuvant radiotherapy may be 
planned or ongoing at study entry and adjuvant hormone therapy is allowed during the 
study. Note that study treatment cannot be initiated within < 2 weeks of surgery but must 
be initiated ≤ 9 weeks from the last administration of systemic neoadjuvant therapy.

No evidence of residual, locally recurrent or metastatic disease after completion of 
surgery. Patients with clinical suspicion of metastases must undergo radiological 
assessments per institutional practice to rule out distant disease.

Wound healing after breast cancer surgery adequate per investigator’s assessment to 
allow initiation of study treatment within ≤ 9 weeks of last systemic neoadjuvant therapy

No adjuvant chemotherapy planned. Note that adjuvant hormonal treatment is allowed 
during the study.
General criteria

Signed Informed Consent Form

Age ≥ 18 years at time of signing Informed Consent Form


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
Ability to comply with the study protocol, in the investigator’s judgment

Eastern Cooperative Oncology Group (ECOG; see Appendix 5) performance status 
0 or 1

Intact skin at planned site of subcutaneous injections (thigh)

LVEF ≥ 55% measured by echocardiogram (ECHO) or multiple-gated acquisition
(MUGA) scan within 28 days of study randomization

No major surgical procedure unrelated to breast cancer within 28 days prior to 
randomization or anticipation of the need for major surgery during the course of study 
treatment

For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to refrain from 
donating eggs, as defined below:
Women must remain abstinent or use non-hormonal contraceptive methods with a failure 
rate of < 1% per year, or 2 effective non-hormonal contraceptive methods during the 
study treatment periods and for 7 months after the last dose of study treatment. Women 
must refrain from donating eggs during this same period. 
A woman is considered to be of childbearing potential if she is post-menarchal, has not 
reached a post-menopausal state (post-menopausal defined as ≥ 12 continuous months 
of amenorrhea with no identified cause other than menopause), and has not undergone 
surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing 
potential may be adapted for alignment with local guidelines or requirements.
Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year 
include bilateral tubal ligation, male sterilization (with appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate) and copper intrauterine devices
(IUDs).
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the study treatment periods and for seven 
months after the last dose of study treatment to avoid exposing the embryo. Men must 
refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not 
acceptable methods of preventing drug exposure. 

A negative serum pregnancy test must be available prior to randomization for women of 
childbearing potential (defined as post-menarchal, has not had ≥ 12 continuous months 


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of amenorrhea with no identified cause other than menopause, and has not undergone 
surgical sterilization [removal of ovaries and/or uterus])
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Cancer-specific criteria

Stage IV (metastatic) breast cancer 

Current or prior history of active malignancy (other than current breast cancer) within the 
last five years. Appropriately treated non-melanoma skin cancer; in situ carcinomas, 
including cervix, colon, or skin; or Stage I uterine cancer within the last five years are 
allowed. 
A patient with previous invasive non-breast cancer is eligible provided he/she has been 
disease free for more than five years.

Previous systemic therapy (including chemotherapy, immunotherapy, HER2-targeted 
agents, endocrine therapy [selective oestrogen receptor modulators, aromatase 
inhibitors], and antitumor vaccines) for treatment or prevention of breast cancer, except 
neoadjuvant Perjeta, Herceptin and chemotherapy for current breast cancer
General criteria:

Investigational treatment within four weeks of enrolment 

Serious cardiac illness or medical conditions including, but not confined to, the following:
−
History of NCI CTCAE v4.0 Grade ≥ 3 symptomatic congestive heart failure (CHF) or 
New York Heart Association (NYHA) Class ≥ II
−
High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate ≥ 100/min 
at rest, significant ventricular arrhythmia [ventricular tachycardia], or higher-grade 
atrioventricular [AV]-block, such as second-degree AV-block Type 2 [Mobitz II] or 
third-degree AV-block)
−
Serious cardiac arrhythmia or severe conduction abnormality not controlled by 
adequate medication 
−
Angina pectoris requiring anti-angina medication
−
Clinically significant valvular heart disease
−
Evidence of transmural infarction on electrocardiogram (ECG)
−
Evidence of myocardial infarction within 12 months prior to randomization
−
Poorly controlled hypertension (e.g., systolic > 180 mm Hg or diastolic > 100 mmHg)

History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as 
structural heart disease (e.g., severe left ventricular systolic dysfunction [LVSD], left 
ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia 
demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., 
hypokalaemia, hypomagnesemia, hypocalcaemia), or family history of sudden 
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
Inadequate bone marrow function, defined by any of:
−
Absolute neutrophil count (ANC) < 1.5 x 109/L
−
Platelet count < 100 x 109/L
−
Haemoglobin < 9 g/dL

Impaired liver function, defined by any of:
−
Serum (total) bilirubin > 1.25 x upper limit of normal (ULN). In case of Gilbert’s 
syndrome: a total bilirubin of 2 x ULN is permitted.
−
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 1.25 x ULN
−
Albumin < 25 g/L

Inadequate renal function with serum creatinine > 1.5 x ULN

Current severe, uncontrolled systemic disease that may interfere with planned treatment 
(e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound-
healing disorders)

Pregnant or breastfeeding, or intending to become pregnant during the study or within 
seven months after the last dose of study treatment. Women of childbearing potential 
must have a negative serum pregnancy test result within seven days prior to initiation of 
study treatment

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in, and completion of, 
the study

Known active liver disease, for example, active viral hepatitis infection (i.e., hepatitis B or 
hepatitis C), autoimmune hepatic disorders, or sclerosing cholangitis

Concurrent, serious, uncontrolled infections, or known infection with human 
immunodeficiency virus (HIV)

Known hypersensitivity to any of the study drugs, excipients, and/or murine proteins

Current chronic daily treatment with corticosteroids (dose > 10 mg methylprednisolone or 
equivalent excluding inhaled steroids)
4.2
METHOD OF TREATMENT ASSIGNMENT 
Eligible patients will be randomly allocated at study entry to either Arm A (P+H IV followed 
by pertuzumab and trastuzumab FDC SC) or Arm B (pertuzumab and trastuzumab FDC SC 
followed by P+H IV). 
Randomization will occur via a web-based response system (IWRS) in a 1:1 ratio. 
Randomization will be stratified according to neoadjuvant chemotherapy regimen
(anthracyclines + taxanes vs. carboplatin + taxanes vs. taxanes only), neoadjuvant treatment 
response (pCR vs. non-pCR), and hormone receptor status (positive [ER-positive and/or 
PgR-positive) or negative [ER-negative and PgR-negative]).


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4.3
STUDY TREATMENT 
The IMPs for this study are pertuzumab and trastuzumab FDC SC (loading dose 
configuration and maintenance dose configuration), Perjeta IV and Herceptin IV. All study 
drugs will be provided by the Sponsor free of charge.
Study drug supplies will be labelled in accordance with applicable legal requirements and will 
be printed in the local language. The storage conditions for each study drug will be 
described on the medication label. Study drug supplies should not be used beyond the 
expiration date provided by the manufacturer.
Please refer to the Pharmacy Manual for all instructions pertaining to study drug supply and 
management.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Pertuzumab and Trastuzumab FDC SC
A loading and maintenance dose of pertuzumab and trastuzumab FDC SC will be provided 
in the following configurations as single vials:

Loading dose: a sterile solution for injection containing L-histidine hydrochloride, 
trehalose, sucrose, polysorbate 20, methionine, and rHuPH20 (2,000 U/mL). Each single 
use 20 mL glass colourless vial contains 1200 mg of pertuzumab and 600 mg of 
trastuzumab in 15 mL of solution.

Maintenance dose: a sterile solution for injection containing L-histidine hydrochloride, 
trehalose, sucrose, polysorbate 20, methionine, and rHuPH20 (2,000 U/mL). Each single 
use 15 mL colourless glass vial contains 600 mg of pertuzumab and 600 mg of 
trastuzumab in 10 mL of solution.
For information on the packaging, handling and storage of pertuzumab and trastuzumab
FDC SC, see the Pharmacy Manual and Perjeta Investigator's Brochure.
4.3.1.2
Perjeta IV
Perjeta IV is provided as a sterile, preservative-free, single use formulation containing 30 
mg/mL pertuzumab in 20 mM L-histidine acetate, 120 mM sucrose, and 0.02% (w/v) 
polysorbate 20 at pH 6.0. Each 20 mL vial contains 420 mg of pertuzumab (14.0 mL/vial).
For information on the packaging, storage and dispensing of Perjeta IV, see the current 
Perjeta Investigator's Brochure and Summary of Product Characteristics (SmPC).
4.3.1.3
Herceptin IV
Herceptin IV is provided in single or multi-dose freeze-dried preparations containing nominal 
trastuzumab amounts of 150 mg/vial or 440 mg/vial, respectively. The drug is formulated in 
histidine/histidine-HCl; α, α-trehalose dehydrate; and polysorbate 20.
For information on the packaging, storage, and dispensing of Herceptin IV, see the current 
Herceptin Investigator's Brochure and SmPC.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1 and below.


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With the exception Herceptin IV dosing which should be modified for changes in body weight 
> 10%, study treatment doses should not be modified. No dose reductions are allowed for 
Perjeta IV, Herceptin IV or pertuzumab and trastuzumab FDC SC. If an accidental overdose 
or medication error occurs, it should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose or medication error, along with 
any associated AEs, should also be reported as described in Section 5.4.4.
Guidelines for treatment interruption or discontinuation for patients who experience AEs are 
provided in Section 5.1.
4.3.2.1
Pertuzumab and Trastuzumab FDC SC
Pertuzumab and trastuzumab FDC SC is given as a fixed dose (i.e. non-weight based). Two 
doses of pertuzumab and trastuzumab FDC SC may be administered in the study: a 15 mL 
loading dose consisting of 1200 mg pertuzumab and 600 mg trastuzumab and a 10 mL 
maintenance dose consisting of 600 mg pertuzumab and 600 mg trastuzumab. Patients who 
have had ≥ 6 weeks since their last neoadjuvant dose of Perjeta IV and Herceptin (IV or SC)
at study entry, or have had ≥ 6 weeks since their last study treatment during the study 
treatment periods, must receive a loading dose before continuing with maintenance doses 
for subsequent administrations. 
All pertuzumab and trastuzumab FDC SC doses are administered by SC injection by the 
investigator or their designee over 5 – 8 minutes at a rate of ≤ 2 mL/min with hand-held 
syringe to the thigh on Day 1 of each 3-week treatment cycle. Patients should be monitored 
for 30 minutes after their first pertuzumab and trastuzumab FDC SC dose administration 
regardless of whether a loading dose is required. Patients should be monitored for 10 –
15 minutes following subsequent administrations. Patients can be observed for longer 
periods at the discretion of the investigator or if necessary, as per local requirements.
4.3.2.2
Perjeta IV
Perjeta IV is administered at a dose of 840 mg (loading dose) or 420 mg (maintenance dose) 
on Day 1 of each 3-week treatment cycle and should be administered prior to Herceptin IV. 
Patients who have had ≥ 6 weeks since their last neoadjuvant dose of Perjeta IV at study 
entry, or have had ≥ 6 weeks since their last study treatment during the study treatment 
periods, must receive a loading dose before continuing with maintenance doses for 
subsequent administrations. 
Perjeta IV loading dose (if required) will be administered as a 60-minute infusion
(± 10 minutes), followed by an observation period of 60 minutes. If the loading dose infusion 
is well tolerated, subsequent maintenance doses can be administered over a period of 
30 minutes (± 10 minutes) with an observation period of 30 minutes. Patients can be 
observed for longer periods at the discretion of the investigator or if necessary, as per local 
requirements. The observation period should be completed prior to the subsequent 
Herceptin IV infusion. 
4.3.2.3
Herceptin IV
Herceptin IV is administered at a dose of 8 mg/kg (loading dose) or 6 mg/kg (maintenance 
dose) on Day 1 of each 3-week treatment cycle and should be administered Perjeta IV 


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infusion and observation period are complete. Patients who have had ≥ 6 weeks since their 
last neoadjuvant dose of Herceptin IV or Herceptin SC at study entry, or have had ≥ 6 weeks 
since their last study treatment during the study treatment periods, must receive a loading 
dose before continuing with maintenance doses for subsequent administrations. 
Herceptin
IV
loading dose (if required) will be administered as an infusion over 
approximately 90 (± 10) minutes after which the patient must be observed for 60 minutes. If 
the loading dose is well tolerated, subsequent maintenance doses can be administered as 
30-minute infusions (± 10 minutes) followed by an observation period of 30 minutes. Patients 
can be observed for longer periods at the discretion of the investigator or if necessary, as 
per local requirements.
If variation in the patient’s weight of ≥ 10% compared with study baseline occurs, the 
Herceptin IV dose will be recalculated. Weight at the time the dose is recalculated will be 
considered as baseline for subsequent evaluations of degree of weight change with respect 
to Herceptin IV dose modification requirements. 
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (pertuzumab and trastuzumab FDC SC, 
Perjeta IV, Herceptin IV) will be provided by the Sponsor. The study site will acknowledge 
receipt of IMPs supplied by the Sponsor. Any damaged shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor for destruction. The site's
method of destroying Sponsor-supplied IMPs must be agreed to by the Sponsor. The site 
must obtain written authorization from the Sponsor before any Sponsor-supplied IMP is 
destroyed, and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to Pertuzumab and Trastuzumab FDC SC, Perjeta IV 
and Herceptin IV
Due to the completion of the standard neo/adjuvant course of Herceptin plus Perjeta (18 
cycles) within the trial, the Sponsor does not plan to provide the Roche IMPs (pertuzumab 
and trastuzumab FDC SC, Perjeta IV, Herceptin IV) or any other study treatments or 
interventions to patients who have completed the study.  
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient 
from seven days prior to initiation of study drug until the End of Treatment Visit.  After the 
End of Treatment Visit and until the end of the study, only medications used for the 
treatment of cancer will be reported. All such medications should be reported to the 
investigator and recorded on the Concomitant Medications eCRF.


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4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Adjuvant hormone therapy for breast cancer

Adjuvant radiotherapy for breast cancer

Contraception: acceptable methods of contraception must be used when the female 
patient is of childbearing potential (i.e. is post-menarchal, has not reached a post-
menopausal state [post-menopausal defined as ≥ 12 continuous months of amenorrhea 
with no identified cause other than menopause], and has not undergone surgical 
sterilization [removal of ovaries and/or uterus]). Acceptable methods of contraception are 
described in Section 5.1.3.

H1-receptor or H2-receptor antagonists (e.g., diphenhydramine, cimetidine)

Cardiovascular medications including angiotensin-converting enzyme (ACE) inhibitors,
angiotensin receptor blockers, beta blockers, calcium channel blockers and diuretics,
beta blockers, calcium channel blockers, digoxin, thrombocyte aggregation inhibitors

Analgesics
/
anti-inflammatories (e.g., paracetamol / acetaminophen, meperidine,
opioids)

Short-term use of corticosteroids to treat or prevent allergic or infusion reactions are 
allowed, however, the dose must not exceed > 20 mg/day of dexamethasone (or 
equivalent) for > 7 consecutive days.

Standard therapies for pre-existing medical conditions and medical or surgical
complications

Any medication intended solely for supportive care (e.g., analgesics, antidiarrheals,
antidepressants) at the investigator’s discretion

Blood transfusions at the investigator’s discretion

Gonadotropin-releasing hormone agonists for fertility preservation

Vitamin and mineral supplements

Bone density modifying agents (to be used in accordance with the approved labelled 
indication and/or nationally recognized treatment guidelines)

Any other medication not included in the list of prohibited medications
In general, investigators should manage a patient's care with supportive therapies as 
clinically indicated, per institutional standard practice.  Patients who experience infusion-
associated symptoms may be treated symptomatically with acetaminophen, ibuprofen, 
diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, cimetidine), or equivalent 
medications per institutional standard practice.  Serious infusion-associated events 
manifested by dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced 
oxygen saturation, or respiratory distress should be managed with supportive therapies as 
clinically indicated (e.g., supplemental oxygen and β2-adrenergic agonists).
4.4.2
Cautionary Therapy
Concomitant use of herbal therapies is not recommended because their PK, safety profiles, 
and potential drug-drug interactions are generally unknown. However, herbal therapies not 


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intended for the treatment of cancer may be used during the study at the discretion of the 
investigator.
4.4.3
Prohibited Therapy
Use of the following concomitant therapies is prohibited as described below:

Any investigational therapy or agent (other than protocol-mandated study treatment) is 
prohibited within 28 days prior to initiation of study treatment and during study treatment

Any anti-cancer treatment other than adjuvant hormone treatment, adjuvant radiotherapy
or bone density modifying treatment

Regular systemic treatment with steroids
Short-term corticosteroid to treat and prevent allergic or infusion reactions are allowed 
however the dose must not exceed > 20 mg/day of dexamethasone (or equivalent) for 
> 7 consecutive days.

Any systemically active oral, injected, or implanted hormonal method of contraception 
(see Section 5.1.3 for acceptable contraception methods) except for progesterone-
coated IUDs that had been previously implanted

Hormone-replacement therapy

Use of erythropoiesis-stimulating agents (e.g., erythropoietin)

Herbal remedies initiated for cancer treatment. Other herbal remedies are discouraged 
but permitted and must be reported on the appropriate eCRF.

Topical oestrogens (including any intra-vaginal preparations), megestrol acetate, and 
selective ER modulators used with prophylactic intent are prohibited
Postmenopausal women with significant vaginal discomfort associated with anti-
oestrogen therapy may be considered for intermittent use of low-dose topical oestrogens
if non-prescription methods are unsuccessful at ameliorating symptoms.
4.5
STUDY ASSESSMENTS 
The Schedule of Activities describing study assessments and collection procedures is 
provided in Appendix 1.  Please refer to the Schedule of Activities for frequency and timing 
of study activities. All study activities must be documented and must be performed as 
outlined in the Schedule of Activities.  
Patients will be closely monitored for safety and tolerability throughout the study.  Patients 
should be assessed for toxicity prior to each study treatment; dosing will occur only if clinical 
assessments and local laboratory test values are acceptable.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before performing 
any study-related procedures. Results of standard-of-care tests or examinations performed 
prior to obtaining informed consent but within 28 or 7 days of randomization (as indicated) 
may be used; such tests do not need to be repeated for screening. Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be maintained at 
the study site.


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All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before enrolment.  The investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening 
failure, as applicable.
4.5.2
Medical History, Concomitant Medication, and Demographic Data
Medical history will be recorded at baseline and will include: clinically significant diseases
within the past five years, surgeries, breast and other cancer history (including prior cancer 
therapies and procedures), complete cardiovascular history, cardiac risk factors, and 
reproductive status.  In addition, all medications (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by the 
patient within seven days prior to initiation of study treatment will be recorded.  
Demographic data collected will include age, sex, and self-reported race / ethnicity.
4.5.3
Pathology
Pathology reports from the initial breast cancer diagnosis and from breast cancer surgery will 
be collected prior to randomization. The report from breast surgery will be used to determine 
pathological response status for randomization stratification.  
Results of HER2 and hormone receptor testing conducted by a local laboratory based on 
breast tumour tissue obtained prior to initiation of neoadjuvant treatment will be collected to 
assure study eligibility (HER2) and for randomization stratification (hormone receptor status).
4.5.4
Physical Examinations
A complete physical examination, performed during Screening and other specified visits, 
should include physical measurements (body weight in kilograms and, at screening only,
height in centimetres) and evaluation of the head; eyes; ears; nose; throat; and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, 
and neurologic systems.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF.
Limited, symptom-directed physical examinations including weight, should be performed at 
specified post-baseline visits and as clinically indicated.  New or worsened clinically 
significant abnormalities should be recorded as AEs on the Adverse Event eCRF.
During the study Follow-up Period, physical examinations should be completed per 
institutional practice or the ACS / ASCO Breast Cancer Survivorship Care Guideline 
[Runowicz et al. 2016, see Appendix 4].
4.5.5
Vital Signs
Vital signs will include temperature and, with the patient in a seated position, heart rate, 
respiration rate, and systolic and diastolic blood pressure.
4.5.6
ECOG Performance status
Performance status will be assessed according to ECOG definitions provided in Appendix 5.


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4.5.7
Clinical Breast Examination
Clinical breast examinations must be performed prior to study entry to assess post-surgery 
wound healing, eligibility for adjuvant treatment initiation, and to detect residual / recurrent 
disease. During the study treatment periods clinical breast examinations must be conducted 
to detect signs of locoregional relapse during the study treatment periods. The examination 
should be conducted per institutional practice and include examination of the breast, axilla, 
and supraclavicular fossa. If the patient shows disease progression post-baseline, this 
should be recorded on the Disease Status eCRF.
During the study Follow-up Period, assessments should be completed per institutional 
practice or the ACS / ASCO Breast Cancer Survivorship Care Guideline [Runowicz et al. 
2016, see Appendix 4].
4.5.8
Mammograms 
Mammograms conducted at the time of diagnosis (before initiation of the neoadjuvant 
treatment) as well as pre-surgery (if performed) will be collected. Mammograms collected 
and/or conducted for the study (including pre-neoadjuvant treatment, pre-surgery, and 
Follow-up Period evaluations) can be replaced by another conventional imaging method 
such as magnetic resonance imaging (MRI) or ultrasound per institutional practice, at the 
investigator’s discretion, but the same method of assessment must be used for each 
evaluation for an individual patient. If a mammogram (or acceptable alternative breast 
imaging evaluation) has been conducted as part of routine care within four months prior to 
the End of Treatment Visit, it may be used in lieu of the End of Treatment Visit evaluation.
4.5.9
Diagnosis of Breast Cancer Recurrence or Second Primary Cancer
All patients must be followed to assess disease recurrence and second primary cancers. 
The designation of disease recurrence whether local, regional or distant, or a diagnosis of 
second primary cancer will be conducted per institutional practice or according to ACS /
ASCO Breast Cancer Survivorship Care Guideline [Runowicz et al. 2016; see Appendix 4] 
but can be made only when clinical, laboratory, radiological and/or histological findings 
support the diagnosis.
The diagnosis of a breast cancer progression, recurrence or a second primary tumour 
should be confirmed histologically whenever clinically possible. The earliest date of 
diagnosis of recurrent disease should be used and recorded. This date should be based on 
objective clinical, radiological, histological, or cytological evidence. The date of disease 
recurrence should be reported as the date of first diagnosis of a lesion (i.e. an objective 
finding), not the date of occurrence of the first symptom.
Recurrent disease includes local, regional, and distant recurrence and contralateral invasive 
breast cancer. Patients who are diagnosed with in situ breast disease or second (non-
breast) malignancies should be maintained in regular follow-up wherever possible to fully 
capture any subsequent recurrent breast cancer events. In cases of diagnostic doubt (e.g. ill-
defined, palpable mass in an irradiated breast), histologic or cytologic confirmation of 
recurrence should be obtained whenever possible.


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Some patients may develop a suspicious recurrence that leads quickly to death without the 
possibility of confirming relapse of disease. Efforts should be made to obtain an autopsy 
report in such patients.
4.5.10
Cardiac Function
Prior to study enrolment, patients must have an assessment for history of cardiac events, a 
physical examination, an ECG (per standard institutional methods), and an LVEF 
assessment (by ECHO or MUGA) to exclude any cardiac condition that would render them 
ineligible for participation in this trial. Cardiac function will be assessed locally according to 
the schedule of activities (see Appendix 1). 
All patients must have an LVEF ≥ 55% by ECHO or MUGA scan in order to be eligible for 
the study. The same LVEF evaluation method should be used throughout the study for each 
patient and should be performed and assessed by the same assessor if possible.  Results of 
LVEF assessments must be reviewed prior to study treatment administration on the 
scheduled visit day.
Investigators must be aware of local institutional regulations regarding the maximum 
allowable frequency of repeat MUGA scans. The repeated administration of radioisotopes is 
limited in some nuclear medicine laboratories, and patients in this study require LVEF 
assessment on more than four occasions within one year. 
4.5.11
Laboratory Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory for 
analysis:

Haematology:  haemoglobin, total white blood count (WBC), ANC / neutrophil count, 
platelet count.

Limited biochemistry:  alkaline phosphatase; AST; ALT; lactate dehydrogenase (LDH); 
total bilirubin; creatinine.  Albumin should be measured at Screening for determining patient 
eligibility.  Bilirubin fractions (direct and indirect) must be included if total bilirubin is 
greater than ULN.

Pregnancy test
For all women of childbearing potential (see Section 4.1.1), pregnancy tests must be 
performed via serum -human chorionic gonadotropin (HCG) at baseline and via urine 
tests thereafter according to Appendix 1 until seven months after discontinuation of study 
treatment. Any positive urine pregnancy test must be confirmed with a serum -HCG 
test. During the study treatment periods, pregnancy test results must be available prior to 
study treatment administration.
For women who are not of childbearing potential, documentation must be present in 
medical history confirming that the patient is not of childbearing potential.
4.5.12
Patient Reported Outcomes
Patient reported outcomes will be collected via paper questionnaires. All questionnaires 
must be completed in their entirety at the specified timepoints during the study (Appendix 1).  
The questionnaires will be translated into the local language as appropriate.


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4.5.12.1
Patient Preference Questionnaire
The PPQ will be completed by each patient immediately after completion of treatment 
administration at the scheduled timepoint. Please refer to Appendix 1 for instructions 
regarding when patients who prematurely discontinue study treatment should complete the 
PPQ.
4.5.12.2
Therapy Administration Satisfaction Questionnaires
Patient assessed satisfaction with P+H IV and pertuzumab and trastuzumab FDC SC will be 
evaluated using the TASQ-IV and TASQ-SC, respectively. Each TASQ will be completed by 
the patient immediately after completion of treatment administration at the scheduled 
timepoint. Please refer to Appendix 1 for instructions regarding when patients who switch
study treatment due to lack of tolerance should complete each TASQ.
4.5.12.3
European Organisation for Research and Treatment of Cancer Quality 
of Life Questionnaire (EORTC QLQ-C30)
Patient reported HRQoL will be assessed via the EORTC QLQ-C30 administered at 
specified timepoints throughout the study including during the Follow-up Period. 
To ensure instrument validity and that data standards meet health authority requirements, 
the EORTC QLQ-C30 will be self-administered before the patient and clinician receives any 
information on disease status and prior to treatment administration on the scheduled visit 
day.
4.5.13
Healthcare Professional Reported Outcomes
4.5.13.1
Healthcare Professional Questionnaire
Healthcare professional reported perception of time and resource use associated with 
pertuzumab and trastuzumab FDC SC will be assessed via two HCPQs (see Appendix 3). 
One HCPQ (HCPQ-Treatment Room) will be completed by an HCP involved in treatment 
preparation and/or administration in the treatment room where study drugs are administered. 
The other HCPQ (HCPQ-Drug Preparation Area) will be completed by an HCP involved in 
study drug preparation. Please refer to each HCPQ in Appendix 3 for personnel qualifying as 
HCPs for each questionnaire.  The HCPQs will be completed by the HCP after preparation 
and/or administration of the study treatment at each scheduled time point (see Appendix 1).  
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize the 
patient's safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Pregnancy 


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
Heart failure (NYHA class III or IV)

Anaphylaxis associated any of the study drugs

Patients who experience disease recurrence will be withdrawn from study treatment and 
treated as clinically indicated, according to local clinical practice
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
Patients who discontinue study treatment prematurely will return to the clinic for an End of 
Treatment Visit 28 days (± 7 days) of the administration of the last dose of study drug and 
will continue in the Follow-up Period (see Appendix 1 for additional details).  Anti-cancer 
treatment for patients who have prematurely discontinued study treatment is at the discretion 
of the investigator as clinically indicated.
4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  In 
addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the study
but have not withdrawn consent.  The primary reason for withdrawal from the study should 
be documented on the appropriate eCRF.  If a patient requests to be withdrawn from the 
study, this request must be documented in the source documents and signed by the 
investigator.  Patients who withdraw from the study will not be replaced.
If a patient withdraws from the study, the study staff may use a public information source to 
obtain information about survival status.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating the 
study may include, but are not limited to, the following:

The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients

Patient enrolment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a study site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment


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
Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Pertuzumab and trastuzumab drug substances in the FDC SC are identical to the drug 
substances in Perjeta IV, Herceptin IV and Herceptin SC. As described in Section 1.2.4, the 
safety profiles and tolerability of Herceptin SC and Herceptin IV have been shown to be 
consistent. As also described in Section 1.2.4, preliminary safety data from healthy 
volunteers and EBC patients treated with pertuzumab SC co-administered or co-mixed with 
Herceptin SC are consistent with prior experience with combined treatment with Perjeta IV 
and Herceptin IV. The safety plans for this study, as well as for the ongoing Phase III Roche 
Study WO40324 (see Section 1.2.4) comparing pertuzumab and trastuzumab FDC SC with 
P+H IV, are therefore based on the anticipated safety risks of Herceptin IV and Perjeta IV, 
alone and in combination, described in the Perjeta and Herceptin Investigator’s Brochures. 
Measures taken to ensure the safety of patients participating in this study include eligibility 
criteria designed to exclude patients at higher risk for toxicities and ongoing safety 
monitoring. Safety monitoring includes assessment of the nature, frequency, and severity of 
AEs and cardiac function evaluations.
The anticipated important safety risks for pertuzumab and trastuzumab are outlined below.
Please refer to the Perjeta and Herceptin Investigator’s Brochures for complete summaries 
of safety information.
5.1.1
Risks Associated with Pertuzumab
5.1.1.1
Hypersensitivity Reactions / Anaphylaxis and Administration-Related 
Reactions 
Like other monoclonal antibodies, Perjeta IV has been associated with ARRs. These include:

Infusion-related reactions (i.e., a systemic reaction with symptoms such as chills, 
diarrhoea, fatigue, headache, nausea and pyrexia).
Such reactions are likely to be due to cytokine release and typically occur during, or very 
shortly after, the administration of monoclonal antibodies, but they may also show a 
delayed onset. In general, infusion-related AEs are more frequent and severe with the 
first infusion, and decrease in number and severity over time. The majority of AEs 
resolve fully.

Injection-related reactions with SC administration may manifest themselves as:
−
Systemic reactions, similar to the infusion-related reactions


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−
Local injection site reactions (ISRs) with signs and symptoms such as erythema, 
induration, swelling, pain, hypoaesthesia and discomfort
Hypersensitivity reactions / anaphylaxis are systemic reactions caused activation of mast 
cells and basophils by antigen-bound IgE that results in degranulation and release of 
inflammatory mediators. Hypersensitivity reactions / anaphylaxis events are likely to start 
mildly and increase in number and severity over time. Severe hypersensitivity, including 
anaphylaxis, has been observed in clinical trials with treatment of Perjeta IV. Patients in this 
study who experience a Grade 4 allergic reaction or acute respiratory distress syndrome 
(ARDS) should be discontinued from study treatment. Since there is a potential for delayed 
onset, patients should be instructed to contact the treating physician with any concerns, 
signs or symptoms subsequent to treatment administration. Administration-related reactions
may be difficult to distinguish from hypersensitivity reactions.
In this study, if a loading dose of Perjeta IV is required, it will be given over 60 (± 10) 
minutes, followed by an observation period of 60 minutes. If the loading dose infusion is well 
tolerated, subsequent infusions may be administered over a period of 30 minutes (± 10) with 
an observation period of 30 minutes. If symptoms occur, the infusion should be slowed down 
or interrupted and appropriate medical therapies should be administered. The observation 
period should be completed prior to the subsequent Herceptin IV infusion. Premedication 
with antipyretics, antihistamines, or corticosteroids may be administered before Perjeta IV 
administration.
For pertuzumab and trastuzumab FDC SC administration, patients should be monitored for 
30 minutes after their first dose regardless of whether a loading dose is required. Patients 
should be monitored for 10 - 15 minutes following subsequent administrations unless a 
loading dose is required. If a patient requires a loading dose after their first pertuzumab and 
trastuzumab FDC SC treatment, they should be monitored for 30 minutes after dosing. If 
ARRs occur, patients must be monitored until complete resolution of signs and symptoms.
Perjeta IV and pertuzumab and trastuzumab FDC SC will be administered by staff who have 
immediate access to emergency equipment and are trained to monitor for, and respond to, 
medical emergencies.
Please refer to the Perjeta Investigator’s Brochure for the most recent data related to the risk 
of hypersensitivity reactions.
5.1.1.2
Symptomatic Left Ventricular Systolic Dysfunction
Similar to trastuzumab, pertuzumab’s interaction with HER2 may be associated with a risk of 
symptomatic LVSD. Cardiac dysfunction may manifest as an asymptomatic or mildly 
symptomatic decrease in LVEF (NCI CTCAE, Grade 1 and Grade 2) or as a symptomatic 
decreased in LVEF / CHF (NCI CTCAE, Grade ≥ 3; NYHA Class III or IV). Please refer to 
Appendix 6 for management of patients with decreased LVEF.
In the Roche pivotal trial WO20698/TOC4129g (CLEOPATRA) in MBC patients, treatment 
with P+H IV and docetaxel was not associated with increases in the incidence of 
symptomatic LVSD or LVEF declines compared with placebo in combination with Herceptin 
IV and docetaxel. The incidence of symptomatic LVSD was 1.5% (6/408) for patients 
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placebo arm. Regardless of treatment arm, patients who had received prior anthracyclines or 
prior radiotherapy to the chest area were at higher risk of decreased LVEF. In the Roche
Phase II WO209697 study (NEOSPHERE) of neoadjuvant P+H IV and docetaxel, the 
incidence of left ventricular dysfunction defined as LVEF decline ≥ 10% to below 50% was 
higher in the Perjeta IV plus docetaxel-treated groups (7.4% with Perjeta IV plus docetaxel,
8.4% P+H IV plus docetaxel) than the Herceptin IV plus docetaxel treated group (1.9%). An 
increased incidence of LVEF declines was observed in patients treated in the Perjeta IV plus 
Herceptin IV and docetaxel. Left ventricular ejection fraction recovered to ≥ 50% in all 
patients. In the ongoing Roche Phase II WO29217 study (BERENICE; neoadjuvant 
anthracycline / taxane based regimens given in combination with P+H IV), the overall 
incidence of LVEF declines and symptomatic LVD in the neoadjuvant period is consistent 
with previous data in the neoadjuvant setting.
Perjeta has not been studied in patients with the following: a pre-treatment LVEF value of 
≤50%; a prior history of CHF; decreases in LVEF to < 50% during prior Herceptin adjuvant
therapy;
conditions that could impair left ventricular function such as uncontrolled
hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment, or 
a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent.
Subjects with significant cardiac disease or baseline LVEF < 55% are not eligible for this
study. As in all Perjeta trials, study patients must undergo routine cardiac monitoring by 
ECHO or MUGA scan. During the screening / baseline period, complete medical history 
information will be collected from all patients to explore possible risk factors for treatment-
associated CHF. Monitoring of LVEF is required while patients are receiving study treatment 
and up to 24 months following discontinuation of study treatment (see Appendix 1). If 
symptomatic LVSD (heart failure; SAE of NCI CTCAE v4.0 Grade 3 or 4; NYHA Class III or 
IV) develops, the patient must be monitored carefully with repeat LVEF assessments.  
Symptomatic LVSD should be treated and followed according to standard medical practice. 
Refer to the algorithm in Appendix 6 for decisions regarding the continuation or
discontinuation of study treatment based on LVEF assessment in asymptomatic patients.
Please refer to the Perjeta Investigator’s Brochure for the most recent data relating to risk of 
LVSD and CHF.
5.1.1.3
Epidermal Growth Factor Receptor (HER1)-Related Toxicities
Pertuzumab inhibits HER2 heterodimerization with other members of the HER family
including HER1/EGFR. As a result, pertuzumab may cause toxicities associated with the use
of EGFR tyrosine kinase inhibitors such as diarrhoea, rash and other dermatologic toxicities 
(e.g., dry skin, pruritus, nail disorders, mucositis).
The most recent data relating to the risk of EGFR-related toxicities are found in the Perjeta
Investigator’s Brochure.
5.1.1.3.1
Diarrhoea
Diarrhoea has been observed in approximately 60% of patients (treatment-related diarrhoea
in 50% of patients) being treated with Perjeta IV in Phase II single-agent studies, and in up 
to 90% of patients in combination therapy studies. Diarrhoea was NCI CTCAE Grade 1 or 2 
in the majority of cases. To prevent dehydration, early treatment of diarrhoea with anti-


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diarrheal medication should be considered and patients treated with fluids and electrolyte 
replacement, as clinically indicated.
5.1.1.3.2
Rash / Skin Reactions
Rash / skin reactions have been observed in approximately 17% of patients treated with
Perjeta IV in the Phase II single-agent studies and in up to 73% of patients in combination 
studies. The rash was generally mild to moderate in intensity and NCI CTCAE Grade 1 or 2.
The rash / skin reaction appeared to be treatable in some patients with standard acne
therapies, including topical and oral antibiotics.
5.1.1.3.3
Mucositis
Mucositis has been observed in approximately 15% of patients treated with Perjeta IV in 
Phase II single-agent studies and in up to 50% of patients in combination studies.  The most 
common preferred terms reported were mucosal inflammation and stomatitis.
5.1.1.3.4
Interstitial Lung Disease
Interstitial lung disease is associated with the use of EGFR inhibitors and therefore could 
occur with pertuzumab. The few reports of interstitial lung disease in Perjeta IV-treated 
patients received to date also had evidence of alternative causes (e.g., concomitant 
medication, preceding / concurrent neutropenia with potential infection or other relevant 
medical history).
In the pivotal study WO20698/TOC4129g (CLEOPATRA; Herceptin IV and docetaxel with 
Perjeta IV or placebo), respiratory events (i.e., dyspnoea, cough), which are unspecific 
symptoms of various conditions, including infusion-related reaction or hypersensitivity /
anaphylaxis, 
cardiac
dysfunction, 
and 
respiratory 
disease, 
were 
reported 
in 
> 10% of Perjeta IV-treated patients.
5.1.2
Risks Associated with Trastuzumab
Serious adverse reactions, including LVSD, ARRs, hypersensitivity, allergic-like reactions, 
and pulmonary events, have been observed in patients receiving Herceptin IV and/or SC. 
5.1.2.1
Administration-Related Reactions, Allergic-Like Reactions, and 
Hypersensitivity
Herceptin IV and SC have been associated with ARRs. ARRs are defined as systemic 
‘infusion-related reactions’ associated with Herceptin IV and systemic reactions associated 
with Herceptin SC. In some studies, local ISRs were excluded from the ARR definitions. A 
revised definition of ARRs potentially associated with IV and SC administration of Herceptin 
was used in Study BO22227 (see Section 1.2.4) and is applicable to all future and ongoing 
Herceptin IV and SC studies. This definition is based on a modified version of the 
anaphylactic reaction Standardised Medical Dictionary for Regulatory Activities (MedDRA)
Query (as modified by the addition of the following four MedDRA Preferred Terms:
hypersensitivity, 
drug 
hypersensitivity, 
infusion-related 
reaction, 
and 
injection-site
hypersensitivity). The revised definition of ARRs differs from that in previous studies in the 
metastatic and early breast cancer settings which reported only ‘infusion reactions’ or 


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‘infusion-related reactions’ associated with Herceptin administration and makes comparison 
of the rates of ARRs between studies difficult.
Serious adverse reactions to Herceptin IV that have been reported infrequently include
dyspnoea, hypotension, wheezing, bronchospasm, asthma, tachycardia, reduced oxygen
saturation, anaphylaxis, respiratory distress, urticaria, and angioedema. Fatalities have 
occurred within hours and up to one week following Herceptin IV administration. On very 
rare occasions, patients have experienced the onset of administration-related symptoms or 
pulmonary symptoms more than six hours after the start of the Herceptin administration. 
Patients should be warned of the possibility of such a late onset and should be instructed to 
contact their physician if these symptoms occur. Patients who have dyspnoea at rest due to 
comorbidities may be at increased risk of a fatal ARR therefore should not be treated with 
trastuzumab. Although such events were not reported in clinical trials with Herceptin SC, 
caution should be exercised, as these events have been associated with the IV formulation.
These reactions were usually associated with the first administration of Herceptin IV and
generally occurred during or immediately following administration. In this study, all patients 
will be pre-treated with Perjeta IV and Herceptin IV or SC in neoadjuvant phase of their 
treatment. Due treatment delays necessary for breast cancer surgery, a loading dose of 
Herceptin IV may be required. If required, the loading dose must be administered over 90 (± 
10) minutes, after which the patient must be observed for 60 minutes. If the loading dose 
infusion is well tolerated, subsequent maintenance doses may be administered over 30 (± 
10) minutes, followed by an observation period of 30 minutes. Premedication with 
antipyretics, antihistamines, or corticosteroids may be administered before Perjeta IV 
administration (which will occur before Herceptin IV administration).
In Study BO22227, the overall incidence of ARRs in the Herceptin IV arm was 37.2% 
(111/298) compared with 47.8% (142/297) in the Herceptin SC arm.  Most of the ARRs 
occurred in the neoadjuvant treatment phase, with an incidence of 32.6% in the Herceptin IV 
arm and 38.4% in the Herceptin SC arm. Fewer ARRs were reported during the adjuvant 
treatment phase of the study. All but one of the ARRs was Grade 1 or Grade 2 in intensity 
and the distribution was balanced between the study phases in terms of the most common 
AEs and MedDRA System Organ Class. There was a higher rate of Herceptin SC injection-
site reactions compared with the Herceptin IV infusion (11.1% in Herceptin SC vs. 0.3% in 
Herceptin IV). With few exceptions, all of these events were of Grade 1 intensity. Serious 
reactions to Herceptin IV have been treated successfully with supportive therapy, such as 
oxygen, β-agonists, and corticosteroids.
In this study, patients should be monitored for 30 minutes after their first pertuzumab and 
trastuzumab FDC SC dose administration regardless of whether a loading dose is required. 
Patients should be monitored for 10 - 15 minutes following subsequent administrations
unless a loading dose is required. If a patient requires a loading dose sometime after their 
first pertuzumab and trastuzumab FDC SC dose, they should be monitored for 30 minutes 
following administration. If ARRs occur, patients must be monitored until complete resolution 
of signs and symptoms.


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Herceptin IV and pertuzumab and trastuzumab FDC SC will be administered by staff with 
immediate access to emergency equipment who are trained to monitor for, and respond to, 
medical emergencies.
Please refer to the Herceptin Investigator’s Brochure for the most recent data related to the 
risk of ARRs, allergic-like reactions, and hypersensitivity reactions.
5.1.2.2
Pulmonary Events
Severe pulmonary events have been reported with the use of the Herceptin IV formulation in 
the post-marketing setting. These events have occasionally been fatal. They may occur as
part of an ARR or with delayed onset. In addition, cases of interstitial lung disease, including 
lung infiltrates, ARDS, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute 
pulmonary oedema, and respiratory insufficiency have been reported with Herceptin IV. 
These events have been most common with the first infusion, and their severity has 
decreased with subsequent infusions. Serious reactions have been treated successfully with 
supportive therapy, such as oxygen, β-agonists, and corticosteroids. Acute respiratory 
distress syndrome has been reported with a fatal outcome.
Please refer to the Herceptin Investigator’s Brochure for the most recent data related to the 
risk of pulmonary events.
5.1.2.3
Symptomatic Left Ventricular Systolic Dysfunction
Heart failure (NYHA Class II - IV) has been observed in patients who have received
Herceptin IV and/or SC alone or in combination with docetaxel following anthracycline
(doxorubicin or epirubicin)-containing chemotherapy. This event may be moderate to severe 
and has been associated with death. Risk factors for Herceptin-associated LVSD include 
increased age, concomitant administration with anthracyclines, and declining LVEF while on 
Herceptin treatment. If symptomatic cardiac failure develops during treatment, it should be 
treated with standard medications for this purpose.
The rates of cardiac dysfunction observed in large Herceptin adjuvant trials in EBC are < 4% 
with event rates comparable across the studies. In Study BO22227 (see Section 1.2.4), the
proportion of patients who experienced a significant decrease in LVEF (defined as a drop in 
LVEF ≥ 10 percentage points to a value of < 50%) was similar in each treatment arm (12 
[4.2%] patients in Herceptin IV and 11 [3.8%] patients in Herceptin SC).
Because the half-life of Herceptin IV is approximately 28 - 38 days, Herceptin may persist in
the circulation for up to 7 months after the last dose of Herceptin. Patients who receive
anthracyclines after the last dose of Herceptin may possibly be at increased risk of LVSD. If 
possible, physicians should avoid anthracycline-based therapy for up to 27 weeks 
(7 months) after stopping Herceptin. If anthracyclines are used, the patient’s cardiac function 
should be monitored carefully.
Most patients who developed heart failure in the Phase III trials of Herceptin IV or SC in 
MBC and EBC improved with standard medical treatment. This treatment included diuretics,
cardiac glycosides, and/or ACE inhibitors. The majority of patients with cardiac symptoms 
and evidence of a clinical benefit of Herceptin treatment continued on weekly therapy with 
Herceptin without experiencing additional clinical cardiac events.


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Please refer to the Herceptin Investigator’s Brochure for the most recent data related to the 
risk of LVSD.
5.1.3
Reproductive Risks Associated with Pertuzumab and Trastuzumab
Reproductive toxicity was identified during nonclinical studies with Perjeta. Perjeta
administered to pregnant cynomolgus monkeys during organogenesis led to delayed renal 
development, oligohydramnios, and embryo-foetal deaths. However, reproductive toxicity 
studies with trastuzumab
conducted in female cynomolgus monkeys revealed no
trastuzumab-related embryotoxicity or effects on foetal development. There are no clinical 
studies of trastuzumab or pertuzumab in pregnant women. IgGs are known to cross the
placental barrier. In the post-marketing setting, cases of oligohydramnios, some associated 
with fatal pulmonary hypoplasia of the foetus, have been reported in pregnant women 
receiving Herceptin. Therefore, neither pertuzumab or trastuzumab should be used during 
pregnancy unless the potential benefit for the mother outweighs the potential risk to the 
foetus.
Due to these risks, female participants of childbearing potential in this study are tested for 
pregnancy prior to study entry and must undergo pregnancy testing during the study and, 
guided be the half-life of Herceptin IV, up to seven months after their last study treatment. 
Pregnancies in female participants or partners of male participants will be monitored. Further, 
participants of childbearing potential (defined as post-menarchal, has not reached a post-
menopausal state [post-menopausal defined as ≥ 12 continuous months of amenorrhea with 
no identified cause other than menopause], and has not undergone surgical sterilization 
[removal of ovaries and/or uterus]), must remain abstinent (refrain from heterosexual 
intercourse) or use non-hormonal contraceptive methods with a failure rate of <1% per year, 
or two effective non-hormonal contraceptive methods during the study treatment periods and 
for 7 months after the last dose of study treatment and must refrain from donating eggs 
during the same period. Women who have had a tubal ligation do not require additional 
contraception. The definition of childbearing potential may be adapted for alignment with 
local guidelines or requirements.
Men with female partners of childbearing potential, or with pregnant female partners,
participating in the study must remain abstinent or use a condom during the study treatment 
periods and for seven months after the last dose of study treatment to avoid exposing the 
embryo. All male participants must also refrain from donating sperm during this same period.
Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year 
include bilateral tubal ligation, male sterilization (with appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate) and copper IUDs.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
Alternatively, two of the following effective forms of contraception may be used instead:

Placement of non-hormonal IUD or intrauterine system


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
Consideration should be given to the type of device being used, as there are higher 
failure rates quoted for certain types (e.g., steel or copper wire).

Condom with spermicidal foam / gel / film / cream / suppository

Occlusive 
cap 
(diaphragm 
or 
cervical / vault 
caps) 
with 
spermicidal
foam / gel / film / cream / suppository
The use of barrier contraceptives should always be supplemented with the use of a
spermicide. The following should be noted:

Failure rates indicate that, when used alone, the diaphragm and condom are not highly 
effective forms of contraception. Therefore, the use of additional spermicides does 
confer additional theoretical contraceptive protection. However, spermicides alone are 
ineffective at preventing pregnancy when the whole ejaculate is spilled. Therefore, 
spermicides are not a barrier method of contraception and should not be used alone.
It should be noted that two forms of effective contraception are required. A double barrier 
method is acceptable, which is defined as condom and occlusive cap (diaphragm or 
cervical / vault caps) with spermicidal foam / gel / film / cream / suppository.
5.1.3.1
Breastfeeding
It is not known whether trastuzumab or pertuzumab are excreted in human milk. Since
maternal IgG is excreted in milk and either trastuzumab or pertuzumab could harm infant 
growth and development, women must discontinue nursing during study treatment and 
should not breastfeed for at least seven months following the last study treatment.
5.1.4
Management of Patients Who Experience Adverse Events
5.1.4.1
Dose Modifications for Perjeta IV, Herceptin IV, and Pertuzumab and 
Trastuzumab FDC SC
Dose modifications of study treatment are not permitted. 
5.1.4.2
Dose Delays and Treatment Interruption for Perjeta IV, Herceptin IV, and 
Pertuzumab and Trastuzumab FDC SC
The administration of study treatment may be delayed to assess or treat AEs, such as 
cardiac AEs.  
During the study treatment period, a dose delay of up to (and including) six weeks (i.e., up to 
and including nine weeks between doses) will be permitted to allow AE recovery to baseline. 
Following a dose delay of less than 3 weeks (i.e., < 6 weeks between doses), study 
treatment does not need to be reloaded (only the maintenance doses needs to be given). 
Patients receiving pertuzumab and trastuzumab FDC SC with ≥ 6 weeks since their last 
study treatment during the study treatment periods, must receive a loading dose consisting 
of 1200 mg pertuzumab and 600 mg trastuzumab FDC SC before continuing with 
maintenance doses for subsequent administrations. Patients should be monitored for 30 
minutes after their first pertuzumab and trastuzumab FDC SC dose administration in the 
study (regardless of whether a loading dose is required) and if a loading dose is required 
during the study. Patients should be monitored for 10 - 15 minutes following maintenance 
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Patients receiving Perjeta IV with ≥ 6 weeks since their last study treatment during the study 
treatment periods, must receive a loading dose of 840 mg before continuing with 
maintenance doses for subsequent administrations. Perjeta IV loading dose (if required) will 
be administered as a 60-minute infusion (± 10 minutes), followed by an observation period of 
60 minutes. If the loading dose infusion is well tolerated, subsequent maintenance doses 
can be administered over a period of 30 minutes (± 10 minutes) with an observation period 
of 30 minutes. The observation period should be completed prior to the subsequent 
Herceptin IV infusion. 
Patients receiving Herceptin IV with had ≥ 6 weeks since their last study treatment during the 
study treatment periods, must receive a loading dose of 8 mg/kg before continuing with 
maintenance doses for subsequent administrations. Herceptin IV loading dose (if required) 
will be administered as an infusion over approximately 90 (± 10) minutes after which the 
patient must be observed for 60 minutes. If the loading dose is well tolerated, subsequent 
maintenance doses can be administered as 30-minute infusions (± 10 minutes) followed by 
an observation period of 30 minutes.
If study treatment is withheld for more than two cycles (> 9 weeks) because of toxicity, the 
patient should be discontinued from study treatment, unless resumption of treatment is 
approved following investigator discussion with the Medical Monitor.  Study treatment may 
be suspended for reasons other than toxicity (e.g., surgical procedures) with Medical Monitor 
approval.  The investigator and the Medical Monitor will determine the acceptable length of
treatment interruption.
Patients who are permanently discontinued from study treatment should be treated at the 
discretion of the investigator as clinically indicated. The patient will continue to be followed 
post-treatment as described in Section 4.6.1.
5.1.4.3
Management Guidelines
Supportive care and medical management of AEs are at the discretion of the investigator, 
unless specifically listed below.
5.1.4.3.1
Symptomatic LVSD and/or LVEF Decline
All patients must have a baseline LVEF ≥55%. LVEF will be monitored regularly according 
to the Schedule of Activities (see Appendix 1).  If an investigator is concerned that an AE
may be related to LVSD, an additional LVEF measurement should be performed as soon as 
possible and within three weeks.
Symptomatic LVSD (CHF) should be assessed as “heart failure” on the basis of NCI CTCAE 
v4.0 and NYHA classification (see Appendix 7). Symptomatic LVSD (CHF) should be treated 
and monitored according to standard medical practice. These patients should be evaluated 
by a certified cardiologist.
Appendix 6 summarizes the management of study medication in patients who develop an 
asymptomatic decrease in LVEF. The decision to initiate study treatment and whether to 
continue or stop therapy should be based on two factors: measured LVEF and changes in 
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confirmed by a second assessment within approximately three weeks showing also a 
significant decrease.
Heart failure and asymptomatic LVEF decline AEs must be graded per NCI CTCAE v4.0 
(see Appendix 7) and reported in the eCRF as described in Table 1.  
5.1.4.3.2
Hypersensitivity / Anaphylaxis and Administration-Related Reactions 
(Infusion or Injection)
Study treatment administration should be stopped in subjects who develop dyspnoea or 
clinically significant hypotension (defined per investigator’s discretion).
Patients who experience any of the following events will be discontinued from study
treatment:

Grade 4 allergic reaction

Grade 3 or 4 hypersensitivity reaction

ARDS

Bronchospasm
Patients who experience ARRs may be managed by:

Slowing or stopping Perjeta IV or Herceptin IV infusion

Stopping the injection of pertuzumab and trastuzumab FDC SC

Supportive care with oxygen, β-agonists, antihistamines, antipyretics, or corticosteroids 
as appropriate at the investigator's discretion, as per institutional practice

Subsequently pre-medicating with analgesia and antihistamines as per institutional
practice
Patients should be monitored until complete resolution of signs and symptoms of any 
systemic reactions.
In order to be able to calculate time to onset of such reactions, the occurrence of associated 
AEs must be documented with the date and time of the onset and duration of the event (i.e., 
resolution of the event).
All ARRs should be recorded as described in Section 5.2.4.3.
5.1.4.3.3
EGFR-Related Toxicities
Diarrhoea
To prevent dehydration, early treatment of diarrhoea with anti-diarrheal medication (e.g.
loperamide) should be considered, and patients should be treated with fluids and electrolyte 
replacement, as clinically indicated.
Rash / Skin Reactions
Treatment recommendations for EGFR-associated rash / skin reactions include topical or
oral antibiotics, topical pimecrolimus, and topical steroids or systemic steroids (for severe 
reactions). These agents may be used in patients experiencing pertuzumab-related rash /
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Mucositis
Mucositis is generally not considered preventable. Although for some cytotoxic agents, 
mucositis may be reduced by cooling the mouth using ice chips before and during the 
infusion.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording AEs (including SAEs and AEs
of special interest), performing protocol-specified safety laboratory assessments, measuring 
protocol-specified vital signs, and conducting other protocol-specified tests that are deemed 
critical to the safety evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in Section
5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an AE is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution.  An AE can therefore be any of the following:

Any unfavourable 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) (see Sections 5.3.5.8 and 5.3.5.9 for more 
information)

Recurrence of an intermittent medical condition (e.g., headache) not present at baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those that 
occur prior to assignment of study treatment (e.g., screening invasive procedures such 
as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the Sponsor)
A serious adverse event is any AE that meets any of the following criteria:

Is fatal (i.e., the AE actually causes or leads to death)

Is life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death)

This does not include any AE that, had it occurred in a more severe form or was allowed 
to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.10)

Results in persistent or significant disability / incapacity (i.e., the AE results in substantial 
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
Is a congenital anomaly / birth defect in a neonate / infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical / surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of an 
AE (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE v4.0; see Section
5.3.3); the event itself may be of relatively minor medical significance (such as severe 
headache without any further findings). Severity and seriousness need to be independently 
assessed for each AE recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to the 
Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see Section
5.4.2 for reporting instructions).  Adverse events of special interest for this study are as 
follows:

An asymptomatic decline in LVEF that requires treatment or that leads to discontinuation 
of study treatment

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law
(see Section 5.3.5.6)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent.  A transmission of an infectious agent may be suspected from clinical symptoms 
or laboratory findings that indicate an infection in a patient exposed to a medicinal 
product.  This term applies only when a contamination of the study drug is suspected.
5.2.4
Selected Adverse Events
Additional data will be collected for the selected AEs described below.
5.2.4.1
Heart Failure
Symptomatic LVSD (referred to as heart failure) should be reported as an SAE. If the 
diagnosis is heart failure, it should be reported as such, and not as individual signs and 
symptoms of heart failure. Heart failure should be graded according to both NCI CTCAE and 
NYHA Class (see Appendix 7). Left ventricular ejection fraction results must also be reported.
Heart failure occurring during the study (including the Follow-up Period) must be reported 
irrespective of causal relationship and followed until one of the following occurs: resolution or 
improvement to baseline status, no further improvement can be expected, or death.








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5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding the 
event, and an evaluation of any potential alternative causes to determine whether an AE is 
considered to be related to the study drug, indicating "yes" or "no" accordingly.  The 
following guidance should be taken into consideration (see also Table 4):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as 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
Table 4
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by the 
patient's clinical state, intercurrent illness, or concomitant therapies; and/or the adverse 
event follows a known pattern of response to the study drug; and/or the adverse event 
abates or resolves upon discontinuation of the study drug or dose reduction and, if 
applicable, reappears upon re challenge.
NO
An adverse event will be considered related, unless it fulfils the criteria specified below.  
Evidence exists that the adverse event has an aetiology other than the study drug (e.g., 
pre-existing medical condition, underlying disease, intercurrent illness, or concomitant 
medication); and/or the adverse event has no plausible temporal relationship to 
administration of the study drug (e.g., cancer diagnosed 2 days after first dose of study 
drug).
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology / concepts when recording AEs on the 
Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one AE term should be recorded in the event field on the Adverse Event eCRF.
Refer to Section 5.2.4 for procedures for recording heart failure, asymptomatic decreases in 
LVEF and ARRs.
5.3.5.1
Diagnosis versus Signs and Symptoms
For AEs other than heart failure and ARRs (see Section 5.2.4), a diagnosis (if known) should 
be recorded on the Adverse Event eCRF rather than individual signs and symptoms (e.g., 
record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be medically 


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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 adverse event report based on the single diagnosis, with a starting date 
that corresponds to the starting date of the first symptom of the eventual diagnosis.
5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, AEs that are 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.  A medically significant secondary AE that is separated in time from the 
initiating event should be recorded as an independent event 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 haemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be reported 
separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported separately 
on the eCRF.
All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to 
whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation timepoints.  Such events should only be recorded once on the Adverse Event 
eCRF.  The initial severity (intensity or grade) of the event will be recorded at the time the 
event is first reported.  If a persistent AE becomes more severe, the most extreme severity 
should also be recorded on the Adverse Event eCRF. If the event becomes serious, it should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning that the 
event became serious; see Section 5.4.2 for reporting instructions).  The Adverse Event 
eCRF should be updated by changing the event from "non-serious" to "serious," providing 
the date that the event became serious, and completing all data fields related to SAEs.
A recurrent AE is one that resolves between patient evaluation timepoints and subsequently 
recurs.  Each recurrence of an AE should be recorded as a separate event on the Adverse 
Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an AE.  A laboratory test result must be 
reported as an AE if it meets any of the following criteria:

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
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 hypokalaemia) or 
a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all laboratory findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should 
be classified as an AE.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) 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 whether the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should be 
recorded as the AE.  For example, an elevated serum potassium level of 7.0 mEq/L should 
be recorded as "hyperkalaemia."
Observations of the same clinically significant laboratory abnormality from visit to visit should 
only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for details on 
recording persistent AEs).
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an AE.  A vital sign result must be reported as 
an AE if it meets any of the following criteria:

Is 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

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should 
be classified as an AE.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high 
blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the Adverse 
Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit should 
only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for details on 
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5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (> 3 baseline) 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 (as 
defined by Hy's Law).  Therefore, investigators must report as an AE the occurrence of 
either of the following:

Treatment-emergent ALT or AST > 3 x baseline value in combination with total bilirubin 
> 2 ULN (of which ≥ 35% is direct bilirubin)

Treatment-emergent ALT or AST > 3 x baseline value in combination with clinical 
jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the event), 
either as an SAE or an AE of special interest (see Section 5.4.2).
5.3.5.7
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol-
specified adverse event reporting period (see Section 5.3.1) that are attributed by the 
investigator solely to recurrence of breast cancer should be recorded on the Death Attributed 
to Progressive Disease eCRF.  All other deaths that occur during the adverse event
reporting period, 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.  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.  The term "sudden death" should be used only 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 after 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. 
Deaths that occur after the adverse event reporting period should be reported as described 
in Section 5.6.
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 AE only if the frequency, severity, 
or character of the condition worsens during the study.  When recording such events on 


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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 Recurrence of Breast Cancer
Events that are clearly consistent with breast cancer recurrence should not be recorded as 
AEs.  These data will be captured as efficacy assessment data only.  Disease recurrence will 
be determined based on the investigator’s assessment as per institutional practice or the 
ACS / ASCO Breast Cancer Survivorship Care Guideline (see Appendix 4). Though a
determination of clinical recurrence could be based on symptomatic deterioration, every 
effort should be made to document recurrence through use of objective criteria.  If there is 
any uncertainty as to whether an event is due to disease recurrence, it should be reported as 
an AE.
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any AE that results in hospitalization (i.e., inpatient admission to a hospital) or prolonged 
hospitalization should be documented and reported as an SAE (per the definition of SAE in 
Section 5.2.2), except as outlined below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an AE or an SAE:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration or 
insertion of access device 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 pre-existing condition
−
The patient has not experienced an AE

Hospitalization due solely to recurrence of breast cancer
An event that leads to hospitalization under the following circumstances is not considered to 
be an SAE, but should be reported as an AE instead:

Hospitalization that was necessary because of patient requirement for outpatient care 
outside of normal outpatient clinic operating hours
5.3.5.11
Patient Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  Because the data collection processes and 
intent of interpretation of investigator-assessed AEs and patient-completed questionnaires 
are inherently different, these data sets will not be reconciled by the Sponsor and should not 
be used as source documents for AE reporting by the investigator.


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5.4
IMMEDIATE REPORTING REQUIREMENTS FROM INVESTIGATOR TO 
SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report such 
events to the Sponsor immediately; under no circumstances should reporting take place 
more than 24 hours after the investigator learns of the event.  The following is a list of events 
that the investigator must report to the Sponsor within 24 hours after learning of the event, 
regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for details 
on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)

Overdoses, medication errors, drug abuse, or drug misuse (see Section 5.4.4 for details 
on reporting requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the information).  
New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting SAEs to the local health 
authority and Institutional Review Board (IRB) / Ethics Committee (EC).
5.4.1
Emergency Medical Call Centre
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 
Responsible (listed above and/or on the Roche Medical Emergency List), 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, as well as Medical Monitor and Medical 
Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and Adverse 
Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only SAEs
caused by a protocol-mandated intervention should be reported.  The paper Clinical Trial 
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investigators should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug and until 28 days from the last study treatment dose all SAEs 
and AEs of special interest will be reported.
After 28 days from the last study treatment, SAEs related to study treatment and all AEs of 
special interest will be reported until 7 months after the last study treatment. Additional 
events that will be reported during this period are described in Section 5.3.1.
After seven months from the last study treatment until the end of the study, SAEs related to 
study treatment will be reported. Additional events that will be reported during this period are 
described in Section 5.6.
Investigators should record all case details that can be gathered immediately (i.e., within 24 
hours after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche Safety 
Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event / Adverse Event of special interest Reporting Form provided to investigators should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 24 
hours after learning of the event), either by faxing or by scanning and emailing the form 
using the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.  
Instructions for reporting SAEs that occur after the end of the study are provided in Section
5.6.
5.4.3
Reporting Requirements for Pregnancies
In addition to the reporting requirements described below, other information will be 
requested by Roche / Genentech Drug Safety in order to learn more about the effects of 
pertuzumab and trastuzumab on pregnancy. This information will be requested on any 
pregnancy or infant exposed to Perjeta IV, Herceptin IV or pertuzumab and trastuzumab 
FDC SC at specific time points (i.e., after having received the initial report during the first 
trimester, at the end of the second trimester, 2 weeks after the expected date of delivery, 
and at 3, 6, and 12 months of the infant’s life). In case of a report of congenital abnormality, 
a guided questionnaire will be sent out by Roche / Genentech Drug Safety.
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within seven months after the final
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators.  Pregnancy should not be recorded 
on the Adverse Event eCRF.  The investigator should discontinue study drug and counsel 


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the patient, discussing the risks of the pregnancy and the possible effects on the foetus.  
Monitoring of the patient should continue until conclusion of the pregnancy. Any SAEs
associated with the pregnancy (e.g., an event in the foetus, an event in the mother during or 
after the pregnancy, or a congenital anomaly / birth defect in the child) should be reported on 
the Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  
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 seven months
after the final dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing the 
form using the fax number or email address provided to investigators.  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.  When permitted by the site, the pregnant partner 
would need to sign an Authorization for Use and Disclosure of Pregnancy Health Information 
to allow for follow-up on her pregnancy.  If the authorization has been signed, the 
investigator should submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  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 foetus, to support 
an informed decision in cooperation with the treating physician and/or obstetrician.
5.4.3.3
Abortions
Any abortion should be classified as an SAE (as the Sponsor considers abortions to be 
medically significant), recorded on the Adverse Event eCRF, and reported to the Sponsor 
immediately (i.e., no more than 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 exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified as 
an SAE, recorded on the Adverse Event eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).
5.4.4
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher than 
the assigned dose

Medication error:  accidental deviation in the administration of a drug 
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Special situations are not in themselves AEs, but may result in AEs. Each AE associated 
with a special situation should be recorded separately on the Adverse Event eCRF.  If the 
associated AE fulfils seriousness criteria, the event should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  
Adverse events associated with special situations should be recorded as described below for 
each situation:

Accidental overdose:  Enter the AE term.  Check the "Accidental overdose" and 
"Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the AE term.  Check the 
"Medication error" box.

Medication error that qualifies as an overdose: 
Enter the AE term.  Check the 
"Accidental overdose" and "Medication error" boxes.
In addition, all special situations associated with study treatment, regardless of whether they 
result in an AE, should be recorded on the Adverse Event eCRF and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event).  Special 
situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event term.  
Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong dosing 
schedule, incorrect route of administration, wrong drug, expired drug administered) as 
the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication error" 
boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication error" as 
the event term.  Check the "Medication error" box.  Enter a description of the error in the 
additional case details.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose and 
one to report the headache.  The "Accidental overdose" and "Medication error" boxes would 
need to be checked on both eCRF pages.
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 considered to 
be related to study drug or trial-related procedures until a final outcome can be reported.
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the patient's medical record to facilitate source data verification.


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All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For SAEs, AEs of special interest, and pregnancies, the Sponsor or a designee may 
follow up by telephone, fax, email, 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
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE EVENT 
REPORTING PERIOD
After the end of the adverse event reporting period (defined as seven months after the last
dose of study treatment), all deaths, regardless of cause, should be reported through use of 
the Long-Term Survival Follow-Up eCRF.
In addition, if the investigator becomes aware of:

an SAE that is believed to be related to prior exposure to study drug

heart failure, AEs of special interest, or non-breast-related second primary malignancies,
regardless of causality
the event should be reported through use of the Adverse Event eCRF.  However, if the 
EDC system is not available, the investigator should report these events directly to the 
Sponsor or its designee, either by faxing or by scanning and emailing the paper Clinical 
Trial Serious Adverse Event / Adverse Event of Special Interest Reporting Form using 
the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, INVESTIGATORS, 
INSTITUTIONAL REVIEW BOARDS, AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all SAEs and AEs of special interest against cumulative 
product experience to identify and expeditiously communicate possible new safety findings 
to investigators, IRBs, ECs, and applicable health authorities based on applicable legislation.
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following reference documents:

Perjeta Investigator's Brochure (source for Perjeta IV and for pertuzumab and 
trastuzumab FDC SC)

Herceptin Investigator’s Brochure (source for Herceptin IV)
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.


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6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The primary study analysis will take place when all study patients have completed their last 
study treatment administration in the Treatment Cross-over Period. Summaries of secondary 
study endpoints, including patient reported TASQ and EORTC QLQ-C30 responses, 
selection of treatment administration method for the Treatment Continuation Period, HCP
reported HCPQ responses and safety endpoints will be included in the primary analysis. 
An interim safety analysis that includes the study safety endpoints may be conducted. The 
decision to conduct an interim safety analysis will be based on ongoing review of safety data 
by the Medical Monitor.An interim analysis will be conducted to support a planned regulatory 
filing for FDC (see Section 6.6 ). 
The final study analysis that includes all secondary endpoints including safety and efficacy 
endpoints will be conducted after the end of the study.
The Intent-to-Treat (ITT) population will include all patients randomized into the study, 
allocated to their randomized treatment arm. Summaries of patient and HCP reported 
outcomes and efficacy endpoints will be based on the ITT population. 
The modified ITT (mITT) population will include all patients who received at least one dose 
of pertuzumab and trastuzumab FDC SC and one dose of P+H IV during the Treatment 
Cross-over Period and subsequently answered at least Question 1 of the PPQ. A sensitivity 
analysis of PROs, including the primary endpoint, and HCP reported outcomes will be based 
on the mITT population.
The Safety population will include all patients who received at least one dose of any study 
drug categorized according to the study drug administered. All safety analyses will be based 
on the Safety population.
Continuous variables will be summarised by the mean, standard deviation, median and 
range (minimum and maximum). Categorical variables will be summarised by number /
percentage of patients.
Further details about the planned analyses will be presented in the Statistical Analysis Plan.
6.1
DETERMINATION OF SAMPLE SIZE
The primary study objective is to estimate the proportion of patients who express a 
preference for pertuzumab and trastuzumab FDC SC.
The planned total sample size of 140 patients is based on an assumed rate of 70% of 
patients preferring pertuzumab and trastuzumab FDC SC. To achieve a distance of 
approximately 
± 8% from the estimated proportion to 95% CI limits, a total of 126 patients are needed for 
the evaluation of preference. The final target sample size was increased to approximately 
140 patients to allow for 10% of the patients not providing an evaluable preference 
assessment.


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6.2
SUMMARIES OF CONDUCT OF STUDY
Enrolment, eligibility violations and patient disposition will be summarized for patients by 
treatment arm. Reasons for patient’s study treatment discontinuation and patient’s reasons 
for study discontinuation will be listed by patient and summarized.  Major protocol deviations 
will be listed and evaluated for their potential effects on the interpretation of study results.
Median follow-up on treatment and on study, estimated with corresponding 95% CI by the 
reverse Kaplan-Meier approach, will be presented.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE CHARACTERISTICS
Demographic variables and other baseline and disease characteristics will be summarized 
overall, by treatment arm using descriptive statistics.
6.4
PRIMARY ENDPOINT ANALYSIS
The primary objective of this study is to evaluate patient preference for pertuzumab and 
trastuzumab FDC SC based on the proportion of patients indicating an overall preference for 
pertuzumab and trastuzumab FDC SC in Question 1 of the PPQ. Question 1 of the PPQ is 
as follows: “All things considered, which method of administration did you prefer?”.
A point estimate with associated 95% CI for the proportion of patients who preferred 
pertuzumab and trastuzumab FDC SC will be calculated for the mITT and ITT populations.
The primary endpoint will also be presented by neoadjuvant chemotherapy regimen 
(anthracyclines + taxanes / carboplatin + taxanes / taxanes only), neoadjuvant treatment 
response (pCR / non-pCR) and hormone receptor status  (positive / negative).
6.5
SECONDARY ENDPOINT ANALYSES
Patient assessed satisfaction with pertuzumab and trastuzumab FDC SC and P+H IV will be 
based on patient responses to Question 1 of the TASQ-SC and TASQ-IV respectively. In 
addition, responses of the TASQ-SC and TASQ-IV will be summarized by domain (physical 
impact, psychological impact, impact on activities of daily living, convenience and 
satisfaction) over time.
The proportion of patients who select each treatment administration route for the Treatment 
Continuation Period will be summarized for all patients who complete the Treatment Cross-
over Period.
EORTC QLQ-C30 scores including change from baseline, will be summarised by treatment 
arm and by time.
Healthcare professional perception of time/resource use and convenience with pertuzumab 
and trastuzumab FDC SC will be assessed by summarizing responses to individual 
questions of the HCPQs.
6.5.1
Safety Analyses
Safety analyses will be conducted based on the Safety Population.


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Analyses will include summaries of the following safety endpoints: 

Incidence, nature and severity of all AEs, ≥ Grade 3 AEs, SAEs and cardiac AEs
(including LVEF events). Cardiac AE analyses will focus on the incidence of patients with 
heart failure (NYHA, NCI-CTCAE [heart failure] Grades 2, 3, 4, and 5). Left ventricular 
ejection fraction data summaries will include the incidence of patients with LVEF 
decreases with an absolute decrease of at least 10 percentage points from baseline and 
to below 50%.

Incidence of premature withdrawal from study treatment 

Targeted vital signs and physical findings

Targeted clinical laboratory test results
The analysis of AEs will focus on treatment-emergent AEs, i.e. AEs occurring on or after the 
day of first study drug administration. Non-treatment emergent AEs (i.e. those occurring 
before start of study treatment) will be listed (with a flag to identify those AEs that continued 
into on-study treatment cycles). Adverse events will be coded using MedDRA. All AEs and 
laboratory abnormalities will be graded according to NCI CTCAE version 4.0.  
The incidence of all AEs, AEs leading to premature discontinuation or interruption of study 
treatment, SAEs, AEs of grade ≥ 3 and cardiac AEs will be summarized according to the 
primary system-organ class and by preferred term. The incidence of deaths and cause of 
deaths will be listed and summarized by treatment arm and overall.
Adverse events will be summarised by treatment arm for the Treatment Cross-over Period, 
Treatment Continuation Period and overall.
Vital signs and targeted physical examination variables will be summarized by treatment arm 
over time.
Clinical laboratory parameters will be presented in shift tables of NCI CTCAE grade at 
baseline against worst grade recorded during each treatment period and overall. Laboratory 
parameters will be summarized by absolute value and change from baseline. 
Concomitant medication will be coded and tabulated in summary tables.
Exposure to study treatment, including the number of cycles administered, duration of 
treatment (calculated from date of first treatment date to the last treatment date) and dosing 
information (e.g. dose interruptions, modifications and delays) will be summarized for each 
treatment arm. 
To evaluate the safety of switching from pertuzumab and trastuzumab FDC SC to P+H IV 
and from P+H IV to pertuzumab and trastuzumab FDC SC, AE summaries will also by 
produced for the Treatment Cross-over Period by treatment arm and actual treatment. An 
AE will be allocated to the treatment received on or before the AE start date. 
Adverse events that started during the first three cycles of the Treatment Cross-over Period 
and continued into subsequent cycles (even if the AE changed severity grade) will be 
summarized by the route of administration during which it first occurred. These AEs will be 
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6.5.2
Efficacy Analyses
Secondary efficacy endpoints include IDFS, IDFS including second primary non-breast 
cancer, DDFS and OS.
IDFS is defined as the time from randomization to the first occurrence of one of the following 
events:

Ipsilateral invasive breast tumour recurrence (i.e., an invasive breast cancer involving the 
same breast parenchyma as the original primary lesion),

Ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast 
cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral 
breast),

Distant recurrence (i.e., evidence of breast cancer in any anatomic site other than the 
two above mentioned sites that has either been histologically confirmed or clinically 
diagnosed as recurrent invasive breast cancer),

Contralateral invasive breast cancer,

Death attributable to any cause, including breast cancer, non-breast cancer, or unknown 
cause (but cause of death should be specified, if possible).
Note: Ipsilateral or contralateral in situ disease and second primary non-breast cancers 
(including in situ carcinomas and non-melanoma skin cancers) will not be counted as 
recurrence.
IDFS including second primary non-breast cancer is defined as IDFS with second primary 
non-breast invasive cancer (with the exception of non-melanoma skin cancers and in situ
carcinoma of any site) included as an event.
DDFS is defined as the time from randomization to the date of distant breast cancer 
recurrence.
OS is defined as the time from randomization to death from any cause.
The time-to-event endpoints IDFS, IDFS including second primary non-breast cancer, DDFS 
and OS will be summarized by treatment arm using the Kaplan Meier approach. The median 
and the corresponding 95% CI will be reported. Patients who have experienced none of 
these events at the time of analysis (clinical-cut off) and patients who are lost to follow up will 
be censored at their last clinical assessment date. A frequency table will also be provided for 
type of IDFS event.
Descriptive analyses will be provided for sub-groups of interest, including neoadjuvant 
chemotherapy regimen (anthracyclines + taxanes / carboplatin + taxanes / taxanes only), 
neoadjuvant treatment response (pCR / non-pCR), and hormone receptor status  (positive / 
negative).
6.6
OPTIONAL INTERIM ANALYSES
An interim safety analysis may be conducted. The decision to perform an interim safety 
analysis will be based on ongoing review of safety data by the Medical Monitor. If conducted, 
the results of this interim analysis will be evaluated by a Sponsor’s Internal Data Monitoring 


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Committee. An interim analysis will be conducted to support a planned regulatory filing for FDC, 
which will consist of a subset of the analyses planned for the primary analysis. The results of this 
interim analysis will be evaluated by a Sponsor’s Internal Monitoring Committee. Further details 
will be specified in the Statistical Analysis Plan.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
A contract research organization (CRO) will be responsible for the data management of this 
study, including quality checking of the data.  Data entered manually will be collected via 
EDC through use of eCRFs.  Sites will be responsible for data entry into the EDC system.  In 
the event of discrepant data, the CRO will request data clarification from the sites, which the 
sites will resolve electronically in the EDC system.  
The Sponsor will perform oversight of the data management of this study.  The CRO will 
produce eCRF Specifications for the study based on Sponsor’s templates including quality 
checking to be performed on the data.
Electronic CRFs and correction documentation will be maintained in the EDC system's audit 
trail.  System backups for data stored by the Sponsor and records retention for the study 
data will be consistent with the Sponsor's standard procedures.
PRO and HCP reported outcomes data will be collected on paper questionnaires. Study site 
staff will enter these data into the EDC system. Paper copies of each questionnaire are 
source documents (see Section 7.3) and will be maintained at the study site.
7.2
ELECTRONIC CASE REPORT FORMS 
Electronic CRFs are to be completed through use of a Sponsor-designated EDC system.  
Sites will receive training and have access to a manual for appropriate eCRF completion.  
Electronic CRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be reviewed 
and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt of 
the data is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site personnel 
are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded and 
documented for the first time.  They include, but are not limited to, hospital records, clinical 
and office charts, laboratory notes, memoranda, patient reported outcomes, evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 


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copies of transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, and 
records kept at pharmacies, laboratories, and medico-technical departments involved in a 
clinical trial.
Before study initiation, the types of source documents that are to be generated will be clearly 
defined in the Trial Monitoring Plan.  This includes any protocol data to be entered directly 
into the eCRFs (i.e., no prior written or electronic record of the data) and considered source 
data.
Source documents that are required to verify the validity and completeness of data entered 
into the eCRFs must not be obliterated or destroyed and must be retained per the policy for 
retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study 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, paper PRO and HCP reported outcome data, Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study or for the 
length of time required by relevant national or local health authorities, whichever is longer.  
After that period of time, the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to another 
party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good Clinical 
Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the 
country in which the research is conducted, whichever affords the greater protection to the 


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individual.  The study will comply with the requirements of the ICH E2A guideline (Clinical 
Safety Data Management:  Definitions and Standards for Expedited Reporting).  Studies 
conducted in the United States or under a U.S. Investigational New Drug (IND) Application 
will comply with U.S. Food and Drug Administration regulations and applicable local, state, 
and federal laws.  Studies conducted in the EU or European Economic Area will comply with 
the EU Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor'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.  The Sponsor or its designee 
must review and approve any proposed deviations from the Sponsor's sample Informed 
Consent Forms or any alternate consent forms proposed by the site (collectively, the 
"Consent Forms") before IRB/EC submission.  The final IRB/EC-approved Consent Forms 
must be provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  Patients 
will be told that they are free to refuse to participate and may withdraw their consent at any 
time for any reason.  A separate, specific signature will be required to document a patient's 
agreement to participate in optional procedures.  Patients who decline to participate will not 
provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures or 
when new information becomes available that may affect the willingness of the patient to 
participate.  The final revised IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information / findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised Consent 
Forms, the case history or clinical records for each patient shall document the informed 
consent process and that written informed consent was obtained using the updated / revised 
Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient's legally 
authorized representative.  All signed and dated Consent Forms must remain in each 
patient's study file or in the site file and must be available for verification by study monitors at 
any time.
For sites in the United States, each Consent Form may also include patient authorization to 
allow use and disclosure of personal health information in compliance with the U.S. Health 


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Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a separate 
Authorization Form for patient authorization for use and disclosure of personal health 
information under the HIPAA regulations, the review, approval, and other processes outlined 
above apply except that IRB review and approval may not be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, and 
relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of the 
study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible for 
promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all AEs to the Sponsor, investigators must 
comply with requirements for reporting SAEs to the local health authority and IRB/EC.  
Investigators may receive written IND safety reports or other safety-related communications 
from the Sponsor.  Investigators are responsible for ensuring that such reports are reviewed 
and processed in accordance with health authority requirements and the policies and 
procedures established by their IRB/EC, and archived in the site's study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the study 
through assignment of a unique patient identification number.  This means that patient 
names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed to 
third parties only 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 national and local health authorities, Sponsor monitors, representatives, 
and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or shared 
with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In addition, 
redacted clinical study reports and other summary reports will be provided upon request.


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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 one year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and governmental 
approval.  In addition, at the end of the study, the investigator will receive the patient data, 
including an audit trail containing a complete record of all changes to data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and data 
integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC policies 
and procedures.  The Sponsor will review all protocol deviations and assess whether any 
represent a serious breach of Good Clinical Practice guidelines and require reporting to 
health authorities.  As per the Sponsor's standard operating procedures, prospective 
requests to deviate from the protocol, including requests to waive protocol eligibility criteria, 
are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for inspection of 
study data, patients' medical records, and eCRFs.  The investigator will permit national and 
local health authorities; Sponsor monitors, representatives, and collaborators; and the 
IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  
A 
CRO
will 
provide 
clinical 
operations 
management, 
medical 
monitoring
and 
pharmacovigilance support. Data Management will be provided by the sponsor’s Data 
Management provider.
This is a multi-centre, multinational study that will enrol approximately 140 patients.  
Enrolment will occur through an IWRS.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges will 
be collected.


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If an interim safety analysis is conducted, the Sponsor’s Internal Data Monitoring Committee
will evaluate the results. The results of the interim analysis will be evaluated by a Sponsor’s 
Internal Monitoring Committee.
9.5
DISSEMINATION OF DATA AND PROTECTION OF TRADE SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to HCPs and to the public, at scientific congresses, in clinical trial 
registries of the U.S. National Institutes of Health and the European Medicines Agency, and 
in peer-reviewed journals. The Sponsor will comply with all requirements for publication of 
study results. Study data may be shared with others who are not participating in this study, 
and redacted clinical study reports and other summary reports will be provided upon request 
(see Section 8.4 for more details). For more information, refer to the Roche Global Policy on 
Sharing of Clinical Trials Data at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application has 
been filed or approved in any country, the Sponsor aims to submit a journal manuscript 
reporting primary clinical trial results within six months after the availability of the respective 
Clinical Study Report.  In addition, for all clinical trials in patients involving an IMP for which a 
marketing authorization application has been filed or approved in any country, the Sponsor 
aims to publish results from analyses of additional endpoints and exploratory data that are 
clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior to 
submission for publication or presentation.  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.
In accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicentre trials only in their entirety and not as individual centre data.  In this 
case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.  Any formal publication of the study in 
which contribution of Sponsor personnel exceeded that of conventional monitoring will be 
considered as a joint publication by the investigator and the appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from the 
use of data from this study will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will be 
submitted to the IRB/EC and to regulatory authorities in accordance with local regulatory 
requirements.


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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.
REFERENCES
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Trastuzumab Administered in a Single Infusion Bag, Followed by Vinorelbine: VELVET 
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Bonifazi M, Franchi M, Rossi M et al. Long term survival of HER2-positive early breast 
cancer treated with trastuzumab-based adjuvant regimen: a large cohort study from 
clinical practice. Breast. 2014 Oct;23(5):573-8.
Cameron D, Piccart-Gebhart MJ, Gelber RD et al. 11 years’ follow-up of trastuzumab after 
adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the 
HERceptin Adjuvant (HERA) trial. Lancet. 2017;389:1195-1205.
Cardoso F, Costa A, Senkus E et al. 3rd ESO-ESMO International Consensus Guidelines for 
Advanced Breast Cancer (ABC 3). Ann Oncol. 2017 Jan 1;28(1):16-33.
Carr JA, Havstad S, Zarbo RJ et al. The association of HER-2/neu amplification with breast 
cancer recurrence. Arch Surg. 2000 Dec;135(12):1469-74.
Coates AS, Winer EP, Goldhirsch A et al. Tailoring therapies--improving the management of 
early breast cancer: St Gallen International Expert Consensus on the Primary Therapy 
of Early Breast Cancer 2015. Ann Oncol. 2015 Aug;26(8):1533-46.
Cobleigh MA, Vogel CL, Tripathy D et al. Multinational study of the efficacy and safety of 
humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing 
metastatic breast cancer that has progressed after chemotherapy for metastatic 
disease. J Clin Oncol 1999;17:2639-2648, 
Curigliano G, Burstein HJ, P Winer E et al. De-escalating and escalating treatments for 
early-stage breast cancer: the St. Gallen International Expert Consensus Conference 
on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol. 2017 Aug 
1;28(8):1700-1712.
Ferlay J, Soerjomataram I, Ervik M et al. GLOBOCAN 2012 v1.0, Cancer Incidence and 
Mortality Worldwide: IARC CancerBase No. 11 [Internet].Lyon, France: International 
Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, 
accessed on 15/May/2015.
Franklin MC, Carey KD, Vajdos FF et al.  Insights into ErbB signaling from the structure of 
the ErbB2-pertuzumab complex.  Cancer Cell 2004;5:317-28.
Gianni L, Eiermann W, Semiglazov V et al. Neoadjuvant chemotherapy with trastuzumab 
followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients 
with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised 
controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010 Jan 
30;375(9712):377-84.
Gianni L, Pienkowski T, Im YH et al. Efficacy and safety of neoadjuvant pertuzumab and 
trastuzumab in women with locally advanced, inflammatory, or early HER2-positive 
breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. 
Lancet Oncology 2012;13(1):25-32.


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Gianni L, Pienkowski T, Im YH et al. 5-Year analysis of neoadjuvant pertuzumab and 
trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-
positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised 
trial. Lancet Oncol 2016; 17(6): 791–800. 
Gradishar WJ, Anderson BO, Aft R et al. NCCN clinical practice guidelines in oncology 
(NCCN Guidelines®). Breast Cancer. Version I.2018 [internet]. Available from: 
https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf.
Graus-Porta D, Beerli RR, Daly JM et al. ErbB-2, the preferred heterodimerization partner of 
all ErbB receptors, is a mediator of lateral signaling. EMBO J. 1997 Apr 1; 16(7): 
1647–1655.
Herceptin Investigator’s Brochure, v18, 2017
Iqbal N, Iqbal N. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: 
Overexpression and Therapeutic Implications. Mol Biol Int. 2014;2014:852748.
Ismael G, Hegg R, Muehlbauer S et al. Subcutaneous versus intravenous administration of 
(neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast 
cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet 
Oncol. 2012 Sep;13(9):869-78.
Jackisch C, Hegg R, Stroyakovskiy D et al. HannaH phase III randomised study: association 
of total pathological complete response with event-free survival in HER2-positive early 
breast cancer treated with neoadjuvant-adjuvant trastuzumab after 2 years of 
treatment-free follow-up. Eur J Cancer 2016;62:62-75.
Kümmel S, Abraham J, Martin M et al. MetaPHER phase IIIb multicenter, open-label, single-
arm safety study of subcutaneous trastuzumab in combination with pertuzumab and 
docetaxel in patients with HER2-positive advanced breast cancer: First results. 
Abstract P4-21-42.SABCS December 2016, San Antonio, USA.
Moasser MM. The oncogene HER2: its signaling and transforming functions and its role in 
human cancer pathogenesis. Oncogene. 2007 Oct 4;26(45):6469-87.
Molina MA, Codony-Servat J, Albanell J et al. Trastuzumab (herceptin), a humanized anti-
Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain 
cleavage in breast cancer cells. Cancer Res. 2001 Jun 15;61(12):4744-9.
Owens MA, Horten BC, Da Silva MM. HER2 amplification ratios by fluorescence in situ 
hybridization and correlation with immunohistochemistry in a cohort of 6556 breast 
cancer tissues. Clin Breast Cancer. 2004 Apr;5(1):63-9.
Ozcelik C, Erdmann B, Pilz B et al. Conditional mutation of the ErbB2 (HER2) receptor in 
cardiomyocytes leads to dilated cardiomyopathy. Proc Natl Acad Sci U S A. 2002 Jun 
25;99(13):8880-5. 
Pivot X, Gligorov J, Müller V et al. Preference for subcutaneous or intravenous 
administration of trastuzumab in patients with HER2-positive early breast cancer 
(PrefHer): an open-label randomised study. Lancet Oncol 2013;14(10):962- 70.
Perjeta Investigator’s Brochure, version 17, February 2018.


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Rituxan Hycela Package Insert 2017. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761064s000lbl.pdf
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for 
operable HER2-positive breast cancer. N Engl J Med 2005;353:1673- 84.
Rosengren S, Dychter SS, Printz MA et al. Clinical Immunogenicity of rHuPH20, a 
Hyaluronidase Enabling Subcutaneous Drug Administration. AAPS J. 2015 Sep; 17(5): 
1144–1156.
Rummel M, Kim TM, Aversa F et al. Preference for subcutaneous or intravenous 
administration of rituximab among patients with untreated CD20+ diffuse large B-cell 
lymphoma or follicular lymphoma: results from a prospective, randomized, open-label, 
crossover study (PrefMab). Ann Oncol. 2017 Apr 1;28(4):836-842.
Runowicz CD, Leach CR, Henry NL et al. American Cancer Society/American Society of 
Clinical Oncology Breast Cancer Survivorship Care Guideline. J Clin Oncol 2016 Feb 
20;34(6):611-35. 
Slamon DJ, Clark GM, Wong SG et al. Human breast cancer: correlation of relapse and 
survival with amplification of the HER-2/neu oncogene. Science. 1987 Jan 
9;235(4785):177-82.
Slamon D, Eiermann W, Robert N et al.  Adjuvant trastuzumab in HER2-positive breast 
cancer. N Engl J Med. 2011 Oct 6;365(14):1273-83.
Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal 
antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl 
J Med 2001;344:783-792. 
Sliwkowski MX, Lofgren JA, Lewis GD et al.  Non clinical studies addressing the mechanism 
of action of trastuzumab (Herceptin).  Semin Oncol 1999;26(Suppl 12):60-70.
Smith I, Procter M, Gelber RD et al. 2-year follow-up of trastuzumab after adjuvant 
chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 
2007 Jan 6;369(9555):29-36.
Swain SM, Kim SB, Cortes J et al. Pertuzumab, trastuzumab, and docetaxel for HER2-
positive metastatic breast cancer (CLEOPATRA study): overall survival results from a 
randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2013; 14: 
461–471.
von Minckwitz G, Procter M, de Azambuja E et al. Adjuvant Pertuzumab and Trastuzumab in 
Early HER2-Positive Breast Cancer. N Engl J Med. 2017 Jul 13;377(2):122-131
Vu T, Claret FX. Trastuzumab: updated mechanisms of action and resistance in breast 
cancer. Front Oncol. 2012 Jun 18;2:62.










Appendix 1: Schedule of Activities (cont’d)
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d.
If study treatment Cycle 12 is planned as last study treatment cycle (i.e. corresponding to Cycle 18 of neo/adjuvant anti-HER2 treatment), all planned 
assessments may be delayed to study treatment Cycle 12
e.
The number of the last treatment cycle in Treatment Continuation Period will depend on number of neoadjuvant cycles with Perjeta and Herceptin. A total 
of 18 cycles of HER2-targeted therapy should be administered over neo/adjuvant treatment (i.e. neoadjuvant cycles + Treatment Cross-over Period 
Cycles + Treatment Continuation Period cycles = 18 neo/adjuvant cycles).
f.
Results of standard-of-care tests or examinations performed prior to obtaining informed consent but within 28 or 7 days of randomization (as indicated) 
may be used; such tests do not need to be repeated for screening.
g.
Pathology reports from initial breast cancer diagnosis and from breast cancer surgery will be collected. Results of local HER2 and hormone receptor 
testing conducted prior to neoadjuvant therapy will also be collected. 
h.
Must be performed pre-dose on study treatment dosing days
i.
Complete physical examinations should include physical measurements (body weight in kilograms and height in centimetres) and evaluation of the head, 
eyes, ears, nose and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  
Any abnormality identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF. Limited physical examinations 
are symptom-directed and, in addition to the scheduled examinations indicated, may be conducted as clinically indicated.  New or worsened clinically 
significant abnormalities observed post-baseline should be recorded as AEs on the Adverse Event eCRF. During the Follow-up Period, physical 
examinations should be conducted in accordance with institutional practice or the American Cancer Society/American Society of Clinical Oncology Breast 
Cancer (ACS/ASCO) Breast Cancer Survivorship Care Guideline [Runowicz et al. 2016, see Appendix 4].
j.
Vital signs (heart rate, blood pressure, temperature, respiration rate) will be taken before and after study treatment administration. Heart rate, blood 
pressure, and respiration rate should be obtained while the patient is seated.
k.
Weight will be measured during screening and on Day 1 of each cycle prior to treatment administration. If variation of ≥10% compared with baseline 
occurs, Herceptin IV dosing should be recalculated. Weight at the time the Herceptin IV dose is recalculated will be considered as baseline for 
subsequent evaluations of degree of weight change with respect to Herceptin IV dose modification requirements.
l.
Clinical breast examination should be performed to detect signs of residual disease / local recurrence prior to study entry and to detect locoregional 
relapse during the Treatment Cross-over and Treatment Continuation Periods, and at the End of Treatment Visit. During the Follow-up Period, clinical 
breast exams should be conducted in accordance with institutional practice or the ACS/ASCO Breast Cancer Survivorship Care Guideline [Runowicz et 
al. 2016, see Appendix 4].
m. LVEF may be assessed by ECHO or MUGA however the same method should be used throughout the study for each patient and should be performed 
and assessed by the same assessor where possible.  During the study treatment periods, results of LVEF assessments must be reviewed prior to study 
treatment administration on the scheduled visit day. During the Follow-up Period, LVEF should be assessed at 6, 12, and 24 months after last study 
treatment or per institutional practice.
n.
Haematology:  haemoglobin, total WBC, ANC / neutrophils, platelet count.  Limited biochemistry:  alkaline phosphatase; AST; ALT; LDH; total bilirubin; 
creatinine.  Albumin should be measured at Screening for determining patient eligibility.  Bilirubin fractions (direct and indirect) must be included if total bilirubin 


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is greater than ULN. During the treatment period, bloods for haematology / biochemistry may be taken within three days prior to study treatment 
administration.
o.
Pregnancy testing is only required for women of childbearing potential:  A woman of childbearing potential is defined as: post-menarchal, has not reached a 
post-menopausal state (post-menopausal defined as ≥12 continuous months of amenorrhea with no identified cause other than menopause), and has 
not undergone surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing potential may be adapted for alignment with local 
guidelines or requirements. For all women of childbearing potential, Ppregnancy tests must be performed via serum -human chorionic gonadotropin 
(HCG) at baseline within seven days prior to first study treatment administration. Urine pregnancy tests should be repeated during the Treatment Cross-
over and Treatment Continuation Periods within seven days prior to every three treatment cycles starting at Cycle 4, Cycle 7, Cycle 11 and Cycle 15 (or at 
last treatment cycle), (and as clinically indicated), with results available prior to study treatment administration, as well as at the End of Treatment Visit and 
at the Follow-up Visit until seven months after discontinuation of study treatment. Any positive urine pregnancy test must be confirmed with a serum 
-HCG test. 
p.
Adverse event reporting period will continue up to seven months after the last dose of study drug. After informed consent, but prior to initiation of study 
treatment, only SAEs caused by a protocol-mandated intervention will be collected. After initiation of study treatment, all AEs regardless of relationship to 
study drug will be reported until 28 days after the last dose of study drug. Between 28 days and 7 months after the last dose of study drug, drug-related 
SAEs, AEs of special interest, heart failure, pregnancies, non−breast-related second primary malignancies and deaths, should continue to be collected.
After the end of the adverse event reporting period (defined as seven months after the last dose of study drug), drug-related SAEs, AEs of special interest, 
heart failure, non−breast-related second primary malignancies and deaths, should continue to be collected should be collected.
q.
All concomitant medications used by the patient from seven days prior to initiation of study drug until the End of Treatment Visit should be reported. After 
the End of Treatment Visit and until the end of the study, only medications used for the treatment of cancer will be reported. 
r.
The Patient Preference Questionnaire (PPQ) must be completed following study treatment administration on Day 1 of Cross-over Treatment Period Cycle 
6. Patients who discontinued study treatment prior to study treatment Cycle 6 should complete the questionnaire at the time of discontinuation as long as 
they have received at least one dose of pertuzumab and trastuzumab FDC SC, Perjeta IV and Herceptin IV post-randomization.
s.
Patients in Arm A will complete the Therapy Administration Satisfaction Questionnaire for IV administration (TASQ-IV) immediately following study 
treatment administration on Day 1 of Cycle 3 of the Treatment Cross-over Period and the Therapy Administration Satisfaction Questionnaire for SC 
administration (TASQ-SC) immediately following study treatment administration on Day 1 of Cycle 6 of the Treatment Cross-over Period. Patients in Arm 
B will complete the TASQ-SC and TASQ-IV immediately following study treatment administration on Day 1 of Cycle 3 and 6 of the Treatment Cross-over 
Period respectively.  Patients who switch study treatment due to investigator-assessed lack of tolerance should complete the TASQ corresponding to the 
study treatment they cannot tolerate prior to switching treatment (i.e. after the decision to change study treatment has been approved by the Medical 
Monitor and before receiving the next study treatment). 
t.
During the study treatment periods, patients must complete the EORTC QLQ-30 before the patient and clinician receives any information on disease 
status and prior to treatment administration on the scheduled visit day. During the Follow-up Period, the EORTC QLQ-30 must be completed at 18 
months, 2 years, and 3 years from randomization.


Appendix 1: Schedule of Activities (cont’d)
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u.
Each Healthcare Professional Questionnaire (HCPQ) will be completed by the applicable HCP after each study treatment preparation and/or
administration for each patient. Applicable HCPs are described in each of the questionnaires (HCPQ-Treatment Room, HCPQ-Drug Preparation Area). 
Instructions for which questions should be completed in each questionnaire at each timepoint are indicated in the introduction to each questionnaire.
v.
Mammograms conducted at the time of diagnosis (before initiation of the neoadjuvant treatment) as well as pre-surgery (if performed) will be collected. 
Mammograms collected and/or conducted for the study (including pre-neoadjuvant treatment, pre-surgery, and study Follow-up Period evaluations) can 
be replaced by another conventional imaging method such as magnetic resonance imaging (MRI) or ultrasound per institutional practice at the 
investigator’s discretion, but the same method of assessment must be used for each evaluation for an individual patient. If a mammogram (or acceptable 
alternative breast imaging evaluation) has been conducted as part of routine care within four months prior to the End of Treatment Visit, it may be used in 
lieu of the End of Treatment Visit evaluation.
w.
After completion of the Treatment Cross-over Period, participating patients will select the study treatment formulation (P+H IV or pertuzumab and 
trastuzumab FDC SC) to complete their 18 cycles of neo/adjuvant HER2-targeted treatment. The number of study treatment cycles administered during 
the Treatment Continuation Period required to complete a total of 18 of neo/adjuvant HER2-targeted treatment will be calculated based on the sum of 
number of P+H cycles received in neoadjuvant treatment (before study entry) plus 6 cycles administered in the Treatment Cross-over Period.


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Appendix 2
Patient Reported Outcome Measures


Appendix 2: Patient Reported Outcome Measures (cont’d)
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Appendix 2: Patient Reported Outcome Measures (cont’d)
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Appendix 2: Patient Reported Outcome Measures (cont’d)
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Appendix 2: Patient Reported Outcome Measures (cont’d)
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Appendix 2: Patient Reported Outcome Measures (cont’d)
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European Organization European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire C30


Appendix 2: Patient Reported Outcome Measures (cont’d)
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Appendix 2: Patient Reported Outcome Measures (cont’d)
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Appendix 3
Healthcare Professional Reported Outcome Measures


Appendix 3: Healthcare Professional Reported Outcome Measures (cont’d)
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Appendix 3: Healthcare Professional Reported Outcome Measures (cont’d)
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Appendix 3: Healthcare Professional Reported Outcome Measures (cont’d)
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Appendix 3: Healthcare Professional Reported Outcome Measures (cont’d)
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Appendix 3: Healthcare Professional Reported Outcome Measures (cont’d)
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Appendix 3: Healthcare Professional Reported Outcome Measures (cont’d)
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Appendix 3: Healthcare Professional Reported Outcome Measures (cont’d)
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Appendix 3: Healthcare Professional Reported Outcome Measures (cont’d)
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Appendix 3: Healthcare Professional Reported Outcome Measures (cont’d)
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Appendix 3: Healthcare Professional Reported Outcome Measures (cont’d)
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Appendix 3: Healthcare Professional Reported Outcome Measures (cont’d)
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Appendix 3: Healthcare Professional Reported Outcome Measures (cont’d)
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Appendix 4
American Cancer Society / American Society of Clinical Oncology 
Breast Cancer Survivorship Care Guideline 
Available at:
http://ascopubs.org/doi/abs/10.1200/JCO.2015.64.3809?url_ver=Z39.88-
2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed




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Appendix 6
Asymptomatic Decline in LVEF:  Algorithm for Continuation and 
Discontinuation of Study Treatment
LVEF = left ventricular ejection fraction
Patients must have an LVEF ≥ 55% measured by echocardiogram (ECHO) or multiple-gated 
acquisition (MUGA) to be eligible for the study.



SAP_001.pdf: 
 
Official Title: 
A Randomized, Multicenter, Open-Label Cross-Over Study to 
Evaluate Patient Preference and Satisfaction of Subcutaneous 
Administration of the Fixed-Dose Combination of Pertuzumab and 
Trastuzumab in Patients With HER2-Positive Early Breast Cancer  
NCT Number: 
NCT03674112 
Document Date: 
SAP Version 1.1: 07-April-2020 
 
 
 


CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO40628 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A RANDOMIZED, MULTICENTER, OPEN-LABEL CROSS-OVER 
STUDY TO EVALUATE PATIENT PREFERENCE AND 
SATISFACTION OF SUBCUTANEOUS ADMINISTRATION OF 
THE FIXED-DOSE COMBINATION OF PERTUZUMAB AND 
TRASTUZUMAB IN PATIENTS WITH HER2-POSITIVE EARLY 
BREAST CANCER 
PROTOCOL NUMBER: 
MO40628 
STUDY DRUG: 
Fixed-dose combination of pertuzumab and trastuzumab 
for subcutaneous administration (RO7198574) 
VERSION NUMBER: 
1.1 
IND NUMBER: 
131009 
EUDRACT NUMBER: 
2018-002153-30 
 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
, Cytel, Inc 
, F. Hoffmann-La Roche Ltd 
DATE FINAL: 
05-Sep-2019 
DATE(S) AMENDED 
See electronic date stamp below. 
STATISTICAL ANALYSIS PLAN APPROVAL  
 
Date and Time(UTC)        Reason for Signing                              Name
07-Apr-2020 16:21:25
Company Signatory


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STATISTICAL ANALYSIS PLAN AMENDMENT 
RATIONALE 
This Statistical Analysis Plan (SAP) for Study MO40628 (PHranceSCa) has been 
amended to incorporate the following changes. 
VERSION 1.1: 
 
Removing the logistic regression in section 4.5.1 to model patient preference 
according to treatment sequence and stratification factors. This was not 
mandated by the protocol and would not provide stable results in this small trial. 
 
Clarification of the subgroups to be analyzed (sections 4.5.1 and 4.5.5) 
 
Aligning the definition of Hy’s law to the current version of the protocol in 
section 4.7.3 
Additional minor changes have been made to improve clarity and consistency. 


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TABLE OF CONTENTS 
1.
BACKGROUND ............................................................................................ 7 
2.
STUDY DESIGN ........................................................................................... 7 
2.1 
Protocol Synopsis .................................................................... 8 
2.2 
Endpoints ................................................................................. 8 
2.2.1 
Primary Endpoint ..................................................................... 8 
2.2.2 
Secondary Endpoints .............................................................. 8 
2.2.2.1 Secondary Safety Endpoints .................................................. 9 
2.2.2.2 Secondary Efficacy Endpoints ................................................ 9 
2.3 
Determination of Sample Size ............................................... 10 
2.4 
Analysis Timing ..................................................................... 10 
3.
STUDY CONDUCT ..................................................................................... 10 
3.1 
Randomization ....................................................................... 10 
3.2 
Independent Review Facility .................................................. 11 
3.3 
Data Monitoring ..................................................................... 11 
4.
STATISTICAL METHODS .......................................................................... 11 
4.1 
Analysis Populations ............................................................. 11 
4.2 
Treatment Periods ................................................................. 12 
4.3 
Analysis of Study Conduct ..................................................... 12 
4.4 
Analysis of Treatment Group Comparability .......................... 12 
4.5 
Analysis ................................................................................. 13 
4.5.1 
Primary Endpoint ................................................................... 13 
4.5.2 
Secondary Endpoints ............................................................ 14 
4.5.2.1 Patient Responses to Questions 2 and 3 of the PPQ ........... 14 
4.5.2.2 Patient Responses to Questions of the TASQ-
SC and TASQ-IV ................................................................. 14 
4.5.2.3 Patient’s Choice of Treatment for the Treatment 
Continuation Period ............................................................. 15 
4.5.2.4 Healthcare Professional Questionnaire (HCPQ) .................. 16 
4.5.2.5 EORTC QLQ-C30 ................................................................ 17 
4.5.3 
Secondary Efficacy Endpoints ............................................... 17 
4.5.3.1 Invasive Disease-Free Survival ............................................ 17 


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4.5.3.2 Invasive Disease-Free Survival Including 
Second Primary Non-Breast Cancer (IDFS2) ...................... 18 
4.5.3.3 Distant Disease-Free Survival (DDFS) ................................. 18 
4.5.3.4 Overall Survival (OS) ............................................................ 18 
4.5.4 
Sensitivity Analyses ............................................................... 18 
4.5.5 
Subgroup Analyses ............................................................... 18 
4.6 
Pharmacokinetic and Pharmacodynamic Analyses ............... 19 
4.7 
Safety Analyses ..................................................................... 19 
4.7.1 
Exposure of Study Medication ............................................... 19 
4.7.2 
Adverse Events ..................................................................... 19 
4.7.3 
Laboratory Data ..................................................................... 23 
4.7.4 
Vital Signs and ECOG Performance Status ........................... 23 
4.7.5 
Electrocardiograms ................................................................ 23 
4.8 
Missing Data .......................................................................... 24 
4.9 
Interim Analyses .................................................................... 24 
5. 
REFERENCES ........................................................................................... 25 
 
 
LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis ....................................................................... 26 
Appendix 2 
Schedule of Assessments ........................................................... 36 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse events 
AESI 
adverse events of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CI 
confidence interval 
CSR 
clinical study report 
DDFS 
distant disease-free survival 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EORTC 
European Organization for the Research and 
Treatment of Cancer 
FDA 
Food and Drug Administration 
FDC SC 
Fixed-dosed combination formulation for subcutaneous 
administration 
HCP 
healthcare professional 
HER2 
human epidermal growth factor receptor 2 
HER2+ 
HER2-positive 
Herceptin IV 
Herceptin for IV administration 
Herceptin SC 
Herceptin for SC administration 
HRQoL 
health-related quality of life 
ICH 
International Conference on Harmonization 
IDFS  
invasive disease-free survival  
ITT 
Intent-to-treat 
IV 
intravenous(ly) 
IxRS 
Interactive voice/web response system 
KM 
Kaplan Meier 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat  
NCI CTCAE 
National Cancer Institute Common Terminology 
Criteria for Adverse Events 
OS 
overall survival 
pCR 
pathologic complete response 
PgR 
progesterone receptor 
PFS 
progression free survival 


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Abbreviation 
Definition 
PPQ 
Patient Preference Questionnaire 
PRO 
patient reported outcome 
PS 
performance status 
PT 
preferred term 
QoL 
quality of life 
SAF 
safety population 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 
SOC 
System Organ Class 
TASQ-IV 
Therapy Administration Satisfaction Questionnaire – 
intravenous 
TASQ-SC 
Therapy Administration Satisfaction Questionnaire – 
subcutaneous  
ULN 
upper limit of normal range 


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1. 
BACKGROUND 
This Statistical Analysis Plan (SAP) describes the analyses that are planned to be 
performed for the Clinical Study Reports (CSRs) of Study MO40628 (PHranceSCa). 
2. 
STUDY DESIGN 
This is a Phase II, randomized, multi-centre, multinational, open-label, cross-over study in 
adult patients who have completed neoadjuvant chemotherapy with neoadjuvant Perjeta 
and Herceptin and have undergone surgical treatment of HER2+ EBC. The primary 
objective for this study is to evaluate patient preference for pertuzumab and trastuzumab 
FDC SC. An overview of the study design is provided in the figure below. 
 
Abbreviations: IV: intravenous; P+H: Perjeta + Herceptin; FDC SC: subcutaneously 
administered fixed-dose combination of pertuzumab and trastuzumab; HCPQs: Healthcare 
Professional Questionnaires; PPQ: Patient Preference Questionnaire; SC subcutaneous; 
TASQ: Therapy Administration Satisfaction Questionnaire 
 
Patients will be randomized following surgery and the completion of (neo)adjuvant 
chemotherapy in a 1:1 ratio to treatment Arm A (P+H IV followed by pertuzumab and 
trastuzumab FDC SC) or treatment Arm B (pertuzumab and trastuzumab FDC SC 
followed by P+H IV). 
Patients randomized to Arm A will receive P+H IV (3 cycles) followed by pertuzumab and 
trastuzumab FDC SC (3 cycles). Patients randomized to Arm B will receive pertuzumab 
and trastuzumab FDC SC (3 cycles) followed by P+H IV (3 cycles). This period of 3+3 
cycles in both treatment arms constitutes the study Treatment Cross-over Period. 
The 6 study treatment cycles of pertuzumab and trastuzumab FDC SC and P+H IV 
received during the Treatment Cross-over Period and Perjeta and Herceptin treatment 
cycles received in the neoadjuvant setting prior to study entry will be considered part of 


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the total 18 anti-HER2 treatment cycles planned for all study patients. Following 
completion of the Treatment Cross-over Period, patients will enter the Treatment 
Continuation Period wherein they will receive the remaining anti-HER2 treatment cycles 
required to complete their 18 planned cycles unless disease recurrence, unacceptable 
toxicity or patient withdrawal from treatment necessitates early treatment cessation. 
Study treatment during this period will be either P+H IV or pertuzumab and trastuzumab 
FDC SC as selected by the patient at the end of the Treatment Cross-over Period. 
Patients who, by the investigator’s assessment, cannot tolerate pertuzumab and 
trastuzumab FDC SC or P+H IV may be allowed to receive P+H IV or pertuzumab and 
trastuzumab FDC SC, respectively, for their remaining planned anti-HER2 treatment cycles. 
The main analysis of the primary endpoint will take place after all patients have received 
3 cycles of pertuzumab and trastuzumab SC and 3 cycles of P+H IV and have 
completed the Patient Preference Questionnaire.  
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1. For additional details, see the Schedule of 
Assessments in Appendix 2. 
2.2 
ENDPOINTS 
2.2.1 
Primary Endpoint 
The primary endpoint is the proportion of patients indicating an overall preference for 
pertuzumab and trastuzumab FDC SC in Question 1 of the Patient Preference 
Questionnaire (PPQ). Question 1 of the PPQ is as follows: “All things considered, which 
method of administration did you prefer?” 
2.2.2 
Secondary Endpoints 
Secondary endpoints linked to secondary objectives are: 
 
Patient responses to Question 1 of the TASQ-SC and TASQ-IV: “How satisfied or 
dissatisfied were you with the SC injection?” and respectively “with the IV infusion?” 
 
Proportion of patients who select pertuzumab and trastuzumab FDC SC for the 
study Treatment Continuation Period  
 
HCP responses to the HCP Questionnaires, by summarizing responses to individual 
questions 
 
Change in treatment-related symptoms and function from baseline and over time as 
assessed by mean and mean change from baseline scores, as assessed by the 
EORTC QLQ-C30  
 
Mean and mean changes from baseline score in HRQoL by cycle as assessed by 
the Global Health Status/HRQoL scale (items 29 and 30) of the EORTC QLQ-C30 
 


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2.2.2.1 
Secondary Safety Endpoints 
The first secondary safety objective is to evaluate the safety and tolerability of 
pertuzumab and trastuzumab FDC SC and P+H IV during the study Treatment Cross-
over Period and the entire adjuvant treatment period (Treatment Crossover Period + 
Treatment Continuation Period) based on the following endpoints: 
 
Incidence, nature and severity of all AEs (adverse events), ≥ Grade 3 AEs, serious 
adverse events (SAEs) and cardiac AEs (including left ventricular ejection fraction 
[LVEF] events)  
 
Incidence of premature withdrawal from study treatment  
 
Targeted vital signs and physical findings 
 
Targeted clinical laboratory test results 
The second safety objective is to evaluate the safety of switching from pertuzumab and 
trastuzumab FDC SC to P+H IV and from P+H IV to pertuzumab and trastuzumab FDC 
SC based on: 
 
Incidence, nature and severity of all AEs, ≥ Grade 3 AEs, SAEs and cardiac AEs 
(including LVEF events) during the study Treatment Cross-over Period by treatment 
sequence and actual treatment. 
For all safety endpoints, AE severity will be determined according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0) 
2.2.2.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints linked to secondary efficacy objectives are: 
 
Invasive Disease-Free Survival (IDFS), defined as the time from randomization to the 
first occurrence of one of the following events: 
− Ipsilateral invasive breast tumour recurrence (i.e., an invasive breast cancer 
involving the same breast parenchyma as the original primary lesion) 
− Ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast 
cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral 
breast) 
− Distant recurrence (i.e., evidence of breast cancer in any anatomic site other than 
the two above mentioned sites that has either been histologically confirmed or 
clinically diagnosed as recurrent invasive breast cancer) 
− Contralateral invasive breast cancer 
− Death attributable to any cause, including breast cancer, non-breast cancer, or 
unknown cause (but cause of death should be specified, if possible) 
Note: Ipsilateral or contralateral in situ disease and second primary non-breast 
cancers (including in situ carcinomas and non-melanoma skin cancers) will not be 
counted as recurrence. 


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 
Invasive disease-free survival including second primary non-breast cancer, defined as 
IDFS with second primary non-breast invasive cancer (with the exception of non-
melanoma skin cancers and in situ carcinoma of any site) included as an event 
 
Distant Disease-Free Survival (DDFS) is defined as the time from randomization to 
the date of distant breast cancer recurrence. 
 
Overall Survival (OS) is defined as the time from randomization to death from any 
cause. 
2.3 
DETERMINATION OF SAMPLE SIZE 
The primary study objective is to estimate the proportion of patients who express a 
preference for pertuzumab and trastuzumab FDC SC. 
The planned total sample size of 140 patients is based on an assumed rate of 70% of 
patients preferring pertuzumab and trastuzumab FDC SC. To achieve a distance of 
approximately ± 8% from the estimated proportion to 95% CI limits, a total of 126 
patients are needed for the evaluation of preference. The final target sample size was 
increased to approximately 140 patients to allow for 10% of the patients not providing an 
evaluable preference assessment. 
There will be no formal hypothesis test for the primary endpoint. 
2.4 
ANALYSIS TIMING 
The primary study analysis will take place when all study patients have completed their 
last study treatment administration in the Treatment Cross-over Period. Summaries of 
secondary study endpoints, including patient reported TASQ and EORTC QLQ-C30 
responses, selection of treatment administration method for the Treatment Continuation 
Period, HCP reported HCPQ responses and safety endpoints will be included in the 
primary analysis.  
An interim analysis will be conducted to support a planned regulatory filing for FDC, 
which will consist of a subset of the analyses planned for the primary analysis. (see 
Section 4.9). The results of this interim analysis will be evaluated by a Sponsor’s Internal 
Monitoring Committee. 
The final study analysis that includes all secondary safety and efficacy endpoints will be 
conducted after the end of the study. 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION 
Randomization to Arm A (P+H IV followed by pertuzumab and trastuzumab FDC SC) or 
Arm B (pertuzumab and trastuzumab FDC SC followed by P+H IV) will occur via a web-
based response system (IWRS) in a 1:1 ratio. 


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Randomization will be stratified according to: 
 
Neoadjuvant chemotherapy regimen (anthracyclines + taxanes vs. carboplatin + 
taxanes vs. taxanes only),  
 
Neoadjuvant treatment response (pCR vs. non-pCR),  
 
Hormone receptor status (positive [ER-positive and/or PgR-positive] vs. negative 
[ER-negative and PgR-negative]). 
 
3.2 
INDEPENDENT REVIEW FACILITY 
Not applicable 
3.3 
DATA MONITORING 
An interim analysis will be conducted to support a planned regulatory filing for FDC, which 
will consist of a subset of the analyses planned for the primary analysis. The results of this 
interim analysis will be evaluated by a Sponsor’s Internal Monitoring Committee. 
The IMC will follow a charter that outlines their roles and responsibilities and ability to 
make recommendations regarding continuation of the study to protect the interests of the 
patients in this study. The IMC will be responsible for monitoring the safety of patients in 
the study and will make recommendations to the Therapeutic Area Head regarding the 
conduct of the study, including study continuation as planned or with modification or early 
discontinuation of the study for excessive toxicity. The operating procedures will be 
detailed in the IMC charter. 
4. 
STATISTICAL METHODS 
The analyses outlined in this SAP supersede those specified in the protocol for the 
purpose of a regulatory filing. 
4.1 
ANALYSIS POPULATIONS 
The analysis populations are defined as follows: 
 
Intent-To-Treat (ITT) Population: All randomized patients, allocated to their 
randomized treatment arm, whether or not the assigned study treatment was 
received. 
 
Modified ITT (mITT) Population: All randomized patients, allocated to their 
randomized treatment arm, who received at least one dose by both SC and IV 
routes of administration during the Treatment Cross-over Period and subsequently 
answered at least Question 1 of the PPQ. 
 
Patient reported outcome (PRO) evaluable Population for analysis of the EORTC 
QLQ-C30: The PRO-evaluable population includes all patients in the ITT population 
with a baseline EORTC QLQ-C30 assessment and at least one post-baseline 
EORTC QLQ-C30 assessment. 


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 
Safety Population: All patients who received at least one dose of any study drug 
categorized according to the study drug administered. 
For all efficacy analyses, patients will be grouped according to the treatment sequence 
assigned at randomization, unless otherwise specified.  
For all safety analyses, patients will be grouped according to the treatment actually 
received, unless otherwise specified. 
4.2 
TREATMENT PERIODS 
In this study, there are 2 main treatment periods:  
 
The Treatment Cross-over Period will consist of maximum 6 study treatment cycles 
of pertuzumab and trastuzumab FDC SC (maximum 3 cycles) and P+H IV 
(maximum 3 cycles). The cross-over period starts immediately after completion of 
the neoadjuvant treatment. 
 
The Treatment Continuation Period: Following completion of the Treatment Cross-
over Period, patients will enter the Treatment Continuation Period wherein they will 
receive the remaining anti-HER2 treatment cycles required to complete their 18 
planned cycles unless disease recurrence, unacceptable toxicity or patient 
withdrawal from treatment necessitates early treatment cessation. Study treatment 
during this period will be either P+H IV or pertuzumab and trastuzumab FDC SC as 
selected by the patient at the end of the Treatment Cross-over Period. 
4.3 
ANALYSIS OF STUDY CONDUCT 
Enrolment, eligibility violations and patient disposition will be summarized by treatment 
sequence and overall in the ITT and mITT populations. Reasons for patient’s study 
treatment discontinuation and patient’s reasons for study discontinuation will be listed by 
patient and summarized in ITT population by treatment sequence and overall. Major 
protocol deviations will be listed and summarized in the ITT and mITT populations by 
treatment sequence and overall and evaluated for their potential effects on the 
interpretation of study results. 
Median follow-up on study, estimated with corresponding 95% CI by the reverse Kaplan-
Meier approach, will be presented. 
Follow-up time is calculated from the date of the Cycle 1 visit. Patients who died on study 
are censored at the time of death. Other patients are considered to have been followed 
until the date of study completion or discontinuation.  If neither of those dates is available, 
the date of the last recorded visit will be used. 
4.4 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Demographic variables such as age, sex, race/ethnicity, weight, stratification variables 
and other relevant baseline characteristics will be summarized using means, standard 
deviations (SDs), medians, ranges and inter-quartile ranges for continuous variables and 


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frequencies and percentages for categorical variables, as appropriate. Summaries will be 
presented overall and by treatment sequence in ITT population. 
Previous and concurrent medical history will be summarized overall and by treatment 
sequence in ITT population. 
Prior and follow-up anti-cancer therapy or surgery, tumor characteristics and pCR results 
at screening will be summarized overall and by treatment sequence in ITT population. 
4.5 
ANALYSIS 
4.5.1 
Primary Endpoint 
The primary objective of this study is to evaluate patient preference for pertuzumab and 
trastuzumab FDC SC based on the proportion of patients indicating an overall 
preference for pertuzumab and trastuzumab FDC SC in Question 1 of the PPQ. 
Question 1 of the PPQ is as follows: “All things considered, which method of 
administration did you prefer?”. 
Patient preference will be summarized by treatment sequence and overall and presented 
in tables based on the mITT population. In order to assess the robustness of the primary 
analysis the analysis of the primary endpoint will be repeated for the ITT population as a 
sensitivity analysis. 
The primary analysis of the primary endpoint will take place once the last patient has 
completed the last study treatment administration in the Treatment Cross-over Period. 
Patient preference will be summarized by presenting the number and percentage of 
patients in each category (SC, IV and No preference). A point estimate with associated 
exact Clopper-Pearson binomial 95% CI for the proportion of patients who preferred 
pertuzumab and trastuzumab FDC SC will be calculated for the mITT and the ITT 
populations and will be described by treatment sequence and overall.  
Patient preference will also be summarized by presenting the number and percentage of 
patients in each category (SC, IV and No preference) by stratification factors: 
neoadjuvant chemotherapy regimen (anthracyclines + taxanes / carboplatin + taxanes / 
taxanes only), neoadjuvant treatment response (pCR / non-pCR) and hormone receptor 
status (positive / negative). 
Exploratory subgroup analyses will be performed for the mITT population by: 
 
Age (<65 years vs. ≥65 years and <75 years vs. ≥ 75 years) 
 
Race (White, Black, Asian, Other) 
 
Body Weight (categories defined by weight percentiles ) 
 
Neoadjuvant treatment response (pCR vs. non-pCR) 


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 
Number of neoadjuvant Perjeta and Herceptin cycles (< 4 cycles vs. ≥4 cycles) 
4.5.2 
Secondary Endpoints 
4.5.2.1 
Patient Responses to Questions 2 and 3 of the PPQ 
For patients who reported a preference for one of the two administration routes in 
question 1 of the PPQ, the strength of their preference (very strong, fairly strong, not 
very strong) and the two main reasons for their preference will be summarized with the 
number and proportion of responses for each category of preference (IV and SC) on the 
mITT and the ITT populations by treatment sequence and overall.  
4.5.2.2 
Patient Responses to Questions of the TASQ-SC and TASQ-IV 
The TASQ is a 12-item questionnaire measuring the impact of the mode of treatment 
administration on five domains: Physical Impact, Psychological Impact, Impact on 
Activities of Daily Living, Convenience, and Satisfaction. The Physical Impact domain 
comprises of 3 items (Q2: Pain experience, Q3: Swelling experience, Q4: Redness 
experience), the Psychological Impact domain contains one item (Q5: Feeling restricted 
by SC injection/IV infusion), The Impact on Activities of Daily Living contains one item (Q8: 
Lost/gained time), The Convenience domain contains 2 items (Q6: Is it convenient to get 
SC injection/IV infusion, Q7: Bothered by the amount of time to get SC injection/IV 
infusion), and the Satisfaction domain includes 2 items (Q1: How satisfied or dissatisfied 
are you with the SC injection/IV infusion, Q12: Would you recommend the way you 
received the treatment). All 9 TASQ items included in the above domains have five 
response options: 
– 
Reverse-coded response values will be created for eight of the TASQ items 
(Q1, Q2, Q3, Q4, Q5, Q6, Q7 and Q12) 
In addition, there are three questions in the TASQ (Q9, Q10, Q11) that are not part of 
the above domains. These three questions will be analyzed separately and presented 
descriptively. 
Patient assessed satisfaction with pertuzumab and trastuzumab FDC SC and P+H IV 
will be based on patient responses to Question 1 of the TASQ-SC and TASQ-IV 
respectively. 
The patient satisfaction will be described by treatment sequence and overall in two 
ways: first as a categorical variable with the number and proportion of patient responses 
to each modality of the question (very satisfied, satisfied, …, very dissatisfied), and 
secondly as a continuous variable with descriptive statistics. 
In addition, the patient responses of the TASQ-SC and TASQ-IV will be summarized by 
domain (physical impact, psychological impact, impact on activities of daily living, 
convenience and satisfaction). 


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For the three domains that contain more than one item (Physical Impact, Convenience 
and Satisfaction), the algorithm will be the following: 
If there are no missing responses, the domain will be scored using the formula: 
Domain score = [(Sum of completed item responses / Number of completed items) - 1] x 
100 / (Maximum possible item response value – Minimum possible item response value) 
However, if there are any missing responses within a domain then the domain will not be 
scored (i.e. a missing value is assigned to the domain). 
Since the maximum possible item response value is 5 and the minimum possible 
response value is 1 for all TASQ items, a simpler way to represent the above formula for 
the TASQ domains is: 
TASQ domain score = (Mean of completed item responses – 1) x 25 
Descriptive statistics will be computed for these three domains by treatment sequence 
and overall. Descriptive p-values, not adjusted for multiple testing, might be calculated to 
assess differences between groups, at timepoints and/or by treatment sequence.  
The two domains that contain only one item (Psychological Impact and Impact on 
Activities of Daily Living) will be described by treatment sequence and overall in the 
same way as the patient satisfaction in Question 1: first as a categorical variable with the 
number and proportion of patient responses to each modality of the question, and 
secondly as a continuous variable with descriptive statistics. 
The three descriptive questions (Q9, Q10, Q11) that are not part of the above domains 
will be summarized individually by the number and proportion of patient responses to 
each modality of the question. 
All TASQ analyses will be performed on the mITT population. 
4.5.2.3 
Patient’s Choice of Treatment for the Treatment Continuation 
Period 
The proportion (and 95%CI) of patients who select each treatment administration route 
for the Treatment Continuation Period will be summarized on the ITT Population. Results 
will be displayed by treatment sequence and overall. 
A consistency table with answer to question 1 of the PPQ will also be provided by 
treatment sequence and overall. For each patient’s preference category as per the 
question 1 of the PPQ (SC, IV and No preference), the number and percentage of 
patients who select each treatment administration route for the Treatment Continuation 
Period (SC, IV) will be summarized. 


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4.5.2.4 
Healthcare Professional Questionnaire (HCPQ) 
Healthcare professional perception of time/resource use and convenience with 
pertuzumab and trastuzumab FDC SC will be assessed by summarizing responses to 
individual questions of the HCPQs on the ITT population by treatment sequence and 
overall. 
Healthcare Professional Questionnaire-Treatment Room 
The number of HCPQs completed, the specialities of Healthcare Professional 
Respondents (Nurse, Pharmacy Technician, Oncologist, Gynaecologist), the number of 
countries and number of patients by country will be summarized overall. 
Experience with FDC SC injection and P+H IV infusion administration 
Responses to individual questions 1b to 1f will be summarized by cycle and stratified by 
route of drug administration (question 1a). 
Responses to individual questions 1b to 1f will also be summarized by cycle and 
stratified by route of drug administration for each healthcare professional speciality and 
each individual country. 
Missing data will be reported by timepoint. 
Impact on Clinical Management and Clinical Efficiency 
Responses to individual questions 2 to 8 will be summarized overall, by healthcare 
professional speciality and by individual country. 
Healthcare Professional Questionnaire-Drug Preparation Room 
The number of HCPQs completed, the specialities of Healthcare Professional 
Respondents (Nurse, Pharmacist, Pharmacy Technician), the number of countries and 
number of patients by country will be summarized overall. 
Experience with FDC SC and P+H IV infusion Dispensing and Preparation 
Response to the question 1b “How long did it take to prepare the treatment for use?” will 
be summarized by cycle and stratified by route of drug administration (question 1a). 
Response to the question 1b “How long did it take to prepare the treatment for use?” will 
also be summarized by cycle and stratified by route of drug administration (question 1a) 
for each healthcare professional speciality and each individual country. 
Impact on Clinical Management and Clinical Efficiency 
Responses to individual questions 2 to 4 will be summarized overall, by healthcare 
professional speciality and by individual country. 


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4.5.2.5 
EORTC QLQ-C30  
EORTC data will be analyzed based on the PRO-evaluable population, unless specified 
otherwise. 
Summary statistics (mean, standard deviation, median, and range) of linearly transformed 
absolute scores and mean changes from baseline will be calculated for all items and 
subscales (treatment-related symptoms and function, Global Health Status/HRQoL) of the 
EORTC QLQ-C30 at each assessment timepoint for each treatment arm.  
The EORTC QLQ-C30 data will be scored according to the EORTC scoring manual 
(Fayers 2001). Missing data will be reported by timepoint. In the event of incomplete data, 
for all questionnaire subscales, if more than 50% of the constituent items are completed, 
a pro-rated score will be computed consistent with the scoring manuals and published 
validation reports. For subscales with less than 50% of the items completed, the subscale 
will be considered as missing. PRO completion, compliance rates, and reasons for missing 
data will be summarized at each timepoint by treatment arm on the ITT population. 
4.5.3 
Secondary Efficacy Endpoints 
All secondary efficacy endpoints will be analyzed on the ITT population. 
4.5.3.1 
Invasive Disease-Free Survival  
 
Invasive disease-free survival is defined as the time from randomization to the first 
occurrence of one of the following events: 
− Ipsilateral invasive breast tumour recurrence (i.e., an invasive breast cancer 
involving the same breast parenchyma as the original primary lesion) 
− Ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast 
cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral 
breast) 
− Distant recurrence (i.e., evidence of breast cancer in any anatomic site other than 
the two above mentioned sites that has either been histologically confirmed or 
clinically diagnosed as recurrent invasive breast cancer) 
− Contralateral invasive breast cancer 
− Death attributable to any cause, including breast cancer, non-breast cancer, or 
unknown cause (but cause of death should be specified, if possible) 
Note: Ipsilateral or contralateral in situ disease and second primary non-breast 
cancers (including in situ carcinomas and non-melanoma skin cancers) will not be 
counted as recurrence. 
Patients who have not experienced invasive disease at the time of analysis will be 
censored i) at the time of the last clinical breast examination if post-baseline clinical 
breast examination ii) on the date of randomization + 1 day if no post-baseline clinical 
breast examination. 


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Kaplan-Meier methodology will be used to estimate median IDFS for each treatment 
sequence and overall and to construct survival curves. The Brookmeyer-Crowley 
methodology will be used to construct the 95% CI for the median IDFS for each 
treatment sequence (Brookmeyer and Crowley 1982).  
In addition, the 12-month, 24-month and 36-month IDFS rates and 95% CI will be 
provided in each treatment sequence and overall. 
Comparable IDFS rates will be explored by neoadjuvant chemotherapy regimen 
(anthracyclines + taxanes / carboplatin + taxanes / taxanes only), neoadjuvant treatment 
response (pCR / non-pCR), hormone receptor status (positive / negative), node status at 
diagnosis (positive / negative), and number of neoadjuvant PH cycles (<4 / >=4). 
4.5.3.2 
Invasive Disease-Free Survival Including Second Primary 
Non-Breast Cancer (IDFS2) 
Invasive disease-free survival including second primary non-breast cancer (IDFS2) is 
defined as IDFS with second primary non-breast invasive cancer (with the exception of 
non-melanoma skin cancers and in situ carcinoma of any site) included as an event.  
IDFS2 will be analyzed in a similar manner as IDFS. 
4.5.3.3 
Distant Disease-Free Survival (DDFS)   
Distant disease-free survival (DDFS) is defined as the time from randomization to the 
date of distant breast cancer recurrence. 
DDFS will be analyzed in a similar manner as IDFS. 
4.5.3.4 
Overall Survival (OS) 
Overall survival is defined as the time from randomization to death due to any cause. 
Patients who are not reported as having died at the time of analysis will be censored at 
the date when they were last known to be alive. Patients who do not have post-baseline 
information will be censored at the date of randomization+ 1 day.  
OS will be analyzed in a similar manner as IDFS. 
4.5.4 
Sensitivity Analyses 
The analyses defined in Section 4.5.1 will serve as the sensitivity analyses. 
In addition, if an unexpected sequencing effect will be observed, more exploratory post-
hoc analyses might be performed. 
4.5.5 
Subgroup Analyses 
The following subgroups will be considered: 
 
Age (<65 years vs. ≥65 years and <75 years vs. ≥75 years) 


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 
Race (White, Black, Asian, Other) 
 
Body Weight (categories defined by weight percentiles ) 
 
Neoadjuvant chemotherapy regimen (anthracyclines + taxanes, carboplatin + 
taxanes, taxanes only) 
 
Neoadjuvant treatment response (pCR,  non-pCR),  
 
Hormone receptor status (positive [ER-positive and/or PgR-positive], negative [ER-
negative and PgR-negative]) 
 
Clinical stage at presentation (II-IIIA; IIIB-IIIC) 
 
Number of prior neoadjuvant PH cycles (<4 vs. ≥4) 
 
Node status at diagnosis (positive, negative) 
 
Tumor diameter (<2 cm vs. ≥2 cm – <5 cm vs. ≥5 cm) 
4.6 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Not applicable 
4.7 
SAFETY ANALYSES 
All safety analyses will be performed on the safety population, unless specified otherwise.  
4.7.1 
Exposure of Study Medication 
Exposure to study drug will be summarized by treatment (Cross-Over Period IV, Cross-
Over Period SC, Continuation Period IV, Continuation Period SC) and by treatment 
sequence (IV/FDC SC, FDC SC/IV). The total number of cycles initiated will be 
summarized both by descriptive statistics and by presenting the number and percentage 
of patients in each category. The number and percentage of patients who have initiated 
their 6th cycle will also be summarized. A patient will be considered as having initiated a 
cycle if at least one (non-null) dose of any study drug has been administered in the 
corresponding cycle. 
Study drug administration details will be summarized by descriptive statistics and will 
include percentage of missed doses, percentage of cycles delayed, average number of 
days delayed and percentage of cycles interrupted. Study drug administration details will 
be summarized by treatment and treatment sequence. 
4.7.2 
Adverse Events 
Verbatim description of adverse events (AEs) will be mapped to Medical Dictionary for 
Regulatory Activities (MedDRA) thesaurus terms and graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI 
CTCAE v4.0). Adverse events will be summarized by MedDRA term, appropriate 
MedDRA levels (system organ class [SOC] and preferred term [PT]), and when specified 
by NCI CTCAE grade. For each patient, if multiple incidences of the same adverse 
events occur, the maximum severity reported will be used in the summaries. 


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Incidence of AEs will be presented by treatment period (FDC SC Cross-Over Period, IV 
Cross-Over Period, FDC SC Continuation Period, IV Continuation Period) and overall. In 
addition, selected tables will be presented by treatment sequence (FDC SC/IV, IV/FDC 
SC) and for the overall cross-over for AEs starting during the cross-over period only. 
Only adverse events occurring on or after the first dose of any study treatment in the 
Cross-Over period will be included in the summary tables. Adverse events occurring 
prior the first dose of any study treatment in the Cross-Over period will be summarized 
separately as ‘baseline signs and symptoms’. 
An AE will be assigned to a route of administration if it occurred on or after the first dose 
by that route and prior to the first (subsequent) date of a treatment by another other 
route. If there is no subsequent treatment by the other route then the 28 day cut off will 
be applied. For a patient completing the 6 cycles of the crossover treatment and 
continuing treatment, the AEs to be included for the crossover period are those up until 
the first dose of continuation medication. AEs during the first 3 cycles of treatment are 
selected if they started during the first 3 cycles of the treatment assigned to period 1. If a 
patient changed treatment before completing all 3 cycles of the period 1 treatment then 
only the AEs starting during the relevant cycles will be selected. If there is no 
subsequent treatment by the other route then the 28 day cut off will be applied. AEs 
starting more than 28 days after the last administration of study treatment will be listed 
only. Where an AE start date is partially or fully missing, and it is unclear to which 
treatment period the AE should be assigned, the AE will be assigned to all relevant 
treatment periods. 
Adverse events will be summarized by presenting the number and percentage of 
patients having any event, events leading to discontinuation or interruption of study drug, 
cardiac events, and events by CTC grade, relationship and outcome. 
This summary will be presented for:  
 
Adverse events 
 
Adverse events during the cross-over period by treatment sequence 
 
Adverse events during the first 3 cycles of treatment versus cycles 4-6 
 
Serious adverse events 
 
Serious adverse events by Age 
 
Serious adverse events during the cross-over period by treatment sequence 
 
Serious adverse events during the first 3 cycles of treatment versus cycles 4-6 
AEs by body weight (categories defined by weight percentiles) will be summarized by 
presenting the number and percentage of patients and number of events for: 
 
Adverse events by Body Weight  


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 
Adverse events by Body Weight during the first 3 cycles of treatment versus cycles 4-6 
 
Serious adverse events by Body Weight  
 
Serious adverse events by Body Weight during the first 3 cycles of treatment versus 
cycles 4-6 
Summary tables by system organ class (SOC) and preferred term of the number and 
percentage of patients having events will be presented for: 
 
Adverse events 
 
Adverse events during the cross-over period by treatment sequence 
 
Serious adverse events 
 
Serious adverse events during the cross-over period by treatment sequence 
 
Serious adverse events by highest NCI CTCAE grade 
 
Serious adverse events by Body Weight 
 
Adverse events Grade 3 or more 
 
Adverse events Grade 3 or more during the cross-over period by treatment sequence 
 
Related adverse events 
 
Related adverse events during the cross-over period by treatment sequence 
 
Related serious adverse events 
 
Related serious adverse events during the cross-over period by treatment sequence 
 
Adverse events leading to study drug discontinuation 
 
Adverse events leading to study drug discontinuation during the cross-over period 
by treatment sequence 
 
Adverse events leading to study drug interruption 
 
Adverse events leading to study drug interruption during the cross-over period by 
treatment sequence 
 
Adverse events resulting in death 
 
Cardiac AEs (including LVEF events) 
 
Cardiac AEs (including LVEF events) during the cross-over period by treatment 
sequence 
 
Adverse events of special interest (see Section 5.2.3 in the protocol) 
 
Adverse events of special interest by highest NCI CTCAE grade 
 
Serious adverse events of special interest 
 
Serious adverse events of special interest by highest NCI CTCAE grade 
 
Infusion-related reactions (Systemic) 
 
Infusion-related reactions (Systemic) during the cross-over period by treatment 
sequence 


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 
Injection-related reactions (Systemic) 
 
Injection-related reactions (Systemic) during the cross-over period by treatment 
sequence 
 
Injection-Site reactions (Local) 
 
Injection-Site reactions (Local) during the cross-over period by treatment sequence 
To evaluate the safety of switching from pertuzumab and trastuzumab FDC SC to P+H 
IV and from P+H IV to pertuzumab and trastuzumab FDC SC, the following summary 
tables by system organ class and preferred term will be presented for the Treatment 
Cross-over Period by treatment sequence and actual treatment: 
 
Adverse events during the first 3 cycles of treatment versus cycles 4-6 by actual 
treatment arm 
 
Serious adverse events during the first 3 cycles of treatment versus cycles 4-6 by 
actual treatment arm 
 
Adverse events Grade 3 or more during the first 3 cycles of treatment versus cycles 
4-6 by actual treatment arm 
 
Related adverse events during the first 3 cycles of treatment versus cycles 4-6 by 
actual treatment arm 
 
Related serious adverse events during the first 3 cycles of treatment versus cycles 
4-6 by actual treatment arm 
 
Adverse events leading to study drug discontinuation during the first 3 cycles of 
treatment versus cycles 4-6 by actual treatment arm 
 
Adverse events leading to study drug interruption during the first 3 cycles of 
treatment versus cycles 4-6 by actual treatment arm 
 
Cardiac AEs (including LVEF events) during the first 3 cycles of treatment versus 
cycles 4-6 by actual treatment arm 
 
Infusion-related reactions (Systemic) during the first 3 cycles of treatment versus 
cycles 4-6 by actual treatment arm 
 
Injection-related reactions (Systemic) during the first 3 cycles of treatment versus 
cycles 4-6 by actual treatment arm 
 
Injection-Site reactions (Local) during the first 3 cycles of treatment versus cycles 4-
6 by actual treatment arm 
In addition, the following summary tables will be provided by preferred term: 
 
Most frequent adverse events by preferred term (>=5% events in any group) 
 
Most frequent adverse events during the cross-over period by treatment sequence 
and preferred term (>=5% events in any group) 
 
Most frequent adverse events during the first 3 cycles of treatment versus cycles 4-6 
by preferred term (>=5% events in any group) 


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A listing of Non-treatment emergent AEs (i.e. those occurring before start of study 
treatment) will be provided. All listings of AEs will include all AEs with onset on or after 
the first study drug treatment up to the data cutoff date.  
All deaths and causes of deaths will be summarized by treatment arm and overall. 
4.7.3 
Laboratory Data 
Laboratory data will be summarized descriptively over time including change from 
baseline by treatment sequence and overall.  
Laboratory data will be classified according to NCI CTCAE 4.0. Highest NCI CTCAE 
grade post-baseline will also be reported and shift tables from baseline to worst post-
baseline will be presented by treatment sequence.  
Potential Hy’s law patients will be listed. Potential Hy’s law cases are defined as either of 
the following: 
 
Treatment-emergent ALT or AST >3xbaseline value (in earlier studies 3xULN) in 
combination with total bilirubin >2xULN (of which ≥35% is direct bilirubin) 
 
Treatment-emergent ALT or AST > 3 x baseline value in combination with 
clinical jaundice. 
4.7.4 
Vital Signs and ECOG Performance Status 
Vital signs parameters include: 
 
Temperature (°C) 
 
Systolic blood pressure (SBP seated position) (mmHg) 
 
Diastolic blood pressure (DBP seated position) (mmHg) 
 
Weight (kg) 
 
Heart rate (beats/min) 
 
Respiratory rate (breaths/min) 
Vital signs and ECOG performance status will be summarized by treatment sequence 
over time and overall. Shift table from baseline versus worst post-baseline will be 
presented by treatment sequence and overall. 
All vital signs data including change from baseline will be listed. 
4.7.5 
Electrocardiograms  
The baseline ECG of the patients and results of on-study ECGs will be summarized by 
treatment sequence and overall. 


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4.8 
MISSING DATA 
For the calculation of time to onset missing day will be replaced with the 1st of the 
month, missing month will be replaced with January. Other missing, unused and 
spurious data will be dealt with as such. There is no intention to implement any 
procedure for replacing any other missing data. 
4.9 
INTERIM ANALYSES 
An interim analysis, which will consist of a subset of the analyses planned for the 
primary analysis, will be conducted to support a planned regulatory filing for FDC. The 
results of this interim analysis will be evaluated by the Sponsor’s Internal Monitoring 
Committee. 
For this interim analysis a cut-off date will be implemented after the first approximately 
50 patients will have completed the cross-over phase. Assuming a drop-out rate of 10% 
after 50 patients accrued there would be 45 evaluable patients. With this sample size, 
the estimation precision (95%CI) for an observed SC preference rate of 75% would be 
60% to 87% and for an observed rate of 85% it would be 70% to 94%. 
The subset of analyses will consist of: demographics, disposition, PPQ, TASQ SC/IV 
and safety. 


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5. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics 1982;38:29-41. 
Fayers PM, Aaronson NK, Bjordal K, et al. on behalf of the EORTC Quality of 
Life Group. The EORTC QLQ-C30 scoring manual (3rd Edition). Published by 
European Organisation for Research and Treatment of Cancer, Brussels 2001. 
Rummel M, Kim TM, Aversa F et al. Preference for subcutaneous or intravenous 
administration of rituximab among patients with untreated CD20+ diffuse large B-
cell lymphoma or follicular lymphoma: results from a prospective, randomized, 
open-label, crossover study (PrefMab). Ann Oncol. 2017 Apr 1;28(4):836-842. 
Runowicz CD, Leach CR, Henry NL et al. American Cancer Society/American 
Society of Clinical Oncology Breast Cancer Survivorship Care Guideline. J Clin 
Oncol 2016 Feb 20;34(6):611-35.  
Pivot X, Gligorov J, Müller V et al. Preference for subcutaneous or intravenous 
administration of trastuzumab in patients with HER2-positive early breast cancer 
(PrefHer): an open-label randomised study. Lancet Oncol 2013;14(10):962- 70. 
 
 
 
 








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Study Design 
Description of Study 
This is a Phase II, randomized, multi-centre, multinational, open-label, cross-over study in adult 
patients who have completed neoadjuvant chemotherapy with neoadjuvant Perjeta and 
Herceptin and have undergone surgical treatment of HER2+ EBC. An overview of the study 
design is provided in the figure below.  A Schedule of Activities is provided in Appendix 2. 
Study Schema 
 
Abbreviations: IV: intravenous; P+H: Perjeta + Herceptin; FDC SC: subcutaneously 
administered fixed-dose combination of pertuzumab and trastuzumab; HCPQs: Healthcare 
Professional Questionnaires; PPQ: Patient Preference Questionnaire; SC subcutaneous; 
TASQ: Therapy Administration Satisfaction Questionnaire 
Eligibility will be assessed within a 28-day screening period. Eligible patients will be enrolled 
and randomly allocated in a 1:1 ratio to treatment Arm A (P+H IV followed by pertuzumab and 
trastuzumab FDC SC) or treatment Arm B (FDC SC followed by P+H IV). Patients will be 
stratified according to neoadjuvant chemotherapy regimen (anthracyclines + taxanes vs. 
carboplatin + taxanes vs. taxanes only), neoadjuvant treatment response (pathologic complete 
response [pCR] vs. non-pCR) and hormone receptor status (oestrogen receptor [ER]-positive 
and/or progesterone receptor [PgR]-positive vs. ER-negative and PgR-negative). Study 
treatment will be initiated ≥ 2 weeks from breast cancer surgery but ≤ 9 weeks from the last 
administration of systemic neoadjuvant therapy and will be administered on Day 1 of each 3-
week treatment cycle. No adjuvant chemotherapy is allowed after surgery, however, adjuvant 
hormone and/or radiation therapy are allowed. 
Patients randomized to Arm A will receive P+H IV for three treatment cycles followed by 
pertuzumab and trastuzumab FDC SC for three treatment cycles. Patients randomized to Arm B 
will receive pertuzumab and trastuzumab FDC SC for three treatment cycles followed by P+H 
IV for three treatment cycles. This period of 3+3 cycles in both treatment arms constitutes the 
study Treatment Cross-over Period. 
The 6 study treatment cycles of pertuzumab and trastuzumab FDC SC and P+H IV received 
during the Treatment Cross-over Period and P+H treatment cycles received in the neoadjuvant 
setting prior to study entry will be considered part of the total 18 anti-HER2 treatment cycles 
planned for all study patients. Following completion of the Treatment Cross-over Period, 
patients will enter the Treatment Continuation Period wherein they will receive the remaining 
anti-HER2 treatment cycles required to complete their 18 planned cycles unless disease 
recurrence, unacceptable toxicity or patient withdrawal from treatment necessitates early 
treatment cessation. Study treatment during this period will be either P+H IV or pertuzumab and 
trastuzumab FDC SC as selected by the patient at the end of the Treatment Cross-over Period.  


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Patients who, by the investigator’s assessment, cannot tolerate pertuzumab and trastuzumab 
FDC SC or P+H IV may be allowed to receive P+H IV or pertuzumab and trastuzumab FDC SC, 
respectively, for their remaining planned anti-HER2 treatment cycles. The investigator must 
obtain approval from the Medical Monitor to switch study treatment.  
Patient preference will be assessed based on the Patient Preference Questionnaire (PPQ) 
(administered following treatment administration on Day 1, Cycle 6 of the Treatment Cross-over 
Period). Treatment satisfaction will be assessed based on the Therapy Administration 
Satisfaction Questionnaire (TASQ) (administered following treatment administration on Day 1 of 
Cycles 3 and 6 of the Treatment Cross-over Period).  Healthcare professionals will record their 
perception of time/resource use and convenience of treatment administration completing the 
Healthcare Professional Questionnaires (HCPQs). Perception of time use will be captured 
during the Treatment Cross-over Period and perception of convenience will be captured after 
administration of each patient’s treatment Cycle 6. Health-related quality of life will be assessed 
based on the European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire C30 (EORTC QLQ-C30 completed at baseline, Cycle 3, Cycle 6, and the end of 
study treatment visits as well as at 18 months, 2 years, and 3 years from randomization. The 
study questionnaires are provided in Appendix 2 and Appendix 3 of the protocol. 
Patients will be assessed for safety by regular evaluation of adverse events (AEs), vital signs, 
routine clinical laboratory tests (haematology, blood chemistry) and left ventricular ejection 
fraction (LVEF) assessments; and by physical examinations. Adverse events will be reported 
and graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events version 4.0 (NCI CTCAE v4.0). Efficacy will be assessed based on investigator-
evaluated disease status determined according to assessments conducted per institutional 
practice or according to the American Cancer Society / American Society of Clinical Oncology 
(ACS/ASCO) Breast Cancer Survivorship Care Guideline [Runowicz et al. 2016, see Appendix 
4 of the protocol]. 
Patients will undergo an End of Treatment Visit approximately 28 days after completing study 
treatment and will enter the Follow-up Period wherein they will be followed for safety, disease 
status, survival and HRQoL (via the EORTC QLQ-C30) for three years from the date the last 
patient is randomized. 
Patients who withdraw from the study following randomization will not be replaced. Patients can 
be screened for the study more than once.    
Number of Patients 
Approximately 140 patients will be randomized in the study to obtain at least 126 evaluable 
patients.  
Target Population 
The target population will consist of adult patients with HER2+ EBC who have received 
neoadjuvant Perjeta and Herceptin, and have completed neoadjuvant chemotherapy and 
subsequently undergone surgery for their breast cancer.   
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
Disease-specific criteria 
 
Female or male with histologically confirmed, HER2+ inflammatory, locally advanced or early-
stage breast cancer who have received neoadjuvant Perjeta + Herceptin and have completed 
neoadjuvant chemotherapy and subsequently undergone surgery for their breast cancer. 
Note: The neoadjuvant chemotherapy regimen (including type and sequencing of selected 
agents) and the number of neoadjuvant Perjeta and Herceptin treatment cycles are at the 
discretion of the treating physician and patient. Subcutaneously administered Herceptin may 
have been used in the neoadjuvant setting. The use of any trastuzumab biosimilars in the 
neoadjuvant setting is not allowed. 
 
HER2+ breast cancer assessed at the local laboratory prior to initiation of neoadjuvant therapy. 
HER2+ status must be determined based on breast biopsy material obtained prior to 


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neoadjuvant treatment and is defined as 3+ by immunohistochemistry (IHC) and/or positive by 
HER2 amplification by in situ hybridization (ISH) with a ratio of ≥ 2 for the number of HER2 
gene copies to the number of chromosome 17 copies 
 
Hormone receptor status of the primary tumour determined by local assessment. Hormone 
receptor status may be either positive (i.e. ER-positive and/or PgR-positive) or negative (i.e. 
ER-negative and PgR-negative) 
 
Completed all neoadjuvant chemotherapy and surgery. Adjuvant radiotherapy may be planned 
or ongoing at study entry and adjuvant hormone therapy is allowed during the study. Note that 
study treatment cannot be initiated within < 2 weeks of surgery but must be initiated ≤ 9 weeks 
from the last administration of systemic neoadjuvant therapy. 
 
No evidence of residual, locally recurrent or metastatic disease after completion of surgery. 
Patients with clinical suspicion of metastases must undergo radiological assessments per 
institutional practice to rule out distant disease. 
 
Wound healing after breast cancer surgery adequate per investigator’s assessment to allow 
initiation of study treatment within ≤ 9 weeks of last systemic neoadjuvant therapy 
 
No adjuvant chemotherapy planned. Note that adjuvant hormonal treatment is allowed during 
the study. 
General criteria 
 
Signed Informed Consent Form 
 
Age ≥ 18 years at time of signing Informed Consent Form 
 
Ability to comply with the study protocol, in the investigator’s judgment 
 
Eastern Cooperative Oncology Group performance status 0 or 1 
 
Intact skin at planned site of subcutaneous (SC) injections (thigh) 
 
LVEF ≥ 55% measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) 
within 28 days of study randomization 
 
No major surgical procedure unrelated to breast cancer within 28 days prior to randomization 
or anticipation of the need for major surgery during the course of study treatment 
 
For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive measures, and agreement to refrain from donating eggs, as 
defined below: 
Women must remain abstinent or use non-hormonal contraceptive methods with a failure rate 
of <1% per year, or 2 effective non-hormonal contraceptive methods during the study treatment 
periods and for 7 months after the last dose of study treatment. Women must refrain from 
donating eggs during this same period.  
A woman is considered to be of childbearing potential if she is post-menarchal, has not reached 
a post-menopausal state (post-menopausal defined as ≥ 12 continuous months of amenorrhea 
with no identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). The definition of childbearing potential may be adapted for 
alignment with local guidelines or requirements. 
Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization (with appropriate post-vasectomy documentation of 
the absence of sperm in the ejaculate) and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical 
trial and the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. 


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 
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below: 
With female partners of childbearing potential or pregnant female partners, men must remain 
abstinent or use a condom during the study treatment periods and for seven months after the 
last dose of study treatment to avoid exposing the embryo. Men must refrain from donating 
sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical 
trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable 
methods of preventing drug exposure.  
 
A negative serum pregnancy test must be available prior to randomization for women of 
childbearing potential (defined as post-menarchal, has not had ≥ 12 continuous months of 
amenorrhea with no identified cause other than menopause, and has not undergone surgical 
sterilization [removal of ovaries and/or uterus]) 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Cancer-specific criteria 
 
Stage IV (metastatic) breast cancer  
 
Current or prior history of active malignancy (other than current breast cancer) within the last 
five years. Appropriately treated non-melanoma skin cancer; in situ carcinomas, including 
cervix, colon, or skin; or Stage I uterine cancer within the last five years are allowed.  
A patient with previous invasive non-breast cancer is eligible provided he/she has been disease 
free for more than five years. 
 
Previous systemic therapy (including chemotherapy, immunotherapy, HER2-targeted agents, 
endocrine therapy [selective oestrogen receptor modulators, aromatase inhibitors], and 
antitumor vaccines) for treatment or prevention of breast cancer, except neoadjuvant Perjeta, 
Herceptin and chemotherapy for current breast cancer 
General criteria: 
 
Investigational treatment within four weeks of enrolment  
 
Serious cardiac illness or medical conditions including, but not confined to, the following: 
− 
History of NCI CTCAE v4.0 Grade ≥ 3 symptomatic congestive heart failure (CHF) or New 
York Heart Association (NYHA) Class ≥ II 
− 
High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate ≥ 100/min at 
rest, significant ventricular arrhythmia [ventricular tachycardia], or higher-grade 
atrioventricular [AV]-block, such as second-degree AV-block Type 2 [Mobitz II] or third-
degree AV-block) 
− 
Serious cardiac arrhythmia or severe conduction abnormality not controlled by adequate 
medication  
− 
Angina pectoris requiring anti-angina medication 
− 
Clinically significant valvular heart disease 
− 
Evidence of transmural infarction on electrocardiogram (ECG) 
− 
Evidence of myocardial infarction within 12 months prior to randomization 
− 
Poorly controlled hypertension (e.g., systolic > 180 mmHg or diastolic > 100 mmHg) 


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 
History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as 
structural heart disease (e.g., severe left ventricular systolic dysfunction [LVSD], left ventricular 
hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by 
diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalaemia, 
hypomagnesemia, hypocalcaemia), or family history of sudden unexplained death or long QT 
syndrome 
 
Inadequate bone marrow function, defined by any of: 
− 
Absolute neutrophil count < 1.5 x 109/L 
− 
Platelet count < 100 x 109/L 
− 
Haemoglobin < 9 g/dL 
 
Impaired liver function, defined by any of: 
− 
Serum (total) bilirubin > 1.25 x upper limit of normal (ULN). In case of Gilbert’s syndrome: 
a total bilirubin of 2 x ULN is permitted. 
− 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 1.25 x ULN 
− 
Albumin < 25 g/L 
 
Inadequate renal function with serum creatinine > 1.5 x ULN 
 
Current severe, uncontrolled systemic disease that may interfere with planned treatment (e.g., 
clinically significant cardiovascular, pulmonary, or metabolic disease; wound-healing disorders) 
 
Pregnant or breastfeeding, or intending to become pregnant during the study or within seven 
months after the last dose of study treatment. Women of childbearing potential must have a 
negative serum pregnancy test result within seven days prior to initiation of study treatment 
 
Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in, and completion of, the 
study 
 
Known active liver disease, for example, active viral hepatitis infection (i.e., hepatitis B or 
hepatitis C), autoimmune hepatic disorders, or sclerosing cholangitis 
 
Concurrent, serious, uncontrolled infections, or known infection with human immunodeficiency 
virus (HIV) 
 
Known hypersensitivity to any of the study drugs, excipients, and/or murine proteins 
 
Current chronic daily treatment with corticosteroids (dose > 10 mg methylprednisolone or 
equivalent excluding inhaled steroids) 
End of Study 
The end of the study is defined the Last Patient, Last Visit (LPLV) which will occur three years 
after the last patient is randomized or the date at which the last data point required for the final 
statistical analysis or safety follow-up is received from the last patient, whichever occurs later. 
In addition, the Sponsor may decide to terminate the study at any time. 
Length of Study 
The study is estimated to last approximately 4 years, based on a recruitment period of up to 10 
months and 3 years of follow-up after the last patient is randomized. 
Investigational Medicinal Products 
The investigational medicinal products (IMPs) for this study are pertuzumab and trastuzumab 
FDC SC, Perjeta IV, and Herceptin IV. 
Test Product (Investigational Drug) 
Pertuzumab and trastuzumab FDC SC is given as a fixed dose (i.e. non-weight based). 
Pertuzumab and trastuzumab FDC SC will be provided in a loading dose configuration and a 
maintenance dose configuration. The 15 mL loading dose consists of 1200 mg pertuzumab and 


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600 mg trastuzumab. The 10 mL maintenance dose consists of 600 mg pertuzumab and 600 
mg trastuzumab. Patients who have had ≥ 6 weeks since their last neoadjuvant dose of Perjeta 
or Herceptin at study entry, or have had ≥ 6 weeks since their last study treatment during the 
study treatment periods, must receive a loading dose before continuing with maintenance doses 
for subsequent administrations. All pertuzumab and trastuzumab FDC SC doses are 
administered by SC injection over 5 – 8 minutes at a rate of ≤ 2 mL/min with hand-held syringe 
to the thigh on Day 1 of each 3-week treatment cycle. Patients should be monitored for 30 
minutes after their first pertuzumab and trastuzumab FDC SC dose administration regardless of 
whether a loading dose is required. Patients should be monitored for 10 - 15 minutes following 
subsequent administrations. Patients can be observed for longer periods at the discretion of the 
investigator or if necessary, as per local requirements. 
Comparator (Active Control) 
Perjeta IV is administered at a dose of 840 mg (loading dose) or 420 mg (maintenance dose) on 
Day 1 of each 3-week treatment cycle and should be administered before Herceptin IV. Patients 
who have had ≥ 6 weeks since their last neoadjuvant dose of Perjeta at study entry, or have 
had ≥ 6 weeks since their last study treatment during the study treatment periods, must receive 
a loading dose before continuing with maintenance doses for subsequent administrations. 
Perjeta IV loading dose (if required) will be administered as a 60-minute infusion (± 10 minutes), 
followed by an observation period of 60 minutes. If the loading dose infusion is well tolerated, 
subsequent maintenance doses can be administered over a period of 30 minutes (± 10 minutes) 
with an observation period of 30 minutes. Patients can be observed for longer periods at the 
discretion of the investigator or if necessary, as per local requirements. The observation period 
should be completed prior to the subsequent Herceptin IV infusion. 
Herceptin IV is administered at a dose of 8 mg/kg (loading dose) or 6 mg/kg (maintenance 
dose) on Day 1 of each 3-week treatment cycle. Patients who have had ≥ 6 weeks since their 
last neoadjuvant dose of Herceptin at study entry, or have had ≥ 6 weeks since their last study 
treatment during the study treatment periods, must receive a loading dose before continuing 
with maintenance doses for subsequent administrations. Herceptin IV loading dose (if required) 
will be administered as an infusion over approximately 90 (± 10) minutes after which the patient 
must be observed for 60 minutes. If the loading dose is well tolerated, subsequent maintenance 
doses can be administered as 30-minute infusions (± 10 minutes) followed by an observation 
period of 30 minutes. Patients can be observed for longer periods at the discretion of the 
investigator or if necessary, as per local requirements. 
Non-Investigational Medicinal Products 
Not applicable.  
Statistical Methods 
Primary Analysis 
The primary objective of this study is to evaluate patient preference for pertuzumab and 
trastuzumab FDC SC based on the proportion of patients indicating an overall preference for 
pertuzumab and trastuzumab FDC SC based on Question 1 of the PPQ. Question 1 of the PPQ 
is as follows: “All things considered, which method of administration did you prefer?”. 
The primary endpoint will be analysed for the intent-to-treat (ITT) population and for the 
modified ITT (mITT) population. The mITT population will include all patients who received at 
least one dose by both SC and IV routes of administration during the Treatment Cross-over 
Period and subsequently answered at least Question 1 of the PPQ.   
A point estimate with associated 95% confidence interval (CI) for the proportion of patients who 
preferred pertuzumab and trastuzumab FDC SC will be calculated for the mITT and ITT 
populations. 
Analysis of the primary study endpoint will take place when all patients have completed their 
last treatment administration during the Treatment Cross-over Period.  
Determination of Sample Size   
The binary primary endpoint (the proportion of patients who express a preference for 
pertuzumab and trastuzumab FDC SC) will be estimated with associated two-sided 95% CI. 
Assuming a rate of 70% of patients preferring pertuzumab and trastuzumab FDC SC and 
aiming at a distance from the estimated proportion to the CI limits of approximately ± 8%, a total 


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of 126 patients are needed for the evaluation of preference. Hence, the observed rate of 70% of 
patients preferring pertuzumab and trastuzumab FDC SC could be estimated to be within 61.9% 
and 78.4% with a probability of 95%. 
To allow for 10% of the patients not providing an evaluable preference assessment, 
approximately 140 patients are targeted to be randomized into the study. 
Interim Analysis 
An interim analysis will be conducted to support a planned regulatory filing for FDC, which will 
consist of a subset of the analyses planned for the primary analysis. The results of this interim 
analysis will be evaluated by a Sponsor’s Internal Monitoring Committee. Further details will be 
specified in the Statistical Analysis Plan. 
 
 
 










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should be administered for EBC treatment unless disease recurrence, unacceptable toxicity or patient withdrawal from treatment necessitates 
early cessation of treatment.  No specific investigations are required per protocol for Cycles 8-10 and Cycles 12-14 during the Treatment 
Continuation Period, although the PI may perform safety laboratory assessments or other tests per institutional practice (these results are not 
required to be reported in the eCRF).  However, information on treatment administration will be collected, and new or worsened 
clinically significant abnormalities should be recorded as AEs on the Adverse Event eCRF.  
b. End of Treatment Visit to be performed within 28 days (± 7 days) of the administration of the last dose of any study drug. 
c. Study patients will be followed for at least three years from randomization. A follow-up visit should occur at least every six months during this 
period. 
d. If study treatment Cycle 12 is planned as last study treatment cycle (i.e. corresponding to Cycle 18 of neo/adjuvant anti-HER2 treatment), all 
planned assessments may be delayed to study treatment Cycle 12 
e. The number of the last treatment cycle in Treatment Continuation Period will depend on number of neoadjuvant cycles with Perjeta and 
Herceptin. A total of 18 cycles of HER2-targeted therapy should be administered over neo/adjuvant treatment (i.e. neoadjuvant cycles + 
Treatment Cross-over Period Cycles + Treatment Continuation Period cycles = 18 neo/adjuvant cycles). 
f. 
Results of standard-of-care tests or examinations performed prior to obtaining informed consent but within 28 or 7 days of randomization (as 
indicated) may be used; such tests do not need to be repeated for screening. 
g. Pathology reports from initial breast cancer diagnosis and from breast cancer surgery will be collected. Results of local HER2 and hormone 
receptor testing conducted prior to neoadjuvant therapy will also be collected.  
h. Must be performed pre-dose on study treatment dosing days 
i. 
Complete physical examinations should include physical measurements (body weight in kilograms and height in centimetres) and evaluation of 
the head, eyes, ears, nose and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and 
neurologic systems.  Any abnormality identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF. 
Limited physical examinations are symptom-directed and, in addition to the scheduled examinations indicated, may be conducted as clinically 
indicated.  New or worsened clinically significant abnormalities observed post-baseline should be recorded as AEs on the Adverse Event eCRF. 
During the Follow-up Period, physical examinations should be conducted in accordance with institutional practice or the American Cancer 
Society/American Society of Clinical Oncology Breast Cancer (ACS/ASCO) Breast Cancer Survivorship Care Guideline [Runowicz et al. 2016, 
see Appendix 4 of the protocol]. 
j. 
Vital signs (heart rate, blood pressure, temperature, respiration rate) will be taken before and after study treatment administration. Heart rate, 
blood pressure, and respiration rate should be obtained while the patient is seated. 
k. Weight will be measured during screening and on Day 1 of each cycle prior to treatment administration. If variation of ≥  10% compared with 
baseline occurs, Herceptin IV dosing should be recalculated. Weight at the time the Herceptin IV dose is recalculated will be considered as 
baseline for subsequent evaluations of degree of weight change with respect to Herceptin IV dose modification requirements. 


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l. 
Clinical breast examination should be performed to detect signs of residual disease / local recurrence prior to study entry and to detect 
locoregional relapse during the Treatment Cross-over and Treatment Continuation Periods, and at the End of Treatment Visit. During the 
Follow-up Period, clinical breast exams should be conducted in accordance with institutional practice or the ACS/ASCO Breast Cancer 
Survivorship Care Guideline [Runowicz et al. 2016, see Appendix 4 of the protocol]. 
m. LVEF may be assessed by ECHO or MUGA however the same method should be used throughout the study for each patient and should be 
performed and assessed by the same assessor where possible.  During the study treatment periods, results of LVEF assessments must be 
reviewed prior to study treatment administration on the scheduled visit day. During the Follow-up Period, LVEF should be assessed at 6, 12, 
and 24 months after last study treatment or per institutional practice. 
n. Haematology:  haemoglobin, total WBC, ANC / neutrophils, platelet count.  Limited biochemistry:  alkaline phosphatase; AST; ALT; LDH; total 
bilirubin; creatinine. Albumin should be measured at Screening for determining patient eligibility. Bilirubin fractions (direct and indirect) must be 
included if total bilirubin is greater than ULN. During the treatment period, bloods for haematology / biochemistry may be taken within three 
days prior to study treatment administration. 
o. Pregnancy testing is only required for women of childbearing potential:  A woman of childbearing potential is defined as: post-menarchal, has 
not reached a post-menopausal state (post-menopausal defined as ≥ 12 continuous months of amenorrhea with no identified cause other than 
menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements.  Pregnancy tests must be performed via serum -human chorionic gonadotropin 
(HCG) at baseline within seven days prior to first study treatment administration. Urine pregnancy tests should be repeated during the 
Treatment Cross-over and Treatment Continuation Periods at Cycle 4, Cycle 7, Cycle 11 and Cycle 15 (or at last treatment cycle), and as 
clinically indicated, with results available prior to study treatment administration, as well as at the End of Treatment Visit and at the Follow-up 
Visit until seven months after discontinuation of study treatment. Any positive urine pregnancy test must be confirmed with a serum -HCG test.  
p. Adverse event reporting period will continue up to seven months after the last dose of study drug. After informed consent, but prior to initiation 
of study treatment, only SAEs caused by a protocol-mandated intervention will be collected. After initiation of study treatment, all AEs 
regardless of relationship to study drug will be reported until 28 days after the last dose of study drug. Between 28 days and 7 months after the 
last dose of study drug, drug-related SAEs, AEs of special interest, heart failure, pregnancies, non−breast-related second primary malignancies 
and deaths, should continue to be collected. After the end of the adverse event reporting period (defined as seven months after the last dose of 
study drug), drug-related SAEs, AEs of special interest, heart failure, non−breast-related second primary malignancies and deaths, should 
continue to be collected should be collected.  
q. All concomitant medications used by the patient from seven days prior to initiation of study drug until the End of Treatment Visit should be 
reported. After the End of Treatment Visit and until the end of the study, only medications used for the treatment of cancer will be reported.  
r. 
The Patient Preference Questionnaire (PPQ) must be completed following study treatment administration on Day 1 of Cross-over Treatment 
Period Cycle 6. Patients who discontinued study treatment prior to study treatment Cycle 6 should complete the questionnaire at the time of 


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42/Statistical Analysis Plan MO40628 
discontinuation as long as they have received at least one dose of pertuzumab and trastuzumab FDC SC, Perjeta IV and Herceptin IV post-
randomization. 
s. Patients in Arm A will complete the Therapy Administration Satisfaction Questionnaire for IV administration (TASQ-IV) immediately following 
study treatment administration on Day 1 of Cycle 3 of the Treatment Cross-over Period and the Therapy Administration Satisfaction 
Questionnaire for SC administration (TASQ-SC) immediately following study treatment administration on Day 1 of Cycle 6 of the Treatment 
Cross-over Period. Patients in Arm B will complete the TASQ-SC and TASQ-IV immediately following study treatment administration on Day 1 
of Cycle 3 and 6 of the Treatment Cross-over Period respectively.  Patients who switch study treatment due to investigator-assessed lack of 
tolerance should complete the TASQ corresponding to the study treatment they cannot tolerate prior to switching treatment (i.e. after the 
decision to change study treatment has been approved by the Medical Monitor and before receiving the next study treatment).  
t. 
During the study treatment periods, patients must complete the EORTC QLQ-30 before the patient and clinician receives any information on 
disease status and prior to treatment administration on the scheduled visit day. During the Follow-up Period, the EORTC QLQ-30 must be 
completed at 18 months, 2 years, and 3 years from randomization. 
u. Each Healthcare Professional Questionnaire (HCPQ) will be completed by the applicable HCP after each study treatment preparation and/or 
administration for each patient. Applicable HCPs are described in each of the questionnaires (HCPQ-Treatment Room, HCPQ-Drug 
Preparation Area). Instructions for which questions should be completed in each questionnaire at each timepoint are indicated in the 
introduction to each questionnaire. 
v. Mammograms conducted at the time of diagnosis (before initiation of the neoadjuvant treatment) as well as pre-surgery (if performed) will be 
collected. Mammograms collected and/or conducted for the study (including pre-neoadjuvant treatment, pre-surgery, and study Follow-up 
Period evaluations) can be replaced by another conventional imaging method such as magnetic resonance imaging (MRI) or ultrasound per 
institutional practice at the investigator’s discretion, but the same method of assessment must be used for each evaluation for an individual 
patient. If a mammogram (or acceptable alternative breast imaging evaluation) has been conducted as part of routine care within four months 
prior to the End of Treatment Visit, it may be used in lieu of the End of Treatment Visit evaluation. 
w. After completion of the Treatment Cross-over Period, participating patients will select the study treatment formulation (P+H IV or pertuzumab 
and trastuzumab FDC SC) to complete their 18 cycles of neo/adjuvant HER2-targeted treatment. The number of study treatment cycles 
administered during the Treatment Continuation Period required to complete a total of 18 of neo/adjuvant HER2-targeted treatment will be 
calculated based on the sum of number of P+H cycles received in neoadjuvant treatment (before study entry) plus 6 cycles administered in the 
Treatment Cross-over Period.