Conditions: Early Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 500
Healthy volunteers: no

Brief summary:
This is a global Phase III, two-arm, open-label, multicenter, randomized study to investigate the pharmacokinetics, efficacy, and safety of the fixed-dose combination (FDC) of pertuzumab and trastuzumab for subcutaneous (SC) administration in combination with chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer in the neoadjuvant/adjuvant setting.

Detailed description:

Arms:
arm 1: Participants will receive 8 cycles of investigator's choice of neoadjuvant chemotherapy. This will include either: 1) 4 cycles of dose-dense doxorubicin plus cyclophosphamide (ddAC) once every 2 weeks (Q2W) (given with granulocyte colony-stimulating factor \[G-CSF\] support as needed according to local guidelines) followed by paclitaxel Q1W for 12 weeks; or 2) 4 cycles of doxorubicin plus cyclophosphamide (AC) once every 3 weeks (Q3W) followed by docetaxel Q3W for 4 cycles. Pertuzumab and trastuzumab will be given intravenously (IV) for 4 cycles Q3W concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants will undergo surgery. Thereafter, participants will receive an additional 14 cycles of pertuzumab IV and trastuzumab IV for a total of 18 cycles. arm 2: Participants will receive 8 cycles of investigator's choice of neoadjuvant chemotherapy. This will include either: 1) 4 cycles of ddAC Q2W (given with G-CSF support as needed according to local guidelines) followed by paclitaxel once every week (QW) for 12 weeks; or 2) 4 cycles of AC Q3W followed by docetaxel Q3W for 4 cycles. The fixed-dose combination (FDC) of pertuzumab and trastuzumab will be given subcutaneously (SC) for 4 cycles (Q3W) concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants will undergo surgery. Thereafter, participants will receive an additional 14 cycles of the FDC of pertuzumab and trastuzumab SC for a total of 18 cycles.

Interventions: intervention 1: Cyclophosphamide intervention 2: Doxorubicin intervention 3: Docetaxel intervention 4: Paclitaxel intervention 5: Pertuzumab IV intervention 6: FDC of Pertuzumab and Trastuzumab SC intervention 7: Trastuzumab IV intervention 8: Trastuzumab SC intervention 9: Surgery intervention 10: Post-operative Radiotherapy intervention 11: Hormone Therapy
Intervention descriptions: intervention 1: Cyclophosphamide 600 mg/m2 will be administered IV on Day 1 of each cycle of treatment (as part of ddAC Q2W or AC Q3W) for Cycles 1-4. intervention 2: Doxorubicin 60 mg/m2 will be administered IV on Day 1 of each cycle of treatment (as part of either ddAC Q2W or AC Q3W) for Cycles 1-4. intervention 3: As part of one of the two investigator's choices of chemotherapy (AC followed by docetaxel), docetaxel 75 mg/m2 will be administered IV on Day 1 of Cycle 5 and then 100 mg/m2 IV at the discretion of the investigator for Cycles 6-8 (Q3W), if no dose-limiting toxicity occurs. intervention 4: As part of one of the two investigator's choices of chemotherapy (ddAC followed by paclitaxel), paclitaxel 80 mg/m2 will be administered IV QW for 12 weeks. intervention 5: Pertuzumab will be administered as a fixed non-weight-based dose of 840-mg IV loading dose and then 420-mg IV maintenance dose Q3W. intervention 6: The FDC of pertuzumab and trastuzumab will be administered SC at a fixed non-weight-based dose. A loading dose of 1200 mg SC pertuzumab and 600 mg SC trastuzumab is then followed by a maintenance dose of 600 mg SC pertuzumab and 600 mg SC trastuzumab Q3W. intervention 7: Trastuzumab will be administered as an 8-mg/kg IV loading dose and then 6 mg/kg IV maintenance dose Q3W. intervention 8: After surgery (from Cycle 9 onwards), participants in Arm A will be allowed to switch from trastuzumab IV to trastuzumab SC, at the discretion of the investigator, in the countries where trastuzumab SC is routinely used. For participants who switch, a fixed dose of 600 mg trastuzumab SC (irrespective of the patient's weight) will be administered in the adjuvant phase. intervention 9: Participants in both cohorts are scheduled to undergo surgery after 8 cycles of neoadjuvant therapy. Participants may undergo breast-conserving surgery or mastectomy according to routine clinical practice. intervention 10: If indicated, radiotherapy is given after chemotherapy and surgery, during adjuvant HER2-targeted therapy and hormone therapy (for hormone-receptor positive disease). intervention 11: For hormone receptor positive breast cancer, tamoxifen or aromatase inhibitors will be allowed as adjuvant hormone therapy for postmenopausal participants and with ovarian suppression or ablation for premenopausal participants in countries where it has been registered for this indication. Its use must be consistent with the registered label. Hormone therapy is given after chemotherapy and surgery during adjuvant HER2-targeted therapy.

Protocol document:
Prot_000.pdf: 
Official Title: A Phase III, Randomized, Multicenter, Open-Label, Two-Arm Study to 
Evaluate the Pharmacokinetics, Efficacy, and Safety of Subcutaneous 
Administration of the Fixed-Dose Combination of Pertuzumab and 
Trastuzumab in Combination with Chemotherapy in Patients with 
HER2-Positive Early Breast Cancer 
NCT Number: 
NCT03493854 
Document Date: 
Protocol Version 2: 12-October-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 WO40324, Version 2
PROTOCOL
TITLE:
A PHASE III, RANDOMIZED, MULTICENTER, 
OPEN-LABEL, TWO-ARM STUDY TO EVALUATE 
THE PHARMACOKINETICS, EFFICACY, AND 
SAFETY OF SUBCUTANEOUS ADMINISTRATION 
OF THE FIXED-DOSE COMBINATION OF 
PERTUZUMAB AND TRASTUZUMAB IN 
COMBINATION WITH CHEMOTHERAPY IN 
PATIENTS WITH HER2-POSITIVE EARLY BREAST 
CANCER
PROTOCOL NUMBER:
WO40324 
VERSION NUMBER:
2
EUDRACT NUMBER:
2017-004897-32
IND NUMBER:
131009
TEST PRODUCT:
Fixed-dose combination (FDC) of pertuzumab and 
trastuzumab for subcutaneous administration
(RO7198574)
MEDICAL MONITOR:
, M.D., Ph.D.
, B.Sc.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  2 February 2018
DATE AMENDED:
Version 2:  See electronic date stamp below.
12-Oct-2018 19:00:20
Title
Approver's Name
Company Signatory
Date and Time (UTC)


SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
2/Protocol WO40324, Version 2
PROTOCOL AMENDMENT, VERSION 2:
RATIONALE
Protocol WO40324 has been amended to provide additional clarifications and to correct 
inconsistencies.  Changes have also been made to account for local guidelines.  The 
main changes to the protocol, along with a rationale for each change, are summarized 
below:

Sections 3.1,
4.1, 4.1.1, and 4.5.10 have been updated to clarify that 
the size of the tumor allowed for entry into the study is 2 cm and not 2cm.  This 
change to 2 cm aligns with Stage II as inclusion criteria.

Section 4.1.1 has been changed to give more clarity on “node-positive” and also to
clarify that suspicious lymph nodes must be confirmed by cytology and/or
histopathology.

The observation period for Herceptin SC has been added to Section 4.3.2.1, along
with instructions for slowing or interrupting the injection if the patient experiences
injection-related symptoms, as this was missing in Version 1.

Additional instructions have been added to Sections 4.3.2.1, 4.3.2.2, and 5.1.1.1 to
allow for extra observation time (at the investigator’s discretion, if deemed
necessary) after administration of Herceptin SC, Herceptin IV, and the fixed-dose
combination of pertuzumab and trastuzuamb for SC injection (the FDC), taking into
account different local requirements for observation time for Herceptin SC and IV.

Sections 4.3.2.3 and 4.3.2.4 have been updated to provide additional guidance for
the management of hypersensitivity reactions that occur following docetaxel and
paclitaxel administrations, respectively.

Sections 4.5.7.2, 4.5.10, and footnote ‘h’ of Appendices 1 and 2 have been updated
to clarify that tumor staging at baseline is not mandatory and should only be
performed if clinically indicated.

Additional details and explanations about the PK sampling process have been
added to Section 4.5.9.1, as this level of detail was not included in Version 1.
Further clarifications on time windows for sampling have also been provided in
Section 4.5.9.2 and are reflected in updates to Appendices 5 and 6.

The definition for pathological complete response (and evaluation) in Section 4.5.11
has been updated to align with the U.S. Food and Drug Administration and
European Medicines Agency guidance for industry on pCR endpoints.

Symptomatic left ventricular systolic dysfunction (LVSD) and/or left ventricular
ejection fraction (LVEF) decline were added as reasons for discontinuing anti-HER2
therapy in Section 5.2.5.1 (Symptomatic LVSD and/or LVEF Decline) to align with
Section 4.7.1 (Study Treatment Discontinuation).

The guidelines for taxane dose delays and modifications have been updated to
provide instructions for patients who experience a Grade 3 enterocolitis event (see
Section 5.2.4 and Table 8).


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3/Protocol WO40324, Version 2

LVEF assessment before surgery has been added to Appendices 1 and 2 to ensure
adequate cardiac function prior to surgery and avoid risks due to anesthesia.

Wording was added to Appendices 14 to allow for an additional pregnancy test at
the Month 7 follow-up visit, if deemed necessary by the investigator, due to the
7-month Herceptin wash out period.
Additional minor changes have been made to improve clarity and consistency and to 
align the protocol with the Sponsor’s current internal guidelines and standard operating 
procedures.  Substantive new information appears in italics.  This amendment 
represents cumulative changes to the original protocol.


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TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................. 14
PROTOCOL SYNOPSIS .................................................................................... 15
1
BACKGROUND .......................................................................................... 30
1.1
Background on HER2-Positive Breast Cancer....................... 30
1.2
Background on Perjeta, Herceptin, and rHuPH20 ................. 32
1.2.1
Background on Herceptin IV and Herceptin SC..................... 32
1.2.1.1
Nonclinical Information on Herceptin SC ............................... 32
1.2.1.2
Clinical Efficacy of Herceptin SC ........................................... 32
1.2.1.3
Clinical Safety of Herceptin SC.............................................. 33
1.2.2
Background on Perjeta IV...................................................... 34
1.2.2.1
Nonclinical Information on Perjeta IV..................................... 34
1.2.2.2
Clinical Pharmacokinetics of Pertuzumab.............................. 34
1.2.2.3
Clinical Information on Perjeta IV .......................................... 35
1.2.2.4
Safety of Perjeta IV................................................................ 38
1.2.3
Pertuzumab SC ..................................................................... 39
1.2.3.1
Nonclinical Information on Pertuzumab SC ........................... 39
1.2.3.2
Clinical Studies with Pertuzumab SC .................................... 41
1.2.4
Background on Recombinant Human 
Hyaluronidase (rHuPH20)...................................................... 43
44
2
OBJECTIVES AND ENDPOINTS ............................................................... 45
3
STUDY DESIGN......................................................................................... 51
3.1
Description of the Study......................................................... 51
3.1.1
Neoadjuvant Phase ............................................................... 54
3.1.2
Surgery.................................................................................. 54
3.1.3
Adjuvant Phase ..................................................................... 54
3.1.4
Safety Data Review ............................................................... 55
3.2
End of Study and Length of Study......................................... 55
55


-
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................. 55 
................. 57 
................. 58 
................. 59 
.......................... 60 
4 
MATERIALS AND METHODS .................................................................... 61 
4.1 
4.1.1 
4.1.2 
4.2 
4.3 
4.3.1 
4.3.1.1 
4.3.1.2 
4.3.1.3 
4.3.1.4 
4.3.1.5 
4.3.2 
4.3.2.1 
4.3.2.2 
4.3.2.3 
Patients .................................................................................. 61 
Inclusion Criteria .................................................................... 61 
Exclusion Criteria ................................................................... 63 
Method of Treatment Assignment and Blinding ..................... 65 
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 66 
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 66 
Perjeta IV ............................................................................... 66 
Herceptin IV ........................................................................... 66 
Herceptin SC ......................................................................... 66 
SC Fixed-Dose Combination of Pertuzumab and 
Trastuzumab .......................................................................... 67 
Chemotherapy, Hormone Therapy, and 
Granulocyte Colony-Stimulating Factor ................................. 67 
Study Treatment Dosage, Administration, and 
Compliance ............................................................................ 67 
Arm A: Perjeta IV plus Herceptin IV ...................................... 68 
Arm B: SC Fixed-Dose Combination of 
Pertuzumab and Trastuzumab .............................................. 69 
AC-Docetaxel + HER2-Targeted Therapy ........................... 71 
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4.3.2.4
ddAC→Paclitaxel HER2-Targeted Therapy........................ 72
4.3.2.5
Other Required Medication.................................................... 73
4.3.3
Investigational Medicinal Product Accountability ................... 74
4.3.4
Continued Access to Perjeta IV, Herceptin IV, 
Herceptin SC, and the FDC................................................... 74
4.4
Concomitant Therapy ............................................................ 75
4.4.1
Surgery.................................................................................. 75
4.4.2
Radiotherapy ......................................................................... 76
4.4.3
Hormone Therapy.................................................................. 76
4.4.4
Permitted Therapy................................................................. 78
4.4.4.1
Herbal Therapies................................................................... 79
4.4.5
Prohibited Therapy ................................................................ 79
4.5
Study Assessments ............................................................... 80
4.5.1
Informed Consent Forms and Screening Log........................ 80
4.5.2
Core Biopsy........................................................................... 80
4.5.3
HER2 Screening for Eligibility and Central 
Assessment of Hormone Receptor Status............................. 80
4.5.4
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 82
4.5.5
Physical Examinations........................................................... 83
4.5.6
Vital Signs.............................................................................. 83
4.5.7
Radiology............................................................................... 83
4.5.7.1
Breast Imaging ...................................................................... 83
4.5.7.2
Tumor Staging....................................................................... 83
4.5.8
Cardiac Function ................................................................... 84
4.5.9
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 84
4.5.9.1
PK Sampling.......................................................................... 86
4.5.10
Clinical Tumor Response Evaluations ................................... 87
4.5.11
Pathologic Response Evaluation........................................... 88
4.5.12
Diagnosis of Breast Cancer Progression or 
Recurrence............................................................................ 89
4.5.13
Optional Samples for Research Biosample 
Repository ............................................................................. 92
4.5.13.1
Overview of the Research Biosample Repository.................. 92


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4.5.13.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 93
4.5.13.3
Sample Collection.................................................................. 93
4.5.13.4
Confidentiality........................................................................ 93
4.5.13.5
Consent to Participate in the Research 
Biosample Repository............................................................ 94
4.5.13.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 94
4.5.13.7
Monitoring and Oversight....................................................... 95
4.6
Timing of Assessments.......................................................... 95
4.6.1
Procedures for Enrollment of Eligible Patients....................... 95
4.6.2
Assessments During Treatment ............................................ 95
4.6.3
Assessments at the Treatment 
Completion/Discontinuation Visit ........................................... 96
4.6.4
Follow-Up Assessments ........................................................ 96
4.7
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 97
4.7.1
Study Treatment Discontinuation........................................... 97
4.7.2
Patient Discontinuation from Study........................................ 98
4.7.3
Study Discontinuation............................................................ 98
4.7.4
Site Discontinuation............................................................... 99
5
ASSESSMENT OF SAFETY....................................................................... 99
5.1
Safety Plan ............................................................................ 99
5.1.1
Risks Associated with Perjeta................................................ 99
5.1.1.1
Hypersensitivity Reactions/Anaphylaxis and 
Administration Related Reactions (Infusion or 
Injection)................................................................................ 99
5.1.1.2
Symptomatic Left Ventricular Systolic 
Dysfunction.......................................................................... 101
5.1.1.3
Epidermal Growth Factor Receptor (HER1)-
Related Toxicities ................................................................ 102
5.1.2
Risks Associated with Herceptin.......................................... 103
5.1.2.1
Administration-Related Reactions, Allergic-Like 
Reactions, and Hypersensitivity........................................... 103
5.1.2.2
Pulmonary Events ............................................................... 104


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5.1.2.3
Symptomatic Left Ventricular Systolic 
Dysfunction.......................................................................... 104
5.1.3
Pregnancy and Contraception (Risks Associated 
with Both Perjeta and Herceptin .......................................... 105
5.1.3.1
Breastfeeding ...................................................................... 107
5.1.4
Warnings and Precautions for Docetaxel, 
Paclitaxel, Doxorubicin, and Cyclophosphamide................. 107
5.1.5
Warnings and Precautions for Anti-Estrogen 
Therapy and Radiotherapy .................................................. 107
5.2
Management of Patients Who Experience 
Specific Adverse Events...................................................... 107
5.2.1
Dose Delays, Discontinuation, and Modifications 
(General) ............................................................................. 107
5.2.2
Dose Delays and Modifications for Perjeta IV, 
Herceptin IV, Herceptin SC, and the FDC ........................... 108
5.2.3
Dose Delays and Modifications for Anthracycline-
Based Chemotherapy (ddAC and AC)................................. 108
5.2.4
Dose Delays and Modifications for Taxanes 
(Docetaxel and Paclitaxel)................................................... 108
5.2.5
Management Guidelines...................................................... 114
5.2.5.1
Symptomatic LVSD and/or LVEF Decline............................ 115
5.2.5.2
Hypersensitivity/Anaphylaxis and Administration-
Related Reactions (Infusion or Injection)............................. 116
5.2.5.3
EGFR-Related Toxicities ..................................................... 117
5.3
Safety Parameters and Definitions ...................................... 117
5.3.1
Adverse Events ................................................................... 118
5.3.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 118
5.3.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 119
5.3.4
Selected Adverse Events..................................................... 119
5.3.4.1
Heart Failure........................................................................ 119
5.3.4.2
Asymptomatic Declines in Left Ventricular 
Ejection Fraction.................................................................. 120
5.3.4.3
Administration-Related Reactions:  Infusion-
Related Reactions, Injection-Related Reactions, 
and Injection Site Reactions ................................................ 121


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5.4
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 122
5.4.1
Adverse Event Reporting Period ......................................... 122
5.4.2
Eliciting Adverse Event Information..................................... 123
5.4.3
Assessment of Severity of Adverse Events ......................... 123
5.4.4
Assessment of Causality of Adverse Events ....................... 123
5.4.5
Procedures for Recording Adverse Events.......................... 124
5.4.5.1
Diagnosis versus Signs and Symptoms............................... 124
5.4.5.2
Adverse Events That are Secondary to Other 
Events.................................................................................. 125
5.4.5.3
Persistent or Recurrent Adverse Events.............................. 125
5.4.5.4
Abnormal Laboratory Values ............................................... 126
5.4.5.5
Abnormal Vital Sign Values ................................................. 126
5.4.5.6
Abnormal Liver Function Tests............................................ 127
5.4.5.7
Deaths ................................................................................. 127
5.4.5.8
Preexisting Medical Conditions............................................ 128
5.4.5.9
Lack of Efficacy or Worsening of Breast Cancer ................. 128
5.4.5.10
Hospitalization or Prolonged Hospitalization........................ 128
5.4.5.11
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 129
5.5
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 129
5.5.1
Emergency Medical Contacts.............................................. 130
5.5.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 130
5.5.2.1
Events That Occur prior to Study Drug Initiation.................. 130
5.5.2.2
Events That Occur after Study Drug Initiation...................... 130
5.5.3
Reporting Requirements for Pregnancies............................ 131
5.5.3.1
Pregnancies in Female Patients.......................................... 131
5.5.3.2
Pregnancies in Female Partners of Male Patients............... 131
5.5.3.3
Abortions ............................................................................. 132
5.5.3.4
Congenital Anomalies/Birth Defects .................................... 132
5.6
Follow-Up of Patients After Adverse Events........................ 132
5.6.1
Investigator Follow-Up......................................................... 132


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5.6.2
Sponsor Follow-Up .............................................................. 133
5.7
Adverse Events That Occur After the End of the
Study .................................................................................. 133
5.8
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 133
6
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 134
6.1
Analysis Populations ........................................................... 134
6.1.1
Per Protocol PK Analysis Population................................... 134
6.1.2
Intent-to-Treat Population.................................................... 134
6.1.3
Safety Analysis Population .................................................. 134
6.2
Determination of Sample Size ............................................. 134
6.3
Primary Analysis.................................................................. 135
6.4
Secondary Analyses............................................................ 135
6.4.1
PK Analyses ........................................................................ 135
6.4.2
Efficacy Analyses ................................................................ 136
6.4.3
Safety Analyses................................................................... 137
6.5
Exploratory Analyses........................................................... 139
6.5.1
PK Analyses ........................................................................ 139
6.5.2
Efficacy Analyses ................................................................ 140
6.5.3
Immunogenicity Analyses.................................................... 140
141
6.6
Interim and Final Analyses................................................. 141
6.7
Summaries of Conduct of Study.......................................... 141
6.8
Summaries of Demographic and Baseline 
Characteristics..................................................................... 141
7
DATA COLLECTION AND MANAGEMENT ............................................. 141
7.1
Data Quality Assurance....................................................... 141
7.2
Electronic Case Report Forms............................................. 142
7.3
Source Data Documentation................................................ 142
7.4
Use of Computerized Systems ............................................ 143
7.5
Retention of Records........................................................... 143
8
ETHICAL CONSIDERATIONS.................................................................. 143


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8.1
Compliance with Laws and Regulations .............................. 143
8.2
Informed Consent................................................................ 144
8.3
Institutional Review Board or Ethics Committee.................. 145
8.4
Confidentiality...................................................................... 145
8.5
Financial Disclosure ............................................................ 146
9
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 146
9.1
Study Documentation .......................................................... 146
9.2
Protocol Deviations.............................................................. 146
9.3
Site Inspections ................................................................... 147
9.4
Administrative Structure....................................................... 147
9.5
Dissemination of Data and Protection of Trade
Secrets ................................................................................ 148
9.6
Protocol Amendments ......................................................... 149
10
REFERENCES ......................................................................................... 150


Table 1 
Table 2 
Table 3 
Table 4 
Table 5 
Table 6 
Table 7 
Table 8 
Table 9 
Table 10 
Table 11 
Table 12 
Figure 1 
Figure 2 
Figure 3 
Appendix 1 
Appendix 2 
Appendix 3 
Appendix 4 
-
-
LIST OF TABLES 
Overview of Key Studies of Neoadjuvant Perjeta in HER2-
Positive Early Breast Cancer ...................................................... 35 
Study Objectives and Endpoints ................................................. 46 
Menopausal Status Definitions .................................................... 77 
Recommendations for Hormone Therapy for Female 
Patients ....................................................................................... 77 
Dose Levels for Docetaxel/Paclitaxel. ....................................... 108 
Dose Modifications for Taxane-Related Neurosensory 
Toxicity ...................................................................................... 11 O 
Dose Modifications for Taxane Musculoskeletal Pain Not 
Controlled by Analgesics .......................................................... 111 
Dose Modifications and Delays for Docetaxel/Paclitaxel 
Alone ......................................................................................... 112 
Reporting Conventions for Left Ventricular Systolic 
Dysfunction/Congestive Heart Failure ....................................... 121 
Reporting Conventions for Infusion-Related Reactions, 
Injection-Related Reactions and Injection-Site Reactions ......... 122 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 123 
Causal Attribution Guidance ..................................................... 124 
LIST OF FIGURES 
Study BO30185 Schema ............................................................ 41 
Study Schema ............................................................................. 53 
HER2 Screening Procedure ........................................................ 82 
LIST OF APPENDICES 
Schedule of Activities for Patients Receiving AC 
Q3W➔Docetaxel in the Neoadjuvant Phase ............................ 156 
Schedule of Activities for Patients Receiving ddAC 
O2W ➔ Paclitaxel in the Neoadjuvant Phase ............................. 162 
Schedule of Activities for All Patients in the Adjuvant 
Pertuzumab and Trastuzumab Treatment Phase ..................... 168 
Schedule of Activities for All Patients in the Treatment-Free 
Follow-U .................................................................................. 172 
174 
176 
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Appendix 7
ECOG Performance Status....................................................... 179
Appendix 8
Asymptomatic Decline in LVEF:  Algorithm for Continuation
and Discontinuation of HER2-Targeted Study Medication........ 180
Appendix 9
NYHA Functional Classification System for Heart Failure and 
LVSD National Cancer Institute Common Terminology 
Criteria for Adverse Events Version 4 Grading ......................... 181
Appendix 10
Pathology Manual ..................................................................... 182
Appendix 11
Radiotherapy Guidelines........................................................... 197
Appendix 12
Precision for Different tpCR Rates (N=500).............................. 200


SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
14/Protocol WO40324, Version 2
PROTOCOL ACCEPTANCE FORM
TITLE:
A PHASE III, RANDOMIZED, MULTICENTER, 
OPEN-LABEL, TWO-ARM STUDY TO EVALUATE 
THE PHARMACOKINETICS, EFFICACY, AND 
SAFETY OF SUBCUTANEOUS ADMINISTRATION 
OF THE FIXED-DOSE COMBINATION OF 
PERTUZUMAB AND TRASTUZUMAB IN 
COMBINATION WITH CHEMOTHERAPY IN 
PATIENTS WITH HER2-POSITIVE EARLY BREAST 
CANCER
PROTOCOL NUMBER:
WO40324
VERSION NUMBER:
2
EUDRACT NUMBER:
2017-004897-32
IND NUMBER:
131009
TEST PRODUCT:
Fixed-dose combination (FDC) of pertuzumab and 
trastuzumab for subcutaneous administration
(RO7198574)
MEDICAL MONITOR:
, M.D., Ph.D.
, B.Sc.
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 by your local study monitor.


SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
15/Protocol WO40324, Version 2
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, RANDOMIZED, MULTICENTER, OPEN-LABEL, TWO-
ARM STUDY TO EVALUATE THE PHARMACOKINETICS, 
EFFICACY, AND SAFETY OF SUBCUTANEOUS 
ADMINISTRATION OF THE FIXED-DOSE COMBINATION OF 
PERTUZUMAB AND TRASTUZUMAB IN COMBINATION WITH 
CHEMOTHERAPY IN PATIENTS WITH HER2-POSITIVE EARLY 
BREAST CANCER
PROTOCOL NUMBER:
WO40324
VERSION NUMBER:
2
EUDRACT NUMBER:
2017-004897-32
IND NUMBER:
131009
TEST PRODUCT:
Fixed-dose combination (FDC) of pertuzumab and trastuzumab for 
subcutaneous administration (RO7198574)
PHASE:
Phase III
INDICATION:
HER2-positive Early Breast Cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the pharmacokinetics, efficacy, and safety of the fixed-dose combination 
(FDC) of pertuzumab and trastuzumab for SC administration compared with the Perjeta IV and 
Herceptin IV formulations in patients with HER2-positive early breast cancer (EBC).
Specific objectives and corresponding endpoints for the study are outlined below.
Primary Objective
Corresponding Endpoint
To demonstrate the non-inferiority of 
the Cycle 7 (pre-dose Cycle 8) serum 
pertuzumab Ctrough of pertuzumab SC 
within the FDC compared with Perjeta 
IV 
Serum pertuzumab Ctrough during Cycle 7 (pre-dose 
Cycle 8) 
Secondary Pharmacokinetic Objective
Corresponding Endpoint
To demonstrate the non-inferiority of 
the Cycle 7 (pre-dose Cycle 8) serum 
trastuzumab Ctrough of trastuzumab SC 
within the FDC compared with 
Herceptin IV
Serum trastuzumab Ctrough during Cycle 7 (pre-dose 
Cycle 8) 


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16/Protocol WO40324, Version 2
Secondary Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of the SC FDC 
of pertuzumab and 
trastuzumab chemotherapy compared 
with Perjeta IV and Herceptin 
IV chemotherapy
tpCR, defined as eradication of invasive disease in 
the breast and axilla (i.e., ypT0/isypN0), according to 
local pathologist assessment
iDFS, defined as the time from the first date of no 
disease (i.e., the date of primary surgery) to the first 
occurrence of one of the following events:
- Ipsilateral invasive breast tumor 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)
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 PD or relapse.
iDFS, including second primary non-breast cancer, 
defined in the same way as iDFS but including second 
primary non-breast invasive cancer as an event (with 
the exception of non-melanoma skin cancers and in 
situ carcinoma of any site)
EFS, defined as the time from enrollment to the first 
occurrence of one of the following events:
- Breast cancer progression (PD)
- Breast cancer recurrence (as defined for iDFS 
endpoint)
- Death from any cause
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 PD or relapse.
EFS, including second primary non-breast cancer is 
defined in the same way as EFS, but including second 
primary non-breast invasive cancer as an event (with 
the exception of non-melanoma skin cancers and in 
situ carcinoma of any site)
DRFI, defined as the time between randomization and 
the date of distant breast cancer recurrence
OS, defined as the time from randomization to death 
from any cause


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17/Protocol WO40324, Version 2
Secondary Safety Objective
Corresponding Endpoints
To evaluate the safety of the SC FDC of 
pertuzumab and trastuzumab compared 
with Perjeta IV and Herceptin IV
Incidence and severity of adverse events and SAEs, 
with severity determined according to NCI CTCAE v4 
Laboratory test abnormalities according to NCI 
CTCAE v4
Primary cardiac endpoints
Incidence of a symptomatic ejection fraction decrease 
(“Heart failure”) of NYHA Class III or IV and a drop in 
LVEF of at least 10-percentage points from baseline 
and to below 50%
Cardiac death, defined as one of the following:

Definite cardiac death, defined as death due to 
heart failure, myocardial infarction, or documented
primary arrhythmia

Probable cardiac death, defined as sudden 
unexpected death within 24 hours of a definite or 
probable cardiac event (e.g., syncope, cardiac arrest, 
chest pain, infarction, arrhythmia) without 
documented etiology
Secondary cardiac endpoint
Incidence of an asymptomatic or mildly symptomatic
left ventricular systolic dysfunction (“Ejection fraction 
decreased”) of NYHA Class II, defined as an LVEF 
decrease of 10-percentage points below the 
baseline measurement to an absolute LVEF value of 
50%, confirmed by a second assessment within 
approximately 3 weeks confirming a decrease of 10-
percentage points below the baseline measurement 
and to an absolute LVEF value of 50%
Exploratory Pharmacokinetic 
Objectives
Corresponding Endpoints
To characterize the pharmacokinetics of 
pertuzumab and trastuzumab following 
administration of the SC FDC
Serum pertuzumab concentrations or PK parameters
Serum trastuzumab concentrations or PK parameters
To compare the pharmacokinetics 
(including PK parameters such as AUC 
and Cmax) following administration of the 
SC FDC versus Perjeta IV and 
Herceptin IV (in combination with 
chemotherapy) 
Serum pertuzumab concentrations or PK parameters 
during Cycle 7 (pre-dose Cycle 8)
Serum trastuzumab concentrations or PK parameters 
during Cycle 7 (pre-dose Cycle 8)
To assess the pertuzumab PK profile 
and observed Ctrough at Cycle 7 (pre-
dose Cycle 8) and Cycle 12 (post-
surgery) following FDC administration
Serum pertuzumab concentrations during Cycle 7 
(pre-dose Cycle 8) and Cycle 12 (pre-dose Cycle 13)
To compare the pertuzumab exposure 
in Cycle 1 between Perjeta IV 840 mg 
and FDC (pertuzumab SC 1200 mg)
Serum pertuzumab concentrations during Cycle 5


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18/Protocol WO40324, Version 2
Exploratory Pharmacokinetic 
Objectives (cont.)
Corresponding Endpoints (cont.)
To evaluate potential relationships 
between pertuzumab exposure and the 
efficacy and safety of the SC FDC via a
pertuzumab exposure-response 
analysis
Relationship between serum concentration or PK 
parameters for pertuzumab and efficacy endpoints
Relationship between serum concentration or PK 
parameters for pertuzumab and safety endpoints
To assess the impact of a potential PK 
DDI between pertuzumab and 
trastuzumab following administration of 
the SC FDC
Serum concentrations or PK parameters for 
pertuzumab given in combination with trastuzumab 
compared with pertuzumab given alone (based on 
historical data)
Serum concentrations or PK parameters for 
trastuzumab given in combination with pertuzumab 
compared with trastuzumab given alone (based on 
historical data)
Exploratory Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of the SC FDC 
of pertuzumab and 
trastuzumabchemotherapy compared 
with Perjeta IV and Herceptin 
IVchemotherapy
bpCR, defined as eradication of invasive disease in 
the breast (i.e., ypT0/is, ypNx)
GBG pCR, defined as eradication of invasive and in 
situ disease in the breast and invasive disease in 
axilla (i.e., ypT0 ypN0)
Clinical response, defined as CR, PR, SD, or PD, 
prior to surgery.  Tumor response will be assessed 
prior to each new cycle of therapy by clinical 
examination, mammography, and/or other methods of 
evaluation as per routine clinical practice.  Response 
will be assessed by the investigator as per routine 
clinical practice.
Exploratory Immunogenicity 
Objectives
Corresponding Endpoints
To evaluate the immune response to 
pertuzumab, trastuzumab, and 
rHuPH20 with the SC FDC compared
with Perjeta IV and Herceptin IV
Incidence of pertuzumab ADAs during the study 
relative to the prevalence of ADAs at baseline
Incidence of trastuzumab ADAs during the study 
relative to the prevalence of ADAs at baseline
Incidence of rHuPH20 ADAs during the study relative 
to the prevalence of ADAs at baseline
To evaluate potential effects of ADAs
Relationship between pertuzumab ADA status and 
efficacy, safety, or PK endpoints
Relationship between trastuzumab ADA status and 
efficacy, safety, or PK endpoints
Relationship between rHuPH20 ADA status and 
efficacy, safety, or PK endpoints


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19/Protocol WO40324, Version 2
Exploratory Biomarker Objectives
Corresponding Endpoint
To explore potential association of 
tissue-based biomarkers or biomarker 
profiles to pCR
To explore changes in biomarker levels 
or biomarker profiles pre- and post-
treatment based on tumor tissue
To assess blood-based biomarkers at 
baseline and longitudinally to explore 
changes over time and potential 
relationship to pCR and long-term 
efficacy endpoints
Presence or absence of biomarker(s) and/or 
biomarker profiles with respect to levels of certain 
biomarkers at specified timepoints and relation to 
efficacy endpoints
ADAanti-drug antibody; bpCRbreast pathologic complete response; Ctroughsteady-state 
concentration; DRFI=distant breast cancer recurrence; DDIdrug-drug interaction; EFSevent-
free survival; FDCfixed-dose combination; GBG German Breast Group; GMRgeometric mean 
ratio; HCPhealth care provider; iDFSinvasive disease-free survival; IVintravenous; LVEFleft 
ventricular ejection fraction; NCI CTCAENational Cancer Institute Common Terminology Criteria 
for Adverse Events ;OSoverall survival; pCRpathologic complete response; PDprogressive 
disease; PKpharmacokinetic; PRpartial response; SCsubcutaneous; SDstable disease; 
tpCRtotal pathological complete response.
Study Design
Description of Study
This is a global Phase III, two-arm, open-label, multicenter, randomized study to investigate the 
pharmacokinetics, efficacy, and safety of the FDC (pertuzumab and trastuzumab for SC 
administration) in combination with chemotherapy in patients with HER2-positive EBC in the 
neoadjuvant/adjuvant setting.  
The study will enroll patients with HER2-positive breast cancer consistent with the indication for 
treatment with neoadjuvant Perjeta and Herceptin and chemotherapy in routine clinical practice 
and as recommended in local guidelines.
Approximately 500 patients with HER2-positive, operable or locally advanced/inflammatory 
breast cancer with a tumor size of 2 cm or node-positive will be randomized to one of the 
following treatment arms in a 1:1 ratio:  

Arm A (Perjeta IV Herceptin IV):  Patients will receive 8 cycles of neoadjuvant 
chemotherapy.  This will include 4 cycles of ddAC every 2 weeks (Q2W) (given with 
granulocyte colony-stimulating factor [G-CSF] support as needed according to local 
guidelines) followed by paclitaxel Q1W for 12 weeks or 4 cycles of doxorubicin plus 
cyclophosphamide (AC) Q3W followed by docetaxel Q3W for 4 cycles.  Perjeta Herceptin 
will be given IV for 4 cycles (Q3W) concurrently with the taxane component of 
chemotherapy.  After completing their neoadjuvant therapy, patients will undergo surgery.  
Thereafter, patients will receive an additional 14 cycles of Perjeta IV and Herceptin IV for a 
total of 18 cycles.  One year of HER2-targeted therapy without any delays would 
encompass 18 cycles. 
After surgery (from Cycle 9 onwards), patients in Arm A will continue Perjeta IV and are 
allowed to switch from Herceptin IV to Herceptin SC, at the discretion of the investigator, in the 
countries where Herceptin SC is routinely used.


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
Arm B (FDC of pertuzumab and trastuzumab for SC administration):  Patients will receive 8 
cycles of neoadjuvant chemotherapy.  This will include 4 cycles of ddAC Q2W (given with 
granulocyte colony-stimulating factor [G-CSF] support as needed according to local 
guidelines) followed by paclitaxel Q1W for 12 weeks or 4 cycles of AC Q3W followed by 
docetaxel Q3W for 4 cycles.  FDC will be given SC for 4 cycles (Q3W) concurrently with the 
taxane component of chemotherapy.  After completing their neoadjuvant therapy, patients 
will undergo surgery.  Thereafter, patients will receive an additional 14 cycles of the FDC for 
a total of 18 cycles.  One year of HER2-targeted therapy without any delays would 
encompass 18 cycles.
The investigator will select one of the two protocol-approved neoadjuvant chemotherapy 
regimens with which to treat the patient.  Once the investigator’s choice of chemotherapy has 
been made and eligibility confirmed, the patient will be randomized to one of the two treatment 
arms using a permuted blocks randomization procedure and stratified according to the following 
factors:  

Hormonal receptor status (based on central assessment): 
–
Estrogen receptor (ER)-positive or progesterone receptor (PgR)-positive 
–
ER-negative and PgR-negative

Clinical stage at presentation:
–
Stage IIIIIA
–
Stage IIIBIIIC

Type of chemotherapy:
–
ddAC followed by paclitaxel
–
AC followed by docetaxel
A patient may only be randomized once in this trial.  Patients randomized into the study will not 
be replaced.  Patients who choose to withdraw after screening, but before randomization, will be 
replaced.
Number of Patients
Approximately 500 patients with centrally confirmed HER2-positive, Stage IIIIIC breast cancer 
with a tumor size of 2 cm, or node-positive disease (clinically or on imaging and node 
positivity confirmed with cytology and/or histopathology) will be randomized in this study.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

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 (ECOG) Performance Status 1

Female and male patients with Stage IIIIIC (T2T4 plus any N, or any T plus N13, M0),
locally advanced, inflammatory, or early-stage, unilateral, and histologically confirmed 
invasive breast cancer
Patients with inflammatory breast cancer must be able to have a core-needle biopsy

Primary tumor 2 cm in diameter, or node-positive disease (clinically or on imaging, and
node positivity confirmed with cytology and/or histopathology)

HER2-positive breast cancer confirmed by a central laboratory prior to study enrollment. 
HER2-positive status will be determined based on pretreatment breast biopsy material and 
defined as 3+ by 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 signals for 
chromosome 17 copies
Patients with multifocal tumors (more than one tumor confined to the same quadrant as 
the primary tumor) are eligible provided at least one focus is sampled and centrally 
confirmed as HER2 positive. 


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
Hormone receptor status of the primary tumor, centrally confirmed
Hormone receptor-positive status can be determined by either known ER-positive 
and/or known PgR-positive status. Hormone receptor-negative status must be 
determined by both known ER-negative and known PgR-negative status

Patient agreement to undergo mastectomy or breast conserving surgery after neoadjuvant 
therapy 

Availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue block for central 
confirmation of HER2 and hormone receptor status and additional biomarker research (e.g., 
PIK3CA mutational analyses)

Baseline LVEF 55% measured by echocardiogram (ECHO) or multiple-gated acquisition 
scan (MUGA)

For women of childbearing potential (WOCBP) who are sexually active: agreement to 
remain abstinent (refrain from heterosexual intercourse) or use one highly effective non-
hormonal contraceptive method with a failure rate of 1% per year, or two effective non-
hormonal contraceptive methods during the treatment period and for 7 months after the last 
dose of HER2-targeted therapy, and agreement to refrain from donating eggs during this 
same period
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
Examples of highly effective 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).
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 postovulation methods) and withdrawal 
are not acceptable methods of contraception (see Section 5.1.3).

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom in combination with a spermicidal foam, gel, film, cream, or suppository, 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 with a spermicidal product during the treatment 
period and for 7 months after the last dose of HER2-targeted therapy 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 postovulation methods) and withdrawal 
are not acceptable methods of contraception (see section 5.1.3).

A negative serum pregnancy test must be available prior to randomization for WOCBP 
(premenopausal women and women 12 months after the onset of menopause), unless 
they have undergone surgical sterilization (removal of ovaries and/or uterus)

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
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Stage IV (metastatic) breast cancer 

Patients with a history of invasive breast cancer


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
Patients with a history of concurrent or previously treated non-breast malignancies except 
for appropriately treated 1) non-melanoma skin cancer and/or 2) in situ carcinomas, 
including cervix, colon, and skin
A patient with previous invasive non-breast cancer is eligible provided he/she has been 
disease free for more than 5 years.

Patients who have received any previous systemic therapy (including chemotherapy,
immunotherapy, HER2-targeted agents, endocrine therapy (selective estrogen receptor 
modulators, aromatase inhibitors, and antitumor vaccines) for treatment or prevention of 
breast cancer, or radiation therapy for treatment of cancer

Patients who have a past history of ductal carcinoma in situ (DCIS) or lobular carcinoma in 
situ (LCIS) if they have received any systemic therapy for its treatment or radiation therapy 
to the ipsilateral breast
Patients are allowed to enter the study if treated with surgery alone.

Patients with high-risk for breast cancer who have received chemopreventative drugs in the 
past are not allowed to enter the study

Patients with multicentric (multiple tumors involving more than one quadrant) breast cancer, 
unless all tumors are HER2-positive

Patients with bilateral breast cancer

Patients who have undergone an excisional biopsy of primary tumor and/or axillary lymph 
nodes

Axillary lymph node dissection (ALND) prior to initiation of neoadjuvant therapy
Patients with clinically negative axilla (by physical examination and radiographic 
imaging) may undergo a core or needle biopsy procedure prior to neoadjuvant systemic 
therapy if in keeping with local practice

Sentinel lymph node biopsy (SLNB) prior to neoadjuvant therapy

Treatment with any investigational drug within 28 days prior to randomization 

Serious cardiac illness or medical conditions including, but not confined to, the following:
–
History of NCI CTCAE (v4) 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 2] or third-
degree AV-block)
–
Serious cardiac arrhythmia not controlled by adequate medication, severe conduction 
abnormality 
–
Angina pectoris requiring anti-anginal medication
–
Clinically significant valvular heart disease
–
Evidence of transmural infarction on ECG
–
Evidence of myocardial infarction within 12 months prior to randomization  
–
Poorly controlled hypertension (e.g., systolic 180 mm Hg or diastolic 100 mmHg)

Inadequate bone marrow function, defined as: 
–
Absolute neutrophil count 1.5 109/L
–
Platelet count 100 109/L 
–
Hemoglobin 9 g/dL 

Impaired liver function, defined as:
–
Serum (total) bilirubin 1.25 upper limit of normal (ULN)
In case of Gilbert’s syndrome: a total bilirubin of 2 ULN is permitted.
–
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 1.25 ULN


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–
Albumin 25 g/L

Inadequate renal function with serum creatinine 1.5 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 7 
months after the last dose of HER2-targeted therapy
Women of childbearing potential must have a negative serum pregnancy test result within 
7 days prior to initiation of study drug.

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 HIV

Known hypersensitivity to study drugs, excipients, and/or murine proteins

Current chronic daily treatment with corticosteroids (dose 10 mg methylprednisolone or 
equivalent excluding inhaled steroids)

History of other malignancy within 5 years prior to screening, except for appropriately 
treated carcinoma in situ of the cervix, colon, skin, and/or non-melanoma skin carcinoma

History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as 
structural heart disease (e.g., severe LVSD, left ventricular hypertrophy), coronary heart 
disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically 
significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), 
or family history of sudden unexplained death or long QT syndrome
End of Study
The end of the study is expected to occur approximately 4.5 years after the last patient is 
randomized to the study.  The end of the study is defined as the date when the last patient, last 
visit (LPLV) occurs or the date at which the last data point required for statistical analysis or 
safety follow-up is received from the last patient (or when all patients have died or the trial is 
terminated by the Sponsor, whichever is earliest).  
Length of Study
The total length of the study, from screening of the first patient to the end of the study is 
expected to be approximately 5.5 years.
Investigational Medicinal Products
The investigational medicinal products (IMPs) for this study are Perjeta® IV, Herceptin® IV, 
Herceptin® SC and the SC FDC of pertuzumab and trastuzumab.
Test Product (Investigational Drug)
For patients randomized to receive the FDC SC, the FDC is given as a fixed nonweight-based 
dose.  A loading dose of 1200 mg SC pertuzumab and 600 mg SC trastuzumab is then followed 
by 600 mg SC pertuzumab and 600 mg SC trastuzumab Q3W.  Chemotherapy should be given 
after the FDC.
After surgery, patients continue to receive the FDC in the adjuvant setting until a total of 18 
cycles of the FDC have been administered during the study.  Adjuvant FDC treatment should 
not start until at least 2 weeks after surgery. If the interval between the first dose of adjuvant 
FDC and the last dose of neoadjuvant FDC is 6 weeks, a reloading dose of FDC (1200 mg of 
pertuzumab and 600 mg of trastuzumab) is required. Subsequent maintenance FDC doses 
(600 mg pertuzumab and 600 mg trastuzumab) will then be given Q3W, starting 3 weeks later.  
The interval between the last dose of neoadjuvant FDC and the first dose of adjuvant FDC 
should be 9 weeks.


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Comparator
For patients randomized to receive the IV formulations of Perjeta and Herceptin, Perjeta is given 
as a fixed nonweight-based dose of 840-mg IV loading dose and then 420-mg IV Q3W.  
Herceptin is given as an 8-mg/kg IV loading dose and then 6 mg/kg IV Q3W.  The order of 
administration of Perjeta and Herceptin is according to investigator preference.  Chemotherapy 
should be given after Perjeta and Herceptin.
After surgery, patients continue to receive Perjeta and Herceptin in the adjuvant setting until a 
total of 18 cycles of Perjeta and Herceptin have been administered during the study
(neoadjuvant and adjuvant).  Adjuvant Perjeta and Herceptin treatment should not start until 2 
weeks after surgery. If the interval between the first dose of adjuvant Perjeta and Herceptin and 
the last dose of neoadjuvant Perjeta and Herceptin exceeds 6 weeks, a reloading dose of 840 
mg of Perjeta and 8 mg/kg of Herceptin is required. The interval between the last dose of 
neoadjuvant Perjeta and Herceptin and the first dose of adjuvant Perjeta and Herceptin should 
be 9 weeks.
Non-Investigational Medicinal Products
Doxorubicin, cyclophosphamide, paclitaxel, docetaxel, G-CSF, and adjuvant hormone therapy 
are administered in accordance with local prescribing information and these drugs are not 
regarded as IMPs.  These drugs will be obtained locally by the investigational sites or will be 
provided by the Sponsor as per country requirements.
Statistical Methods
Primary Analysis
The primary endpoint of this study is observed pertuzumab trough concentration (Ctrough) at 
Cycle 7 (i.e., the measured pre-dose concentration value at Cycle 8), following 3 cycles of 
Perjeta IV and Herceptin IV or FDC (pertuzumab and trastuzumab SC).  Pertuzumab Ctrough
will be analyzed at the time of the primary analysis, which will occur after the last patient has 
completed (all) neoadjuvant therapy and has undergone surgery. 
The non-inferiority of the SC and IV dose of pertuzumab will be assessed by a one-sided testing 
procedure. The CtroughSC/CtroughIV GMR of the SC dose of pertuzumab relative to the IV dose 
will be estimated together with the two-sided 90% CI based on the log-transformed trough 
concentration values. The null hypothesis will be rejected and non-inferiority will be concluded if 
the lower bound of the 90% CI of the GMR is 0.8.
Determination of Sample Size  
The study is designed to have at least 80% power to demonstrate non-inferiority of the Cycle 7 
(i.e., pre-dose Cycle 8) pertuzumab serum Ctrough from pertuzumab SC within FDC to the Perjeta 
IV formulation in patients with HER2-positive EBC. 
The hypothesis to be tested for the primary endpoint, observed pertuzumab Ctrough, is:

H0:  The SC dose is inferior to the IV dose (i.e., the CtroughSC/CtroughIV GMR of the SC dose 
of pertuzumab relative to the IV dose is not greater than 0.8) versus

H1:  The SC dose is non-inferior to the IV dose (i.e., CtroughSC/CtroughIV GMR of the SC dose 
of pertuzumab relative to the IV dose is equal to or greater than 0.8)
The null-hypothesis will be rejected if the lower bound of the 90% CI for the GMR is equal or 
greater than 0.8.
PK sample size calculations are based on the coefficient of variation (CV)% for the Ctrough of 
trastuzumab observed from previous studies in MBC and EBC patients after Q3W treatment. 
With a CV of 60% assumed, a minimum or 130 patients per arm (i.e., a total of 260 patients) is 
needed to demonstrate Ctrough non-inferiority with a power of 80% if the true means of the two 
formulations do not differ by more than 5%. An additional 240 patients will also be recruited to 
provide a substantial database to assess tpCR and safety profile comparability. Therefore, a 
total of approximately 500 patients (~250 patients per arm) will provide a sufficient sample size 
to test the primary PK hypothesis and also assess efficacy and safety profile comparability. 
A hierarchical testing procedure for key secondary endpoints will be used to control the overall 
type I error rate at a one-sided 5% significance level.


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Interim And Final Analyses
No formal, statistical interim analyses are planned prior to the primary analysis.  
The final analysis will occur 3 years after the last patients last treatment.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AC
doxorubicin (Adriamycin®) plus cyclophosphamide
ADA
anti-drug antibody
ADCC
antibody-dependent cell-mediated cytotoxicity
ALND
axillary lymph node dissection
ARDS
acute respiratory distress syndrome
ARR
administration-related reaction
ASCO
American Society of Clinical Oncology
AUC
area under the concentrationtime curve
AV
atrioventricular
BSA
body surface area
BCS
Breast Conserving Surgery
bpCR
breast pathologic complete response
CBE
clinical breast examination
CHF
congestive heart failure
CISH
chromogenic in situ hybridization
Cmax
maximum serum concentration
Cmin
minimum serum concentration
CR
complete response
CT 
computed tomography (scan)
Ctrough
steady-state concentration at the end of a dosing 
interval (i.e., just prior to next drug administration)
CV
coefficient of variation
DCIS
ductal carcinoma in situ
dd
dose-dense
ddAC
dose-dense doxorubicin (Adriamycin®) plus 
cyclophosphamide
DDI
drug-drug interaction
DFS
disease-free survival
DRFI
EBC
distant recurrence-free inverval
early breast cancer
EC
Ethics Committee
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form


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EDC
electronic data capture
EFS
event-free survival
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
ER
estrogen receptor
ESMO
European Society for Medical Oncology
FDA
Food and Drug Administration
FDC
fixed-dose combination of pertuzumab and 
trastuzumab for SC administration
FEC
5-fluorouracil, epirubicin, and cyclophosphamide
FFPE
formalin-fixed paraffin-embedded
FISH
fluorescent in situ hybridization
GBG
German Breast Group
G-CSF
granulocyte colony-stimulating factor
GLP
Good Laboratory Practice
GMR
geometric mean ratio
HCP
healthcare provider
GnRH
gonadotropin-releasing hormone
H
Herceptin (trastuzumab)
HER2
human epidermal growth factor receptor 2
HR
hazard ratio
HIPAA
Health Insurance Portability and Accountability Act
HMV
healthy male volunteer
HR
hazard ratio
ICH
International Council for Harmonization
iDFS
invasive disease-free survival
iDCC
independent Data Cooridinating Center
iDMC
independent Data Monitoring Committee
IMP
investigational medicinal product
IHC
immunohistochemistry
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
ISH
in situ hybridization
ISR
injection-site reaction
ITT
intent-to-treat (population)
IUD
intrauterine device
IxRS
interactive voice or web-based response system


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LCIS
lobular carcinoma in situ
LPLV
last patient, last visit
LVEF
left ventricular ejection fraction
LVSD
left ventricular systolic dysfunction
MBC
metastatic breast cancer
MRI
magnetic resonance imaging
MUGA
multiple-gated acquisition (scan)
NCCN
National Comprehensive Cancer Network
NCI CTCAE
National Cancer Institute Common Terminology Criteria 
for Adverse Events
NYHA
New York Heart Association
OS
overall survival
pCR
pathological complete response
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PgR
progesterone receptor
PI3K
phosphoinositide 3-kinase
PK
pharmacokinetic
popPK
population PK
PR
partial response
PVC
polyvinyl chloride
QW
once a week
Q2W
every 2 weeks
Q3W
every 3 weeks
RBR
Research Biosample Repository
rHuPH20
recombinant human PH20 hylauronidase
SAP
Statistical Analysis Plan
SD
stable disease
SID
single-use injection device
SISH
silver in situ hybridization
SLNB
sentinel lymph node biopsy
SMQ
Standardised MedDRA Query
SOC
System Organ Class
TCH
docetaxel (Taxotere), cyclophosphamide, and 
trastuzumab (Herceptin) 
tpCR
total pathological complete response


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TTE
time-to-event
ULN
upper limit of normal
WOCBP
women of childbearing potential
WES
whole exome sequencing
WGS
whole genome sequencing


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1
BACKGROUND
1.1
BACKGROUND ON HER2-POSITIVE BREAST CANCER
Breast cancer is the second most common invasive malignancy and the most common 
form of cancer in women (Ferlay et al. 2015).  Approximately 20% of breast cancers 
strongly overexpress human epidermal growth factor receptor 2 (HER2). This is usually 
the result of amplification of the gene encoding HER2, which is found on chromosome 
17 (Wolff et al. 2007). HER2 belongs to the family of human epidermal growth factor 
receptors (HER) (which also includes HER1 [also known as epidermal growth factor 
receptor (EGFR)], HER3, and HER4) that mediate normal cell growth, survival, and 
differentiation (for details, see the Herceptin and PerjetaInvestigator’s Brochures). 
These receptors may be activated by external ligands and by dimerization with other 
HER family members. HER2 activity is mediated by homodimerization (with other HER2 
receptors) or heterodimerization (with other HER family receptors), leading to activation 
of multiple intracellular signaling pathways, including the phosphoinositide 3-kinase 
(PI3K)/Akt and RAS/Raf/mitogen-activated protein kinase (MAPK) pathways (Olaylioye 
et al. 2000). In the case of HER2, activation may also be achieved by proteolytic 
cleavage of the extracellular domain (shedding) to leave an activated truncated internal 
domain. HER2 is also known to play a role in the normal development of myocardial 
tissue and in the repair of damaged myocardium (Sawyer et al. 2002; Timolati et al. 
2006; Zhao et al. 2006).
Primary breast cancers with HER2 amplification and overexpression were found to have 
a poor prognosis, including a greater risk of relapse and shortened survival, compared 
with tumors without this abnormality (Slamon et al. 1987, 1989; Toikkanen et al. 1992; 
Andrulis et al. 1998; Pauletti et al. 2000; Rubin and Yarden 2001).  Breast cancers that 
overexpress HER2 have been shown to be susceptible to treatment with the anti-HER2 
monoclonal antibody, trastuzumab (Herceptin®), as well as other HER2-targeted agents, 
including pertuzumab (rhuMAb 2C4; Perjeta®), trastuzumab emtansine (T-DM1; 
Kadcyla®), lapatinib (Tykerb®; Tyverb®), and neratinib (Nerlynx®).
The combination of Perjeta with Herceptin and chemotherapy has become standard of 
care for treating HER2-positive early and metastatic breast cancer (Coates et al. 2015; 
Cardoso et al. 2014; Gradisher et al. 2016).
F. Hoffman-La Roche (hereafter referred to as Roche) has developed a new product 
combining pertuzumab and trastuzumab in one fixed-dose combination for SC injection 
(hereafter referred to as “the FDC”).  The FDC is a ready-to-use formulation of 
pertuzumab and trastuzumab co-formulated with recombinant human PH20 
hylauronidase (rHuPH20) developed to improve dispersion of large volumes of drugs 
when administered subcutaneously (i.e., it functions as a permeation enhancer).
In this Phase III neoadjuvant/adjuvant study, the FDC will be compared to Perjeta and 
Herceptin IV formulations in patients with HER2-positive early breast cancer (EBC). 


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Neoadjuvant and Adjuvant Therapy of Early Breast Cancer and 
Patholgoical Complete Response in Breast Cancer
Neoadjuvant therapy is given prior to surgery and was originally developed for patients 
with large or inoperable tumors to enable definitive surgery to be performed. Studies 
comparing adjuvant with neoadjuvant systemic therapy for breast cancer have shown no 
difference in the rates of death, disease progression, or disease recurrence relative to 
the timing of the systemic therapy (Mauri et al. 2005; Bear et al. 2006). Accordingly, 
neoadjuvant therapy is now also used in selected patients with operable EBC (see 
National Comprehensive Cancer Network [NCCN], European Society for Medical 
Oncology [ESMO], St Gallen, and other international guidelines [Berruti et al. 2011; 
Harbeck et al. 2013; Senkus et al. 2013; Theriault et al. 2013]). Aside from the potential 
clinical benefits that are achieved by down-staging, neoadjuvant therapy allows direct 
and early observation of the response to treatment (Gralow et al. 2008).  Numerous 
studies and meta-analyses have demonstrated that the burden of pathologically 
detected residual disease after neoadjuvant chemotherapy is associated with long-term 
prognosis. Typically, these studies showed that achieving pathological complete 
response (pCR) following neoadjuvant therapy is associated with a significantly 
decreased risk of disease recurrence and improvement in survival across the various 
breast cancer subtypes, including HER2-positive breast cancer (Cortazar et al. 2014;
Broglio et al. 2016; Spring et al. 2016). Therefore, pCR is considered a surrogate 
marker for survival outcomes as newer, targeted therapies are evaluated in the 
neoadjuvant setting (Mazouni et al. 2007; Symmans et al. 2007).
Several studies have evaluated Perjeta- and Herceptin-based neoadjuvant regimens in 
patients with HER2-positive breast cancer.  An overview of key neoadjuvant studies in 
HER2-positive EBC with Perjeta and Herceptin including pCR rates in the Perjeta + 
Herceptin arm only is provided in Table 1.  Although these studies differ with regard to 
the type of chemotherapy, the number of cycles, the administration of Perjeta and 
Herceptin (i.e., concurrent with the beginning of chemotherapy or starting with the 
taxane component of regimen), overall, patients with all tumor and nodal stages of 
HER2-positive, EBC had a higher pCR rate with Perjeta-containing therapy than control 
groups without Perjeta. Based on data from two neoadjuvant Phase II studies
(NEOSPHERE and TRYPHAENA), Perjeta was approved in combination with Herceptin 
and docetaxel as neoadjuvant therapy of HER2-positive breast cancer. The BERENICE 
study confirmed the tolerability and efficacy of Perjeta and Herceptin when combined 
with the doxorubicine containing regimen in HER2-positive EBC, establishing the safety 
of Perjeta as part of a doxorubicin-containing regimen.
In the adjuvant setting, Perjeta and Herceptin-based regimens were evaluated in a 
single, large, Phase III randomized study BO25126 (APHINITY). The study 
demonstrated that treatment with Perjeta, Herceptin and chemotherapy resulted in 
improvement in invasive disease-free survival (iDFS) compared with treatment with 
Herceptin and chemotherapy, providing confirmatory data for the benefit of Perjeta and 
Herceptin-based treatment in EBC setting.


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For details about these studies, please refer to Section 1.2.2.2.
1.2
BACKGROUND ON PERJETA, HERCEPTIN, AND RHUPH20
1.2.1
Background on Herceptin IV and Herceptin SC
Trastuzumab (Herceptin®) is a humanized monoclonal antibody directed at the HER2 
receptor.  Binding of trastuzumab to the sub-domain IV of the HER2 receptor inhibits 
ligand-independent HER2 signaling, which prevents the proteolytic cleavage of its 
extracellular domain and the subsequent constitutive activation of the associated
downstream intracellular signaling pathways.  As a result, trastuzumab has been shown, 
in both in vitro assays and in nonclinical animal models, to inhibit the proliferation of 
human tumor cells that overexpress HER2.  
Herceptin (trastuzumab) is indicated for the treatment of patients with HER2-positive
breast cancer in the neoadjuvant, adjuvant, and metastatic settings.  The addition of 
Herceptin to standard chemotherapy increases time to progressive disease (PD) or the 
length of progression-free survival (PFS) and improves overall survival (OS) when given 
with chemotherapy to women with HER2-positive breast cancer (Slamon et al. 2001; 
Romond et al. 2005).
Herceptin can also be administered subcutaneously.  Herceptin SC is approved in many 
countries as treatment for patients with HER2-positive EBC and MBC.
For a more detailed overview of nonclinical and clinical studies with Herceptin IV and 
Herceptin SC please refer to the Herceptin Investigator’s Brochure.
1.2.1.1
Nonclinical Information on Herceptin SC
For details on nonclinical studies of Herceptin SC, please refer to the Herceptin
Investigator’s Brochure.
1.2.1.2
Clinical Efficacy of Herceptin SC
Herceptin SC (formulated with rHuPH20) has been studied in several clinical trials
(BP22023, BO22227 [HannaH], MO22982 [PrefHer], and BO29159 [MetaPHer]) that 
used conventional handheld syringes and hypodermic needles to administer the study 
drug, and two studies (MO28048 [SafeHER] and BO25532) that additionally assessed 
the safety of assisted- and self-administered Herceptin SC and Herceptin SC single-use 
injection device (SID) as therapy in patients with operable HER2-positive EBC.
In the Phase Ib dose-finding study (BP22023), the dose of Herceptin SC that resulted in 
exposure comparable to that achieved with Herceptin IV was selected.  The 
pharmacokinetic (PK) modeling of fixed Herceptin SC dose selection indicated that a flat 
and a weight-based dosing strategy would result in a comparable range of exposure. A
fixed dose of 600 mg resulted in steady-state concentrations at the end of a dosing 
interval (Ctrough) values that were at least as high as the every-3-week (Q3W) IV regimen 
(i.e., 8-mg/kg loading dose followed by 6-mg/kg maintenance dose).


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In the pivotal neoadjuvant/adjuvant study BO2227 (HannaH), in which EBC patients 
were randomized to Herceptin SC or Herceptin IV with chemotherapy, non-inferiority of 
trastuzumab SC was established if the lower limit of the two-sided 90% CI of the 
geometric mean ratio (GMR) of Ctrough SC/IV was 0.8 or more.  The study showed that 
trastuzumab SC was non-inferior to trastuzumab IV in terms of Ctrough.  The GMR was 
1.33 (90% CI: 1.24, 1.44), with the lower limit of the two-sided 90% CI being greater than 
the pre-specified non-inferiority margin. The analysis of pCR (the efficacy co-primary 
endpoint) demonstrated pCR rates of 40.7% (95% CI: 34.7%, 46.9%) in the Herceptin IV 
arm and 45.4% (95% CI: 39.2%, 51.7%) in the Herceptin SC arm, a difference of 4.7 
percentage points in favor of the Herceptin SC arm.  The 4.7% (95% CI: 4.0%, 13.4%) 
pCR difference between SC and IV crossed the pre-specified non-inferiority margin of 
12.5%, demonstrating that pCR rates of Herceptin SC were non-inferior to Herceptin IV
(Ismael et al. 2012). The long-term efficacy results of the BO22227 (HannaH) study (i.e., 
6-year event-free survival [EFS] and OS) supported the established non-inferiority of 
trastuzumab SC (Jackisch et al. 2016). 
For further details on the clinical efficacy of Herceptin SC, please see the Herceptin
Investigator’s Brochure.
1.2.1.3
Clinical Safety of Herceptin SC
Data from the Herceptin SC trials show that Herceptin SC injections were generally well 
tolerated.  The safety profiles of Herceptin SC formulations are comparable and 
consistent with the known safety profile of Herceptin IV.  There were no notable 
differences in the type and frequency of all-grade adverse events across study arms.  No 
new adverse event or safety signals were identified either for Herceptin SC vial or SID
administration.  Safety and tolerability results were consistent with the known safety 
profile for Herceptin IV.
Herceptin SC has a similar cardiac safety profile to that of Herceptin IV.  Administration-
related reactions (ARRs) and hypersensitivity (such as chills and/or fever, dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, respiratory distress) have been 
frequently reported following Herceptin IV or SC administration.  These reactions were
usually mild to moderate (Grades 1 and 2) and were more common in the Herceptin SC 
arm in the BO22227 (HannaH) study.
A higher rate of anti-drug antibodies (ADAs) against trastuzumab was observed in the
BO22227 (HannaH) study for the Herceptin SC formulation compared with Herceptin IV 
(18.0% [53/295] of patients in the Herceptin SC arm vs. 11.1% [33/296] of patients in the 
Herceptin IV arm).  One patient treated with the IV formulation and 2 patients treated 
with the SC formulation developed neutralizing ADAs.  However, the higher incidence of 
ADAs in the SC arm was not associated with adverse events or altered 
pharmacokinetics (Ismael et al. 2012).


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For further details on the clinical safety of Herceptin SC, please see the Herceptin 
Investigator’s Brochure.
1.2.2
Background on Perjeta IV
Pertuzumab (Perjeta®) is a fully humanized monoclonal antibody based on the human 
IgG1 framework sequences.  It consists of two heavy chains (449 residues) and two light 
chains (214 residues).  Pertuzumab is directed against the extracellular domain of HER2.  
It binds to subdomain 2 of HER2 (Franklin et al. 2004) and prevents heterodimerization 
of HER2 with other members of the HER family (HER1, HER3, and HER4). As a result, 
pertuzumab inhibits ligand-initiated intracellular signaling supporting cell growth arrest 
and apoptosis, respectively.
Pertuzumab and trastuzumab bind to distinct epitopes on the HER2 receptor without
competing with each other and have complementary mechanisms for disrupting HER2 
signaling.  This results in augmented anti-proliferative activity in vitro and in vivo when 
pertuzumab and trastuzumab are given in combination.  Additionally, the Fc portion of 
both their IgG1 framework provides for potent activation of antibody-dependent 
cell-mediated cytotoxicity (ADCC).  In addition, in vitro, both trastuzumab and 
pertuzumab ADCC are exerted preferentially on HER2-overexpressing cancer cells 
compared with cancer cells that do not overexpress HER2.  
1.2.2.1
Nonclinical Information on Perjeta IV
For details on nonclinical studies of Perjeta IV, please refer to the Perjeta Investigator’s 
Brochure.
1.2.2.2
Clinical Pharmacokinetics of Pertuzumab
A comprehensive population PK (popPK) analysis was conducted using pertuzumab 
concentration data obtained from 481 patients across 11 Phase I/II clinical trials in a 
variety of solid tumors and the pivotal Phase III trial CLEOPATRA in MBC.  In the popPK 
analysis, pertuzumab pharmacokinetics were described by using a linear two-
compartment model with a systemic serum clearance of 0.235 L/day and a median 
terminal half-life of 18 days at doses ranging from 2.0 to 25.0 mg/kg (equivalent to 
1401750 mg for a 70-kg patient).  The model supports the use of fixed, 
non-weightbased dosing regardless of body weight, albumin, age, sex, race (Japanese 
vs. non-Japanese), laboratory variables related to hepatic and renal function, and 
disease variables in patients with MBC and other solid tumors included in the model.  
The pertuzumab pharmacokinetics observed in Study WO20697 (NEOSPHERE) and 
Study BO25126 (APHINITY) were consistent with the previous popPK model 
predictions, suggesting similarity in pertuzumab pharmacokinetics between the patient 
population included in the NEOSPHERE and APHINITY studies (patients with locally 
advanced breast cancer, inflammatory breast cancer, or EBC) and patients with 
advanced malignancies, including the first-line MBC population.


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Data from the Phase II trial WO20697 (NEOSPHERE), Phase III trial BO25126 
(APHINITY) and the Phase IIl trial WO20698/TOC4129g (CLEOPATRA) demonstrated 
that there is no evidence of drug-drug interactions (DDIs) between pertuzumab and 
trastuzumab or between pertuzumab and docetaxel, paclitaxel, or carboplatin.
1.2.2.3
Clinical Information on Perjeta IV
Perjeta IV in combination with Herceptin and chemotherapy has been studied in several 
EBC and MBC studies.  Currently, Perjeta is approved in the neoadjuvant treatment of 
HER2-positive, locally advanced, inflammatory or EBC and for treatment of HER2-
positive metastatic or locally recurrent unresectable breast cancer who have not 
received prior anti-HER2 therapy or chemotherapy for their metastatic disease. Recently,
Perjeta, in combination with Herceptin and chemotherapy, was also approved for the 
adjuvant treatment of HER2-positive EBC.
1.2.2.3.1
Neoadjuvant Setting Studies with Perjeta and Herceptin
Perjeta and Herceptin based regimens were evaluated in several neoadjuvant HER2-
positive breast cancer studies.  A summary of Perjeta and Herceptin studies in the 
neoadjuvant setting, including treatment arms and pCR rates, is presented in Table 1.
Table 1
Overview of Key Studies of Neoadjuvant Perjeta in HER2-Positive
Early Breast Cancer
Study
Neoadjuvant 
Treatment
Patients, n
Efficacy Results (%)
tpCR
bpCR
GBG pCR
NEOSPHEREa
HD
107
21.5
29.0
12.1
PtzHD
107
39.3
45.8
32.7
PtzH
107
11.2
16.8
5.6
PtzD
96
17.7
24.0
13.5
TRYPHAENAb
PtzHFEC →
PtzHD
73
56.2
61.6
50.7
FEC → PtzHD
75
54.7
57.3
45.3
PtzTCH
77
63.6
66.2
51.9
BERENICEc#
ddAC → 
Pac PtzH
199
61.8
67.3
48.7
FEC → DPtzH
201
60.7
65.7
48.8
KRISTINEd#
TCHPtz
221
55.7
45.7
59.7
T-DM1Ptz
223
44.4
35.0
50.2


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Table 1
Overview of Key Studies of Neoadjuvant Perjeta in HER2-Positive 
Early Breast Cancer (cont.)
Study
Neoadjuvant 
Treatment
Patients, n
Efficacy Results (%)
tpCR
bpCR
GBG pCR
GeparSeptoe
Ptz H Pac
197


53.8
Ptz H nab-Pac
198


61.8
NSABP B52f
TCHPtz
154
41
44

TCHPtzAI
157
46
47

AI aromatase inhibitor; bpCR breast pathological complete response; D docetaxel; 
ddAC dose-dense doxorubicin and cyclophosphamide; ER estrogen receptor; 
FEC 5-fluorouracil, epirubicin, and cyclophosphamide; GBG pCR German Breast Group 
pathological complete response (pT0/N0); H Herceptin; Pac paclitaxel; Ptz Perjeta; 
PgR progesterone receptor; T paclitaxel; T-DM1 trastuzumab emtansine (Kadcyla); 
TCH docetaxel (Taxotere), carboplatin and Herceptin; tpCR total pathological complete 
response. 
#  Included both neoadjuvant and adjuvant treatment with Perjeta and Herceptin.
* Includes NX and N0 patients
a  Gianni et al. 2012.
b Schneeweiss et al. 2013.
c  Primary Clinical Study ReportWO29217. Report 1070920. December 2016.
d  Primary Clinical Study ReportBO28408. Report 1068872. August 2016.
e  Untch et al. 2016.
f  Rimawi et al. 2016.
Although these studies are different in terms of backbone chemotherapy and number of 
cycles administered, all consistently demonstrated that with the use of dual anti-HER2 
therapy and longer duration of chemotherapy higher pCR rates are achieved.
Duration of chemotherapy is also important and impacts pCR rates. In NEOSPHERE,
patients received 4 cycles of neoadjuvant therapy, and the highest pCR rate (39.3%) 
was achieved in the arm where Perjetawas added to Herceptin and chemotherapy. In 
TRYPHENA and BERENICE, patients received 6 and 8 cycles of neoadjuvant therapy,
respectively, and further increases in pCR rates were observed. pCR rates in 
TRYPHENA ranged from 54.7%63.6%, and in BERENICE, the overall rate of total 
pathological complete response (tpCR) was around 62%.
For additional information on the neoadjuvant studies, please see the Perjeta 
Investigator’s Brochure.
1.2.2.3.2
Adjuvant Setting Study with Perjeta and Herceptin
Perjeta and Herceptin-based regimens were evaluated in a single, large, adjuvant,
Phase III study. BO25126 (APHINITY) is the randomized, double-blind, placebo-
controlled two-arm Phase III study of adjuvant Perjeta plus Herceptin and standard 


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chemotherapy (PerjetaHerceptinchemotherapy) versus adjuvant placebo plus 
Herceptin and standard chemotherapy (placeboHerceptinchemotherapy), in patients 
with operable HER2-positive primary breast cancer. 
Treatment of patients with Perjeta, Herceptin, andchemotherapy resulted in a 
statistically significant and clinically meaningful improvement in iDFS, corresponding to a 
19% reduction in the risk of relapse or death, as compared with placebo, Herceptinand 
chemotherapy (stratified hazard ratio [HR]0.81, 95% CI: 0.66, 1.00; p0.0446), in a 
setting with curative intent.  Estimates of iDFS event-free rates were 94.06% vs. 93.24% 
at 3 years and 92.28% vs. 90.58% at 4 years in the Perjeta, Herceptin, and 
chemotherapy versus placebo, Herceptin, and chemotherapy arms, respectively. High-
risk patients, who were pre-defined by clinical and biologic risk criteria, had the greatest 
clinical benefit. Patients with node-positive or hormone-receptor negative status had a
HR0.77 (95% CI: 0.62, 0.96) or a HR0.76 (95% CI: 0.56, 1.04), respectively.  There
were numerically fewer deaths in the Perjeta, Herceptin, and chemotherapy arm 
(80 deaths [3.3%]) compared to the placebo, Herceptin, and chemotherapy arm (89 
deaths [3.7%]) at the first interim analysis of survival.
For additional information on APHINITY, please see the Perjeta Investigator’s Brochure.
1.2.2.3.3
Metastatic Setting Study with Perjeta and Herceptin
The Perjeta and Herceptin based regimen was evaluated in the Phase III study 
WO20698/TOC4129g (CLEOPATRA).
The CLEOPATRA study is a randomized, double-blind, placebo-controlled study of 
Perjeta and Herceptin with docetaxel compared to placebo and Herceptin with docetaxel 
in patients with untreated HER2-positive locally recurrent, unresectable or MBC.  
The Perjeta-based regimen significantly improved PFS, as assessed by an Independent 
Review Committee (IRC) (median PFS18.5 months vs. 12.4 months; HR0.62, 95% 
CI: 0.51, 0.75; p0.0001).  The addition of Perjeta to standard Herceptin-based 
treatment also resulted in a statistically significant and clinically meaningful improvement 
in survival time. Based on the latest data from the trial (the median OS was 56.5 months 
(95% CI: 49.3 months, NR [not reached]) in the PerjetaHerceptindocetaxel arm
compared to 40.8 months (95% CI: 35.8, 48.3) in the placeboHerceptindocetaxel
arm (HR0.68; 95% CI: 0.56, 0.84; p0.001), a prolongation of OS of 15.7 months.  
The magnitude of clinical benefit and the acceptable safety profile of Perjeta in 
combination with Herceptin and docetaxel compared with placebo in combination with 
Herceptin and docetaxel were maintained throughout the study.
For additional information, please see the Perjeta Investigator’s Brochure.


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1.2.2.4
Safety of Perjeta IV
The cumulative clinical experience in approximately 11,089 patients (since Development 
International Birth Date [11 September 2001] until 07 June 2017) who received Perjeta 
IV in company-sponsored interventional Perjeta trials has demonstrated that Perjeta is 
well tolerated as monotherapy or in combination with Herceptin and a range of other 
therapeutic agents, with manageable additional toxicity.  No unexpected toxicities were 
encountered other than those that are known for agents that target the HER family of 
receptors.
Serious or severe infusion-related symptoms have been rarely observed in patients 
receiving Perjeta.  A low level of cardiac toxicities, predominantly asymptomatic declines 
in left ventricular ejection fraction (LVEF), has been reported.
1.2.2.4.1
Single-Agent Therapy
There are only a few early and very small studies with single-agent Perjeta. The most 
commonly reported adverse events in patients receiving single-agent Perjeta were 
diarrhea, fatigue, nausea, vomiting, and decreased appetite.  The majority of adverse 
events reported were National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) Grade 1 or 2 in severity, and the proportion of patients 
across the Perjeta program who discontinued study drug as a result of an adverse event 
was low.
1.2.2.4.2
Safety of Combination Therapy 
Perjeta has been shown to be well tolerated in combination with Herceptin (WO20697 
[NEOSPHERE], BO22280 [TRYPHAENA], WO29217 [BERENICE], WO20698 
[CLEOPATRA], MO22324 [PHEREXA], and BO25126 [APHINITY]), with an increase in 
the incidence but not severity of the common adverse events seen with Perjeta (notably, 
diarrhea, rash/skin reactions, and fatigue).  Perjeta also added little toxicity 
(predominantly diarrhea, mucosal inflammation, rash/skin reactions, and 
neutropenia/febrile neutropenia) to the adverse event profile of Herceptin and docetaxel 
when all three drugs were used concurrently, and had little effect on the doses received, 
or on interruptions, discontinuations, or treatment-related mortality.  Serious or severe 
infusion-related symptoms have been rarely observed in patients receiving Perjeta.
Results from the TRYPHAENA and BERENICE studies showed that Perjeta and 
Herceptin in combination with an anthracycline-containing chemotherapy (including the 
dose-dense doxorubicin plus cyclophosphamide [ddAC] regimen used in the BERENICE 
study) are safe and well tolerated in patients with EBC.
Importantly, despite targeting the same HER2 pathway, Perjeta adds no significant 
cardiac toxicity and, in particular, does not increase incidence of symptomatic left 
ventricular systolic dysfunction (LVSD) when given with Herceptin (with or without 
chemotherapy).


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In the pivotal Phase III study WO20698/TOC4129g (CLEOPATRA), the rates of 
symptomatic and asymptomatic LVSD were not higher in patients receiving 
Perjeta, Herceptin, and docetaxel than in those receiving placebo, Herceptin, and 
docetaxel. The incidence of LVSD and LVEF decline in PHEREXA in the pertuzumab 
arm were similar to the control arm and also in line with other pertuzumab studies in 
MBC and EBC. Cardiac safety profiles for the anthracycline-based treatment regimens
ddAC→paclitaxel with pertuzumab and trastuzumab and 5-fluorouracil, epirubicin, and 
cyclophosphamide (FEC)→docetaxel with pertuzumab and trastuzumab in Study 
WO29217 (BERENICE) (using similar chemotherapy as in the WO40324 study) during 
the neoadjuvant treatment period were consistent with the known cardiac safety profiles 
of Perjeta and Herceptin in other studies.
For a more detailed overview of the safety of Perjeta IV, please refer to the Perjeta 
Investigator’s Brochure.
1.2.3
Pertuzumab SC
1.2.3.1
Nonclinical Information on Pertuzumab SC
1.2.3.1.1
Pharmacokinetic Studies 
Three nonclinical PK studies with pertuzumab SC have been conducted:  one with 
mini-pigs and two with cynomolgus monkeys.
Mini-Pig
A study in mini-pigs (Roche Study 1038750) was conducted to determine the absolute 
bioavailability of a single dose of pertuzumab.  Perjeta was administered at 10 mg/kg IV
to animals in Group 1.  Each animal in Group 2 and Group 3 received 120 mg SC of 
pertuzumab (co-formulated with 2000 U/mL rHuPH20).  In addition, animals in Group 3 
received a separate subcutaneously administered dose of 120-mg Herceptin (co-
formulated with 2000 U/mL rHuPH20).  For animals assigned to Group-3, the two 
different formulations were administered sequentially.
The mini-pig was chosen because of the similarities between mini-pig and human skin 
structure.
Following SC administration, pertuzumab was relatively rapidly absorbed with maximum 
plasma levels observed at 748 hours post-dose.  The half-life of 524 hours for
pertuzumab SC was similar to that following IV administration.  The average 
bioavailability of pertuzumab SC was estimated at 73.8%.  Co-administration of 
Herceptin SC had no obvious effect on the SC absorption of 120 mg pertuzumab.  No 
accelerated clearance was observed in any of the 15 animals studied.
Cynomolgus Monkey
Studies with cynomolgus monkeys were conducted to assess the single- and 
repeat-dose pharmacokinetics/toxicokinetics and toxicity.  


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In the single-dose study (Genentech Study 00-564-1821, Good Laboratory Practice 
[GLP]), serum levels of pertuzumab following a single dose of 50 mg/kg of pertuzumab 
SC have been assessed.  Results demonstrate that after SC administration, maximum 
serum concentrations of pertuzumab (meanstandard deviation [SD]: 53641.2 µg/mL) 
were reached at approximately 2.28 days.  Mean apparent clearance (CL/F) was 
estimated at 6.4 mL/d/kg.
In the repeat-dose study (Genentech Study 00-604-1560, GLP), serum levels of 
pertuzumab following QW 250 mg/kg for 5 doses of pertuzumab SC have been 
assessed.  Results demonstrate that after SC administration, maximum serum 
concentrations of pertuzumab (meanstandard deviation: 3400223 µg/mL) were 
reached at approximately 30 days.  The area under the serum concentrationtime curve 
(AUC) from 0 to 7 days was approximately (meanstandard deviation) 137001300 
day µg/mL, and the AUC from 14 to 21 days was approximately (meanstandard 
deviation) 207001320-day µg/mL.
1.2.3.1.2
Toxicology Studies with Pertuzumab SC
One study in mini-pig and two studies in cynomolgus monkeys were conducted to 
assess the single- and repeat-dose pharmacokinetics/toxicokinetics and toxicity.  
Mini-Pig
In the mini-pig study (Roche Study 1038750, non-GLP), single-dose pertuzumab SC 
given alone or co-administered with Herceptin SC (see Section 1.2.1.2) was well 
tolerated.  There were no drug-related effects on mortality, clinical observations, food 
intake, or body weight in male mini-pigs.  
Cynomolgus Monkey
Both single-dose SC administration of pertuzumab at 50 mg/kg to male and female 
cynomolgus monkeys (Genentech Study 00-564-1821, GLP) and repeat-dose SC 
administration of pertuzumab at 250 mg/kg QW to female cynomolgus monkeys for 
4 weeks (Genentech Study 00-604-1560, GLP) were well tolerated.  There were no 
drug-related effects on mortality, clinical observations, body weight, or, as evaluated in 
Study 00-604-1560 only, clinical pathology parameters.  Exposure to pertuzumab was 
confirmed and no ADAs were detected.
For further information on the nonclinical experience with pertuzumab, please see the
Perjeta Investigator’s Brochure.
Based on nonclinical studies conducted to date with Perjeta IV and pertuzumab SC,
together with the nonclinical and clinical experience with Herceptin IV and SC, no further 
toxicology evaluation of pertuzumab SC is planned.


1.2.3.2 
Clinical Studies with Pertuzumab SC 
Pertuzumab SC has been studied in a Phase lb study (BO30185). This study is an 
open-label, two-part, two-center study that is designed to identify and subsequently 
confirm the SC dose of Perjeta (pertuzumab) for the FDC formulation. The dose of 
Herceptin SC (trastuzumab, 600 mg) was already established in the Phase I study 
BP22023 and confirmed in the BO22227 (HannaH) study. 
The overall schema of BO30185 is shown in Figure 1. 
Figure 1 Study 8030185 Schema 
Cohort 1 (n=6) 
Perjeta 420 mg rv
Cohort 2 (n=6) 
PerjeCa 400 mg SC 
Cohort 3 (n=6) 
PerjeCa 600 mg SC 
Cohort 4 (n=6) 
a,> 
U> 
(1) 
U> 
(1) 
Cohort /Jf (n=20) 
PerjeCa SC 
+ Herceptin 
Target Dose 
600 mg SC 
c only if FOC not feasible 
OR 
Peljela 1200 mg SC 
g_ 
Target SC 
Dose(s)• of 
Perjeta 
Determined? 
Yes 
Cohort 5 (n=6) 
Herceptin 600 mg SC 
Cohort 6 (n=6) 
Petjeta 400 mg SC + 
Herceptin 600 mg SC 
Cohort 7 ( n=6) 
Petjela 1200 mg SC + 
Herceptin 600 mg SC 
Cohort 8 (n=6) • 
Perjeta 1200 mg SC + 
Herceptin 600 mg SC 
• rHuPH20 concentration 
= 667 U/ml only 
!I) 
!I) 
:r 
o·
U> 
!I) a. 
No 
Possible Additional Cohorts 
• If pertuzumab exposure 
different from target 
concentration, .!l! 
• If PK variability too high to 
determine dose 
• Calculated to deliver a simlar 
exposure as a 42<kng IV dose 
Part 1: Dose Finding 
Single Dose in Healthy Male Volunteers 
Cohort B (n=20) 
Petjeta SC Target Dose + 
Herceptin 600 mg SC 
AND 
Cohort C (n=20) 
Perjeta SC Target Dose + 
Herceptin 600 mg SC 
L 
Part 2: Dose Confirmation 
J 
Single Dose in Patients with Ear1y Breast 
Cancer 
D Perjeta alone/separately 
D Herceptin alone/separately 
D Perjeta + Herceptin co-mixed 
D Perjeta + Herceptin FDC 
FDC=fixed-dose combination; PK=pharmacokinetic; rHuPH20=recombinant human PH20 
hyaluronidase. 
The objective of Part 1 of the study was dose finding, in which the loading and 
maintenance doses of pertuzumab SC for the FDC formulation were determined in 
healthy male volunteers (HMVs). Pertuzumab SC was given alone or co-mixed with 
Herceptin SC as a single injection, both with rHuPH20. The objective of Part 2 of the 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab-F. Hoffmann-La Roche Ltd 
41/Protocol WO40324, Version 2 


SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
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study was to confirm the maintenance dose of pertuzumab SC in female EBC patients 
who have completed standard breast cancer therapy. Enrollment in Part 2 began after
the doses of Perjeta SC had been established in Part 1.  The overall schema for Part 2 
was Cohort A only (co-administration of Perjeta SC [with rHuPH20] and Herceptin SC 
[with rHuPH20], each agent administered separately) or otherwise Cohort B (Perjeta and 
Herceptin SC co-mixed product) and Cohort C (the FDC).  Cohort A was only to be 
enrolled if there was a PK interaction between Perjeta and Herceptin observed in Part 1, 
or if the development of the FDC was not feasible. The Perjeta and Herceptin SC co-
mixed product serves as a surrogate for the FDC as the drug substances (pertuzumab 
and trastuzumab) in the FDC are considered comparable to the drug substances in the 
individual SC formulations, and the drug product FDC formulations and the co-mixed 
solution are also similar.  
The PK results from Part 1 and Part 2 (Cohort B) of the study showed that pertuzumab 
SC, given as a loading dose of 1200 mg and maintenance dose of 600 mg provides 
similar Ctrough and AUC as Perjeta IV 840 mg and 420 mg, respectively, as determined in 
HMVs. Pertuzumab SC 600-mg dose in EBC patients provides similar Ctrough and AUC 
to the 420 mg IV and 600 mg SC cohorts in HMVs in Part 1 and dose proportionality 
through PK linearity confirms a pertuzumab SC 1200 mg loading dose. 
The safety profile of Perjeta SC in the study was consistent with the known safety profile 
of Perjeta IV and is well tolerated when given in combination with Herceptin SC.  There 
were no new safety signals identified.  In Part 1 (Cohorts 18), a total of 148 adverse 
events were reported in 44 out of 48 (91.7%) HMVs. The majority of adverse events 
were reported of low intensity (Grade 1 or 2).  The most common System Organ Class 
(SOC) was Infections and Infestations, with 22 (45.8%) HMVs experiencing a total of 33 
adverse events in this category, of which a majority of events were considered not 
related to study drug by the investigator.  The most commonly observed adverse events 
(by Prefered Term) across different cohorts were: upper respiratory tract infection (13 
[27.1%] HMVs), headache (9 [18.8%] HMVs), drug eruption (9 [18.8%] HMVs), and 
diarrhea (9 [18.8%] HMVs). Among these common adverse events, study drug related 
adverse events (assessed by the investigator) were reported in 4 (8.3%), 8 (16.7%), 9 
(18.8%), and 7 (14.6%) HMVs. All adverse events that occurred in Part 1 had resolved 
by the end of Part 1.
In Part 2, all 20 (100%) female EBC patients experienced at least one adverse event, 
with a total of 102 adverse events reported by the time of clinical data cut-off.  The 
majority of adverse events were reported of low intensity (Grade 1 or 2). The most 
common SOCs were nervous system disorders (14 [70%] patients), gastrointestinal
disorders (10 [50%] patients), and musculoskeletal and connective tissue disorders (10 
[50%] patients). The most commonly observed adverse events (by Preferred Term) 
reported in at least 20% of patients were headache (13 [65%] patients), myalgia (7 [35%]
patients), diarrhea (6 [30%] patients), injection-site reaction (ISR: 6 [30%] patients), and 
nausea (4 [20%] patients).  Among these common adverse events, study drugrelated 


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adverse events (assessed by the investigator) were reported in 9 (45%), 6 (30%), 4 
(20%), 6 (30%), and 1 (5%) patient, respectively.
Both Cohorts 68 (HMVs) of Part 1 and Cohort B (EBC patients) of Part 2 received a co-
mixed injection of Perjeta and Herceptin. The types of adverse events that were 
reported with Perjeta SC and Herceptin SC are consistent with the known risks 
associated with the combination therapy.  ISRs, all of Grade 1 or 2, occurred with higher 
frequency in EBC patients compared with HMVs (6 [30%] patients vs. 1 [5.6%] patient).
The majority of HMVs in Part 1 and all EBC patients in Cohort B in Part 2 experienced at 
least one adverse event.  There were two Grade 3 adverse events in Part 1 and one 
Grade-3 adverse event in Part 2 during the study.  The remainder of the adverse events 
was of low intensity (Grade 1 or 2).  There were no serious adverse events, deaths, or 
adverse events leading to withdrawals during the study.
The safety, tolerability and PK results of this Phase I study support further development 
of the FDC.  The recommended FDC SC formulation is as follows:

Loading dose SC: Perjeta 1200 mgHerceptin 600 mg, with rHuPH20 2,000 U/mL 

Maintenance dose SC: Perjeta 600 mgHerceptin 600 mg, with rHuPH20 2,000 
U/mL
For additional information on the clinical experience with the FDC, please see the 
Pertuzumab and Trastuzumab FDC Investigator’s Brochure.
1.2.4
Background on Recombinant Human Hyaluronidase (rHuPH20)
The feasibility and patient acceptability of SC administration of any drug are dependent 
on the volume of drug that must be administered.
The enzyme rHuPH20 (Hylenex®) has been developed to improve dispersion and 
absorption of SC formulations, enabling larger volumes to be administered without 
reduced tolerability and with improved patient acceptability.  Hyaluronidase acts primarily 
as a permeation enhancer to increase the dispersion and absorption of other 
co-administered drugs.  Hyaluronidase transiently hydrolyses hyaluronan, a component 
of the SC matrix, leading to reduced viscosity of the extracellular matrix of the 
hypodermis and, thus, to an improved delivery of subcutaneously administered drugs to 
the systemic circulation (Hylenex Prescribing Information 2014).
The rHuPH20 used in the current study is produced from a second generation of the 
Hylenex process that has improved yield and purity.  This formulation has been 
combined with trastuzumab to allow safe and comfortable SC injection of volumes of
25 mL.  The concentration of rHuPH20 is guided by data from a mini-pig study in which 
trastuzumab was administered subcutaneously.  In the presence of either 2,000 or 
6,000 U/mL of rHuPH20, there was a more rapid absorption of subcutaneously 
administered trastuzumab from rHuPH20-containing formulations, while the effect on the 


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absorption rate of trastuzumab was comparable with both rHuPH20 concentrations.  
Therefore, the lower rHuPH20 concentration of 2000 U/mL was selected.
The highest total rHuPH20 dose administered in a clinical study was 96,000 U 
(Study HZ2-07-02).  This Phase I study investigated the SC injection of adalimumab with 
different rHuPH20 concentrations in healthy volunteers using different SC volumes of 
injection (2, 8, and 16 mL).  All injections were well tolerated, with no serious adverse 
events reported.  All ISRs such as erythema, pain, and induration were mild (98%) or 
moderate (2%).  Common ISRs observed were erythema, ecchymosis, pain, and 
induration.
Currently, two monoclonal antibodies (Herceptin and MabThera®/Rituxan HycelaTM
[rituximab]) are approved in more then 80 countries for SC therapy in oncology.  The 
MabThera/Rituxan SC 1400 mg dose is delivered in a volume of 11.7 mL and was well 
tolerated (Davies et al 2014).  The amount of rHuPh20 (23,400 U) in MabThera/Rituxan
SC exceeds the Herceptin SC (10,000 U) and proposed Perjeta maintenance SC 
rHuPH20 dose that will be administered in this study. All three products use the same 
rHuPH20 concentration of 2000 U/mL.
For additional details on nonclinical and clinical studies of rHuPh20, please see the local 
prescribing information (Hylenex Prescribing Information 2014).


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2
OBJECTIVES AND ENDPOINTS
This study will evaluate the pharmacokinetics, efficacy, and safety of the FDC of 
pertuzumab and trastuzumab for SC administration compared with the Perjeta IV and
Herceptin IV formulations in patients with HER2-positive EBC.
Specific objectives and corresponding endpoints for the study are outlined below in
Table 2.


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Table 2
Study Objectives and Endpoints
Primary Objective
Corresponding Endpoint
To demonstrate the non-inferiority of 
the Cycle 7 (pre-dose Cycle 8) serum 
pertuzumab Ctrough of pertuzumab SC 
within the FDC compared with Perjeta 
IV 
Serum pertuzumab Ctrough during Cycle 7 (pre-dose 
Cycle 8) 
Secondary Pharmacokinetic Objective
Corresponding Endpoint
To demonstrate the non-inferiority of 
the Cycle 7 (pre-dose Cycle 8) serum 
trastuzumab Ctrough of trastuzumab SC 
within the FDC compared with 
Herceptin IV
Serum trastuzumab Ctrough during Cycle 7 (pre-dose 
Cycle 8) 
Secondary Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of the SC FDC 
of pertuzumab and 
trastuzumab chemotherapy compared 
with Perjeta IV and Herceptin 
IV chemotherapy
tpCR, defined as eradication of invasive disease in 
the breast and axilla (i.e., ypT0/isypN0), according to 
local pathologist assessment
iDFS, defined as the time from the first date of no 
disease (i.e., the date of primary surgery) to the first 
occurrence of one of the following events:
- Ipsilateral invasive breast tumor 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)
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 PD or relapse.
ADAanti-drug antibody; bpCRbreast pathologic complete response; Ctroughsteady-state 
concentration; DRFI=distant breast cancer recurrence; DDIdrug-drug interaction; 
EFSevent-free survival; FDCfixed-dose combination; GBGGerman Breast Group; 
GMRgeometric mean ratio; HCPhealth care provider; iDFSinvasive disease-free survival; 
IVintravenous; LVEFleft ventricular ejection fraction; NCI CTCAENational Cancer Institute 
Common Terminology Criteria for Adverse Events ;OSoverall survival; pCRpathologic 
complete response; PDprogressive disease; PKpharmacokinetic; PRpartial response; 
SCsubcutaneous; SDstable disease; tpCRtotal pathological complete response.


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Table 2
Study Objectives and Endpoints (cont.)
Secondary Efficacy Objective (cont.)
Corresponding Endpoints (cont.)
To evaluate the efficacy of the SC FDC 
of pertuzumab and 
trastuzumabchemotherapy compared 
with Perjeta IV and Herceptin 
IVchemotherapy
iDFS, including second primary non-breast cancer, 
defined in the same way as iDFS but including second 
primary non-breast invasive cancer as an event (with 
the exception of non-melanoma skin cancers and in 
situ carcinoma of any site)
EFS, defined as the time from enrollment to the first 
occurrence of one of the following events:
- Breast cancer progression (PD)
- Breast cancer recurrence (as defined for iDFS 
endpoint)
- Death from any cause
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 PD or relapse.
EFS, including second primary non-breast cancer is 
defined in the same way as EFS, but including second 
primary non-breast invasive cancer as an event (with 
the exception of non-melanoma skin cancers and in 
situ carcinoma of any site)
DRFI, defined as the time between randomization and 
the date of distant breast cancer recurrence
OS, defined as the time from randomization to death 
from any cause
ADAanti-drug antibody; bpCRbreast pathologic complete response; Ctroughsteady-state 
concentration; DRFI=distant breast cancer recurrence; DDIdrug-drug interaction; 
EFSevent-free survival; FDCfixed-dose combination; GBGGerman Breast Group; 
GMRgeometric mean ratio; HCPhealth care provider; iDFSinvasive disease-free survival; 
IVintravenous; LVEFleft ventricular ejection fraction; NCI CTCAENational Cancer Institute 
Common Terminology Criteria for Adverse Events ;OSoverall survival; pCRpathologic 
complete response; PDprogressive disease; PKpharmacokinetic; PRpartial response; 
SCsubcutaneous; SDstable disease; tpCRtotal pathological complete response.


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Table 2
Study Objectives and Endpoints (cont.)
Secondary Safety Objective
Corresponding Endpoints
To evaluate the safety of the SC FDC of 
pertuzumab and trastuzumab compared 
with Perjeta IV and Herceptin IV
Incidence and severity of adverse events and SAEs, 
with severity determined according to NCI CTCAE v4 
Laboratory test abnormalities according to NCI 
CTCAE v4
Primary cardiac endpoints
Incidence of a symptomatic ejection fraction decrease 
(“Heart failure”) of NYHA Class III or IV and a drop in 
LVEF of at least 10-percentage points from baseline 
and to below 50%
Cardiac death, defined as one of the following:

Definite cardiac death, defined as death due to 
heart failure, myocardial infarction, or documented 
primary arrhythmia

Probable cardiac death, defined as sudden 
unexpected death within 24 hours of a definite or 
probable cardiac event (e.g., syncope, cardiac arrest, 
chest pain, infarction, arrhythmia) without 
documented etiology
Secondary cardiac endpoint
Incidence of an asymptomatic or mildly symptomatic
left ventricular systolic dysfunction (“Ejection fraction 
decreased”) of NYHA Class II, defined as an LVEF 
decrease of 10-percentage points below the 
baseline measurement to an absolute LVEF value of 
50%, confirmed by a second assessment within 
approximately 3 weeks confirming a decrease of 10-
percentage points below the baseline measurement 
and to an absolute LVEF value of 50%
Exploratory Pharmacokinetic 
Objectives
Corresponding Endpoints
To characterize the pharmacokinetics of 
pertuzumab and trastuzumab following 
administration of the SC FDC
Serum pertuzumab concentrations or PK parameters
Serum trastuzumab concentrations or PK parameters
ADA anti-drug antibody; bpCR breast pathologic complete response; Ctrough steady-state 
concentration; DRFI=distant breast cancer recurrence; DDI drug-drug interaction; 
EFS event-free survival; FDC fixed-dose combination; GBG German Breast Group; 
GMR geometric mean ratio; HCP health care provider; iDFS invasive disease-free survival; 
IV intravenous; LVEF left ventricular ejection fraction; NCI CTCAE National Cancer Institute 
Common Terminology Criteria for Adverse Events ;OS overall survival; pCR pathologic 
complete response; PD progressive disease; PK pharmacokinetic; PR partial response; 
SC subcutaneous; SD stable disease; tpCR total pathological complete response.


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Table 2
Study Objectives and Endpoints (cont.)
Exploratory Pharmacokinetic 
Objectives (cont.)
Corresponding Endpoints (cont.)
To compare the pharmacokinetics 
(including PK parameters such as AUC 
and Cmax) following administration of the 
SC FDC versus Perjeta IV and 
Herceptin IV (in combination with 
chemotherapy) 
Serum pertuzumab concentrations or PK parameters 
during Cycle 7 (pre-dose Cycle 8)
Serum trastuzumab concentrations or PK parameters 
during Cycle 7 (pre-dose Cycle 8)
To assess the pertuzumab PK profile 
and observed Ctrough at Cycle 7 (pre-
dose Cycle 8) and Cycle 12 (post-
surgery) following FDC administration
Serum pertuzumab concentrations during Cycle 7 
(pre-dose Cycle 8) and Cycle 12 (pre-dose Cycle 13)
To compare the pertuzumab exposure 
in Cycle 1 between Perjeta IV 840 mg 
and FDC (pertuzumab SC 1200 mg)
Serum pertuzumab concentrations during Cycle 5
To evaluate potential relationships 
between pertuzumab exposure and the 
efficacy and safety of the SC FDC via a
pertuzumab exposure-response 
analysis
Relationship between serum concentration or PK 
parameters for pertuzumab and efficacy endpoints
Relationship between serum concentration or PK 
parameters for pertuzumab and safety endpoints
To assess the impact of a potential PK 
DDI between pertuzumab and 
trastuzumab following administration of 
the SC FDC
Serum concentrations or PK parameters for 
pertuzumab given in combination with trastuzumab 
compared with pertuzumab given alone (based on 
historical data)
Serum concentrations or PK parameters for 
trastuzumab given in combination with pertuzumab 
compared with trastuzumab given alone (based on 
historical data)
ADA anti-drug antibody; bpCR breast pathologic complete response; Ctrough steady-state 
concentration; DRFI=distant breast cancer recurrence; DDI drug-drug interaction; 
EFS event-free survival; FDC fixed-dose combination; GBG German Breast Group; 
GMR geometric mean ratio; HCP health care provider; iDFS invasive disease-free survival; 
IV intravenous; LVEF left ventricular ejection fraction; NCI CTCAE National Cancer Institute 
Common Terminology Criteria for Adverse Events ;OS overall survival; pCR pathologic 
complete response; PD progressive disease; PK pharmacokinetic; PR partial response; 
SC subcutaneous; SD stable disease; tpCR total pathological complete response.


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Table 2
Study Objectives and Endpoints (cont.)
Exploratory Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of the SC FDC 
of pertuzumab and 
trastuzumabchemotherapy compared 
with Perjeta IV and Herceptin 
IVchemotherapy
bpCR, defined as eradication of invasive disease in 
the breast (i.e., ypT0/is, ypNx)
GBG pCR, defined as eradication of invasive and in 
situ disease in the breast and invasive disease in 
axilla (i.e., ypT0 ypN0)
Clinical response, defined as CR, PR, SD, or PD, 
prior to surgery.  Tumor response will be assessed 
prior to each new cycle of therapy by clinical 
examination, mammography, and/or other methods of 
evaluation as per routine clinical practice.  Response 
will be assessed by the investigator as per routine 
clinical practice.
Exploratory Immunogenicity 
Objectives
Corresponding Endpoints
To evaluate the immune response to 
pertuzumab, trastuzumab, and 
rHuPH20 with the SC FDC compared
with Perjeta IV and Herceptin IV
Incidence of pertuzumab ADAs during the study 
relative to the prevalence of ADAs at baseline
Incidence of trastuzumab ADAs during the study 
relative to the prevalence of ADAs at baseline
Incidence of rHuPH20 ADAs during the study relative 
to the prevalence of ADAs at baseline
To evaluate potential effects of ADAs
Relationship between pertuzumab ADA status and
efficacy, safety, or PK endpoints
Relationship between trastuzumab ADA status and 
efficacy, safety, or PK endpoints
Relationship between rHuPH20 ADA status and 
efficacy, safety, or PK endpoints
ADA anti-drug antibody; bpCR breast pathologic complete response; Ctrough steady-state 
concentration; DRFI=distant breast cancer recurrence; DDI drug-drug interaction; EFS event-
free survival; FDC fixed-dose combination; GBG German Breast Group; GMR geometric 
mean ratio; HCP health care provider; iDFS invasive disease-free survival; IV intravenous; 
LVEF left ventricular ejection fraction; NCI CTCAE National Cancer Institute Common 
Terminology Criteria for Adverse Events ;OS overall survival; pCR pathologic complete 
response; PD progressive disease; PK pharmacokinetic; PR partial response; 
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Table 2
Study Objectives and Endpoints (cont.)
Exploratory Biomarker Objectives
Corresponding Endpoint
To explore potential association of 
tissue-based biomarkers or biomarker 
profiles to pCR
To explore changes in biomarker levels 
or biomarker profiles pre- and post-
treatment based on tumor tissue
To assess blood-based biomarkers at 
baseline and longitudinally to explore 
changes over time and potential 
relationship to pCR and long-term 
efficacy endpoints
Presence or absence of biomarker(s) and/or 
biomarker profiles with respect to levels of certain 
biomarkers at specified timepoints and relation to 
efficacy endpoints
ADAanti-drug antibody; bpCRbreast pathologic complete response; Ctroughsteady-state 
concentration; DRFI=distant breast cancer recurrence; DDIdrug-drug interaction; EFSevent-
free survival; FDCfixed-dose combination; GBG German Breast Group; GMRgeometric mean 
ratio; HCPhealth care provider; iDFSinvasive disease-free survival; IVintravenous; LVEFleft 
ventricular ejection fraction; NCI CTCAENational Cancer Institute Common Terminology Criteria 
for Adverse Events ;OSoverall survival; pCRpathologic complete response; PDprogressive 
disease; PKpharmacokinetic; PRpartial response; SCsubcutaneous; SDstable disease; 
tpCRtotal pathological complete response.
3
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a global Phase III, two-arm, open-label, multicenter, randomized study to 
investigate the pharmacokinetics, efficacy, and safety of the FDC (pertuzumab and 
trastuzumab for SC administration) in combination with chemotherapy in patients with 
HER2-positive EBC in the neoadjuvant/adjuvant setting. 
The study will enroll patients with HER2-positive breast cancer consistent with the 
indication for treatment with neoadjuvant Perjeta and Herceptin and chemotherapy in 
routine clinical practice and as recommended in local guidelines.
Approximately 500 patients with HER2-positive, operable or locally 
advanced/inflammatory breast cancer with a tumor size of 2 cm or node-positive will be 
randomized to one of the following treatment arms in a 1:1 ratio:  

Arm A (Perjeta IVHerceptin IV):  Patients will receive 8 cycles of neoadjuvant 
chemotherapy.  This will include 4 cycles of ddAC every 2 weeks (Q2W) (given with 
granulocyte colony-stimulating factor [G-CSF] support as needed according to local 
guidelines) followed by paclitaxel Q1W for 12 weeks or 4 cycles of doxorubicin plus 
cyclophosphamide (AC) Q3W followed by docetaxel Q3W for 4 cycles. 
PerjetaHerceptin will be given IV for 4 cycles (Q3W) concurrently with the taxane 
component of chemotherapy.  After completing their neoadjuvant therapy, patients 
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Perjeta IV and Herceptin IV for a total of 18 cycles. One year of HER2-targeted
therapy without any delays would encompass 18 cycles. 
After surgery (from Cycle 9 onwards), patients in Arm A will continue Perjeta IV and are 
allowed to switch from Herceptin IV to Herceptin SC, at the discretion of the investigator, 
in the countries where Herceptin SC is routinely used.

Arm B (FDC of pertuzumab and trastuzumab for SC administration): Patients will 
receive 8 cycles of neoadjuvant chemotherapy.  This will include 4 cycles of ddAC 
Q2W (given with granulocyte colony-stimulating factor [G-CSF] support as needed 
according to local guidelines) followed by paclitaxel Q1W for 12 weeks or 4 cycles of 
AC Q3W followed by docetaxel Q3W for 4 cycles. FDC will be given SC for 4 cycles 
(Q3W) concurrently with the taxane component of chemotherapy.  After completing 
their neoadjuvant therapy, patients will undergo surgery. Thereafter, patients will 
receive an additional 14 cycles of the FDC for a total of 18 cycles. One year of 
HER2-targeted therapy without any delays would encompass 18 cycles.
The investigator will select one of the two protocol-approved neoadjuvant chemotherapy 
regimens with which to treat the patient. Once the investigator’s choice of chemotherapy 
has been made and eligibility confirmed, the patient will be randomized to one of the two 
treatment arms using a permuted blocks randomization procedure and stratified 
according to the following factors:  

Hormonal receptor status (based on central assessment):
–
Estrogen receptor (ER)-positive or progesterone receptor (PgR)-positive 
–
ER-negative and PgR-negative

Clinical stage at presentation:
–
Stage IIIIIA
–
Stage IIIBIIIC

Type of chemotherapy:
–
ddAC followed by paclitaxel
–
AC followed by docetaxel
A patient may only be randomized once in this trial. Patients randomized into the study 
will not be replaced. Patients who choose to withdraw after screening, but before 
randomization, will be replaced.
Figure 2 presents an overview of the study design. The schedules of activities are
provided in Appendix 1, Appendix 2, Appendix 3, and Appendix 4.


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Figure 2
Study Schema
*Herceptin SC may be used in the adjuvant period from Cycle 9 and onward, at the discretion of 
the investigator.
ACdoxorubicin plus cyclophosphamide; BC breast cancer; ddACdose-dense doxorubicin 
plus cyclophosphamide; FDCfixed-dose combination of pertuzumab and trastuzumab SC; 
HHerceptin; Nnode positive; PPerjeta; QW once a week; Q2W every 2 weeks; 
Q3W every 3 weeks.
Note:  For Arms A and B, the doses of AC are doxorubicin 60 mg/m2 IV and cyclophosphamide 
600 mg/m2 IV (AC is given Q3W; ddAC is given Q2W).  The dose of paclitaxel is 80 mg/m2 IV 
(given QW for 12 weeks).  The starting dose of docetaxel is 75 mg/m2 IV in Cycle 5 (the first 
docetaxel cycle) and then 100 mg/m2 IV at the discretion of the investigator for Cycles 68, if no 
dose-limiting toxicity occurs (given Q3W).
Post-operative radiotherapy will be administered as per local practice, without 
interruption of the HER2-targeted therapy.  Hormone receptor-positive patients should 
receive adjuvant hormonal treatment as per local practice. 
After the end of study treatment, patients will be followed for safety and efficacy for at 
least 3 years (36 months).  
An independent Data Monitoring Committee (iDMC) will be established to monitor and 
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recruitment and the study should continue based on each evaluation.  A study Steering 
Committee will also be formed (see Section 9.4 for more details).
3.1.1
Neoadjuvant Phase
Neoadjuvant therapy will be administered for a total of 8 cycles. In the event of disease 
progression, unacceptable toxicity, withdrawal of consent, or study termination by the 
Sponsor, whichever occurs first, neoadjuvant therapy will be discontinued prior to the 
completion of these 8 cycles. For patients in both arms the 8 cycles will take about 
2024 weeks. 
With the exception of patients who experience disease progression, patients whose 
neoadjuvant chemotherapy is discontinued due to toxicity prior to completion of these 
8 cycles, and patients who did not receive non-protocol neoadjuvant therapy will be 
allowed to continue HER2-targeted adjuvant study treatment as per randomization.
Patients who discontinue neoadjuvant therapy as a result of disease progression must 
be discontinued from all study treatment and will be managed as per local practice. 
Any patient who receives non-protocol cancer-directed therapy prior to surgery will be
discontinued from study treatment and will be managed as per local practice. 
If the HER2-targeted therapy is held for more than 9 weeks or needs to be permanently 
discontinued, the patient will be withdrawn from all study treatment, and the patient will 
continue to be followed post-treatment for at least 3 years after last dose of 
HER2-targeted therapy, as described in Section 4.6.4.
All patients who discontinue planned study treatment will remain on study for follow-up of 
secondary and exploratory endpoints, safety and survival unless consent for study 
participation is withdrawn.
3.1.2
Surgery 
Patients in both cohorts are scheduled to undergo surgery after 8 cycles of neoadjuvant 
therapy. Surgery will be performed no earlier than 14 days following the last infusion or 
injection of neoadjuvant therapy. 
See Section 4.4.1 for details about surgical management of patients.
3.1.3
Adjuvant Phase 
All patients who have undergone surgery will continue to receive the same 
HER2-directed therapy in the adjuvant phase as was administered in the neoadjuvant 
phase of the study (i.e., Arm A Perjeta IV and Herceptin IV; Arm B the SC FDC of 
pertuzumab and trastuzumab). In the adjuvant period, patients in Arm A are allowed to 
switch from Herceptin IV to Herceptin SC at the discretion of the investigator, in the 
countries were Herceptin SC is routinely used. Treatment will be given so that in total, 


18 cycles of HER2-directed therapy are administered, inclusive of therapy given both in 
the neoadjuvant and adjuvant setting. 
The interval between the last dose of neoadjuvant Perjeta IV and Herceptin IV or the 
FDC and the first dose of adjuvant Perjeta IV and Herceptin IV or the FDC must be 
.s;-9 weeks otherwise the patient will be withdrawn from all study treatment. Adjuvant 
therapy will be discontinued in the event of invasive disease recurrence, second primary 
invasive malignancy, unacceptable toxicity, withdrawal of consent, or study termination 
by the Sponsor, whichever occurs first. Patients whose adjuvant study treatment is 
discontinued prior to completion of planned therapy will still be followed as per protocol 
for secondary endpoints unless consent to participate is withdrawn. 
After surgery, radiotherapy is to be given as clinically indicated and as per local practice 
(Section 4.4.2). 
Patients with ER-positive and/or PgR-positive tumors should receive adjuvant endocrine 
therapy (e.g., tamoxifen, aromatase inhibitor, ovarian ablation) as per local clinical 
practice. 
3.1.4 
Safety Data Review 
The Sponsor's study team will review adverse events, serious adverse events, and other 
safety data in the study on a regularly scheduled basis and at the time of the primary 
analysis. 
The iDMC will also monitor and evaluate patient safety. Further details about the iDMC 
are in Section 9.4 and in a separate iDMC Charter. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of the study is expected to occur approximately 4.5 years after the last patient is 
randomized to the study. The end of the study is defined as the date when the last 
patient, last visit (LPL V) occurs or the date at which the last data point required for 
statistical analysis or safety follow-up is received from the last patient (or when all 
patients have died or the trial is terminated by the Sponsor, whichever is earliest). 
The total length of the study, from screening of the first patient to the end of the study is 
expected to be approximately 5.5 years. 
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4
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 500 patients with centrally confirmed HER2-positive, Stage IIIIIC breast 
cancer with a tumor size of 2 cm, or node-positive disease (clinically or on imaging and
node positivity confirmed with cytology and/or histopathology) will be randomized in 
this study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

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 (ECOG) Performance Status 1

Female and male patients with Stage IIIIIC (T2T4 plus any N, or any T plus
N13, M0), locally advanced, inflammatory, or early-stage, unilateral, and 
histologically confirmed invasive breast cancer
Patients with inflammatory breast cancer must be able to have a core-needle 
biopsy

Primary tumor 2 cm in diameter, or node-positive disease (clinically or on imaging, 
and node positivity confirmed with cytology and/or histopathology)

HER2-positive breast cancer confirmed by a central laboratory prior to study 
enrollment. HER2-positive status will be determined based on pretreatment breast 
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in situ hybridization (ISH) with a ratio of 2 for the number of HER2 gene copies to 
the number of signals for chromosome 17 copies
Patients with multifocal tumors (more than one tumor confined to the same 
quadrant as the primary tumor) are eligible provided at least one focus is 
sampled and centrally confirmed as HER2 positive. 

Hormone receptor status of the primary tumor, centrally confirmed
Hormone receptor-positive status can be determined by either known 
ER-positive and/or known PgR-positive status. Hormone receptor-negative 
status must be determined by both known ER-negative and known 
PgR-negative status

Patient agreement to undergo mastectomy or breast conserving surgery after 
neoadjuvant therapy 

Availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue block for 
central confirmation of HER2 and hormone receptor status and additional biomarker 
research (e.g., PIK3CA mutational analyses)

Baseline LVEF 55% measured by echocardiogram (ECHO) or multiple-gated 
acquisition scan (MUGA)

For women of childbearing potential (WOCBP) who are sexually active: agreement 
to remain abstinent (refrain from heterosexual intercourse) or use one highly 
effective non-hormonal contraceptive method with a failure rate of 1% per year, or 
two effective non-hormonal contraceptive methods during the treatment period and 
for 7 months after the last dose of HER2-targeted therapy, and agreement to refrain 
from donating eggs during this same period
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of highly effective 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).
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 postovulation 
methods) and withdrawal are not acceptable methods of contraception (see 
Section 5.1.3).

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom in combination with a spermicidal foam, gel, film, cream, or 
suppository, 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 with a spermicidal product during 
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therapy 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 postovulation 
methods) and withdrawal are not acceptable methods of contraception (see 
section 5.1.3).

A negative serum pregnancy test must be available prior to randomization for 
WOCBP (premenopausal women and women 12 months after the onset of 
menopause), unless they have undergone surgical sterilization (removal of ovaries 
and/or uterus)

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
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Stage IV (metastatic) breast cancer 

Patients with a history of invasive breast cancer

Patients with a history of concurrent or previously treated non-breast malignancies 
except for appropriately treated 1) non-melanoma skin cancer and/or 2) in situ 
carcinomas, including cervix, colon, and skin
A patient with previous invasive non-breast cancer is eligible provided he/she 
has been disease free for more than 5 years.

Patients who have received any previous systemic therapy (including chemotherapy, 
immunotherapy, HER2-targeted agents, endocrine therapy (selective estrogen 
receptor modulators, aromatase inhibitors, and antitumor vaccines) for treatment or 
prevention of breast cancer, or radiation therapy for treatment of cancer

Patients who have a past history of ductal carcinoma in situ (DCIS) or lobular 
carcinoma in situ (LCIS) if they have received any systemic therapy for its treatment 
or radiation therapy to the ipsilateral breast
Patients are allowed to enter the study if treated with surgery alone.

Patients with high-risk for breast cancer who have received chemopreventative 
drugs in the past are not allowed to enter the study

Patients with multicentric (multiple tumors involving more than one quadrant) breast 
cancer, unless all tumors are HER2-positive

Patients with bilateral breast cancer

Patients who have undergone an excisional biopsy of primary tumor and/or axillary 
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
Axillary lymph node dissection (ALND) prior to initiation of neoadjuvant therapy
Patients with clinically negative axilla (by physical examination and 
radiographic imaging) may undergo a core or needle biopsy procedure prior to 
neoadjuvant systemic therapy if in keeping with local practice

Sentinel lymph node biopsy (SLNB) prior to neoadjuvant therapy

Treatment with any investigational drug within 28 days prior to randomization 

Serious cardiac illness or medical conditions including, but not confined to, the 
following:
–
History of NCI CTCAE (v4) 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 2] or third-degree AV-block)
–
Serious cardiac arrhythmia not controlled by adequate medication, severe 
conduction abnormality 
–
Angina pectoris requiring anti-anginal medication
–
Clinically significant valvular heart disease
–
Evidence of transmural infarction on ECG
–
Evidence of myocardial infarction within 12 months prior to randomization  
–
Poorly controlled hypertension (e.g., systolic 180 mm Hg or diastolic 100 
mmHg)

Inadequate bone marrow function, defined as: 
–
Absolute neutrophil count 1.5109/L
–
Platelet count 100109/L 
–
Hemoglobin 9 g/dL 

Impaired liver function, defined as:
–
Serum (total) bilirubin 1.25upper limit of normal (ULN)
In case of Gilbert’s syndrome: a total bilirubin of 2ULN is permitted.
–
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)
1.25ULN
–
Albumin 25 g/L

Inadequate renal function with serum creatinine 1.5ULN

Current severe, uncontrolled systemic disease that may interfere with planned 
treatment (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; 
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
Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 7 months after the last dose of HER2-targeted therapy
Women of childbearing potential must have a negative serum pregnancy test 
result within 7 days prior to initiation of study drug.

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 HIV

Known hypersensitivity to study drugs, excipients, and/or murine proteins

Current chronic daily treatment with corticosteroids (dose 10 mg 
methylprednisolone or equivalent excluding inhaled steroids)

History of other malignancy within 5 years prior to screening, except for 
appropriately treated carcinoma in situ of the cervix, colon, skin, and/or 
non-melanoma skin carcinoma

History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such 
as structural heart disease (e.g., severe LVSD, left ventricular hypertrophy), 
coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic 
testing), clinically significant electrolyte abnormalities (e.g., hypokalemia, 
hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or 
long QT syndrome
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label study with approximately 500 patients randomized to two treatment 
arms in approximately 120 sites.
The investigator will select one of the protocol-approved neoadjuvant chemotherapy 
regimens with which to treat the patient (see Section 3.1). Switching from one type of 
chemotherapy to another is not permitted. 
Using an interactive voice or web-based response system (IxRS), patients will be 
randomized in a 1:1 ratio to one of the two treatment arms using a permuted-blocks 
randomization procedure and stratified according to the following factors:  

Hormonal-receptor status (based on central assessment):
–
ER-positive or PgR-positive
–
ER-negative and PgR-negative 

Clinical stage at presentation 
–
Stage IIIIIA
–
Stage IIIBIIIC


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
Type of chemotherapy:
–
ddAC followed by paclitaxel 
–
AC followed by docetaxel
The Study Management Team is, by definition, unblinded given the open-label nature of 
this study. However, to further protect the integrity of the study, any treatment 
assignment information, such as the randomization file from the IxRS and PK data, will 
be withheld from the Sponsor until the primary analysis. Data for safety purposes will 
not be reviewed at an aggregate level prior to the primary analysis by the Study 
Management Team.
For data reviews by the iDMC, there will be blinded and unblinded analyses conducted 
by an independent Data Coordination Center (iDCC). Further details are in Section 9.4
and will be written into a separate iDMC Charter.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are Perjeta® IV, 
Herceptin® IV, Herceptin® SC, and the SC FDC of pertuzumab and trastuzumab.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Perjeta IV
Pertuzumab (RO4368451/F01-01) will be supplied by the Sponsor as a single-use vial 
containing 14 mL preservative free sterile, colorless to slightly brownish concentrate at a 
concentration of 30 mg/mL for dilution in a 250 mL polyvinyl chloride (PVC) or non-PVC 
polyolefin infusion bag of 0.9% sodium chloride. The IV formulation contains 30 mg/mL
in L-histidine acetate buffer with excipients sucrose and polysorbate 20. Each vial of 
drug product concentrate contains a total 420 mg of pertuzumab.
For information on the formulation and handling of Perjeta IV, see the 
Perjeta Investigator's Brochure.
4.3.1.2
Herceptin IV
Trastuzumab IV (RO0452317/V03-03) will be supplied by the Sponsor and is supplied 
for use as a freeze-dried preparation at a nominal content of 150 mg per vial for 
parenteral administration. The drug is formulated in histidine/histidine-HCl, ,
-trehalose dihydrate, and polysorbate 20.
For information on the formulation and handling of Herceptin IV, see the 
Herceptin Investigator's Brochure.
4.3.1.3
Herceptin SC
Herceptin SC (RO0452317/F07-02) will be supplied by the Sponsor as a sterile, 
colorless to slightly brownish concentrate solution for SC injection containing 120-mg/mL 


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of RO0452317 in L-histidine/histidine-HCl buffer containing excipients trehalose, 
polysorbate 20, methionine, and rHuPh20 (2000 U/mL). Each 5-mL vial contains 
600 mg RO0452317 (5.0 mL/vial).
For information on the formulation and handling of Herceptin SC, see the 
Herceptin Investigator's Brochure.
4.3.1.4
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab
Two different doses of the FDC of pertuzumab and trastuzumab will be supplied by the 
sponsor:

FDC loading dose (RO7198574/F03-01) is a sterile, colorless to slightly brownish 
solution for injection containing histidine, hydrochloric acid, trehalose, sucrose, 
polysorbate 20, methionine, and rHuPH20 (2,000 U/mL). Each 20ml vial contains 
1200 mg of pertuzumab (RO4368451) and 600 mg of trastuzumab (RO0452317) in 
15mL of solution.

FDC maintenance dose (RO7198574/F04-01) is a sterile, colorless to slightly 
brownish solution for injection containing histidine, hydrochloric acid, trehalose, 
sucrose, polysorbate 20, methionine, and rHuPH20 (2,000 U/mL). Each 15ml vial 
contains 600 mg of pertuzumab (RO4368451) and 600mg of trastuzumab 
(RO0452317) in 10mL of solution.
For information on the formulation and handling of the FDC of pertuzumab and 
trastuzumab, see the Pertuzumab and Trastuzumab FDC Investigator's Brochure.
4.3.1.5
Chemotherapy, Hormone Therapy, and Granulocyte 
Colony-Stimulating Factor
Doxorubicin, cyclophosphamide, paclitaxel, docetaxel, G-CSF, and adjuvant hormone 
therapy are administered in accordance with local prescribing information and these 
drugs are not regarded as IMPs. These drugs will be obtained locally by the 
investigational sites or will be provided by the Sponsor as per country requirements. 
Refer to the respective Summary of Product Characteristics (SmPC) or other appropriate 
local reference document for information on formulation, preparation, administration, 
contraindications, and patient monitoring. 
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
Any overdose or incorrect administration of Perjeta IV, Herceptin IV, Herceptin SC, or 
the SC FDC of pertuzumab and trastuzumab should be noted on the Study Drug 
Administration electronic Case Report Form (eCRF).  Adverse events associated with an 
overdose or incorrect administration of any of the study treatments should be recorded
on the Adverse Event eCRF. Section 5.4.5.11 summarizes available safety data related 
to overdosing of Perjeta IV, Herceptin IV, Herceptin SC, or the SC FDC of pertuzumab 
and trastuzumab.


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Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.2.1.
4.3.2.1
Arm A:  Perjeta IV plus Herceptin IV
In Arm A, Perjeta is given as a fixed nonweight-based dose of 840-mg IV loading dose 
and then 420-mg IV Q3W.  Herceptin is given as an 8-mg/kg IV loading dose and then 
6 mg/kg IV Q3W.  The order of administration of Perjeta and Herceptin is according to 
investigator preference.  Chemotherapy should be given after Perjeta and Herceptin.
Treatment will continue as scheduled (see Sections 4.3.2.3 and 4.3.2.4), or until 
investigator-assessed radiographic or clinical progression or recurrence of disease or 
unmanageable toxicity.
Weight should be recorded during screening and on Day 1 of each cycle for all patients.  
The baseline weight for a patient will be that measured on Cycle 1, Day 1.  The amount 
of Herceptin to be administered must be recalculated if the patient’s body weight has 
changed by 10% (increased or decreased) from the Cycle 1, Day 1 weight.  The 
amount of Herceptin administered is calculated according to the patient’s actual body 
weight with no upper limit.
The dose of doxorubicin, cyclophosphamide, paclitaxel, and docetaxel is calculated 
according to the patient’s body surface area (BSA).  The BSA and the dose of drug 
administered must be recalculated if the patient’s body weight has changed by 10% 
(increased or decreased) from the Cycle 1, Day 1 weight.  Recalculation of the dose of 
drug administered on the basis of smaller changes in body weight or BSA is at the 
investigator’s discretion.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Sections 5.2.15.2.4.  No dose reductions are allowed for Perjeta or 
Herceptin.  If the patient misses a dose of Perjeta or Herceptin for any cycle and the time 
between doses is 6 weeks, a reloading dose of Perjeta or Herceptin (840 mg and 8 
mg/kg, respectively) should be given.  Subsequent maintenance Perjeta (420 mg) and 
Herceptin (6 mg/kg) doses will then be given every 3 weeks, starting 3 weeks later.  In 
the neoadjuvant period, if the time between doses is 9 weeks, then the patient will 
discontinue study treatment and enter follow-up.
After surgery, patients continue to receive Perjeta and Herceptin in the adjuvant setting 
until a total of 18 cycles of Perjeta and Herceptin have been administered during the 
study (neoadjuvant and adjuvant).  Adjuvant Perjeta and Herceptin treatment should not 
start until 2 weeks after surgery. If the interval between the first dose of adjuvant Perjeta 
and Herceptin and the last dose of neoadjuvant Perjeta and Herceptin exceeds 6 weeks, 
a reloading dose of 840 mg of Perjeta and 8 mg/kg of Herceptin is required. The interval 
between the last dose of neoadjuvant Perjeta and Herceptin and the first dose of 
adjuvant Perjeta and Herceptin should be 9 weeks.


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Perjeta IV
The initial dose of Perjeta IV will be administered over 60 (10) minutes, and patients 
will be observed for an additional 60 minutes.  The infusion should be slowed or 
interrupted if the patient experiences infusion-related symptoms.  If the infusion is well 
tolerated, subsequent infusions may be administered over 30 (10) minutes, and 
patients will be observed for an additional 30 minutes for infusion-related symptoms 
such as fever or chills.  All infusion-related symptoms must have resolved before 
Herceptin or chemotherapy is given or the patient is discharged.  Patients who 
experience infusion-related symptoms may be premedicated with analgesics and 
antihistamines for subsequent infusions. Dose reductions for toxicity are not allowed.
Herceptin IV
The initial dose of Herceptin IV will be administered over 90 (10) minutes, and patients 
will be observed for at least 30 minutes from the end of the infusion for infusion-related 
symptoms such as fever or chills.  Interruption or slowing of the infusion may help control 
such symptoms and may be resumed when symptoms abate.  If the infusion is well 
tolerated, subsequent infusions may be administered over 30 (10) minutes, and 
patients will be observed for an additional 30 minutes.  All infusion-related symptoms 
must have resolved before Perjeta or chemotherapy is given or the patient is discharged.  
Patients who experience infusion-related symptoms may be premedicated with 
analgesics and antihistamines for subsequent infusions. Dose reductions for toxicity are 
not allowed. Patients can be observed for a longer period at the discretion of the 
investigator or, if necessary, as per local requirements.
Herceptin SC
From Cycle 9 onwards, patients in Arm A are allowed to switch from Herceptin IV to 
Herceptin SC, at the discretion of the investigator, in the countries where Herceptin SC 
is routinely used. For patients who switch, a fixed dose of 600-mg Herceptin SC 
(irrespective of the patient’s weight) will be administered in the adjuvant phase. All 
doses of Herceptin SC will be administered as a subcutaneous injection into the thigh 
over about 5 minutes at a rate of no more than 2 mL/min. Patients will be observed for 
30 minutes after all Herceptin SC injections to monitor for injection-related symptoms. 
The injection should be slowed or interrupted if the patient experiences injection-
related symptoms. Patients can be observed for a longer period at the discretion of the 
investigator or if necessary, as per local requirements. Injection-related symptoms must
have resolved before chemotherapy is started unless deemed clinically not significant by 
the investigator. Patients who experience injection-related symptoms may be pre-
medicated with paracetamol and antihistamines for subsequent injections. Dose
reductions for toxicity are not permitted.
4.3.2.2
Arm B:  SC Fixed-Dose Combination of Pertuzumab and 
Trastuzumab
In Arm B, the FDC is given as a fixed nonweight-based dose.  A loading dose of 
1200 mg SC pertuzumab and 600 mg SC trastuzumab is then followed by 600 mg SC 


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pertuzumab and 600 mg SC trastuzumab Q3W. Chemotherapy should be given after 
the FDC.
Treatment will continue as scheduled (see Sections 4.3.2.3 and 4.3.2.4), or until 
investigator-assessed radiographic or clinical progression or recurrence of disease or 
unmanageable toxicity.
Weight should be recorded during screening and on Day 1 of each cycle for all patients.  
The baseline weight for a patient will be the weight measured on Cycle 1, Day 1.  The 
dose of doxorubicin, cyclophosphamide, paclitaxel, and docetaxel is calculated 
according to the patient’s BSA.  The BSA and the dose of drug administered must be 
recalculated if the patient’s body weight has changed by 10% from baseline.  
Recalculation of the dose of drug administered on the basis of smaller changes in body 
weight or BSA is at the investigator’s discretion.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Sections 5.2.15.2.4.  No dose reductions are allowed for the FDC.  If the 
patient misses a dose of the FDC for any cycle and the time between doses is 6 weeks,
a reloading dose of the FDC (1200 mg pertuzumab and 600 mg trastuzumab) should be 
given.  Subsequent maintenance the FDC doses (600 mg pertuzumab and 600 mg 
trastuzumab) will then be given Q3W, starting 3 weeks later.  In the neoadjuvant period, 
if the time between doses is 9 weeks then the patient will discontinue study treatment
and enter follow-up.
After surgery, patients continue to receive the FDC in the adjuvant setting until a total of 
18 cycles of the FDC have been administered during the study.  Adjuvant FDC treatment 
should not start until at least 2 weeks after surgery. If the interval between the first dose 
of adjuvant FDC and the last dose of neoadjuvant FDC is 6 weeks, a reloading dose of 
FDC (1200 mg of pertuzumab and 600 mg of trastuzumab) is required. Subsequent 
maintenance FDC doses (600 mg pertuzumab and 600 mg trastuzumab) will then be 
given Q3W, starting 3 weeks later.  The interval between the last dose of neoadjuvant 
FDC and the first dose of adjuvant FDC should be 9 weeks.
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab
All doses of the FDC will be administered over 58 minutes as a SC injection into the 
thigh at a rate of no more than 2 mL/min.  The loading dose should be administered over 
8 minutes, and the maintenance dose should be administered over 5 minutes. The 
injection rate should be adjusted to a rate that is comfortable for the patient. After the 
first (loading dose) injection, patients will be observed for 30 minutes from the end of the 
injection for injection-related symptoms. The injection should be slowed or interrupted if 
the patient experiences injection-related symptoms. If the first injection is well tolerated, 
patients will be observed for 15 minutes after subsequent injections. Patients can be 
observed for a longer period at the discretion of the investigator or, if necessary, as per 
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chemotherapy is started unless deemed clinically not significant by the investigator. 
Patients who experience injection-related symptoms may be pre-medicated with 
analgesics and antihistamines for subsequent injections. Dose reductions for toxicity are 
not permitted.
The thigh is the only location where the FDC should be administered. The injection site 
of the FDC should be alternated between the left and right thigh. New injections 
should be given at a distance of at least 2.5 cm from the old site and never into areas 
where the skin is red, bruised, tender, or hard.  The entire SC injection (10 mL volume 
for the maintenance dose; 15 mL volume for the loading dose) must be given in one site. 
Splitting the volume into two syringes or injecting at two different sites is not 
permitted.
4.3.2.3
AC→DocetaxelHER2-Targeted Therapy 
Patients receive doxorubicin 60mg/m2 IV and cyclophosphamide 600mg/m2 IV (AC)
Q3W for 4 cycles (Cycles 14). AC is followed (3 weeks later) by docetaxel 75 mg/m2IV,
escalating to 100 mg/m2 IV if no dose-limiting toxicity occurs (at the discretion of the 
investigator). HER2-targeted therapy (Perjeta IV plus Herceptin IV or the FDC) is given 
Q3W from the start of docetaxel (Cycles 58; i.e., 4 cycles in total during the 
neoadjuvant period).  
After surgery, patients continue to receive HER2-targeted therapy in the adjuvant setting 
(Cycles 922) until a total of 18 cycles of HER2-targeted therapy have been given.  
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Sections 5.2.15.2.4.
Doxorubicin
Doxorubicin 60mg/m2 will be administered on Day 1 of each cycle of AC treatment as an 
IV bolus over 35 minutes or as an infusion over 1530 minutes, in accordance with 
local policy.  Patients with BSA of 2 m2 should have their dose capped at 120 mg.  
Dose delays and dose reductions for toxicity are permitted. 
Cyclophosphamide
Cyclophosphamide 600 mg/m2 will be administered on Day 1 of each cycle of treatment 
as an IV bolus over 3-5 minutes or as an infusion, in accordance with local policy.  
Patients with BSA of 2 m2 should have their dose capped at 1200 mg.  Dose delays 
and dose reductions for toxicity are permitted. Oral cyclophosphamide is not permitted.
Docetaxel
Docetaxel is administered as an IV infusion over 60 (10) minutes, after HER2- targeted
therapy, at a starting dose of 75 mg/m2 for the first cycle (Cycle 5). At the investigator’s 
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provided no dose-limiting toxicity occurs. See Section 5.2.4 for details of dose-limiting 
toxicity and guidance on dose escalation and dose reductions.
Premedication, including corticosteroids, should be administered according to routine 
practice.  Patients must be closely observed from the start of the infusion for 
hypersensitivity reactions, which may occur within minutes.  Severe hypotension, 
bronchospasm, or generalized rash/skin reactions/erythema requires immediate 
discontinuation of docetaxel and appropriate treatment.  The infusion may be slowed for 
minor symptoms, such as flushing or local cutaneous reactions.  Patients experiencing 
severe hypersensitivity reactions should be discontinued from study treatment but 
maintained in the schedule of activities unless consent is withdrawn.  Prophylactic 
G-CSF may be used to mitigate the risk of hematologic toxicities according to local 
policies and guidelines.  Treatment of neutropenia with G-CSF is permitted according 
to local policies.  In all cases, G-CSF will not be considered as a study drug and will 
not be provided by the Sponsor. For patients with a history of inflammatory digestive 
disease, it is recommended to refer them to their gastroenterologist for assessment 
before initiating treatment with docetaxel.
4.3.2.4
ddAC→PaclitaxelHER2-Targeted Therapy  
Patients receive doxorubicin 60mg/m2 IV and cyclophosphamide 600mg/m2 IV, Q2W for 
four cycles (ddAC, Cycles 14) with G-CSF support as per local clinical practice. This is 
followed (2 weeks later) by paclitaxel 80 mg/m2 QW for 12 weeks. HER2- targeted
therapy (PerjetaHerceptin IV or the FDC) is given Q3W from the start of paclitaxel
(Cycles 58; i.e., four cycles in total during the neoadjuvant period).  After surgery, 
patients continue to receive HER2-targeted therapy in the adjuvant setting (Cycles 922) 
until a total of 18 cycles of HER2-targeted therapy have been given.  
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Sections 5.2.15.2.4.
Doxorubicin
Doxorubicin 60mg/m2 will be administered on Day 1 of each cycle of ddAC treatment. It 
may be given as an IV bolus over 35 minutes or as an infusion over 1530 minutes, in 
accordance with local policy.  Patients with BSA of 2 m2 should have their dose capped 
at 120 mg.  Dose delays and dose reductions for toxicity are permitted, and patients 
should receive G-CSF support according to local practice guidelines.
Cyclophosphamide
Cyclophosphamide 600 mg/m2 will be administered on Day 1 of each cycle of ddAC 
treatment. It should be given as an IV bolus over 3-5 minutes or as an infusion, in 
accordance with local policy.  Patients with BSA of 2 m2 should have their dose 
capped at 1200 mg.  Dose delays and dose reductions for toxicity are permitted, and 
patients should receive G-CSF support according to local practice guidelines. Oral 
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Paclitaxel
Paclitaxel is administered as an IV infusion over 60 (10) minutes, after HER2- targeted
therapy at a dose of 80 mg/m2.  See Section 5.2.4 for guidance on dose reductions.
Premedication, including corticosteroids, should be administered according to routine 
practice. Patients must be closely observed from the start of the infusion for 
hypersensitivity reactions, which may occur within minutes.  Severe hypotension, 
bronchospasm, or generalized rash/skin reactions/erythema require immediate 
discontinuation of paclitaxel and appropriate treatment.  The infusion may be slowed for 
minor symptoms, such as flushing or local cutaneous reactions.  Patients experiencing 
severe hypersensitivity reactions should be discontinued from study treatment but 
maintained in the schedule of activities unless consent is withdrawn.  Prophylactic 
G-CSF may be used to mitigate the risk of hematologic toxicities according to local 
policies and guidelines.  Treatment of neutropenia with G-CSF is permitted according to 
local policies.  In all cases, G-CSF will not be considered as a study drug and will not be 
provided by the Sponsor. For patients with a history of inflammatory digestive disease, 
it is recommended to refer them to their gastroenterologist for assessment before 
initiating treatment with paclitaxel.
4.3.2.5
Other Required Medication
After surgery, patients with hormone receptor-positive disease should receive adjuvant 
hormone therapy according to guidelines provided in Section 4.4.3.  Postoperative 
radiotherapy is to be given as clinically indicated and as per local practice (see
Section 4.4.2 and Appendix 11). 
All patients may receive full supportive care including anti-emetics (e.g., serotonin 
antagonists such as ondansetron, benzodiazepines), antidiarrheal agents 
(e.g., loperamide), short-term corticosteroids to treat or prevent allergic or infusion 
reactions, H1 and H2 antagonists (e.g., diphenhydramine, cimetidine), analgesics 
(e.g., paracetamol or acetaminophen, meperidine, opioids), and antibiotics as clinically 
indicated.
All concomitant medication (administered within 7 days prior to initiation of study drug) 
and treatment for breast cancer must be reported in the eCRF including:

Date and extent of primary surgery and subsequent re-excision surgery (for positive 
margins), if applicable.  Medication given in association with the surgical procedure 
(e.g., the premedication and anesthetic) need not be reported.

Any locoregional radiation therapy (extent or volume and total dose)

Any hormone therapy or surgical and radiation-induced ovarian ablation and 
drug-induced ovarian suppression (type, drug name, dose and schedule, anticipated 
duration of therapy)

Bisphosphonate therapy

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All concomitant medications are to be reported until the end of study treatment visit 
(28 days after the last dose of study treatment).  Thereafter, only medication applicable 
for long-term reporting must be reported, including:

Breast cancer treatments (e.g., hormone therapy) 

Anti-cancer treatments given to treat a recurrence

Medications related to the treatment of serious adverse events that are applicable 
for long-term reporting (e.g., treatment for heart failure)
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (Perjeta® IV, Herceptin® IV, Herceptin® SC 
and the FDC) will be provided by the Sponsor where required by local health authority 
regulations.  The study site will acknowledge receipt of IMPs, using the IxRS to confirm 
the shipment condition and content.  Any damaged shipments will be replaced.
IMPs either will be disposed of at the study site according to the study site’s institutional 
standard operating procedure or will be returned to the Sponsor (if supplied by the 
Sponsor) with the appropriate documentation.  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 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 Perjeta IV, Herceptin IV, Herceptin SC,
and the FDC
Currently, the Sponsor does not have any plans to provide study drugs (Perjeta IV, 
Herceptin IV, Herceptin SC and the FDC) or any other study treatments or interventions 
to patients who have completed the study.  The Sponsor may evaluate whether to 
continue providing Perjeta IV, Herceptin IV, Herceptin SC, and the FDC in accordance 
with the Roche Global Policy on Continued Access to Investigational Medicinal Product, 
available at the following web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf


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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 in addition to protocol-mandated treatment from 7 days prior to initiation of 
study drug to the treatment completion/discontinuation visit.  All such medications should 
be reported to the investigator and recorded on the Concomitant Medications eCRF.
4.4.1
Surgery
Patients in both cohorts are scheduled to undergo surgery after eight cycles of 
neoadjuvant therapy. Patients may undergo breast-conserving surgery or mastectomy 
according to routine clinical practice.
Before starting neoadjuvant treatment, the primary tumor site should be marked using 
the method, which is routine clinical practice (e.g., skin tattoo or surgical clip) to enable 
appropriate surgical excision in case of tumor regression during neoadjuvant therapy. 
Patients with clinically positive axillary nodes by physical examination or by any 
radiographic imaging at baseline must undergo fine-needle aspiration or core-needle
biopsy prior to randomization. SLNB is not allowed prior to neoadjuvant therapy.
Surgical management options for axillary lymph nodes include SLNB (after neoadjuvant 
treatment) and ALND of Level I and II lymphatics at the moment of breast surgery. The 
choice of the axillary procedure will be based on the clinical status of axilla, T stage, and 
local practice. 
In patients with clinically negative axillary nodes at baseline, axillary surgical
management after completion of neoadjuvant therapy should include SLNB or ALND. 
SLNB is the preferred method of axillary surgical management, if an experienced team is 
available. If SLNB is conducted, it is strongly recommended that more than one lymph 
node (2 to 3 minimum) be removed. All patients with positive macrometastases in 
sentinel nodes should undergo ALND regardless of the number of positive nodes, and it 
is recommended that at least 10 lymph nodes be removed for pathologic examination.
Patients with clinically positive axillary lymph nodes at baseline should undergo ALND at 
time of definitive surgery (after neoadjuvant therapy).  It is recommended that at least 10 
lymph nodes be removed for pathologic examination.
For sentinel nodes involving the internal mammary chain, refer to local, national, or 
international guidelines.
Level III axillary dissections should only be performed for patients with gross disease in 
the Level II nodes.
Investigators may follow more up-to-date guidelines on axilla management based on 
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international guidelines (e.g., NCCN, ESMO, St. Gallen, Lisbon Conference, or 
American Society of Clinical Oncology [ASCO] Clinical Practice Guidelines).
Following completion of neoadjuvant therapy and surgery, pCR (ypT0/is, ypN0) will be 
established via local review. Pathologists who review study specimens must utilize the 
evaluations and assessments outlined in the Pathology Manual. Further details 
regarding pathology evaluation and assessment are outlined in the Pathology Manual
(see Appendix 10).
For patients whose tumor remains inoperable after neoadjuvant treatment, locoregional 
and/or systemic management will be done as per local standard practice. These 
patients will be withdrawn from study treatment and will remain on study for follow-up of 
secondary and exploratory endpoints unless they have withdrawn consent from study 
participation.
Copies of the pathology report(s) from the patient's primary (main) surgery must be 
submitted to the Sponsor within 6 weeks of the date of surgery. If additional information 
on lymph nodes at surgery is present in other reports, these reports should also be 
submitted to the Sponsor. A standardized pathology summary form must also be 
completed and sent to the Sponsor.
Pathology report(s) along with pathology summary forms will be reviewed centrally by an 
independent pathologist.
4.4.2
Radiotherapy 
Before actively enrolling patients, each center must define a radiotherapy policy for 
treating patients in the trial.  General guidelines are given in Appendix 11. If indicated, 
radiotherapy is given after chemotherapy and surgery, during adjuvant HER2-targeted 
therapy and hormone therapy (for hormone-receptor positive disease).
4.4.3
Hormone Therapy 
Before actively enrolling patients, each center must set a policy for the use of tamoxifen, 
ovarian ablation, or both for patients in the trial.  Study sites must also set their local 
policy for the use of registered aromatase inhibitors. For hormone receptor positive-
breast cancer, aromatase inhibitors will be allowed as adjuvant hormone therapy for 
postmenopausal patients and with ovarian suppression or ablation for premenopausal 
patients in countries where it has been registered for this indication.  Its use must be 
consistent with the registered label.  Hormone therapy is given after chemotherapy and 
surgery during adjuvant antibody therapy.
No other hormone therapy for primary breast cancer is allowed, including pure 
anti-estrogens and progestational agents, unless it becomes approved for adjuvant 
therapy during the conduct of the trial.


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Female patients must be classified according to one of the menopausal status definitions 
described in Table 3.
Female patients should be treated according to the recommendations in Table 4;
however, investigators may follow local practice guidelines.  Male patients should be 
treated according to local practice.
Table 3
Menopausal Status Definitions
Status
Criteria
Premenopausal
12 months since last menstrual period, AND
No prior bilateral ovariectomy, AND
Not receiving estrogen replacement, OR
Biochemical evidence of premenopausal status, according 
to local practice
Postmenopausal
12 months since last menstrual period with no prior 
hysterectomy, OR
Prior bilateral ovariectomy, OR
Biochemical evidence of postmenopausal status, 
according to local practice
Table 4
Recommendations for Hormone Therapy for Female Patients
Clinical Scenario
Hormone Therapy
Hormone receptor-negative
Not permitted
Hormone receptor-positive a
and premenopausal b
The following regimens are permitted:  
Tamoxifen for 510 years with or without ovarian 
suppression, as per local policy
Ovarian suppression or ablation with aromatase inhibitors 
5 years) 
Hormone receptor-positive a
and postmenopausal b
The following regimens are permitted: 
Aromatase inhibitor for 5 years
Aromatase inhibitor for 23 years, followed by tamoxifen 
to complete a total of 5 years
Tamoxifen for 23 years, followed by an aromatase 
inhibitor to complete a total of 5 years
Tamoxifen for 510 years, as per local policy
Tamoxifen for 5 years, followed by an aromatase inhibitor 
for 5 years
a Hormone receptor positivity is defined as positive estrogen receptor or progesterone 
receptor or both.  The investigator may treat the patient with adjuvant hormone therapy 
according to local or central results, but central results of hormone receptor status will be 
used in data analyses for the study.  (see Section 4.5.3)
b Menopausal status criteria:  see Table 3.


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4.4.4
Permitted 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 in addition to protocol-mandated treatment from 7 days prior to initiation of 
study drug to the treatment completion/ discontinuation visit.  All such medications 
should be reported to the investigator and recorded on the Concomitant Medications 
eCRF. Patients are permitted to use the following therapies during the study:

Acceptable methods of contraception must be used when the female patient or male 
partner is not surgically sterilized or does not meet the study definition of
postmenopausal (12 months of amenorrhea). See Section 5.1.3 for a list of 
permitted methods of contraception

H1 and H2 antagonists (e.g., diphenhydramine, cimetidine)

Cardiovascular medications: angiotensin-converting enzyme (ACE) inhibitors,
angiotensin receptor blockers, beta blockers, calcium channel blockers and diuretics  
(for treatment of arterial hypertension with a goal to reduce blood pressure < 
140/90mmHg), beta blockers, calcium channel blockers and digoxin (for heart rate
control), 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 

Standard premedications for neoadjuvant chemotherapy, including corticosteroids 
and antiemetics

Standard therapies for (preexisting medical conditions and) medical and/or surgical 
complications

Any medication intended solely for supportive care (e.g., analgesics, antidiarrheals, 
antidepressants) at the investigator’s discretion

Colony-stimulating factors (e.g., G-CSF)

Blood transfusions at the investigator’s discretion 

Estrogen-receptor (ER) antagonists (e.g., tamoxifen) or aromatase inhibitor (AI) for 
postmenopausal patients or tamoxifen with or without ovarian suppression for 
premenopausal patients or aromatase inhibitor with ovarian suppression for 
premenopausal patients initated after surgery, as per local practice and guidelines in 
Section 4.4.3  
Endocrine therapy must not be given concurrently with neoadjuvant therapy. 

Gonadotropin-releasing hormone (GnRH) agonists for fertility preservation

Vitamin and mineral supplements

Bisphosphonates (to be used in accordance with the approved labeled indication 
and/or nationally recognized treatment guidelines)

Any other medication not included in the list of prohibited medications


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In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, per local standard practice.  Patients who experience an
infusion-related reaction may be treated symptomatically with acetaminophen, ibuprofen, 
diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, cimetidine), or 
equivalent medications per local standard practice.  Serious infusion- and injection-
related reactions manifested by dyspnea, hypotension, wheezing, bronchospasm, 
tachycardia, reduced oxygen saturation, or respiratory distress should be managed with 
supportive therapies as clinically indicated (e.g., supplemental oxygen and 2-adrenergic 
agonists).
4.4.4.1
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential DDIs are generally unknown.  However, 
herbal therapies not intended for the treatment of cancer may be used during the study 
at the discretion of the investigator.
4.4.5
Prohibited Therapy
Use of the following concomitant therapies is prohibited as described below:

Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 28 days prior to initiation of study treatment and during study treatment

Any targeted anti-cancer therapy (e.g., lapatinib, neratinib)

Regular systemic treatment with steroids
Exceptions include short-term corticosteroid only to treat and prevent allergic or 
infusion reactions. In the case of short-term corticosteroid administration, the 
dose must not exceed 20 mg/day of dexamethasone (or equivalent) for 7 
consecutive days.

Any investigational agent, except for those used for this study

Any systemically active oral, injected, or implanted hormonal method of 
contraception (see Section 5.1.3 for acceptable contraception methods) except for 
progesterone-coated intrauterine devices (IUDs) that had been previously implanted

Hormone-replacement therapy (HRT) 

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 estrogens (including any intra-vaginal preparations), megestrol acetate, and 
selective ER modulators used with prophylactic intent are prohibited
In the adjuvant setting, postmenopausal women with significant vaginal 
discomfort associated with anti-estrogen therapy may be considered for 
intermittent use of low-dose topical estrogens if non-prescription methods are 
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4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1, 
Appendix 2, Appendix 3, and Appendix 4.  All activities must be performed and 
documented for each patient.  
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment 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 (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  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
Core Biopsy
The diagnosis of primary breast cancer will be performed as per local standard of care. 
Submission of tumor tissue from the core biopsy of the primary tumor (preferred) or 
involved lymph node (if primary tumor cannot be biopsied) is mandatory for the trial.  The 
tissue will be used to confirm HER2 and ER/progesterone receptor (PgR) status and for 
subsequent biomarker research.  Samples must be FFPE, and tumor blocks are 
preferred.  If it is not possible to submit tumor blocks, sites must provide 15 freshly cut 
slides.  Tumor blocks will be returned to the site if there is any remaining tissue after 
central testing and sampling for biomarker research; slides will not be returned.  Patients
will be asked to donate any leftover tissue slides or derivatives thereof (after central 
testing and sampling for mandatory biomarker research) for future optional research 
(see Section 4.5.13).
A 14-gauge needle is recommended, using an automatic device fired 34 times into the 
lesion to collect sufficient tumor tissue.  
4.5.3
HER2 Screening for Eligibility and Central Assessment of 
Hormone Receptor Status
Patients should be initially screened for HER2 status by the local laboratory and should 
have an HER2 score of 3by IHC or HER2 (c-erbB2) gene amplification by ISH (i.e., 
fluorescence in situ hybridization [FISH], silver in situ hybridization [SISH], or 
chromogenic in situ hybridization [CISH]) to qualify for central laboratory screening (see 
Figure 3). 


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For central confirmation, HER2 positivity is defined as IHC 3in 10% of 
immunoreactive cells or c-erbB2 gene amplification by ISH (ratio of c-erbB2 gene signals 
to centromere 17 signals 2.0). 
Central laboratory confirmation of a positive HER2 status is required prior to enrollment 
in the study.  The outcome of this assessment will be communicated to the investigator. 
In addition, central assessment of hormone receptor status (ER and PgR) will be 
conducted according to ASCO/College of American Pathologists guidelines (Hammond 
et al. 2010).  The results will be communicated to the investigator.  The investigator may 
treat the patient with adjuvant hormone therapy according to local or central results, but 
central results of hormone receptor status will be used in data analyses for the study.  
Only patients who are HER2-positive by central confirmation will be allowed to enter the 
study; patients with overall negative and equivocal scores will be excluded from entry 
into the study.


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Figure 3
HER2 Screening Procedure 
CISHchromogenic in situ hybridization; HER2 human epidermal growth factor receptor 2; 
IHCimmunohistochemistry; ISHimmunohistochemistry; FISHfluorescence in situ 
hybridization; SISH silver in situ hybridization.
Note:  HER2 positivity by central testing is defined as the following: IHC 3in 10% of 
immunoreactive cells or HER2 gene amplification by ISH (ratio of HER2 gene signals to 
centromere 17 signals 2.0).
4.5.4
Medical History, Concomitant Medication, and Demographic 
Data
Medical history will include clinically significant diseases within the last 5 years, breast 
cancer history (including prior cancer therapies and procedures and tumor 
characteristics [e.g., hormone receptor status, local HER2 status]), complete 
cardiovascular history, cardiac risk factors, smoking history, and all medications
(e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
nutritional supplements) used by the patient within 7 days prior to initiation of study drug.
Demographic data will include age, sex, and self-reported race/ethnicity.  Race/ethnicity 
is recorded because racial and regional differences in toxicity have been reported in 
previous Perjeta trials.  These differences are thought to be due to known 
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4.5.5
Physical Examinations
Physical examination includes an assessment of vital signs, physical measurements 
(body weight in kilograms and height in centimeters), and an examination of the breast, 
neck, axilla, chest, and abdomen. ECOG Performance Status will also be assessed. 
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.
The initial breast cancer assessment should be performed by the physician who will 
assess the patient’s tumor for clinical response during neoadjuvant therapy.  
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF form. If the patient shows 
disease progression, this should be recorded on the Disease Status eCRF form.
4.5.6
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure (while the patient is in a seated position), and temperature.
4.5.7
Radiology
4.5.7.1
Breast Imaging 
Bilateral mammogram must be obtained at screening and at treatment completion or 
treatment discontinuation visit. A mammogram prior to surgery (at Cycle 8) is
recommended. Mammograms are mandated every 12 months during the follow-up 
period. Patients who have undergone mastectomy do not require mammograms of 
reconstructed breast(s).  
The bilateral mammogram at screening, pre-surgery, and study completion or early 
termination can be replaced by another conventional imaging method, such as magnetic 
resonance imaging (MRI) or ultrasound per local medical practice, at the investigator’s 
discretion, but the same method of assessment must be used throughout for an 
individual patient.
4.5.7.2
Tumor Staging
Baseline distant sites tumor staging procedures are not mandatory and should be 
performed as per local practice, in alignment with national guidelines and as clinically 
indicated, within 28 days prior to randomization.
As a reference, as per NCCN guidelines, staging procedures are based on clinical stage:

Stage IIAIIB: Bone scan is to be performed in presence of bone pain and/or 
elevated ALP; abdominal/pelvic PET/CT scan in case of elevated ALP, abnormal 
liver function tests, abdominal symptoms or abnormal physical examination; and 
chest PET/CT scan if pulmonary symptoms are present.


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
Stage IIIAIIIC: Bone scan and PET/CT scan of chest, abdomen, pelvis; liver 
imaging, and/or other radiographic modalities may be considered when clinically
indicated to exclude metastatic disease.
4.5.8
Cardiac Function
All patients must have a LVEF measurement of at least 55% by ECHO (preferably) or 
MUGA scan prior to enrollment. The same method of LVEF assessment (ECHO or 
MUGA) should be used for the same patient throughout the study and, to the extent 
possible, should be obtained at the same institution. 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 monitoring on more than four 
occasions within 1 year. Patients must also have an assessment for history of cardiac 
events, a physical examination, and a baseline ECG prior to enrollment to exclude any 
cardiac condition that would render them ineligible for participation in this trial.  An ECG
will also be performed after completion of anthracycline chemotherapy (and prior to the 
first cycle of HER-2 targeted therapy/taxane) and thereafter as clinically indicated. 
Cardiac function will be assessed locally according to the schedule of activities (see
Appendix 1, Appendix 2, Appendix 3, and Appendix 4).  ECG, ECHO, and MUGA scan 
reports are considered source documents and should be retained in the patient's 
medical records.
4.5.9
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology: white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, 
hematocrit, platelet count, differential count (percentage or absolute for neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells).  During adjuvant
HER2-targeted treatment, complete blood counts, including differential and platelets, 
are scheduled as per local practice for adjuvant Herceptin monotherapy. 

Serum chemistry:  sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen (BUN) or urea, creatinine, albumin, total bilirubin, ALP, ALT, AST, total 
bilirubin and direct/indirect bilirubin (if needed).  Bilirubin fractions (direct and 
indirect) need to be measured only if total bilirubin is greater than ULN.  Bicarbonate 
should only be tested at sites where this test is part of the standard safety laboratory 
panel.
Limited serum chemistry includes only creatinine, ALP, AST, ALT, total 
bilirubin, and direct/indirect bilirubin (if needed).  Bilirubin fractions (direct and 
indirect) need to be measured only if total bilirubin is greater than ULN.

Pregnancy test:  all women of childbearing potential (see definition in Section 4.1.1) 
will have a serum pregnancy test at a local laboratory within 7 days prior to the first 
administration of study medication.  For all other women, documentation must be 
present in medical history confirming that the patient is not of childbearing potential.  
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indicated) according to the Schedule of Activities (see Appendix 1, Appendix 2, 
Appendix 3, and Appendix 4).  Any positive urine pregnancy test must be confirmed 
with a serum (beta-human chorionic gonadotropin) -HCG evaluation at the local 
laboratory.  Pregnancy test results must be available prior to the next scheduled 
study treatment.  Women who have undergone surgical sterilization or are 
postmenopausal are exempt from pregnancy assessments.
The following samples will be sent to the Sponsor or a designee for analysis:

Serum and plasma samples for immunogenicity (ADA) assessments (pertuzumab, 
trastuzumab, rHuPH20)

Serum and plasma samples for PK analysis (pertuzumab, trastuzumab, rHuPH20)

Newly collected tumor tissue sample obtained at baseline for determination of HER2, 
ER and PgR status (mandatory) and for exploratory research on biomarkers
A representative FFPE tumor specimen in a paraffin block (preferred) or at 
least 15 slides containing unstained, freshly cut, serial sections must be 
submitted along with an associated pathology report prior to study enrollment.  
If only 1014 slides are available, the patient may still be eligible for the study, 
after Medical Monitor approval has been obtained. In case the submitted tumor 
tissue specimen is not sufficient to allow eligibility at screening the submission
of an additional sample is required.
Tumor tissue should be of good quality based on total and viable tumor content
with cellular context and tissue architecture preserved regardless of needle 
gauge or retrieval method. Samples collected via resection, core-needle 
biopsy, or incisional, punch, or forceps biopsy are acceptable. Fine-needle 
aspiration (defined as samples that do not preserve tissue architecture and 
yield cell suspension and/or smears), brushing, cell pellets from pleural 
effusion, and lavage samples are not acceptable. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.13), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exception(s):

Serum and plasma samples collected for PK and immunogenicity analysis may be 
needed for additional immunogenicity characterization and PK and immunogenicity 
assay development and validation; therefore, these samples will be destroyed no 
later than 5 years after the final Clinical Study Report has been completed.

Tumor tissue and blood based samples collected for biomarker research will be 
destroyed no later than 5 years after the final Clinical Study Report has been 
completed.


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
For enrolled patients, remaining tissue blocks will be returned to the site upon 
request or 18 months after final closure of the study database, whichever occurs 
first.  For patients who are not enrolled, remaining tissue blocks will be returned to 
the site no later than 6 weeks after eligibility determination.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
4.5.9.1
PK Sampling
The primary endpoint of this study is Ctrough and therefore adherence to the PK 
assessment schedule is of utmost importance. For each day of a scheduled PK 
assessment, the exact time of Perjeta and Herceptin or FDC administration and blood 
collection for PK assessments will need to be recorded in the eCRF. 
Blood samples for PK analysis will be collected as described in Appendix 1, Appendix 2, 
Appendix 3, and Appendix 4. 
For PK samples that are required on the day of IV dosing, the PK blood samples need to 
be drawn from the arm not receiving the Perjeta and Herceptin infusion for patients in 
Arm A. If a patient is unable to provide venous access of the opposite arm from the 
infusion arm, the hand or leg may be used for PK blood sampling. 
For patients in Arm B, blood should be drawn from the arm. If a patient is unable to 
provide venous access from the arm, the hand or leg may be used for PK blood sampling. 
If the leg is used to collect a PK blood sample, the area where the FDC has been 
administered must be avoided. 
Collecting blood for PK samples from a central line and/or port is not allowed. 
However, if there is no possible way to avoid a central line and/or port, it is better to 
collect the PK sample than to not collect it at all, but the site of collection must be 
documented on the sample requisition form. For cases where a central line/port must be 
used, the PK sample must be collected prior to chemotherapy administration.  If the 
central line and/or port has been used for a saline flush, avoid collecting the PK sample 
until 5 minutes has passed, to avoid dilution of the PK sample. 
Blood samples drawn prior to drug administration will give information on serum trough 
levels of pertuzumab and trastuzumab.


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The time of sampling at the end of the Perjeta and Herceptin infusions (IV arm) must be 
within 15 minutes after each infusion has ended and before chemotherapy is administered. 
On dosing days, PK samples must be taken on the exact day when HER2-targeted 
therapy is administered (no window allowed). On non-dosing days (SC and IV arms) all
samples must be taken on the exact day of the visit schedule whenever possible (a 
2 day window is allowed if necessary). 
If a patient's Cycle 8 dose is going to be delayed by more than 2 days, the Cycle 7 
Ctrough (i.e., pre-dose Cycle 8) sample should be collected 21 days after the infusion in 
Cycle 7.
The time of sampling is at the discretion of the investigator with the requirement to 
record the exact date and time of sampling.
For patients receiving paclitaxel, if a PK sample needs to be collected on the same day 
that paclitaxel will be administered (i.e., on Day 15 of Cycle 5 and on Days 8 and 15 of 
Cycle 7), the PK sample must be taken before paclitaxel administration.
For the follow-up Months 3 and 6 samples, a window of 7 days from the scheduled 
visit date is allowed.
The procedures for the collection, handling, and shipping of PK samples are specified in 
the laboratory manual.
4.5.10
Clinical Tumor Response Evaluations
Clinical breast examination (CBE) includes examination of the breast, axilla, and 
supraclavicular fossa.  Patients with breast tumors 2 cm at baseline will have their 
clinical response assessed as complete response (CR), partial response (PR), stable 
disease (SD), or progressive disease (PD), as determined by CBE. Other methods of 
evaluation (i.e., mammogram or ultrasound) can be used in addition, as per local 
practice.  Patients whose disease does not meet this criterion (i.e., those with only 
node-positive disease and tumors 2 cm) will have their clinical response assessed as 
CR, SD, or PD (but not as PR, since the tumors are too small to measure this response 
accurately), as determined by CBE. Other methods of evaluation (i.e., mammogram or 
ultrasound) can be used in addition, as per local practice.  All patients, irrespective of 
the size and measurability of the primary tumor and locoregional lymph nodes, are 
evaluable for disease progression by CBE (with other methods of evaluation in addition, 
as per local practice) and will be included in the calculation of clinical response rate.
During the neoadjuvant treatment period (prior to surgery), tumor response will be 
assessed prior to each new cycle of therapy by CBE (mandatory) and other methods of 
evaluation in addition, (as per local medical practice) according to the schedule of 
activities (see Appendix 1 and Appendix 2). Response will be assessed as CR, PR, SD,


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or PD by the investigator. Provided that the patient’s clinical status has not changed, the 
screening mammogram can be performed up to 42 days prior to the start of treatment.  
The mammogram at screening, presurgery, and final visit/withdrawal can be replaced by 
MRI or ultrasound at the investigator’s discretion, but the same method of assessment 
must be used throughout for an individual patient. Tumor measurements should be 
made by the same investigator or radiologist for each patient during the study to the 
extent that this is feasible.  In case of clinically measurable superficial (such as skin) 
lesions, repeated photographs should be used to document tumor response.  These 
photos must include a ruler for documentation purposes. 
After completion of neoadjuvant therapy and prior to surgery, an additional tumor 
response assessment is required, including a CBE and mammogram. Other methods of 
evaluation can be used in addition. 
After surgery, CBE will continue according to the schedule of activities (see Appendix 3
and Appendix 4) to detect signs of locoregional relapse.
Results of any additional methods of assessment (such as ultrasound, X-rays, or MRI) 
may be included in the assessment of response as per routine practice (results and 
modalities will be collected in the eCRF).  If the lesion shows clear signs of progression, 
the patient will be withdrawn from study treatment and provided with the local standard 
of care. 
Discovery of ipsilateral or contralateral DCIS or LCIS during neoadjuvant treatment 
period will not be considered PD.  However, invasive contralateral breast carcinoma will 
be classified as PD.
Clinical responses will be assessed locally and will not be independently reviewed.
4.5.11
Pathologic Response Evaluation
Pathologic response will be assessed by the local pathologist using guidelines provided 
in a Pathology Manual (see Appendix 10).  A complete pathologic response (pCR) is 
defined as the absence of residual invasive disease on hematoxylin and eosin 
evaluation of the complete resected breast specimen and all sampled regional lymph 
nodes (tpCR; i.e., ypT0 or ypTis, ypN0) based on microscopic examination of the surgical 
specimen following neoadjuvant therapy, in line with the U.S FDA and European 
Medicines Agency (EMA) guidance for industry on pCR endpoints.  tpCR rate is the 
main efficacy endpoint of the study. Molecular assay for analysis of sentinel lymph 
nodes after neoadjuvant therapy is not allowed.
Copies of the pathology report(s) from the patient's primary (main) surgery must be 
submitted to the Sponsor within 6 weeks of the date of surgery. If additional information 
on lymph nodes at surgery is present in other reports, these reports should also be 


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submitted to the Sponsor. In addition, a standardized pathology summary form must
also be completed and sent to the Sponsor along with the pathology reports.
Pathology report(s) along with pathology summary forms will be reviewed centrally, by 
an independent pathologist who will be blinded to treatment arm.
4.5.12
Diagnosis of Breast Cancer Progression or Recurrence
During the neoadjuvant treatment, diagnosis of disease progression or second primary 
breast cancer should be supported by clinical, laboratory, radiological, and/or histological 
finding. In the adjuvant period, all patients must be followed to assess disease 
recurrence, second primary cancer, and survival. The designation of disease 
recurrence, whether local, regional or distant, or a diagnosis of a second primary cancer 
can be made only when clinical, laboratory, radiological and/or histological findings 
support diagnosis. During the adjuvant portion of this study, disease status should be 
clinically evaluated and documented every 3 months for up to 1 year after completion of 
HER2-targeted therapy and at intervals of every 6 months for up to 3 years, thereafter.
The diagnosis of a breast cancer progression, recurrence or second primary tumor 
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. 
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.
Types of recurrent disease are listed below, along with acceptable methods of
confirmation of recurrence. The method of assessment used to confirm recurrence 
should be as per local practice. Invasive disease must be positively identified in
accordance with the pathology guidance.
a)
Local invasive recurrence

In the ipsilateral breast after previous lumpectomy
Defined as evidence of invasive tumor (except DCIS and LCIS) in the ipsilateral 
breast after lumpectomy. Patients who develop clinical evidence of tumor 


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recurrence in the remainder of the ipsilateral breast should have a biopsy of the 
suspicious lesion to confirm the diagnosis. 
–
Positive histology or cytology

Ipsilateral after previous mastectomy
Defined as evidence of invasive tumor in any soft tissue or skin of the ipsilateral 
chest wall. This includes the area bounded by the midline of the sternum, extending 
superiorly to the clavicle, and inferiorly to the costal margin. Soft tissue recurrences 
in this area extending into the bony chest wall or across the midline will be 
considered as evidence of local recurrence.
–
Positive histology or cytology
b)
Regional recurrence
Defined as the development of tumor in the ipsilateral internal mammary lymph 
nodes, ipsilateral axillary lymph nodes or supraclavicular lymph nodes as well as 
extranodal soft tissue of the ipsilateral axilla. Regional recurrence does not include 
tumor in the opposite breast.
–
Positive histology or cytology, or
–
Chest X-ray, PET/CT-scan or MRI (especially in case of internal mammary 
lymph nodes, if no biopsy was performed)
c)
Distant recurrence
Defined as evidence of tumor in all areas, with the exception of those described in 
Sections a) and b) above
The following criteria apply:

Skin, subcutaneous tissue, and lymph nodes (other than local or regional)
–
Positive cytology, aspirate or biopsy, or
–
Radiological (by PET/CT scan or MRI or ultrasound) evidence of 
metastatic disease

Bone
–
X-ray, PET/CT scan, or MRI evidence of lytic or blastic lesions consistent 
with bone metastasis, or
–
Bone scan (requires additional radiological investigation, alone not 
acceptable in case of diagnostic doubt), or
–
Biopsy proof of bone metastases or cytology

Bone marrow
–
Positive cytology or histology or MRI scan

Lung
–
Radiologic evidence of multiple pulmonary nodules consistent with 
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Positive cytology or histology (practically rarely performed with the 
exception of solitary nodules)
Note:  For solitary lung lesions, cytological or histological confirmation should 
be obtained in case of diagnostic doubt. Proof of neoplastic pleural effusions 
should be established by cytology or pleural biopsy.

Liver
–
Abdominal PET/CT scan, liver scan, ultrasound, or MRI consistent with 
liver metastases, or
–
Liver biopsy or fine-needle aspiration
Note:  If radiological findings are not definitive (especially with solitary liver 
nodules) a liver biopsy is recommended; however, if a biopsy is not performed, 
serial scans should be obtained if possible to document stability or progression.

CNS (please note that these recurrences should be reported at any time)
–
MRI or PET/CT scan, usually in a patient with neurologic symptoms,
consistent with CNS metastases or
–
Biopsy or cytology (e.g., for a diagnosis of meningeal involvement). 
However, meningeal involvement may also be diagnosed by PET/CT scan 
or MRI and depending from the general status of the patient additional 
investigations (including cytology of the cerebrospinal fluid).
d)
Contralateral invasive breast cancer
–
Positive cytology or histology
e)
Second primary malignancy (breast or other cancer)
Any positive diagnosis of a second (non-breast) primary cancer, with the exception 
of non-melanoma skin cancers and carcinoma in situ of any site, will be considered
an event in the analysis of the invasive disease-free survival including second 
primary non-breast cancer endpoint, however, they will not be included in the iDFS 
endpoint.
LCIS of the breast and myelodysplastic syndrome are not considered progression 
events.
The diagnosis of a second primary cancer must be confirmed histologically.
All second primary malignancies are to be reported whenever they occur during the
study.
Note:  Patients diagnosed with a second primary malignancy not requiring systemic
therapy (i.e., chemotherapy, hormonal therapy, targeted treatment, etc) and with no
evidence of breast cancer recurrence will remain on study and should continue with 
study treatment according to the protocol and schedule of activities, if considered by 
the investigator to be in the patient’s best interest, whenever possible.
f)
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Any death occurring without prior breast cancer recurrence or second (non-breast)
malignancy is considered an event for the following endpoints: iDFS, iDFS including 
second primary non-breast cancer, DFS, and OS.
g)
Other events
The following events are NOT considered recurrent disease, but must be recorded:

Ipsilateral and contralateral LCIS 

Ipsilateral and contralateral DCIS

Carcinoma in situ of the cervix

Basal or squamous cell carcinoma of the skin
Following recurrence, all patients should be followed for survival according to the 
schedule of activities (see Appendix 4).  In addition, LVEF assessments should continue 
to be performed every 6 months for 2 years after discontinuation of IV or the FDC and
then annually for an additional year.  Heart failure occurring at any time during the study 
and for up to 3 years after the last patient completed HER2-targeted therapy must be 
reported irrespective of the initiation of alternative treatment and irrespective of any 
causal relationship.  Pregnancy tests should also continue and pregnancies should be 
reported until 7 months after the last dose of study treatment, irrespective of disease 
progression or relapse or the initiation of alternative treatment.  Related serious adverse 
events and non-breast second primary malignancies (reportable as serious adverse 
events) should also be reported until the end of the study.
4.5.13
Optional Samples for Research Biosample Repository
4.5.13.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research. RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
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4.5.13.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RBR sampling, this section of the protocol (Section 4.5.13) will not be 
applicable at that site.
4.5.13.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to breast cancer:

Leftover or unused tumor tissue submitted at baseline (with the exception of 
remaining archival tissue blocks, which will be returned to sites) 

Residual tumor (in patients with residual disease) or tumor bed (in patients with no 
residual disease) obtained from surgical specimens after completion of neoadjuvant 
therapy (for details, see Appendix 10 for the Pathology Manual)

Left over or unused blood-based samples (e.g., plasma or serum) collected for 
biomarker research, PK or ADA and any derivatives thereof (e.g., DNA, RNA, 
proteins, peptides)
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic mutations via whole genome sequencing (WGS), whole exome sequencing 
(WES), next-generation sequencing (NGS), or other genomic analysis methods. 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches.  Data will be analyzed in the 
context of this study but will also be explored in aggregate with data from other studies.  
The availability of a larger dataset will assist in identification of important pathways, 
guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.13.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification 
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Patient medical information associated with RBR specimens 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.
Given the complexity and exploratory nature of the analyses of RBR specimens, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.13.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.
4.5.13.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
consent at any time for any reason.  However, if RBR specimens have been tested prior 
to withdrawal of consent, results from those tests will remain as part of the overall 
research data.  If a patient wishes to withdraw consent to the testing of his or her 
specimens, the investigator must inform the Medical Monitor in writing of the patient's 
wishes through use of the appropriate RBR Subject Withdrawal Form and, if the trial is 
ongoing, must enter the date of withdrawal on the RBR Research Sample Withdrawal of 
Informed Consent eCRF.  The patient will be provided with instructions on how to 
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does not, by itself, constitute withdrawal of specimens from the RBR.  Likewise, a 
patient's withdrawal from the RBR does not constitute withdrawal from Study WO40324.
If a patient wishes to withdraw consent to the testing of his or her specimens after 
closure of the site, the investigator must inform the Sponsor by emailing the study 
number and patient number to the following email address:
global_rcr-withdrawal@roche.com
4.5.13.7
Monitoring and Oversight
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.
4.6
TIMING OF ASSESSMENTS
4.6.1
Procedures for Enrollment of Eligible Patients
After written informed consent has been obtained, the study site will report preliminary 
screening of the patient to the Sponsor or the Sponsor’s representatives. After all 
required screening test results have been performed (according to the inclusion and 
exclusion requirements) and central HER2 positivity has been confirmed, the patient can 
be enrolled into the study by using the IxRS. Baseline tests not obtained during the 
screening period or within the specified window should then be completed. Patient 
identification numbers will be allocated sequentially in the order in which patients are 
screened. Patients should receive their first dose of study drug on the day of 
randomization, if possible. If this is not possible, the first dose should occur no later 
than 3 days after randomization.
The investigator or designee will then enter the patient’s data into the eCRF, which will 
be used for electronic data capture (EDC). A patient enrollment list must be maintained 
by the investigator.
4.6.2
Assessments During Treatment
Please see Appendix 1, Appendix 2, and Appendix 3 for the schedule of activities to be 
performed during the treatment period.
All assessments must be performed on the day of the specified visit, unless a time 
window is specified in the schedule of activities (see Appendix 1, Appendix 2, and
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day of study treatment administration should be performed prior to administration of 
study treatment, unless otherwise noted in the schedule of activities.
Otherwise, during the treatment period, a window of 3 days applies to all visits, unless 
otherwise specified.
All assessments must be performed before study treatment administration on Day 1 of 
the cycle or up to 3 days prior, unless otherwise specified.
During the treatment period, pregnancy test and LVEF results must be available prior to 
the administration of the next treatment cycle.
4.6.3
Assessments at the Treatment Completion/Discontinuation 
Visit
Patients who complete study treatment (defined as 8 cycles of chemotherapy and 
18 cycles of HER2-targeted therapy) or discontinue from all study treatment early will be 
asked to return to the clinic 28 days (3 days) after the last dose of study drug for a 
follow-up visit. If a patient has PD or relapse, the visit at which this is determined may 
be used as the treatment completion/early discontinuation visit.
Please see Appendix 3 for the schedule of activities to be performed at the treatment
completion/discontinuation visit.
4.6.4
Follow-Up Assessments
After study treatment is complete and the end of study treatment safety follow-up visit 
has taken place, all patients should continue to be followed according to the schedule 
outlined in Appendix 4. In the case of premature discontinuation of chemotherapy (but 
continuation of HER2-targeted therapy), patients should continue to be followed as per 
Appendix 1, Appendix 2, and Appendix 3. If all study treatment is discontinued early (for 
disease progression, relapse, or another reason), patients should continue to be 
followed according to Appendix 4.
All patients must be followed until approximately 3 years after the last patient’s last 
treatment, even if their assigned treatment is discontinued early. For this reason, some 
patients will be followed for more than 5 years (because of the 12-month projected 
recruitment period).
All participating sites will be informed of the approximate end of follow-up date for the 
study shortly after the last patient is enrolled.
The schedule of follow-up visits and tests for this study (see Appendix 4) is the minimum 
required.  Investigators may wish to see their patients more frequently according to their 
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After the treatment completion/discontinuation visit, adverse events should be followed 
as outlined in Section 5.6 and Section 5.7. See Appendix 4 for the schedule of follow-up 
assessments.
Details of whether a patient completed the full treatment and follow-up period or 
withdrew from participation in the study early (see Section 4.5.12) will be captured in the 
eCRF (study completion/discontinuation visit).
4.7
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.7.1
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 determines it is in the best interest of the patient

Pregnancy (patients must discontinue all study medication)

Heart failure (NYHA Class III and IV; patients must discontinue all study 
medication)

A confirmed significant LVEF decrease (LVEF decrease 10 percentage points 
from baseline and to an LVEF value of below 50% [see Appendix 8]). 
Confirmation should be completed within approximately 3 weeks (patients must 
discontinue all study medication).

Anaphylaxis (patients must discontinue the relevant study drug if it is clear which 
drug was responsible. If Perjeta or Herceptin or the FDC are deemed responsible,
then the patient must discontinue all study medication).  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 whose disease progresses before the end of neoadjuvant therapy will be 
withdrawn from study treatment and treated as clinically indicated, according to local
clinical practice
For further details on study drug modifications and discontinuations see 
Sections 5.2.15.2.4.  Patients who discontinue study drug prematurely will be asked to 
return to the clinic for a treatment discontinuation visit (see Section 4.6.3) and may 
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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 will return to the clinic for a treatment completion or treatment discontinuation 
visit 28 (3) days after the last dose of study drug (see Appendix 1 for additional details).
After study treatment discontinuation, information on survival follow-up and new anti-
cancer therapy (if applicable) will be collected via telephone calls, patient medical 
records, and/or clinic visits approximately every 3 months for the first year and every 6 
monthly thereafter until end of study or death (unless the patient withdraws consent or 
the Sponsor terminates the study).  
4.7.2
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.  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 
(e.g., county records) to obtain information about survival status.
4.7.3
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 adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
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4.7.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International 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
The pertuzumab and trastuzumab drug substance in the FDC for SC administration is 
identical to the drug substance in the IV formulations. Therefore, the safety plan for 
patients in this study is based on clinical experience with Perjeta IV and with Herceptin 
IV and SC in completed and ongoing studies, as well as the clinical experience with 
Perjeta SC (alone or co-mixed with Herceptin) in the Phase I Study BO30185.
The anticipated important safety risks for Perjeta and Herceptin are outlined below.  
Please refer to the most recent Perjeta Investigator’s Brochure (for important safety risks 
for Perjeta IV administration), the Herceptin Investigator’s Brochure (for important 
safety risks for Herceptin IV and SC administration), and the Pertuzumab and 
Trastuzumab FDC Investigator’s Brochure for a complete summary of safety 
information.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events, including criteria for dosage modification and treatment interruption or 
discontinuation, are provided below. An iDMC will be formed and perform review of 
safety data for the study, refer to Section 3.1 and 9.4 for details.
5.1.1
Risks Associated with Perjeta
5.1.1.1
Hypersensitivity Reactions/Anaphylaxis and Administration 
Related Reactions (Infusion or Injection)
Like other monoclonal antibodies, Perjeta IV has been associated with administration-
related reactions (ARRs). ARRs include:

Infusion-related reactions (i.e., a systemic reaction with symptoms such as chills, 
diarrhea, fatigue, headache, nausea, and pyrexia). 


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Such reactions are likely to be due to a release of cytokine(s) 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 adverse 
events are more frequent and severe with the first infusion, and decrease in 
number and severity over time. The majority of adverse events resolve fully.

Injection-related reactions may manifest themselves as
–
Systemic reactions, similar to the infusion-related reactions
–
Local injection-site reactions (ISRs) with signs and symptoms such as 
erythema, induration, swelling, pain, hypoaesthesia and discomfort  
Hypersensitivity reactions/anaphylaxis is a systemic reaction, mediated by interactions 
between factors released from IgE and mast cells, resulting in an antigen-antibody 
reaction. Hypersensitivity reactions/anaphylaxis AEs are likely to start mildly and 
increase in number and severity over time. Patients who experience a Grade 4 allergic 
reaction or acute respiratory distress syndrome (ARDS) should be discontinued from 
treatment. Since there is the potential for a delayed onset, patients should be instructed 
to contact the treating physician with any concerns.  ARRs may be difficult to distinguish 
from hypersensitivity reaction; therefore, the true relation of an event to administration of 
study treatment is difficult to ascertain, particularly when treatment regimens involve 
combination therapy.  
Perjeta will be administered by staff trained to monitor for and respond to medical 
emergencies in a setting with emergency equipment.
For patients in Arm A, the initial IV infusion of Perjeta will be given over 60 (10) minutes,
followed by an observation period of 60 minutes. If the initial infusion is well tolerated, 
subsequent infusions may be administered over a period of 30 minutes (10) with an 
observation period of 30 minutes. The observation period should be completed prior to 
the subsequent Herceptin infusion. The initial IV infusion of Herceptin will be 
administered over 90 (10) minutes, after which the patient will be observed for 
30 minutes. If the initial infusion is well tolerated, subsequent infusions may be 
administered over 30 (10) minutes, followed by an observation period of 30 minutes.
Patients can be observed for a longer period at the discretion of the investigator or, if 
necessary, as per local requirements.
Premedication with antipyretics, antihistamines, or corticosteroids may be administered 
before infusions of Perjeta and Herceptin.
Patients in Arm B (receiving the FDC) will be monitored for at 30 minutes after the first 
FDC loading dose and 15 minutes following subsequent injections for any adverse 
effects. If ARRs occur, patients will be monitored until complete resolution of signs and 
symptoms. Patients can be observed for a longer period at the discretion of the 
investigator or, if necessary, as per local requirements.


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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
Like Herceptin, Perjeta is directed at the HER2 receptor and 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). A LVEF decline 10
percentage points from baseline to an absolute value of 50% requires clinical follow-up
for Perjeta studies. 
A low level of cardiac toxicities, predominantly asymptomatic declines in left ventricular 
ejection fraction (LVEF), has been reported in Perjeta studies. In the pivotal Phase III 
trial WO20698/TOC4129g (CLEOPATRA), the rates of symptomatic and asymptomatic 
LVSD were not higher in patients receiving Perjeta than in those patients receiving 
placebo. The incidence of symptomatic LVSD was 1.5% (6/408) for patients receiving 
Perjeta with Herceptin and docetaxel (events in the treatment period only) and 1.5% 
(7/396) in placebo arm.
In BERENICE, in the neoadjuvant period, a total of 3 patients (1.5%) in dose-dense
docetaxel arm and no patients (0%) in the FEC-docetaxel arm experienced four NYHA 
III/IV Heart Failure events, all of which occurred during treatment with the anti-HER2 
therapy. 
The overall incidence of primary cardiac events in APHINITY (defined as heart failure 
[NYHA Class III or IV] and a drop in LVEF of at least 10 ejection fraction (EF) points from 
baseline AND to below 50%, or cardiac death was low (1% of patients in pertuzumab 
and placebo arms).
In summary, the incidence of symptomatic cardiac failure (defined by incidence of 
investigator-assessed symptomatic LVSD/CHF as per study protocol in each 
combination therapy study, or by the Standardised MedDRA Query [SMQ] ‘Cardiac 
Failure [wide] for the pooled single-agent population across Perjeta studies, where the 
pooled data were available) was low (approximately 1.0%1.5%).  Patients who have 
received prior anthracyclines or prior radiotherapy to the chest area may be at higher 
risk of decreased LVEF. The majority of cases of symptomatic heart failure reported in 
the adjuvant setting were in patients who received anthracycline-based chemotherapy.
Perjeta has not been studied in patients with a pretreatment 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 


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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, enrolled patients need to 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 subjects are 
receiving study treatment and for 3 years following discontinuation of IV HER2-targeted 
therapy or the FDC, (see Appendix 1, Appendix 2, Appendix 3, and Appendix 4).  
If symptomatic LVSD (heart failure; SAE of NCI CTCAE v4 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 8 for decisions regarding the continuation or
discontinuation of anti-HER2 study medication 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
Although Perjeta targets HER2, because of its role in heterodimerization with other 
members of the HER family (e.g., EGFR), it may cause toxicities associated with the use 
of EGFR tyrosine kinase inhibitors, which include diarrhea, rash/skin reactions and 
mucositis.
Diarrhea
Diarrhea has been observed in approximately 50% of patients treated with pertuzumab 
in the Phase II single-agent studies and in up to 90% of patients in combination therapy 
studies.  Diarrhea was NCI CTCAE Grade 1 or 2 in the majority of cases.
Rash/Skin Reactions
Rash/skin reactions have been observed in approximately 17% of patients treated with 
pertuzumab 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. 
Mucositis
Mucositis has been observed in approximately 15% of patients treated with pertuzumab
in the Phase II single-agent studies and in up to 50% of patients in combination studies. 
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It is possible that mucositis and/or diarrhea that occur with the addition of pertuzumab to 
docetaxel plus trastuzumab may lead to an increase in leukopenic events. Breaches in 
mucosal surfaces may allow the entry of microorganisms into the circulation, resulting in 
a higher incidence of fever/infection in patients with neutropenia.
Please refer to the Perjeta Investigator’s Brochure for the most recent data relating to 
the risk of EGFR-related toxicities.
5.1.2
Risks Associated with Herceptin
Serious adverse reactions, including LVSD, ARRs, hypersensitivity, allergic-like 
reactions, and pulmonary events, have been observed in patients receiving Herceptin 
therapy.  For some patients, symptoms progressively worsened and led to further 
pulmonary complications.  Initial improvement followed by clinical deterioration and 
delayed reactions with rapid clinical deterioration have also been reported.
Fatalities have occurred within hours and up to 1 week following Herceptin IV 
administration.  On very rare occasions, patients have experienced the onset of 
administration-related symptoms or pulmonary symptoms more than 6 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 are experiencing dyspnea at rest due to complications of 
co-morbidities may be at increased risk of a fatal infusion-related reaction. Therefore, 
these patients should not be treated with Herceptin. 
5.1.2.1
Administration-Related Reactions, Allergic-Like Reactions, and 
Hypersensitivity
Herceptin has been associated with administration-related reactions (ARRs).  ARRs are 
defined as systemic ‘infusion-related reactions’ associated with IV administration of 
Herceptin and systemic reactions associated with SC administration.  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 the 
BO22227 (HannaH) study 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 
SMQ (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 MBC and EBC settings which reported only ‘infusion reactions’ or ‘infusionrelated 
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 
dyspnea, hypotension, wheezing, bronchospasm, asthma, tachycardia, reduced oxygen 
saturation, anaphylaxis, respiratory distress, urticaria, and angioedema.  Although such 


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events were not reported in the clinical trial 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 and 
generally occurred during or immediately following administration.  
In the pivotal BO22227 (HannaH) study, 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 SOCs.
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, -agonists, and corticosteroids.
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
Caution is recommended with the use of the Herceptin SC formulation as 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, acute respiratory distress syndrome (ARDS), pneumonia, 
pneumonitis, pleural effusion, respiratory distress, acute pulmonary edema, 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, -agonists, and corticosteroids.  ARDS 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 therapy 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 


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LVSD include increased age, concomitant administration with anthracyclines, and 
declining LVEF while on Herceptin treatment.  If symptomatic cardiac failure develops 
during Herceptin therapy, 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 the HannaH study, 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 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 in MBC and 
EBC improved with standard medical treatment.  This treatment included diuretics, 
cardiac glycosides, and/or angiotensin-converting enzyme 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.
Please refer to the Herceptin Investigator’s Brochure for the most recent data related to 
the risk of LVSD.
5.1.3
Pregnancy and Contraception (Risks Associated with Both 
Perjeta and Herceptin
ICH M3 Guidance requires precautions to be taken to minimize risk to fetus or embryo 
when enrolling women of childbearing potential.  This includes the use of one highly 
effective or two effective contraceptive measures, excluding pregnancy at baseline 
(serum test) (see Section 4.1.1), continued pregnancy testing up to 7 months following 
Perjeta and Herceptin administration (follow-up period based on PK considerations), and 
continued monitoring of HER2-targeted therapy-exposed pregnancy.
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-fetal deaths. However, reproductive 
toxicity studies with Herceptin conducted in female cynomolgus monkeys revealed no 
trastuzumab-related embryotoxicity or effects on fetal development. There are no 
clinical studies of Herceptin or Perjeta 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 fetus, have been reported in pregnant 


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women receiving Herceptin.  Therefore, neither Perjeta nor Herceptin should be used 
during pregnancy unless the potential benefit for the mother outweighs the potential risk 
to the fetus.
For women of childbearing potential (i.e., women who have not reached menopause yet
[12 continuous months of amenorrhea with no identified cause other than menopause]) 
who have not undergone removal of ovaries and/or uterus, agreement must be obtained 
to use one highly effective (resulting in a failure rate of 1% per year) non-hormonal 
form of contraception or two effective forms of non-hormonal contraception by the 
patient or partner, or both, while receiving study treatment and for 7 months following the 
last dose of Perjeta and Herceptin or FDC.  Women who have had a tubal ligation or 
bilateral ovariectomy do not require additional contraception.  
Men with female partners of childbearing potential participating in the study must agree 
to take reliable and effective contraceptive measures while receiving study treatment 
and for 7 months following the last dose of Perjeta and Herceptin or FDC. Men must 
refrain from donating sperm during this same period.  Male study participants whose 
partners are pregnant must remain abstinent or use a condom during the entire 
pregnancy to avoid exposing the embryo.
Methods of birth control that result in a low failure rate (i.e., less than 1% per year) when 
used consistently and correctly are considered highly effective forms of contraception.  
The following non-hormonal methods of contraception are acceptable:

True abstinence when this is in line with the preferred and usual lifestyle of the 
patient
Periodic abstinence (e.g., calendar, ovulation, symptothermal postovulation 
methods), and withdrawal are not acceptable methods of contraception

Male sterilization (with appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate)
For female patients, the vasectomized male partner should be the sole partner.
Alternatively, two of the following effective forms of contraception may be used instead:

Placement of non-hormonal IUD or intrauterine system
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 
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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.
Based on PK considerations, contraception methods must continue for the duration of 
study treatment and for at least 7 months after the dose of Perjeta and Herceptin.
5.1.3.1
Breastfeeding
It is not known whether Herceptin or Perjeta is excreted in human milk.  As maternal IgG 
is excreted in milk and either monoclonal antibody could harm infant growth and 
development, women should be advised to discontinue nursing during Perjeta and
Herceptin or FDC therapy and not to breastfeed for at least 7 months following the last 
dose.
5.1.4
Warnings and Precautions for Docetaxel, Paclitaxel,
Doxorubicin, and Cyclophosphamide
No evidence available at the time of finalization of this study protocol indicated that 
special warnings and precautions were appropriate other than those noted in the 
currently approved prescribing information for docetaxel, paclitaxel, doxorubicin and 
cyclophosphamide.  
5.1.5
Warnings and Precautions for Anti-Estrogen Therapy and
Radiotherapy
No evidence available at the time of finalization of this study protocol indicated that 
special warnings and precautions were appropriate other than those noted in the 
currently approved prescribing information for anti-estrogen therapy and radiotherapy.
5.2
MANAGEMENT OF PATIENTS WHO EXPERIENCE SPECIFIC 
ADVERSE EVENTS
5.2.1
Dose Delays, Discontinuation, and Modifications (General)
If any of the individual study drugs must be delayed for a day or more, all agents should 
be delayed for the same time frame, with the possible exception of delays for LVEF 
decline after anthracycline therapy (see Section 5.2.5.1).


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Patients who discontinue chemotherapy due to toxicity should not be automatically 
withdrawn from all study treatments.  Perjeta and Herceptin IV or the FDC SC should be 
completed for a total of 18 cycles as per protocol, but surgery may be brought forward if 
clinically indicated.
If HER2-targeted therapy is withheld for more than 2 cycles (9 weeks) or needs to be 
permanently discontinued for treatment-related toxicity, the patient will be withdrawn 
from all study treatment and treated at the discretion of the investigator as clinically 
indicated.  The patient will continue to be followed post-treatment as described in 
Section 4.6.4.
5.2.2
Dose Delays and Modifications for Perjeta IV, Herceptin IV, 
Herceptin SC, and the FDC
HER2-targeted therapy dose modifications are not permitted.  Administration may be 
delayed to assess or treat adverse events, such as cardiac adverse events or 
myelosuppression, and to maintain synchrony with chemotherapy administration.
During the neoadjuvant and adjuvant treatment periods, a dose delay of up to (and 
including) 6 weeks (i.e., up to and including 9 weeks between doses) will be permitted to 
allow recovery to baseline.  Following a dose delay of less than 3 weeks (i.e., 6 weeks 
between doses), HER2-targeted therapies do not need to be reloaded (only the 
maintenance dose needs to be given).  For a dose delay of 3 weeks or more (i.e., 
6 weeks between doses), a reloading dose of Perjeta and Herceptin (840 mg and 
8 mg/kg, respectively) or the FDC (1200 mg pertuzumab and 600 mg trastuzumab) 
should be administered.
5.2.3
Dose Delays and Modifications for Anthracycline-Based
Chemotherapy (ddAC and AC)
Dose reduction and dose delays will be allowed as indicated in the relevant local
prescribing information and managed as per local practice.
5.2.4
Dose Delays and Modifications for Taxanes (Docetaxel and
Paclitaxel)
All dose modifications for docetaxel/paclitaxel alone are based on the dose level 
changes outlined below in Table 5.
Table 5
Dose Levels for Docetaxel/Paclitaxel
Dose Level 0
Dose Level 1
Dose Level 2
Dose Level 3
Paclitaxel (mg/m2)
80
(starting dose)
64
Discontinue

Docetaxel (mg/m2)
100
75
(starting dose)
60
Discontinue


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Re-escalation is not permitted following a dose reduction.
A dose-limiting toxicity to docetaxel is defined as the occurrence of one or more of the 
following:

Febrile neutropenia

Grade 4 neutropenia (neutrophils 0.5109/L) for 5 days or a neutrophil count 
0.1109/L for more than 1 day

Grade 2 non-hematologic adverse events (NCI CTCAE, v4), such as peripheral 
neuropathy, unless the toxicity is deemed manageable by the investigator (e.g., 
nausea and vomiting)
General dose modification guidelines:

If a Grade 3 or 4 non-hematologic toxicity is experienced, docetaxel may be reduced 
from 100 mg/m2 to 75 mg/m2, and again to 60 mg/m2, if required.  For paclitaxel, the 
dose may be reduced from 80 mg/m2 to 64 mg/m2.

If a taxane-related hypersensitivity reaction occurs despite premedication, treatment 
as medically indicated will be instituted. 

For hypersensitivity reaction of Grade 3, continuation of docetaxel/paclitaxel is at 
the investigator’s discretion. 

If a Grade 4 hypersensitivity is experienced, docetaxel/paclitaxel must be 
permanently discontinued.

If a Grade 3 enterocolitis is experienced, permanent discontinuation of 
docetaxel/paclitaxel is recommended.

Taxane-related fluid retention will be treated as per the investigator’s discretion.

If the taxane must be discontinued before completion of the scheduled cycles, the 
remaining Perjeta IV and Herceptin IV or the FDC SC doses should be administered.
See Table 6 for the management of taxane-related neurosensory toxicity and 
Table 7 for taxane-related musculoskeletal pain.  Instructions for management of all 
other toxicities related to docetaxel/paclitaxel are listed in Table 8.


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Table 6
Dose Modifications for Taxane-Related Neurosensory Toxicity
Paresthesias/Dysesthesias
17 Days Duration
Persistent for 7 Days or 
Causing the Next Cycle to be 
Delayed
Grade 1 
Paresthesias/dysesthesias that 
do not interfere with function
Maintain docetaxel/paclitaxel 
dose.
Maintain docetaxel/paclitaxel 
dose.
Grade 2 
Paresthesias/dysesthesias 
interfering with function, but not 
activities of daily living
Maintain docetaxel/paclitaxel 
dose. a
Decrease 
docetaxel/paclitaxel by one 
dose level. b
Grade 3 
Paresthesias/dysesthesias with 
pain or with function 
impairment interfering with 
activities of daily living c
First episode: Decrease 
docetaxel/paclitaxel one dose 
level. a
Second episode: 
Discontinue 
docetaxel/paclitaxel.
Discontinue 
docetaxel/paclitaxel.
a Must be resolved to Grade 1 on Day 1 of the next cycle.
b Hold docetaxel/paclitaxel for persistent Grade 2 neurotoxicity.  When Grade 1, resume 
treatment with dose modification for docetaxel/paclitaxel.  If Grade 2 toxicity persists after 
3 weeks of delay, discontinue docetaxel/paclitaxel.
c For persistent paresthesias and dysesthesias that are disabling or life-threatening, 
docetaxel/paclitaxel should be discontinued.


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Table 7
Dose Modifications for Taxane Musculoskeletal Pain Not 
Controlled by Analgesics
a
Musculoskeletal 
Pain
17 Day Duration
Persistent for 7 Days or Causing 
the Next Cycle to be Delayed
Grade 1
Maintain docetaxel/paclitaxel dose.
Maintain docetaxel/paclitaxel dose.
Grade 2
Maintain docetaxel/paclitaxel dose.
Maintain docetaxel/paclitaxel dose, 
OR
Decrease docetaxel/paclitaxel one 
dose level. b
Grade 3
First episode: Decrease 
docetaxel/paclitaxel one dose 
level.
First episode: Decrease 
docetaxel/paclitaxel one dose levelb, 
OR
Discontinue docetaxel/paclitaxel.
Second episode:
Discontinue docetaxel/paclitaxel.
Second episode:
Discontinue docetaxel/paclitaxel.
a The use of narcotics and non-steroidal anti-inflammatory drugs (NSAIDs) is encouraged to 
maintain the dose of docetaxel/paclitaxel, if possible.
b Delay docetaxel/paclitaxel for persistent Grade 2 or 3 musculoskeletal pain.  When the 
symptom achieves Grade 1, resume treatment with dose modification for 
docetaxel/paclitaxel.  If Grade 2 or Grade 3 toxicity persists after delay, discontinue 
docetaxel/paclitaxel. 


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Table 8
Dose Modifications and Delays for Docetaxel/Paclitaxel Alone
Adverse Event 
(Category) a
Modifications for AEs That Occur 
during a Cycle but Resolve prior 
to the Next Treatment Cycle b
Modifications for AEs that Require a 
Delay in Administration of the 
Treatment Cycle c
Hematologic:  neutrophil count decreased (investigations)
Grades 2, 3, and 4
Maintain dose.
Docetaxel:
Hold until 1500/mm3.
For recovery that takes 
13 weeks, maintain dose and 
add G-CSF.
If receiving G-CSF and recovery 
takes:
–
1 week:  Maintain dose.
–
23 weeks:  Decrease 
one dose level.
Paclitaxel:
Hold until 1000/mm3. 
If recovery takes 13 weeks, 
maintain dose and add G-CSF.
If receiving G-CSF and recovery 
takes:
–
1 week:  Maintain dose.
–
23 weeks:  Decrease 
one dose level.
Hematologic:  platelet count decreased (investigations)
Grades 2, 3
Maintain dose.
Hold until 75,000/mm3. 
If recovery takes:
–
1 week:  Maintain dose.
–
23 weeks:  Decrease 
one dose level.
Grade 4
Decrease by one dose level.
Decrease by one dose level.
AEadverse event; G-CSF granulocyte colony-stimulating factor; NCI CTCAE v4 National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0.
Notes:  Dose modifications must be based on AEs that occur during the cycle (Column 2) and 
AEs present on the scheduled cycle Day 1 (Column 3).  Dose modifications must be based on 
the AE requiring the greatest modification.
a NCI CTCAE v4.
b Resolved means that AEs requiring dose modification are Grade 1 (except absolute 
neutrophil/granulocyte count [which must be 1500/mm3 for docetaxel and 1000/mm3 for 
paclitaxel] and bilirubin [which must be less than or equal to the baseline grade]) on Day 1 
of the next scheduled cycle (i.e., treatment can be given without delay).
c Hold and check weekly.  With the exception of absolute neutrophil/granulocyte count and 
bilirubin, resume treatment when toxicity is Grade 1.  If toxicity has not resolved after 
3 weeks of delay, discontinue docetaxel and proceed with targeted therapy as planned to 
complete 18 cycles of treatment.


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Table 8
Dose Modifications and Delays for Docetaxel/Paclitaxel Alone
(cont.)
Adverse Event 
(Category) a
Modifications for AEs That Occur 
during a Cycle but Resolve prior 
to the Next Treatment Cycle b
Modifications for AEs That Require 
a Delay in Administration of the 
Treatment Cycle c
Blood and lymphatic system disorders:  febrile neutropenia
Grades 3, 4
Decrease by one dose level, add G-CSF support, or discontinue.
Gastrointestinal disorders (if related to chemotherapy):  diarrhea
Grade 2
Maintain dose.
Decrease by one dose level.
Grade 3
Decrease by one dose level.
Decrease by one dose level.
Grade 4
Decrease by two dose levels or 
discontinue.
Decrease by two dose levels or 
discontinue.
Gastrointestinal disorders (if related to chemotherapy):  mucositis oral (stomatitis) 
Grade 2
Maintain dose.
Decrease by one dose level.
Grade 3
Decrease by one dose level.
Decrease by one dose level.
Grade 4
Decrease by two dose levels or 
discontinue.
Decrease by two dose levels or 
discontinue.
Gastrointestinal disorders (if related to chemotherapy):  vomiting (despite antiemetics) 
Grade 2
Decrease by one dose level 
(optional).
Decrease by one dose level.
Grades 3, 4
Decrease by one dose level or 
discontinue.
Decrease by two dose levels or 
discontinue.
AEadverse event; G-CSF granulocyte colony-stimulating factor; NCI CTCAE v4 National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0..
Notes:  Dose modifications must be based on AEs that occur during the cycle (Column 2) and 
AEs present on the scheduled cycle Day 1 (Column 3).  Dose modifications must be based on 
the AE requiring the greatest modification.
a NCI CTCAE v4.
b Resolved means that AEs requiring dose modification are Grade 1 (except absolute 
neutrophil/granulocyte count [which must be 1500/mm3 for docetaxel and 1000/mm3 for 
paclitaxel] and bilirubin [which must be less than or equal to the baseline grade]) on Day 1 
of the next scheduled cycle (i.e., treatment can be given without delay).
c Hold and check weekly.  With the exception of absolute neutrophil/granulocyte count and 
bilirubin, resume treatment when toxicity is Grade 1.  If toxicity has not resolved after 
3 weeks of delay, discontinue docetaxel and proceed with targeted therapy as planned to 
complete 18 cycles of treatment.


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Table 8
Dose Modifications and Delays for Docetaxel/Paclitaxel Alone
(cont.)
Adverse Event 
(Category) a
Modifications for AEs That Occur 
during a Cycle but Resolve prior 
to the Next Treatment Cycle b
Modifications for AEs That Require 
a Delay in Administration of the 
Treatment Cycle c
Gastrointestinal disorders (if related to chemotherapy):  enterocolitis d
Grades 3, 4
Provide immediate supportive care and discontinue (at the discretion of 
the investigator)
Hepatic function:  bilirubin or AST or ALP increased (investigations)
Grade 2 
Decrease by one dose level.
Hold until bilirubin returns to the 
baseline grade, and AST and ALP 
have returned to Grade 1.
Subsequently decrease by one 
dose level.
Grade 3
Decrease by two dose levels.
Decrease by two dose levels.
Grade 4
Discontinue.
Discontinue.
Other clinically significant AEs e
Grade 3
Decrease by one dose level.
Decrease by one dose level.
Grade 4
Decrease by two dose levels or 
discontinue.
Discontinue.
AEadverse event; G-CSF granulocyte colony-stimulating factor; NCI CTCAE v4 National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0..
Notes:  Dose modifications must be based on AEs that occur during the cycle (Column 2) and 
AEs present on the scheduled cycle Day 1 (Column 3).  Dose modifications must be based on 
the AE requiring the greatest modification.
a NCI CTCAE v4.
b Resolved means that AEs requiring dose modification are Grade 1 (except absolute 
neutrophil/granulocyte count [which must be 1500/mm3 for docetaxel and 1000/mm3 for 
paclitaxel] and bilirubin [which must be less than or equal to the baseline grade]) on Day 1 
of the next scheduled cycle (i.e., treatment can be given without delay).
c Hold and check weekly.  With the exception of absolute neutrophil/granulocyte count and 
bilirubin, resume treatment when toxicity is Grade 1.  If toxicity has not resolved after 
3 weeks of delay, discontinue docetaxel and proceed with targeted therapy as planned to 
complete 18 cycles of treatment.
d Recognition of symptoms of severe enterocolitis is critical as this requires appropriate 
supportive care. In case of symptoms of abdominal pain with tenderness, fever, diarrhea 
and mucositis, with or without neutropenic fever, supportive care should be started 
immediately.
e
Determination of clinically significant AEs is at the discretion of the investigator.
5.2.5
Management Guidelines
Supportive care and medical management of adverse events are at the discretion of the 
investigator and as per local policy, unless specifically listed below.


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5.2.5.1
Symptomatic LVSD and/or LVEF Decline
There is a risk of LVSD with Perjeta, as with Herceptin, because each of these 
antibodies is directed at the HER2 receptor, which is present in cardiac tissue.
All patients enrolled in Perjeta studies undergo regular LVEF monitoring by ECHO
(preferred) or MUGA scan.  A decrease in LVEF has been observed in patients receiving 
Perjeta and Herceptin; however, the majority of patients show improvement or return to 
baseline function on follow-up (see Sections 1.2.1.3 and 1.2.2.4).
Patients in both arms should not start anti-HER2 drugs if their LVEF is 50% after 
anthracycline therapy.
Patients who experience an asymptomatic decrease in LVEF after anthracycline therapy 
may continue to receive the taxane component of chemotherapy at the discretion of the 
investigator.  HER2-targeted therapy may be subsequently initiated (or restarted) in 
accordance with the algorithm in Appendix 8. The delay in initiating (or restarting) 
HER2-targeted therapy should not exceed 6 weeks.
Monitoring of LVEF is required as per the schedule of activities.  If severe symptomatic 
LVSD (CHF) develops (NYHA Class III or IV) or there is a confirmed significant LVEF 
decrease (LVEF decrease 10 percentage points from baseline and to an absolute
LVEF value of 50%), the patient must discontinue HER2-targeted therapy. This
should be recorded in the eCRF as per Table 9.  Symptomatic LVSD (CHF) should be 
treated and monitored according to standard medical practice.  These patients should be 
evaluated by a certified cardiologist, and the results of this evaluation should be reported 
on the eCRF.
Appendix 8 summarizes the management of study medication in patients who develop 
an asymptomatic decrease in LVEF.  The decision to initiate HER2-targeted therapy and 
whether to continue or stop therapy should be based on two factors:  measured LVEF 
and changes in LVEF from baseline. If a significant LVEF decrease occurs, this 
decrease should be confirmed by a second assessment within approximately 3 weeks 
showing also a significant decrease.
All patients must have a baseline LVEF 55%.  LVEF will be monitored regularly 
according to the Schedule of Activities (see Appendix 1, Appendix 2, Appendix 3, and 
Appendix 4).  If an investigator is concerned that an adverse event may be related to 
LVSD, an additional LVEF measurement should be performed as soon as possible and 
within 3 weeks.
Symptomatic LVSD (CHF) will be assessed as “heart failure” on the basis of NCI CTCAE 
criteria v4 and NYHA classification (see Appendix 9). 
CHF should be treated and monitored according to standard medical practice.


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Asymptomatic LVEF decline (LVEF assessment scheduled in Appendix 1, Appendix 2, 
Appendix 3, and Appendix 4) will be reported in the eCRF as per NCI CTCAE criteria v4
(see Table 9).  The intensity of asymptomatic LVEF decline described above will be 
reported on the basis of NCI CTCAE criteria v4 (“ejection fraction decreased“). 
The incidence of CHF will also be recorded throughout the study.
5.2.5.2
Hypersensitivity/Anaphylaxis and Administration-Related 
Reactions (Infusion or Injection)
Administration of monoclonal antibodies, including Perjeta and Herceptin, may cause 
ARRs (please refer to Sections 5.1.1.1 and 5.1.2.1).  
Local-site reactions are captured separately from systemic reaction in the eCRF. 
Patients with pre-existing pulmonary compromise who are treated with Herceptin may be 
at increased risk of severe or serious ARRs.  Therefore, careful consideration must be 
made before enrolling patients with chronic pulmonary disease into the study. 
Study treatment will be administered by staff trained to monitor for and respond to 
medical emergencies in a setting with emergency equipment. 
Infusion of Perjeta should be stopped in subjects who develop dyspnea 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 the Perjeta or Herceptin IV infusion

Stopping the injection of FDC or Herceptin SC

Providing supportive care with oxygen, -agonists, antihistamines, antipyretics, or 
corticosteroids as appropriate at the investigator's discretion, as per local practice

Subsequently premedicating with analgesia and antihistamines as per local practice
In order to be able to calculate time to onset of such reactions, the occurrence of 
adverse events has to be documented with the date and time of the onset and duration 
of the event (i.e., resolution of the event). 


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If a subject experiences an ARR, the diagnosis should be used for the primary adverse 
event term (e.g., “administration-related reaction,” or “anaphylactic reaction”). 
The individual sign(s) and symptom(s) of the reaction should then be captured on the 
dedicated Infusion-Related Reaction or Injection Reaction eCRF forms (see Section
5.4.5).
If a patient experiences a local and a systemic reaction following administration of the 
study drug, two separate adverse events will need to be recorded. 
Patients will be monitored until complete resolution of signs and symptoms of any 
systemic reactions. 
5.2.5.3
EGFR-Related Toxicities
Although Perjeta targets the HER2 receptor, it inhibits heterodimerization with other 
members of the HER family (e.g., EGFR [HER1]).  Accordingly, it may cause toxicities
associated with the use of EGFR inhibitors such as diarrhea, mucositis, and skin 
reactions (e.g., dry skin, pruritus, or nail disorders).
Diarrhea
To prevent dehydration, early treatment of diarrhea with anti-diarrheal medication 
(e.g., loperamide) should be considered and patients should be treated with fluids and 
electrolyte replacement, as clinically indicated. In the case of no improvement of 
diarrhea despite anti-diarrheal treatment, HER2-targeted therapy should be held. 
HER2-targeted therapy can resume once the diarrhea is under control.  
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 Perjeta-related
rash/skin reactions, as clinically indicated, although they have not been studied in this 
context.
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.
5.3
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events 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.


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Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.5.
5.3.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.4.5.8 and 
5.4.5.9 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)
5.3.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.4.5.10)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

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)


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The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.4.3; the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.5.2 for 
reporting instructions).
5.3.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest (AESI) 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 5.5.2 for reporting instructions).  AESIs for this study are as follows:

An asymptomatic decline in LVEF that requires treatment or that leads to 
discontinuation of HER2-targeted therapies must be reported in an expedited 
manner with use of the Serious Adverse Event Form and classifying the event as an
Event of Special Interest that is immediately reportable

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 5.4.5.6)

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.
5.3.4
Selected Adverse Events
Additional data will be collected for the following selected adverse events:

Heart failure

Asymptomatic declines in LVEF
5.3.4.1
Heart Failure
Symptomatic LVSD (referred to as heart failure) should be reported as a serious adverse 
event.  If the diagnosis is heart failure, it should be reported as such, and not as 
individual signs and symptoms of heart failure.  In the eCRF, signs and symptoms 
should be recorded.  A cardiac consultation is recommended for patients who develop 
symptomatic LVSD (heart failure).  Heart failure should be graded according to 


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NCI CTCAE v4 (Grade 2, 3, 4, or 5), as well as according to the NYHA the AE term to 
describe symptomatic dysfunction, as per NCI CTCAE v4.
Heart failure occurring during the study and up to 3 years after the last patient 
discontinues HER2-targeted therapy 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.
5.3.4.2
Asymptomatic Declines in Left Ventricular Ejection Fraction 
Asymptomatic declines in LVEF should not be reported as adverse events because 
LVEF data are collected separately in the eCRF.  Exceptions to this rule are as follows:

An asymptomatic decline in LVEF of 10 percentage-points from baseline to an 
LVEF 50% must be reported as an adverse event with the term of ejection fraction 
decreased, as per NCI CTCAE v4.  In addition, a comment in the adverse events 
comments field should confirm that the event was asymptomatic.

An asymptomatic decline in LVEF requiring treatment or leading to discontinuation 
of Perjeta and Herceptin must be reported in an expedited manner as a non-serious 
AESI on the serious adverse event form, and a comment should be added to the 
adverse events comments field, confirming that the event was asymptomatic.
Both cases should be reported as “ejection fraction decreased” and graded according to 
NCI CTCAE v4 (see Section 5.4.3).
Table 9 summarizes the reporting conventions for LVSD and heart failure.


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Table 9
Reporting Conventions for Left Ventricular Systolic
Dysfunction/Congestive Heart Failure
Observation
How to Report
Term to be 
Reported
Grading
Asymptomatic decline in 
LVEF of 10 percentage
points from baseline or to 
an LVEF of 50%
No additional reporting 
required; LVEF results to 
be reported on eCRF.
NA
NA
Asymptomatic decline in 
LVEF of 10 percentage
points from baseline to 
an LVEF of 50%
AE a (eCRF AE eForm)
Ejection fraction 
decreased a
NCI CTCAE for 
“ejection fraction 
decreased”
Asymptomatic decline in 
LVEF requiring treatment 
or leading to 
discontinuation of Perjeta 
and Herceptin or the 
FDC
AE (eCRF AE eForm) 
and report as a non-
serious AESI on an 
SAE form
Ejection fraction 
decreased a
NCI CTCAE for 
“ejection fraction 
decreased”
Heart failure/CHF 
(symptomatic LVSD) b
AE (eCRF AE eForm) 
and SAE (SAE form)
“Heart failure”
NCI CTCAE for 
"heart failure" and 
NYHA class
AEadverse event; AESIadverse event of special interest; CHFcongestive heart failure; 
eCRFelectronic Case Report Form; e-Form electronic form; LVEFleft ventricular ejection 
fraction; LVSDleft ventricular systolic dysfunction; NAnot applicable; NCI CTCAENational 
Cancer Institute Common Terminology Criteria for Adverse Events; NYHANew York Heart 
Association; SAEserious adverse event.
a Report the status as asymptomatic and provide the LVEF value in the comments field as 
appropriate. 
b Any symptomatic LVSD event must be reported as “heart failure.”
5.3.4.3
Administration-Related Reactions:  Infusion-Related Reactions, 
Injection-Related Reactions, and Injection Site Reactions
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion or injection should be captured as a 
specific diagnosis (e.g., "infusion-related reaction", “injection-related reaction”, "injection-
site reaction", "anaphylactic reaction") on the Adverse Event eCRF.  If possible, avoid 
ambiguous terms such as "systemic reaction."  Associated signs and symptoms should 
be recorded on the dedicated Infusion-Related Reaction eCRF, Injection Reaction eCRF,
or Injection-Site Reaction eCRF.  If a patient experiences both a local and systemic 
reaction to the same dose of study drug, each reaction should be recorded separately on 
the Adverse Event eCRF, with signs and symptoms also recorded separately on the 
dedicated Infusion-Related Reaction eCRF or Injection Reaction eCRF.
See Table 10 for the reporting conventions for infusion-related reactions, injection-
related reactions, and injection-site reactions.


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Table 10 Reporting Conventions for Infusion-Related Reactions, Injection-
Related Reactions and Injection-Site Reactions
Adverse Event
Term to Be Used on AE eCRF 
Form
Symptoms to Be Entered on
eCRF Form
Systemic Infusion 
Reaction
“Infusion-related reaction”
Infusion-related reaction
Systemic Injection 
Reaction
“Injection-related reaction”
Injection-related reaction 
Local Injection Reaction
“Injection-site reaction”
Injection-site reaction 
5.4
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.3.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.55.7.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.3.2 for seriousness criteria), severity (see 
Section 5.4.3), and causality (see Section 5.4.4).  
5.4.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.5.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events irrespective of relationship to study drug 
will be reported until the treatment completion or discontinuation visit (28 days after the 
last dose of study drug). After this period, only drug-related serious adverse events, 
heart failure, pregnancies, and non−breast-related second primary malignancies, 
irrespective of causal relationship, should continue to be collected (see Sections 5.3.4
and 5.5.2).
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.7.


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5.4.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation time points.  Examples of 
non-directive questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.4.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4) will be used for 
assessing adverse event severity.  Table 11 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 11 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4), which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.5.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.3.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.5.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.3.2.
5.4.4
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 
adverse event is considered to be related to the study drug, indicating "yes" or "no"


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accordingly.  The following guidance should be taken into consideration (see also 
Table 12):

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 12 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 fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting 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).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.4.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.4.5.1
Diagnosis versus Signs and Symptoms
For adverse events other than infusion-related, injection-related, or ISRs (see Section
5.3.4.3), a diagnosis (if known) should be recorded on the Adverse Event eCRF rather 
than individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 


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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 adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.4.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events 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 adverse event 
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 hemorrhage 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 adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.4.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event 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 5.5.2 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 serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.


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5.4.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event 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 (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP 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 adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.4.5.3 for 
details on recording persistent adverse events).
5.4.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event 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 


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It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.4.5.3 for 
details on recording persistent adverse events).
5.4.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) 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 adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3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 5.4.5) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.5.2).
5.4.5.7
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.4.1) that are attributed 
by the investigator solely to progression 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 5.5.2). An independent monitoring committee will monitor the frequency of 
deaths from all causes.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported. 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 


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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 not 
be used unless combined with the presumed cause of death (e.g. “sudden cardiac 
death”).  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.7.
5.4.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.4.5.9
Lack of Efficacy or Worsening of Breast Cancer
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on clinical, laboratory, radiological, and/or histological findings.  
In rare cases, the determination of clinical progression will be based on symptomatic 
deterioration.  However, every effort should be made to document progression through 
use of objective criteria.  If there is any uncertainty as to whether an event is due to 
disease progression, it should be reported as an adverse event.
5.4.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.3.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration,
insertion of access device for study drug administration). 
Hospitalization for re-excision surgery for residual breast cancer following 
primary surgery, breast reconstruction surgery, prophylactic contralateral 
mastectomy, prophylactic ovariectomy, and ovariectomy (to induce premature 
menopause) are also not considered adverse events in this trial.


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
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying cancer
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.4.5.11
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
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 5.5.2).
5.5
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 5.3.2; see Section 5.5.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.3.3; see Section 5.5.2 for 
details on reporting requirements)

Pregnancies (see Section 5.5.3 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


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
Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.5.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites
Roche Medical Responsible:
, M.D., Ph.D. (Primary)
Telephone No.:
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center 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. 
5.5.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.5.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
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.
5.5.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until the treatment completion or discontinuation visit (28 days
after the last dose of study drug). Thereafter, related serious adverse events, heart 
failure (reportable as a serious adverse event), and non-breast second primary 
malignancies (reportable as a serious adverse event) should be reported until the end of 
the study. 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 EDC system.  A report will be generated and sent to Roche Safety 
Risk Management by the EDC system.


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In the event that the EDC system is unavailable, 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 serious adverse events that occur after the end of the study are 
provided in Section 5.7.
5.5.3
Reporting Requirements for Pregnancies
5.5.3.1
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 7 months after the last 
dose of Perjeta and Herceptin or the FDC.  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 all study drugs and counsel the patient, discussing the 
risks of the pregnancy and the possible effects on the fetus.  Monitoring of the patient 
should continue until conclusion of the pregnancy.  Any serious adverse events 
associated with the pregnancy (e.g., an event in the fetus, 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 order to learn more about the effects 
of pertuzumab and trastuzumab on pregnancy, additional information on any Perjeta-
and/or Herceptin-exposed pregnancy and infant will be requested by Roche/Genentech 
Drug Safety 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.
The investigator will submit a paper Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy or the infant is 
requested or becomes available.  
5.5.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
7 months after the last dose of study drug.  A paper 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 


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outcome of any pregnancy in the partner of a male patient exposed to study drug.  When 
permitted by the site, the pregnant partner will need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  If
the authorization has been signed, the investigator will 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 fetus, to support an informed decision in cooperation with the treating physician 
and/or obstetrician.
5.5.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (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 5.5.2).
If a therapeutic or elective abortion was performed because of an underlying maternal 
or embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.5.3.4
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 a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.5.2).
5.6
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.6.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
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All pregnancies reported during the study should be followed until pregnancy outcome.
5.6.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case.
5.7
ADVERSE EVENTS THAT OCCUR AFTER THE END OF THE 
STUDY
After the end of the study, if the investigator becomes aware of a serious adverse event 
that is believed to be related to prior exposure to study drug, the event should be 
reported directly to Roche Safety Risk Management via telephone or fax machine using 
the paper Serious Adverse Event Reporting Form and fax cover sheet. .
5.8
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Perjeta Investigator's Brochure

Herceptin Investigator's Brochure

Pertuzumab and Trastuzumab FDC Investigator's Brochure  
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
An iDMC will monitor the incidence of adverse events during the study.  An aggregate 
report of any clinically relevant imbalances that do not favor the test product will be 
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6
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
6.1
ANALYSIS POPULATIONS
6.1.1
Per Protocol PK Analysis Population
The primary analysis will be performed in the Per Protocol PK analysis population. 
Patients will be assigned to treatment groups as treated.
The Per Protocol PK analysis population will include all patients enrolled who adhered to 
the protocol.  Patients will be excluded from the Per Protocol PK analysis population if 
they significantly violate the inclusion or exclusion criteria, deviate significantly from the 
protocol, or if data are unavailable or incomplete, where the PK analysis might be 
influenced. 
Reasons for exclusion may include patients missing the Ctrough pre-dose Cycle 8 PK 
sample, patients with a Ctrough sample collected with at least 2 days deviation from the
planned date on Day 21 (i.e., before Day 19 or after Day 23), patients given a dose 
amount that significantly deviates from the planned dose, patients with a dose delay of 
more than 7 days, an injection site other than thigh is used, etc. Excluded cases will be 
documented, including the reason for exclusion. All decisions on exclusions from the 
analysis will be made prior to database closure.
6.1.2
Intent-to-Treat Population
Additional analyses will be performed in the intent-to-treat (ITT) population. The ITT 
population is defined as all randomized patients. Patients will be assigned to treatment 
groups as randomized by the IxRS.
6.1.3
Safety Analysis Population
The safety analysis population will include all patients who receive at least one dose of 
study medication (i.e., chemotherapy, Perjeta and Herceptin IV, Herceptin SC or the
FDC). Patients who do not receive any dose of their study medication 
(i.e., chemotherapy, Perjeta and Herceptin IV, Herceptin SC, or the FDC) will be 
excluded from the safety-evaluable population. Patients will be assigned to treatment 
groups as treated.
6.2
DETERMINATION OF SAMPLE SIZE
The study is designed to have at least 80% power to demonstrate non-inferiority of the 
Cycle 7 (i.e., pre-dose Cycle 8) pertuzumab serum Ctrough from pertuzumab SC within 
FDC to the Perjeta IV formulation in patients with HER2-positive EBC. 
The hypothesis to be tested for the primary endpoint, observed pertuzumab Ctrough, is:

H0:  The SC dose is inferior to the IV dose (i.e., the CtroughSC/CtroughIV GMR of the
SC dose of pertuzumab relative to the IV dose is not greater than 0.8) versus


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
H1:  The SC dose is non-inferior to the IV dose (i.e., CtroughSC/CtroughIV GMR of the 
SC dose of pertuzumab relative to the IV dose is equal to or greater than 0.8)
The null-hypothesis will be rejected if the lower bound of the 90% CI for the GMR is 
equal or greater than 0.8.
PK sample size calculations are based on the coefficient of variation (CV)% for the Ctrough
of trastuzumab observed from previous studies in MBC and EBC patients after Q3W
treatment. With a CV of 60% assumed, a minimum or 130 patients per arm (i.e., a total 
of 260 patients) is needed to demonstrate Ctrough non-inferiority with a power of 80% if 
the true means of the two formulations do not differ by more than 5%. An additional 240 
patients will also be recruited to provide a substantial database to assess tpCR and 
safety profile comparability. Therefore, a total of approximately 500 patients (~250 
patients per arm) will provide a sufficient sample size to test the primary PK hypothesis 
and also assess efficacy and safety profile comparability.
A hierarchical testing procedure for key secondary endpoints will be used to control the 
overall type I error rate at a one-sided 5% significance level.
6.3
PRIMARY ANALYSIS
The primary endpoint of this study is observed pertuzumab trough concentration (Ctrough) 
at Cycle 7 (i.e., the measured pre-dose concentration value at Cycle 8), following 3 
cycles of Perjeta IV and Herceptin IV or FDC (pertuzumab and trastuzumab SC). 
Pertuzumab Ctrough will be analyzed at the time of the primary analysis, which will 
occur after the last patient has completed (all) neoadjuvant therapy and has undergone
surgery.
The Per Protocol PK analysis population as described in Section 6.1.1 will be the 
primary analysis population used for this analysis.
The non-inferiority of the SC and IV dose of pertuzumab will be assessed by a one-sided 
testing procedure. The CtroughSC/CtroughIV GMR of the SC dose of pertuzumab relative to 
the IV dose will be estimated together with the two-sided 90% CI based on the log-
transformed trough concentration values. The null hypothesis will be rejected and non-
inferiority will be concluded if the lower bound of the 90% CI of the GMR is 0.8.
6.4
SECONDARY ANALYSES
For all secondary analyses the Per Protocol PK analysis population (see Section 6.1.1) 
will be used. The ITT population will also be used for key secondary endpoint analyses
and will be described further in the Statistical Analysis Plan (SAP).
6.4.1
PK Analyses
The non-inferiority of the SC and IV dose of trastuzumab will be assessed using the 
same criteria as for the primary analysis (see Section 6.3) and will be tested in a 


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hierarchical order to adjust for multiple statistical testing and control the type I error at a 
one-sided 5% significance level.
The following hypotheses will be tested:

H0:  The SC dose is inferior to the IV dose (i.e., the CtroughSC/CtroughIV GMR of the 
SC dose of trastuzumab relative to the IV dose is not greater than 0.8) versus

H1:  The SC dose is non-inferior to the IV dose (i.e. the CtroughSC/CtroughIV GMR of 
the SC dose of trastuzumab relative to the IV dose is equal or greater than 0.8)
The hierarchical testing procedure will follow the steps below:
1.
Test the primary endpoint, Cycle 7 pertuzumab serum CtroughSC/CtroughIV, at a 
one-sided 5% significance level. If positive, continue to Step 2; otherwise, stop.
2.
Test the secondary endpoint, Cycle 7 trastuzumab serum CtroughSC/CtroughIV, at a 
one-sided 5% significance level.
The non-inferiority of the SC and IV dose of pertuzumab will be assessed by a one-sided 
testing procedure. The null hypothesis will be rejected and non-inferiority will be 
concluded if the lower bound of the 90% CI of the GMR is 0.8.
6.4.2
Efficacy Analyses
The following analyses (see Table 2 for endpoint definitions) will be analyzed outside of 
a hypothesis-testing framework and according to the methodology provided below. 
Further details on this will be written in the SAP.
Rates of tpCR will be calculated in each treatment arm and will be assessed using the 
difference between FDC tpCR rate and IV tpCR rate and corresponding 95% Clopper 
Pearson CIs.  The difference between the FDC tpCR rate and IV tpCR rates along with 
corresponding 95% Hauck-Anderson CIs will also be calculated. The lower bound of the 
CI will reliably reflect the largest pCR difference that could be considered unlikely.  The 
observed tpCR difference and 95% CI will form the basis of a discussion around the 
differences in efficacy that can be ruled out.  See Appendix 12 for a range of possible 
tpCR differences and 95% CIs under a number of scenarios to demonstrate the 
precision for each outcome with the proposed sample size of N500.  Assessment of 
pCR will be analyzed at the primary analysis.
For all time-to-event (TTE) endpoints, iDFS, iDFS including second primary non-breast 
cancer, EFS, EFS including second primary non-breast cancer, distant recurrence-free 
interval (DRFI), and OS described in Table 2, the Kaplan-Meier approach will be used 
for analysis. Estimates of the proportion of patients who are event-free at landmark 
timepoints for each treatment cohort will be provided. The estimated HR and 
corresponding CI will also be obtained using Cox regression models. Patients who are 
either without distant disease recurrence, alive, or lost to follow-up for the respective 
endpoints will be censored at their last known date in the study and event free. Patients 
with no post-baseline assessments will be censored at the date of enrollment plus 1 day. 


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The TTE endpoints will not be analyzed at the time of the primary analysis; further 
details on censoring and timing will be written in the SAP.
6.4.3
Safety Analyses
The safety analysis population will consist of all randomized patients who received at 
least one dose of study drug and will be grouped according to actual treatment received:  
Arm A to Perjeta IV and Herceptin IV; Arm B to the FDC of pertuzumab and trastuzumab. 
Patients in Arm A, who switched to Herceptin SC after surgery, will be analyzed as a 
separate subset of Arm A.  Patients who do not receive any amount of their study 
medication (i.e., chemotherapy, Perjeta and Herceptin IV, or the FDC) will be excluded 
from the safety population. Safety will be evaluated by the use of descriptive analyses of 
incidence and severity of AEs and SAEs; laboratory test abnormalities; incidence of a 
symptomatic LVSD (otherwise referred to as heart failure), defined as the occurrence of 
symptomatic LVEF decrease or definite or probable cardiac death; and incidence of 
LVSD, defined as an absolute decrease in LVEF of at least 10 percentage points below 
the baseline measurement and to below 50%) by LVEF measurements over the course 
of the study. 
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms and adverse event severity will be graded 
according to the NCI-CTCAE, v4. CHF, in addition, will be graded according to the 
New York Heart Association (NYHA) functional classification. All AEs, including SAEs, 
will be summarized by treatment arm and CTCAE grade. In addition, AEs leading to 
discontinuation of study treatment will be summarized by treatment arm. For each 
patient’s AEs, the maximum severity recorded will be used in the summaries. 
Laboratory toxicities will be defined based on local laboratory normal ranges and NCI-
CTCAE, v4. Selected laboratory abnormalities such as worst toxicity grade and toxicity 
grade shift from baseline will be summarized by treatment arm. Change from baseline 
in targeted vital signs and laboratory results will also be assessed. 
Selected AEs of particular importance (see Section 5.3.4) will also be analyzed, similar 
to the method for AEs.  
For this study the following will be used to characterize reactions related to the 
administration of study drug(s):

Investigator-assessed ARRs, including:
–
ISRs (local), defined as any local morphological or physiological change at or 
near the SC injection site
–
Injection-related reactions (systemic), defined as any system reaction in 
response to the SC injection of study drug 


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–
Infusion-related reactions (systemic), defined as any system reaction in 
response to the IV infusion of study drug 
ARRs potentially associated with IV or SC administration of study drug(s), defined as 
AEs in the SMQ “Anaphylactic Reaction (wide)”, Roche Standard AEGT “Anaphylaxis 
and Hypersensitivity” and “Infusion-Related Reactions and Hypersensitivity”, or the 
dictionary-derived term “Cytokine Release Syndrome” occurring during infusion/injection 
or within 24 hours of the end of administration, should be assessed as to whether 
considered related or unrelated to study drug by the investigator.  Please see Sections 
5.1.1.1 and 5.2.5.2 for additional information about ARRs.
Cardiac-specific AEs will focus on the incidence of patients with heart failure (NYHA, 
NCI-CTCAE [heart failure] Grades 2, 3, 4, and 5). LVEF 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%.  
Cardiac AEs will be categorized according to the following endpoint criteria:

Primary cardiac endpoint:
–
Incidence of a symptomatic ejection fraction decrease (“heart failure”) of NYHA 
Class III or IV and a drop in LVEF of at least 10-percentage points from 
baseline and to below 50%
–
Cardiac death, defined as either:
o
Definite cardiac death (due to heart failure, myocardial infarction, or 
documented primary arrhythmia); or
o
Probable cardiac death (sudden unexpected death within 24 hours of a 
definite or probable cardiac event [e.g., syncope, cardiac arrest, chest pain, 
infarction, arrhythmia] without documented etiology)

Secondary cardiac endpoints:
–
Incidence of an asymptomatic or mildly symptomatic LVSD (“ejection fraction 
decreased”) of NYHA Class II, defined as an LVEF decrease of 10 percentage 
points below the baseline measurement to an absolute LVEF value of 50%, 
confirmed by a second assessment within approximately 3 weeks confirming a 
decrease of 10 percentage points below the baseline measurement and to an 
absolute LVEF value of 50%
The assessment of the cardiac endpoint will be based on data from randomization until 
the start of any new therapy for recurrence of disease.  Therefore, any asymptomatic or 
mildly symptomatic (NYHA Class II) significant drop in LVEF should be confirmed within 
approximately 3 weeks, even during follow-up phase.
Safety analyses will be performed at the primary analysis and may be performed at 
additional timepoint during the study as necessary.


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6.5
EXPLORATORY ANALYSES
6.5.1
PK Analyses
Exploratory analyses will include characterization of the pharmacokinetics of pertuzumab
and trastuzumab following FDC SC administration. PK variables will be presented by 
listings and descriptive summary statistics including arithmetic mean, geometric mean, 
median, range, standard deviation and CV, and 95% CIs. 
Modeling of the PK data may be performed using a population approach based on a 
model previously developed on a combined SC and IV dataset from the BO30185 study. 
The structural and statistical model will be defined using a non-linear mixed-effects
model (NONMEM). The model will be parametrized in terms of clearances and volumes,
and the individual measures of exposure (i.e., Ctrough and AUC0-τ) will be predicted from 
the final PK model. 
Predicted Ctrough may be considered as a supportive endpoint of the measured/observed
Ctrough. The aim of using predicted Ctrough is to take into account possible deviations from 
the protocol (i.e., sampling schedule or dosing interval) and extra-noise (i.e., precision of 
analytical measurement). Any potential differences between the outcomes of the 
statistical test performed on observed and predicted Ctrough will be discussed in the final 
study report.
Comparability of the SC and IV dose of pertuzumab may be assessed by comparing the 
AUC0-τ resulting from the administration of each formulation.
Comparability of the pertuzumab Ctrough level observed at Cycle 12 in the post-surgery 
period following IV and SC administration may be assessed as an exploratory analysis 
(i.e., the measured pre-dose concentration value at Cycle 13). Additionally, the full 
pertuzumab PK profile at Cycle 7 and Cycle 12 may also be assessed.
Potential exposure-response relationships may be assessed through exploratory 
analyses in terms of efficacy and safety of the FDC and pertuzumab exposure. The 
primary efficacy variable will be pCR and safety variables will be dependent on study 
data. Exposure metrics may include pertuzumab Cmax, minimum serum concentration 
(Cmin), and AUC. 
An assessment of PK drug-drug interaction (DDI) may be evaluated in an exploratory 
analysis. The impact of pertuzumab on the PK of trastuzumab will be evaluated by 
comparing trastuzumab PK after FDC administration and after Herceptin SC 
administration for patients who switch post-surgery from Herceptin IV to Herceptin SC. 
Additionally, trastuzumab PK data collected in this study can be compared to historical 
data evaluating Herceptin SC monotherapy to confirm no apparent impact of 
pertuzumab on trastuzumab. 


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A comparison of pertuzumab exposure in Cycle 1 between Perjeta IV 840 mg and FDC 
(pertuzumab 1200 mg SC) may be regarded as exploratory.
6.5.2
Efficacy Analyses
To further assess the tpCR endpoint, exploratory analyses will be conducted analyzing 
different definitions of pCR including:  

Breast pathological complete response (bpCR), defined as eradication of invasive 
disease in the breast (i.e., ypT0/is, ypNx) 

German Breast Group (GBG) pCR, defined as eradication of invasive and in situ 
disease in the breast and invasive disease in axilla (i.e., ypT0 ypN0)
Analysis methods of the exploratory pCR endpoints will be the same as those for the 
secondary tpCR endpoint.
In the neoadjuvant period, clinical response will also be analyzed and response will be 
assessed as CR, PR, SD, or PD by the investigator as per routine clinical practice
(see 
additionaly Section 4.5.12). Clinical response rate prior to surgery will be summarized 
and reported. For patients who have clinical response assessed during neoadjuvant 
therapy but not immediately prior to surgery, and patients who do not undergo surgery, 
the last recorded clinical response assessment will be considered in the analysis. 
Patients without any assessment of clinical response prior to surgery will be considered 
non-responders in the analysis.
6.5.3
Immunogenicity Analyses
The immunogenicity analysis population will consist of all patients with at least one ADA 
assessment.  Patients will be grouped according to treatment received.
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after baseline (post-baseline incidence) will be 
summarized by treatment group.  When determining post baseline incidence, patients 
are considered to be ADA positive if they are ADA negative or have missing data at 
baseline but develop an ADA response following study-drug exposure (treatment-
induced ADA response), or if they are ADA positive at baseline and the titer of one or 
more post baseline samples is at least 4-fold greater (i.e., 0.60 titer units or 4 times 
the dilution factor) than the titer of the baseline sample (treatment-enhanced ADA 
response).  Patients are considered to be negative for ADAs if they are ADA negative at 
all timepoints.  Patients are considered to be treatment unaffected if they are ADA 
positive at baseline but do not have any post baseline samples with a titer that is at least 
4-fold greater than the titer of the baseline sample. Patients are considered to be ADA 
negative if they are ADA negative or have missing data at baseline and all post baseline
samples are negative, or if they are ADA positive at baseline but do not have any post 
baseline samples with a titer that is at least 4-fold greater than the titer of the baseline 
sample (treatment unaffected).


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The relationship between ADA status and safety, efficacy, and PK endpoints will be 
analyzed and reported via descriptive statistics (as data allow).
 
 
 
 
  
 
 
 
 
 
6.6
INTERIM AND FINAL ANALYSES
No formal, statistical interim analyses are planned prior to the primary analysis.  
The final analysis will occur 3 years after the last patient’s last treatment.
6.7
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized. Reasons for patient discontinuations from the study treatment and from 
the study will be listed and summarized. Enrollment, study treatment administration, and 
major protocol deviations will be evaluated for their potential effects on the interpretation 
of study results. 
For safety-evaluable patients, study drug administration and dose modifications data will 
be tabulated or listed by cohort, using descriptive statistics to summarize the total doses 
where applicable.
6.8
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics will be summarized using descriptive statistics
(e.g., means, standard deviations, medians, and ranges for continuous variables and 
proportions for categorical variables, as appropriate).  Summaries will be presented 
overall and by treatment group
7
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 


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eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Non-eCRF data will be sent directly to the 
Sponsor, using the Sponsor’s standard procedures to handle and process the electronic 
transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs 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.  
eCRFs 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 on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification 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, evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies of transcriptions 
that are certified after verification as being accurate and complete, microfiche, 
photographic negatives, microfilm or magnetic media, X-rays, patient files, and records 
kept at pharmacies, laboratories, and medico-technical departments involved in a clinical 
trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.


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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 
IMPs, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 


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Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
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.


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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 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 adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may 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.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 


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be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5).
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.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (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.


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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 study is being sponsored by F. Hoffmann-La Roche Ltd. The Sponsors will perform 
study management, including project management, data management, and clinical 
monitoring. Source data verification for critical parameters will be conducted for all 
patients enrolled.
Approximately 120 sites globally will participate to enroll approximately 500 patients.  
Randomization will occur through an IxRS.
Central facilities will be used for certain study assessments throughout the study (e.g., 
specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
An iDMC will be established to monitor and evaluate patient safety throughout the study.  
The iDMC members will be external to Roche and independent of the trial. The iDMC will 
be comprised of a fixed number of permanent members with experience in clinical 
studies in oncology and will include at least one statistician. The iDMC will follow a 
charter that outlines their roles and responsibilities and ability to make recommendations 
regarding continuation of the study to ensure integrity and viability of the trial, as well as 
acceptable risk to patients in the trial. The iDMC will be responsible for monitoring the 
safety of patients in the study and will make recommendations to the Sponsor through 
the Data Review Board regarding the conduct of the study, including study continuation 
as planned or with protocol amendment or early discontinuation of the study for 
excessive toxicity. 
The first iDMC meeting will approximately take place after the first 50 patients have been 
randomized into the study and have completed their full course of neoadjuvant therapy 
(8 cycles). Additional review meetings are planned to occur when approximately 200 
and 500 patients have been randomized and have completed their full course of 
neoadjuvant therapy. Thereafter, further review meetings will take place approximately 
every 6 months until the primary analysis. The iDMC schedule may be modified based 
on the recommendation of its members or request by the Sponsor. The operating 
procedures for the meetings will be detailed in the iDMC Charter.
An iDCC will prepare the unblinded data packages for the iDMC meetings.
Enrollment will not be deferred while the iDMC performs a review. 


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A Steering Committee will be set up to provide guidance on the protocol and study 
design and to provide guidance on review of any relevant study-related documents or 
procedures in order to be confident that the data collected will be timely, accurate and 
complete. A separate Steering Committee Charter will outline the committee’s 
composition, meeting timelines, and the members’ roles and responsibilities. Members 
will provide input on and agree on the composition of the iDMC. The Steering 
Committee will be kept informed of the outcome of decisions made by IDMC.
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 healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries of the U.S. National Institutes of Health and the 
EMA, 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 web site:
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 6 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 multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 


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monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10
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156/Protocol WO40324, Version 2
Appendix 1 Schedule of Activities for Patients Receiving AC Q3WDocetaxel in the Neoadjuvant 
Phase
This study is driven by the primary endpoint Ctrough.  Therefore, adherence to the PK assessment schedule is of utmost importance.
Screening
Baseline
Treatment Period
3-Week Cycles
3-Week Cycles
Cycle
1
2
3
4
5
6
7
8
Surgery a
Day
–28 to –1
–7 to –1
1
1
1
1
1
2
15
1
1
2
4
8
15
1
1
Informed consent b
x
Medical history and 
demographics
x
Complete physical examination
c, d
x
x
x
Limited physical examination d
x
x
x
x
x
x
Vital signs e, d
x
x
x
x
x
x
x
x
x
ECOG Performance Status c, d, f
x
x g
x
x
x
x
x
x
x
Height d
x
Weight c, d, h
x
x
x
x
x
x
x
x
x
Tumor staging i
x
Bilateral mammogram (or 
another imaging method as per 
local practice) j
x
x
Clinical tumor 
assessment/breast examination
d, k
x
x
x
x
x
x
x
x
x


Appendix 1 Schedule of Activities for Patients Receiving AC Q3WDocetaxel in the Neoadjuvant 
Phase (cont.)
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
157/Protocol WO40324, Version 2
Screening
Baseline
Treatment Period
3-Week Cycles
3-Week Cycles
Cycle
1
2
3
4
5
6
7
8
Surgery a
Day
–28 to –1
–7 to –1
1
1
1
1
1
2
15
1
1
2
4
8
15
1
1
ECG (12-lead)
x
x
LVEF (ECHO or MUGA) l
x
x m
x
x
Hematology/Biochemistry n
x
x g
x
x
x
x
x
x
x
Pregnancy test o
x
x
x
FFPE tumor tissue sample for 
central HER2/HR testing and 
exploratory biomarker research p
x
Local HER2 and hormone 
receptor status (HER2, ER, 
PgR) q
x
Tumor sample r
x
Pathologist post-surgery 
pathologic response tumor 
assessment s
x
PK sampling: 
Pertuzumab/Trastuzumab IV 
(Arm A) t
x
u,v
x
x
x
u,v
x
u,v
x
x
x
x
x
u,v
ADA sampling: 
Pertuzumab/Trastuzumab IV
(Arm A)
x w
x u


Appendix 1 Schedule of Activities for Patients Receiving AC Q3WDocetaxel in the Neoadjuvant 
Phase (cont.)
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
158/Protocol WO40324, Version 2
Screening
Baseline
Treatment Period
3-Week Cycles
3-Week Cycles
Cycle
1
2
3
4
5
6
7
8
Surgery a
Day
–28 to –1
–7 to –1
1
1
1
1
1
2
15
1
1
2
4
8
15
1
1
PK sampling: 
Pertuzumab/Trastuzumab SC 
(Arm B) t
x x
x
x
x x
x x
x
x
x
x
x x
ADA sampling: 
Pertuzumab/Trastuzumab/
rHuPH20 SC (Arm B)
x w
x x
Plasma sample for ctDNA
(biomarker) y
x w
x
Perjeta IV (Arm A) z
x
x
x
x
Herceptin IV (Arm A) z
x
x
x
x
FDC SC (Arm B) aa
x
x
x
x
Doxorubicin bb
x
x
x
x
Cyclophosphamide bb
x
x
x
x
Docetaxel cc
x
x
x
x
Adverse events dd
All AEs and SAEs (see Section 5.3)
Concomitant medication ee
x
Continuous
ACdoxorubicin and cyclophosphamide; ADA anti-drug antibody; -HCG human chorionic gonadotripin; CBE clinical breast examination; 
CTcomputed tomography; ctDNA circulating tumor DNA; Ctrough steady-state concentration; ECHO echocardiogram; ECOG Eastern 
Cooperative Oncology Group; ER estrogen receptor; FDCfixed-dose combination of pertuzumab and trastuzumab for SC administration; 


Appendix 1 Schedule of Activities for Patients Receiving AC Q3WDocetaxel in the Neoadjuvant 
Phase (cont.)
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
159/Protocol WO40324, Version 2
FFPE formalin-fixed, paraffin-embedded; LVEF left ventricular ejection fraction; MRI magnetic resonance imaging; MUGAmultiple-gated 
acquistion; NCCNNational Comprehensive Cancer Network; PgR progesterone receptor; PK pharmacokinetic; Q3W every three weeks; 
RBR Research Biosample Repository; rHuPH20 recombinant human PH20 hyaluronidase; SAE serious adverse event.
Notes:  Cycle 1, Day 1first dose of study drug.  Patients should receive their first dose of study drug on the day of randomization, if 
possible. If this is not possible, the first dose should occur no later than 3 days after randomization. Clinical visits must be scheduled 
within3 days of the day specified. On dosing days, PK samples need to be taken on the exact day of the visit schedule.  On non-dosing 
days, PK samples must be taken within 2 days of the required sampling day, with the timing of PK sampling during the day left to the 
investigator (however, the time should be carefully recorded).
a Surgery will be performed no earlier than 14 days following the last infusion or injection of neoadjuvant therapy.  The interval between the 
last dose of neoadjuvant Perjeta and Herceptin IV or FDC and the first dose of adjuvant Perjeta and Herceptin IV or FDC should be 
9 weeks.
b Results of standard-of-care tests or examinations performed prior to obtaining informed consent may be used; such tests do not need to be 
repeated for screening.
c Must be performed pre-dose on dosing days.
d Assessment may be done within 3 days prior to treatment day.
e
Vital signs (respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature) 
will be taken before the administration of study treatment and before and after Perjeta and Herceptin infusions/FDC injections.
f
ECOG Performance Status should be assessed when the patient undergoes clinical tumor assessment and breast examination (i.e., prior to 
each new cycle of therapy during neoadjuvant treatment and at least every 3 months during the adjuvant treatment period [Cycle 9, 
Cycle 13, Cycle 17, and Cycle 21] and at the treatment completion or discontinuation visit).  
g Screening measurements can be used as Day 1 assessments if performed within 3 days prior to Cycle 1.
h Weight will be measured during screening and on Day 1 of each cycle.  If variation of 10% occurs, as compared with baseline, the 
Herceptin IV and chemotherapy doses will be recalculated.
i
Baseline tumor staging procedures are not mandatory and should be performed as per local practice, in alignment with national guidelines
and as clinically indicated within 28 days of randomization. See Section 4.5.7.2.
j
Provided that the patient’s clinical status has not changed, the screening mammogram can be performed up to 42 days prior to the start of 
treatment.  The mammogram at screening, pre-surgery, and treatment completion or discontinuation visit can be replaced by other 
conventional imaging methods such as MRI or ultrasound per local medical practice, at the investigator’s discretion, but the same method of 
assessment must be used throughout for an individual patient. If another method is used, this must be performed within the 28-day 
screening window.  If a mammogram has been conducted as part of routine preventive care within 4 months of the treatment completion or 


Appendix 1 Schedule of Activities for Patients Receiving AC Q3WDocetaxel in the Neoadjuvant 
Phase (cont.)
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
160/Protocol WO40324, Version 2
discontinuation visit, it may be used in lieu of the end-of-study mammogram.
k Clinical breast examination (CBE) will be performed at screening. During the neoadjuvant treatment period, tumor response assessment 
will be performed prior to each new cycle of therapy by CBE (mandatory) and other methods of evaluation as per routine clinical practice.
l
For patients whose LVEF cannot be assessed by ECHO, LVEF may be assessed by MUGA.  The same method should be used throughout 
the study for each patient and is preferably performed and assessed by the same assessor.  All LVEF assessments will be performed 
during Days 1521 of three-week cycles prior to the cycle indicated here to allow evaluation of the results before the next treatment cycle. 
LVEF assessment may also be performed on Day 1 of treatment but results must be available before treatment is administered.  
m Patients should not start HER2-targeted therapy if their LVEF is 50% after anthracycline treatment.  This ECHO/MUGA assessment 
should be performed prior to administration of any treatment at Cycle 5.
n Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (% or absolute for neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells).  Biochemistry:  sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, 
creatinine, albumin, ALP, ALT, AST, total bilirubin and direct/indirect bilirubin (if needed).  Bilirubin fractions (direct and indirect) need to be 
measured only if total bilirubin is greater than ULN.  Bicarbonate should only be tested at sites where this test is part of the standard safety 
laboratory panel. During the treatment period, bloods for hematology/biochemistry must be taken predose but may be taken within 3 days 
prior to treatment day.
o For all women of childbearing potential and for all women not meeting the definition of postmenopausal (refer to Section 5.1.3 for 
definition), pregnancy test must be performed via serum -HCG at baseline within 7 days prior to the first administration of study medication
(with result available prior to dosing).  Urine pregnancy tests should be repeated during the treatment period within 7 days prior to every 
third treatment cycle starting at Cycle 4 (and as clinically indicated), as well as at the treatment discontinuation visit and every 3 months 
thereafter until 6 months after discontinuation of study treatment.  Any positive urine pregnancy test must be confirmed with a serum -HCG 
test.  Treatment period pregnancy test results must be available prior to the drug infusion/injection. A pregnancy test at 7 months
(i.e., between 69 months follow up) can be performed if indicated. Note that patients are required to continue contraception for 7 
months after study treatment is complete.
p FFPE tumor tissue sample will be collected for mandatory central confirmation of HER2 and hormone receptor status. Additional 
mandatory exploratory biomarker analysis (such as PIK3CA), storage, and analysis, as part of the RBR (optional) only, apply for 
randomized patients. Retrieval, submission, and central testing of tumor tissue sample can occur outside the 28-day screening period.
q Hormone receptorpositive patients are to be prescribed endocrine therapy according to the guidelines after completion of pre-operative 
chemotherapy and surgery. Local HER2/HR assessment can occur outside the 28-day screening period.
r
Optional submission of post-treatment samples obtained from resection specimens from all consenting patients for exploratory biomarkers.
s
Pathological response assessment to be performed using the resected specimen by the local pathologist on the basis of guidelines to be 
provided in the Pathology Manual.


Appendix 1 Schedule of Activities for Patients Receiving AC Q3WDocetaxel in the Neoadjuvant 
Phase (cont.)
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
161/Protocol WO40324, Version 2
t
The date and time of PK sampling must be carefully recorded in all cases. On dosing days, PK samples must be taken on the exact day 
when HER2-targeted therapy is administered (no window allowed).  On non-dosing days, all samples must be taken on the exact day of 
the visit schedule whenever possible (2 days is allowed if necessary), with the timing of PK sampling during the day left to the investigator 
(however, the time should be carefully recorded) 
If the Cycle 8 dose administration is going to be delayed by more than 
2 days, the Cycle 8 pre-dose sample must be taken 21 days after Cycle 7 administration.  This exception does not apply to any other 
cycles.
u Take sample pre-infusion.
v Take additional PK sample at the end of the infusion. The time of sampling must be within 15 minutes after each infusion has ended.
w Sample can be taken after randomization but prior to drug administration on Cycle 1, Day 1.
x Take sample pre-injection.
y Mandatory plasma samples collected at baseline, at Cycles 8 and 10, the treatment completion or treatment discontinuation visit and at 
3-year follow up.
z All patients in Arm A receive a Perjeta loading dose of 840 mg IV on Cycle 5, Day 1 (the first day of paclitaxel treatment).  Thereafter 
(Cycles 622), all patients receive a Perjeta maintenance dose of 420 mg IV. All patients in Arm A receive a Herceptin loading dose of 
8 mg/kg IV on Cycle 5, Day 1 (the first day of paclitaxel treatment).  Thereafter (Cycles 622), all patients receive Herceptin at 6 mg/kg IV.  
The order of administration of Perjeta and Herceptin is according to the investigator’s preference.
aa All patients in Arm B receive a FDC SC loading dose of 1200mg pertuzumab and 600mg trastuzumab on Cycle 5, Day 1 (the first day of 
paclitaxel treatment).  Thereafter (Cycles 622), all patients receive maintenance dose of 600mg pertuzumab and 600mg trastuzumab.
bb All patients receive doxorubicin 60 mg/m2 IV and cyclophosphamide 600 mg/m2 IV given every 3 weeks, for four cycles (Cycles 14), 
according to local practice guidelines.
cc The starting dose of docetaxel is 75mg/m2 IV in Cycle 5 given every 3 weeks. At the investigator’s discretion, the dose may be escalated to 
100 mg/m2 IV for subsequent cycles (Cycles 68) provided no dose-limiting toxicity occurs.
dd After informed consent has been obtained, but prior to initiation of study drug, only serious adverse events caused by protocol-mandated 
intervention should be reported.  After initiation of study drugs, all adverse events and serious adverse events will be collected until the 
treatment completion or discontinuation visit (28 days after the last dose of study drug).  Non-serious adverse events occurring prior to 
study drug administration (Cycle 1, Day 1) will be reported in the medical history unless adverse event reporting is deemed more 
appropriate.  After the treatment completion or discontinuation visit, drug-related serious adverse events and adverse events and serious 
adverse events that qualify for long-term reporting will continue to be collected (see Sections 5.3.4 and 5.5.2).
ee Concomitant medications will be recorded until the end of the treatment period.


SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
162/Protocol WO40324, Version 2
Appendix 2 Schedule of Activities for Patients Receiving ddAC Q2WPaclitaxel in the 
Neoadjuvant Phase
This study is driven by the primary endpoint Ctrough.  Therefore, adherence to the PK assessment schedule is of utmost importance.
Screening
Baseline
Treatment Period
2-Week Cycles
3-Week Cycles
Cycle
1
2
3
4
5
6
7
8
Surgery a
Day
–28 to –1
–7 to –1
1
1
1
1
1
2
15
1
1
2
4
8
15
1
1
Informed consent b
x
Medical history and 
demographics
x
Complete physical examination
c, d
x
x
x
Limited physical examination c, d
x
x
x
x
x
x
Vital signs d, e
x
x
x
x
x
x
x
x
x
ECOG Performance Status c, d, f
x
x g
x
x
x
x
x
x
x
Height d
x
Weight c, d, h
x
x
x
x
x
x
x
x
x
Tumor staging i
x
Bilateral mammogram (or 
another imaging method as, per 
local practice) j
x
x
Clinical tumor
assessment/breast examination
d, k
x
x
x
x
x
x
x
x
x


Appendix 2 Schedule of Activities for Patients Receiving ddAC Q2WPaclitaxel in the 
Neoadjuvant Phase (cont.)
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
163/Protocol WO40324, Version 2
Screening
Baseline
Treatment Period
2-Week Cycles
3-Week Cycles
Cycle
1
2
3
4
5
6
7
8
Surgery a
Day
–28 to –1
–7 to –1
1
1
1
1
1
2
15
1
1
2
4
8
15
1
1
ECG (12-lead)
x
x
LVEF (ECHO or MUGA) l
x
x m
x
x
Hematology/Biochemistry n
x
x g
x
x
x
x
x
x
x
Pregnancy test o
x
x
x
FFPE tumor tissue sample for 
central HER2/HR testing and 
exploratory biomarker research p
x
Local HER2 and hormone 
receptor status (HER2, ER, 
PgR) q
x
Tumor sample r
x
Pathologist post-surgery 
pathologic response tumor 
assessment s
x
PK sampling: 
Pertuzumab/Trastuzumab IV 
(Arm A) t
x
u,v
x
x
x
u,v
x
u,v
x
x
x
x
x
u,v
ADA sampling: 
Pertuzumab/Trastuzumab IV
(Arm A)
x w
x u
PK sampling: 
Pertuzumab/Trastuzumab SC 
(Arm B) t
x x
x
x
x x
x x
x
x
x
x
x x


Appendix 2 Schedule of Activities for Patients Receiving ddAC Q2WPaclitaxel in the 
Neoadjuvant Phase (cont.)
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
164/Protocol WO40324, Version 2
Screening
Baseline
Treatment Period
2-Week Cycles
3-Week Cycles
Cycle
1
2
3
4
5
6
7
8
Surgery a
Day
–28 to –1
–7 to –1
1
1
1
1
1
2
15
1
1
2
4
8
15
1
1
ADA sampling: 
Pertuzumab/Trastuzumab/
rHuPH20 SC (Arm B)
x w
x x
Plasma sample for ctDNA
(biomarker) y
x w
x
Perjeta IV (Arm A) z
x
x
x
x
Herceptin IV (Arm A) z
x
x
x
x
FDC SC (Arm B) aa
x
x
x
x
ddDoxorubicin bb
x
x
x
x
ddCyclophosphamide bb
x
x
x
x
Paclitaxel cc
Weekly for 12 weeks
Adverse events dd
All AEs and SAEs (see Section 5.3)
Concomitant medication ee
x
Continuous
ADA anti-drug antibody; AE adverse event; -HCG human chorionic gonadotripin; CBE clinical breast examination; CT computed 
tomography; ctDNA circulating tumor DNA; Ctrough steady-state concentration; ddAC dose-dense doxorubicin and cyclophosphamide;
ECHO echocardiogram; ECOG Eastern Cooperative Oncology Group; ER estrogen receptor; FDC fixed-dose combination of 
pertuzumab and trastuzumab for SC administration; FFPE formalin-fixed, paraffin-embedded; LVEF left ventricular ejection fraction; 
MRI magnetic resonance imaging; MUGA multiple-gated acquistion; NCCN National Comprehensive Cancer Network; 
PgR progesterone receptor; PK pharmacokinetic; Q2W every 2 weeks; RBR Research Biosample Repository; rHuPH20 recombinant 
human PH20 hyaluronidase; SAE serious adverse event.


Appendix 2 Schedule of Activities for Patients Receiving ddAC Q2WPaclitaxel in the 
Neoadjuvant Phase (cont.)
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
165/Protocol WO40324, Version 2
Notes:  Cycle 1, Day 1first dose of study drug. Patients should receive their first dose of study drug on the day of randomization, if 
possible. If this is not possible, the first dose should occur no later than 3 days after randomization. Clinical visits must be scheduled 
within3 days of the day specified.  On dosing days, PK samples need to be taken on the exact day of the visit schedule.  On non-dosing 
days, PK samples must be taken within 2 days of the required sampling day, with the timing of PK sampling during the day left to the 
investigator (however, the time should be carefully recorded).
a Surgery will be performed no earlier than 14 days following the last infusion or injection of neoadjuvant therapy.  The interval between the 
last dose of neoadjuvant Perjeta and Herceptin IV or FDC and the first dose of adjuvant Perjeta and Herceptin IV or FDC should be 
9 weeks.
b Results of standard-of-care tests or examinations performed prior to obtaining informed consent may be used; such tests do not need to be 
repeated for screening.
c Must be performed pre-dose on dosing days.
d Assessment may be done within 3 days prior to treatment day.
e
Vital signs (respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature) 
will be taken before the administration of study treatment and before and after Perjeta and Herceptin infusions/FDC injections.
f
ECOG Performance Status should be assessed when the patient undergoes clinical tumor assessment and breast examination (i.e., prior 
to each new cycle of therapy during neoadjuvant treatment and at least every 3 months during the adjuvant treatment period [Cycle 9, 
Cycle 13, Cycle 17, and Cycle 21] and at the treatment completion or discontinuation visit).
g Screening measurements can be used as Day 1 assessments if performed within 3 days prior to Cycle 1.
h Weight will be measured during screening and on Day 1 of each cycle.  If variation of 10% occurs, as compared with baseline, the 
Herceptin IV and chemotherapy doses will be recalculated.
i
Baseline tumor staging procedures are not mandatory and should be performed as per local practice, in alignment with national guidelines
and as clinically indicated within 28 days of randomization (see Section 4.5.7.2).
j
Provided that the patient’s clinical status has not changed, the screening mammogram can be performed up to 42 days prior to the start of 
treatment.  The mammogram at screening, pre-surgery, and treatment completion or discontinuation visit can be replaced by other 
conventional imaging methods such as MRI or ultrasound per local medical practice, at the investigator’s discretion, but the same method 
of assessment must be used throughout for an individual patient. If another method is used, this must be performed within the 28-day 
screening window. If a mammogram has been conducted as part of routine preventive care within 4 months of the treatment completion or 
discontinuation visit, it may be used in lieu of the end-of-study mammogram.
k Clinical breast examination (CBE) will be performed at screening. During the neoadjuvant treatment period, tumor response assessment 
will be performed prior to each new cycle of therapy by CBE (mandatory) and other methods of evaluation as per routine clinical practice.
l
For patients whose LVEF cannot be assessed by ECHO, LVEF may be assessed by MUGA.  The same method should be used throughout 
the study for each patient and is preferably performed and assessed by the same assessor.  All LVEF assessments will be performed 
during Days 1521 of 3-week cycles prior to the cycle indicated to allow evaluation of the results before the next treatment cycle. LVEF 


Appendix 2 Schedule of Activities for Patients Receiving ddAC Q2WPaclitaxel in the 
Neoadjuvant Phase (cont.)
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
166/Protocol WO40324, Version 2
assessment may also be performed on Day 1 of treatment but results must be available before treatment is administered.
m Patients should not start HER2-targeted therapy if their LVEF is 50% after anthracycline treatment.  This ECHO/MUGA assessment 
should be performed prior to administration of any treatment at Cycle 5.
n Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (% or absolute for neutrophils, eosinophils,
basophils, monocytes, lymphocytes, other cells).  Biochemistry:  sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, 
creatinine, albumin, ALP, ALT, AST, total bilirubin and direct/indirect bilirubin (if needed).  Bilirubin fractions (direct and indirect) need to be 
measured only if total bilirubin is greater than ULN.  Bicarbonate should only be tested at sites where this test is part of the standard safety 
laboratory panel.  During the treatment period, bloods for hematology/biochemistry must be taken predose but may be taken within 3 days 
prior to treatment day.
o For all women of childbearing potential and for all women not meeting the definition of postmenopausal (refer to Section 5.1.3 for 
definition), pregnancy tests must be performed via serum -HCG at baseline within 7 days prior to the first administration of study 
medication (with result available prior to dosing).  Urine pregnancy tests should be repeated during the treatment period within 7 days prior 
to every third treatment cycle starting at Cycle 4 (and as clinically indicated), as well as at the treatment discontinuation visit and every 
3 months thereafter until 6 months after discontinuation of study treatment.  Any positive urine pregnancy test must be confirmed with a 
serum -HCG test.  Treatment period pregnancy test results must be available prior to the drug infusion/injection. A pregnancy test at 
7 months (i.e. between 6-9 month follow up) can be performed if indicated. Note that patients are required to continue contraception for
7 months after study treatment is complete.
p FFPE tumor tissue sample will be collected for mandatory central confirmation of HER2 and hormone receptor status.  Additional 
mandatory exploratory biomarker analysis (such as PIK3CA), storage, and analysis, as part of the RBR (optional) only, apply for 
randomized patients. Retrieval, submission, and central testing of tumor tissue sample can occur outside the 28-day screening period.
q Hormone receptorpositive patients are to be prescribed endocrine therapy according to the guidelines after completion of pre-operative 
chemotherapy and surgery. Local HER2/HR assessment can occur outside the 28-day screening period.
r
Optional submission of post-treatment samples obtained from resection specimens from all consenting patients for exploratory biomarkers. 
s
Pathological response assessment to be performed using the resected specimen by the local pathologist on the basis of guidelines to be 
provided in a Pathology Manual.  
t
The date/time of PK sampling must be carefully recorded in all cases. On dosing days, PK samples must be taken on the exact day when 
HER2-targeted therapy is administered (no window allowed). On non-dosing days, all samples must be taken on the exact day of the 
visit schedule whenever possible (2 days is allowed if necessary, with the timing of PK sampling during the day left to the investigator 
(however, the time should be carefully recorded) 
If the Cycle 8 dose administration is going to be delayed by more than 
2 days, the Cycle 8 pre-dose sample must be taken 21 days after Cycle 7 administration. This exception does not apply to any other 
cycles.
u Take sample pre-infusion.
v Take additional PK sample at the end of the infusion. The time of sampling must be within 15 minutes after each infusion has ended.
w Sample can be taken after randomization but prior to drug administration on Cycle 1, Day 1.


Appendix 2 Schedule of Activities for Patients Receiving ddAC Q2WPaclitaxel in the 
Neoadjuvant Phase (cont.)
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
167/Protocol WO40324, Version 2
x Take sample pre-injection.
y Mandatory plasma samples collected at baseline, at Cycles 8 and 10, the treatment completion or treatment discontinuation visit and at 
3-year follow up.
z All patients in Arm A receive a Perjeta loading dose of 840 mg IV on Cycle 5, Day 1 (the first day of paclitaxel treatment).  Thereafter 
(Cycles 622), all patients receive a Perjeta maintenance dose of 420 mg IV. All patients in Arm A receive a Herceptin loading dose of 
8 mg/kg IV on Cycle 5, Day 1 (the first day of paclitaxel treatment).  Thereafter (Cycles 622), all patients receive Herceptin at 6 mg/kg IV.  
The order of administration of Perjeta and Herceptin is according to the investigator’s preference.
aa All patients in Arm B receive a FDC SC loading dose of 1200mg pertuzumab and 600mg trastuzumab on Cycle 5, Day 1 (the first day of 
paclitaxel treatment).  Thereafter (Cycles 622), all patients receive maintenance dose of 600mg pertuzumab and 600mg trastuzumab.
bb All patients receive doxorubicin 60 mg/m2 IV and cyclophosphamide 600 mg/m2 IV given every 2 weeks, for four cycles (Cycles 14), 
according to local practice guidelines.
cc All patients receive paclitaxel 80 mg/m2 IV weekly for 12 weeks starting no sooner than 2 weeks after the last dose of doxorubicin and 
cyclophosphamide.
dd After informed consent has been obtained, but prior to initiation of study drug, only serious adverse events caused by protocol-mandated 
intervention should be reported.  After initiation of study drugs, all adverse events and serious adverse events will be collected until the 
treatment completion or discontinuation visit (28 days after the last dose of study drug).  Non-serious adverse events occurring prior to 
study drug administration (Cycle 1, Day 1) will be reported in the medical history unless adverse event reporting is deemed more 
appropriate.  After the treatment completion or discontinuation visit, drug-related serious adverse events and adverse events and serious 
adverse events that qualify for long-term reporting will continue to be collected (see sections 5.3.4 and 5.5.2).
ee Concomitant medications will be recorded until the end of the treatment period.


SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
168/Protocol WO40324, Version 2
Appendix 3 Schedule of Activities for All Patients in the Adjuvant Pertuzumab and Trastuzumab
Treatment Phase
This study is driven by the primary endpoint Ctrough.  Therefore, adherence to the PK assessment schedule is of utmost importance.
Cycle (3 weeks)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Treatment 
Completion/ 
Discontinuation a
Day
1
1
1
1
2
4
8
15
1
1
1
1
1
1
1
1
1
1
Complete physical 
examination
x
Limited physical examination b
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signs b
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECOG Performance Status b, c
x
x
x
x
x
Weight b, d
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Bilateral mammogram (or 
another imaging method as, 
per local practice) e
x
Clinical breast examination b, f
x
x
x
x
x
LVEF (ECHO or MUGA) g
x
x
x
x
x
x
Hematology/Limited Biochemistry h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Pregnancy test i
x
x
x
x
x
x
Perjeta IV (Arm A) j
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Herceptin IV (Arm A) j
x
x
x
x
x
x
x
x
x
x
x
x
x
x
FDC SC (Arm B) k
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PK sampling: 
Pertuzumab/Trastuzumab IV 
(Arm A) l
x
m,n
x
m,n
x
m,n
x
m,n
x
x
x
x
x m
x m
x m


Appendix 3 Schedule of Activities for All Patients in the Adjuvant Pertuzumab and Trastuzumab 
Treatment Phase (cont.)
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
169/Protocol WO40324, Version 2
Cycle (3 weeks)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Treatment 
Completion/ 
Discontinuation a
Day
1
1
1
1
2
4
8
15
1
1
1
1
1
1
1
1
1
1
ADA sampling: 
Pertuzumab/Trastuzumab IV
(Arm A)
x m
x m
x m
x m
PK sampling: 
Pertuzumab/Trastuzumab SC 
(Arm B) l
x o
x o
x o
x o
x
x
x
x
x o
x o
x o
ADA sampling: 
Pertuzumab/Trastuzumab/
rHuPH20 SC (Arm B)
x o
x o
x o
x o
Plasma sample for ctDNA 
(biomarker)
x
x
Adverse events
All AEs and SAEs (see Section 5.3)
Concomitant medication
Continuous
ADA anti-drug antibody; AE adverse event; -HCG human chorionic gonadotripin; CT computed tomography; ctDNA circulating tumor 
DNA; Ctrough steady-state concentration; ECHO echocardiogram; ECOG Eastern Cooperative Oncology Group; FDC fixed-dose 
combination of pertuzumab and trastuzumab for SC administration; LVEF left ventricular ejection fraction; MRI magnetic resonance imaging; 
MUGA multiple-gated acquistion; PK pharmacokinetic; rHuPH20 recombinant human PH20 hyaluronidase; SAE serious adverse event; 
ULN upper limit of normal.
Notes:  Cycle 1, Day 1 first dose of study drug.  Clinical visits must be scheduled within 3 days of the day specified.  On dosing days, PK 
samples need to be taken on the exact day of the visit schedule.  On non-dosing days, PK samples must be taken within 2 days of the required 
sampling day, with the timing of PK sampling during the day left to the investigator (however, the time should be carefully recorded).
a Treatment completion or discontinuation visits will optimally be scheduled for 28 (3 days) following the last dose of study medication and will 
include all evaluations scheduled for the final visit.
b Assessment may be done within 3 days prior to treatment day.
c
ECOG Performance Status should be assessed when the patient undergoes clinical tumor assessment and breast examination (i.e., at least 
every 3 months during the adjuvant treatment period [Cycle 9, Cycle 13, Cycle 17, and Cycle 21] and at the treatment completion or 
discontinuation visit).


Appendix 3 Schedule of Activities for All Patients in the Adjuvant Pertuzumab and Trastuzumab 
Treatment Phase (cont.)
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
170/Protocol WO40324, Version 2
d Weight will be measured during screening and on Day 1 of each cycle.  If variation of 10% occurs, as compared with baseline, the Herceptin 
IV and chemotherapy doses will be recalculated.
e
Provided that the patient’s clinical status has not changed, the screening mammogram can be performed up to 42 days prior to the start of 
treatment.  The mammogram at screening, pre-surgery, and treatment completion or discontinuation visit can be replaced by other 
conventional imaging methods such as MRI or ultrasound as per local medical practice, at the investigator’s discretion, but the same method 
of assessment must be used throughout for an individual patient.  If a mammogram has been conducted as part of routine preventive care 
within 4 months of the treatment completion or discontinuation visit, it may be used in lieu of the end of study mammogram.
f
During the adjuvant treatment period, clinical breast examination should be performed to detect signs of locoregional relapse at least every 
3 months (Cycle 13, Cycle 17, and Cycle 21) and at the treatment completion or discontinuation visit.
g For patients whose LVEF cannot be assessed by ECHO, LVEF may be assessed by MUGA.  The same method should be used throughout 
the study for each patient and is preferably performed and assessed by the same assessor.  All LVEF assessments will be performed during 
Days 1521 of 3-week cycles prior to the cycle indicated here to allow evaluation of the results before the next treatment cycle.  LVEF 
assessment may be performed on Day 1 of treatment but results must be available before treatment is administered.
h Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (% or absolute for neutrophils, eosinophils,
basophils, monocytes, lymphocytes, other cells).  Limited biochemistry: creatinine, alkaline phosphatase (ALP), AST, ALT, total bilirubin, and 
direct/indirect bilirubin (if needed).  Bilirubin fractions (direct and indirect) need to be measured only if total bilirubin is greater than ULN.
During the treatment period, bloods for hematology/biochemistry must be taken pre dose, but may be taken within 3 days prior to treatment 
day.
i
For all women of childbearing potential and for all women not meeting the definition of postmenopausal (12 months of amenorrhea) who 
have not undergone surgical sterilization, pregnancy tests must be performed via serum -HCG at baseline within 7 days prior to the first 
administration of study medication (with result available prior to dosing).  Urine pregnancy tests should be repeated during the treatment 
period within 7 days prior to every third treatment cycle starting at Cycle 4 (and as clinically indicated), as well as at the treatment 
discontinuation visit and every 3 months thereafter until 6 months after discontinuation of study treatment.  Any positive urine pregnancy test 
must be confirmed with a serum -HCG test.  Treatment period pregnancy test results must be available prior to the drug infusion/injection.
Pregnancy test at 7 months (i.e., between 69 month follow-up) can be performed if indicated. Note that patients are required to continue 
contraception for 7 months after study treatment is complete.
j
All patients receive a Perjeta maintenance dose of 420 mg IV.  All patients receive Herceptin at 6 mg/kg IV.  The order of administration of 
Perjeta and Herceptin is according to investigator preference. After surgery (from Cycle 9 onwards), patients in Arm A are allowed to switch 
from Herceptin IV to Herceptin SC, at the discretion of the investigator, in the countries where Herceptin SC is routinely used.
k All patients receive maintenance dose of 600 mg SC pertuzumab and 600 mg SC trastuzumab.


Appendix 3 Schedule of Activities for All Patients in the Adjuvant Pertuzumab and Trastuzumab 
Treatment Phase (cont.)
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
171/Protocol WO40324, Version 2
l
The date and time of PK sampling must be carefully recorded in all cases. On dosing days, PK samples must be taken on the exact day when 
HER2-targeted therapy is administered (no window allowed).  On non-dosing days, all samples must be taken on the exact day of the visit 
schedule whenever possible (2 days is allowed if necessary) with the timing of PK sampling during the day left to the investigator (however, 
the time should be carefully recorded).
m Take sample pre-infusion.
n Take additional PK sample at the end of the infusion.  The time of sampling must be within 15 minutes after each infusion has ended.
o Take sample pre-injection.


SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
172/Protocol WO40324, Version 2
Appendix 4 Schedule of Activities for All Patients in the Treatment-Free Follow-Up
Follow-up Visits a
Month from the last dose of study drug
3
6
9
12
18
24
30
36
Every 6 months until end of study
Limited physical examination b
x
x
x
x
x
x
x
x
x
Vital signs b
x
x
x
x
x
x
x
x
x
ECOG Performance Status b
x
x
x
x
x
x
x
x
x
Assessment for recurrence c
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
Clinical breast examination
x
x
x
x
x
x
x
x
x
Bilateral mammogram
x
x
x
Hematology/Limited Biochemistry d
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
LVEF (ECHO or MUGA) e
x
x
x
x
x
Pregnancy test f
x
x
PK sampling: Pertuzumab/Trastuzumab IV (Arm A) g
x
x
ADA sampling: Pertuzumab/Trastuzumab IV (Arm A)
x
x
x
x
x
x
x
PK sampling: Pertuzumab/Trastuzumab SC (Arm B) g
x
x
ADA sampling: Pertuzumab/Trastuzumab/rHuPH20 SC
(Arm B)
x
x
x
x
x
x
x
Plasma samples for ctDNA (biomarker)
x
Survival
x
x
x
x
x
x
x
x
x
Adverse events
AEs and SAEs are continuously monitored (see Section 5.4.1).


Appendix 4   Schedule of Activities for All Patients in the Treatment-Free Follow-Up (cont.)
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
173/Protocol WO40324, Version 2
ADAanti-drug antibody; AEadverse event; -HCG human chorionic gonadotripin; ctDNA circulating tumor DNA; 
ECHO echocardiogram; ECOGEastern Cooperative Oncology Group; LVEFleft ventricular ejection fraction; MUGAmultiple-gated 
acquistion; PKpharmacokinetic; rHuPH20 recombinant human PH20 hyaluronidase; SAEserious adverse event.
Notes:  Parentheses (x) indicate that the item is optional and required only if symptoms or clinical suspicion are present.
a Visit to be performed within 15 days. These visits are based on time from last dose of study drug and not time from treatment 
completion/discontinuation visit, (i.e., 3-Month Follow-Up Visit is 3 months after last dose of study drug). After recurrence, all patients should 
continue to follow Appendix 4 for survival, LVEF assessments and pregnancy tests (pregnancies should be reported until 7 months after the 
last dose of study treatment, irrespective of disease progression or relapse or the initiation of alternative treatment).  Related serious adverse 
events and non-breast second primary malignancies (reportable as serious adverse events) should also be reported until the end of the study.
b To be followed up every 3 months for 1 year, then every 6 months for an additional 2 years, then according to routine practice.  After disease 
progression or relapse, patients need to only be followed for survival (i.e., physical examination, vital signs, and Performance Status do not 
need to be assessed).
c Assessment of distant disease recurrence to be performed if clinically indicated to exclude metastatic disease and within a timelines as per 
current standard of practice (see Section 4.5.12)
d Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (% or absolute for neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells). Limited biochemistry: creatinine, ALP, AST, ALT, total bilirubin, and direct/indirect bilirubin 
(if needed).  Bilirubin fractions (direct and indirect) need to be measured only if total bilirubin is greater than ULN
e After completion of HER2-directed therapy, LVEF is to be performed every 6 months for 2 years, then again 1 year later.  For patients who 
discontinue HER2-directed therapy early for disease progression/relapse or due to adverse events (other than heart failure or LVEF decline), 
LVEF assessments should be performed every 6 months for 2 years, then annually for an additional year or until the initiation of alternative 
systemic therapy.  For patients who discontinue HER2-directed therapy for heart failure or LVEF decline, LVEF assessments should be 
continued regardless of initiation of alternative systemic anti-cancer therapy until resolution, improvement to baseline status, no further 
improvement can be expected, or death.  Additional LVEF assessments may be required for these patients (beyond those specified in the 
table) according to the investigator’s clinical judgment.  The results of these assessments should be reported.
f
At 3 and 6 months after the last dose of study treatment. Any positive urine pregnancy test must be confirmed with a serum β-HCG test.  
Pregnancy test at 7 months (i.e., between 69 month follow up) can be performed if indicated. Note that patients are required to continue 
contraception for 7 months after study treatment is complete.
g The date and time of PK sampling must be carefully recorded in all cases.  During follow-up, samples must be taken 7 days of the required 
sampling day, with the timing of PK sampling during the day left to the investigator (however, the time should be carefully recorded).  


SC Fixed-Dose Combination of Pertuzumab and Trastuzumab-F. Hoffmann-La Roche Ltd 
17 4/Protocol WO40324, Version 2 


SC Fixed-Dose Combination of Pertuzumab and Trastuzumab-F. Hoffmann-La Roche Ltd 
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SC Fixed-Dose Combination of Pertuzumab and Trastuzumab-F. Hoffmann-La Roche Ltd 
176/Protocol WO40324, Version 2 


SC Fixed-Dose Combination of Pertuzumab and Trastuzumab-F. Hoffmann-La Roche Ltd 
177/Protocol WO40324, Version 2 


SC Fixed-Dose Combination of Pertuzumab and Trastuzumab-F. Hoffmann-La Roche Ltd 
178/Protocol WO40324, Version 2 


SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
179/Protocol WO40324, Version 2
Appendix 7
ECOG Performance Status
Grade
ECOG
0
Fully active; able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light house work, office work)
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed 
or chair.
5
Dead
ECOGEastern Cooperative Oncology Group.
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 1982;5:64955.


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Appendix 8 Asymptomatic Decline in LVEF:  Algorithm for Continuationa and Discontinuation of 
HER2-Targeted Study Medication
LVEF left ventricular ejection fraction.
a Patients should not start anti-HER2 drugs if their LVEF is 50% after anthracycline treatment. LVEF should recover to ≥50% before starting 
anti-HER2 drugs.


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Appendix 9
NYHA Functional Classification System for Heart 
Failure and LVSD National Cancer Institute Common 
Terminology Criteria for Adverse Events Version 4 Grading
NYHA Functional Classification System for Heart Failure
Class
Description
I
No limitation of physical activity.  Ordinary physical activity does not 
cause undue fatigue, palpitation, or dyspnea.
II
Slight limitation of physical activity.  Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, or dyspnea.
III
Marked limitation of physical activity.  Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation, or dyspnea.
IV
Inability to carry on any physical activity without discomfort. Symptoms 
of cardiac insufficiency at rest.  If any physical activity is undertaken, 
discomfort is increased.
LVSD National Cancer Institute Common Terminology Criteria for AEs Version 4 Grading
Investigations
Grade
1
2
3
4
5
Ejection 
fraction (EF) 
decreased a

Resting EF
50%40%; 
10%19% drop 
from baseline
Resting EF 
39%20%; 20%
drop from baseline
Resting EF 
50%

Cardiac Disorders
Grade
1
2
3
4
5
Heart failure b
Asymptomatic 
with laboratory 
(e.g., BNP [B-
natriuretic 
peptide]) or 
cardiac 
imaging 
abnormalities 
Symptoms with 
mild to 
moderate 
exertion
Severe with 
symptoms at rest or 
with minimal activity 
or exertion; 
intervention 
indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated (e.g., 
continuous IV 
therapy or 
mechanical 
hemodynamic 
support)
Death
BNPB-natriuretic peptide; EFejection fraction; LVSDleft ventricular systolic dysfunction.
a Definition:  the percentage computed when the amount of blood ejected during a ventricular 
contraction of the heart is compared to the amount that was present prior to the contraction.
b Definition:  a disorder characterized by the inability of the heart to pump blood at an adequate volume 
to meet tissue metabolic requirements, or the ability to do only at an elevation in the filing pressure.
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf


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Appendix 10 Pathology Manual
F. HOFFMANN-LA ROCHE LTD
Fixed-Dose Combination of Pertuzumab and Trastuzumab for SC
administration (FDC)
(RO7198574)
Study WO40324:
Manual for Pathological Response Evaluation Following 
Neoadjuvant Chemotherapy
Definition of Pathologic Complete Response (pCR) 


Appendix 10 Pathology Manual (cont.)
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1
INTRODUCTION
For patients with operable breast cancer, pre-operative (also known as “neoadjuvant”) 
therapy has been shown in several randomized trials to result in survival outcomes 
similar to those with adjuvant therapy, with the added benefit of improving breast 
conservation rates (Mauri et al. 2005).  In trials of pre-operative therapy, it has been 
consistently demonstrated that patients who have eradication of invasive disease in the 
breast (and lymph nodes) (i.e., those who achieve a pathologic complete response 
[pCR]) have an improved prognosis compared with those who have residual invasive 
disease present in the surgical specimen after completion of pre-operative therapy 
(non-pCR). (Mauriac et al. 1991; Semiglazov et al. 1994; von Minckwitz et al., 2012).  
For example, in the National Surgical Adjuvant Breast and Bowel Project Studies B-18 
and B-27, the hazard ratios (HRs) for disease-free survival (DFS) were 0.47 and 0.49, 
respectively, for patients who achieved a pCR compared with those who did not; the 
HRs for overall survival (OS) were 0.32 and 0.36, respectively (Rastogi et al. 2008).
Various definitions of pCR have been commonly utilized in clinical trials, but all have
demonstrated prognostic value.  In the earliest studies of pre-operative therapy, the 
absence of residual disease in the breast alone (referred to as breast pCR; bpCR; ypT0 
or ypTis) was mainly considered.  However, it has been reported that a pCR in both
breast and residual nodes (total pCR; tpCR; ypT0 or ypTis, ypN0) is associated with a 
prolonged DFS and possibly OS (Hennessy et al. 2005) when compared with patients 
who have residual disease in the axilla after neoadjuvant therapy.  Furthermore, axillary 
nodal involvement at initial diagnosis is a well-established risk factor for breast cancer 
recurrence and death, and thus, the eradication of all malignant disease from the breast 
and ipsilateral axillary lymph nodes is a common primary goal of systemic neoadjuvant 
therapy.  The presence of residual ductal carcinoma in situ (DCIS) or lobular carcinoma 
in situ (LCIS) following neoadjuvant therapy should be reported, but its prognostic 
significance remains controversial (Mazouni et al. 2007, von Minckwitz et al., 2012).  
Pathological complete response with eradication of invasive and in situ disease in the 
breast and invasive disease in the lymph nodes, a more stringent definition than bpCR 
and tpCR, has been used as the definition of pCR for studies conducted by the German 
Breast Group (GBG pCR; ypT0, ypN0).  Although any in situ residue will be subjected to 
surgery and radiotherapy in the course of normal practice, there is also concern that 
residual in situ disease alone might sometimes be an indicator of residual invasive 
disease that was missed. Any residual invasive carcinoma detected by pathological 
examination in the breast or lymph nodes precludes posttreatment classification as a 
complete pathological response (pCR).
Patients with isolated tumor foci in lymph nodes (ypN0 (i+)) are not classified as 
having a complete pathological response. The presence of axillary nodal tumor deposits 


Appendix 10 Pathology Manual (cont.)
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of any size, including cell clusters 0.2 mm or smaller, excludes a complete pathological 
response. 
Residual disease after neoadjuvant systemic therapy includes a broad range of 
responses from minimal residual disease (with a similar prognosis to pCR) to bulky 
disease indicating frank resistance to treatment.  The prognosis for patients with residual 
disease is worse than for those with a pCR however there is a spectrum of risk based 
upon the extent of residual disease.  
For the purposes of this study, the definition of tpCR after neoadjuvant systemic 
therapy is the absence of any residual invasive cancer on hematoxylin and eosin 
evaluation of the complete resected breast specimen and all sampled regional 
lymph nodes (ypT0/is, ypN0). bpCR and GBG pCR rates are important exploratory 
endpoints in the study.
2
GENERAL GUIDANCE
It is recommended that the “Protocol for the Examination of Specimens From Patients 
with Invasive Carcinoma of the Breast” maintained and available online by the College of 
American Pathologists be used as a general reference guidance to supplement the 
material found in this manual as needed. 
At the time of publication of this manual the web address for the College of American 
Pathologists is:
www.cap.org
At the time of publication of this manual, the guidance may be found in the following 
section:
CAP Home >Protocols and Guidelines > Cancer Protocols >Invasive Breast
3
SURGICAL COMMUNICATION AND SPECIMEN HANDLING
Breast surgery after neoadjuvant systemic therapy should be performed according to 
locally approved guidelines for breast surgery.  It is advised that when possible, the area 
of carcinoma be removed in a single specimen.  The pathologist should be informed of 
the site of the primary tumor in the breast (particularly within mastectomy specimens) as 
well as the presence of any accompanying markers (e.g., metallic clips) or clustered 
microcalcification that would indicate the presence of the residual tumor bed, and 
whether there is more than one primary tumor in the breast. 


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Sutures or similar identifiers should be placed by the surgeon post specimen removal to 
orient the specimen. The specimen should be sent within an hour to a pathology 
laboratory.
Guidance for surgeons regarding axillary management is provided in the protocol. 
4
SPECIMEN HANDLING AND FIXATION 
Multiple ink colors are recommended to identify each of the oriented margins of the 
specimen.  See Section 5 for details of specimen imaging and description of the 
macroscopic findings.  The sliced specimen (described below) should be allowed to fix in 
formalin (twice the volume of the specimen) for at least 24 hours.  It is at the 
pathologist’s discretion as to whether the sections for histopathologic analysis are taken 
before or after the specimen slices have been fixed.  Note that some procedures (see 
Section 5 and Section 6) are performed on the fresh tissue, prior to fixation. 
5
IDENTIFICATION OF THE TUMOR BED
Placement of clips (or other markers) into the tumor bed will have been conducted prior 
to neoadjuvant systemic therapy.  The surgeon and pathologist should discuss the 
patient’s clinical history and response to therapy to ensure optimal evaluation of the 
tumor site.  This is critically important because pCR is defined by exclusion and is 
therefore reliant on appropriate sampling of the correct area in the breast. 
For patients with significant clinical response, the breast resection specimen should be 
radiographed to identify that the tumor clips/markers have been adequately excised.  If 
the surgery was “lumpectomy”, then the specimen should be radiographed upon receipt, 
and then radiographed a second time after the specimen margins have been oriented 
and inked, and the specimen has been serially sliced. In this manner, removal of any 
clips and microcalcifications is confirmed in the intact specimen and location can be 
determined within the specimen.  For “total mastectomy” specimens, it is only necessary 
to radiograph the specimen after it has been inked and sliced.  If radiographs are not 
obtained (e..g, a mass of poorly responsive tumor), then digital photographs or detailed 
diagrams should represent the specimen slices. 
The macroscopic appearance of tumor bed after neoadjuvant treatment is commonly an 
ill-defined fibrous density, rather than a discrete tumor mass.  Also, the tumor bed might 
be better identified by combined visual inspection and gentle palpation of the tissue 
slices than by visual inspection alone.  Therefore, it is important to have an experienced 
pathologist or assistant perform careful macroscopic examination of the tissues and 
correlate those findings with the images and clinical history of the location and response 
of the primary tumor. 


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The macroscopic residual primary tumor bed must be measured and reported in 
three dimensions. Also, any additional tumors in the breast should be measured 
and reported in three dimensions, with an estimated location and measurement of 
their distance from the main tumor bed.  The distance of any tumor bed from 
surgical margins must also be reported. 
It should be noted that the residual tumor bed may have poorly delineated borders, and 
it is better to consider adjacent “satellite tumors” as part of the main tumor unless they 
are more than 1 cm distant or clearly a separate tumor. Even then, sections for 
histopathologic analysis should be taken from the intervening tissues to rule out 
extension of the main tumor. 
Images of the macroscopic findings (radiographs, digital photographs, or detailed 
diagrams) provide important documentation of the macroscopic findings and the 
accuracy and extent of sampling for histopathologic assessment, and can be very helpful 
for the pathologist when they are used as “a map” for the macroscopic description and 
the site of each section that is prepared for histopathologic examination.  Furthermore, 
accurate mapping leads to more precise examination for the presence of residual 
disease, more accurate measurement of the pathologic tumor size for pathologic staging 
and more precise estimation of the residual tumor bed for assessment of cancer 
cellularity. 
See Section 9 and Section 10 for specific details. 
6
SELECTION OF SAMPLES FOR BIOMARKER STUDIES
Biomarker studies of residual tumor or tumor bed are optional in this study.  Pathology 
assessment of the presence/extent of residual disease must take priority over collection 
of samples for biomarker studies.  Therefore, procedures for biomarker sample 
collection in this trial are described below according to whether or not there is obviously 
residual macroscopic tumor. 
If grossly identifiable tumor is clearly present, we suggest that three cores (suggest 
18 gauge) or three punch biopsies (suggest 4 mm), should be obtained from the sliced 
tumor.  One sample should be frozen in a cryovial in OCT media (as used for frozen 
sections) or immediately snap-frozen using local procedures.  In addition, two samples 
should be formalin-fixed and paraffin-embedded (FFPE).  If there is not capability to 
obtain frozen samples, then three FFPE samples should be obtained for the biomarker 
studies. 
If no grossly identifiable tumor is present but microscopic disease is subsequently 
identified, a representative block that would be comparable with the volume of 


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three FFPE core biopsies can be submitted for the biomarker studies (optional consent 
required).
If the final interpretation is pCR, then a representative block from the fibrous tumor bed 
can be submitted for the biomarker studies (optional consent required).  
7
EVALUATION OF THE TUMOR BED WHEN THERE HAS BEEN 
A SIGNIFICANT CLINICAL RESPONSE 
The key information to be obtained after careful macroscopic and microscopic 
evaluation is accurate measurement of the three-dimensional extent of residual 
invasive cancer, the extent and proportion of in situ cancer component, presence 
of any lymphatic/vascular invasion, the status of surgical margins, and the 
presence and measurement of additional tumors in the breast.  
Section 5 describes the important steps for imaging of the specimen and identification 
and description of the tumor bed.  The specimen should be carefully oriented and the 
surgical margins should be inked. 
The specimen should be cut as thinly as possible, into 35 mm slices.  The sliced 
specimen should then be radiographed with radiologist review of the films to determine 
presence/extent of residual disease.  The pathologist should examine the gross 
specimen (visually and by gentle palpation) to identify suspicious areas and proximity to 
margins, and correlate those findings with the radiologic findings.  Review of the 
pathologic and radiographic examination should be discussed with the surgeon 
regarding adequacy of tissue removal and possible need for additional surgical resection. 
Preferably, this should be performed in the intra-operative setting to facilitate a single 
surgery. 
The macroscopic dimensions of the residual fibrous tumor bed must be measured and 
reported in the three largest dimensions (see Section 5). 
Images of the macroscopic findings (radiographs, digital photographs, or detailed 
diagrams) provide “a map” for the macroscopic description and the site of each section 
that is prepared for histopathologic examination.  Furthermore, accurate mapping leads 
to more precise examination for the presence of residual disease, more accurate 
measurement of the pathologic tumor size for pathologic staging and more precise 
estimation of the residual tumor bed for assessment of cancer cellularity. 
It is strongly recommended that a map be prepared for the pathologist and 
annotated with relevant measurements and the site of every tissue section 
obtained for histopathologic evaluation. 


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FFPE sections should be obtained from the suspicious areas as well as margins.  The 
largest cross-sectional area of the residual tumor bed should be submitted for FFPE 
sections, and the pathology report should describe those sections and their relative 
orientation.  A hypothetical example of the section code would be: “slides A1A10;
slice 4, largest tumor bed area, starting from anterior to posterior, from superior row 
(A1A3) to inferior row (A8A10)”.  This will allow accurate correlation of 
histopathologic findings with macroscropic findings and lead to more accurate 
assessment of final tumor size and pathologic stage.  Also note that an annotated map 
(radiograph, digital image, or detailed diagram) makes this much easier for the 
pathologist. 
The number of sections taken is based upon gross inspection of the specimen, 
radiographic features, and overall size of the surgical specimen.  Some pathologists 
employ cytologic evaluation of the freshly sliced tumor bed (touch imprint or gentle 
scrape preparation and smear) to confirm the presence of cancer cells at the time of 
gross examination, although that is optional. 
The largest cross section of presumed tumor bed should be submitted for histologic 
evaluation, including any firm/suspicious appearing tissue. It is expected that a 
minimum of 1015 blocks will be needed in cases where there is macroscopic complete 
response, to rule out residual microscopic disease.  If the original tumor and/or resected 
specimen was/is large, it is recommended that at least one block should be taken per 
10 mm of the pretreatment tumor size with additional samples to represent the specimen 
margins.  If these blocks do not show tumor, further sampling should be carried out.  If 
the residual tumor bed is small (3 cm) but not macroscopically malignant, then it should 
be completely submitted for histopathologic study.  If larger than 3 cm, then at least 
15 blocks from the tumor bed should be submitted. 
Two points to note to avoid missing residual invasive cancer. First, clips are indicators
and are not the actual lesion.  Sometimes metallic clips migrate in the breast.  Also, clips 
are placed as only focal indicators of a more extensive tumor.  So it is important to 
carefully study the macroscopic and radiographic findings of surrounding tissues and not 
solely focus on the metallic indicator.  Second, microcalcifications tend to remain stable 
in the treated breast, but might only represent the in situ component of the tumor.  
Therefore, microcalcifications are a helpful indicator for the tumor bed but are not 
necessarily the best indicator of the invasive component of the tumor. Since 
HER2-positive breast cancers can have extensive and distant in situ components, the 
microcalcifications should be sampled but not assumed to represent the site and extent 
of all residual invasive disease. 


Appendix 10 Pathology Manual (cont.)
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8
EVALUATION OF TUMOR BED WHEN THIS IS A RESIDUAL 
PALPABLE MASS
The key information to be obtained after careful macroscopic and microscopic 
evaluation is accurate measurement of the three-dimensional extent of residual 
invasive cancer, the extent and proportion of in situ cancer component, presence 
of any lymphatic/vascular invasion, the status of surgical margins, and the 
presence and measurement of additional tumors in the breast.  
For specimens with residual palpable mass, the resection specimen is inked and 
sectioned into 35 mm slices.  On the basis of gross evaluation of the slices, the 
pathologist determines the tumor size and confirms with microscopic evaluation.  
Macroscopic tumor size should be reported in three dimensions, and distance from the 
resection margins within 10 mm should be reported in the macroscropic description.  For 
tumors measuring up to 20 mm, the entire tumor should be submitted (after any 
biomarker sampling).  For larger tumors, the largest cross-sectional area of the tumor 
should either be submitted entirely, or submitted as at least five representative tumor 
blocks. 
9
EVALUATION OF AXILLARY LYMPH NODES
The key information to be obtained is the number of nodes containing metastases, 
the size of the largest metastasis, and the largest dimension of any extranodal 
extension. 
If sentinel lymph nodes are biopsied by the surgeon, these should be evaluated as usual. 
There should be thin slices of the sentinel node (23 mm) submitted entirely.  At 
minimum, an H&E stain or an H&E stain and deeper level, should be examined.  Note 
that the literature for micrometastases and isolated tumor cells has not addressed their 
prognostic relevance in the post-neoadjuvant treatment setting.  Therefore, all positive 
findings should be described and accurately reported.  Use of molecular assays to 
assess sentinel lymph node status after neoadjuvant therapy is not allowed, because 
these assays are not designed to detect isolated tumor cells or very tiny 
micrometastases. 
Lymph nodes may be difficult to recognize after neoadjuvant chemotherapy secondary 
to fibrosis and atrophy.  In the case that lymph nodes are difficult to identify, fibrotic 
areas of the axillay fat and sections surrounding vessels should be submitted. 
All lymph nodes removed should be examined histologically by serial gross sectioning.  
For lymph nodes with macroscopic evidence of malignancy, examination should be done 
by representative cross section, to represent the largest metastatic area.  For lymph 
nodes without clearly identifiable malignancy upon macroscopic review, the lymph nodes 


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should be completely submitted for FFPE sections for histological examination.  If 
possible, these lymph nodes should be bisected along the longitudinal axis or cut into 
slices with a thickness of 23 mm.  At least one representative histologic section should 
be evaluated by hematoxylin and eosin (H&E) per paraffin block. Immunohistochemical 
staining for cytokeratin is not routinely performed on negative non-sentinel nodes. 
10
REPORTING RESULTS
10.1
PRIMARY TUMOR
Neoadjuvant systemic therapy can result in a range of responses from no identifiable 
response to complete absence of tumor. The tumor bed must be identified to reliably 
diagnose pCR.  Characteristic changes include edematous fibrous tissue with residual 
vascularity and scattered mast cells and lymphocytic infiltrate, histiocytic cells with 
cytopathic degenerative vacuolization, hyalinized vascular stroma, fat necrosis, 
hemosiderin-laden macrophages, and absence of glandular tissue can indicate the 
tumor bed.  However, there is no doubt that accurate clinical-pathologic correlation at the 
time of macroscopic examination and sectioning remains the most precise method to 
identify the tumor bed. 
Standard pathology reporting of tumor bed size, residual tumor size, type of cancer, 
DCIS status, vascular invasion status, excision status, and distance to margin should be 
reported where applicable. 
In the absence of gross tumor, significant residual disease may still be present 
microscopically.  Extensive sampling must be done to confirm that there is no residual 
invasive disease. 
The postneoadjuvant therapy pathological T category (ypT) is based on the largest focus 
of residual tumor, if present. Treatment-related fibrosis adjacent to residual invasive 
carcinoma is not included in the ypT maximum dimension. When multiple foci of residual 
tumor are present, the (m) modifier is included. The pathology report should include a 
description of the extent of residual tumor explaining the basis for the ypT categorization 
and, when possible, also should document the pretreatment cT category.
Residual cancer cells can have an unexpected, unusual bizarre appearance, or might 
have subtle signet ring, plasmacytoid, or histiocytoid apppearance.  On occasion, 
immunochistochemical stains to distinguish between histiocytes (CD68) and epithelial 
cells (cytokeratins AE1/AE3 or cytokeratin 7) might be necessary to detect residual 
tumor cells in the tumor bed, surgical margins and/or lymphatics. 
If residual disease is noted, standard histolopathologic parameters such as type, size, 
vascular invasion, and margin status should be recorded.  Grade is affected by
treatment changes and has not been validated as independently prognostic in residual 


Appendix 10 Pathology Manual (cont.)
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disease.  Refer to the electronic case report form to ensure information needed for all 
data fields is recorded.
For the purposes of pathologic response, intralymphatic or intravascular cancer alone 
(without invasive cancer) must be distinguished from in situ carcinoma, and should be 
considered to be residual invasive disease. 
Alterations of cellularity may lead to a false impression of multifocality.  IHC examination 
can often demonstrate altered tumor cells in fibrosis.  If multifocality is suspected, then 
sampling of the intervening tissues is advised to look for subtle extension of the main 
tumor.  Also, representative sections of the tissues adjacent to the tumor bed are helpful 
to look for residual invasive cancer and to ensure accurate tumor measurement. 
Residual invasive cancer is not necessarily contiguous because treatment can eliminate 
some regions of the tumor. Therefore, residual tumor size should be based upon the 
total histopathological extent of tumor after macroscopic and microscopic correlatioin, 
and not the size of the largest individual lesion. Diagrammatic mapping of sections to 
macroscopic findings is the most accurate method to measure, stage, and evaluate the 
residual disease.  Therefore, the macroscopic dimensions of the residual tumor bed (in 
three dimensions) might be adjusted up or down after the histopathologic evaluation of 
the corresponding tissue sections from the tumor bed and representative surrounding 
tissues. The postneoadjuvant therapy pathological T category (ypT) is based on the 
largest focus of residual tumor, if present. Treatment-related fibrosis adjacent to residual 
invasive carcinoma is not included in the ypT maximum dimension. When multiple foci 
of residual tumor are present, the (m) modifier is included. The pathology report should 
include a description of the extent of residual tumor explaining the basis for the ypT 
categorization and, when possible, also should document the pretreatment cT category.


Appendix 10 Pathology Manual (cont.)
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Figure 1 - Illustration of Macroscopic-Microscopic Correlations to Define 
Final Dimensions of Residual Cancer
In Figure 1, the macroscopic tumor bed dimensions in Examples A, C, D also define the 
final dimensions of the residual tumor bed after microscopic review.  However, the 
macroscopic tumor bed dimensions in Example B overestimate the extent of residual 
cancer, and so the dimensions of the residual tumor bed (d1 and d2) would be revised 
after microscopic evaluation of the extent of residual cancer in the corresponding slides 
from the gross tumor bed.  In a different example (E), microscopic residual cancer 
extends beyond the confines of the macroscopic tumor bed.  Again, the dimensions of 
the residual tumor bed (d1 and d2) would be revised after microscopic evaluation of the 
recognizable extent of residual cancer beyond the macroscopic tumor bed.
10.2
LYMPH NODES
Response to neoadjuvant systemic therapy may cause lymph node metastases to be 
replaced by hyaline stromal scars, mucin pools, and/or aggregates of histocytes without 
any visible tumor cells.  The presence of a large scar in a lymph node without identifiable 
tumor cells is indicative of complete response to therapy.  Furthermore, the appearance 


Appendix 10 Pathology Manual (cont.)
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of a metastatic focus is often altered by prior neoadjuvant therapy.  Cells may be 
scattered, rather than in a discrete mass.  The measurement of the metastasis should 
represent the extent of the metastasis (from one end to the opposite) and does not 
require that tumor cells be confluent in their distribution.  Also, the tumor cells can have 
bizarre appearance, or might have subtle signet ring, plasmacytoid, or histiocytoid 
apppearance.  In difficult cases regarding determination of residual invasive disease, 
immunochistochemical stains to distinguish between histiocytes (CD68) and epithelial 
cells (cytokeratins, suggest AE1/AE3 or cytokeratin 7) may be used to detect residual 
tumor cells.  AJCC definition and classification for node-positivity, including isolated
tumor cell clusters (ITC), by immunohistochemistry must be followed in order to
render the appropriate nodal status (i.e., positive or negative). [Table 1].  The largest 
focus of residual tumor in the lymph nodes, if present, is used for ypN categorization. 
Treatment-related fibrosis adjacent to residual lymph node tumor deposits is not 
included in the ypN dimension and classification.
Table 1: American Joint Committee on Cancer (AJCC, 8th edition): 
Pathologic Nodal Staging Classification
Pathologic Nodal
Stage*
Definition
pNx
Regional lymph nodes cannot be assessed (e.g., previously
removed, or not removed at all)
pN0 
No regional lymph node metastasis histologically
(i-)

No regional lymph node metastases histologically

Negative IHC
(i+)
Malignant cells in reginal lymph node(s) no greater then 0.2 mm 
(detected by H&E or IHC, including ITCs) 
(mol-)

No regional lymph node metastases histologically

Negative molecular findings (RT-PCR)
(mol+)

No regional lymph node metastases detected by histological
or IHC

Positive molecular findings (RT-PCR)
pN1 

Micrometastases or metastases in 13 axillary lymph nodes, 
and/or 

Clinically negative internal mammary lymph nodes with 
micrometastases, or 

Macrometastases by sentinel lymph node biopsy
mi
Micrometastases 0.2 mm and/or 200 cells, but none 2.0 mm
a
Metastases in 1 3 axillary lymph nodes, at least 1 metastasis 2.0
mm
b

Metastases in internal mammary nodes with micrometastases,
or

Macrometastases detected by sentinel lymph node biopsy but
not clinically detected


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Pathologic Nodal
Stage*
Definition
c
Metastases in 1 3 axillary lymph nodes and in internal mammary
lymph nodes with micrometastases or macrometastases detected
by sentinel lymph node biopsy but not clinically detected
pN2 

Metastases in 49 axillary lymph nodes, or 

Clinically detected*** internal mammary lymph nodes in the 
absence of axillary lymph node metastases
a
Metastases in 49 axillary lymph nodes (at least 1 tumor
deposit 2.0mm)
b
Metastases in clinically detected*** internal mammary lymph nodes
in the absence of axillary lymph node metastases
pN3 

Metastases in 10 or more axillary lymph nodes, or 

Metastases in infraclavicular (Level III axillary) lymph nodes, or 

Clinically detected*** ipsilateral internal mammary lymph nodes 
in the presence of one or more positive Level I and II axillary 
lymph nodes, or

Metastses in more than 3 axillary lymph nodes and ipsilateral 
internal mammary lymph nodes with micrometastases, or 

Macrometastases detected by sentinel lymph node biopsy but 
not clinically detected***, or 

Macrometastases in ipsilateral supraclavicular lymph node
a

Metastases in 10 axillary lymph nodes (at least 1 tumor
deposit 2.0mm), or

Metastases to the infraclavicular (Level III axillary) lymph
nodes
b

Metastases in clinically detected*** ipsilateral internal
mammary lymph nodes in the presence of 1 positive Level I,
II axillary lymph nodes, or

Metastases in 3 axillary lymph nodes and in internal
mammary lymph nodes with micrometastases or
macrometastases detected by sentinel lymph node biopsy but
not clinically detected***
c
Metastases in ipsilateral supraclavicular lymph nodes
*Classification is based on axillary lymph node dissection with or without sentinel lymph node 
biopsy. Classification is based solely on sentinel lymph node biopsy without subsequent 
axillary lymph node dissection and is designated (sn) for “sentinel node” (e.g., pN0[sn])
**Isolated Tumor Cell Clusters (ITCs) are detected by routine H&E or by IHC and defined as:
Small clusters of cells 0.2mm, or
A single tumor cell, or
A cluster of 200 cells in a single histological cross-section
***Clinically detected is defined by imaging studies (excluding lymphoscintigraphy) or by
clinical examination and having characteristics highly suspicious for malignancy or a
presumed pathologic macrometastasis based on the FNA biopsy with cytologic examination.


Appendix 10 Pathology Manual (cont.)
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
195/Protocol WO40324, Version 2
10.3
EVALUATION OF MARGINS
Special attention should be paid to margins, which may be more difficult to evaluate after 
neoadjuvant therapy. 
Discontinuous fibrous lesions in close relationship to the resected margin should be 
carefully examined to rule out residual disease. Also, the tumor cells can have an 
unexpected, unusual bizarre appearance, or might have subtle signet ring, plasmacytoid, 
or histiocytoid apppearance. On occasion, immunochistochemical stains to distinguish 
between histiocytes (CD68) and epithelial cells (cytokeratins AE1/AE3 or cytokeratin 7) 
might be necessary to detect residual tumor cells. However, one must also recognize
that treatment changes in proliferative fibrocystic tissues can mimic in situ or even 
invasive disease. 
11
REFERENCES AND SUGGESTED READING
Giuliano AE, Connolly JL, Edge SB et al. Breast Cancer—Major Changes in the 
American Joint Committee on Cancer Eighth Edition Cancer Staging Manual. Ca 
Cancer J Clin 2017;67:290303.
Hennessy BT, Hortobagyi GN, Rouzier R, et al. Outcome after pathologic complete 
eradication of cytologically proven breast cancer axillary node metastases 
following primary chemotherapy. J Clin Oncol 2005;23:930411.
Loi S, Symmans WF, Bartlett JM, et al. Proposals for uniform collection of biosamples 
from neoadjuvant breast cancer clincial trials: timing and specimen types. Lancet 
Oncol, 2011;12:116268.
Mauri D, Pavlidis N, Ioannidis J. Neoadjuvant versus adjuvant systemic treatment in 
breast cancer: a meta-analysis. J Natl Cancer Inst 2005;97:18894.
Mauriac L, Durand M, Avril A, et al. Effects of primary chemotherapy in conservative 
treatment of breast cancer patients with operable tumors larger than 3 cm. Results 
of a randomized trial in a single centre. Ann Oncol 1991;2:34754.
Mazouni C, Peintinger F, Wan-Kau S, et al. Residual ductal carcinoma in situ in patients 
with complete eradication of invasive breast cancer after neoadjuvant 
chemotherapy does not adversely affect patient outcome. J Clin Oncol
2007;125:26505.
Provenzano E, Bossuyt V, Viale G, et al: Standardization of pathologic evaluation and 
reporting of postneoadjuvant specimens in clinical trials of breast cancer: 
recommendations from an international working group. Mod Pathol
2015;28:1185201.


Appendix 10 Pathology Manual (cont.)
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
196/Protocol WO40324, Version 2
Rastogi P, Anderson S, Bear H, et al. Preoperative chemotherapy: updates of National 
Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 
2008;26:77885.
Semiglazov VF, Topuzov EE, Bavli JL, et al. Primary (neoadjuvant) chemotherapy and 
radiotherapy compared with primary radiotherapy alone in stage IIb-IIIa breast 
cancer. Ann Oncol, 1994;5:5915.
von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic 
complete response on prognosis after neoadjuvant chemotherapy in various 
intrinsic breast cancer subtypes. J Clin Oncol 2012;30:1796804.
Hortobagyi GN et al. AJCC Cancer Staging Manaul, Eighth Edition. Breast. The 
American Colleague or surgeons (ACS), Chicago, Illinois.  


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Appendix 11 Radiotherapy Guidelines
I.  BREAST CONSERVING THERAPY
MANDATORY:   Breast Radiotherapy after Complete Local Excision
Breast radiotherapy (RT) may be contraindicated in patients with significant comorbidity 
(for example, scleroderma and systemic lupus erythematosus). Reasons for not 
delivering breast RT after complete local excision of the primary breast cancer should be 
documented in the electronic case report form (eCRF). 
Target Volume

Whole breast including the primary tumor bed

Primary tumor bed boost in conjunction with whole breast RT may be used as per 
local policy declared by the center prior to local activation. 

Partial breast RT may be used as per local policy declared by the center prior to local 
activation.

Regional nodal RT:  Refer to Item III below.
Dose Fractionation 

Whole breast - recommended schedules: 
h)
50 Gy in 25 fractions, 5 fractions per week; or
i)
42.5 Gy in 16 fractions, 5 fractions per week; or
j)
40 Gy in 15 fractions, 5 fractions per week. 
Other schedules may be used as per local policy declared by the center prior to local 
activation. 

Primary tumor bed boost in conjunction with whole breast RT:  As per local policy 
declared by the center prior to local activation.

Partial breast RT:  As per local policy declared by the center prior to local activation.
Treatment planning

Computed tomography (CT)-based treatment planning is strongly recommended for 
whole breast RT and tumor bed boost.

CT-based treatment planning is mandatory for partial breast irradiation delivered 
using external beam RT.
II.   POST-MASTECTOMY RADIOTHERAPY
MANDATORY:
a)
4 or more positive axillary nodes or 
b)
Pathologic T4 disease.


Appendix 11 Radiotherapy Guidelines (cont.)
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
198/Protocol WO40324, Version 2
c)
‘Non-resectable’ microscopic positive deep margin (invasive carcinoma or ductal 
carcinoma in situ [DCIS]) 
OPTIONAL:   
d)
13 positive axillary nodes or 
e)
Higher risk node negative disease (for example T3 primary in the presence of high 
histologic grade and/or lymphovascular invasion)
Target Volume

Whole chest wall

Primary tumor bed boost in conjunction with chest wall RT may be used as per local 
policy declared by the center prior to local activation. 

Regional nodal RT:  Refer to Item III below.
Dose Fractionation 

Whole breast:  Recommended schedule is 50 Gy in 25 fractions, 5 fractions per 
week.  Other schedules may be used as per local policy declared by the center prior 
to local activation.

Primary tumor bed boost in conjunction with chest wall RT:  As per local policy 
declared by the center prior to local activation.
Treatment planning

CT-based treatment planning is strongly recommended for chest wall RT.
III.   REGIONAL NODAL RADIOTHERAPY
For patients who have completed sentinel node biopsy (SNB) alone or axillary lymph 
node dissection (ALND) as per protocol
RECOMMENDED:
Any breast surgery, 4 or more positive axillary nodes
OPTIONAL:
Any breast surgery, 03 positive axillary nodes, pathological T4 (pT4) disease
Target volume

Required:  
f)
Supraclavicular fossa if there are 4 or more positive axillary nodes; 
g)
Internal mammary nodes if tumor involvement is biopsy confirmed.


Appendix 11 Radiotherapy Guidelines (cont.)
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd
199/Protocol WO40324, Version 2

Optional:  
h)
Supraclavicular fossa if there are 03 positive axillary nodes; 
i)
Axilla as per local policy declared by the center prior to local activation (for example, 
known or high risk of residual axillary disease postsurgery); 
j)
Internal mammary nodes if there is a high risk of tumor involvement as per local 
policy declared by the center prior to local activation.
Dose fractionation 

Recommended schedule: 50 Gy in 25 fractions, 5 fractions per week.  Other 
schedules may be used as per local policy declared by the center prior to local 
activation.  Hypofractionated schedules are not recommended.
Treatment planning

CT-based treatment planning is strongly recommended for supraclavicular fossa 
and/or axillary RT.

CT-based treatment planning is mandatory for internal mammary nodal RT.


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200/Protocol WO40324, Version 2
Appendix 12 Precision for Different tpCR Rates (N=500)
P IVH IV
pCR rate
The FDC SC 
pCR rate
Difference in 
tpCR rates
Lower 95% CI for 
difference
Upper 95% CI for 
difference
50%
45%
5%
13.96%
3.96%
50%
50%
0%
8.98%
8.98%
50%
55%
5%
3.96%
13.96%
55%
50%
5%
13.96%
3.96%
55%
55%
0%
8.94%
8.94%
55%
60%
5%
3.87%
13.87%
60%
55%
5%
13.87%
3.87%
60%
60%
0%
8.81%
8.81%
60%
65%
5%
3.69%
13.69%
65%
60%
5%
13.69%
3.69%
65%
65%
0%
8.58%
8.58%
65%
70%
5%
3.42%
13.42%
CIHauk-Anderson 95% Confidence Intervals; FDCfixed-dose combination of pertuzumab and 
trastuzumab for SC administration; Htrastuzumab; P pertuzumab; pCRpathological complete 
response; tpCRtotal pathological complete response.
Note:  The table above shows a range of possible tpCR differences under a number of scenarios to 
demonstrate the precision for each outcome.  For example, if a 60% pCR rate is observed in both 
arms, i.e., a difference of 0%, with 250 patients per arm it can be ruled out with high probability that 
the true difference is ~9%, or that the SC tpCR rate is more than 9% lower than the IV pCR rate.

SAP_001.pdf: 
 
Official Title: 
A Phase III, Randomized, Multicenter, Open-Label, Two-Arm 
Study to Evaluate the Pharmacokinetics, Efficacy, and Safety of 
Subcutaneous Administration of the Fixed-Dose Combination of 
Pertuzumab and Trastuzumab + Chemotherapy in Patients With 
HER2-Positive Early Breast Cancer 
NCT Number: 
NCT03493854  
Document Date: 
SAP Version 3: 23-August-2019 
 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL
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.
Pertuzumab—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan WO40324 Version 3
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE III, RANDOMIZED, MULTICENTER, 
OPEN-LABEL, TWO-ARM STUDY TO EVALUATE THE 
PHARMACOKINETICS, EFFICACY, AND SAFETY OF 
SUBCUTANEOUS ADMINISTRATION OF THE 
FIXED-DOSE COMBINATION OF PERTUZUMAB AND 
TRASTUZUMAB CHEMOTHERAPY IN PATIENTS WITH 
HER2-POSITIVE EARLY BREAST CANCER
PROTOCOL NUMBER:
WO40324
STUDY DRUG:
Fixed-Dose Combination (FDC) of pertuzumab 
and trastuzumab for subcutaneous 
administration
(RO7198574)
VERSION NUMBER:
3
IND NUMBER:
131009
EUDRACT NUMBER:
2017-004897-32
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
, PhD.
DATE FINAL:
See electronic date stamp below
Date and Time(UTC)        Reason for Signing                              Name
23-Aug-2019 08:32:27
Company Signatory


Pertuzumab—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan WO40324 Version 3
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE
This Statistical Analysis Plan (SAP) for Study WO40324 (FeDeriCa) has been amended 
to incorporate the following changes.
VERSION 2:
Two changes concerning exploratory efficacy endpoints:

Removing Per Protocol PK analysis population from exploratory efficacy analysis 
Section 4.5.5. 
This line was to be removed in previous version but due to error was retained in 
the final version 1. This was changed in version 2 to align with initial strategy 
described in section 4.5.

Addition of text 'the non-inferiority margin' to make the clear that the pre-
established non-inferiority margin is -12.5% (absolute percentage points).
VERSION 3:

Addition of two new exclusion criteria in section 4.1.1 Per Protocol PK analysis 
population: 
–
If pre-dose and post-dose samples were switched
–
Assay error impacting Ctrough measurement.
Additional minor changes have been made to improve clarity and consistency.


Pertuzumab—F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan WO40324 Version 3
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 5
2.
STUDY DESIGN........................................................................................... 5
2.1
Determination of Sample Size ................................................. 7
2.2
Analysis Timing ....................................................................... 8
3.
STUDY CONDUCT....................................................................................... 8
3.1
Randomization Issues ............................................................. 8
3.2
Data Monitoring ....................................................................... 9
4.
STATISTICAL METHODS ............................................................................ 9
4.1
Analysis Populations ............................................................... 9
4.1.1
Per Protocol PK Analysis Population....................................... 9
4.1.2
Intent-to-Treat population ...................................................... 10
4.1.3
Safety Analysis Population .................................................... 10
4.2
Analysis of Study Conduct..................................................... 10
4.3
Analysis of Treatment Group Comparability .......................... 10
4.4
Primary Analysis.................................................................... 11
4.5
Secondary ANALYSEs .......................................................... 11
4.5.1
PK Analysis ........................................................................... 11
4.5.2
Efficacy Analyses .................................................................. 12
4.5.3
Exploratory Endpoints - PK, pCR, Immunogenicty 
    
and Biomarker Endpoints ...................................................... 13
4.5.4
Exploratory PK Analyses ....................................................... 14
4.5.5
Exploratory Efficacy Analyses ............................................... 14
4.5.6
Immunogenicity Analyses...................................................... 15
15
4.5.8
Sensitivity Analyses............................................................... 15
4.5.9
Subgroup Analyses ............................................................... 15
4.6
Safety Analyses..................................................................... 16
4.6.1
Exposure of Study Medication............................................... 18
4.6.2
Adverse Events ..................................................................... 18
4.6.3
Laboratory Data..................................................................... 18
4.6.4
Vital Signs.............................................................................. 18
4.7
Missing Data.......................................................................... 19




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1.
BACKGROUND
Study WO40324 is a global Phase III study to investigate pharmacokinetics (PK), 
efficacy, and safety of the fixed-dose combination (FDC) of pertuzumab and 
trastuzumab in combination with chemotherapy in patients with human epidermal growth 
factor receptor 2 (HER2)-positive early breast cancer (EBC) in the neo-adjuvant/adjuvant 
setting.
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the proposed 
analyses of this study for regulatory submissions.
2.
STUDY DESIGN
WO40324 is a two-arm, open-label, multicenter, randomized study (see Figure 1).  The 
study will enroll patients with HER2-positive breast cancer consistent with the indication 
for treatment with neo-adjuvant Perjeta and Herceptin in combination with chemotherapy 
in routine clinical practice and as recommended in local guidelines.
The study is designed to assess PK non-inferiority in pertuzumab Ctrough for patients 
treated with the FDC compared to treatment with Perjeta(pertuzumab) and Herceptin
(trastuzumab) intravenous (IV) formulations.


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Figure 1
: Study Design Schema
Approximately 500 patients with HER2-positive, operable or locally 
advanced/inflammatory breast cancer with a tumor size of either2 cm in diameter or 
node-positive will be randomized to one of the following treatment arms in a 1:1 ratio:

Arm A (Perjeta IVHerceptin IV):  Patients will receive 8 cycles of neo-adjuvant 
chemotherapy.  This will include 4 cycles of dose-dense doxorubicin (Adriamycin) 
plus cyclophosphamide (ddAC) every two weeks (Q2W; given with granulocyte 
colony-stimulating factor [G-CSF] support as needed according to local guidelines) 
followed by paclitaxel Q1W for 12 weeks or 4 cycles of doxorubicin (Adriamycin) 
plus cyclophosphamide (AC) every three weeks (Q3W) followed by docetaxel Q3W 
for 4 cycles. PerjetaHerceptin will be given IV for 4 cycles (Q3W) concurrently 
with the taxane component of chemotherapy.  After completing their neoadjuvant 
therapy, patients will undergo surgery.  Thereafter, patients will receive an additional 
14 cycles of Perjeta IV and Herceptin IV for a total of 18 cycles.  One year of 
HER2-targeted therapy without any delays would encompass 18 cycles.
After surgery (from Cycle 9 onwards), patients in Arm A are allowed to switch from 
Herceptin IV to Herceptin subcutaneous (SC), at the discretion of the investigator, in the 
countries where Herceptin SC is routinely used.

Arm B (FDC of pertuzumab and trastuzumab for SC administration): Patients will 
receive 8 cycles of neoadjuvant chemotherapy.  This will include 4 cycles of ddAC 


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Q2W (given with granulocyte colony-stimulating factor [G-CSF] support as needed 
according to local guidelines) followed by paclitaxel Q1W for 12 weeks or 4 cycles of 
AC Q3W followed by docetaxel Q3W for 4 cycles.  FDC will be given SC for 4 cycles 
(Q3W) concurrently with the taxane component of chemotherapy.  After completing 
their neo-adjuvant therapy, patients will undergo surgery.  Thereafter, patients will 
receive an additional 14 cycles of the FDC for a total of 18 cycles.  One year of 
HER2-targeted therapy without any delays would encompass 18 cycles.
The investigator will select one of the two protocol-approved neoadjuvant chemotherapy 
regimens with which to treat the patient. Once the investigator’s choice of chemotherapy 
has been made and eligibility confirmed, the patient will be randomized to one of the two 
treatment arms.
After the end of the study treatment, patients will be followed for safety and efficacy for 
3 years (36 months) after the last patient’s last dose.  The end of the study is defined as 
the date when the last patient last visit (LPLV) occurs or the date at which the last data 
point required for statistical analysis or safety follow-up is received from the last patient 
(or when all patients have died or the trial is terminated by the Sponsor, whichever is 
earliest).
The total length of the study, from screening of the first patient to the end of the study is 
expected to be approximately 5.5 years.
Endpoints and objectives are listed in the Protocol Synopsis, see Appendix 1.  For 
additional details, see the Schedule of Assessments in Appendix 2.
2.1
DETERMINATION OF SAMPLE SIZE
The study is designed to have at least 80% power to demonstrate non-inferiority of the 
Cycle 7 (i.e., pre-dose Cycle 8) pertuzumab serum Ctrough from pertuzumab SC within 
FDC to the Perjeta IV formulation in patients with HER2-positive EBC.
PK sample size calculations are based on the coefficient of variation (CV)% for the Ctrough
of trastuzumab observed from previous studies in metastatic breast cancer and EBC 
patients after Q3W treatment. With a CV of 60% assumed, a minimum of 130 patients 
per arm (i.e., a total of 260 patients) is needed to demonstrate Ctrough non-inferiority with 
a power of 80% if the true means of the two formulations do not differ by more than 5%. 
An additional 240 patients will also be recruited to provide a substantial database to 
assess total pathological complete response (tpCR) and safety profile comparability. 
Therefore, a total of approximately 500 patients (~250 per arm) will provide a sufficient 
sample size to test the primary PK hypothesis and also assess efficacy and safety profile 
comparability.


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2.2
ANALYSIS TIMING
The primary analysis for PK will occur when all patients have completed neoadjuvant 
therapy (i.e., completed Cycle 8) and had surgery.  At this timepoint, secondary 
endpoints of trastuzumab Ctrough, exploratory PK (where available), tpCR (and the 
exploratory pCR), Immunogenicity, Biomarkers (as available) and safety will also be 
analyzed.
A final analysis will occur when all patients have completed 36 months of treatment 
free-follow up. At this timepoint, invasive disease-free survival (iDFS), iDFS including 
second primary non-breast cancer, event-free survival (EFS), EFS including second 
primary non-breast cancer, distant recurrence-free interval (DRFI), overall survival (OS) 
and safety will be analyzed. Exploratory analyses for PK (those not performed at the 
primary analysis) will also be assessed.
3.
STUDY CONDUCT
3.1
RANDOMIZATION ISSUES
Randomization will occur through an interactive voice/web-based response system 
(IxRS).  On verification of inclusion and exclusion criteria, eligible patients will be 
randomized using the method of stratified permuted blocks in a 1:1 ratio to receive either 
treatment Arm A or Arm B.  Patients will be stratified according to the following factors:

Hormonal Receptor Status (based on central assessment):
–
Estrogen receptor (ER)-positive or progesterone receptor (PgR)-positive
–
ER-negative and PgR-negative 

Clinical stage at presentation:
–
Stage II−IIIA
–
Stage IIIB−IIIC

Type of chemotherapy:
–
ddAC followed by paclitaxel 
–
AC followed by docetaxel
A patient may only be randomized once in this trial. Patients randomized into the study 
will not be replaced. Patients who choose to withdraw after screening but before 
randomization will be replaced.
Review of dummy randomization lists along with User Acceptance Testing (UAT) within 
the IxRS system will be performed to ensure the randomization procedure is set up and 
performed correctly.


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3.2
DATA MONITORING
An Independent Data Monitoring Committee (iDMC) will be established to monitor and 
evaluate patient safety throughout the study.  The iDMC members will be external to 
Roche and independent of the trial. The iDMC will be comprised of a fixed number of 
permanent members with experience in clinical studies in oncology and will include at 
least one statistician. The iDMC will follow a charter that outlines their roles and 
responsibilities and ability to make recommendations regarding continuation of the study 
to ensure integrity and viability of the trial, as well as acceptable risk to patients in the 
trial. The iDMC will be responsible for monitoring the safety of patients in the study and 
will make recommendations to the Sponsor through the Data Review Board (DRB) 
regarding the conduct of the study, including study continuation as planned or with
protocol amendment or early discontinuation of the study for excessive toxicity.
The first iDMC meeting will approximately take place after the first 50 patients have been 
randomized into the study and have completed their full course of neo-adjuvant therapy 
(8 cycles).  Additional review meetings are planned to occur when approximately 
200 and 500 patients have been randomized and have completed their full course of 
neoadjuvant therapy. Thereafter, further review meetings will take place approximately 
every 6 months until the primary analysis. The iDMC schedule may be modified based 
on the recommendation of its members or request by the Sponsor. The operating 
procedures for the meetings will be detailed in the iDMC charter.
The Study Management Team is, by definition, unblinded given the open-label nature of 
this study. However, to further protect the integrity of the study, any treatment 
assignment information, such as the randomization file from the IxRS and PK data, will 
be withheld from the Sponsor until the primary analysis.  Review of data for safety 
purposes will not be reviewed at an aggregate level prior to the primary analysis.
For data reviews by the iDMC, the independent data co-ordinating center (iDCC) will 
prepare the data packages for safety review, and will create an unblinded data package 
for the iDMC review and a blinded package for non-IDMC member review.  Further 
details will be written into the iDMC charter.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
4.1.1
Per Protocol PK Analysis Population
The primary analysis will be performed in the Per Protocol PK analysis population. 
Patients will be assigned to treatment groups as treated.
The Per Protocol PK analysis population will include all patients enrolled who adhered to 
the protocol.  Exclusions from the Per Protocol PK analysis population will be made for 
the following reasons: patients are missing the Ctrough pre-dose Cycle 8 PK sample, 
patients with a Ctrough sample collected with at least 2 days deviation from the planned 


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date on Day 21 (i.e., before Day 19 or after Day 23), patients given a dose amount that 
deviates from the planned dose by > 20% within 3 cycles (from Cycle 5), patients with a 
dose delay of more than 7 days, a subcutaneous injection site other than thigh is used, if 
pre-dose and post-dose samples were switched and assay error impacting Ctrough
measurement.  Excluded cases will be documented, including the reason for exclusion. 
All decisions on exclusions from the analysis will be made prior to database closure.
4.1.2
Intent-to-Treat population
Additional analyses will be performed in the intent-to-treat (ITT) population.  The ITT 
population is defined as all randomized patients.  Patients will be assigned to treatment 
groups as randomized by the IxRS.
4.1.3
Safety Analysis Population
The safety analysis population will include all patients who receive at least one dose of 
study medication (i.e., chemotherapy, Perjeta IV, Herceptin IV, Herceptin SC or the
FDC).  Patients who do not receive any amount of their study medication (i.e., 
chemotherapy, Perjeta IV, Herceptin IV, Herceptin SC or the FDC) will be excluded from 
the safety-evaluable population.  Patients will be assigned to treatment groups as 
treated.
Patients in Arm A, who switch to Herceptin SC after surgery, will be analyzed as a 
separate subset of Arm A.
4.2
ANALYSIS OF STUDY CONDUCT
The number of patients who enroll, discontinue (from treatment and/or study), or 
complete the study will be summarized. Reasons for patient discontinuations from the 
study treatment and from the study will be listed and summarized. Enrollment, study 
treatment administration, and major protocol deviations will be evaluated for their 
potential effects on the interpretation of study results.
For safety-evaluable patients, study drug administration and dose modifications data will 
be tabulated or listed by cohort, using descriptive statistics to summarize the total doses 
where applicable.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
The evaluation of treatment group comparability between the two treatment arms will 
include summaries of demographics, medical history, concomitant medication and a 
summary of the randomization stratification factors.
Demographic and baseline characteristics will be summarized using descriptive statistics
(e.g., means, standard deviations, medians, and ranges for continuous variables and 
proportions for categorical variables, as appropriate).  Summaries will be presented by 
treatment group and separated where relevant into the neo-adjuvant period, adjuvant 
period and follow up period.  Where applicable for the neo-adjuvant period, summaries 


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will be presented by treatment arm and chemotherapy regimen.  Patients in the adjuvant 
period, who switch from Herceptin IV to Herceptin SC will be presented under two 
summary tables: overall whereby these patients even though switch will remain under a 
treatment label of Pertuzumab IVHerceptin IV, and then where applicable for safety a 
second table whereby these patients are counted only from their switch onwards, under 
Pertuzumab IVHerceptin SC.  Frequency counts will be presented by randomized 
treatment arm for categorical variables.
4.4
PRIMARY ANALYSIS
The primary endpoint of this study is observed pertuzumab trough concentration (Ctrough) 
at Cycle 7 (i.e., the measured pre-dose concentration value at Cycle 8), following 
3 cycles of Perjeta IV and Herceptin IV or FDC (pertuzumab and trastuzumab SC). 
Pertuzumab Ctrough will be analyzed at the time of the primary analysis, which will occur
after the last patient has completed (all) neo-adjuvant therapy and has undergone 
surgery.
The Per Protocol PK analysis population as described in Section 4.1.1 will be the 
primary analysis population used for this analysis.
The non-inferiority of the SC and IV dose of pertuzumab will be assessed by a one-sided 
testing procedure. The CtroughSC/CtroughIV GMR of the SC dose of pertuzumab relative to 
the IV dose will be estimated together with the two sided 90% CI based on the 
log-transformed trough concentration values. 
The hypothesis to be tested for the primary endpoint, observed pertuzumab Ctrough, is:

H0:  The SC dose is inferior to the IV dose (i.e., the CtroughSC/CtroughIV geometric 
mean ratio [GMR] of the SC dose of pertuzumab relative to the IV dose is not 
greater than 0.8) versus

H1:  The SC dose is non-inferior to the IV dose (i.e., CtroughSC/CtroughIV GMR of the 
SC dose of pertuzumab relative to the IV dose is equal or greater than 0.8).
The null hypothesis will be rejected and non-inferiority will be concluded if the lower 
bound of the 90% CI of the GMR is0.8.A hierarchical testing procedure for key 
secondary endpoints (that is, for trastuzumab serum CtroughSC/CtroughIV) will be used to 
control the overall type I error rate at a one sided 5% significance level.
4.5
SECONDARY ANALYSES
For all secondary PK analyses the per protocol PK analysis population (see 
Section 4.1.1) will be used.  The ITT population will be used for key secondary endpoint 
analyses such as, but not limited to, pCR, EFS, DFS and OS.
4.5.1
PK Analysis
The non-inferiority of the SC and IV dose of trastuzumab will be assessed using the 
same criteria as for the primary analysis (see Section 4.4) and will be tested in a 


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hierarchical order to adjust for multiple statistical testing and control the type I error at 
one sided 5% significance level.
The following hypotheses will be tested:

H0:  The SC dose is inferior to the IV dose (i.e., the CtroughSC/CtroughIV GMR of the 
SCdose of trastuzumab relative to the IV dose is not greater than 0.8) vs.

H1:  The SC dose is non-inferior to the IV dose (i.e., the CtroughSC/CtroughIV GMR of 
the SC dose of trastuzumab relative to the IV dose is equal or greater than 0.8).
The hierarchical testing procedure will follow the steps below:
1. Test the primary endpoint, Cycle 7 pertuzumab serum CtroughSC/CtroughIV, at a 
one-sided 5% significance level. If positive, continue to step 2; otherwise, stop.
2. Test the secondary endpoint, Cycle 7 trastuzumab serum CtroughSC/CtroughIV, at a 
one-sided 5% significance level.
The non-inferiority of the SC and IV dose of pertuzumab will be assessed by a one-sided 
testing procedure.  The null hypothesis will be rejected and non-inferiority will be 
concluded if the lower bound of the 90% CI of the GMR is 0.8.
4.5.2
Efficacy Analyses
The following secondary endpoints will be analyzed outside of a hypothesis-testing 
framework and according to the methodology provided below.
Total pCR is defined as eradication of invasive disease in the breast and axilla; that is, 
ypT0/is ypN0, according to the local pathologists’ assessment.  Pathologic response to 
therapy is defined at the time of surgery, and the tpCR rate is the proportion of patients 
in the ITT population who achieve a tpCR.  Rates of tpCR will be calculated in each 
treatment arm and will be assessed using the difference between FDC tpCR rate and IV 
tpCR rate and corresponding 95% Clopper-Pearson CIs.  The difference between the 
FDC tpCR rate and IV tpCR rates along with corresponding 95% Hauck-Anderson CIs 
will also be calculated. The lower bound of the CI will reliably reflect the largest tpCR 
difference that can be considered unlikely. The observed tpCR difference and 95% CIs
will form the basis of a discussion around the differences in efficacy that can be ruled 
out. See Table 1 for a range of possible tpCR differences and 95% CIs under various 
scenarios to demonstrate the precision for each outcome with the proposed sample size 
of N 500.  An assessment of tpCR will be analysed at the time of primary analysis.


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Table 1
Precision for different tpCR rates (N500)
PIV HIV
pCR rate
FDC SC 
pCR rate
Difference in tpCR 
rates
Lower 95% CI for 
difference
Upper 95% CI for 
difference
50%
45%
-5%
-13.96%
3.96%
50%
50%
0%
-8.98%
8.98%
50%
55%
5%
-3.96%
13.96%
55%
50%
-5%
-13.96%
3.96%
55%
55%
0%
-8.94%
8.94%
55%
60%
5%
-3.87%
13.87%
60%
55%
-5%
-13.87%
3.87%
60%
60%
0%
-8.81%
8.81%
60%
65%
5%
-3.69%
13.69%
65%
60%
-5%
-13.69%
3.69%
65%
65%
0%
-8.58%
8.58%
65%
70%
5%
-3.42%
13.42%
CIHauk-Anderson 95% Confidence Intervals; FDCfixed-dose combination; HHerceptin; 
IVintravenous; PPerjeta; pCRpathological complete response; SCsubcutaneous; tpCRtotal 
pathological complete response.
Note:  The table above shows a range of possible tpCR differences under a number of scenarios to 
demonstrate the precision for each outcome.  For example, if a 60% pCR rate is observed in both arms, 
i.e., a difference of 0%, with 250 patients per arm it can be ruled out with high probability that the true 
difference is ~9% , or that the SC tpCR rate is more than 9% lower than the IV pCR rate.
For the additional secondary time-to-event (TTE) endpoints, iDFS, iDFS including 
second primary non-breast cancer, EFS, EFS including second primary non-breast 
cancer, DRFI and OS (see Protocol Synopsis in Appendix 1 for definitions), the 
Kaplan-Meier approach will be used for analysis. Estimates of the proportion of patients 
who are event-free at landmark timepoints for each treatment cohort will be provided. 
The estimated hazard ratio and corresponding CI will also be obtained using stratified 
Cox regression models. Patients who are either without distant disease recurrence, 
alive or lost to follow-up for the respective endpoints will be censored at the date they 
were last known to be event free. Patients with no post-baseline assessments will be 
censored at the date of randomization plus 1 day. The TTE endpoints will not be 
analyzed at the time of the primary analysis, but will be analyzed at the final analysis.
4.5.3
Exploratory Endpoints - PK, pCR, Immunogenicty and 
Biomarker Endpoints
Exploratory analyses will be performed based on sufficient data, and is not limited to 
those listed here.


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4.5.4
Exploratory PK Analyses
The exploratory PK analyses and modelling (see Section 6.5.1 in protocol synopsis) will 
include characterization of the pharmacokinetics of pertuzumab and trastuzumab 
following FDC SC administration. PK variables will be presented by listings and 
descriptive summary statistics including arithmetic mean, geometric mean, median, 
range, standard deviation and CV, and 95% confidence intervals. Modelling of the PK 
data may be performed using a population approach based on a model previously 
developed on a combined SC and IV dataset from the BO30185 study. The structural 
and statistical model will be defined using a non-linear mixed effect model (NONMEM). 
The model will be parametrized in terms of clearances and volumes, and the individual 
measures of exposure (i.e., Ctrough and AUC0-τ) will be predicted from the final PK model.
These analyses will be assessed by the clinical pharmacology group and analysis details 
will be provided in a separate PK analysis plan.
4.5.5
Exploratory Efficacy Analyses
To further assess the tpCR endpoint, exploratory analyses will be conducted analyzing 
different definitions of pCR including:

Breast pathological complete response (bpCR), defined as eradication of invasive 
disease in the breast (i.e., ypT0/is, ypNx) 

German Breast Group (GBG) pCR, defined as eradication of invasive and in situ 
disease in the breast and invasive disease in axilla (i.e., ypT0 ypN0)
Analysis methods will be the same as those for the secondary tpCR endpoint (see 
Section 4.5.2).  The ITT population as defined in Section 4.1.3 will be used for analyses.
Additionally, tpCR (as per definition of the secondary endpoint, Section 4.5.2) will also 
be assessed with respect to non-inferiority for descriptive purposes, acknowledging this 
is not type-1 error (alpha) controlled. Non-inferiority in tpCR rate will be assessed using 
the criteria that the lower limit of the one-sided 97.5% confidence interval for the 
difference in tpCR rate using the continuity correction of Anderson and Hauck (1986) is 
above non-inferiority margin of  12.5% (absolute percentage points). The difference in 
pCR rate is defined as the tpCR rate in the SC pertuzumab arm minus the tpCR rate in 
the IV pertuzumab arm.
In the neoadjuvant period, clinical response will be analyzed and response will be 
assessed as complete response, partial response, stable disease, or progressive 
disease by the investigator as per routine clinical practice (see Section 4.5.12 in 
protocol). Clinical response rate prior to surgery will be summarized and reported.  For 
patients who have clinical response assessed during neo-adjuvant therapy but not 
immediately prior to surgery, and patients who do not undergo surgery, the last recorded 
clinical response assessment will be considered in the analysis.  Patients without any 
assessment of clinical response prior to surgery will be considered non-responders in 
the analysis.


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4.5.6
Immunogenicity Analyses
The immunogenicity analysis population will consist of all patients with at least one 
anti-drug antibody (ADA) assessment, 
.  Patients will be 
grouped according to treatment received.
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after baseline (post-baseline incidence) will be 
summarized by treatment group (see additional detail around baseline characterization 
and positive/negative status in protocol section 6.5.3).  The relationship between ADA 
status and safety, efficacy, and PK endpoints will be analyzed and reported via 
descriptive statistics (as data allow). The relationship between neutralizing antibody 
(NAb) status and efficacy and PK will also be assessed (NAb is a subset of ADA positive 
patients).
 
 
 
 
 
 
  
 
 
 
4.5.8
Sensitivity Analyses
The analyses defined in Section 4.5.4 and Section 4.5.5 will serve as the sensitivity 
analyses.
4.5.9
Subgroup Analyses
For the primary endpoint of PK pertuzumab Ctrough, there are no prespecified subgroup 
analyses planned.
Exploratory analyses will be performed for tpCR to assess whether magnitude of the 
effectiveness of FDC differs according to patient subgroups. Subgroup analyses will be 
performed for the randomization stratification factors using the categories defined in 
Section 3.1, as well as for other disease-or patient-related prognostic or predictive 
factors, such as but not limited to:

Age: 65, 65

Race: White; Black; Asian; Other


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
Hormonal receptor status (per central lab): ER and/or PgR positive; ER/PgR 
negative

Hormonal receptor status (per local lab): ER and/or PgR positive; ER/PgR negative

Clinical stage at presentation: stage II-IIIA; stage IIIB-IIIC

Type of chemotherapy: ddAC-weekly paclitaxel; AC-docetaxel

Menopausal status at randomization: pre-menopausal; post-menopausal

Histological grade at baseline: Grade 1; Grade 2; Grade 3

Histological subtype: Invasive carcinoma of no special type (NST), Invasive lobular 
carcinoma, Invasive micropapillary carcinoma, Mucinous carcinoma, Apocrine 
carcinoma, Other 
Subgroup analyses will be performed in an exploratory manner using forest plots with 
descriptive statistics summarizing tpCR rates and 95% CIs, by treatment arm.
4.6
SAFETY ANALYSES
The safety analysis population will consist of all randomized patients who received at 
least one dose of study drug and will be grouped according to actual treatment received:  
Arm A to Perjeta IV and Herceptin IV; Arm B to FDC of pertuzumab and trastuzumab 
(see Section 4.1.3 for population details).
Safety will be evaluated by the use of descriptive analyses of incidence and severity of 
adverse events (AEs) and serious adverse events (SAEs); laboratory test abnormalities;
incidence of a symptomatic left ventricular systolic dysfunction (LVSD; otherwise 
referred to as heart failure), defined as the occurrence of symptomatic left ventricular 
ejection fraction (LVEF) decrease or definite or probable cardiac death; and incidence of 
LVSD, defined as an absolute decrease in LVEF of at least 10 percentage points below 
the baseline measurement and to below 50% by LVEF measurements over the course 
of the study.
All verbatim AE terms will be mapped to Medical Dictionary for Regulatory Activities
(MedDRA) thesaurus terms and AE severity will be graded according to the National 
Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), v4.  
Congestive heart failure, in addition, will be graded according to the New York Heart 
Association (NYHA) functional classification. All AEs, including SAEs, will be 
summarized by treatment arm and CTCAE grade.  System Organ Class and Preferred 
Term will be presented.  In addition, AEs leading to discontinuation of study treatment 
will be summarized by treatment arm. For each patient’s AEs, the maximum severity 
recorded will be used in the summaries.
Laboratory toxicities will be defined based on local laboratory normal ranges and 
NCI-CTCAE, v4. Selected laboratory abnormalities such as worst toxicity grade and 


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toxicity grade shift from baseline will be summarized by treatment arm. Change from 
baseline in targeted vital signs and laboratory results will also be assessed.
Selected AEs of particular importance (see Section 5.3.4 in the protocol) will also be 
analyzed, similar to the method for AEs.
For this study the following will be used to characterize reactions related to the 
administration of study drug(s):

Investigator-assessed Administration Related Reactions (ARRs), including:
–
Injection-site reactions (Local), defined as any local morphological or 
physiological change at or near the SC injection site
–
Injection-related reactions (Systemic), defined as any system reaction in 
response to the SC injection of study drug
–
Infusion-related reactions (Systemic), defined as any system reaction in 
response to the IV infusion of study drug
ARRs potentially associated with IV or SC administration of study drug(s), defined as 
AEs in the SMQ “Anaphylactic Reaction (wide)”, Roche Standard AEGT “Anaphylaxis 
and Hypersensitivity” and “Infusion-Related Reactions and Hypersensitivity”, or the 
dictionary-derived term “Cytokine Release Syndrome” occurring during infusion/injection
or within 24 hours of the end of administration, should be assessed as to whether 
considered related or unrelated to study drug by the investigator (see Sections 5.1.1.1 
and 5.2.5.2 in the protocol for additional information about ARRs).
Cardiac-specific AEs will focus on the incidence of patients with heart failure (NYHA
Grade 3 or 4, NCI-CTCAE [heart failure] Grades 2, 3, 4, and 5). LVEF 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%.
Cardiac AEs will be categorized according to the following endpoint criteria:

Primary cardiac endpoint:
–
Incidence of a symptomatic ejection fraction decrease (“Heart failure”) of NYHA 
Class III or IV and a drop in LVEF of at least 10-percentage points from 
baseline and to below 50%
–
Cardiac death, defined as either:
o
Definite cardiac death (due to heart failure, myocardial infarction, or 
documented primary arrhythmia); or 
o
Probable cardiac death (sudden unexpected death within 24 hours of a 
definite or probable cardiac event [e.g., syncope, cardiac arrest, chest pain, 
infarction, arrhythmia] without documented etiology))


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
Secondary cardiac endpoints:
–
Incidence of an asymptomatic or mildly symptomatic LVSD (“Ejection fraction 
decreased”) of NYHA Class II, defined as an LVEF decrease of 10%-points 
below the baseline measurement to an absolute LVEF value of 50%, 
confirmed by a second assessment within approximately 3 weeks confirming a 
decrease of 10%-points below the baseline measurement and to an absolute 
LVEF value of 50%.
Other cardiac events, such as acute coronary syndrome, acute myocardial infarction, 
severe rhythm disturbances requiring treatment, etc., will be reported.
The assessment of the cardiac endpoint will be based on data from randomization until 
the start of any new therapy for recurrence of disease.
4.6.1
Exposure of Study Medication
The number of patients who experience a dose delay, dose modification, dose 
discontinuation, and reasons for the study treatment discontinuation will be summarized 
by treatment arm. Descriptive statistics will be presented for number of cycles received, 
total cumulative dose, dose intensity, and weeks of exposure for chemotherapy, 
trastuzumab, and pertuzumab.
4.6.2
Adverse Events
Verbatim descriptions of treatment-emergent AEs will be mapped to MedDRA thesaurus 
terms and graded according to the NCI CTCAE v4. All AEs, including SAEs, will be 
summarized by treatment arm and NCI CTCAE grade. In addition, AEs leading to 
discontinuation of the study treatment will be summarized by treatment arm. The 
maximum severity recorded for each AE will be used in the summaries.
4.6.3
Laboratory Data
Clinical laboratory tests will be performed at local laboratories. Laboratory abnormalities 
will be defined based on local laboratory normal ranges and NCI CTCAE v4.0. Select 
laboratory abnormalities such as worst toxicity grade and toxicity grade shift from 
baseline will be summarized by treatment arm.  Roche Standard Reference Ranges will 
be implemented before any data is summarized for reporting and analysis, and the lab 
standardization process will be detailed in the Data Analysis Plan (DAP) Module 2.
4.6.4
Vital Signs
Vital signs (including systolic and diastolic blood pressure, pulse rate, and body
temperature) and physical measurements (including body weight and height) recorded 
before administration of the study treatment and recorded before and after 
HER2-directed therapy will be listed and summarized with changes from baseline. Vital 
signs collected at unscheduled visits will be excluded from the summary table. The 
mean, standard deviation, median, and minimum and maximum values will be presented 
by treatment arm.


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4.7
MISSING DATA
Patients with missing PK data (such as Cycle 7 Ctrough) at time of the primary endpoint 
Cycle 7 Ctrough (pre-dose Cycle 8) will be excluded from the per protocol PK 
population.
Patients with missing data for tpCR (i.e., do not undergo surgery or have an invalid pCR 
assessment) will be included in the analysis and will be classed as non-responders.
For iDFS, iDFS including second primary non-breast cancer, EFS, EFS including 
secondary primary non-breast cancer, and OS data from all randomized patients will be 
analyzed.  Data for patients who are randomized without any post-baseline assessments 
will be censored at the time of randomization plus 1 day.  For iDFS, patients who do not 
undergo surgery will be excluded from the analysis.  Patients without any post-surgery 
assessment will be censored at time of surgery plus 1 day.  For OS, patients not 
experiencing an event will be censored at the date when they were last known to be 
alive and event-free.


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Appendix 1
Protocol Synopsis
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, RANDOMIZED, MULTICENTER, OPEN-LABEL, TWO-
ARM STUDY TO EVALUATE THE PHARMACOKINETICS, 
EFFICACY, AND SAFETY OF SUBCUTANEOUS 
ADMINISTRATION OF THE FIXED-DOSE COMBINATION OF 
PERTUZUMAB AND TRASTUZUMAB IN COMBINATION WITH 
CHEMOTHERAPY IN PATIENTS WITH HER2-POSITIVE EARLY 
BREAST CANCER
PROTOCOL NUMBER:
WO40324
VERSION NUMBER:
2
EUDRACT NUMBER:
2017-004897-32
IND NUMBER:
131009
TEST PRODUCT:
Fixed-dose combination (FDC) of pertuzumab and trastuzumab for 
subcutaneous administration (RO7198574)
PHASE:
Phase III
INDICATION:
HER2-positive Early Breast Cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the pharmacokinetics, efficacy, and safety of the fixed-dose combination 
(FDC) of pertuzumab and trastuzumab for SC administration compared with the Perjeta IV and 
Herceptin IV formulations in patients with HER2-positive early breast cancer (EBC).
Specific objectives and corresponding endpoints for the study are outlined below.
Primary Objective
Corresponding Endpoint
To demonstrate the non-inferiority of 
the Cycle 7 (pre-dose Cycle 8) serum 
pertuzumab Ctrough of pertuzumab SC 
within the FDC compared with Perjeta 
IV 
Serum pertuzumab Ctrough during Cycle 7 (pre-dose 
Cycle 8) 
Secondary Pharmacokinetic Objective
Corresponding Endpoint
To demonstrate the non-inferiority of 
the Cycle 7 (pre-dose Cycle 8) serum 
trastuzumab Ctrough of trastuzumab SC 
within the FDC compared with 
Herceptin IV
Serum trastuzumab Ctrough during Cycle 7 (pre-dose 
Cycle 8) 


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Secondary Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of the SC FDC 
of pertuzumab and 
trastuzumab chemotherapy compared 
with Perjeta IV and Herceptin 
IV chemotherapy
tpCR, defined as eradication of invasive disease in 
the breast and axilla (i.e., ypT0/isypN0), according to 
local pathologist assessment
iDFS, defined as the time from the first date of no 
disease (i.e., the date of primary surgery) to the first 
occurrence of one of the following events:
- Ipsilateral invasive breast tumor 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)
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 PD or relapse.
iDFS, including second primary non-breast cancer, 
defined in the same way as iDFS but including second 
primary non-breast invasive cancer as an event (with 
the exception of non-melanoma skin cancers and in 
situ carcinoma of any site)
EFS, defined as the time from enrollment to the first 
occurrence of one of the following events:
- Breast cancer progression (PD)
- Breast cancer recurrence (as defined for iDFS 
endpoint)
- Death from any cause
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 PD or relapse.
EFS, including second primary non-breast cancer is 
defined in the same way as EFS, but including second 
primary non-breast invasive cancer as an event (with 
the exception of non-melanoma skin cancers and in 
situ carcinoma of any site)
DRFI, defined as the time between randomization and 
the date of distant breast cancer recurrence
OS, defined as the time from randomization to death 
from any cause


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Secondary Safety Objective
Corresponding Endpoints
To evaluate the safety of the SC FDC of 
pertuzumab and trastuzumab compared 
with Perjeta IV and Herceptin IV
Incidence and severity of adverse events and SAEs, 
with severity determined according to NCI CTCAE v4 
Laboratory test abnormalities according to NCI 
CTCAE v4
Primary cardiac endpoints
Incidence of a symptomatic ejection fraction decrease 
(“Heart failure”) of NYHA Class III or IV and a drop in 
LVEF of at least 10-percentage points from baseline 
and to below 50%
Cardiac death, defined as one of the following:

Definite cardiac death, defined as death due to 
heart failure, myocardial infarction, or documented 
primary arrhythmia

Probable cardiac death, defined as sudden 
unexpected death within 24 hours of a definite or 
probable cardiac event (e.g., syncope, cardiac arrest, 
chest pain, infarction, arrhythmia) without 
documented etiology
Secondary cardiac endpoint
Incidence of an asymptomatic or mildly symptomatic
left ventricular systolic dysfunction (“Ejection fraction 
decreased”) of NYHA Class II, defined as an LVEF 
decrease of 10-percentage points below the 
baseline measurement to an absolute LVEF value of 
50%, confirmed by a second assessment within 
approximately 3 weeks confirming a decrease of 10-
percentage points below the baseline measurement 
and to an absolute LVEF value of 50%
Exploratory Pharmacokinetic 
Objectives
Corresponding Endpoints
To characterize the pharmacokinetics of 
pertuzumab and trastuzumab following 
administration of the SC FDC
Serum pertuzumab concentrations or PK parameters
Serum trastuzumab concentrations or PK parameters
To compare the pharmacokinetics 
(including PK parameters such as AUC 
and Cmax) following administration of the 
SC FDC versus Perjeta IV and 
Herceptin IV (in combination with 
chemotherapy) 
Serum pertuzumab concentrations or PK parameters 
during Cycle 7 (pre-dose Cycle 8)
Serum trastuzumab concentrations or PK parameters 
during Cycle 7 (pre-dose Cycle 8) 
To assess the pertuzumab PK profile 
and observed Ctrough at Cycle 7 (pre-
dose Cycle 8) and Cycle 12 (post-
surgery) following FDC administration
Serum pertuzumab concentrations during Cycle 7 
(pre-dose Cycle 8) and Cycle 12 (pre-dose Cycle 13)
To compare the pertuzumab exposure 
in Cycle 1 between Perjeta IV 840 mg 
and FDC (pertuzumab SC 1200 mg)
Serum pertuzumab concentrations during Cycle 5


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Exploratory Pharmacokinetic 
Objectives (cont.)
Corresponding Endpoints (cont.)
To evaluate potential relationships 
between pertuzumab exposure and the 
efficacy and safety of the SC FDC via a
pertuzumab exposure-response 
analysis
Relationship between serum concentration or PK 
parameters for pertuzumab and efficacy endpoints
Relationship between serum concentration or PK 
parameters for pertuzumab and safety endpoints
To assess the impact of a potential PK 
DDI between pertuzumab and 
trastuzumab following administration of 
the SC FDC
Serum concentrations or PK parameters for 
pertuzumab given in combination with trastuzumab 
compared with pertuzumab given alone (based on 
historical data)
Serum concentrations or PK parameters for 
trastuzumab given in combination with pertuzumab 
compared with trastuzumab given alone (based on 
historical data)
Exploratory Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of the SC FDC 
of pertuzumab and 
trastuzumabchemotherapy compared 
with Perjeta IV and Herceptin 
IVchemotherapy
bpCR, defined as eradication of invasive disease in 
the breast (i.e., ypT0/is, ypNx)
GBG pCR, defined as eradication of invasive and in 
situ disease in the breast and invasive disease in 
axilla (i.e., ypT0 ypN0)
Clinical response, defined as CR, PR, SD, or PD, 
prior to surgery.  Tumor response will be assessed 
prior to each new cycle of therapy by clinical 
examination, mammography, and/or other methods of 
evaluation as per routine clinical practice.  Response 
will be assessed by the investigator as per routine 
clinical practice.
Exploratory Immunogenicity 
Objectives
Corresponding Endpoints
To evaluate the immune response to 
pertuzumab, trastuzumab, and 
rHuPH20 with the SC FDC compared
with Perjeta IV and Herceptin IV
Incidence of pertuzumab ADAs during the study 
relative to the prevalence of ADAs at baseline
Incidence of trastuzumab ADAs during the study 
relative to the prevalence of ADAs at baseline
Incidence of rHuPH20 ADAs during the study relative 
to the prevalence of ADAs at baseline
To evaluate potential effects of ADAs
Relationship between pertuzumab ADA status and 
efficacy, safety, or PK endpoints
Relationship between trastuzumab ADA status and 
efficacy, safety, or PK endpoints
Relationship between rHuPH20 ADA status and 
efficacy, safety, or PK endpoints


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24/Statistical Analysis Plan WO40324 Version 3
Exploratory Biomarker Objectives
Corresponding Endpoint
To explore potential association of 
tissue-based biomarkers or biomarker 
profiles to pCR
To explore changes in biomarker levels 
or biomarker profiles pre- and post-
treatment based on tumor tissue
To assess blood-based biomarkers at 
baseline and longitudinally to explore 
changes over time and potential 
relationship to pCR and long-term 
efficacy endpoints
Presence or absence of biomarker(s) and/or 
biomarker profiles with respect to levels of certain 
biomarkers at specified timepoints and relation to 
efficacy endpoints
ADAanti-drug antibody; bpCRbreast pathologic complete response; Ctroughsteady-state 
concentration; DRFI=distant breast cancer recurrence; DDIdrug-drug interaction; EFSevent-
free survival; FDCfixed-dose combination; GBG German Breast Group; GMRgeometric mean 
ratio; HCPhealth care provider; iDFSinvasive disease-free survival; IVintravenous; LVEFleft 
ventricular ejection fraction; NCI CTCAENational Cancer Institute Common Terminology Criteria 
for Adverse Events ;OSoverall survival; pCRpathologic complete response; PDprogressive 
disease; PKpharmacokinetic; PRpartial response; SCsubcutaneous; SDstable disease; 
tpCRtotal pathological complete response.
Study Design
Description of Study
This is a global Phase III, two-arm, open-label, multicenter, randomized study to investigate the 
pharmacokinetics, efficacy, and safety of the FDC (pertuzumab and trastuzumab for SC 
administration) in combination with chemotherapy in patients with HER2-positive EBC in the 
neoadjuvant/adjuvant setting.  
The study will enroll patients with HER2-positive breast cancer consistent with the indication for 
treatment with neoadjuvant Perjeta and Herceptin and chemotherapy in routine clinical practice 
and as recommended in local guidelines.
Approximately 500 patients with HER2-positive, operable or locally advanced/inflammatory 
breast cancer with a tumor size of 2 cm or node-positive will be randomized to one of the 
following treatment arms in a 1:1 ratio:  

Arm A (Perjeta IV Herceptin IV):  Patients will receive 8 cycles of neoadjuvant 
chemotherapy.  This will include 4 cycles of ddAC every 2 weeks (Q2W) (given with 
granulocyte colony-stimulating factor [G-CSF] support as needed according to local 
guidelines) followed by paclitaxel Q1W for 12 weeks or 4 cycles of doxorubicin plus 
cyclophosphamide (AC) Q3W followed by docetaxel Q3W for 4 cycles.  Perjeta Herceptin 
will be given IV for 4 cycles (Q3W) concurrently with the taxane component of 
chemotherapy.  After completing their neoadjuvant therapy, patients will undergo surgery.  
Thereafter, patients will receive an additional 14 cycles of Perjeta IV and Herceptin IV for a 
total of 18 cycles.  One year of HER2-targeted therapy without any delays would 
encompass 18 cycles. 
After surgery (from Cycle 9 onwards), patients in Arm A will continue Perjeta IV and are 
allowed to switch from Herceptin IV to Herceptin SC, at the discretion of the investigator, in the 
countries where Herceptin SC is routinely used.


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
Arm B (FDC of pertuzumab and trastuzumab for SC administration):  Patients will receive 8 
cycles of neoadjuvant chemotherapy.  This will include 4 cycles of ddAC Q2W (given with 
granulocyte colony-stimulating factor [G-CSF] support as needed according to local 
guidelines) followed by paclitaxel Q1W for 12 weeks or 4 cycles of AC Q3W followed by 
docetaxel Q3W for 4 cycles.  FDC will be given SC for 4 cycles (Q3W) concurrently with the 
taxane component of chemotherapy.  After completing their neoadjuvant therapy, patients 
will undergo surgery.  Thereafter, patients will receive an additional 14 cycles of the FDC for 
a total of 18 cycles.  One year of HER2-targeted therapy without any delays would 
encompass 18 cycles.
The investigator will select one of the two protocol-approved neoadjuvant chemotherapy 
regimens with which to treat the patient.  Once the investigator’s choice of chemotherapy has 
been made and eligibility confirmed, the patient will be randomized to one of the two treatment 
arms using a permuted blocks randomization procedure and stratified according to the following 
factors:  

Hormonal receptor status (based on central assessment): 
–
Estrogen receptor (ER)-positive or progesterone receptor (PgR)-positive 
–
ER-negative and PgR-negative

Clinical stage at presentation:
–
Stage IIIIIA
–
Stage IIIBIIIC

Type of chemotherapy:
–
ddAC followed by paclitaxel
–
AC followed by docetaxel
A patient may only be randomized once in this trial.  Patients randomized into the study will not 
be replaced.  Patients who choose to withdraw after screening, but before randomization, will be 
replaced.
Number of Patients
Approximately 500 patients with centrally confirmed HER2-positive, Stage IIIIIC breast cancer 
with a tumor size of 2 cm, or node-positive disease (clinically or on imaging and node 
positivity confirmed with cytology and/or histopathology) will be randomized in this study.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

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 (ECOG) Performance Status 1

Female and male patients with Stage IIIIIC (T2T4 plus any N, or any T plus N13, M0),
locally advanced, inflammatory, or early-stage, unilateral, and histologically confirmed 
invasive breast cancer
Patients with inflammatory breast cancer must be able to have a core-needle biopsy

Primary tumor 2 cm in diameter, or node-positive disease (clinically or on imaging, and
node positivity confirmed with cytology and/or histopathology)

HER2-positive breast cancer confirmed by a central laboratory prior to study enrollment. 
HER2-positive status will be determined based on pretreatment breast biopsy material and 
defined as 3+ by 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 signals for 
chromosome 17 copies
Patients with multifocal tumors (more than one tumor confined to the same quadrant as 
the primary tumor) are eligible provided at least one focus is sampled and centrally 
confirmed as HER2 positive. 


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
Hormone receptor status of the primary tumor, centrally confirmed
Hormone receptor-positive status can be determined by either known ER-positive 
and/or known PgR-positive status. Hormone receptor-negative status must be 
determined by both known ER-negative and known PgR-negative status

Patient agreement to undergo mastectomy or breast conserving surgery after neoadjuvant 
therapy 

Availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue block for central 
confirmation of HER2 and hormone receptor status and additional biomarker research (e.g., 
PIK3CA mutational analyses)

Baseline LVEF 55% measured by echocardiogram (ECHO) or multiple-gated acquisition 
scan (MUGA)

For women of childbearing potential (WOCBP) who are sexually active: agreement to 
remain abstinent (refrain from heterosexual intercourse) or use one highly effective non-
hormonal contraceptive method with a failure rate of 1% per year, or two effective non-
hormonal contraceptive methods during the treatment period and for 7 months after the last 
dose of HER2-targeted therapy, and agreement to refrain from donating eggs during this 
same period
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
Examples of highly effective 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).
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 postovulation methods) and withdrawal 
are not acceptable methods of contraception (see Section 5.1.3).

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom in combination with a spermicidal foam, gel, film, cream, or suppository, 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 with a spermicidal product during the treatment 
period and for 7 months after the last dose of HER2-targeted therapy 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 postovulation methods) and withdrawal 
are not acceptable methods of contraception (see section 5.1.3).

A negative serum pregnancy test must be available prior to randomization for WOCBP 
(premenopausal women and women 12 months after the onset of menopause), unless 
they have undergone surgical sterilization (removal of ovaries and/or uterus)

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
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Stage IV (metastatic) breast cancer 

Patients with a history of invasive breast cancer


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
Patients with a history of concurrent or previously treated non-breast malignancies except 
for appropriately treated 1) non-melanoma skin cancer and/or 2) in situ carcinomas, 
including cervix, colon, and skin
A patient with previous invasive non-breast cancer is eligible provided he/she has been 
disease free for more than 5 years.

Patients who have received any previous systemic therapy (including chemotherapy, 
immunotherapy, HER2-targeted agents, endocrine therapy (selective estrogen receptor 
modulators, aromatase inhibitors, and antitumor vaccines) for treatment or prevention of 
breast cancer, or radiation therapy for treatment of cancer

Patients who have a past history of ductal carcinoma in situ (DCIS) or lobular carcinoma in 
situ (LCIS) if they have received any systemic therapy for its treatment or radiation therapy 
to the ipsilateral breast
Patients are allowed to enter the study if treated with surgery alone.

Patients with high-risk for breast cancer who have received chemopreventative drugs in the 
past are not allowed to enter the study

Patients with multicentric (multiple tumors involving more than one quadrant) breast cancer, 
unless all tumors are HER2-positive

Patients with bilateral breast cancer

Patients who have undergone an excisional biopsy of primary tumor and/or axillary lymph 
nodes

Axillary lymph node dissection (ALND) prior to initiation of neoadjuvant therapy
Patients with clinically negative axilla (by physical examination and radiographic 
imaging) may undergo a core or needle biopsy procedure prior to neoadjuvant systemic 
therapy if in keeping with local practice

Sentinel lymph node biopsy (SLNB) prior to neoadjuvant therapy

Treatment with any investigational drug within 28 days prior to randomization 

Serious cardiac illness or medical conditions including, but not confined to, the following:
–
History of NCI CTCAE (v4) 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 2] or third-
degree AV-block)
–
Serious cardiac arrhythmia not controlled by adequate medication, severe conduction 
abnormality 
–
Angina pectoris requiring anti-anginal medication
–
Clinically significant valvular heart disease
–
Evidence of transmural infarction on ECG
–
Evidence of myocardial infarction within 12 months prior to randomization  
–
Poorly controlled hypertension (e.g., systolic 180 mm Hg or diastolic 100 mmHg)

Inadequate bone marrow function, defined as: 
–
Absolute neutrophil count 1.5 109/L
–
Platelet count 100 109/L 
–
Hemoglobin 9 g/dL 

Impaired liver function, defined as:
–
Serum (total) bilirubin 1.25 upper limit of normal (ULN)
In case of Gilbert’s syndrome: a total bilirubin of 2 ULN is permitted.
–
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 1.25 ULN


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–
Albumin 25 g/L

Inadequate renal function with serum creatinine 1.5 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 7 
months after the last dose of HER2-targeted therapy
Women of childbearing potential must have a negative serum pregnancy test result within 
7 days prior to initiation of study drug.

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 HIV

Known hypersensitivity to study drugs, excipients, and/or murine proteins

Current chronic daily treatment with corticosteroids (dose 10 mg methylprednisolone or 
equivalent excluding inhaled steroids)

History of other malignancy within 5 years prior to screening, except for appropriately 
treated carcinoma in situ of the cervix, colon, skin, and/or non-melanoma skin carcinoma

History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as 
structural heart disease (e.g., severe LVSD, left ventricular hypertrophy), coronary heart 
disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically 
significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), 
or family history of sudden unexplained death or long QT syndrome
End of Study
The end of the study is expected to occur approximately 4.5 years after the last patient is 
randomized to the study.  The end of the study is defined as the date when the last patient, last 
visit (LPLV) occurs or the date at which the last data point required for statistical analysis or 
safety follow-up is received from the last patient (or when all patients have died or the trial is 
terminated by the Sponsor, whichever is earliest).  
Length of Study
The total length of the study, from screening of the first patient to the end of the study is 
expected to be approximately 5.5 years.
Investigational Medicinal Products
The investigational medicinal products (IMPs) for this study are Perjeta® IV, Herceptin® IV, 
Herceptin® SC and the SC FDC of pertuzumab and trastuzumab.
Test Product (Investigational Drug)
For patients randomized to receive the FDC SC, the FDC is given as a fixed nonweight-based 
dose.  A loading dose of 1200 mg SC pertuzumab and 600 mg SC trastuzumab is then followed 
by 600 mg SC pertuzumab and 600 mg SC trastuzumab Q3W.  Chemotherapy should be given 
after the FDC.
After surgery, patients continue to receive the FDC in the adjuvant setting until a total of 18 
cycles of the FDC have been administered during the study.  Adjuvant FDC treatment should 
not start until at least 2 weeks after surgery. If the interval between the first dose of adjuvant 
FDC and the last dose of neoadjuvant FDC is 6 weeks, a reloading dose of FDC (1200 mg of 
pertuzumab and 600 mg of trastuzumab) is required. Subsequent maintenance FDC doses 
(600 mg pertuzumab and 600 mg trastuzumab) will then be given Q3W, starting 3 weeks later.  
The interval between the last dose of neoadjuvant FDC and the first dose of adjuvant FDC 
should be 9 weeks.


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Comparator
For patients randomized to receive the IV formulations of Perjeta and Herceptin, Perjeta is given 
as a fixed nonweight-based dose of 840-mg IV loading dose and then 420-mg IV Q3W.  
Herceptin is given as an 8-mg/kg IV loading dose and then 6 mg/kg IV Q3W.  The order of 
administration of Perjeta and Herceptin is according to investigator preference.  Chemotherapy 
should be given after Perjeta and Herceptin.
After surgery, patients continue to receive Perjeta and Herceptin in the adjuvant setting until a 
total of 18 cycles of Perjeta and Herceptin have been administered during the study
(neoadjuvant and adjuvant).  Adjuvant Perjeta and Herceptin treatment should not start until 2 
weeks after surgery. If the interval between the first dose of adjuvant Perjeta and Herceptin and 
the last dose of neoadjuvant Perjeta and Herceptin exceeds 6 weeks, a reloading dose of 840 
mg of Perjeta and 8 mg/kg of Herceptin is required. The interval between the last dose of 
neoadjuvant Perjeta and Herceptin and the first dose of adjuvant Perjeta and Herceptin should 
be 9 weeks.
Non-Investigational Medicinal Products
Doxorubicin, cyclophosphamide, paclitaxel, docetaxel, G-CSF, and adjuvant hormone therapy 
are administered in accordance with local prescribing information and these drugs are not 
regarded as IMPs.  These drugs will be obtained locally by the investigational sites or will be 
provided by the Sponsor as per country requirements.
Statistical Methods
Primary Analysis
The primary endpoint of this study is observed pertuzumab trough concentration (Ctrough) at 
Cycle 7 (i.e., the measured pre-dose concentration value at Cycle 8), following 3 cycles of 
Perjeta IV and Herceptin IV or FDC (pertuzumab and trastuzumab SC).  Pertuzumab Ctrough
will be analyzed at the time of the primary analysis, which will occur after the last patient has 
completed (all) neoadjuvant therapy and has undergone surgery. 
The non-inferiority of the SC and IV dose of pertuzumab will be assessed by a one-sided testing 
procedure. The CtroughSC/CtroughIV GMR of the SC dose of pertuzumab relative to the IV dose 
will be estimated together with the two-sided 90% CI based on the log-transformed trough 
concentration values. The null hypothesis will be rejected and non-inferiority will be concluded if 
the lower bound of the 90% CI of the GMR is 0.8.
Determination of Sample Size  
The study is designed to have at least 80% power to demonstrate non-inferiority of the Cycle 7 
(i.e., pre-dose Cycle 8) pertuzumab serum Ctrough from pertuzumab SC within FDC to the Perjeta 
IV formulation in patients with HER2-positive EBC. 
The hypothesis to be tested for the primary endpoint, observed pertuzumab Ctrough, is:

H0:  The SC dose is inferior to the IV dose (i.e., the CtroughSC/CtroughIV GMR of the SC dose 
of pertuzumab relative to the IV dose is not greater than 0.8) versus

H1:  The SC dose is non-inferior to the IV dose (i.e., CtroughSC/CtroughIV GMR of the SC dose 
of pertuzumab relative to the IV dose is equal to or greater than 0.8)
The null-hypothesis will be rejected if the lower bound of the 90% CI for the GMR is equal or 
greater than 0.8.
PK sample size calculations are based on the coefficient of variation (CV)% for the Ctrough of 
trastuzumab observed from previous studies in MBC and EBC patients after Q3W treatment. 
With a CV of 60% assumed, a minimum or 130 patients per arm (i.e., a total of 260 patients) is 
needed to demonstrate Ctrough non-inferiority with a power of 80% if the true means of the two 
formulations do not differ by more than 5%. An additional 240 patients will also be recruited to 
provide a substantial database to assess tpCR and safety profile comparability. Therefore, a 
total of approximately 500 patients (~250 patients per arm) will provide a sufficient sample size 
to test the primary PK hypothesis and also assess efficacy and safety profile comparability. 
A hierarchical testing procedure for key secondary endpoints will be used to control the overall 
type I error rate at a one-sided 5% significance level.


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Interim And Final Analyses
No formal, statistical interim analyses are planned prior to the primary analysis.  
The final analysis will occur 3 years after the last patients last treatment.


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Appendix 2 Schedule of Activities for Patients Receiving AC Q3WDocetaxel in the Neoadjuvant 
Phase
This study is driven by the primary endpoint Ctrough.  Therefore, adherence to the PK assessment schedule is of utmost importance.
Screening
Baseline
Treatment Period
3-Week Cycles
3-Week Cycles
Cycle
1
2
3
4
5
6
7
8
Surgery a
Day
–28 to –1
–7 to –1
1
1
1
1
1
2
15
1
1
2
4
8
15
1
1
Informed consent b
x
Medical history and 
demographics
x
Complete physical examination
c, d
x
x
x
Limited physical examination  d
x
x
x
x
x
x
Vital signs e, d
x
x
x
x
x
x
x
x
x
ECOG Performance Status c, d, f
x
x g
x
x
x
x
x
x
x
Height d
x
Weight c, d, h
x
x
x
x
x
x
x
x
x
Tumor staging i
x
Bilateral mammogram (or 
another imaging method as per 
local practice) j
x
x
Clinical tumor 
assessment/breast examination
d, k
x
x
x
x
x
x
x
x
x


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Appendix 2 Schedule of Activities for Patients Receiving AC Q3WDocetaxel in the Neoadjuvant 
Phase (cont.)
Screening
Baseline
Treatment Period
3-Week Cycles
3-Week Cycles
Cycle
1
2
3
4
5
6
7
8
Surgery a
Day
–28 to –1
–7 to –1
1
1
1
1
1
2
15
1
1
2
4
8
15
1
1
ECG (12-lead)
x
x
LVEF (ECHO or MUGA) l
x
x m
x
x
Hematology/Biochemistry n
x
x g
x
x
x
x
x
x
x
Pregnancy test o
x
x
x
FFPE tumor tissue sample for 
central HER2/HR testing and 
exploratory biomarker research p
x
Local HER2 and hormone 
receptor status (HER2, ER, 
PgR) q
x
Tumor sample r
x
Pathologist post-surgery 
pathologic response tumor 
assessment s
x
PK sampling: 
Pertuzumab/Trastuzumab IV 
(Arm A) t
x
u,v
x
x
x
u,v
x
u,v
x
x
x
x
x
u,v


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Appendix 2 Schedule of Activities for Patients Receiving AC Q3WDocetaxel in the Neoadjuvant 
Phase (cont.)
Screening
Baseline
Treatment Period
3-Week Cycles
3-Week Cycles
Cycle
1
2
3
4
5
6
7
8
Surgery a
Day
–28 to –1
–7 to –1
1
1
1
1
1
2
15
1
1
2
4
8
15
1
1
ADA sampling: 
Pertuzumab/Trastuzumab IV
(Arm A)
x w
x u
PK sampling: 
Pertuzumab/Trastuzumab SC 
(Arm B) t
x x
x
x
x x
x x
x
x
x
x
x x
ADA sampling: 
Pertuzumab/Trastuzumab/
rHuPH20 SC (Arm B)
x w
x x
Plasma sample for ctDNA
(biomarker) y
x w
x
Perjeta IV (Arm A) z
x
x
x
x
Herceptin IV (Arm A) z
x
x
x
x
FDC SC (Arm B) aa
x
x
x
x
Doxorubicin bb
x
x
x
x
Cyclophosphamide bb
x
x
x
x
Docetaxel cc
x
x
x
x


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Appendix 2 Schedule of Activities for Patients Receiving AC Q3WDocetaxel in the Neoadjuvant 
Phase (cont.)
Screening
Baseline
Treatment Period
3-Week Cycles
3-Week Cycles
Cycle
1
2
3
4
5
6
7
8
Surgery a
Day
–28 to –1
–7 to –1
1
1
1
1
1
2
15
1
1
2
4
8
15
1
1
Adverse events dd
All AEs and SAEs (see Section 5.3)
Concomitant medication ee
x
Continuous
AC doxorubicin and cyclophosphamide; ADA anti-drug antibody; -HCG human chorionic gonadotripin; CBE clinical breast 
examination; CT computed tomography; ctDNA circulating tumor DNA; Ctrough steady-state concentration; ECHO echocardiogram; 
ECOG Eastern Cooperative Oncology Group; ER estrogen receptor; FDC fixed-dose combination of pertuzumab and trastuzumab for SC 
administration; 
FFPE formalin-fixed, paraffin-embedded; LVEF left ventricular ejection fraction; MRI magnetic resonance imaging; MUGA multiple-
gated acquistion; NCCN National Comprehensive Cancer Network; PgR progesterone receptor; PK pharmacokinetic; Q3W every three 
weeks; RBR Research Biosample Repository; rHuPH20 recombinant human PH20 hyaluronidase; SAE serious adverse event.
Notes:  Cycle 1, Day 1 first dose of study drug.  Patients should receive their first dose of study drug on the day of randomization, if 
possible.  If this is not possible, the first dose should occur no later than 3 days after randomization.  Clinical visits must be 
scheduled within 3 days of the day specified. On dosing days, PK samples need to be taken on the exact day of the visit schedule.  On 
non-dosing days, PK samples must be taken within 2 days of the required sampling day, with the timing of PK sampling during the day left to 
the investigator (however, the time should be carefully recorded).
a Surgery will be performed no earlier than 14 days following the last infusion or injection of neoadjuvant therapy.  The interval between the 
last dose of neoadjuvant Perjeta and Herceptin IV or FDC and the first dose of adjuvant Perjeta and Herceptin IV or FDC should be 
9 weeks.
b Results of standard-of-care tests or examinations performed prior to obtaining informed consent may be used; such tests do not need to be 
repeated for screening.
c
Must be performed pre-dose on dosing days.
d Assessment may be done within 3 days prior to treatment day.
e Vital signs (respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature) 
will be taken before the administration of study treatment and before and after Perjeta and Herceptin infusions/FDC injections.
f
ECOG Performance Status should be assessed when the patient undergoes clinical tumor assessment and breast examination (i.e., prior to


Pertuzumab—F. Hoffmann-La Roche Ltd
35/Statistical Analysis Plan WO40324 Version 3
Appendix 2 Schedule of Activities for Patients Receiving AC Q3WDocetaxel in the 
Neoadjuvant Phase (cont.)
   each new cycle of therapy during neoadjuvant treatment and at least every 3 months during the adjuvant treatment period [Cycle 9, 
Cycle 13, Cycle 17, and Cycle 21] and at the treatment completion or discontinuation visit).  
g
Screening measurements can be used as Day 1 assessments if performed within 3 days prior to Cycle 1.
h
Weight will be measured during screening and on Day 1 of each cycle.  If variation of 10% occurs, as compared with baseline, the 
Herceptin IV and chemotherapy doses will be recalculated.
i
Baseline tumor staging procedures are not mandatory and should be performed as per local practice, in alignment with national guidelines 
and as clinically indicated within 28 days of randomization.  See Section 4.5.7.2.
j
Provided that the patient’s clinical status has not changed, the screening mammogram can be performed up to 42 days prior to the start of 
treatment.  The mammogram at screening, pre-surgery, and treatment completion or discontinuation visit can be replaced by other 
conventional imaging methods such as MRI or ultrasound per local medical practice, at the investigator’s discretion, but the same method 
of assessment must be used throughout for an individual patient.  If another method is used, this must be performed within the 28-day 
screening window.  If a mammogram has been conducted as part of routine preventive care within 4 months of the treatment completion or 
discontinuation visit, it may be used in lieu of the end-of-study mammogram.
k
Clinical breast examination (CBE) will be performed at screening.  During the neoadjuvant treatment period, tumor response assessment 
will be performed prior to each new cycle of therapy by CBE (mandatory) and other methods of evaluation as per routine clinical practice.
l
For patients whose LVEF cannot be assessed by ECHO, LVEF may be assessed by MUGA.  The same method should be used throughout
the study for each patient and is preferably performed and assessed by the same assessor.  All LVEF assessments will be performed during 
Days 15 21 of three-week cycles prior to the cycle indicated here to allow evaluation of the results before the next treatment cycle. LVEF 
assessment may also be performed on Day 1 of treatment but results must be available before treatment is administered.  
m
Patients should not start HER2-targeted therapy if their LVEF is 50% after anthracycline treatment.  This ECHO/MUGA assessment 
should be performed prior to administration of any treatment at Cycle 5.
n
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (% or absolute for neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells).  Biochemistry:  sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, 
creatinine, albumin, ALP, ALT, AST, total bilirubin and direct/indirect bilirubin (if needed).  Bilirubin fractions (direct and indirect) need to be 
measured only if total bilirubin is greater than ULN.  Bicarbonate should only be tested at sites where this test is part of the standard safety 
laboratory panel.  During the treatment period, bloods for hematology/biochemistry must be taken predose but may be taken within 3 days 
prior to treatment day.
o
For all women of childbearing potential and for all women not meeting the definition of postmenopausal (refer to Section 5.1.3 for definition), 
pregnancy test must be performed via serum -HCG at baseline within 7 days prior to the first administration of study medication (with result 
available prior to dosing).  Urine pregnancy tests should be repeated during the treatment period within 7 days prior to every third treatment 
cycle starting at Cycle 4 (and as clinically indicated), as well as at the treatment discontinuation visit and every 3 months 


Pertuzumab—F. Hoffmann-La Roche Ltd
36/Statistical Analysis Plan WO40324 Version 3
Appendix 2 Schedule of Activities for Patients Receiving AC Q3WDocetaxel in the 
Neoadjuvant Phase (cont.)
      thereafter until 6 months after discontinuation of study treatment.  Any positive urine pregnancy test must be confirmed with a serum -HCG 
test.  Treatment period pregnancy test results must be available prior to the drug infusion/injection.  A pregnancy test at 7 months 
(i.e., between 69 months follow up) can be performed if indicated.  Note that patients are required to continue contraception for 7 months 
after study treatment is complete.
p
FFPE tumor tissue sample will be collected for mandatory central confirmation of HER2 and hormone receptor status. Additional mandatory 
exploratory biomarker analysis (such as PIK3CA), storage, and analysis, as part of the RBR (optional) only, apply for randomized patients.  
Retrieval, submission, and central testing of tumor tissue sample can occur outside the 28-day screening period.
q
Hormone receptorpositive patients are to be prescribed endocrine therapy according to the guidelines after completion of pre-operative 
chemotherapy and surgery.  Local HER2/HR assessment can occur outside the 28-day screening period.
r
Optional submission of post-treatment samples obtained from resection specimens from all consenting patients for exploratory biomarkers.
s
Pathological response assessment to be performed using the resected specimen by the local pathologist on the basis of guidelines to be 
provided in the Pathology Manual.
t
The date and time of PK sampling must be carefully recorded in all cases.  On dosing days, PK samples must be taken on the exact day 
when HER2-targeted therapy is administered (no window allowed).  On non-dosing days, all samples must be taken on the exact day of the 
visit schedule whenever possible (2 days is allowed if necessary), with the timing of PK sampling during the day left to the investigator 
(however, the time should be carefully recorded) 
.  If the Cycle 8 dose administration is going to be delayed by more than 2 
days, the Cycle 8 pre-dose sample must be taken 21 days after Cycle 7 administration.  This exception does not apply to any other cycles.
u
Take sample pre-infusion.
v
Take additional PK sample at the end of the infusion.  The time of sampling must be within 15 minutes after each infusion has ended.
w
Sample can be taken after randomization but prior to drug administration on Cycle 1, Day 1. 
x
Take sample pre-injection.
y     Mandatory plasma samples collected at baseline, at Cycles 8 and 10, the treatment completion or treatment discontinuation visit and at 
3-year follow up.
z
All patients in Arm A receive a Perjeta loading dose of 840 mg IV on Cycle 5, Day 1 (the first day of paclitaxel treatment).  Thereafter 
(Cycles 6 22), all patients receive a Perjeta maintenance dose of 420 mg IV.  All patients in Arm A receive a Herceptin loading dose of 
8 mg/kg IV on Cycle 5, Day 1 (the first day of paclitaxel treatment).  Thereafter (Cycles 6 22), all patients receive Herceptin at 6 mg/kg IV.  
The order of administration of Perjeta and Herceptin is according to the investigator’s preference.


Pertuzumab—F. Hoffmann-La Roche Ltd
37/Statistical Analysis Plan WO40324 Version 3
Appendix 2 Schedule of Activities for Patients Receiving AC Q3WDocetaxel in the 
Neoadjuvant Phase (cont.)
aa
All patients in Arm B receive a FDC SC loading dose of 1200mg pertuzumab and 600mg trastuzumab on Cycle 5, Day 1 (the first day of 
paclitaxel treatment).  Thereafter (Cycles 6 22), all patients receive maintenance dose of 600mg pertuzumab and 600mg trastuzumab.
bb
All patients receive doxorubicin 60 mg/m2 IV and cyclophosphamide 600 mg/m2 IV given every 3 weeks, for four cycles (Cycles 1 4), 
according to local practice guidelines.
cc
The starting dose of docetaxel is 75mg/m2 IV in Cycle 5 given every 3 weeks.  At the investigator’s discretion, the dose may be escalated to 
100 mg/m2 IV for subsequent cycles (Cycles 6 8) provided no dose-limiting toxicity occurs.
dd
After informed consent has been obtained, but prior to initiation of study drug, only serious adverse events caused by protocol-mandated 
intervention should be reported.  After initiation of study drugs, all adverse events and serious adverse events will be collected until the 
treatment completion or discontinuation visit (28 days after the last dose of study drug).  Non-serious adverse events occurring prior to study 
drug administration (Cycle 1, Day 1) will be reported in the medical history unless adverse event reporting is deemed more appropriate.  
After the treatment completion or discontinuation visit, drug-related serious adverse events and adverse events and serious adverse events 
that qualify for long-term reporting will continue to be collected (see Sections 5.3.4 and 5.5.2).
ee
Concomitant medications will be recorded until the end of the treatment period.


Pertuzumab—F. Hoffmann-La Roche Ltd
38/Statistical Analysis Plan WO40324 Version 3
Appendix 3 Schedule of Activities for Patients Receiving ddAC Q2WPaclitaxel in the 
Neoadjuvant Phase
This study is driven by the primary endpoint Ctrough.  Therefore, adherence to the PK assessment schedule is of utmost importance.
Screening
Baseline
Treatment Period
2-Week Cycles
3-Week Cycles
Cycle
1
2
3
4
5
6
7
8
Surgery a
Day
–28 to –1
–7 to –1
1
1
1
1
1
2
15
1
1
2
4
8
15
1
1
Informed consent b
x
Medical history and 
demographics
x
Complete physical examination
c, d
x
x
x
Limited physical examination c, d
x
x
x
x
x
x
Vital signs d, e
x
x
x
x
x
x
x
x
x
ECOG Performance Status c, d, f
x
x g
x
x
x
x
x
x
x
Height d
x
Weight c, d, h
x
x
x
x
x
x
x
x
x
Tumor staging i
x
Bilateral mammogram (or 
another imaging method as, per 
local practice) j
x
x
Clinical tumor 
assessment/breast examination
d, k
x
x
x
x
x
x
x
x
x


Pertuzumab—F. Hoffmann-La Roche Ltd
39/Statistical Analysis Plan WO40324 Version 3
Screening
Baseline
Treatment Period
2-Week Cycles
3-Week Cycles
Cycle
1
2
3
4
5
6
7
8
Surgery a
Day
–28 to –1
–7 to –1
1
1
1
1
1
2
15
1
1
2
4
8
15
1
1
ECG (12-lead)
x
x
LVEF (ECHO or MUGA) l
x
x m
x
x
Hematology/Biochemistry n
x
x g
x
x
x
x
x
x
x
Pregnancy test o
x
x
x
FFPE tumor tissue sample for 
central HER2/HR testing and 
exploratory biomarker research p
x
Local HER2 and hormone 
receptor status (HER2, ER, 
PgR) q
x
Tumor sample r
x
Pathologist post-surgery 
pathologic response tumor 
assessment s
x
PK sampling: 
Pertuzumab/Trastuzumab IV 
(Arm A) t
x
u,v
x
x
x
u,v
x
u,v
x
x
x
x
x
u,v
ADA sampling: 
Pertuzumab/Trastuzumab IV
(Arm A)
x w
x u
PK sampling: 
Pertuzumab/Trastuzumab SC 
(Arm B) t
x x
x
x
x x
x x
x
x
x
x
x x


Pertuzumab—F. Hoffmann-La Roche Ltd
40/Statistical Analysis Plan WO40324 Version 3
Screening
Baseline
Treatment Period
2-Week Cycles
3-Week Cycles
Cycle
1
2
3
4
5
6
7
8
Surgery a
Day
–28 to –1
–7 to –1
1
1
1
1
1
2
15
1
1
2
4
8
15
1
1
ADA sampling: 
Pertuzumab/Trastuzumab/
rHuPH20 SC (Arm B)
x w
x x
Plasma sample for ctDNA
(biomarker) y
x w
x
Perjeta IV (Arm A) z
x
x
x
x
Herceptin IV (Arm A) z
x
x
x
x
FDC SC (Arm B) aa
x
x
x
x
ddDoxorubicin bb
x
x
x
x
ddCyclophosphamide bb
x
x
x
x
Paclitaxel cc
Weekly for 12 weeks
Adverse events dd
All AEs and SAEs (see Protocol Section 5.3)
Concomitant medication ee
x
Continuous
ADA anti-drug antibody; AE adverse event; -HCG human chorionic gonadotripin; CBE clinical breast examination; CT computed 
tomography; ctDNA circulating tumor DNA; Ctrough steady-state concentration; ddAC dose-dense doxorubicin and cyclophosphamide;
ECHO echocardiogram; ECOG Eastern Cooperative Oncology Group; ER estrogen receptor; FDC fixed-dose combination of 
pertuzumab and trastuzumab for SC administration; FFPE formalin-fixed, paraffin-embedded; LVEF left ventricular ejection fraction; 
MRI magnetic resonance imaging; MUGA multiple-gated acquistion; NCCN National Comprehensive Cancer Network; 
PgR progesterone receptor; PK pharmacokinetic; Q2W every 2 weeks; RBR Research Biosample Repository; rHuPH20 recombinant 
human PH20 hyaluronidase; SAE serious adverse event.


Pertuzumab—F. Hoffmann-La Roche Ltd
41/Statistical Analysis Plan WO40324 Version 3
Notes:  Cycle 1, Day 1first dose of study drug. Patients should receive their first dose of study drug on the day of randomization, if 
possible.  If this is not possible, the first dose should occur no later than 3 days after randomization. Clinical visits must be scheduled 
within3 days of the day specified.  On dosing days, PK samples need to be taken on the exact day of the visit schedule.  On non-dosing 
days, PK samples must be taken within 2 days of the required sampling day, with the timing of PK sampling during the day left to the 
investigator (however, the time should be carefully recorded).
a Surgery will be performed no earlier than 14 days following the last infusion or injection of neoadjuvant therapy.  The interval between the 
last dose of neoadjuvant Perjeta and Herceptin IV or FDC and the first dose of adjuvant Perjeta and Herceptin IV or FDC should be 
9 weeks.
b Results of standard-of-care tests or examinations performed prior to obtaining informed consent may be used; such tests do not need to be 
repeated for screening.
c Must be performed pre-dose on dosing days.
d Assessment may be done within 3 days prior to treatment day.
e
Vital signs (respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature) 
will be taken before the administration of study treatment and before and after Perjeta and Herceptin infusions/FDC injections.
f
ECOG Performance Status should be assessed when the patient undergoes clinical tumor assessment and breast examination (i.e., prior 
to each new cycle of therapy during neoadjuvant treatment and at least every 3 months during the adjuvant treatment period [Cycle 9, 
Cycle 13, Cycle 17, and Cycle 21] and at the treatment completion or discontinuation visit).
g Screening measurements can be used as Day 1 assessments if performed within 3 days prior to Cycle 1.
h Weight will be measured during screening and on Day 1 of each cycle.  If variation of 10% occurs, as compared with baseline, the 
Herceptin IV and chemotherapy doses will be recalculated.
i
Baseline tumor staging procedures are not mandatory and should be performed as per local practice, in alignment with national guidelines
and as clinically indicated within 28 days of randomization (see Protocol Section 4.5.7.2).
j
Provided that the patient’s clinical status has not changed, the screening mammogram can be performed up to 42 days prior to the start of treatment.  The 
mammogram at screening, pre-surgery, and treatment completion or discontinuation visit can be replaced by other conventional imaging methods such as 
MRI or ultrasound per local medical practice, at the investigator’s discretion, but the same method of assessment must be used throughout for an 
individual patient. If another method is used, this must be performed within the 28-day screening window. If a mammogram has been conducted as 
part of routine preventive care within 4 months of the treatment completion or discontinuation visit, it may be used in lieu of the end-of-study mammogram. 
k Clinical breast examination (CBE) will be performed at screening.  During the neoadjuvant treatment period, tumor response assessment 
will be performed prior to each new cycle of therapy by CBE (mandatory) and other methods of evaluation as per routine clinical practice.
l
For patients whose LVEF cannot be assessed by ECHO, LVEF may be assessed by MUGA.  The same method should be used throughout 
the study for each patient and is preferably performed and assessed by the same assessor.  All LVEF assessments will be performed 
during Days 1521 of 3-week cycles prior to the cycle indicated to allow evaluation of the results before the next treatment cycle. LVEF 
assessment may also be performed on Day 1 of treatment but results must be available before treatment is administered.


Pertuzumab—F. Hoffmann-La Roche Ltd
42/Statistical Analysis Plan WO40324 Version 3
m Patients should not start HER2-targeted therapy if their LVEF is 50% after anthracycline treatment.  This ECHO/MUGA assessment 
should be performed prior to administration of any treatment at Cycle 5.
n Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (% or absolute for neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells).  Biochemistry:  sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, 
creatinine, albumin, ALP, ALT, AST, total bilirubin and direct/indirect bilirubin (if needed).  Bilirubin fractions (direct and indirect) need to be 
measured only if total bilirubin is greater than ULN.  Bicarbonate should only be tested at sites where this test is part of the standard safety 
laboratory panel.  During the treatment period, bloods for hematology/biochemistry must be taken predose but may be taken within 3 days 
prior to treatment day.
o For all women of childbearing potential and for all women not meeting the definition of postmenopausal (refer to Section 5.1.3 for 
definition), pregnancy tests must be performed via serum -HCG at baseline within 7 days prior to the first administration of study 
medication (with result available prior to dosing).  Urine pregnancy tests should be repeated during the treatment period within 7 days prior 
to every third treatment cycle starting at Cycle 4 (and as clinically indicated), as well as at the treatment discontinuation visit and every 
3 months thereafter until 6 months after discontinuation of study treatment.  Any positive urine pregnancy test must be confirmed with a 
serum -HCG test.  Treatment period pregnancy test results must be available prior to the drug infusion/injection.  A pregnancy test at 
7 months (i.e. between 6-9 month follow up) can be performed if indicated.  Note that patients are required to continue contraception for 
7 months after study treatment is complete.
p FFPE tumor tissue sample will be collected for mandatory central confirmation of HER2 and hormone receptor status.  Additional 
mandatory exploratory biomarker analysis (such as PIK3CA), storage, and analysis, as part of the RBR (optional) only, apply for 
randomized patients.  Retrieval, submission, and central testing of tumor tissue sample can occur outside the 28-day screening period.
q Hormone receptorpositive patients are to be prescribed endocrine therapy according to the guidelines after completion of pre-operative 
chemotherapy and surgery.  Local HER2/HR assessment can occur outside the 28-day screening period.
r
Optional submission of post-treatment samples obtained from resection specimens from all consenting patients for exploratory biomarkers.  
s
Pathological response assessment to be performed using the resected specimen by the local pathologist on the basis of guidelines to be 
provided in a Pathology Manual.  
t
The date/time of PK sampling must be carefully recorded in all cases.  On dosing days, PK samples must be taken on the exact day when 
HER2-targeted therapy is administered (no window allowed).  On non-dosing days, all samples must be taken on the exact day of the 
visit schedule whenever possible (2 days is allowed if necessary, with the timing of PK sampling during the day left to the investigator 
(however, the time should be carefully recorded) 
. If the Cycle 8 dose administration is going to be delayed by more than 
2 days, the Cycle 8 pre-dose sample must be taken 21 days after Cycle 7 administration.  This exception does not apply to any other 
cycles.
u Take sample pre-infusion.
v Take additional PK sample at the end of the infusion.  The time of sampling must be within 15 minutes after each infusion has ended.
w Sample can be taken after randomization but prior to drug administration on Cycle 1, Day 1.
x Take sample pre-injection.


Pertuzumab—F. Hoffmann-La Roche Ltd
43/Statistical Analysis Plan WO40324 Version 3
y Mandatory plasma samples collected at baseline, at Cycles 8 and 10, the treatment completion or treatment discontinuation visit and at 
3-year follow up.
z All patients in Arm A receive a Perjeta loading dose of 840 mg IV on Cycle 5, Day 1 (the first day of paclitaxel treatment). Thereafter 
(Cycles 622), all patients receive a Perjeta maintenance dose of 420 mg IV. All patients in Arm A receive a Herceptin loading dose of 
8 mg/kg IV on Cycle 5, Day 1 (the first day of paclitaxel treatment).  Thereafter (Cycles 622), all patients receive Herceptin at 6 mg/kg IV.  
The order of administration of Perjeta and Herceptin is according to the investigator’s preference.
aa All patients in Arm B receive a FDC SC loading dose of 1200mg pertuzumab and 600mg trastuzumab on Cycle 5, Day 1 (the first day of 
paclitaxel treatment).  Thereafter (Cycles 622), all patients receive maintenance dose of 600mg pertuzumab and 600mg trastuzumab.
bb All patients receive doxorubicin 60 mg/m2 IV and cyclophosphamide 600 mg/m2 IV given every 2 weeks, for four cycles (Cycles 14), 
according to local practice guidelines.
cc All patients receive paclitaxel 80 mg/m2 IV weekly for 12 weeks starting no sooner than 2 weeks after the last dose of doxorubicin and 
cyclophosphamide.
dd After informed consent has been obtained, but prior to initiation of study drug, only serious adverse events caused by protocol-mandated 
intervention should be reported.  After initiation of study drugs, all adverse events and serious adverse events will be collected until the 
treatment completion or discontinuation visit (28 days after the last dose of study drug).  Non-serious adverse events occurring prior to 
study drug administration (Cycle 1, Day 1) will be reported in the medical history unless adverse event reporting is deemed more 
appropriate.  After the treatment completion or discontinuation visit, drug-related serious adverse events and adverse events and serious 
adverse events that qualify for long-term reporting will continue to be collected (see sections 5.3.4 and 5.5.2).
ee Concomitant medications will be recorded until the end of the treatment period.


Pertuzumab—F. Hoffmann-La Roche Ltd
44/Statistical Analysis Plan WO40324 Version 3
Appendix 4 Schedule of Activities for All Patients in the Adjuvant Pertuzumab and Trastuzumab 
Treatment Phase
This study is driven by the primary endpoint Ctrough.  Therefore, adherence to the PK assessment schedule is of utmost importance.
Cycle (3 weeks)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Treatment 
Completion/ 
Discontinuation a
Day
1
1
1
1
2
4
8
15
1
1
1
1
1
1
1
1
1
1
Complete physical 
examination
x
Limited physical examination b
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signs b
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECOG Performance Status b, c
x
x
x
x
x
Weight b, d
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Bilateral mammogram (or 
another imaging method as, 
per local practice) e
x
Clinical breast examination b, f
x
x
x
x
x
LVEF (ECHO or MUGA) g
x
x
x
x
x
x
Hematology/Limited Biochemistry h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Pregnancy test i
x
x
x
x
x
x
Perjeta IV (Arm A) j
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Herceptin IV (Arm A) j
x
x
x
x
x
x
x
x
x
x
x
x
x
x
FDC SC (Arm B) k
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PK sampling: 
Pertuzumab/Trastuzumab IV 
(Arm A) l
x
m,n
x
m,n
x
m,n
x
m,n
x
x
x
x
x m
x m
x m


Pertuzumab—F. Hoffmann-La Roche Ltd
45/Statistical Analysis Plan WO40324 Version 3
Appendix 4 Schedule of Activities for All Patients in the Adjuvant Pertuzumab and Trastuzumab 
Treatment Phase (cont.)
Cycle (3 weeks)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Treatment 
Completion/ 
Discontinuation a
Day
1
1
1
1
2
4
8
15
1
1
1
1
1
1
1
1
1
1
ADA sampling: 
Pertuzumab/Trastuzumab IV
(Arm A)
x m
x m
x m
x m
PK sampling: 
Pertuzumab/Trastuzumab SC 
(Arm B) l
x o
x o
x o
x o
x
x
x
x
x o
x o
x o
ADA sampling: 
Pertuzumab/Trastuzumab/
rHuPH20 SC (Arm B)
x o
x o
x o
x o
Plasma sample for ctDNA 
(biomarker)
x
x
Adverse events
All AEs and SAEs (see Section 5.3)
Concomitant medication
Continuous


Pertuzumab—F. Hoffmann-La Roche Ltd
46/Statistical Analysis Plan WO40324 Version 3
Appendix 4 Schedule of Activities for All Patients in the Adjuvant Pertuzumab and 
Trastuzumab Treatment Phase (cont.)
ADA anti-drug antibody; AE adverse event; -HCG human chorionic gonadotripin; CT computed tomography; ctDNA circulating tumor 
DNA; Ctrough steady-state concentration; ECHO echocardiogram; ECOG Eastern Cooperative Oncology Group; FDC fixed-dose 
combination of pertuzumab and trastuzumab for SC administration; LVEF left ventricular ejection fraction; MRI magnetic resonance imaging; 
MUGA multiple-gated acquistion; PK pharmacokinetic; rHuPH20 recombinant human PH20 hyaluronidase; SAE serious adverse event; 
ULN upper limit of normal.
Notes:  Cycle 1, Day 1 first dose of study drug.  Clinical visits must be scheduled within 3 days of the day specified.  On dosing days, PK 
samples need to be taken on the exact day of the visit schedule.  On non-dosing days, PK samples must be taken within 2 days of the required 
sampling day, with the timing of PK sampling during the day left to the investigator (however, the time should be carefully recorded).
a Treatment completion or discontinuation visits will optimally be scheduled for 28 (3 days) following the last dose of study medication and will 
include all evaluations scheduled for the final visit.
b Assessment may be done within 3 days prior to treatment day.
c
ECOG Performance Status should be assessed when the patient undergoes clinical tumor assessment and breast examination (i.e., at least 
very 3 months during the adjuvant treatment period [Cycle 9, Cycle 13, Cycle 17, and Cycle 21] and at the treatment completion or 
discontinuation visit).
d Weight will be measured during screening and on Day 1 of each cycle.  If variation of 10% occurs, as compared with baseline, the Herceptin 
IV and chemotherapy doses will be recalculated.
e
Provided that the patient’s clinical status has not changed, the screening mammogram can be performed up to 42 days prior to the start of 
treatment.  The mammogram at screening, pre-surgery, and treatment completion or discontinuation visit can be replaced by other 
conventional imaging methods such as MRI or ultrasound as per local medical practice, at the investigator’s discretion, but the same method 
of assessment must be used throughout for an individual patient.  If a mammogram has been conducted as part of routine preventive care 
within 4 months of the treatment completion or discontinuation visit, it may be used in lieu of the end of study mammogram.
f
During the adjuvant treatment period, clinical breast examination should be performed to detect signs of locoregional relapse at least every 
3 months (Cycle 13, Cycle 17, and Cycle 21) and at the treatment completion or discontinuation visit.
g For patients whose LVEF cannot be assessed by ECHO, LVEF may be assessed by MUGA.  The same method should be used throughout 
the study for each patient and is preferably performed and assessed by the same assessor.  All LVEF assessments will be performed during 
Days 1521 of 3-week cycles prior to the cycle indicated here to allow evaluation of the results before the next treatment cycle.  LVEF 
assessment may be performed on Day 1 of treatment but results must be available before treatment is administered.
h Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (% or absolute for neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells).  Limited biochemistry: creatinine, alkaline phosphatase (ALP), AST, ALT, total bilirubin, and 
direct/indirect bilirubin (if needed).  Bilirubin fractions (direct and indirect) need to be measured only if total bilirubin is greater than ULN.  
During the treatment period, bloods for hematology/biochemistry must be taken pre dose, but may be taken within 3 days prior to treatment 


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Appendix 4 Schedule of Activities for All Patients in the Adjuvant Pertuzumab and 
Trastuzumab Treatment Phase (cont.)
day.
i
For all women of childbearing potential and for all women not meeting the definition of postmenopausal (12 months of amenorrhea) who 
have not undergone surgical sterilization, pregnancy tests must be performed via serum -HCG at baseline within 7 days prior to the first 
administration of study medication (with result available prior to dosing).  Urine pregnancy tests should be repeated during the treatment 
period within 7 days prior to every third treatment cycle starting at Cycle 4 (and as clinically indicated), as well as at the treatment 
discontinuation visit and every 3 months thereafter until 6 months after discontinuation of study treatment.  Any positive urine pregnancy test 
must be confirmed with a serum -HCG test.  Treatment period pregnancy test results must be available prior to the drug infusion/injection.  
Pregnancy test at 7 months (i.e., between 69 month follow-up) can be performed if indicated.  Note that patients are required to continue 
contraception for 7 months after study treatment is complete.
j
All patients receive a Perjeta maintenance dose of 420 mg IV.  All patients receive Herceptin at 6 mg/kg IV.  The order of administration of 
Perjeta and Herceptin is according to investigator preference. After surgery (from Cycle 9 onwards), patients in Arm A are allowed to switch 
from Herceptin IV to Herceptin SC, at the discretion of the investigator, in the countries where Herceptin SC is routinely used.
k
All patients receive maintenance dose of 600 mg SC pertuzumab and 600 mg SC trastuzumab.The date and time of PK sampling must be 
carefully recorded in all cases. On dosing days, PK samples must be taken on the exact day when HER2-targeted therapy is administered (no 
window allowed).  On non-dosing days, all samples must be taken on the exact day of the visit schedule whenever possible (2 days is 
allowed if necessary) with the timing of PK sampling during the day left to the investigator (however, the time should be carefully recorded).
l
The date and time of PK sampling must be carefully recorded in all cases. On dosing days, PK samples must be taken on the exact day 
when HER2-targeted therapy is administered (no window allowed).  On non-dosing days, all samples must be taken on the exact day of the 
visit schedule whenever possible (2 days is allowed if necessary) with the timing of PK sampling during the day left to the investigator 
(however, the time should be carefully recorded).
m Take sample pre-infusion.
n Take additional PK sample at the end of the infusion.  The time of sampling must be within 15 minutes after each infusion has ended.
o Take sample pre-injection.


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Appendix 5 Schedule of Activities for All Patients in the Treatment-Free Follow-Up
Follow-up Visits a
Month from the last dose of study drug
3
6
9
12
18
24
30
36
Every 6 months until end of study
Limited physical examination b
x
x
x
x
x
x
x
x
x
Vital signs b
x
x
x
x
x
x
x
x
x
ECOG Performance Status b
x
x
x
x
x
x
x
x
x
Assessment for recurrence c
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
Clinical breast examination
x
x
x
x
x
x
x
x
x
Bilateral mammogram
x
x
x
Hematology/Limited Biochemistry d
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
LVEF (ECHO or MUGA) e
x
x
x
x
x
Pregnancy test f
x
x
PK sampling: Pertuzumab/Trastuzumab IV (Arm A) g
x
x
ADA sampling: Pertuzumab/Trastuzumab IV (Arm A)
x
x
x
x
x
x
x
PK sampling: Pertuzumab/Trastuzumab SC (Arm B) g
x
x
ADA sampling: Pertuzumab/Trastuzumab/rHuPH20 SC
(Arm B)
x
x
x
x
x
x
x
Plasma samples for ctDNA (biomarker)
x
Survival
x
x
x
x
x
x
x
x
x
Adverse events
AEs and SAEs are continuously monitored (see Section 5.4.1).


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Appendix 5 Schedule of Activities for All Patients in the Treatment-Free Follow-Up (cont.)
ADAanti-drug antibody; AEadverse event; -HCG human chorionic gonadotripin; ctDNA circulating tumor DNA; ECHO echocardiogram; 
ECOGEastern Cooperative Oncology Group; LVEFleft ventricular ejection fraction; MUGAmultiple-gated acquistion; PKpharmacokinetic;
rHuPH20 recombinant human PH20 hyaluronidase; SAEserious adverse event.
Notes:  Parentheses (x) indicate that the item is optional and required only if symptoms or clinical suspicion are present.
a Visit to be performed within 15 days. These visits are based on time from last dose of study drug and not time from treatment 
completion/discontinuation visit, (i.e., 3-Month Follow-Up Visit is 3 months after last dose of study drug). After recurrence, all patients should 
continue to follow Appendix 4 for survival, LVEF assessments and pregnancy tests (pregnancies should be reported until 7 months after the last 
dose of study treatment, irrespective of disease progression or relapse or the initiation of alternative treatment).  Related serious adverse events 
and non-breast second primary malignancies (reportable as serious adverse events) should also be reported until the end of the study.
b To be followed up every 3 months for 1 year, then every 6 months for an additional 2 years, then according to routine practice.  After disease 
progression or relapse, patients need to only be followed for survival (i.e., physical examination, vital signs, and Performance Status do not need 
to be assessed).
c Assessment of distant disease recurrence to be performed if clinically indicated to exclude metastatic disease and within a timelines as per 
current standard of practice (see Section 4.5.12)
d Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (% or absolute for neutrophils, eosinophils,
basophils, monocytes, lymphocytes, other cells). Limited biochemistry: creatinine, ALP, AST, ALT, total bilirubin, and direct/indirect bilirubin (if 
needed).  Bilirubin fractions (direct and indirect) need to be measured only if total bilirubin is greater than ULN
e After completion of HER2-directed therapy, LVEF is to be performed every 6 months for 2 years, then again 1 year later.  For patients who 
discontinue HER2-directed therapy early for disease progression/relapse or due to adverse events (other than heart failure or LVEF decline), 
LVEF assessments should be performed every 6 months for 2 years, then annually for an additional year or until the initiation of alternative 
systemic therapy.  For patients who discontinue HER2-directed therapy for heart failure or LVEF decline, LVEF assessments should be 
continued regardless of initiation of alternative systemic anti-cancer therapy until resolution, improvement to baseline status, no further 
improvement can be expected, or death.  Additional LVEF assessments may be required for these patients (beyond those specified in the table) 
according to the investigator’s clinical judgment.  The results of these assessments should be reported.
f
At 3 and 6 months after the last dose of study treatment. Any positive urine pregnancy test must be confirmed with a serum β-HCG test.  
Pregnancy test at 7 months (i.e., between 69 month follow up) can be performed if indicated.  Note that patients are required to continue 
contraception for 7 months after study treatment is complete.


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Appendix 5 Schedule of Activities for All Patients in the Treatment-Free Follow-Up (cont.)
g
The date and time of PK sampling must be carefully recorded in all cases.  During follow-up, samples must be taken 7 days of 
the required sampling day, with the timing of PK sampling during the day left to the investigator (however, the time should be carefully 
recorded)