Clinical trial NCT05275010
Conditions: Healthy Male Subjects
Sponsor: Hoffmann-La Roche
Start date: 2022-05-30; Completion date: 2023-10-03
Enrollment: 151 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, open-label, 2-arm, parallel-group, single-dose, multi-center study in healthy male subjects to investigate the comparability of the pharmacokinetics of the fixed-dose combination of pertuzumab and trastuzumab administered subcutaneously using the proprietary on-body delivery system or a handheld syringe with hypodermic needle.

Detailed description:

Arms: arm 1: A single dose of PH FDC SC (600 mg pertuzumab/600 mg trastuzumab) will be administered by a healthcare professional subcutaneously (SC) into the participant's anterior thigh on Day 1, using a handheld syringe with hypodermic needle. arm 2: A single dose of PH FDC SC (600 mg pertuzumab/600 mg trastuzumab) will be administered by a healthcare professional subcutaneously (SC) into the participant's anterior thigh on Day 1, using the on-body delivery system (OBDS).
Interventions: intervention 1: Fixed-Dose Combination of Pertuzumab and Trastuzumab SC (PH FDC SC) intervention 2: Handheld Syringe with Hypodermic Needle intervention 3: On-Body Delivery System
Intervention descriptions: intervention 1: A single dose of PH FDC SC (600 mg pertuzumab/600 mg trastuzumab) will be administered by a healthcare professional subcutaneously (SC) into the anterior thigh, using either a handheld syringe with hypodermic needle (Arm 1) or the on-body delivery system (Arm 2). intervention 2: A single 10-mL dose of PH FDC SC will be administered as a subcutaneous (SC) injection using a handheld manual syringe. intervention 3: A single 10-mL dose of PH FDC SC will be administered as a subcutaneous (SC) injection using the on-body delivery system (OBDS).

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
A Randomized, Open-Label, 2-arm, Parallel Group, Single Dose, 
Multi-Centre Study in Healthy Male Subjects to Investigate the 
Comparability of Pharmacokinetics of the Fixed-Dose Combination of 
Pertuzumab and Trastuzumab Administered Subcutaneously Using a 
Handheld Syringe or Using the On-Body Delivery System 
NCT Number: 
NCT05275010 
Document Date: 
Protocol Version 4: 13 December 2022 
 
 
 


CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
Protocol WP42873, Version 4 
PROTOCOL 
TITLE: 
A RANDOMIZED, OPEN-LABEL, 2-ARM, PARALLEL 
GROUP, SINGLE DOSE, MULTI-CENTRE STUDY IN 
HEALTHY MALE SUBJECTS TO INVESTIGATE THE 
COMPARABILITY OF PHARMACOKINETICS OF THE 
FIXED-DOSE COMBINATION OF PERTUZUMAB AND 
TRASTUZUMAB ADMINISTERED SUBCUTANEOUSLY 
USING A HANDHELD SYRINGE OR USING THE 
ON-BODY DELIVERY SYSTEM 
PROTOCOL NUMBER: 
WP42873 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
Not Applicable 
IND NUMBER: 
Not Applicable 
NCT NUMBER: 
NCT05275010 
TEST PRODUCT: 
Fixed-dose combination (FDC) of pertuzumab and 
trastuzumab for subcutaneous administration 
(RO7198574) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document. 


 
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2/Protocol WP42873, Version 4 
PROTOCOL HISTORY 
Version 
Date Final 
4 
See electronic date stamp on the final page of this document. 
3 
21 July 2022 
2 
21 April 2022 
1 
27 April 2021 
 
 


 
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3/Protocol WP42873, Version 4 
PROTOCOL AMENDMENT, VERSION 4: 
RATIONALE 
Protocol WP42873 Version 4 has been amended to update the reasons for excluding 
subjects from the pharmacokinetic (PK) analysis population for the co-primary endpoints.  
With this update, the reasons for exclusion have been modified so fewer subject will fall 
into the PK non-evaluable population, therefore enabling more subjects to be included in 
the primary analysis. 
Changes to the protocol, along with a rationale for each change, are summarized below: 
 
Personal identifiable information (i.e., name and telephone number) for the Medical 
Monitors has been removed from the protocol (Section 5.4.1).  Medical Monitor 
contact information has been replaced with a sentence indicating that this 
information will be provided separately to sites. 
 
The following changes have been made to Section 6.4:  
– 
The analysis population has been updated to clarify the primary population. 
– 
For analysis of AUC062 days, the PK sampling time window has been increased 
from  48 hours to  120 hours, so subjects with a Day 63 PK sample time 
deviation outside of a  120-hour window of planned sampling time will now be 
excluded.   
– 
For analysis of Cmax, the number of missing PK samples allowed has been 
increased from 0 to 1, so now subjects with two or more missing PK 
concentration data on any of Days 3, 5, 7, 9, or 11 will be excluded.  
 
The description of the secondary endpoint analyses have been simplified and 
aligned with the wording in the statistical analysis plan (Section 6.5). 
 
The Sponsor record retention policy has been clarified (Section 7.1). 
 
A description of the technical and organizational security measures taken to protect 
personal data has been added to align with CTR requirements (Section 8.4). 
 
Due to certain local requirements and an alignment of Sponsor process, it has been 
clarified that summaries of clinical study results may be available in health authority 
databases for public access in addition to redacted Clinical Study Reports 
(Section 8.4). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 10 
PROTOCOL SYNOPSIS .................................................................................... 11 
1. 
BACKGROUND ............................................................................ 18 
1.1 
Background on HER2-Positive Breast Cancer......................... 18 
1.2 
Background on Study Medication ............................................ 20 
1.2.1 
Study Drug Nomenclature ....................................................... 20 
1.2.2 
Background on Pertuzumab and Trastuzumab Fixed-dose 
Combination for Subcutaneous Administration (PH FDC 
SC) .......................................................................................... 20 
1.3 
Study Rationale and Benefit-Risk Assessment ........................ 22 
1.3.1 
Study Rationale ....................................................................... 22 
1.3.2 
Benefit-Risk Assessment ......................................................... 22 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 24 
2.1 
Primary Objective .................................................................... 24 
2.2 
Secondary Objectives .............................................................. 24 
2.2.1 
Pharmacokinetic Objectives..................................................... 24 
2.2.2 
Safety Objectives ..................................................................... 25 
2.2.3 
Device Monitoring Objectives .................................................. 25 
2.3 
Exploratory Objectives ............................................................. 26 
2.3.1 
Immunogenicity Objectives ...................................................... 26 
3. 
STUDY DESIGN ........................................................................... 26 
3.1 
Description of the Study ........................................................... 26 
3.1.1 
Overview of the Study Design .................................................. 26 
3.2 
End of Study and Length of Study ........................................... 27 
3.3 
Rationale for Study Design ...................................................... 27 
3.4 
Rationale for PH FDC SC Dose and Schedule ........................ 27 
3.5 
Rationale for subject Population .............................................. 28 
4. 
MATERIALS AND METHODS ...................................................... 28 
4.1 
Subjects ................................................................................... 28 
4.1.1 
Inclusion Criteria ...................................................................... 28 


 
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4.1.2 
Exclusion Criteria ..................................................................... 29 
4.2 
Method of Treatment Assignment ............................................ 30 
4.2.1 
Treatment Assignment ............................................................. 30 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 31 
4.3.1 
Study Treatment Formulation and Packaging .......................... 31 
4.3.1.1 
PH FDC SC ............................................................................. 31 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 31 
4.3.2.1 
Administration of PH FDC SC by handheld syringe and 
needle ...................................................................................... 32 
4.3.2.2 
Administration of PH FDC SC by OBDS .................................. 32 
4.3.3 
Investigational Medicinal Product Handling and 
Accountability ........................................................................... 35 
4.4 
Concomitant Therapy, special dietary requirements and 
Additional Restrictions ............................................................. 36 
4.5 
Study Assessments ................................................................. 36 
4.5.1 
Informed Consent Forms and Screening Log .......................... 36 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................... 37 
4.5.3 
Physical Examinations ............................................................. 37 
4.5.4 
Vital Signs ................................................................................ 37 
4.5.5 
Laboratory, Biomarker, and Other Biological Samples ............ 38 
4.5.6 
Electrocardiograms .................................................................. 39 
4.5.7 
Left Ventricular Ejection Fraction ............................................. 40 
4.5.8 
Clinical Outcome Assessments ............................................... 40 
4.5.8.1 
Data Collection Methods for Clinical Outcome 
Assessments ........................................................................... 41 
4.5.9 
Device Monitoring Assessments .............................................. 41 
4.6 
Treatment, subject, Study, and Site Discontinuation ............... 42 
4.6.1 
Study Treatment Discontinuation ............................................. 42 
4.6.2 
Subject Discontinuation from the Study ................................... 43 
4.6.3 
Study Discontinuation .............................................................. 43 
4.6.4 
Site Discontinuation ................................................................. 43 
5. 
ASSESSMENT OF SAFETY ......................................................... 44 


 
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5.1 
Safety Plan .............................................................................. 44 
5.1.1 
Risks Associated with PH FDC SC .......................................... 44 
5.1.1.1 
Hypersensitivity Reactions/Anaphylaxis and 
Administration-Related Reactions ............................................ 44 
5.1.1.2 
Symptomatic Left Ventricular Dysfunction ............................... 45 
5.1.1.3 
Diarrhea ................................................................................... 47 
5.1.1.4 
Rash/Skin Reactions ............................................................... 47 
5.1.1.5 
Mucositis .................................................................................. 47 
5.1.1.6 
Reproductive Risks Associated with Pertuzumab, 
Trastuzumab, and PH FDC SC ................................................ 47 
5.1.1.7 
Interstitial Lung Disease .......................................................... 48 
5.1.2 
Management of Subjects Who Experience Adverse Events .... 48 
5.1.2.1 
Management of Symptomatic LVSD and/or LVEF Decline ...... 48 
5.1.2.2 
Management of Hypersensitivity/Anaphylaxis and 
Administration-Related Reactions ............................................ 49 
5.1.2.3 
EGFR-Related Toxicities ......................................................... 50 
5.2 
Safety Parameters and Definitions .......................................... 50 
5.2.1 
Adverse Events ........................................................................ 50 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 51 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 52 
5.2.4 
Selected Adverse Events ......................................................... 52 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 54 
5.3.1 
Adverse Event Reporting Period .............................................. 54 
5.3.2 
Eliciting Adverse Event Information ......................................... 54 
5.3.3 
Assessment of Severity of Adverse Events ............................. 54 
5.3.4 
Assessment of Causality of Adverse Events............................ 55 
5.3.5 
Procedures for Recording Adverse Events .............................. 56 
5.3.5.1 
Injection Reactions .................................................................. 56 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................... 57 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ............. 57 
5.3.5.4 
Persistent or Recurrent Adverse Events .................................. 58 
5.3.5.5 
Abnormal Laboratory Values ................................................... 58 


 
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5.3.5.6 
Abnormal Vital Sign Values ..................................................... 59 
5.3.5.7 
Abnormal Liver Function Tests ................................................ 59 
5.3.5.8 
Deaths ..................................................................................... 60 
5.3.5.9 
Preexisting Medical Conditions ................................................ 60 
5.3.5.10 
Hospitalization or Prolonged Hospitalization ............................ 60 
5.3.5.11 
Cases of Accidental Overdose or Medication Error ................. 61 
5.3.5.12 
Patient-Reported Outcome Data .............................................. 62 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 62 
5.4.1 
Medical Monitors and Emergency Medical Contacts ............... 63 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 63 
5.4.2.1 
Events That Occur prior to Study Drug Initiation ...................... 63 
5.4.2.2 
Events That Occur after Study Drug Initiation .......................... 63 
5.4.3 
Reporting Requirements for Pregnancies ................................ 63 
5.4.3.1 
Pregnancies in Female Partners of Male Subjects .................. 63 
5.4.3.2 
Congenital Anomalies/Birth Defects ........................................ 64 
5.4.4 
Reporting Requirements for Medical Device Complaints ......... 64 
5.5 
Follow-Up of Subjects after Adverse Events ............................ 65 
5.5.1 
Investigator Follow-Up ............................................................. 65 
5.5.2 
Sponsor Follow-Up .................................................................. 65 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period ...................................................................... 65 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 65 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 66 
6.1 
Determination of Sample Size ................................................. 66 
6.2 
Summaries of Conduct of Study .............................................. 66 
6.3 
Summaries of Treatment Group Comparability ........................ 66 
6.4 
Primary Endpoint Analyses ...................................................... 67 
6.5 
Secondary Endpoints ............................................................... 68 
6.5.1 
Pharmacokinetic Analyses ....................................................... 68 
6.5.2 
Safety Analyses ....................................................................... 69 
6.5.3 
Device Related Analyses ......................................................... 69 


 
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6.6 
Exploratory Analyses ............................................................... 70 
6.6.1 
Immunogenicity Analyses ........................................................ 70 
7. 
DATA COLLECTION AND MANAGEMENT ................................. 70 
7.1 
Data Quality Assurance ........................................................... 70 
7.2 
Electronic Case Report Forms ................................................. 71 
7.3 
Source Data Documentation .................................................... 71 
7.4 
Use of Computerized Systems ................................................ 72 
7.5 
Retention of Records ............................................................... 72 
8. 
ETHICAL CONSIDERATIONS ...................................................... 72 
8.1 
Compliance with Laws and Regulations .................................. 72 
8.2 
Informed Consent .................................................................... 73 
8.3 
Institutional Review Board or Ethics Committee ...................... 74 
8.4 
Confidentiality .......................................................................... 74 
8.5 
Financial Disclosure ................................................................. 75 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ....................................................................... 75 
9.1 
Study Documentation .............................................................. 75 
9.2 
Protocol Deviations .................................................................. 75 
9.3 
Management of Study Quality .................................................. 76 
9.4 
Site Inspections ....................................................................... 76 
9.5 
Administrative Structure ........................................................... 76 
9.6 
Dissemination of Data and Protection of Trade Secrets .......... 76 
9.7 
Protocol Amendments ............................................................. 77 
10. 
REFERENCES.............................................................................. 78 
 
 
LIST OF TABLES 
Table 1 
Reporting Conventions for Left Ventricular Systolic 
Dysfunction/Congestive Heart Failure ......................................... 53 
Table 2 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 55 
Table 3 
Causal Attribution Guidance ....................................................... 56 
Table 4 
Reporting Conventions for Injection-Related Reactions and 
Injection-Site Reactions .............................................................. 57 


 
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LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 26 
Figure 2 
OBDS with PH FDC SC cartridge ............................................... 34 
 
 
LIST OF APPENDICES 
Appendix 1 
 Schedule of Activities ................................................................. 83 
Appendix 2 
 Schedule of Procedures on Day 1 (hours post-dose) ................ 87 
Appendix 3 
 Schedule of Pharmacokinetic and Immunogenicity Samples ..... 88 
Appendix 4 
 Subcutaneous Injection Using Handheld Syringe and 
Needle ........................................................................................ 89 
Appendix 5 
 Subcutaneous Injection Using On-Body Delivery system .......... 90 
Appendix 6 
 NYHA Functional Classification System for Heart Failure 
and LVSD NCI CTCAE Version 5.0 Grading............................... 93 
Appendix 7 
Correction Formulas for QTc Intervals ........................................ 94 
 


 
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10/Protocol WP42873, Version 4 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A RANDOMIZED, OPEN-LABEL, 2-ARM, PARALLEL 
GROUP, SINGLE DOSE, MULTI-CENTRE STUDY IN 
HEALTHY MALE SUBJECTS TO INVESTIGATE THE 
COMPARABILITY OF PHARMACOKINETICS OF THE 
FIXED-DOSE COMBINATION OF PERTUZUMAB AND 
TRASTUZUMAB ADMINISTERED SUBCUTANEOUSLY 
USING A HANDHELD SYRINGE OR USING THE 
ON-BODY DELIVERY SYSTEM 
PROTOCOL NUMBER: WP42873 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
Not Applicable 
IND NUMBER: 
Not Applicable 
NCT NUMBER: 
NCT05275010 
TEST PRODUCT: 
Fixed-dose combination (FDC) of pertuzumab and 
trastuzumab for subcutaneous administration 
(RO7198574) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name  (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor. 
 


 
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11/Protocol WP42873, Version 4 
PROTOCOL SYNOPSIS 
TITLE: 
A RANDOMIZED, OPEN-LABEL, 2-ARM, PARALLEL GROUP, 
SINGLE DOSE, MULTI-CENTRE STUDY IN HEALTHY MALE 
SUBJECTS TO INVESTIGATE THE COMPARABILITY OF 
PHARMACOKINETICS OF THE FIXED-DOSE COMBINATION OF 
PERTUZUMAB AND TRASTUZUMAB ADMINISTERED 
SUBCUTANEOUSLY USING A HANDHELD SYRINGE OR USING 
THE ON-BODY DELIVERY SYSTEM 
PROTOCOL NUMBER: 
WP42873 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
Not Applicable 
IND NUMBER: 
Not Applicable 
IND NUMBER: 
To be determined 
TEST PRODUCT: 
Fixed-dose combination (FDC) of pertuzumab and trastuzumab for 
subcutaneous administration (RO7198574) 
PHASE: 
Phase I 
INDICATION: 
Not Applicable 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the pharmacokinetics and safety of the fixed-dose combination of 
pertuzumab and trastuzumab for subcutaneous administration (PH FDC SC) given by the 
on-body delivery system (OBDS) compared to hypodermic needle and syringe in healthy male 
subjects.  Specific objectives and corresponding endpoints for the study are outline below. 
 
Primary Pharmacokinetic Objective 
Corresponding Endpoints 
 
To demonstrate comparability of single-
dose AUC062 and Cmax for pertuzumab 
and trastuzumab within PH FDC SC, 
administered either by the OBDS or by 
a handheld syringe with hypodermic 
needle 
 
Serum pertuzumab AUC062 and Cmax 
 
Serum trastuzumab AUC062 and Cmax 
Secondary Pharmacokinetic Objectives 
Corresponding Endpoints 
 
To demonstrate the comparability of 
CDay21 values for pertuzumab and 
trastuzumab within PH FDC SC, 
administered either by the OBDS or by 
a handheld syringe with hypodermic 
needle 
 
Serum pertuzumab CDay21 
 
Serum trastuzumab CDay21 
 


 
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 
To demonstrate the comparability of 
CDay62 values for pertuzumab and 
trastuzumab within PH FDC SC, 
administered either by the OBDS or by 
a handheld syringe with hypodermic 
needle 
 
Serum pertuzumab CDay62 
 
Serum trastuzumab CDay62 
 
To further characterize additional PK 
parameters for pertuzumab and 
trastuzumab within PH FDC SC, 
administered either by the OBDS or by 
a handheld syringe with hypodermic 
needle 
 
AUC0 
 
tmax 
 
t1/2 
 
CL/F 
 
Vd/F 
Secondary Safety Objectives 
Corresponding Endpoints 
 
To demonstrate comparable safety and 
tolerability of PH FDC SC administered 
by either the OBDS or by a handheld 
syringe with hypodermic needle 
 
Incidence and severity of adverse 
events, with severity determined 
according to the NCI CTCAE 
Version 5.0 
 
Change from baseline in vital signs, 
LVEF, and ECG parameters 
 
Change from baseline in clinical 
laboratory test results 
 
To demonstrate the safety of the OBDS 
 
Pain at the injection site assessed by 
the subject using the 100 mm VAS 
 
Skin irritation and sensitization 
reactions at the site of injection 
assessed by the study staff using the 
device monitoring questionnaire in the 
eCRF 
Secondary Device Monitoring Objectives 
Corresponding Endpoints 
 
To demonstrate the performance of the 
OBDS 
 
Comfort of wearing the device, as 
reported by the subject using the device 
monitoring questionnaire 
Details of performance and ease of use 
of the OBDS reported by site staff, 
using the device monitoring 
questionnaire in the eCRF 
Exploratory Immunogenicity Objectives 
Corresponding Endpoints 
 
To evaluate the immune response to 
pertuzumab, trastuzumab, and 
rHuPH20 within the PH FDC SC, 
administered using an OBDS compared 
to a hand-held syringe with hypodermic 
needle 
 
Incidence of pertuzumab ADAs during 
the study relative to the prevalence of 
ADAs at baseline 
 
Incidence of trastuzumab ADAs during 
the study relative to the prevalence of 
ADAs at baseline 
 
Incidence of rHuPH20 ADAs during the 
study relative to the prevalence of ADAs 
at baseline 


 
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ADA  anti-drug antibody; AUC062  area under the timeconcentration curve from the start of 
dosing to 63 days; AUC0  area under the time–concentration curve from the start of dosing 
extrapolated to infinity; CDay21  serum concentration on Day 22; CDay62  serum concentration 
on Day 63; CL/F  apparent drug clearance; Cmax  maximum concentration; eCRF  electronic 
Case Report Form; LVEF  Left Ventricular Ejection Fraction; NCI CTCAE  National Cancer 
Institute Common Terminology Criteria for Adverse Events; OBDS  on-body delivery system; 
PH FDC SC  fixed-dose combination of pertuzumab and trastuzumab for subcutaneous 
administration; PK  pharmacokinetic; rHuPH20  recombinant human PH20 hyaluronidase; 
tmax  observed time to maximum concentration; t1/2  terminal elimination half-life; VAS  Visual 
Analog Scale; Vd/F  apparent volume of distribution 
 
STUDY DESIGN 
DESCRIPTION OF STUDY 
This is a randomized, open-label, 2-arm parallel-group, single-dose, multi-center study in 
healthy male subjects to investigate the comparability of pharmacokinetics (PKs) of pertuzumab 
and trastuzumab within the PH FDC SC administered using the proprietary OBDS or 
a handheld syringe with hypodermic needle.  Subjects will be randomized to one of two dosing 
arms (Arm 1 or Arm 2) in a 1:1 ratio to receive a single dose of PH FDC SC administered by 
a healthcare professional subcutaneously into the anterior thigh using either the OBDS or 
a handheld syringe with hypodermic needle.  The study will be conducted at clinical research 
facilities in New Zealand and Australia. 
NUMBER OF SUBJECTS 
Approximately 144 male subjects will be randomized. 
TARGET POPULATION 
Inclusion Criteria 
Subjects must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Healthy male subjects age 1845 years at time of signing Informed Consent Form 
 
Ability to comply with the study protocol 
 
Agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, 
and agreement to refrain from donating sperm, as defined below: 
With a female partner of childbearing potential or pregnant female partner, men must 
remain abstinent or use a condom during the treatment period and for 7 months after 
the dose of PH FDC SC to avoid exposing the embryo.  Men must refrain from 
donating sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the subject.  Periodic 
abstinence (e.g., according to female partner calendar, ovulation, symptothermal, or 
postovulation 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. 
 
A body mass index (BMI) between 18 and 32 kg/m2, inclusive 
 
Intact normal skin without potentially obscuring tattoos, pigmentation, or lesions in the area 
for intended injection on the thighs 
 
Baseline LVEF  55% measured by echocardiogram (ECHO) 
 
No history of hypersensitivity or confirmed, clinically significant and clinically relevant 
allergic reactions, either spontaneously or following any drug administration 
 
No history of any clinically significant and clinically relevant cardiac condition 
 
No history of previous anticancer treatments including pertuzumab, trastuzumab, 
anthracyclines, or any cardiotoxic drugs 


 
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 
No apparent family history of clinically significant and clinically relevant hypersensitivity, 
allergy, and severe cardiac diseases 
 
No contraindications from detailed medical and surgical history and physical examinations 
 
No previous enrollment in this study protocol and no concurrent enrollment in any other 
study protocol 
 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from study entry: 
 
Positive urine test for drugs of abuse as per local standard (for alcohol abuse, positive 
breath test is also acceptable) 
 
Positive test result for hepatitis B virus (HBV), hepatitis C virus (HCV), or HIV 1 or 2.  
Showing: 
History of exposure to HBV, HCV, or HIV 
or 
Active viral hepatitis infection (HBV or HCV) or HIV infection 
 
Systolic blood pressure (BP)  140 mmHg or  90 mmHg, or diastolic BP  90 mmHg 
or  50 mmHg 
 
Use of prohibited medications, including non-prescription medications, nutraceuticals, 
nutritional supplements, or any herbal remedies taken within 10 days or 5 times the 
elimination half-life (whichever is longer) prior to randomization into the study 
 
Concomitant subcutaneous, intravenous, or any parenteral drugs within 90 days prior to 
screening 
 
Participation in an investigational drug or device study within 90 days or 5 times the 
elimination half-life (whichever is longer) prior to screening 
 
Donation of blood over 500 mL within 3 months prior to enrollment 
 
Known severe hypersensitivity to plaster, medical adhesive tapes, or bandages 
 
Known allergy to murine proteins, hyaluronidase, bee, or vespid venom, or any other 
ingredient in the formulation of recombinant human PH20 hyaluronidase (rHuPH20) 
(Hylenex recombinant [hyaluronidase human injection]) or any other ingredients and 
excipients in the formulation of PH FDC SC 
 
Clinically significant abnormalities in laboratory test results (including hepatic and renal 
panels, CBC, chemistry panel, and urinalysis) 
 
Clinically relevant ECG abnormalities on screening or Day 1 ECG: 
Corrected QT interval (QTc) (QT interval corrected through use of Fridericia’s formula 
[QTcF]  450 msec) 
notable resting bradycardia (heart rate [HR]  40 bpm) 
notable resting tachycardia (HR  100 bpm) 
difference between highest and lowest durations of any baseline QTc at a specific time 
point  30 msec 
measurement of QT interval imprecise (i.e., flat T waves, arrhythmias, etc.) 
evidence of atrial fibrillation, atrial flutter, right or left bundle branch block, 
Wolf-Parkinson-White Syndrome, or cardiac pacemaker 
any other significant abnormality 
 
History of any cardiac condition 
 
Lower extremity edema or pathology (e.g., cellulitis, lymphatic disorder or prior surgery, 
pre-existing pain syndrome, previous lymph node dissection etc.) that could interfere with 
any protocol-specified outcome assessment 
 
Any history of clinically significant and clinically relevant allergies, oncologic, psychiatric, 
gastrointestinal, renal, hepatic, cardiovascular or pulmonary disease 


 
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 
Concomitant disease or condition that could interfere with, or for which the treatment might 
interfere with, the conduct of the study, or that would pose an unacceptable risk to the 
subject in this study 
 
Any clinically relevant history of systemic disease (e.g., malignancy, diabetes mellitus, 
gastrointestinal, renal, hepatic, cardiovascular, rheumatological, or pulmonary disease) 
 
History of breast cancer or treatment for breast cancer 
 
Current chronic daily treatment (continuous for  3 months) with corticosteroids 
(dose  10 mg/day methylprednisolone), excluding inhaled corticosteroids 
 
Receipt of IV antibiotics for infection within 7 days prior to enrollment into the study 
 
END OF STUDY 
The end of the study is defined as the date when the last subject, last visit occurs.  This is 
expected to occur 7 months after the last subject is enrolled (i.e., when the last subject has 
completed the safety follow-up visit at 7 months after administration of study drug). 
LENGTH OF STUDY 
The length of study will be a maximum of 35 weeks per subject, from screening to follow-up 
(4 weeks screening, plus 7 months [~31 weeks] follow-up after dose).  The total length of the 
study from screening of the first subject to the end of the study is expected to be approximately 
11 months. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
The IMP for this study is PH FDC SC (600 mg pertuzumab/600 mg trastuzumab/ 20,000U 
rHuPH20). 
Subjects in Arm 1 will receive a single dose of PH FDC SC administered by a healthcare 
professional using a handheld syringe with hypodermic needle. 
Subjects in Arm 2 will receive a single dose of PH FDC SC administered by a healthcare 
professional using the OBDS. 
STATISTICAL METHODS 
The analysis of primary and secondary endpoints will be performed after all subjects have 
completed the Day 63 assessments.  A follow-up analysis for safety will be performed once all 
subjects have completed the 7-month follow-up visit. 
DETERMINATION OF SAMPLE SIZE 
Approximately 144 subjects will be enrolled, taking into account an assumed drop-out rate of 
10%.  A total of 130 healthy subjects with fully evaluable pharmacokinetic profiles are required 
to demonstrate comparability of area under the time-concentration curve from the start of dosing 
to 63 days (AUC062days) and maximum concentration (Cmax) values between the handheld 
syringe injection administration (reference) and the OBDS (test) with 80% power at 5% 
significance level, assuming a between-subject coefficient of variation (CV) of 40% and ‘test’ to 
‘reference’ ratio of 0.95.  Standard bioequivalence ranges of 0.8 and 1.25 are used to 
demonstrate comparability of AUC062days and Cmax values for pertuzumab and trastuzumab 
administered as PH FDC SC, either by the OBDS or by handheld syringe.  Subjects that have 
non-evaluable PK data may be replaced at the discretion of the Sponsor. 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AC 
doxorubicin plus cyclophosphamide 
ADA 
anti-drug antibody 
ARDS 
Acute Respiratory Distress Syndrome 
ARR 
administration related reaction 
AUC062days 
area under the timeconcentration curve from the start 
of dosing to 63 days 
AUC0 
area under the timeconcentration curve from the start 
of dosing extrapolated to infinity 
BMI 
body mass index 
BP 
blood pressure 
CDay21 
serum concentration on Day 22 
CDay62 
serum concentration on Day 63 
CHF 
congestive heart failure 
ClinRO 
clinician reported outcome 
CL/F 
apparent drug clearance 
Cmax 
maximum serum concentration 
Ctrough 
trough serum concentration 
CV 
coefficient of variation 
ddAC 
dose-dense doxorubicin plus cyclophosphamide 
EBC 
early breast cancer 
EC 
Ethics Committee 
ECHO 
echocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
FDA 
Food and Drug Administration 
GMR 
geometric mean ratio 
HBV 
hepatitis B virus 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HCP 
health care personnel 
HR 
heart rate 
ICH 
International Council for Harmonisation 
ILD 
interstitial lung disease 
IMP 
investigational medicinal product 


 
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Abbreviation 
Definition 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IxRS 
interactive voice or web-based response system 
LVEF 
left ventricular ejection fraction 
LVSD 
left ventricular systolic dysfunction 
MAb 
monoclonal antibody 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
NYHA 
New York Heart Association 
OBDS 
on-body delivery system 
pCR 
pathologic complete response 
PH FDC SC 
fixed-dose combination of pertuzumab and 
trastuzumab for subcutaneous administration  
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
PT 
preferred term 
QTc 
corrected QT interval 
QTcF 
QT interval corrected through use of Fridericia's 
formula 
rHuPH20 
recombinant human PH20 hyaluronidase 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous 
t1/2 
terminal elimination half-life 
tmax 
observed time to maximum concentration 
ULN 
upper limit of normal 
VAS 
visual analog scale 
Vd/F 
apparent volume of distribution 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON HER2-POSITIVE BREAST CANCER 
Breast cancer is the second most common invasive malignancy and the most common 
form of cancer in women (Bray et al. 2018).  Approximately 20% of breast cancers 
overexpress human epidermal growth factor receptor 2 (HER2).  This is usually the 
result of amplification of the gene encoding HER2, which is found on chromosome 17 
(Wolff et al. 2007).  HER2 belongs to the family of human epidermal growth factor 
receptors (HER) (which also includes HER1 [also known as epidermal growth factor 
receptor (EGFR)], HER3, and HER4) that mediate normal cell growth, survival, and 
differentiation (Bublil and Yarden 2007). 
These receptors may be activated by external ligands and by dimerization with other 
HER family members.  HER2 activity is mediated by homodimerization (with other HER2 
receptors) or heterodimerization (with other HER family receptors), leading to activation 
of multiple intracellular signaling pathways, including the phosphoinositide 
3-kinase/protein kinase B and RAS/Raf/mitogen-activated protein kinase pathways 
(Olayioye et al. 2000).  In the case of HER2, activation may also be achieved by 
proteolytic cleavage of the extracellular domain (shedding) to leave an activated 
truncated internal domain.  HER2 is also known to play a role in the normal development 
of myocardial tissue and in the repair of damaged myocardium (Sawyer et al. 2002; 
Timolati et al. 2006; Zhao et al. 2006). 
Primary breast cancers with HER2 amplification and overexpression (hereafter referred 
to as HER2+ breast cancer) 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 advent and clinical incorporation of the 
monoclonal antibody (MAb) trastuzumab (Herceptin), capable of blocking 
HER2 oncogenic signaling and thereby effectively killing HER2+ cancer cells, has 
markedly improved the prognosis of patients with HER2+ breast cancer (Hudis 2007).  
Subsequently, pertuzumab (Perjeta), a second MAb that binds to a distinct epitope of 
HER2 than Herceptin, was shown to provide a complementary mechanism for disrupting 
HER2 signaling and, thereby, enhanced anti-tumor activity (Eiger et al. 2019).  
Compared to single HER2 blockade, dual HER2 blockade with Perjeta and Herceptin 
has been shown to improve various clinically relevant outcomes, such as pathological 
complete response rates, invasive disease-free survival and overall survival (Gianni et 
al. 2012; Piccart et al. 2021, Swain et al. 2020).  In this sense, the combination of 
Perjeta with Herceptin and chemotherapy has become standard of care for treating 
HER2+ early and metastatic breast cancer (Denduluri et al. 2018; Giodarno et al. 2018; 
Cardoso et al. 2019 and 2020).  Currently, anti-HER2 therapies with distinct 
mechanisms of action have become available for the treatment of early-stage (neratinib 
and ado-trastuzumab emtansine) and metastatic (lapatinib, neratinib, tucatinib, pyrotinib, 
ado-trastuzumab emtansine, trastuzumab-deruxtecan, and margetuximab) HER2+ 


 
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breast cancer patients (Cameron et al. 2008; Diéras et al. 2017; von Minckwitz et al. 
2019; Modi et al. 2020; Saura et al. 2020; Murthy et al. 2020; Chan et al. 2021; Rugo et 
al. 2021; Xu et al. 2021). 
Herceptin has been developed in a formulation for subcutaneous (SC) administration 
that can be delivered in under 5 minutes versus the 3090 minute infusions required for 
administration of the IV formulation.  Herceptin SC has been shown to be preferred over 
Herceptin IV by HER2+ early breast cancer (EBC) patients in a randomized, cross-over 
study (Pivot et al. 2013).  Besides, Herceptin SC can not only save patient’s chair time 
and active healthcare professional’s time per session compared to Herceptin IV, it also 
holds costs-saving potentials in various healthcare settings (Lopez-Vivanco et al. 2017; 
Tjalma et al. 2018; O’Brien et al. 2019).  Herceptin SC is currently approved in the 
United States, European Union and more than 100 countries for use in the (neo)adjuvant 
and metastatic HER2+ breast cancer settings.  Data from a Phase IIIb, single-arm safety 
study of combined treatment with Herceptin SC and Perjeta have shown a safety profile 
consistent with combined treatment with Herceptin and Perjeta given intravenously 
(Kümmel et al. 2020). 
Roche has developed a new product combining pertuzumab and trastuzumab in one 
fixed-dose combination for SC injection (hereafter referred to as “PH FDC SC”).  The 
PH FDC SC is a ready-to-use formulation of pertuzumab and trastuzumab co-formulated 
in a single vial for SC injection use with recombinant human PH20 hyaluronidase 
(rHuPH20), a permeation enhancer developed to improve dispersion of large volumes of 
drugs when administered subcutaneously. 
The PH FDC SC administration has been proven equivalent to IV Herceptin and Perjeta 
from a pharmacokinetic (PK), efficacy, and safety perspective (Tan et al. 2020).  
PH FDC SC can be administered in 5-8 minutes versus hours and is preferred by most 
patients, as compared to IV administration of Herceptin and Perjeta (O’Shaughnessy 
et al. 2020).  Currently, PH FDC SC (PHESGO®) is approved in the United States and 
can be administered at home by an HCP (FDA Press release 2020), in the European 
Union and several other countries in the world.  The indications cover the use in patients 
with early-stage and metastatic HER2-positive breast cancer. 
Roche is currently developing an on-body delivery system (OBDS) named 
SmartDose Gen II for self- or lay caregiver-SC administration of PH FDC SC to enable 
a flexible care setting in which healthcare providers and patients can select the place of 
drug administration according to individual preferences and capabilities worldwide.  
Improved convenience is particularly important when patients are treated for prolonged 
periods of time. 
In this study, healthy male subjects between 1845 years will be randomly allocated to 
receive PH FDC SC administered via an OBDS or via a handheld syringe with 


 
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hypodermic needle in order to investigate the comparability of PK parameter values and 
safety between both administration methods. 
1.2 
BACKGROUND ON STUDY MEDICATION 
1.2.1 
Study Drug Nomenclature 
Pertuzumab and trastuzumab are both monoclonal antibodies developed by Roche.  
Throughout the protocol, their international non-proprietary names (pertuzumab, 
trastuzumab) are used when describing their PK and other properties and when referring 
to PH FDC SC. 
To distinguish the source of trastuzumab that is an investigational medicinal product 
(IMP) in referenced Roche-sponsored clinical studies, the trade name “Herceptin” is 
used throughout the protocol when referring to the commercially available trastuzumab 
drug product.  For consistency, the trade name “Perjeta” is also used when referring to 
the commercially available pertuzumab drug product. 
1.2.2 
Background on Pertuzumab and Trastuzumab Fixed-dose 
Combination for Subcutaneous Administration (PH FDC SC) 
The PH FDC SC represents a combination of both pertuzumab and trastuzumab in 
a fixed-dose combination. 
A Phase III, randomized, multicenter, open-label, two-arm study (FeDeriCa) compared 
the PK, efficacy, and safety of PH FDC SC versus Perjeta  Herceptin IV (P  H IV) as 
neoadjuvant treatment with chemotherapy for EBC in 500 patients with Stage IIIII 
HER2+ breast cancer (Study WO40324; Tan et al. 2020).  The primary objective was 
non-inferiority of the pre-dose Cycle 8 pertuzumab serum trough concentration (Ctrough) 
within the PH FDC SC versus pertuzumab IV (non-inferiority margin for the lower bound 
of the 90% CI of the geometric mean ratio [GMR]:  0.8).  Cycle 7 (pre-dose Cycle 8) 
serum pertuzumab Ctrough within PH FDC SC was demonstrated as non-inferior 
compared to Perjeta in the Perjeta  Herceptin IV arm.  The GMR of Cycle 7 (pre-dose 
Cycle 8) serum pertuzumab Ctrough, SC/Ctrough, IV values was 1.22 (90% CI: 1.141.31).  
The observed lower limit of the two-sided 90% CI of 1.14 was above the prespecified 
non-inferiority margin of 0.8.  The Cycle 7 (pre-dose Cycle 8) serum trastuzumab Ctrough 
with PH FDC SC, a key secondary PK endpoint of Study WO40324, was also 
demonstrated to be non-inferior compared to that with Herceptin IV (P  H IV arm). 
Total pathologic complete response (pCR) rates in the intent-to-treat population was 
59.7% (95% CI, 53.3-65.8) vs 59.5% (95% CI, 53.2-65.6) for the SC and IV arms, 
respectively.  Incidences of the most common adverse events (occurring in  30% of 
patients) in the SC and IV arms, respectively, included alopecia (77% and 70.2%), 
nausea (58.9% and 60.3%), diarrhea (58.5% and 55.2%), anemia (33.9% and 40.9%), 
and asthenia (28.2% and 30.2%).  The incidence of primary cardiac events (New York 
Heart Association [NYHA] Class III/IV heart failure [HF] and cardiac death) was low (0% 


 
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in the IV arm and 0.8% in the SC arm), as well as the incidence of secondary cardiac 
events (confirmed left ventricular ejection fraction [LVEF] decrease of  10 points from 
baseline and below 50%) (0.8% in the IV arm vs. 0.4% in the SC arm).  The incidence of 
diarrhea was comparable between arms (55.2% in the IV arm vs. 58.5% in the SC arm), 
with a majority of low-grade events.  The incidence of anaphylaxis and hypersensitivity 
was low in both arms as well (2% vs. 1.6%, respectively), and most cases were low 
grade.  Except for Grade 12 adverse events associated with subcutaneous route of 
administration (local injection site reactions), the safety was comparable between 
PH FDC SC arm and Perjeta  Herceptin IV arm, and no unexpected safety signals 
emerged. 
In the Phase II, randomized, multicenter international, open-label, cross-over 
PHranceSCa study (Study MO40628), 160 patients with HER2+ EBC previously 
submitted to neoadjuvant systemic therapy and breast/axillary surgery were randomized 
1:1 to receive adjuvant Perjeta and Herceptin IV for 3 cycles, followed by 3 cycles of 
PH FDC SC or to receive adjuvant PH FDC SC for 3 cycles followed by 3 cycles of 
Perjeta  Herceptin IV, in order to assess patients’ preferences and satisfaction 
(O’Shaughnessy et al. 2020).  PH FDC SC administration was preferred by 85.0% 
patients, while Perjeta  Herceptin IV administration was preferred by only 13.8%.  
Two patients had no preference (1.3%). 
The most commonly reported reasons for PH FDC SC administration preference were 
“requires less time in the clinic” and “feels more comfortable during administration.”  The 
majority of patients (92.6%) indicated a “very strong” or “fairly strong” preference with 
PH FDC SC administration, compared to only 63.6% of patients with Perjeta  Herceptin 
IV administration.  Patient preference results were supported by patient satisfaction 
results.  The vast majority of patients (88.1%) were “very satisfied” or “satisfied” with the 
PH FDC SC administration, while 67.5% were “very satisfied” or “satisfied” with the 
Perjeta  Herceptin IV administration.  When asked specific questions about their 
experience with both PH FDC SC and Perjeta  Herceptin IV, patients more often cited 
PH FDC SC administration as being the less restrictive route of administration and as 
allowing more time for other activities.  The choice of SC administration during the 
treatment continuation period was consistent with patient preference, with 86.9% of 
patients choosing to continue their treatment with PH FDC SC administration during the 
treatment continuation period. 
Health care personnel (HCP) indicated time savings and the need for less resource use 
when using PH FDC SC.  The median preparation time for PH FDC SC administration 
was 5 minutes and the median administration time ranged from 78 minutes (compared 
with median Perjeta  Herceptin IV preparation times of 1520 minutes and 
60150 minute administration times).  The median overall time the patient spent in the 
treatment room for PH FDC SC treatment ranged from 3350 minutes (compared with 
130300 minutes for Perjeta  Herceptin IV treatment).  PH FDC SC was well tolerated 


 
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with a safety profile consistent with the Perjeta  Herceptin IV formulation and no new 
safety signals. 
PH FDC SC (PHESGO) is approved in the United States, European Union and other 
countries for the treatment of HER-2 positive breast cancer in adults.  For further details 
of nonclinical and clinical studies, please refer to the PH FDC SC Investigator’s 
Brochure, and the Perjeta and Herceptin Investigator’s Brochures. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
1.3.1 
Study Rationale 
The PH FDC SC administration by lay caregivers or self-administration by patients at 
home using an OBDS could increase convenience for patients while simultaneously 
decreasing health-care costs associated with several clinics and/or hospitals visits.  
Lay caregiver or self-administration at home with the OBDS holds the potential to allow 
patients more time to engage in other activities and increase the compliance of those 
who live far from a hospital or clinic, or experience difficulty travelling (Bittner et al. 2018; 
Viola et al. 2018). 
In order to establish such modalities as laid out above, bioequivalence between an 
administration with the OBDS and the currently approved handheld injection with 
a syringe should be shown.  The aim of the present study is to demonstrate that the PK 
and safety profiles of a single dose of PH FDC SC in healthy male subjects are 
comparable between administration with the OBDS versus administration with handheld 
syringe with hypodermic needle. 
This is the first clinical study in which PH FDC SC will be administered using the OBDS, 
and it is intended to support the bridging of PH FDC SC handheld syringe with 
hypodermic needle administration to OBDS administration.  In the context of the present 
study, all PH FDC SC injections, either via OBDS or via handheld syringe will be 
administered by a healthcare professional in a healthcare setting. 
This is a PK study in healthy male subjects 1845 years of age designed to investigate 
the comparability of PK parameter values derived after two different ways of 
administering PH FDC SC, using either the OBDS or handheld syringe with hypodermic 
needle. 
1.3.2 
Benefit-Risk Assessment 
As described in Section 1.1, Perjeta plus Herceptin-based therapies for HER2-positive 
breast cancer patients have been shown to improve various clinically relevant outcomes, 
both in the early and in the metastatic setting.  PH FDC SC, a combination of both 
pertuzumab and trastuzumab in a fixed-dose combination, has been shown equivalent in 
terms of PK, efficacy, and safety compared to both MAbs administered intravenously, 
except for low-grade adverse events associated with the subcutaneous route of 
administration (local injection site reactions), as described in Section 1.2.2.  The 


 
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advantages of PH FDC SC compared to Perjeta and Herceptin IV are the higher rates of 
patient preference and satisfaction, as well as timesaving and the need of less resources 
as indicated by HCP.  Transitioning PH FDC SC administration by handheld syringe with 
hypodermic needle to the OBDS is not expected to change the benefit-risk profile of 
PH FDC SC.  Moreover, as the OBDS provides a “hands-free” PH FDC SC 
administration modality, it has the potential to improve the workflow and alleviate burden 
to HCP, as well as to pave the way for home-based administration. 
Several studies have demonstrated benefits associated with home administration of 
SC biotherapeutics, namely its general preference by patients and reduced resource use 
for drug delivery (Gardulf et al. 2006; Beaute et al. 2010).  Given these benefits, efforts 
are ongoing to assess the feasibility of administering MAbs in the home environment.  
Previous experiences with the bridging of SC MAbs administration by healthcare 
professional to patient self-administration at home with the aid of ready-to-use devices 
has been successful (Bittner et al. 2018). 
The initial experience with Herceptin SC home administration by healthcare 
professionals has been promising, with safety consistent with that in a hospital setting 
(Cocquyt et al. 2017).  Multiple programs and pilot studies in European countries show 
that Herceptin SC can be effectively administered in the patient’s home (Denys et al. 
2020; ten Tije et al. 2020). 
The benefits of SC home administration become particularly relevant when external 
factors like the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
pandemic disrupt and limit usual clinic work flow and increase the risk of exposure to 
life-threatening clinical conditions to patients with cancer.  From the beginning of the 
SARS-CoV-2 epidemic in China in late 2019 (Zhu et al. 2020) to its rapid worldwide 
spread, much academic, pharma, and government-driven effort has been directed 
towards new solutions for oncologic care, focusing especially in decreasing patients’ 
exposure to and risk of acquiring SARS-CoV-2 infection.  It has been demonstrated that 
cancer patients are at higher risk of complications and have higher fatality rates than the 
general population when infected with SARS-CoV-2 (de Azambuja et al. 2020; 
Garassino et al. 2020).  Perjeta and Herceptin are normally given for 1 year (18 cycles) 
for patients with HER2+EBC or longer to patients with metastatic disease, ultimately 
leading to frequent visits to clinics and/or hospitals of a population at a higher risk of 
complications by SARS-CoV-2 infection.  In this sense, PH FDC SC administered at 
home with the OBDS can potentially reduce high-risk patients’ exposure to SARS-CoV-2 
while maintaining continuity of treatment, and simultaneously enable a refocusing of 
resources and HCP to fight the SARS-CoV-2 pandemic.  An expanded access, 
single-arm, multicenter study is currently ongoing in the United States, where 
PH FDC SC home administration by HCP is already approved by the FDA, to assess the 
safety of PH FDC SC when administered at home by a home health nursing provider to 
patients with HER2+EBC (Study AL42478). 


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As summarized above, while the benefit-risk profile of switching PH FDC SC 
administration with a handheld syringe with hypodermic needle to the OBDS is expected 
to be unchanged, PH FDC SC administration with the OBDS has the potential to 
improve the workflow and alleviate burden to HCP, as well as to enable home-based 
administration.  This has the potential to increase patient’s convenience, decrease the 
exposure of an at-risk population to SARS-CoV-2 infection, and enable a refocusing of 
resources and HCP.  Altogether, the benefit-risk assessment for administration of 
PH FDC SC with the OBDS is deemed positive. 
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the pharmacokinetics and safety of the PH FDC SC 
administered by the OBDS compared to hypodermic needle and syringe in healthy male 
subjects. 
Specific objectives and corresponding endpoints for the study are outlined below. 
2.1 
PRIMARY OBJECTIVE 
The objective for this study is below. 
To demonstrate comparability of single-dose area under the timeconcentration curve 
from the start of dosing to 63 days (AUC062) and maximum serum concentration (Cmax) 
for pertuzumab and trastuzumab within PH FDC SC, administered either by the OBDS 
or by a handheld syringe with hypodermic needle, on the basis of the following 
co-primary endpoints: 

Serum pertuzumab AUC062 and Cmax

Serum trastuzumab AUC062 and Cmax
2.2 
SECONDARY OBJECTIVES 
2.2.1 
Pharmacokinetic Objectives 
The secondary PK objectives for this study are below. 
To demonstrate the comparability of observed serum concentration on Day 22 (CDay21)
values for pertuzumab and trastuzumab within PH FDC SC, administered either by the 
OBDS or by a handheld syringe with hypodermic needle, on the basis of the following 
end points: 

Serum pertuzumab CDay21

Serum trastuzumab CDay21
To demonstrate the comparability of observed serum concentration on Day 63 (CDay62) 
values for pertuzumab and trastuzumab within PH FDC SC, administered either by the 


 
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OBDS or by a handheld syringe with hypodermic needle, on the basis of the following 
end points: 
 
Serum pertuzumab CDay62 
 
Serum trastuzumab CDay62 
 
To further characterize additional PK parameters for pertuzumab and trastuzumab within 
PH FDC SC, administered either by the OBDS or by a handheld syringe with 
hypodermic needle, on the basis of the following end points: 
 
Area under the time–concentration curve from the start of dosing extrapolated to 
infinity (AUC0) 
 
Observed time to maximum concentration (tmax) 
 
Terminal elimination half-life (t1/2) 
 
Apparent drug clearance (CL/F) 
 
Apparent volume of distribution (Vd/F) 
 
2.2.2 
Safety Objectives 
The safety objectives for this study are below. 
To demonstrate comparable safety and tolerability of PH FDC SC administered by either 
the OBDS or by a handheld syringe with hypodermic needle, on the basis of the 
following endpoints: 
 
Incidence and severity of adverse events, with severity determined according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events 
Version 5.0 (NCI CTCAE) 
 
Change from baseline in vital signs, LVEF, and ECG parameters 
 
Change from baseline in clinical laboratory test results 
 
To demonstrate the safety of the OBDS, on the basis of the following end points: 
 
Pain at the injection site assessed by the subject using the 100 mm 
Visual Analog Scale (VAS) 
 
Skin irritation and sensitization reactions at the site of injection assessed by the 
study staff using the device monitoring questionnaire in the electronic Case Report 
Form (eCRF) 
 
2.2.3 
Device Monitoring Objectives 
The device monitoring objectives are to demonstrate the performance of the OBDS on 
the basis of the following end points: 
 
Comfort of wearing the device, as reported by the subject using the device 
monitoring questionnaire 
 
Details of performance and ease of use of the OBDS reported by site staff, using the 
device monitoring questionnaire in the eCRF (see Section 4.5.9) 


 
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2.3 
EXPLORATORY OBJECTIVES 
2.3.1 
Immunogenicity Objectives 
The exploratory immunogenicity objectives for this study are below. 
To evaluate the immune response to pertuzumab, trastuzumab, and rHuPH20 within the 
PH FDC SC, administered using an OBDS compared to a hand-held syringe with 
hypodermic needle, on the basis of the following endpoints: 
 
Incidence of pertuzumab anti-drug antibodies (ADAs) during the study relative to the 
prevalence of ADAs at baseline 
 
Incidence of trastuzumab ADAs during the study relative to the prevalence of ADAs 
at baseline 
 
Incidence of rHuPH20 ADAs during the study relative to the prevalence of ADAs at 
baseline 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of the Study Design 
This is a randomized, open-label, 2-arm, parallel-group, single-dose, multi-center study 
in healthy male subjects to investigate the comparability of PK of pertuzumab and 
trastuzumab within the PH FDC SC administered using the proprietary OBDS or 
a handheld syringe with hypodermic needle.  Figure 1, presents an overview of the study 
design.  The study will be conducted at clinical research facilities in New Zealand and 
Australia. 
Figure 1 Study Schema 
 
Approximately 144 male subjects will be randomized to one of two dosing arms in 
a 1:1 ratio to receive a single dose of PH FDC SC (600 mg pertuzumab/600 mg 
trastuzumab) administered by a healthcare professional subcutaneously into the anterior 
thigh using either the OBDS or a handheld syringe with hypodermic needle.  The 
randomization will be stratified by weight ( 75 kg,  75 kg) at Day 1. 
Arm 1:  PH FDC SC administered using a handheld syringe with hypodermic needle. 
Arm 2:  PH FDC SC administered using the OBDS. 
 


 
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During the study period, subjects will be admitted to the clinical research unit on Day 1 
and the study drug will be given on the morning of Day 1.  The subjects will be 
discharged after the assessments are performed on Day 2. 
Subjects will be followed according to the Schedule of Activities from Day 1 
(Appendix 1).  The total duration of the study for each subject will be a maximum of 
35 weeks: 
 
Screening:  Up to 4 weeks 
 
Study period:  Day 1 to Day 63, including in-clinic period from Day 1 to Day 2 
 
Safety Follow-up:  Day 64 to Month 7 (~35 weeks) 
 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of the study is defined as the date when the last subject, last visit occurs.  This 
is expected to occur 7 months after the last subject is enrolled (i.e., when the last subject 
has completed the safety follow-up visit at 7 months after administration of study drug). 
The length of study will be a maximum of 35 weeks per subject, from screening to 
follow-up (4 weeks screening, plus 7 months [~31 weeks] follow-up after dose).  The 
total length of the study from screening of the first subject to the end of the study is 
expected to be approximately 11 months. 
3.3 
RATIONALE FOR STUDY DESIGN 
Subcutaneous administration of PH FDC SC by ODBS is being investigated to support 
home-administration and possible self-administration by the patient.  The aim of this 
OBDS PK qualification study is to demonstrate that the PK and safety profiles of a single 
dose of PH FDC SC in healthy subjects are comparable between administration by the 
OBDS versus administration by handheld syringe with hypodermic needle. 
This is the first clinical study in which PH FDC SC will be administered using the OBDS.  
It is a PK study in healthy male subjects 1845 years of age designed to investigate the 
comparability of PK parameter values derived following two different ways of 
administering PH FDC SC, using either the OBDS or a handheld syringe with 
hypodermic needle. 
3.4 
RATIONALE FOR PH FDC SC DOSE AND SCHEDULE 
The dose selected to be used in this study is consistent with the approved maintenance 
dose of PH FDC SC (600 mg pertuzumab/600 mg trastuzumab/20,000 units rHuPH20) 
investigated in Study WO40324 that confirmed non-inferior Cycle 7 Ctrough and 
comparable efficacy/safety of pertuzumab/trastuzumab SC versus 
pertuzumab/trastuzumab IV in patients with EBC (Tan et al. 2019). 
Whereas the vial presentations of PH FDC SC occur as two different strengths, 
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evaluated to administer the maintenance dose only.  The loading dose will have no 
OBDS alternative and will remain available only under the vial presentation. 
3.5 
RATIONALE FOR SUBJECT POPULATION 
According to EMA Guidelines (EMA guideline on investigation of bioequivalence), in 
order to reduce variability not related to differences between investigational products, 
bioequivalence studies should normally be performed in healthy subjects, unless the 
drug carries safety concerns that make this unethical.  Healthy female subjects of 
childbearing potential were excluded from this study as they would be exposed 
unnecessarily to potentially teratogenic drugs.  This approach is also supported by Food 
and Drug Administration (FDA) guidance (FDA Guidance for industry Bioavailability and 
Bioequivalence Studies).  Additionally, as anti-pertuzumab and anti-trastuzumab 
antibodies might be developed following injection, the decision was made to perform the 
study in healthy male subjects as a precaution, to avoid pre-exposing female subjects to 
pertuzumab and trastuzumab.  A similar approach is common and was successfully 
used in Study BO30185 (dose-finding, Phase I trial to identify the dose of pertuzumab for 
SC administration in PH FDC SC), where healthy male subjects were also recruited. 
4. 
MATERIALS AND METHODS 
4.1 
SUBJECTS 
Approximately 144 healthy male subjects, aged 1845 years will be enrolled in this 
study. 
4.1.1 
Inclusion Criteria 
Subjects must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Healthy male subjects age 1845 years at time of signing Informed Consent Form 
 
Ability to comply with the study protocol 
 
Agreement to remain abstinent (refrain from heterosexual intercourse) or use 
a condom, and agreement to refrain from donating sperm, as defined below: 
With a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for 
7 months after the dose of PH FDC SC to avoid exposing the embryo.  Men 
must refrain from donating sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject.  
Periodic abstinence (e.g., according to female partner calendar, ovulation, 
symptothermal, or postovulation 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. 


 
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 
A body mass index (BMI) between 18 and 32 kg/m2, inclusive 
 
Intact normal skin without potentially obscuring tattoos, pigmentation, or lesions in 
the area for intended injection on the thighs 
 
Baseline LVEF  55% measured by echocardiogram (ECHO) 
 
No history of hypersensitivity or confirmed, clinically significant and clinically 
relevant allergic reactions, either spontaneously or following any drug administration 
 
No history of any clinically significant and clinically relevant cardiac condition 
 
No history of previous anticancer treatments including pertuzumab, trastuzumab, 
anthracyclines, or any cardiotoxic drugs 
 
No apparent family history of clinically significant and clinically relevant 
hypersensitivity, allergy, and severe cardiac diseases 
 
No contraindications from detailed medical and surgical history and physical 
examinations 
 
No previous enrollment in this study protocol and no concurrent enrollment in any 
other study protocol 
 
4.1.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from study entry: 
 
Positive urine test for drugs of abuse as per local standard (for alcohol abuse, 
positive breath test is also acceptable) 
 
Positive test result for hepatitis B virus (HBV), hepatitis C virus (HCV), or HIV 1 or 2, 
showing: 
History of exposure to HBV, HCV, or HIV 
or 
Active viral hepatitis infection (HBV or HCV) or HIV infection 
 
Systolic blood pressure (BP)  140 mmHg or  90 mmHg, or diastolic BP  90 mmHg 
or  50 mmHg 
 
Use of prohibited medications, including non-prescription medications, 
nutraceuticals, nutritional supplements, or any herbal remedies taken within 10 days 
or 5 times the elimination half-life (whichever is longer) prior to randomization into 
the study 
 
Concomitant subcutaneous, intravenous, or any parenteral drugs within 90 days 
prior to screening 
 
Participation in an investigational drug or device study within 90 days or five times 
the elimination half-life (whichever is longer) prior to screening 
 
Donation of blood over 500 mL within 3 months prior to enrollment 
 
Known severe hypersensitivity to plaster, medical adhesive tapes, or bandages 
 
Known allergy to murine proteins, hyaluronidase, bee, or vespid venom, or any 
other ingredient in the formulation of rHuPH20 (Hylenex recombinant 


 
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[hyaluronidase human injection]) or any other ingredients and excipients in the 
formulation of PH FDC SC 
 
Clinically significant abnormalities in laboratory test results (including hepatic and 
renal panels, CBC, chemistry panel, and urinalysis) 
 
Clinically relevant ECG abnormalities on screening or Day   1 ECG: 
– 
Corrected QT interval (QTc) (QT interval corrected through use of Fridericia’s 
formula [QTcF]  450 msec) 
– 
Notable resting bradycardia (HR  40 bpm) 
– 
Notable resting tachycardia (HR  100 bpm) 
– 
Difference between highest and lowest durations of any baseline QTc at 
a specific time point  30 msec 
– 
Measurement of QT interval imprecise (i.e., flat T waves, arrhythmias, etc.) 
– 
Evidence of atrial fibrillation, atrial flutter, right or left bundle branch block, 
Wolf-Parkinson-White Syndrome, or cardiac pacemaker 
– 
Any other significant abnormality 
 
History of any cardiac condition 
 
Lower extremity edema or pathology (e.g., cellulitis, lymphatic disorder or prior 
surgery, pre-existing pain syndrome, previous lymph node dissection etc.) that could 
interfere with any protocol-specified outcome assessment 
 
Any history of clinically significant and clinically relevant allergies, oncologic, 
psychiatric, gastrointestinal, renal, hepatic, cardiovascular or pulmonary disease 
 
Concomitant disease or condition that could interfere with, or for which the treatment 
might interfere with, the conduct of the study, or that would pose an unacceptable 
risk to the subject in this study 
 
Any clinically relevant history of systemic disease (e.g., malignancy, diabetes 
mellitus, gastrointestinal, renal, hepatic, cardiovascular, rheumatological, or 
pulmonary disease) 
 
History of breast cancer or treatment for breast cancer 
 
Current chronic daily treatment (continuous for  3 months) with corticosteroids 
(dose  10 mg/day methylprednisolone), excluding inhaled corticosteroids 
 
Receipt of IV antibiotics for infection within 7 days prior to enrollment into the study 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT 
4.2.1 
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 subject, the study site will obtain the subject's 
identification number and treatment assignment from an interactive voice or web-based 
response system (IxRS). 


 
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Male subjects will be randomly assigned to one of two drug administration arms to 
receive a single dose of PH FDC SC administered either using the OBDS or 
handheld syringe and needle.  Randomization will occur in a 1:1 ratio through use of 
a permuted-block randomization method to ensure a balanced assignment to each 
treatment arm.  Randomization will be stratified according to the following criteria: 
 
Weight (  75 kg,  75 kg) at Day 1 
 
Eligible subjects will report to the unit on Day   1 for baseline assessments and will stay 
overnight until Day 2.  Randomization can occur either on Day 1 or on Day 1 pre-dose. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The IMP for this study is PH FDC SC 
(600 mg pertuzumab/600 mg trastuzumab/20,000U rHuPH20). 
4.3.1 
Study Treatment Formulation and Packaging 
4.3.1.1 
PH FDC SC 
The PH FDC SC (maintenance dose:  RO7198574/F04-01) will be supplied by the 
Sponsor as a sterile, colorless to slightly brownish solution for injection 
containing histidine, hydrochloric acid, trehalose, sucrose, polysorbate 20, methionine, 
and rHuPH20 (2000 U/mL). 
For administration via handheld syringe and needle, PH FDC SC will be supplied in 
10 mL solution in a 15 mL vial. 
For administration via OBDS, the PH FDC SC will be supplied in a prefilled cartridge with 
a 10.25 mL drug volume. 
Both the vial and prefilled cartridge contain the same formulation of 600 mg 
of pertuzumab (RO4368451) and 600mg of trastuzumab (RO0452317).  For information 
on the PH FDC SC formulation, see the PH FDC SC Investigator's Brochure. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1.1.  Study drug will be 
administered on the morning of Day 1.  The OBDS (plus adhesive paper) and the 
handheld syringe with needle (plus cover) will be weighed before injection (loaded with 
prefilled cartridge and with drug drawn, respectively) and after the injection using 
a precision balance that measures up to around 100 g with at least two decimal places. 
Refer to the pharmacy manual for detailed instructions on drug preparation.  Refer to the 
pharmacy manual and Appendix 4 and Appendix 5 for details on drug administration. 
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration eCRF.  Cases of accidental overdose or medication error, 


 
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along with any associated adverse events, should be reported as described in 
Section 5.3.5.11. 
Guidelines for discontinuation for subjects who experience specific adverse events are 
provided in Section 5.1.2. 
4.3.2.1 
Administration of PH FDC SC by handheld syringe and needle 
A single 10-mL dose of PH FDC SC (PHESGO) will be administered as a SC injection 
using a handheld manual syringe, into the anterior thigh midway between the anterior 
iliac crest and the cephalad border of the patella, while the subject is in a semi-supine 
position according to the steps in Appendix 4.  The goal of the placement angle and 
needle depth is to achieve uniform placement into every subject’s SC tissue.  To 
promote uniformity of needle placement across the study subjects, wherever possible, 
one of three designated, medically trained healthcare professionals at each site should 
place the needle in every subject, and needle placement should be uniform from subject 
to subject. 
The dose will be injected over approximately 5 minutes, at a rate of no more than 
2 mL/min.  The injection rate should be adjusted to a rate that is comfortable for the 
subject.  If there is a request by the subject to interrupt the injection due to discomfort, 
the pressure on the syringe should initially be eased to alleviate the pain.  If the pain is 
not alleviated, the injection should be stopped, and the subject should be asked when 
they are comfortable to resume the injection.  The start and end times of the injection 
and overall injection time (minutes/seconds) should be recorded. 
The injection should be slowed or interrupted if the subject experiences injection-related 
symptoms. 
The entire SC injection must be given in one site.  Splitting the volume into two syringes 
or injecting at two different sites is not permitted. 
After the injection, subjects will be observed for 30 minutes from the end of the injection 
for injection-related symptoms. 
The syringe (including needle and cover) will be weighed prior to injection (after the 
correct amount of medication has been drawn) and after injection using a balance with 
the precision specified in Section 4.3.2.  The weights must be recorded on the eCRF, 
along with the temperature of the room, and the actual amount of drug administered will 
be calculated. 
4.3.2.2 
Administration of PH FDC SC by OBDS 
A single 10-mL dose of PH FDC SC (PHESGO) will be administered by OBDS as a SC 
injection, into the anterior thigh midway between the anterior iliac crest and the cephalad 
border of the patella, while the subject is sitting down (semi-supine), according to the 
steps in Appendix 5.  To promote uniformity of OBDS placement across the study 


 
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subjects and of device monitoring, wherever possible, one of three designated, medically 
trained healthcare professionals at each site should perform the OBDS injection for 
every subject, and placement should be uniform from subject to subject. 
The OBDS is supplied as a kit containing one device (injector) and one cartridge 
pre-filled with PH FDC SC (Figure 2). 
When taken out of the refrigerator (28°C), the OBDS/cartridge kit needs to be kept at 
room temperature for approximately 45 minutes to allow the device and drug 
temperature to equilibrate. 
Following removal of the OBDS from the packaging, the cartridge door of the device is 
opened by the user, which powers the device.  The device is now active and must be 
used within 30 minutes.  The user inserts the prefilled cartridge, closes the door, 
removes the adhesive paper, and attaches the loaded OBDS to the skin.  Pressing the 
start button automatically inserts the needle into the SC tissue and automatically initiates 
drug administration.  The needle is protected within the device by an orange-colored 
needle guard and can only be deployed when the prefilled cartridge is in place, the 
cartridge door is closed, the device is adhered to the subject, and the start button has 
been pressed.  Dose administration is started automatically and stops automatically 
upon completion of the drug delivery.  Both visual (status light) and auditory notifications 
provide feedback on the progress of drug administration.  In the event of a drug delivery 
error, visual and auditory notification will prompt the user (refer to the pharmacy manual 
for details of the different visual and auditory notifications). 


 
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Figure 2 
OBDS with PH FDC SC cartridge 
 
OBDS  on-body delivery system; PH FDC SC  fixed-dose combination of pertuzumab and 
trastuzumab for subcutaneous administration. 
 
The overall administration time by OBDS, from activation by pressing the start button, to 
completion of the injection is approximately 510 minutes.  The start and end times of 
the injection and overall injection time (minutes/seconds) should be recorded. 
After the injection, subjects will be observed for 30 minutes from the end of the injection 
for injection-related symptoms. 
The OBDS (including adhesive paper) will be weighed prior to injection (after the 
prefilled cartridge has been inserted) and after injection (including the cartridge and 
adhesive paper) using a balance with the precision specified in Section 4.3.2.  The 
weights must be recorded on the eCRF, along with the temperature of the room, and the 
actual amount of drug administered will be calculated. 
Device monitoring information will be recorded in the eCRF as shown in Section 4.5.9, 
Appendix 1, and Appendix 2. 
Any device-related issues and remarks will be reported in the eCRF by the 
investigational staff members and as described in Section 5.4.4. 


 
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All devices used in the study will be returned to the Sponsor.  Refer to the pharmacy 
manual for instructions on the return of the devices. 
4.3.3 
Investigational Medicinal Product Handling 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]) is responsible for 
maintaining records of IMP delivery to the site, IMP inventory at the site, IMP use by 
each subject, and disposition or return of unused IMP, thus enabling reconciliation of all 
IMP received, and for ensuring that subjects 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 the IxRS to 
confirm the shipment condition and content.  Any damaged shipments will be replaced.  
The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit, either by time monitoring (shipment arrival date and 
time) or temperature monitoring, for all IMPs received and that any discrepancies have 
been 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 subjects enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs. 
The 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.  All devices will be returned to the Sponsor (refer to the 
pharmacy manual for instructions). 
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. 
Refer to the pharmacy manual and/or the PH FDC SC Investigator's Brochure for 
information on IMP handling, including preparation and storage, and accountability. 


 
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4.4 
CONCOMITANT THERAPY, SPECIAL DIETARY 
REQUIREMENTS AND ADDITIONAL RESTRICTIONS 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a subject in addition to protocol-mandated treatment from 30 days 
prior to initiation of study drug to the 7 month follow up visit.  All such medications should 
be reported to the investigator and recorded on the Concomitant Medications eCRF.  As 
a general rule, no concomitant medication will be permitted, with the exception of 
medications to treat adverse events, unless the rationale for exception is discussed and 
clearly documented between the investigator and Roche. 
No prescription medicines, over-the-counter medicines, or herbal remedies are allowed 
for at least 10 days before study drug dose, through the end of the study unless agreed 
by the study doctor and Roche. 
Meals will be similar in composition and time of administration across both study arms 
during the in-clinic period from Day   1 to Day 2.  The consumption of foods and 
beverages containing caffeine (e.g., tea, coffee, chocolate, and soft drinks) and alcohol 
will not be permitted from Day   1 to Day 2.  The use of tobacco is not permitted during 
the in-clinic portion of the study. 
Light ambulatory activities will be permitted, with the level of activities kept as similar as 
possible on all days in the clinical research unit. 
Subjects should/must refrain from vigorous activity that might affect absorption of 
PH FDC SC from the injection site, especially activities involving the thighs, from Day 1 
to Day 10. 
4.5 
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each subject. 
The study will consist of the following: 
 
Screening:  Day   28 to Day   2 
 
Study period:  Day   1 to Day 63, including in-clinic period from Day   1 to Day 2 
 
Safety Follow Up:  Day 64 to 7 months. 
 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled subjects and for subjects who are not subsequently enrolled 
will be maintained at the study site. 


 
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All screening evaluations must be completed and reviewed to confirm that subjects meet 
all eligibility criteria before enrollment.  Individuals who do not meet the criteria for 
participation in this study (screen failure) may qualify for 1 rescreening opportunity (for 
a total of 2 screenings per individual) at the investigator's discretion.  Individuals are not 
required to re-sign the consent form if they are re-screened within 28 days after 
previously signing the consent form.  Assessments that meet the eligibility criteria do not 
need to be repeated if they still fall within the applicable time windows for screening and 
baseline.  The investigator will maintain detailed record of all subjects screened and, to 
document eligibility or record reasons for screening failure, as applicable. 
4.5.2 
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data 
Medical history, including clinically significant diseases, surgeries, reproductive status, 
smoking history, and use of alcohol and drugs of abuse, will be recorded at baseline.  In 
addition, all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, 
herbal or homeopathic remedies, nutritional supplements) used by the subject within 
30 days prior to dosing will be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examinations 
A complete physical examination, performed at screening should include an evaluation 
of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, and neurologic systems.  Weight and 
height will also be collected.  Any abnormality identified at baseline should be recorded 
on the General Medical History and Baseline Conditions eCRF. 
At other visits, as indicated in the schedule of activities, abbreviated physical 
examination will consist of checking the normality or abnormality of the following body 
systems:  general appearance, weight, and cardiorespiratory examination.  Any 
abnormality will be recorded in the subject notes and on the eCRF. 
4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, temperature, and 
systolic and diastolic blood pressure after the subject has remained in a 
semi-supine position for at least 5 minutes.  Record abnormalities observed at baseline 
on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, 
record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 


 
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4.5.5 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells) 
 
Chemistry panel (serum or plasma):  sodium, potassium, chloride, glucose, BUN or 
urea, creatinine, total protein, albumin, phosphate, calcium, total bilirubin, ALP, ALT, 
AST 
 
HIV serology:  HIV-1/2 antibody 
 
HBV serology:  hepatitis B surface antigen (HBsAg), hepatitis B surface antibody 
(HBsAb), and total hepatitis B core antibody (HBcAb), for all subjects; HBV DNA for 
subjects with negative HBsAg and HBcAb tests and a positive total HBcAb test 
 
HCV serology:  HCV antibody for all subjects; HCV RNA for subjects with a positive 
HCV antibody test 
If a subject has a positive HCV antibody test at screening, an HCV RNA test 
must also be performed to determine if the subject has an HCV infection. 
 
Urinalysis, including dipstick (pH, glucose, protein, blood).  If there is a clinically 
significant positive blood and/or protein result, additional microscopic examination 
will be performed (sediment, RBCs, WBCs, casts, crystals, epithelial cells, bacteria) 
 
Alcohol:  Breath or urine 
 
Drugs of abuse:  Urine test according to local standards including cannabinoids, 
amphetamines, opiates, methadone, cocaine, benzodiazepines, and barbiturates 
 
Additional blood or urine samples may be taken at the discretion of the investigator if the 
results of any test fall outside the reference ranges, or clinical symptoms necessitate 
additional testing to monitor subject safety.  Where the clinical significance of abnormal 
lab results is considered uncertain, screening lab tests may be repeated before 
randomization to confirm eligibility.  If there is an alternative explanation for a positive 
urine or blood test for drugs of abuse (e.g., previous occasional intake of a medication or 
food containing for example codeine, benzodiazepines, or opiates) the test could be 
repeated to confirm washout. 
In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated immediately and followed up until they have returned to the 
normal range and/or an adequate explanation of the abnormality is found.  Results of 
clinical laboratory testing will be recorded on the eCRF. 
The following samples will be sent to one or several central laboratories, the Sponsor, or 
a designee for analysis: 
 
Serum samples for PK analysis 


 
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 
Plasma and serum samples for immunogenicity analysis 
 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  For sampling timepoints, please refer to Appendix 3. 
When PK assessments, vital sign assessment, ECG recording, and standard meal are 
scheduled at the same time points, the following sequence should be followed: 
 
ECG recording 
 
Vital sign assessment 
 
PK blood sampling 
 
Standard meal 
 
Biological samples will be destroyed no later than the time of completion of the final 
Clinical Study Report, with the following exceptions: 
 
Plasma and/or serum samples collected for PK or immunogenicity analysis may be 
needed for additional immunogenicity characterization and for PK or immunogenicity 
assay development and validation; therefore, these samples will be destroyed no 
later than 5 years after the final Clinical Study Report has been completed. 
 
When a subject withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the subject specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
4.5.6 
Electrocardiograms 
Triplicate ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1).  Three interpretable ECG recordings (e.g., 
without artifacts) must be obtained at each timepoint ( 5 minutes).  The average of the 
three readings will be used to determine ECG intervals (e.g., PR, QRS, QT).  
Single ECG recordings may be obtained at unscheduled timepoints as indicated. 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the subject has been resting in a semi-supine position for at least 
5 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, 


 
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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 subject's permanent 
study file at the site.  Digital recordings will be stored at site.  The following should be 
recorded in the appropriate eCRF:  heart rate, QRS interval, PR duration, uncorrected 
QT interval, and QTcF based on the machine readings of the individual ECG tracings.  
For any post-dose ECG, QTcF only needs to be calculated and recorded in the eCRF if 
the QTcB reading is  450 msec (see Appendix 7 for correction formulas for QTc 
intervals).  Any morphologic waveform changes or other ECG abnormalities must be 
documented on the eCRF.  If considered appropriate by the Sponsor, ECGs may be 
analyzed retrospectively at a central laboratory. 
If at a particular post-dose timepoint the mean QTcF is  500 ms and/or 60 ms longer 
than the baseline value, another triplicate ECG must be recorded, ideally within the next 
5 minutes, and triplicate 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.  If a PK sample is not 
scheduled for that timepoint, an unscheduled PK sample should be obtained.  The 
investigator should also evaluate the subject for potential concurrent risk factors 
(e.g., electrolyte abnormalities, co-medications known to prolong the QT interval, severe 
bradycardia). 
4.5.7 
Left Ventricular Ejection Fraction 
Echocardiography will be used to assess LVEF values.  The screening LVEF 
assessment should be performed within  28 days prior to randomization and the LVEF 
value must be  55% to be eligible for the study. 
Echocardiography will be conducted as specified in the schedule of activities. 
4.5.8 
Clinical Outcome Assessments 
Patient-reported outcome (PRO) instrument will be completed in both study arms to 
assess the level of pain experienced by the subject in relation to the injection of 
PH FDC SC.  On Day 1, pain assessments will be performed prior to, during, and 
immediately after injection of PH FDC SC when the needle or device is removed, and 
2 hours after injection.  A questionnaire will also be completed after the injection by 
subjects in the OBDS arm, to assess the comfort of wearing the OBDS. 
A Clinician-reported outcome (ClinRO) questionnaire will be completed to assess any skin 
irritation or sensitization reactions caused by the adhesion of the OBDS to the skin. 
The PRO data will be collected through use of the following instruments:  100 mm VAS 
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be collected through use of the following instrument:  Device Monitoring questionnaire 
(skin irritation and sensitization reactions to the OBDS). 
4.5.8.1 
Data Collection Methods for Clinical Outcome Assessments 
The PRO instruments will be self-administered or interviewer-administered (as 
appropriate) at the clinic at specified timepoints on Day 1 (see schedule of activities in 
Appendix 1 and Section 4.5.8). 
During Day 1, PRO instruments (VAS pain score and Device Monitoring questionnaire 
on comfort of wearing the OBDS) should be administered as outlined below: 
 
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 subjects to complete the instruments, estimated 
to be 12 minutes at each specified timepoint. 
 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions. 
 
Subjects 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. 
 
Subjects 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 subject to 
rectify any response that is not clearly marked in the appropriate location.  If 
a response is missing, site staff should ask the subject to complete the item or 
confirm that the item was intentionally left blank. 
 
The ClinRO instrument (Device Monitoring questionnaire on skin irritation or 
sensitization reactions) will be completed at the clinic on Day 1 (see schedule of 
activities in Appendix 1).  The ClinRO instrument will be self-administered before and 
after the injection of study drug with the OBDS.  The instrument will be completed on the 
designated eCRF. 
4.5.9 
Device Monitoring Assessments 
Details of the performance and ease of use of the OBDS will be collected and recorded 
in the eCRF using the Device Monitoring questionnaire.  This will include: 
 
Preparation of the injection site 
 
Preparation of the OBDS 
 
Assessment of skin irritation and sensitization reactions (dermal or other effects) 
before and after injection 
 
Pre-filled cartridge inspection before insertion in the OBDS 


 
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 
Positioning and attachment of the OBDS on the anterior thigh 
 
Drug delivery 
 
Removal of the OBDS 
 
OBDS administration failures 
 
Ease of OBDS attachment, attachment during the injection, ease of OBDS removal, and 
overall clarity of handling instructions will each be rated on a three-point scale as “good,” 
“acceptable,” or “poor” by the healthcare professional who administered the SC injection.  
Subjects will also be asked to rate overall wearing comfort on the same scale (see 
Section 4.5.8 and Section 4.5.8.1). 
Skin irritation and sensitization reactions will be assessed before and after the injection. 
In addition, adverse events due to the OBDS will be summarized separately. 
Medical Device Complaints 
In case of any medical device complaints related to the OBDS, the investigator should 
report these complaints to the Sponsor as per the instructions in Section 5.4.4. 
All devices should be returned to the Sponsor (refer to the pharmacy manual for 
instructions). 
4.6 
TREATMENT, SUBJECT, STUDY, AND SITE 
DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Subjects will receive one dose of study drug.  The administration of that study drug must 
stop if during administration they experience any of the following: 
 
Severe drug-related adverse event 
 
NCI CTCAE Grade  3 hypersensitivity reaction 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the subject's safety if he continues to receive study drug 
 
Investigator determination that drug discontinuation is in the best interest of the 
subject 
 
The primary reason for study drug discontinuation should be documented on the 
appropriate eCRF.  Subjects who discontinue study drug will not be replaced. 
If a subject requests to be withdrawn from treatment or follow-up assessments, this 
request must be documented in the source documents and signed by the investigator. 


 
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4.6.2 
Subject Discontinuation from the Study 
Subjects have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a subject from the study at any 
time. 
Reasons for subject discontinuation from the study may include, but are not limited to, 
the following: 
 
Subject withdrawal of consent 
 
Study termination or site closure 
 
Adverse event 
 
Loss to follow-up 
 
Every effort should be made to obtain a reason for subject discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a subject requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Subjects 
who withdraw from the study will not be replaced unless they have non-evaluable 
PK data (PK non-evaluable), in which case the subject may be replaced at the discretion 
of the Sponsor. 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates 
a potential health hazard to subjects 
 
Subject enrollment is unsatisfactory 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all subjects have completed the study and all obligations have 
been fulfilled) 
 


 
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5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
The pertuzumab and trastuzumab drug substances in PH FDC SC are identical to the 
drug substances in the Perjeta, Herceptin IV, and Herceptin SC formulations.  The safety 
plan for subjects in this study is based on the anticipated safety risks of PH FDC SC as 
observed in Phase III Study WO40324 and Phase II Study MO40628 and on clinical 
experience with Perjeta IV and with Herceptin IV and SC, in completed and ongoing 
studies.  The anticipated important safety risks for PH FDC SC are outlined below.  
Please refer to the PH FDC SC, and the Perjeta and Herceptin Investigator's Brochures 
for a complete summary of safety information. 
Several measures will be taken to ensure the safety of subjects participating in this 
study.  Eligibility criteria have been designed to exclude subjects at higher risk for 
toxicities.  Subjects will undergo safety monitoring during the study, including 
assessment of the nature, frequency, and severity of adverse events.  In addition, 
guidelines for managing adverse events, including criteria for discontinuation, are 
provided below. 
5.1.1 
Risks Associated with PH FDC SC 
5.1.1.1 
Hypersensitivity Reactions/Anaphylaxis and 
Administration-Related Reactions 
In Phase III Study WO40324, administration related reactions (ARRs) occurring within 
24 hours of HER2-targeted therapy were slightly higher in the PH FDC SC arm 
compared to the P  H IV arm (34 [13.5%] P  H IV vs. 43 [17.3%] PH FDC SC patients).  
The most frequently reported preferred terms (PTs) (in  5% of cases) included injection 
site reaction:  1 (0.4%) P  H IV (occurred in a patient who switched to Herceptin SC 
during the adjuvant treatment period) versus 32 (12.9%) PH FDC SC patients; and 
infusion-related reaction:  25 (9.9%) P  H IV versus 0 (0%) PH FDC SC patients.  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 ARRs were Grade 1 and 2, with Grade 1 events more frequent in the 
PH FDC SC arm (18 [7.1%] P  H IV vs. 38 [15.3%] PH FDC SC patients).  Three 
patients in the P  H IV arm and none in the PH FDC SC arm experienced 
Grade 3 events. 
The majority of ARR events occurred during the neoadjuvant phase of the study.  The 
ARRs led to withdrawal from the study for two patients (one in each arm). 
Overall, hypersensitivity and anaphylaxis events occurred with low and comparable 
incidence across the treatment arms (5 [2.0%] P  H IV vs. 4 [1.6%] PH FDC SC 
patients).  Except for one event (Grade 3 hypersensitivity related to a concomitant 
medication at study Cycle 4 in the P  H IV arm), all events occurred after study Cycle 5 


 
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(first administration of HER2-targeted therapy) and were related to HER2-targeted 
therapy (4 [1.6%] patients in each arm).  The reported events by PT were 
injection-related reaction, hypersensitivity, and drug hypersensitivity.  All events were 
Grade 1 (three patients per arm) or Grade 2 (one patient per arm). 
The majority of anaphylaxis and hypersensitivity events occurred during the 
neoadjuvant phase of the study.  The incidence of anaphylaxis and hypersensitivity 
adverse events related to HER2 reported during or within 24 hours of administration 
were low in both arms (2 [0.8%] P  H IV vs. 2 [0.8%] PH FDC SC), 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.  Patients 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 
IV pertuzumab in combination with trastuzumab and chemotherapy. 
For PH FDC SC administration, subjects should be monitored for at least 30 minutes 
after their dose.  If ARRs occur, subjects must be monitored until complete resolution of 
signs and symptoms. 
Please refer to the PH FDC SC, and the Perjeta and Herceptin Investigator’s Brochures 
for the most recent data related to the risk of hypersensitivity reactions. 
5.1.1.2 
Symptomatic Left Ventricular Dysfunction 
In Phase III Study WO40324, 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: 
Definite cardiac death, defined as death due to heart failure, myocardial 
infarction, or documented primary arrhythmia 
Probable cardiac death, defined as sudden unexpected death within 24 hours 
of a definite or probable cardiac event (e.g., syncope, cardiac arrest, chest pain, 
infarction, arrhythmia) without documented etiology 
 
There were no patients in the P  H IV arm and 2 (0.8%) patients in the PH FDC SC arm 
who met the criteria for a primary cardiac event:  1 (0.4%) patient had heart failure with 
LVEF drop of at least 10 percentage points from baseline and to below 50%, and 
1 (0.4%) patient with cardiac death. 


 
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The event of heart failure was reported in an elderly patient in the PH FDC SC arm.  The 
onset of the adverse event occurred 18 days after Cycle 4 Day 1 of doxorubicin 
(Adriamycin®) plus cyclophosphamide (AC) every 3 weeks, 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 patient in the PH FDC SC arm.  
The event was due to an acute myocardial infarction which occurred after Cycle 2 of 
dose-dense doxorubicin 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 patients in the adjuvant or treatment-free 
follow-up period. 
Secondary cardiac events were only counted for patients who had not experienced 
a primary cardiac event (i.e., patients could only be counted in one of these categories).  
Those events not counted as a secondary cardiac event were still captured as part of 
adverse event reporting (ejection fraction decreased) and under LVEF assessment. 
Overall, 9 (3.6%) versus 4 (1.6%) patients had at least one LVEF decrease of 10 % 
below the baseline measurement to an absolute LVEF value of  50% in the P  H IV and 
PH FDC SC arms, respectively.  Of these, the initial LVEF decline was confirmed by 
a second LVEF assessment for 2 (0.8%) patients in the P  H IV arm and 1 (0.4%) 
patient in the PH FDC SC arm; therefore overall, 3 patients fulfilled the criteria for 
secondary cardiac events. 
Secondary cardiac events occurred throughout all phases of the study.  Some patients 
are counted in multiple outputs if they had events occurring in more than one phase of 
the study.  The number of patients who experienced at least one LVEF decrease of 10% 
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 and PH FDC SC arms, 
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 arms, 
respectively, which occurred during the adjuvant phase 
 
Three (1.2%) and one (0.4%) events in the P  H IV arm and PH FDC SC arms, 
respectively, which occurred during the follow-up phase 
 
Subjects with significant cardiac disease or baseline LVEF  55% are not eligible for this 
study.  Similar to all Perjeta trials, subjects must undergo routine cardiac monitoring by 
ECHO.  During the screening/baseline period, complete medical history information will 
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congestive heart failure (CHF).  If symptomatic left ventricular systolic dysfunction 
(LVSD) (heart failure; serious adverse event of NCI CTCAE v5.0 Grade 3 or 4; NYHA 
Class III or IV) develops, the subject must be monitored carefully with repeat LVEF 
assessments.  Symptomatic LVSD should be treated and followed according to standard 
medical practice.  Please refer to the PH FDC SC, and the Perjeta and Herceptin 
Investigator’s Brochures for the most recent data relating to risk of LVSD and CHF. 
5.1.1.3 
Diarrhea 
In Phase III Study WO40324, the incidence and severity of diarrhea events were 
comparable between the two treatment arms (55.2% P  H IV patients vs. 58.5% 
PH FDC SC patients).  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%] P  H IV vs. 17 [6.9%] PH FDC SC patients).  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% P  H IV vs. 30.6% PH FDC SC patients).  
Grade 34 diarrhea events related to HER2 were reported in 5 (2.0%) P  H IV versus 
9 (3.6%) PH FDC SC patients.  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 subjects should 
be treated with fluids and electrolytes replacement, as clinically indicated. 
5.1.1.4 
Rash/Skin Reactions 
In the Phase III Study WO40324, 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 patients with standard acne 
therapies, including topical and oral antibiotics. 
5.1.1.5 
Mucositis 
In the Phase III Study WO40324, the incidence of serious mucositis events was low in 
both treatment arms (4/252 patients [1.6%] in P  H IV arm vs. 3/248 patients [1.2%] in 
PH FDC SC arm), with the majority of them (in 6 patients overall) being Grade 3 in 
severity. 
5.1.1.6 
Reproductive Risks Associated with Pertuzumab, 
Trastuzumab, and PH FDC SC 
Reproductive toxicity was identified during nonclinical studies with Perjeta.  Perjeta 
administered to pregnant cynomolgus monkeys during organogenesis led to delayed 
renal development, oligohydramnios, and embryo-fetal deaths.  However, reproductive 
toxicity studies with trastuzumab conducted in female cynomolgus monkeys revealed no 
trastuzumab-related embryotoxicity or effects on fetal development.  There are no 


 
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clinical studies of trastuzumab or pertuzumab in pregnant women.  The 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 Herceptin.  Therefore, neither pertuzumab nor trastuzumab 
should be used during pregnancy unless the potential benefit for the mother outweighs 
the potential risk to the fetus. 
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 and 
for 7 months after the dose of study drug to avoid exposing the embryo.  All male 
participants must also refrain from donating sperm during this same period.  
Pregnancies in female partners of male participants will be monitored. 
5.1.1.7 
Interstitial Lung Disease 
In the Phase III Study WO40324, incidence of interstitial lung disease (ILD) adverse 
events was low and balanced between the two treatment arms (2 [0.8%] P  H IV vs. 
3 [1.2%] PH FDC SC patients).  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, serious adverse events were reported in 1 (0.4%) and 2 (0.8%) 
patients with ILD which were assessed by the investigator as related to 
AC chemotherapy and HER2- targeted therapy, respectively.  All events were Grade 2 
and had resolved by the time of clinical cut-off date. 
5.1.2 
Management of Subjects Who Experience Adverse Events 
Supportive care and medical management of adverse events are at the discretion of the 
investigator and as per local policy, unless specifically listed below. 
5.1.2.1 
Management of Symptomatic LVSD and/or LVEF Decline 
All subjects must have a baseline LVEF  55%.  LVEF will be monitored regularly 
according to the Schedule of Activities (see Appendix 1).  If an investigator is concerned 
that an adverse event may be related to LVSD, an additional LVEF measurement should 
be performed as soon as possible and within 3 weeks. 
Symptomatic LVSD (CHF) will be assessed as “heart failure” on the basis of 
NCI CTCAE v5.0 and NYHA classification (see Appendix 6). 
Congestive heart failure should be treated and monitored according to standard medical 
practice.  These subjects should be evaluated by a certified cardiologist, and the results 
of this evaluation should be reported in the eCRF. 
Heart failure and asymptomatic LVEF decline adverse events must be graded per 
NCI CTCAE v5.0 (see Appendix 6) and reported in the eCRF Form as described in 
Table 2. 


 
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5.1.2.2 
Management of Hypersensitivity/Anaphylaxis and 
Administration-Related Reactions 
Subjects should be observed closely for hypersensitivity reactions (see Section 5.1.2).  
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 Perjeta IV in combination with 
Herceptin IV and chemotherapy. 
Hypersensitivity reactions/anaphylaxis is a systemic reaction, mediated by interactions 
between factors released from IgE and mast cells, resulting in an antigen-antibody 
reaction. 
Study drug administration should be stopped in subjects who develop dyspnea or 
clinically significant hypotension (defined per investigator’s discretion). 
Subjects who experience any of the following events will be discontinued from 
study drug: 
 
Grade 4 allergic reaction 
 
Grade 3 or 4 hypersensitivity reaction 
 
Acute Respiratory Distress Syndrome (ARDS) 
 
Bronchospasm 
 
Administration Related Reactions include: 
 
Injection-Related Reaction.  A systemic reaction with symptoms such as chills, 
diarrhea, fatigue, headache, nausea, and pyrexia 
Such reactions are likely to be due to a release of cytokine(s) and typically 
occur during, or very shortly after, the administration of monoclonal antibodies, 
but they may also show a delayed onset.  The majority of adverse events 
resolve fully. 
 
Injection-Site Reaction.  A local reaction to the site of the injection, with signs and 
symptoms such as erythema, induration, swelling, pain, hypoaesthesia and 
discomfort 
 
Subjects who experience ARRs may be managed by: 
 
Stopping or slowing the injection of PH FDC SC 
 
Supportive care with antihistamines, antipyretics, corticosteroids or epinephrine as 
clinically indicated 
 
Subjects should be monitored until complete resolution of signs and symptoms of any 
systemic reactions. 


 
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In order to be able to calculate time to onset of such reactions, the occurrence of 
associated adverse events must be documented with the date and time of the onset and 
duration of the event (i.e., resolution of the event). 
All ARRs should be recorded as described in Section 5.3.5.1. 
5.1.2.3 
EGFR-Related Toxicities 
Diarrhea 
To prevent dehydration, early treatment of diarrhea with anti-diarrheal medication 
(e.g., loperamide) should be considered, and subjects 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 subjects experiencing 
pertuzumab-related rash/skin reactions, as clinically indicated, although they have not 
been studied in this context. 
Mucositis 
Mucositis is generally not considered preventable.  Although for some cytotoxic agents, 
mucositis may be reduced by cooling the mouth using ice chips before and during the 
infusion. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered 
a pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 


 
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 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9 
and 5.3.5.10 for more information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
subject at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the subject's ability to conduct normal life 
functions) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
subject or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
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5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows: 
 
An asymptomatic decline in LVEF that requires treatment or that leads to 
discontinuation of HER2-targeted therapies must be reported in an expedited 
manner with use of the Serious Adverse Event Form and classifying the event as an 
Event of Special Interest that is immediately reportable 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7) 
 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a subject exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 
5.2.4 
Selected Adverse Events 
Additional data will be collected for the following selected adverse events: 
Heart Failure 
Symptomatic LVSD (referred to as heart failure) should be reported as a serious adverse 
event (see Table 2).  If the diagnosis is heart failure, it should be reported as such, and 
not as individual signs and symptoms of heart failure.  Signs and symptoms should be 
recorded in the Additional Details section of the Serious Adverse Event eCRF.  A cardiac 
consultation is recommended for subjects who develop symptomatic LVSD.  Heart 
failure should be graded according to both NCI CTCAE v5.0 and NYHA Class.  LVEF 
results must also be reported.  See Section 5.1.2.1 for management of Symptomatic 
LVSD and/or LVEF Decline. 
Heart failure occurring during the study must be reported (up to Day 63 irrespective of 
causal relationship and up to the 7 month follow up visit if related to study drug [see 
Section 5.3.1]) and followed until one of the following occurs:  resolution or improvement 
to baseline status, no further improvement can be expected, or death. 
Asymptomatic Declines in Left Ventricular Ejection Fraction 
Asymptomatic declines in LVEF should not be reported as adverse events because 
LVEF data are collected separately in the eForm.  Exceptions to this rule are as follows: 
 
An asymptomatic decline in LVEF of  10 percentage-points from baseline to an 
LVEF  50% must be reported as an adverse event with the term of “ejection fraction 


 
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decreased”, as per NCI CTCAE v5.0 (see Appendix 6).  In addition, a comment in 
the adverse events comments field should confirm that the event was 
asymptomatic. 
 
An asymptomatic decline in LVEF requiring treatment or leading to discontinuation 
of study treatment is an adverse event of special interest and must be reported in an 
expedited manner (see Section 5.2.3).  The event must be reported as an adverse 
event with the term of “ejection fraction decreased”, as per NCI CTCAE v5.0 (see 
Appendix 6) and a comment should be added to the adverse events comments field 
confirming that the event was asymptomatic. 
 
Table 1 summarizes the reporting conventions for LVSD and heart failure. 
Table 1 
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 eForms 
NA 
NA 
Asymptomatic decline in 
LVEF of  10 percentage 
points from baselinea to 
an LVEF of  50% 
AEb (AE eForm)  
Ejection fraction 
decreaseda 
NCI CTCAE for 
“ejection fraction 
decreased” 
Asymptomatic decline in 
LVEF requiring treatment 
or leading to study 
treatment discontinuation  
AE (AE eForm) and 
report as a 
non-serious AEs of 
special interest on 
an SAE eForm 
Ejection fraction 
decreaseda  
NCI CTCAE for 
“ejection fraction 
decreased” 
Heart failure / CHF 
(symptomatic LVSD)c 
AE (AE eForm) and 
SAE (SAE eForm) 
“Heart failure” 
NCI CTCAE for 
"heart failure" and 
NYHA class 
AE  adverse event; CHF  congestive heart failure; 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 Baseline is considered the last LVEF prior to enrolling in study 
b Report the status as asymptomatic and provide the LVEF value in the comments field as 
appropriate. 
c Any symptomatic LVSD event must be reported as “heart failure.” 
 
Administration-Related Reactions:  Injection-Related Reactions and Injection 
Site Reactions 
The ARRs will be collected during the study.  See Sections Section 5.1.2 and 
Section 5.3.5.1 for details. 


 
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5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4 and  5.6.  The 
investigator is also responsible for reporting medical device complaints (see 
Section 5.4.4). 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each subject contact.  All 
adverse events, whether reported by the subject or noted by study personnel, will be 
recorded in the subject's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported (see 
Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until Day 63 after the 
dose of study drug.  After this point only death, serious adverse events, adverse events, 
or adverse event of special interest that are related to study drug will be reported until 
7 month follow up.  Instructions for reporting adverse events that occur after the adverse 
event reporting period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all subject evaluation timepoints.  Examples of 
non-directive questions include the following: 
 
"How have you felt since your last clinic visit?" 
 
"Have you had any new or changed health problems since you were last here?" 
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 2 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 


 
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Table 2 
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 subjects who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the subject, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration: 
 
Temporal relationship of event onset to the initiation of study drug 
 
Known association of the event with the study drug or with similar treatments 
 
Presence of risk factors in the subject or use of concomitant medications known to 
increase the occurrence of the event 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
Association of the event with use of the device only and not the study drug 
 


 
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Table 3 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the subject's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below. 
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Injection Reactions 
Adverse events that occur during or within 24 hours after study drug administration, that 
are judged to be related to study drug injection and meet the criteria of an ARR (see 
Section 5.1.2) should be captured as a diagnosis (e.g., "injection-related reaction or 
"injection-site reaction" or "anaphylactic reaction") on the Adverse Event eCRF.  If 
possible, avoid ambiguous terms such as "systemic reaction."  Associated signs and 
symptoms should be recorded on the dedicated Injection Reaction eCRF.  If a subject 
experiences both a local and systemic reaction to a single administration of study 
treatment, each reaction should be recorded separately on the Adverse Event eCRF, 
with signs and symptoms also recorded separately on the dedicated Injection Reaction 
eCRF. 
Table 4 details the reporting conventions for injection-related reactions and injection-site 
reactions. 


 
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Table 4 
Reporting Conventions for Injection-Related Reactions and 
Injection-Site Reactions 
Adverse Event 
Term to Be Used on AE eCRF 
Form 
eCRF Form to Be Used to 
Record Symptoms 
Systemic Injection 
Reaction 
“Injection-related reaction” 
Injection reaction form 
Local Injection Reaction 
“Injection-site reaction” 
Injection reaction form a 
AE  adverse event; eCRF  electronic Case Report Form. 
a Symptoms of Injection-site reactions should include ‘at injection site’ in the description 
 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
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. 
5.3.5.3 
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. 
 
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. 


 
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5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
subject evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between subject evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as 
a separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5  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." 


 
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Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment 
 
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. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an elevated 
total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (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  ULN in combination with 
total bilirubin  2  ULN 
 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 


 
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5.3.5.8 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2). 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.9 
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"). 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), 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: 
 
Planned hospitalization required by the protocol (e.g., for overnight stays Day   1 to 
Day 2) 


 
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Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The subject has not experienced an adverse event 
 
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 subject requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.11 
Cases of Accidental Overdose or Medication Error 
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 
Special situations are not in themselves adverse events but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  For PH FDC SC, adverse events associated with special 
situations should be recorded as described below for each situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
In addition, all special situations associated with PH FDC SC, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF as described 
below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 


 
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 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
5.3.5.12 
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. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
Medical device complaints (see Section 5.4.4 for details on reporting requirements) 
 
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 becoming aware of the information).  New significant information 
includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 


 
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 
Change in the event's outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and Institutional Review Board (IRB)/Ethics 
Committee (EC). 
5.4.1 
Medical Monitors and Emergency Medical Contacts 
To ensure the safety of study participants, access to the Medical Monitors is available 
24 hours per day, 7 days per week.  Details will be provided separately. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention 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 learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until Day 63 after the dose of study drug.  Investigators should 
record all case details that can be gathered immediately (i.e., within 24 hours after 
learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to 
Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial 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 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system. 
Instructions for reporting serious adverse events that occur  63 days after the dose of 
study drug are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Partners of Male Subjects 
Male subjects will be instructed through the Informed Consent Form to immediately 
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7 months after the dose of PH FDC SC.  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 
subject exposed to study drug.  When permitted by the site, the pregnant partner would 
need to sign an Authorization for the Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  If the authorization has been 
signed, the investigator should submit a Clinical Trial Pregnancy Reporting Form with 
additional 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 Disclosure 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 subject or his pregnant partner may 
provide information on the risks of the pregnancy and the possible effects on the fetus, 
to support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
5.4.3.2 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to the female partner of a male 
subject exposed to study drug should be classified as a serious adverse event, recorded 
on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5.4.2). 
5.4.4 
Reporting Requirements for Medical Device Complaints 
In this study, the OBDS is considered a medical device.  The investigator must report all 
medical device complaints to the Sponsor.  The investigator should document as much 
information as possible on the IMP Deviation Form, including the product batch number, 
and forward the form to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event) (refer to the pharmacy manual for further details).  If the medical 
device results in an adverse event to the study subject, the event must be reported on 
the Adverse Event eCRF and submitted through the EDC system.  If the event is 
serious, the Adverse Event eCRF must be completed immediately (i.e., no more than 
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5.5 
FOLLOW-UP OF SUBJECTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the subject 
is lost to follow-up, or the subject withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study treatment or 
trial-related procedures until a final outcome can be reported. 
During the adverse event reporting period (defined in Section 5.3.1), resolution of 
adverse events (with dates) should be documented on the Adverse Event eCRF and in 
the subject's medical record to facilitate source data verification. 
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 
Section 5.4.3. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any death, serious 
adverse event, adverse event, or adverse event of special interest that occurs after the 
end of the adverse event reporting period (defined as 63 days after the dose of study 
drug), if the event is believed to be related to prior exposure to study drug.  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. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
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To determine reporting requirements for single 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, and Perjeta and Herceptin Investigator's 
Brochures  
PH FDC SC  fixed-dose combination of pertuzumab and trastuzumab for subcutaneous 
administration. 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The analysis of primary and secondary endpoints will be performed after all subjects 
have completed the Day 63 assessments.  A follow-up analysis for safety will be 
performed once all subjects have completed the 7-month follow-up visit. 
6.1 
DETERMINATION OF SAMPLE SIZE 
Approximately 144 subjects will be enrolled, taking into account an assumed drop-out 
rate of 10%.  A total of 130 healthy subjects with fully evaluable pharmacokinetic profiles 
are required to demonstrate comparability of AUC062days and Cmax values between the 
handheld syringe injection administration (reference) and the OBDS (test) with 
80% power at 5% significance level, assuming a between-subject coefficient of variation 
(CV) of 40% and ‘test’ to ‘reference’ ratio of 0.95.  Standard bioequivalence ranges of 
0.8 and 1.25 are used to demonstrate comparability of AUC062days and Cmax values for 
pertuzumab and trastuzumab administered as PH FDC SC, either by the OBDS or by 
handheld syringe.  PK non-evaluable subjects may be replaced at the discretion of the 
Sponsor. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of subjects who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study discontinuation will be listed and 
summarized.  Enrollment and major protocol deviations will be listed and evaluated for 
their potential effects on the interpretation of study results. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
The evaluation of comparability between the treatment arms will include summaries of 
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variables will be summarized using means, standard deviations, medians, and ranges.  
Categorical variables will be summarized by counts and proportions. 
6.4 
PRIMARY ENDPOINT ANALYSES 
The co-primary endpoints of this study are single-dose AUC062days and Cmax values for 
both pertuzumab and trastuzumab either after administration of PH FDC SC using the 
handheld syringe with hypodermic needle or using the OBDS. 
The analysis will be performed using a per protocol PK population which would include 
all subjects randomized and adherent to the pre-specified protocol criteria.  Subjects will 
be excluded from the pharmacokinetic analysis population for the following reasons: 
 
The subject violates the following inclusion or exclusion criteria: 
A body mass index (BMI) between 18 and 32 kg/m2, inclusive 
Use of prohibited medications, including non-prescription medications, 
nutraceuticals, nutritional supplements, or any herbal remedies taken within 
10 days or 5 times the elimination half-life (whichever is longer) prior to 
randomization into the study 
Concomitant subcutaneous, intravenous, or any parenteral drugs within 
90 days prior to screening 
Participation in an investigational drug or device study within 90 days or 5 times 
the elimination half-life (whichever is longer) prior to screening 
Current chronic daily treatment (continuous for  3 months) with corticosteroids 
(dose  10 mg/day methylprednisolone), excluding inhaled corticosteroids 
Receipt of IV antibiotics for infection within 7 days prior to enrollment into the 
study 
 
A subcutaneous injection site other than thigh is used 
 
Any subject whose injection is not successfully performed (see Appendix 4 and 
Appendix 5) will be considered as non-evaluable for the PK analysis; however, all 
data including PK and ADA samples will be collected 
 
The subject deviates significantly from the PK collection schedule: 
For analysis of AUC062days, subjects with missing Day 63 PK concentration data 
or with a Day 63 PK sample time deviation outside a  120-hour window of 
planned sampling time will be excluded 
For analysis of Cmax, subjects with 2 or more missing PK concentration data on 
any of Days 3, 5, 7, 9, or 11 will be excluded 
 
Subjects who deviate significantly from the PK collection schedule and are therefore 
PK non-evaluable may be replaced at the discretion of the Sponsor. 
Exclusion of subjects will be documented together with the reason for exclusion.  All 
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Serum concentrations of pertuzumab and trastuzumab at each sampling time point will 
be presented by listings.  Summary statistics of PK parameter values including means, 
geometric means, medians, ranges, standard deviations and coefficients of variations 
will be presented. 
The bioequivalence of the two administration methods will be assessed by a two 
one-sided testing procedure.  The GMR of the administration by the OBDS relative to the 
administration by handheld syringe will be estimated together with the two-sided 90% CI 
based on the log-transformed AUC062days and Cmax values. 
The hypothesis to be tested for the co-primary endpoints, observed pertuzumab and 
trastuzumab AUC062days and Cmax is: 
 
H0:  the administration by OBDS is not bioequivalent to the administration by the 
handheld syringe with hypodermic needle (i.e., the GMR is not within the standard 
bioequivalence margins [0.8; 1.25]), versus 
 
H1:  the administration by OBDS is bioequivalent to the administration by the 
handheld syringe with hypodermic needle (i.e., the GMR is within the standard 
bioequivalence margins [0.8; 1.25]) 
 
The null hypothesis will be rejected, and bioequivalence will be concluded if the bounds 
of the 90% CI of the geometric mean ratio of AUC0-62days and Cmax values for pertuzumab 
and trastuzumab administration by the OBDS relative to the administration by the 
handheld syringe with hypodermic needle are entirely contained within the standard 
bioequivalence margins (0.8; 1.25) for all co-primary endpoints.  Comparability between 
the two methods will be concluded only if bioequivalence is established for both 
pertuzumab and trastuzumab AUC0-62days and Cmax. 
The GMR and corresponding 90% CI will be estimated using the analysis of variance 
method with the log-transformed AUC0-62days and Cmax values as the dependent variable 
and treatment arm as a covariate. 
6.5 
SECONDARY ENDPOINTS 
6.5.1 
Pharmacokinetic Analyses 
All secondary pharmacokinetic parameter values including CDay 21, CDay 62, AUC0, tmax, 
t1/2, CL/F, and Vd/F will be presented by listings and descriptive summary statistics 
(such as mean, median, min, max, standard deviation, %CV) separately by groups.  
Details of the analysis of the secondary PK endpoints are included in the Statistical 
Analysis Plan. 
Actual dose delivered will be calculated based on the weight difference of the syringe or 
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6.5.2 
Safety Analyses 
The safety analysis population will include all subjects who have received all or part of 
the single dose of study medication, with subjects grouped according to method of 
administration of study medication. 
Safety and tolerability will be assessed using reporting of exposure to study treatment, 
adverse events, changes in clinical laboratory test results and physical examination, 
including vital signs, electrocardiograms, and echocardiography.  As appropriate, 
listings, summary tables and graphs (subject plots and/or mean plots) will be provided 
for the safety assessments, using descriptive statistics.  Study treatment exposure (such 
as treatment duration and total dose received) will be summarized with descriptive 
statistics. 
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded 
according to NCI CTCAE v5.0.  For adverse events for which the Common Terminology 
Criteria for Adverse Events v5.0 does not provide a grading scale, the standard 
four-point scale (mild, moderate, severe, life-threatening) will be used.  All adverse 
events, serious adverse events, adverse events leading to death, adverse events of 
special interest, and adverse events leading to study treatment discontinuation that 
occur on or after the first dose of study treatment (i.e., treatment-emergent adverse 
events) 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.  
Deaths and cause of death will be summarized.  Relevant laboratory, vital sign (pulse 
rate, respiratory rate, blood pressure, pulse oximetry, and temperature), LVEF, and ECG 
data will be displayed by time, with grades identified where appropriate.  Additionally, 
a shift table of selected laboratory tests will be used to summarize the baseline and 
maximum post-baseline severity grade.  Changes in vital signs, LVEF and ECGs will be 
summarized. 
Adverse events due to the OBDS itself will be summarized separately. 
6.5.3 
Device Related Analyses 
Details of the performance and ease of use of the OBDS will be collected and recorded 
on the eCRF.  This will include: 
 
Preparation of the injection site 
 
Preparation of the OBDS 
 
Assessment of skin irritation and sensitization reactions (dermal or other effects) 
before and after injection 
 
Prefilled cartridge inspection before insertion in the OBDS 
 
Positioning and attachment of the OBDS on the anterior thigh 
 
Drug delivery 


 
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 
Removal of the OBDS 
 
OBDS administration failures 
 
Ease of OBDS attachment, attachment during the injection, ease of OBDS removal, 
overall wearing comfort, and overall clarity of handling instructions will each be rated on 
a three-point scale as “good”, “acceptable”, or “poor.”  Summaries of device assessment 
will be summarized by counts and proportions. 
Comparability of evaluation of pain assessment, and skin irritation and sensitization 
reactions in the syringe and the OBDS group will include summaries and listings. 
6.6 
EXPLORATORY ANALYSES 
6.6.1 
Immunogenicity Analyses 
The immunogenicity analysis population will consist of all subjects with at least one 
ADA assessment.  Subjects will be grouped according to treatment received or, if no 
treatment is received prior to study discontinuation, according to treatment assigned. 
The numbers and proportions of ADA-positive subjects and ADA-negative subjects at 
baseline (baseline prevalence) and after drug administration (post-baseline incidence) 
will be summarized by treatment group.  When determining post-baseline incidence, 
subjects are considered to be ADA positive if they are ADA negative or have missing 
data at baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more post-baseline samples is at least 0.60 titer unit greater than the titer of 
the baseline sample (treatment-enhanced ADA response).  Subjects are considered to 
be ADA negative if they are ADA negative or have missing data at baseline and all 
post-baseline samples are negative, or if they are ADA positive at baseline but do not 
have any post-baseline samples with a titer that is at least 0.60 titer unit greater than the 
titer of the baseline sample (treatment unaffected). 
The relationship between ADA status and safety and PK endpoints may be analyzed 
and reported via descriptive statistics. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
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. 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 


 
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discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Non-eCRF data will be sent directly to the 
Sponsor, using the Sponsor's standard procedures to handle and process the electronic 
transfer of these data. 
The eCRFs and correction documentation will be maintained in the EDC system's audit 
trail.  System backups for data stored by the Sponsor and records retention for the study 
data will be consistent with the Sponsor's standard procedures. 
Data will be collected on paper questionnaires.  The data from the questionnaires will be 
entered into the EDC system by site staff. 
7.2 
ELECTRONIC CASE REPORT FORMS 
Electronic Case Report Forms are to be completed through use of a Sponsor-designated 
EDC system.  Sites will receive training and have access to a manual for appropriate 
eCRF completion.  The eCRFs will be submitted electronically to the Sponsor and 
should be handled in accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  The eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive subject data for his or her site in 
a readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 


 
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entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO and ClinRO data (if applicable), 
Informed Consent Forms, laboratory test results, and medication inventory records, and 
images, must be retained by the Principal Investigator for 15 years after completion or 
discontinuation of the study or for the length of time required by relevant national or local 
health authorities, whichever is longer.  After that period of time, the documents may be 
destroyed, subject to local regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
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. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 


 
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and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S.  
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trials Directive (2001/20/EC) 
or Clinical Trials Regulation (536/2014) and applicable local, regional, and national 
laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each subject the 
objectives, methods, and potential risks associated with each optional procedure.  
Subjects will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a subject's agreement to participate in optional procedures.  Subjects who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the subject or the subjects’ legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each subject shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the 
subject to participate.  The final revised IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes. 
If the Consent Forms are revised (through an amendment or an addendum) to 
communicate information that might affect a subject’s willingness to continue in the 
study, the subject or a legally authorized representative must re-consent by signing the 
most current version of the Consent Forms or the addendum, in accordance with 
applicable laws and IRB/EC policy.  For any updated or revised Consent Forms, the 
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process and that written informed consent was obtained using the updated/revised 
Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the subject or the subject's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each subject's study file or in the site file and must be available for verification by study 
monitors at any time. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the subject, 
and relevant supporting information must be submitted to the IRB/EC by the 
Principal Investigator and reviewed and approved by the IRB/EC before the study is 
initiated.  In addition, any subject recruitment materials must be approved by the 
IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.7). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC and 
archived in the site's study file. 
8.4 
CONFIDENTIALITY 
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. 
The Sponsor maintains confidentiality standards by coding each subject enrolled in the 
study through assignment of a unique patient identification number.  This means that 
subject names are not included in data sets that are transmitted to any Sponsor location. 
Subject medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
subject, unless permitted or required by law. 


 
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Medical information may be given to a subject's personal physician or other appropriate 
medical personnel responsible for the subject's welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
subjects unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.6). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and/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 (see Section 9.6). 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the subject data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on subject safety and 


 
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data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor has implemented a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring subject safety and data integrity.  The 
Sponsor identified potential risks associated with critical trial processes and data and 
implemented plans for evaluating and controlling these risks.  Risk evaluation and 
control included the selection of risk-based parameters (e.g., adverse event rate, 
protocol deviation rate) and the establishment of quality tolerance limits for these 
parameters.  Detection of deviations from quality tolerance limits will trigger an 
evaluation to determine if action is needed.  Details on the establishment and monitoring 
of quality tolerance limits are provided in a Quality Tolerance Limit Management Plan. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.5 
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 two sites globally will participate to enroll approximately 144 subjects.  
Enrollment will occur through an IxRS. 
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected. 
9.6 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 


 
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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 made available 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/  
http:///The results of this study may be published or presented at scientific congresses.  
For all clinical trials in subject involving an IMP for which a marketing authorization 
application has been filed or approved in any country, the Sponsor aims to submit a 
journal manuscript reporting primary clinical trial results within 6 months after the 
availability of the respective Clinical Study Report.  In addition, for all clinical trials in 
subjects involving an IMP for which a marketing authorization application has been filed 
or approved in any country, the Sponsor aims to publish results from analyses of 
additional endpoints and exploratory data that are clinically meaningful and statistically 
sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting subjects, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.7 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to subjects or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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10. 
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Appendix 1  
Schedule of Activities 
 
Screening and 
Baseline a 
Study Period 
Follow-
up a 
Day 
(Window) 
D –28 to 
D 2 
D –1 
D1 
D2 
D3 
D5 
D7 
D9 
D11 
D15 
D20 D22 
D35 
D49 
D56 
D63 
Month 
7 
Informed consent 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination b 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Randomization c 
 
x c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs d 
x 
x 
x 
x 
 
 
x 
 
 
 
 
x 
 
 
 
x 
 
12-Lead ECG e 
x 
x 
x 
x 
 
 
x 
 
 
 
 
x 
 
 
 
x 
 
LVEF f 
x 
 
 
 
 
 
 
 
 
 
x f 
 
x f 
 
Hematology g 
x 
x 
x 
x 
 
 
x 
 
 
 
 
x 
 
 
 
x 
 
Blood Chemistry h 
x 
x 
x 
x 
 
 
x 
 
 
 
 
x 
 
 
 
x 
 
Urinalysis i 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Serology j 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Test k 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drugs of Abuse l 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix 1  
Schedule of Activities (cont.)  
 
Screening and 
Baseline a 
Study Period 
Follow-up a 
Day 
(Window) 
D –28 to 
D 2 
D –1 
D1 
D2 
D3 
D5 
D7 
D9 
D11 
D15 D20 D22 
D35 
D49 D56 
D63 
Month 7 
Standardized Meal  
 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
PH FDC SC 
administration m 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pain assessment 
injection site n 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Device monitoring o 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK sampling 
(pertuzumab/ 
trastuzumab)  
 
 
x p 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
Pertuzumab/Trastuzumab 
/rHuPH20 ADA (Plasma 
and serum) q 
 
 
x 
 
 
 
 
 
 
x 
 
x 
 
 
 
x 
x 
Pregnancy follow-up of 
female partner 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Concomitant 
medications r 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Adverse Events s 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Overnight stay 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix 1  
Schedule of Activities (cont.)  
ADA  anti-drug antibody; CTCAE v5.0  Common Toxicity Criteria for Adverse Events; ECG  electrocardiogram; LVEF  left ventricular ejection fraction; 
OBDS PH FDC SC  600mg pertuzumab/600mg trastuzumab; PK  pharmacokinetic; RBC  erythrocyte (count); rHuPH20  human hyaluronidase; 
WBC  total leukocyte (count). 
a 7 months  10 days after the subject received their dose of PH FDC SC.  1 month  30 days.  For subjects with ongoing cardiac events (regardless of 
cause) or study treatment-related serious adverse events, adverse events, or adverse events of special interest on Day 63 or study treatment-related 
serious adverse events, adverse events, or adverse events of special interest occurring between the Day 63 visit and the follow-up visit, subjects 
should attend the clinic for the follow-up visit and PK/ADA sample collection.  For subjects with no cardiac events (regardless of cause) or study 
treatment-related serious adverse events, adverse events, or adverse events of special interest ongoing at Day 63 and none occurring between Day 63 
visit and the follow-up visit, only the pregnancy follow-up of female partners is required, and this visit may be performed by phone call. 
b A complete physical examination will be performed at screening (including height and weight).  An abbreviated exam will be performed on Day 1 
(day before dosing), and on Day 63, height will be recorded only at screening. 
c Randomization either Day 1 or Day1. 
d Body temperature (oral or aural) will be collected at screening, Day 1 (day of dosing), and Day 63 and as indicated for follow up for AE.  Blood 
pressure, respiration rate, and pulse rate will be taken at screening, on Days 1, 1, 2, 7, 22, and 63.  All measurements to be taken after the subject 
has rested in a semi-supine position for at least 5 minutes. 
e All ECG measurements in triplicate. 
f LVEF will be measured by echocardiography on three occasions:  at screening, between Days 20 and 35, and between Days 56 and 63. 
g Hematology includes:  hemoglobin, hematocrit, erythrocytes (RBC), platelets, total leukocytes (WBC), and WBC differential count. 
h Blood chemistry includes:  AST, ALT, total bilirubin, alkaline phosphatase, albumin, creatinine, urea, total protein, sodium, chloride, potassium, 
calcium, phosphate, glucose. 
i Urinalysis:  a midstream, clean-catch urine specimen will be collected for dipstick analysis of protein, blood, glucose, and pH.  If there is 
a clinically significant positive blood and/or protein result, urine will be sent to the local laboratory for microscopy and culture. 
j Serology includes:  HIV-1 and -2, Hepatitis B and C. 
k Alcohol test:  either breath test or urine test. 
l Drugs of abuse:  according to local standards including cannabinoids, amphetamines, opiates, methadone, cocaine, benzodiazepines and barbiturates. 
m The OBDS (with cartridge inserted and along with adhesive paper) and the handheld syringe (including needle and cover) will be weighed before and 
after the injection to measure the amount of study drug administered.  The injection must be given in the anterior thigh midway between the anterior 
iliac crest and the cephalad border of the patella while the subject is in a semi-supine position.  Study drug should not be injected into moles, scars, or 
bruises or tattooed areas.  The duration of the injection in minutes and seconds will be recorded. 


 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
86/Protocol WP42873, Version 4 
Appendix 1  
Schedule of Activities (cont.)  
n Intensity of injection site pain will be assessed in both study arms using a 100 mm Visual Analog Scale at the following time points:  1) on Day 1 
pre-dose, 2) during drug injection, 3) after drug injection while removing the device or syringe, and 4) 2 hours after drug injection. 
o Detailed OBDS monitoring including preparation of the injection site, preparation of the OBDS, prefilled cartridge inspection, positioning and attachment 
of device at anterior thigh, drug delivery and removal of OBDS, assessment of skin irritation and sensitization reactions (dermal or other effects), AEs 
due to OBDS injection and administration failure will be reported. 
p PK sampling on Day 1:  pre-dose, then 2 hours, 6 hours, and 12 hours post-dose (see Appendix 3). 
q Anti-Pertuzumab, anti-trastuzumab and anti-rHuPH20 antibodies will be measured on Day 1 pre-dose and on Days 15, 22, and 63.  Samples may also 
be taken at Follow-Up visit (see footnote a). 
r Concomitant medication will be collected from Day 1 through Day 63. 
s Intensity of adverse events will be graded according to CTCAE v5.0.  For Adverse Events for which the CTCAE does not provide a grading scale, 
a four-point scale (mild, moderate, severe and life-threatening) will be used.  All adverse events are collected from the time Informed Consent is signed 
until Day 63.  After this point only death, serious adverse events, adverse events or adverse event of special interest that are related to study drug will 
be reported until 7 month follow up. 
 


 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
87/Protocol WP42873, Version 4 
Appendix 2  
Schedule of Procedures on Day 1 (hours post-dose) 
 
Pre-dose 
Post-dose (hours) 
Procedure 
 
0 
1.5 
2 
4 
6 
9 
12 
PH FDC SC Administration 
 
x 
 
 
 
 
 
 
Device monitoring a 
 
x 
 
 
 
 
 
 
Standardized Meals 
 
 
x 
 
x 
 
x 
 
Weighing of syringe and 
needle or OBDS b 
x 
x 
 
 
 
 
 
 
Vital Signs 
x 
 
 
 
 
 
 
 
12-Lead ECG c 
x 
 
 
 
 
 
 
 
Haematology 
x 
 
 
 
 
 
 
 
Urinalysis 
x 
 
 
 
 
 
 
 
Blood Chemistry 
x 
 
 
 
 
 
 
 
Pharmacokinetic Sampling 
(pertuzumab/trastuzumab) d 
x 
 
 
x 
 
x 
 
x 
Anti-pertuzumab, 
trastuzumab and anti-
rHuPH20 Anti-bodies 
x 
 
 
 
 
 
 
 
Pain assessment injection 
site e 
x 
x 
 
x 
 
 
 
 
AE  adverse event; OBDS  on-body delivery system; PH FDC SC  fixed-dose combination of 
pertuzumab and trastuzumab for subcutaneous administration; rHuPH20  human hyaluronidase 
a Detailed device monitoring, including preparation of the skin, preparation of the OBDS, 
cartridge inspection, positioning and attachment of device at anterior thigh (before and during 
injection), drug delivery and removal of OBDS, AEs due to OBDS injection, administration 
failures 
b The syringe and needle (including cover) or OBDS (including adhesive paper) should be 
weighed prior to drug injection (when full) and after drug injection 
c The subjects should be at rest and semi-supine for at least 5 minutes before recording and 
remain resting and semi-supine during recordings. 
d When PK blood draw, vital sign assessment, ECG recording, and standard meals are 
scheduled at the same time points, the following sequence should be followed:  (1) ECG 
recording; (2) vital sign assessment; (3) PK blood sampling and (4) provide standard meal. 
e In both study arms by Visual Analog Scale 1) pre-dose, 2) during drug injection, 3) after drug 
injection while removing the device or syringe, and 4) 2 hours after drug injection. 
 


 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
88/Protocol WP42873, Version 4 
Appendix 3  
Schedule of Pharmacokinetic and Immunogenicity Samples 
Visit 
Timepointa 
Sample Type 
Day 1  
Pre-doseb 
Pertuzumab/Trastuzumab PK (serum) 
Pertuzumab/Trastuzumab ADA (serum) 
rHuPH20 ADA (plasma) 
2 hours, 6 hours, 
12 hours, post-dose 
Pertuzumab/Trastuzumab PK (serum) 
Day 2, 3, 5, 7, 9 and 11 
NA 
Pertuzumab/Trastuzumab PK (serum) 
Day 15 and 22 
NA 
Pertuzumab/Trastuzumab PK (serum) 
Pertuzumab/Trastuzumab ADA (serum) 
rHuPH20 ADA (plasma) 
Day 35 and 49  
NA 
Pertuzumab/Trastuzumab PK (serum) 
Day 63 
NA 
Pertuzumab/Trastuzumab PK (serum) 
Pertuzumab/Trastuzumab ADA (serum) 
rHuPH20 ADA (plasma) 
Follow-Upc 
NA 
Pertuzumab/Trastuzumab PK (serum) 
Pertuzumab/Trastuzumab ADA (serum) 
rHuPH20 ADA (plasma) 
ADA  anti-drug antibody; PK  pharmacokinetic; rHuPH20  human hyaluronidase. 
All samples will be taken in relation to Day 1 (the day of drug administration); therefore, Day 2 and Day 3 PK 
sampling refers to 24 and 48 hours, respectively, after study drug administration.  PK samples will have the following 
collection time windows allowed: 
 
Day 1:   10 minutes with the exception of the pre-dose sample, which must be taken before administration starts 
 
Days 2, 3, and 5 (24, 48, and 96 hours):   2 hours 
 
Days 7, 9, 11 and 15:   24 hours 
 
Days 22, 35, 49, and 63:   48 hours 
 
Follow-up visit:   10 days 
a Exact date and time of sample collection will be recorded 
b Pre-dose sample must be taken on the same day of drug administration and before administration starts. 
c Only for subjects with ongoing cardiac events (regardless of cause) or study treatment-related serious adverse 
events, adverse events, or adverse events of special interest on Day 63 or study treatment-related serious adverse 
events, adverse events, or adverse events of special interest occurring between the Day 63 visit and the follow-up 
visit 
 
 


 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
89/Protocol WP42873, Version 4 
Appendix 4  
Subcutaneous Injection Using Handheld Syringe and Needle 
The appropriate amount of PH FDC SC solution for administration should be withdrawn 
from the vial.  Refer to the pharmacy manual for instructions. 
The 27-gauge needle should be attached to the syringe and the volume adjusted to 
exactly 10 mL. 
Weigh the syringe and needle with cover using the balance specified in Section 4.3.2.  
Record the temperature of the room in the eCRF. 
Insert the needle under sterile technique into the SC space in the anterior thigh midway 
between the anterior iliac crest and the cephalad border of the patella according to the 
instructions provided below. 
 
Choose a site on one thigh.  Avoid areas such as: 
Skin folds 
Moles 
Tattooed areas 
Tender, bruised, red, or hard skin 
Scars or stretch marks 
If the subject has a skin condition such as psoriasis, try to avoid any raised, 
thick, red, or scaly skin patches or lesions 
 
The subject’s leg should be fully extended at the knee to facilitate the placement of 
the needle and remain extended during the injection. 
 
Clean the area of skin to be used for the injection with an alcohol swab.  Allow the 
alcohol to dry and without compromising sterility, slightly pinch and lift the skin of the 
thigh so that the subcutaneous space can be accessed by the needle.  To enter the 
subcutaneous space, pick up a fold of skin and insert the needle under the skin, 
parallel to the long axis of the skin fold, at approximately a 30-degree angle to the 
surface of the skin.  A uniform pinch from subject to subject is optimal. 
 
The needle should be fully inserted, being careful that the tip of the needle is deeper 
than the dermis but not as deep as the underlying muscle.  The goal of the 
placement angle and needle depth is to achieve uniform placement into every 
subject’s subcutaneous space.  The skin should be pinched, and the needle 
inserted before the skin is released and the pressure on the syringe can be applied.  
The injection should be manually pushed at a flow rate of no more than 2 mL/min. 
 
After the injection, weigh the syringe and needle with cover, using the same balance that 
was used before the injection and record the weight on the eCRF. 


 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
90/Protocol WP42873, Version 4 
Appendix 5  
Subcutaneous Injection Using On-Body Delivery system 
The injection will be performed in the anterior thigh midway between the anterior iliac 
crest and the cephalad border of the patella, while the subject is sitting down 
(semi-supine) according to the instructions provided below. 
 
Remove the PH FDC SC (PHESGO) OBDS package from the refrigerator and 
leave at room temperature for approximately 45 minutes to warm the drug and 
device to room temperature.  Do not warm the package in any other way (for 
example, do not warm it in a microwave or in hot water).  Additionally, do not leave 
the medicine exposed to direct sunlight. 
 
Check the expiration date on the carton.  Do not use it if the date has passed the 
last day of the month shown.  Do not use the product if any part of the packaging is 
damaged, missing or has been dropped on a hard surface. 
 
Wash your hands before opening the packaging. 
 
Remove the injector tray from the carton, and peel away the tray’s cover.  Do not 
use the injector if the tray cover on the plastic tray is damaged or missing.  Do not 
yet remove the adhesive paper 
 
Hook your thumb under the small plastic guard covering the injector.  Remove the 
plastic guard.  Do not use the injector if the plastic guard is damaged or missing. 
 
Remove and inspect the injector for damage.  Do not use the injector if it has been 
damaged or dropped onto a hard surface.  Retain the packaging for the return of the 
device after administration. 
 
Gently lift up and open the cartridge door.  You will hear three quick beeps, and you 
will see a flashing blue status light (see Figure 2).  This means the injector is now 
active and must be used within 30 minutes. 
 
Remove and inspect the prefilled cartridge.  Check the expiration date on the 
cartridge.  Do not use it if the date has passed the last day of the month shown. 
 
Check the PHESGO in the cartridge.  The medication should be clear and colorless 
to slightly brown.  Do not use if the PHESGO is cloudy, discolored or contains 
particles.  Do not shake the cartridge. 
 
Clean the cartridge tip with an alcohol wipe. 
 
Place the clean cartridge, tip first, into the open cartridge door area.  Close the 
cartridge door.  You will hear or feel a “click”.  This means the cartridge door is 
locked, and the injector is loaded.  Do not touch the blue start button until you have 
placed the loaded injector on the skin. 
 
Weigh the device (without removing the adhesive paper) using a balance with the 
precision specified in Section 4.3.2, and record the weight on the eCRF.  Record the 
temperature of the room in the eCRF. 
 


 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
91/Protocol WP42873, Version 4 
Choosing and Preparing an Injection Site 
 
Choose a site on one thigh (anterior thigh midway between the anterior iliac crest 
and the cephalad border of the patella). 
 
Avoid areas which would affect the performance of the device such as: 
Skin folds 
Moles 
Tattooed areas 
Hairy areas (trim/shave the site before using the device) 
Tender, bruised, red, or hard skin 
Scars or stretch marks 
If the subject has a skin condition such as psoriasis, try to avoid any raised, 
thick, red, or scaly skin patches or lesions 
 
Injecting PH FDC SC using the OBDS subcutaneously 
 
Clean an area on the skin at least 2 inches larger than the injector with an alcohol 
swab. 
 
Allow the alcohol to dry thoroughly before applying the device.  Maintain sterility 
while preparing the device to be placed on the skin. 
 
Pick up the OBDS and without touching the blue tab, completely peel away the 
adhesive paper to expose the sticky adhesive (Figure 1).  Retain the adhesive paper 
to weigh with the device after the injection. 
 
Figure 1 Preparation of the OBDS 
 
 
 
With the blue tab facing the stomach, place the injector on the cleaned injection site.  
The status light will continue to flash blue until you press the start button.  With the 
injector flat against the thigh, run a finger around the adhesive edges to secure the 
injector to the skin. 


 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
92/Protocol WP42873, Version 4 
Appendix 5  
Subcutaneous Injection Using On-Body Delivery system (cont.) 
 
Firmly press the start button until it clicks, then release.  A flashing green status light 
and three quick beeps signal the injection has started.  Make sure you see 
a continuous flashing green status light.  Once the injection has started, watch the 
PHESGO window.  The white plunger in the cartridge will begin to move in the 
window as PHESGO is injected. 
 
The injection takes about 5 to 10 minutes to complete.  Three quick beeps and 
a solid green status light signal the injection is completed. 
Removal of the OBDS 
 
When the injection is complete, grab the blue tab.  Carefully lift and remove the 
injector off the skin. 
 
Once removed, you will hear three quick beeps, and the solid green status light will 
turn off.  Use a gauze pad to wipe away fluid or apply a bandage.  Do not touch the 
orange needle guard. 
 
Check to see that the white plunger has completely filled the PHESGO window.  If 
the white plunger does not completely fill the PHESGO window, this means the 
subject may not have received the complete dose. 
 
Weigh the device together with the adhesive paper using the same balance used to 
weigh the device before the injection and record the weight on the eCRF. 
 
Place the device back into the packaging for return to the Sponsor.  Refer to the 
pharmacy manual for details. 


 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
93/Protocol WP42873, Version 4 
Appendix 6  
NYHA Functional Classification System for Heart Failure and 
LVSD NCI CTCAE Version 5.0 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; 
NYHA  New York Heart Association. 
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. 


 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
94/Protocol WP42873, Version 4 
Appendix 7 Correction Formulas for QTc Intervals 
 
Bazett’s correction for QTc Measurement - QTcB 
QTcB (msec) 
= 
QT (msec) 
1000
/)
sec
 
m
(
RR
 
 
Example: QTcB of a subject with a QT of 386 msec and a RR of 848 msec 
QT (msec) = 386 
RR (msec) = 848 
QT (msec) 
= 
419 msec 
1000
/)
sec
 
m
(
RR
 
 
Fridericia’s correction for QTc Measurement - QTcF 
QTcF (msec) 
= 
QT (ms) 
3
1000
/)
ms
(
RR
 
 
Example: QTcF of a subject with a QT of 386 msec and a RR of 848 msec 
QT (msec) = 386 
RR (msec) = 848 
QT (msec) 
= 
408 msec 
3
1000
/)
sec
 
m
(
RR
 
 


Signature Page for Protocol - WP42873 - PHESGO - v4 - Global/Core- Published
System identifier: RIM-CLIN-460873
Approval Task
Company Signatory
13-Dec-2022 12:39:15 GMT+0000

SAP_001.pdf: 
 
Official Title: 
A Randomized, Open-Label, 2-Arm, Parallel Group, Single Dose, 
Multi-Centre Study in Healthy Male Subjects to Investigate the 
Comparability of Pharmacokinetics of the Fixed-Dose Combination 
of Pertuzumab and Trastuzumab Administered Subcutaneously 
Using a Handheld Syringe or Using the on-Body Delivery System 
 
NCT Number: 
NCT05275010 
 
Document Date: 
SAP Version 3: 12-May-2023 


STATISTICAL ANALYSIS PLAN APPROVAL 
SPONSOR: 
LEGAL REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd
Grenzacherstrasse 124
4070 Basel, Switzerland
APPROVAL DATE: 
See electronic date stamp on the final page of this 
document.  
CONFIDENTIAL 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WP42873, Version 3 
STATISTICAL ANALYSIS PLAN 
STUDY TITLE: 
A RANDOMIZED, OPEN-LABEL, 2-ARM, PARALLEL 
GROUP, SINGLE DOSE, MULTI-CENTRE STUDY IN 
HEALTHY MALE SUBJECTS TO INVESTIGATE THE 
COMPARABILITY OF PHARMACOKINETICS OF THE 
FIXED-DOSE COMBINATION OF PERTUZUMAB AND 
TRASTUZUMAB ADMINISTERED 
SUBCUTANEOUSLY USING A HANDHELD SYRINGE 
OR USING THE ON-BODY DELIVERY SYSTEM 
STUDY NUMBER: 
WP42873 
VERSION NUMBER: 
3 
ROCHE 
COMPOUND(S): 
Fixed-dose combination (FDC) of pertuzumab and 
trastuzumab for subcutaneous administration 
(RO7198574) 
EUDRACT NUMBER: 
Not Applicable 
IND NUMBER: 
Not Applicable  
NCT NUMBER: 
To be determined 
PLAN PREPARED BY: 
 


 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WP42873, Version 3 
2 
STATISTICAL ANALYSIS PLAN VERSION HISTORY 
This SAP was developed based on the Roche SAP model document v2.0. 
SAP Version 
Approval Date 
Based on Protocol  
(Version, Approval Date) 
1 
24 November 2021 
v1, 27 April 2021 
2 
1 0October 2022 
v2, 21 April 2022 
3 
See electronic date stamp on 
the final page of this document. 
v4, 13 December 2022 


 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WP42873, Version 3 
3 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE 
This Statistical Analysis Plan (SAP) for Study WP42873 has been amended primarily to 
align with Protocol WP42873, Version 4.  Key changes to the SAP, along with the 
rationale(s) for each change, are summarized below. 
Section 
Description of Change 
Rationale for Change 
SAP v3 
1.1 
Combined secondary PK objectives serum 
concentration at Day 22 (CDay21), serum 
concentration at Day 63 (CDay62), (AUC0−∞), 
Observed time to maximum concentration (tmax), 
Terminal elimination half-life (t1/2), Apparent drug 
clearance (CL/F), Apparent volume of distribution 
(Vd/F) as one objective. 
The Pharmacokinetics (PK) 
analysis plan for CDay21 and 
CDay62 will be the same as the 
rest of PK parameters and no 
hypothesis test will be 
performed for these two PK 
parameters.  
4 
 
For analysis of AUC0-62 days, the PK sampling 
time window has been increased from 
 48 hours to  120 hours, so subjects with a 
Day 63 PK sample time deviation outside of 
a  120-hour window of planned sampling 
time will now be excluded.  
 
For analysis of Cmax, the number of missing 
PK samples allowed has been increased 
from 0 to 1, so now subjects with two or 
more missing PK concentration data on any 
of Days 3, 5, 7, 9, or 11 will be excluded.  
Per protocol amendment v4. 
 
Additional minor changes have been made to 
improve clarity and consistency. 
 
SAP v2 
1.2.1 
PK data removed from the list of data containing 
Treatment Assignment Information. 
 
3 
Updated to state that ‘approximately 
144 subjects’ will be enrolled instead of ‘a total of 
144 subjects.’ 
Per protocol amendment. 
4 
- 
PK analysis population further defined for 
Cmax and AUC0-62 for pertuzumab and 
trastuzumab. 
- 
Text added to allow for the possibility of PK 
non-evaluable subjects to be replaced at the 
discretion of Sponsor. 
Per protocol. 
 
Additional minor changes have been made to 
improve clarity and consistency. 
 
 


 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WP42873, Version 3 
4 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................. 8 
1.1 
Objectives and Endpoints .......................................................... 8 
1.2 
Study Design ............................................................................. 9 
1.2.1 
Treatment Assignment and Blinding ........................................ 11 
1.2.2 
Independent Review Facility .................................................... 11 
1.2.3 
Data Monitoring ....................................................................... 12 
2. 
STATISTICAL HYPOTHESES ...................................................... 12 
3. 
SAMPLE SIZE DETERMINATION ................................................ 12 
4. 
ANALYSIS POPULATIONS .......................................................... 12 
5. 
STATISTICAL ANALYSES ........................................................... 14 
5.1 
General Consideration ............................................................. 14 
5.2 
Participant Disposition ............................................................. 15 
5.3 
Primary Endpoint(s) Analysis ................................................... 15 
5.3.1 
Definition of Primary Endpoint(s) ............................................. 15 
5.3.2 
Main Analytical Approach for Primary Endpoint(s) ................... 15 
5.4 
Secondary Endpoints Analyses ............................................... 16 
5.4.1 
Pharmacokinetic Analyses ....................................................... 16 
5.4.2 
Safety Analyses ....................................................................... 16 
5.4.2.1 
Adverse Events ........................................................................ 16 
5.4.2.2 
Laboratory Data ....................................................................... 18 
5.4.2.3 
Vital Signs  ............................................................................... 18 
5.4.2.4 
ECGs ....................................................................................... 18 
5.4.2.5 
LVEF ........................................................................................ 18 
5.4.3 
Device Related Analyses  ........................................................ 18 
5.5 
Exploratory Endpoint(s) Analysis ............................................. 19 
5.5.1 
Immunogenicity Analyses  ....................................................... 19 
5.6 
Other Safety Analyses ............................................................. 20 
5.6.1 
Extent of Exposure .................................................................. 20 
5.6.2 
Adverse Events ........................................................................ 20 




 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WP42873, Version 3 
6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Description 
ADA 
anti-drug antibody  
AE 
adverse event 
AEGTs 
adverse event grouped terms 
AESI 
adverse event of special interest 
ARR 
administration related reaction 
AUC 
Area under the time−concentration curve  
BMI 
body mass index 
CHF 
congestive heart failure 
CI 
confidence interval 
CSR 
Clinical Study Report 
 
CL/F 
apparent drug clearance 
CV 
coefficient of variation 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
FDC 
Fixed dose combination 
GMR 
Geometric mean ratio 
IA 
interim analysis 
ICH 
International Council on Harmonization 
iDMC 
independent Data Monitoring Committee 
IMC 
Internal Monitoring Committee 
IRF 
Independent Review Facility 
ITT 
intent to treat 
IxRS 
interactive voice/web-based response system 
LLoQ 
lower limit of quantification 
LVEF 
Left Ventricular Ejection Fraction 
LVSD 
Left Ventricular Systolic Dysfunction 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NYHA 
New York Heart Association 
OBDS 
on-body delivery system 
OBI 
on-body injector 
PFS 
progression-free survival 
PRO 
patient-reported outcomes 
PT 
preferred term 
PD 
pharmacodynamic 


 
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PK 
pharmacokinetic 
rHuPH20 
recombinant human PH20 hyaluronidase 
SAE 
serious adverse events 
SAP 
Statistical Analysis Plan 
SMQs 
standardized MedDRA queries 
SC 
Subcutaneous 
VAS 
Visual Analog Scale; 
Vd/F 
apparent volume of distribution 
 
 


 
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1. 
INTRODUCTION 
Study WP42873 is a Phase I, single dose, multi-center study to investigate the 
comparability of pharmacokinetics of the fixed-dose combination (FDC) of pertuzumab 
and trastuzumab administered subcutaneously in healthy male subjects using a 
handheld syringe or using the on-body delivery system (OBDS), also referred to as on-
body injector (OBI). The terminology OBDS will be used in the Statistical Analysis Plan 
(SAP), this will be referred to as OBI in the outputs. 
This SAP provides details of the planned analyses and statistical methods for Study 
WP42873. For detailed background information on the study, refer to the Study 
WP42873 protocol. 
1.1 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the pharmacokinetics and safety of the FDC of pertuzumab and 
trastuzumab for subcutaneous administration (PH FDC SC) given by the OBDS 
compared to hypodermic needle and syringe in healthy male subjects. Specific 
objectives and corresponding endpoints for the study are outlined below. 
Table 1 
Objectives and Corresponding Endpoints 
Primary Objectives 
Corresponding Endpoints 
 
To demonstrate comparability of single-
dose area under the time-concentration 
curve from the start of dosing to 63 days 
(AUC0→62days ) and maximum serum 
concentration (Cmax ) for pertuzumab and 
trastuzumab within PH FDC SC, 
administered either by the OBDS or by a 
handheld syringe with hypodermic needle  
 
serum pertuzumab AUC0→62days and Cmax  
 
serum trastuzumab AUC0→62days and 
Cmax  
Secondary Objectives 
Corresponding Endpoints 
 
To further characterize additional PK 
parameters for pertuzumab and 
trastuzumab within PH FDC SC, 
administered either by the OBDS or by a 
handheld syringe with hypodermic needle  
 
serum concentration at Day 22 (CDay21) 
 
serum concentration at Day 63 (CDay62) 
 
Area under the time-concentration curve 
from the start of dosing extrapolated to 
infinity (AUC0−∞) 
 
Observed time to maximum 
concentration (tmax) 
 
Terminal elimination half-life (t1/2) 
 
Apparent drug clearance (CL/F) 
 
Apparent volume of distribution (Vd/F) 
 
 
 


 
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Table 1 
Objectives and Corresponding Endpoints (cont.) 
Safety Objectives 
Corresponding Endpoints 
 
To demonstrate comparable safety and 
tolerability of PH FDC SC administered by 
either the OBDS or by a handheld syringe 
with hypodermic needle 
 
Incidence and severity of adverse 
events, with severity determined 
according to the NCI CTCAE v 5.0 
 
Change from baseline in vital signs, 
LVEF, and ECG parameters 
 
Change from baseline in clinical 
laboratory test results 
 
To demonstrate the safety of the OBDS 
 
Pain at the injection site assessed by 
the subject using the 100 mm VAS 
 
Skin irritation and sensitization reactions 
at the site of injection assessed by the 
study staff using the device monitoring 
questionnaire in the eCRF 
Device Monitoring Objectives 
Corresponding Endpoints 
 
To demonstrate the performance of the 
OBDS 
 
Comfort of wearing the device, as 
reported by the subject using the device 
monitoring questionnaire 
 
Details of performance and ease of use 
of the OBDS reported by site staff, using 
the device monitoring questionnaire in 
the eCRF 
Exploratory Objectives 
Exploratory Endpoints 
 
To evaluate the immune response to 
pertuzumab, trastuzumab, and rHuPH20 
within the PH FDC SC, administered using 
an OBDS compared to a hand-held 
syringe with hypodermic needle 
 
Incidence of pertuzumab ADAs during 
the study relative to the prevalence of 
ADAs at baseline 
 
Incidence of trastuzumab ADAs during 
the study relative to the prevalence of 
ADAs at baseline 
 
Incidence of rHuPH20 ADAs during the 
study relative to the prevalence of ADAs 
at baseline 
ADA  anti-drug antibody; AUC0→62days   area under the time−concentration curve from the start 
of dosing to Day 63; AUC0−∞   area under the time–concentration curve from the start of dosing 
extrapolated to infinity; CDay21   serum concentration on Day 22; CDay62  serum concentration on 
Day 63; CL/F  apparent drug clearance; Cmax  maximum concentration; eCRF  electronic 
Case Report Form; LVEF  Left Ventricular Ejection Fraction; NCI CTCAE  National Cancer 
Institute Common Terminology Criteria for Adverse Events; OBDS  on-body delivery system; 
PH FDC SC  fixed-dose combination of pertuzumab and trastuzumab for subcutaneous 
administration; PK  pharmacokinetic; rHuPH20  recombinant human PH20 hyaluronidase; 
tmax  observed time to maximum concentration; t1/2  terminal elimination half-life; VAS  Visual 
Analog Scale; Vd/F  apparent volume of distribution. 
 
1.2 
STUDY DESIGN 
Study WP42873 is a randomized, open-label, 2-arm, parallel-group, single-dose, 
multi-center study in healthy male subjects to investigate the comparability of PK of 


 
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pertuzumab and trastuzumab within the PH FDC SC administered using the proprietary 
OBDS or a handheld syringe with hypodermic needle. The study will be conducted at 
two clinical research facilities in New Zealand. 
The study schema is shown in Figure 1. 
Figure 1 Study Schema  
 
Approximately 144 male subjects will be randomized to one of two dosing arms in a 1:1 
ratio to receive a single dose of PH FDC SC (600 mg pertuzumab/600 mg trastuzumab) 
administered by a healthcare professional subcutaneously into the anterior thigh using 
either the OBDS or a handheld syringe with hypodermic needle. The randomization will 
be stratified by weight ( 75 kg,  75 kg) at Day−1. 
 
Arm 1: PH FDC SC administered using a handheld syringe with hypodermic needle.  
 
Arm 2: PH FDC SC administered using the OBDS. 
 
During the study period subjects will be admitted to the clinical research unit on Day 1 
and the study drug will be given on the morning of Day 1. The subjects will be 
discharged after the assessments are performed on Day 2. 
Subjects will be followed according to the Schedule of Activities from Day 1 
(Appendix 2). The total duration of the study for each subject will be a maximum of 
35 weeks. 
 
Screening:  Up to 4 weeks 
 
Study period:  Day  1 to Day 63, including in-clinic period from Day 1 to Day 2 
 
Safety Follow-up:  Day 64 to Month 7 
 
The end of the study is defined as the date when the last subject, last visit occurs. This 
is expected to occur 7 months after the last subject is enrolled (i.e., when the last 
subject has completed the safety follow-up visit at 7 months after administration of 
study drug). 
The length of study will be a maximum of 35 weeks per subject, from screening to 
follow-up (4 weeks screening, plus 7 months [~31 weeks] follow-up after dose). The total 


 
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length of the study from screening of the first subject to the end of the study is expected 
to be approximately 11 months. 
Endpoints and objectives are listed in Section 1.1. For additional details, see the 
schedule of activities in Appendix 2. 
The analysis of primary, secondary, and exploratory endpoints will be performed after all 
subjects have completed the Day 63 assessments. A follow-up analysis for safety will be 
performed once all subjects have completed the 7-month follow-up visit. 
1.2.1 
Treatment Assignment and Blinding 
After initial written informed consent has been obtained, all screening procedures and 
assessments have been completed, and eligibility has been established for a subject, 
the study site will obtain the subject's identification number and treatment assignment 
from an interactive voice or web-based response system (IxRS). 
Male subjects will be randomly assigned to one of two drug administration arms to 
receive a single dose of PH FDC SC (600 mg pertuzumab/600 mg trastuzumab/ 
20,000U rHuPH20) administered either using the OBDS or handheld syringe and 
needle. Randomization will occur in a 1:1 ratio through use of a permuted-block 
randomization method to ensure a balanced assignment to each treatment arm. 
Randomization will be stratified by weight ( 75 kg,  75 kg) at Day 1. 
A subject may only be randomized once in this trial. Subjects randomized into the study 
will not be replaced. Subjects who choose to withdraw after screening but before 
randomization will be replaced. PK non-evaluable subjects may be replaced at the 
discretion of the Sponsor, as specified in Section 4. 
Review of dummy randomization lists along with User Acceptance Testing (UAT) within 
the IxRS system will be performed to ensure the randomization procedure is set up and 
performed correctly. 
For additional details of administration of PH FDC SC using the OBDS or handheld 
syringe and needle, see the Study WP42873 protocol.  
The Study Management Team is, by definition, unblinded given the open-label nature of 
this study. However, to further protect the integrity of the study, any treatment 
assignment information, such as the randomization file from the IxRS, will be withheld 
from the Sponsor until the primary analysis.  
1.2.2 
Independent Review Facility 
Given the nature of the study and objective, the Independent Review Facility (IRF) or 
Reading Center is not applicable. 


 
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1.2.3 
Data Monitoring 
Given the nature of study design and shorter study duration, no independent Data 
Monitoring Committee (iDMC)/Internal Monitoring Committee (IMC) is used to monitor 
the safety data during the study. Review of data for safety purposes will not be reviewed 
at an aggregate level prior to the primary analysis. 
2. 
STATISTICAL HYPOTHESES 
The hypothesis to be tested for the co-primary endpoints, observed pertuzumab and 
trastuzumab AUC0→62days and Cmax is: 
 
H0:  the administration by OBDS is not bioequivalent to the administration by the 
handheld syringe with hypodermic needle (i.e., the GMR is not within the standard 
bioequivalence margins [0.8; 1.25]), versus 
 
H1:  the administration by OBDS is bioequivalent to the administration by the 
handheld syringe with hypodermic needle (i.e., the GMR is within the standard 
bioequivalence margins [0.8; 1.25]) 
 
3. 
SAMPLE SIZE DETERMINATION 
Approximately 144 subjects will be enrolled, taking into account an assumed drop-out 
rate of 10%. A total of 130 healthy subjects with fully evaluable pharmacokinetic profiles 
are required to demonstrate comparability of AUC0→62days and Cmax values between the 
handheld syringe injection administration (reference) and the OBDS (test) with 80% 
power at 5% significance level, assuming a between-subject coefficient of variation (CV) 
of 40% and ‘test’ to ‘reference’ ratio of 0.95. Standard bioequivalence ranges of 0.8 and 
1.25 are used to demonstrate comparability of AUC0→62days and Cmax values for 
pertuzumab and trastuzumab administered as PH FDC SC, either by the OBDS or by 
handheld syringe. 
4. 
ANALYSIS POPULATIONS 
The primary and secondary PK endpoints analysis will be performed using a per protocol 
PK population which would include all subjects randomized and adherent to the pre-
specified protocol criteria specified later in this section.  


 
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The following populations are defined: 
Population 
Definition 
ITT (intent to treat) 
All randomized participants, independent of whether the 
participant received the assigned treatment. 
Safety-evaluable 
All randomized participants who received at least one dose of 
study treatment. 
PK analysis (PAP) 
A per protocol PK analysis population (PAP) which would include 
all randomized participants who were treated and adhered to the 
*pre-specified protocol criteria (listed separately below i, ii, iii).  
PPAP1 (Per protocol PK 
analysis population for 
pertuzumab AUC0→62) 
This population is a subset of PAP.  
For the analysis of AUC0→62days, subjects from PAP with missing 
Day 63 PK pertuzumab concentration data or with a Day 63 PK 
sample time deviation outside a  120-hour window of planned 
sampling time will be excluded. 
PPAP2 (Per protocol PK 
analysis population for 
pertuzumab Cmax) 
This population is a subset of PAP. 
For analysis of Cmax, subjects from PAP with two or more missing 
PK pertuzumab concentration data on any of Days 3, 5, 7, 9 or 11 
will be excluded.  
 TPAP1 (Per protocol PK 
analysis population for 
trastuzumab AUC0→62) 
This population is a subset of PAP. 
For analysis of AUC0→62days, subjects from PAP with missing 
Day 63 PK trastuzumab concentration data or with a Day 63 PK 
sample time deviation outside a  120-hour window of planned 
sampling time will be excluded. 
TPAP2 (Per protocol PK 
analysis population for 
trastuzumab Cmax) 
This population is a subset of PAP.  
For analysis of Cmax, subjects from PAP with two or more missing 
PK trastuzumab concentration data on any of Days 3, 5, 7, 9 or 11 
will be excluded. 
Immunogenicity analysis  
The immunogenicity analysis population will consist of all 
participants with at least one ADA assessment. 
ITT  intent to treat, PK  pharmacokinetic.  
*List of pre specified protocol criteria is listed below. Participants will be excluded from 
the Per Protocol Pharmacokinetic Population (PAP) for the following reasons: 
1. 
The subject violates the following inclusion or exclusion criteria: 
 
A body mass index (BMI) between 18 and 32 kg/m2, inclusive 
 
Use of prohibited medications including non-prescription medications, 
nutraceuticals, nutritional supplements or any herbal remedies taken within 10 
days or 5 times the elimination half-life (whichever is longer) prior to 
randomization into the study 
 
Concomitant subcutaneous, intravenous, or any parenteral drugs within 90 
days prior to screening 
 
Participation in an investigational drug or device study within 90 days or 5 times 
the elimination half-life (whichever is longer) prior to screening 


 
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 
Current chronic daily treatment (continuous for >3 months) with corticosteroids 
(dose ≥10 mg/day methylprednisolone), excluding inhaled corticosteroids 
 
Receipt of IV antibiotics for infection within 7 days prior to enrollment into the 
study 
2. 
A subcutaneous injection site other than thigh is used 
3. 
Any subject whose injection is not successfully performed (see the 
Study WP42873 protocol, Appendices 4 and 5) will be considered as non-
evaluable for the PK analysis; however, all data including PK and ADA samples will 
be collected 
 
Subjects who deviate significantly from the PK collection schedule, as defined in 
PPAP1, PPAP2, TPAP1, and TPAP2 are therefore PK non-evaluable, will be replaced 
at the discretion of the Sponsor.  
5. 
STATISTICAL ANALYSES 
The primary analysis of primary and secondary endpoints will be performed after all 
subjects have completed the Day 63 assessments. In addition to safety analysis at the 
time of primary analysis a follow-up analysis for safety will be performed once all 
subjects have completed the 7-month follow-up visit. 
5.1 
GENERAL CONSIDERATION 
All primary and secondary PK endpoints analyses will be performed in one of the pre-
defined per protocol PK analysis population (defined in section 4), unless otherwise 
specified. Participants will be assigned to treatment groups according to the treatment 
they actually received. 
Exclusion of subjects from the per protocol PK analysis population will be documented 
together with the reason for exclusion. All decisions on exclusions from the analysis will 
be made prior to database closure. 
All safety analyses will be performed in the safety-evaluable population, unless 
otherwise specified. Participants will be assigned to treatment groups according to the 
treatment they actually received. 
The evaluation of comparability between the arms will include summaries of 
demographic and baseline characteristics, medical history demographics, medical 
history, concomitant medication and a summary of the randomization stratification 
factors will be done based on the ITT population. Participants will be assigned to 
treatment groups as randomized by the IxRS. Listing of randomization assignments at 
IxRS will be generated. Continuous variables will be summarized using means, standard 
deviations, medians and ranges. Categorical variables will be summarized by counts 
and proportions. Summaries will be presented by treatment groups. 


 
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5.2 
PARTICIPANT DISPOSITION 
The number of participants who enroll, discontinue, or complete the study will be 
summarized. Reasons for premature discontinuation will be listed and summarized. 
Enrollment and major protocol deviations will be evaluated for their potential effects on 
the interpretation of study results. 
5.3 
PRIMARY ENDPOINT(S) ANALYSIS 
The co-primary endpoints of this study are single-dose AUC0→62days and Cmax values for 
both pertuzumab and trastuzumab either after administration of PH FDC SC using the 
handheld syringe with hypodermic needle or using the OBDS. 
The analysis will be performed using one of the pre-defined per protocol PK analysis 
population (PPAP1, PPAP2, TPAP1, TPAP2). Subjects will be excluded from the 
pharmacokinetic analysis population as per the specified criteria listed in section 4.  
5.3.1 
Definition of Primary Endpoint(s) 
To demonstrate comparability single-dose area under the time−concentration curve from 
the start of dosing to 63 days AUC(0→62days) and maximum serum concentration (Cmax) for 
pertuzumab and trastuzumab within PH FDC SC, administered either by the OBDS or by 
a handheld syringe with hypodermic needle, on the basis of the following co-primary 
endpoints: 
 
serum pertuzumab AUC0→62days and Cmax  
 
serum trastuzumab AUC0→62days and Cmax 
 
5.3.2 
Main Analytical Approach for Primary Endpoint(s) 
The bioequivalence of the two administration methods will be assessed by a two one-
sided testing procedure. The GMR of the administration by the OBDS relative to the 
administration by handheld syringe will be estimated together with the two-sided 90% CI 
based on the log-transformed AUC0→62days and Cmax values. 
The null hypothesis will be rejected and bioequivalence will be concluded if the bounds 
of the 90% CI of the geometric mean ratio of AUC0-62days and Cmax values for pertuzumab 
and trastuzumab administration by the OBDS relative to the administration by the 
handheld syringe with hypodermic needle are entirely contained within the standard 
bioequivalence margins (0.8; 1.25) for all co-primary endpoints. Comparability between 
the two methods will be concluded only if bioequivalence is established for both 
pertuzumab and trastuzumab AUC0→62days and Cmax. 
The GMR together with the two-sided 90% CI will be estimated using analysis of 
variance method with log-transformed AUC0→62days and Cmax values as the dependent 
variables and treatment arm as a covariate for pertuzumab and trastuzumab. 


 
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Serum concentrations of pertuzumab and trastuzumab at each sampling time point will 
be presented by listings. Serum concentration plots over the time for pertuzumab and 
trastuzumab will be generated. Summary statistics of PK parameter values including 
means, geometric means, medians, ranges, standard deviations and coefficients of 
variations will be presented. All excluded subjects will be presented by listings with the 
reason for exclusion. 
5.4 
SECONDARY ENDPOINTS ANALYSES 
The secondary pharmacokinetic, safety and device-related endpoints are detailed in 
Section 1.1. 
5.4.1 
Pharmacokinetic Analyses 
PK parameters including CDay21, CDay62,  AUC0−∞, t1/2, CL/F, and Vd/F will be analyzed on 
pre-defined per protocol PK population for pertuzumab AUC (0−62) (PPAP1) and 
trastuzumab AUC (0−62)) (TPAP1).  tmax will be analyzed on the pre-defined per protocol 
PK population for pertuzumab Cmax  (PPAP2) and trastuzumab Cmax (TPAP2). All 
secondary pharmacokinetic parameter values will be presented by listings and 
descriptive summary statistics (such as mean, median, min, max, standard 
deviation, %CV) separately by treatment groups. Subjects will be analyzed according to 
the treatment received. 
5.4.2 
Safety Analyses 
The safety analysis population will include all subjects who have received all or part of 
the single dose of study medication, with subjects grouped according to method of 
administration of study medication. After initiation of study drug, all adverse events will 
be reported until Day 63 after the dose of study drug. After this point only death, serious 
adverse events, adverse events, or adverse events of special interest that are related to 
study drug will be reported until 7 months follow up. 
Safety will be assessed using reporting of adverse events, severity of adverse events, 
changes in clinical laboratory test results, including vital signs, LVEF, electrocardiograms 
and echocardiography. As appropriate, listings, summary tables and graphs (subject 
plots and/or mean plots) will be provided for the safety assessments, using descriptive 
statistics.  
5.4.2.1 
Adverse Events 
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded 
according to NCI CTCAE Version 5.0. For adverse events for which the CTCAE v5.0 
does not provide a grading scale, the standard four-point scale (mild, moderate, severe, 
life-threatening) will be used.  
All adverse events, serious adverse events, adverse events leading to death, adverse 
events of special interest, and adverse events leading to study treatment discontinuation 


 
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that occur on or after the first dose of study treatment (i.e., treatment-emergent adverse 
events) 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. 
Deaths and cause of death will be summarized.  
Adverse events due to the OBDS itself will be summarized separately. 
Additionally, for this study the following will be used to characterize cardiac adverse 
events and will be summarized by mapped term, appropriate thesaurus level, and 
severity grade as appropriate. 
Investigator-assessed cardiac adverse event, based on: 
 
LVEF using preferred term ‘Ejection fraction decreased’ 
 
Heart failure/CHF (symptomatic LVSD) Preferred term ‘Heart failure’ 
 
Standardized MedDRA Queries (SMQs) are used when available because this 
constitutes a globally recognized and consistent set of preferred terms (PTs) by 
regulatory authorities. Where no SMQs are available baskets of Roche Standard 
MedDRA Adverse Event Grouped Terms (AEGTs) will be used. 
For this study the following will be used to characterize reactions related to the 
administration of study drug(s) and will be summarized by mapped term, appropriate 
thesaurus level, and severity grade as appropriate. 
Investigator-assessed Administration Related Reactions (ARRs), including: 
 
Injection-related reactions (Systemic), defined as any systemic reaction in response 
to the SC injection of study drug 
 
Injection-site reactions (Local), defined as any local morphological or physiological 
change at or near the SC injection site 
 
Additionally, ARRs potentially associated with SC administration of study drug(s), 
defined as adverse events in the SMQ “Anaphylactic Reaction (wide)”, Roche Standard 
AEGT “Anaphylaxis and Hypersensitivity” and “Infusion-Related Reactions and 
Hypersensitivity”, or the dictionary-derived term “Cytokine Release Syndrome” occurring 
during injection or within 24 hours of the end of administration, should be assessed as to 
whether considered related or unrelated to study drug by the investigator (see the 
Study WP42873 protocol for additional information about ARRs).  
Standard Perjeta SMQ search criteria will be used to summarize adverse events to 
monitor (includes ARRs, hypersensitivity and anaphylaxis, diarrhoea, rash, neutropenia 
or febrile neutropenia, mucositis, interstitial lung disease, and reproductive risks) by 
treatment regimen. 


 
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5.4.2.2 
Laboratory Data 
Clinical laboratory tests will be performed at local laboratories. Laboratory abnormalities 
will be defined based on local laboratory normal ranges and NCI CTCAE Version 5.0. 
Relevant laboratory parameters and change from baseline will be displayed by time. 
Roche Standard Reference Ranges will be implemented before any data is summarized 
for reporting and analysis. 
5.4.2.3 
Vital Signs  
Vital signs (including systolic and diastolic blood pressure, pulse rate, and body 
temperature) will be summarized by time. Changes from baseline will also be 
summarized. The mean, standard deviation, median, minimum, and maximum values 
will be presented by treatment groups.  
5.4.2.4 
ECGs 
ECG data will be displayed by time, with abnormality identified where appropriate. 
Changes from baseline in ECG will be also listed. Summary of ECG abnormality will be 
displayed by count and proportion. 
5.4.2.5 
LVEF 
LVEF (%) descriptive summary (mean, standard deviation, median, and minimum and 
maximum values) will be displayed and changes in LVEF will be also summarized by 
treatment groups.  
5.4.3 
Device Related Analyses  
Details of the performance and ease of use of the OBDS will be collected and recorded 
on the eCRF. This will include:  
 
Preparation of the injection site  
 
Preparation of the OBDS 
 
Assessment of skin irritation and sensitization reactions (dermal or other effects) 
before and after injection  
 
Prefilled cartridge inspection before insertion in the OBDS  
 
Positioning and attachment of the OBDS on the anterior thigh  
 
Drug delivery  
 
Removal of the OBDS  
 
OBDS administration failures  
 
Ease of OBDS attachment, attachment during the injection, ease of OBDS removal, 
overall wearing comfort, and overall clarity of handling instructions will each be rated on 
a three-point scale as “good”, “acceptable”, or “poor.” Summaries of device assessment 
will be summarized by counts and proportions. Appropriate listings will be produced. 


 
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Skin irritation and sensitization reactions to the OBDS will be assessed on a scale 
between 0 to 7 using the Device (OBDS) Monitoring Assessment eCRF page in two 
sub-categories:  1) dermal effects and 2) other effects. Summaries of device monitoring 
assessments will be listed for both sub-categories. 
Injection site preparation, injection device preparation, body positioning of the device 
compliance, cartridge inspection (before, during, and after injection), issues with the 
attachment of the device to the body, any device failure, needle insertion, and other 
device usage will be summarized by counts and proportions for OBDS. Appropriate 
listings will be generated. 
Comparability of evaluation of pain assessment in the syringe and the OBDS group will 
include descriptive summaries and listings. Pain intensity scores will be assessed using 
the Visual Analog Scale (VAS) on a line measuring between 0mm (“no pain”) and 
100mm (“unbearable pain”). Pain will be assessed at baseline prior to injection, during 
injection, immediately post-injection while removing the injection material and 2h after 
injection. 
5.5 
EXPLORATORY ENDPOINT(S) ANALYSIS 
The exploratory Immunogenicity endpoints are detailed in Section 1.1. 
5.5.1 
Immunogenicity Analyses  
The immunogenicity analysis population will consist of all subjects with at least one 
ADA assessment. Subjects will be grouped according to treatment received or, if no 
treatment is received prior to study discontinuation, according to treatment assigned. 
The analysis will be done for anti-pertuzumab antibodies, anti-trastuzumab antibodies, 
and anti-rHuPH20 antibodies. Listings will also be generated as appropriate.  
The numbers and proportions of ADA-positive subjects and ADA-negative subjects at 
baseline (baseline prevalence) and after drug administration (post-baseline incidence) 
will be summarized by treatment group. When determining post-baseline incidence, 
subjects are considered to be ADA positive if they are ADA negative or have missing 
data at baseline and develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more post-baseline samples is at least 0.60 titer unit greater than the titer of 
the baseline sample (treatment-enhanced ADA response). Subjects are considered to 
be ADA negative if they are ADA negative or have missing data at baseline and all 
post-baseline samples are negative, or if they are ADA positive at baseline but do not 
have any post-baseline samples with a titer that is at least 0.60 titer unit greater than the 
titer of the baseline sample (treatment unaffected).  
The relationship between ADA status and safety, and PK endpoints will be analyzed and 
reported via descriptive statistics (as data allow).  


 
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5.6 
OTHER SAFETY ANALYSES 
The safety analysis population will include all subjects who have received all or part of 
the single dose of study medication, with subjects grouped according to method of 
administration of study medication. 
5.6.1 
Extent of Exposure 
Study treatment exposure (such as total dose received) will be summarized with 
descriptive statistics. Actual dose delivered will be calculated based on the weight 
difference of the syringe or OBDS before and after administration. 
5.6.2 
Adverse Events 
Adverse events to monitor, cardiac adverse events and administration-related reactions 
will be summarized separately. 
5.6.3 
Concomitant Medications 
All concomitant medications will be summarized by treatment groups. 
5.7 
OTHER ANALYSES 
5.7.1 
Optional Sensitivity Analyses 
An optional sensitivity analysis will be performed for bioequivalence establishment of the 
two methods for both pertuzumab and trastuzumab AUC0→62days and Cmax by including 
the baseline weight ( 75 kg,  75 kg). The GMR together with the two-sided 90% CI will 
be estimated using analysis of variance method with log-transformed AUC0→62days and 
Cmax values as the dependent variables and treatment arm, weight as a covariates for 
pertuzumab and trastuzumab. 
5.8 
INTERIM ANALYSES  
No Interim analysis is planned. 


 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WP42873, Version 3 
29 
6. 
REFERENCES 
1) International Conference on Harmonization, 1998. Statistical Principles for 
Clinical Trials - ICH Harmonised Tripartite Guideline. Guidance for Industry, E9, 
FDA federal register. 1998;63:p49583. Available at: 
http://www.fda.govieder/guidance .  
2) U.S. Department of Health and Human Services Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER). Statistical Approaches to 
Establishing Bioequivalence. 2001.  Available at: 
https://www.fda.gov/media/70958/download . 


 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WP42873, Version 3 
21 
Appendix 1  
Changes to Protocol-Planned Analyses 
No change from the protocol planned analysis.


Appendix 2  
Schedule of Activities 
 
Screening and 
Baseline a 
Study Period 
Follow-
up a 
Day 
(Window) 
D –28 to 
D 2 
D –1 
D1 
D2 
D3 
D5 
D7 
D9 
D11 
D15 
D20 D22 
D35 
D49 
D56 
D63 
Month 
7 
Informed consent 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination b 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Randomization c 
 
x c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs d 
x 
x 
x 
x 
 
 
x 
 
 
 
 
x 
 
 
 
x 
 
12-Lead ECG e 
x 
x 
x 
x 
 
 
x 
 
 
 
 
x 
 
 
 
x 
 
LVEF f 
x 
 
 
 
 
 
 
 
 
 
x f 
 
x f 
 
Hematology g 
x 
x 
x 
x 
 
 
x 
 
 
 
 
x 
 
 
 
x 
 
Blood Chemistry h 
x 
x 
x 
x 
 
 
x 
 
 
 
 
x 
 
 
 
x 
 
Urinalysis i 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Serology j 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Test k 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drugs of Abuse l 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 2: Schedule of Activities (cont.) 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd Statistical Analysis Plan WP42873, Version 3
 
23 
 
Screening and 
Baseline a 
Study Period 
Follow-up a 
Day 
(Window) 
D –28 to 
D 2 
D –1 
D1 
D2 
D3 
D5 
D7 
D9 
D11 
D15 D20 D22 
D35 
D49 D56 
D63 
Month 7 
Standardized Meal  
 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
PH FDC SC 
administration m 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pain assessment 
injection site n 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Device monitoring o 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK sampling 
(pertuzumab/ 
trastuzumab)  
 
 
x p 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
Pertuzumab/Trastuzumab 
/rHuPH20 ADA (Plasma 
and serum) q 
 
 
x 
 
 
 
 
 
 
x 
 
x 
 
 
 
x 
x 
Pregnancy follow-up of 
female partner 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Concomitant 
medications r 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Adverse Events s 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Overnight stay 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 2: Schedule of Activities (cont.) 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd Statistical Analysis Plan WP42873, Version 3
 
24 
ADA  anti-drug antibody; CTCAE v5.0  Common Toxicity Criteria for Adverse Events; D  day; ECG  electrocardiogram; LVEF  left ventricular 
ejection fraction; OBDS PH FDC SC  600mg pertuzumab/600mg trastuzumab; PK  pharmacokinetic; RBC  erythrocyte (count); rHuPH20  human 
hyaluronidase; WBC  total leukocyte (count). 
a 7 months ( 10 days) after the subject received their dose of PH FDC SC.  1 month  30 days.  For subjects with ongoing cardiac events 
(regardless of cause) or study treatment-related serious adverse events, adverse events, or adverse events of special interest on Day 63 or 
study treatment-related serious adverse events, adverse events, or adverse events of special interest occurring between the Day 63 visit and the 
follow-up visit, subjects should attend the clinic for the follow-up visit and PK/ADA sample collection.  For subjects with no cardiac events 
(regardless of cause) or study treatment-related serious adverse events, adverse events, or adverse events of special interest ongoing at Day 63 
and none occurring between Day 63 visit and the follow-up visit, only the pregnancy follow-up of female partners is required, and this visit may 
be performed by phone call. 
b A complete physical examination will be performed at screening (including height and weight), on Day 1(day before dosing), and on Day 63, 
height will be recorded only at screening. 
c Randomization either Day 1 or Day1. 
d Body temperature (oral or aural) will be collected at screening, Day 1 (day of dosing), and Day 63 and as indicated for follow up for AE.  Blood 
pressure, respiration rate, and pulse rate will be taken at screening, on Days 1, 1, 2, 7, 22, and 63.  All measurements to be taken after the 
subject has rested in a semi-supine position for at least 5 minutes. 
e All ECG measurements in triplicate. 
f LVEF will be measured by echocardiography on three occasions:  at screening, between Days 20 and 35, and between Days 56 and 63. 
g Hematology:  hemoglobin, hematocrit, erythrocytes (RBC), platelets, total leukocytes (WBC), and WBC differential count. 
h Blood chemistry:  AST, ALT, total bilirubin, alkaline phosphatase, albumin, creatinine, urea, total protein, sodium, chloride, potassium, 
calcium, phosphate, glucose. 
i Urinalysis:  a midstream, clean-catch urine specimen will be collected for dipstick analysis of protein, blood, glucose, and pH.  If there is a 
clinically significant positive blood and/or protein result, urine will be sent to the laboratory for microscopy and culture. 
j Serology:  HIV-1 and -2, Hepatitis B and C. 
k Alcohol test:  either breath test or urine test. 
l Drugs of abuse:  according to local standards including cannabinoids, amphetamines, opiates, methadone, cocaine, benzodiazepines and 
barbiturates. 
m The OBDS (with cartridge inserted and along with adhesive paper) and the handheld syringe (including needle and cover) will be weighed before 
and after the injection to measure the amount of study drug administered.  The injection must be given in the anterior thigh midway between the 
anterior iliac crest and the cephalad border of the patella while the subject is in a semi-supine position.  Study drug should not be injected into 
moles, scars, or bruises or tattooed areas.  The duration of the injection in minutes and seconds will be recorded. 
n Intensity of injection site pain will be assessed in both study arms using a 100 mm Visual Analog Scale at the following time points:  1) on Day 1 
pre-dose, 2) during drug injection, 3) after drug injection while removing the device or syringe, and 4) 2 hours after drug injection. 


Appendix 2: Schedule of Activities (cont.) 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd Statistical Analysis Plan WP42873, Version 3
 
25 
o Detailed OBDS monitoring including preparation of the injection site, preparation of the OBDS, prefilled cartridge inspection, positioning and 
attachment of device at anterior thigh, drug delivery and removal of OBDS, assessment of skin irritation and sensitization reactions (dermal or 
other effects), AEs due to OBDS injection and administration failure will be reported. 
p PK sampling on Day 1:  pre-dose, then 2 hours, 6 hours, and 12 hours post-dose (see Appendix 3). 
q Anti-pertuzumab, anti-trastuzumab and anti-rHuPH20 antibodies will be measured on Day 1 pre-dose and on Days 15, 22, and 63.  Samples 
may also be taken at Follow-Up visit (see footnote a). 
r Concomitant medication will be collected from Day 1 through Day 63. 
s Intensity of adverse events will be graded according to NCI CTCAE v5.0.  For Adverse Events for which the CTCAE does not provide a grading 
scale, a four-point scale (mild, moderate, severe, and life-threatening) will be used.  All adverse events are collected from the time Informed 
Consent is signed until Day 63.  After this point only death, serious adverse events, adverse events, or adverse event of special interest that are 
related to study drug will be reported until 7 month follow up. 


 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WP42873, Version 3 
26 
Appendix 3  
Schedule of Pharmacokinetic and Immunogenicity Samples 
Visit 
Timepointa 
Sample Type 
Day 1  
Pre-doseb 
Pertuzumab/Trastuzumab PK (serum) 
Pertuzumab/Trastuzumab ADA (serum) 
rHuPH20 ADA (plasma) 
2 hours, 6 hours, 
12 hours, post-dose 
Pertuzumab/Trastuzumab PK (serum) 
Day 2, 3, 5, 7, 9 and 11 
NA 
Pertuzumab/Trastuzumab PK (serum) 
Day 15 and 22 
NA 
Pertuzumab/Trastuzumab PK (serum) 
Pertuzumab/Trastuzumab ADA (serum) 
rHuPH20 ADA (plasma) 
Day 35 and 49  
NA 
Pertuzumab/Trastuzumab PK (serum) 
Day 63 
NA 
Pertuzumab/Trastuzumab PK (serum) 
Pertuzumab/Trastuzumab ADA (serum) 
rHuPH20 ADA (plasma) 
Follow-Upc 
NA 
Pertuzumab/Trastuzumab PK (serum) 
Pertuzumab/Trastuzumab ADA (serum) 
rHuPH20 ADA (plasma) 
ADA  anti-drug antibody; PK  pharmacokinetic; rHuPH20  human hyaluronidase. 
Notes:  All samples will be taken in relation to Day 1 (the day of drug administration); therefore, Day 2 
and Day 3 PK sampling refers to 24 and 48 hours, respectively, after study drug administration. PK 
samples will have the following collection time windows allowed: 
 
Day 1:   10 minutes with the exception of the pre-dose sample, which must be taken before 
administration starts 
 
Days 2, 3, and 5 (24, 48, and 96 hours):   2 hours 
 
Days 7, 9, 11 and 15:   24 hours 
 
Days 22, 35, 49, and 63:   48 hours 
 
Follow-up visit:   10 days 
a Exact date and time of sample collection will be recorded. 
b Pre-dose samples must be taken on the same day of drug administration and before administration 
starts. 
c Only for subjects with ongoing cardiac events (regardless of cause) or study treatment-related 
serious adverse events, adverse events, or adverse events of special interest on Day 63 or study 
treatment-related serious adverse events, adverse events, or adverse events of special interest 
occurring between the Day 63 visit and the follow-up visit. 


 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WP42873, Version 3 
27 
Appendix 4  
NYHA Functional Classification System for Heart Failure and 
LVSD NCI CTCAE Version 5.0 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 Version 5 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; 
NYHA  New York Heart Association. 
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. 


 
SC Fixed-Dose Combination of Pertuzumab and Trastuzumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WP42873, Version 3 
28 
Appendix 5  
Correction Formulas for QTC Intervals 
Bazett’s correction for QTc Measurement - QTcB 
QTcB (msec) 
= 
QT (msec) 
1000
/)
sec
 
m
(
RR
 
 
Example: QTcB of a subject with a QT of 386 msec and a RR of 848 msec 
QT (msec)  386 
RR (msec)   848 
QT (msec) 
   
419 msec 
1000
/)
sec
 
m
(
RR
 
 
Fridericia’s correction for QTc Measurement - QTcF 
QTcF (msec)    
QT (ms) 
3
1000
/)
ms
(
RR
 
 
Example: QTcF of a subject with a QT of 386 msec and a RR of 848 msec 
QT (msec)   386 
RR (msec)  848 
QT (msec) 
   
408 msec 
3
1000
/)
sec
 
m
(
RR
 
 


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