Clinical trial NCT02896855
Conditions: Breast Cancer
Sponsor: Hoffmann-La Roche
Start date: 2016-09-13; Completion date: 2021-01-22
Enrollment: 243 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial in China will evaluate the efficacy and safety of pertuzumab + trastuzumab + docetaxel compared with placebo + trastuzumab + docetaxel in participants with previously untreated HER2-positive metastatic breast cancer.

Detailed description:

Arms: arm 1: Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram \[mg/kg\] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter \[mg/m\^2\]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. arm 2: Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Interventions: intervention 1: Docetaxel intervention 2: Pertuzumab intervention 3: Placebo intervention 4: Trastuzumab
Intervention descriptions: intervention 1: Docetaxel (75-mg/m\^2) was administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity. intervention 2: Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles) was administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity. intervention 3: Placebo matched to pertuzumab was administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity. intervention 4: Trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles) was administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.

Protocol documents:
Prot_002.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, 
especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its 
control) and therefore is provided to you in confidence as an investigator, potential investigator, 
or consultant, for review by you, your staff, and an applicable Ethics Committee or Institutional 
Review Board.  It is understood that this information will not be disclosed to others without 
written authorization from Roche except to the extent necessary to obtain informed consent from 
persons to whom the drug may be administered.
Pertuzumab—F. Hoffmann-La Roche Ltd
Protocol YO29296, Version 4
PROTOCOL
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED CLINICAL TRIAL TO 
EVALUATE THE EFFICACY AND SAFETY OF 
PERTUZUMABHERCEPTINDOCETAXEL 
VERSUS PLACEBOHERCEPTINDOCETAXEL IN 
PREVIOUSLY UNTREATED HER2-POSITIVE 
METASTATIC BREAST CANCER
PROTOCOL NUMBER:
YO29296
VERSION NUMBER:
4
EUDRACT NUMBER:
Not applicable
IND NUMBER:
Not applicable
NCT NUMBER
NCT02896855
TEST PRODUCT:
Pertuzumab (RO4368451)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann–La Roche Ltd
DATE FINAL:
Version 1:  19 November 2013
DATE AMENDED:
Version 2:  19 April 2016
Version 3:  10 May 2017
Version 4:  See electronic date stamp below
07-Mar-2020 16:18:59
Title
Approver's Name
Company Signatory
Date and Time (UTC)


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PROTOCOL AMENDMENT, VERSION 4:
RATIONALE
Protocol YO29296 has been amended primarily to incorporate a crossover option for 
patients in Arm A (placeboHerceptindocetaxel) who are still receiving study 
treatment to receive pertuzumab in place of placebo. Changes to the protocol, along 
with a rationale for each change, are summarized below:

At the primary analysis (2018), clinically meaningful improvement in the primary 
efficacy endpoint of investigator-assessed PFS was demonstrated.  As a result, and 
given a high unmet need in patients with HER2 metastatic breast cancer in China, 
patients in Arm A who are still receiving study treatment will be offered the option to 
cross over and receive pertuzumab (in place of placebo) in addition to Herceptin 
and docetaxel, upon approval of protocol YO29296 Version 4 (Sections 3.1, 4.2, 
4.3.1.1, and 4.3.2.1).  

All patients who are still receiving study treatment at the time of the end of the study 
will continue to be offered study treatment until disease progression or unacceptable 
toxicity (Sections 3.1 and 4.3.4).  

Patients may be eligible to receive pertuzumab as part of an extension study
(Study MO29406), if eligible (Sections 3.1, 3.1.1, and 4.3.4).

The definition of end of study has been updated to reflect patient cross-over from 
Arm A to the pertuzumab arm and continuation of treatment as outlined above 
(Section 3.2).
Other changes made to the protocol are as follows:

Language has been added to the safety objective to clarify that patients in Arm A 
who cross over or continue to receive study treatment without placebo will be 
included as an independent population in safety analyses (Section 2.2).

The frequency of tumor assessments and prospective collection of tumor scans has 
been modified to align with local clinical practice (Sections 3.1 and 4.5.6; 
Appendix 1).

The obligation for confirmation of complete and partial responses has been removed 
from tumor and response evaluations, as these confirmations are not required per 
RECIST v1.1 (Section 4.5.6).

Language regarding the adverse event reporting period and reporting of adverse 
events that occur after the adverse event reporting period has been updated to align 
with current guidelines (Sections 5.3.1, 5.4.2.2, and 5.6).

Emergency Medical Contact information has been updated with new primary and 
secondary contacts (Section 5.4.1).  The Medical Monitor has also been updated 
where applicable in the protocol.

The study visit window has been modified to accommodate the possibility of 
holidays, vacations, and unforeseen major life events (Appendix 1).


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
The time window for acceptable results from standard-of-care tests or examinations 
performed prior to the initiation of study treatment has been clarified (Appendix 1).
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 .......................................... 11
PROTOCOL SYNOPSIS .................................................................................... 12
1.
BACKGROUND .......................................................................................... 20
1.1
Background on Breast Cancer............................................... 20
1.2
Human Epidermal Growth Factor Receptors......................... 21
1.3
Background on Treatments ................................................... 22
1.3.1
Herceptin ............................................................................... 22
1.3.2
Pertuzumab ........................................................................... 23
1.3.2.1
Phase I and II Clinical Studies in Solid Tumors ..................... 24
1.3.2.2
Phase III Clinical Study in Metastatic Breast 
Cancer................................................................................... 25
1.3.3
Docetaxel............................................................................... 25
1.4
Rationale for the Study .......................................................... 26
2.
OBJECTIVES.............................................................................................. 26
2.1
Efficacy Objectives ................................................................ 26
2.1.1
Primary Efficacy Objective..................................................... 26
2.1.2
Secondary Efficacy Objectives .............................................. 26
2.1.3
Exploratory Objective............................................................. 26
2.2
Safety Objective .................................................................... 26
3.
STUDY DESIGN......................................................................................... 27
3.1
Description of Study .............................................................. 27
3.1.1
Open-Label Extension Study MO29406 ................................ 29
3.1.2
Interim Analyses .................................................................... 29
3.2
End of Study.......................................................................... 29
3.3
Rationale for Study Design.................................................... 30
3.3.1
Rationale for Including Patients Who Have 
Received Prior Hormonal Treatment for 
Metastatic Breast Cancer ...................................................... 30
3.3.2
Rationale for Using the Combination of Herceptin 
and Docetaxel for Patients with HER2-Positive 
Metastatic Breast Cancer ...................................................... 30


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3.3.3
Rationale for Using the Combination of Herceptin, 
Pertuzumab, and Docetaxel for Patients with 
HER2-Positive Metastatic Breast Cancer .............................. 30
3.3.4
Rationale for Dosage Selection of Pertuzumab, 
Herceptin, and Docetaxel ...................................................... 31
3.3.5
Rationale for Exploratory Biomarker Analyses ...................... 32
3.4
Outcome Measures ............................................................... 32
3.4.1
Efficacy Outcome Measures.................................................. 32
3.4.1.1
Primary Efficacy Outcome Measure ...................................... 32
3.4.1.2
Secondary Efficacy Outcome Measures................................ 32
3.4.1.3
Exploratory Efficacy Outcome Measures............................... 33
3.4.2
Safety Outcome Measures .................................................... 33
4.
MATERIALS AND METHODS .................................................................... 33
4.1
Patients.................................................................................. 33
4.1.1
Inclusion Criteria.................................................................... 33
4.1.2
Exclusion Criteria................................................................... 35
4.2
Method of Treatment Assignment and Blinding..................... 37
4.3
Study Treatment.................................................................... 38
4.3.1
Formulation, Packaging, and Handling.................................. 38
4.3.1.1
Pertuzumab and Placebo ...................................................... 38
4.3.1.2
Herceptin ............................................................................... 39
4.3.1.3
Docetaxel............................................................................... 41
4.3.2
Dosage, Administration, and Compliance.............................. 41
4.3.2.1
Pertuzumab (or Placebo) Dose and Schedule....................... 42
4.3.2.2
Herceptin Dose and Schedule............................................... 43
4.3.2.3
Docetaxel............................................................................... 43
4.3.3
Investigational Medicinal Product Accountability ................... 43
4.3.4
Post-Trial Access to Pertuzumab .......................................... 44
4.4
Concomitant Therapy and Procedures .................................. 45
4.4.1
Permitted Therapy and Procedures....................................... 45
4.4.2
Prohibited Therapy ................................................................ 46
4.5
Study Assessments............................................................... 46
4.5.1
Informed Consent Forms and Screening Log........................ 46
4.5.2
Medical History and Demographic Data ................................ 47


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4.5.3
Central Assessment of HER2 and ER/PgR 
Status and Biomarker Analyses............................................. 47
4.5.4
Physical Examinations........................................................... 48
4.5.5
Vital Signs.............................................................................. 48
4.5.6
Tumor and Response Evaluations......................................... 48
4.5.7
Cardiac Assessments............................................................ 50
4.5.7.1
Electrocardiograms................................................................ 50
4.5.8
Left Ventricular Ejection Fraction........................................... 50
4.5.9
Laboratory Assessments ....................................................... 51
4.5.10
Post-Study Follow-up............................................................. 52
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 52
4.6.1
Patient Discontinuation.......................................................... 52
4.6.2
Study Treatment Discontinuation........................................... 53
4.6.3
Study and Site Discontinuation.............................................. 53
5.
ASSESSMENT OF SAFETY....................................................................... 54
5.1
Safety Plan ............................................................................ 54
5.1.1
Management of Risks Associated with 
Pertuzumab and Herceptin.................................................... 54
5.1.1.1
Infusion Hypersensitivity Reactions (Including 
Anaphylaxis).......................................................................... 54
5.1.1.2
Symptomatic Left Ventricular Systolic 
Dysfunction and Asymptomatic Decrease in Left 
Ventricular Ejection Fraction.................................................. 55
5.1.1.3
Epidermal Growth Factor Receptor (HER1)-
Related Toxicities .................................................................. 56
5.1.2
Dosage Modification and Treatment Interruption 
or Discontinuation.................................................................. 57
5.1.3
Pregnancy and Contraception ............................................... 59
5.1.4
Breastfeeding ........................................................................ 59
5.2
Safety Parameters and Definitions ........................................ 59
5.2.1
Adverse Events ..................................................................... 60
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 60
5.2.3
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 61


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5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 61
5.3.1
Adverse Event Reporting Period ........................................... 62
5.3.2
Eliciting Adverse Event Information....................................... 62
5.3.3
Assessment of Severity of Adverse Events ........................... 62
5.3.4
Assessment of Causality of Adverse Events ......................... 63
5.3.5
Procedures for Recording Adverse Events............................ 64
5.3.5.1
Infusion-Related Reactions.................................................... 64
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 64
5.3.5.3
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 64
5.3.5.4
Persistent or Recurrent Adverse Events................................ 65
5.3.5.5
Abnormal Laboratory Values ................................................. 65
5.3.5.6
Abnormal Vital Sign Values ................................................... 66
5.3.5.7
Abnormal Liver Function Tests.............................................. 66
5.3.5.8
Deaths ................................................................................... 67
5.3.5.9
Preexisting Medical Conditions.............................................. 67
5.3.5.10
Lack of Efficacy or Worsening of Breast Cancer ................... 67
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 68
5.3.5.12
Overdoses ............................................................................. 68
5.3.5.13
Cardiac Adverse Events ........................................................ 68
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 70
5.4.1
Emergency Medical Contacts................................................ 70
5.4.2
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 71
5.4.2.1
Events Occurring prior to Initiation of Study Drug.................. 71
5.4.2.2
Events Occurring after Initiation of Study Drug...................... 71
5.4.3
Reporting Requirements for Pregnancies.............................. 71
5.4.3.1
Pregnancies in Female Patients............................................ 71
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 72
5.4.3.3
Abortions ............................................................................... 72
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 73


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5.5
Follow-Up of Patients after Adverse Events .......................... 73
5.5.1
Investigator Follow-Up........................................................... 73
5.5.2
Sponsor Follow-Up ................................................................ 73
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 73
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 74
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 74
6.1
Determination of Sample Size ............................................... 74
6.2
Summaries of Conduct of Study............................................ 75
6.3
Summaries of Treatment Group Comparability ..................... 75
6.4
Efficacy Analyses .................................................................. 75
6.4.1
Primary Efficacy Endpoint...................................................... 75
6.4.2
Secondary Efficacy Endpoints............................................... 76
6.4.3
Exploratory Analyses............................................................. 76
6.4.3.1
Overall Survival ..................................................................... 76
6.4.3.2
Objective Response Rate...................................................... 77
6.4.3.3
Duration of Response............................................................ 77
6.5
Safety Analyses..................................................................... 77
6.5.1
Study Drug Exposure ............................................................ 77
6.5.2
Adverse Events ..................................................................... 77
6.5.3
Cardiac Safety....................................................................... 78
6.5.4
Laboratory Data..................................................................... 78
6.6
Exploratory Analyses............................................................. 78
6.7
Interim Analyses .................................................................... 78
7.
DATA COLLECTION AND MANAGEMENT ............................................... 78
7.1
Data Quality Assurance......................................................... 78
7.2
Electronic Case Report Forms............................................... 79
7.3
Source Data Documentation.................................................. 79
7.4
Use of Computerized Systems .............................................. 80
7.5
Retention of Records............................................................. 80
8.
ETHICAL CONSIDERATIONS.................................................................... 80


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8.1
Compliance with Laws and Regulations ................................ 80
8.2
Informed Consent.................................................................. 81
8.3
Institutional Review Board or Ethics Committee.................... 82
8.4
Confidentiality........................................................................ 82
8.5
Financial Disclosure .............................................................. 83
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 83
9.1
Study Documentation ............................................................ 83
9.2
Protocol Violations................................................................. 83
9.3
Site Inspections ..................................................................... 83
9.4
Administrative Structure......................................................... 84
9.5
Publication of Data and Protection of Trade 
Secrets .................................................................................. 84
9.6
Protocol Amendments ........................................................... 84
10. REFERENCES ........................................................................................... 85


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LIST OF TABLES
Table 1
Study Treatment Schedule.......................................................... 42
Table 2
Actions to Be Taken for Toxicities Related to Herceptin or 
Pertuzumab................................................................................. 58
Table 3
Docetaxel Dose Adjustments...................................................... 58
Table 4
Adverse Event Severity Grading Scale ....................................... 63
Table 5
Reporting Conventions for Left Ventricular Systolic 
Dysfunction ................................................................................. 69
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 29
Figure 2
Algorithm for Continuation or Discontinuation of Study 
Treatment Based on LVEF Assessments ................................... 56
LIST OF APPENDICES
Appendix 1
Schedule of Assessments........................................................... 89
Appendix 2
ECOG Performance Status Scale............................................... 94
Appendix 3
NYHA Classification and NCI CTCAE v. 4.0 Grading for Left 
Ventricular Systolic Dysfunction.................................................. 95
Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication ................................. 97
Appendix 5
Nomogram for the Determination of Body Surface Area........... 109


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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED CLINICAL TRIAL TO 
EVALUATE THE EFFICACY AND SAFETY OF 
PERTUZUMABHERCEPTINDOCETAXEL 
VERSUS PLACEBOHERCEPTINDOCETAXEL IN 
PREVIOUSLY UNTREATED HER2-POSITIVE 
METASTATIC BREAST CANCER
PROTOCOL NUMBER:
YO29296
VERSION NUMBER:
4
EUDRACT NUMBER:
Not applicable
IND NUMBER:
Not applicable
NCT NUMBER
NCT02896855
TEST PRODUCT:
Pertuzumab (RO4368451)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann–La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
this form to your local study monitor.


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PROTOCOL SYNOPSIS
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED CLINICAL TRIAL TO EVALUATE THE EFFICACY
AND SAFETY OF PERTUZUMABHERCEPTINDOCETAXEL 
VERSUS PLACEBOHERCEPTINDOCETAXEL IN 
PREVIOUSLY UNTREATED HER2-POSITIVE METASTATIC 
BREAST CANCER
PROTOCOL NUMBER:
YO29296
VERSION NUMBER:
4
TEST PRODUCT:
Pertuzumab (RO4368451)
PHASE:
III
INDICATION:
HER2-positive metastatic breast cancer that has not been treated 
with chemo or biologic therapy
SPONSOR:
F. Hoffmann–La Roche Ltd
Objectives
Efficacy Objectives
The primary efficacy objective for this study is as follows:

To evaluate the efficacy of pertuzumab plus Herceptin plus docetaxel compared with 
placebo plus Herceptin plus docetaxel in patients with previously untreated HER2-positive 
metastatic breast cancer (MBC), as measured by investigator-assessed progression-free 
survival (PFS)
The secondary efficacy objectives for this study are as follows:

To compare overall survival (OS) between the two treatment arms

To compare the objective response rate between the two treatment arms

To compare the duration of objective response between the two treatment arms
Exploratory Objective
The exploratory objective for this study is as follows:

To explore the relationship of biomarkers, such as PI3K status, HER2/3 mRNA, PD-L1, and 
CD8 expression, with efficacy (response rate, PFS, and OS)
Safety Objective
The safety objective for this study is as follows:

To compare the safety profile between the two treatment arms (including crossover patients 
and those no longer receiving placebo)
Study Design
Description of Study
This study is a Phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial 
in China.  Patients who have HER2-positive MBC and have not received chemotherapy or 
biologic therapy (including approved or investigational tyrosine kinase/HER inhibitors or 


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vaccines) for their metastatic disease are eligible for the study.  Patients who have received one 
prior hormonal treatment for MBC are eligible.  Patients may have received systemic breast 
cancer treatment in the neoadjuvant or adjuvant setting, provided that the patient experienced a 
diseasefree interval (DFI) of 12 months from completion of systemic treatment (excluding 
hormonal therapy) to metastatic diagnosis.  Patients may have received Herceptin and/or a 
taxane in the neoadjuvant or adjuvant setting.  HER2-positive status determined using archival, 
paraffin-embedded tumor tissue will be confirmed in a central laboratory by 
immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH).
Number of Patients
A total of 240 patients will be randomized in a 1:1 ratio to one of two treatment arms
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form, obtained prior to any study procedure

Age 18 years

Histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent 
or metastatic disease that is suitable for chemotherapy
Patients with measurable or nonmeasurable disease are eligible.  
Patients with only bone metastases are eligible provided that some bone metastases 
have not been previously irradiated and that tumor tissue samples from the primary 
tumor are available for central HER2 testing.
Locally recurrent disease must not be amenable to resection with curative intent.

HER2-positive MBC (defined as 3by IHC and/or ISH amplification ratio 2.0) confirmed by 
a Sponsor-designated central laboratory
It is strongly recommended that a formalinfixed paraffinembedded (FFPE) tissue 
block from the primary tumor (or metastatic lesion if the primary is not available) be 
submitted for central laboratory confirmation of HER2 eligibility.  However, if that is not 
possible, unstained and freshly cut slides need to be submitted (see Section 4.5.3 for 
further details).  Tissue will subsequently be used for assessment of biomarkers.

Left ventricular ejection fraction (LVEF) 55% at baseline (within 42 days prior to 
randomization) as determined by either echocardiography (ECHO) or multiplegated 
acquisition (MUGA) scan (ECHO is the preferred method)
If the patient is randomized, the same method of LVEF assessment, ECHO or MUGA, 
must be used throughout the study, and to the extent possible, be obtained at the 
same institution (see Section 4.5.8).  Any prestudy LVEF values obtained during and 
after Herceptin neoadjuvant or adjuvant treatment will be obtained, as applicable.

Eastern Cooperative Oncology Group Performance Status of 0 or 1

For women who are not postmenopausal (postmenopausal defined as 12 months of 
nontherapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  
agreement to remain abstinent or use single or combined nonhormonal contraceptive 
methods that result in a failure rate of 1% per year during the treatment period and for at 
least 7 months after the last dose of study treatment (Herceptin and/or pertuzumab)
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of contraception.
Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year 
include tubal ligation, male sterilization, and certain non-hormonal intrauterine 
devices. Alternatively, two methods (e.g., two barrier methods such as a condom and 
a cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier 
methods must always be supplemented with the use of a spermicide


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
For men: agreement to remain abstinent or use a condom plus an additional contraceptive 
method that together result in a failure rate of 1% per year during the treatment period and 
for at least 7 months after the last dose of study treatment (Herceptin and/or pertuzumab)
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of contraception.
Negative serum pregnancy test in women of childbearing potential, premenopausal or 
less than 12 months of amenorrhea post-menopause, and who have not undergone 
surgical sterilization.
Able to comply with the study protocol, in the investigator’s judgment
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History of anticancer therapy for MBC, with the exception of one prior hormonal regimen for 
MBC, which must be stopped prior to randomization
Anticancer therapy for MBC includes any epidermal growth factor receptor or 
anti-HER2 agents or vaccines, cytotoxic chemotherapy, or more than one prior 
hormonal regimen for MBC.  
One prior hormonal regimen for MBC may include more than one hormonal therapy.  If 
a patient is switched to a different hormonal therapy for reasons other than disease 
progression (e.g., toxicity or local standard practice), this will be counted as one 
regimen.  If a patient is switched to a different hormonal therapy because of disease 
progression, this will be counted as two regimens, and the patient will not be eligible 
for the study. 

History of approved or investigative tyrosine kinase/HER inhibitors for breast cancer in any 
treatment setting, except Herceptin used in the neoadjuvant or adjuvant setting

History of systemic breast cancer treatment in the neoadjuvant or adjuvant setting with a 
DFI from completion of systemic treatment (excluding hormonal therapy) to metastatic 
diagnosis of 12 months

History of persistent Grade 2 hematologic toxicity resulting from previous neoadjuvant or 
adjuvant therapy (all grades based on National Cancer Institute Common Toxicity Criteria 
for Adverse Events, Version 4.0 [NCI CTCAE v 4.0])

Grade 3 peripheral neuropathy at randomization

History of other malignancy within the previous 5 years, except for carcinoma in situ of the 
cervix or non-melanoma skin carcinoma that has been previously treated with curative 
intent

Current clinical or radiographic evidence of CNS metastases
A computed tomography (CT) or magnetic resonance imaging (MRI) scan of the brain 
is mandatory within 28 days before randomization in cases of clinical suspicion of brain 
metastases.

History of exposure to the following cumulative doses of anthracyclines: 
Doxorubicin or liposomal doxorubicin 360 mg/m2
Epirubicin 720 mg/m2
Mitoxantrone 120 mg/m2 and idarubicin 90 mg/m2
Other anthracycline greater than the equivalent of 360 mg/m2 of doxorubicin
If more than one anthracycline has been used, the cumulative dose must not 
exceed the equivalent of 360 mg/m2 of doxorubicin.

Current uncontrolled hypertension (systolic blood pressure 150 mmHg and/or diastolic 
blood pressure 100 mmHg) or unstable angina



History of congestive heart failure of any New York Heart Association classification, or
serious cardiac arrhythmia requiring treatment (excluding atrial fibrillation or paroxysmal
supraventricular tachycardia)

History of myocardial infarction within 6 months prior to randomization

History of LVEF decrease to 50% during or after prior Herceptin neoadjuvant or adjuvant
therapy

Current dyspnea at rest due to complications of advanced malignancy, or other diseases
that require continuous oxygen therapy

Inadequate organ function, evidenced by the following laboratory results within 28 days
prior to randomization:
Absolute neutrophil count 1500 cells/L
Platelet count 100,000 cells/L
Hemoglobin 9 g/dL 
Total bilirubin greater than the upper limit of normal (ULN) (unless the patient has 
documented Gilbert’s syndrome)
AST or ALT 2.5 ULN (5 ULN in patients with liver metastases)
AST (SGOT) or ALT (SGPT) 1.5 ULN with concurrent serum ALP 2.5 ULN
Serum ALP may be 2.5 ULN only if bone metastases are present and AST 
and ALT are 1.5 ULN.  
Serum creatinine 2.0 mg/dL or 177 mol/L
INR and aPTT or PTT 1.5 ULN (unless on therapeutic anti-coagulation)

Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular,
pulmonary, or metabolic disease; wound healing disorders; ulcers; bone fractures)

Major surgical procedure or significant traumatic injury within 28 days prior to randomization
or anticipation of the need for major surgery during the course of study treatment

Pregnant or lactating or intending to become pregnant during the study

Treatment with any investigational treatment within 28 days prior to randomization

Current known infection with HIV, hepatitis C virus, or active hepatitis B virus (HBV)
Patients who are known carriers of HBV may be included in the study.  Active HBV is 
defined as presence of each of the following:  positive test for hepatitis B surface 
antigen, detectable levels of HBV DNA, and ALT ULN.

Receipt of intravenous (IV) antibiotics for infection within 14 days prior to randomization

Current chronic daily treatment with corticosteroids (dose of 10 mg/day
methylprednisolone equivalent), excluding inhaled corticosteroids

Known hypersensitivity to any of the protocolspecified study treatments

Concurrent participation in an interventional or noninterventional study
Length of Study
A total of approximately 240 patients (approximately 120 per arm) will be enrolled.  The 
recruitment period is estimated to be 15 months.
The primary analysis of PFS will be performed after 123 PFS events have occurred, and the 
required PFS events will be reached at approximately 23 months after the first patient is 
enrolled into the study.
End of Study
The end of the study is defined as 3 years after the date when the last patient is enrolled 
(LPI), or when the last patient, last visit (LPLV) occurs, whichever occurs later.
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Outcome Measures
Efficacy Outcome Measures
The efficacy outcome measures for this study are as follows:

PFS, defined as the time from randomization to the first occurrence of disease progression, 
as determined by the investigator using Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v 1.1; Therasse et al. 2000), or death from any cause within 18 weeks 
after the final tumor assessment, whichever occurs first
Assessments will be based on review of radiological images (e.g., MRI scans, CT 
scans, bone scans, chest X-rays), as well as cytologic (e.g., relevant cytology reports 
documenting malignant pleural effusions, bone marrow aspirations, cerebral spinal 
fluid) and photographic data, if available.
The secondary efficacy outcome measures for this study are as follows:

OS, defined as the time from randomization to death from any cause

Objective response, defined as a complete response or partial response that is confirmed 
2842 days later, as determined by the investigator using RECIST v 1.1

Duration of objective response, defined as the time from the first occurrence of a 
documented objective response to the time of disease progression, as determined by the 
investigator using RECIST v 1.1, or death from any cause, whichever occurs first
Exploratory Outcome Measures
The exploratory outcome measures for this study may include, but are not limited to, the 
following:

Expression level of HER2/3 mRNA as measured by quantitative real-time polymerase chain 
reaction

PIK3CA status (i.e., mutation not detected or mutation detected by PCR based mutational 
analyses or by other technologies suited for mutational analyses)

Expression of PD-L1 and CD8 as assessed by IHC or by other suitable technologies
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence of symptomatic left ventricular systolic dysfunction

Incidence of asymptomatic LVEF events

LVEF measurements over the course of the study

Incidence and severity of adverse events and serious adverse events NCI CTCAE v 4.0)

Changes in clinical laboratory results during the study
Investigational Medicinal Products
Herceptin, pertuzumab, and placebo are investigational medicinal products in this study.  
Treatments will be administered on Day 1 of each specified cycle.
All patients will receive Herceptin by IV infusion in 3-week cycles, as follows:
Herceptin (8 mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles)
Herceptin will be administered until disease progression or unacceptable toxicity.  
Test Product
Patients in Arm B will receive pertuzumab (840 mg loading dose for Cycle 1, followed by 
420 mg for subsequent cycles) by IV infusion every 3 weeks until disease progression or 
unacceptable toxicity.


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Comparator
Patients in Arm A will receive placebo by IV infusion every 3 weeks until disease progression or 
unacceptable toxicity.  Note that upon approval of protocol YO29296 Version 4, placebo will 
no longer be administered to patients in Arm A who are still receiving study treatment.
Non-Investigational Medicinal Products
Docetaxel is a non-investigational medicinal product in this study.  Sites will obtain and utilize 
commercially available docetaxel.  Treatments will be administered on Day 1 of each specified 
cycle.
All patients will receive docetaxel in 3-week cycles, as follows:
Docetaxel (75 mg/m2)
Prior to completion of Cycle 6, docetaxel should be discontinued only for disease 
progression or unacceptable toxicity.  After completion of Cycle 6, discontinuation of 
docetaxel treatment is at the discretion of the patient and treating physician.
Statistical Methods
Primary Analysis
The primary analysis of PFS will be performed after 123 PFS events have occurred, and the 
required PFS events are expected to be reached at around 23 months.
Determination of Sample Size  
To reliably determine the predefined consistency value, a simulation method was used to 
estimate the required sample size.  A total of 240 patients randomized in a 1:1 ratio and 
123 PFS events in the two treatment arms are required, providing an appropriate 
83% probability of showing consistency.  
The sample size estimation was based on the following assumptions:

The median PFS is 11 months in the control arm, with a PFS hazard ratio of 0.68

The recruitment period is estimated to be 15 months
Interim Analyses
No interim analysis of efficacy is planned.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AE 
adverse event
CHF 
congestive heart failure
CR 
complete response
CT
computed tomography
CVAD
central venous access device
DFI
disease-free interval
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EGFR
epidermal growth factor receptor
ER
estrogen receptor
ESF
Eligibility Screening Form
FFPE
formalin-fixed paraffin-embedded
FISH
fluorescence in situ hybridization
HBV
active hepatitis B virus
HER2
human epidermal growth factor receptor 2
ICH
International Council for Harmonization
IHC
immunohistochemistry
IMP
investigational medicinal product
IND
Investigational New Drug
IRB/IEC
Institutional Review Board/Independent Ethics 
Committee
IRF
Independent Review Facility
IRR
infusion-related reaction
IV
intravenous
IxRS
interactive voice or Webbased response system
JVP
jugular venous pressure
LLN
lower limit of normal
LVEF
left ventricular ejection fraction
LVSD
left ventricular systolic dysfunction
MBC
metastatic breast cancer
MRI
magnetic resonance imaging
MUGA
multiple-gated acquisition
NCI CTCAE
National Cancer Institute/ Common Terminology 
Criteria for Adverse Events


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Abbreviation
Definition
NYHA
New York Heart Association
ORR
objective response rate
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PgR
progesterone receptor
PK
pharmacokinetic
PR
partial response
qRT-PCR
quantitative real-time polymerase chain reaction
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SD
stable disease
SWFI
sterile water for injection
ULN
upper limit of normal


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1.
BACKGROUND
1.1
BACKGROUND ON BREAST CANCER
Breast cancer is the most frequently occurring cancer among women, with an estimated
1.4 million new cancer cases diagnosed worldwide in 2008.  Breast cancer is the most
frequent cause of cancer death in women in both developed and developing regions
(Jemal et al. 2011), although the incidence varies around the world and is higher in
developed regions (80 cases per 100,000) compared with developing areas 
(40 cases per 100,000) (Ferlay et al. 2010).  In Asia, 528,927 new breast cancer cases
were diagnosed in 2008 (Ferlay et al. 2010).  In China, the incidence is increasing; 
nearly 170,000 new cases were reported in 2008, compared with 126,000 cases in 
2002 (Ferlay et al. 2010).  Additionally, breast cancer accounts for 16.81% of all female 
cancers in China.  In 2009, the incidence of female breast cancer in China was 
42.55 per 100,000.  After standardizing by age, the incidence was 23.16 per 100,000 
in China versus 28.99 per 100,000 in the rest of the world (Chinese Cancer Registry 
Annual Report 2012).  Consequently, breast cancer has been identified as a priority for 
cancer prevention, early detection, and therapy in China (Ferlay et al. 2010).
Although the treatment of metastatic breast cancer (MBC) is usually palliative in intent, 
this malignancy readily responds to systemic agents, and prolongation of survival and 
symptom palliation are now possible with modern medical management.  Systemic 
treatments are in continual evolution as more active chemotherapeutic agents become 
available and biological factors have been incorporated into treatment.  There are many 
agents available for the treatment of MBC that are used singly or in combination,
according to the clinical situation.  The most active drugs are anthracyclines, taxanes, 
alkylating agents, and vinca alkaloids.  Used as single agents, they produce response 
rates of 20%80%; however, the rare complete responses are short lived, and 
progression of disease is almost inevitable (Bernard-Marty et al. 2003; 
Chung and Carlson 2003).
The introduction of paclitaxel and docetaxel in the 1990s led to additional improvements 
in the management of MBC.  The now common use of anthracyclines in the adjuvant 
treatment of early breast cancer has both increased the incidence of 
anthracycline-resistant MBC and restricted the use of anthracyclines in later stages of 
the disease, in order to avoid dose-limiting toxicity.  There is also an increasing trend 
toward using taxanes earlier in the management of MBC in patients with no or minimal 
prior anthracycline exposure or in combination with anthracyclines or both.
With the growing understanding of the biology of breast cancer, multiple new targets for 
anticancer therapies are being identified.  Trastuzumab (Herceptin), which targets 
human epidermal growth factor receptor 2 (HER2), is globally approved for use as 
monotherapy or in combination with chemotherapy in the metastatic setting and in 
combination with chemotherapy as adjuvant treatment for HER2-positive breast cancer
In China, in the adjuvant setting, Herceptin is approved for use as a single agent for the 


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adjuvant treatment of HER2-overexpressing breast cancer in patients who have received 
surgery and anthracycline-based chemotherapy and radiotherapy.  The optimal 
management of MBC now takes into account not only a patient’s general condition, 
medical history, tumor burden, and receptor status, but also the patient's HER2 status.  
Pertuzumab (Perjeta), a recombinant humanized monoclonal antibody, binds to the 
dimerization epitope of HER2, thereby inhibiting dimerization of HER2 to other HER 
family members (HER1, HER3, and HER4).  The combination of pertuzumab and 
Herceptin provides more complete HER pathway blockade because of their 
complementary modes of action (Baselga et al. 2012; Swain et al. 2013).  
There is a significant need in China for new agents with novel mechanisms of action and 
non-overlapping toxicity that can be combined with established treatments for breast 
cancer.
1.2
HUMAN EPIDERMAL GROWTH FACTOR RECEPTORS
Evidence suggests that dysregulation of ligands and receptors of the HER family are 
important in the pathogenesis of cancer.  The HER tyrosine kinase receptor family is 
composed of four receptors: HER1 (epidermal growth factor receptor [EGFR]), 
HER2, HER3, and HER4, these receptors mediate tumor cell growth, survival, and 
differentiation (Sundaresan et al. 1999; Yarden and Sliwkowski 2001).  HER receptors 
normally exist as inactive monomers.  Activation of HER receptors occurs following 
ligand binding, leading to receptor dimerization and cell signaling through the 
PI3-kinase/AKT pathway for promotion of tumor cell survival and through the 
mitogen-activated protein kinase pathway for cellular proliferation. Overexpression of 
HER2 is observed in 15%20% of primary breast cancer (Chia et al. 2008; 
Ross et al. 2009; Pathmanathan et al. 2012; Bilous et al. 2012).  In China, the number of 
patients recruited into this prospective multicenter study to investigate the expression of 
the HER2 in human breast carcinomas by comparing the concordance between
immunohistochemistry (IHC) staining and fluorescence in situ hybridization (FISH) that 
were HER2 positive (2or 3) was 42.6% (1342 of 3149) as detected by FISH and 
46.9% (1477 of 3149) as detected by IHC.  Overall, the authors concluded that there 
was good correlation between IHC and FISH in demonstrating HER2/neu 
overexpression and gene amplification (Xiao hong 2010).  Several lines of scientific and 
clinical evidence support a direct role for HER2 overexpression in aggressive growth and 
poor prognosis (Slamon et al. 1987).  
HER2 and HER3 have unique characteristics compared with HER1 and HER4.  
HER2 has no known ligand and in a state of overexpression can form active 
homodimers and initiate tyrosine kinase signaling without ligand stimulation.  
Additionally, as HER2 concentrations increase, the incidence of HER2 interactions with 
other receptors is also increased, resulting in a broad recruitment of a number of 
proteins (Jones et al. 2006).  Recent data obtained using microarray technology suggest 
that the HER2 receptor can bind to more than 17 different proteins and may recruit 


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proteins that other HER receptors cannot recruit.  These activities highlight the 
promiscuity of HER2 in its ability to bind to other HER receptors and initiate tyrosine 
kinase signaling through several mechanisms (Jones et al. 2006).  HER3 differs from the 
other HER receptors in that it has no intracellular tyrosine kinase domain and cannot 
initiate cellular signaling without binding to either HER1, HER2, or HER4 
(Guy et al. 1994).  The prognostic significance of HER3 in breast cancer is controversial, 
because HER3 expression has been associated with both poor and favorable prognosis 
(Pawlowski et al. 2000; Bieche et al. 2003; Witton et al. 2003).
HER2 is thought to be the preferred partner for HER3 dimerization because it exists in 
an open configuration, mimicking a ligand-bound state (Sliwkowski 2003).  In vitro data 
involving multiple HER2-positive cell lines have demonstrated higher mRNA levels of 
HER3 versus EGFR, suggesting that the HER2-HER3 interaction may represent a 
potent stimulus for tyrosine kinase signal transduction.  These data support the 
hypothesis that the HER2-HER3 pair is the most transforming heterodimer and is the 
most mitogenic compared with other heterodimer pairs (Jones et al. 2006).
HER2 has emerged as an important prognostic and potential predictive factor in breast 
cancer.  In the laboratory, HER2 overexpression results in oncogenic transformation and 
more aggressive tumor behavior.  Despite associations with other known negative 
prognostic factors, HER2 overexpression has been independently associated with 
poorer disease-free survival and overall survival (OS) compared with tumors that do not 
overexpress HER2 (Pauletti et al. 2000).  
1.3
BACKGROUND ON TREATMENTS
1.3.1
Herceptin
Herceptin, a humanized monoclonal antibody directed at the HER2 receptor, is indicated 
for the treatment of patients with HER2-positive breast cancer both in the adjuvant 
treatment setting and in the metastatic treatment setting.  The addition of Herceptin to 
standard chemotherapy prolongs time to progressive disease, or progression-free 
survival (PFS), and improves survival when given with chemotherapy to women with 
HER2-positive breast cancer (Slamon et al. 2001; Romond et al. 2005).  
Clinical benefits are greatest in patients with tumors strongly overexpressing HER2, 
graded 3by IHC, and/or with HER2 gene amplification, as determined by FISH.  In an 
evaluation of tissue from patients who participated in a randomized Phase III study of 
chemotherapy plus Herceptin versus chemotherapy alone (Slamon et al. 2001), as 
measured by relative risk for time to disease progression, patients treated with Herceptin
plus chemotherapy achieved greater benefit if they had HER2 assay results of 3by
IHC (relative risk: 0.42; 95% CI: 0.33, 0.54) or FISH positive (relative risk: 0.44; 95% CI: 
0.34, 0.57), compared with HER2 assay results of IHC 2(relative risk: 0.76; 95% CI: 
0.5, 1.15) or IHC 2and FISH positive (relative risk: 0.54; 95% CI: 0.21, 1.35) 
(HerceptinU.S. Package Insert, November 2006).


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A Phase II randomized study evaluated Herceptin and docetaxel versus docetaxel alone 
as a first-line treatment for HER2-positive MBC (Marty et al. 2005).  A total of 
186 patients received at least one dose of protocol therapy.  The addition of Herceptin to 
100 mg/m2 docetaxel for at least six cycles resulted in superior clinical efficacy with 
improved overall response rates (61% vs. 34%; p0.0002), OS (median, 31.2 months vs.
22.7 months; p0.0325), time to progressive disease (median, 11.7 months vs.
6.1 months; p0.0001), time to treatment failure (median, 9.8 months vs. 5.3 months; 
p0.0001), and duration of response (median, 11.7 months vs. 5.7 months; p0.009).  
There was little difference in the number and severity of adverse events (AEs) between 
the treatment arms.  Grade 3 or 4 neutropenia was seen more commonly with 
combination treatment (32%) than with docetaxel alone (22%), and there was a slightly 
higher incidence of febrile neutropenia in the combination arm (23% vs. 17%, 
respectively).  More patients in the combination arm had decreases in left ventricular 
ejection fraction (LVEF) compared with the docetaxel-alone arm (17% vs. 8%, 
respectively), and 1 (1%) patient in the combination arm experienced symptomatic heart 
failure.  An additional patient in the combination arm experienced congestive heart 
failure (CHF) after discontinuation of study treatment and during treatment with an 
investigational anthracycline.  The CHF event in this second patient was assessed by 
the investigator as related to the investigational anthracycline (Marty et al. 2005). A
Phase III, randomized, multicenter, double-blind, placebo-controlled trial, Study 
WO20698/TOC4129g (CLEOPATRA), is of 808 patients with HER2-positive MBC, in 
which patients were randomized in a 1:1 ratio to receive either placebo in combination 
with Herceptin plus docetaxel or pertuzumab in combination with Herceptin plus 
docetaxel.  This data is presented below in Section 1.3.2.2.
Herceptin is well tolerated both as a single agent and in combination with standard 
chemotherapy for breast cancer (Cobleigh et al. 1998; Slamon et al. 2001).  The most 
significant AE observed in patients who receive Herceptin is cardiac dysfunction, 
reflected by asymptomatic decreases in LVEF and, less frequently, by clinically
symptomatic CHF.  Risk factors for cardiac failure in the setting of Herceptin treatment 
include co-administration with anthracyclinebased chemotherapy, increasing age, a 
decreasing LVEF during treatment to below the lower limit of normal (LLN), and the use 
of anti-hypertensive medications (Tan-Chiu et al. 2005).
1.3.2
Pertuzumab
Pertuzumab is a fully humanized monoclonal antibody based on the human IgG1 () 
framework sequences and consisting of two heavy chains (449 residues) and two light 
chains (214 residues).  Like Herceptin, pertuzumab is directed against the extracellular 
domain of HER2.  However, it differs from Herceptin in the epitopebinding regions of 
the light chain (12amino acid difference) and heavy chain (29amino acid difference).  
As a result, pertuzumab binds to an epitope within what is known as subdomain 2 of 
HER2 whereas the epitope for Herceptin is localized to subdomain 4 (Cho et al. 2003; 
Franklin et al. 2004).


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Pertuzumab acts by blocking the association of HER2 with other HER family members, 
including HER1 (EGFR), HER3, and HER4.  As a result, pertuzumab inhibits 
ligandinitiated intracellular signaling through two major signal pathways: MAP kinase 
and PI3 kinase.  Inhibition of these signaling pathways can result in growth arrest and 
apoptosis, respectively (Hanahan and Weinberg 2000).
Recent data from a clinical trial of lapatinib supports the hypothesis that HER2 plays an
active role in tumor biology even with the administration of Herceptin (Geyer et al. 2006).  
These data suggest that a broader blockade of HER2 through interruption of 
heterodimerization may provide clinical benefit.
Both pertuzumab and Herceptin target the HER2 receptor but bind at distinct epitopes 
on the receptor, with different modes of action, including ADCC (antibody dependent 
cellular cytotoxicity, inhibition of downstream signaling, and inhibition of receptor 
heterodimerization).
1.3.2.1
Phase I and II Clinical Studies in Solid Tumors
Pertuzumab has been studied in several Phase I and II clinical trials in solid tumors, 
including breast, prostate, ovarian, and lung cancer.  Pertuzumab was given until 
evidence of progressive disease or toxicity.
AEs reported in trials of single-agent pertuzumab (n353) were commonly Grade 1 or 2 
in severity and included diarrhea (58%), fatigue (32%), nausea (31%), abdominal pain 
(24%), vomiting (22%), anorexia (19%), and rash (17%).  Grade 3 or 4 AEs were less 
frequently reported, with the more frequent events including Grade 3 diarrhea (7%), 
Grade 3 vomiting (5%), and Grade 3 nausea (4%).  Decreases in LVEF were reported in 
14% of patients.  LVEF decreases of 10 percentage points to an LVEF of 50% were 
reported in 21 of 203 patients (10%) who had a baseline LVEF and at least one 
postbaseline LVEF assessment.
Overall, CHF has been observed in 3 patients.  One patient with symptomatic 
Grade 3 cardiac dysfunction received pertuzumab plus Herceptin for relapsed 
HER2-positive MBC, another patient received pertuzumab plus gemcitabine for platinum 
refractory ovarian cancer, and the third patient received pertuzumab as a single agent 
for HER2-negative MBC.
Pertuzumab has been evaluated in Phase II studies in combination with Herceptin in 
patients with HER2-positive MBC who have previously received Herceptin for metastatic 
disease.  One study, conducted by the National Cancer Institute (NCI), enrolled 11
patients with previously treated HER2-positive MBC.  Two of the 11 patients exhibited a 
partial response (PR) (Portera et al. 2008).  In the second study, BO17929, 66 patients 
who had previously been treated with Herceptin for HER2-positive MBC received the 
combination of pertuzumab and Herceptin every 3 weeks until disease progression.  In a
preliminary analysis of 42 of the 66 patients, 1 patient had a complete response (CR), 


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5 patients had a PR, and 17 patients had stable disease (SD) of at least two cycles in 
duration (Baselga et al. 2007).
1.3.2.2
Phase III Clinical Study in Metastatic Breast Cancer
CLEOPATRA is a Phase III, randomized, multicenter, double-blind, placebo-controlled 
trial of 808 patients with HER2-positive MBC, in which patients were randomized in a 
1:1 ratio to receive either placebo in combination with Herceptin plus docetaxel or 
pertuzumab in combination with Herceptin plus docetaxel.  
The primary endpoint of this randomized trial was PFS as assessed by an independent 
review facility (IRF).  The results from this randomized trial demonstrated a statistically 
significant improvement in IRF-assessed PFS in the pertuzumab group compared with 
the placebo group (hazard ratio: 0.62; 95% CI: 0.51, 0.75; p0.0001) and an increase in 
median PFS of 6.1 months (18.5 months in the pertuzumab group versus 12.4 months 
in the placebo group) (Baselga et al. 2012).  CLEOPATRA Study has also 
shown a statistically significant improvement in OS for the pertuzumab group
(hazard ratio: 0.68; 95% CI: 0.56, 0.84; p0.001).  The median OS was 56.5 months in
the pertuzumab group compared to 40.8 months in the control group (Swain et al. 2015).
In CLEOPATRA, the addition of pertuzumab to Herceptin did not increase the rates of 
symptomatic or asymptomatic cardiac dysfunction.  A low level of cardiac toxicities, 
predominantly asymptomatic declines in LVEF have been reported in both arms in 
CLEOPATRA. The most frequently reported cardiac-related AE was left ventricular 
systolic dysfunction (LVSD), with a total of 34 patients [8.6%] in the PlaTD arm 
versus 22 patients [5.4%] in the PtzTD arm).  AEs (any grade) of diarrhea, rash, 
mucosal inflammation, febrile neutropenia, and dry skin were reported more frequently in 
the pertuzumab group than in the placebo group.  The events were mostly Grade 1 or 2 
and occurred during the period of concomitant docetaxel administration.  Compared with 
the placebo group, the pertuzumab group had an increased incidence of Grade 3 or 
worse febrile neutropenia (13.8% vs. 7.6%, respectively) and diarrhea (7.9% vs. 5%, 
respectively).  
1.3.3
Docetaxel
Docetaxel is an anti-neoplastic agent that binds to free tubulin and promotes the 
assembly of tubulin into stable microtubules while simultaneously inhibiting their 
disassembly.  This leads to the production of microtubule bundles without normal 
function and to the stabilization of microtubules, blocking cells in the M-phase of the cell 
cycle and leading to cell death.  Extensive Phase II and III data have led to regulatory 
approvals for docetaxel use either in combination or as monotherapy for the treatment of 
breast cancer.  For further information on the efficacy, safety, and pharmacokinetics of 
docetaxel, please refer to the currently approved prescribing information.


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1.4
RATIONALE FOR THE STUDY
Pertuzumab represents a new anti-HER2 agent with a novel mechanism of action 
targeting inhibition of HER2 dimerization.  Nonclinical and clinical data generated to date 
suggest that pertuzumab may provide broader HER2 blockade through inhibition of 
HER2 homo- and heterodimerization.  Pertuzumab has been shown in both nonclinical 
and clinical experiments to have superior antitumor effects when combined with other 
anti-HER2 treatments such as Herceptin.
Pertuzumab is already approved in many countries (including the United States, the 
European Union, Japan, the Republic of Korea, and Taiwan) for use in combination with 
Herceptin plus docetaxel for the treatment of patients with HER2-positive MBC who have 
not received prior anti-HER2 therapy or chemotherapy for metastatic disease.  The 
pertuzumab treatment effect is unlikely to be sensitive to ethnic factors because of its
mechanism of action, the biological similarities in HER2-positive disease throughout the 
world, and similarities in medical practice between Asian and Western countries.  
Nevertheless, the safety and efficacy of pertuzumab treatment in Chinese patients with 
MBC will be evaluated in this study.
2.
OBJECTIVES
2.1
EFFICACY OBJECTIVES
2.1.1
Primary Efficacy Objective
The primary efficacy objective for this study is as follows:

To evaluate the efficacy of pertuzumab plus Herceptin plus docetaxel compared 
with placebo plus Herceptin plus docetaxel in patients with previously untreated 
HER2-positive MBC, as measured by investigator-assessed PFS
2.1.2
Secondary Efficacy Objectives
The secondary efficacy objectives for this study are as follows:

To compare OS between the two treatment arms

To compare the objective response rate (ORR) between the two treatment arms

To compare the duration of objective response between the two treatment arms
2.1.3
Exploratory Objective
The exploratory objective for this study is as follows:

To explore the relationship of biomarkers, such as PI3K status, HER2/3 mRNA, 
PD-L1, and CD8 expression, with efficacy (response rate, PFS, and OS)
2.2
SAFETY OBJECTIVE
The safety objective for this study is as follows:

To compare the safety profile between the two treatment arms (including crossover 
patients and those no longer receiving placebo)


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3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
This study is a Phase III, randomized, double-blind, placebo-controlled, multicenter
clinical trial in China.  Patients who have HER2-positive MBC and have not received
chemotherapy or biologic therapy (including approved or investigational tyrosine 
kinase/HER inhibitors or vaccines) for their metastatic disease are eligible for the study.  
Patients who have received one prior hormonal treatment for MBC are eligible.  Patients 
may have received systemic breast cancer treatment in the neoadjuvant or adjuvant 
setting, provided that the patient experienced a diseasefree interval (DFI) of
12 months from completion of systemic treatment (excluding hormonal therapy) to 
metastatic diagnosis.  Patients may have received Herceptin and/or a taxane in the
neoadjuvant or adjuvant setting.  HER2-positive status determined using archival,
paraffin-embedded tumor tissue will be confirmed in a central laboratory by IHC and/or 
FISH.
A total of 240 patients will be randomized in a 1:1 ratio to one of two treatment arms:
Arm A

Placebo, administered by intravenous (IV) infusion every 3 weeks until disease 
progression or unacceptable toxicity

Herceptin (8 mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent 
cycles), administered by IV infusion every 3 weeks until disease progression or 
unacceptable toxicity

Docetaxel (75 mg/m2), administered by IV infusion every 3 weeks
Prior to completion of Cycle 6, docetaxel should be discontinued only for 
disease progression or unacceptable toxicity.  After completion of Cycle 6, 
discontinuation of docetaxel treatment is at the discretion of the patient and 
treating physician.
Arm B

Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent 
cycles), administered by IV infusion every 3 weeks until disease progression or 
unacceptable toxicity

Herceptin (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent 
cycles), administered by IV infusion every 3 weeks until disease progression or 
unacceptable toxicity

Docetaxel (75-mg/m2), administered by IV infusion every 3 weeks
Prior to completion of Cycle 6, docetaxel should only be discontinued for 
disease progression or unacceptable toxicity.  After completion of Cycle 6, 
discontinuation of docetaxel treatment is at the discretion of the patient and 
treating physician.


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Study treatment will be discontinued at the time of disease progression or unacceptable 
toxicity, with the possible exception of docetaxel, as described above.  Tumor 
assessments will be performed as per local clinical practice, regardless of treatment 
delays, until disease progression (see Figure 1).
At the primary analysis (2018), clinically meaningful improvement in the primary 
efficacy endpoint of investigator-assessed PFS was demonstrated.  As a result, upon 
approval of protocol YO29296 Version 4, patients in Arm A who are still receiving 
study treatment will be offered the option to cross over and receive pertuzumab (in 
place of placebo) in addition to Herceptin and docetaxel until disease progression or 
unacceptable toxicity.  For patients in Arm A who do not choose the crossover option, 
placebo will be discontinued and study treatment with Herceptin and docetaxel will 
continue until disease progression or unacceptable toxicity.
Patients who are still receiving study treatment at the time of the end of this study will 
continue to be offered study treatment until disease progression or unacceptable 
toxicity.  Patients may receive pertuzumab as part of an open-label extension (OLE) 
Study MO29406, if eligible (see Section 3.1.1).   Criteria for continued access to Roche 
IMPs after the end of Study YO29296 are provided in Section 4.3.4.
After discontinuation of study treatment, information on survival and cancer-related 
therapies and medical or surgical procedures will be collected by telephone every 
18 weeks until the end of the study, death, loss to follow-up, withdrawal of consent, or 
study termination by the Sponsor.  Under no circumstances are patients who enroll in 
this study permitted to be re-randomized to this study and enrolled for a second course 
of treatment. The study design is presented graphically in Figure 1.  A schedule of 
assessments is provided in Appendix 1.


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Figure 1
Study Schema
HER2human epidermal growth factor receptor 2.
Note:  Upon approval of protocol YO29296 Version 4, tumor assessments will be performed as 
per local clinical practice.
a Prior to completion of Cycle 6, docetaxel should be discontinued only for disease progression 
or unacceptable toxicity.  After completion of Cycle 6, discontinuation of docetaxel treatment is 
at the discretion of the patient and treating physician.
3.1.1
Open-Label Extension Study MO29406
Patients may have the opportunity to continue treatment with pertuzumab as part of 
OLE Study MO29406, if protocol-defined criteria are met (see Section 4.3.4).
3.1.2
Interim Analyses
No interim analysis of efficacy is planned.
3.2
END OF STUDY
The end of the study is defined as 3 years after the date when the last patient is enrolled 
(LPI), or when the last patient, last visit (LPLV) occurs, whichever occurs later.


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3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Including Patients Who Have Received Prior
Hormonal Treatment for Metastatic Breast Cancer
Patients who have received one prior hormonal treatment for MBC will be eligible for this 
trial. The results of a randomized, controlled study suggested that prior hormonal 
treatments did not appear to have a significant effect on the benefit of Herceptin (Slamon 
et al. 2001).  Approximately 25% of all enrolled patients had received prior hormonal 
therapy in the MBC treatment setting.  Efficacy gains were similar in patients with tumors 
that were estrogen receptor (ER) or progesterone receptor (PgR) positive, or both.  
3.3.2
Rationale for Using the Combination of Herceptin and 
Docetaxel for Patients with HER2-Positive Metastatic Breast 
Cancer
Currently, there is no single chemotherapy regimen that can be considered the global 
standard of care for MBC.  However, on the basis of positive results from two large,
pivotal trials (Studies H0648g and M77001), the combination of Herceptin with a taxane 
is now established as a first-line treatment of choice for patients with HER2-positive 
MBC (Slamon et al. 2001; Marty et al. 2005).
The objectives of Study H0648g were to evaluate the efficacy and safety of Herceptin in 
combination with first-line chemotherapy regimens, including paclitaxel.  The study 
enrolled 469 patients.  The results of Study H0648g demonstrated that the combination 
of Herceptin and paclitaxel significantly prolonged the time to progressive disease 
compared with paclitaxel alone (median, 7.4 months versus 4.6 months; p 0.001).  
Patients treated with Herceptin and paclitaxel had an increased response rate
(50% versus 32%; p0.001) and an improved OS (median, 25.1 months versus
20.3 months; p0.046) compared with paclitaxel alone (Slamon et al. 2001).
Similar results were obtained in a randomized, multicenter trial (Study M77001) of 
Herceptin combined with docetaxel versus docetaxel alone, as first-line therapy for 
HER2overexpressing MBC (Marty et al. 2005), as detailed in Section 1.1.
3.3.3
Rationale for Using the Combination of Herceptin, Pertuzumab, 
and Docetaxel for Patients with HER2-Positive Metastatic 
Breast Cancer
Pertuzumab, a recombinant humanized monoclonal antibody to the HER2 receptor, 
exerts its activity by inhibiting HER2 homo- and heterodimerization.  Herceptin, another 
humanized monoclonal antibody to the HER2 receptor, blocks HER2 signaling pathways 
when HER2 is overexpressed on breast tumor cells.  These two monoclonal antibodies 
bind to distinct epitopes on the HER2 receptor without competing with each other, 
resulting in two distinct mechanisms for disrupting HER2 signaling.  These mechanisms 
are complementary and result in augmented therapeutic efficacy when pertuzumab and
Herceptin are given in combination.


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Nonclinical data suggest at least additive efficacy when the two agents are administered 
together, resulting in significantly reduced tumor volume compared with either agent 
alone.  Clinically, pertuzumab may have optimal therapeutic effects when given in 
combination with Herceptin to patients with HER2-positive cancers, as evidenced by 
data generated in a Phase II study of patients with previously treated HER2-positive 
MBC (Baselga et al. 2007) and confirmed by data from a Phase III, global, multicenter
CLEOPATRA (Swain et al. 2013).
In this study, docetaxel will be included in the standard treatment plan, because it has 
been proven efficacious when combined with Herceptin in women with HER2-positive 
MBC and should provide clinical benefit independent of pertuzumab.
3.3.4
Rationale for Dosage Selection of Pertuzumab, Herceptin, and 
Docetaxel
The dose of pertuzumab was based on pharmacokinetic (PK) studies demonstrating 
similar pharmacokinetics observed across doses with a range or 2.0-15.0 mg/kg 
(140 mg-1050 mg for a 70-kg patient) (Agus et al. 2005).  A two-compartment model 
adequately described the concentration-time data, with a systemic serum clearance of 
approximately 0.24 L/day and a terminal half-life of approximately 17 days for a typical 
patient.  On the basis of these data, a dosing interval of 3 weeks is recommended in 
clinical studies.  In the Phase II studies, a loading dose of 840 mg (followed by 420 mg
every 3 weeks) was capable of attaining steady-state trough and peak concentrations by 
the second cycle.  Population PK modeling of data from Phase Ia and Phase II studies 
supports the continued use of fixed, nonweight-based dosing in female patients 
(Ng et al. 2006).  Additionally, there was no evidence of an impact of pertuzumab on the
pharmacokinetics of co-administered chemotherapeutic agents docetaxel and 
capecitabine in Phase Ib studies.
One study, that evaluated docetaxel in doses of 60, 75, or 100 mg/m2, demonstrated 
similar PFS and OS outcomes between patients who received docetaxel 75 mg/m2 and 
patients who received docetaxel 100 mg/m2, suggesting that either dose may be 
effective (Harvey et al. 2006).  The study also demonstrated a dosetoxicity effect with 
respect to myelosuppression and the incidence of febrile neutropenia.  Therefore, 
docetaxel 75 mg/m2 IV every 3 weeks may be equally efficacious with a more favorable 
safety profile compared with docetaxel 100 mg/m2 IV every 3 weeks.  Given the prior 
safety experience with docetaxel and pertuzumab, and the recognized risk of Grade 3 or 
4 neutropenia or febrile neutropenia with Herceptin plus docetaxel, the docetaxel dose 
employed in this trial will be 75 mg/m2.  Safety data are available for Herceptin given 
every 3 weeks (8-mg/kg loading dose, followed by 6-mg/kg for subsequent doses), either 
alone (Study WO16229) or with paclitaxel (Study BO15935).  These data suggest that 
there is no clinically important difference in the safety profile when Herceptin is given 
every 3 weeks versus every week (i.e., according to the approved schedule).


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3.3.5
Rationale for Exploratory Biomarker Analyses
Within CLEOPATRA a panel of biomarkers have been assessed to explore a potential 
prognostic and predictive value. While no predictive value could be determined for any of 
the markers tested, a strong prognostic impact was observed for PIK3CA status with 
patients whose tumors carried a PIK3CA mutation showing significantly poorer 
prognosis compared to patients whose tumors were tested wild type for PIK3CA 
(Baselga et al. 2012). A similar but less strong effect was observed for HER2 mRNA 
levels.  As the number of Chinese patients in WO20698 was very small, it is planned to 
explore these two markers PIK3CA and HER2/3 mRNA in this study to explore the 
incidence of PIK3CA mutation and the levels of HER2/3 mRNA in the Chinese 
population and the potential value as prognostic and/or predictive markers.
With the evolving field of cancer immunotherapy and newly emerging data on 
association of immune markers in response to HER2 targeted therapy, PD-L1 and CD8 
may be assessed as well, if tissue availability allows for it. This may allow exploration of
the impact of PD-L1 expression on outcome, as well as relationship of degree of 
infiltration of tumor and stromal tissue by cytotoxic T-cells, as assessed by CD8 IHC 
staining.
Additional markers may be assessed based on tissue availability and scientific interest 
and requirement.
3.4
OUTCOME MEASURES 
3.4.1
Efficacy Outcome Measures
3.4.1.1
Primary Efficacy Outcome Measure
The primary efficacy outcome measure for this study is as follows:

PFS, defined as the time from randomization to the first occurrence of disease 
progression, as determined by the investigator using Response Evaluation Criteria 
in Solid Tumors, Version 1.1 (RECIST v 1.1; Therasse et al. 2000), or death from 
any cause within 18 weeks after the final tumor assessment, whichever occurs first
Assessments will be based on review of radiological images (e.g., magnetic 
resonance imaging [MRI] scans, computed tomography [CT] scans, bone 
scans, chest X-rays), as well as cytologic (e.g., relevant cytology reports 
documenting malignant pleural effusions, bone marrow aspirations, cerebral 
spinal fluid) and photographic data, if available.
3.4.1.2
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures for this study are as follows:

OS, defined as the time from randomization to death from any cause

Objective response, defined as a CR or PR that is confirmed 2842 days later, as 
determined by the investigator using RECIST v 1.1

Duration of objective response, defined as the time from the first occurrence of a 
documented objective response to the time of disease progression, as determined 
by the investigator using RECIST v 1.1, or death from any cause, whichever occurs 
first


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3.4.1.3
Exploratory Efficacy Outcome Measures
The exploratory outcome measures for this study may include, but are not limited to, the 
following:

Expression level of HER2/3 mRNA as measured by quantitative real-time 
polymerase chain reaction (qRT-PCR)

PIK3CA status(i.e., mutation not detected or mutation detected by PCR based 
mutational analyses or by other technologies suited for mutational analyses)

Expression of PD-L1 and CD8 as assessed by IHC or by other suitable technologies
3.4.2
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence of symptomatic LVSD

Incidence of asymptomatic LVEF events

LVEF measurements over the course of the study

Incidence and severity of AEs and serious adverse events (SAEs) based on 
National Cancer Institute Common Toxicity Criteria for Adverse Events, Version 4.0
(NCI CTCAE v 4.0)

Changes in clinical laboratory results during the study
4.
MATERIALS AND METHODS
4.1
PATIENTS
The study population for this trial is patients with HER2-positive MBC who have not been 
previously treated with chemotherapy and/or biologic therapy for their MBC.  Patients 
with Stage IV disease at initial disease presentation as well as those who have 
progressed following either neoadjuvant or adjuvant therapy with a DFI of 12 months 
will be included, and they may have received Herceptin and/or taxanes in the 
neoadjuvant or adjuvant setting.  
4.1.1
Inclusion Criteria
Patients must meet the following inclusion criteria to be eligible for study entry:

Signed Informed Consent Form, obtained prior to any study procedure

Age 18 years

Histologically or cytologically confirmed adenocarcinoma of the breast with locally 
recurrent or metastatic disease that is suitable for chemotherapy
Patients with measurable or nonmeasurable disease are eligible.  
Patients with only bone metastases are eligible provided that some bone 
metastases have not been previously irradiated and that tumor tissue samples 
from the primary tumor are available for central HER2 testing.
Locally recurrent disease must not be amenable to resection with curative intent.


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
HER2-positive MBC (defined as 3by IHC and/or ISH amplification ratio 2.0)
confirmed by a Sponsor-designated central laboratory
It is strongly recommended that a formalinfixed paraffinembedded (FFPE) 
tissue block from the primary tumor (or metastatic lesion if the primary is not 
available) be submitted for central laboratory confirmation of HER2 eligibility.  
However, if that is not possible, unstained and freshly cut slides need to be
submitted (see Section 4.5.3 for further details).  Tissue will subsequently be 
used for assessment of biomarkers.

LVEF 55% at baseline (within 42 days prior to randomization) as determined by 
either echocardiography (ECHO) or multiplegated acquisition (MUGA) scan
(ECHO is the preferred method)
If the patient is randomized, the same method of LVEF assessment, ECHO or
MUGA, must be used throughout the study, and to the extent possible, be 
obtained at the same institution (see Section 4.5.8).  Any prestudy LVEF values 
obtained during and after Herceptin neoadjuvant or adjuvant treatment will be 
obtained, as applicable.

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

For women who are not postmenopausal (postmenopausal defined as 12 months 
of nontherapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or 
uterus):  agreement to remain abstinent or use single or combined nonhormonal 
contraceptive methods that result in a failure rate of 1% per year during the 
treatment period and for at least 7 months after the last dose of study treatment
(Herceptin and/or pertuzumab)
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle 
of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception.
Examples of non-hormonal contraceptive methods with a failure rate of 1% 
per year include tubal ligation, male sterilization, and certain non-hormonal 
intrauterine devices.  Alternatively, two methods (e.g., two barrier methods such 
as a condom and a cervical cap) may be combined to achieve a failure rate 
of 1% per year. Barrier methods must always be supplemented with the use 
of a spermicide

For men: agreement to remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of 1% per year during the 
treatment period and for at least 7 months after the last dose of study treatment
(Herceptin and/or pertuzumab)
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle 
of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not acceptable methods of 
contraception.


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
Negative serum pregnancy test in women of childbearing potential, premenopausal 
or less than 12 months of amenorrhea post-menopause, and who have not 
undergone surgical sterilization.

Able to comply with the study protocol, in the investigator’s judgment
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History of anticancer therapy for MBC, with the exception of one prior hormonal 
regimen for MBC, which must be stopped prior to randomization
Anticancer therapy for MBC includes any EGFR or anti-HER2 agents or 
vaccines, cytotoxic chemotherapy, or more than one prior hormonal regimen for 
MBC.  
One prior hormonal regimen for MBC may include more than one hormonal 
therapy.  If a patient is switched to a different hormonal therapy for reasons 
other than disease progression (e.g., toxicity or local standard practice), this will 
be counted as one regimen.  If a patient is switched to a different hormonal 
therapy because of disease progression, this will be counted as two regimens, 
and the patient will not be eligible for the study. 

History of approved or investigative tyrosine kinase/HER inhibitors for breast cancer 
in any treatment setting, except Herceptin used in the neoadjuvant or adjuvant 
setting

History of systemic breast cancer treatment in the neoadjuvant or adjuvant setting 
with a DFI from completion of systemic treatment (excluding hormonal therapy) to 
metastatic diagnosis of 12 months

History of persistent Grade 2 hematologic toxicity resulting from previous 
neoadjuvant or adjuvant therapy (all grades based on NCI CTCAE v 4.0)

Grade 3 peripheral neuropathy at randomization

History of other malignancy within the previous 5 years, except for carcinoma in situ 
of the cervix or non-melanoma skin carcinoma that has been previously treated with 
curative intent

Current clinical or radiographic evidence of CNS metastases
A CT or MRI scan of the brain is mandatory within 28 days before
randomization in cases of clinical suspicion of brain metastases.

History of exposure to the following cumulative doses of anthracyclines: 
Doxorubicin or liposomal doxorubicin 360 mg/m2
Epirubicin 720 mg/m2
Mitoxantrone 120 mg/m2 and idarubicin 90 mg/m2
Other anthracycline greater than the equivalent of 360 mg/m2 of doxorubicin
If more than one anthracycline has been used, the cumulative dose must 
not exceed the equivalent of 360 mg/m2 of doxorubicin.


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
Current uncontrolled hypertension (systolic blood pressure 150 mmHg and/or 
diastolic blood pressure 100 mmHg) or unstable angina

History of CHF of any New York Heart Association (NYHA) classification, or serious 
cardiac arrhythmia requiring treatment (excluding atrial fibrillation or paroxysmal 
supraventricular tachycardia)

History of myocardial infarction within 6 months prior to randomization

History of LVEF decrease to 50% during or after prior Herceptin neoadjuvant or 
adjuvant therapy

Current dyspnea at rest due to complications of advanced malignancy, or other 
diseases that require continuous oxygen therapy

Inadequate organ function, evidenced by the following laboratory results within 
28 days prior to randomization:
Absolute neutrophil count 1500 cells/L
Platelet count 100,000 cells/L
Hemoglobin 9 g/dL 
Total bilirubin greater than the upper limit of normal (ULN) (unless the patient 
has documented Gilbert’s syndrome)
AST or ALT 2.5 ULN ( 5 ULN in patients with liver metastases)
AST (SGOT) or ALT (SGPT) 1.5 ULN with concurrent serum ALP
2.5 ULN
Serum ALP may be 2.5 ULN only if bone metastases are present and 
AST and ALT are 1.5 ULN.  
Serum creatinine 2.0 mg/dL or 177 mol/L
INR and aPTT or PTT 1.5 ULN (unless on therapeutic anti-coagulation)
Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, or metabolic disease; wound healing disorders; 
ulcers; bone fractures)

Major surgical procedure or significant traumatic injury within 28 days prior to 
randomization or anticipation of the need for major surgery during the course of 
study treatment

Pregnant or lactating or intending to become pregnant during the study

Treatment with any investigational treatment within 28 days prior to randomization

Current known infection with HIV, hepatitis C virus, or active hepatitis B virus (HBV)
Patients who are known carriers of HBV may be included in the study. Active 
HBV is defined as presence of each of the following:  positive test for 
hepatitis B surface antigen, detectable levels of HBV DNA, and ALT ULN.

Receipt of IV antibiotics for infection within 14 days prior to randomization


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
Current chronic daily treatment with corticosteroids (dose of 10 mg/day 
methylprednisolone equivalent), excluding inhaled corticosteroids

Known hypersensitivity to any of the protocolspecified study treatments

Concurrent participation in an interventional or noninterventional study
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
A total of approximately 240 patients (approximately 120 per treatment arm) will be 
enrolled from approximately 20 sites in China.  An interactive voice or Webbased 
response system (IxRS) will be utilized to collect patient screening information and to 
randomize eligible patients in a 1:1 ratio to one of two treatment arms.
A permuted block randomization scheme will be applied to achieve balance in treatment
assignment within each of four strata:  disease type (visceral disease vs. non-visceral 
disease) and hormone receptor status (ER and PgR negative or ER and/or PgR positive).
Non-visceral disease will include tumors located in the breast, bone, bone marrow,
lymph nodes, skin and soft tissue. All other locations will be classed as visceral disease. 
Patients with tumors in multiple locations that cover both visceral and non-visceral
disease (e.g., a patient with a tumor in the liver and bone lesions) will be classed as 
having "visceral disease" for the purposes of the analysis.
Treatment unblinding should be considered only when knowledge of the treatment 
assignment is deemed essential for the patient’s care by the investigator or a regulatory 
body.  In general, unblinding of participant’s treatment assignment during the conduct of 
the clinical study is not allowed unless there are compelling medical or safety reasons. If 
unblinding is necessary for patient management (e.g., in the case of a serious adverse 
event for which patient management might be affected by knowledge of treatment 
assignment), the investigator will be able to break the treatment code by accessing the 
IxRS.  Treatment codes should not be broken except in emergency situations.  If the 
investigator wishes to know the identity of the study drug for any other reason, he or she 
should contact the Medical Monitor directly.  The investigator should document and 
provide an explanation for any premature unblinding (e.g., accidental unblinding, 
unblinding due to a serious adverse event).
Unblinding will occur for Sponsor personnel involved in analyzing, reporting, and 
submitting the results of the primary analysis to regulatory authorities.
Upon approval of protocol YO29296 Version 4, the treatment assignment of patients in 
Arm A who are still on study treatment will be unblinded, allowing the investigators to 
present those patients with the option to cross over and receive pertuzumab (in place of 
placebo) in addition to Herceptin and docetaxel.


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4.3
STUDY TREATMENT 
Eligible patients will be treated in 3-week cycles with placebo, Herceptin, and docetaxel 
(Arm A) or pertuzumab, Herceptin, and docetaxel (Arm B).  Patients will receive 
pertuzumab and Herceptin until disease progression or unacceptable toxicity.  Prior to 
completion of Cycle 6, docetaxel should be discontinued only for disease progression or 
unacceptable toxicity.  After completion of Cycle 6, discontinuation of docetaxel 
treatment is at the discretion of the patient and treating physician.
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Pertuzumab and Placebo
Pertuzumab and placebo will be supplied by F. Hoffmann-La Roche (the Sponsor) and 
will be labeled according to the regulatory requirements in China and the International 
Conference of Harmonization (ICH) guideline for Good Clinical Practice.  Note that upon 
approval of protocol YO29296 Version 4, placebo will no longer be administered to 
patients in Arm A who are still receiving study treatment (see Section 3.1).
Pertuzumab is provided as a single-use formulation containing 30 mg/mL pertuzumab 
formulated in 20 mM L-histidine (pH 6.0), 120 mM sucrose, and 0.02% polysorbate 20.  
Each 20-cc vial contains approximately 420 mg of pertuzumab (14.0 mL/vial).  
Pertuzumab for use in China is intended only in clinical trials.
The formulation for placebo is equivalent to that for pertuzumab, without the active agent.  
Vials of pertuzumab and placebo will be shipped at a temperature of 2C8C 
(36F46F), must be placed in a refrigerator (same temperature range) immediately 
upon receipt to ensure optimal retention of physical and biochemical integrity, and 
should remain refrigerated until immediately prior to use.  Temperature logs must be 
maintained (in accordance with local pharmacy practice) on the refrigerator to ensure 
proper storage conditions.  If a temperature deviation from the allowed 2C8C is found
during shipment or storage, contact the Sponsor to determine whether the drug is still 
appropriate for use.  
DO NOT FREEZE and DO NOT SHAKE the pertuzumab (or placebo) vials.  Store all 
vials within the outer carton, and protect them from light.  
The medication must not be used beyond the expiration date stamped on the outer 
carton.  
Because the pertuzumab (or placebo) formulation does not contain a preservative, the 
vial seal may be punctured only once.  Any remaining solution should be discarded.
Appropriate aseptic techniques should be used.  Pertuzumab (or placebo) should be 
carefully handled during reconstitution.  The indicated volume of pertuzumab (or placebo)
solution should be withdrawn from the vials and added to a 250-cc IV bag of


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0.9% Sodium Chloride Injection.  Gently invert the bag to mix the solution.  DO NOT 
SHAKE VIGOROUSLY.  Visually inspect the solution for particulates and discoloration 
prior to administration.  The entire volume within the bag should be administered as a 
continuous IV infusion.  The volume contained in the administration tubing should be 
completely flushed using a 0.9% Sodium Chloride Injection.
The solution of pertuzumab (or placebo) for infusion diluted in polyvinyl chloride (PVC) or 
non-PVC polyolefin bags containing 0.9% Sodium Chloride Injection may be stored at 
2C8C (36F46F) for up to 24 hours prior to use.  Diluted pertuzumab has been 
shown to be stable for up to 24 hours at room temperature (2C25C).  However, since 
diluted pertuzumab (or placebo) contains no preservative, the aseptically diluted solution 
should be stored refrigerated (2C8C) for no more than 24 hours.
A rateregulating device may be used for all study drug infusions.  
Should extravasation of the study drug infusion occur, the following steps should be 
taken:

Discontinue the infusion

Treat the extravasation according to institutional guidelines for extravasation of a 
non-caustic agent

If a significant volume of study drug remains, restart the infusion at a more proximal 
site in the same limb or on the opposite side
For further details, see the pertuzumab Investigator's Brochure.
4.3.1.2
Herceptin
Investigational Herceptin will be supplied by the Sponsor and will be labeled according to 
the regulatory requirements in China and the ICH guideline for Good Clinical Practice.
Herceptin will be provided as a freezedried preparation at a nominal content of 440 mg 
per vial.  Herceptin is formulated in histidine, trehalose, and polysorbate 20.  Once 
reconstituted, each solution contains 21 mg/mL of active drug at a pH of 
approximately 6.0.
Vials of Herceptin will be shipped at a temperature of 2C8C (36F46F), must be 
placed in a refrigerator (same temperature range) immediately upon receipt to ensure 
optimal retention of physical and biochemical integrity, and should remain refrigerated 
until immediately prior to use.  Temperature logs must be maintained (in accordance 
with local pharmacy practice) on the refrigerator to ensure proper storage conditions.  If 
a temperature deviation from the allowed 2C8C is found either during shipment or 
storage, contact the Sponsor to determine whether the drug is still appropriate for use.  
DO NOT FREEZE and DO NOT SHAKE the Herceptin vials.  Store all vials within the 
outer carton, and protect them from light.  


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The medication must not be used beyond the expiration date stamped on the outer 
carton.  
Each vial of Herceptin 440 mg is reconstituted with 20 mL of either Sterile Water for 
Injection (SWFI) or Bacteriostatic Water for Injection, USP, 1.1% benzyl alcohol 
preserved.  If the Herceptin is reconstituted with SWFI, it is suitable for single use only.
Use of other reconstitution solvents is not allowed.  
Appropriate aseptic techniques should be used.  Herceptin should be carefully handled 
during reconstitution.  Using a sterile syringe, slowly inject the SWFI in the vial 
containing the lyophilized Herceptin, directing the stream into the lyophilized cake.  Swirl 
the vial gently to aid reconstitution.  Herceptin may be sensitive to shearinduced stress 
(e.g., agitation or rapid expulsion from a syringe).  DO NOT SHAKE.  Vigorous handling 
of solutions of Herceptin results in aggregation of the protein and may create cloudy 
solutions.  Causing excessive foaming during reconstitution or shaking the reconstituted 
Herceptin may result in problems with the amount of Herceptin that can be withdrawn 
from the vial.
Slight foaming of the product upon reconstitution is not unusual. Allow the vial to stand 
undisturbed for approximately 5 minutes.  The reconstituted Herceptin results in a 
colorless to pale yellow transparent solution and should be essentially free of visible 
particulates.
The reconstituted solution contains 21 mg/mL of Herceptin, at a pH of approximately 6.0, 
and the appropriate calculated volume will be added in to 250 mL of 0.9% Sodium 
Chloride Injection.  
Herceptin should not be mixed or diluted with other drugs.  Do not administer as an 
IV push or bolus dose.
Determine the volume of the solution required on the basis of a loading dose of 8 mg of 
Herceptin per kilogram body weight, or a subsequent dose of 6 mg of Herceptin per 
kilogram body weight:
Volume (in mL)Body Weight (in kg)Dose (8 mg/kg or 6 mg/kg)
21 mg/mL (concentration of reconstituted solution) 
The appropriate amount of solution should be withdrawn from the vial and added to an 
infusion bag containing 250 mL of 0.9% Sodium Chloride Injection.  Do not use with 
glucosecontaining solutions, since it causes aggregation of the protein.  The bag 
should be gently inverted to mix the solution to avoid foaming.  Parenteral solutions 
should be inspected visually for particulates and discoloration prior to administration.  
Once the infusion is prepared, it should be administered immediately.  If diluted 


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aseptically, it may be stored for a maximum of 24 hours from reconstitution (do not 
store above 30 C).  No incompatibilities between Herceptin and PVC or polyethylene 
bags have been observed.
For further details, see the Herceptin local prescribing information and the Herceptin
Investigator's Brochure.
4.3.1.3
Docetaxel
Docetaxel will be obtained locally by the investigational sites.  Refer to the docetaxel 
prescribing information for information on formulation, preparation, and administration.
4.3.2
Dosage, Administration, and Compliance
Study treatment cycles are 3 weeks (213 days) in length.  The first dose of study 
treatment (Day 1 of Cycle 1) should be administered within 3 days after the date of 
randomization.  Study treatments will be administered in the following sequence: 
Pertuzumab (or Placebo) → Herceptin → Docetaxel
The treatment schedule, including details on dose, infusion duration, and observation 
period for each treatment, is summarized in Table 1.


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Table 1
Study Treatment Schedule
Cycle
Blinded Pertuzumab
(or Placebo)
Herceptin
Docetaxel
Cycle 1  
Timepoint:  Day 1
Timepoint:  Day 1
Timepoint:  Day 1
Timing:  After pertuzumab
(or placebo) observation 
period 
Timing:  After Herceptin
observation period 
Dose:  840 mg
Dose:  8 mg/kg
Dose:  75 mg/m2
Infusion duration:  60 min 
Infusion duration:  90 min
Infusion duration:  60 min
Observation period:  
60 min
Observation period:  
60 min
Observation period:  
According to institution 
standards
Subsequent
cycles
Timepoint:  Day 1
Timepoint:  Day 1
Timepoint:  Day 1
Timing:  After pertuzumab
(or placebo) observation 
period 
Timing:  After Herceptin
observation period 
Dose:  420 mg a
Dose:  6 mg/kg d
Dose:  75 mg/m2
Infusion duration:  30 min 
or 60 min b
Infusion duration:  30 min 
or 90 min e
Infusion duration:  60 min
Observation period:  
30 min or 60 min c
Observation period:  
30 min or 60 min c
Observation period:  
According to institution 
standards
a If a patient misses a dose of pertuzumab (or placebo) (i.e., two sequential administration times 
are 6 weeks or more apart), a re-loading dose of 840 mg should be given.  Subsequent doses 
of 420 mg will then be given every 3 weeks, starting 3 weeks later.  
b If the first infusion of pertuzumab (or placebo) is tolerated without infusionassociated adverse 
events (fever and/or chills), the subsequent infusions may be delivered over 30 minutes.
c If the first infusion of pertuzumab (or placebo) or Herceptin is well tolerated without 
infusionassociated adverse events, the subsequent observational periods may be reduced 
from 60 minutes to 30 minutes.
d If a patient misses a dose of Herceptin (i.e., two sequential administration times are 6 weeks or 
more apart), a re-loading dose of 8 mg/kg should be given.  Subsequent doses of 6 mg/kg will 
then be given every 3 weeks, starting 3 weeks later.
e If the first infusion of Herceptin is tolerated without infusionassociated adverse events (fever 
and/or chills), the second and subsequent infusions may be delivered over 30 minutes.
4.3.2.1
Pertuzumab (or Placebo) Dose and Schedule
Pertuzumab (or placebo) will be administered by IV infusion on Day 1 of each 3-week 
cycle, at a loading dose of 840 mg for Cycle 1 and a dose of 420 mg for subsequent 
cycles, until disease progression or unacceptable toxicity.  The pertuzumab dose is not
adjusted for any changes in body weight.  No dose reduction will be allowed.  
Administration may be delayed to assess or treat AEs such as cardiac AEs or 
myelosuppression.  If a patient misses a dose of pertuzumab (or placebo) for one cycle 
(i.e., two sequential administration times are 6 weeks or more apart), a re-loading dose 
of 840 mg should be given.  Subsequent doses of 420 mg will then be given every 
3 weeks, starting 3 weeks later.  
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.2.


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4.3.2.2
Herceptin Dose and Schedule
Herceptin will be administered by IV infusion on Day 1 of each 3-week cycle, at a loading 
dose of 8 mg/kg for Cycle 1 and a dose of 6 mg/kg for subsequent cycles, until disease 
progression or unacceptable toxicity.  Baseline body weight will be used to calculate 
required doses of Herceptin.  The dose of Herceptin will be re-calculated if a patient's
body weight changes from baseline by10%. If the dose is recalculated because of a 
10% change in weight from baseline, this weight will then be used as the new baseline 
to calculate Herceptin dose in subsequent cycles.  No dose reduction will be allowed, 
except in the case of body weight changes.
Administration may be delayed to assess or treat AEs such as cardiac AEs or 
myelosuppression. If a patient misses a dose of Herceptin for one cycle (i.e., two
sequential administration times are 6 weeks or more apart), a reloading dose of 8 mg/kg
should be given.  Subsequent doses of 6 mg/kg will then be given every 3 weeks, 
starting 3 weeks later. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.2.
4.3.2.3
Docetaxel
Docetaxel 75 mg/m2 will be administered by IV infusion on Day 1 of each 3-week cycle.  
Prior to completion of Cycle 6, docetaxel should be discontinued only for disease 
progression or unacceptable toxicity.  After completion of Cycle 6, discontinuation of 
docetaxel treatment is at the discretion of the patient and treating physician.
Baseline body surface area will be used to calculate required doses of docetaxel.  
Weight and height should be recorded at baseline, and weight should be recorded at 
every scheduled visit. Height should be remeasured if the investigator thinks it is 
possible that the patient's height may have changed. Docetaxel dose adjustments due 
to changes in weight should be recalculated if the patient’s weight has increased or
decreased by 10% from baseline. If the dose is recalculated because of a 10%
change in weight from baseline, this weight will then be used as the new baseline to 
calculate docetaxel dose in subsequent cycles. A nomogram will be provided for the 
determination of body surface area (see Appendix 5).
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.2.
4.3.3
Investigational Medicinal Product Accountability
All investigational medicinal products (IMPs) required for completion of this study 
(pertuzumab, placebo, and Herceptin) will be provided by the Sponsor. The 
investigational site will acknowledge receipt of IMPs and confirm the shipment condition 
and content.  Any damaged shipments will be replaced.  Sites will obtain and utilize 
commercially available docetaxel.  


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IMPs will be either disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed upon by the 
Sponsor.  The site must obtain written authorization from the Sponsor before any IMP is 
destroyed, and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
4.3.4
Post-Trial Access to Pertuzumab
The Sponsor will offer continued access to Roche IMPs (pertuzumab and Herceptin) 
free of charge to eligible patients in accordance with the Roche Global Policy on 
Continued Access to Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive Roche IMPs (pertuzumab and Herceptin) after 
completing the study if all of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them
A patient will not be eligible to receive Roche IMPs (pertuzumab and Herceptin) after 
completing the study if any of the following conditions are met:

The Roche IMP is commercially marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's insurance or 
wouldn't otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the IMP or data suggest that the 
IMP is not effective for HER2-positive MBC

The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
HER2-positive MBC

Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
Patients may be eligible to receive pertuzumab as part of an extension study, as 
described in Section 3.1.1.


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4.4
CONCOMITANT THERAPY AND PROCEDURES
4.4.1
Permitted Therapy and Procedures
All concomitant medications (e.g., prescription drugs, over-the-counter drugs, 
herbal/homeopathic remedies, nutritional supplements) should be reported to the 
investigator and recorded on the Concomitant Medications electronic Case Report Form 
(eCRF).  
Patients should receive full supportive care (e.g., transfusion of blood and blood 
products, antibiotics) according to standard of care when necessary.
All protocolallowed medications taken by the patient for concomitant disease should 
continue as necessary during the study and be recorded on the Concomitant 
Medications eCRF.  The following list of permitted medications is provided as guidance.  
Treatments prescribed to patients should be adapted according to the local 
standard-of-care practices.  
The following treatments and procedures are permitted:

Paracetamol (acetaminophen) or other analgesics, and diphenhydramine, 
chlorpheniramine, or other antihistamines may be used according to local clinical 
practice for the prevention and treatment of infusion reactions associated with 
pertuzumab and/or Herceptin

Medication to treat diarrhea (e.g., loperamide)

Granulocyte colony-stimulating factor may be used according to the product license 
and according to the currently approved prescribing information for docetaxel and 
American Society of Clinical Oncology clinical guidelines (Smith et al. 2015)

Steroids for docetaxel premedication and anti-emetics according to routine practice 
at each clinical site 

Inhaled steroids for asthma

Bisphosphonates may be given according to their product license and routine 
clinical practice, at the investigator’s discretion 

Palliative surgical procedures
Any diagnostic, therapeutic, or surgical procedure performed during the study 
period should be recorded, including the dates, description of the procedure,
and any clinical findings.

Placement of a central venous access device (CVAD)
As a precautionary measure, it is recommended but not strictly required that
CVAD placement be performed at least 7 days prior to initiation of study 
treatment.  The date of CVAD placement should be noted in the medical record 
and recorded in the eCRF.  Episodes of CVAD replacement should be recorded, 
as should CVADrelated thrombosis, infection, or dysfunction.  


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
Anticoagulation therapy for maintenance of patency of permanent indwelling 
IV catheters

Palliative radiotherapy
Radiotherapy is allowed only during the study treatment period for treatment of 
bone lesions present at baseline, if it is non-target lesion.  If a patient requires 
radiation therapy to a new lesion, that new lesion would, per RECIST v 1.1,
qualify as progressive disease.

Acceptable non-hormonal methods of contraception (i.e., single or combined 
non-hormonal contraceptive methods that result in a failure rate of 1% per year)
4.4.2
Prohibited Therapy
The following treatments are not permitted:

Treatment with other systemic anticancer agents (e.g., chemotherapy, hormonal 
therapy, immunotherapy) or nonprotocol-specified anticancer therapies

Any oral, injected, or implanted hormonal methods of contraception

Concurrent investigational agents of any type

Initiation of herbal remedies for cancer treatment
Herbal remedies initiated prior to study entry and continuing during the study 
are permitted and must be reported on the appropriate eCRF.
The following treatments should be avoided because of the risk of immunosuppression:

Chronic or high-dose oral corticosteroid therapy

TNF-inhibitors

AntiT cell antibodies
4.5
STUDY ASSESSMENTS 
See Appendix 1 for the schedule of assessments performed during the study.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site.
An Eligibility Screening Form (ESF) documenting the patient’s fulfillment of the entry 
criteria is to be completed by the investigator or a designee for all patients considered for 
the study and subsequently included or excluded.  All ESFs should be kept in the study 
files at the sites.  Additionally, copies of records of all prior Herceptin dosing in 
neoadjuvant or adjuvant setting and ECHO/MUGA reports should be retained with the 
study files at the investigative sites, for randomized and screen-failure patients.


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4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases within the previous 5 years, breast 
cancer history (including tumor characteristics such as hormone-receptor status), prior 
cancer therapies and procedures (including any Herceptin treatment), complete 
cardiovascular history (including all prior LVEF values), smoking history, and all 
medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic 
remedies, nutritional supplements) used by the patient within 90 days prior to the 
screening visit.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Central Assessment of HER2 and ER/PgR Status and 
Biomarker Analyses
Mandatory tumor samples from the primary tumor (or metastatic sites, if the primary 
tumor is not available) will be submitted from all subjects during screening and submitted 
to a central pathology laboratory for assessment of HER2 via IHC and ISH for study 
eligibility, as well as for the assessment of ER/PgR status for patient stratification.  
Furthermore, tumor tissue biomarkers (e.g., PIK3CA mutation status and HER2/3 mRNA 
levels), will be determined to assess potential impact on prognosis of patients and/or 
pertuzumab/Herceptin response prediction.  Markers, such as PD-L1 and CD8, may be 
assessed to explore association of immune markers to clinical outcome and benefit from 
HER2 targeted therapy.
Tumor tissue samples will be submitted in the form of either paraffin blocks or unstained, 
freshly cut slides containing formalin-fixed tumor tissue. Because uncontrolled oxidation 
processes on the slides may affect slides, tumor tissue blocks are preferred. However, if 
a tumor block is not available, 13 unstained freshly cut slides will be submitted, up to 15 
slides as needed.  From submitted tumor blocks, at the central laboratory, a maximum of 
15 slides will be cut. The remaining part of the tumor block will be returned to the 
institution. HER2 and ER/PgR testing will be prioritized and the tissue will subsequently 
be used for assessment of biomarkers. A variety of technologies may be applied to 
assess the exploratory markers, which may include, but will not be limited to IHC, ISH, 
pCR-based methods, and sequencing technologies.
4.5.4
Physical Examinations
A complete physical examination should include measurements of height and weight 
and an evaluation of the head, and eyes, ears, nose, and throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and 
neurological systems.  Particular care should be taken with regard to cardiovascular 
signs and symptoms (e.g., elevated jugular venous pressure [JVP], sinus tachycardia, 
tachypnea, the presence of an S3 heart sound, crackles on chest auscultation).  Any 
abnormality identified at baseline should be recorded on the General Medical History 
and Baseline Conditions eCRF.


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At subsequent visits (or as clinically indicated), limited, symptomdirected physical 
examinations, including weight measurement, should be performed.  Particular care 
should be taken with regard to cardiovascular signs and symptoms (e.g., elevated JVP, 
sinus tachycardia, tachypnea, the presence of an S3 heart sound, crackles on chest 
auscultation).  Changes from baseline abnormalities should be recorded in patient notes.  
New or worsened clinically significant abnormalities should be recorded as AEs on the 
Adverse Event eCRF.
4.5.5
Vital Signs
Vital signs will include measurement of heart rate and systolic and diastolic blood 
pressures while the patient is in a seated position and temperature.  Vital signs will be 
recorded before and after infusion of each study medication (pertuzumab [or placebo], 
Herceptin, and docetaxel).
4.5.6
Tumor and Response Evaluations
Tumor assessments will be performed as per local clinical practice and will continue
until progressive disease or patient's death.  For patients who discontinue study 
treatment for reasons other than death, withdrawn consent, or investigator-determined 
progression events, efforts should be made to continue performing scheduled tumor 
assessments as per local clinical practice until patients’ death or 
investigator-determined progressive disease.  CT or MRI scans that were performed 
before a patient signed consent to take part in the study may be used to provide 
baseline tumor status as long as they were performed within 28 days prior to the start of 
treatment, at the same hospital, with the same technique or machine, and preferably by 
the same individual as those for tumor assessments during the study.  This should be 
documented in the study files at the site.
RECIST v 1.1 (unidimensional tumor measurement) will be used to evaluate response 
and assess progressive disease.  A summary of RECIST v 1.1 is provided in Appendix 4.


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The minimum screening examinations should include the following:

CT or MRI scan of the chest and abdomen (including liver, spleen, and adrenals)
Positron emission tomography (PET) scans will not be considered for 
assessment of efficacy at any time during the study (except as specified for 
bone scans in the absence of radioactive isotopes).  
CT scans should be performed with a contrast agent.  The CT portion of a 
combination PET/CT scan is generally not performed with contrast; therefore,
PET/CTs are generally not acceptable.  However, if the site has acquired a 
high-quality diagnostic CT scan including the application of contrast agent 
(which may be performed with modern PET/CT scanners), the CT scan portion 
may be adequate for submission and evaluation.  For patients with known 
allergies to the contrast media, it is acceptable to perform a chest CT scan 
without contrast and an MRI scan for the abdomen (ideally at baseline and 
every tumor assessment thereafter).  

CT or MRI scan of the brain and/or spine if there is clinical suspicion of CNS 
metastases

An isotope bone scan (with bone X-rays, as necessary) at baseline
In the absence of radioactive isotopes, an MRI scan (with gadolinium 
enhancement, if required) or 18F-fluorodeoxyglucose PET scan is an 
acceptable form of assessment of the skeleton for the presence of bone 
metastases.  Skeletal survey with plain X-rays is acceptable if there is no 
suitable alternative.  The bone scan should be repeated in the event of clinical 
suspicion of progression of existing bone lesions or the appearance of new 
bone lesions.

Medical photography to monitor chest wall recurrences (i.e., subcutaneous skin 
lesions)
The same assessment technique must be used throughout the study for evaluating a 
particular lesion (e.g., if a CT scan is used to assess metastatic lung lesions at baseline,
a CT scan must be used at all subsequent tumor assessments to assess metastatic lung 
lesions).  The same technique should also be used for cytologic (e.g., relevant cytology 
reports documenting malignant pleural effusions, bone marrow aspirations, cerebral 
spinal fluid) and photographic data, if available.  The same investigator should assess all 
tumor responses for each patient.
For patients with multiple measurable lesions, a maximum of 2 lesions per organ and 
5 lesions in total that are representative of all involved organs should be designated as 
target lesions and recorded and measured at screening.  All other lesions should be 
identified as non-target lesions and should be recorded at baseline.  Measurements of 
these lesions are not required, but the presence or absence of each should be noted 
throughout the treatment period and follow-up, if applicable, until confirmed evidence of 
progressive disease.  Tumor lesions that are situated within a field of previous irradiation 
can be considered measurable if these lesions have shown clinical evidence of 


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progression and can be reproducibly measured over time.  Patients who have metastatic 
disease that is confined to the bone are not eligible for response evaluation but will be 
included in the PFS analysis if the criteria for progressive disease are satisfied 
(i.e., new bone lesions after treatment initiation).
Per RECIST v1.1, confirmatory measurements of complete and partial responses are not 
required.  Stable disease must be confirmed at least 6 weeks after the RECIST v 1.1
criteria for stable disease have been met.
If there is suspicion of progression before the next scheduled tumor assessment, an 
unscheduled assessment is to be performed.  The reason for the unscheduled 
assessment will be reported on the eCRF.
4.5.7
Cardiac Assessments
4.5.7.1
Electrocardiograms
Twelve-lead ECGs for each patient should be obtained from the same machine 
whenever possible.  To minimize variability, it is important that patients be in a resting 
position for 10 minutes prior to each ECG evaluation.  Body position should be 
consistently maintained for each ECG evaluation to prevent changes in heart rate.  
Environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording.  ECGs should be 
performed prior to any scheduled vital sign measurements and blood draws.
4.5.8
Left Ventricular Ejection Fraction
All patients must have their LVEF assessed by 2D ECHO or MUGA scan as part of the 
screening process.  The baseline LVEF assessment should be performed as close as 
possible to but a maximum of 42 days prior to, randomization.  LVEF will be performed
every 9 weeks from the date of randomization until the treatment discontinuation visit, or 
more frequently as needed for cardiac safety.  If an LVEF assessment must be 
performed early or late, subsequent assessments should be conducted according to the 
original schedule of every 9 weeks from the date of randomization.  After the treatment 
discontinuation visit, LVEF measurements will be performed every 6 months in the first 
year, then annually for up to 3 years until the end of the study. Patients for whom study 
treatment is permanently discontinued because of a decrease in LVEF should continue 
to have LVEF assessments repeated as clinically indicated, with a maximum interval 
between LVEF assessments of 3 months, until the LVEF returns to 50% or until 1 year 
after the treatment discontinuation visit, whichever occurs first.  Thereafter, LVEF 
assessments will be performed annually for up to 3 years until the end of the study after 
the treatment discontinuation visit.
ECHO is the preferred method because it can detect wall-motion abnormalities.  LVEF is 
to be calculated using the modified Simpson method and must be 55% at baseline as 
determined by the local facility before a patient can be enrolled in the study.  The 
investigator must decide which method of LVEF assessment (ECHO or MUGA scan) will 


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be used for each patient at baseline, and the same method and the same facility should 
be used throughout the study, to the extent possible.  The LLN for the LVEF facility will 
be reported along with the LVEF result.  Any prestudy LVEF values obtained during and 
after Herceptin neoadjuvant or adjuvant treatment will be obtained, as applicable.
4.5.9
Laboratory Assessments
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, 
differential count [neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells])
Additional tests may be performed per the institution’s standard practice.

Serum chemistry
Baseline and treatment discontinuation visit:  sodium, potassium, chloride, 
bicarbonate, glucose, BUN or urea, creatinine, total protein, albumin, 
phosphorus, calcium, total and direct bilirubin, ALP, ALT, AST, uric acid, LDH
Subsequent timepoints:  potassium, creatinine, total bilirubin, ALP, ALT, AST
Additional tests may be performed per the institution’s standard practice.

Coagulation (INR and aPTT or PT)

Pregnancy test
All women who are not postmenopausal (postmenopausal defined as 
12 months of nontherapy-induced amenorrhea) or surgically sterile will have 
a serum pregnancy test at screening.  Urine pregnancy tests will be performed 
at specified subsequent visits.  If a urine pregnancy test result is positive, it 
must be confirmed by a serum pregnancy test.  For all other women, 
documentation must be present in medical history confirming that the patient is 
not of childbearing potential.
The following samples will be sent to a central laboratory for analysis of HER2 and 
ER/PgR status:

Tissue sample from the primary tumor for central determination of HER2 status by 
IHC and/or ISH and ER/PgR status by IHC
A patient’s HER2 status will be considered positive if the central laboratory 
confirms a score of 3by IHC in 10% of immunoreactive cells and/or HER2
gene amplification (ratio of HER2 gene signals to centromere 17 signals 2.0)
by ISH. The diagnosis should be made on the primary breast cancer specimen 
or on a biopsy of a metastatic site, if primary tumor is not available.  


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It is strongly recommended that an FFPE tissue block from the primary tumor 
(or metastatic site if the primary is not available) be submitted for central 
laboratory confirmation of HER2 eligibility.  However, if that is not possible,
unstained and freshly cut slides need to be submitted (See Section 4.5.3 for 
further details).  The remaining part of the tumor block will be returned to the 
institution. 
The patient’s hormone receptor status will be determined by the central lab 
according to the American Society of Clinical Oncology-College of American 
Pathologists guidelines (Hammond et al. 2011). The ER and PgR status will be 
used as stratification factor but is not relevant to determine patient’s eligibility.
Tumors are considered hormone receptor positive if ER and/or PgR status is 
positive, tumors are considered negative if both ER and PgR are confirmed 
negative at central lab.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Tissue blocks submitted at baseline for eligibility screening and exploratory biomarker 
research will be returned in a batched manner every 6 months after the patient has been 
randomized into the trial. Slides will not be returned. Blocks can be returned 
immediately to sites upon request, in which case the number of slides needed for 
biomarker analyses will be freshly cut, and the block returned.
Stained slides will be kept as raw data for 15 years, and extracted material (DNA and 
RNA) will be stored for at least 5 years after clinical database closure.
4.5.10
Post-Study Follow-up
Patients who discontinue from the study for progressive disease or other reasons will 
receive treatment according to the local standard of care.  After discontinuation of study 
treatment, information on survival and cancer-related therapies and medical or surgical
procedures will be collected by telephone every 18 weeks until death until the end of the 
study, loss to follow-up, withdrawal of consent, or study termination by the Sponsor.
4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include but are not limited to the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient


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Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced.
4.6.2
Study Treatment Discontinuation
For further details on study drug modification and discontinuation, see Sections 5.1.1
and 5.1.2.
Patients must discontinue study treatment if they experience any of the following:

Pregnancy

Symptomatic left ventricular dysfunction (NCI CTCAE Grade 3 or 4) with a decrease
in LVEF consistent with cardiac failure

NCI CTCAE Grade 4 allergic reaction or acute respiratory distress syndrome
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.
4.6.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include but are not limited to the following:

The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients.

Patient enrollment is unsatisfactory.
The investigator will be notified if the Sponsor decides to discontinue the study.  
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 ICH guideline for Good Clinical Practice

No study activity (i.e., all patients have completed and all obligations have been 
fulfilled)


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5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
5.1.1
Management of Risks Associated with Pertuzumab and 
Herceptin
Specific instructions for management of infusion hypersensitivity reactions (including 
anaphylaxis), symptomatic LVSD or asymptomatic decreases in LVEF, and 
HER1related toxicities are provided below.
5.1.1.1
Infusion Hypersensitivity Reactions (Including Anaphylaxis)
Monoclonal antibodies may cause infusionassociated symptoms such as nausea, 
pyrexia, diarrhea, chills, fatigue, and headache.  Such reactions typically occur during or 
shortly after an infusion.  
In general (and in common with other antibody-associated infusion reactions), 
pertuzumab and Herceptin infusionassociated reactions are more frequent and severe 
with the first infusion, decrease in frequency and severity over time, and resolve fully.  
Infusion-associated reactions with pertuzumab are not affected by prior or concurrent 
Herceptin therapy; the incidence and severity of such reactions are similar regardless of 
prior or concurrent Herceptin.  
Administration of pertuzumab and Herceptin should be performed in a setting with 
emergency equipment and staff who are trained to monitor medical situations and 
respond to medical emergencies.  Patients will be monitored for any adverse effects 
during each infusion, for at least 60 minutes after the first pertuzumab (or placebo)
infusion, and for at least 60 minutes after the first Herceptin infusion.  The observation 
time for subsequent infusions can be decreased to 30 minutes if the infusions are well 
tolerated during Cycle 1.
Infusion of pertuzumab or Herceptin should be slowed or interrupted if the patient 
experiences infusionassociated symptoms (e.g., fever, chills, headache, fatigue, 
pruritus, nausea, vomiting, or diarrhea).  Supportive care with oxygen, -agonists, 
antihistamines, antipyretics, and corticosteroids may help alleviate symptoms.  All 
infusion-associated symptoms must be resolved before Herceptin is given.  Patients who 
experience infusion-related symptoms during or after infusions may be premedicated 
with analgesics and antihistamines for subsequent infusions.  Patients who experience a 
Grade 4 allergic reaction or acute respiratory distress syndrome should be discontinued 
from treatment.  Since there is the potential for a delayed onset of infusion-associated 
reactions, patients should be instructed to contact the treating physician with any 
concerns.  


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5.1.1.2
Symptomatic Left Ventricular Systolic Dysfunction and 
Asymptomatic Decrease in Left Ventricular Ejection Fraction
There is a risk of cardiac dysfunction with pertuzumab, as with Herceptin, because each 
of these antibodies is directed at the HER2 receptor.  A decrease in LVEF has been 
observed in patients receiving pertuzumab; however, the majority of patients show 
improvement or return to baseline function on follow up (see Section 1.3.2.1).
All patients will undergo regular LVEF monitoring by ECHO or MUGA.  Monitoring of 
LVEF is required while patients are receiving pertuzumab (or placebo) and Herceptin as 
well as after treatment completion as per the schedule of assessments (see Appendix 1).
If symptomatic LVSD symptoms develop, the patient must discontinue all study 
treatment.  Symptomatic LVSD (heart failure) should be treated and monitored according 
to standard medical practice.  These patients should be evaluated by a certified 
cardiologist, and the results of this evaluation should be reported on the eCRF.
Figure 2 summarizes the management of study treatment for patients who have an
asymptomatic decrease in LVEF.  The decision to continue or stop study treatment 
should be based on two factors: measured LVEF value and change in LVEF value from 
baseline.


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Figure 2
Algorithm for Continuation or Discontinuation of Study 
Treatment Based on LVEF Assessments
LVEFleft ventricular ejection fraction.
Notes:  Treatment is Herceptin and pertuzumab/placebo.  LVEF drop should be evaluated using 
percentage points as unit.
Patients for whom study treatment was permanently discontinued because of a 
decrease in LVEF should continue to have LVEF assessments repeated as clinically 
indicated, with a maximum interval between LVEF assessments of 3 months, until the 
LVEF returns to 50%, or 1 year after the treatment discontinuation visit, whichever 
occurs first.  Thereafter, LVEF assessments will be performed annually for up to 3 years 
after the treatment discontinuation visit.
5.1.1.3
Epidermal Growth Factor Receptor (HER1)-Related Toxicities
Although pertuzumab targets HER2, because of its role in heterodimerization with other 
members of the HER family (e.g., EGFR), it may cause toxicities associated with the use 
of EGFR tyrosine kinase inhibitors.  Diarrhea has been observed in approximately 
60% of patients treated with pertuzumab in Phase II, single-agent studies (up to 90% of 
patients receiving pertuzumab in combination studies) and was Grade 1 or 2 in the 
majority of cases.  For patients experiencing diarrhea, early intervention with loperamide 
should be recommended and patients should be treated with fluids and electrolyte 
replacement, as clinically indicated.


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Rash has also been observed with EGFR tyrosine kinase inhibitors.  The rash was 
generally mild to moderate in intensity and appeared to be treatable in some patients 
with standard acne therapies, including topical and oral antibiotics.  To date, rash has 
been observed in approximately 17% of patients receiving pertuzumab in Phase II,
singleagent studies (up to 40% of patients receiving pertuzumab in combination studies) 
and was generally Grade 1 or 2 in severity.
Mucositis has been observed in approximately 15% of patients receiving pertuzumab in 
Phase II single-agent studies and in up to 50% of patients in combination studies. The 
most common preferred terms reported were mucosal inflammation and stomatitis. 
Mucositis is generally not considered preventable, although for some cytotoxic agents, it
may be reduced by cooling the mouth using ice chips before and during the infusion.
5.1.2
Dosage Modification and Treatment Interruption or 
Discontinuation
If any of the individual study drugs must be delayed for a day or more, all three agents 
should be delayed for the same timeframe.
Dosage modifications are not permitted for Herceptin (except in the case of body weight 
changes) or pertuzumab. Treatment interruption or discontinuation is permitted for 
toxicity, including cardiotoxicity (see Sections 4.6.2 and 5.1.1.2 for further information).
Actions to be taken for toxicities related to Herceptin or pertuzumab are outlined in
Table 2. The infusion should be slowed or interrupted if the patient experiences
infusion-associated symptoms (e.g., fever, chills, headache, fatigue, pruritus, nausea,
vomiting, and diarrhea; see Section 5.1.1.1). Supportive care with oxygen, -agonists,
antihistamines, antipyretics, and corticosteroids may help alleviate symptoms. All
infusion-associated symptoms must be resolved before docetaxel is given or the patient
is discharged. Patients who experience infusion-related symptoms during or after
infusions may be premedicated with analgesics and antihistamines for subsequent
infusions, with the first infusion administered over 60 (10) minutes, followed by a 60-
minute observation period. Patients who experience a Grade 4 allergic reaction or acute 
respiratory distress syndrome should be discontinued from treatment.
If pertuzumab/placebo or Herceptin is held for more than two cycles or needs to be 
permanently discontinued, the patient will be withdrawn from all study treatment and will 
continue to be followed post-treatment, as described in Section 5.3.1.
Additionally, delays provided in Table 2 also apply to docetaxel.
Docetaxel may be delayed because of toxicity.  If docetaxel is delayed for more than 
3 weeks with no recovery, the patient should be withdrawn from docetaxel treatment.  If 
docetaxel needs to be permanently discontinued, the patient will continue on 
pertuzumab (or placebo) and Herceptin.  


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Docetaxel dose reduction will be allowed for myelosuppression, hepatic dysfunction, and 
other toxicities (see Table 3).
Table 2
Actions to Be Taken for Toxicities Related to Herceptin or 
Pertuzumab
Toxicity
Action
Neutropenia
Hold all study treatment for up to 6 weeks.  If 
recovery to ANC count 1000 cells/L occurs 
within 6 weeks, resume all treatment.  If recovery 
to ANC count 1000 cells/L does not occur 
within 6 weeks, discontinue docetaxel.
Symptomatic LVSD
Discontinue all study treatment.
Asymptomatic decrease in LVEF
Follow instructions for holding, continuing, or 
discontinuing treatment as outlined above in
Figure 2
Allergic reaction or acute respiratory 
distress syndrome:  Grade 4
Discontinue all study treatment.
Other non-hematologic toxicities: a  
Grade 1 or 2
Continue all study treatment.
Other non-hematologic toxicities: a  
Grade 3 or 4
Hold all study treatment for up to 6 weeks.  If 
recovery to Grade 2 occurs within 6 weeks, 
resume all treatment.  If recovery to Grade 2 
does not occur within 6 weeks, discontinue all 
study treatment.
ANCabsolute neutrophil count; NCI CTCAENational Cancer Institute/ Common 
Terminology Criteria for Adverse Events; LVEFleft ventricular ejection fraction; LVSDleft 
ventricular systolic dysfunction.
Notes:  Severity grades for all events are based on NCI CTCAE v 4.0, with the exception of 
symptomatic LVSD, which should be graded according to NCI CTCAE v 4.0 for “heart failure” 
(Grade 2, 3, 4, or 5) and the New York Heart Association (NYHA) classification 
(see Appendix 5).
Study treatment refers to Herceptin, pertuzumab/placebo, and docetaxel.
a Includes non-hematologic toxicities not described above (e.g., cardiac toxicities other than 
symptomatic LVSD or asymptomatic decrease in LVEF).
Table 3
Docetaxel Dose Adjustments
Docetaxel Dose
Criteria
75 mg/m2
Starting dose
Administer only if neutrophil count is 1500 cells/L
55 mg/m2 
Reduce dose in case of any of the following toxicities:
Febrile neutropenia or neutrophils 500 cells/L for more than 
1 week (after fully recovering to a neutrophil count 1500 cells/L)
Platelets 100,000 cells/L (after recovering to a platelet count
100,000 cells/L)
Severe or cumulative cutaneous reactions


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Docetaxel Dose
Criteria
Permanently 
discontinue 
docetaxel 
After any of the following toxicities:
Severe hypersensitivity reactions 
Grade 3 peripheral neuropathy 
Severe or cumulative cutaneous reactions that continue at a dose of 
55 mg/m2 without recovery
Febrile neutropenia or neutrophils 500 cells/L without recovery
Platelets 100,000 cells/L without recovery
Total bilirubin ULN without recovery
AST or ALT 1.5 ULN concurrent with serum ALP 2.5 ULN
without recovery
ULNupper limit of normal.
5.1.3
Pregnancy and Contraception
Women who are not postmenopausal (12 months of nontherapy-induced amenorrhea) 
or surgically sterile (absence of ovaries and/or uterus) must agree to remain abstinent or 
use single or combined contraceptive methods that results in a failure rate of 1% per 
year during the treatment period and for at least 7 months after the last dose of study 
treatment (based on PK).  
Men participating in the study must agree to remain abstinent or use a condom plus an 
additional contraceptive method that together result in a failure rate of 1% per year 
during the treatment period and for at least 7 months after the last dose of study 
treatment.  
Male study participants whose partners are pregnant should use condoms for the 
duration of the pregnancy.  
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.
5.1.4
Breastfeeding
It is not known whether Herceptin or pertuzumab is excreted in human milk.  Because
maternal IgG is excreted in milk and either monoclonal antibody could harm infant 
growth and development, women should be advised to discontinue nursing during 
pertuzumab or Herceptin therapy and not to breastfeed for at least 7 months following 
the last dose of either monoclonal antibody.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording AEs, including SAEs and 
non-serious AEs of special interest; measurement of protocol-specified safety laboratory 
assessments; measurement of protocol-specified vital signs; and other 
protocol-specified tests that are deemed critical to the safety evaluation of the study.


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Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an AE is any untoward 
medical occurrence in a clinical investigation subject administered a pharmaceutical 
product, regardless of causal attribution.  An AE can therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10

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

AEs 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 
biopsy sample collection)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
An SAE is any AE that meets any of the following criteria:

Fatal (i.e., the AE actually causes or leads to death)

Life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death)
This does not include any AE that had it occurred in a more severe form or was 
allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions)

Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)


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The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity 
of an AE (rated as mild, moderate, or severe, or according to NCI CTCAE criteria; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each AE recorded on 
the eCRF.
SAEs are required to be reported by the investigator to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2 for reporting 
instructions).
5.2.3
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor)
Non-serious adverse events of special interest (AESIs) 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).  AEs of special interest for this 
study include the following:

A non-serious asymptomatic decrease in LVEF requiring treatment or leading to 
discontinuation of pertuzumab (or placebo) and Herceptin (must be reported in an 
expedited manner by using the SAE form and classifying the event as Non-Serious 
Event of Special Interest)

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 indicating an infection 
in a patient exposed to a medicinal product.  This term only applies when a 
contamination of the study drug is suspected.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all AEs (see Section 5.2.1 for definition) 
are recorded on the Adverse Event eCRF and reported to the Sponsor in accordance 
with instructions provided in this section and in Section 5.4 through Section
For each AE recorded on the Adverse Event eCRF, the investigator will make an 
assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  


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5.3.1
Adverse Event Reporting Period
Investigators will seek information on AEs at each patient contact.  All AEs, whether 
reported by the patient or noted by study personnel, will be recorded in the patient’s 
medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
SAEs caused by a protocol-mandated intervention (e.g., invasive procedures such as 
biopsy sample collections, discontinuation of medications) should be reported
(see Section 5.4.2 for instructions for reporting SAEs).
After initiation of study drug, all AEs, regardless of relationship to study drug, will be 
reported through the treatment discontinuation visit, 28 days after the last dose of study 
drug.  Instructions for reporting adverse events that occur after the adverse event
reporting period are provided in Section.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting AE
information at all patient 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 AE severity grading scale for the NCI CTCAE v 4.0 will be used for assessing 
severity of AEs.  Table 4 will be used for assessing severity for AEs that are not 
specifically listed in the NCI CTCAE.


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Table 4
Adverse Event Severity Grading Scale
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or noninvasive 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 (v 4.0), 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 patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of 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 patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
AE is considered to be related to the study drug, indicating "yes" or "no" accordingly.  
The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.


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5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording AEs on 
the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one AE term should be recorded in the event field on the Adverse Event eCRF.
5.3.5.1
Infusion-Related Reactions
AEs that occur during or within 24 hours after study drug administration and judged to be 
related to study drug infusion should be captured as a diagnosis (e.g., "infusion-related 
reaction" [IRR] 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 InfusionRelated Reaction eCRF.  If a patient 
experiences both a local and systemic reaction to the same dose of study drug, each 
reaction should be recorded separately on the Adverse Event eCRF, with signs and 
symptoms also recorded separately on the dedicated InfusionRelated Reaction eCRF.
5.3.5.2
Diagnosis versus Signs and Symptoms
For AEs other than IRRs (see Section 5.3.5.1), 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 AEs based on signs and symptoms 
should be nullified and replaced by one AE report based on the single diagnosis, with a 
starting date that corresponds to the starting date of the first symptom of the eventual 
diagnosis.
5.3.5.3
Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events.  However, medically significant AEs occurring secondary to 
an initiating event that are separated in time should be recorded as independent events 
on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.


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


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If a clinically significant abnormal laboratory value is not a sign of a disease or syndrome, 
the abnormal value should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the abnormal laboratory value can 
be characterized by a precise clinical term per standard definitions, the clinical term 
should be recorded as the AE.  For example, an elevated serum potassium level of 7.0 
mEq/L should be recorded as “hyperkalemia.”
Observations of the same clinically significant abnormal laboratory value from visit to 
visit should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.6
Abnormal Vital Sign Values
Not every abnormal vital sign qualifies as an AE.  A vital sign result must be reported as 
an AE if it meets any of the following criteria:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated abnormal vital sign should 
be classified as an AE.
If a clinically significant abnormal vital sign is a sign of a disease or syndrome (e.g., high 
blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the 
Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.7
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.  
Therefore, investigators must report as an AE the occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin
2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice


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The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as an SAE or a non-serious AESI (see Section 5.4.2).
5.3.5.8
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified AE reporting period (see Section 5.3.1) that are attributed by the 
investigator solely to progression of breast cancer should be recorded only on the Study 
Completion/Early Discontinuation eCRF.  All other on-study deaths, regardless of 
relationship to study drug, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 5.4.2).  
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  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").
During survival follow-up, deaths attributed to progression of breast cancer should be 
recorded.
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 AE 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
Lack of Efficacy or Worsening of Breast Cancer
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as AEs.  These data will be captured as 
efficacy assessment data only.  In most cases, the expected pattern of progression will 
be based on RECIST v 1.1.  In rare cases, the determination of clinical progression will 
be based on symptomatic deterioration.  However, every effort should be made to 
document progression using objective criteria.  If there is any uncertainty as to whether 
an event is due to disease progression, it should be reported as an AE.


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5.3.5.11
Hospitalization or Prolonged Hospitalization
Any AE that results in hospitalization (i.e., inpatient admission to a hospital) or prolonged 
hospitalization should be documented and reported as a SAE (per the definition of SAE 
in Section 5.2.2, except as outlined below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration) 

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled 
during the study when elective surgery became necessary because of 
the expected normal progression of the disease
The patient has not suffered an AE

Hospitalization due solely to progression of the underlying cancer
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Overdoses
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an AE, but it may result in an AE.  All AEs associated with an overdose or incorrect 
administration of study drug should be recorded on the Adverse Event eCRF.  If the 
associated AE fulfills serious criteria, the event should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2).
No safety data related to overdosing of pertuzumab or Herceptin are available.
5.3.5.13
Cardiac Adverse Events
All cardiac AEs occurring during the study and up to 12 months after last administration
of study medications must be reported irrespective of causal relationship or seriousness.  
Grade 2 heart failure (symptomatic LVSD) must be reported for up to 3 years after last 
administration of study medications.
Symptomatic Left Ventricular Systolic Dysfunction (Heart Failure)
Symptomatic LVSD (heart failure) is a SAE that should be reported as a diagnosis, not 
as individual signs and symptoms thereof, on Adverse Events page.  Specific related
signs and symptoms will be entered on the eCRF.  Symptomatic LVSD should be 


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graded according to NCI CTCAE v 4.0 (for "heart failure") and the NYHA classification 
(see Appendix 3).
Asymptomatic Left Ventricular Systolic Dysfunction
In general, asymptomatic decreases in LVEF should not be reported as AEs since LVEF 
data are collected separately in the eCRF.  Exceptions to this rule are as follows:

An asymptomatic decreases in LVEF of 10 percentage points from baseline to an 
LVEF of 50% must be reported as an AE.

An asymptomatic decreases in LVEF requiring treatment or leading to 
discontinuation of pertuzumab (or placebo) and Herceptin must be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions) as a non-serious AESI.
Asymptomatic decreases in LVEF should be reported as "ejection fraction decreased"
and graded according to NCI CTCAE v 4.0.  Table 5 summarizes the reporting 
conventions for LVSD.
Table 5
Reporting Conventions for Left Ventricular Systolic Dysfunction
Observation
How to Report
Term to be 
Reported
Grading
Asymptomatic decrease
in LVEF of 10
percentage points from 
baseline to an LVEF
50%
Adverse event (eCRF)
"Ejection fraction 
decreased" 
NCI CTCAE for "
ejection fraction 
decreased "
Asymptomatic decrease
in LVEF requiring 
treatment or leading to 
discontinuation of 
pertuzumab (or placebo)
and Herceptin
Non-serious adverse event 
of special interest (eCRF),
with expedited reporting 
(see Section 5.4.2)
"Ejection fraction 
decreased" 
NCI CTCAE for "
ejection fraction 
decreased "
Symptomatic left 
ventricular systolic 
dysfunction (congestive 
heart failure)
Serious adverse event 
(eCRF) and Symptomatic 
Left Ventricular Systolic 
Dysfunction eCRF, with
expedited reporting 
(see Section 5.4.2)
"Heart failure"
NCI CTCAE for "
heart failure" and 
NYHA 
classification
Asymptomatic decrease
in LVEF of 10
percentage points from 
baseline or to an LVEF
50%
No adverse event
reporting required; LVEF 
values to be reported on 
eCRF
NA
NA
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events; 
eCRFelectronic Case Report Form; LVEFleft ventricular ejection fraction; NAnot 
applicable; NYHANew York Heart Association.  


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5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events

Non-serious adverse events of special interest

Pregnancies
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting SAEs to the local 
health authority and Institutional Review Board/Independent Ethics Committee (IRB/EC).
5.4.1
Emergency Medical Contacts
Medical Monitor (F. Hoffmann-La Roche Medical Responsible) Contact Information
Primary Contact
Medical Monitor:
, M.D.
Telephone No.:
Mobile Telephone No.:
Secondary Contact
Medical Monitor:
, M.D.
Telephone No.:
Mobile Telephone No.:


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To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the F. Hoffmann-La Roche Medical Emergency List, escalate emergency 
medical calls, provide medical translation service (if necessary), connect the investigator 
with a Roche Medical Monitor, and track all calls.  The Emergency Medical Call Center 
Help Desk will be available 24 hours per day, 7 days per week.  Toll-free numbers for 
the Help Desk and Medical Monitor contact information will be distributed to all 
investigators (see "Protocol Administrative and Contact Information & List of 
Investigators").  
5.4.2
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest
5.4.2.1
Events Occurring prior to Initiation of Study Drug
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocolmandated intervention should be reported. A paper Serious 
Adverse Event Reporting Form and fax cover sheet should be completed and faxed to 
Roche Safety Risk Management or its designee immediately (i.e., no more than 
24 hours after learning of the event), using the fax numbers provided to investigators 
(see "Protocol Administrative and Contact Information & List of Investigators").
5.4.2.2
Events Occurring after Initiation of Study Drug
After initiation of study drug, SAEs and non-serious AEs of special interest will be 
reported through the treatment discontinuation visit. 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, a paper Adverse Event of Special 
Interest Reporting Form and fax cover sheet should be completed and faxed to Roche 
Safety Risk Management or its designee immediately (i.e., no more than 24 hours after 
learning of the event), using the fax numbers provided to investigators (see "Protocol 
Administrative and Contact Information & List of Investigators").  Once the EDC system 
is available, all information will need to be entered and submitted via the EDC system.
Instructions for reporting serious adverse events that occur 28 days after the final dose 
of study treatment are provided in Section.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 7 months after the last 
dose of study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 


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Roche Safety Risk Management.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any SAEs associated 
with the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.
In the event that the EDC system is unavailable, a paper Clinical Trial Pregnancy 
Reporting Form and fax cover sheet should be completed and faxed to Roche Safety 
Risk Management or its designee immediately (i.e., no more than 24 hours after learning 
of the pregnancy), using the fax numbers provided to investigators (see "Protocol 
Administrative and Contact Information & List of Investigators").  Once the EDC system 
is available, all information will need to be entered and submitted via the EDC system.
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
7 months after the last dose of study drug.  A Pregnancy Report eCRF should be 
completed by the investigator immediately (i.e., no more than 24 hours after learning of 
the pregnancy) and submitted via the EDC system.  Attempts should be made to collect 
and report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study drug.  The pregnant partner will need to sign an Authorization 
for Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy.  Once the authorization has been signed, the investigator will update the 
Pregnancy Report eCRF with additional information on the course and outcome of the 
pregnancy.  An investigator who is contacted by the male patient or his pregnant partner 
may provide information on the risks of the pregnancy and the possible effects on the 
fetus, to support an informed decision in cooperation with the treating physician and/or 
obstetrician.
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1.
5.4.3.3
Abortions
Any abortion should be classified as a SAE (because the Sponsor considers abortions to 
be medically significant), recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).  


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5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a SAE, recorded on the Adverse Event eCRF, and reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the investigator, the patient is lost to follow up, 
or the patient withdraws consent.  Every effort should be made to follow all SAEs 
considered to be related to study drug or trialrelated procedures until a final outcome 
can be reported.
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.  
All pregnancies reported during the study or within 7 months after the last dose of study 
medication should be followed until pregnancy outcome.  If the EDC system is not 
available at the time of pregnancy outcome, follow reporting instructions provided in 
Section 5.4.3.1.
5.5.2
Sponsor Follow-Up
For SAEs, non-serious AESI, and pregnancies, the Sponsor or a designee may follow up 
by telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case 
details and outcome information (e.g., from hospital discharge summaries, consultant 
reports, autopsy reports) in order to perform an independent medical assessment of the 
reported case.
Additional information on any pertuzumab-exposed pregnancy (and an infant resulting 
from that pregnancy) will be requested by Roche Drug Safety at specific time points 
(i.e., at the end of the second trimester, 2 weeks after expected date of delivery, and at 
3, 6, and 12 months of the infant’s life).
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the AE reporting period (as defined in Section 5.3.1), all deaths, 
regardless of cause, should be reported through use of the Long-Term Survival Follow-
Up eCRF.
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study drug, the event should be reported through use 


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of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all SAEs and non-serious AESI against cumulative 
product experience to identify and expeditiously communicate possible new safety 
findings to investigators, IRBs, ECs, and applicable health authorities based on 
applicable legislation.
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following reference documents:

Pertuzumab Investigator's Brochure

Local prescribing information for Herceptin
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
An aggregate report of any clinically relevant imbalances that do not favor the test 
product will be submitted to health authorities.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
6.1
DETERMINATION OF SAMPLE SIZE
The primary objective of this study is to assess whether the addition of pertuzumab to 
the combination of Herceptin and docetaxel prolongs PFS in Chinese patients in a 
manner consistent with the results from CLEOPATRA.  A consistency threshold is 
defined as a hazard ratio of 0.81, which maintains 50% of the risk reduction 
determined in CLEOPATRA (hazard ratio, 0.62).  


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To reliably determine the predefined consistency value, a simulation method was used 
to estimate the required sample size.  A total of 240 patients randomized in a 1:1 ratio 
and 123 PFS events in the two treatment arms are required, providing an appropriate 83% 
probability of showing consistency.  
The sample size estimation was based on the following assumptions:

The median PFS is 11 months in the control arm, with a PFS hazard ratio of 0.68

The recruitment period is estimated to be 15 months
The primary analysis of PFS will be performed after 123 PFS events have occurred, and 
the required PFS events are expected to be reached at around 23 months.
6.2
SUMMARIES OF CONDUCT OF STUDY
Patient enrollment, duration of follow-up, and discontinuation from the study and reasons 
for discontinuation will be summarized by treatment arm for all randomized patients.  In 
addition, major protocol violations will be summarized by treatment arm.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographics and baseline characteristics, such as age, weight, ECOG Performance 
Status, ER/PgR status, HER2 status (IHC test score of 3and/or ISH amplification ratio 
of 2.0), prior treatments for breast cancer, treatmentfree survival, and involvement of 
visceral sites, will be summarized by treatment arm.  
Descriptive statistics (mean, median, standard deviation, 25th percentile, 75th percentile, 
and range) will be presented for continuous variables, and proportions will be presented 
for categorical variables.
6.4
EFFICACY ANALYSES
The primary and secondary efficacy analyses will include all randomized patients, 
following the intent-to-treat principle, with patients grouped according to the treatment 
assigned at randomization.  For objective response, only patients with measurable 
disease at baseline will be included in the analysis.  For duration of response, only 
patients with an objective response will be included in the analysis.
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is PFS based on investigator assessments.  PFS is 
defined as the time from randomization to the first occurrence of progressive disease, as 
determined by the investigator using RECIST v 1.1, or death from any cause within 
18 weeks after the final tumor assessment, whichever occurs first.  


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At the time of data cutoff for the PFS analysis, data for patients who do not have 
documented progressive disease or who have not died within 18 weeks of the last tumor 
assessment will be censored at the time of the last tumor assessment (or, if no tumor 
assessments are performed after the baseline visit, at the time of randomization plus 
1 day).  
The Kaplan-Meier approach will be used to estimate median PFS for each treatment arm.  
The Cox proportional hazards model, stratified by disease type (visceral disease vs. 
non-visceral disease) and hormone receptor status (ER and PgR negative or ER and/or 
PgR positive), will be used to estimate the hazard ratio between the two treatment arms 
and its 95% CI.  The unstratified hazard ratio will also be provided.  The two-sided 
stratified logrank test will be used to compare PFS between the two treatment arms.  
The unstratified log-rank test result will also be provided.  
Sensitivity analyses are planned for PFS to account for the potential bias introduced by 
missed visits, timing of death, and nonprotocol-specified anticancer therapy.  Details 
will be described in the Statistical Analysis Plan.
6.4.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints in this study include OS, objective response rate, and 
duration of objective response.
6.4.3
Exploratory Analyses
Biomarker analyses will be of exploratory nature only and all analyses will be of 
descriptive nature.
6.4.3.1
Overall Survival
OS is defined as the time from randomization to death from any cause.  Patients who 
are alive or lost to follow-up at the time of the analysis will be censored at the date they 
were last known to be alive.  Patients with no post-baseline information will be censored 
at the time of randomization plus 1 day.  Analysis methods are the same as those 
described for the primary endpoint.  
OS data will be summarized at the time of final PFS analysis, at approximately 
23 months.  A final analysis of OS will be performed at approximately 3 years after 
randomization of the last patient.  
The 1-year survival rate will also be estimated using the Kaplan-Meier method.  A 2-year 
landmark analysis will be performed, in the form of a truncated survival analysis at 
2 years.  A truncated survival endpoint at 2 years is considered a robust and clinically 
highly relevant endpoint for capturing clinical benefit of a new therapy.  In this analysis, 
only those deaths occurring within 2 years of randomization will be counted as events.  


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6.4.3.2
Objective Response Rate
ORR is defined as a CR or PR that is confirmed 2842 days later, as determined by the 
investigator using RECIST v 1.1.  Only patients with measurable disease at baseline will 
be included in the analysis of ORR.  Patients without a post-baseline tumor assessment 
will be considered non-responders.  
An estimate of the ORR and its 95% CI (Pearson-Clopper) will be calculated for each 
treatment arm.  The difference in ORR will also be provided with 95% CIs (using
Hauck-Anderson method).  The Mantel-Haenszel 2 test, stratified by disease type 
(visceral disease vs. non-visceral disease) and hormone receptor status (ER and PgR 
negative or ER and/or PgR positive) will be used to compare the ORR between the two 
treatment arms.  An unadjusted Fisher’s exact test result will also be provided.
6.4.3.3
Duration of Response
Duration of response is defined as the time from the first occurrence of a documented 
objective response to the time of disease progression, as determined by the investigator 
using RECIST v 1.1, or death from any cause, whichever occurs first.  Only patients with 
an objective response will be included in the analysis.  The method for handling 
censoring is the same as that described for the primary endpoint.  
Median duration of objective response for each treatment arm will be estimated using 
the Kaplan-Meier approach.  The hazard ratio between the two treatment arms will also 
be estimated using Cox regression.
6.5
SAFETY ANALYSES
Safety analyses will be performed on the safety analysis population, which will consist of 
all patients who receive at least one dose of any of the study drugs, with patients 
grouped according to the treatment actually received.
6.5.1
Study Drug Exposure
The numbers of patients who experience any dose interruption (including dose delays), 
dose modification, or dose discontinuation will be summarized by treatment arm.  
Descriptive statistics will be presented for total cumulative dose, number of cycles, and 
patient frequency of treatment cycles.
6.5.2
Adverse Events
Verbatim descriptions of treatmentemergent adverse events will be mapped to 
MedDRA thesaurus terms and graded according to NCI CTCAE v 4.0.  All AEs, including 
SAEs, will be summarized by treatment arm and NCI CTCAE grade.  In addition, AEs
leading to discontinuation of study treatment will be summarized by treatment arm.  For 
each patient’s AE, the maximum severity recorded will be used in the summaries.
Deaths reported during the study treatment period and those reported after patient 
treatment discontinuation will be summarized by treatment group.


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6.5.3
Cardiac Safety
The number and percentage of patients with symptomatic LVSD at any time during the 
study will be summarized by treatment arm.  In addition, the number and percentage of 
patients with significant asymptomatic decrease in LVEF (defined as an absolute 
decrease of 10 percentage points from baseline to an LVEF of 50%) at any time 
during the study will be summarized by treatment arm.
LVEF measurements and change in LVEF from baseline will be summarized by 
treatment arm.  
6.5.4
Laboratory Data
Clinical laboratory tests will be performed at local laboratories.  Changes in laboratory 
data will be summarized by grade using NCI CTCAE v 4.0 for each treatment arm.  
Selected abnormal laboratory values, such as worst toxicity grade and toxicity grade 
shift from baseline, will be summarized by treatment arm.
6.6
EXPLORATORY ANALYSES
To assess the consistency of treatment benefit with respect to the primary efficacy 
endpoint, PFS, across important subgroups, forest plots (including estimated hazard 
ratios) will be provided for the following variables:  age, disease type (visceral disease vs. 
non-visceral disease), ECOG Performance Status, adjuvant/neoadjuvant therapy,
treatmentfree interval (2 years versus 2 years vs. no prior therapy), hormone 
receptor status (ER and/or PgR positive versus ER and PgR negative), HER2 status by 
central testing.  
If applicable, expanded analyses will be performed using Cox regression models to 
estimate treatment effect by adjusting covariates in an exploratory manner.  Variables to 
be considered are the stratification factors as well as other diseaseor patientrelated 
prognostic or predictive factors.
6.7
INTERIM ANALYSES
There are no interim analyses planned.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC using eCRFs.  
Sites will be responsible for data entry into the EDC system.  In the event of discrepant 
data, the Sponsor will request data clarification from the sites, which the sites will resolve 
electronically in the EDC system.


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The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Local laboratory data will be sent directly 
to the Sponsor, using the Sponsor’s standard procedures to handle and process the 
electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
Radiographic tumor assessment films (including but not limited to chest X-rays, CT
scans, MRI scans, and bone scans), and ECHO/MUGA cardiac assessments will not be 
reported through the EDC system.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed using a Sponsordesignated EDC system.  Sites will receive 
training and have access to a manual for appropriate eCRF completion.  eCRFs will be 
submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies of transcriptions 
that are certified after verification as being accurate and complete, microfiche, 
photographic negatives, microfilm or magnetic media, X-rays, patient files, and records 
kept at pharmacies, laboratories, and medico-technical departments involved in a clinical 
trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.


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Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification, 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 investigational 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, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study, or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).


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8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Caregiver's 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.
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Patients will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  A 
separate, specific signature will be required to document a patient's agreement to allow 
any remaining specimens to be used for exploratory research.  Patients who decline to 
participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.


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8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  In 
addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all AEs to the Sponsor, investigators must 
comply with requirements for reporting SAEs to the local health authority and IRB/EC.  
Investigators may receive written Investigational New Drug (IND) safety reports or other 
safetyrelated communications from the Sponsor.  Investigators are responsible for 
ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. Food and Drug Administration and other national and local 
health authorities, Sponsor monitors, representatives, and collaborators, and the IRB/EC 
for each study site, as appropriate.


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8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., 3 years after the 
last patient is enrolled or progressive disease is identified in all patients, whichever is 
earlier).
9.
STUDY DOCUMENTATION, MONITORING, AND
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, which includes an audit trail containing a complete record of all changes 
to data.
9.2
PROTOCOL VIOLATIONS
The investigator should document and explain any protocol violations.  The investigator 
should promptly report any violations that might impact patient safety and data integrity 
to the Sponsor and to the IRB/EC in accordance with established IRB/EC policies and 
procedures. The Sponsor will review all protocol deviations and assess whether any
represent a serious breach of Good Clinical Practice guidelines and require reporting to 
health authorities.  As per the Sponsor's standard operating procedures, prospective 
requests to deviate from the protocol, including requests to waive protocol eligibility 
criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.


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9.4
ADMINISTRATIVE STRUCTURE
This study is sponsored by Roche.  An IxRS will be utilized to collect patient screening 
information and to randomize eligible patients to one of the two treatment arms.  Up to 
approximately 20 sites in China will participate in this study, enrolling approximately 
240 patients.  Roche will provide clinical operations oversight, data management support, 
and medical monitoring.
Tumor tissue samples will be sent to a central laboratory for analysis.  Sample analysis 
will be performed by an external vendor or Roche.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
prior to submission.  This allows the Sponsor to protect proprietary information and to 
provide comments based on information from other studies that may not yet be available 
to the investigator.
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of 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 patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC.  Approval must be obtained from the IRB/EC before 
implementation of any changes, except for changes necessary to eliminate an 
immediate hazard to patients or changes that involve logistical or administrative aspects 
only (e.g., change in Medical Monitor or contact information).


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10.
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Appendix 1
Schedule of Assessments
Day
Screening a,b
Treatment Period a
Follow-Up a
–28 to 
–1
–7 to 
–1
Every Cycle 
(21 days)
Every 3 
Cycles
Treat.
Discon. Visit
Week 18 
after Treat.
Discon. Visit
Every 18 Weeks  
after Treat.
Discon. Visit
Up to 3 Years 
after Treat.
Discon. Visit
1
2842 Days 
after Final 
Treatment c
126 Days 
after Treat.
Discon. Visit
Every 126 Days
after Treat.
Discon. Visit
Informed consent
x d
Archival tumor tissue for HER2 
eligibility, ER/PgR status, and 
exploratory BM analyses to central 
laboratory
x d
Complete medical history
x
Review of eligibility criteria
x
Complete physical examination e and 
vital signs f
x
Symptom-directed physical 
examination g and vital signs f
x
x
LVEF by ECHO or MUGA
x h
Every 9 weeks from 
randomization i
x
Every 6 months in the first year, then annually 
for up to 3 years j
12-Lead ECG
x
Every 9 weeks, at same 
time as LVEF i
x
Chest X-ray
x
If indicated
x k
If indicated
ECOG Performance Status
x
x
x
Tumor assessments
x l,m
As per clinical practice l,n


Appendix 1
Schedule of Assessments (cont.)
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Day
Screening a,b
Treatment Period a
Follow-Up a
–28 to 
–1
–7 to 
–1
Every Cycle 
(21 days)
Every 3 
Cycles
Treat.
Discon. Visit
Week 18 
after Treat.
Discon. Visit
Every 18 Weeks  
after Treat.
Discon. Visit
Up to 3 Years 
after Treat.
Discon. Visit
1
2842 Days 
after Final 
Treatment c
126 Days 
after Treat.
Discon. Visit
Every 126 Days  
after Treat.
Discon. Visit
Bone scan
x
If indicated o
Brain scan
x p
Every 9 weeks from 
randomization q
Adverse events
x r
Ongoing s
Concomitant medications and 
cancer-related surgery/procedures
x t
Ongoing
Ongoing
Pertuzumab/placebo administration
x u,v
Herceptin administration
x u,w
Docetaxel administration
x u,x
Hematology, at local laboratory
x y,z
x y,z
x z
Chemistry, at local laboratory
x y,aa
x y,bb
x aa
INR and aPTT or PTT, at local 
laboratory
x
x cc
x
Pregnancy test, at local laboratory
x dd
x dd
x dd
3 and 7 months after treatment 
discontinuation visit dd
Cancer-related procedures and 
therapies
x ee
Survival information
x ee


Appendix 1
Schedule of Assessments (cont.)
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aPTTactivated partial thromboplastin time; ECHOechocardiogram; ECOG Eastern Cooperative Oncology Group; eCRFelectronic Case 
Report Form; ERestrogen receptor; HER2human epidermal growth factor receptor 2; INRinternational normalized ratio; LVEFleft 
ventricular ejection fraction; MUGAmultiple-gated acquisition; PET positron emission tomography; PgRprogesterone receptor; PTTpartial 
thromboplastin time; Treat. Discon.Treatment Discontinuation.
a Unless otherwise noted, a window of 3 days will apply to all visits and assessments, except for collection of follow-up survival information,
which will have a window of 7 days.  Study assessments/cycles may be adjusted slightly to accommodate holidays, vacations, and 
unforeseen major life events.  Documentation justifying this decision should be provided.
b Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to first study 
treatment may be used; such tests do not need to be repeated for screening, with the exception of INR, aPTT/ PTT, chemistry, hematology, 
and pregnancy evaluations performed prior to obtaining informed consent and 7 days prior to Day 1 of Cycle 1.
c The treatment discontinuation visit should occur 2842 days after the last administration of study treatment (pertuzumab (or placebo), 
Herceptin, or docetaxel), whichever is discontinued last.
d Signing of the Informed Consent Form and submission of tumor sample for HER2 eligibility are not limited to the 28-day window prior to Day 1
of Cycle 1.
e Includes measurements of height and weight and an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems.  Particular care should be taken with 
regard to cardiovascular signs and symptoms (e.g., elevated jugular venous pressure, sinus tachycardia, tachypnea, the presence of an S3 
heart sound, crackles on chest auscultation).
f
Vital signs (blood pressure, pulse rate, and body temperature) will be recorded before and after infusion of each study medication (pertuzumab
(or placebo), Herceptin, and docetaxel).
g Perform a limited, symptom-directed examination, including weight measurement, at specified timepoints or as clinically indicated.  Particular 
care should be taken with regard to cardiovascular signs and symptoms.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF.
h Perform as close as possible to, but a maximum of 42 days prior to, randomization.  Any prestudy LVEF values obtained during and after 
Herceptin neoadjuvant or adjuvant treatment will be obtained, as applicable.
i
Perform every 9 weeks from the date of randomization until the treatment discontinuation visit, or more frequently as needed for cardiac safety.  
If an LVEF assessment must be performed early or late, subsequent assessments should be conducted according to the original schedule of 
every 9 weeks from the date of randomization.  Perform a 12-lead ECG at the same time as the LVEF assessment.


Appendix 1
Schedule of Assessments (cont.)
Pertuzumab—F. Hoffmann-La Roche Ltd
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j
Patients for whom study treatment is permanently discontinued because of a drop in LVEF should continue to have LVEF assessments 
repeated as clinically indicated, with a maximum interval between LVEF assessments of 3 months, until the LVEF returns to 50%, or 1 year 
after the treatment discontinuation visit, whichever occurs first.  Thereafter, LVEF assessments will be performed annually for up to 3 years 
after the treatment discontinuation visit.
k If not performed within 28 days prior to the treatment discontinuation visit.
l
The same assessment technique must be used throughout the study for evaluating a particular lesion.  The same technique should also be 
used for cytologic (e.g., relevant cytology reports documenting malignant pleural effusions, bone marrow aspirations, cerebral spinal fluid) and 
photographic data, if available.  The same investigator should assess all tumor responses for each patient.
m MRI or CT scans that were performed before a patient signed consent to take part in the study may be used to provide baseline tumor status 
as long as they were performed within 28 days prior to the start of treatment, at the same hospital, with the same technique or machine, and 
preferably by the same individual as those for tumor assessments during the study.  This should be documented in the study files at the site.
n Tumor assessments will be performed as per local clinical practice and will continue until progressive disease or patient's death.  All 
patients should undergo, at a minimum, a chest and abdomen CT or MRI scan.  PET scans will not be considered for assessment of efficacy 
at any time during the study (except as specified for bone scans in the absence of radioactive isotopes).
o A bone scan should be performed in the event of clinical suspicion of progression of existing bone lesions or the appearance of new bone 
lesions.  If treatment is discontinued because of disease progression at sites other than bone, a bone scan should be performed immediately.  
In the absence of radioactive isotopes, an MRI scan (with gadolinium enhancement, if required) or 18F-fluorodeoxyglucose PET scan is an 
acceptable form of assessment of the skeleton for the presence of bone metastases.  Skeletal survey with plain X-rays is acceptable if there is 
no suitable alternative.
p CT or MRI scan of the brain and/ or spine within 28 days before randomization in cases of clinical suspicion of brain metastases.
q CT or MRI scan of the brain and/or spine if there is clinical suspicion of CNS metastases.
r
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.
s After initiation of study drug, all adverse events will be reported through the treatment discontinuation visit.  After this period, the investigator is 
not required to actively monitor patients for adverse events; however, the Sponsor should be notified if the investigator becomes aware of any 
poststudy serious adverse events or non-serious adverse events of special interest (see Section 5.6).  The investigator should follow each 
adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events considered to be related to study 
drug or trial-related procedures until a final outcome can be reported.
t
Includes all medications taken within 90 days prior to randomization.


Appendix 1
Schedule of Assessments (cont.)
Pertuzumab—F. Hoffmann-La Roche Ltd
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u Patients will receive study treatment (pertuzumab (or placebo) followed by Herceptin and then docetaxel) by IV infusion on Day 1 of each 
3-week cycle.  The first dose of study treatment (Day 1 of Cycle 1) must be administered within 3 days of randomization.  Treatment with 
pertuzumab (or placebo) and Herceptin will continue until disease progression or unacceptable toxicity.  Prior to completion of Cycle 6, 
docetaxel should only be discontinued for disease progression or unacceptable toxicity.  After completion of Cycle 6, discontinuation of 
docetaxel treatment is at the discretion of the patient and treating physician.  See Section 4.3 for additional details.
v Patients will receive either placebo or pertuzumab at a loading dose of 840 mg for Cycle 1, followed by 420 mg for subsequent cycles.
w Patients will receive Herceptin at a loading dose of 8 mg/kg for Cycle 1, followed by 6 mg/kg for subsequent cycles.
x Patients will receive docetaxel at a dose of 75 mg/m2.
y Laboratory tests must be performed within 3 days prior to each study drug administration, and results must be available prior to each study 
drug infusion.  In general, if baseline laboratory assessments are performed within 7 days prior to study treatment start, they will not need to be 
repeated on Day 1 of the start of study treatment.
z Includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells).
aa Includes sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and 
direct bilirubin, ALP, ALT, AST, uric acid, LDH.
bb Includes potassium, creatinine, total bilirubin, ALP, ALT, AST.
cc During the treatment period, patients receiving therapeutic doses of anti-coagulants should have INR and aPTT or PTT measurements 
repeated before the start of every chemotherapy cycle.  Results must be available prior to each study drug infusion.
dd All women who are not postmenopausal (postmenopausal defined as 12 months of non-therapy-induced amenorrhea) or surgically sterile will 
have a serum pregnancy test at screening.  A urine pregnancy test will be performed at all other specified timepoints (and as clinically 
indicated).  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  Baseline and treatment period pregnancy 
test results must be available prior to drug infusion.
ee After discontinuation of study treatment, information on survival and cancer-related therapies and medical or surgical procedures will be 
collected by telephone every 18 weeks until death, loss to follow-up, withdrawal of consent, or study termination by the Sponsor.  Immediately 
prior to the data cutoff for the primary progression-free survival analysis and for any overall survival analysis, the investigative sites will contact 
every patient that is alive to confirm current survival status.


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Appendix 2
ECOG Performance Status Scale 
Grade
Scale
0
Fully active, able to carry on all pre-disease performance without 
restriction
1
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, i.e., light housework, 
office work 
2
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours
4
Completely disabled.  Cannot carry out any self-care.  Totally 
confined to bed or chair
5
Dead


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Appendix 3
NYHA Classification and NCI CTCAE v. 4.0 Grading for Left 
Ventricular Systolic Dysfunction
NYHA Classification for Symptomatic Left Ventricular Systolic Dysfunction 
(Heart Failure)
Class I
Patients with cardiac disease but without resulting limitations of physical activity.  
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnoea or 
angina pain.
Class II
Patients with cardiac disease resulting in slight limitations of physical activity.  They 
are comfortable at rest.  Ordinary physical activity results in fatigue, palpitation, 
dyspnoea or anginal pain.
Class III
Patients with cardiac disease resulting in marked limitations of physical activity.  They 
are comfortable at rest.  Less than ordinary physical activity causes fatigue, 
palpitation, dyspnoea or anginal pain.
Class IV
Patients with cardiac disease resulting in inability to carry on any physical activity 
without discomfort.  Symptoms of cardiac insufficiency or of the angina syndrome 
may be present even at rest.  If any physical activity is undertaken, discomfort is 
increased.
Oxford textbook of internal medicine.  Vol 2, pp 2228.  Oxford University Press.  1997
NCI CTCAE Version 4.0 Grading for Heart Failure and Ejection Fraction 
Decreased
Heart Failure (Symptomatic Left Ventricular Systolic Dysfunction)
Grade1
Asymptomatic with laboratory or cardiac imaging abnormalities
Grade 2
Symptoms with mild to moderate activity or exertion
Grade 3
Severe with symptoms at rest or with minimal activity or exertion; intervention 
indicated
Grade 4
Life-threatening consequences; urgent intervention indicated
Grade 5
Death
Please refer to the NCI CTCAE v 4.0 for further details.


Appendix 3
NYHA Classification and NCI CTCAE v. 4.0 Grading for Left 
Ventricular Systolic Dysfunction (cont.)
Pertuzumab—F. Hoffmann-La Roche Ltd
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Ejection Fraction Decreased (Asymptomatic Left Ventricular Systolic Dysfunction)
Grade1
-
Grade 2
Resting ejection fraction (EF) 50 - 40%; 10 -19% decrease from baseline
Grade 3
Resting ejection fraction (EF) 39 - 20%; 20% decrease from baseline
Grade 4
Resting ejection fraction (EF) 20%
Grade 5
-
Please refer to the NCI CTCAE v 4.0 for further details. 
-  N/A


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Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1,1 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2
MEASURABILITY OF TUMOR AT BASELINE
DEFINITIONS
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-
measurable as described below.
Measurable Tumor Lesions
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size 
as follows: 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm)
10-mm caliper measurement by clinical examination (lesions that cannot be accurately 
measured with calipers should be recorded as non-measurable)
20 mm by chest X-ray
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and follow-up, 
only the short axis will be measured and followed.  See also notes below on “Baseline 
Documentation of Target and Non-Target Lesions” for information on lymph node 
measurement.
                                           
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228–47.
2 For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made.


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont)
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Non-Measurable Tumor Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 but 15 mm) as well as truly non-
measurable lesions.  Lesions considered truly non-measurable include leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone Lesions:
Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques for measuring bone lesions.  However, these 
techniques can be used to confirm the presence or disappearance of bone lesions.
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can 
be considered as measurable lesions if the soft tissue component meets the 
definition of measurability described above.
Blastic bone lesions are non-measurable.
Cystic Lesions:
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts.
Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if 
non-cystic lesions are present in the same patient, these are preferred for selection 
as target lesions.
Lesions with Prior Local Treatment:
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Study protocols should detail the conditions 
under which such lesions would be considered measurable.


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont)
Pertuzumab—F. Hoffmann-La Roche Ltd
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TARGET LESIONS:  SPECIFICATIONS BY METHODS OF MEASUREMENTS 
Measurement of Lesions
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.
Method of Assessment
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option.
Clinical Lesions.  Clinical lesions will only be considered measurable when they are 
superficial and 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For 
the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested.
Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions.  However, lesions on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung.
CT, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease, and should 
be optimized to allow for comparison with the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions on a different modality 


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont)
Pertuzumab—F. Hoffmann-La Roche Ltd
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and interpretation of non-target disease or new lesions, since the same lesion may 
appear to have a different size using a new modality.
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of 
these techniques for objective tumor evaluation cannot generally be advised.
TUMOR RESPONSE EVALUATION
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least one 
measurable lesion, as detailed above.
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be recorded as non-measurable lesions (even if the size is 10 mm by CT scan).  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont)
Pertuzumab—F. Hoffmann-La Roche Ltd
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reported as two dimensions in the plane in which the image is obtained (for CT this is 
almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, or 
coronal).  The smaller of these measures is the short axis.  For example, an abdominal 
node that is reported as being 20 mm30 mm has a short axis of 20 mm and qualifies 
as a malignant, measurable node.  In this example, 20 mm should be recorded as the 
node measurement.  All other pathological nodes (those with short axis 10 mm but 
15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
10 mm are considered non-pathological and should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should 
be identified as non-target lesions and should also be recorded at baseline.  
Measurements are not required and these lesions should be followed as “present,” 
“absent,” or in rare cases “unequivocal progression.”
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).
RESPONSE CRITERIA
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.
Complete response (CR):  Disappearance of all target lesions
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to 10 mm.
Partial response (PR):  At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum of diameters
Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (nadir), including baseline
In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.
The appearance of one or more new lesions is also considered progression.


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont)
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Stable disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum on study
Special Notes on the Assessment of Target Lesions
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to 10 mm on study.  This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero 
even if complete response criteria are met, since a normal lymph node is defined as 
having a short axis of 10 mm.
Target Lesions That Become Too Small to Measure.  During the study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements
recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  However, 
sometimes lesions or lymph nodes that are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being too small to measure.  When this occurs, it 
is important that a value be recorded on the CRF, as follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.

If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and BML (below measurable limit) should 
be ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by 
fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should 
be assigned in this circumstance as well and BML should also be ticked).
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm, and in that case BML should not be ticked.
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximum 
longest diameter for the coalesced lesion.


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont)
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Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the protocol.

Complete response (CR):  Disappearance of all non-target lesions and (if applicable) 
normalization of tumor marker level
All lymph nodes must be non-pathological in size (10 mm short axis).

Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits

Progressive disease (PD):  Unequivocal progression of existing non-target lesions
The appearance of one or more new lesions is also considered progression.
Special Notes on Assessment of Progression of Non-Target Disease
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease in a magnitude that, even in the 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest increase in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in non-
target disease in the face of SD or PR of target disease will therefore be extremely rare.
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have measurable disease.  
The same general concepts apply here as noted above; however, in this instance there 
is no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition:  if all lesions are truly non-measurable), a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if the 
increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for 
measurable disease, that is, an increase in tumor burden representing an additional 73% 
increase in volume (which is equivalent to a 20% increase in diameter in a measurable 
lesion).  Examples include an increase in a pleural effusion from “trace” to “large” or an 
increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as “sufficient to require a change in therapy.”  If unequivocal progression is 


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont)
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seen, the patient should be considered to have had overall PD at that point.  While it 
would be ideal to have objective criteria to apply to non-measurable disease, the very 
nature of that disease makes it impossible to do so; therefore, the increase must be 
substantial.
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show partial or 
complete response.  For example, necrosis of a liver lesion may be reported on a CT 
scan report as a “new” cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan.
EVALUATION OF RESPONSE
Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint
for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont)
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105/Protocol YO29296, Version 4
Table 1
Timepoint Response:  Patients with Target Lesions
(with or without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; 
PRpartial response; SDstable disease.
Table 2
Timepoint Response:  Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for non-target 
disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some trials; thus, assigning “stable disease” 
when no lesions can be measured is not advised.
Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) 


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont)
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106/Protocol YO29296, Version 4
would not change the assigned timepoint response.  This would be most likely to happen 
in the case of PD.  For example, if a patient had a baseline sum of 50 mm with three 
measured lesions and during the study only two lesions were assessed, but those gave 
a sum of 80 mm, the patient will have achieved PD status, regardless of the contribution 
of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression.  Overall response would be “unable to assess” if either the target response 
or the non-target response is “unable to assess” except where this is clear evidence of 
progression, as this equates with the case being not evaluable at that timepoint.


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont)
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Table 3
Best Overall Response When Confirmation Is Required
Overall Response at First 
Timepoint
Overall Response at 
Subsequent Timepoint
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR a
CR
SD
SD, provided minimum 
duration for SD was met; 
otherwise, PD
CR
PD
SD, provided minimum 
duration for SD was met; 
otherwise, PD
CR
NE
SD, provided minimum 
duration for SD was met; 
otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD, provided minimum 
duration for SD was met; 
otherwise, PD
PR
NE
SD, provided minimum 
duration for SD was met; 
otherwise, NE
NE
NE
NE
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, even 
disease meeting PR criteria relative to baseline, qualifies as PD at that point (since disease 
must have reappeared after CR).  Best response would depend on whether the minimum 
duration for SD was met.  However, sometimes CR may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the patient had PR, not CR, at the first 
timepoint.  Under these circumstances, the original CR should be changed to PR and the best 
response is PR.
Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont)
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108/Protocol YO29296, Version 4
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Tables 1–3.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate.  This is to avoid an incorrect assessment of complete response if 
the primary tumor is still present but not evaluated as a target or non-target lesion.


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Appendix 5
Nomogram for the Determination of Body Surface Area
Height
Body surface
Mass
Based on the Formula from Du Bois and Du Bois, Arch.intern.Med., 17, 863 (1916): 0 = M0,425xL0,725+x71,84 resp. log0 =logMx0,425+logLx0,725+1,8564
(0: Body surface [in cm2], M; Body mass [in kg]: L: Body length [in cm]

SAP_001.pdf: 
 
 
Official Title:  
 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED CLINICAL TRIAL TO EVALUATE THE EFFICACY 
AND SAFETY OF PERTUZUMAB + HERCEPTIN + DOCETAXEL 
VERSUS PLACEBO + HERCEPTIN + DOCETAXEL IN 
PREVIOUSLY UNTREATED HER2-POSITIVE METASTATIC 
BREAST CANCER 
NCT Number: 
NCT02896855 
Document: 
Version & Date:  
STATISTICAL ANALYSIS PLAN 
Version 1: 28 March 2018 
 


STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Pertuzumab — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan YO29296
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED CLINICAL TRIAL TO 
EVALUATE THE EFFICACY AND SAFETY OF 
PERTUZUMAB+HERCEPTIN+DOCETAXEL 
VERSUS PLACEBO+HERCEPTIN+DOCETAXEL 
IN PREVIOUSLY UNTREATED HER2-POSITIVE 
METASTATIC BREAST CANCER
PROTOCOL NUMBER:
YO29296
STUDY DRUG:
Pertuzumab
VERSION NUMBER:
1
IND NUMBER:
Not applicable
EUDRACT NUMBER:
Not applicable
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
, Ph.D.
DATE FINAL:
See electronic date stamp below
Name                                                             Reason for Signing                              Date and Time
(UTC)
28-Mar-2018 06:14:43
Company Signatory


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2/Statistical Analysis Plan YO29296
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 4
2.
STUDY DESIGN........................................................................................... 4
2.1
Protocol Synopsis.................................................................... 6
2.2
Determination of Sample Size ................................................. 6
2.3
Analysis Timing ....................................................................... 7
3.
STUDY CONDUCT....................................................................................... 7
3.1
Randomization Procedure ....................................................... 7
4.
STATISTICAL METHODS ............................................................................ 7
4.1
Analysis Populations ............................................................... 7
4.1.1
Intent-to-Treat Population........................................................ 7
4.1.2
Safety Population .................................................................... 7
4.2
Analysis of Study Conduct....................................................... 7
4.3
Analysis of Treatment Group Comparability ............................ 7
4.4
Efficacy Analysis...................................................................... 8
4.4.1
Primary Efficacy Endpoint........................................................ 8
4.4.2
Secondary Efficacy Endpoints................................................. 8
4.4.2.1
Overall Survival ....................................................................... 8
4.4.2.2
Objective Response ................................................................ 9
4.4.2.3
Duration of Objective Response.............................................. 9
4.4.3
Exploratory Efficacy Endpoints................................................ 9
4.4.4
Sensitivity Analyses................................................................. 9
4.4.5
Subgroup Analyses ............................................................... 10
4.5
Safety Analyses..................................................................... 11
4.5.1
Exposure of Study Medication............................................... 11
4.5.2
Adverse Events ..................................................................... 11
4.5.3
Cardiac Safety....................................................................... 11
4.5.4
Laboratory Data..................................................................... 12
4.5.5
Vital Signs.............................................................................. 12
4.6
Missing Data.......................................................................... 12
4.7
Interim Analyses .................................................................... 12


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3/Statistical Analysis Plan YO29296
5.
REFERENCES ........................................................................................... 13
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 6
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 14
Appendix 2
Schedule of Assessments........................................................... 20


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4/Statistical Analysis Plan YO29296
1.
BACKGROUND
Study YO29296 (“PUFFIN”) is a Phase III, randomized, double-blind, placebo-controlled 
bridging clinical trial conducted in mainland China.  This trial will evaluate the efficacy 
and safety of pertuzumabHerceptindocetaxel versus placeboHerceptindocetaxel in 
Chinese patients with previously untreated human epidermal growth factor 2 
(HER2)-positive metastatic breast cancer (MBC).
CLEOPATRA study (Study WO20698), a global Phase III trial, has demonstrated a 
statistically significant improvement in progression free survival (PFS) in the pertuzumab 
group compared with the placebo group (hazard ratio [HR]: 0.62; 95% CI: 0.51, 0.75; 
p0.0001) and an increase in median PFS of 6.1 months (18.5 months in the 
pertuzumab group versus 12.4 months in the placebo group) (Baselga et al. 2012).  The 
CLEOPATRA study has also shown a statistically significant improvement in overall 
survival (OS) for the pertuzumab group (HR: 0.68; 95% CI: 0.56, 0.84; p0.001).  The 
median OS was 56.5 months in the pertuzumab group compared to 40.8 months in the 
control group (Swain et al. 2015).
The purpose of Study YO29296 is to evaluate the efficacy and safety of pertuzumab in a 
randomized, controlled, and comparative setting for Chinese patients with previously 
untreated HER2-positive MBC.
The purpose of this Statistical Analysis Plan (SAP) is to pre-specify the analyses prior to 
the database lock for the primary analysis in order to maintain objectivity.  The SAP 
overrides the analyses described in the statistical section of the protocol, as applicable.  
This document will be approved by the Sponsor prior to the primary analysis.  Deviations 
from this plan will be noted in the Clinical Study Report for Study YO29296.
2.
STUDY DESIGN
This study is a Phase III, randomized, double-blind, placebo-controlled, multicenter 
clinical trial conducted in China.  Patients who have HER2-positive MBC and have not 
received chemotherapy or biologic therapy (including approved or investigational 
tyrosine kinase/HER inhibitors or vaccines) for their metastatic disease are eligible for 
the study.  Patients who have received one prior hormonal treatment for MBC are 
eligible.  Patients may have received systemic breast cancer treatment in the 
neoadjuvant or adjuvant setting, provided that the patient experienced a disease-free 
interval (DFI) of 12 months from completion of systemic treatment (excluding hormonal 
therapy) to metastatic diagnosis.  Patients may have received Herceptin and/or a taxane 
in the neoadjuvant or adjuvant setting.  HER2-positive status determined using archival, 
paraffin-embedded tumor tissue will be confirmed in a central laboratory by 
immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH).


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5/Statistical Analysis Plan YO29296
Approximately 240 patients will be randomized in a 1:1 ratio to one of two treatment 
arms:
Arm A

Placebo, administered by intravenous (IV) infusion every 3 weeks until disease 
progression (PD) or unacceptable toxicity

Herceptin (8 mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent 
cycles), administered by IV infusion every 3 weeks until PD or unacceptable toxicity

Docetaxel (75 mg/m2), administered by IV infusion every 3 weeks
Prior to completion of Cycle 6, docetaxel should be discontinued only for PD or 
unacceptable toxicity.  After completion of Cycle 6, discontinuation of docetaxel 
treatment is at the discretion of the patient and treating physician.
Arm B

Pertuzumab (840 mg loading dose for Cycle 1, followed by 420 mg for subsequent 
cycles), administered by IV infusion every 3 weeks until PD or unacceptable toxicity

Herceptin (8 mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent 
cycles), administered by IV infusion every 3 weeks until PD or unacceptable toxicity

Docetaxel (75 mg/m2), administered by IV infusion every 3 weeks.
Prior to completion of Cycle 6, docetaxel should only be discontinued for PD or 
unacceptable toxicity.  After completion of Cycle 6, discontinuation of docetaxel
treatment is at the discretion of the patient and treating physician.
Study treatment will be discontinued at the time of PD or unacceptable toxicity, with the 
possible exception of docetaxel, as described above.  Tumor assessments will be 
performed every 9 weeks from the date of randomization, regardless of treatment delays 
until PD (see Figure 1).  After discontinuation of study treatment, information on survival 
and cancer-related therapies and medical or surgical procedures will be collected by 
telephone every 18 weeks until the end of the study, death, loss to follow-up, withdrawal 
of consent, or study termination by the Sponsor.  Under no circumstances are patients 
who enroll in this study permitted to be re-randomized to this study and enrolled for a 
second course of treatment.
The study design is presented graphically in Figure 1.


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6/Statistical Analysis Plan YO29296
Figure 1
Study Schema
HER2human epidermal growth factor receptor 2.
a
Prior to completion of Cycle 6, docetaxel should be discontinued only for disease 
progression or unacceptable toxicity.  After completion of Cycle 6, discontinuation of docetaxel 
treatment is at the discretion of the patient and treating physician.
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis for Study YO29296 is provided in Appendix 1.  For additional 
details, see the Schedule of Assessments in Appendix 2.
2.2
DETERMINATION OF SAMPLE SIZE
The primary objective of Study YO29296 is to assess whether the addition of 
pertuzumab to the combination of Herceptin and docetaxel prolongs PFS in Chinese 
patients in a manner consistent with the results from CLEOPATRA study.  A consistency 
threshold is defined as a HR of 0.81, which maintains 50% of the risk reduction 
determined in CLEOPATRA study (HR:  0.62).
To reliably determine the predefined consistency value, a simulation method was used 
to estimate the required sample size.  Approximately 240 patients randomized in a 
1:1 ratio and 123 PFS events in the two treatment arms are required, providing an 
appropriate 83% probability of showing consistency.
The sample size estimation was based on the following assumptions: 

The median PFS is 11 months in the control arm, with a PFS HR of 0.68.


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7/Statistical Analysis Plan YO29296

The recruitment period is estimated to be 15 months.
2.3
ANALYSIS TIMING
No interim analysis of efficacy is planned.  The primary analysis of PFS will be 
performed after 123 PFS events have occurred, and the required PFS events are 
expected to be reached at around 23 months after the first patient is enrolled into the 
study.
3.
STUDY CONDUCT
3.1
RANDOMIZATION PROCEDURE
Patients who are eligible for study entry are randomly assigned (1:1) to a treatment arm 
via the interactive voice or Web-based response system (IxRS) through use of a 
permuted block randomization scheme.
Randomization procedures use two stratification factors:

Disease type (visceral disease vs. non-visceral disease) and

Hormone receptor status (estrogen receptor [ER]- and progesterone receptor 
[PgR]- negative or ER- and/or PgR-positive).
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
4.1.1
Intent-to-Treat Population
The intent-to-treat (ITT) population consists of all randomized patients.  Patients are 
assigned to the treatment group to which they were randomized.  The ITT population will 
be used for the primary and secondary efficacy analyses.  For objective response, only 
patients with measurable disease at baseline will be included in the analysis.  For 
duration of response, only patients with an objective response will be included in the 
analysis.
4.1.2
Safety Population
Safety population will consist of all randomized patients who receive at least one dose of 
any of the study drugs, with patients grouped according to the treatment actually 
received, defined by whether at least one dose of pertuzumab was received.
4.2
ANALYSIS OF STUDY CONDUCT
Patient enrollment, duration of follow-up, and discontinuation from treatment and study
will be summarized by treatment arm.  In addition, major protocol violations will be 
summarized by treatment arm.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographics and baseline characteristics, such as age, weight, Eastern Cooperative 
Oncology Group (ECOG) Performance Status, ER/PgR status, HER2 status, prior 


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8/Statistical Analysis Plan YO29296
treatments for breast cancer, treatment-free interval, and involvement of visceral sites, 
will be summarized by treatment arm.
Descriptive statistics (mean, median, SD, and range) will be presented for continuous 
variables, and proportions will be presented for categorical variables.
4.4
EFFICACY ANALYSIS
The emphasis of efficacy analyses is to assess whether the treatment benefit in 
Chinese patients is consistent with the benefit observed in CLEOPATRA study, thus the 
hypothesis testing is considered exploratory in this bridging study.
4.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is PFS based on investigator assessment.  PFS is defined 
as the time from randomization to the first occurrence of progressive disease, as 
determined by the investigator using Response Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST v1.1), or death from any cause within 18 weeks after the last tumor 
assessment, whichever occurs first.
At the time of data cutoff for the PFS analysis, data for patients who do not have 
documented progressive disease or who have not died within 18 weeks of the last tumor 
assessment will be censored at the time of the last tumor assessment (or, if no tumor 
assessments are performed after the baseline visit, at the time of randomization plus 
1 day).
The Kaplan-Meier approach will be used to estimate median PFS for each treatment arm.  
The Cox proportional hazards model, stratified by disease type (visceral disease vs. 
non-visceral disease) and hormone receptor status (ER- and PgR-negative or 
ER- and/or PgR-positive), will be used to estimate the hazard ratio between the two 
treatment arms and its 95% CI.  The eCRF or central lab data will be used in the primary 
analysis.  The unstratified hazard ratio will also be provided.  The two-sided stratified 
log-rank test will be used to compare PFS between the two treatment arms.  The 
unstratified log-rank test result will also be provided.
4.4.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints in this study include OS, objective response, and 
duration of objective response (DOR).
4.4.2.1
Overall Survival
Overall survival is defined as the time from randomization to death from any cause.  
Patients who are alive or lost to follow-up at the time of the analysis will be censored at 
the date they were last known to be alive.  Patients with no post-baseline information will 
be censored at the time of randomization plus 1 day.  Analysis methods are the same as 
those described for the primary endpoint.


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Overall survival data will be summarized at the time of final PFS analysis, at 
approximately 23 months.  A final analysis of OS will be performed at approximately 
3 years after randomization of the last patient.
The 1-year survival rate will also be estimated using the Kaplan-Meier method.  A 2-year
landmark analysis will be performed, in the form of a truncated survival analysis at 
2 years.  A truncated survival endpoint at 2 years is considered a robust and clinically 
highly relevant endpoint for capturing clinical benefit of a new therapy.  In this analysis, 
only those deaths occurring within 2 years of randomization will be counted as events.
4.4.2.2
Objective Response
Objective response is defined as a complete response or partial response, as 
determined by the investigator using RECIST v1.1.  Only patients with measurable 
disease at baseline will be included in the analysis of ORR.  Patients without a 
post-baseline tumor assessment will be considered non-responders.
An estimate of the ORR and its 95% CI (Pearson-Clopper) will be calculated for each 
treatment arm.  The difference in ORR will also be provided with 95% CIs (using 
HauckAnderson method).  The MantelHaenszel 2 test, stratified by disease type 
(visceral disease vs. non-visceral disease) and hormone receptor status (ER- and 
PgR-negative or ER- and/or PgR-positive) will be used to compare the ORR between 
the two treatment arms.  An unadjusted Fisher’s exact test result will also be provided.
4.4.2.3
Duration of Objective Response 
Duration of objective response is defined as the time from the first occurrence of a 
documented objective response to the time of PD, as determined by the investigator 
using RECIST v1.1, or death from any cause within 18 weeks after the last tumor 
assessment whichever occurs first.  Only patients with an objective response will be 
included in the analysis.  The method for handling censoring is the same as that 
described for the primary endpoint.
Median duration of objective response for each treatment arm will be estimated using 
the Kaplan-Meier approach.  The HR between the two treatment arms will also be 
estimated using Cox regression.
4.4.3
Exploratory Efficacy Endpoints
The relationship of biomarkers, such as phosphatidylinositol-4,5-bisphosphate 3-kinase 
(PI3K) status, HER2/3 mRNA, PD-L1, and cluster of differentiation 8 (CD8) expression, 
with efficacy (response rate, PFS, and OS) may be explored when appropriate.
4.4.4
Sensitivity Analyses
Cox proportional hazards model for PFS will be performed using IxRS-recorded
stratification level.


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A summary table and Kaplan-Meier plot of the time to censoring in the two treatment 
arms will be produced to investigate differences in follow-up time.  In this analysis, 
patients who had events in the primary analysis (progressive disease or death within 
18 weeks of the last tumor assessment) are censored at the date of their event and 
patients without an event are regarded as having had an event at the censoring date.
In addition to this, the robustness of the primary analysis will be evaluated through 
sensitivity analyses:
1.
Potential bias introduced by missed visits (If missed two or more consecutive visits 
before PD, censoring at the last response assessment before PD)
2.
Timing of death (including all progression and deaths as an event)
3.
Censoring at the time of Next Anti-Cancer Therapy (NACT)
Sensitivity analyses 2 and 3 will be performed as planned.  The data associated with 
sensitivity analysis 1 will be evaluated in the following manner to determine whether this 
additional sensitivity analysis will need to be performed.
Tabulation of the incidence of PDs identified at a tumor assessment immediately 
following two or more missing tumor assessment.
If the incidence of these events is minimal (e.g.,2% in each treatment group), the 
sensitivity analysis 1 will be deemed unnecessary.
Other sensitivity analyses not listed here might be explored when appropriate.
4.4.5
Subgroup Analyses
To assess the consistency of treatment benefit with respect to the primary efficacy 
endpoint, PFS, across important subgroups, forest plots (including estimated hazard 
ratios) will be provided for the following variables: 

Age-group (65, 65 years),

Disease type (stratification factor: visceral disease vs. non-visceral disease),

Hormone receptor status (stratification factor: ER- and/or PgR-positive versus 
ER- and PgR-negative),

ECOG Performance Status,

Prior treatment status (de novo, adjuvant/neoadjuvant therapy),

Treatment-free interval (2 years versus 2 years vs. no prior therapy),

HER2 status by central testing (IHC3+ regardless of FISH status, IHC2+/FISH+ and 
IHC0/1+/FISH+).
If applicable, expanded analyses will be performed using Cox regression models to 
estimate treatment effect by adjusting covariates in an exploratory manner.  Variables to 


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be considered are the stratification factors as well as other disease- or patient-related
prognostic or predictive factors.
4.5
SAFETY ANALYSES
Safety analyses will be performed on the safety population, defined in Section 4.1.2.
4.5.1
Exposure of Study Medication
The numbers of patients who experience any dose interruption, dose modification, or 
dose discontinuation for any component of the study treatment will be summarized by 
treatment arm.  Descriptive statistics will be presented for total cumulative dose, number 
of cycles, and number of patients at each treatment cycle.
4.5.2
Adverse Events
Verbatim descriptions of adverse events (AEs) will be mapped to Medical Dictionary for 
Regulatory Activities (MedDRA) thesaurus terms and graded according to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
Version 4.  All AEs, including serious adverse events (SAEs) that occur on or after the
date of the first study drug administration will be summarized by treatment arm and 
NCI CTCAE grade (v4.0).  In addition, AEs leading to discontinuation of study treatment 
will be summarized by treatment arm.  Adverse events of special interest (AESIs) 
defined in Section 5.2.3 of the Protocol will be summarized.
For each patient’s AE, the maximum severity recorded will be used in the summaries.
Deaths reported during the study treatment period and those reported after patient 
treatment discontinuation will be summarized by treatment group.
AE summaries will be presented for overall treatment period and listing for post-
treatment follow-up.  For the definition of AE reporting period, please refer to 
Section 5.3.1 of the Protocol.
Separate summaries for adverse events may be provided for the docetaxel period and 
the period following discontinuation of docetaxel (chemo-free period) as indicated.
4.5.3
Cardiac Safety
Cardiac events (AE and SAEs) will be summarized by SOC Cardiac disorders.
The number and percentage of patients with Symptomatic LVSD at any time during the 
study will be summarized by treatment arm.  Symptomatic LVSD will be evaluated by the 
assessment of NCI CTCAE v4.0.
SAEs “Cardiac Failure” (using basket SMQ wide “Cardiac Failure”) will be summarized 
as well.


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12/Statistical Analysis Plan YO29296
LVEF data analyses will include the following: 
The baseline LVEF value and the maximum absolute decrease (or minimum 
absolute increase if patients’ post-baseline LVEF measures are all larger than the 
baseline value) in LVEF measure from baseline will be summarized.  The 95% 
two-sided confidence limits for the maximum absolute decrease in LVEF measure 
and the difference between the two treatment arms will be presented.  LVEF 
measurements and change in LVEF from baseline will be summarized by treatment 
arm and time point in graphical and tabular format.
In addition, LVEF will be summarized by presenting frequencies over time by treatment 
group for the following categories:

Increase or no change in Ejection Fraction (EF)

Decrease from baseline 10 EF points 

Absolute value 50% and decrease from baseline 10 EF points

Absolute value 50% and decrease from baseline 15 EF points

Absolute value 50% and decrease from baseline 10 EF points
4.5.4
Laboratory Data
Clinical laboratory tests will be performed at local laboratories.  Changes in laboratory 
data will be summarized by grade using NCI CTCAE v4.0 for each treatment arm.  
Selected abnormal laboratory values, such as worst toxicity grade and toxicity grade 
shift from baseline, will be summarized by treatment arm.
4.5.5
Vital Signs
Changes in selected vital signs will be summarized by treatment arm and by change 
over time including change from baseline.  Baseline is defined as the measurement 
obtained on Cycle 1, Day 1 prior to first dose of study drug.
4.6
MISSING DATA
No values will be imputed for missing data for the primary and secondary efficacy 
analyses except as specified in Sections 4.4.1 and 4.4.2 for the PFS, OS, and ORR.
4.7
INTERIM ANALYSES
There are no interim analyses planned.


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5.
REFERENCES
Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for 
metastatic breast cancer. N Engl J Med. 2012;366:109-19
Swain SM, Baselga José, Kim Sung-Bae, et al. Pertuzumab, Trastuzumab, and 
Docetaxel in HER2-Positive Metastatic Breast Cancer (CLEOPATRA study). N 
Engl J Med 2015;372:724-734.


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Appendix 1
Protocol Synopsis
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED CLINICAL TRIAL TO EVALUATE THE EFFICACY
AND SAFETY OF PERTUZUMABHERCEPTINDOCETAXEL 
VERSUS PLACEBOHERCEPTINDOCETAXEL IN 
PREVIOUSLY UNTREATED HER2-POSITIVE METASTATIC 
BREAST CANCER
PROTOCOL NUMBER:
YO29296
VERSION NUMBER:
3
TEST PRODUCT:
Pertuzumab (RO4368451)
PHASE:
III
INDICATION:
HER2-positive metastatic breast cancer that has not been treated 
with chemo or biologic therapy
SPONSOR:
F. Hoffmann–La Roche Ltd
Objectives
Efficacy Objectives
The primary efficacy objective for this study is as follows:

To evaluate the efficacy of pertuzumab plus Herceptin plus docetaxel compared with 
placebo plus Herceptin plus docetaxel in patients with previously untreated HER2-positive 
metastatic breast cancer (MBC), as measured by investigator-assessed progression-free 
survival (PFS)
The secondary efficacy objectives for this study are as follows:

To compare overall survival (OS) between the two treatment arms

To compare the objective response rate between the two treatment arms

To compare the duration of objective response between the two treatment arms
Exploratory Objective
The exploratory objective for this study is as follows:

To explore the relationship of biomarkers, such as PI3K status, HER2/3 mRNA, PD-L1, and 
CD8 expression, with efficacy (response rate, PFS, and OS)
Safety Objective
The safety objective for this study is as follows:

To compare the safety profile between the two treatment arms


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Appendix 1
Protocol Synopsis (cont.)
Study Design
Description of Study
This study is a Phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial 
in China.  Patients who have HER2-positive MBC and have not received chemotherapy or 
biologic therapy (including approved or investigational tyrosine kinase/HER inhibitors or 
vaccines) for their metastatic disease are eligible for the study.  Patients who have received one 
prior hormonal treatment for MBC are eligible.  Patients may have received systemic breast 
cancer treatment in the neoadjuvant or adjuvant setting, provided that the patient experienced a 
diseasefree interval (DFI) of 12 months from completion of systemic treatment (excluding 
hormonal therapy) to metastatic diagnosis.  Patients may have received Herceptin and/or a 
taxane in the neoadjuvant or adjuvant setting.  HER2-positive status determined using archival, 
paraffin-embedded tumor tissue will be confirmed in a central laboratory by 
immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH).
Number of Patients
A total of 240 patients will be randomized in a 1:1 ratio to one of two treatment arms
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form, obtained prior to any study procedure

Age 18 years

Histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent 
or metastatic disease that is suitable for chemotherapy
Patients with measurable or nonmeasurable disease are eligible.  
Patients with only bone metastases are eligible provided that some bone metastases 
have not been previously irradiated and that tumor tissue samples from the primary 
tumor are available for central HER2 testing.
Locally recurrent disease must not be amenable to resection with curative intent.

HER2-positive MBC (defined as 3by IHC and/or ISH amplification ratio 2.0) confirmed by 
a Sponsor-designated central laboratory
It is strongly recommended that a formalinfixed paraffinembedded (FFPE) tissue 
block from the primary tumor (or metastatic lesion if the primary is not available) be 
submitted for central laboratory confirmation of HER2 eligibility.  However, if that is not 
possible, unstained and freshly cut slides need to be submitted (see Section 4.5.3 for 
further details).  Tissue will subsequently be used for assessment of biomarkers.

Left ventricular ejection fraction (LVEF) 55% at baseline (within 42 days prior to 
randomization) as determined by either echocardiography (ECHO) or multiplegated 
acquisition (MUGA) scan (ECHO is the preferred method)
If the patient is randomized, the same method of LVEF assessment, ECHO or MUGA, 
must be used throughout the study, and to the extent possible, be obtained at the 
same institution (see Section 4.5.8).  Any prestudy LVEF values obtained during and 
after Herceptin neoadjuvant or adjuvant treatment will be obtained, as applicable.

Eastern Cooperative Oncology Group Performance Status of 0 or 1


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Appendix 1
Protocol Synopsis (cont.)

For women who are not postmenopausal (postmenopausal defined as 12 months of 
nontherapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  
agreement to remain abstinent or use single or combined nonhormonal contraceptive 
methods that result in a failure rate of 1% per year during the treatment period and for at 
least 7 months after the last dose of study treatment (Herceptin and/or pertuzumab)
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of contraception.
Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year 
include tubal ligation, male sterilization, and certain non-hormonal intrauterine 
devices. Alternatively, two methods (e.g., two barrier methods such as a condom and 
a cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier 
methods must always be supplemented with the use of a spermicide

For men:  agreement to remain abstinent or use a condom plus an additional contraceptive 
method that together result in a failure rate of 1% per year during the treatment period and 
for at least 7 months after the last dose of study treatment (Herceptin and/or pertuzumab)
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not acceptable methods of contraception.

Negative serum pregnancy test in women of childbearing potential, premenopausal or less 
than 12 months of amenorrhea post-menopause, and who have not undergone surgical 
sterilization.

Able to comply with the study protocol, in the investigator’s judgment
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History of anticancer therapy for MBC, with the exception of one prior hormonal regimen for 
MBC, which must be stopped prior to randomization
Anticancer therapy for MBC includes any epidermal growth factor receptor or 
anti-HER2 agents or vaccines, cytotoxic chemotherapy, or more than one prior 
hormonal regimen for MBC.  
One prior hormonal regimen for MBC may include more than one hormonal therapy.  If 
a patient is switched to a different hormonal therapy for reasons other than disease 
progression (e.g., toxicity or local standard practice), this will be counted as one 
regimen.  If a patient is switched to a different hormonal therapy because of disease 
progression, this will be counted as two regimens, and the patient will not be eligible 
for the study. 

History of approved or investigative tyrosine kinase/HER inhibitors for breast cancer in any 
treatment setting, except Herceptin used in the neoadjuvant or adjuvant setting

History of systemic breast cancer treatment in the neoadjuvant or adjuvant setting with a 
DFI from completion of systemic treatment (excluding hormonal therapy) to metastatic 
diagnosis of 12 months

History of persistent Grade 2 hematologic toxicity resulting from previous neoadjuvant or 
adjuvant therapy (all grades based on National Cancer Institute Common Toxicity Criteria 
for Adverse Events, Version 4.0 [NCI CTCAE v 4.0])

Grade 3 peripheral neuropathy at randomization

History of other malignancy within the previous 5 years, except for carcinoma in situ of the 
cervix or non-melanoma skin carcinoma that has been previously treated with curative 
intent


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Appendix 1
Protocol Synopsis (cont.)

Current clinical or radiographic evidence of CNS metastases
A computed tomography (CT) or magnetic resonance imaging (MRI) scan of the brain 
is mandatory within 28 days before randomization in cases of clinical suspicion of 
brain metastases.

History of exposure to the following cumulative doses of anthracyclines: 
Doxorubicin or liposomal doxorubicin 360 mg/m2
Epirubicin 720 mg/m2
Mitoxantrone 120 mg/m2 and idarubicin 90 mg/m2
Other anthracycline greater than the equivalent of 360 mg/m2 of doxorubicin
If more than one anthracycline has been used, the cumulative dose must not 
exceed the equivalent of 360 mg/m2 of doxorubicin.

Current uncontrolled hypertension (systolic blood pressure 150 mmHg and/or diastolic 
blood pressure 100 mmHg) or unstable angina

History of congestive heart failure of any New York Heart Association classification, or 
serious cardiac arrhythmia requiring treatment (excluding atrial fibrillation or paroxysmal 
supraventricular tachycardia)

History of myocardial infarction within 6 months prior to randomization

History of LVEF decrease to 50% during or after prior Herceptin neoadjuvant or adjuvant 
therapy 

Current dyspnea at rest due to complications of advanced malignancy, or other diseases 
that require continuous oxygen therapy

Inadequate organ function, evidenced by the following laboratory results within 28 days 
prior to randomization:
Absolute neutrophil count 1500 cells/L
Platelet count 100,000 cells/L
Hemoglobin 9 g/dL 
Total bilirubin greater than the upper limit of normal (ULN) (unless the patient has 
documented Gilbert’s syndrome)
AST or ALT 2.5 ULN (> 5 × ULN in patients with liver metastases)
AST (SGOT) or ALT (SGPT) 1.5 ULN with concurrent serum ALP 2.5 ULN
Serum ALP may be 2.5 ULN only if bone metastases are present and AST 
and ALT are 1.5 ULN.  
Serum creatinine 2.0 mg/dL or 177 mol/L
INR and aPTT or PTT 1.5 ULN (unless on therapeutic anti-coagulation)

Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary, or metabolic disease; wound healing disorders; ulcers; bone fractures)

Major surgical procedure or significant traumatic injury within 28 days prior to randomization 
or anticipation of the need for major surgery during the course of study treatment

Pregnant or lactating or intending to become pregnant during the study

Treatment with any investigational treatment within 28 days prior to randomization

Current known infection with HIV, hepatitis C virus, or active hepatitis B virus (HBV)
Patients who are known carriers of HBV may be included in the study.  Active HBV is 
defined as presence of each of the following:  positive test for hepatitis B surface 
antigen, detectable levels of HBV DNA, and ALT ULN.

Receipt of intravenous (IV) antibiotics for infection within 14 days prior to randomization


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Appendix 1
Protocol Synopsis (cont.)

Current chronic daily treatment with corticosteroids (dose of 10 mg/day 
methylprednisolone equivalent), excluding inhaled corticosteroids

Known hypersensitivity to any of the protocolspecified study treatments

Concurrent participation in an interventional or noninterventional study
Length of Study
A total of approximately 240 patients (approximately 120 per arm) will be enrolled.  The 
recruitment period is estimated to be 15 months.
The primary analysis of PFS will be performed after 123 PFS events have occurred, and the 
required PFS events will be reached at approximately 23 months after the first patient is 
enrolled into the study.
End of Study
The end of the study will occur approximately 3 years after the last patient is enrolled or the trial 
is terminated by the Sponsor, whichever is earlier.
Outcome Measures
Efficacy Outcome Measures
The efficacy outcome measures for this study are as follows:

PFS, defined as the time from randomization to the first occurrence of disease progression, 
as determined by the investigator using Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v 1.1; Therasse et al. 2000), or death from any cause within 18 weeks 
after the final tumor assessment, whichever occurs first
Assessments will be based on review of radiological images (e.g., MRI scans, CT 
scans, bone scans, chest X-rays), as well as cytologic (e.g., relevant cytology reports 
documenting malignant pleural effusions, bone marrow aspirations, cerebral spinal 
fluid) and photographic data, if available.
The secondary efficacy outcome measures for this study are as follows:

OS, defined as the time from randomization to death from any cause

Objective response, defined as a complete response or partial response that is confirmed 
2842 days later, as determined by the investigator using RECIST v 1.1

Duration of objective response, defined as the time from the first occurrence of a 
documented objective response to the time of disease progression, as determined by the 
investigator using RECIST v 1.1, or death from any cause, whichever occurs first
Exploratory Outcome Measures
The exploratory outcome measures for this study may include, but are not limited to, the 
following:

Expression level of HER2/3 mRNA as measured by quantitative real-time polymerase chain 
reaction

PIK3CA status (i.e., mutation not detected or mutation detected by PCR based mutational 
analyses or by other technologies suited for mutational analyses)

Expression of PD-L1 and CD8 as assessed by IHC or by other suitable technologies
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence of symptomatic left ventricular systolic dysfunction

Incidence of asymptomatic LVEF events

LVEF measurements over the course of the study


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Appendix 1
Protocol Synopsis (cont.)

Incidence and severity of adverse events and serious adverse events NCI CTCAE v 4.0)

Changes in clinical laboratory results during the study
Investigational Medicinal Products
Herceptin, pertuzumab, and placebo are investigational medicinal products in this study.  
Treatments will be administered on Day 1 of each specified cycle.
All patients will receive Herceptin by IV infusion in 3-week cycles, as follows:

Herceptin (8 mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles)

Herceptin will be administered until disease progression or unacceptable toxicity.  
Test Product
Patients in Arm B will receive pertuzumab (840 mg loading dose for Cycle 1, followed by 
420 mg for subsequent cycles) by IV infusion every 3 weeks until disease progression or 
unacceptable toxicity.
Comparator
Patients in Arm A will receive placebo by IV infusion every 3 weeks until disease progression or 
unacceptable toxicity.
Non-Investigational Medicinal Products
Docetaxel is a non-investigational medicinal product in this study. Sites will obtain and utilize 
commercially available docetaxel.  Treatments will be administered on Day 1 of each specified 
cycle.
All patients will receive docetaxel in 3-week cycles, as follows:

Docetaxel (75 mg/m2)
Prior to completion of Cycle 6, docetaxel should be discontinued only for disease 
progression or unacceptable toxicity.  After completion of Cycle 6, discontinuation of 
docetaxel treatment is at the discretion of the patient and treating physician.
Statistical Methods
Primary Analysis
The primary analysis of PFS will be performed after 123 PFS events have occurred, and the 
required PFS events are expected to be reached at around 23 months.
Determination of Sample Size  
To reliably determine the predefined consistency value, a simulation method was used to 
estimate the required sample size.  A total of 240 patients randomized in a 1:1 ratio and 
123 PFS events in the two treatment arms are required, providing an appropriate 
83% probability of showing consistency.  
The sample size estimation was based on the following assumptions:

The median PFS is 11 months in the control arm, with a PFS hazard ratio of 0.68

The recruitment period is estimated to be 15 months
Interim Analyses
No interim analysis of efficacy is planned.


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Appendix 2
Schedule of Assessments
Day
Screening a,b
Treatment Period a
Follow-Up a
–28 to 
–1
–7 to 
–1
Every Cycle 
(21 days)
Every 3 
Cycles
Treat. 
Discon. Visit
Week 18 
after Treat. 
Discon. Visit
Every 18 Weeks  
after Treat. 
Discon. Visit
Up to 3 Years 
after Treat. 
Discon. Visit
1
2842 Days 
after Final 
Treatment c
126 Days 
after Treat. 
Discon. Visit
Every 126 Days 
after Treat. 
Discon. Visit
Informed consent
x d
Archival tumor tissue for HER2 
eligibility, ER/PgR status, and 
exploratory BM analyses to central 
laboratory
x d
Complete medical history
x
Review of eligibility criteria
x
Complete physical examination e and 
vital signs f
x
Symptom-directed physical 
examination g and vital signs f
x
x
LVEF by ECHO or MUGA
x h
Every 9 weeks from 
randomization i
x
Every 6 months in the first year, then annually 
for up to 3 years j
12-Lead ECG
x
Every 9 weeks, at same 
time as LVEF i
x
Chest X-ray
x
If indicated
x k
If indicated
ECOG Performance Status
x
x
x
Tumor assessments
x l,m
Every 9 weeks from randomization l,n


Appendix 2 Schedule of Assessments (cont.)
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Day
Screening a,b
Treatment Period a
Follow-Up a
–28 to 
–1
–7 to 
–1
Every Cycle 
(21 days)
Every 3 
Cycles
Treat. 
Discon. Visit
Week 18 
after Treat. 
Discon. Visit
Every 18 Weeks  
after Treat. 
Discon. Visit
Up to 3 Years 
after Treat. 
Discon. Visit
1
2842 Days 
after Final 
Treatment c
126 Days 
after Treat. 
Discon. Visit
Every 126 Days  
after Treat. 
Discon. Visit
Bone scan
x
If indicated o
Brain scan
x p
Every 9 weeks from 
randomization q
Adverse events
x r
Ongoing s
Concomitant medications and 
cancer-related surgery/procedures
x t
Ongoing
Ongoing
Pertuzumab/placebo administration
x u,v
Herceptin administration
x u,w
Docetaxel administration
x u,x
Hematology, at local laboratory
x y,z
x y,z
x z
Chemistry, at local laboratory
x y,aa
x y,bb
x aa
INR and aPTT or PTT, at local 
laboratory
x
x cc
x
Pregnancy test, at local laboratory
x dd
x dd
x dd
3 and 7 months after treatment 
discontinuation visit dd
Cancer-related procedures and 
therapies
x ee
Survival information
x ee
aPTTactivated partial thromboplastin time; ECHO echocardiogram; ECOGEastern Cooperative Oncology Group; eCRFelectronic Case 
Report Form; ERestrogen receptor; HER2human epidermal growth factor receptor 2; INRinternational normalized ratio; LVEF left 


Appendix 2 Schedule of Assessments (cont.)
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ventricular ejection fraction; MUGAmultiple-gated acquisition; PET positron emission tomography; PgRprogesterone receptor; PTTpartial 
thromboplastin time; Treat. Discon.Treatment Discontinuation.
a Unless otherwise noted, a window of 3 days will apply to all visits and assessments, except for collection of follow-up survival information, 
which will have a window of 7 days.
b Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 7 days prior to Day 1 may be used; 
such tests do not need to be repeated for screening.
c The treatment discontinuation visit should occur 2842 days after the last administration of study treatment (pertuzumab (or placebo), 
Herceptin, or docetaxel), whichever is discontinued last.
d Signing of the Informed Consent Form and submission of tumor sample for HER2 eligibility are not limited to the 28-day window prior to Day 1 
of Cycle 1.
e Includes measurements of height and weight and an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems.  Particular care should be taken with 
regard to cardiovascular signs and symptoms (e.g., elevated jugular venous pressure, sinus tachycardia, tachypnea, the presence of an S3 
heart sound, crackles on chest auscultation).
f
Vital signs (blood pressure, pulse rate, and body temperature) will be recorded before and after infusion of each study medication (pertuzumab 
(or placebo), Herceptin, and docetaxel).
g Perform a limited, symptom-directed examination, including weight measurement, at specified timepoints or as clinically indicated.  Particular 
care should be taken with regard to cardiovascular signs and symptoms.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF.
h Perform as close as possible to, but a maximum of 42 days prior to, randomization.  Any prestudy LVEF values obtained during and after 
Herceptin neoadjuvant or adjuvant treatment will be obtained, as applicable.
i
Perform every 9 weeks from the date of randomization until the treatment discontinuation visit, or more frequently as needed for cardiac safety.  
If an LVEF assessment must be performed early or late, subsequent assessments should be conducted according to the original schedule of 
every 9 weeks from the date of randomization.  Perform a 12-lead ECG at the same time as the LVEF assessment.
j
Patients for whom study treatment is permanently discontinued because of a drop in LVEF should continue to have LVEF assessments 
repeated as clinically indicated, with a maximum interval between LVEF assessments of 3 months, until the LVEF returns to 50%, or 1 year 
after the treatment discontinuation visit, whichever occurs first.  Thereafter, LVEF assessments will be performed annually for up to 3 years 
after the treatment discontinuation visit.
k If not performed within 28 days prior to the treatment discontinuation visit.
l
The same assessment technique must be used throughout the study for evaluating a particular lesion.  The same technique should also be 
used for cytologic (e.g., relevant cytology reports documenting malignant pleural effusions, bone marrow aspirations, cerebral spinal fluid) and 
photographic data, if available.  The same investigator should assess all tumor responses for each patient.


Appendix 2 Schedule of Assessments (cont.)
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m MRI or CT scans that were performed before a patient signed consent to take part in the study may be used to provide baseline tumor status 
as long as they were performed within 28 days prior to the start of treatment, at the same hospital, with the same technique or machine, and 
preferably by the same individual as those for tumor assessments during the study.  This should be documented in the study files at the site.
n Tumor assessments will be performed every 9 weeks (3 days) from the date of randomization until disease progression.  If a tumor 
assessment must be performed early or late, subsequent assessments should be conducted according to the original schedule of every 9 
weeks from the date of randomization.  All patients should undergo, at a minimum, a chest and abdomen CT or MRI scan.  PET scans will not 
be considered for assessment of efficacy at any time during the study (except as specified for bone scans in the absence of radioactive 
isotopes).
o A bone scan should be performed in the event of clinical suspicion of progression of existing bone lesions or the appearance of new bone 
lesions.  If treatment is discontinued because of disease progression at sites other than bone, a bone scan should be performed immediately.  
In the absence of radioactive isotopes, an MRI scan (with gadolinium enhancement, if required) or 18F-fluorodeoxyglucose PET scan is an 
acceptable form of assessment of the skeleton for the presence of bone metastases.  Skeletal survey with plain X-rays is acceptable if there is 
no suitable alternative.
p CT or MRI scan of the brain and/ or spine within 28 days before randomization in cases of clinical suspicion of brain metastases.
q CT or MRI scan of the brain and/or spine if there is clinical suspicion of CNS metastases.
r
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.
s After initiation of study drug, all adverse events will be reported through the treatment discontinuation visit.  After this period, the investigator is 
not required to actively monitor patients for adverse events; however, the Sponsor should be notified if the investigator becomes aware of any 
poststudy serious adverse events or non-serious adverse events of special interest (see Section 5.6).  The investigator should follow each 
adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events considered to be related to study 
drug or trial-related procedures until a final outcome can be reported.
t
Includes all medications taken within 90 days prior to randomization.
u Patients will receive study treatment (pertuzumab (or placebo) followed by Herceptin and then docetaxel) by IV infusion on Day 1 of each 
3-week cycle.  The first dose of study treatment (Day 1 of Cycle 1) must be administered within 3 days of randomization.  Treatment with 
pertuzumab (or placebo) and Herceptin will continue until disease progression or unacceptable toxicity.  Prior to completion of Cycle 6, 
docetaxel should only be discontinued for disease progression or unacceptable toxicity.  After completion of Cycle 6, discontinuation of 
docetaxel treatment is at the discretion of the patient and treating physician.  See Section 4.3 for additional details.
v Patients will receive either placebo or pertuzumab at a loading dose of 840 mg for Cycle 1, followed by 420 mg for subsequent cycles.
w Patients will receive Herceptin at a loading dose of 8 mg/kg for Cycle 1, followed by 6 mg/kg for subsequent cycles.
x Patients will receive docetaxel at a dose of 75 mg/m2.


Appendix 2 Schedule of Assessments (cont.)
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y Laboratory tests must be performed within 3 days prior to each study drug administration, and results must be available prior to each study 
drug infusion.  In general, if baseline laboratory assessments are performed within 7 days prior to study treatment start, they will not need to be 
repeated on Day 1 of the start of study treatment.
z Includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells).
aa Includes sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and 
direct bilirubin, ALP, ALT, AST, uric acid, LDH.
bb Includes potassium, creatinine, total bilirubin, ALP, ALT, AST.
cc During the treatment period, patients receiving therapeutic doses of anti-coagulants should have INR and aPTT or PTT measurements 
repeated before the start of every chemotherapy cycle.  Results must be available prior to each study drug infusion.
dd All women who are not postmenopausal (postmenopausal defined as 12 months of non-therapy-induced amenorrhea) or surgically sterile will 
have a serum pregnancy test at screening.  A urine pregnancy test will be performed at all other specified timepoints (and as clinically 
indicated).  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  Baseline and treatment period pregnancy 
test results must be available prior to drug infusion.
ee After discontinuation of study treatment, information on survival and cancer-related therapies and medical or surgical procedures will be 
collected by telephone every 18 weeks until death, loss to follow-up, withdrawal of consent, or study termination by the Sponsor.  Immediately 
prior to the data cutoff for the primary progression-free survival analysis and for any overall survival analysis, the investigative sites will contact 
every patient that is alive to confirm current survival status.