A Phase IIIB, Multinational, Multicenter, Randomized, Open-Label Study to Evaluate Patient Preference for Home Administration of Fixed-Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Administration in Participants With Early or Locally Advanced/Inflammatory HER2-Positive Breast Cancer
Phase: PHASE3
Conditions: Early Breast Cancer, Locally Advanced Breast Cancer, Inflammatory Breast Cancer
Sponsor: Hoffmann-La Roche



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 The information contained in this document, especially any unpublished data, 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. 
 
PH FDC SC—F. Hoffmann-La Roche Ltd 
Protocol MO43110, Version 3 
PROTOCOL 
PROTOCOL TITLE: 
A PHASE IIIB, MULTINATIONAL, MULTICENTER, 
RANDOMIZED, OPEN-LABEL STUDY TO 
EVALUATE PATIENT PREFERENCE FOR HOME 
ADMINISTRATION OF FIXED-DOSE 
COMBINATION OF PERTUZUMAB AND 
TRASTUZUMAB FOR SUBCUTANEOUS 
ADMINISTRATION IN PARTICIPANTS WITH 
EARLY OR LOCALLY ADVANCED/ 
INFLAMMATORY HER2-POSITIVE BREAST 
CANCER 
PROTOCOL NUMBER: MO43110 
STUDY NAME: 
ProHer 
VERSION NUMBER: 
3 
TEST PRODUCTS: 
Fixed-dose combination of pertuzumab and 
trastuzumab for subcutaneous (PH FDC SC) 
administration (RO7198574) 
Pertuzumab IV (RO4368451) 
Trastuzumab IV (RO45-2317) 
Trastuzumab emtansine IV (RO5304020) 
STUDY PHASE: 
Phase IIIb 
REGULATORY 
AGENCY 
IDENTIFIERS: 
IND Number:  Not applicable 
EudraCT Number:  2021-002346-33 
EU CT Number:  2023-506380-33-00 
NCT Number:  NCT05415215 

PH FDC SC—F. Hoffmann-La Roche Ltd 
2/Protocol MO43110, Version 3 
SPONSOR’S NAME 
AND LEGAL 
REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd 
Grenzacherstrasse 124 
4070 Basel, Switzerland 
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document. 

PH FDC SC—F. Hoffmann-La Roche Ltd 
3/Protocol MO43110, Version 3 
PROTOCOL HISTORY 
 
Protocol 
Version 
Date Final 
3 
See electronic date stamp on the final 
page of this document 
2 
15 November 2022 
1 
02 February 2022 
 

PH FDC SC—F. Hoffmann-La Roche Ltd 
4/Protocol MO43110, Version 3 
PROTOCOL AMENDMENT, VERSION 3  
RATIONALE  
Protocol MO43110 has been amended to align with the requirements for E.U. Clinical 
trials Regulation No 536/2014.  Substantive changes to the protocol, along with a 
rationale for each change, are summarized below. 
 
The EU CT number has been added to the protocol/synopsis title pages. 
 
A new table summarizing several key aspects of the trial has been added to the 
synopsis.  
 
Text describing cardiac assessments has been revised to clarify the timing of the 
assessments and to indicate that the investigator may request additional 
assessment based on the individual participant's cardiovascular function (Tables 1–
4, Section 1.3; Section 8.2.4, Appendix 19). 
 
New footnotes have been added to the Schedule of Activities (SoAs) for the 
neoadjuvant phase to indicate that the randomization and the Day 1, Cycle 1 visit 
should take place within 3 days of the screening visit and that the timing of the pre-
surgery mammography and ECG assessments should be as per local practice 
/guidance (Tables 1–3, Section 1.3). 
 
Footnote ‘q’ in the SoAs for the neoadjuvant phase has been updated to indicate 
that the assessment of hematology / limited biochemistry prior to surgery can be 
done as per local clinical practice; however, the results must be available prior to the 
surgery (Tables 1–3, Section 1.3). 
 
Footnote ‘n’ in the SoA Table 2 and 3 has been revised to match the text describing 
tumor assessment in SoA Table 1 footnote ‘n’ (Table 2 and 3, Section 1.3). 
 
Footnote w in the SoA Table 3 has been updated to indicate that the time period 
between Cycle 4 and Cycle 5 can be either 2 or 3 weeks, as per local practice or 
investigator discretion. (Table 3, Section 1.3). 
 
The SoA for the adjuvant phase has been split into two tables: Table 4 should be 
used for participants in Arms C or D (Adjuvant treatment period – PH FDC SC) and 
Table 5 should be used for participants in Arm E (Adjuvant treatment period – 
Trastuzumab emtansine IV) (Section 1.3).  
 
A footnote has been added to the SoA table row describing the Hematology / limited 
biochemistry assessments for Arm C and D during the adjuvant phase to indicate 
that these assessments at cycle 9 may be done within 3 days prior to treatment day 
(within the hospital) for participants who selected to be treated at home during the 
treatment continuation period (Table 4, Section 1.3). The wording of this footnote 
has also been clarified. 
 
A footnote has been added to Table 5 to indicate that trastuzumab emtansine 
cannot be initiated if the platelet count is 100,000/L at Cycle 1. Trastuzumab 
emtansine has not been studied in patients with platelet counts 100,000/L prior to 
initiation of treatment (Table 5, Section 1.3). 

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5/Protocol MO43110, Version 3 
 
Text has been expanded to clarify that limited physical examinations may be 
conducted by a mobile HCP as clinically indicated and in accordance with 
institutional practice or the American Cancer Society/American Society of Clinical 
Oncology Breast Cancer (ACS/ASCO) Breast Cancer Survivorship Care Guideline 
(Footnote ‘g’ in SoA Table 4, Section 1.3, and Section 8.2.1). 
 
Text has been revised to clarify that the ‘baseline’ patient weight used to determine 
if subsequent doses of trastuzumab emtansine should be adjusted is the baseline 
weight after surgery (and not screening as previously stated) (Footnote ‘i’ in SoA 
Table 5, and Section 6.1.3). 
 
A new secondary endpoint investigating the patient’s choice of setting for the 
treatment continuation period has been added (Section 3). 
 
The text describing treatment during the adjuvant phase has been revised to better 
differentiate between treatment for participants who have achieved pCR after 
surgery and participants who have residual disease after surgery (Section 4.1.2). 
 
The guidance on the post-surgery radiotherapy, including its timing, has been 
clarified (Section 4.1.2.2 and Section 6.8.2). 
 
The use of hormonal contraceptives is now prohibited regardless of the hormone 
receptor status. Inclusion criteria and the list of prohibited therapies have been 
updated (Sections 5.1.1 and 6.8.4). 
 
Non-investigational medicinal products have been renamed auxiliary medicinal 
products (AxMPs) (Sections 6, 6.1, 6.1.4, 6.1.5, and 6.1.6). 
 
The tumor disease staging descriptions of ‘operable’ and ‘locally advanced’ used for 
patient stratification have been updated (Section 6.3.1). 
 
Text describing regulatory reporting requirements for serious adverse events has 
been updated (Section 8.3.4). 
 
Text describing the provision of Medical Monitor contact information and the 
Emergency Medical Call Centre has been revised for clarity (Section 8.3.9). 
 
The description of the statistical analyses has been updated to clarify that all data in 
this study will be analyzed in a descriptive manner (Section 9.4.1). 
 
Reasons for terminating the study have been added to the protocol (Section A1–9). 
 
The guidance for recording injection/infusion reactions, diagnoses vs signs and 
symptoms, and special situations (accidental overdose and/or medication error) 
have been restructured for clarity (Section A2–7.1 and A2–8). 
 
Minor edits have been made to the Health Care Professional Questionnaires for 
clarity (Appendices 6, 7, 9, and 10). 
 
Text describing the pulmonary toxicity and hematologic toxicity associated with 
trastuzumab emtansine (Sections A3–6.1 and A3–6.5) and the text describing the 
management of participants who experience pulmonary or hematologic toxicities 
during treatment with trastuzumab emtansine (Section A3–9.2) has been updated to 
align to the Kadcyla Investigator Brochure, v17. 

PH FDC SC—F. Hoffmann-La Roche Ltd 
6/Protocol MO43110, Version 3 
 
A new Appendix has been added describing the designations of the Investigational 
and Auxiliary Medicinal Products (Appendix 20). 
 
Additional minor changes have been made to improve clarity and consistency. 
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 

PH FDC SC—F. Hoffmann-La Roche Ltd 
7/Protocol MO43110, Version 3 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 17 
1. 
PROTOCOL SUMMARY ............................................................................. 18 
1.1 
Synopsis ................................................................................ 18 
1.2 
Study Schema ....................................................................... 23 
1.3 
Schedule of Activities ............................................................ 24 
2. 
INTRODUCTION ........................................................................................ 47 
2.1 
Study Rationale ..................................................................... 47 
2.2 
Background ........................................................................... 48 
2.3 
Benefit–Risk Assessment ...................................................... 48 
3. 
OBJECTIVES AND ENDPOINTS ............................................................... 50 
4. 
STUDY DESIGN ......................................................................................... 52 
4.1 
Overall Design ....................................................................... 52 
4.1.1 
Treatment During the Neoadjuvant Phase............................. 52 
4.1.2 
Treatment During the Adjuvant Phase ................................... 53 
4.1.2.1 
Participants Who Have Achieved pCR After 
Surgery ................................................................................. 53 
4.1.2.2 
Participants Who Have Residual Disease After 
Surgery ................................................................................. 54 
4.2 
Rationale for Study Design .................................................... 55 
4.2.1 
Rationale for Study Population .............................................. 55 
4.2.2 
Rationale for Randomized Cross-over Design ....................... 55 
4.2.3 
Rationale for Non-Standard Clinical Outcome 
Assessments ......................................................................... 56 
4.3 
Justification for Dose and Schedule ...................................... 56 
4.4 
End of Study Definition .......................................................... 57 
4.5 
Duration of Participation ........................................................ 57 
5. 
STUDY POPULATION ................................................................................ 57 
5.1 
Inclusion Criteria .................................................................... 57 
5.1.1 
General Inclusion Criteria ...................................................... 58 
5.1.2 
Disease-specific Inclusion Criteria ......................................... 59 

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5.1.3 
Inclusion Criteria for Treatment with Adjuvant 
PH FDC SC ........................................................................... 60 
5.2 
Exclusion Criteria ................................................................... 60 
5.2.1 
General Exclusion Criteria ..................................................... 60 
5.2.2 
Cancer-specific Exclusion Criteria for 
Neoadjuvant Phase ............................................................... 62 
5.2.3 
Exclusion Criterion for Treatment with Adjuvant 
Trastuzumab Emtansine (Arm E) .......................................... 63 
5.3 
Lifestyle Considerations......................................................... 63 
5.3.1 
Meals and Dietary Restrictions .............................................. 63 
5.3.2 
Caffeine, Alcohol, and Tobacco ............................................. 63 
5.3.3 
Activity ................................................................................... 63 
5.3.4 
Contraception Requirements ................................................. 63 
5.4 
Screen Failures ..................................................................... 63 
5.5 
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of 
Study Intervention .................................................................. 64 
6. 
STUDY TREATMENT, OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN, AND CONCOMITANT THERAPY .................... 64 
6.1 
Study Treatments Administered ............................................ 64 
6.1.1 
PH FDC SC Loading and Maintenance Dose ........................ 66 
6.1.2 
Pertuzumab and Trastuzumab .............................................. 67 
6.1.3 
Trastuzumab Emtansine ........................................................ 68 
6.1.4 
Chemotherapy and Endocrine Therapy ................................. 69 
6.1.5 
Pre-medications ..................................................................... 70 
6.1.6 
Anaphylaxis Medication ......................................................... 70 
6.2 
Preparation, Handling, Storage, and 
Accountability ........................................................................ 71 
6.3 
Treatment Assignment........................................................... 72 
6.3.1 
Treatment Assignment........................................................... 72 
6.4 
Study Treatment Compliance ................................................ 73 
6.5 
Dose Modification .................................................................. 73 
6.6 
Continued Access to Study Treatment after the 
End of the Study .................................................................... 73 
6.7 
Treatment of Overdose .......................................................... 73 

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6.8 
Concomitant Therapy ............................................................ 74 
6.8.1 
Surgery .................................................................................. 74 
6.8.2 
Permitted Therapy ................................................................. 75 
6.8.3 
Cautionary Therapy ............................................................... 77 
6.8.3.1 
Medications Given with Precaution due to Effects 
Related to CYP Enzymes ...................................................... 77 
6.8.3.2 
Herbal Therapies ................................................................... 77 
6.8.3.3 
Therapies Given for Chemotherapy Induced 
Thrombocytopenia ................................................................ 77 
6.8.4 
Prohibited Therapy ................................................................ 77 
7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL .......................... 78 
7.1 
Assessments at the Treatment 
Completion/Discontinuation Visit ........................................... 78 
7.2 
Discontinuation of Study Treatment ....................................... 78 
7.3 
Participant Discontinuation or Withdrawal from 
the Study ............................................................................... 79 
7.4 
Participants Lost to Follow-Up ............................................... 80 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................... 80 
8.1 
Efficacy Assessments ............................................................ 82 
8.2 
Safety Assessments .............................................................. 82 
8.2.1 
Physical Examinations ........................................................... 82 
8.2.2 
Vital Signs .............................................................................. 82 
8.2.3 
Electrocardiograms ................................................................ 83 
8.2.4 
Cardiac Function ................................................................... 84 
8.2.5 
Clinical Breast Examination ................................................... 84 
8.2.6 
Mammograms ........................................................................ 85 
8.2.7 
Diagnosis of Breast Cancer Recurrence or 
Second Primary Cancer ........................................................ 85 
8.2.8 
Clinical Safety Laboratory Assessments................................ 86 
8.2.9 
Pregnancy Testing ................................................................. 86 
8.3 
Adverse Events, Serious Adverse Events, and 
Other Safety Reporting .......................................................... 86 

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8.3.1 
Time Period and Frequency for Collecting 
Adverse Event and Serious Adverse Event 
Information ............................................................................ 87 
8.3.2 
Method of Detecting Adverse Events and Serious 
Adverse Events ..................................................................... 87 
8.3.3 
Follow-Up of Adverse Events and Serious 
Adverse Events ..................................................................... 88 
8.3.4 
Regulatory Reporting Requirements for Serious 
Adverse Events ..................................................................... 88 
8.3.5 
Pregnancy ............................................................................. 89 
8.3.6 
Cardiovascular and Death Events ......................................... 89 
8.3.7 
Anticipated Events Not Qualifying for Expedited 
Reporting .............................................................................. 89 
8.3.8 
Adverse Events of Special Interest ........................................ 89 
8.3.9 
Medical Monitors and Emergency Medical 
Contacts ................................................................................ 90 
8.4 
Pathology ............................................................................... 90 
8.5 
Pharmacokinetics .................................................................. 90 
8.6 
Pharmacodynamics ............................................................... 90 
8.7 
Genetics ................................................................................ 90 
8.8 
Biomarker Assessments ........................................................ 90 
8.9 
Immunogenicity Assessments ............................................... 91 
8.10 
Health Economics and Medical Resource 
Utilization ............................................................................... 91 
8.11 
Clinical Outcome Assessments ............................................. 91 
8.11.1 
Data Collection Methods for Clinical Outcome 
Assessments ......................................................................... 91 
8.11.2 
Description of Clinical Outcome Assessment 
Instruments ........................................................................... 92 
8.11.2.1 
Patient Preference Questionnaire .......................................... 92 
8.11.2.2 
EORTC QLQ-C30 .................................................................. 93 
8.11.2.3 
Healthcare Professional Questionnaire ................................. 93 
8.12 
Additional Assessments and Procedures 
Requiring Separate Consent or Performed 
Only at Participating Sites ...................................................... 94 
9. 
STATISTICAL CONSIDERATIONS ............................................................ 94 

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9.1 
Statistical Hypotheses ........................................................... 94 
9.2 
Sample Size Determination ................................................... 94 
9.3 
Analysis Sets ......................................................................... 95 
9.4 
Statistical Analyses ................................................................ 96 
9.4.1 
General Considerations ......................................................... 96 
9.4.2 
Primary Endpoint(s) ............................................................... 96 
9.4.3 
Secondary Endpoints ............................................................ 97 
9.4.3.1 
Summaries of Conduct of Study ............................................ 99 
9.4.3.2 
Summaries of Demographics and Baseline 
Characteristics ...................................................................... 99 
9.5 
Interim Analysis ..................................................................... 99 
9.6 
Independent Data Monitoring Committee .............................. 99 
9.7 
Internal Monitoring Committee ............................................. 100 
10. REFERENCES ......................................................................................... 101 
APPENDIX 1 
REGULATORY, ETHICAL, AND STUDY 
OVERSIGHT CONSIDERATIONS ............................................................ 104 
A1–1 
Regulatory and Ethical Considerations ................................ 105 
A1–2 
Financial Disclosure ............................................................ 105 
A1–3 
Informed Consent Process .................................................. 106 
A1–4 
Data Protection .................................................................... 106 
A1–5 
Administrative Structure....................................................... 107 
A1–6 
Dissemination of Clinical Study Data ................................... 107 
A1–7 
Data Quality Assurance ....................................................... 107 
A1–8 
Source Documents .............................................................. 108 
A1–9 
Study and Site Closure ........................................................ 109 
A1–10 
Publication Policy ................................................................ 110 
A1–11 
Protocol Deviations .............................................................. 110 
APPENDIX 2 
SAFETY PARAMETERS:  DEFINITIONS AND 
PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-
UP, AND REPORTING ............................................................................. 111 
A2–1 
Definition of Adverse Event ................................................. 113 
A2–2 
Definition of Serious Adverse Event .................................... 114 
A2–3 
Recording and Follow-Up of Adverse Events and 
Serious Adverse Events ...................................................... 115 

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A2–3.1 
Adverse Event and Serious Adverse Event 
Recording ............................................................................ 115 
A2–3.2 
Assessment of Severity ....................................................... 116 
A2–3.3 
Assessment of Causality ..................................................... 117 
A2–3.4 
Follow-up of Adverse Events and Serious 
Adverse Events ................................................................... 118 
A2–3.4.1 
Investigator Follow-Up ......................................................... 118 
A2–3.4.2 
Sponsor Follow-Up .............................................................. 119 
A2–4 
Reporting of Serious Adverse Events .................................. 119 
A2–4.1 
Serious Adverse Event Reporting to The 
Sponsor via an Electronic Collection Tool ........................... 119 
A2–4.2 
Serious Adverse Event Reporting to The 
Sponsor via Paper CRF ...................................................... 120 
A2–5 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ................... 120 
A2–5.1 
Events That Occur Prior to Study Treatment 
Initiation ............................................................................... 120 
A2–5.2 
Events That Occur After Study Treatment 
Initiation ............................................................................... 120 
A2–6 
Reporting Adverse Events That Occur after the 
Adverse Event Reporting Period ......................................... 121 
A2–7 
Procedures for Recording Adverse Events .......................... 121 
A2–7.1 
Diagnosis Versus Signs And Symptoms ............................. 121 
A2–7.1.1 
Injection/Infusion Reactions ............................................... 121 
A2–7.1.2 
Other Adverse Events.......................................................... 122 
A2–7.2 
Asymptomatic Declines in Left Ventricular 
Ejection Fraction ................................................................. 122 
A2–7.3 
Adverse Events that are Secondary to Other 
Events ................................................................................. 123 
A2–7.4 
Persistent or Recurrent Adverse Events .............................. 124 
A2–7.5 
Abnormal Laboratory Values ............................................... 124 
A2–7.6 
Abnormal Vital Sign Values ................................................. 125 
A2–7.7 
Abnormal Liver Function Tests ............................................ 126 
A2–7.8 
Deaths ................................................................................. 126 
A2–7.9 
Preexisting Medical Conditions ............................................ 127 
A2–7.10 
Lack of Efficacy or Worsening of Breast Cancer ................. 127 

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A2–7.11 
Hospitalization or Prolonged Hospitalization ........................ 127 
A2–7.12 
Patient-Reported Outcome Data ......................................... 128 
A2–8 
Special Situations (Accidental Overdose And/Or 
Medication Error) ................................................................ 128 
APPENDIX 3 
SAFETY PLAN: MANAGEMENT OF 
IDENTIFIED AND POTENTIAL RISKS ..................................................... 130 
A3–1 
Risks Associated with Pertuzumab ...................................... 133 
A3–1.1 
Hypersensitivity Reactions / Anaphylaxis and 
Administration-Related Reactions ....................................... 133 
A3–1.2 
Symptomatic Left Ventricular Systolic 
Dysfunction ......................................................................... 134 
A3–1.3 
Epidermal Growth Factor Receptor (HER1)-
Related Toxicities ................................................................ 135 
A3–1.4 
Diarrhea ............................................................................... 135 
A3–1.5 
Rash / Skin Reactions ......................................................... 135 
A3–1.6 
Mucositis .............................................................................. 135 
A3–1.7 
Interstitial Lung Disease ...................................................... 136 
A3–2 
Risks Associated with Trastuzumab .................................... 136 
A3–2.1 
Administration-Related Reactions, Allergic-Like 
Reactions, and Hypersensitivity .......................................... 136 
A3–2.2 
Pulmonary Events ............................................................... 137 
A3–2.3 
Symptomatic Left Ventricular Systolic 
Dysfunction ......................................................................... 138 
A3–3 
Risks Associated with PH FDC SC ...................................... 139 
A3–3.1 
Hypersensitivity Reactions / Anaphylaxis and 
Administration-Related Reactions ....................................... 139 
A3–3.2 
Left Ventricular Dysfunction ................................................. 140 
A3–3.3 
Diarrhea ............................................................................... 142 
A3–3.4 
Rash / Skin Reactions ......................................................... 143 
A3–3.5 
Interstitial Lung Disease ...................................................... 143 
A3–4 
Reproductive Toxicity Associated with 
Pertuzumab and Trastuzumab ............................................ 143 
A3–4.1 
Breastfeeding Toxicity ......................................................... 144 
A3–5 
Infection During COVID-19 Pandemic ................................. 144 
A3–6 
Risks Associated with Trastuzumab Emtansine .................. 145 

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A3–6.1 
Pulmonary Toxicity .............................................................. 145 
A3–6.2 
Hepatotoxicity ...................................................................... 145 
A3–6.3 
Left Ventricular Dysfunction ................................................. 146 
A3–6.4 
Infusion-Related Reactions and Hypersensitivity 
Reactions ............................................................................ 147 
A3–6.5 
Hematologic Toxicity ........................................................... 147 
A3–6.6 
Hemorrhage ......................................................................... 148 
A3–6.7 
Neurotoxicity ........................................................................ 148 
A3–6.8 
Extravasation ....................................................................... 149 
A3–7 
Risks Associated with Chemotherapy Drugs, 
Hormone Therapy, And Radiotherapy ................................. 149 
A3–8 
Management of Participants Who Experience 
Adverse Events During Treatment with PH FDC 
SC and P+H IV .................................................................... 149 
A3–8.1 
Dose Modifications .............................................................. 149 
A3–8.2 
Treatment Interruption ......................................................... 149 
A3–8.3 
Management Guidelines For Participants who 
Experience Adverse Events During Treatment 
with PH FDC SC and P+H IV .............................................. 150 
A3–9 
Management of Participants who Experience 
Adverse Events During Treatment with 
Trastuzumab Emtansine ...................................................... 152 
A3–9.1 
Dose Modifications and Interruptions .................................. 152 
A3–9.2 
Management Guidelines For Participants who 
Experience Adverse Events During Treatment 
with Trastuzumab Emtansine .............................................. 153 
A3–10 
Management of Participants who Require Dose 
Delays and Modifications for Chemotherapy 
Drugs ................................................................................... 159 
A3–10.1 
Dose Delays and Modifications for Anthracycline-
Based Chemotherapy (ddAC and AC) ................................ 159 
A3–10.2 
Dose Delays and Modifications for Taxanes 
(Docetaxel and Paclitaxel) .................................................. 159 
APPENDIX 4 
COLLECTION OF PREGNANCY 
INFORMATION ......................................................................................... 166 
A4–1 
Pregnancies in Female Participants .................................... 167 

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A4–2 
Pregnancies in Female Partners of Male 
Participants .......................................................................... 167 
A4–3 
Abortions ............................................................................. 168 
A4–4 
Abnormal Pregnancy Outcomes .......................................... 168 
APPENDIX 5 
PATIENT PREFERENCE QUESTIONNAIRE 
FOR THE ADJUVANT PHASE ................................................................. 169 
APPENDIX 6 
HEALTHCARE PROFESSIONAL 
QUESTIONNAIRE:  NEOADJUVANT PHASE – DRUG 
PREPARATION AREA .............................................................................. 170 
APPENDIX 7 
HEALTHCARE PROFESSIONAL 
QUESTIONNAIRE:  NEOADJUVANT PHASE – 
ADMINISTERING TREATMENT ............................................................... 176 
APPENDIX 8 
HEALTH-RELATED QUALITY OF LIFE 
QUESTIONNAIRE .................................................................................... 183 
APPENDIX 9 
HEALTHCARE PROFESSIONAL 
QUESTIONNAIRE:  ADJUVANT PHASE – DRUG 
PREPARATION AREA .............................................................................. 185 
APPENDIX 10 
HEALTHCARE PROFESSIONAL 
QUESTIONNAIRE:  ADJUVANT PHASE – ADMINISTERING 
TREATMENT ............................................................................................ 190 
APPENDIX 11 
CLINICAL SAFETY LABORATORY TESTS ........................ 197 
APPENDIX 12 
EASTERN COOPERATIVE ONCOLOGY 
GROUP PERFORMANCE STATUS SCALE ............................................ 198 
APPENDIX 13 
ANAPHYLAXIS PRECAUTIONS ......................................... 199 
APPENDIX 14 
NYHA FUNCTIONAL CLASSIFICATION 
SYSTEM FOR HEART FAILURE AND LVSD NCI CTCAE 
V5.0 GRADING ......................................................................................... 200 
APPENDIX 15 
HOME ADMINISTRATION INSTRUCTIONS 
FOR MOBILE HEALTHCARE PROFESSIONAL ...................................... 201 
APPENDIX 16 
ASYMPTOMATIC DECLINE IN LVEF:  
ALGORITHM FOR CONTINUATION  AND 
DISCONTINUATION OF PH FDC SC....................................................... 203 
APPENDIX 17 
SAFETY REPORTING OF COVID-19 IN STUDY 
PARTICIPANTS ........................................................................................ 204 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
17/Protocol MO43110, Version 3 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
 
PROTOCOL TITLE: 
A PHASE IIIB, MULTINATIONAL, MULTICENTER, 
RANDOMIZED, OPEN-LABEL STUDY TO 
EVALUATE PATIENT PREFERENCE FOR HOME 
ADMINISTRATION OF FIXED-DOSE COMBINATION 
OF PERTUZUMAB AND TRASTUZUMAB FOR 
SUBCUTANEOUS ADMINISTRATION IN 
PARTICIPANTS WITH EARLY OR LOCALLY 
ADVANCED/ INFLAMMATORY HER2-POSITIVE 
BREAST CANCER 
PROTOCOL NUMBER: MO43110 
STUDY NAME 
ProHer 
VERSION NUMBER: 
3 
TEST PRODUCTS: 
Fixed-dose combination of pertuzumab and 
trastuzumab for subcutaneous (PH FDC SC) 
administration (RO7198574) 
Pertuzumab IV (RO4368451) 
Trastuzumab IV (RO45-2317) 
Trastuzumab emtansine IV (RO5304020) 
SPONSOR NAME: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files. Please return a copy of 
the signed form as instructed by your local study monitor.

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
18/Protocol MO43110, Version 3 
1. 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
PROTOCOL TITLE: 
A PHASE IIIB, MULTINATIONAL, MULTICENTER, 
RANDOMIZED, OPEN-LABEL STUDY TO EVALUATE 
PATIENT PREFERENCE FOR HOME ADMINISTRATION OF 
FIXED-DOSE COMBINATION OF PERTUZUMAB AND 
TRASTUZUMAB FOR SUBCUTANEOUS ADMINISTRATION   
IN PARTICIPANTS WITH EARLY OR LOCALLY 
ADVANCED/ INFLAMMATORY HER2-POSITIVE BREAST 
CANCER 
 
REGULATORY 
AGENCY 
IDENTIFIERS: 
IND Number:  Not applicable 
EudraCT Number:  2021-002346-33 
EU CT Number:  2023-506380-33-00 
NCT Number:  NCT05415215 
Study Rationale 
The purpose of this study is to evaluate the patient-reported preference for the pertuzumab and 
trastuzumab (PH) fixed-dose combination (FDC) for subcutaneous (SC) administration 
(PH FDC SC) in the home setting compared with the hospital setting in participants with early or 
locally advanced/inflammatory human epidermal growth factor receptor 2-positive (HER2+) 
breast cancer. 
The SC delivery of biotherapeutics is well-established as a route of administration that is 
effective and well-tolerated across many therapeutic areas (Collins et al. 2020). It can offer 
several advantages over intravenous (IV) administration, including the convenience of self-
administration, improved patient experience, reduced treatment burden and lower healthcare 
costs.  
Moreover, the reduction in hospital time of the patient will reduce the patient’s exposure to 
nosocomial pathogens and reduce the burden on healthcare systems. 
Objectives and Endpoints 
This study will evaluate the patient-reported preference of PH FDC SC administration in the 
home setting compared with the hospital setting during the cross-over period of adjuvant 
treatment in participants with early or locally advanced/inflammatory HER2+ breast cancer.  
The administration of PH FDC SC in the home setting will be conducted by healthcare 
professionals (HCPs). 
Specific primary and secondary objectives and corresponding endpoints for the study are 
outlined below. 
 
Primary Objective 
Corresponding Endpoint 
 To evaluate patient preference of 
PH FDC SC administration in the 
home setting during the cross-over 
period of the adjuvant phase of the 
study 
 Proportion of participants who preferred the 
administration of PH FDC SC in the home setting 
compared with the hospital setting in Question 1 of 
Patient Preference Questionnaire (PPQ) (Appendix 5) 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
19/Protocol MO43110, Version 3 
Secondary Objectives 
Corresponding Endpoints 
 To evaluate the perception of 
HCPs of time/resource use and 
convenience of PH FDC SC 
compared to pertuzumab IV and 
trastuzumab IV (P+H IV) during 
the neoadjuvant phase of the 
study 
 Responses of HCPs to the Healthcare Professional 
Questionnaire (HCPQ) by individual questions in the 
neoadjuvant phase (Appendix 6 and Appendix 7) 
 Collect pathologic complete 
response (pCR) data post-surgery 
 Proportion of participants achieving pCR, defined as 
eradication of invasive disease in the breast and axilla 
(i.e., ypT0/Tis ypN0), according to local pathologist 
assessment following the AJCC criteria (FDA 2020) 
 To evaluate Health-related Quality 
of Life (HRQoL) during the 
neoadjuvant phase of the study 
 HRQoL assessed by EORTC QLQ-C30 scores in the 
neoadjuvant phase (Appendix 8) 
 To evaluate HRQoL with PH FDC 
SC administered during the 
adjuvant phase of the study 
 HRQoL assessed by EORTC QLQ-C30 scores in the 
participants treated with PH FDC SC during the 
adjuvant phase (Appendix 8) 
 To evaluate the perception of 
HCPs of time/resource use of PH 
FDC SC during the adjuvant 
cross-over period 
 Responses of HCPs to the HCPQ by individual 
questions in the adjuvant cross-over period 
(Appendix 9 and Appendix 10) 
 To evaluate HRQoL for 
participants treated with 
trastuzumab emtansine IV during 
the adjuvant phase 
 HRQoL assessed by EORTC QLQ-C30 scores in the 
participants treated with trastuzumab emtansine IV 
during the adjuvant phase (Appendix 8)  
 To evaluate patient’s choice of 
setting for the treatment 
continuation period 
 Proportion of participants who selected the 
administration of PH FDC SC in the home setting 
compared with the hospital setting in the treatment 
continuation period 
Secondary Safety Objectives 
Corresponding Endpoints 
 To evaluate the safety and 
tolerability of PH FDC SC and 
P+H IV during the neoadjuvant 
phase of the study 
 Incidence, nature and severity of all adverse events 
(AEs), Grade ≥ 3 AEs, SAEs, and cardiac AEs 
(including left ventricular ejection fraction [LVEF] 
events) with severity determined according to National 
Cancer Institute common terminology criteria for 
adverse events (NCI CTCAE) v5.0 (Appendix 14 and 
Appendix 16) 
 Incidence of premature withdrawal from the 
neoadjuvant treatment with PH FDC SC and P+H IV 
 Targeted vital signs and physical findings 
 Targeted clinical laboratory test results 
 To evaluate the safety and 
tolerability of PH FDC SC 
administered in the home setting 
and hospital setting during the 
cross-over period and the entire 
adjuvant treatment period 
 Incidence, nature, and severity of all AEs,  
Grade ≥ 3 AEs, SAEs, and cardiac AEs (including 
LVEF events) with severity determined according to 
NCI CTCAE v5.0 (Appendix 14 and Appendix 16) 
 Incidence of premature withdrawal from the adjuvant 
treatment with PH FDC SC 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
20/Protocol MO43110, Version 3 
 Targeted vital signs and physical findings 
 Targeted clinical laboratory test results 
 To evaluate the safety and 
tolerability of trastuzumab 
emtansine IV during the adjuvant 
phase of the study 
 Incidence, nature, and severity of all AEs,  
Grade ≥ 3 AEs, SAEs, and cardiac AEs (including 
LVEF events) with severity determined according to 
NCI CTCAE v5.0 (Appendix 14 and Appendix 16) 
 Incidence of premature withdrawal from the treatment 
with trastuzumab emtansine IV  
 Targeted vital signs and physical findings 
 Targeted clinical laboratory test results 
AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; 
EORTC = European Organisation for Research and Treatment of Cancer; HCP = healthcare 
professional; HCPQ = Healthcare Professional Questionnaire; IV = intravenous; LVEF = Left 
ventricular ejection fraction; NCI = National Cancer Institute; pCR = pathologic complete 
response; PPQ = Patient Preference Questionnaire; SAE = serious adverse event. 
 
Overall Design 
This is a phase IIIb, multinational, multicenter, randomized, open-label study to evaluate the 
patient preference of PH FDC SC administration in the home setting compared with the hospital 
setting during the cross-over period of adjuvant treatment in participants with early or locally 
advanced/inflammatory HER2+ breast cancer. 
This study will consist of two phases.  
1. During the neoadjuvant phase, participants will be randomized in a 1:2 ratio to receive 
treatment in the hospital with either P+H IV plus chemotherapy (Arm A) or PH FDC SC 
plus chemotherapy (Arm B). Participants in both cohorts are scheduled to undergo 
surgery after the completion of neoadjuvant therapy. This could be after 6 or 8 cycles 
depending on the chosen neoadjuvant scheme.  
After surgery, local pathologists interpreting surgical specimens will determine whether 
pCR has been achieved following the AJCC criteria (FDA 2020). 
2. During the adjuvant phase, participants who achieve pCR after surgery will be treated 
with 2 cycles of PH FDC SC in the hospital. Then, participants will be randomized in a 
1:1 ratio to two treatment arms in a cross-over manner, Arm C (3 cycles of PH FDC SC 
treatment in the hospital followed by another 3 cycles of PH FDC SC treatment in the 
home setting) and Arm D (3 cycles of PH FDC SC in the home setting followed by 
3 cycles of PH FDC SC in the hospital). To complete a total of 18 cycles of treatment 
with pertuzumab and trastuzumab in the (neo)adjuvant setting, the last cycles of 
PH FDC SC will be administered in the hospital or in the home setting, as selected by 
the participant at the end of cross-over period. 
Participants can request to change from home administration to hospital administration 
(and vice-versa) during the treatment continuation period, but not during the treatment 
cross-over period. This change can occur once only. 
Participants with pathologic evidence of residual invasive carcinoma in the breast or 
axillary lymph nodes following completion of preoperative therapy and surgery will be 
treated with trastuzumab emtansine for 14 cycles (Arm E). Trastuzumab emtansine will 
be administered IV in the hospital as per prescribing information. 
 
A study schema is provided in Section 1.2 (see Figure 1). The schedules of activities are 
provided in Section 1.3 (see Table 1, Table 2, Table 3, Table 4, and Table 5). 
This is an interventional study with randomized, parallel and crossover groups in two phases. 
There are a total of five arms within this study all of which are open-label. 
Several key aspects of the study design and study population are summarized below.  
 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
21/Protocol MO43110, Version 3 
Phase: 
Phase IIIb 
Population Type: 
Adult patients 
Control Method: 
 
Population Diagnosis 
or Condition: 
HER2+ early or locally 
advanced/inflammatory 
breast cancer 
Interventional 
Model: 
Randomized, open-
label, cross-over 
design 
Population Age: 
≥ 18 years 
Test Product{s}: 
Fixed-dose 
combination of 
pertuzumab and 
trastuzumab for 
subcutaneous (PH 
FDC SC) 
administration 
(RO7198574) 
Pertuzumab IV 
(RO4368451) 
Trastuzumab IV 
(RO45-2317) 
Trastuzumab 
emtansine IV 
(RO5304020) 
Site Distribution: 
Multinational, 
multicenter 
Active Comparator: Not applicable 
Study Treatment 
Assignment Method: 
Randomization and 
stratification 
Number of Arms: 
2 (neoadjuvant 
phase) and 3 
(adjuvant phase) 
Number of 
Participants to Be 
Enrolled: 
Approximately 330 
participants will be 
enrolled for the 
neoadjuvant phase of 
study treatment such 
that approximately 150 
evaluable participants 
enter Arm C and D 
and complete the cross-
over period. 
 
Note:  "Enrolled" means a participant's, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. Potential 
participants who are screened for the purpose of determining eligibility for the study, but do not 
participate in the study, are not considered enrolled unless otherwise specified by the protocol. 
Study Treatment 
The investigational medicinal products (IMPs) for this study are: 
 
Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous administration 
(PH FDC SC) 
 
Pertuzumab IV  
 
Trastuzumab IV 
 
Trastuzumab emtansine IV 
Duration of Participation 
The total duration of study participation for each individual is expected to be approximately 
1.5 to 2 years. 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
22/Protocol MO43110, Version 3 
Committees 
 
Independent Committees: Not applicable 
Other Committees: 
Internal Monitoring Committee (IMC) 
 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
24/Protocol MO43110, Version 3 
1.3 
SCHEDULE OF ACTIVITIES 
Table 1 
Schedule of Activities for Neoadjuvant Phase: Treatment Option 1 
 
 
Neoadjuvant treatment period – Treatment Option 1 
TCb q3w x 6 plus HER2-targeted therapy 
 
 
3-week cycles 
 
 
Cycle 
Screening 
[a] 
1 
2 
3 
4 
5 
6 
Surgery 
[b]  
Treatment 
discontinuati
on [z] 
Day 
–28 to –1 
1 
1 
1 
1 
1 
1 
1 
 
Informed consent [c] 
x 
 
 
 
 
 
 
 
 
Medical history and 
demographics 
x 
 
 
 
 
 
 
 
 
Complete physical  
examination [d] [e] 
x 
x 
 
 
 
 
x 
 
x 
Local HER2 and hormone 
receptor status (HER2, ER, 
PgR) [f] 
x 
 
 
 
 
 
 
 
 
Limited physical  
examination [d] [g] 
 
 
x 
x 
x 
x 
 
 
 
Vital signs [d] [h] 
x 
x 
x 
x 
x 
x 
x 
 
x 
ECOG Performance Status [d] [i] 
 
x [j] 
 
 
 
x 
 
x 
(Prior surgery) 
x 
Height [d] 
x 
 
 
 
 
 
 
 
 
Weight [d] [k] 
x 
x 
x 
x 
x 
x 
x 
 
x 
Tumor staging [l] 
x 
 
 
 
 
 
 
 
 
Bilateral mammogram (or 
another imaging method as per 
local practice) [m] 
x 
 
 
 
 
 
 
x 
(Prior surgery) 
x 
Clinical tumor assessment / 
breast examination [d] [n] 
x 
x 
x 
x 
x 
x 
x 
 
x 
ECG (12-lead) 
x 
 
 
 
x 
 
 
x [aa] 
(Prior surgery) 
 
LVEF (ECHO or MUGA) [o] 
x 
 
 
 
 
x [p] 
 
 
x 
Hematology / limited 
biochemistry [q] 
x 
x [j] 
x 
x 
x 
x 
x 
x 
(Prior surgery) 
x 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
25/Protocol MO43110, Version 3 
 
 
Neoadjuvant treatment period – Treatment Option 1 
TCb q3w x 6 plus HER2-targeted therapy 
 
 
3-week cycles 
 
 
Cycle 
Screening 
[a] 
1 
2 
3 
4 
5 
6 
Surgery 
[b]  
Treatment 
discontinuati
on [z] 
Day 
–28 to –1 
1 
1 
1 
1 
1 
1 
1 
 
Pregnancy test [r]  
x 
 
 
x 
 
 
x 
 
x 
HIV, HBV, and HCV serology 
x 
 
 
 
 
 
 
 
 
HCPQ-Drug Preparation Area 
(Questions 1a–1b) - Appendix 6 
 
x 
x 
x 
x 
x 
x 
 
 
HCPQ-Drug Preparation Area 
(Questions 2–4) - Appendix 6 
 
 
 
 
 
 
x 
 
 
HCPQ-Administering Treatment 
(Questions 1a–1g) - Appendix 7 
 
x 
x 
x 
x 
x 
x 
 
 
HCPQ-Administering Treatment 
(Questions 2–11) - Appendix 7 
 
 
 
 
 
 
x 
 
 
EORTC QLQ-C30 - Appendix 8 
[s]  
 
x 
 
 
 
 
x 
 
 
Arm A – P+H IV [t] (q3w x 6) 
 
x 
(Loading 
dose) 
x 
x 
x 
x 
x 
 
 
Arm B – PH FDC SC [u] 
(q3w x 6) 
 
x 
(Loading 
dose) 
x 
x 
x 
x 
x 
 
 
Docetaxel (q3w x 6) [v] 
 
x 
x 
x 
x 
x 
x 
 
 
Carboplatin (q3w x 6) [v] 
 
x 
x 
x 
x 
x 
x 
 
 
pCR post-surgery 
 
 
 
 
 
 
 
x [w] 
 
Adverse events [x] 
x 
All adverse events and serious adverse events 
Concomitant medication [y] 
x 
Continuous 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
26/Protocol MO43110, Version 3 
Cb = carboplatin; ECG  electrocardiogram; ECHO  echocardiogram; ECOG  Eastern Cooperative Oncology Group; ER  estrogen receptor; 
HBV  hepatitis B virus; HCV  hepatitis C virus; HCPQ  healthcare professional questionnaires; HIV  human immunodeficiency virus; 
IV  Intravenous; LVEF  left ventricular ejection fraction; MUGA  multiple-gated acquisition (scan); pCR  pathologic complete response; 
PgR  progesterone receptor; SAE  serious adverse event; T  docetaxel. 
Note: Unless otherwise specified, assessments should be performed within three days of the scheduled visit. On treatment days, all 
assessments should be performed prior to dosing, unless otherwise specified. For all protocol-mandated study visits, a time window of ± 3 days 
is allowed. If a protocol mandated study visit coincides with a holiday and/or weekend that preclude the visit, the visit should be scheduled on 
the nearest following feasible date. Unscheduled visits may be performed if clinically indicated. The following assessments should be performed 
at a minimum: concomitant medications, adverse events, and vital signs. Additional assessments may be performed as clinically indicated, per 
investigator discretion. Participants may change from P+H IV (Arm A) treatment to PH FDC SC (Arm B) treatment, in exceptional circumstances 
and as per investigator discretion. As such, these participants will continue on the study with the planned neoadjuvant and adjuvant phase of 
the study. Participants requesting to change from PH FDC SC to P+H IV in the neoadjuvant phase will be discontinued from the study. As such, 
these participants will be treated as per standard of care. 
If participants discontinue from study treatment early, they will be asked to return to the clinic for a treatment completion / treatment 
discontinuation visit 28 days (± 7 days) after the final dose of study drug (see Table 4 for additional details).  
 
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent but within 28 or 7 days of randomization (as 
indicated) may be used; such tests do not need to be repeated for screening.  Individuals who do not meet the criteria for participation in this 
study may qualify for one re screening opportunities (for a total of two screenings per individual) at the investigator's discretion, as described 
in Section 5.4. Randomization and the Day 1, Cycle 1 visit should take place within 3 days of the screening visit.  
b The surgery cannot be performed ≤ 2 weeks from the last systemic neoadjuvant therapy and must be performed ≤ 6 weeks after the last 
systemic neoadjuvant therapy. If surgery is significantly delayed (>42 days since the last P+H IV or PH FDC SC administration), a maximum 
of two additional cycles of P+H IV or PH FDC SC (depending on the treatment arm (A or B) assigned to the participant at randomization), 
can be administered at the investigator’s discretion before surgery, in order to maintain adequate serum levels of pertuzumab and 
trastuzumab. See Appendix 18 for details of the assessments that should be conducted for participants who require additional cycles of P+H 
IV or PH FDC SC due to a delay with surgery. PH FDC SC cannot be initiated within ≤ 2 weeks of surgery but must be initiated ≤ 9 weeks 
from the last administration of systemic neoadjuvant therapy. 
c Informed consent must be documented before any study-specific screening procedure is performed and may be obtained more than 28 days 
before initiation of study treatment. 
d Assessment may be done within 3 days prior to the treatment day.  
e Complete physical examinations should include physical measurements (body weight in kilograms and height in centimeters) and evaluation 
of the head, eyes, ears, nose and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, 
and neurologic systems. Any abnormality identified at screening should be recorded on the General Medical History and Baseline 
Conditions CRF. 
f 
Results of previous HER2/hormone receptor status diagnoses can be used to determine eligibility if the sample was tested in the 90 days 
prior to enrollment. Reassessment of HER2/hormone receptor status is not mandatory in these cases but can be done as per local decision. 
Hormone receptor-positive participants are to be prescribed endocrine therapy according to the local guidelines after completion of pre-
operative chemotherapy and surgery. Endocrine therapy will be obtained locally by the investigational sites or will be provided by the 
Sponsor as per country requirements.  

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
27/Protocol MO43110, Version 3 
g Limited physical examinations are symptom-directed and, in addition to the scheduled examinations indicated, may be conducted by a 
mobile HCP as clinically indicated. New or worsened clinically significant abnormalities observed post-screening should be recorded as AEs 
on the Adverse Event electronic form. After the End of Treatment, physical examinations should be conducted by treating physician in 
accordance with institutional practice or the American Cancer Society/American Society of Clinical Oncology Breast Cancer (ACS/ASCO) 
Breast Cancer Survivorship Care Guideline (Runowicz et al. 2016). 
h Vital signs (respiratory rate, pulse rate, and systolic and diastolic blood pressure while the participant is in a seated position, and 
temperature) will be taken before and after study treatment administration. 
i 
ECOG Performance Status should be assessed at least every 3 months during the neoadjuvant treatment period, prior to surgery, and at the 
treatment completion or discontinuation visit (if applicable).  
j 
Screening measurements can be used as Day 1 assessments if performed within 3 days prior to Cycle 1. 
k Weight will be measured during screening and on Day 1 of each cycle. If variation of ± 10% occurs, as compared with screening, the 
trastuzumab IV and chemotherapy doses will be recalculated. 
l 
Screening 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. 
m Provided that the participant’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 participant. If another method is used, this must be performed within the 28-day 
screening window. The timing between the pre-surgery mammogram and surgery should be as per local practice /guidance. 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. 
n Tumor response assessment will be performed at screening, prior to each new cycle of therapy, and at treatment discontinuation (if 
applicable), by clinical breast examination (mandatory) and other methods of evaluation as per routine clinical practice. 
o If the participant has not had an LVEF measured in the last 12 weeks, an ECHO or MUGA should be performed at the baseline screening 
visit. For participants whose LVEF cannot be assessed by ECHO, LVEF may be assessed by MUGA. The same method should be used 
throughout the study for each participant 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, LVEF assessment may also be performed on Day 1 of 
treatment. The results must be available before treatment is administered. Apart from the specified mandatory LVEF assessment, the 
investigator may request additional assessment based on the individual participant's cardiovascular function with a minimum f requency 
of 3–4 months. 
p Participants 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. 
q Hematology: WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (% or absolute for neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells). Limited biochemistry:  alkaline phosphatase; AST; ALT; LDH; total bilirubin; creatinine. 
Albumin should be measured at Screening for determining participant eligibility. Bilirubin fractions (direct and indirect) must be included if 
total bilirubin is greater than ULN. During the treatment period, bloods for hematology / biochemistry may be taken within three days prior to 
study treatment administration. The assessment of hematology / limited biochemistry prior to surgery can be done as per local clinical 
practice; however, the results must be available prior to the surgery. 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
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r 
All female participants of childbearing potential (refer to Section 5.1.1 for definition) will have a serum pregnancy test performed at screening 
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 cycle 3 and at last cycle of neoadjuvant phase (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 β-HCG test. Treatment period urine pregnancy test results must be available 
prior to the drug infusion/injection. Pregnancy test at 7 months (i.e., between 6–9 months follow up) can be performed if indicated. Note that 
participants are required to continue contraception for 7 months after study treatment is complete. 
s Completed before treatment is administered on Day 1 of the indicated treatment cycles. 
t 
All participants in Arm A receive a pertuzumab loading dose of 840 mg IV and a trastuzumab loading dose of 8 mg/kg IV followed by the 
maintenance dose of pertuzumab 420 mg IV and of trastuzumab 6 mg/kg IV. Participants who have had ≥ 6 weeks since their last 
pertuzumab and trastuzumab treatment must receive a loading dose before continuing with maintenance doses for subsequent 
administrations.  
u All participants in Arm B receive a PH FDC SC loading dose of 1200 mg pertuzumab and 600 mg trastuzumab followed by the maintenance 
dose of PH FDC SC with 600 mg of pertuzumab and 600 mg of trastuzumab. Participants who have had ≥ 6 weeks since their last PH FDC 
SC treatment must receive a loading dose before continuing with maintenance doses for subsequent administrations.  
v Participants receive docetaxel 75 mg/m² and carboplatin AUC 5–6 (area under the plasma concentration-time curve) given every 3 weeks, 
for 6 cycles (Cycles 1–6). 
w Pathologic 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.  
x After informed consent has been obtained, but prior to initiation of study treatment, only serious adverse events caused by 
protocol-mandated intervention should be reported. After initiation of study treatment, all adverse events will be reported until 28 days after 
the last dose of study treatment. After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be 
notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior exposure to study treatment 
(see Appendix 2). 
y All concomitant medications used by the participant from 7 days prior to initiation of study treatment until the End of Treatment Visit will be 
reported. 
z Treatment discontinuation visits will optimally be scheduled for 28 (± 7 days) following the last dose of study medication.  All patients will 
return to the study site for a safety follow-up visit 6–9 months after the last dose of study treatment (see Table 4 for details). 
aa The timing between the pre-surgery ECG and surgery should be as per local practice /guidance. 
 
 
 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
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Table 2 
Schedule of Activities for Neoadjuvant Phase: Treatment Option 2 
 
 
Neoadjuvant treatment period – Treatment Option 2 
AC q3w x 4 followed by a taxane plus HER2-targeted therapy 
 
 
3-week cycles 
 
 
Cycle 
Screening 
[a] 
1 
2 
3 
4 
5 
6 
7 
8 
Surgery 
[b]  
Treatment 
discontinua
tion [aa] 
Day 
–28 to –1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
 
Informed consent [c] 
x 
 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
x 
 
 
 
 
 
 
 
 
 
 
Complete physical  
examination [d] [e] 
x 
x 
 
 
 
 
 
 
x  
 
x 
Local HER2 and hormone receptor 
status (HER2, ER, PgR) [f] 
x 
 
 
 
 
 
 
 
 
 
 
Limited physical  
examination [d] [g] 
 
 
x 
x 
x 
x 
x 
x 
 
 
 
Vital signs [d] [h] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
ECOG Performance Status [d] [i] 
 
x [j] 
 
 
 
x 
 
 
 
x 
(Prior surgery) 
x 
Height [d] 
x 
 
 
 
 
 
 
 
 
 
 
Weight [d] [k] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
Tumor staging [l] 
x 
 
 
 
 
 
 
 
 
 
 
Bilateral mammogram (or another 
imaging method as per local 
practice) [m] 
x 
 
 
 
 
 
 
 
 
x 
(Prior surgery) 
x 
Clinical tumor assessment / breast 
examination [d] [n] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
ECG (12-lead) 
x 
 
 
 
x 
 
 
 
 
x [ab] 
(Prior surgery) 
 
LVEF (ECHO or MUGA) [o] 
x 
 
 
 
 
x [p] 
 
 
 
 
x 
Hematology / limited biochemistry 
[q] 
x 
x [j] 
x 
x 
x 
x 
x 
x 
x 
x 
(Prior surgery) 
x 
Pregnancy test [r]  
x 
 
 
x 
 
 
 
 
x 
 
x 
HIV, HBV, and HCV serology 
x 
 
 
 
 
 
 
 
 
 
 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
30/Protocol MO43110, Version 3 
 
 
Neoadjuvant treatment period – Treatment Option 2 
AC q3w x 4 followed by a taxane plus HER2-targeted therapy 
 
 
3-week cycles 
 
 
Cycle 
Screening 
[a] 
1 
2 
3 
4 
5 
6 
7 
8 
Surgery 
[b]  
Treatment 
discontinua
tion [aa] 
Day 
–28 to –1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
 
HCPQ-Drug Preparation Area 
(Questions 1a–1b) - Appendix 6 
 
 
 
 
 
x 
x 
x 
x 
 
 
HCPQ-Drug Preparation Area 
(Questions 2–4) - Appendix 6 
 
 
 
 
 
 
 
 
x 
 
 
HCPQ-Administering Treatment 
(Questions 1a–1g) - Appendix 7 
 
 
 
 
 
x 
x 
x 
x 
 
 
HCPQ-Administering Treatment 
(Questions 2–11) - Appendix 7 
 
 
 
 
 
 
 
 
x 
 
 
EORTC QLQ-C30 - Appendix 8 [s]  
 
x 
 
 
 
 
 
 
x 
 
 
Arm A – P+H IV [t] (q3w x 4) 
 
 
 
 
 
x 
(Loading 
dose) 
x 
x 
x 
 
 
Arm B – PH FDC SC [u] (q3w x 4) 
 
 
 
 
 
x 
(Loading 
dose) 
x 
x 
x 
 
 
Doxorubicin (q3w x 4) [v] 
 
x 
x 
x 
x 
 
 
 
 
 
 
Cyclophosphamide (q3w x 4) [v] 
 
x 
x 
x 
x 
 
 
 
 
 
 
Docetaxel (q3w x 4) [w] 
 
 
 
 
 
x 
x 
x 
x 
 
 
Paclitaxel (qw x 12) [w] 
 
 
 
 
 
Weekly for 12 weeks 
 
 
pCR post-surgery 
 
 
 
 
 
 
 
 
 
x [x] 
 
Adverse events [y] 
x 
All adverse events and serious adverse events 
Concomitant medication [z] 
x 
Continuous 
 
AC  doxorubicin plus cyclophosphamide; ECG  electrocardiogram; ECHO  echocardiogram; ECOG  Eastern Cooperative Oncology 
Group; ER  estrogen receptor; HBV  hepatitis B virus; HCV  hepatitis C virus; HCPQ  healthcare professional questionnaires;  
HIV  human immunodeficiency virus; IV  Intravenous; LVEF  left ventricular ejection fraction; MUGA  multiple-gated acquisition (scan); 
pCR  pathologic complete response; PgR  progesterone receptor; SAE  serious adverse event. 
Note: Unless otherwise specified, assessments should be performed within three days of the scheduled visit. On treatment days, all 
assessments should be performed prior to dosing, unless otherwise specified. For all protocol-mandated study visits, a time window of 
± 3 days is allowed. If a protocol mandated study visit coincides with a holiday and/or weekend that preclude the visit, the visit should be 
scheduled on the nearest following feasible date. Unscheduled visits may be performed if clinically indicated.  The following assessments 
should be performed at a minimum: concomitant medications, adverse events, and vital signs. Additional assessments may be performed as 
clinically indicated, per investigator discretion.  Participants may change from P+H IV (Arm A) treatment to PH FDC SC (Arm B) treatment, in 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
31/Protocol MO43110, Version 3 
exceptional circumstances and as per investigator discretion. As such, these participants will continue on the study with the planned 
neoadjuvant and adjuvant phase of the study. Participants requesting to change from PH FDC SC to P+H IV in the neoadjuvant phase will be 
discontinued from the study. As such, these participants will be treated as per standard of care. 
If participants discontinue from study treatment early, they will be asked to return to the clinic for a treatment completion / treatment 
discontinuation visit 28 days (± 7 days) after the final dose of study drug (see Table 4 for additional details).  
 
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent but within 28 or 7 days of randomization 
(as indicated) may be used; such tests do not need to be repeated for screening.  Individuals who do not meet the criteria for participation 
in this study may qualify for one re screening opportunities (for a total of two screenings per individual) at the investigator's discretion, as 
described in Section 5.4. Randomization and the Day 1, Cycle 1 visit should take place within 3 days of the screening visit.  
b The surgery cannot be performed ≤ 2 weeks from the last systemic neoadjuvant therapy and must be performed ≤ 6 weeks after the last 
systemic neoadjuvant therapy.  If surgery is significantly delayed (>42 days since the last P+H IV or PH FDC SC administration), a 
maximum of two additional cycles of P+H IV or PH FDC SC (depending on the treatment arm (A or B) assigned to the participant at 
randomization), can be administered at the investigator’s discretion before surgery, in order to maintain adequate serum levels of 
pertuzumab and trastuzumab. See Appendix 18 for details of the assessments that should be conducted for participants who require 
additional cycles of P+H IV or PH FDC SC due to a delay with surgery. PH FDC SC cannot be initiated within ≤ 2 weeks of surgery but 
must be initiated ≤ 9 weeks from the last administration of systemic neoadjuvant therapy. 
c Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained more than 28 
days before initiation of study treatment. 
d Assessment may be done within 3 days prior to the treatment day.  
e Complete physical examinations should include physical measurements (body weight in kilograms and height in centimeters) and 
evaluation of the head, eyes, ears, nose and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems. Any abnormality identified at screening should be recorded on the General Medical History and 
Baseline Conditions CRF. 
f 
Results of previous HER2/hormone receptor status diagnoses can be used to determine eligibility if the sample was tested in the 90 days 
prior to enrollment. Reassessment of HER2/hormone receptor status is not mandatory in these cases but can be done as per local 
decision. Hormone receptor-positive participants are to be prescribed endocrine therapy according to the local guidelines after completion 
of pre-operative chemotherapy and surgery. Endocrine therapy will be obtained locally by the investigational sites or will be provided by 
the Sponsor as per country requirements.  
g Limited physical examinations are symptom-directed and, in addition to the scheduled examinations indicated, may be conducted by a 
mobile HCP as clinically indicated. New or worsened clinically significant abnormalities observed post-screening should be recorded as 
AEs on the Adverse Event electronic form. After the End of Treatment, physical examinations should be conducted by treating physician 
in accordance with institutional practice or the American Cancer Society/American Society of Clinical Oncology Breast Cancer 
(ACS/ASCO) Breast Cancer Survivorship Care Guideline (Runowicz et al. 2016). 
h Vital signs (respiratory rate, pulse rate, and systolic and diastolic blood pressure while the participant is in a seated position, and 
temperature) will be taken before and after study treatment administration. 
i 
ECOG Performance Status should be assessed at least every 3 months during the neoadjuvant treatment period, prior to surgery, and at 
the treatment completion or discontinuation visit (if applicable).  
j 
Screening measurements can be used as Day 1 assessments if performed within 3 days prior to Cycle 1. 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
32/Protocol MO43110, Version 3 
k Weight will be measured during screening and on Day 1 of each cycle. If variation of ± 10% occurs, as compared with screening, the 
trastuzumab IV and chemotherapy doses will be recalculated. 
l 
Screening 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. 
m Provided that the participant’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 participant. If another method is used, this must be performed within the 28-day 
screening window.  The timing between the pre-surgery mammogram and surgery should be as per local practice /guidance. 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. 
n Tumor response assessment will be performed at screening, prior to each new cycle of therapy, and at treatment discontinuation (if 
applicable), by clinical breast examination (mandatory) and other methods of evaluation as per routine clinical practice. 
o If the participant has not had an LVEF measured in the last 12 weeks, an ECHO or MUGA should be performed at the baseline screening 
visit. For participants whose LVEF cannot be assessed by ECHO, LVEF may be assessed by MUGA. The same method should be used 
throughout the study for each participant 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, LVEF assessment may also be performed on Day 1 of 
treatment. The results must be available before treatment is administered. Apart from the specified mandatory LVEF assessment, the 
investigator may request additional assessment based on the individual participant's cardiovascular function with a minimum 
frequency of 3–4 months. 
p Participants 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. 
q Hematology: WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (% or absolute for neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells). Limited biochemistry:  alkaline phosphatase; AST; ALT; LDH; total bilirubin; creatinine. 
Albumin should be measured at Screening for determining participant eligibility. Bilirubin fractions (direct and indirect) must be included if 
total bilirubin is greater than ULN. During the treatment period, bloods for hematology / biochemistry may be taken within three days prior 
to study treatment administration. Hematology / limited biochemistry assessments should be conducted at a minimum of every 3 weeks 
and can be conducted more frequently as per local practice. The assessment of hematology / limited biochemistry prior to surgery can 
be done as per local clinical practice; however, the results must be available prior to the surgery.  
r 
All female participants of childbearing potential (refer to Section 5.1.1 for definition) will have a serum pregnancy test performed at 
screening 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 cycle 3 and at last cycle of neoadjuvant phase (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 β-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 months follow up) can be performed if 
indicated. Note that participants are required to continue contraception for 7 months after study treatment is complete. 
s Completed before treatment is administered on Day 1 of the indicated treatment cycles. 
t 
All participants in Arm A receive a pertuzumab loading dose of 840 mg IV and a trastuzumab loading dose of 8 mg/kg IV followed by the 
maintenance dose of pertuzumab 420 mg IV and of trastuzumab 6 mg/kg IV. Participants who have had ≥ 6 weeks since their last 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
33/Protocol MO43110, Version 3 
 
 
 
pertuzumab and trastuzumab treatment must receive a loading dose before continuing with maintenance doses for subsequent 
administrations.   
u All participants in Arm B receive a PH FDC SC loading dose of 1200 mg pertuzumab and 600 mg trastuzumab followed by the 
maintenance dose of PH FDC SC with 600 mg of pertuzumab and 600 mg of trastuzumab. Participants who have had ≥ 6 weeks since 
their last PH FDC SC treatment must receive a loading dose before continuing with maintenance doses for subsequent administrations.  
v Participants receive doxorubicin 60 mg/m2 IV and cyclophosphamide 600 mg/m2 IV given every 3 weeks, for four cycles (Cycles 1–4). 
w Participants receive either docetaxel (75–100 mg/m²) given every 3 weeks, for four cycles (Cycles 5–8) or paclitaxel (80 mg/m²) every 
week for 12 weeks during Cycles 5–8). 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. 
x Pathologic 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.  
y After informed consent has been obtained, but prior to initiation of study treatment, only serious adverse events caused by 
protocol-mandated intervention should be reported. After initiation of study treatment, all adverse events will be reported until 28 days 
after the last dose of study treatment. After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor 
should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior exposure to study 
treatment (see Appendix 2). 
z All concomitant medications used by the participant from 7 days prior to initiation of study treatment until the End of Treatment Visit will 
be reported. 
aa Treatment discontinuation visits will optimally be scheduled for 28 (± 7 days) following the last dose of study medication.  All patients will 
return to the study site for a safety follow-up visit 6–9 months after the last dose of study treatment (see Table 4 for details). 
ab The timing between the pre-surgery ECG and surgery should be as per local practice /guidance. 
 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
34/Protocol MO43110, Version 3 
Table 3 
Schedule of Activities for Neoadjuvant Phase: Treatment Option 3 
 
 
Neoadjuvant treatment period – Treatment Option 3 
ddAC q2w x 4 followed by a taxane plus HER2-targeted therapy 
 
 
2-weekly cycles 
3-weekly cycles 
 
 
Cycle 
Screening 
[a] 
1 
2 
3 
4 
5 
6 
7 
8 
Surgery 
[b]  
Treatment 
discontinua
tion [aa] 
Day 
–28 to –1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
 
Informed consent [c] 
x 
 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
x 
 
 
 
 
 
 
 
 
 
 
Complete physical  
examination [d] [e] 
x 
x 
 
 
 
 
 
 
x  
 
x 
Local HER2 and hormone receptor 
status (HER2, ER, PgR) [f] 
x 
 
 
 
 
 
 
 
 
 
 
Limited physical  
examination [d] [g] 
 
 
x 
x 
x 
x 
x 
x 
 
 
 
Vital signs [d] [h] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
ECOG Performance Status [d] [i] 
 
x [j] 
 
 
 
x 
 
 
 
x 
(Prior surgery) 
x 
Height [d] 
x 
 
 
 
 
 
 
 
 
 
 
Weight [d] [k] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
Tumor staging [l] 
x 
 
 
 
 
 
 
 
 
 
 
Bilateral mammogram (or another 
imaging method as per local 
practice) [m] 
x 
 
 
 
 
 
 
 
 
x 
(Prior surgery) 
x 
Clinical tumor assessment / breast 
examination [d] [n] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
ECG (12-lead) 
x 
 
 
 
x 
 
 
 
 
x [ab] 
(Prior surgery) 
 
LVEF (ECHO or MUGA) [o] 
x 
 
 
 
 
x [p] 
 
 
 
 
x 
Hematology / limited biochemistry 
[q] 
x 
x [j] 
x 
x 
x 
x 
x 
x 
x 
x 
(Prior surgery) 
x 
Pregnancy test [r]  
x 
 
 
x 
 
 
 
 
x 
 
x 
HIV, HBV, and HCV serology 
x 
 
 
 
 
 
 
 
 
 
 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
35/Protocol MO43110, Version 3 
 
 
Neoadjuvant treatment period – Treatment Option 3 
ddAC q2w x 4 followed by a taxane plus HER2-targeted therapy 
 
 
2-weekly cycles 
3-weekly cycles 
 
 
Cycle 
Screening 
[a] 
1 
2 
3 
4 
5 
6 
7 
8 
Surgery 
[b]  
Treatment 
discontinua
tion [aa] 
Day 
–28 to –1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
 
HCPQ-Drug Preparation Area 
(Questions 1a–1b) - Appendix 6 
 
 
 
 
 
x 
x 
x 
x 
 
 
HCPQ-Drug Preparation Area 
(Questions 2–4) - Appendix 6 
 
 
 
 
 
 
 
 
x 
 
 
HCPQ-Administering Treatment 
(Questions 1a–1g) - Appendix 7 
 
 
 
 
 
x 
x 
x 
x 
 
 
HCPQ-Administering Treatment 
(Questions 2–11) - Appendix 7 
 
 
 
 
 
 
 
 
x 
 
 
EORTC QLQ-C30 - Appendix 8 [s]  
 
x 
 
 
 
 
 
 
x 
 
 
Arm A – P+H IV [t] (q3w x 4) 
 
 
 
 
 
x 
(Loading 
dose) 
x 
x 
x 
 
 
Arm B – PH FDC SC [u] (q3w x 4) 
 
 
 
 
 
x 
(Loading 
dose) 
x 
x 
x 
 
 
ddDoxorubicin (q2w x 4) [v] 
 
x 
x 
x 
x 
 
 
 
 
 
 
ddCyclophosphamide (q2w x 4) [v] 
 
x 
x 
x 
x 
 
 
 
 
 
 
Docetaxel (q3w x 4) [w] 
 
 
 
 
 
x 
x 
x 
x 
 
 
Paclitaxel (qw x 12) [w] 
 
 
 
 
 
Weekly for 12 weeks 
 
 
pCR post-surgery 
 
 
 
 
 
 
 
 
 
x [x] 
 
Adverse events [y] 
x 
All adverse events and serious adverse events 
Concomitant medication [z] 
x 
Continuous 
 
dd  dose-dense; AC  doxorubicin plus cyclophosphamide; ECG  electrocardiogram; ECHO  echocardiogram; ECOG  Eastern 
Cooperative Oncology Group; ER  estrogen receptor;  HBV  hepatitis B virus; HCV  hepatitis C virus; HCPQ  healthcare professional 
questionnaires;  HIV  human immunodeficiency virus; IV  Intravenous; LVEF  left ventricular ejection fraction; MUGA  multiple-gated 
acquisition (scan); pCR  pathologic complete response; PgR  progesterone receptor; SAE  serious adverse event. 
Note: Unless otherwise specified, assessments should be performed within three days of the scheduled visit. On treatment days, all 
assessments should be performed prior to dosing, unless otherwise specified. For all protocol-mandated study visits, a time window of 
± 3 days is allowed. If a protocol mandated study visit coincides with a holiday and/or weekend that preclude the visit, the visit should be 
scheduled on the nearest following feasible date. Unscheduled visits may be performed if clinically indicated.  The following assessments 
should be performed at a minimum: concomitant medications, adverse events, and vital signs. Additional assessments may be performed as 
clinically indicated, per investigator discretion.  Participants may change from P+H IV (Arm A) treatment to PH FDC SC (Arm B) treatment, in 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
36/Protocol MO43110, Version 3 
exceptional circumstances and as per investigator discretion. As such, these participants will continue on the study with the planned 
neoadjuvant and adjuvant phase of the study. Participants requesting to change from PH FDC SC to P+H IV in the neoadjuvant phase will be 
discontinued from the study. As such, these participants will be treated as per standard of care. 
If participants discontinue from study treatment early, they will be asked to return to the clinic for a treatment completion / treatment 
discontinuation visit 28 days (± 7 days) after the final dose of study drug (see Table 4 for additional details).  
 
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent but within 28 or 7 days of randomization 
(as indicated) may be used; such tests do not need to be repeated for screening.  Individuals who do not meet the criteria for participation 
in this study may qualify for one re screening opportunities (for a total of two screenings per individual) at the investigator's discretion, as 
described in Section 5.4. Randomization and the Day 1, Cycle 1 visit should take place within 3 days of the screening vis it. 
b The surgery cannot be performed ≤ 2 weeks from the last systemic neoadjuvant therapy and must be performed ≤ 6 weeks of the last 
systemic neoadjuvant therapy.  If surgery is significantly delayed (>42 days since the last P+H IV or PH FDC SC administration), a 
maximum of two additional cycles of P+H IV or PH FDC SC (depending on the treatment arm (A or B) assigned to the participant at 
randomization), can be administered at the investigator’s discretion before surgery, in order to maintain adequate serum levels of 
pertuzumab and trastuzumab. See Appendix 18 for details of the assessments that should be conducted for participants who require 
additional cycles of P+H IV or PH FDC SC due to a delay with surgery. PH FDC SC cannot be initiated within ≤ 2 weeks of surgery but 
must be initiated ≤ 9 weeks from the last administration of systemic neoadjuvant therapy. 
c Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained more than 28 
days before initiation of study treatment. 
d Assessment may be done within 3 days prior to the treatment day.  
e Complete physical examinations should include physical measurements (body weight in kilograms and height in centimeters) and 
evaluation of the head, eyes, ears, nose and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems. Any abnormality identified at screening should be recorded on the General Medical History and 
Baseline Conditions CRF. 
f 
Results of previous HER2/hormone receptor status diagnoses can be used to determine eligibility if the sample was tested in the 90 days 
prior to enrollment. Reassessment of HER2/hormone receptor status is not mandatory in these cases but can be done as per local 
decision. Hormone receptor-positive participants are to be prescribed endocrine therapy according to the local guidelines after completion 
of pre-operative chemotherapy and surgery. Endocrine therapy will be obtained locally by the investigational sites or will be provided by 
the Sponsor as per country requirements.  
g Limited physical examinations are symptom-directed and, in addition to the scheduled examinations indicated, may be conducted by a 
mobile HCP as clinically indicated. New or worsened clinically significant abnormalities observed post-screening should be recorded as 
AEs on the Adverse Event electronic form. After the End of Treatment, physical examinations should be conducted by treating physician 
in accordance with institutional practice or the American Cancer Society/American Society of Clinical Oncology Breast Cancer 
(ACS/ASCO) Breast Cancer Survivorship Care Guideline (Runowicz et al. 2016). 
h Vital signs (respiratory rate, pulse rate, and systolic and diastolic blood pressure while the participant is in a seated position, and 
temperature) will be taken before and after study treatment administration. 
i 
ECOG Performance Status should be assessed at least every 3 months during the neoadjuvant treatment period, prior to surgery, and at 
the treatment completion or discontinuation visit (if applicable).  
j 
Screening measurements can be used as Day 1 assessments if performed within 3 days prior to Cycle 1. 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
37/Protocol MO43110, Version 3 
k Weight will be measured during screening and on Day 1 of each cycle. If variation of ± 10% occurs, as compared with screening, the 
trastuzumab IV and chemotherapy doses will be recalculated. 
l 
Screening 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. 
m Provided that the participant’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 participant. If another method is used, this must be performed within the 28-day 
screening window.  The timing between the pre-surgery mammogram and surgery should be as per local practice /guidance. 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. 
n Tumor response assessment will be performed at screening, prior to each new cycle of therapy, and at treatment discontinuation (if 
applicable), by clinical breast examination (mandatory) and other methods of evaluation as per routine clinical practice. 
o If the participant has not had an LVEF measured in the last 12 weeks, an ECHO or MUGA should be performed at the baseline screening 
visit. For participants whose LVEF cannot be assessed by ECHO, LVEF may be assessed by MUGA. The same method should be used 
throughout the study for each participant 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, LVEF assessment may also be performed on Day 1 of 
treatment. The results must be available before treatment is administered. Apart from the specified mandatory LVEF assessment , the 
investigator may request additional assessment based on the individual participant's cardiovascular function with a minimum 
frequency of 3–4 months. 
p Participants 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. 
q Hematology: WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (% or absolute for neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells). Limited biochemistry:  alkaline phosphatase; AST; ALT; LDH; total bilirubin; creatinine. 
Albumin should be measured at Screening for determining participant eligibility. Bilirubin fractions (direct and indirect) must be included if 
total bilirubin is greater than ULN. During the treatment period, bloods for hematology / biochemistry may be taken within three days prior 
to study treatment administration.  Hematology / limited biochemistry assessments should be conducted at a minimum of every 3 weeks 
and can be conducted more frequently as per local practice. The assessment of hematology / limited biochemistry prior to surgery can 
be done as per local clinical practice; however, the results must be available prior to the surgery.  
r 
All female participants of childbearing potential (refer to Section 5.1.1 for definition) will have a serum pregnancy test performed at 
screening 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 cycle 3 and at last cycle of neoadjuvant phase (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 β-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 months follow up) can be performed if 
indicated. Note that participants are required to continue contraception for 7 months after study treatment is complete. 
s Completed before treatment is administered on Day 1 of the indicated treatment cycles. 
t 
All participants in Arm A receive a pertuzumab loading dose of 840 mg IV and a trastuzumab loading dose of 8 mg/kg IV followed by the 
maintenance dose of pertuzumab 420 mg IV and of trastuzumab 6 mg/kg IV. Participants who have had ≥ 6 weeks since their last 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
38/Protocol MO43110, Version 3 
 
 
pertuzumab and trastuzumab treatment must receive a loading dose before continuing with maintenance doses for subsequent 
administrations.   
u All participants in Arm B receive a PH FDC SC loading dose of 1200 mg pertuzumab and 600 mg trastuzumab followed by the 
maintenance dose of PH FDC SC with 600 mg of pertuzumab and 600 mg of trastuzumab. Participants who have had ≥ 6 weeks since 
their last PH FDC SC treatment must receive a loading dose before continuing with maintenance doses for subsequent administrations.  
v Participants receive dose-dense doxorubicin 60 mg/m2 IV and cyclophosphamide 600 mg/m2 IV given every 2 weeks, for four cycles 
(Cycles 1–4).  
w The time period between Cycle 4 and Cycle 5 can be either 2 or 3 weeks, as per local practice or investigator discretion. Participants 
receive either docetaxel 75–100 mg/m² given every 3 weeks, for four cycles (Cycles 5–8) or paclitaxel 80 mg/m² (every week for 12 
weeks during Cycles 5–8).  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. 
 x Pathologic 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.  
y After informed consent has been obtained, but prior to initiation of study treatment, only serious adverse events caused by 
protocol-mandated intervention should be reported. After initiation of study treatment, all adverse events will be reported until 28 days 
after the last dose of study treatment. After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor 
should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior exposure to study 
treatment (see Appendix 2). 
z All concomitant medications used by the participant from 7 days prior to initiation of study treatment until the End of Treatment Visit will 
be reported. 
aa Treatment discontinuation visits will optimally be scheduled for 28 (± 7 days) following the last dose of study medication.  All patients will 
return to the study site for a safety follow-up visit 6–9 months after the last dose of study treatment (see Table 4 for details). 
ab The timing between the pre-surgery ECG and surgery should be as per local practice /guidance. 
 
 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
39/Protocol MO43110, Version 3 
Table 4 
Schedule of Activities: Adjuvant treatment period – PH FDC SC (Arms C and D) 
 
Adjuvant Treatment Period 
F/U 
(6–9 
months 
post last 
dose) 
 
Run-in period [a] 
Cross-over Period 
Treatment  
continuation  
period 
Treatment 
Completion
/ disc. [c] 
Cycle 
1 (Baseline 
status) 
2 
3 
4 
5 
6 
7 
8 
9 
Until a total of 
18 cycles [b] 
 
 
Day 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
- 
 
Complete physical examination 
[d] [e] 
 
 
 
 
 
 
 
 
 
x [f] 
(Last cycle) 
x 
 
Limited physical examination  
[d] [g] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(Except for  
last cycle) 
 
 
Vital signs [d] [h] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
ECOG performance  
status [d] [i] 
x 
 
x 
 
 
x 
 
 
x 
x 
(Last cycle) 
x 
 
Weight [d] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Clinical breast examination  
[d] [j] 
x 
 
 
 
x 
(Arm C) 
x 
(Arm D) 
 
 
x 
[f] 
x [f] 
(Last cycle) 
x 
 
Bilateral mammogram (or 
another imaging method as, per 
local practice) [k] 
 
 
 
 
 
 
 
 
 
 
x 
 
LVEF (ECHO or MUGA) [l] 
x 
 
 
 
x 
(Arm C) 
x 
(Arm D) 
 
 
x 
[f] 
x [f] 
(Last cycle) 
x 
 
Pregnancy test [m]  
x 
 
 
 
x  
(Arm C) 
x 
(Arm D) 
 
 
x [f] 
x [f] 
(Last cycle) 
x 
x 
Hematology / limited 
biochemistry [n] 
x 
 
 
 
x  
(Arm C) 
x 
(Arm D) 
 
 
x [f] 
x [f] 
(Last cycle) 
 
x 
 
General health status (site staff) 
[o] 
 
 
x 
(Arm D) 
x 
(Arm D) 
x 
(Arm D) 
x 
(Arm C) 
x 
(Arm C) 
x 
(Arm C) 
x 
x 
 
 
Health status (mobile HCP) [p] 
 
 
x 
(Arm D) 
x 
(Arm D) 
x 
(Arm D) 
x 
(Arm C) 
x 
(Arm C) 
x 
(Arm C) 
x 
x 
 
 
Arm C: PH FDC SC (q3w) [q] 
x 
(At hospital) 
x 
(At hospital) 
x 
(At hospital) 
x 
(At hospital) 
x 
(At hospital) 
x 
(At home) 
x 
(At home) 
x 
(At home) 
x 
[r] 
x 
[r] 
 
 
Arm D: PH FDC SC (q3w) [q] 
x 
(At hospital) 
x 
(At hospital) 
x 
(At home) 
x 
(At home) 
x 
(At home) 
x 
(At hospital) 
x 
(At hospital) 
x 
(At hospital) 
x 
[r] 
x 
[r] 
 
 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
40/Protocol MO43110, Version 3 
 
Adjuvant Treatment Period 
F/U 
(6–9 
months 
post last 
dose) 
 
Run-in period [a] 
Cross-over Period 
Treatment  
continuation  
period 
Treatment 
Completion
/ disc. [c] 
Cycle 
1 (Baseline 
status) 
2 
3 
4 
5 
6 
7 
8 
9 
Until a total of 
18 cycles [b] 
 
 
Day 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
- 
 
PPQ – Appendix 5  
 
 
 
 
 
 
 
x 
[s] 
 
 
 
 
HCPQ-Drug Preparation Area  
Questions 1a–1c – Appendix 9 
 
 
 
 
x 
 
 
x 
 
 
 
 
HCPQ-Drug Preparation Area  
Questions 2–4 – Appendix 9 
 
 
 
 
 
 
 
x 
 
 
 
 
HCPQ-Administering Treatment  
Questions 1a–1i – Appendix 10 
 
 
 
 
x 
 
 
x 
 
 
 
 
HCPQ-Administering Treatment  
Questions 1j–1l & 2–7 – 
Appendix 10 
 
 
 
 
 
 
 
x 
 
 
 
 
EORTC QLQ-C30 [t] – 
Appendix 8 
x 
 
x 
 
x 
 
 
x 
 
x 
(Last cycle) 
 
 
The participant selects the 
setting for further treatment  
 
 
 
 
 
 
 
x 
[u] 
 
 
 
 
Adverse events [v] 
All adverse events and serious adverse events 
x 
Concomitant medication [w] 
Continuous 
 
 
ECHO  echocardiogram; ECOG  Eastern Cooperative Oncology Group; F/U  follow-up; HCPQ  healthcare professional questionnaires; 
IV  Intravenous; LVEF  left ventricular ejection fraction; MUGA  multiple-gated acquisition (scan); PPQ  patient preference questionnaire. 
 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
41/Protocol MO43110, Version 3 
Note: Unless otherwise specified, assessments should be performed within three days of the scheduled visit. On treatment days, all assessments 
should be performed prior to dosing, unless otherwise specified. For all protocol-mandated study visits, a time window of ± 3 days is allowed. If a 
protocol mandated study visit coincides with a holiday and/or weekend that preclude the visit, the visit should be scheduled on the nearest following 
feasible date. Unscheduled visits may be performed if clinically indicated.  The following assessments should be performed at a minimum: 
concomitant medications, adverse events, and vital signs. Additional assessments may be performed as clinically indicated, per investigator 
discretion. The assessments at Cycles 6, 7, and 8 of Arm C, Cycles 3, 4, and 5 of Arm D, and Cycle 9 onwards for both arms (if the participant has 
selected home administration for the remaining treatment cycles) will be performed by the mobile healthcare professional, unless otherwise 
indicated. The mobile healthcare professional will contact the participant within 3 working days before the visit to confirm the time and place of the 
visit.   
 
a In the event of delays/ interruptions of radiotherapy, PH FDC SC can be provided for one additional cycle during the run-in period (maximum 3 
cycles of PH FDC SC during run-in) and the assessments listed for Cycle 2 should be repeated for this additional cycle.  At the next treatment 
cycle, the sites should follow the assessments listed for the first cycle of the cross-over period (cycle 3 in Table 4). 
b Treatment will be given so that in total, 18 cycles of HER2-directed therapy (P+H IV or PH FDC SC) are administered, inclusive of therapy given 
both in the neoadjuvant and adjuvant setting unless disease recurrence (per institutional practice or according to the American Cancer 
Society/American Society of Clinical Oncology Breast Cancer (ACS/ASCO) Breast Cancer Survivorship Care Guideline; Runowicz et al. 2016; 
see Section 8.2.7), unacceptable toxicity, or participant withdrawal. 
c Treatment completion or discontinuation visits will optimally be scheduled for 28 (± 7 days) following the last dose of study medication and will 
include all evaluations scheduled for the final visit. 
d Assessment may be done within 3 days prior to the treatment day.  
e Complete physical examinations should include physical measurements (body weight in kilograms and height in centimeters) and evaluation of 
the head, eyes, ears, nose and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and 
neurologic systems. After the End of Treatment, physical examinations should be conducted by treating physician in accordance with 
institutional practice or the ACS/ASCO Breast Cancer Survivorship Care Guideline (Runowicz et al. 2016). 
f 
Assessment may be done within 3 days prior to treatment day (within the hospital) for participants who selected to be treated at home during 
the treatment continuation period. 
g Limited physical examinations are symptom-directed and, in addition to the scheduled examinations indicated, may be conducted by a mobile 
HCP as clinically indicated and in accordance with institutional practice or the ACS/ASCO Breast Cancer Survivorship Care Guideline 
(Runowicz et al. 2016). New or worsened clinically significant abnormalities observed post-baseline should be recorded as AEs on the Adverse 
Event electronic form. 
h Vital signs (respiratory rate, pulse rate, and systolic and diastolic blood pressure while the participant is in a seated position, and temperature) 
will be taken before and after study treatment administration.  Additional vital sign measurement will be done after administering anaphylactic 
medication if the participant experiences hypersensitivity or other administration-related reactions during administration of PH FDC SC (see 
Section 8.2.2). 
i 
ECOG Performance Status should be assessed by the HCP at least every 3–4 months during the adjuvant treatment period and at the 
treatment completion or discontinuation visit. 
j 
During the adjuvant treatment period, clinical breast examination should be performed to detect signs of locoregional relapse at least every 3–4 
months (Cycle 1, Cycle 5 or 6, Cycle 9, and last cycle) and at the treatment completion or discontinuation visit. 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
42/Protocol MO43110, Version 3 
k The mammogram at 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 participant. 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. 
l 
For participants whose LVEF cannot be assessed by ECHO, LVEF may be assessed by MUGA. The same method should be used throughout 
the study for each participant 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, LVEF assessment may also be performed on Day 1 of treatment. Results of 
LVEF assessments must be available before treatment is administered and according to the scheduled timepoints. Apart from the  specified 
mandatory LVEF assessment, the investigator may request additional assessment based on the individual participant's cardiovas cular 
function with a minimum frequency of 3–4 months. 
m All female participants of childbearing potential (refer to Section 5.1.1 for definition) will have a urine pregnancy test (as clinically indicated) at 
cycle 1, 5 or 6, 9, and last cycle during adjuvant phase; 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 months follow-
up) can be performed if indicated. Note that participants are required to continue contraception for 7 months after study treatment is complete. 
n Hematology: WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (% or absolute for neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells). Limited biochemistry:  alkaline phosphatase; AST; ALT; LDH; total bilirubin; creatinine. 
Albumin should be measured at Screening for determining participant eligibility. Bilirubin fractions (direct and indirect) must be included if total 
bilirubin is greater than ULN. During the treatment period, bloods for hematology / biochemistry may be taken within three days prior to study 
treatment administration. 
o  The general health status check, via phone call, by the treating physician/ site study nurse can be done up to 5 days prior to home treatment 
visit.  The treating physician will provide authorization for the home visit. 
p During home visits, the mobile healthcare professional will complete the study assessments as requested by the study site (in line with the 
schedule of activities). The mobile healthcare professional will provide the information collected to the treating physician (via phone call), who 
will determine if the participant should receive the next PH FDC SC treatment. If required, the study investigator may request the participant 
attends the hospital for assessment by the treating physician. 
q All participants receive maintenance dose of 600 mg pertuzumab and 600 mg trastuzumab. Participants who have had ≥ 6 weeks since their 
last pertuzumab and trastuzumab/PH FDC SC treatment must receive a loading dose before continuing with maintenance doses for subsequent 
administrations.  
r After the cross-over treatment period, participants will receive the remaining PH FDC SC treatment cycles required, to complete the planned 
18 cycles unless disease recurrence, unacceptable toxicity, or participant withdrawal. Study treatment during this treatment continuation period 
will be administered either in the hospital or in the home setting, as selected by the participant at the end of the cross-over period. 
s The Patient Preference Questionnaire (PPQ) must be completed once the participant has completed the cross-over period of adjuvant treatment 
(i.e., following study treatment administration on Day 1, Cycle 8, or Day 1, Cycle 9, if an additional cycle of PH FDC SC was administered due to 
delays/ interruptions of radiotherapy [see Section 4.1.2]). Participants who discontinued study treatment prior to the last cycle of the cross-over 
period should complete the questionnaire at the time of discontinuation as long as they have received at least one dose PH FDC SC in the 
home setting. 
t Completed before treatment is administered on Day 1 of the indicated treatment cycles. 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
43/Protocol MO43110, Version 3 
u Immediately after the PPQ has been completed (i.e., once the participant has completed the cross-over period), the participant will choose 
whether to receive the remaining cycles of PH FDC SC in the home or hospital setting (to complete a total of 18 cycles of treatment with 
pertuzumab and trastuzumab in the (neo)adjuvant setting). Participants can request to change from home administration to hospital 
administration (and vice-versa) during the treatment continuation period, but not during the treatment cross-over period. This change can occur 
once only. 
v After informed consent has been obtained, but prior to initiation of study treatment, only serious adverse events caused by protocol-mandated 
intervention should be reported. After initiation of study treatment, all adverse events will be reported until 28 days after the last dose of study 
treatment. After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator 
becomes aware of any serious adverse event that is believed to be related to prior exposure to study treatment (see Appendix 2). 
w All concomitant medications used by the participant from 7 days prior to initiation of study treatment until the End of Treatment Visit will be 
reported. 
 
 
 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
44/Protocol MO43110, Version 3 
Table 5 
Schedule of Activities: Adjuvant treatment period – Trastuzumab emtansine IV (Arm E) 
 
Adjuvant Treatment Period 
F/U 
(6–9 
months 
post last 
dose) 
Cycle 
1 (Baseline 
status) [a] 
2 
3 
4 
5 
6 
7 
8 
9 
Until a total 
of 14 cycles 
[b] 
Treatment 
Completio
n/ disc. [c] 
Day 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
- 
 
Complete physical examination 
[d] [e] 
 
 
 
 
 
 
 
 
 
x 
(Last cycle) 
x 
 
Limited physical examination  
[d] [f] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(Except for  
last cycle) 
 
 
Vital signs [d] [g] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
ECOG performance  
status [d] [h] 
x 
 
x 
 
 
x 
 
 
x 
x 
(Last cycle) 
x 
 
Weight [d] [i] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Clinical breast examination  
[d] [j] 
x 
 
 
 
x 
 
 
 
x 
x 
(Last cycle) 
x 
 
Bilateral mammogram (or 
another imaging method as, per 
local practice) [k] 
 
 
 
 
 
 
 
 
 
 
x 
 
LVEF (ECHO or MUGA) [l] 
x 
 
 
 
x 
 
 
 
x 
x 
(Last cycle) 
x 
 
Pregnancy test [m]  
x 
 
 
 
x  
 
 
 
x 
x 
(Last cycle) 
x 
x 
Hematology / limited 
biochemistry [n] 
x 
x 
x 
x 
x [o] 
x [o] 
x [o] 
x [o] 
x [o] 
x [o]  
(Until completion of 
14 cycles) 
x [o] 
 
Trastuzumab emtansine IV 
(q3w) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(until 14 cycles) 
 
 
EORTC QLQ-C30 [p] – 
Appendix 8 
x 
 
 
 
 
 
x 
 
 
x 
(Cycle 14) 
 
 
Adverse events [q] 
All adverse events and serious adverse events 
x 
Concomitant medication [r] 
Continuous 
 
 
ECHO  echocardiogram; ECOG  Eastern Cooperative Oncology Group; F/U  follow-up; IV  Intravenous; LVEF  left ventricular 
ejection fraction; MUGA  multiple-gated acquisition (scan). 
 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
45/Protocol MO43110, Version 3 
Note: Unless otherwise specified, assessments should be performed within three days of the scheduled visit. On treatmen t days, all assessments 
should be performed prior to dosing, unless otherwise specified. For all protocol-mandated study visits, a time window of ± 3 days is allowed. If 
a protocol mandated study visit coincides with a holiday and/or weekend that preclude the visit, the visit should be scheduled on the nearest 
following feasible date. Unscheduled visits may be performed if clinically indicated.  The following assessments should be pe rformed at a 
minimum: concomitant medications, adverse events, and vital signs. Additional assessments may be performed as clinically indicated, per 
investigator discretion.   
 
a Radiotherapy should be given as clinically indicated and the timing to start the radiotherapy should be based on the local pr actices, but it 
must start within 6 weeks after surgery. 
b For a total of 14 cycles. See Section 4.1.2 for guidance on how to treat participants who develop an intolerance to trastuzumab emtansine. 
Trastuzumab emtansine cannot be initiated if the platelet count is <100,000/mL at Cycle 1. Trastuzumab emtansine has not been studied in 
patients with platelet counts <100,000/mL prior to initiation of treatment. 
c Treatment completion or discontinuation visits will optimally be scheduled for 28 (± 7 days) following the last dose of study medication and 
will include all evaluations scheduled for the final visit. 
d Assessment may be done within 3 days prior to the treatment day.  
e Complete physical examinations should include physical measurements (body weight in kilograms and height in centimeters) and evaluation 
of the head, eyes, ears, nose and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, 
and neurologic systems. After the End of Treatment, physical examinations should be conducted by treating physician in accord ance with 
institutional practice or the ACS/ASCO Breast Cancer Survivorship Care Guideline (Runowicz et al. 2016). 
f 
Limited physical examinations are symptom-directed and, in addition to the scheduled examinations indicated, may be conducted by the 
treating physician in accordance with institutional practice or the ACS/ASCO Breast Cancer Survivorship Care Guideline (Runowicz et al. 
2016). New or worsened clinically significant abnormalities observed post-baseline should be recorded as AEs on the Adverse Event 
electronic form. 
g Vital signs (respiratory rate, pulse rate, and systolic and diastolic blood pressure while the participant is in a seated position, and 
temperature) will be taken before and after study treatment administration.  Additional vital sign measurement will be done a fter 
administering anaphylactic medication if the participant experiences hypersensitivity or other administration-related reactions during 
administration of trastuzumab emtansine (see Section 8.2.2). 
h ECOG Performance Status should be assessed by the HCP at least every 3–4 months during the adjuvant treatment period and at the 
treatment completion or discontinuation visit. 
i 
Weight is to be measured up to 3 days prior to Day 1 of each cycle and compared with the baseline weight after surgery to determine if the 
dose of trastuzumab emtansine should be adjusted. 
j 
During the adjuvant treatment period, clinical breast examination should be performed to detect signs of locoregional relapse at least every 
3–4 months (Cycle 1, Cycle 5 or 6, Cycle 9, and last cycle) and at the treatment completion or discontinuation visit.  
k The mammogram at 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 th roughout for an 
individual participant. 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.  

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
46/Protocol MO43110, Version 3 
l 
For participants whose LVEF cannot be assessed by ECHO, LVEF may be assessed by MUGA. The same method should be used throughout 
the study for each participant and is preferably performed and assessed by the same assessor. All LVEF assessments will be pe rformed during 
Days 15–21 of 3-week cycles prior to the cycle indicated, LVEF assessment may also be performed on Day 1 of treatment. Results of LVEF 
assessments must be available before treatment is administered and according to the scheduled timepoints. Apart from the spec ified 
mandatory LVEF assessment, the investigator may request additional assessment based on the individual participant's cardiovascular 
function with a minimum frequency of 3–4 months. 
m All female participants of childbearing potential (refer to Section 5.1.1 for definition) will have a urine pregnancy test (as clinically 
indicated) at cycle 1, 5 or 6, 9, and last cycle during adjuvant phase; 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 months follow-up) can be performed if indicated. Note that participants are required to continue contraception for 7  months 
after study treatment is complete. 
n Hematology: WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (% or absolute for ne utrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells). Limited biochemistry:  alkaline phosphatase; AST; ALT; LDH; total bilirubin;  creatinine. 
Albumin should be measured at Screening for determining participant eligibility. Bilirubin fra ctions (direct and indirect) must be included 
if total bilirubin is greater than ULN. During the treatment period, bloods for hematology / biochemistry may be taken within  three days 
prior to study treatment administration. 
o  After the first 4 cycles, if there are no Grade 3/4 toxicities, hematology tests should be done at every subsequent cycle, and  biochemistry tests 
should be done every 3 cycles, i.e., Cycle 7, Cycle 10, Cycle 13.  
p Completed before treatment is administered on Day 1 of the indicated treatment cycles. 
q After informed consent has been obtained, but prior to initiation of study treatment, only serious adverse events caused by 
protocol-mandated intervention should be reported. After initiation of study treatment, all adverse events will be reported until 28 days after 
the last dose of study treatment. After this period, all deaths, regardless of cause, should be reported.  In addition, the S ponsor should be 
notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior exposure to study treatment (see 
Appendix 2). 
r All concomitant medications used by the participant from 7 days prior to initiation of study treatment until the End of Treatment Visit will 
be reported. 
 
 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
47/Protocol MO43110, Version 3 
2. 
INTRODUCTION 
2.1 
STUDY RATIONALE 
The purpose of this study is to evaluate the patient-reported preference for the 
pertuzumab and trastuzumab (PH) fixed-dose combination (FDC) for subcutaneous (SC) 
administration (PH FDC SC) in the home setting compared with the hospital setting in 
participants with early or locally advanced/inflammatory human epidermal growth factor 
receptor 2-positive (HER2+) breast cancer.  
Moreover, safety and tolerability of SC versus IV administration of pertuzumab and 
trastuzumab will be assessed using the following treatment: 
 
Pertuzumab and trastuzumab administered by IV infusion in the hospital (P+H IV) 
 
Fixed-dose combination of pertuzumab and trastuzumab administered by SC 
injections in the hospital and the home setting (PH FDC SC). 
 
The in-hospital setting may include any care level with Oncology services other than 
primary care level facilities, either private or public. 
The administration of PH FDC SC in the home setting during the adjuvant phase in this 
study will be conducted by healthcare professionals (HCPs) provided by a mobile HCP 
vendor. In exceptional circumstances, as approved by the Sponsor, HCPs from study 
sites may undertake the home health visits.  
The SC delivery of biotherapeutics is well-established as a route of administration that is 
effective and well-tolerated across many therapeutic areas (Collins et al. 2020). It can 
offer several advantages over IV administration, including the convenience of self-
administration, improved patient experience, reduced treatment burden and lower 
healthcare costs.  
Moreover, the reduction in hospital time of the patient will reduce the patient’s exposure 
to nosocomial pathogens and reduce the burden on healthcare systems.  
Clinical data from Studies BO30185, WO40324 (FeDeriCa), and MO40628 
(PHranceSCa) showed that PH FDC SC is well tolerated, with the safety profile 
generally consistent with the safety profile of pertuzumab and trastuzumab IV, except for 
adverse events associated with subcutaneous route of administration.  No new safety 
signals were identified from these studies.  The safety of PH FDC SC administered at 
home by nurse providers in patients receiving maintenance HER2-targeted therapy is 
being investigated in a U.S. Expanded Access Program (Study AL42478).  Study 
MO43110 will provide insights on patient’s preference for home administration of PH 
FDC SC, for which data are limited.  In addition, study MO43110 will collect safety and 
tolerability data for PH FDC SC administered in the home setting and hospital setting 
during the cross-over period and the entire adjuvant treatment period, to generate further 
information on the safety and tolerability of PH FDC SC. 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
48/Protocol MO43110, Version 3 
2.2 
BACKGROUND 
According to the Global Cancer Observatory, breast cancer is number one in incidence 
and mortality compared to all cancers (Ferlay et al. 2020). Approximately 20% of breast 
cancers strongly overexpress HER2 (Artega et al. 2011). This is usually the result of 
amplification of the gene encoding HER2, which is found on chromosome 17 (Wolff et al. 
2018). 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. 
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; Toikkanen et al. 1992; Andrulis 
et al. 1998; Pauletti et al. 2000; Rubin and Yarden 2001).  
The combination of pertuzumab and trastuzumab with chemotherapy has become the 
standard of care for treating HER2+ early and metastatic breast cancer (Gradisher et al. 
2021).  
PH FDC SC is a ready-to-use formulation of pertuzumab and trastuzumab co-formulated 
with recombinant human PH20 hyaluronidase (rHuPH20) developed to improve 
dispersion of large volumes of drugs when administered subcutaneously (i.e., it functions 
as a permeation enhancer). PH FDC SC was approved by the U.S. Food and Drug 
Administration (FDA) on 29th June 2020 (FDA 2020a; FDA 2020b), by the European 
Medicines Agency (EMA) on 21st December 2020 (EMA 2020), and in numerous other 
major countries worldwide. 
PH FDC SC is indicated in combination with chemotherapy to treat patients with HER2+ 
early breast cancer and in combination with docetaxel in adult patients with HER2+ 
metastatic or locally recurrent unresectable breast cancer, who have not received 
previous anti-HER2 therapy or chemotherapy for their metastatic disease. 
Detailed information on PH FDC SC is provided in the PH FDC SC Investigator's 
Brochure. 
2.3 
BENEFIT–RISK ASSESSMENT 
The purpose of this study is to evaluate the patient-reported preference for PH FDC SC 
in the home setting compared with the hospital setting in participants with early or locally 
advanced/inflammatory HER2+ breast cancer.  
The marketing approvals for PH FDC SC were based on results from the pivotal phase 
III FeDeriCa study (WO40324; Tan et al. 2021); this study assessed the 
pharmacokinetics, effectiveness, and safety of PH FDC SC in the hospital vs P+H IV 
among participants with HER2+ early breast cancer in the neoadjuvant–adjuvant setting. 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
49/Protocol MO43110, Version 3 
The primary endpoint of the FeDeriCa study was non-inferiority of the cycle 7 
pertuzumab serum trough concentration (Ctrough; i.e., cycle 8 pre-dose pertuzumab 
concentration) within PH FDC SC versus P+H IV in the per-protocol pharmacokinetic 
population. 
The primary endpoint of this study was met; the pertuzumab cycle 7 trough 
concentration within PH FDC SC (88.7 µg/mL) showed non-inferiority to that of 
pertuzumab (72.4 µg/mL), with a geometric mean ratio of 1.22 (90% confidence interval 
[CI] = 1.14–1.31). Moreover, the overall safety, including cardiac safety, was comparable 
between arms. The most common adverse events in both arms were alopecia, nausea, 
diarrhea, and anemia. 
A phase II randomized, multicenter, open-label cross-over study  was conducted to 
evaluate patient preference and satisfaction of SC administration of the PH FDC SC in 
the hospital in participants with HER2+ early breast cancer (MO40628; O’Shaughnessy 
et al. 2020). The primary analysis of study MO40628 (PHranceSCa) showed that 85% 
(136/160) of people receiving treatment for HER2+ breast cancer preferred SC treatment 
to IV administration due to less time in the clinic and more comfortable treatment 
administration (O’Shaughnessy et al. 2020; O’Shaughnessy et al. 2021). 
The SC delivery of biotherapeutics is well-established as a route of administration that is 
effective and well-tolerated across many therapeutic areas (Collins et al. 2020). It can 
offer several advantages over IV administration, including the convenience of self-
administration, improved patient experience, reduced treatment burden and lower 
healthcare costs.  
There have been successful examples of drugs initially approved for IV administration 
that can now be safely administered as an SC injection in the out-of-hospital setting by 
HCPs (Denys et al. 2020; Wolfromm et al. 2017; Walsh et al. 2007). The out-of-hospital 
administration improves the patient quality of life and is more convenient, particularly for 
patients who live far from a hospital or have difficulty travelling.  An ongoing Expanded 
Access Program in the U.S. is investigating PH FDC SC administration in the home 
setting (Study AL42478). 
Refer to Appendix 3 for information on anticipated risks for PH FDC SC, P+H IV, and 
trastuzumab emtansine, and risk mitigation measures, including guidelines for managing 
adverse events associated with PH FDC SC, P+H IV, or trastuzumab emtansine. 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of PH FDC SC, as well as the other study 
treatments (P+H IV and trastuzumab emtansine) may be found in the PH FDC SC, 
pertuzumab, and trastuzumab emtansine Investigator’s Brochures, and trastuzumab 
Summary of Product Characteristics (SmPC). 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
50/Protocol MO43110, Version 3 
Considering the efficacy data in patients with early or locally advanced/inflammatory 
HER2+ breast cancer, the safety profile for PH FDC SC, and the risk mitigation 
measures for the study, the benefitrisk ratio is expected to be acceptable for the 
administration of PH FDC SC in the home setting.  
3. 
OBJECTIVES AND ENDPOINTS  
This study will evaluate the patient-reported preference of PH FDC SC administration in 
the home setting compared with the hospital setting during the cross-over period of 
adjuvant treatment in participants with early or locally advanced/inflammatory HER2+ 
breast cancer.  
Specific objectives and corresponding endpoints for the study are outlined in Table 6. 
In this protocol, "study treatment" refers to the combination of treatments assigned to 
participants as part of this study (i.e., fixed-dose combination of pertuzumab and 
trastuzumab for subcutaneous administration [PH FDC SC], alone or with 
chemotherapy; pertuzumab and trastuzumab IV [P+H IV] plus chemotherapy; and 
trastuzumab emtansine).  
Table 6 
Objectives and Corresponding Endpoints 
Primary Objective 
Corresponding Endpoint 
 To evaluate patient preference of PH FDC 
SC administration in the home setting 
during the cross-over period of the adjuvant 
phase of the study 
 Proportion of participants who preferred the 
administration of PH FDC SC in the home 
setting compared with the hospital setting in 
Question 1 of Patient Preference 
Questionnaire (PPQ) (Appendix 5) 
Secondary Objectives 
Corresponding Endpoints 
 To evaluate the perception of HCPs of 
time/resource use and convenience of PH 
FDC SC compared to P+H IV during the 
neoadjuvant phase of the study 
 Responses of HCPs to the Healthcare 
Professional Questionnaire (HCPQ) by 
individual questions in the neoadjuvant phase 
(Appendix 6 and Appendix 7) 
 Collect pathologic complete response (pCR) 
data post-surgery 
 Proportion of participants achieving pCR, 
defined as eradication of invasive disease in 
the breast and axilla (i.e., ypT0/Tis ypN0), 
according to local pathologist assessment 
following the AJCC criteria (FDA 2020) 
 To evaluate Health-related Quality of Life 
(HRQoL) during the neoadjuvant phase of 
the study 
 HRQoL assessed by EORTC QLQ-C30 
scores in the neoadjuvant phase 
(Appendix 8) 
 To evaluate HRQoL with PH FDC SC 
administered during the adjuvant phase of 
the study 
 HRQoL assessed by EORTC QLQ-C30 
scores in the participants treated with PH 
FDC SC during the adjuvant phase 
(Appendix 8) 

 
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 To evaluate the perception of HCPs of 
time/resource use of PH FDC SC during the 
adjuvant cross-over period 
 Responses of HCPs to the HCPQ by 
individual questions in the adjuvant cross-
over period (Appendix 9 and Appendix 10) 
 To evaluate HRQoL for participants treated 
with trastuzumab emtansine IV during the 
adjuvant phase 
 HRQoL assessed by EORTC QLQ-C30 
scores in the participants treated with 
trastuzumab emtansine IV during the 
adjuvant phase (Appendix 8)  
 To evaluate patient’s choice of setting for 
the treatment continuation period 
 Proportion of participants who selected the 
administration of PH FDC SC in the home 
setting compared with the hospital setting in 
the treatment continuation period 
Secondary Safety Objectives 
Corresponding Endpoints 
 To evaluate the safety and tolerability of PH 
FDC SC and P+H IV during the 
neoadjuvant phase of the study 
 Incidence, nature and severity of all AEs,  
Grade ≥ 3 AEs, SAEs, and cardiac AEs 
(including LVEF events) with severity 
determined according to National Cancer 
Institute common terminology criteria for 
adverse events (NCI CTCAE) v5.0 
(Appendix 14 and Appendix 16) 
 Incidence of premature withdrawal from the 
neoadjuvant treatment with PH FDC SC and 
P+H IV 
 Targeted vital signs and physical findings 
 Targeted clinical laboratory test results 
 To evaluate the safety and tolerability of PH 
FDC SC administered in the home setting 
and hospital setting during the cross-over 
period and the entire adjuvant treatment 
period 
 Incidence, nature, and severity of all AEs,  
Grade ≥ 3 AEs, SAEs, and cardiac AEs 
(including LVEF events) with severity 
determined according to NCI CTCAE v5.0 
(Appendix 14 and Appendix 16) 
 Incidence of premature withdrawal from the 
adjuvant treatment with PH FDC SC 
 Targeted vital signs and physical findings 
 Targeted clinical laboratory test results 
 To evaluate the safety and tolerability of 
trastuzumab emtansine IV during the 
adjuvant phase of the study 
 Incidence, nature, and severity of all AEs,  
Grade ≥ 3 AEs, SAEs, and cardiac AEs 
(including LVEF events) with severity 
determined according to NCI CTCAE v5.0 
(Appendix 14 and Appendix 16) 
 Incidence of premature withdrawal from the 
treatment with trastuzumab emtansine IV  
 Targeted vital signs and physical findings 
 Targeted clinical laboratory test results 
AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; 
EORTC = European Organisation for Research and Treatment of Cancer; HCP = healthcare 
professional; HCPQ = Healthcare Professional Questionnaire; IV = intravenous; LVEF = Left 
ventricular ejection fraction; NCI = National Cancer Institute; pCR = pathologic complete 
response; PPQ = Patient Preference Questionnaire; SAE = serious adverse event. 
  

 
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4. 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
This is a phase IIIb, multinational, multicenter, randomized, open-label study to evaluate 
the patient preference of PH FDC SC administration in the home setting compared with 
the hospital setting during the cross-over period of adjuvant treatment in participants with 
early or locally advanced/inflammatory HER2+ breast cancer. 
The hospital setting for treatment administration may include any care level with 
Oncology services, other than primary care level facilities, either private or public. 
The study will enroll participants with early or locally advanced/inflammatory HER2+ 
breast cancer consistent with the indication for treatment with neoadjuvant P+H IV plus 
chemotherapy or PH FDC SC plus chemotherapy in routine clinical practice and as 
recommended in local guidelines. Eligibility will be assessed within a 28-day screening 
period.  
This study will consist of two phases.  
4.1.1 
Treatment During the Neoadjuvant Phase 
During the neoadjuvant phase, the enrolled participants will be randomized in a ratio of 
1:2, in one of the following treatment arms: 
 
Arm A: P+H IV every 3 weeks (q3w) plus chemotherapy (standard regimen) in the 
hospital.  
 
Arm B: PH FDC SC q3w plus chemotherapy (standard regimen) in the hospital. 
 
In both arms, the investigator can select from one of three neoadjuvant chemotherapy 
options: 
 
Option 1: Docetaxel (75 mg/m²) and carboplatin (AUC 5–6 [area under the plasma 
concentration-time curve]) q3w for 6 cycles plus HER2-targeted therapy (Table 1) 
 
Option 2: Doxorubicin (60 mg/m²) plus cyclophosphamide (600 mg/m²) q3w for 
4 cycles, followed by a taxane (docetaxel [75–100 mg/m²] q3w for 4 cycles or 
paclitaxel [80 mg/m²] every week for 12 cycles) plus HER2-targeted therapy 
(Table 2) 
 
Option 3: Dose-dense doxorubicin (60 mg/m²) plus cyclophosphamide (600 mg/m²) 
q2w for 4 cycles, followed by a taxane (docetaxel [75–100 mg/m²] q3w for 4 cycles 
or paclitaxel [80 mg/m²] every week for 12 cycles) plus HER2-targeted therapy 
(Table 3) 
Randomization will be stratified by disease stage at screening (operable, locally 
advanced, or inflammatory, as defined in Section 6.3.1) and neoadjuvant chemotherapy 
option (anthracycline-free or anthracycline-based, as defined in Section 6.3.1). 

 
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Participants may change from P+H IV (Arm A) treatment to PH FDC SC (Arm B) 
treatment, in exceptional circumstances and as per investigator discretion. As such, 
these participants will continue on the study with the planned neoadjuvant and adjuvant 
phase of the study. Participants requesting to change from PH FDC SC to P+H IV in the 
neoadjuvant phase will be discontinued from the study. As such, these participants will 
be treated as per standard of care. 
After completing their neoadjuvant therapy, participants from both arms will undergo 
surgical resection for early or locally advanced HER2+ breast cancer (if eligible for 
surgery; see Section 6.8.1). Surgery will be performed no earlier than 2 weeks after the 
last systemic neoadjuvant therapy and must be performed ≤ 6 weeks of the last systemic 
neoadjuvant therapy.  
If surgery is significantly delayed (>42 days since the last P+H IV or PH FDC SC 
administration), a maximum of two additional cycles of P+H IV or PH FDC SC 
(depending on the treatment arm (A or B) assigned to the participant at randomization), 
can be administered at the investigator’s discretion before surgery, in order to maintain 
adequate serum levels of pertuzumab and trastuzumab.  See Appendix 18 for details of 
the assessments that should be conducted for participants who require additional cycles 
of P+H IV or PH FDC SC due to a delay with surgery. 
Local pathologists interpreting surgical specimens will determine if pCR has been 
achieved. pCR is defined as the absence of residual invasive cancer on hematoxylin and 
eosin evaluation of the complete resected breast specimen and all sampled regional 
lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypT0/Tis ypN0), 
according to the current American Joint Committee on Cancer (AJCC) staging system 
classification (FDA 2020).  
Participants ineligible for surgery will be managed as per local practice and be withdrawn 
from study treatment. They will remain on study for follow-up of secondary and 
exploratory endpoints unless they have withdrawn consent from study participation. 
4.1.2 
Treatment During the Adjuvant Phase 
4.1.2.1 
Participants Who Have Achieved pCR After Surgery 
Participants who have achieved pCR after surgery will first be treated with 2 cycles of 
PH FDC SC in the hospital (run-in period).  The study treatment PH FDC SC cannot be 
initiated within ≤ 2 weeks of surgery but must be initiated ≤ 9 weeks from the last 
administration of systemic neoadjuvant therapy.  If the interval between the 
administration of the first dose of PH FDC SC in the adjuvant phase and the 
administration of the last dose of PH FDC SC or P+H IV in the neoadjuvant phase is 
≥ 6 weeks, a loading dose of PH FDC SC is required (see Section 6.1.1). 
After surgery, radiotherapy is to be given as clinically indicated as per radiotherapy 
guidelines following the institutional standards.  The selected radiotherapy regimen 

 
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should be initiated within 4–6 weeks after surgery, ideally after wound healing.  
Adjuvant HER2-targeted therapy should be delivered concurrently with radiotherapy 
in the run-in period and the selected radiotherapy regimen should not last longer than 5 
weeks.  In the event of delays/ interruptions of radiotherapy, PH FDC SC can be 
provided for one additional cycle during the run-in period (maximum 3 cycles of PH FDC 
SC during run-in). The radiotherapy regimen has to be completed within the run-in-
period. 
Randomization will occur after completion of the last cycle of radiotherapy and last cycle 
of PH FDC SC during the run-in period. Sites will be provided with a separate manual of 
radiotherapy guidelines.  
Participants will then be randomized with a ratio of 1:1 into one of two treatment arms in 
a cross-over treatment period to receive the next 6 cycles of PH FDC SC treatment: 
 
Arm C: 3 cycles of PH FDC SC in the hospital and then 3 cycles of PH FDC SC in 
the home setting. 
 
Arm D: 3 cycles of PH FDC SC in the home setting and then 3 cycles of 
PH FDC SC in the hospital.  
Randomization in the adjuvant phase will be stratified by disease stage at screening 
(same as above), type of surgery (conservative or mastectomy), and neoadjuvant 
chemotherapy option (anthracycline-free or anthracycline-based, as defined in Section 
6.3.1).  
After the cross-over treatment period, participants will receive the remaining PH FDC SC 
treatment cycles required to complete the planned 18 cycles of HER2-directed therapy, 
unless of disease recurrence (per institutional practice or according to the ACS / ASCO 
Breast Cancer Survivorship Care Guideline; Runowicz et al. 2016; see Section 8.2.7), 
unacceptable toxicity, or participant withdrawal. Study treatment during this treatment 
continuation period will be administered either in the hospital or in the home setting as 
selected by the participant at the end of the crossover period. 
Participants can request to change from home administration to hospital administration 
(and vice-versa) during the treatment continuation period, but not during the treatment 
cross-over period. This change can occur once only. 
4.1.2.2 
Participants Who Have Residual Disease After Surgery 
Participants with pathologic evidence of residual invasive carcinoma in the breast or 
axillary lymph nodes following completion of preoperative therapy and surgery will enter 
Arm E:  
 
Arm E: Trastuzumab emtansine IV for 14 cycles.  
 

 
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Trastuzumab emtansine will be administered IV in the hospital as per prescribing 
information. Trastuzumab emtansine cannot be initiated within ≤ 2 weeks of surgery but 
must be initiated ≤ 6 weeks of surgery. 
Participants in Arm E developing an intolerance to trastuzumab emtansine may require 
temporary interruption, dose reduction or treatment discontinuation (see Section 6.1.3 
and Appendix 3 for more information on the management of participants who experience 
adverse events during treatment with trastuzumab emtansine). Participants who remain 
intolerant to trastuzumab emtansine after dose reduction can be discontinued from the 
study (and be treated as per standard of care) or can remain in the study and be treated 
with PH FDC SC in the hospital as to complete 14 cycles of HER2-directed adjuvant 
study treatment in total. This decision is at the discretion of the treating physician. See 
Appendix 19 for details of the assessments to be conducted in these participants. 
Participants who discontinue trastuzumab emtansine because of toxicity that may be 
attributed to the trastuzumab component (e.g., hypersensitivity, cardiac toxicity, 
pneumonitis) may not continue to receive PH FDC SC after discontinuation of 
trastuzumab emtansine. 
No adjuvant chemotherapy is allowed after surgery, however, adjuvant hormone, 
bisphosphonate, and/or radiation therapy are allowed as per local guidelines. 
Radiotherapy should be given as clinically indicated and the timing to start the 
radiotherapy should be based on the local practices, but it must start within 6 weeks 
after surgery. 
All patients will return to the study site for a safety follow-up visit 6–9 months after the 
last dose of study treatment for assessment of adverse events, and for a pregnancy test 
for female participants of childbearing age. 
4.2 
RATIONALE FOR STUDY DESIGN 
4.2.1 
Rationale for Study Population  
The participant population included in this study is consistent with the indication for 
treatment with P+H IV or PH FDC SC, trastuzumab emtansine, and chemotherapy in 
routine clinical practice and as recommended in local guidelines.  
4.2.2 
Rationale for Randomized Cross-over Design 
Randomization reduces the bias and confounding in the process of participant 
assignment. Stratified randomization can further prevent the confounding in the 
interpretation of study endpoints, caused by the known factors of disease stage, 
neoadjuvant chemotherapy, and type of surgery. The cross-over design allows the 
participants to be exposed to both the home and in-hospital settings and act as their own 
control for assessment of clinical outcomes. Exposure to both settings also allows a 

 
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realistic, instead of hypothetical, evaluation through the PPQ, which is the primary 
endpoint of this study. 
4.2.3 
Rationale for Non-Standard Clinical Outcome Assessments  
The PPQ used to assess the primary study endpoint has been developed in clinical trials 
assessing patient preference for SC administered monoclonal antibodies. 
An interview-based assessment was first developed to assess patient preference for 
trastuzumab SC in a clinical trial of adjuvant trastuzumab SC and IV in HER2+ early 
breast cancer (Study MO22982, Pivot et al. 2013). Interview questions were based on 
input from experienced clinicians, chemotherapy nurses and psychologists and were 
tested with patient volunteers prior to use in the study. The three interview questions 
identified as most informative in the trastuzumab MO22982 study were then 
administered as the patient-completed PPQ in a subsequent lymphoma study evaluating 
preference for SC or IV administered rituximab (PrefMab study, Rummel et al. 2017). 
Notably, PPQ endpoints collected in this study were considered adequate evidence for 
preference claims included in rituximab SC product labelling (Rituxan Hycela™; FDA 
2017).  
The PPQ was also used to evaluate the patient preference for PH FDC SC compared to 
P+H IV in the PHranceSCa study (Study MO40628, O’Shaughnessy et al. 2020). In this 
phase II study, 85% (136/160) of people receiving treatment for HER2+ breast cancer 
preferred treatment under the skin to IV administration due to less time in the clinic and 
more comfortable treatment administration (O’Shaughnessy et al. 2020; O’Shaughnessy 
et al. 2021). 
A similar PPQ is currently used in the study investigating PH FDC SC administration at 
home during the coronavirus disease 2019 (COVID-19) pandemic (Study AL42478). The 
PPQ will be completed by the participant in Study AL42478 using an electronic platform 
provided by the healthcare provider at the End of Treatment Visit. 
4.3 
JUSTIFICATION FOR DOSE AND SCHEDULE 
The doses and scheduling of P+H IV in the study are the approved doses for the 
treatment of early breast cancer. The doses of PH FDC SC selected to be used in this 
study are consistent with the approved loading (1200 mg pertuzumab/600mg 
trastuzumab/30,000 units rHuPH20) and maintenance doses of PH FDC SC (600 mg 
pertuzumab/600 mg trastuzumab/20,000 units rHuPH20) investigated in the pivotal 
WO40324 FeDeriCa study that confirmed non-inferior Cycle 7 Ctrough and comparable 
efficacy of pertuzumab/trastuzumab SC versus pertuzumab/trastuzumab IV in 
participants with early breast cancer (Tan et al. 2021). 
The doses and scheduling of trastuzumab emtansine IV infusions in the study are the 
approved doses for the treatment of HER2+ advanced breast cancer. The globally 
approved regimen of trastuzumab emtansine is 3.6 mg/kg q3w as confirmed in Study 

 
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TDM4370g/BO21977 (Verma et al. 2012), the pivotal phase III trial comparing 
trastuzumab emtansine to lapatinib plus capecitabine in participants with HER2+ 
metastatic breast cancer who were previously treated with trastuzumab and a taxane.  
The scheduling of all HER2-targeted treatments (every 3 weeks) is based on 
pharmacokinetic (PK) studies comparing IV and SC administrations of each molecule 
(BO22227, Jackisch et al. 2019; and BO30185; Kirschbrown et al. 2019) and the 
approved scheduling for the administration of P+H IV and of trastuzumab for SC 
injection.  
Participants experiencing severe hypersensitivity reactions should be discontinued from 
study treatment but maintained in the schedule of activities unless consent is withdrawn. 
Refer to the PH FDC SC, pertuzumab, and trastuzumab emtansine Investigator’s 
Brochures, and trastuzumab SmPC, for additional information. 
4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all 
phases of the study, including the last visit shown in the schedule of activities (see 
Section 1.3). 
The end of this study is defined as the date of the last scheduled procedure shown in the 
schedule of activities (i.e., 6–9 months after the last dose of study treatment) for the last 
participant in the study globally or the date at which the last data point required for 
statistical analysis (i.e., PPQ, HRQoL, and HCPQ) or safety follow-up is received from 
the last participant, whichever occurs later. The end of the study is expected to occur 
approximately 18 months after the last participant is enrolled. 
In addition, the Sponsor may decide to terminate the study at any time. 
4.5 
DURATION OF PARTICIPATION 
The total duration of study participation for an individual is expected to be approximately 
1.5 to 2 years. 
5. 
STUDY POPULATION 
Approximately 330 participants with HER2+ early or locally advanced/inflammatory 
breast cancer will be enrolled in this study. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 

 
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5.1.1 
General Inclusion Criteria 
 
 
Signed Informed Consent Form 
 
Age ≥ 18 years at the time of signing Informed Consent Form 
 
Ability to comply with the study protocol 
 
Eastern Cooperative Oncology Group (ECOG) performance status 01 
(Appendix 12)  
 
Intact skin at planned site of SC injections (thigh) 
 
Left ventricular ejection fraction (LVEF) ≥ 55% by echocardiogram (ECHO) or 
multiple-gated acquisition scan (MUGA). If the participant has not had an LVEF 
measured in the last 12 weeks, an ECHO or MUGA should be performed at the 
screening visit (Appendix 16) 
 
Negative human immunodeficiency virus (HIV) test at screening with the following 
exception: participants with a positive HIV test at screening are eligible provided 
they are stable on anti-retroviral therapy, have a CD4 count ≥ 200/μL, have an 
undetectable viral load and provided that they have not had a history of AIDS-
defining opportunistic infections within 12 months prior to randomization. 
Investigators need to consider potential drug-drug interactions between study 
treatment and anti-retroviral therapies before enrolling participants 
 
Negative hepatitis B surface antigen (HBsAg) test at screening 
 
Positive hepatitis B surface antibody (HbsAb) test at screening, or negative HbsAb 
at screening accompanied by either of the following: 
- 
Negative total hepatitis B core antibody (HbcAb) 
- 
Positive total HbcAb test followed by a negative (per local laboratory 
definition) hepatitis B virus (HBV) DNA test 
 
Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV 
antibody test followed by a negative HCV RNA test at screening  
The HCV RNA test is only required for participants who have a positive HCV 
antibody test. 
 
For female participants of childbearing potential: agreement to remain abstinent 
(refrain from heterosexual intercourse) or use non-hormonal contraception and 
agree to refrain from donating eggs as defined below: 
Female participants must remain abstinent or use non-hormonal 
contraceptive methods with a failure rate of  1% per year, or two effective 
contraceptive methods during the treatment period and for 7 months after the 
final dose of the study treatment.  
Female participants must refrain from donating eggs during this same period. 
A female participant is considered to be of childbearing potential if she is 
post-menarchal, has not reached a post-menopausal state ( 12 continuous 
months of amenorrhea with no identified cause other than menopause), and 
is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian 

 
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tubes, and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis). Per this definition, a female participant with a tubal 
ligation is considered to be of childbearing potential. The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
regulations. 
Examples of non-hormonal contraceptive methods with a failure rate of 
 1% per year include bilateral tubal ligation, male sterilization (with 
appropriate post-vasectomy documentation of the absence of sperm in the 
ejaculate), and copper intrauterine devices. Hormonal contraceptives are not 
allowed. 
Patients who have had a progesterone-coated device in place prior to 
screening are not required to have it removed.  However, newly inserted 
devices after screening should not contain estrogen or progesterone. 
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 
individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
post-ovulation methods) and withdrawal are not adequate methods of 
contraception. If required per local guidelines or regulations, locally 
recognized adequate methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form. 
Female participants of childbearing potential must have a negative serum 
pregnancy test result within seven days prior to initiation of study treatment 
 
For male participants: agreement to remain abstinent (refrain from heterosexual 
intercourse) or use a condom, and agree to refrain from donating sperm, as defined 
below: 
With a female partner of childbearing potential or pregnant female partner, 
male participants must remain abstinent or use a condom during the 
treatment period and for 7 months after the final dose of study treatment to 
avoid exposing the embryo. Male participants 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 
individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
post-ovulation methods) and withdrawal are not adequate methods of 
preventing drug exposure. If required per local guidelines or regulations, 
information about the reliability of abstinence will be described in the local 
Informed Consent Form. 
 
5.1.2 
Disease-specific Inclusion Criteria 
 
Female and male participants with stage II-IIIC early or locally 
advanced/inflammatory HER2+ breast cancer. Assessment of HER2 protein 
overexpression and HER2 gene amplification should be performed using FDA-
approved tests or a locally validated HER2 test by laboratories with demonstrated 
proficiency.  

 
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 
Primary tumor > 2 cm in diameter, or node-positive disease (clinically or on 
imaging).  
 
HER2+ breast cancer confirmed by a local laboratory prior to study enrollment. 
HER2+ status will be determined based on pretreatment breast biopsy material and 
defined as 3+ by Immunohistochemistry (IHC) and/or positive by HER2 amplification 
by in situ hybridization (ISH) following American Society of Clinical Oncology 
(ASCO)/College of American Pathologists (CAP) guidelines 2018 and updates 
(Wolff et al. 2018). 
Participants with multifocal tumor (more than one tumor confined to the same 
quadrant as the primary tumor) are eligible and at least one focus should be 
sampled and confirmed as HER2 positive as per clinical practices 
 
Hormone receptor status of the primary tumor determined by local assessment 
following ASCO/CAP guidelines 2020 and updates (Allison et al. 2020). Hormone 
receptor status may be either positive (i.e., estrogen receptor [ER]-positive and/or 
progesterone receptor [PgR]-positive) or negative (i.e., ER-negative and PgR-
negative). 
 
Agreement to undergo mastectomy or breast conserving surgery after neoadjuvant 
therapy, including the axillary nodes (sentinels and/or not sentinels). 
 
Availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue block for local 
confirmation of HER2 and hormone receptor status following current ASCO/CAP 
guidelines. 
Note: The neoadjuvant chemotherapy regimen (including type and sequencing of 
selected agents) is at the discretion of the treating physician and participant based on 
the three alternatives of this study. 
 
5.1.3 
Inclusion Criteria for Treatment with Adjuvant PH FDC SC 
 
 
Completed the neoadjuvant phase of this study and underwent surgery, and 
achieved pCR, defined as eradication of invasive disease in the breast and axilla 
(i.e., ypT0/Tis ypN0) according to the current American Joint Committee on Cancer 
(AJCC) staging system classification (FDA 2020), and using the resected specimen 
by the local pathologist on the basis of guidelines to be provided in a Pathology 
Manual 
 
Adequate wound healing after breast cancer surgery per investigator’s assessment 
to allow initiation of study treatment within ≤ 9 weeks of last systemic neoadjuvant 
therapy 
  
5.2 
EXCLUSION CRITERIA 
Participants are excluded from the study if any of the following criteria apply: 
 
5.2.1 
General Exclusion Criteria 
 
 
Stage IV (metastatic) breast cancer 

 
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 
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 participant with previous invasive non-breast 
cancer is eligible provided he/she has been disease free for more than 5 years 
 
Participants who are pregnant or breastfeeding or intending to become pregnant 
during the study or within 7 months after the final dose of study treatments.  
Female participants of childbearing potential must have a negative serum 
pregnancy test result within seven days prior to initiation of study treatment 
 
Treatment with investigational therapy within 28 days prior to initiation of study 
treatment 
 
Active, unresolved infections at screening requiring treatment. Participants with any 
severe infection within 28 days prior to initiation of study treatment, including, but 
not limited to, hospitalization for complications of infections should not be enrolled in 
the trial (in the current situation, this also applies to participants with suspected or 
confirmed COVID-19 infection) 
 
Participants who may have had a recent episode of thromboembolism and are still 
trying to optimize the anticoagulation dose and/or have not normalized their 
International Normalized Ratio (INR) 
 
Serious cardiac illness or medical conditions including, but not confined to, the 
following: 
- 
History of NCI CTCAE v5.0 Grade ≥ 3 symptomatic congestive heart 
failure (CHF) or New York Heart Association (NYHA) Class ≥ II 
- 
High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate 
≥ 100/min at rest, significant ventricular arrhythmia [ventricular 
tachycardia], or higher-grade atrioventricular [AV]-block, such as second-
degree AV-block Type 2 [Mobitz II] or third-degree AV-block) 
- 
Serious cardiac arrhythmia or severe conduction abnormality not 
controlled by adequate medication  
- 
Angina pectoris requiring anti-angina medication 
- 
Clinically significant valvular heart disease 
- 
Evidence of transmural infarction on electrocardiogram (ECG) 
- 
Evidence of myocardial infarction within 12 months prior to enrollment 
- 
Poorly controlled hypertension (e.g., systolic > 180 mm Hg or 
diastolic > 100 mmHg) 
- 
Significant symptoms (Grade ≥ 2) relating to left ventricular dysfunction, 
cardiac arrhythmia, or cardiac ischemia while or since receiving 
preoperative therapy 
- 
Requirement for continuous oxygen therapy 
 
History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such 
as structural heart disease (e.g., severe left ventricular systolic dysfunction [LVSD], 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
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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.  
 
Inadequate bone marrow function, defined by any of: 
- 
Participants who have an absolute neutrophil count (ANC) < 1.5 x 109/L 
- 
Platelet count < 100 x 109/L 
- 
Hemoglobin < 9 g/dL 
 
Impaired liver function, defined by any of: 
- 
Serum (total) bilirubin > 1.25 x upper limit of normal (ULN). In case of 
Gilbert’s syndrome: a total bilirubin of 2 x ULN is permitted. 
- 
Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) > 1.25 x ULN 
- 
Albumin < 25 g/L 
 
Renal function with creatinine clearance < 50 mL/min using the Cockroft-Gault 
formula and serum creatinine > 1.5 x ULN 
 
Major surgical procedure unrelated to breast cancer within 28 days prior to study 
entry or anticipation of the need for major surgery during the course of study 
treatment 
 
Current severe, uncontrolled systemic disease that may interfere with planned 
treatment (e.g., clinically significant cardiovascular, pulmonary, or metabolic 
disease; wound-healing disorders) 
 
Any serious medical condition or abnormality in clinical laboratory tests that 
precludes an individual’s safe participation in and completion of the study 
 
Treatment with a live vaccine (e.g., FluMist) in the 30 days prior to initiation of study 
treatment, or anticipation of need for such a vaccine during treatment or within 90 
days after the final dose of study treatment 
 
Known active liver disease, for example, active viral hepatitis infection (i.e., hepatitis 
B or hepatitis C), autoimmune hepatic disorders, or sclerosing cholangitis 
 
Known hypersensitivity to any of the study drugs, excipients, and/or murine proteins 
or a history of severe allergic or immunological reactions, e.g., difficult to control 
asthma 
 
Current chronic daily treatment with corticosteroids (dose >10 mg 
methylprednisolone or equivalent excluding inhaled steroids) 
 
Assessment by the investigator as being unable or unwilling to comply with the 
requirements of the protocol 
 
5.2.2 
Cancer-specific Exclusion Criteria for Neoadjuvant Phase 
 
 
Participants who have received any previous systemic therapy (including 
chemotherapy, immunotherapy, HER2-targeted agents, endocrine therapy [selective 

 
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estrogen receptor modulators, aromatase inhibitors], and antitumor vaccines for 
treatment or prevention of breast cancer), or previous chest irradiation (radiation 
therapy) for the treatment of cancer 
 
Participants 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 ipsi- or contralateral breast cancer. Participants are 
allowed to enter the study if treated with surgery alone 
 
Participants with high-risk for breast cancer who have received chemopreventive 
drugs in the past are not allowed to enter the study 
 
Participants with multicentric (multiple tumors involving more than one quadrant) 
breast cancer, unless all tumors are HER2+ 
 
Participants with bilateral breast cancer 
 
Participants 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. 
Participants 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 
 
5.2.3 
Exclusion Criterion for Treatment with Adjuvant Trastuzumab 
Emtansine (Arm E) 
 
Current Grade ≥ 3 peripheral neuropathy (according to the NCI CTCAE v5.0) 
 
5.3 
LIFESTYLE CONSIDERATIONS 
5.3.1 
Meals and Dietary Restrictions 
This study has no meal or dietary restrictions. 
5.3.2 
Caffeine, Alcohol, and Tobacco 
This study has no caffeine, alcohol, or tobacco restrictions. 
5.3.3 
Activity 
This study has no activity restrictions. 
5.3.4 
Contraception Requirements 
During the study, participants must use contraception or take other precautions as 
described in Section 5.1.1. 
5.4 
SCREEN FAILURES 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
qualify for one re-screening opportunity (for a total of two screenings per individual) at 
the investigator’s discretion.  Individuals must re-sign the consent form prior to 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
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rescreening.  The investigator will maintain a record of reasons for screen failure (see 
Section 8). 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY 
INTERVENTION 
The following conditions may allow a participant to be enrolled/randomized/administer 
study treatment once the conditions have resolved and the participant is otherwise 
eligible for participation in the study:  
 
Participants who have had a serious infection requiring oral or IV antibiotics within 
28 days prior to screening trial (in the current situation, this would also apply to 
participants with suspected or confirmed COVID-19 infection). 
 
6. 
STUDY TREATMENT, OTHER TREATMENTS RELEVANT TO 
THE STUDY DESIGN, AND CONCOMITANT THERAPY 
Study treatment refers to the combination of treatments assigned to participants as part 
of this study (i.e., fixed-dose combination of pertuzumab and trastuzumab for 
subcutaneous administration [PH FDC SC], alone or with chemotherapy; pertuzumab 
and trastuzumab IV [P+H IV] plus chemotherapy; and trastuzumab emtansine). 
The investigational medicinal products (IMPs) for this study are PH FDC SC (loading 
dose configuration and maintenance dose configuration, see Section 6.1.1), P+H IV, and 
trastuzumab emtansine.  
Appendix 20 identifies all investigational medicinal products and auxiliary medicinal 
products (AxMPs) for this study. 
All the IMPs will be provided by the Sponsor free of charge. 
Chemotherapy drugs and endocrine therapy (Section 6.1.4), pre-medications (Section 
6.1.5) and anaphylaxis medications (Section 6.1.6) are regarded as AxMPs.  AxMPs 
will be obtained locally by the investigational sites or will be provided by the Sponsor as 
per country requirements. 
Study drug supplies will be labelled in accordance with applicable legal requirements 
and will be printed in the local language. Study drug supplies should not be used beyond 
the expiration date provided by the manufacturer. 
6.1 
STUDY TREATMENTS ADMINISTERED 
Table 7 provides a description of study treatments for this study. 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
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Table 7 
Study Treatment Description 
AxMP  auxiliary medical product; IMP  investigational medicinal product; IV  intravenous injection; PH FDC 
SC  fixed-dose combination of pertuzumab and trastuzumab for subcutaneous administration; SC  subcutaneous 
injection. 
 
For information on the formulation and handling of the PH FDC SC, see the PH FDC SC 
Investigator’s Brochure. 
For information on the packaging, storage and dispensing of pertuzumab for IV infusion, 
see the current pertuzumab Investigator’s Brochure. 
For information on the packaging, storage, and dispensing of trastuzumab for IV 
infusion, see the current trastuzumab SmPC. 
 
PH FDC SC 
(Loading 
dose) 
PH FDC SC 
(Maintenance 
dose) 
Pertuzumab 
IV 
Trastuzumab 
IV 
Trastuzumab 
emtansine 
IV 
Chemotherapy 
and endocrine 
therapy 
Use 
Experimental 
Experimental 
Experimental 
Experimental 
Experimental 
Background 
therapy 
Type of 
medicinal 
product 
IMP 
IMP 
IMP 
IMP 
IMP 
AxMP 
Drug form 
Liquid 
Liquid 
Liquid 
Freeze-dried 
preparations 
Sterile 
powder 
 Refer to local 
prescribing 
information for 
docetaxel, 
carboplatin, 
doxorubicin, 
paclitaxel, 
cyclophosphamide
, and endocrine 
therapy 
Unit Dose 
Strengths 
15 mL of 
solution 
10 mL of 
solution 
420 mg/vial 
150 mg/vial  
160 mg/vial 
Dosage 
Levels 
1200 mg of 
pertuzumab 
and 600 mg of 
trastuzumab  
600 mg of  
pertuzumab 
and 600 mg of 
trastuzumab  
840 mg  
(Loading 
dose) 
or 420 mg  
(Maintenance 
dose) 
8 mg/kg 
 (Loading dose) 
or 6 mg/kg 
(Maintenance 
dose) 
3.6 mg/kg 
given as an 
intravenous 
infusion 
Formulatio
ns 
 L-histidine/L-
histidine-HCl 
monohydrate,  
α, α-trehalose 
dihydrate, 
Sucrose, L-
methionine, 
Polysorbate 
20, rHuPH20 
(2000 IU/mL) 
 L-histidine/L-
histidine-HCl 
monohydrate,  
α, α-trehalose 
dihydrate, 
Sucrose, L-
methionine, 
Polysorbate 
20, rHuPH20 
(2000 IU/mL) 
L-histidine 
acetate, 
sucrose, 
polysorbate 
20 at pH 6.0 
histidine/histidin
e-HCl; α, α-
trehalose 
dehydrate; 
polysorbate 20 
Trastuzumab 
emtansine, 
sucrose, 
sodium 
succinate and 
polysorbate 
20  
Packaging 
15 mL vial 
10 mL vial 
20 mL vial 
15 mL vial 
20 mL vial 
Labeling 
Per local requirements 
Route of 
administrat
ion 
SC injection 
SC injection 
IV infusion 
IV infusion 
IV infusion 
Source 
Sponsor 
Sponsor 
Sponsor  
Sponsor 
Sponsor 
Site or Sponsor 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
66/Protocol MO43110, Version 3 
For information on the packaging, storage, and dispensing of trastuzumab emtansine for 
IV infusion, see the current trastuzumab emtansine Investigator’s Brochure. 
A Mobile Clinical Services Training Manual is provided to participating study sites for 
reference only and is specifically intended as training and instruction material for the 
HCPs preparing and administering PH FDC SC doses in the home setting, see 
Appendix 15. The manuals do not replace the protocol. 
The treatment regimens are summarized in Section 4.1. 
Guidelines for treatment interruption or discontinuation for participants who experience 
adverse events are provided in Appendix 2. 
6.1.1 
PH FDC SC Loading and Maintenance Dose  
PH FDC SC is given as a fixed dose (i.e., non-weight based). Two dosage 
configurations of PH FDC SC may be administered in the study: a 15 mL loading dose 
consisting of 1200 mg pertuzumab and 600 mg trastuzumab and a 10 mL maintenance 
dose consisting of 600 mg pertuzumab and 600 mg trastuzumab.  Participants who have 
had ≥ 6 weeks since their last pertuzumab and trastuzumab treatment (PH FDC SC or 
P+H IV) must receive a loading dose before continuing with maintenance doses for 
subsequent administrations. 
PH FDC SC is administered by SC injection by the HCP in the home setting or in the 
hospital on Day 1 of each 3-week treatment cycle. Self-administration is not allowed. 
Participants should be monitored for 30 minutes after their first dose of PH FDC SC and 
if another loading dose is required during the study. Participants should be monitored for 
15 minutes following subsequent administrations. Participants can be observed for 
longer periods at the discretion of the HCP or, if necessary, as per local requirements. 
Pre-medication with antipyretics, antihistamines, or corticosteroids, according to local 
practice and investigator discretion, may be administered before PH FDC SC 
administration. 
PH FDC SC should be administered by an HCP after proper training in SC injection 
technique (See Appendix 15). 
PH FDC SC vials must be stored in a refrigerator at 2 °C to 8 °C (36 °F to 46 °F) in the 
original carton to protect from light until time of use. 
Medications to treat hypersensitivity reactions (e.g., H1-receptor or H2-receptor 
antagonists and steroids) must be available for immediate use (see Section 6.1.6). 
For injection-related reactions, the injection should be slowed or paused if the participant 
experiences symptoms. 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
67/Protocol MO43110, Version 3 
6.1.2 
Pertuzumab and Trastuzumab 
The order of administration of pertuzumab IV and trastuzumab IV is according to 
investigator preference.  
Pertuzumab is given as a fixed nonweight-based dose of 840-mg IV administered as 
loading dose and then 420-mg IV administered as maintenance dose every 3 weeks. 
Participants who have had ≥ 6 weeks since their last study treatment with pertuzumab 
during the study treatment periods, must receive a loading dose before continuing with 
maintenance doses for subsequent administrations.  
Pertuzumab IV loading dose (if required) will be administered as a 60-minute infusion 
(± 10 minutes), followed by an observation period of 60 minutes. If the loading dose 
infusion is well tolerated, subsequent maintenance doses can be administered over a 
period of 30 minutes (± 10 minutes) with an observation period of 30 minutes. 
Participants can be observed for longer periods at the discretion of the investigator or if 
necessary, as per local requirements. 
Pre-medication with antipyretics, antihistamines, or corticosteroids, according to local 
practice and investigator discretion, may be administered before pertuzumab IV 
administration. 
For information on the packaging, storage and dispensing of pertuzumab IV, see the 
current pertuzumab Investigator’s Brochure.  
Trastuzumab is given as an 8-mg/kg IV administered as loading dose and then 6-mg/kg 
IV administered as maintenance dose every 3 weeks. Participants who have had ≥ 6 
weeks since their last study treatment with trastuzumab during the study treatment 
periods, must receive a loading dose before continuing with maintenance doses for 
subsequent administrations. 
Trastuzumab IV loading dose (if required) will be administered as an infusion over 
approximately 90 (± 10) minutes after which the participant must be observed for 60 
minutes. If the loading dose is well tolerated, subsequent maintenance doses can be 
administered as 30-minute infusions (± 10 minutes) followed by an observation period of 
30 minutes. Participants can be observed for longer periods at the discretion of the 
investigator or if necessary, as per local requirements. 
Pre-medication with antipyretics, antihistamines, or corticosteroids may be administered 
before trastuzumab IV administration. 
If variation in the participant’s weight of ≥ ± 10% compared with study screening occurs, 
the trastuzumab IV dose will be recalculated. Weight at the time the dose is recalculated 
will be considered as baseline for subsequent evaluations of degree of weight change 
with respect to trastuzumab IV dose modification requirements. 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
68/Protocol MO43110, Version 3 
For information on the packaging, storage, and dispensing of trastuzumab IV, see the 
current trastuzumab SmPC. 
6.1.3 
Trastuzumab Emtansine 
Trastuzumab emtansine is given as a vial containing 160 mg powder for concentrate for 
solution for infusion. After reconstitution, one vial of 8 mL solution contains 20 mg/mL of 
trastuzumab emtansine. For information on the trastuzumab emtansine formulation, 
dosage and administration; see the Pharmacy Manual and the trastuzumab emtansine 
Investigator’s Brochure. 
Trastuzumab emtansine will be given at a dose of 3.6 mg/kg by IV infusion, q3w. The 
dose of trastuzumab emtansine will be administered based on the participant’s baseline 
weight after surgery. Weight will be measured at each visit (or in the 3 days prior) and 
dose must be re-adjusted for weight changes ≥ 10% compared to the previous visit or 
baseline. Administration may be delayed to assess or treat AEs. If trastuzumab 
emtansine is discontinued because of toxicity, it should not be re-administered. 
The initial dose should be administered as a 90-minute (± 10 minutes) intravenous 
infusion. Participants should be observed during the infusion and for at least 90 minutes 
following the initial infusion for fever, chills, or other infusion-related reactions. The 
infusion site should be closely monitored for possible subcutaneous infiltration during 
administration. If the prior infusion was well tolerated, subsequent doses of trastuzumab 
emtansine may be administered as 30-minute (± 10 minutes) infusions. Participants 
should be observed during the infusion and for at least 30 minutes after infusion. 
Pre-medication with antipyretics, antihistamines, or corticosteroids, according to local 
practice and investigator discretion, may be administered before trastuzumab emtansine 
administration. 
Trastuzumab emtansine cannot be initiated within ≤ 2 weeks of surgery but must be 
initiated ≤ 6 weeks of surgery. 
Trastuzumab emtansine IV dose should not be re-escalated after a dose reduction is 
made. If a planned dose is delayed or missed, it should be administered as soon as 
possible; do not wait until the next planned cycle. The schedule of administration should 
be adjusted to maintain a 3-week interval between doses. The infusion may be 
administered at the dose and rate the participant tolerated in the most recent infusion. 
The infusion rate of trastuzumab emtansine should be slowed or interrupted if the 
participant develops an infusion-related reaction. Permanently discontinue trastuzumab 
emtansine for life-threatening infusion-related reactions. 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
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Management of increased serum transaminases, hyperbilirubinemia, left ventricular 
dysfunction, thrombocytopenia, pulmonary toxicity, or peripheral neuropathy may require 
temporary interruption, dose reduction or treatment discontinuation. 
Recommended dose reduction schedule for adverse events: 
Dose Reduction Schedule 
Dose Level 
Starting dose 
3.6 mg/kg 
First dose reduction 
3 mg/kg 
Second dose reduction 
2.4 mg/kg 
Requirement for further dose reduction 
Discontinue treatment 
  
Trastuzumab emtansine dose should not be re-escalated after a dose reduction is made.  
See Appendix 3 for more information on the management of participants who experience 
adverse events during treatment with trastuzumab emtansine. 
Participants in Arm E who remain intolerant to trastuzumab emtansine after dose 
reduction can be discontinued from the study (and be treated as per standard of care) or 
can remain in the study and be treated with PH FDC SC in the hospital as to complete 
14 cycles of HER2-directed adjuvant study treatment in total. This decision is at the 
discretion of the treating physician. See Appendix 19 for details of the assessments to 
be conducted in these participants.  
Participants who discontinue trastuzumab emtansine because of toxicity that may be 
attributed to the trastuzumab component (e.g., hypersensitivity, cardiac toxicity, 
pneumonitis) may not continue to receive PH FDC SC after discontinuation of 
trastuzumab emtansine. 
6.1.4 
Chemotherapy and Endocrine Therapy 
Doxorubicin and cyclophosphamide treatments (neoadjuvant chemotherapy options 2 
and 3) should be given before HER2-targetting therapies (PH FDC SC or P+H IV). 
Taxanes (docetaxel or paclitaxel) and carboplatin should be given after HER2-targetting 
therapies (see Figure 1). 
The neoadjuvant chemotherapeutic treatments such as carboplatin, doxorubicin, 
cyclophosphamide, docetaxel, and paclitaxel are regarded as AxMPs. 
Chemotherapeutic drugs and endocrine therapy will be administered in accordance with 
local prescribing information according to the study scheme (see Figure 1 and Section 
4.1). 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
70/Protocol MO43110, Version 3 
Refer to the respective SmPC or other appropriate local reference document for 
information on formulation, preparation, administration, contraindications, and participant 
monitoring.  
6.1.5 
Pre-medications 
Pre-medications and other supportive medications are regarded as AxMPs. All 
participants may receive medications, at the discretion of the treating physician, to treat 
or prevent allergic or infusion reactions as mentioned in Section 6.8.2, permitted 
therapies. 
If pre-medication is required prior to administration of PH FDC SC in the home setting, 
the treating physician should prescribe pre-medications in tablet form. 
6.1.6 
Anaphylaxis Medication 
Anaphylaxis medications listed in Section 6.8.2 are permitted and are regarded as 
AxMPs. These are to be used only by the HCP in the event of a severe hypersensitivity 
reaction during or after administration of study treatment (PH FDC SC, pertuzumab IV, 
trastuzumab IV, or trastuzumab emtansine).  
Anaphylaxis kits are currently used in the study investigating the SC administration of 
PH FDC SC at home during the COVID-19 pandemic (Study AL42478).  
The sponsor will provide anaphylaxis kits for use in the home setting.  These kits must 
be available before the first home administration of PH FDC SC and should only be used 
by the mobile healthcare professional. Additional kits will be provided if kits expire, are 
damaged or are used during the study. 
Anaphylaxis kits will contain: 
 
x2 Diphenhydramine (30 mg [2 mL ampoule]) for intramuscular (IM*) injection or 
equivalent 
 
x1 Hydrocortisone sodium succinate (100 mg [2 mL vial]) for IM injection or 
equivalent 
 
x2 Epinephrine, USP Auto-Injector 0.3 mg for IM injection or equivalent 
 
*IM needles will be supplied by the mobile healthcare professional.   
See the Mobile Clinical Services Training Manual for guidance on the assessments to 
conduct if anaphylaxis medications are administered in the home setting.  
If anaphylaxis medications are administered during site administration of study 
treatments, participants should be treated according to local standard of care. 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
71/Protocol MO43110, Version 3 
6.2 
PREPARATION, HANDLING, STORAGE, AND 
ACCOUNTABILITY 
All IMPs required for completion of this study will be provided by the Sponsor. The study 
site (i.e., investigator or other authorized personnel e.g., pharmacist or HCPs) is 
responsible for maintaining records of IMP delivery to the site, IMP inventory at the site, 
IMP use by each participant, and disposition or return of unused IMP, thus enabling 
reconciliation of all IMP received, and for ensuring that participants are provided with 
doses specified by the protocol. 
The study site should follow all instructions included with each shipment of IMP. The 
study site will acknowledge receipt of IMPs supplied by the Sponsor, using an interactive 
voice or web-based response system (IxRS) to confirm the shipment condition and 
content. Any damaged shipments will be replaced. Temperature conditions for all IMPs 
will be monitored during transit, and any discrepancies will be reported and resolved 
before use of the IMPs. All IMPs must be stored in a secure, environmentally controlled, 
and monitored (manual or automated) area in accordance with the labeled storage 
conditions, with access limited to the investigator and authorized staff. 
Only participants enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or be returned to the Sponsor 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 Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log. 
For home administration of PH FDC SC, the PH FDC SC, pre-medication (if applicable), 
and anaphylactic medication will be delivered by courier from the site to the participant’s 
home at the time of the scheduled visit and received by the mobile healthcare 
professional. PH FDC SC and pre-medication (if applicable) will be delivered at every 
home visit. Anaphylactic medication will be delivered at the first home visit in a locked 
medication box and will be kept at room temperature in the patient’s home. Only the 
mobile healthcare professional will have the code for the lock box. If replacements of the 
medications are needed (i.e., because they expired or were used), the site will provide 
the replacement medication with the next shipment of PH FDC SC to the patient’s home. 
The mobile healthcare professional will confirm the supplies were handled appropriately 
during transit and will be responsible for returning any used and unused drugs and other 
supplies to the study site. See the Mobile Clinical Services Training Manual for more 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
72/Protocol MO43110, Version 3 
information on the delivery and handling of study treatments and other medications for 
administration in the home setting. 
Refer to the Pharmacy Manual and/or the PH FDC SC, pertuzumab, and trastuzumab 
emtansine Investigator’s Brochures, and the trastuzumab SmPC, for information on IMP 
preparation, storage, handling, and accountability.  
6.3 
TREATMENT ASSIGNMENT  
6.3.1 
Treatment Assignment 
This is a randomized, open-label study. After initial written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a participant, the study site will obtain the participant’s 
identification number and treatment assignment from an IxRS. Randomization in both 
the neoadjuvant and adjuvant phases will occur through the use of a permuted-block 
randomization method to ensure a balanced assignment to each treatment arm.  
During the neoadjuvant phase, the enrolled participants will be randomly allocated, in a 
ratio of 1:2, to Arm A or Arm B (defined in Section 4.1.1). Randomization in the 
neoadjuvant phase will be stratified by disease stage at screening (operable [T2–3, N0–
1, M0, or T1/N1/M0], locally advanced [T1–3, N2–3, M0 or T4a–c, any N, M0], or 
inflammatory [T4d, any N, M0]) and neoadjuvant chemotherapy option (see Section 
4.1.1: anthracycline-free [chemotherapy option 1] or anthracycline-based [chemotherapy 
options 2 or 3]). 
After completing their neoadjuvant therapy, participants from both arms will undergo 
surgical resection for early or locally advanced HER2+ breast cancer (if eligible for 
surgery). Participants who have achieved pCR after surgery will continue adjuvant 
treatment with PH FDC SC, while participants with pathologic evidence of residual 
invasive carcinoma in the breast or axillary lymph nodes following completion of 
preoperative therapy and surgery will undergo adjuvant treatment with trastuzumab 
emtansine IV in Arm E (see Section 4.1.2). 
Participants who have achieved pCR after surgery will receive the first 2 cycles of 
PH FDC SC in the hospital. Then, participants will be randomized to Arm C or Arm D 
(see Section 4.1.2) with a ratio of 1:1 in a cross-over treatment period to receive the next 
6 cycles of PH FDC SC treatment. Randomization will occur after completion of the last 
cycle of radiotherapy (if applicable, see Section 4.1.2) and last cycle of PH FDC SC 
(during the run-in period). Randomization in the adjuvant phase will be stratified by 
disease stage at screening (same as above), type of surgery (conservative or 
mastectomy), and neoadjuvant chemotherapy option (same as above). 
After the cross-over treatment period, participants will receive the remaining PH FDC SC 
treatment cycles as described in Section 4.1.2.  

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
73/Protocol MO43110, Version 3 
 
6.4 
STUDY TREATMENT COMPLIANCE 
When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed.  
When participants are dosed at the site or at home, they will receive study treatment 
directly from the investigator or designee, under medical supervision. The date and time 
of each dose administered in the clinic will be recorded in the source documents and 
recorded on the electronic Case Report Form (eCRF). The dose of study treatment and 
study participant identification will be confirmed at the time of dosing by a member of the 
study site staff other than the person administering the study treatment. 
Details on treatment administration (e.g., dose and timing) should be noted in the source 
documents and on the Study Drug Administration eCRF. Cases of accidental overdose or 
medication error, along with any associated adverse events, should be reported as 
described in Appendix 2. 
6.5 
DOSE MODIFICATION 
Modification of the PH FDC SC dose or P+H IV dose is not permitted.  
For trastuzumab emtansine, management of symptomatic adverse events may require 
temporary interruption, dose reduction, or treatment discontinuation of trastuzumab 
emtansine IV as per guidelines provided in local label. Trastuzumab emtansine IV dose 
should not be re-escalated after a dose reduction is made. Refer to Section 6.1.3 for 
details of dose modification. 
6.6 
CONTINUED ACCESS TO STUDY TREATMENT AFTER THE 
END OF THE STUDY 
Currently, the Sponsor does not have any plans to provide Roche IMPs (PH FDC SC, 
pertuzumab IV, trastuzumab IV, trastuzumab emtansine IV) or any other study 
treatments to participants who have completed the study.  The Sponsor may evaluate 
whether to continue providing PH FDC SC, pertuzumab IV, trastuzumab IV, trastuzumab 
emtansine IV in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
 
6.7 
TREATMENT OF OVERDOSE 
An overdose is the administration of a drug in a quantity that is higher than the assigned 
dose. There is no known antidote for treating an overdose. Cases of overdose, along 
with any associated adverse events, should be reported as described in Appendix 2. 
In the event of an overdose, the investigator should take the following steps: 
1. 
Contact the Medical Monitor  

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
74/Protocol MO43110, Version 3 
2.  Closely monitor the participant for any adverse event or serious adverse event and 
laboratory abnormalities until the study treatment can no longer be detected 
systemically (at least 28 days). 
  
6.8 
CONCOMITANT THERAPY 
Any medication (including over-the-counter or prescription medicines, vitamins, and 
herbal supplements) and vaccine used by a participant in addition to protocolmandated 
treatment from 7 days prior to initiation of study treatment to the end of the treatment 
visit must be recorded on the concomitant medications form (CMF) and eCRF along with 
the following information: 
 
Reason for use 
 
Dates of administration, including start and end dates 
 
Dosage information, including dose and frequency 
 
The Medical Monitor may be consulted if there are any questions related to concomitant 
or prior therapy. 
6.8.1 
Surgery 
Participants in both arms are scheduled to undergo surgery after completing their 
neoadjuvant therapy.  Participants may undergo breast-conserving surgery or 
mastectomy according to routine clinical practice. The surgery cannot be performed ≤ 2 
weeks from the last systemic neoadjuvant therapy and must be performed ≤ 6 weeks 
after the last systemic neoadjuvant therapy. 
If surgery is significantly delayed (>42 days since the last P+H IV or PH FDC SC 
administration), a maximum of two additional cycles of P+H IV or PH FDC SC 
(depending on the treatment arm (A or B) assigned to the participant at randomization), 
can be administered at the investigator’s discretion before surgery, in order to maintain 
adequate serum levels of pertuzumab and trastuzumab. See Appendix 18 for details of 
the assessments that should be conducted for participants who require additional cycles 
of P+H IV or PH FDC SC due to a delay with surgery. 
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. 
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.  

 
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In participants with clinically negative axillary nodes at screening, 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 participants 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. 
Participants with clinically positive axillary lymph nodes at screening 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 participants with gross disease 
in the Level II nodes. 
Investigators may follow more up-to-date guidelines on axilla management based on 
emerging data once they have been incorporated into institutional, local, national, or 
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 
and in Section 8.4. 
For participants not eligible for surgery (for example, those whose tumor remains 
inoperable after neoadjuvant treatment), locoregional and/or systemic management will 
be done as per local standard practice.  These participants 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. 
6.8.2 
Permitted Therapy  
Participants are permitted to use the following therapies during the study: 
 
Hormone therapy for breast cancer as per local guidelines 
 
Bisphosphonate therapy as per local guidelines 

 
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 
Adjuvant radiotherapy for breast cancer. After surgery, radiotherapy is to be given 
as clinically indicated and as per local practice or institutional standards  
For participants who have achieved pCR, the selected radiotherapy regimen 
should be initiated within 4–6 weeks after surgery and should not last longer 
than 5 weeks (see Section 4.1.2) 
 
Contraception: acceptable methods of contraception must be used when the female 
participant is of childbearing potential (i.e., is post-menarchal, has not reached a 
post-menopausal state [post-menopausal defined as ≥ 12 continuous months of 
amenorrhea with no identified cause other than menopause], and has not 
undergone surgical sterilization [removal of ovaries and/or uterus]). Acceptable 
methods of contraception are described in Section 5.1.1 
 
H1-receptor or H2-receptor antagonists (e.g., diphenhydramine, cimetidine) 
 
Cardiovascular medications including angiotensin-converting enzyme (ACE) 
inhibitors, angiotensin receptor blockers, beta blockers, calcium channel blockers 
and diuretics, beta blockers, calcium channel blockers, digoxin, thrombocyte 
aggregation inhibitors 
 
Analgesics / anti-inflammatories (e.g., paracetamol / acetaminophen, meperidine, 
opioids) 
 
Short-term use of corticosteroids to treat or prevent allergic or infusion reactions are 
allowed, however, the dose must not exceed > 20 mg/day of dexamethasone (or 
equivalent) for > 7 consecutive days. 
 
Standard therapies for pre-existing medical conditions and medical or surgical 
complications 
 
Any medication intended solely for supportive care (e.g., analgesics, antidiarrheals, 
antidepressants) at the investigator’s discretion 
 
Colony-stimulating factors (e.g., G-CSF)  
 
Blood transfusions at the investigator’s discretion 
 
Gonadotropin-releasing hormone agonists for fertility preservation 
 
Vitamin and mineral supplements 
 
Bone density modifying agents (to be used in accordance with the approved labelled 
indication and/or nationally recognized treatment guidelines) 
 
COVID-19 vaccine could be administered at the investigator’s discretion as the 
situation for every participant is different in different parts of the world 
 
Any other medication not included in the list of prohibited medications 
 
In general, investigators should manage a participant’s care with supportive therapies as 
clinically indicated, per institutional standard practice. Participants who experience 
infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, 
cimetidine), or equivalent medications per institutional standard practice. Serious 
infusion-associated events manifested by dyspnea, hypotension, wheezing, 

 
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bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and β2-adrenergic agonists). 
6.8.3 
Cautionary Therapy 
6.8.3.1 
Medications Given with Precaution due to Effects Related to 
CYP Enzymes 
In vitro data suggest that DM1, a component of trastuzumab emtansine is metabolized 
mainly by cytochrome p450 (CYP) CYP3A4 and, to a lesser extent, by CYP3A5, and 
there is a moderate to high potential for drug-drug interaction with any medication that is 
metabolized by or strongly inhibits or induces these enzymes. DM1 does not induce or 
inhibit P450-mediated metabolism in vitro. Therefore, the medications listed below 
should be avoided. If use of one of these medications is necessary, the risks and 
benefits should be assessed by the investigator prior to concomitant administration with 
trastuzumab emtansine. The Medical Monitor is available to advise as needed. 
 
Strong CYP3A4/CYP3A5 inhibitors, including, but not limited to, ketoconazole and 
itraconazole 
 
The investigator should consult the prescribing information when determining whether a 
concomitant medication can be safely administered with study treatment. In addition, the 
Medical Monitor is available to advise if questions arise regarding medications not listed 
above. If a strong CYP3A4/5 inhibitor needs to be co-administered with trastuzumab 
emtansine, patients should be closely monitored for adverse reactions.” 
6.8.3.2 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their PK, safety 
profiles, and potential drug-drug interactions are generally unknown. However, herbal 
therapies not intended for the treatment of cancer may be used during the study at the 
discretion of the investigator. 
6.8.3.3 
Therapies Given for Chemotherapy Induced Thrombocytopenia 
Concomitant use of therapies for prevention and treatment of thrombocytopenia induced 
by chemotherapy, e.g., thrombopoietin receptor agonists, recombinant thrombopoietins, 
recombinant interleukin, should be avoided. Adherence to the relevant safety 
management guidelines to institute appropriate dose modifications of trastuzumab 
emtansine in case of thrombocytopenia is recommended (Appendix 3). If any of those 
agents needs to be co-administered with trastuzumab emtansine in line with local 
standard clinical practice, patients should be closely monitored for adverse reactions and 
overlapping toxicities. 
6.8.4 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
 
Any investigational therapy or agent (other than protocol-mandated study treatment) 
within 28 days prior to initiation of study treatment and during study treatment 

 
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 
Any anti-cancer treatment other than adjuvant hormone treatment, adjuvant 
radiotherapy or bone density modifying treatment 
 
Regular systemic treatment with steroids. Short-term corticosteroid to treat and 
prevent allergic or infusion reactions are allowed however the dose must not 
exceed > 20 mg/day of dexamethasone (or equivalent) for > 7 consecutive days. 
 
Any systemically active oral, injected, or implanted hormonal method of 
contraception (see Section 5.1.1 or acceptable contraception methods) except for 
progesterone-coated IUDs that had been previously implanted 
 
Hormone-replacement therapy 
 
Use of erythropoiesis-stimulating agents (e.g., erythropoietin) 
 
Herbal remedies initiated for cancer treatment. Other herbal remedies are 
discouraged but permitted and must be reported on the appropriate eCRF 
 
Live attenuated vaccines (e.g., FluMist) in the 30 days prior to initiation of study 
treatment, during study treatment, and for 90 days after the final dose of study 
treatment. Treatment with live vaccines is permitted for participants receiving 
adjuvant treatment with trastuzumab emtansine (Arm E)  
 
For participants with hormone-receptor positive tumors: Topical estrogens (including 
any intra-vaginal preparations), megestrol acetate, and selective ER modulators 
used with prophylactic intent are prohibited. Post-menopausal 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 unsuccessful at ameliorating symptoms. 
 
7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL 
Study and site closure is described in Appendix 1. 
7.1 
ASSESSMENTS AT THE TREATMENT 
COMPLETION/DISCONTINUATION VISIT 
Participants who complete study treatment (all cycles of chemotherapy and HER2-
targeted therapy) or discontinue from all study treatment early will be asked to return to 
the clinic for a treatment completion / treatment discontinuation visit 28 days (± 7 days) 
after the final dose of study drug (see Table 4 or Table 5 for additional details).  If a 
participant has progressive disease or relapse, the visit at which this is determined may 
be used as the treatment completion/early discontinuation visit. 
7.2 
DISCONTINUATION OF STUDY TREATMENT 
It may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study treatment. If study treatment is definitively discontinued, the 
participant will not remain in the study for additional assessments. Refer to the schedule 
of activities (see Section 1.3) for data to be collected at the time of discontinuation of 
study treatment and for any further follow-up evaluations that need to be completed. 

 
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Participants must permanently discontinue study treatment if any of the following criteria 
are met: 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the participant’s safety if he or she continues to receive study treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the participant 
 
Pregnancy  
 
Heart failure (NYHA class III or IV) 
 
Anaphylaxis associated with any of the study drugs 
 
Participants who experience disease recurrence or progression will be withdrawn 
from study treatment and referred back to the treating physician 
 
Participants who experience severe infusion/injection related reactions with P+H IV 
or PH FDC SC.  
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. Participants who discontinue study treatment prematurely will not be 
replaced. 
Participants will return to the clinic for a treatment completion / treatment discontinuation 
visit 28 days (± 7 days) after the final dose of study drug (see Table 4 or Table 5 for 
additional details). Anti-cancer treatment for participants who have prematurely 
discontinued study treatment is at the discretion of the investigator as clinically indicated. 
7.3 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL FROM 
THE STUDY 
A participant may withdraw from the study at any time at his or her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. 
Every effort should be made to obtain a reason for participant discontinuation from the 
study. The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF. If a participant requests to be withdrawn from the study, this 
request must be documented in the source documents and signed by the investigator. 
At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the schedule of activities (see Section 1.3). Refer to 
the schedule of activities for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
The participant will be permanently discontinued both from the study treatment and from 
the study at that time. Participants who withdraw from the study will not be replaced. 

 
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If a participant withdraws consent from the study, the Sponsor may retain and continue 
to use any data collected before withdrawal of consent. Samples collected prior to 
withdrawal may be analyzed, unless the participant specifically requests that the 
samples be destroyed (as documented in the source documents) 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.  
7.4 
PARTICIPANTS LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
 
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule. If the participant is unable or unwilling to comply with study 
visits, site personnel should assess reasons the participant is unable or unwilling to 
return to the clinic, and determine if there are ways to support participant 
participation.  
 
Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, three 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 
 
Should the participant continue to be unreachable, he or she will be considered lost 
to follow-up and will be withdrawn from the study.  
  
8. 
STUDY ASSESSMENTS AND PROCEDURES 
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 individuals and for individuals who are not subsequently 
enrolled will be maintained at the study site. 
Study procedures and their timing are summarized in the schedule of activities (see 
Section 1.3). Protocol waivers or exemptions are not allowed. 
Urgent safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment. 
Adherence to the study design requirements, including those specified in the schedule of 
activities, is essential and required for study conduct. 

 
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All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a detailed record of 
all participants screened, to document eligibility or record reasons for screening failure, 
as applicable. 
Procedures conducted as part of the participant’s routine clinical management 
(e.g., complete blood count) and obtained before signing of the Informed Consent Form 
may be utilized for screening purposes provided the procedures meet the 
protocol-specified criteria and are performed within the timeframe defined in the 
schedule of activities. 
Medical history and baseline conditions, including clinically significant diseases, 
surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, smoking history, and use of alcohol and drugs of abuse will be recorded at 
screening. Any vaccine and/or medication (including over-the-counter or prescription 
medicines, vitamins, and/or herbal supplements) used by the participant within 7 days 
prior to initiation of study treatment will be recorded. Demographic data, including age, 
sex, and self-reported race or ethnicity, will also be recorded. At the time of each follow-
up physical examination, an interval medical history should be obtained and any 
changes in medications and allergies should be recorded. 
Participants will be closely monitored for safety throughout the study. Participants should 
be assessed for toxicity prior to each dose; treatment will be administered only if the 
clinical assessment and local laboratory test values are acceptable. Urgent safety 
concerns should be discussed with the Sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study treatment. 
Certain study assessments will be performed by a mobile healthcare professional at the 
participant’s home as per the schedule of activities (see Section 1.3, Table 4) to improve 
access and convenience for participants participating in the study. The Sponsor will 
select a healthcare company that will be responsible for providing mobile healthcare 
professional services for participating sites (the mobile healthcare professional vendor).  
The mobile healthcare professional vendor is responsible for ensuring that all mobile 
healthcare professionals are licensed, qualified, and in good standing, as per applicable 
regulations, and that appropriate background checks have been performed. The mobile 
healthcare professional network will communicate with the participant and the 
participant’s site. Mobile healthcare professional visits will be scheduled on specified 
visit days, to allow for relevant assessments to be performed by the mobile healthcare 
professional. The mobile healthcare professional will contact the participant within 3 
business days before the visit, to confirm the time and place of the visit. During home 
visits, the mobile healthcare professional will complete the study assessments as 
requested by the study site (in line with the schedule of activities [Table 4]). The mobile 
healthcare professional will provide the information collected to the treating physician 
(via phone call) who will determine if the participant should receive the next PH FDC SC 

 
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treatment. If required, the study investigator may request the participant attends the 
hospital for assessment by the treating physician.  The schedule of activities (see 
Section 1.3, Table 4) will specify the assessments that may be performed by a mobile 
healthcare professional (see also the Mobile Clinical Services Training Manual). 
In exceptional circumstances, as approved by the Sponsor, HCPs from study sites may 
undertake the home health visits instead. 
8.1 
EFFICACY ASSESSMENTS 
Pathologic response will be evaluated after surgery by the pathologists in the local 
laboratories.  
Achievement of pCR is defined as the absence of residual invasive cancer on 
hematoxylin and eosin evaluation of the complete resected breast specimen and all 
sampled regional lymph nodes following completion of neoadjuvant systemic therapy 
(i.e., ypT0/Tis ypN0), according to the current AJCC staging system classification (FDA 
2020).  
8.2 
SAFETY ASSESSMENTS 
8.2.1 
Physical Examinations 
Physical examination should be conducted as outlined in the schedule of activities 
(see Section 1.3). A complete physical examination will include, at a minimum, 
assessments of physical measurements (body weight in kilograms and, at screening 
only, height in centimeters) and evaluation of the head; eyes; ears; nose; throat; and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems. ECOG Performance Status will also be 
assessed. Any abnormality identified at screening should be recorded on the General 
Medical History and Baseline Conditions eCRF. 
Limited symptom-directed physical examinations including weight should be performed 
at specified post-screening visits and as clinically indicated. Investigators should pay 
special attention to clinical signs related to previous serious illnesses. Changes from 
abnormalities identified at screening should be recorded in participant notes. New or 
worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF. In the adjuvant setting, the mobile HCP should complete the 
limited physical examinations in accordance with local practice/regulations. 
Physical examinations should be conducted in accordance with institutional practice or 
the American Cancer Society/American Society of Clinical Oncology Breast Cancer 
(ACS/ASCO) Breast Cancer Survivorship Care Guideline (Runowicz et al. 2016). 
8.2.2 
Vital Signs 
Vital signs should be conducted as outlined in the schedule of activities 
(see Section 1.3). Temperature, pulse rate, respiratory rate, and systolic and diastolic 

 
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blood pressure will be assessed before and after study treatment administration. Vital 
signs will be measured once at visits where no study treatment is administered. 
Blood pressure, respiratory and pulse measurements will be assessed while the 
participant is in a seated position with a completely automated device. Manual 
techniques will be used only if an automated device is not available.  
Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (e.g., television, cell phones). 
Vital signs (to be taken before blood collection for laboratory tests while the participant is 
in a seated position) will consist of one pulse and one blood pressure measurement. 
If anaphylactic medications are administered at the study site due to hypersensitivity 
and/or anaphylactic reaction, vital signs monitoring will be conducted according to local 
standard of care. 
During home administration of study treatment, if a participant experiences 
hypersensitivity and/or anaphylactic that necessitate the administration of anaphylactic 
medications (see Section 6.1.6), blood pressure and respiratory rate will be measured 
approximately every 5 minutes by the mobile healthcare professional. Pulse rate and 
oxygen saturation will be continuously monitored using the pulse oximeter. Vital signs 
will be measured until symptoms have fully resolved or emergency medical services 
arrive. The mobile healthcare professional will promptly contact the site and specify 
details of the event.  
8.2.3 
Electrocardiograms 
Single 12-lead ECGs will be obtained as outlined in the schedule of activities (see 
Section 1.3) using an ECG machine that automatically calculates the heart rate and 
measures PR interval, QRS interval and QT interval. Refer to Appendix 3 for withdrawal 
criteria and any additional readings that may be necessary. 
Lead placement should be as consistent as possible. ECG recordings must be 
performed after the participant has been resting in a supine position for at least 
10 minutes. All ECGs are to be obtained prior to other procedures scheduled at that 
same time (e.g., vital sign measurements, blood draws) and should not be obtained 
within 3 hours after any meal. Circumstances that may induce changes in heart rate, 
including environmental distractions (e.g., television, radio, conversation) should be 
avoided during the preECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
reports. Paper copies of ECG tracings will be kept as part of the participant’s permanent 
study file at the site. Digital recordings (if available) will be stored at the site.  The 
following should be recorded on the appropriate eCRF:  heart rate, RR interval, QRS 

 
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interval, PR duration, uncorrected QT interval, and QTcF based on machine readings of 
the individual ECG tracings. Any morphologic waveform changes or other ECG 
abnormalities must be documented on the eCRF. 
If at a particular postdose time point the mean QTcF is  500 ms and/or  60 ms longer 
than the screening (baseline) value, another ECG must be recorded, ideally within the 
next 5 minutes, and ECG monitoring should continue until QTcF has stabilized on two 
successive ECGs. The Medical Monitor should be notified. Standard-of-care treatment 
may be instituted at the investigator’s discretion. A decision on study drug 
discontinuation should be made, as described in Appendix 3 (Section A3–2.3). The 
investigator should also evaluate the participant for potential concurrent risk factors 
(e.g., electrolyte abnormalities, co-medications known to prolong the QT interval, severe 
bradycardia). 
8.2.4 
Cardiac Function  
Assessment of cardiac function should be conducted as outlined in the schedule of 
activities (see Section 1.3). All participants must have a prior LVEF ≥ 55% by ECHO or 
MUGA scan in order to be eligible for the study. If the participant has not had an LVEF 
measured in the last 12 weeks, an ECHO or MUGA should be performed at the 
screening visit. If possible, the same LVEF evaluation method should be used 
throughout the study for each participant and should be 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, LVEF assessment may also be performed on Day 1 of treatment. The 
results must be available before treatment is administered. Apart from the specified 
mandatory LVEF assessment, the investigator may request additional assessment based 
on the individual participant's cardiovascular function with a minimum frequency of 
3–4 months.  
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 participants in this 
study require LVEF assessment on more than four occasions within one year.  
8.2.5 
Clinical Breast Examination 
Clinical breast examination should be conducted as outlined in the schedule of activities 
(see Section 1.3). During the neoadjuvant treatment period, tumor response assessment 
will be performed at screening, prior to each new cycle of therapy, and at treatment 
discontinuation (if applicable), by clinical breast examination (mandatory) and other 
methods of evaluation as per routine clinical practice. Assessment may be done within 
3 days prior to treatment day.  

 
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All measurable and/or evaluable lesions should be assessed and documented at 
screening. Tumor assessments performed as standard of care prior to obtaining 
informed consent and within 28 days prior to initiation of study treatment do not have to 
be repeated at screening so long as they meet the criteria defined. 
Assessments should be conducted by treating physician in accordance with institutional 
practice or the American Cancer Society/American Society of Clinical Oncology Breast 
Cancer (ACS/ASCO) Breast Cancer Survivorship Care Guideline (Runowicz et al. 2016). 
8.2.6 
Mammograms 
Mammograms should be conducted as outlined in the schedule of activities 
(see Section 1.3). Bilateral mammogram must be obtained at screening and at treatment 
completion or treatment discontinuation visit. A mammogram prior to surgery (after the 
last cycle of neoadjuvant treatment) is also required. Participants who have undergone a 
mastectomy and have had breast reconstruction do not require mammograms.  
If the participant’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 magnetic resonance imaging (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 participant. 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. 
8.2.7 
Diagnosis of Breast Cancer Recurrence or Second Primary 
Cancer 
Diagnosis of breast cancer recurrence or second primary cancer should be conducted 
as outlined in the schedule of activities (see Section 1.3). All participants must be 
followed to assess disease recurrence and second primary cancers. The designation of 
disease recurrence whether local, regional or distant, or a diagnosis of second primary 
cancer will be conducted per institutional practice or according to ACS / ASCO Breast 
Cancer Survivorship Care Guideline (Runowicz et al. 2016) but can be made only when 
clinical, laboratory, radiological and/or histological findings support the diagnosis. 
The diagnosis of a breast cancer progression, recurrence or a second primary 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 or suspicion of 
progression. 

 
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Recurrent disease includes local, regional, and distant recurrence and contralateral 
invasive breast cancer. Participants 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 participants 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 participants. 
8.2.8 
Clinical Safety Laboratory Assessments 
See Appendix 11 for the list of clinical laboratory tests to be performed and the schedule 
of activities (see Section 1.3) for the timing and frequency. Samples for the laboratory 
tests will be sent to the study sites local laboratory for analysis.  
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the Adverse Event eCRF (see 
Appendix 2).  
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study treatment should 
be repeated until the values return to normal or baseline or are considered to be stable 
and no longer considered clinically significant by the investigator. If such values do not 
return to normal or baseline within a period judged reasonable by the investigator, the 
etiology should be identified, and the Sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 11, must be 
conducted in accordance with the schedule of activities. 
If laboratory values from non-protocol-specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., serious adverse event or 
adverse event or dose modification), the results must be recorded on the eCRF. 
Samples collected for safety laboratory tests will be destroyed no later than the time of 
completion of the final Clinical Study Report. 
8.2.9 
Pregnancy Testing 
The schedule for pregnancy testing for enrolled female participants is outlined in 
Section 1.3 and will be conducted as outlined in Appendix 11.  
8.3 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND OTHER 
SAFETY REPORTING 
The definitions of adverse event and serious adverse event can be found in Appendix 2. 

 
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Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an adverse event or serious adverse 
event and remain responsible for following up adverse events that are serious, are 
considered related to the study treatment or study procedures, or caused the participant 
to discontinue the study treatments (see Section 7). 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information 
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 
(see Appendix 2). All other medical occurrences that begin before the start of study 
treatment but after obtaining informed consent will be recorded on the General Medical 
History and Baseline Conditions eCRF, not the Adverse Event eCRF. 
All adverse events will be reported from the start of treatment until 28 days after the final 
dose of study treatment or until it is resolved, whichever is longer and at the time points 
specified in the schedule of activities (see Section 1.3). 
All serious adverse events will be recorded and reported to the Sponsor or designee 
immediately, and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 2. The investigator will submit any updated serious adverse event data to the 
Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek adverse event or serious adverse event 
information after conclusion of study participation. However, if the investigator learns of 
any serious adverse event, including death, at any time after a participant has been 
discharged from the study, and he or she considers the event to be reasonably related to 
the study treatment or study participation, the investigator must promptly notify the 
Sponsor. 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events 
The method of recording, evaluating, and assessing causality of adverse events and 
serious adverse events and the procedures for completing and transmitting serious 
adverse event reports are provided in Appendix 2. 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events. Open-ended and non-leading verbal questioning of the participant is the 
preferred method to inquire about adverse event occurrences. 

 
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8.3.3 
Follow-Up of Adverse Events and Serious Adverse Events 
After the initial adverse event or serious adverse event report, the investigator is 
required to proactively follow each participant at subsequent visits or contacts. All 
adverse events will be followed until the event has resolved to baseline grade or better, 
the event is assessed as stable by the investigator, the participant is lost to follow-up (as 
defined in Section 7.4), or the participant withdraws consent. Further information on 
follow-up procedures is provided in Appendix 2. 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events 
Prompt notification (i.e., within 24 hours of awareness) by the investigator to the Sponsor 
of a serious adverse event is essential so that legal obligations and ethical 
responsibilities towards the safety of participants and the safety of a study treatment 
under clinical investigation are met. 
The Sponsor has a legal responsibility to notify regulatory authorities about the safety of 
a study treatment under clinical investigation. The Sponsor will comply with regulatory 
requirements for expedited safety reporting to regulatory authorities (which includes the 
use of applicable systems, such as EudraVigilance), Institutional Review Boards or 
Ethics Committees (IRBs/ECs), and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Sponsor policy and forwarded 
to investigators as necessary. 
To determine reporting requirements for serious adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below: 
Drug 
Document 
PH FDC SC 
PH FDC SC Investigator’s Brochure  
Pertuzumab IV 
Pertuzumab Investigator’s Brochure  
Trastuzumab IV 
Trastuzumab E.U. Summary of Product Characteristics 
Trastuzumab emtansine IV 
Trastuzumab emtansine 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 investigator who receives an investigator safety report describing a serious adverse 
event or other specific safety information (e.g., summary or listing of serious adverse 

 
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events) from the Sponsor will review and then file it along with the Investigator’s 
Brochure and the Summary of Product Characteristics and will notify the IRB/EC, if 
appropriate according to local requirements. 
8.3.5 
Pregnancy 
If a pregnancy is reported, the investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4. 
All pregnancies reported during the study should be followed until pregnancy outcome, 
with follow-up information on the infant collected according to procedures outlined in 
Appendix 4. The Sponsor or a designee may follow up by telephone, fax, email, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 
8.3.6 
Cardiovascular and Death Events 
Information on reporting deaths is provided in Appendix 2. 
8.3.7 
Anticipated Events Not Qualifying for Expedited Reporting 
Events not qualifying for expedited reporting will not be defined for this study.  
8.3.8 
Adverse Events of Special Interest  
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after the investigator becomes aware 
of the event; see Appendix 2 Section A2–5 for reporting instructions). Adverse events of 
special interest for this study are as follows: 
 
An asymptomatic decline in LVEF that requires treatment or that leads to 
discontinuation of study treatment  
 
Congestive heart failure (CHF) 
 
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 Appendix 2 Section A2–7.7) 
 
Suspected transmission of an infectious agent by a study treatment, 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 participant exposed to a medicinal product. This term applies 
only when a contamination of the study treatment is suspected. 

 
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Descriptions of risks and management of the above-listed adverse events are provided 
in Appendix 3. 
8.3.9 
Medical Monitors and Emergency Medical Contacts 
 
Investigators will be provided with contact information for the Medical Monitor. An 
Emergency Medical Call Center will also be available 24 hours per day, 7 days per 
week. The Emergency Medical Call Center will connect the investigator with an 
Emergency Medical Contact, provide medical translation service if necessary, and track 
all calls. Contact information, including toll-free numbers for the Emergency Medical Call 
Center, will be distributed to investigators.  
8.4 
PATHOLOGY 
Disease stage will be determined prior to randomization to determine study eligibility and 
for randomization stratification in the neoadjuvant phase. Tumor staging at screening is 
not mandatory if the results of staging performed as per local practice, in alignment with 
national guidelines and as clinically indicated, within 28 days of randomization are 
available. 
Results of HER2 and hormone receptor testing conducted by a local laboratory based on 
breast tumor tissue obtained prior to initiation of neoadjuvant treatment will be collected 
to assure study eligibility. Results of previous HER2/hormone receptor status diagnoses 
can be used to determine eligibility if the sample was tested in the 90 days prior to 
enrollment. Reassessment of HER2/hormone receptor status is not mandatory in these 
cases but can be done as per local decision. 
After surgery, pathologic response will be assessed by the local pathologist using 
guidelines provided in a Pathology Manual.  See Section 8.1 for the definition of pCR.  
Molecular assay for analysis of sentinel lymph nodes after neoadjuvant therapy is not 
allowed. 
8.5 
PHARMACOKINETICS 
Pharmacokinetic parameters are not evaluated in this study. 
8.6 
PHARMACODYNAMICS 
Pharmacodynamic biomarker assessments will not be performed in this study. 
8.7 
GENETICS 
Genetic biomarker assessments will not be performed in this study. 
8.8 
BIOMARKER ASSESSMENTS 
Biomarker assessments will not be performed in this study. 

 
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8.9 
IMMUNOGENICITY ASSESSMENTS 
Immunogenicity assessments will not be performed in this study. 
8.10 
HEALTH ECONOMICS AND MEDICAL RESOURCE 
UTILIZATION 
Health economics and medical resource utilization assessments will not be performed in 
this study. 
8.11 
CLINICAL OUTCOME ASSESSMENTS  
Patient-reported outcome (PRO) and clinician-reported outcome (ClinRO) instruments 
will be completed to assess participant preference for study treatment administration in 
the home setting and in the hospital setting, treatment impact on quality of life, and 
HCPs experience with study treatment administration. 
PRO data will be collected through use of the following instruments:  
 
PPQ: Patient preference data will be collected through the PPQ (Appendix 5).  
 
HRQoL: Health-related Quality of Life will be assessed based on the European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire 
C30 (EORTC QLQ-C30) completed at specified timepoints throughout the study 
(Appendix 8).  
 
ClinRO data will be collected through use of the following instruments:  
 
HCPQ: Healthcare professionals’ perception of the use of time/resources and the 
convenience of administering the treatment will be assessed through HCPQs 
administered in the neoadjuvant phase (Appendix 6 and Appendix 7) and the 
adjuvant phase (Appendix 9 and Appendix 10). 
 
8.11.1 
Data Collection Methods for Clinical Outcome Assessments 
PRO instruments will be self-administered (or interviewer-administered if required, such 
as in cases of participant illiteracy) at specified timepoints during the study (see 
schedule of activities in Section 1.3). The PRO instruments will be administered before 
the participant receives any information on disease status, prior to the performance of 
non-PRO assessments, and prior to the administration of study treatment, unless 
otherwise specified. 
PRO instruments, translated into the local language as appropriate, will be provided by 
the Sponsor in paper form to enable the appropriate instruments to be administered in 
the correct order at each specified timepoint. 
Participants should be given the following instructions for completing PRO instruments at 
home: 
 
Participants should complete the instruments in a quiet area with minimal 
distractions and disruptions. 

 
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 
Participants should answer questions to the best of their ability; there are no right or 
wrong answers. 
 
Participants should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
During clinic visits and visits conducted by a mobile healthcare professional, PRO 
instruments should be administered as outlined below: 
 
Participants’ health status should not be discussed prior to administration of the 
instruments. 
 
Sites must administer the official version of each instrument, as provided by the 
Sponsor. Instruments must not be copied from the protocol. 
 
Sites should allow sufficient time for participants to complete the instruments, 
estimated to be 5–15 minutes at each specified visit. 
 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions. 
 
Participants should be instructed to answer questions to the best of their ability; 
there are no right or wrong answers. 
 
Site staff should not interpret or explain questions, but may read questions verbatim 
upon request. 
 
Participants should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
 
Site staff should review all completed instruments and should ask the participants to 
rectify any response that is not clearly marked in the appropriate location. If a response 
is missing, site staff should ask the participants to complete the item or confirm that the 
item was intentionally left blank.  
ClinRO instruments will be completed at specified timepoints during the study (see 
schedule of activities in Section 1.3). The instruments will be provided by the Sponsor in 
paper form. Clinicians must complete the official version of each ClinRO instrument, as 
provided by the Sponsor. Instruments must not be copied from the protocol.  
8.11.2 
Description of Clinical Outcome Assessment Instruments 
 
8.11.2.1 
Patient Preference Questionnaire  
The PPQ was used to evaluate the patient preference for PH FDC SC compared to 
P+H IV in the PhranceSCa study (Study MO40628, O’Shaughnessy et al. 2020). In this 
phase II study, 85% (136/160) of people receiving treatment for HER2+ breast cancer 
preferred SC treatment to IV administration due to less time in the clinic and more 
comfortable treatment administration (O’Shaughnessy et al. 2020; O’Shaughnessy et al. 
2021). 
A similar PPQ is currently used in the study investigating the SC administration of 
PH FDC SC at home during the COVID-19 pandemic (Study AL42478). For the Study 

 
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AL42478, the PPQ will be completed at home in its entirety by the participant using an 
electronic platform provisioned by the healthcare provider at the End of Treatment Visit. 
In this study, the PPQ will be given in paper form to participants in Arm C and D 
following treatment administration on Day 1 of the last cycle in the cross-over period (in 
the adjuvant treatment phase; Appendix 5). Participants who discontinued study 
treatment prior to the last cycle of the cross-over period should complete the 
questionnaire at the time of discontinuation as long as they have received at least one 
dose PH FDC SC in the home setting. 
8.11.2.2 
EORTC QLQ-C30  
In this study, Health-related Quality of Life (HRQoL) will be assessed based on the 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire C30 (EORTC QLQ-C30). This instrument will be completed before 
treatment is administered on Day 1 of the treatment cycles indicated in Table 1 
(neoadjuvant phase, treatment option 1), Table 2 (neoadjuvant phase, treatment 
option 2), Table 3 (neoadjuvant phase, treatment option 3) and Table 4 (adjuvant phase 
Arms C and D) or Table 5 (adjuvant phase Arm E). The study questionnaire is provided 
in Appendix 8. 
The QLQ-C30 is a validated, reliable self-report measure (Aaronson et al. 1993; 
Fitzsimmons et al. 1999) (see Appendix 8). It consists of 30 questions that assess five 
aspects of participant functioning (physical, emotional, role, cognitive, and social), 
three symptom scales (fatigue, nausea and vomiting, and pain), global health status and 
quality of life (QoL), and six single items (dyspnea, insomnia, appetite loss, constipation, 
diarrhea, and financial difficulties) with a recall period of the previous week. Scale scores 
can be obtained for the multi-item scales. The functioning and symptoms items are 
scored on a 4-point scale that ranges from “not at all” to “very much,” and the global 
health status and QoL items are scored on a 7-point scale that ranges from “very poor” 
to “excellent.” The QLQ-C30 module takes approximately 10 minutes to complete.  
 
8.11.2.3 
Healthcare Professional Questionnaire  
Two HCPQs will be used to capture the perception of time/resource use and perception 
of convenience during this study. 
One HCPQ will be given during the neoadjuvant phase of this study (HCPQ-neoadjuvant 
phase) (Appendix 6 and Appendix 7).  
The other HCPQ will be given during the adjuvant phase of this study in participants who 
achieved pCR (HCPQ-adjuvant phase) (Appendix 9 and Appendix 10).  
These questionnaires will be completed after administration of each participant’s 
treatment during the neoadjuvant and adjuvant phase of the study and according to the 
schedule of activities (see Table 1, Table 2, Table 3, and Table 4). 

 
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The HCPQs given during the neoadjuvant and adjuvant phases both have two parts: 
 
HCPQ – Drug Preparation Area will be completed by an HCP involved in study drug 
preparation (Appendix 6 [neoadjuvant phase] and Appendix 9 [adjuvant phase]).  
 
HCPQ – Administering Treatment will be completed by an HCP involved in 
treatment preparation and/or administration in the treatment area where study drugs 
are administered (Appendix 7 [neoadjuvant phase] and Appendix 10 [adjuvant 
phase]). 
 
The HCPQs will be completed by the HCP after preparation and/or administration of the 
study treatment at the scheduled time point (see Table 1, Table 2, Table 3, and Table 4). 
8.12 
ADDITIONAL ASSESSMENTS AND PROCEDURES 
REQUIRING SEPARATE CONSENT OR PERFORMED 
ONLY AT PARTICIPATING SITES 
There are no additional assessments and procedures requiring separate consent or 
performed only at participating sites. 
9. 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESES 
The primary endpoint of this study is the proportion of participants who prefer 
PH FDC SC administered by an HCP in the home setting compared with the hospital 
setting during the adjuvant phase. No formal statistical hypotheses will be tested for this 
study.  
The primary analysis will take place when all study participants entering the PH FDC SC 
cross-over period have completed their last study treatment and all scheduled 
assessment in the cross-over period. Summaries of secondary study endpoints, EORTC 
QLQ-C30 responses, selection of treatment administration method for the treatment 
continuation period, HCPQ responses and planned safety endpoints will be included in 
the primary analysis.  
The final analysis that includes all data collected during the study will be conducted after 
the end of the study. 
9.2 
SAMPLE SIZE DETERMINATION 
Approximately 330 participants will be enrolled for the neoadjuvant phase of study 
treatment such that approximately 150 evaluable participants enter Arm C and D and 
complete the cross-over period.  
To achieve a distance approximately 8% from the estimated proportion to 95% 
confidence interval limits, a total of 128 participants are needed for the evaluation of 
patient preference rate at the end of the cross-over period, with an underlying assumed 
preference rate of 70% for the home setting (Figure 2). To allow for 15% dropout during 

 
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adjuvant phase and/or non-evaluable PPQ outcome up to the completion of the cross-
over period, the study needs approximately 150 participants entering Arm C and D. The 
planned total enrollment from the neoadjuvant phase would be approximately 330 
participants, considering a pCR of 50% (Schneeweiss et al. 2013) after surgery and 8% 
dropout in the neoadjuvant phase. 
Note: “Enrolled” means a participant’s, or their legally acceptable representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process. Potential participants who are screened for the purpose of determining eligibility 
for the study, but do not participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol. 
Figure 2 Sample size for estimating one proportion with two-sided 95% CI 
 
9.3 
ANALYSIS SETS  
The following populations are defined: 
Participant Analysis Set 
Description 
Neoadjuvant analysis set 
All participants randomly assigned to study treatment and 
receiving at least one planned study treatment in the neoadjuvant 
phase. 
This analysis set will be used for the analysis of pCR and clinical 
outcome assessments (HCPQ and HRQoL), as well as for the 
safety analysis in the neoadjuvant phase. 

 
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Participant Analysis Set 
Description 
Adjuvant analysis set for 
PH FDC SC cohort 
All participants with pCR entering the PH FDC SC cohort in the 
adjuvant phase and receiving at least one dose of PH FDC SC. 
This analysis set will be used for the analysis of safety, HRQoL 
and other clinical outcome assessments in the entire adjuvant 
phase. 
Adjuvant analysis set for 
trastuzumab emtansine 
IV cohort 
All participants with residual disease entering the trastuzumab 
emtansine IV arm of the adjuvant phase and receiving at least one 
dose of trastuzumab emtansine IV. 
This analysis set will be used for the analysis of HRQoL and safety 
in the trastuzumab emtansine IV arm. 
Adjuvant cross-over 
modified Intention-to-
Treat (mITT) analysis set 
All participants randomly assigned into the cross-over period, 
receiving at least one PH FDC SC treatment in the cross-over 
period, and having a valid response to Question 1 of PPQ. 
This analysis set will be used for the analysis of the primary 
endpoint and HCPQ in the crossover period. 
Adjuvant cross-over ITT 
analysis set 
All participants randomly assigned into the cross-over period of 
PH FDC SC treatment, whether or not the assigned study 
treatment was received or a valid response to PPQ Question 1. 
This analysis set will be used for the analysis of the primary 
endpoint and HCPQ in the crossover period as a sensitivity 
analysis. 
Adjuvant cross-over 
safety analysis set 
All participants randomly assigned into the cross-over period and 
receiving at least one PH FDC SC treatment in the cross-over 
period. 
This analysis set will be used for the safety analysis in the cross-
over period. 
 
9.4 
STATISTICAL ANALYSES 
The Statistical Analysis Plan will be finalized prior to the first statistical analysis of study 
data, and it will include a more technical and detailed description of the statistical 
analyses described in this section. This section is a summary of the planned statistical 
analyses of the most important endpoints, including primary and key secondary 
endpoints. The analyses specified in the Statistical Analysis Plan supersede those 
specified here. 
9.4.1 
General Considerations 
All data collected in this study will be analyzed in a descriptive manner. The analysis for 
neoadjuvant and adjuvant phases will be separated. A general rule for baseline 
measurement is the last available measurement before the first administration of study 
drug(s) for the corresponding study phase.  
9.4.2 
Primary Endpoint(s) 
The primary endpoint is the proportion of participants who prefer PH FDC SC 
administered by an HCP in the home setting compared with the hospital setting during 

 
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the cross-over period of the adjuvant phase in the study, as defined in Section 3 (see 
Table 6). 
The primary endpoint will be assessed through Question 1 of PPQ (Appendix 5). The 
PPQ will be completed by the participants in Arm C and D who have entered the cross-
over period of the study, using a paper form provided by the Sponsor. The PPQ will be 
completed on Day 1 of the last cycle of the cross-over period (see Table 4). Participants 
who entered the cross-over period but discontinued study treatment prior to the last 
cycle of the cross-over period should also complete the questionnaire at the time of 
discontinuation as long as they have received at least one dose PH FDC SC in the home 
setting. 
The primary endpoint will be analyzed using the adjuvant cross-over mITT analysis set 
(Section 9.3). A point estimate will be calculated with associated 95% Clopper–Pearson 
CI for the proportion of participants who prefer PH FDC SC administered by HCP in the 
home setting, as well as in the hospital setting. The analysis will be repeated using the 
adjuvant cross-over ITT analysis set as a sensitivity analysis (Section 9.3). Missing 
answer(s) for Question 1 of PPQ will be considered as not preferring administration in 
the home setting. 
The primary endpoint will also be presented by stratification factors in a descriptive 
manner. 
9.4.3 
Secondary Endpoints 
Analysis of secondary endpoints will be performed separately for the neoadjuvant and 
adjuvant phases. 
The secondary endpoints for the neoadjuvant phase are: 
 
HCPQ collected for PH FDC SC or P+H IV during the neoadjuvant phase of the 
study 
 
HRQoL for participants treated with PH FDC SC or P+H IV during the neoadjuvant 
phase of the study  
 
The pCR data post-surgery 
 
The safety and tolerability of PH FDC SC and P+H IV during neoadjuvant phase of 
the study, as measured by 
- 
Incidence, nature and severity of all AEs, Grade ≥ 3 AEs, SAEs and cardiac AEs 
(including LVEF events) with severity determined according to NCI CTCAE v5.0 
(Appendix 14 and Appendix 16) 
- 
Incidence of premature withdrawal from the neoadjuvant treatment with 
PH FDC SC and P+H IV 
- 
Targeted vital signs and physical findings 
- 
Targeted clinical laboratory test results 

 
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The secondary endpoints for the adjuvant phase are: 
 
HCPQ collected for PH FDC SC administration during the adjuvant cross-over 
period of the study 
 
HRQoL for participants treated with PH FDC SC during the adjuvant phase of the 
study  
 
HRQoL for participants treated with trastuzumab emtansine IV during the adjuvant 
phase 
 
Patient’s choice of setting for the treatment continuation period 
 
The safety and tolerability of PH FDC SC for the cross-over period as well as the 
entire adjuvant phase of the study, as measured by the same safety metrics as 
above 
 
The safety and tolerability of the trastuzumab emtansine IV during the adjuvant 
phase of the study, as measured by the same safety metrics as above 
 
HCPQ will be assessed by summarizing responses to individual questions by time and 
corresponding treatment, using corresponding analysis sets (see Section 9.3).  
HRQoL, as measured by EORTC QLQ-C30 scores including change from baseline, will 
be summarized by time, and corresponding treatment, using corresponding analysis sets 
(see Section 9.3). Baseline is defined as Day 1 Cycle 1 measurement in the 
corresponding study phase. Comparison between the home and hospital settings in 
EORTC QLQ-C30 data during the cross-over period will be explored.  
The proportion of participants who choose the home or the hospital administration of PH 
FDC SC for the treatment continuation period of the adjuvant phase will be reported. 
The analysis of AEs will focus on treatment-emergent AEs, i.e., AEs occurring on or after 
the day of first study drug administration. Non-treatment emergent AEs (i.e., those 
occurring before start of study treatment) will be listed (with a flag to identify those AEs 
that continued into on-study treatment cycles). All verbatim adverse event terms will be 
mapped to Medical Dictionary for Regulatory Activities thesaurus terms, and adverse 
event severity will be graded according to NCI CTCAE v5.0. All AEs, Grade ≥ 3 AEs, 
SAEs, AESIs, AEs leading to death, and AEs leading to study treatment discontinuation 
that occur on or after the first dose of study treatment (i.e., treatmentemergent AEs) will 
be summarized by mapped term, appropriate thesaurus level, and severity grade. For 
events of varying severity, the highest grade will be used in the summaries. The 
incidence of deaths and cause of deaths will be listed and summarized by corresponding 
treatment, neoadjuvant/adjuvant phase and overall.  
Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, pulse 
oximetry, and temperature), and ECG data will be displayed by time, with grades 
identified where appropriate. Additionally, a shift table of selected laboratory tests will be 

 
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used to summarize the baseline (screening) and maximum post-baseline severity grade. 
Changes in vital signs and ECGs will be summarized.  
The ECOG performance status will be summarized via the number and percentage of 
participants for each combination of baseline and post-baseline ECOG scores, by 
treatment arm(s) in the corresponding analysis set (see Section 9.3). Baseline here 
refers to Day 1 Cycle 1 outcome in the corresponding study phase.  
Data collected in the treatment arm of trastuzumab emtansine IV, such as HRQoL and 
safety, will be descriptive only. 
Study treatment exposure (such as treatment duration, total dose received, and number 
of cycles and dose modifications) will be summarized with descriptive statistics. 
Concomitant medication will be coded and tabulated in summary tables. The use of 
anaphylactic medications will be summarized as part of safety outcome. 
9.4.3.1 
Summaries of Conduct of Study 
Enrollment, study treatment administration, and discontinuation from the study will be 
summarized by treatment and neoadjuvant/adjuvant phase. The reasons for study 
treatment discontinuation or study discontinuation will also be tabulated. Major protocol 
deviations, including major deviations with regard to the inclusion and exclusion criteria, 
will be summarized by treatment. 
9.4.3.2 
Summaries of Demographics and Baseline Characteristics 
Demographics and baseline characteristics (including but not limited to age, sex, race, 
ethnicity, country, early or locally advanced/inflammatory breast cancer status) will be 
summarized by treatment arm and neoadjuvant/adjuvant phase. Baseline data are the 
last data obtained prior to initiation of study treatment in the corresponding phase. 
Descriptive statistics (mean, standard deviation, median, and range) will be presented 
for continuous variables and counts and percentages will be presented for categorical 
variables. 
9.5 
INTERIM ANALYSIS 
Given the exploratory nature of this study, the Sponsor may choose to conduct interim 
analyses. The decision to conduct an optional interim analysis and the timing of the 
analysis will be documented in the Sponsor’s trial master file prior to the conduct of the 
interim analysis. If conducted, the results of this interim analysis will be evaluated by the 
Sponsor study core team personnel. 
9.6 
INDEPENDENT DATA MONITORING COMMITTEE 
There is no independent Data Monitoring Committee for this study. 

 
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9.7 
INTERNAL MONITORING COMMITTEE 
The Sponsor’s Internal Monitoring Committee (IMC) would be established to monitor and 
evaluate participant safety and composed of selected members representing medical, 
safety, and statistics functions. 
The IMC will follow a charter that outlines their roles and responsibilities and ability to 
make recommendations regarding continuation of the study to protect the interests of the 
participants in this study. The IMC will be responsible for monitoring the safety of 
participants in the study and making recommendations regarding the conduct of the 
study, including study continuation as planned or with modification or early 
discontinuation of the study for excessive toxicity. The operating procedures are detailed 
in the IMC charter. 

 
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10. 
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Appendix 1  
Regulatory, Ethical, and Study Oversight Considerations 
TABLE OF CONTENTS 
A1–1 
Regulatory and Ethical Considerations ................................ 105 
A1–2 
Financial Disclosure ............................................................ 105 
A1–3 
Informed Consent Process .................................................. 106 
A1–4 
Data Protection .................................................................... 106 
A1–5 
Administrative Structure....................................................... 107 
A1–6 
Dissemination of Clinical Study Data ................................... 107 
A1–7 
Data Quality Assurance ....................................................... 107 
A1–8 
Source Documents .............................................................. 108 
A1–9 
Study and Site Closure ........................................................ 109 
A1–10 
Publication Policy ................................................................ 110 
A1–11 
Protocol Deviations .............................................................. 110 
 
 

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A1–1 
REGULATORY AND ETHICAL CONSIDERATIONS 
This study will be conducted in accordance with the protocol and with the following: 
 
Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences international ethical guidelines 
 
Applicable International Council for Harmonisation (ICH) E6 Guideline for Good 
Clinical Practice 
 
Applicable laws and regulations. 
 
The protocol, Informed Consent Form, PH FDC SC, pertuzumab, and trastuzumab 
emtansine Investigator’s Brochures, trastuzumab SmPC, and other relevant documents 
(e.g., advertisements) must be submitted to an Institutional Review Board or Ethics 
Committee (IRB/EC) by the investigator; and reviewed and approved by the IRB/EC 
before the study is initiated. 
Any substantial amendments to the protocol will require IRB/EC and health authority 
approval (as locally required) before implementation of changes, with the exception of 
administrative changes or changes necessary to eliminate an immediate hazard to study 
participants. 
The investigator will be responsible for the following: 
 
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 
 
Notifying the IRB/EC of serious adverse events or other significant safety findings, 
as required by IRB/EC procedures 
 
Providing oversight of the conduct of the study at the site and ensuring adherence to 
requirements of 21 CFR (U.S. sites only), the ICH Guideline for Good Clinical 
Practice, the IRB/EC, Clinical Trials Directive (2001/20/EC) or Clinical Trials 
Regulations (536/2014) (EEA sites only), and all other applicable local regulations 
 
A1–2 
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 
study and for 1 year after completion of the study (see definition of end of study in 
Section 4.4). 

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A1–3 
INFORMED CONSENT PROCESS 
The investigator or authorized designee will explain the nature of the study, including the 
risks and benefits, to the participant or their legally authorized representative and 
answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50 (U.S. sites only), the ICH Guideline for Good 
Clinical Practice, and the IRB/EC. 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the 
Informed Consent Form. 
If the Informed Consent Form is revised (through an amendment or an addendum) to 
communicate information that might affect a participant’s willingness to continue in the 
study, the participant or their legally authorized representative must re-consent by 
signing the most current version of the Informed Consent Form or the addendum, in 
accordance with applicable laws and IRB/EC policy. 
A copy of each Informed Consent Form must be provided to the participant or their 
legally authorized representative. 
A1–4 
DATA PROTECTION 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or access.  
In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; the 
participant’s name or any information that would make the participant identifiable will not 
be transferred. 
Participants must be informed that their personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to participants, who will be required to give consent for their data to be 
used as described in the Informed Consent Form. 

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Participants must be informed that their medical records may be examined by auditors or 
other authorized individuals representing the Sponsor or Sponsor collaborators and 
licensees, by appropriate IRB/EC members, and by inspectors from health authorities. 
A1–5 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd. The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 
Approximately 65 sites globally will participate to enroll approximately 330 participants. 
Enrollment will occur through an interactive voice or web-based response system.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected. 
A Steering Committee will be established to provide scientific and medical guidance on 
the study protocol and study design, provide scientific and medical advice during the 
study and review any relevant study related documents or procedures to help ensure the 
timely collection of data that are accurate and complete, including implementation of IMC 
recommendations. The Steering Committee will be made up of HCPs and Sponsor 
representatives. 
A separate Steering Committee Charter outlines the committee’s composition, members’ 
roles and responsibilities, and the frequency of meetings. 
A1–6 
DISSEMINATION OF CLINICAL STUDY DATA 
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/or other summaries of clinical study results 
may be available in health authority databases for public access, as required by local 
regulation, and will be provided upon request. For more information, refer to the Roche 
Global Policy on Sharing of Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
A1–7 
DATA QUALITY ASSURANCE 
All participant data relating to the study will be recorded on printed or electronic CRFs 
unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 

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The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as risk management 
and mitigation strategies and analytical risk-based monitoring), methods, responsibilities, 
and requirements, including handling of non-compliance issues and monitoring 
techniques (central, remote, or on-site monitoring), are provided prior to study 
initiation, in the various functional monitoring plans (including, but not limited to, Quality 
Tolerance Limit Management Plan and Trial Monitoring Plan). 
The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
Study monitors will perform ongoing monitoring activities as specified in the Trial 
Monitoring Plan to confirm that data entered into the CRF by authorized site personnel 
are accurate, complete, and verifiable from source documents; that the safety and rights 
of participants are being protected; and that the study is being conducted in accordance 
with the currently approved protocol and any other study agreements, the ICH Guideline 
for Good Clinical Practice, and all applicable regulatory requirements. 
Records and documents pertaining to the conduct of this study, including signed 
Informed Consent Forms, must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention 
period. No records may be destroyed during the retention period without the written 
approval of the Sponsor. No records may be transferred to another location or party 
without written notification to the Sponsor. 
The Sponsor will retain study data for 25 years after the final study results have been 
reported or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
A1–8 
SOURCE DOCUMENTS 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 

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Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents, or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
Definition of what constitutes source data and its origin can be found in the Trial 
Monitoring Plan. 
A1–9 
STUDY AND SITE CLOSURE 
The Sponsor or designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of the Sponsor. Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to participants 
 
Participant enrollment is unsatisfactory 
 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform 
the investigators, the IRBs/ECs, the health authorities, and any contract research 
organizations used for the study of the reason for termination or suspension, as 
specified by the applicable regulatory requirements.  The investigators shall promptly 
inform the participants and should ensure appropriate participant therapy and/or 
follow up. 
Study sites will be closed upon study completion. A study site is considered closed when 
all required documents and study supplies have been collected and a site closure visit 
has been performed. 
The investigator may initiate site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include, 
but are not limited to, the following: 
 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the Sponsor’s procedures, or the ICH Guideline 
for Good Clinical Practice 
 
Inadequate recruitment of participants by the investigator 
 
Discontinuation of further study treatment development 
 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform 
the investigators, the IRBs/ECs, the health authorities, and any contract research 

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organizations used for the study of the reason for termination or suspension, as 
specified by the applicable regulatory requirements. The Investigator shall promptly 
inform the participants and should ensure appropriate participant therapy and/or 
follow-up. 
A1–10 
PUBLICATION POLICY 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments. 
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of results of multicenter studies only in their entirety and not as 
individual site 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. 
A1–11 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on participant 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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Appendix 2  
Safety Parameters:  Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting 
TABLE OF CONTENTS 
A2–1 
Definition of Adverse Event ................................................. 113 
A2–2 
Definition of Serious Adverse Event .................................... 114 
A2–3 
Recording and Follow-Up of Adverse Events and 
Serious Adverse Events ...................................................... 115 
A2–3.1 
Adverse Event and Serious Adverse Event 
Recording ............................................................................ 115 
A2–3.2 
Assessment of Severity ....................................................... 116 
A2–3.3 
Assessment of Causality ..................................................... 117 
A2–3.4 
Follow-up of Adverse Events and Serious 
Adverse Events ................................................................... 118 
A2–3.4.1 
Investigator Follow-Up ......................................................... 118 
A2–3.4.2 
Sponsor Follow-Up .............................................................. 119 
A2–4 
Reporting of Serious Adverse Events .................................. 119 
A2–4.1 
Serious Adverse Event Reporting to The 
Sponsor via an Electronic Collection Tool ........................... 119 
A2–4.2 
Serious Adverse Event Reporting to The 
Sponsor via Paper CRF ....................................................... 120 
A2–5 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ................... 120 
A2–5.1 
Events That Occur Prior to Study Treatment 
Initiation ............................................................................... 120 
A2–5.2 
Events That Occur After Study Treatment 
Initiation ............................................................................... 120 
A2–6 
Reporting Adverse Events That Occur after the 
Adverse Event Reporting Period ......................................... 121 
A2–7 
Procedures for Recording Adverse Events .......................... 121 
A2–7.2 
Asymptomatic Declines in Left Ventricular 
Ejection Fraction .................................................................. 122 
A2–7.3 
Adverse Events that are Secondary to Other 
Events.................................................................................. 123 
A2–7.4 
Persistent or Recurrent Adverse Events .............................. 124 
A2–7.5 
Abnormal Laboratory Values ............................................... 124 

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Follow-Up, and Reporting 
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A2–7.6 
Abnormal Vital Sign Values ................................................. 125 
A2–7.7 
Abnormal Liver Function Tests ............................................ 126 
A2–7.8 
Deaths ................................................................................. 126 
A2–7.9 
Preexisting Medical Conditions ............................................ 127 
A2–7.10 
Lack of Efficacy or Worsening of Breast Cancer ................. 127 
A2–7.11 
Hospitalization or Prolonged Hospitalization ........................ 127 
A2–7.12 
Patient-Reported Outcome Data ......................................... 128 
A2–8 
Special Situations (Accidental Overdose And/Or 
Medication Error) ................................................................ 128 
 
 
 

Appendix 2:  Safety Parameters:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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A2–1 
DEFINITION OF ADVERSE EVENT 
Adverse Event Definition 
An adverse event is any untoward medical occurrence in a patient or clinical study 
participant temporally associated with the use of a study treatment, whether or not 
considered related to the study treatment. 
Note:  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
Events Meeting the Adverse Event Definition 
The following events meet the definition of adverse event: 
 
Any abnormal laboratory test results (hematology or clinical chemistry) or other 
safety assessments (e.g., ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, or are considered clinically significant in 
the medical and scientific judgment of the investigator (i.e., not related to 
progression of underlying disease) 
 
Exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency and/or intensity of the condition 
 
New condition detected or diagnosed after study treatment administration, even 
though it may have been present before the start of the study 
 
Signs, symptoms, or clinical sequelae of a suspected drugdrug interaction 
 
Signs, symptoms, or clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication 
Overdose per se will not be reported as an adverse event or serious adverse 
event unless it is an intentional overdose taken with possible suicidal or 
self-harming intent. Such overdoses should be reported regardless of sequelae. 
 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as adverse events or serious adverse events if they fulfill the definition of 
an adverse event or serious adverse event. “Lack of efficacy” or “failure of expected 
pharmacological action” also constitutes an adverse event or serious adverse event 
(see Section A2–7.10). 
 
Events NOT Meeting the Definition of Adverse Event 
The following events do not meet the definition of adverse event: 
 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition 

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Follow-Up, and Reporting 
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 
The disease or disorder being studied or expected progression, signs, or symptoms 
of the disease or disorder being studied, unless more severe than expected for the 
participant’s condition 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy) 
The condition that leads to the procedure is the adverse event. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
 
Anticipated day-to-day fluctuations of a preexisting disease or condition present or 
detected at the start of the study that do not worsen 
 
A2–2 
DEFINITION OF SERIOUS ADVERSE EVENT 
If an event is not an adverse event per the definition in Section A2–1, it cannot be a 
serious adverse event even if serious conditions are met (e.g., hospitalization for signs 
or symptoms of the disease under study, death due to progression of disease). 
A serious adverse event is defined as any untoward medical occurrence that, at any 
dose: 
 
Results in death 
 
Is life threatening 
The term “life-threatening” in the definition of “serious” refers to an event in 
which the participant was at risk of death at the time of the event. It does not 
refer to an event that hypothetically might have caused death if it were more 
severe. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are adverse events. If a complication prolongs hospitalization or 
fulfills any other seriousness criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the adverse event should 
be considered serious. 
Hospitalization for elective treatment of a preexisting condition that did not 
worsen from baseline is not considered an adverse event. 
 
Results in persistent disability or incapacity 
The term “disability” means a substantial disruption of a person’s ability to 
conduct normal life functions. 

Appendix 2:  Safety Parameters:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) that may interfere with 
or prevent everyday life functions but do not constitute a substantial disruption. 
 
Is a congenital anomaly or birth defect 
 
Other situations: 
Medical or scientific judgment should be exercised in deciding whether serious 
adverse event reporting is appropriate in other situations such as important 
medical events that may not be immediately life threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development 
of drug dependency or drug abuse. 
 
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 National 
Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE]; 
see Section A2–3.2); 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 electronic Case Report Form (eCRF). 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after the investigator becomes aware of the 
event) (see Section A2–5 for reporting instructions). 
A2–3 
RECORDING AND FOLLOW-UP OF ADVERSE EVENTS AND 
SERIOUS ADVERSE EVENTS 
A2–3.1 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT 
RECORDING 
When an adverse event or serious adverse event occurs, it is the responsibility of the 
investigator to review all documentation (e.g., hospital progress notes, laboratory 
reports, and diagnostics reports) related to the event. 
The investigator will then record all relevant adverse event or serious adverse event 
information on the eCRF. 

Appendix 2:  Safety Parameters:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
PH FDC SC—F. Hoffmann-La Roche Ltd 
116/Protocol MO43110, Version 3 
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the Adverse Event eCRF. 
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor. 
The investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs or symptoms) will be documented as the adverse event or serious 
adverse event. 
A2–3.2 
ASSESSMENT OF SEVERITY 
The investigator will assess the severity of each adverse event reported during the study 
through use of the NCI CTCAE (v 5.0) grading scale. The investigator will use the 
grading scale in Table 1 for assessing the severity of adverse events that are not 
specifically listed in the NCI CTCAE. 

Appendix 2:  Safety Parameters:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
PH FDC SC—F. Hoffmann-La Roche Ltd 
117/Protocol MO43110, Version 3 
Table 1 
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 
CTCAE  Common Terminology Criteria for Adverse Events; NCI  National Cancer Institute. 
Note: Based on the most recent version of NCI CTCAE (v 5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm 
 
a Examples of instrumental activities of daily living include 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 participants 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 A2–5 for reporting instructions), per the definition of serious 
adverse event in Section A2–2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section A2–5 for 
reporting instructions), per the definition of serious adverse event in Section A2–2. 
  
A2–3.3 
ASSESSMENT OF CAUSALITY 
The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each adverse event or serious adverse event. 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out. The investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as underlying diseases, concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment 
administration, will be considered and investigated. 
The investigator will also consult the Investigator’s Brochure (for PH FDC SC, 
pertuzumab, and trastuzumab emtansine) or SmPC (for trastuzumab) in his or her 
assessment. 

Appendix 2:  Safety Parameters:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
PH FDC SC—F. Hoffmann-La Roche Ltd 
118/Protocol MO43110, Version 3 
For each adverse event or serious adverse event, the investigator must document in the 
medical notes that he or she has reviewed the adverse event or serious adverse event 
and has provided an assessment of causality. 
There may be situations in which a serious adverse event has occurred, and the 
investigator has minimal information to include in the initial report to the Sponsor. 
However, it is very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the serious adverse event data 
to the Sponsor. 
The investigator may change his or her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated causality 
assessment. 
For participants receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
A2–3.4 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS 
A2–3.4.1 
Investigator Follow-Up 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the adverse event or serious adverse 
event as fully as possible. This may include additional laboratory tests or investigations, 
histopathologic examinations, or consultation with other healthcare professionals. 
If a participant dies during participation in the study, the investigator will provide the 
Sponsor with a copy of any post-mortem findings (if available), including histopathology 
(if available). 
New or updated information should be recorded on the originally completed Adverse 
Event eCRF. For serious adverse events and adverse events of special interest, the 
investigator must report new significant follow-up information to the Sponsor immediately 
(i.e., no more than 24 hours after the investigator becomes aware of the information). 
New significant information includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 

Appendix 2:  Safety Parameters:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
PH FDC SC—F. Hoffmann-La Roche Ltd 
119/Protocol MO43110, Version 3 
 
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 
 
During the adverse event reporting period (defined in Section 8.3.1), resolution of adverse 
events (with dates) should be documented on the Adverse Event eCRF and in the 
participant’s medical record to facilitate source data verification. 
A2–3.4.2 
Sponsor Follow-Up 
For serious adverse events and adverse events of special interest, the Sponsor or a 
designee may follow up by telephone, fax, email, and/or a monitoring visit to obtain 
additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
A2–4 
REPORTING OF SERIOUS ADVERSE EVENTS 
A2–4.1 
SERIOUS ADVERSE EVENT REPORTING TO THE SPONSOR 
VIA AN ELECTRONIC COLLECTION TOOL 
The primary mechanism for reporting a serious adverse event to the Sponsor will be the 
electronic data collection tool, as described in Section A2–5. 
If the electronic system is unavailable, the site will use the paper Clinical Trial Adverse 
Event/Special Situations form, as described in Section A2–5, to report the event within 
24 hours. 
The site will enter the serious adverse event data into the electronic system as soon as it 
becomes available. 
After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data. 
If a site receives a report of a new serious adverse event from a study participant or 
receives updated data on a previously reported serious adverse event after the 
electronic data collection tool has been taken offline, the site can report this information 
on a paper Clinical Trial Adverse Event/Special Situations form, as described in Section 
A2–5. 

Appendix 2:  Safety Parameters:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
PH FDC SC—F. Hoffmann-La Roche Ltd 
120/Protocol MO43110, Version 3 
A2–4.2 
SERIOUS ADVERSE EVENT REPORTING TO THE SPONSOR 
VIA PAPER CRF 
Under certain circumstances, serious adverse events may be reported to the Sponsor 
through use of a paper Clinical Trial Adverse Event/Special Situations form, as 
described in Section A2–5. 
A2–5 
REPORTING REQUIREMENTS FOR SERIOUS ADVERSE 
EVENTS AND ADVERSE EVENTS OF SPECIAL INTEREST 
A2–5.1 
EVENTS THAT OCCUR PRIOR TO STUDY TREATMENT 
INITIATION 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention (e.g., biopsy, 
discontinuation of medications) should be reported. The paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
the investigator becomes aware of the event), either by faxing or by scanning and 
emailing the form, using the fax number or email address provided to investigators. 
A2–5.2 
EVENTS THAT OCCUR AFTER STUDY TREATMENT 
INITIATION 
Investigators will seek information on AEs at each patient contact. All AEs, whether 
reported by the patient or noted by study personnel and/or the mobile healthcare 
professional will be recorded. 
After initiation of study treatment, serious adverse events and adverse events of special 
interest will be reported until 28 days after the final dose of study treatment. Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after the investigator becomes aware of the event) on the Adverse Event eCRF and 
submit the report via the electronic data capture (EDC) system. A report will be 
generated and sent to Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
the investigator becomes aware 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.  

Appendix 2:  Safety Parameters:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
PH FDC SC—F. Hoffmann-La Roche Ltd 
121/Protocol MO43110, Version 3 
Instructions for reporting serious adverse events that occur more than 28 days after the 
final dose of study treatment, whichever is longer, are provided in Section A2–6. 
A2–6 
REPORTING ADVERSE EVENTS THAT OCCUR AFTER THE 
ADVERSE EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
more than 28 days after the final dose of study treatment) if the event is believed to be 
related to prior exposure to study treatment. These events should be reported through 
use of the Adverse Event eCRF. However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Adverse Event/Special 
Situations Form, using the fax number or email address provided to investigators. 
A2–7 
PROCEDURES FOR RECORDING ADVERSE EVENTS 
When an adverse event occurs, it is the responsibility of the investigator to review all 
documentation related to the event (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports). The investigator will then record all relevant adverse event 
information on the Adverse Event eCRF. It is not acceptable for the investigator to send 
photocopies of the participant’s medical records to the Medical Monitor in lieu of 
completion of the eCRF. Investigators should use correct medical terminology and 
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 of the Adverse Event eCRF. 
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor. 
A2–7.1 
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS 
A2–7.1.1 
Injection/Infusion Reactions 
Adverse events that occur during or within 24 hours after study treatment 
administration and are judged to be related to study treatment infusion or injection 
should be captured as a diagnosis (e.g., “infusion-related reaction” or “injection-related 
reaction” or “injection-site 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 and Injection Reaction eCRF. If 
a participant experiences both a local and systemic reaction to a single administration 

Appendix 2:  Safety Parameters:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
PH FDC SC—F. Hoffmann-La Roche Ltd 
122/Protocol MO43110, Version 3 
of study treatment, each reaction should be recorded as a separate event on the Adverse 
Event eCRF, with associated signs and symptoms also recorded separately on the 
dedicated Infusion-Related Reaction and Injection Reaction eCRF. 
A2–7.1.2 
Other Adverse Events 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases). However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF. If a diagnosis is subsequently established, all previously reported 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. 
A2–7.2 
ASYMPTOMATIC DECLINES IN LEFT VENTRICULAR 
EJECTION FRACTION 
Asymptomatic declines in LVEF should not be reported as AEs 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 AE with the term of “ejection fraction 
decreased”, as per NCI CTCAE v5.0 (see Appendix 14 and Appendix 16). In 
addition, a comment in the AEs comments field should confirm that the event was 
asymptomatic. 
 
An asymptomatic decline in LVEF requiring treatment or leading to discontinuation 
of study treatment is an AE of special interest and must be reported in an expedited 
manner (see A2–5). The event must be reported as an AE with the term of “ejection 
fraction decreased”, as per NCI CTCAE v5.0 (see Appendix 14 and Appendix 16) 
and a comment should be added to the AEs comments field confirming that the 
event was asymptomatic. 
Table 2 summarizes the reporting conventions for LVSD and heart failure. 

Appendix 2:  Safety Parameters:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
PH FDC SC—F. Hoffmann-La Roche Ltd 
123/Protocol MO43110, Version 3 
Table 2 
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 study 
treatment discontinuation  
AE (eCRF AE 
eForm) and report 
as a non-serious 
AEs of special 
interest 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; CHF = congestive heart failure; eCRF = electronic Case Report Form; 
eForm = 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.” 
 
A2–7.3 
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 

Appendix 2:  Safety Parameters:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
PH FDC SC—F. Hoffmann-La Roche Ltd 
124/Protocol MO43110, Version 3 
 
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. 
A2–7.4 
PERSISTENT OR RECURRENT ADVERSE EVENTS 
A persistent adverse event is one that extends continuously, without resolution, between 
participant evaluation time points. 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 the investigator becomes aware that the event became 
serious; see Section A2–5 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 participant evaluation time 
points and subsequently recurs. Each recurrence of an adverse event should be 
recorded as a separate event on the Adverse Event eCRF. 
A2–7.5 
ABNORMAL LABORATORY VALUES 
Not every abnormal laboratory value qualifies as an adverse event. A laboratory value 
abnormality that is associated with the underlying disease should not be reported as an 
adverse event unless judged by the investigator to be more severe than expected. A 
laboratory value abnormality that is not associated with the underlying disease 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., dose 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  
 

Appendix 2:  Safety Parameters:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
PH FDC SC—F. Hoffmann-La Roche Ltd 
125/Protocol MO43110, Version 3 
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  upper limit of normal (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 A2–7.4 for 
details on recording persistent adverse events). 
A2–7.6 
ABNORMAL VITAL SIGN VALUES 
Not every abnormal vital sign value qualifies as an adverse event. A vital sign 
abnormality that is associated with the underlying disease should not be reported as an 
adverse event unless judged by the investigator to be more severe than expected. A 
vital sign abnormality that is not associated with the underlying disease 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., dose modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an 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 (e.g., hypertension) should be recorded 
on the Adverse Event eCRF. 

Appendix 2:  Safety Parameters:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
PH FDC SC—F. Hoffmann-La Roche Ltd 
126/Protocol MO43110, Version 3 
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 A2–7.4 for 
details on recording persistent adverse events). 
A2–7.7 
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 A2–7.3) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after the 
investigator becomes aware of the event), either as a serious adverse event or an 
adverse event of special interest (see Section A2–5). 
A2–7.8 
DEATHS 
For this protocol, mortality is an efficacy endpoint. Deaths that occur during the protocol-
specified adverse event reporting period (see Section 8.3.1) 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 treatment, must be recorded 
on the Adverse Event eCRF and immediately reported to the Sponsor (see Section A2–
5). An internal 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 
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”). 

Appendix 2:  Safety Parameters:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
PH FDC SC—F. Hoffmann-La Roche Ltd 
127/Protocol MO43110, Version 3 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section A2–6. 
A2–7.9 
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”). 
A2–7.10 
LACK OF EFFICACY OR WORSENING OF BREAST CANCER 
Deterioration that is judged by the investigator to have unexpectedly worsened in 
severity or frequency or changed in nature (i.e., deterioration beyond the expected 
pattern of progression of the underlying disease) should be recorded as an adverse 
event. When recording an unanticipated worsening of breast cancer on the Adverse 
Event eCRF, it is important to convey the concept that the condition has changed by 
including applicable descriptors (e.g., “accelerated 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 the investigator’s assessment as per institutional practice. 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. 
A2–7.11 
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 A2–2), 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 

Appendix 2:  Safety Parameters:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
PH FDC SC—F. Hoffmann-La Roche Ltd 
128/Protocol MO43110, Version 3 
 
Planned hospitalization required by the protocol (e.g., for study treatment 
administration or insertion of access device for study treatment administration) 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
– 
The participant was hospitalized for an elective procedure that was planned 
prior to the study, was scheduled during the study despite the fact that the 
condition had not worsened, or was scheduled during the study when treatment 
became necessary because of the expected normal progression of the 
condition 
– 
The participant 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 participant requirement for outpatient 
care outside of normal outpatient clinic operating hours 
  
A2–7.12 
PATIENT-REPORTED OUTCOME DATA 
Adverse event reports will not be derived from PRO data by the Sponsor. Sites are not 
expected to review the PRO data for adverse events. 
A2–8 
SPECIAL SITUATIONS (ACCIDENTAL OVERDOSE AND/OR 
MEDICATION ERROR) 
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations") are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is 
higher than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug (e.g., wrong 
drug, expired drug, accidental overdose, underdose, wrong dosing schedule, 
incorrect route of administration) 
 
After initiation of study drug, special situations associated with PH FDC SC, 
pertuzumab, trastuzumab, and trastuzumab emtansine IV, and any associated adverse 
events will be reported until 28 days after the final dose of study drug.   
Special situations, regardless of whether they result in an adverse event, should be 
reported on the Special Situations eCRF.  If there are any associated adverse events, 
each event should be recorded separately on the Adverse Event eCRF.   

Appendix 2:  Safety Parameters:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
PH FDC SC—F. Hoffmann-La Roche Ltd 
129/Protocol MO43110, Version 3 
Special situations and any associated adverse events should be reported within 30 days 
after the investigator becomes aware of the situation.  However, if an associated adverse 
event fulfills seriousness criteria or qualifies as an adverse event of special interest, 
both the event and the special situation should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after the investigator becomes aware of the event), as 
described in Section A2–5. 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
130/Protocol MO43110, Version 3 
Appendix 3  
Safety Plan: Management of Identified and Potential Risks 
TABLE OF CONTENTS 
A3–1 
Risks Associated with Pertuzumab ...................................... 133 
A3–1.1 
Hypersensitivity Reactions / Anaphylaxis and 
Administration-Related Reactions ....................................... 133 
A3–1.2 
Symptomatic Left Ventricular Systolic 
Dysfunction .......................................................................... 134 
A3–1.3 
Epidermal Growth Factor Receptor (HER1)-
Related Toxicities ................................................................ 135 
A3–1.4 
Diarrhea ............................................................................... 135 
A3–1.5 
Rash / Skin Reactions ......................................................... 135 
A3–1.6 
Mucositis .............................................................................. 135 
A3–1.7 
Interstitial Lung Disease ...................................................... 136 
A3–2 
Risks Associated with Trastuzumab .................................... 136 
A3–2.1 
Administration-Related Reactions, Allergic-Like 
Reactions, and Hypersensitivity ........................................... 136 
A3–2.2 
Pulmonary Events ............................................................... 137 
A3–2.3 
Symptomatic Left Ventricular Systolic 
Dysfunction .......................................................................... 138 
A3–3 
Risks Associated with PH FDC SC ...................................... 139 
A3–3.1 
Hypersensitivity Reactions / Anaphylaxis and 
Administration-Related Reactions ....................................... 139 
A3–3.2 
Left Ventricular Dysfunction ................................................. 140 
A3–3.3 
Diarrhea ............................................................................... 142 
A3–3.4 
Rash / Skin Reactions ......................................................... 143 
A3–3.5 
Interstitial Lung Disease ...................................................... 143 
A3–4 
Reproductive Toxicity Associated with 
Pertuzumab and Trastuzumab ............................................ 143 
A3–4.1 
Breastfeeding Toxicity ......................................................... 144 
A3–5 
Infection During COVID-19 Pandemic ................................. 144 
A3–6 
Risks Associated with Trastuzumab Emtansine .................. 145 
A3–6.1 
Pulmonary Toxicity .............................................................. 145 
A3–6.2 
Hepatotoxicity ...................................................................... 145 
A3–6.3 
Left Ventricular Dysfunction ................................................. 146 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
131/Protocol MO43110, Version 3 
A3–6.4 
Infusion-Related Reactions and Hypersensitivity 
Reactions ............................................................................. 147 
A3–6.5 
Hematologic Toxicity ........................................................... 147 
A3–6.6 
Hemorrhage ......................................................................... 148 
A3–6.7 
Neurotoxicity ........................................................................ 148 
A3–6.8 
Extravasation ....................................................................... 149 
A3–7 
Risks Associated with Chemotherapy Drugs, 
Hormone Therapy, And Radiotherapy ................................. 149 
A3–8 
Management of Participants Who Experience 
Adverse Events During Treatment with PH FDC 
SC and P+H IV .................................................................... 149 
A3–8.1 
Dose Modifications .............................................................. 149 
A3–8.2 
Treatment Interruption ......................................................... 149 
A3–8.3 
Management Guidelines For Participants who 
Experience Adverse Events During Treatment 
with PH FDC SC and P+H IV .............................................. 150 
A3–9 
Management of Participants who Experience 
Adverse Events During Treatment with 
Trastuzumab Emtansine ...................................................... 152 
A3–9.1 
Dose Modifications and Interruptions .................................. 152 
A3–9.2 
Management Guidelines For Participants who 
Experience Adverse Events During Treatment 
with Trastuzumab Emtansine .............................................. 153 
A3–10 
Management of Participants who Require Dose 
Delays and Modifications for Chemotherapy 
Drugs ................................................................................... 159 
A3–10.1 
Dose Delays and Modifications for Anthracycline-
Based Chemotherapy (ddAC and AC) ................................. 159 
A3–10.2 
Dose Delays and Modifications for Taxanes 
(Docetaxel and Paclitaxel) ................................................... 159 
 
 
 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
132/Protocol MO43110, Version 3 
Pertuzumab and trastuzumab drug substances in PH FDC SC are identical to the drug 
substances in pertuzumab for IV infusion and trastuzumab for IV infusion and SC 
injections. The safety profiles and tolerability of trastuzumab for SC injections and for IV 
infusions have been shown to be consistent (Roche Study BO22227).  
The safety plans for this study, are based on the anticipated safety risks of PH FDC SC, 
as seen in the Phase III Roche Study WO40324, and trastuzumab IV/SC and 
pertuzumab alone and in combination, described in the PH FDC SC, pertuzumab, and 
trastuzumab emtansine Investigator’s Brochures, and trastuzumab SmPC.  
Measures taken to ensure the safety of participants in this study include eligibility criteria 
designed to exclude participants at higher risk for toxicities and ongoing safety 
monitoring. Safety monitoring includes assessment of the nature, frequency, and 
severity of AEs and cardiac function evaluations. 
The anticipated important safety risks for PH FDC SC, pertuzumab, trastuzumab, and 
trastuzumab emtansine are outlined below. Please refer to the PH FDC SC, 
pertuzumab, and trastuzumab emtansine Investigator’s Brochures, and trastuzumab 
SmPC, for complete summaries of safety information. 
 
 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
133/Protocol MO43110, Version 3 
A3–1 
RISKS ASSOCIATED WITH PERTUZUMAB 
A3–1.1 
HYPERSENSITIVITY REACTIONS / ANAPHYLAXIS AND 
ADMINISTRATION-RELATED REACTIONS  
Like other monoclonal antibodies, pertuzumab has been associated with ARRs. These 
include: 
 
Infusion-related reactions (i.e., a systemic reaction with symptoms such as chills, 
diarrhoea, fatigue, headache, nausea and pyrexia). 
Such reactions are likely to be due to cytokine release and typically occur 
during, or very shortly after, the administration of monoclonal antibodies, but 
they may also show a delayed onset. In general, infusion-related AEs are more 
frequent and severe with the first infusion, and decrease in number and severity 
over time. The majority of AEs resolve fully. 
 
Injection-related reactions with SC administration may manifest themselves as: 
– 
Systemic reactions, similar to the infusion-related reactions 
– 
Local injection site reactions (ISRs) with signs and symptoms such as 
erythema, induration, swelling, pain, hypoesthesia and discomfort 
Hypersensitivity reactions / anaphylaxis are systemic reactions caused activation of mast 
cells and basophils by antigen-bound IgE that results in degranulation and release of 
inflammatory mediators. Hypersensitivity reactions / anaphylaxis events are likely to start 
mildly and increase in number and severity over time. Severe hypersensitivity, including 
anaphylaxis, has been observed in clinical trials with treatment of pertuzumab. 
Participants in this study who experience a Grade 4 allergic reaction or acute respiratory 
distress syndrome (ARDS) should be discontinued from study treatment. Since there is a 
potential for delayed onset, participants should be instructed to contact the treating 
physician with any concerns, signs or symptoms subsequent to treatment administration. 
Administration-related reactions may be difficult to distinguish from hypersensitivity 
reactions. 
In this study, a loading dose of pertuzumab will be given over 60 (± 10) minutes, 
followed by an observation period of 60 minutes. If the loading dose infusion is well 
tolerated, subsequent infusions may be administered over a period of 30 minutes (± 10) 
with an observation period of 30 minutes. If symptoms occur, the infusion should be 
slowed down or interrupted and appropriate medical therapies should be administered. 
The observation period should be completed prior to the subsequent trastuzumab IV 
infusion. Pre-medication with antipyretics, antihistamines, or corticosteroids may be 
administered before pertuzumab administration. 
Pertuzumab will be administered by staff who have immediate access to emergency 
equipment and are trained to monitor for, and respond to, medical emergencies. 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
134/Protocol MO43110, Version 3 
Please refer to the pertuzumab Investigator’s Brochure for the most recent data related 
to the risk of hypersensitivity reactions. 
A3–1.2 
SYMPTOMATIC LEFT VENTRICULAR SYSTOLIC 
DYSFUNCTION 
Similar to trastuzumab, pertuzumab’s interaction with HER2 may be associated with a 
risk of symptomatic LVSD. Cardiac dysfunction may manifest as an asymptomatic or 
mildly symptomatic decrease in LVEF (NCI CTCAE, Grade 1 and Grade 2) or as a 
symptomatic decreased in LVEF / CHF (NCI CTCAE, Grade ≥ 3; NYHA Class III or IV). 
Please refer to Appendix 16 for management of participants with decreased LVEF. 
In the Roche pivotal trial WO20698/TOC4129g (CLEOPATRA) in metastatic breast 
cancer patients, treatment with P+H IV and docetaxel was not associated with increases 
in the incidence of symptomatic LVSD or LVEF declines compared with placebo in 
combination with trastuzumab IV and docetaxel. The incidence of symptomatic LVSD 
was 1.5% (6/408) for participants receiving P+H IV and docetaxel (events in the 
treatment period only) and 1.5% (7/396) in the placebo arm. Regardless of treatment 
arm, participants who had received prior anthracyclines or prior radiotherapy to the chest 
area were at higher risk of decreased LVEF. In the Roche Phase II WO209697 study 
(NEOSPHERE) of neoadjuvant P+H IV and docetaxel, the incidence of left ventricular 
dysfunction defined as LVEF decline ≥ 10% to below 50% was higher in the pertuzumab 
plus docetaxel-treated groups (7.4% with pertuzumab plus docetaxel, 8.4% P+H IV plus 
docetaxel) than the trastuzumab IV plus docetaxel treated group (1.9%). An increased 
incidence of LVEF declines was observed in participants treated in the pertuzumab plus 
trastuzumab IV and docetaxel. Left ventricular ejection fraction recovered to ≥ 50% in all 
participants. In the ongoing Roche Phase II WO29217 study (BERENICE; neoadjuvant 
anthracycline / taxane based regimens given in combination with P+H IV), the overall 
incidence of LVEF declines and symptomatic LVD in the neoadjuvant period is 
consistent with previous data in the neoadjuvant setting. 
Pertuzumab has not been studied in patients with the following: a pre-treatment LVEF 
value of ≤ 50%; a prior history of CHF; decreases in LVEF to < 50% during prior 
trastuzumab adjuvant therapy; conditions that could impair left ventricular function such 
as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia 
requiring treatment, or a cumulative prior anthracycline exposure to > 360 mg/m2 of 
doxorubicin or its equivalent. 
Subjects with significant cardiac disease or baseline LVEF < 55% are not eligible for this 
study. As in all pertuzumab trials, study participants must undergo routine cardiac 
monitoring by ECHO or MUGA scan. During the screening / baseline period, complete 
medical history information will be collected from all participants to explore possible risk 
factors for treatment-associated CHF. Monitoring of LVEF is required while participants 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
135/Protocol MO43110, Version 3 
are receiving study treatment and during the follow-up period following discontinuation of 
study treatment (see Section 1.3). If symptomatic LVSD (heart failure; SAE of NCI 
CTCAE v4.0 Grade 3 or 4; NYHA Class III or IV) develops, the participant 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 16 for decisions regarding the continuation or discontinuation of study 
treatment based on LVEF assessment in asymptomatic participants. 
Please refer to the pertuzumab Investigator’s Brochure for the most recent data relating 
to risk of LVSD and CHF. 
A3–1.3 
EPIDERMAL GROWTH FACTOR RECEPTOR (HER1)-RELATED 
TOXICITIES 
Pertuzumab inhibits HER2 heterodimerization with other members of the HER family 
including HER1/EGFR. As a result, pertuzumab may cause toxicities associated with the 
use of EGFR tyrosine kinase inhibitors such as diarrhea, rash and other dermatologic 
toxicities (e.g., dry skin, pruritus, nail disorders, mucositis). 
The most recent data relating to the risk of EGFR-related toxicities are found in the 
pertuzumab Investigator’s Brochure. 
A3–1.4 
DIARRHEA 
Diarrhea has been observed in approximately 60% of patients (treatment-related 
diarrhea in 50% of patients) being treated with pertuzumab in Phase II single-agent 
studies, and in up to 90% of participants in combination therapy studies. Diarrhea was 
NCI CTCAE Grade 1 or 2 in the majority of cases. To prevent dehydration, early 
treatment of diarrhea with anti-diarrheal medication should be considered and 
participants treated with fluids and electrolyte replacement, as clinically indicated. 
A3–1.5 
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. 
A3–1.6 
MUCOSITIS 
Mucositis has been observed in approximately 15% of patients treated with pertuzumab 
in Phase II single-agent studies and in up to 50% of patients in combination studies.  
The most common preferred terms reported were mucosal inflammation and stomatitis. 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
136/Protocol MO43110, Version 3 
A3–1.7 
INTERSTITIAL LUNG DISEASE 
Interstitial lung disease is associated with the use of EGFR inhibitors and therefore could 
occur with pertuzumab. The few reports of interstitial lung disease in pertuzumab-treated 
patients received to date also had evidence of alternative causes (e.g., concomitant 
medication, preceding / concurrent neutropenia with potential infection or other relevant 
medical history). 
In the pivotal study WO20698/TOC4129g (CLEOPATRA; trastuzumab IV and docetaxel 
with pertuzumab or placebo), respiratory events (i.e., dyspnea, cough), which are 
unspecific symptoms of various conditions, including infusion-related reaction or 
hypersensitivity / anaphylaxis, cardiac dysfunction, and respiratory disease, were 
reported in > 10% of pertuzumab-treated patients. 
A3–2 
RISKS ASSOCIATED WITH TRASTUZUMAB 
Serious adverse reactions, including LVSD, ARRs, hypersensitivity, allergic-like 
reactions, and pulmonary events, have been observed in patients receiving trastuzumab 
IV and/or SC.  
A3–2.1 
ADMINISTRATION-RELATED REACTIONS, ALLERGIC-LIKE 
REACTIONS, AND HYPERSENSITIVITY 
Trastuzumab IV and SC have been associated with ARRs. ARRs are defined as 
systemic ‘infusion-related reactions’ associated with trastuzumab IV and systemic 
reactions associated with trastuzumab SC. In some studies, local ISRs were excluded 
from the ARR definitions. A revised definition of ARRs potentially associated with IV and 
SC administration of trastuzumab was used in Study BO22227 and is applicable to all 
future and ongoing trastuzumab IV and SC studies. This definition is based on a 
modified version of the anaphylactic reaction Standardised Medical Dictionary for 
Regulatory Activities (MedDRA) Query (as modified by the addition of the following four 
MedDRA Preferred Terms: hypersensitivity, drug hypersensitivity, infusion-related 
reaction, and injection-site hypersensitivity). The revised definition of ARRs differs from 
that in previous studies in the metastatic and early breast cancer settings which reported 
only ‘infusion reactions’ or ‘infusion-related reactions’ associated with trastuzumab 
administration and makes comparison of the rates of ARRs between studies difficult. 
Serious adverse reactions to trastuzumab IV that have been reported infrequently 
include dyspnea, hypotension, wheezing, bronchospasm, asthma, tachycardia, reduced 
oxygen saturation, anaphylaxis, respiratory distress, urticaria, and angioedema. 
Fatalities have occurred within hours and up to one week following trastuzumab IV 
administration. On very rare occasions, patients have experienced the onset of 
administration-related symptoms or pulmonary symptoms more than six hours after the 
start of the trastuzumab administration. Patients should be warned of the possibility of 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
137/Protocol MO43110, Version 3 
such a late onset and should be instructed to contact their physician if these symptoms 
occur. Patients who have dyspnea at rest due to comorbidities may be at increased risk 
of a fatal ARR therefore should not be treated with trastuzumab. Although such events 
were not reported in clinical trials with trastuzumab 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 trastuzumab IV 
and generally occurred during or immediately following administration. In this study a 
loading dose of trastuzumab IV is required. The loading dose must be administered over 
90 (± 10) minutes, after which the patient must be observed for 60 minutes. If the loading 
dose infusion is well tolerated, subsequent maintenance doses may be administered 
over 30 (± 10) minutes, followed by an observation period of 30 minutes.  
In Study BO22227, the overall incidence of ARRs in the trastuzumab IV arm was 37.2% 
(111/298) compared with 47.8% (142/297) in the trastuzumab SC arm.  Most of the 
ARRs occurred in the neoadjuvant treatment phase, with an incidence of 32.6% in the 
trastuzumab IV arm and 38.4% in the trastuzumab SC arm. Fewer ARRs were reported 
during the adjuvant treatment phase of the study. All but one of the ARRs was Grade 1 
or Grade 2 in intensity and the distribution was balanced between the study phases in 
terms of the most common AEs and MedDRA System Organ Class. There was a higher 
rate of trastuzumab SC injection-site reactions compared with the trastuzumab IV 
infusion (11.1% in trastuzumab SC vs. 0.3% in trastuzumab IV). With few exceptions, all 
of these events were of Grade 1 intensity. Serious reactions to trastuzumab IV have 
been treated successfully with supportive therapy, such as oxygen, β-agonists, and 
corticosteroids. 
In this study, patients should be monitored for 60 minutes after their first pertuzumab and 
trastuzumab IV dose administration. Patients should be monitored for 30 minutes 
following subsequent administrations unless a loading dose is required. If ARRs occur, 
patients must be monitored until complete resolution of signs and symptoms. 
Trastuzumab IV will be administered by staff with immediate access to emergency 
equipment who are trained to monitor for, and respond to, medical emergencies.  
Please refer to the trastuzumab SmPC for the most recent data related to the risk of 
ARRs, allergic-like reactions, and hypersensitivity reactions. 
A3–2.2 
PULMONARY EVENTS 
Severe pulmonary events have been reported with the use of the trastuzumab IV 
formulation in the post-marketing setting. These events have occasionally been fatal. 
They may occur as part of an ARR or with delayed onset. In addition, cases of interstitial 
lung disease, including lung infiltrates, ARDS, pneumonia, pneumonitis, pleural effusion, 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
138/Protocol MO43110, Version 3 
respiratory distress, acute pulmonary edema, and respiratory insufficiency have been 
reported with trastuzumab IV. These events have been most common with the first 
infusion, and their severity has decreased with subsequent infusions. Serious reactions 
have been treated successfully with supportive therapy, such as oxygen, β-agonists, and 
corticosteroids. Acute respiratory distress syndrome has been reported with a fatal 
outcome. 
Please refer to the trastuzumab SmPC for the most recent data related to the risk of 
pulmonary events. 
A3–2.3 
SYMPTOMATIC LEFT VENTRICULAR SYSTOLIC 
DYSFUNCTION 
Heart failure (NYHA Class II - IV) has been observed in patients who have received 
trastuzumab IV and/or SC alone or in combination with docetaxel following anthracycline 
(doxorubicin or epirubicin)-containing chemotherapy. This event may be moderate to 
severe and has been associated with death. Risk factors for trastuzumab-associated 
LVSD include increased age, concomitant administration with anthracyclines, and 
declining LVEF while on trastuzumab treatment. If symptomatic cardiac failure develops 
during treatment, it should be treated with standard medications for this purpose. 
The rates of cardiac dysfunction observed in large trastuzumab adjuvant trials in EBC 
are < 4% with event rates comparable across the studies. In Study BO22227, 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 trastuzumab IV and 11 [3.8%] patients in trastuzumab SC). 
Because the half-life of trastuzumab IV is approximately 28–38 days, trastuzumab may 
persist in the circulation for up to 7 months after the last dose of trastuzumab. Patients 
who receive anthracyclines after the last dose of trastuzumab 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 trastuzumab. 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 trastuzumab IV or SC 
in metastatic breast cancer and early breast cancer improved with standard medical 
treatment. This treatment included diuretics, cardiac glycosides, and/or ACE inhibitors. 
The majority of patients with cardiac symptoms and evidence of a clinical benefit of 
trastuzumab treatment continued on weekly therapy with trastuzumab without 
experiencing additional clinical cardiac events. 
Please refer to the trastuzumab SmPC for the most recent data related to the risk of 
LVSD. 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
139/Protocol MO43110, Version 3 
A3–3 
RISKS ASSOCIATED WITH PH FDC SC 
A3–3.1 
HYPERSENSITIVITY REACTIONS / ANAPHYLAXIS AND 
ADMINISTRATION-RELATED REACTIONS 
In the Phase III Roche Study WO40324 (FeDeriCa), administration-related reactions 
(ARR) AEs occurring within 24 hours of HER2-targeted therapy were slightly higher in 
the PH FDC SC arm (43 [17.3%] participants) compared to the P+H IV arm (34 [13.5%] 
participants) and were of low Grade for the majority. Three participants in the P+H IV 
arm and none in the PH FDC SC arm experienced Grade 3 events. 
The most frequently reported preferred terms (PTs) (in 5% of cases) included injection 
site reaction: one (0.4%) in the P+H IV (in a participant who switched to trastuzumab SC 
during the adjuvant treatment period) vs. 32 (12.9%) participants in the PH FDC SC arm; 
and infusion-related reaction: 25 (9.9%) participants in the P+H IV vs. 0 (0%) participants 
in the PH FDC SC arm. The injection site reactions, related to the SC route of 
administration of PH FDC SC, are the main reason for the observed numerical 
imbalance of ARRs. 
The majority of ARR events occurred during the neoadjuvant phase of the study. ARRs 
led to withdrawal from the study for two participants overall (one in each arm).  
Overall, hypersensitivity and anaphylaxis events occurred with low and comparable 
incidence across the treatment arms (five [2.0%] participants in the P+H IV arm vs. four 
[1.6%] participants in the PH FDC SC arm). Except for one event (Grade 3 
hypersensitivity related to a concomitant medication at study Cycle 4), all events 
occurred after study Cycle 5 and were related to HER2-targeted therapy (four [1.6%] 
participants in each arm). The reported events by PT were injection-related reaction, 
hypersensitivity, and drug hypersensitivity. All events related to HER2-targeted therapy 
were Grade 1 (three participants per arm) or Grade 2 (one participant per arm). 
The majority of anaphylaxis and hypersensitivity events occurred during the neoadjuvant 
phase of the study. The incidence of anaphylaxis and hypersensitivity AEs related to 
HER2 reported during or within 24 hours of administration were low in both arms (two 
[0.8%] participants in the P+H IV arm vs. two [0.8%] participants in the PH FDC SC 
arm), and all low grade (Grade 1 and Grade 2). Three of the events occurred during the 
first administration of HER2-targeted therapy (study Cycle 5), and one event occurred 
during the sixth administration of HER2-targeted therapy (study Cycle 10). Of these, two 
events (one in each arm) occurred during/immediately after HER2-targeted therapy, both 
during the first administration of HER2-targeted therapy study Cycle 5. Each of these 
events led to withdrawal from HER2-targeted therapy. Participants should be observed 
closely for hypersensitivity reactions. Although severe hypersensitivity reactions, 
including anaphylaxis and events with fatal outcomes, have not been observed in 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
140/Protocol MO43110, Version 3 
patients treated with PH FDC SC, caution should be exercised as these have been 
associated with intravenous pertuzumab in combination with trastuzumab and 
chemotherapy. 
For PH FDC SC administration, participants should be monitored for at least 30 minutes 
after their first dose regardless of whether a loading dose is required. Participants should 
be monitored for at least 15 minutes following subsequent administrations unless a 
loading dose is required. If a participant requires a loading dose after their first 
PH FDC SC treatment, they should be monitored for at least 30 minutes after dosing. If 
ARRs occur, participants must be monitored until complete resolution of signs and 
symptoms. 
PH FDC SC will be administered by staff who have immediate access to emergency 
equipment and are trained to monitor for, and respond to, medical emergencies. An 
anaphylaxis kit will be provided by the Sponsor (See Section 6.1.6). 
Participants who experience an NCI-CTCAE version 5.0 Grade 4 allergic reaction, acute 
respiratory distress syndrome (ARDS), or bronchospasm will be discontinued from study 
treatment. 
Pre-medication with corticosteroids, antihistamines, and antipyretics may be used before 
subsequent PH FDC SC injections at the investigator’s discretion. If injection associated 
symptoms occur, participants will be monitored until complete resolution of signs and 
symptoms 
Please refer to the PH FDC SC and pertuzumab Investigator’s Brochures, and the 
trastuzumab SmPC, for the most recent data related to the risk of hypersensitivity 
reactions. 
A3–3.2 
LEFT VENTRICULAR DYSFUNCTION 
In the Phase III Roche Study WO40324 (FeDeriCa), primary cardiac events were 
defined as either: 
 
Symptomatic ejection fraction decrease (Heart Failure) 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: 
o Definite cardiac death, defined as death due to heart failure, myocardial 
infarction, or documented primary arrhythmia 
o 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 
 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
141/Protocol MO43110, Version 3 
There were no participants in the P+H IV arm and two (0.8%) participants in the 
PH FDC SC arm who met the criteria for a primary cardiac event: one (0.4%) participant 
had heart failure with LVEF drop of at least 10 percentage points from baseline and to 
below 50%, and one (0.4%) participant with cardiac death. 
The event of heart failure was reported in an elderly participant in the PH FDC SC arm. 
The onset of the AE occurred 18 days after Cycle 4 Day 1 of doxorubicin (Adriamycin®) 
plus cyclophosphamide (AC) (Q3W) and became serious 12 days after Cycle 6 Day 1 of 
PH FDC SC. The overall diagnosis was an event of heart failure (NYHA Class IV) 
assessed by the investigator as related to HER2 treatment. It led to withdrawal of 
PH FDC SC treatment and had resolved at the time of the clinical cut-off date.  
The event of cardiac death was reported in an elderly participant in the PH FDC SC arm. 
The event was due to an acute myocardial infarction which occurred after Cycle 2 of 
dose-dense doxorubicin (Adriamycin®) plus cyclophosphamide (ddAC), i.e., prior to the 
start of HER2-targeted therapy. 
Both primary cardiac events occurred during the neoadjuvant phase of the study. No 
primary cardiac events were reported in participants in the adjuvant or treatment-free 
follow-up period. 
Secondary cardiac events were only counted for participants who had not experienced a 
primary cardiac event (i.e., participants could only be counted in one of these 
categories). Those events not counted as a secondary cardiac event were still captured 
as part of AE reporting (ejection fraction decreased) and under LVEF assessment. 
Overall, nine (3.6%) participants in the P+H IV arm vs. four (1.6%) participants in the 
PH FDC SC arm, had at least one LVEF decrease of 10 percentage points below the 
baseline measurement to an absolute LVEF value of < 50%. Of these, the initial LVEF 
decline was confirmed by a second LVEF assessment for two (0.8%) participants in the 
P+H IV arm and one (0.4%) participant in the PH FDC SC arm; hence overall, three 
participants fulfilled the criteria for secondary cardiac events. 
Secondary cardiac events occurred throughout all phases of the study. Some 
participants are counted in multiple outputs if they had events occurring in more than 
one phase of the study. The number of participants who experienced at least one LVEF 
decrease of 10 percentage points below the baseline measurement to an absolute LVEF 
value of < 50% during study were: 
 
Four (1.6%) and one (0.4%) events in the P+H IV arm and PH FDC SC arm, 
respectively, which occurred during the neoadjuvant phase 
 
Four (1.6%) and three (1.2%) events in the P+H IV arm and PH FDC SC arm, 
respectively, which occurred during the adjuvant phase 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
142/Protocol MO43110, Version 3 
 
Three (1.2%) and one (0.4%) events in the P+H IV arm and PH FDC SC arm, 
respectively, which occurred during the follow-up phase 
Participants with significant cardiac disease or baseline LVEF < 50% are not eligible for 
this study. As in all pertuzumab trials, study participants must undergo routine cardiac 
monitoring by ECHO or MUGA scan. During the screening / baseline period, complete 
medical history information will be collected from all participants to explore possible risk 
factors for treatment-associated CHF. Monitoring of LVEF is required while participants 
are receiving study treatment (see Appendix 16). If symptomatic LVSD (heart failure; 
SAE of NCI CTCAE v5.0 Grade 3 or 4; NYHA Class III or IV) develops, the participant 
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 16 for decisions regarding the continuation or discontinuation of study 
treatment based on LVEF assessment in asymptomatic participants. 
Please refer to the PH FDC SC and pertuzumab Investigator’s Brochures, and the 
trastuzumab SmPC, for the most recent data relating to risk of LVSD and CHF. 
Left ventricular function will be monitored by measurement of ejection fraction using 
echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scans as described in 
Section 8.2. and the schedule of activities (see Section 1.3). 
A3–3.3 
DIARRHEA 
In the Phase III Roche Study WO40324 (FeDeriCa), the incidence and severity of 
diarrhea events were comparable between the two treatment arms (55.2% of 
participants in the P+H IV arm vs. 58.5% of participants in the PH FDC SC arm). The 
majority of diarrhea events were Grade 1 and 2 in both arms. The incidence of Grade 3 
diarrhea was low and balanced between the two treatment arms (11 [4.4%] participants 
in the P+H IV arm vs. 17 [6.9%] participants in the PH FDC SC arm). There was one 
Grade 4 event in the P+H IV arm which was assessed as related to paclitaxel by the 
investigator. No Grade 5 (fatal) events occurred in either arm. 
Incidence of all grade diarrhea related to HER2 was comparable between the two 
treatment arms (32.5% of participants in the P+H IV arm vs. 30.6% of participants in the 
PH FDC SC arm). Grade 3–4 diarrhea events related to HER2 were reported in five 
(2.0%) participants in the P+H IV arm vs. nine (3.6%) participants in the PH FDC SC 
arm. No events of diarrhea led to withdrawal of HER2-targeted therapy. 
To prevent dehydration, early treatment of diarrhea with anti-diarrheal medication (e.g., 
loperamide) should be considered, and participants should be treated with fluids and 
electrolyte replacement, as clinically indicated. 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
143/Protocol MO43110, Version 3 
A3–3.4 
RASH / SKIN REACTIONS 
In the Phase III Roche Study WO40324 (FeDeriCa), there was only one event of serious 
rash/skin reaction in the PH FDC SC arm, classified as Grade 2 (erythema event). 
The rash / skin reaction appeared to be treatable in some participants with standard 
acne therapies, including topical and oral antibiotics. 
A3–3.5 
INTERSTITIAL LUNG DISEASE 
In the Phase III Roche Study WO40324 (FeDeriCa) incidence of interstitial lung disease 
(ILD) AEs was low and balanced between the two treatment arms (two [0.8%] 
participants in the P+H IV arm vs. three [1.2%] participants in the PH FDC SC arm). Both 
events in the P+H IV arm occurred prior to HER2-targeted therapy and were assessed 
as related to chemotherapy.  
In the PH FDC SC arm, SAEs were reported in one (0.4%) and two (0.8%) participants 
with ILD which were assessed by the investigator as related to doxorubicin plus 
cyclophosphamide chemotherapy and HER2-targeted therapy, respectively. All events 
were Grade 2 and had resolved by the time of clinical cut-off date.  
A3–4 
REPRODUCTIVE TOXICITY ASSOCIATED WITH PERTUZUMAB 
AND TRASTUZUMAB 
Reproductive toxicity was identified during nonclinical studies with pertuzumab. 
Pertuzumab administered to pregnant cynomolgus monkeys during organogenesis led to 
delayed renal development, oligohydramnios, and embryo-fetal deaths. However, 
reproductive toxicity studies with trastuzumab conducted in female cynomolgus monkeys 
revealed no trastuzumab-related embryotoxicity or effects on fetal development. There 
are no clinical studies of trastuzumab or pertuzumab in pregnant women. IgGs are 
known to cross the placental barrier. In the post-marketing setting, cases of 
oligohydramnios, some associated with fatal pulmonary hypoplasia of the fetus, have 
been reported in pregnant women receiving trastuzumab. Therefore, neither pertuzumab 
or trastuzumab should be used during pregnancy unless the potential benefit for the 
mother outweighs the potential risk to the fetus. 
Due to these risks, female participants of childbearing potential in this study are tested 
for pregnancy prior to study entry and must undergo pregnancy testing during the study 
and, up to 7 months after their last study treatment. Pregnancies in female participants 
or partners of male participants will be monitored. Further, participants of childbearing 
potential (defined as post-menarchal, has not reached a post-menopausal state [post-
menopausal defined as  12 continuous months of amenorrhea with no identified cause 
other than menopause], and has not undergone surgical sterilization [removal of ovaries 
and/or uterus]), must remain abstinent (refrain from heterosexual intercourse) or use 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
144/Protocol MO43110, Version 3 
contraceptive methods with a failure rate of 1% per year, or two effective contraceptive 
methods during the study treatment periods and for 7 months after the last dose of study 
treatment and must refrain from donating eggs during the same period. Women who 
have had a tubal ligation do not require additional contraception. The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
requirements. 
Men with female partners of childbearing potential, or with pregnant female partners, 
participating in the study must remain abstinent or use a condom during the study 
treatment periods and for seven months after the last dose of study treatment to avoid 
exposing the embryo. All male participants must also refrain from donating sperm during 
this same period. 
A3–4.1 
BREASTFEEDING TOXICITY 
It is not known whether trastuzumab or pertuzumab are excreted in human milk. Since 
maternal IgG is excreted in milk and either trastuzumab or pertuzumab could harm infant 
growth and development, women must discontinue nursing during study treatment and 
should not breastfeed for at least seven months following the last study treatment. 
A3–5 
INFECTION DURING COVID-19 PANDEMIC 
This study may place vulnerable patient populations at increased risk, including those 
with cancer, among other comorbidities (Liang et al. 2020). There is currently limited 
clinical data available for COVID-19 and there is currently no data on the use of 
pertuzumab and trastuzumab in patients diagnosed with COVID-19.  
Individuals with any severe infection within 28 days prior to initiation of study treatment 
will be excluded. Participants will be assessed for COVID-19 at screening and during 
study if indicated.  
For participants with fever or other symptoms of infection (cough, difficulty breathing):  
 
Participants must be advised to immediately contact the investigator 
 
A comprehensive evaluation should be performed as per usual medical practice and 
institutional guidelines 
 
If the diagnosis of COVID-19 is confirmed the prescriber should follow standard 
clinical management plans and start the study treatment after the COVID-19 is 
resolved. 
 
See Appendix 17 for COVID-19-related safety reporting instructions. 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
145/Protocol MO43110, Version 3 
A3–6 
RISKS ASSOCIATED WITH TRASTUZUMAB EMTANSINE 
A3–6.1 
PULMONARY TOXICITY 
Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute 
respiratory distress syndrome or a fatal outcome, have been reported in clinical trials 
with trastuzumab emtansine. Signs and symptoms include dyspnea, cough, fatigue, and 
pulmonary infiltrates.  
It is recommended that treatment with trastuzumab emtansine be permanently 
discontinued in patients who are diagnosed with ILD or pneumonitis of  Grade 2, 
except for radiation pneumonitis in the adjuvant setting, where trastuzumab emtansine 
should be permanently discontinued for  Grade 3 or for Grade 2 not responding to 
standard treatment. For pneumonitis of Grade 1 that is not induced by radiation, 
trastuzumab emtansine should be withheld until resolution of the event; once resolved, 
treatment with one dose level reduction may proceed. 
Patients with dyspnea at rest due to complications of advanced malignancy, 
comorbidities and receiving concurrent pulmonary radiation therapy may be at increased 
risk of pulmonary events. 
Guidelines for management of trastuzumab emtansine in patients who develop ILD or 
pneumonitis are provided in Section A3–9.2.  
A3–6.2 
HEPATOTOXICITY 
Hepatotoxicity, predominantly in the form of asymptomatic increases in the 
concentrations of serum transaminases (Grade 1  4 transaminitis), has been observed 
while on treatment with trastuzumab emtansine in clinical trials.  Transaminase 
elevations were generally transient with peak elevation at day 8 after therapy and 
subsequent recovery to Grade 1 or less prior to the next cycle.  A cumulative effect of 
trastuzumab emtansine on transaminases has also been observed.  Patients with 
elevated transaminases improved to Grade 1 or normal within 30 days of the last dose of 
trastuzumab emtansine in the majority of the cases.  Serious hepatobiliary disorders, 
including nodular regenerative hyperplasia (NRH) of the liver and some with a fatal 
outcome due to drug-induced liver injury have been observed in patients treated with 
trastuzumab emtansine in clinical trials.  Some of the observed cases may have been 
confounded by comorbidities and/or concomitant medications with known hepatotoxic 
potential. 
Liver function should be monitored prior to initiation of treatment and each trastuzumab 
emtansine dose. 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
146/Protocol MO43110, Version 3 
Trastuzumab emtansine has not been studied in patients with serum transaminases 
 2.5 x upper limit of normal (ULN) or total bilirubin  1.5 x ULN prior to initiation of 
treatment.  Trastuzumab emtansine treatment in patients with serum transaminases  3 
x ULN and concurrent total bilirubin  2 x ULN should be permanently discontinued. 
Cases of NRH of the liver have been identified from liver biopsies in patients treated with 
trastuzumab emtansine.  NRH is a rare liver condition characterized by widespread 
benign transformation of hepatic parenchyma into small regenerative nodules; NRH may 
lead to non-cirrhotic portal hypertension.  NRH should be considered in all patients with 
clinical symptoms of portal hypertension and/or cirrhosis-like pattern seen on the 
computed tomography (CT) scan of the liver, but with normal transaminases and no 
manifestations of cirrhosis.  Signs and symptoms of portal hypertension may include 
ascites, hepatic encephalopathy, esophageal or gastric varices.  All of these would 
require the patient to seek medical attention. Diagnosis of NRH requires histological 
confirmation.  Upon diagnosis of NRH, trastuzumab emtansine treatment must be 
permanently discontinued. 
Patients must meet specified hepatic laboratory test requirements to be included in this 
study (Section 5.2.1).  
Hepatic laboratory parameters will be monitored as described in the schedule of 
activities (Section 1.3). 
Guidelines for management of trastuzumab emtansine in patients who develop 
increased serum transaminases, increased serum bilirubin, or NRH are provided 
in Section A3–9.2.  
A3–6.3 
LEFT VENTRICULAR DYSFUNCTION 
Patients treated with trastuzumab emtansine are at increased risk of developing left 
ventricular dysfunction.  Left ventricular ejection fraction  40% has been observed in 
patients treated with trastuzumab emtansine and therefore symptomatic CHF is a 
potential risk. Symptoms may include shortness of breath at rest, chest pain, peripheral 
edema, or tachycardia. 
Risk factors include previous anthracycline therapy, prior or concurrent exposure to 
taxanes, patients over the age of 50 years, prior or concurrent anti-hypertensive 
medication use and low LVEF levels prior to or following the use of paclitaxel.  In 
contrast to anthracycline-induced cardiac toxicity, trastuzumab-related cardiac 
dysfunction does not appear to increase with cumulative dose or to be associated with 
ultrastructural changes in the myocardium and is generally reversible. 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
147/Protocol MO43110, Version 3 
Patients must meet specified LVEF requirements to be included in this study 
(Section 5.1).  
Left ventricular function will be monitored by measurement of ejection fraction using 
ECHO) or MUGA scans as described in Section 8.2.4 and the schedule of activities 
(Section 1.3). 
Guidelines for patient monitoring and management of trastuzumab emtansine in patients 
who develop left ventricular dysfunction are provided in Section A3–9.2. 
A3–6.4 
INFUSION-RELATED REACTIONS AND HYPERSENSITIVITY 
REACTIONS 
Infusion-related reactions (IRRs) and hypersensitivity reactions have been reported with 
administration of trastuzumab emtansine.  Despite the different pathophysiology of IRRs 
(reactions involving cytokine release) and hypersensitivity (allergic) reactions, the clinical 
manifestations are the same.  In general, IRRs are expected to be more frequent and 
severe with the first infusion and to decrease in number and severity over time.  
The severity of true hypersensitivity reactions would be expected to increase with 
subsequent infusions. 
Infusion-related reactions, characterized by one or more of the following 
symptoms  flushing, chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm, 
and tachycardia  have been reported in clinical trials of trastuzumab emtansine.  In 
general, these symptoms were not severe.  In most patients, these reactions resolved 
over the course of several hours to a day after the infusion was terminated. 
Hypersensitivity reactions, including serious anaphylactic-like reactions, have been 
observed in clinical trials of trastuzumab emtansine.  Patients with a history of 
intolerance to trastuzumab will be excluded from this study (Section 5.2.1 ). 
 
Administration of trastuzumab emtansine will be performed in a setting with access to 
emergency facilities and staff who are trained to monitor and respond to medical 
emergencies.  Patients should be closely monitored for IRRs during and after each 
infusion of study treatment, as described in Section A3–9.2. 
Guidelines for management of patients who experience IRRs or hypersensitivity 
reactions are provided in Section A3–9.2.  
A3–6.5 
HEMATOLOGIC TOXICITY 
Thrombocytopenia has been reported in patients enrolled in clinical trials of trastuzumab 
emtansine.  The majority of these patients had Grade 1 or 2 events (platelet count 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
148/Protocol MO43110, Version 3 
 50,000/L), with the nadir occurring by Day 8 and generally improving to Grade 1 
(platelet count  75,000/L) by the next scheduled dose (i.e., within 3 weeks).  
Evaluation of this safety parameter across various clinical studies has shown a higher 
incidence and severity of thrombocytopenia in Asian patients.   
Patients with thrombocytopenia ( 100,000/L) and patients on anti-coagulant treatment 
should be monitored closely during treatment with trastuzumab emtansine.  It is 
required that platelet counts are monitored prior to each trastuzumab emtansine dose. 
Rare cases of severe prolonged thrombocytopenia defined as persisting ( Grade 3 
thrombocytopenia events lasting for more than 90 days) have been reported with 
trastuzumab based on cumulative data review. In most of these cases, patients received 
concomitant recombinant human thrombopoietin (rhTPO). Trastuzumab emtansine has 
not been studied in patients with platelet counts 100,000/L prior to initiation of 
treatment.  In the event of decreased platelet count to Grade 3 (50,000/L), do not 
administer trastuzumab emtansine until platelet counts recover to Grade 1 (75,000/L).  
Declines in other hematopoietic lineages, for example, leukopenia, neutropenia, and 
anemia, were less frequent than that observed for platelets. 
Patients must meet specified hematologic laboratory test requirements to be included in 
this study (Section 5.2.1).  
Hematologic laboratory parameters will be monitored as described in Section 8.2.8 and 
Appendix 11 and the schedule of activities (Section 1.3).  Patients will require monitoring 
of platelets prior to each dose of trastuzumab emtansine.  Patients on anticoagulant or 
antiplatelet treatment should be monitored closely.  
Guidelines for management of trastuzumab emtansine in patients who develop 
hematologic toxicity are provided in Section A3–9.2. 
A3–6.6 
HEMORRHAGE 
Cases of hemorrhagic events, including central nervous system, respiratory, and 
gastrointestinal hemorrhage, have been reported with trastuzumab emtansine.  Some of 
these bleeding events resulted in fatal outcomes.  In some of the observed cases, the 
patients were also receiving anti-coagulation therapy, antiplatelet therapy, or had 
thrombocytopenia; in others, there were no known additional risk factors.  Caution 
should be used with these agents, and additional monitoring should be considered when 
concomitant use with trastuzumab emtansine is medically necessary. 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
149/Protocol MO43110, Version 3 
A3–6.7 
NEUROTOXICITY 
Peripheral neuropathy, mainly Grade 1 and predominantly sensory, has been reported in 
clinical trials of trastuzumab emtansine.  The most common symptoms of peripheral 
neuropathy include parasthesia or hypoesthesia. 
Patients with Grade  3 peripheral neuropathy will be excluded from joining Arm E of this 
study (Section 5.2.3). 
Patients will be clinically monitored on an ongoing basis for signs or symptoms of 
peripheral neuropathy as described in Section 8.2.1 and the schedule of activities 
(Section 1.3).  
Guidelines for management of trastuzumab emtansine in patients who develop 
peripheral neuropathy are provided in Section A3–9.2. 
A3–6.8 
EXTRAVASATION 
In trastuzumab emtansine clinical studies, reactions secondary to extravasation have 
been observed.  These reactions were usually mild and comprised erythema, 
tenderness, skin irritation, pain, or swelling at the infusion site.  These reactions have 
been observed more frequently within 24 hours of infusion.  In the post marketing 
setting, very rare cases of epidermal injury or necrosis following extravasation have 
been observed.  Specific treatment for trastuzumab emtansine extravasation is unknown 
at this time.  The infusion site should be closely monitored for possible subcutaneous 
infiltration during drug administration, as described in Section 6.1.3. 
Patients should be managed symptomatically per local institutional guidelines. 
A3–7 
RISKS ASSOCIATED WITH CHEMOTHERAPY DRUGS, 
HORMONE 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 carboplatin, doxorubicin, 
cyclophosphamide, docetaxel, paclitaxel, anti-estrogen therapy and radiotherapy. 
A3–8 
MANAGEMENT OF PARTICIPANTS WHO EXPERIENCE 
ADVERSE EVENTS DURING TREATMENT WITH PH FDC SC AND P+H IV 
A3–8.1 
DOSE MODIFICATIONS 
Dose modification of PH FDC SC or P+H IV is not permitted.  

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
150/Protocol MO43110, Version 3 
A3–8.2 
TREATMENT INTERRUPTION 
The administration of PH FDC SC or P+H IV may be delayed to assess or treat AEs, 
such as cardiac AEs. 
During the study treatment period, a dose delay of up to (and including) 6 weeks (i.e., up 
to and including nine weeks between doses) will be permitted to allow AE recovery to 
baseline. Following a dose delay of less than 3 weeks (i.e., < 6 weeks between doses), 
study treatment does not need to be reloaded (only the maintenance doses need to be 
given). 
Participants receiving pertuzumab plus trastuzumab (either PH FDC SC or P+H IV) with 
≥ 6 weeks since their last P+H IV infusions or PH FDC SC treatment must receive a 
loading dose consisting (of PH FDC SC or P+H IV, as applicable) before continuing with 
maintenance doses for subsequent administrations.  
Participants should be monitored for 30 minutes after their first PH FDC SC dose 
administration in the study and if another loading dose is required. Participants should 
be monitored for 15 minutes following subsequent PH FDC SC maintenance dose 
administrations. 
Participants should be monitored for 60 minutes after their first P+H IV dose 
administration in the study and if another loading dose is required. Participants should 
be monitored for 30 minutes following subsequent P+H maintenance dose 
administrations. 
Participants can be observed for longer periods at the discretion of the HCP or, if 
necessary, as per local requirements. 
If study treatment is withheld for more than two cycles (> 9 weeks) because of toxicity, 
the participant should be discontinued from study treatment, unless resumption of 
treatment is approved by the investigator following consultation with the Medical Monitor. 
Study treatment may be suspended for reasons other than toxicity (e.g., surgical 
procedures) at the investigator’s discretion following consultation with the Medical 
Monitor. The investigator may consult the Medical Monitor to determine the acceptable 
length of treatment interruption. 
Participants who are permanently discontinued from study treatment should be treated 
at the discretion of the investigator as clinically indicated. The participant will continue to 
be followed post-treatment as described in Section 7. 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
151/Protocol MO43110, Version 3 
A3–8.3 
MANAGEMENT GUIDELINES FOR PARTICIPANTS WHO 
EXPERIENCE ADVERSE EVENTS DURING TREATMENT WITH PH FDC SC 
AND P+H IV 
Supportive care and medical management of AEs are at the discretion of the 
investigator, unless specifically listed below. Guidelines for management of specific 
adverse events are provided in the subsections below. 
Symptomatic LVSD and/or LVEF Decline 
All participants must have a baseline LVEF ≥ 55%. LVEF will be monitored regularly 
according to the Schedule of Activities (see Table 1 [neoadjuvant phase, treatment 
option 1], Table 2 [neoadjuvant phase, treatment option 2], Table 4 [neoadjuvant phase, 
treatment option 3], Table 4 [adjuvant phase, Arm C and D], and Table 5 [adjuvant 
phase, Arm E]). If an investigator is concerned that an AE may be related to LVSD, an 
additional LVEF measurement should be performed as soon as possible and within 
3 weeks. Symptomatic LVSD (CHF) should be assessed as “heart failure” on the basis 
of NCI CTCAE v5.0 and NYHA classification (see Appendix 16 and Appendix 14). 
Symptomatic LVSD (CHF) should be treated and monitored according to standard 
medical practice. These participants should be evaluated by a certified cardiologist 
locally. 
Appendix 16 summarizes the management of study medication in participants who 
develop an asymptomatic decrease in LVEF. The decision to initiate study treatment and 
whether to continue or stop therapy should be based on two factors: measured LVEF 
and changes in LVEF from baseline. If a significant LVEF decrease occurs, this 
decrease should be confirmed by a second assessment within approximately 3 weeks 
also showing a significant decrease.  
Heart failure and asymptomatic LVEF decline AEs must be graded per NCI CTCAE v5.0 
(see Appendix 16) and reported in the eCRF as described in Appendix 2. 
Management: Hypersensitivity / Anaphylaxis and Administration-Related 
Reactions 
Participants should be observed closely for hypersensitivity reactions. Although severe 
hypersensitivity reactions, including anaphylaxis and events with fatal outcomes, have 
not been observed in patients treated with PH FDC SC, caution should be exercised as 
these have been associated with pertuzumab for IV infusions in combination with 
trastuzumab for IV infusions and chemotherapy. 
Study treatment administration should be stopped in subjects who develop dyspnea or 
clinically significant hypotension (defined per investigator’s discretion). 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
152/Protocol MO43110, Version 3 
Participants 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 
 
Participants who experience ARRs may be managed by: 
 
Stopping the injection of PH FDC SC or infusion of P+H IV 
 
Supportive care with antihistamines, antipyretics, corticosteroids or epinephrine as 
clinically indicated 
 
Subsequently pre-medicating with analgesia and antihistamines as per institutional 
practice 
 
Vital signs will be monitored as described Section 8.2.2.  Participants should be 
monitored until complete resolution of signs and symptoms of any systemic reactions. 
In order to be able to calculate time to onset of such reactions, the occurrence of 
associated AEs must be documented with the date and time of the onset and duration of 
the event (i.e., resolution of the event).  
EGFR-Related Toxicities 
Diarrhea 
To prevent dehydration, early treatment of diarrhea with anti-diarrheal medication (e.g., 
loperamide) should be considered, and participants should be treated with fluids and 
electrolyte replacement, as clinically indicated. 
Rash / Skin Reactions 
Treatment recommendations for EGFR-associated rash / skin reactions include topical 
or oral antibiotics, topical pimecrolimus, and topical steroids or systemic steroids (for 
severe reactions). These agents may be used in participants experiencing pertuzumab-
related rash / skin reactions, as clinically indicated, although they have not been studied 
in this context. 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
153/Protocol MO43110, Version 3 
A3–9 
MANAGEMENT OF PARTICIPANTS WHO EXPERIENCE 
ADVERSE EVENTS DURING TREATMENT WITH TRASTUZUMAB 
EMTANSINE 
A3–9.1 
DOSE MODIFICATIONS AND INTERRUPTIONS  
Management of symptomatic adverse events may require temporary interruption, dose 
reduction, or treatment discontinuation of trastuzumab emtansine IV as per guidelines 
provided in local label (and described in Section 6.1.3). Trastuzumab emtansine IV dose 
should not be re-escalated after a dose reduction is made. 
A3–9.2 
MANAGEMENT GUIDELINES FOR PARTICIPANTS WHO 
EXPERIENCE ADVERSE EVENTS DURING TREATMENT WITH 
TRASTUZUMAB EMTANSINE 
Supportive care and medical management of AEs are at the discretion of the 
investigator, unless specifically listed below. Guidelines for management of specific 
adverse events are provided in the subsections below. 
Pulmonary Events 
Participants who have experienced a pulmonary event should be carefully evaluated 
before commencing trastuzumab emtansine treatment.  It is recommended that 
treatment with trastuzumab emtansine be permanently discontinued in participants who 
are diagnosed with ILD or pneumonitis of  Grade 2, except for radiation pneumonitis 
in the adjuvant setting, where trastuzumab emtansine should be permanently 
discontinued for  Grade 3 or for Grade 2 not responding to standard treatment. For 
pneumonitis of Grade 1 that is not induced by radiation, trastuzumab emtansine should 
be withheld until resolution of the event; once resolved, treatment with one dose level 
reduction may proceed. 
Hepatic Events 
Hepatic events observed were predominantly asymptomatic increases in serum 
transaminases.  Participants are required to undergo frequent monitoring of liver function 
(prior to receiving each dose) to determine eligibility to continue treatment and to 
prevent more severe events.   
See Table 1 for management guidelines for increased transaminases (AST/ALT) and 
hepatic events.  See Table 2 for dose modifications of trastuzumab emtansine for 
hyperbilirubinemia. 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
PH FDC SC—F. Hoffmann-La Roche Ltd 
154/Protocol MO43110, Version 3 
Table 1 
Management Guidelines for Increased Transaminases (AST/ALT) 
and Hepatic Events 
Severity 
Action to Be Taken 
ALT or AST increase that meets 
Hy's law criteria:  ALT or AST 
 3  ULN in combination with TBILI 
 2  ULN or clinical jaundice 
Discontinue trastuzumab emtansine treatment. 
ALT or AST increase that does not 
meet Hy's law criteria 
ALT/AST Grade 1 
( 1-03.0  ULN) 
Treat at the same dose level. 
ALT/AST Grade 2 
( 3.05.0  ULN)  
Treat at the same dose level. 
ALT/AST Grade 3 
( 5.020.0  ULN) 
Withhold trastuzumab emtansine dose. 
Do not administer trastuzumab emtansine until 
recovery to Grade  2, and then resume with dose 
reduction by one level. Discontinue trastuzumab 
emtansine treatment if the event has not resolved to 
Grade  2 within 42 days after the last dose received. 
ALT/AST Grade 4 
( 20.0  ULN) 
Discontinue trastuzumab emtansine treatment. 
Laboratory tests may be repeated (within 24 hours) to 
exclude laboratory error prior to discontinuing 
trastuzumab emtansine. 
NRH 
If there are signs of portal 
hypertension (e.g., ascites and/or 
varices) and/or a cirrhosis-like 
pattern is seen on a CT scan of the 
liver, the possibility of NRH should 
be considered.   
Discontinue trastuzumab emtansine treatment and 
have the patient evaluated by a hepatologist. 
ALT   alanine aminotransferase; AST   aspartate aminotransferase; NRH  nodular 
regenerative hyperplasia; TBILI  total bilirubin; ULN  upper limit of normal. 

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Table 2 
Trastuzumab Emtansine Dose Modification Guidelines for 
Hyperbilirubinemia  
Severity 
Action to be Taken 
Grade 2 
( 1.5 to  3  ULN) 
Withhold until total bilirubin recovers to Grade  1 and 
then resume at the same dose level. 
Grade 3 
( 3 to  10  ULN) 
Withhold until total bilirubin recovers to Grade  1 and 
then resume by one dose level reduction.   
Grade 4 
( 10  ULN) 
Discontinue trastuzumab emtansine treatment. 
ULN  upper limit of normal. 
 
Cardiotoxicity 
Participants without significant cardiac history and with a baseline LVEF of  55% as 
determined by ECHO or MUGA scan are eligible for study participation.  Cardiac 
monitoring (ECHO/MUGA) will be performed in all participants enrolled in the Study. 
Assessments will occur during the screening period, pretreatment during Cycle 5 in the 
neoadjuvant treatment period, and pretreatment during Cycle 1, 5 (Arm C/ Arm E), 6 
(Arm D), and 9 of the adjuvant treatment period, and at the treatment 
completion/discontinuation visit. See Section 8.2.4 and the schedule of activities 
(Section 1.3) for details. 
Figure 1 summarizes the management of trastuzumab emtansine on the basis of LVEF 
measurements and changes in LVEF from baseline in participants.  If an investigator is 
concerned that an adverse event may be related to cardiac dysfunction, an additional 
LVEF measurement may be performed.  Trastuzumab emtansine will be discontinued in 
any participant who develops symptomatic CHF.  CHF should be treated and monitored 
according to standard medical practice. 
The decision to stop or continue trastuzumab emtansine treatment should be on the 
basis of the algorithm shown in Figure 1 or asymptomatic declines in LVEF.   
Trastuzumab emtansine should be discontinued in participants with symptomatic CHF 
and temporarily withheld in participants whose LVEF is between 4550% and decreased 
10% points from baseline, until clarification of LVEF change is obtained.  Trastuzumab 
emtansine should be permanently discontinued in participants whose LVEF has been 
confirmed to have decreased below 45% and in participants with confirmed LVEF 
between 4550% that has not recovered more than 10% points from baseline. 

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See Table 3 for management guidelines for trastuzumab emtansineassociated 
infusion-related reactions and hypersensitivity reactions. 
Table 3 
Management Guidelines for Trastuzumab Emtansine 
Infusion-Related Reactions (Caused by Cytokine Release) or 
Hypersensitivity (Allergic) Reaction 
Event 
Action to Be Taken  
Grade 2 
reaction  
Decrease trastuzumab emtansine infusion rate or interrupt infusion.  Administer 
supportive care with oxygen, -agonists, antihistamines, antipyretics, 
or corticosteroids, as clinically indicated.  Monitor patient until complete resolution of 
symptoms.   
May continue trastuzumab emtansine at the same dose level at the investigator’s 
discretion.   In the event of a true hypersensitivity reaction (in which severity of 
reaction increases with subsequent infusions), discontinue trastuzumab emtansine. 
Pre-medication for infusion reactions (e.g., antihistamines such as diphenhydramine 
or corticosteroids) may be given as clinically indicated. 
Grade 3 
reaction  
Stop trastuzumab emtansine infusion.  Administer supportive care with oxygen, 
agonists, antihistamines, antipyretics, or corticosteroids, as clinically indicated.  
Monitor patient until complete resolution of symptoms.   
May continue trastuzumab emtansine at the same dose level at the investigator’s 
discretion.  In the event of a true hypersensitivity reaction (in which severity of 
reaction increases with subsequent infusions), discontinue trastuzumab 
emtansine.   
Pre-medication for infusion reactions (e.g., antihistamines such as diphenhydramine 
or corticosteroids) may be given as clinically indicated.  
Grade 4 
reaction 
Stop trastuzumab emtansine infusion.  Administer supportive care with oxygen, 
β-agonists, antihistamines, antipyretics, or corticosteroids, as appropriate, as 
clinically indicated.  Monitor patient until complete resolution of symptoms. 
Discontinue trastuzumab emtansine. 
 

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Hematologic Toxicities 
See Table 4 for trastuzumab emtansine dose modification guidelines for hematological 
toxicities, including thrombocytopenia. 
Table 4 
Trastuzumab Emtansine Dose Modification Guidelines for 
Hematological Toxicity 
Event 
Action to Be Taken 
Grade ≥ 3 hematologic toxicity 
(other than thrombocytopenia) 
Withhold trastuzumab emtansine until recovery to Grade 
 1. Weekly CBC assessments should be performed until 
recovery, or as medically indicated. 
A maximum dose delay of 42 days from the last 
administered dose is allowed; otherwise, patients must be 
discontinued from trastuzumab emtansine. 
Grade 2 thrombocytopenia 
(50,000 to 75,0000/L) 
Assess platelet counts weekly or as medically indicated until 
recovery.   
Hold trastuzumab emtansine until Grade  1.  Resume 
treatment without dose reduction.   
If a patient requires two delays due to thrombocytopenia, 
consider reducing dose by one level. 
Grade 3 thrombocytopenia 
(25,000 to  50,000/L) 
Withhold trastuzumab emtansine until recovery to Grade  1 
( 75,000/L).  Following recovery, resume trastuzumab 
emtansine at the same dose level.   
Discontinue trastuzumab emtansine if the event has not 
resolved to Grade  1 within 42 days after the last dose 
received. 
Grade 4 thrombocytopenia 
( 25,000/L) at any time 
Assess platelet counts weekly or as medically indicated 
until recovery. Hold trastuzumab emtansine until Grade 
 1, then resume with one dose level reduction (i.e., from 
3.6 mg/kg to 3 mg/kg or from 3 mg/kg to 2.4 mg/kg).  If 
event occurs with 2.4 mg/kg dose, discontinue 
trastuzumab emtansine. 
Discontinue trastuzumab emtansine if the event has not 
resolved to Grade  1 within 42 days after the last dose 
received. 
 
If a participant with EBC requires two delays due to thrombocytopenia, consider 
reducing dose by one level. 
Neuropathy 
See Table 5 for trastuzumab emtansine dose modification guidelines for neuropathy. 

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Table 5 
Trastuzumab Emtansine Dose Modification Guidelines for 
Neuropathy 
Event 
Action to Be Taken 
Grade  3 peripheral 
neuropathy 
Withhold trastuzumab emtansine until recovery to Grade  2.  
Following recovery, resume trastuzumab emtansine at the 
same dose level or with one dose level reduction, at the 
investigator's discretion.  Discontinue trastuzumab emtansine 
if the event has not resolved to Grade  2 within 42 days after 
the last dose received. 
 
 
A3–10 
 
MANAGEMENT OF PARTICIPANTS WHO REQUIRE DOSE 
DELAYS AND MODIFICATIONS FOR CHEMOTHERAPY DRUGS 
A3–10.1 
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. 
A3–10.2 
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 6. 
Table 6 
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 
 
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 

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 
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 pre-medication, 
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 7 for the management of taxane-related neurosensory toxicity and  
Table 8 for taxane-related musculoskeletal pain.  Instructions for management of all 
other toxicities related to docetaxel/paclitaxel are listed in Table 9. 

Appendix 3:  Safety Plan:  Management of Identified and Potential Risks 
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161/Protocol MO43110, Version 3 
Table 7 
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 8 
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 level b, 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 9 
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 GCSF. 
 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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164/Protocol MO43110, Version 3 
Table 9 
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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165/Protocol MO43110, Version 3 
Table 9 
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. 
 
 

 
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Appendix 4  
Collection of Pregnancy Information 
TABLE OF CONTENTS 
 
A4–1 
Pregnancies in Female Participants .................................... 167 
A4–2 
Pregnancies in Female Partners of Male 
Participants .......................................................................... 167 
A4–3 
Abortions ............................................................................. 168 
A4–4 
Abnormal Pregnancy Outcomes .......................................... 168 
 
 

Appendix 4:  Collection of Pregnancy Information 
PH FDC SC—F. Hoffmann-La Roche Ltd 
167/Protocol MO43110, Version 3 
A4–1 
PREGNANCIES IN FEMALE PARTICIPANTS 
Female participants will be instructed through the Informed Consent Form to 
immediately inform the investigator if they become pregnant during the study or within 
seven months after the final dose of study drug. A paper Clinical Trial Pregnancy 
Reporting Form should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after the investigator becomes aware of the 
pregnancy), either by faxing or by scanning and emailing the form, using the fax number 
or email address provided to investigators. Pregnancy should not be recorded on the 
Adverse Event eCRF. The investigator should discontinue study treatment and counsel 
the participant, discussing the risks of the pregnancy and the possible effects on the 
fetus. Monitoring of the participant 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 or birth 
defect in the child) should be reported on the Adverse Event eCRF. In addition, the 
investigator will submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  
Attempts should be made to collect and report infant health information. When permitted 
by the site, an Authorization for the Use and Sharing of Infant Health Information would 
need to be signed by one or both parents (as per local regulations) to allow for follow-up 
on the infant. If the authorization has been signed, the infant's health status at birth 
should be recorded on the Clinical Trial Pregnancy Reporting Form. In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
A4–2 
PREGNANCIES IN FEMALE PARTNERS OF MALE 
PARTICIPANTS 
Male participants will be instructed through the Informed Consent Form to immediately 
inform the investigator if a female partner becomes pregnant during the study or within 
seven months after the final dose of study drug. The investigator should report the 
pregnancy on the paper Clinical Trial Pregnancy Reporting Form and submit the form to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators. Attempts should be made to collect and 
report details of the course and outcome of any pregnancy in the partner of a male 
participant exposed to study treatment. When permitted by the site, the pregnant partner 
would need to sign an Authorization for the Use and Sharing of Pregnancy Health 
Information to allow for follow-up on her pregnancy. If the authorization has been signed, 
the investigator should submit a Clinical Trial Pregnancy Reporting Form with additional 

Appendix 4:  Collection of Pregnancy Information 
PH FDC SC—F. Hoffmann-La Roche Ltd 
168/Protocol MO43110, Version 3 
information on the pregnant partner and the course and outcome of the pregnancy as it 
becomes available. 
Attempts should be made to collect and report infant health information. When permitted 
by the site, an Authorization for the Use and Sharing of Infant Health Information would 
need to be signed by one or both parents (as per local regulations) to allow for follow-up 
on the infant. If the authorization has been signed, the infant's health status at birth 
should be recorded on the Clinical Trial Pregnancy Reporting Form. In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
An investigator who is contacted by the male participant 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. 
A4–3 
ABORTIONS 
A spontaneous abortion in a female participant exposed to study treatment or the female 
partner of a male participant exposed to study treatment 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 the investigator becomes aware of the event; see Section A2–
5). 
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 the investigator becomes aware of the event; see 
Section A2–5). 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.  
A4–4 
ABNORMAL PREGNANCY OUTCOMES 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomaly, birth defect, ectopic pregnancy) in a female participant exposed to 
study treatment or the female partner of a male participant exposed to study treatment 
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 the 
investigator becomes aware of the event; see Section A2–5)

 
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
169/Protocol MO43110, Version 3 
Appendix 5  
Patient Preference Questionnaire for the Adjuvant Phase 
PATIENT PREFERENCE QUESTIONNAIRE 
During the second phase of treatment, given after surgery, pertuzumab + trastuzumab 
(fixed dose combination) can be administered in 2 settings: 
1. 
through a needle injected into your thigh, called a subcutaneous or SC injection at 
home 
2. 
through a needle injected into your thigh, called a subcutaneous or SC injection in 
the hospital 
We are interested in understanding your experiences and your preferences for this 
phase of your treatment. 
Please answer the following question about your experience. There are no right or 
wrong answers. 
 
1) All things considered, which setting for your treatment did you prefer? 
□ Hospital 
 
□ Home  
□ No preference 
 
2) If you have a preference for one of the settings for your treatment, how strong is this 
preference? 
□ Very strong  
 
□ Fairly strong   
□ Not very strong 
 
3) If you have a preference for one of the settings for your treatment, what are the TWO 
main reasons for your preference? 
 
□ Less stressful  
□ Time and cost saving 
□ Feels safe 
□ Feels more comfortable 
□ Reduces my risk of infection, such as COVID-19 
□ I can continue with my cancer treatment 
□ Other reason; please specify: ……………………..……………… 
 
Please use the space below for any other comments you would like to add: 
 

 
 
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
170/Protocol MO43110, Version 3 
Appendix 6  
Healthcare Professional Questionnaire:  
Neoadjuvant Phase – Drug Preparation Area 
Healthcare Professional Experiences and Preferences for either Pertuzumab and 
Trastuzumab Fixed-Dose Combination Subcutaneous Injection (PH FDC SC / Phesgo®) or 
Pertuzumab® and Trastuzumab® Intravenous Infusion (P+H IV) for the Treatment of 
Patients with Early or Locally Advanced/Inflammatory HER2-positive Breast Cancer.  
Healthcare Professional Survey 
This Qualitative Survey is to be completed by healthcare professionals (HCPs) who have had 
experience in preparing and/or administering both pertuzumab and trastuzumab fixed-dose 
combination (FDC) for subcutaneous (SC) injection (Phesgo), and/or pertuzumab intravenous 
and trastuzumab intravenous (P+H IV) infusions, as part of the MO43110 clinical study.  
An HCP is defined as any personnel involved in the drug preparation and/or drug administration 
processes. Patient chair time (see Table 1) includes P+H IV and PH FDC SC administration time 
and should be based on “time of day” measurements (min/h). Active HCP time will be measured 
for chronologically listed, pre-selected tasks (Table 2) for P+H IV and PH FDC SC preparation / 
administration, both in the drug preparation area (DPA, drug preparation time) and treatment area 
(drug administration time). Active HCP time should be based on “stopwatch time” measurements 
(min/sec). 
Table 1 Study definitions 
Term 
Definition 
Patient chair time 
Time between entry and exit of the infusion chair 
Treatment administration duration 
Time between initiation and completion of the treatment 
administration 
Active HCP time 
Time spent by staff member carrying out pre-specified 
tasks dedicated to a patient  
Treatment area 
The place where P+H IV or PH FDC SC treatments are 
administered 
Drug preparation area 
The place where P+H IV and PH FDC SC are prepared 
before they are administered. This may refer to the 
hospital pharmacy or day oncology unit 
 

Appendix 6:  HCPQ for Neoadjuvant Phase – Drug Preparation Area 
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
171/Protocol MO43110, Version 3 
Table 2 Chronological listing of tasks 
Task 
P+H IV 
PH FDC SC 
Drug preparation area 
 
 
Collection of pertuzumab and trastuzumab (includes IV 
consumables and time to reach aseptic preparation area; SC vial 
checks), reconstitution of IV pertuzumab and trastuzumab, SC 
filling, sign-off of prepared IV pertuzumab and trastuzumab 
bags/dispensed SC formulation 
X 
X 
Treatment area 
 
 
Installation of venous catheter/line flushing 
Pre-medication administration (if indicated) 
Bringing IV bag to patient chair 
PH FDC SC vial check and filling (if not done in drug 
preparation area) 
P+H IV infusion initiations 
PH FDC SC administration and immediate monitoring 
Patient monitoring during infusion 
Disconnecting infusion/flushing line/disposing of materials 
Disposing of PH FDC SC vials and syringes 
Patient monitoring post-infusion/post-injection (only “active” 
monitoring time in the treatment area to be collected) 
X 
X 
X 
 
 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
 
IV, intravenous; SC, subcutaneous. 
 
This survey will take approximately 5 minutes to complete. 
You are being invited to complete this survey because your centre is a MO43110 clinical study 
site. 

Appendix 6:  HCPQ for Neoadjuvant Phase – Drug Preparation Area 
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
172/Protocol MO43110, Version 3 
Questions 1a – 1b should be completed for every patient after each treatment cycle with P+H IV 
or PH FDC SC, during the neoadjuvant phase of the study. 
Questions 2 – 4 should be completed for each patient after the last treatment cycle at the 
conclusion of the neoadjuvant phase. 
The objective of this survey is to obtain feedback from key HCPs within the 
pharmacy/drug preparation area where Perjeta®, Herceptin® and Phesgo® are prepared 
and dispensed. We are interested in the following: 
1. HCP’s perceived differences in the management of Perjeta-Herceptin® treatments at the 
healthcare centre, comparing PH FDC SC injection with P+H IV infusion 
2. HCP’s treatment preferences and perceptions of the time required to complete tasks 
associated with PH FDC SC injection compared with P+H IV infusion 
Your confidentiality will be respected, and none of the information we receive will be used 
in a way that could identify you. 
Study ID: _________________ 
Site ID: _________________ 
Patient ID: _________________ 
Cycle Number: _________________ 
Date of treatment: _________________ (dd/mm/yyyy) 
Healthcare Professional Respondent (please indicate): 
 Pharmacist / Pharmacy Technician  
 Nurse 
Other (specify): ____________________________ 
DATE OF COMPLETION: ___/___ / ____ (dd/mm/yyyy) 
 
 
 

Appendix 6:  HCPQ for Neoadjuvant Phase – Drug Preparation Area 
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
173/Protocol MO43110, Version 3 
Experience with PH FDC SC and P+H IV infusion dispensing and preparation 
Please complete Questions 1a and 1b for each patient treatment cycle. 
1a. Please indicate which treatment preparation the estimates relate to: 
 PH FDC SC 
 P+H IV 
1b. How long did it take to prepare the treatment for use? 
……………………….. (Please estimate to the nearest minute) 
Please indicate any factors during the preparation that may have affected the timing estimate (if 
any): 
…………………………………………………………………………………………………………………
…………………………………………………………………………………………………………………
…………………………………………………………………………………………………………………
…………………………………………………………………………………………………………………
…………………………………………………………… 
 
 

Appendix 6:  HCPQ for Neoadjuvant Phase – Drug Preparation Area 
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
174/Protocol MO43110, Version 3 
2. In your opinion, if all P+H IV infusions were switched to PH FDC SC injections, please 
indicate how strongly you agree or disagree with each of the following statements1. 
 
One “X” only 
 
Strongly Disagree 
Disagree 
Neutral 
Agree 
Strongly Agree 
Not applicable 
a. Staff will have increased availability for other tasks in the pharmacy 
(e.g. reconstituting other drugs, performing more frequent or timely 
inventory checks, more timely responses to queries from other 
departments, etc.)  
 
 
 
 
 
 
b. Administrative procedures related to PH FDC SC require less time 
(i.e., worksheet, release form, labels, etc.)  
 
 
 
 
 
 
c. Using PH FDC SC provides more flexibility for pharmacy staff in 
managing their workload  
 
 
 
 
 
 
d. As PH FDC SC is fixed-dose, potential dosing errors are avoided  
 
 
 
 
 
 
e. As PH FDC SC is fixed-dose, there is less drug wastage (i.e. un-used / 
leftover drug in IV vial)  
 
 
 
 
 
 
f. Less storage space for PH FDC SC-related supplies is required in the 
pharmacy, as there is no need for reconstitution 
 
 
 
 
 
 
g. Number of preparation steps and staff time commitment are reduced 
 
 
 
 
 
 
Please use this box for any additional comments: 
1 Statements are hypotheses and not actual claims 
 
 

Appendix 6:  HCPQ for Neoadjuvant Phase – Drug Preparation Area 
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
175/Protocol MO43110, Version 3 
Questions 3 and 4 are only applicable for patients who switched from Arm A to Arm B. If the 
patient did not switch, please select ‘not applicable’. 
Considering the drug preparation of Perjeta (IV), Herceptin (IV) and PH FDC SC (Phesgo 
SC): 
3. Which took less time (excluding observation period)? 
 P+H IV  
 PH FDC SC    no difference    not applicable 
4. Which required less use of institutional resources (e.g. staff time, facility costs, 
equipment use)? 
 P+H IV  
 PH FDC SC    no difference    not applicable 
 

 
 
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
176/Protocol MO43110, Version 3 
Appendix 7  
Healthcare Professional Questionnaire:  
Neoadjuvant Phase – Administering Treatment 
Healthcare Professional Experiences and Preferences for either Pertuzumab and 
Trastuzumab Fixed-Dose Combination Subcutaneous Injection (PH FDC SC / Phesgo®) or 
Pertuzumab® and Trastuzumab® Intravenous Infusion (P+H IV) for the Treatment of 
Patients with Early or Locally Advanced/Inflammatory HER2-positive Breast Cancer. 
Healthcare Professional Survey 
This Qualitative Survey is to be completed by healthcare professionals (HCPs) who have had 
experience in preparing and/or administering both pertuzumab and trastuzumab fixed-dose 
combination (FDC) for subcutaneous (SC) injection (Phesgo), and pertuzumab intravenous and 
trastuzumab intravenous (P+H IV) infusions, as part of the MO43110 clinical study.  
An HCP is defined as any personnel involved in the drug preparation and/or drug administration 
processes. Patient chair time (see Table 1) includes P+H IV and PH FDC SC administration time 
and should be based on “time of day” measurements (min/h). Active HCP time will be measured 
for chronologically listed, pre-selected tasks (Table 2) for P+H IV and PH FDC SC preparation / 
administration, both in the drug preparation area (DPA, drug preparation time) and treatment area 
(drug administration time). Active HCP time should be based on “stopwatch time” measurements 
(min/sec).  
Table 1 Study definitions 
Term 
Definition 
Patient chair time 
Time between entry and exit of the infusion chair 
Treatment administration duration 
Time between initiation and completion of the 
treatment administration 
Active HCP time 
Time spent by staff member carrying out pre-specified 
tasks dedicated to a patient 
Treatment area 
The place where P+H IV or PH FDC SC treatments 
are administered 
Drug preparation area 
The place where P+H IV and PH FDC SC are 
prepared before they are administered. This may refer 
to the hospital pharmacy or day oncology unit 
 

Appendix 7:  HCPQ for Neoadjuvant Phase – Administering Treatment 
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
177/Protocol MO43110, Version 3 
Table 2 Chronological listing of observed tasks 
Task 
P+H IV 
PH FDC SC 
Drug preparation area 
 
 
Collection of pertuzumab and trastuzumab (includes IV 
consumables and time to reach aseptic preparation area; SC vial 
checks), reconstitution of IV pertuzumab and trastuzumab, SC 
filling, sign-off of prepared IV pertuzumab and trastuzumab 
bags/dispensed SC formulation 
X 
X 
Treatment area 
 
 
Installation of venous catheter/line flushing 
Pre-medication administration (if indicated) 
Bringing IV bag to patient chair 
PH FDC SC vial check and filling (if not done in drug 
preparation area) 
P+H IV infusion initiations 
PH FDC SC administration and immediate monitoring 
Patient monitoring during infusion 
Disconnecting infusion/flushing line/disposing of materials 
Disposing of PH FDC SC vials and syringes 
Patient monitoring post-infusion/post-injection (only “active” 
monitoring time in the treatment area to be collected) 
X 
X 
X 
 
 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
 
IV, intravenous; SC, subcutaneous. 
 
This survey will take approximately 5 minutes to complete. 
You are being invited to complete this survey because your centre is a MO43110 clinical study 
site. 

Appendix 7:  HCPQ for Neoadjuvant Phase – Administering Treatment 
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
178/Protocol MO43110, Version 3 
Questions 1a – 1g should be completed for every patient after each treatment cycle with P+H IV 
or PH FDC SC during the neoadjuvant phase of the study. 
Questions 2 – 11 should be completed for each patient after the last treatment cycle at the 
conclusion of the neoadjuvant phase. 
The objective of this survey is to obtain feedback from key HCPs in the treatment area 
where Perjeta®, Herceptin® and Phesgo® are administered. We are interested in the 
following:  
1. 
HCP’s perceived differences in the management of Perjeta-Herceptin® treatments at the 
healthcare centre, comparing PH FDC SC injection with P+H IV infusion 
2. 
HCP’s treatment preferences and perceptions of the time required to complete tasks 
associated with PH FDC SC injection compared with P+H IV infusion 
Your confidentiality will be respected, and none of the information we receive will be used 
in a way that could identify you. 
Study ID: _________________  
Site ID: _________________  
Patient ID: _________________  
Cycle Number: _________________ 
Date of treatment: _________________ (dd/mm/yyyy) 
Healthcare Professional Respondent (please indicate):  
 Nurse 
 Treating Doctor 
Other (specify): ____________________________  
DATE OF COMPLETION:      /     /      (dd/mm/yyyy) 
 
 
 

Appendix 7:  HCPQ for Neoadjuvant Phase – Administering Treatment 
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
179/Protocol MO43110, Version 3 
Experience with PH FDC SC injection and P+H IV infusion administration 
Please complete Questions 1a – 1g for each patient treatment cycle. 
1a. Please indicate which treatment the estimates relate to: 
 PH FDC SC (proceed to Q1f) 
 P+H IV (proceed to Q1b) 
1b. Did the patient have existing IV access? 
 YES (proceed to Q1d) 
 NO (proceed to Q1c)    
1c. If new IV access was needed for this cycle of treatment, please indicate what 
type of IV access was provided and how long (in minutes) this took to set up? 
 peripheral vein cannulation 
 PICC, peripherally inserted central catheter 
 Port-a-Cath 
 tunneled central venous catheter 
……………………….. (Please estimate to the nearest minute) 
1d. What type of existing IV access did the patient have? Assumes indwelling IV 
access 
 PICC, peripherally inserted central catheter 
 Port-a-Cath 
 tunneled central venous catheter 
1e. When did the existing IV access place? Assumes indwelling IV access 
 within 7 days prior today      
 > 7 < 14 days prior today      
 > 14 < 30 days prior today           
 Other. Please specify: ……………………… 
1f. How long (in minutes) did it take to administer the treatment (P+H IV or 
PH FDC SC)? 
……………………….. (Please estimate to the nearest minute) 
1g. How long (in minutes) was the patient in the Treatment Area in total? 
……………………….. (Please estimate to the nearest minute) 

Appendix 7:  HCPQ for Neoadjuvant Phase – Administering Treatment 
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
180/Protocol MO43110, Version 3 
Please indicate any factors during the treatment in the Treatment Area that may have affected the 
timing estimate (if any): 
……………………………………………………………………………………………………
……………………………………………………………………………………………………
…………………………………………………………………………………………………… 
Impact on Clinical Management and Clinical Efficiency 
2. In your opinion, if all P+H IV infusions were switched to PH FDC SC injections, please 
indicate how strongly you agree or disagree with each of the following statements1. When 
answering question 2, please only consider P+H IV and PH FDC SC and not other IV treatment 
options. 
 
One “X” only 
 
Strongly Disagree 
Disagree 
Neutral 
Agree 
Strongly Agree 
Not applicable 
a. Patients may be moved out of the Treatment Area (for infusion treatment) to 
receive PH FDC SC injections (e.g., outpatient procedure room) 
 
 
 
 
 
 
b. PH FDC SC’s SC route of administration allows for more flexible treatment 
scheduling (i.e., patient visits are not confined to availability of infusion chairs)  
 
 
 
 
 
 
c. Frees up infusion chairs for patients whose treatments can only be given IV 
 
 
 
 
 
 
d. Waiting list for any P+H IV treatment at the Treatment Area is reduced  
 
 
 
 
 
 
e. Staff’s work burden is reduced, enhancing work performance 
 
 
 
 
 
 
f. More interaction time between HCPs and patients (e.g., for patient education)  
 
 
 
 
 
 
g. Staff have more time for further professional education/development.  
 
 
 
 
 
 
h. Staff has more time for administrative tasks (e.g., efficient chart completion, 
appointment scheduling, returning patient phone calls, etc.)  
 
 
 
 
 
 
i. Patients on PH FDC SC spend less time in the Treatment Area 
 
 
 
 
 
 
j. Patients prefer PH FDC SC to P+H IV 
 
 
 
 
 
 
Please use this box to add any additional comments: 
1 Statements are hypotheses and not actual claims 
[Please consider the standard practice at your site, even if the process deviates somewhat from what is 
described below.] 
 

Appendix 7:  HCPQ for Neoadjuvant Phase – Administering Treatment 
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
181/Protocol MO43110, Version 3 
Questions 3–11 are only applicable for patients who switched from Arm A to Arm B. If the 
patient did not switch, please select ‘not applicable’. 
Considering the administration of Perjeta (IV), Herceptin (IV) versus PH FDC SC 
(Phesgo SC): 
3. Which was more convenient for the patient? 
 
 P+H IV 
 PH FDC SC 
 no difference 
 unsure 
 not applicable 
4. Which was better for optimising patient care at your institution? 
 
 P+H IV 
 PH FDC SC 
 no difference 
 unsure 
 not applicable 
5. Which required less time to administer (excluding observation period)? 
 
 P+H IV 
 PH FDC SC 
 no difference 
 not applicable 
6. Which required less use of institutional resources (e.g., staff time, facility costs, 
equipment use)? 
 
 P+H IV 
 PH FDC SC 
 no difference 
 not applicable 
7. Which required less time to administer all the treatment (including IV 
chemotherapy): 
 
 P+H IV 
 PH FDC SC 
 no difference 
 not applicable 
8. Which allowed for attending to more patients because of time savings from the 
mode of administration of pertuzumab and trastuzumab? 
 
 P+H IV 
 PH FDC SC 
 no difference 
 not applicable 
9. During this neoadjuvant phase you had to administer IV chemotherapy through 
patient´s IV access. You prefer to accompany IV chemotherapy with: 
 
 P+H IV 
 PH FDC SC 
 no difference 
 not applicable 
 
 

Appendix 7:  HCPQ for Neoadjuvant Phase – Administering Treatment 
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
182/Protocol MO43110, Version 3 
10. Which was preferred by patients? 
 
 P+H IV 
 PH FDC SC 
 no difference 
 unsure 
 not applicable 
Please provide a reason for your choice of response to Q10:  
……………………………………………………………………………………………………………
……………………………………………………………………………………………………………
……………………………………………………………………………………………………………
……………………………………………………… 
11. How frequently would you recommend PH FDC SC administration to your patients 
in the future? 
  always 
 sometimes 
 never 
 not applicable 
 

 
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
185/Protocol MO43110, Version 3 
Appendix 9  
Healthcare Professional Questionnaire:  
Adjuvant Phase – Drug Preparation Area 
Healthcare Professional Experience and Preference for Pertuzumab and Trastuzumab 
Fixed-Dose Combination Subcutaneous Injection (PH FDC SC; Phesgo®) administered at 
Home or in Hospital, for the Treatment of Patients with Early or Locally 
Advanced/Inflammatory HER2-positive Breast Cancer. 
Healthcare Professional Survey 
This Qualitative Survey is to be completed by healthcare professionals (HCPs) who have had 
experience in preparing and/or administering pertuzumab and trastuzumab fixed-dose 
combination (FDC) for subcutaneous (SC) injection (Phesgo) in hospital or in the patient’s home, 
as part of the MO43110 Clinical Study. 
An HCP is defined as any personnel involved in the drug preparation and/or drug administration 
processes. Patient treatment time (see Table 1) includes PH FDC SC administration time and 
should be based on “time of day” measurements (min/h). Active HCP time will be measured for 
chronologically listed, pre-selected tasks (Table 2) for PH FDC SC processes. Active HCP time 
should be based on “stopwatch time” measurements (min/sec). 
Table 1 Study definitions 
Term 
Definition 
Patient treatment time 
Time between entry and exit of the patient’s home or 
hospital treatment area 
SC administration duration 
Time between initiation and completion of SC injection 
Active HCP time 
Time spent by staff member carrying out pre-specified 
tasks dedicated to a patient  
Treatment area 
The place where PH FDC SC is administered 
Drug preparation area 
The place where PH FDC SC is prepared before it is 
administered. This may refer to the patient’s home, 
hospital pharmacy or day oncology unit 
 

Appendix 9:  HCPQ for Adjuvant Phase – Drug Preparation Area  
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
186/Protocol MO43110, Version 3 
Table 2 Chronological listing of tasks 
Task 
PH FDC SC 
Drug preparation area 
 
Collection of PH FDC SC (includes time to reach aseptic 
preparation area where applicable; and SC vial checks), SC filling, 
sign-off of dispensed SC formulation 
X 
Treatment area 
 
Pre-medication administration (if indicated) 
PH FDC SC vial check and filling (if not done in drug 
preparation area) 
PH FDC SC administration and immediate monitoring 
Disposing of PH FDC SC vials and syringes 
Patient monitoring post-injection (only “active” monitoring time in 
the treatment area to be collected) 
X 
X 
 
X 
X 
X 
 
SC, subcutaneous. 
 
This survey will take approximately 5 minutes to complete. 
You are being invited to complete this survey because your centre is a MO43110 clinical study 
site. 
Questions 1a – 1c should be completed for every patient after treatment with PH FDC SC twice 
during the cross over period: once after the last cycle of PH FDC SC administered in the home 
setting during the cross-over period and once after the last cycle of PH FDC SC administered in 
the hospital setting during the cross-over period. 
Questions 2 – 4 should be completed for each patient after administration of the last cycle of 
study treatment in the cross-over period. 
 

Appendix 9:  HCPQ for Adjuvant Phase – Drug Preparation Area  
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
187/Protocol MO43110, Version 3 
The objective of this survey is to obtain feedback from key HCPs regarding the time spent 
and resources required for PH FDC SC preparation in hospital or at the patient´s home.  
Your confidentiality will be respected, and none of the information we receive will be used 
in a way that could identify you. 
Study ID: _________________  
Site ID: _________________  
Patient ID: _________________  
Cycle Number: _________________ 
Date of treatment: _________________ (dd/mm/yyyy) 
Healthcare Professional Respondent (please indicate):  
 Nurse 
 Pharmacist / Pharmacy Technician 
Other (specify): ____________________________ 
DATE OF COMPLETION: ___/___ / ____ (dd/mm/yyyy) 
PH FDC SC administration setting: 
 Hospital  
 Patient´s home  
 
 

Appendix 9:  HCPQ for Adjuvant Phase – Drug Preparation Area  
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
188/Protocol MO43110, Version 3 
1a. Where was the treatment prepared? 
 Patient´s home  
 Hospital pharmacy   
 Day oncology unit 
 Other. Please specify: ………………………………… 
If the preparation was in a place other than patient´s home, please specify the reason: 
…………………………………………………………………………………………………………… 
1b. How long did it take to prepare the treatment for use? 
If the preparation was in a place other than the patient's home, please also include the time from 
the preparation place to reach the patient's home. 
Time for treatment preparation: …….…….. (Please estimate to the nearest minute) 
Time from the preparation place to reach the patient's home: …………...  
(Please estimate to the nearest minute only if applies) 
1c. Which healthcare professionals were involved in the treatment preparation processes? 
 Physician   
 Nurse  
 Pharmacist  
 
 All of them  
 Others: ………………………………………………………………… 
Please indicate any factors during the preparation that may have affected the timing estimate (if 
any): 
…………………………………………………………………………………………………………………
…………………………………………………………………………………………………………………
…………………………………………………………………………………………………………………
…………………………………………………… 
 
 

Appendix 9:  HCPQ for Adjuvant Phase – Drug Preparation Area  
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
189/Protocol MO43110, Version 3 
2. If all PH FDC SC injections were switched from an in-hospital setting to the patient´s 
home, please indicate how strongly you agree or disagree with each of the following 
statements1. 
Strongly 
Disagree 
Disagree 
Neutral 
Agree 
Strongly  
Agree 
Not applicable 
a. Staff will have increased availability for other tasks in the 
hospital´s pharmacy (e.g., reconstituting other drugs, performing 
more frequent or timely inventory checks, more timely responses 
to queries from other departments, etc.) 
  
  
  
  
  
  
b. Administrative procedures related to PH FDC SC will require 
less time (i.e., worksheet, release form, labels, etc.) 
  
  
  
  
  
  
c. Number of preparation steps and staff time commitment are 
reduced 
  
  
  
  
  
  
Please use this box to add any additional comments: 
1Statements are hypotheses and not actual claims 
 
Considering the drug preparation of PH FDC SC: 
3. Which took less time? 
 Patient´s home   In Hospital  
 no difference  
 unsure 
4. Which required less use of institutional resources (e.g., staff time, facility costs, 
equipment use)? 
 Patient´s home   In Hospital  
 no difference  
 unsure 
 

 
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
190/Protocol MO43110, Version 3 
Appendix 10  
Healthcare Professional Questionnaire:  
Adjuvant Phase – Administering Treatment 
Healthcare Professional Experience and Preference for Pertuzumab and Trastuzumab 
Fixed-Dose Combination Subcutaneous Injection (PH FDC SC; Phesgo®) administered at 
Home or in Hospital, for the Treatment of Patients with Early or Locally 
Advanced/Inflammatory HER2-positive Breast Cancer.  
Healthcare Professional Survey 
This Qualitative Survey is to be completed by healthcare professionals (HCPs) who have had 
experience in preparing and/or administering pertuzumab and trastuzumab fixed-dose 
combination (FDC) for subcutaneous (SC) injection (Phesgo) in hospital or in the patient’s home, 
as part of the MO43110 Clinical Study. 
An HCP is defined as any personnel involved in the drug preparation and/or drug administration 
processes. Patient treatment time (see Table 1) includes PH FDC SC administration time and 
should be based on “time of day” measurements (min/h). Active HCP time will be measured for 
chronologically listed, pre-selected tasks (Table 2) for PH FDC SC processes. Active HCP time 
should be based on “stopwatch time” measurements (min/sec). 
Table 1 Study definitions 
Term 
Definition 
Patient treatment time 
Time between entry and exit of the patient’s home or 
hospital treatment area 
SC administration duration 
Time between initiation and completion of SC injection 
Active HCP time 
Time spent by staff member carrying out pre-specified 
tasks dedicated to a patient  
Treatment area 
The place where PH FDC SC is administered 
Drug preparation area 
The place where PH FDC SC is prepared before it is 
administered. This may refer to the patient’s home, 
hospital pharmacy or day oncology unit 
 

Appendix 10:  HCPQ for Adjuvant Phase – Administering Treatment  
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
191/Protocol MO43110, Version 3 
Table 2 Chronological listing of observed tasks 
Task 
PH FDC SC 
Drug preparation area 
 
Collection of PH FDC SC (includes time to reach aseptic 
preparation area where applicable; SC vial checks), SC filling, 
sign-off of dispensed SC formulation 
X 
Treatment area 
 
Pre-medication administration (if indicated) 
PH FDC SC vial check and filling (if not done in drug 
preparation area) 
PH FDC SC administration and immediate monitoring 
Disposing of PH FDC SC vials and syringes 
Patient monitoring post-injection (only “active” monitoring time in 
the treatment area to be collected) 
X 
X 
 
X 
X 
X 
 
SC, subcutaneous. 
 
This survey will take approximately 5 minutes to complete. 
You are being invited to complete this survey because your centre is a MO43110 clinical study 
site. 
Questions 1a – 1i should be completed for every patient after the treatment with PH FDC SC 
twice during the cross over period: once after the last cycle of PH FDC SC administered in the 
home setting during the cross-over period and once after the last cycle of PH FDC SC 
administered in the hospital setting during the cross-over period. 
Questions 1j – 1l and 2 – 7 should be completed for each patient after administration of the last 
cycle of study treatment in the cross-over period. 
 
 

Appendix 10:  HCPQ for Adjuvant Phase – Administering Treatment  
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
192/Protocol MO43110, Version 3 
The objective of this survey is to obtain feedback from key HCPs regarding the time spent 
and resources required for PH FDC SC administration in hospital or at the patient´s home.  
Your confidentiality will be respected, and none of the information we receive will be used 
in a way that could identify you. 
Study ID: _________________  
Site ID: _________________  
Patient ID: _________________  
Cycle Number: _________________ 
Date of treatment:  _________________ (dd/mm/yyyy) 
Healthcare Professional Respondent (please indicate):  
 Nurse 
 Treating Doctor 
Other (specify): ____________________________ 
DATE OF COMPLETION: ___/___ / ____ (dd/mm/yyyy) 
PH FDC SC administration setting: 
 Hospital  
 Patient´s home  
 
 
 

Appendix 10:  HCPQ for Adjuvant Phase – Administering Treatment  
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
193/Protocol MO43110, Version 3 
1a. How long did it take to travel to the patient´s home to administer PH FDC SC? 
……………………….. (Please estimate to the nearest minute) 
 N/A  
1b. How long did it take for the patient to travel to the hospital to receive PH FDC SC? Ask 
the patient. 
……………………….. (Please estimate to the nearest minute) 
 N/A  
1c. How long (in minutes) did it take to administer PH FDC SC, i.e., SC administration 
duration? 
……………………….. (Please estimate to the nearest minute) 
1d. How long (in minutes) was the patient treatment time? (see Table 1 for definition, 
includes monitoring time) 
……………………….. (Please estimate to the nearest minute) 
1e. If receiving PH FDC SC in hospital, how much time (in minutes) did the patient spend in 
hospital? From arrival to departure time. Ask patient her hospital arrival time. 
……………………….. (Please estimate to the nearest minute) 
 N/A 
1f. If receiving PH FDC SC at home, how much time (in minutes) did you spend at the 
patient’s home? From arrival to departure time 
……………………….. (Please estimate to the nearest minute) 
 N/A  
Please indicate any factors during the treatment in the Treatment Area that may have affected the 
timing estimate (if any): 
…………………………………………………………………………………………………………………
…………………………………………………………………………………………………………………
………………………………………………………………………… 
1g. Does the patient still have implanted (e.g., Port-a-Cath, PICC line) IV access?  
 Yes 
  No  
 

Appendix 10:  HCPQ for Adjuvant Phase – Administering Treatment  
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
194/Protocol MO43110, Version 3 
1h. If your answer in the question 1g. was “No”, when was the IV access removed? 
 After surgery and before initiating adjuvant treatment  
 After initiating adjuvant treatment  
 N/A 
Based on your answer, please specify the date: ………………………… 
1i. If your answer in the question 1g. was “Yes”: 
What is the main reason to keep the IV access? Mark all that apply 
 Local protocol           Risk of recurrence 
 
 Patient preference          ◻ N/A       
 Other. Please specify: …………………………… 
1j. How long do you keep implanted IV access in early HER2-positive Breast Cancer 
patients with pCR following surgery in your institution? 
 < 12 months      ≥ 12 months       18 months 
     < 24 months       ≥ 24 months 
1k. When is the decision point for you to decide to remove IV access for early HER2-
positive Breast Cancer patients? 
 Before surgery 
 After surgery 
 After pCR results 
 After completion of full adjuvant therapy 
 After completion of IV antineoplastic within adjuvant therapy 
 Other. Please specify: …………………………… 
1l. Do you consider it necessary to keep implanted IV access knowing that the patient's 
treatment will be SC until the full 18 cycles? 
 Yes 
 
 No 
 
 Unsure 
 

Appendix 10:  HCPQ for Adjuvant Phase – Administering Treatment  
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
195/Protocol MO43110, Version 3 
2. If all PH FDC SC injections were switched from an in-hospital setting to the patient´s 
home, please indicate how strongly you agree or disagree with each of the following 
statements1. 
 
Strongly Disagree 
Disagree 
Neutral 
Agree 
Strongly Agree 
Not applicable 
a. PH FDC SC’s SC route of administration allows for more flexible 
treatment scheduling (i.e., patient visits are not confined to availability 
of infusion chairs) 
  
  
  
  
  
  
b. Frees up infusion chairs or outpatient procedure rooms used to 
administer SC injections  
  
  
  
  
  
  
c. Waiting list for infusion chairs or outpatient procedure rooms is 
reduced 
  
  
  
  
  
  
d. Staff’s work burden is reduced, enhancing work performance 
  
  
  
  
  
  
e. More interaction time between HCPs and patients on IV treatment 
(e.g., for patient education) 
  
  
  
  
  
  
f. Staff has more time for administrative tasks (e.g., efficient chart 
completion, appointment scheduling, returning patient phone calls, 
etc.) 
  
  
  
  
  
  
g. Patients will spend less time in hospital 
  
  
  
  
  
  
h. Patients prefer PH FDC SC at home 
  
  
  
  
  
  
Please use this box to add any additional comments: 
1Statements are hypotheses and not actual claims 
 
 
 

Appendix 10:  HCPQ for Adjuvant Phase – Administering Treatment  
Copyright © [2022], Roche Products Limited. All Rights Reserved. 
PH FDC SC—F. Hoffmann-La Roche Ltd 
196/Protocol MO43110, Version 3 
Considering the administration of PH FDC SC: 
3. Which was more convenient for the patient? 
 Patient´s home   In Hospital  
 no difference  
 unsure 
4. Which was better for optimising patient care? 
 Patient´s home   In Hospital  
 no difference  
 unsure 
5. Which required less use of institutional resources (e.g., staff time, facility costs, 
equipment use)? 
 Patient´s home   In Hospital  
 no difference  
 unsure 
6. Which was preferred by patients? 
 Patient´s home   In Hospital  
 no difference  
 unsure 
7. How frequently would you recommend PH FDC SC at home to your patients in the 
future? 
 always  
 sometimes   never 
Please provide a reason for your choice of response to Q7: 
…………………………………………………………………………………………………………………
…………………………………………………………………………………………………………………
…………………………………………………………………………………………………………………
……… 
 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
197/Protocol MO43110, Version 3 
Appendix 11  
Clinical Safety Laboratory Tests 
All female participants of childbearing potential (refer to Section 5.1.1 for definition) will 
have a serum pregnancy test performed at screening 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 
Cycle 3 and at last cycle of neoadjuvant phase (and as clinically indicated), at Cycle 1, 5 
or 6, 9, and last cycle during adjuvant phase, 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 β-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 months follow up) can 
be performed if indicated. 
The tests detailed in Table 1 below will be performed by the local laboratory. 
Additional tests may be performed at any time during the study if determined to be 
necessary by the investigator or if required by local regulations. 
Table 1 
Protocol-Required Safety Laboratory Assessments 
Local Laboratory Tests 
 Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential 
count (% or absolute for neutrophils, eosinophils, basophils, monocytes, lymphocytes, other 
cells).  
 Limited biochemistry: alkaline phosphatase; AST; ALT; LDH; total bilirubin; creatinine. 
Albumin should be measured at Screening for determining participant eligibility. Bilirubin 
fractions (direct and indirect) must be included if total bilirubin is greater than ULN. 
 HIV serology:  HIV-1 antibody/ HIV-2 antibody 
 HBV serology:  HBsAg, HBsAb, and total HBcAb for all individuals; HBV DNA for individuals 
with negative HBsAg and HBsAb tests and a positive total HBcAb test  
 HCV serology:  HCV antibody for all individuals; HCV RNA for individuals with a positive HCV 
antibody test 
 Pregnancy test 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; HBcAb  hepatitis B core 
antibody; HBsAb  hepatitis B surface antibody; HBsAg  hepatitis B surface antigen; 
HBV  hepatitis B virus; HCV  hepatitis C virus; LDH = lactate dehydrogenase; RBC = red 
blood cell; ULN = upper limit of normal; WBC  white blood cell. 
  
Investigators must document their review of each laboratory safety report.  

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
198/Protocol MO43110, Version 3 
Appendix 12  
Eastern Cooperative Oncology Group Performance Status Scale 
Grade 
Description 
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 housework or office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about > 50% of waking hours 
3 
Capable of only limited selfcare, confined to a bed or chair > 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
199/Protocol MO43110, Version 3 
Appendix 13  
Anaphylaxis Precautions 
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures. 
REQUIRED EQUIPMENT AND MEDICATION 
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment administration in a clinical setting: 
 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
 
Oxygen 
 
Epinephrine or equivalent for intramuscular (preferred route), subcutaneous, 
intravenous, or endotracheal administration in accordance with institutional 
guidelines 
 
Antihistamines 
 
Corticosteroids 
 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment administration, 
the following procedures should be performed: 
1. Stop the study treatment administration, if possible.  
2. Call for additional medical assistance. 
3. Maintain an adequate airway. 
4. Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible.  
During home administration of study treatment, blood pressure and respiratory 
rate should be measured approximately every 5 minutes. Pulse rate and oxygen 
saturation will be continuously monitored using the pulse oximeter. Vital signs 
will be measured until symptoms have fully resolved or emergency medical 
services arrive. 
5. Administer antihistamines, epinephrine or equivalent, or other medications and IV 
fluids as required by participant status and as directed by the physician in 
charge. 
6. Continue to observe the participant and document observations. 
 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
200/Protocol MO43110, Version 3 
Appendix 14  
NYHA Functional Classification System for Heart Failure and 
LVSD NCI CTCAE V5.0 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 NCI CTCAE V5 Grading 
Investigations 
 
Grade 
1 
2 
3 
4 
5 
EF 
decreased 
[a]  
— 
Resting EF 
50% - 40%; 
10% - 19% 
drop from 
baseline 
Resting EF 
39% - 20%; 
 20% drop 
from baseline 
Resting EF  
< 20% 
— 
Cardiac Disorders 
 
Grade 
1 
2 
3 
4 
5 
Heart failure 
[b]  
Asymptomatic 
with 
laboratory 
(e.g., BNP) or 
cardiac 
imaging 
abnormalities 
Symptoms 
with 
moderate 
exertion 
Symptoms at 
rest or with 
minimal 
activity or 
exertion; 
hospitalization; 
new onset of 
symptoms 
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 so only at an elevation in the filling pressure. 
https://www.eortc.be/services/doc/ctc/CTCAE_v5_Quick_Reference_5x7.pdf  

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
201/Protocol MO43110, Version 3 
Appendix 15  
Home Administration Instructions for Mobile Healthcare 
Professional 
Pertuzumab and trastuzumab fixed-dosed combination formulation for subcutaneous 
administration (PH FDC SC) should be administered by a healthcare professional. Self-
administration is not allowed. 
The Mobile Clinical Services Training Manual contains additional detail on the 
administration of PH FDC SC in the home setting. The mobile healthcare professional 
should follow the instructions in the Mobile Clinical Services Training Manual. 
Materials needed for Subcutaneous Injection in the Home Setting 
 
PH FDC SC vials 
 
Syringe 
 
Transfer needle (18 – 21G hypodermic needle) 
 
25G-27G (3/8”-5/8”) hypodermic injection needle 
 
Sharps disposal container 
 
Alcohol wipes 
Preparation for Administration 
 
PH FDC SC vials should be stored at 2oC to 8oC (36oF to 46oF) in the original carton 
until time of use. Keep PH FDC SC out of the reach of children and pets. 
 
Before use, allow the PH FDC SC vial to warm up to room temperature for about 15 
minutes before preparing an injection.  
 
PH FDC SC should be inspected for particulate matter and discoloration before 
administration. Do not use vial if particulates or discoloration is present. Do not 
shake. 
 
Both dose strengths are ready to use for subcutaneous injection and should not be 
diluted. 
 
A syringe, a transfer needle and an injection needle are needed to withdraw 
PH FDC SC solution from the vial and inject it subcutaneously. PH FDC SC may be 
injected using 25G-27G (3/8”-5/8”) hypodermic injection needles. 
 
To avoid needle clogging, attach the hypodermic injection needle to the syringe 
immediately prior to administration followed by volume adjustment to 15 mL (loading 
dose) and 10 mL (maintenance dose). 
 
PH FDC SC is compatible with stainless steel, polypropylene, polycarbonate, 
polyethylene, polyurethane, polyvinyl chloride, and fluorinated ethylene 
polypropylene. 
 
If the dose is not to be administered immediately, prepare the dosing syringe in 
controlled and validated aseptic conditions. 

Appendix 15:  Home Administration Instructions for Mobile Healthcare Professional 
PH FDC SC—F. Hoffmann-La Roche Ltd 
202/Protocol MO43110, Version 3 
 
After the solution of PH FDC SC is withdrawn from the vial and into the syringe, 
replace the transfer needle with a syringe closing cap.  
 
Administer PH FDC SC within 24 hours. If the syringe containing PH FDC SC is not 
used immediately, the syringe can be stored in the refrigerator (2°C to 8°C) and at 
room temperature (20°C to 25°C, 68°F to 77°F) for up to 4 hours. 
 
PH FDC SC is for single use only. Discard any unused portion remaining in the vial. 
 
Dispose of transfer needles, injection needles, caps, and used syringes in a sharps 
disposal container. Keep the sharps disposal container out of reach of children and 
pets. 
 
Administration 
The thigh is the only location where PH FDC SC should be administered. The 
subcutaneous injection site should be alternated between the left and right thigh. New 
injections should be given at a distance of at least 1 inch/2.5 cm from the previous site 
on healthy skin and never into areas where the skin is red, bruised, tender, or hard. Do 
not split the dose between two syringes or between two sites of administration. During 
the treatment course with PH FDC SC, other medications for subcutaneous 
administration should preferably be injected at different sites. 
All doses of the PH FDC SC will be administered over 5–8 minutes as a SC injection into 
the thigh at a rate of no more than 2 mL/min. Participants who have had ≥ 6 weeks since 
their last P+H IV or PH FDC SC treatment must receive a loading dose before continuing 
with maintenance doses for subsequent administrations. The loading dose should be 
administered over approximately 8 minutes. Participants should be monitored for at least 
30 minutes after a loading dose or after their first PH FDC SC dose administration to 
observe for injection-related symptoms. 
The maintenance dose should be administered over approximately 5 minutes. If the prior 
injection is well tolerated, participants will be observed for at least 15 minutes for 
subsequent injections. Participants can be observed for longer periods at the discretion 
of the healthcare provider (i.e., mobile healthcare provider) if necessary. 
The injection should be slowed or interrupted if the participant experiences injection-
related symptoms. Refer to the Mobile Clinical Services Training Manual for more 
details. Participants who experience injection-related symptoms may be pre-medicated 
with analgesics and antihistamines for subsequent injections. Dose reductions for 
toxicity are not permitted.

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
204/Protocol MO43110, Version 3 
Appendix 17  
Safety Reporting of COVID-19 in Study Participants 
The purpose for this guidance is to provide direction to Investigators/Study Coordinators 
about reporting events experienced by trial subjects diagnosed with coronavirus disease 
(COVID-19) or who may be at risk for developing COVID-19 due to recent travel or 
possible exposure to someone with COVID-19. 
For any Adverse Events, the subjects should be reminded to seek medical care at the 
nearest hospital or medical clinic. However, if subjects experience the following 
symptoms, fever, cough or difficulty breathing, they should contact their healthcare 
profession or other medical advice services and follow local/national guidance in order to 
limit possible exposure to COVID-19. 
When reporting cases of COVID-19: 
 
 
Any cases of confirmed/suspected COVID-19 infections should follow the 
general Adverse Event (AE) reporting requirements defined in the protocol. 
– 
While unavoidable changes in dose or schedule due to COVID-19 need to be 
captured as protocol deviations, these do not need to be reported as AEs. Changes 
in dosing or visit schedule are not considered medication errors or misuse. 
 
For any confirmed/suspected cases, the Investigators are responsible for assessing 
if an event should be reported as a Serious Adverse Event (SAE) using their clinical 
judgement and referencing protocol- specific definitions. All SAEs should be 
reported to the Sponsor per the protocol-required timeline (i.e., within 24 hours). 
 
The event term should be reported as a diagnosis and not symptoms, such as 
COVID-19 infection or Coronavirus infection. Test results, Coronavirus test positive 
or Coronavirus test negative, can also be reported. Should a definitive diagnosis not 
be possible, ‘suspected COVID-19 infection’ may be reporting initially. Please 
provide a diagnosis confirmation once additional information has been obtained. 
Please consider if the diagnosis meets the criteria of being a significant medical 
event. 
 
Complications from the virus infection should follow the reporting guidelines in the 
study protocol, detailed in the section “Adverse Events That Are Secondary to Other 
Events” (Section A2–7.3). 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 electronic form or paper reporting form. Please see this 
section in the protocol for examples. 
 
For confirmed cases, provide the method by which diagnosis was provided in the 
“Additional Case Details” section of the AE electronic form or paper reporting form. 
o Was the diagnosis confirmed by a laboratory test ordered by a physician 
or public health department? 
o Was the diagnosis based on clinical symptoms and history of travel or 
exposure? 

Appendix 17:  Safety Reporting of Covid-19 in Study Participants 
PH FDC SC—F. Hoffmann-La Roche Ltd 
205/Protocol MO43110, Version 3 
 
For all cases, please provide as much detail as available in the “Additional Case 
Details” section of the AE electronic form or paper reporting form. 
o Contact/travel history during the 14 days prior to symptom onset 
o Clinical signs/symptoms (fever, cough, shortness of breath or other acute 
respiratory symptoms) 
o Radiology exam (chest CT scan or X-rays) 
o Hematology tests, such as a real-time reverse transcription polymerase 
chain reaction (rRT- PCR) or serological testing (IgM or IgG detection via 
enzyme-linked immunoassay, ELISA). Please include the results if 
positive or negative. 
o If hospitalized, please provide details about the hospitalization course, 
such as if and how long mechanical ventilation may have been needed. 
 
Provide treatment details as per usual electronic form reporting processes. 
 
Assessing Severity: When assessing the severity of the event, please use the 
grading scale referenced in the study protocol. Refer to the section “Assessment of 
Severity” (Section A2–3.2) in the study protocol for the specific grading scale used. 
Below are two examples: 
 
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 (v5.0), 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 participants who are not bedridden. 
c If an event is assessed as a “significant medical event,” it must be reported as a serious adverse event, per the definition of 
serious adverse event see the study protocol. 
d Grade 4 and 5 events must be reported as serious adverse events, per the definition of serious adverse event see the 
study protocol. 

Appendix 17:  Safety Reporting of Covid-19 in Study Participants 
PH FDC SC—F. Hoffmann-La Roche Ltd 
206/Protocol MO43110, Version 3 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in WHO 
Toxicity Grading Scale 
 
Grade 
Severity 
1 
Mild; transient or mild discomfort (< 48 hours); no medical intervention or 
therapy required 
2 
Moderate; mild to moderate limitation in activity; some assistance may be 
needed; no or minimal medical intervention or therapy required 
3 
Severe; marked limitation in activity; some assistance usually required; medical 
intervention or therapy required; hospitalization possible 
4 
Life-threatening; extreme limitation in activity; significant assistance required; 
significant medical intervention or therapy required, hospitalization or hospice 
care probable 
Notes: Developed by the Division of Microbiology and Infectious Diseases. 
Regardless of severity, some events may also meet seriousness criteria. Refer to definition of a serious adverse event in 
the study protocol. 
 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
207/Protocol MO43110, Version 3 
Appendix 18  
Assessments for Participants who Require Additional Cycles of 
P+H IV or PH FDC SC Due to a Delay With Surgery  
The following assessments should be conducted for participants who require additional 
cycles of P+H IV or PH FDC SC due to a delay with surgery (see Section 4.1.1). 
 
Assessments at each 
additional cycle 
Limited physical examination [a] [b] 
x 
Vital signs [a] [c] 
x 
Weight [a] [d] 
x 
Clinical tumor assessment / breast examination [a] [e] 
x 
Hematology / limited biochemistry [f] 
x 
Treatment (P+H IV or PH FDC SC) 
x 
Adverse events [g] 
x 
Concomitant medication [h] 
x 
a Assessment may be done within 3 days prior to the treatment day.  
b Limited physical examinations are symptom-directed and, in addition to the scheduled 
examinations indicated, may be conducted by a mobile HCP as clinically indicated. New or 
worsened clinically significant abnormalities observed post-baseline should be recorded as 
AEs on the Adverse Event electronic form. After the End of Treatment, physical 
examinations should be conducted by treating physician in accordance with institutional 
practice or the American Cancer Society/American Society of Clinical Oncology Breast 
Cancer (ACS/ASCO) Breast Cancer Survivorship Care Guideline (Runowicz et al. 2016). 
c Vital signs (respiratory rate, pulse rate, and systolic and diastolic blood pressure while the 
participant is in a seated position, and temperature) will be taken before the administration 
of study treatment and before and after P+H IV/PH FDC SC injection. 
d Weight will be measured during screening and on Day 1 of each cycle. If variation of ± 10% 
occurs, as compared with baseline, the trastuzumab IV and chemotherapy doses will be 
recalculated. 
e Performed by clinical breast examination (mandatory) and other methods of evaluation as 
per routine clinical practice. 
f 
Hematology: WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential 
count (% or absolute for neutrophils, eosinophils, basophils, monocytes, lymphocytes, other 
cells). Limited biochemistry:  alkaline phosphatase; AST; ALT; LDH; total bilirubin; 
creatinine. Bilirubin fractions (direct and indirect) must be included if total bilirubin is greater 
than ULN. During the treatment period, bloods for hematology / biochemistry may be taken 
within three days prior to study treatment administration. 
g After initiation of study drugs, all adverse events will be reported until 28 days after the last 
dose of study treatment. After this period, all deaths, regardless of cause, should be 
reported.  In addition, the Sponsor should be notified if the investigator becomes aware of 
any serious adverse event that is believed to be related to prior exposure to study treatment 
(see Appendix 2). 
h All concomitant medications used by the participant from 7 days prior to initiation of study 
drug until the End of Treatment Visit will be reported. 
 

Appendix 18: Assessments for Participants who Require Additional Cycles of P+H IV or PH 
FDC Due to a Delay With Surgery 
PH FDC SC—F. Hoffmann-La Roche Ltd 
208/Protocol MO43110, Version 3 
Reference 
Runowicz CD, Leach CR, Henry NL, et al. American Cancer Society/American Society of 
Clinical Oncology Breast Cancer Survivorship Care Guideline. J Clin Oncol 
2016;34:611–35. 
 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
209/Protocol MO43110, Version 3 
Appendix 19  
Assessments for Participants from Arm E who Discontinue 
Trastuzumab Emtansine (Due to Intolerance) and who Switch to 
PH FDC SC 
Participants in Arm E who discontinue trastuzumab emtansine (due to intolerance) can 
be discontinued from the study (and be treated as per standard of care) or can remain in 
the study and be treated with PH FDC SC in the hospital as to complete 14 cycles of 
HER2-directed adjuvant study treatment in total. This decision is at the discretion of the 
treating physician. 
Assessment 
Timing During  
Adjuvant Phase [a] 
Treatment 
Completion/ 
Discontinuation 
[b] 
F/U 
(6–9 mo 
post last 
dose) 
Complete physical examination [c] [d] 
Last cycle 
x 
 
Limited physical examination [c] [e] 
Every cycle but the last cycle 
 
 
Vital signs [c] [f] 
Every cycle 
x 
 
ECOG performance status [c] [g] 
Cycles 1, 3, 6, 9, and last cycle 
x 
 
Weight [c] 
Every cycle 
x 
 
Clinical breast examination [c] [h] 
Cycle 1, 5, 9 and last cycle 
x 
 
Bilateral mammogram (or another 
imaging method as, per local 
practice) [i] 
 
x 
 
LVEF (ECHO or MUGA) [j] 
Cycle 1, 5, 9 and last cycle 
x 
 
Pregnancy test [k]  
Cycle 1, 5, 9 and last cycle 
x 
x 
Hematology / limited biochemistry [l] 
Every cycle  
x 
 
PH FDC SC (q3w) [m] 
Every cycle 
 
 
EORTC QLQ-C30 [n] – Appendix 8 
Cycle 7 and 14 
 
 
Adverse events [o] 
Continuous 
x 
x 
Concomitant medication [p] 
Continuous 
x 
 
ECHO  echocardiogram; ECOG  Eastern Cooperative Oncology Group; LVEF  left 
ventricular ejection fraction; MUGA  multiple-gated acquisition (scan). 
 
Note: Unless otherwise specified, assessments should be performed within three days of the 
scheduled visit. On treatment days, all assessments should be performed prior to dosing, 
unless otherwise specified. For all protocol-mandated study visits, a time window of ± 3 days 
is allowed. If a protocol mandated study visit coincides with a holiday and/or weekend that 
preclude the visit, the visit should be scheduled on the nearest following feasible date. 
Unscheduled visits may be performed if clinically indicated.  The following assessments 
should be performed at a minimum: concomitant medications, adverse events, and vital 
signs. Additional assessments may be performed as clinically indicated, per investigator 
discretion. 
 
a Treatment will be given so that in total, 14 cycles of HER2-directed therapy (trastuzumab 
emtansine or PH FDC SC) are administered in the adjuvant setting. Cycle numbers represent 
a continuation of the adjuvant treatment phase cycle numbers (Table 4). 

Appendix 19: Assessments for Patients from Arm E who Discontinue Trastuzumab 
Emtansine (Due to Intolerance) and who Switch to PH FDC SC 
PH FDC SC—F. Hoffmann-La Roche Ltd 
210/Protocol MO43110, Version 3 
b Treatment completion or discontinuation visits will optimally be scheduled for 28 (± 7 days) 
following the last dose of study medication and will include all evaluations scheduled for the 
final visit. 
c Assessment may be done within 3 days prior to the treatment day.  
d Complete physical examinations should include physical measurements (body weight in 
kilograms and height in centimeters) and evaluation of the head, eyes, ears, nose and throat, 
and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  
e Limited physical examinations are symptom-directed and, in addition to the scheduled 
examinations indicated, may be conducted by a mobile HCP as clinically indicated. Physical 
examinations may be physician-guided remotely with the HCP assisting in the participant’s 
home. New or worsened clinically significant abnormalities observed post-baseline should be 
recorded as AEs on the Adverse Event electronic form. After the End of Treatment, physical 
examinations should be conducted by treating physician in accordance with institutional 
practice or the American Cancer Society/American Society of Clinical Oncology Breast 
Cancer (ACS/ASCO) Breast Cancer Survivorship Care Guideline (Runowicz et al. 2016). 
f 
Vital signs (respiratory rate, pulse rate, and systolic and diastolic blood pressure while the 
participant is in a seated position, and temperature) will be taken before and after PH FDC SC 
injection. 
g ECOG Performance Status should be assessed by the HCP at least every 3–4 months during 
the adjuvant treatment period and at the treatment completion or discontinuation visit. 
h During the adjuvant treatment period, clinical breast examination should be performed to 
detect signs of locoregional relapse at least every 3–4 months (Cycle 1, Cycle 5, Cycle 9 and 
last cycle) and at the treatment completion or discontinuation visit. 
i 
The mammogram at the 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 participant. 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. 
j 
For participants whose LVEF cannot be assessed by ECHO, LVEF may be assessed by 
MUGA. The same method should be used throughout the study for each participant 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, LVEF 
assessment may also be performed on Day 1 of treatment. Results of LVEF assessments 
must be available before treatment is administered and according to the scheduled 
timepoints. Apart from the specified mandatory LVEF assessment, the investigator may 
request additional assessment based on the individual participant's cardiovascular function 
with a minimum frequency of 3–4 months. 
k All female participants of childbearing potential (refer to Section 5.1.1 for definition) will have a 
urine pregnancy test at cycle 1, 5 or 6, 9, and last cycle during adjuvant phase; 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 months follow-up) can 
be performed if indicated. Note that participants are required to continue contraception for 
7 months after study treatment is complete. 

Appendix 19: Assessments for Patients from Arm E who Discontinue Trastuzumab 
Emtansine (Due to Intolerance) and who Switch to PH FDC SC 
PH FDC SC—F. Hoffmann-La Roche Ltd 
211/Protocol MO43110, Version 3 
l 
Hematology: WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential 
count (% or absolute for neutrophils, eosinophils, basophils, monocytes, lymphocytes, other 
cells). Limited biochemistry:  alkaline phosphatase; AST; ALT; LDH; total bilirubin; creatinine. 
Bilirubin fractions (direct and indirect) must be included if total bilirubin is greater than ULN. 
During the treatment period, bloods for hematology / biochemistry may be taken within three 
days prior to study treatment administration. 
m PH FDC SC should not be initiated within < 3 weeks from last dose of trastuzumab 
emtansine. All participants receive maintenance dose of 600 mg pertuzumab and 600 mg 
trastuzumab. Participants who have had ≥ 6 weeks since their last trastuzumab emtansine 
treatment must receive a PH FDC SC loading dose before continuing with maintenance doses 
for subsequent administrations. 
n Completed before treatment is administered on Day 1 of the indicated treatment cycles. 
o After initiation of study drugs, all adverse events will be reported until 28 days after the last 
dose of study treatment. After this period, all deaths, regardless of cause, should be reported.  
In addition, the Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that is believed to be related to prior exposure to study treatment (see 
Appendix 2). 
p All concomitant medications used by the participant from 7 days prior to initiation of study 
drug until the End of Treatment Visit will be reported. 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
212/Protocol MO43110, Version 3 
Appendix 20  
Investigational and Auxiliary Medicinal Product Designations 
(for Use in European Economic Area) 
Product Name 
IMP/AxMP 
Designation 
Marketing 
Authorization Status 
in EEA 
Used within 
Marketing 
Authorization 
PH FDC SC 
(RO7198574) 
IMP (test product) 
Approved 
Yes 
Pertuzumab 
(RO4368451) 
IMP (test product) 
Approved 
Yes 
Trastuzumab  
(RO45-2317) 
IMP (test product) 
Approved 
Yes 
Trastuzumab 
emtansine 
(RO5304020) 
IMP (test product) 
Approved 
Yes 
Docetaxel 
AxMP 
(background therapy) 
Approved 
Yes 
Carboplatin 
AxMP 
(background therapy) 
Approved 
Yes 
Doxorubicin 
AxMP 
(background therapy) 
Approved 
Yes 
Paclitaxel 
AxMP 
(background therapy) 
Approved 
Yes 
Cyclophosphamide 
AxMP 
(background therapy) 
Approved 
Yes 
Endocrine therapy 
AxMP 
(background therapy) 
Approved 
Yes 
Premedications 
AxMP 
(other) 
Approved 
Yes 
Diphenhydramine 
AxMP 
(rescue medication) 
Approved 
Yes 
Solu-Cortef 
AxMP 
(rescue medication) 
Approved 
Yes 
Epinephrine 
AxMP 
(rescue medication) 
Approved 
Yes 
AxMP  auxiliary medicinal product; EEA 
 European Economic Area; IMP   investigational 
medicinal product.  
 

 
PH FDC SC—F. Hoffmann-La Roche Ltd 
213/Protocol MO43110, Version 3 
Appendix 21  
Abbreviations 
Abbreviation or Term 
Definition 
AC 
Doxorubicin plus cyclophosphamide 
ACE 
Angiotensin-converting enzyme 
ACS/ASCO 
American Cancer Society/American Society of 
Clinical Oncology Breast Cancer 
AE 
Adverse event 
AJCC 
American Joint Committee on Cancer 
ALND 
Axillary lymph node dissection 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ARR 
Administration-related reactions 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
AxMP 
Auxiliary medicinal product 
CAP 
College of American Pathologists 
CHF 
Congestive heart failure  
CI 
Confidence interval 
ClinRO 
Clinician-reported outcome 
CMF 
Concomitant medications form 
COVID-19 
Coronavirus disease 2019 
CRF 
Case report form 
CTCAE 
Common terminology criteria for adverse 
events 
DCIS 
Ductal carcinoma in situ  
ddAC 
Dose-dense doxorubicin plus 
cyclophosphamide 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern cooperative oncology group  
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EMEA 
European medicines agency 
EORTC QLQ-30 
European Organization for Research and 
Treatment of Cancer core quality of life 
questionnaire 

Appendix 21: 
Abbreviations 
PH FDC SC—F. Hoffmann-La Roche Ltd 
214/Protocol MO43110, Version 3 
Abbreviation or Term 
Definition 
ER 
Estrogen receptor 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed, paraffin-embedded 
HBcAb 
Hepatitis B Core Antibody 
HBsAb 
Hepatitis B Surface Antibody 
HBsAg 
Hepatitis B Surface Antigen 
HBV/HCV 
Hepatitis B/C Virus  
HCP 
Healthcare professional 
HCPQ 
Healthcare professional questionnaires  
HER2 
Human epidermal growth factor receptor 2 
HIV 
Human immunodeficiency virus 
HRQoL 
Health-related quality of life 
ICH 
International Council for Harmonisation 
IHC 
Immunohistochemistry 
IM 
Intramuscular 
IMC 
Internal Monitoring Committee 
IMP 
Investigational medicinal product 
IND 
Investigational new drug (application) 
INR 
International normalized ratio  
IRB 
Institutional review board 
ISH 
In situ hybridization 
ITT 
Intention-to-treat 
IV 
Intravenous 
IxRS 
Interactive voice or web-based response 
system 
LCIS 
Lobular carcinoma in situ 
LDH 
Lactate dehydrogenase 
LVEF 
Left ventricular ejection fraction 
LVSD 
Left ventricular systolic dysfunction 
mITT 
Modified intention-to-treat 
MRI 
Magnetic resonance imaging 
MUGA 
Multiple-gated acquisition (scan) 
NCI CTCAE 
National Cancer Institute Common 
Terminology Criteria for Adverse Events 
NYHA 
New York heart association 

Appendix 21: 
Abbreviations 
PH FDC SC—F. Hoffmann-La Roche Ltd 
215/Protocol MO43110, Version 3 
Abbreviation or Term 
Definition 
P+H IV 
IV administration of pertuzumab and 
trastuzumab 
pCR 
Pathologic complete response 
PgR 
Progesterone receptor 
PH FDC SC  
Pertuzumab and trastuzumab fixed-dose 
combination for subcutaneous use 
PK 
Pharmacokinetic 
PPQ 
Patient preference questionnaire 
PRO 
Patient-reported outcome 
q2w 
Every 2 weeks 
q3w 
Every 3 weeks 
QTcF 
QT interval corrected through use of 
Fridericia's formula 
RBC 
Red blood cell 
rhTPO 
Recombinant thrombopoeitin 
rHuPH20 
Recombinant human PH20 hyaluronidase 
SAE 
Serious adverse event; 
SC  
Subcutaneous 
SLNB 
Sentinel lymph node biopsy  
TCb 
docetaxel and carboplatin 
TM 
Trademark 
ULN 
Upper limit of normal 
WBC 
White blood cell 
β-HCG 
Beta human chorionic gonadotropin 
 

Signature Page for Protocol - MO43110 - PHESGO - v3 - Global/Core - Published
System identifier: RIM-CLIN-512227
Approval Task
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25-Jan-2024 12:52:42 GMT+0000