Clinical trial NCT02586025
Conditions: Breast Cancer
Sponsor: Hoffmann-La Roche
Start date: 2016-03-14; Completion date: 2022-03-14
Enrollment: 329 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an Asia-Pacific regional, randomized, double-blind, multicenter trial designed to evaluate treatment with trastuzumab + pertuzumab + docetaxel compared with trastuzumab + placebo + docetaxel in chemotherapy-naïve participants with early-stage or locally advanced HER2-positive breast cancer. The anticipated treatment duration is approximately 17 months.

Detailed description:

Arms: arm 1: Prior to surgery: trastuzumab, pertuzumab, and docetaxel for 4 cycles (1 cycle = 21 days). After surgery/chemotherapy with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC): trastuzumab and pertuzumab up to 1 year total. arm 2: Prior to surgery: trastuzumab, placebo, and docetaxel for 4 cycles (1 cycle = 21 days). After surgery/FEC chemotherapy: trastuzumab and placebo up to 1 year total.
Interventions: intervention 1: FEC Chemotherapy intervention 2: Surgery intervention 3: Docetaxel intervention 4: Pertuzumab intervention 5: Placebo intervention 6: Trastuzumab
Intervention descriptions: intervention 1: Fluorouracil 500-600 milligrams per square meter (mg/m2), epirubicin 90-120 mg/m2, and cyclophosphamide 500-600 mg/m2 by intravenous (IV) infusion every 3 weeks for three cycles (Cycles 5-7). FEC chemotherapeutic agents will be administered following surgery on Day 1 of each specified cycle. intervention 2: All participants who are eligible for surgery will undergo surgery and have their pathologic response evaluated. intervention 3: Docetaxel IV infusion in 3-week cycles. Neoadjuvant treatment: 75 mg/m2 for Cycles 1-4. intervention 4: Pertuzumab IV infusion in 3-week cycles. Prior to surgery (neoadjuvant treatment): 840 milligrams (mg) loading dose for Cycle 1, followed by 420 mg for Cycles 2-4. After surgery and 3 cycles of FEC chemotherapy (adjuvant treatment): 840 mg loading dose for Cycle 8, followed by 420 mg for Cycles 9-20) intervention 5: Placebo by IV infusion in 3-week cycles as neoadjuvant treatment (Cycles 1-4)and as adjuvant treatment (Cycles 8-20) intervention 6: Trastuzumab IV infusion in 3-week cycles. Neoadjuvant treatment: 8 milligrams per kilogram (mg/kg) loading dose for Cycle 1, followed by 6 mg/kg for Cycles 2-4. Adjuvant treatment: 8 mg/kg loading dose for Cycle 8, followed by 6 mg/kg for Cycles 9-20.

Protocol documents:
Prot_000.pdf: 
 
 
Official Title:  
 
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PLACEBO-
CONTROLLED, PHASE III STUDY TO EVALUATE PERTUZUMAB 
IN COMBINATION WITH DOCETAXEL AND TRASTUZUMAB AS 
NEOADJUVANT THERAPY, AND PERTUZUMAB IN 
COMBINATION WITH TRASTUZUMAB AS ADJUVANT THERAPY 
AFTER SURGERY AND CHEMOTHERAPY IN PATIENTS WITH 
EARLY-STAGE OR LOCALLY ADVANCED HER2-POSITIVE 
BREAST CANCER 
NCT Number: 
NCT02586025 
Document Date: 
PROTOCOL 
Version 4: 06 December 2016 
 


 
Title
06-Dec-2016 18:25:11
Date and Time (UTC)
Company Signatory
Approver's Name
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 YO28762, Version 4 
PROTOCOL 
TITLE: 
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PHASE III STUDY TO 
EVALUATE PERTUZUMAB IN COMBINATION WITH 
DOCETAXEL AND TRASTUZUMAB AS 
NEOADJUVANT THERAPY, AND PERTUZUMAB IN 
COMBINATION WITH TRASTUZUMAB AS 
ADJUVANT THERAPY AFTER SURGERY AND 
CHEMOTHERAPY IN PATIENTS WITH 
EARLY-STAGE OR LOCALLY ADVANCED 
HER2-POSITIVE BREAST CANCER 
PROTOCOL NUMBER: YO28762 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
Not applicable 
TEST PRODUCT: 
Pertuzumab (RO4368451) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  5 March 2013 
DATES AMENDED: 
Version 2:  4 August 2014 
Version 3:  15 August 2014 
Version 4:  See electronic date stamp below. 


Pertuzumab—F. Hoffmann-La Roche Ltd 
2/Protocol YO28762, Version 4 
PROTOCOL AMENDMENT, VERSION 4: 
RATIONALE 
Protocol YO28762 has been amended to change the timing of the primary efficacy 
analysis.  The primary efficacy objective of the study is to evaluate the total pathologic 
complete response (tpCR) rate as assessed by an Independent Review Committee.  
The timing for the primary efficacy analysis has been changed to occur when all patients 
who are eligible for surgery have completed surgical treatment with the assessment of 
pathological response (i.e., after surgical treatment following neoadjuvant therapy).  The 
previous timing specified that the analysis would occur when all patients had completed 
the treatment completion or discontinuation visit (i.e., after completion of all neoadjuvant 
and adjuvant study treatments).  To conduct the primary analysis after surgery when all 
patients can be assessed for the primary efficacy endpoint is consistent with 
globally-accepted scientific conduct of neoadjuvant studies.  The timing of the primary 
analysis after surgery is also consistent with other pertuzumab neoadjuvant studies that 
have been accepted as the basis for regulatory approvals in the United States and the 
European Union (Section 6.4.1). 
Additional changes to the protocol are as follows: 
• 
The clinical experience of patients with early-stage breast cancer who were treated 
with pertuzumab in Studies WO20697 (NeoSphere) and BO22280 (TRYPHAENA) 
studies has been updated (Section 1.2.2). 
• 
The eligibility requirement that the baseline tumor must be > 2 cm in the longest 
diameter includes all enrolled patients and has been clarified in Sections 3.1.1 and 
4.5.1.4, respectively. 
• 
The planned Safety Monitoring Committee has been replaced by the Sponsor’s 
study team, which will review adverse events, serious adverse events, and any 
other safety data in the study on a regular and ongoing basis.  The study team will 
be responsible to review accumulating safety data, assess and monitor ongoing 
safety in patients, evaluate potential changes to the clinical study protocol, and 
ultimately safeguard patient safety (Sections 1.4 and 3.1.3).  Overall data to date 
indicate that pertuzumab is well tolerated as a monotherapy and that it can be 
administered in combination with trastuzumab and other therapeutic agents with 
manageable additional toxicity. 
As of 7 December 2015, an estimated 10,215 patients (which includes Asian and 
Chinese patients) had received pertuzumab in Roche-sponsored studies in which 
pertuzumab is an investigational medicinal product.  No unexpected toxicities were 
encountered other than those that are known for agents that target human 
epidermal growth factor (HER) receptors. 
• 
The exploratory objectives for biomarkers have been updated to include 
programmed death−ligand 1 (PD-L1) and other biomarkers that are relevant to 
breast cancer (Section 2.3).  The rationale for biomarker and laboratory 
assessments has been revised accordingly (Sections 3.3.6 and 4.5.1.5). 


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3/Protocol YO28762, Version 4 
• 
The number of participating sites has been updated from 28 sites to approximately 
24 sites (Section 3.1.1). 
• 
The types of hormonal therapy for premenopausal women have been clarified to 
include aromatase inhibitor with ovarian suppression for consistency with the 
National Comprehensive Cancer Network’s recommendations and standard practice 
(Sections 3.1.1 and 4.4.2). 
• 
The membership of the Independent Review Committee has been updated to reflect 
that the committee comprises of three rather than five pathologists (Sections 3.1.2 
and 9.3). 
• 
The statement that 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) 
treatment will be separated from pertuzumab treatment by a minimum interval of 
5 weeks has been clarified to be consistent with the treatment regimen that is used 
in this protocol.  The 5-week delay refers to the interval between the end of 
neoadjuvant treatment with pertuzumab and the start of adjuvant treatment with 
FEC (Section 3.3.3). 
• 
The exclusion criterion for patients with a history of other malignancies has been 
revised to specify a 5-year window before screening to permit enrollment of patients 
with prior malignancies who might benefit from the study treatment (Section 4.1.2). 
• 
The use of pharmacokinetic (PK) and HER2 extracellular domain (ECD) samples 
has been clarified that, although samples from patients in the pertuzumab and 
placebo arms will be obtained to maintain blinding to the study treatment, only 
samples from patients who are treated with pertuzumab will be tested (Section 4.2).  
Patients’ treatment assignment will be unblinded for the personnel responsible to 
perform PK and HER2 ECD assays so they can identify the appropriate PK and 
HER2 ECD samples to be analyzed. 
• 
The instructions for the calculation of the chemotherapy dosage with use of body 
surface area have been updated to clarify that the nomogram that is provided in 
Appendix 7 may but is not required to be used for the determination of body surface 
area.  Investigators may use equivalent formulas for body surface area calculations 
(Section 4.3.2). 
• 
The use of prohibited therapies has been clarified to include herbal remedies only if 
they are used for the treatment of cancer.  This change has been made because the 
term herbal remedy is too general for a prohibition to be applied consistently but 
herbal remedy use is prohibited for the treatment of cancer (Section 4.4.3). 
• 
Instructions have been added for patients with an allergy to magnetic resonance 
imaging contrast agents that cannot be managed with premedication and allows the 
use of ultrasound or molybdenum target mammography (Section 4.5.1.4). 
• 
The instructions for urinalysis have been revised to allow urinalysis with a laboratory 
test at investigational sites that do not test with use of a dipstick (Section 4.5.1.5). 
• 
Resection specimens for exploratory research on candidate biomarkers have been 
clarified and are required samples from all patients (Section 4.5.1.5). 


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4/Protocol YO28762, Version 4 
• 
The requirement to further test tumor specimens from patients who do not meet the 
study entry eligibility criteria has been removed (Section 4.5.1.5). 
• 
The instructions for cardiac assessments have been clarified.  Only abnormal, 
clinically-significant ECGs should be documented on the Adverse Event electronic 
Case Report Form.  If an abnormal ECG is not clinically significant, it does not need 
to be documented as an adverse event (Section 4.5.1.10). 
• 
The observation time of patients after the first infusion of trastuzumab has been 
corrected to 30 minutes (Section 5.1.1.1). 
• 
The secondary emergency medical contact for the study has been changed 
(Section 5.4.1). 
• 
The timing of the efficacy analysis for assessment of tpCR, breast pathologic 
complete response, and response rate endpoints has been revised to occur when 
all patients who are eligible for surgery have completed surgical treatment with the 
assessment of pathological response (i.e., after surgical treatment following 
neoadjuvant therapy).  Safety and PK endpoints will also be evaluated at this time.  
The rationale is to allow the primary efficacy analysis to occur at the time of data 
availability. 
• 
The following types of samples that are required for all randomized patients at 
baseline have been clarified to exclude samples from patients who do not meet the 
study eligibility requirements.  Patients who are not eligible for enrollment in the 
study will not be asked to donate blood for these analyses as indicated in the 
Schedule of Activities (Appendix 1) and the biomarker and PK and ATA sampling 
schedules (Appendix 2 and Appendix 3). 
Serum sample for HER2 ECD, HER ligands, and other exploratory biomarkers 
Serum sample for antibodies to pertuzumab 
Blood sample for clinical genotyping (optional) 
• 
Footnotes in the Schedule of Activities has been corrected and reference to 
Cycle 21 has been deleted because there is no Cycle 21 in the study (Appendix 1). 
• 
The Standardized Guideline for Surgical Sampling following Neoadjuvant Therapy 
has been revised to remove the statement that a more detailed description for 
sentinel lymph node biopsy will be described in a separate guidance document 
(Appendix 8).  The guidance document is no longer required after Amendment 3 of 
this protocol and guidance is provided in Section 4.4.1. 
 
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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PROTOCOL AMENDMENT, VERSION 4: 
SUMMARY OF CHANGES 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.2.2.1:  Pertuzumab Clinical Efficacy 
HER2-Positive Early-Stage Breast Cancer 
Study WO20697 (NeoSphere) iwas a Phase II, randomized, multicenter, four-armed 
study to compare the safety and efficacy of trastuzumab + docetaxel (Arm A) versus 
pertuzumab + trastuzumab + docetaxel (Arm B) versus pertuzumab + trastuzumab (Arm C) 
versus pertuzumab + docetaxel (Arm D) in the neoadjuvant setting in patients with locally 
advanced, inflammatory, or early-stage HER2-positive breast cancer…. 
A 5-year follow-up analysis was conducted of the prespecified secondary endpoints of 
PFS (defined as the time from randomization to the first documentation of progressive 
disease or death), disease-free survival (DFS; time from the first date of no disease 
[i.e., date of surgery] to the first documentation of progressive disease or death), and 
safety for the overall and adjuvant treatment periods (Gianni et al. 2016). 
The 5-year PFS rates were 81% (95% CI: 71, 87) for Arm A, 86% (95% CI: 77, 91) for 
Arm B, 73% (95% CI: 64, 81) for Arm C, and 73% (95% CI: 63, 81) for Arm D 
(hazard ratio [HR] = 0.69 [95% CI: 0.34, 1.40] Arm B vs. Arm A).  The 5-year PFS rate 
was 85% (95% CI: 76, 91) for patients who achieved a tpCR compared with 76% 
(95% CI: 71, 81) for patients who did not achieve a tpCR (HR = 0.54 [95% CI: 0.29, 
1.00]) in all arms combined.  DFS results were consistent with PFS results 
(Gianni et al. 2016). 
No new or long-term safety concerns were identified after 5 years of follow-up.  The 
overall tolerability profile was similar across the treatment arms and consistent with 
the profile that was previously reported for the neoadjuvant period without any 
additional or long-term cardiotoxicity (Gianni et al. 2016). 
Study BO22280 (TRYPHAENA) iwas a Phase II, randomized, multicenter, multinational, 
three-arm study in patients with locally advanced, operable, and inflammatory (T2−4d) 
HER2-positive breast cancer who awere scheduled for neoadjuvant therapy.  Patients 
awere treated with one of three treatment regimens:  5-fluorouracil (5-FU), epirubicin, 
and cyclophosphamide (FEC) + trastuzumab + pertuzumab followed by 
docetaxel + trastuzumab + pertuzumab (Arm A); FEC followed by 
docetaxel + trastuzumab + pertuzumab (Arm B); or 
docetaxel + carboplatin + trastuzumab + pertuzumab (Arm C; Schneeweiss et al. 2011). 
All three treatment regimens awere active and the majority of patients achieved a bpCR.  
The bpCR (ypT0/is) rates were similar across the treatment arms for the intent-to-treat 


Pertuzumab—F. Hoffmann-La Roche Ltd 
6/Protocol YO28762, Version 4 
(ITT) population (Arm A: 61.6%; Arm B: 57.3%; and Arm C: 66.2%).  A similar pattern of 
responses was observed when other definitions of pathologic complete response (pCR) 
were used, such as tpCR (see Section 3.4.1.1) or German Breast Group pCR, (defined 
as ypT0, ypN0), except that the pCR rate decreased as the stringency of the increased 
definition (Schneeweiss et al. 2013). 
The results of Study BO22280 demonstrated that neoadjuvant pertuzumab can be 
added toand trastuzumab can be administered concurrently or sequentially in 
combination with commonly used anthracycline  orFEC-docetaxel chemotherapy or 
concurrently with a carboplatin-based chemotherapy regimens without substantial 
additions to the cardiac toxicity or the adverse event burden, or interrupting or 
delaying the delivery of standard chemotherapy regimens with trastuzumab 
(Schneeweiss et al. 2013). 
HER2-Positive Metastatic Breast Cancer 
In a Phase III study (Study WO20698/TOC4129g [CLEOPATRA]) of patients with 
previously-untreated HER2-positive metastatic breast cancer (MBC), a 
statistically-significant and clinically-meaningful improvement in PFS was observed in 
patients who were treated with pertuzumab + trastuzumab + docetaxel compared with 
patients who received placebo + trastuzumab + docetaxel.  Median PFS was prolonged 
by 6.1 months and the risk of disease progression or death was reduced by 38% 
(HR = 0.62; p< 0.0001).  Median PFS was 12.4 months in the control group and 
18.5 months in the pertuzumab group.  Secondary endpoints of investigator-assessed 
PFS (HR = 0.65; 95% CI: 0.54, 0.78) and objective response rate (ORR; patients who 
achieve a complete response [CR] or partial response [PR]; 69% vs. 80%; 
95% CI: 4.2, 17.5) all supported the primary endpoint.  At the second interim analysis of 
overall survival, a statistically-significant reduction in the risk of death was demonstrated 
(HR = 0.66; 95% CI: 0.52, 0.84; p = 0.0008).  At the time of the final analysis of OS, the 
median OS for patients in the pertuzumab-combination group was 56.5 months 
(95% CI: 49.3 to NR) compared with 40.8 months (95% CI, 35.8−48.3) for patients in 
the placebo-combination group (HR 0.68; 95% CI, 0.56-0.84; p< 0.001).  The analysis 
was not adjusted for crossover to pertuzumab (Swain et al. 2015).  These study results 
led to the approval of pertuzumab in combination with trastuzumab and docetaxel for the 
first-line treatment of patients with HER2-positive MBC in some countries 
(i.e., United States and within the European Union) and this application is currently 
under review in other countries (Baselga et al. 2012a, 2012b). 
SECTION 1.2.2.2:  Pertuzumab Clinical Safety 
As of 30 November 20137 December 2015, more than 3116an estimated total of 
10,215 patients with cancer haved been treated with pertuzumab in Roche-sponsored 
studies.  The most commonly reported adverse events in patients who received single-
agent pertuzumab (n = 386) were diarrhea, fatigue, nausea, vomiting, and decreased 
appetite.  The majority of adverse events that were reported were National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0 


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7/Protocol YO28762, Version 4 
Grade 1 or 2 in severity and the proportion of patients across the entire pertuzumab 
program who discontinued study treatment as a result of an adverse event was 
12.8%low. 
Symptomatic Left Ventricular Systolic Dysfunction or Asymptomatic 
Decrease in Left Ventricular Ejection Fraction 
Pertuzumab has not been studied in patients with a pretreatment LVEF value of ≤ 50%, 
a prior history of congestive heart failure, decreases in LVEF to < 50% during prior 
trastuzumab adjuvant therapy, or conditions that could impair left ventricular function 
such as uncontrolled hypertension, recent myocardial infarction, serious cardiac 
arrhythmia that requires treatment, or a cumulative prior anthracycline exposure to 
> 360 mg/m2 of doxorubicin or its equivalent. 
Infusion-Associated Reactions, Hypersensitivity Reactions 
(Including Anaphylaxis) 
In single-agent pertuzumab studies, 8 cases (2.1%) of anaphylaxis or hypersensitivity 
(Grades 1−4) were reported.  In Study BO17929, involving patients with MBC who 
received pertuzumab and trastuzumab, the incidence of anaphylaxis and 
hypersensitivity was 4.8%.  All events were Grade 1 or 2 in severity.  In 
Study WO20697/TOC4129g, 0.9% of patients (1 of 107) with EBC who received 
pertuzumab and trastuzumab had a Grade ≥ 3 event, 7%-13% in all treatment arms 
that included treatment with pertuzumab versus 2% in the trastuzumab + docetaxel 
arm had an event of anaphylaxis and/or hypersensitivity.  Of these, 2 patients who 
received treatment with trastuzumab + pertuzumab + docetaxel (Arm B) and 3 patients 
who received treatment with trastuzumab + pertuzumab (Arm C) had a Grade ≥ 3 event. 
In Study WO20698/TOC4129g, 10.811.3% of patients in the pertuzumab arm had a 
hypersensitivity event (Grades 1−4), compared with 9.13% in the placebo arm.  Overall, 
the reactions were mild or moderate in severity and resolved with treatment.  
Eight patients in the pertuzumab arm had a Grade ≥ 3 event.  Most reactions were 
assessed as secondary to docetaxel infusions. 
In the same study, the initial dose of pertuzumab or placebo (Day 1, Cycle 1) was 
administered the day before trastuzumab and docetaxel were administered to allow for 
the examinationevaluation of pertuzumab infusion−associated reactions.  On 
Day 1, Cycle 1 (i.e., after pertuzumab only), the overall frequency of infusion-associated 
reactions was 159.8% in the placebo arm and 1913.2% in the pertuzumab arm with 
the majority of reactions reported as mild or moderate.  The most common 
infusion-associated reactions (≥ 1.50%) in the pertuzumab arm were pyrexia, chills, 
fatigue, headache, nauseaasthenia, hypersensitivity, and diarrheavomiting.  During 
Cycle 2 when all drugs were administered on the same day, the incidence of adverse 
events was higher (34% in the placebo arm vs. 29% in the pertuzumab arm).  The most 
common infusion-associated reactions (≥ 1.50%) in the pertuzumab arm were fatigue, 
drug hypersensitivity, alopecia, nausea, decreased appetite, constipation, diarrhea, 


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stomatitis, and (this list includes events that occurred within 24 hours after the first 
treatment).  Over all cycles, the proportion of patients who experienced at least one 
adverse event on the day of infusion was 83% in the pertuzumab arm compared with 
79% in the placebo arm.  Few patients had an adverse event that started during a 
pertuzumab or placebo infusion (9% in the pertuzumab arm and 5% in the placebo arm), 
and the majority of these events occurred in the first two cyclesdysgeusia, 
hypersensitivity, myalgia, and vomiting. 
SECTION 1.4:  STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Although initial safety data to date with pertuzumab in previously-untreated patients in 
the neoadjuvant (Gianni et al. 2012) and metastatic settings (Baselga et al. 2012a) 
appear acceptable, athe safety monitoring plan for this study, includinges appropriate 
eligibility criteria, dose modification guidelines, and interim safety analyses as well as 
regular monitoring of accumulating patient safety data by a Safety Monitoring 
Committee,the Sponsor’s study team and has been put in place to minimize any 
potential risk in the study patient population. 
SECTION 2.3:  EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
• 
To analyze biomarkers in tumor tissue or serumtaken at baseline or at the time of 
resection (e.g.,markers analyzed may include but are not limited to HER2/3 mRNA 
and/or protein, PI3K3CA, phosphatase and tensin homolog [PTEN], programmed 
death−ligand 1 [PD-L1], and cluster of differentiation 8 [CD8]), and serum 
(e.g., HER ligands, and HER2 ECD) and evaluate correlations with clinical 
outcomes and, if applicable, safety outcomes 
 
SECTION 3.1.1:  Overview of Study Design 
This is an Asia-Pacific regional, randomized, double-blind, Phase III, multicenter study 
to evaluate treatment with trastuzumab + pertuzumab + docetaxel compared with 
trastuzumab + placebo + docetaxel in patients who are chemotherapy-naive with 
early-stage (T2-3, N0-1, M0) or locally advanced (T2-3, N2 or N3, M0; T4, any N, M0) 
HER2-positive breast cancer.  A primary tumor with athe longest diameter of > 2 cm is 
required for patients with early stage breast cancer. 
Approximately 328 eligible patients will be enrolled at approximately 2824 sites, resulting 
in approximately 219 patients in Arm A and 109 patients in Arm B.  Randomization will 
be stratified by disease category (early-stage or locally advanced) and hormone-receptor 
status (positive for estrogen receptor [ER] and/or progesterone receptor [PgR] or 
negative for both). 
For patients with tumors that are ER and/or PgR positive, hormonal agents (tamoxifen or 
an aromatase inhibitor for postmenopausal patients or tamoxifen, with or without ovarian 
suppression, or aromatase inhibitor with ovarian suppression for premenopausal 
patients) should be started at the end of FEC chemotherapy and given for at least 


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5 years.  Radiotherapy is to be given as clinically indicated at the end of FEC 
chemotherapy. 
Patients will be evaluated for clinical response prior to surgery (i.e., during Cycles 1−4) 
in accordance with RECIST v1.1.  Patients will be evaluated for pathologic response 
after surgery and evaluated for disease recurrence.  The primary efficacy objective will 
be evaluated when all patients who are eligible for surgery have completed their 
surgical treatment completion/discontinuation visit (i.e., after completion of all 
neoadjuvant and adjuvant study treatment)with the assessment of pathological response.  
Patients will be evaluated for safety throughout the study with laboratory tests and 
adverse event reports.  Serum samples will be collected from a subset of approximately 
50 Chinese patients for characterization of pertuzumab pharmacokinetics. 
SECTION 3.1.2:  Independent Review Committee 
An IRC that consists of independent experts who are not involved in the study (including 
approximately fivethree pathologists) will evaluate the pathologic response. 
SECTION 3.1.3:  Safety Monitoring CommitteeData Review 
A Safety Monitoring Committee (including the Sponsor’s Medical Monitor, a drug safety 
physician, and representatives from any other function as needed and/or selected study 
investigators) The Sponsor’s study team will review blinded adverse events, serious 
adverse events, and any other safety data in the study on a regularly scheduled basis. 
It is the responsibility of the Safety Monitoring Committeestudy team to review 
accumulating safety data, assess and monitor evolvingongoing safety trends of patients, 
evaluate potential changes to the clinical study protocol (including dose modification 
criteria, based on available safety analyses), and ultimately safeguard patient safety. 
Details of the composition, roles, and responsibilities of the Safety Monitoring Committee 
will be provided in a separate charter. 
SECTION 3.3.2:  Rationale for Neoadjuvant Therapy 
Adjuvant systemic therapies for breast cancer (i.e., drugs to reduce the risk of breast 
cancer recurrence) historically have been administered after definitive breast surgery.  
Preoperative or neoadjuvant systemic chemotherapy that was once reserved for patients 
with locally advanced breast cancer infor whom the goal was to render large breast 
cancers operable has become increasingly common.  There are several potential 
rationales for neoadjuvant treatment for early-stage breast cancer.  Giving preoperative 
chemotherapy permits breast conservation in some patients who would otherwise 
require mastectomy and may improve cosmesis in existing candidates for breast 
conservation (Fisher et al. 2002; Alm El-Din and Taghian 2009).  Preoperative therapy 
also enables the oncologist to evaluate tumor response and discontinue ineffective 
therapy or substitute an alternative systemic therapy.  Further, a patient’s response to 
neoadjuvant chemotherapy may provide prognostic information that can supplement 


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conventional prognostic data such as initial staging, tumor grade, and receptor status.  
Finally, the neoadjuvant setting provides investigators with the unique opportunity to 
examine modulation of tumor tissue biomarkers from the time of biopsy to the time of 
definitive breast surgery after completion of preoperative systemic therapy in patients 
who have residual disease. 
SECTION 3.3.3:  Rationale for Adjuvant Therapy 
…It is possible that pertuzumab will be equally tolerable when given in combination with 
anthracyclines to similarly selected patients.  However, in the interest of patient safety, 
adjuvant FEC treatment will be separated from neoadjuvant pertuzumab treatment by a 
minimum of 5 weeks. 
SECTION 3.3.4:  Rationale for Docetaxel Dosage 
To increase the tolerability of the combined regimen, the initial dose of docetaxel used in 
this study will be 75 mg/m2. 
SECTION 3.3.6:  Rationale for Biomarker Assessments 
Such molecules that are considered for analyses may include but are not limited to 
PTEN, PIK3CA mutations, HER3 and HER2 mRNA, PD-L1, CD8, and protein 
expressionsother markers that are relevant to breast cancer. 
If appropriate, a refinement of the translational research plan canmay be implemented 
prior to the data cutoff date to take into account emerging data in the literature and allow 
for the latest state-of-the-art technology to be applied. 
SECTION 3.4.3:  Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
Expression levels or incidence of biomarkers at baseline and in resection specimen 
tissue, especially for patients with residual disease, at the time of surgery (i.e., after 
neoadjuvant treatment) and their relationship to efficacy or safety parameters 
 
SECTION 4.1.1:  Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
HER2-positive breast cancer confirmed by a Sponsor-designated central laboratory 
and defined as 3+ score by IHC in > 10% of immunoreactive cells or HER2 gene 
amplification (ratio of HER2 gene signals to centromere 17 signals ≥ 2.0) by in situ 
hybridization (ISH) 
A tumor sample that consists of a tumor block or eight unstained, freshly cut 
slides must be available for central laboratory HER2 testing by IHC and ISH.  
Note that up to sevenan additional seven slides are required for exploratory 
biomarker research.  Therefore, 15 slides are requested at screening. 
 


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SECTION 4.1.2:  Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
History of other malignancy within 5 years prior to screening, except for 
appropriately-treated carcinoma in situ of the cervix or squamous or basal cell, 
non-melanoma skin carcinoma, or Stage I uterine cancer 
 
SECTION 4.2:  METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
The investigator and the patient will be blinded to the treatment assignment.  All other 
individuals who are directly involved in this study will remain blinded to the treatment 
assignment until completion of the primary analysis.  Patients treatment assignment will 
not be unblinded until after the final 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. 
Although PK and HER2 ECD samples must also be obtained from patients who are 
randomized to the placebo arm to maintain the blinding to the treatment assignment, 
only the PK and HER2 ECD samples from patients who are treated with pertuzumab 
and enrolled in the PK substudy in China will be tested.  The study personnel that are 
responsible to perform the PK and HER2 ECD assays will be unblinded to a patient’s 
treatment assignment to identify the appropriate PK and HER2 ECD samples to be 
analyzed. 
SECTION 4.3.1.2:  Pertuzumab and Placebo 
Pertuzumab is provided as a single-use formulation containing 30 mg/mL pertuzumab 
formulated in 20 mM L-histidine-acetate (pH 6.0), 120 mM sucrose, and 
0.02% polysorbate 20.  Each 20-mL vial (14.0 mL solution per vial) contains 
approximately 420 mg of pertuzumab.  Pertuzumab-matching placebo has the identical 
formulation but does not contain the antibody. 
SECTION 4.3.2.2:  Docetaxel 
…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 beis provided, which may be used for the determination of body 
surface area (see Appendix 7). 
SECTION 4.3.2.4:  5-Fluorouracil, Epirubicin, and Cyclophosphamide 
Chemotherapy 
…A nomogram will beis provided, which may be used for the determination of body 
surface area (see Appendix 7). 


Pertuzumab—F. Hoffmann-La Roche Ltd 
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SECTION 4.4.1:  Surgery 
Before the initiation of neoadjuvant treatment, the primary tumor site shouldmust be 
physically marked per the standard local practice (e.g., skin tattoo or surgical clip) to 
enable appropriate surgical excision in case of tumor regression during neoadjuvant 
therapy. 
In the event that a biopsy of the sentinel lymph node is performed, it is recommended 
that both dye and/or isotope be used.  The dye and isotope should not be injected into 
the tumor itself because they may alter the tissue and affect the molecular analyses to 
be performed on the tumor tissue sample. 
SECTION 4.4.2:  Permitted Therapy 
The following treatments are permitted during the study: 
• 
For patients with tumors that are ER and/or PgR positive:  hormonal agents 
(tamoxifen or an aromatase inhibitor for postmenopausal patients; tamoxifen with or 
without ovarian suppression, or aromatase inhibitor with ovarian suppression for 
premenopausal patients) initiated at the end of FEC chemotherapy and 
administered for at least 5 years 
• 
Anti-emetic treatments (e.g., approved prophylactic serotonin-antagonists, and 
benzodiazepines, ondansetron) 
 
SECTION 4.4.3:  Prohibited Therapy 
Use of the following therapies is prohibited during the treatment period of the study: 
• 
Herbal remedies initiated during the studyfor cancer treatment 
Other Hherbal remedies initiated prior to study entry and continuing during the 
study are discouraged but permitted and must be reported on the appropriate 
eCRF. 
 
SECTION 4.5.1.4:  Tumor and Response Evaluations 
The baseline breast tumor must be > 2 cm in diameter for all patients with early stage 
breast cancer.  Baseline tumor assessments will include a breast magnetic resonance 
imaging (MRI) scan and a clinical breast examination (CBE; including breast, axilla, and 
supraclavicular fossa).  If a patient has an allergy to an MRI contrast agent that cannot 
be managed with premedication per standard practice, then an ultrasound or 
molybdenum target mammography may be used.  Disease status should also be 
evaluated by additional conventional methods such as mammogram, ultrasound, 
computed tomography (CT) scans, or X-rays per local medical practice.  A baseline 
bone scan is mandatory.  In the absence of radioactive isotopes, an MRI scan (with 
gadolinium enhancement if required) or positron emission tomography (PET) scan is an 
acceptable form of assessment of the skeleton for the presence of bone metastases. 


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SECTION 4.5.1.5:  Laboratory Assessments 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• 
Urinalysis, includingwhich may be performed by dipstick (pH, specific gravity, 
glucose, protein, ketones, blood) and microscopic examination where applicable 
(e.g., if the dipstickurinalysis result is positive, then a microscopic examination 
should be performed; sediment, RBCs, WBCs, casts, crystals, epithelial cells, and 
bacteria) 
• 
Mandatory tumor tissue sample obtained at screening for prospective central 
determination of HER2 status by IHC and ISH and exploratory biomarker research: 
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 or HER2 gene 
amplification (ratio of HER2 gene signals to centromere 17 signals ≥ 2.0) by ISH 
prior to randomization.  Paraffin-embedded tumor tissue block or a partial block 
must be obtained.  If sites are unable to send a tissue block because of local 
regulations, at least eight15 unstained, freshly cut slides should be sent for 
HER2 testing and up to seven additional unstained slides should be sent for 
exploratory biomarker research (see below).  The slides should be cut from 
consecutive slices from the same block. 
After completion of HER2 testing for eligibility criteria, patient samples may also 
be tested with other HER2 assays to establish performance characteristics of 
these assays for diagnostic development but if generated, these data will have 
no impact on the study eligibility of the patient.  Testing could be performed 
on all screened patients (both patients who are enrolled and those who failed 
screening).  These testing data will have no impact on eligibility and testing will 
be performed only after eligibility is established for each patientAdditional 
testing will not be performed on patients who failed screening. 
• 
Tumor tissue resection specimen taken at the time of surgery for evaluation of tpCR 
and bpCR 
• 
Remaining Ttumor tissue sample obtained from enrolled patients at screening (and 
up to seven additional slides, as mentioned above) and residual tissue specimens 
taken at the time of surgery,will be used for exploratory research on candidate 
biomarkers; such analyses may include but will not be limited to the following:  
HER2/3 mRNA and/or protein, PI3K3CA mutation, PTEN, PD-L1, CD8, and other 
biomarkers that are relevant to breast cancer 
• 
Mandatory resection tissue specimen obtained at the time of surgery for 
determination of HER2 status and for assessment of exploratory biomarkers 
A paraffin-embedded resection tissue block or up to 15 unstained, freshly-cut 
slides should be sent.  The slides should be from consecutive slices from the 
same block. 


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• 
Optional tumor tissue and/or serum sample collection at the time of disease 
progression or recurrence 
A paraffin-embedded disease progression or recurrence tumor tissue block or 
up to 15 unstained, freshly-cut slides should be sent.  The slides should be 
from consecutive slices from the same block. 
 
Samples listed above will be destroyed at the end of the study, with the following 
exceptions: 
• 
Tissue blocks that are submitted at baseline for eligibility screening and exploratory 
biomarker research will be returned in a batched manner to the sites after all 
patients have completed the neoadjuvant phase of the study.  All other tissue 
blocks that are submitted will be returned to the sites in batches at the latest 
5 years after the last patient in.  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. 
 
SECTION 4.5.1.10:  Cardiac Assessments 
Electrocardiograms 
Single 12-lead ECGs will be performed locally and assessed at the time of screening 
and otherwise as clinically indicated.  For safety monitoring purposes, any abnormalities 
on the ECGs must be documented on the Adverse Event eCRF.  The investigator or 
designee must review, sign, and date all ECG tracings.  Paper copies will be kept as part 
of the patient's permanent study file at the site.  For ECG tracings that will fade over time 
(e.g., ECGs on thermal paper), lasting legible copies should be filed together with the 
original. 
SECTION 4.6.2:  Study and Site Discontinuation 
The Sponsor has the right to replace a site at any time.  Reasons for the replacement of 
a site may include but are not limited to: 
• 
No study activity (i.e., all patients have completed the study and all obligations 
have been fulfilled) 
 
SECTION 5.1.1.1:  Infusion-Associated Reactions, Hypersensitivity 
Reactions (Including Anaphylaxis) 
The administration of pertuzumab and trastuzumab 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 9030 minutes after the first/ and each subsequent trastuzumab 
infusion.  If the pertuzumab infusion is well tolerated during Cycle 1, the observation time 
can be decreased to 30 minutes for subsequent infusions. 


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SECTION 5.2:  SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non serious adverse events 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. 
SECTION 5.2.3:  Non Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) 
Non serious aAdverse events of special interest must 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). 
SECTION 5.3.5.4:  Abnormal Laboratory Test Values 
Not every laboratory test result abnormality qualifies as an adverse event.  A laboratory 
test result must be reported as an adverse event if it meets any of the following criteria: 
• 
Is clinically significant in the investigator’s judgment 
Note:  For oncology studies, certain abnormal values may not qualify as 
adverse events. 
 
SECTION 5.3.5.5:  Abnormal Vital Sign Values 
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(see Section 5.3.5.4 for 
details on recording persistent adverse events). 
SECTION 5.3.5.6:  Abnormal Liver Function Tests 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory test values should be recorded on the Adverse Event eCRF 
(see Section 5.3.5.1) and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event) either as a serious adverse event or an non serious 
adverse event of special interest (see Section 5.4.2). 
SECTION 5.3.5.7:  Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to the progression of breast cancer should be recorded on the 
Study Completion/Early Discontinuation eCRF and Study Drug Completion/Early 
Discontinuation eCRF, if applicable.  All other deaths that occur during the study, 
regardless of the relationship to the study drug, must be recorded on the Adverse Event 
eCRF and immediately reported to the Sponsor (see Section 5.4.2). 


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SECTION 5.4:  IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
…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 (see Section 5.4.2 for further details) 
• 
Non serious aAdverse events of special interest (see Section 5.4.2 for further 
details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 
SECTION 5.4.1:  Emergency Medical Contacts 
Medical Monitor (Roche Medical Responsible) Contact Information 
Secondary Contact 
Medical Monitor: 
, M.D., Ph.D. 
Telephone No.: 
 
Mobile Telephone No.: 
 
 
SECTION 5.4.2:  Reporting Requirements for Serious Adverse Events and 
Non Serious Adverse Events of Special Interest 
SECTION 5.4.2.1:  Events that Occur prior to Initiation of Study Drug 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events that are caused by a protocol-mandated intervention should be 
reported.  A paper Serious Adverse Event/Non Serious Adverse Event of Special 
Interest CRF and Fax Coversheet 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) with use of the fax numbers provided to investigators (see "Protocol 
Administrative and Contact Information & List of Investigators").  Patients who undergo 
screening procedures but do not enroll in the study will only have serious adverse events 
recorded in the Roche Drug Safety database and not in the study’s clinical database. 
SECTION 5.4.2.2:  Events that Occur after Initiation of Study Drug 
After initiation of the study drug, serious adverse events and non serious adverse events 
of special interest will be reported until study completion.  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 Serious Adverse 
Event/Non Serious Adverse Event of Special Interest CRF and Fax Coversheet 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) with use of the fax numbers 
provided to investigators (see "Protocol Administrative and Contact Information & List of 


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Investigators").  Once the EDC system is available, all information will need to be 
entered and submitted via the EDC system. 
Instructions for reporting serious adverse events that occur after study completion are 
provided in Section 5.6. 
SECTION 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 eCRFClinical Trial Pregnancy Reporting 
Form should be completed by the investigatorand submitted to the Sponsor or its 
designee 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 Roche Safety Risk Management, either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF…. 
SECTION 5.4.3.3:  Abortions 
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers spontaneous abortions to be medically significant events), 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). 
SECTION 5.5.1:  Investigator Follow-Up 
All pregnancies that are reported during the study should be followed until the pregnancy 
outcome (see Section 5.4.3).  If the EDC system is not available at the time of pregnancy 
outcome, follow reporting instructions provided in Section 5.4.3.1. 
SECTION 5.5.2:  Sponsor Follow-Up 
For serious adverse events, non serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information 
(e.g., from hospital discharge summaries, consultant reports, autopsy reports) to perform 
an independent medical assessment of the reported case. 
SECTION 5.7:  EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and non serious adverse 
events of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, ECs, and 
applicable health authorities based on applicable legislation. 


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SECTION 6.4.1:  Primary Efficacy Endpoint 
…The primary analysis will be performed when all patients who are eligible for surgery 
have completed their surgical treatment completion/discontinuation visitwith an 
assessment of pathological response.  The analysis will be based on the ITT population 
with patients grouped by the treatment assigned at the time of randomization.  In the 
ITT population, patients whose tpCR assessment is missing or invalid are counted as 
not achieving tpCR. 
SECTION 6.4.2.6:  Disease-Free Survival 
Only patients who undergo surgery will be included in the analysis.  It is assumed that all 
patients who undergo surgery are disease free and; hence, patients are known to be 
disease free if they have undergone surgery and no recurrence of disease is reported 
thereafter.  PData from patients who have not had an event at the time of the analysis 
will be censored as of the date they were last known to be alive and event free.  
The methods for data analysis are similar to those described for EFS.  Note that the 
analysis for DFS is exploratory because of the non-randomized patient population. 
SECTION 6.4.2.7:  Overall Survival 
Overall survival is defined as the time from randomization to death from any cause.  
Data from Ppatients who are alive at the time of the analysis will be censored as of the 
last date they were known to be alive.  The methods for data analysis are similar to 
those described for EFS. 
SECTION 6.5:  SAFETY ANALYSES 
Safety analyses will be performed on the safety analysis population, which will consist of 
all patients who received at least one dose of study drugs and patients will be grouped 
by the treatment they actually received.  The safety analyses will be performed at the 
same time as the primary efficacy analysis, the final analyses, and when all patients 
have completed the treatment completion or study discontinuation visit. 
SECTION 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. 
SECTION 6.7:  INTERIM ANALYSES 
There is no interim analysis planned for the primary efficacy outcome measure tpCR.  
EFS and DFS data will be summarized descriptively when all patients have completed 
the treatment completion/discontinuation visitat the time of the primary efficacy analysis.  
Note that a final analysis of EFS, DFS, and overall survival will be performed at the end 
of the study approximately 5 years after randomization of the last patient. 


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SECTION 8.4:  CONFIDENTIALITY 
Given the complexity and exploratory nature of the analyses, data derived from 
exploratory biomarker specimens will generally not be provided to study investigators 
or patients unless required by law.  The aggregate results of any conducted research 
will be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5). 
SECTION 9.2:  PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The 
investigator should promptly report any deviations that might have an impact on 
patient safety and data integrity to the Sponsor and to the IRB and/or EC in accordance 
with established IRB and/or EC policies and procedures. 
SECTION 9.4:  ADMINISTRATIVE STRUCTURE 
An IRC that consists of independent experts who are not involved in the study (including 
approximately fivethree pathologists) will evaluate pathologic response.  The details of 
the composition, roles, and responsibilities of the IRC will be provided in a charter. 
A Safety Monitoring Committee (including the Sponsor’s Medical Monitor, a drug safety 
physician, and representatives from any other function as needed and/or selected study 
investigators) will review adverse events in the study on a regularly scheduled basis.  
The details of the composition, roles, and responsibilities of the Safety Monitoring 
Committee will be provided in a charter. 
SECTION 9.5:  PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on the study to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the 
Roche Global Policy on Sharing of Clinical Study Information at the following Web site:  
http://www.roche.com/dam/jcr:1c46aa73-cea0-4b9b-8eaa-
e9a788ed021b/en/roche_global_policy_on_sharing_of_clinical_study_informati
on.pdf 
The results of this study may be published or presented at scientific meetings.  For all 
clinical studies conducted in patients that involve an IMP for which a marketing 
authorization application has been filed or approved in any country, the Sponsor aims 
to submit a journal manuscript reporting primary clinical study results within 
6 months after the availability of the respective Clinical Study Report.  In addition, for 
all clinical studies conducted in patients that involve an IMP for which a marketing 
authorization application has been filed or approved in any country, the Sponsor aims 
to publish results from analyses of additional endpoints and exploratory data that are 
clinically meaningful and statistically sound.  


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If this is foreseen, tThe investigator must agrees to submit all manuscripts or abstracts 
to the Sponsor prior to submission for publication or presentation.  This allows the 
Sponsor to protect proprietary information and 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 the publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support only publication of multicenter studies in their entirety and not as individual 
center data.  In this case, a coordinating investigator will be designated by mutual 
agreement. 
TABLE 2:  Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE 
Only the title for Table 2 has been revised. 
APPENDIX 1:  Schedule of Activities 
The schedule of assessments has been revised to reflect the changes to the protocol. 
APPENDIX 2:  Schedule of Biomarker and Pharmacokinetic Activities 
Appendix 2 has been revised to change screening visit to baseline visit. 
APPENDIX 3:  Schedule of Anti-Therapeutic Antibody Activities 
Appendix 3 has been revised to change screening visit to baseline visit. 
APPENDIX 8:  Standardized Guideline for Surgical Sampling following 
Neoadjuvant Therapy 
All identified axillary lymph nodes should be sent for histologic examination.  A more 
detailed description for sentinel lymph node biopsy will be described in a separate 
guidance document. 
 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 28 
PROTOCOL SYNOPSIS .................................................................................... 29 
1. 
BACKGROUND .......................................................................................... 38 
1.1 
Background on Breast Cancer............................................... 38 
1.2 
Background on Pertuzumab .................................................. 38 
1.2.1 
Nonclinical Experience with Pertuzumab............................... 39 
1.2.2 
Clinical Experience with Pertuzumab .................................... 39 
1.2.2.1 
Pertuzumab Clinical Efficacy ................................................. 39 
1.2.2.2 
Pertuzumab Clinical Safety.................................................... 41 
1.2.2.3 
Immunogenicity ..................................................................... 43 
1.2.2.4 
Pharmacokinetics of Pertuzumab.......................................... 44 
1.3 
Background on Trastuzumab................................................. 46 
1.3.1 
Trastuzumab Safety Data...................................................... 46 
1.3.2 
Pharmacokinetics of Trastuzumab ........................................ 47 
1.4 
Study Rationale and Benefit-Risk Assessment...................... 47 
2. 
OBJECTIVES.............................................................................................. 47 
2.1 
Efficacy Objectives ................................................................ 47 
2.1.1 
Primary Efficacy Objective..................................................... 47 
2.1.2 
Secondary Efficacy Objective................................................ 48 
2.2 
Safety Objective .................................................................... 48 
2.3 
Exploratory Objectives........................................................... 48 
3. 
STUDY DESIGN ......................................................................................... 49 
3.1 
Description of Study .............................................................. 49 
3.1.1 
Overview of Study Design ..................................................... 49 
3.1.2 
Independent Review Committee............................................ 51 
3.1.3 
Safety Data Review ............................................................... 51 
3.2 
End of Study.......................................................................... 51 
3.3 
Rationale for Study Design.................................................... 51 
3.3.1 
Rationale for Combining Pertuzumab, 
Trastuzumab, and Docetaxel................................................. 51 
3.3.2 
Rationale for Neoadjuvant Therapy ....................................... 52 


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3.3.3 
Rationale for Adjuvant Therapy ............................................. 53 
3.3.4 
Rationale for Docetaxel Dosage............................................ 53 
3.3.5 
Rationale for Trastuzumab and Pertuzumab 
Dosages ................................................................................ 54 
3.3.6 
Rationale for Biomarker Assessments................................... 54 
3.4 
Outcome Measures ............................................................... 54 
3.4.1 
Efficacy Outcome Measures.................................................. 54 
3.4.1.1 
Primary Efficacy Outcome Measure ...................................... 54 
3.4.1.2 
Secondary Efficacy Outcome Measures................................ 55 
3.4.2 
Safety Outcome Measures .................................................... 55 
3.4.3 
Exploratory Outcome Measures ............................................ 56 
4. 
MATERIALS AND METHODS .................................................................... 56 
4.1 
Patients.................................................................................. 56 
4.1.1 
Inclusion Criteria.................................................................... 56 
4.1.2 
Exclusion Criteria................................................................... 57 
4.2 
Method of Treatment Assignment and Blinding..................... 58 
4.3 
Study Treatment.................................................................... 59 
4.3.1 
Formulation, Packaging, and Handling.................................. 59 
4.3.1.1 
Trastuzumab.......................................................................... 59 
4.3.1.2 
Pertuzumab and Placebo ...................................................... 60 
4.3.1.3 
Docetaxel............................................................................... 60 
4.3.1.4 
FEC Chemotherapy............................................................... 60 
4.3.2 
Dosage, Administration, and Compliance.............................. 61 
4.3.2.1 
Trastuzumab.......................................................................... 61 
4.3.2.2 
Pertuzumab and Placebo ...................................................... 62 
4.3.2.3 
Docetaxel............................................................................... 63 
4.3.2.4 
5-Fluorouracil, Epirubicin, and 
Cyclophosphamide Chemotherapy........................................ 64 
4.3.3 
Investigational Medicinal Product Accountability ................... 65 
4.3.4 
Post-Study Access to Pertuzumab ........................................ 65 
4.4 
Concomitant Therapy ............................................................ 65 
4.4.1 
Surgery.................................................................................. 66 
4.4.2 
Permitted Therapy ................................................................. 66 


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4.4.3 
Prohibited Therapy ................................................................ 67 
4.5 
Study Assessments ............................................................... 68 
4.5.1 
Description of Study Assessments ........................................ 68 
4.5.1.1 
Medical History and Demographic Data ................................ 68 
4.5.1.2 
Physical Examinations........................................................... 68 
4.5.1.3 
Vital Signs.............................................................................. 68 
4.5.1.4 
Tumor and Response Evaluations......................................... 68 
4.5.1.5 
Laboratory Assessments ....................................................... 69 
4.5.1.6 
Pathologic Response Evaluation........................................... 72 
4.5.1.7 
Diagnosis of Relapse or Recurrence ..................................... 72 
4.5.1.8 
Pharmacokinetic Assessments.............................................. 73 
4.5.1.9 
Anti-Therapeutic Antibody Assessments ............................... 74 
4.5.1.10 
Cardiac Assessments............................................................ 74 
4.5.1.11 
Assessments at Unplanned Visits ......................................... 74 
4.5.2 
Timing of Study Assessments ............................................... 74 
4.5.2.1 
Screening Assessments ........................................................ 74 
4.5.2.2 
Assessments during Treatment............................................. 75 
4.5.2.3 
Assessments at Treatment Completion or 
Discontinuation Visit .............................................................. 75 
4.5.2.4 
Follow-Up Assessments ........................................................ 75 
4.6 
Patient, Study, and Site Discontinuation................................ 75 
4.6.1 
Patient Discontinuation.......................................................... 75 
4.6.1.1 
Discontinuation from Study Treatment .................................. 76 
4.6.1.2 
Withdrawal from the Study..................................................... 76 
4.6.2 
Study and Site Discontinuation.............................................. 77 
5. 
ASSESSMENT OF SAFETY....................................................................... 77 
5.1 
Safety Plan ............................................................................ 77 
5.1.1 
Management of Risks that are Associated with 
Pertuzumab and Trastuzumab .............................................. 77 
5.1.1.1 
Infusion-Associated Reactions, Hypersensitivity 
Reactions (Including Anaphylaxis)......................................... 77 
5.1.1.2 
Symptomatic Left Ventricular Systolic 
Dysfunction and Asymptomatic Decrease in Left 
Ventricular Ejection Fraction.................................................. 78 


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5.1.1.3 
Epidermal Growth Factor Receptor−Related 
Toxicities................................................................................ 79 
5.1.2 
Dosage Modification and Treatment Interruption 
or Discontinuation.................................................................. 80 
5.1.2.1 
Trastuzumab, Pertuzumab or Placebo, and 
Docetaxel............................................................................... 80 
5.1.2.2 
5-Fluorouracil, Epirubicin, and 
Cyclophosphamide Chemotherapy........................................ 81 
5.1.3 
Pregnancy and Contraception ............................................... 81 
5.1.4 
Breastfeeding ........................................................................ 82 
5.2 
Safety Parameters and Definitions ........................................ 82 
5.2.1 
Adverse Events ..................................................................... 82 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 83 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 84 
5.3 
Methods and Timing to Capture and Assess 
Safety Parameters................................................................. 84 
5.3.1 
Adverse Event Reporting Period ........................................... 84 
5.3.2 
Eliciting Adverse Event Information ....................................... 85 
5.3.3 
Assessment of Severity of Adverse Events ........................... 85 
5.3.4 
Assessment of Causality of Adverse Events ......................... 85 
5.3.5 
Procedures to Record Adverse Events.................................. 86 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 86 
5.3.5.2 
Adverse Events that Occur Secondary to Other 
Events.................................................................................... 86 
5.3.5.3 
Persistent, Intermittent, or Recurrent Adverse 
Events.................................................................................... 87 
5.3.5.4 
Abnormal Laboratory Test Values ......................................... 87 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 88 
5.3.5.6 
Abnormal Liver Function Tests.............................................. 89 
5.3.5.7 
Deaths ................................................................................... 89 
5.3.5.8 
Preexisting Medical Conditions.............................................. 90 
5.3.5.9 
Lack of Efficacy or Worsening of Breast Cancer ................... 90 
5.3.5.10 
Hospitalization or Prolonged Hospitalization.......................... 90 
5.3.5.11 
Overdoses ............................................................................. 90 


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5.3.5.12 
Symptomatic Left Ventricular Systolic 
Dysfunction and Asymptomatic Decrease in Left 
Ventricular Ejection Fraction.................................................. 91 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 92 
5.4.1 
Emergency Medical Contacts................................................ 93 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 93 
5.4.2.1 
Events that Occur prior to Initiation of Study Drug................. 93 
5.4.2.2 
Events that Occur after Initiation of Study Drug..................... 94 
5.4.3 
Reporting Requirements for Pregnancies.............................. 94 
5.4.3.1 
Pregnancies in Female Patients............................................ 94 
5.4.3.2 
Pregnancies in Female Partners of Male Patients................. 95 
5.4.3.3 
Abortions ............................................................................... 95 
5.4.3.4 
Congenital Anomalies and/or Birth Defects ........................... 95 
5.5 
Follow-Up of Patients after Adverse Events .......................... 95 
5.5.1 
Investigator Follow-Up........................................................... 95 
5.5.2 
Sponsor Follow-Up ................................................................ 96 
5.6 
Post-Study Adverse Events................................................... 96 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 96 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 97 
6.1 
Determination of Sample Size ............................................... 97 
6.2 
Summaries of Conduct of Study............................................ 97 
6.3 
Summaries of Treatment Group Comparability ..................... 97 
6.4 
Efficacy Analyses .................................................................. 97 
6.4.1 
Primary Efficacy Endpoint...................................................... 98 
6.4.2 
Secondary Efficacy Endpoints............................................... 98 
6.4.2.1 
Total Pathologic Complete Response Rate as 
Assessed by the Local Pathologist........................................ 98 
6.4.2.2 
Breast Pathologic Complete Response Rate as 
Assessed by the Independent Review Committee ................ 98 
6.4.2.3 
Breast Pathologic Complete Response Rate as 
Assessed by the Local Pathologist........................................ 98 


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6.4.2.4 
Response Rates .................................................................... 99 
6.4.2.5 
Event-Free Survival ............................................................... 99 
6.4.2.6 
Disease-Free Survival ........................................................... 99 
6.4.2.7 
Overall Survival ................................................................... 100 
6.5 
Safety Analyses................................................................... 100 
6.5.1 
Study Drug Exposure........................................................... 100 
6.5.2 
Adverse Events ................................................................... 100 
6.5.3 
Cardiac Safety..................................................................... 100 
6.5.4 
Laboratory Data................................................................... 101 
6.6 
Exploratory Analyses........................................................... 101 
6.6.1 
Exploratory Pharmacokinetic Analyses................................ 101 
6.6.2 
Sensitivity and Subgroup Analyses ..................................... 101 
6.6.3 
Biomarker Analyses............................................................. 102 
6.6.4 
Anti-Therapeutic Antibody Analyses.................................... 102 
6.7 
Interim Analyses.................................................................. 102 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 102 
7.1 
Data Quality Assurance....................................................... 102 
7.2 
Electronic Case Report Forms............................................. 103 
7.3 
Source Data Documentation................................................ 103 
7.4 
Use of Computerized Systems ............................................ 103 
7.5 
Retention of Records........................................................... 104 
8. 
ETHICAL CONSIDERATIONS.................................................................. 104 
8.1 
Compliance with Laws and Regulations .............................. 104 
8.2 
Informed Consent ................................................................ 104 
8.3 
Institutional Review Board or Ethics Committee.................. 105 
8.4 
Confidentiality...................................................................... 106 
8.5 
Financial Disclosure ............................................................ 106 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 106 
9.1 
Study Documentation .......................................................... 106 
9.2 
Protocol Deviations.............................................................. 107 
9.3 
Site Inspections ................................................................... 107 


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9.4 
Administrative Structure....................................................... 107 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 107 
9.6 
Protocol Amendments ......................................................... 108 
10. REFERENCES ......................................................................................... 109 
 
 
LIST OF TABLES 
Table 1 
Actions to be Taken for Toxicities Related to Study 
Treatment.................................................................................... 80 
Table 2 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 85 
Table 3 
Reporting Conventions for Asymptomatic Decrease in LVEF 
or Symptomatic LVSD................................................................. 92 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema............................................................................. 50 
Figure 2 
Algorithm for the Continuation or Discontinuation of Study 
Treatment on the Basis of Asymptomatic Decline in LVEF......... 79 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities................................................................ 113 
Appendix 2 
Schedule of Biomarker and Pharmacokinetic Activities ............ 120 
Appendix 3 
Schedule of Anti-Therapeutic Antibody Activities...................... 121 
Appendix 4 
Response Evaluation Criteria in Solid Tumors: Modified 
Excerpt from Original Publication.............................................. 122 
Appendix 5 
Eastern Cooperative Oncology Group (ECOG) Performance 
Status Scale.............................................................................. 133 
Appendix 6 
New York Heart Association Functional Classification 
System for Heart Failure ........................................................... 134 
Appendix 7 
Nomogram for Determination of Body Surface Area................. 135 
Appendix 8 
Standardized Guideline for Surgical Sampling following 
Neoadjuvant Therapy................................................................ 136 
Appendix 9 
Flowchart for Breast Tissue Sampling ...................................... 139 


Pertuzumab—F. Hoffmann-La Roche Ltd 
28/Protocol YO28762, Version 4 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PHASE III STUDY 
EVALUATING PERTUZUMAB IN COMBINATION 
WITH DOCETAXEL AND TRASTUZUMAB AS 
NEOADJUVANT THERAPY, AND PERTUZUMAB IN 
COMBINATION WITH TRASTUZUMAB AS 
ADJUVANT THERAPY FOLLOWING SURGERY 
AND CHEMOTHERAPY IN PATIENTS WITH 
EARLY-STAGE OR LOCALLY ADVANCED 
HER2-POSITIVE BREAST CANCER 
PROTOCOL NUMBER: YO28762 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
Not applicable 
TEST PRODUCT: 
Pertuzumab (RO4368451) 
MEDICAL MONITOR: 
, M.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 return the original of the form to your local study monitor.  Please retain a copy 
for your study files. 
 


 
Pertuzumab—F. Hoffmann-La Roche Ltd 
29/Protocol YO28762, Version 4 
PROTOCOL SYNOPSIS 
TITLE: 
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PHASE III STUDY EVALUATING 
PERTUZUMAB IN COMBINATION WITH DOCETAXEL AND 
TRASTUZUMAB AS NEOADJUVANT THERAPY, AND 
PERTUZUMAB IN COMBINATION WITH TRASTUZUMAB AS 
ADJUVANT THERAPY FOLLOWING SURGERY AND 
CHEMOTHERAPY IN PATIENTS WITH EARLY-STAGE OR 
LOCALLY ADVANCED HER2-POSITIVE BREAST CANCER 
PROTOCOL NUMBER: 
YO28762 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
Not applicable 
TEST PRODUCT: 
Pertuzumab (RO4368451) 
PHASE: 
III 
INDICATION: 
HER2-positive breast cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Efficacy Objectives 
The primary efficacy objective for this study is as follows: 
• 
To evaluate the efficacy of trastuzumab + pertuzumab + docetaxel compared with 
trastuzumab + placebo + docetaxel as neoadjuvant treatment prior to surgery in patients 
who are chemotherapy-naive with early-stage or locally advanced human epidermal growth 
factor receptor 2 (HER2)−positive breast cancer as measured by total pathologic complete 
response (tpCR) rate as assessed by an Independent Review Committee (IRC) 
The secondary efficacy objectives for this study are to evaluate the efficacy of 
trastuzumab + pertuzumab + docetaxel compared with trastuzumab + placebo + docetaxel 
as neoadjuvant treatment prior to surgery in patients with early-stage or locally advanced 
HER2-positive breast cancer as measured by the following: 
• 
tpCR rate assessed by the local pathologist 
• 
Breast pathologic complete response (bpCR) rate assessed by the IRC 
• 
bpCR rate assessed by the local pathologist 
• 
Clinical response rates during Cycles 1−4 in accordance with Response Evaluation Criteria 
in Solid Tumors (RECIST), Version 1.1 
• 
Event-free survival (EFS) 
• 
Disease-free survival (DFS) 
• 
Overall survival 
 


 
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Safety Objective 
The safety objective for this study is as follows: 
• 
To evaluate the safety and tolerability of each treatment regimen 
 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To explore relationships between findings from the sentinel lymph node (SLN) biopsy tissue 
samples (if biopsy is performed) and the axillary lymph node dissection (ALND) tissue 
sample from the surgery undertaken after neoadjuvant treatment 
• 
To characterize the pharmacokinetics of pertuzumab after intravenous (IV) infusion in a 
subset of Chinese patients with early-stage or locally advanced HER2-positive breast 
cancer 
• 
To analyze biomarkers in tumor tissue taken at baseline or at the time of resection 
(markers analyzed may include but are not limited to HER2/3 mRNA and/or protein, 
PIK3CA, phosphatase and tensin homolog, programmed death−ligand 1, and cluster of 
differentiation 8), and serum (e.g., HER ligands and HER2 extracellular domain [ECD]) 
and evaluate correlations with clinical outcomes and, if applicable, safety outcomes 
• 
To analyze the effect of HER2 ECD on pharmacokinetics of pertuzumab 
• 
To analyze the effect of anti-therapeutic antibodies (ATAs) on pharmacokinetics, safety, 
and efficacy 
• 
To assess tpCR in relation to clinical response rate, EFS, DFS, and overall survival 
 
Study Design 
Description of Study 
This is an Asia-Pacific regional, randomized, double-blind, Phase III, multicenter study to 
evaluate treatment with trastuzumab + pertuzumab + docetaxel compared with 
trastuzumab + placebo + docetaxel in patients who are chemotherapy-naive with early-stage 
(T2-3, N0-1, M0) or locally advanced (T2-3, N2 or N3, M0; T4, any N, M0) HER2-positive breast 
cancer.  A primary tumor with the longest diameter of > 2 cm is required. 
Patients will be randomized in a 2:1 ratio to Arm A or Arm B, respectively, and treated every 
3 weeks for four cycles prior to surgery as follows: 
• 
Arm A 
Trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for Cycles 2−4) 
Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for Cycles 2−4) 
Docetaxel (75 mg/m2 for Cycles 1−4) 
• 
Arm B 
Trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for Cycles 2−4) 
Placebo (Cycles 1−4) 
Docetaxel (75 mg/m2 for Cycles 1−4) 
 
After completing four cycles of neoadjuvant treatment, all patients who are eligible for surgery 
will undergo surgery and have their pathologic response evaluated.  After surgery, patients will 
receive 500−600 mg/m2 5-fluorouracil (5-FU), 90−120 mg/m2 epirubicin, and 500−600 mg/m2 
cyclophosphamide (FEC) every 3 weeks for three cycles (Cycles 5−7).  Patients will then 
continue HER2-targeted therapy in accordance with the initial randomization every 3 weeks until 
disease recurrence (as assessed by the investigator) or unacceptable toxicity for up to 1 year 
total (17 cycles with inclusion of four cycles in the neoadjuvant setting) as follows: 
• 
Arm A 
Trastuzumab (8-mg/kg loading dose for Cycle 8, followed by 6 mg/kg for Cycles 9−20) 
Pertuzumab (840-mg loading dose for Cycle 8, followed by 420 mg for Cycles 9−20) 


 
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• 
Arm B 
Trastuzumab (8-mg/kg loading dose for Cycle 8, followed by 6 mg/kg for Cycles 9−20) 
Placebo (Cycles 8−20) 
 
For patients with tumors that are estrogen receptor (ER) and/or progesterone receptor (PgR) 
positive, hormonal agents (tamoxifen or an aromatase inhibitor for postmenopausal patients or 
tamoxifen, with or without ovarian suppression, or aromatase inhibitor with ovarian 
suppression for premenopausal patients) should be started at the end of FEC chemotherapy 
and given for at least 5 years.  Radiotherapy is to be given as clinically indicated at the end of 
FEC chemotherapy. 
Patients who discontinue neoadjuvant (preoperative) HER2-targed therapy as a result of toxicity 
and patients who are not eligible for surgery will be managed as per local practice.  Patients 
who discontinue adjuvant (postoperative) chemotherapy as a result of chemotherapy-related 
toxicity will continue with HER2-targeted therapy until they have received a total of 17 cycles of 
treatment.  Approximately 28 days after the last dose of study treatment, a final safety 
assessment will be performed before a patient enters long-term safety follow up.  Patients will 
be followed for disease recurrence and survival or until 5 years after randomization of the last 
patient. 
Patients will be evaluated for clinical response prior to surgery (i.e., during Cycles 1−4) in 
accordance with RECIST v1.1.  Patients will be evaluated for pathologic response after surgery 
and evaluated for disease recurrence.  The primary efficacy objective will be evaluated when all 
patients who are eligible for surgery have completed their surgical treatment with the 
assessment of pathological response.  Patients will be evaluated for safety throughout the study 
with laboratory tests and adverse event reports.  Serum samples will be collected from a subset 
of approximately 50 Chinese patients for characterization of pertuzumab pharmacokinetics. 
Number of Patients 
Approximately 328 eligible patients will be enrolled at approximately 24 sites, resulting in 
approximately 219 patients in Arm A and 109 patients in Arm B.  Randomization will be stratified 
by disease category (early-stage or locally advanced) and hormone-receptor status (positive for 
ER and/or PgR or negative for both). 
Target Population 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form 
• 
Age ≥ 18 years 
• 
Breast cancer that meets the following criteria: 
Histologically confirmed invasive breast carcinoma with a primary tumor size of > 2 cm 
by standard local assessment technique 
Stage at presentation:  early-stage (T2-3, N0-1, M0) or locally advanced (T2-3, N2 or N3, 
M0; T4, any N, M0) 
• 
HER2-positive breast cancer confirmed by a Sponsor-designated central laboratory and 
defined as 3+ score by immunohistochemistry (IHC) in > 10% of immunoreactive cells or 
HER2 gene amplification (ratio of HER2 gene signals to centromere 17 signals ≥ 2.0) by 
in situ hybridization (ISH) 
A tumor sample that consists of a tumor block or eight unstained, freshly cut slides 
must be available for central laboratory HER2 testing by IHC and ISH.  Note that up to 
an additional seven slides are required for exploratory biomarker research.  Therefore, 
15 slides are requested at screening. 
• 
Known hormone receptor status (ER and PgR) 
• 
Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 
• 
Completion of all necessary baseline laboratory and radiologic investigations prior to 
randomization 
• 
Baseline left ventricular ejection fraction (LVEF) ≥ 55% measured by echocardiography 
(ECHO; preferred) or multiple-gated acquisition (MUGA) scan 


 
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• 
For women who are not postmenopausal (≥ 12 months of amenorrhea) or surgically sterile 
(absence of ovaries and/or uterus):  agreement to remain abstinent or use one highly 
effective form of non-hormonal contraception or two effective forms of non-hormonal 
contraception during the treatment period and for at least 7 months after the last dose of 
study treatment  
• 
For men:  agreement to use reliable and effective contraceptive measures during the 
treatment period and for at least 7 months after the last dose of study treatment  
• 
Able to comply with the study protocol in the investigator’s judgment 
 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Stage IV (metastatic) breast cancer 
• 
Inflammatory breast cancer 
• 
Previous anti-cancer therapy or radiotherapy for any malignancy 
• 
History of other malignancy within 5 years prior to screening, except for 
appropriately-treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or 
Stage I uterine cancer 
• 
Concurrent anti-cancer treatment in another investigational study, including hormone 
therapy, bisphosphonate therapy, or immunotherapy 
• 
Major surgical procedure that is unrelated to breast cancer within 4 weeks prior to 
randomization or from which the patient has not fully recovered 
• 
Serious cardiac illness or medical condition including but not limited to the following: 
History of documented heart failure or systolic dysfunction (LVEF < 50%) 
High-risk uncontrolled arrhythmia, such as atrial tachycardia with a heart rate 
> 100 bpm at rest, significant ventricular arrhythmia (e.g., ventricular tachycardia), or 
higher-grade atrioventricular (AV) block (i.e., Mobitz II second-degree AV block or 
third-degree AV block) 
Angina pectoris requiring anti-angina medication 
Clinically-significant valvular heart disease 
Evidence of transmural infarction on ECG 
Poorly-controlled hypertension (systolic blood pressure > 180 mmHg and/or diastolic 
blood pressure > 100 mmHg) 
• 
Other concurrent serious diseases that may interfere with planned treatment, including 
severe pulmonary conditions/illness 
• 
Any of the following abnormal laboratory test results immediately prior to randomization: 
Total bilirubin > 1.5 × upper limit of normal (ULN) or, for cases of known Gilbert’s 
syndrome, total bilirubin > 2 × ULN 
AST and/or ALT > 1.25 × ULN 
Alkaline phosphatase > 2.5 × ULN 
Serum creatinine > 1.5 × ULN 
Total WBC count < 2500 cells/μL 
Absolute neutrophil count < 1500 cells/μL 
Platelet count < 100,000 cells/μL 
• 
Sensitivity to any of the study medications, any of the ingredients or excipients of these 
medications, or benzyl alcohol 
• 
Pregnant or lactating 
A negative serum pregnancy test result is required for all women who are not 
postmenopausal (≥ 12 months of amenorrhea). 
 


 
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Length of Study 
Recruitment is expected to last approximately 13 months.  On the basis of a treatment length of 
17 months for each patient, the analysis of the primary efficacy outcome measure, tpCR, will 
take place approximately 30 months after randomization of the first patient, when all patients 
have completed the treatment completion/discontinuation visit. 
Approximately 28 days after the last dose of study treatment, a final safety assessment will be 
performed before a patient enters long-term safety follow-up.  Patients will be followed for 
disease recurrence and survival or until 5 years after randomization of the last patient. 
End of Study 
The study will formally end approximately 5 years after the date of randomization of the last 
patient. 
Efficacy Outcome Measures 
The primary efficacy outcome measure is tpCR, defined as the absence of any residual invasive 
cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled 
ipsilateral lymph nodes after completion of neoadjuvant therapy and surgery (i.e., ypT0/is, ypN0 
in accordance with the current American Joint Committee on Cancer [AJCC] staging system) as 
assessed by the IRC. 
The secondary efficacy outcome measures are as follows: 
• 
tpCR assessed by local pathologist 
• 
bpCR defined as the absence of any residual invasive cancer on hematoxylin and eosin 
evaluation of the resected breast specimen after completion of neoadjuvant therapy and 
surgery (i.e., ypT0/is in accordance with the current AJCC staging system) as assessed by 
the IRC 
• 
bpCR assessed by local pathologist 
• 
Clinical response during Cycles 1−4, in accordance with RECIST v1.1 
• 
EFS defined as time from randomization to the first documentation of one of the following 
events: 
Disease progression (before surgery) as determined by the investigator with use of 
RECIST v1.1 
Any evidence of in situ contralateral disease will not be identified as progressive 
disease (PD). 
Any evidence of invasive contralateral disease will be considered disease 
progression 
Disease recurrence (local, regional, distant, or contralateral) after surgery 
Death from any cause 
• 
DFS defined as the time from the first date of no disease (i.e., date of surgery) to the first 
documentation of one of the following events: 
Disease recurrence (local, regional, distant, or contralateral) after surgery 
Death from any cause 
• 
Overall survival defined as the time from randomization to death from any cause 
 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Incidence, type, and severity of adverse events and serious adverse events 
• 
Incidence of symptomatic left ventricular systolic dysfunction (heart failure) defined as the 
occurrence of symptomatic LVEF decrease or definite or probable cardiac death 
• 
Incidence of asymptomatic decline in LVEF, defined as an absolute decrease of 
≥ 10 percentage points from baseline to an LVEF of < 50% 
• 
LVEF values over the course of the study 
• 
Laboratory test result abnormalities 


 
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Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
To explore relationships between pathology findings from the SLN biopsy tissue sample, if 
biopsy is performed, and the ALND tissue sample, from the surgery undertaken after 
neoadjuvant treatment 
• 
Observed pertuzumab concentrations at all specified pharmacokinetic (PK) sampling 
timepoints 
• 
Observed pertuzumab concentrations compared with concentrations in Caucasian patients 
with HER2-positive breast cancer from other studies 
• 
Observed pertuzumab concentrations during neoadjuvant treatment compared with 
concentrations during adjuvant treatment (postoperative) 
• 
Expression levels or incidence of biomarkers at baseline and in resection specimen tissue, 
especially for patients with residual disease, at the time of surgery (i.e., after neoadjuvant 
treatment) and their relationship to efficacy or safety parameters 
• 
To analyze the effect of HER2 ECD on pharmacokinetics of pertuzumab 
• 
Incidence of ATAs and relationship with PK, safety, and efficacy outcome measures 
• 
tpCR in relation to clinical response, EFS, DFS, and overall survival 
 
Investigational Medicinal Products 
Trastuzumab, pertuzumab, and placebo are investigational medicinal products (IMPs) in this 
study.  Depending on local legislation, docetaxel may also be considered an IMP in this study.  
Where permitted by regulatory requirements, sites will obtain and utilize commercially available 
docetaxel.  Treatments will be administered on Day 1 of each specified cycle. 
All patients will receive docetaxel and trastuzumab by intravenous (IV) infusion in 3-week cycles 
as follows: 
• 
Neoadjuvant treatment (prior to surgery) 
Trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for Cycles 2−4) 
Docetaxel (75 mg/m2 for Cycles 1−4) 
• 
Adjuvant treatment (after surgery and three cycles of FEC chemotherapy) 
Trastuzumab (8-mg/kg loading dose for Cycle-8, followed by 6 mg/kg for Cycles 9−20) 
 
Test Product 
Patients in Arm A will receive pertuzumab by IV infusion in 3-week cycles as follows: 
• 
Neoadjuvant treatment (prior to surgery) 
Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for Cycles 2−4) 
• 
Adjuvant treatment (after surgery and three cycles of FEC chemotherapy) 
Pertuzumab (840-mg loading dose for Cycle 8, followed by 420 mg for Cycles 9−20) 
 
Comparator 
Patients in Arm B will receive placebo by IV infusion in 3-week cycles as neoadjuvant treatment 
(Cycles 1−4) and as adjuvant treatment (Cycles 8−20). 
Non-Investigational Medicinal Products 
5-fluorouracil (5-FU), 90−120 mg/m2 epirubicin, and 500−600 mg/m2 cyclophosphamide are 
non-investigational medicinal products (non-IMPs) in this study.  Depending on local legislation, 
docetaxel may also be considered a non-IMP in this study.  After surgery, all patients will 
receive FEC (5-FU 500−600 mg/m2, epirubicin 90−120 mg/m2, and cyclophosphamide 
500−600 mg/m2) by IV infusion every 3 weeks for three cycles (Cycles 5−7).  
FEC chemotherapeutic agents will be administered on Day 1 of each specified cycle. 


 
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Statistical Methods 
Primary Analysis 
The primary efficacy outcome measure is tpCR, defined as the absence of any residual invasive 
cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled 
ipsilateral lymph nodes after completion of neoadjuvant therapy and surgery (i.e., ypT0/is, ypN0 
in accordance with the current AJCC staging system) as assessed by the IRC.  The primary 
analysis will be performed when all patients who are eligible for surgery have completed their 
surgical treatment with an assessment of pathological response.  The analysis will be based on 
the intent-to-treat (ITT) population with patients grouped by treatment assigned at the time of 
randomization.  In the ITT population, patients whose tpCR assessment is missing or invalid are 
counted as not achieving tpCR. 
The tpCR rate as assessed by the IRC will be summarized for each treatment arm, and 95% 
CIs will be calculated using the Clopper-Pearson method.  The two-sided 
Cochran-Mantel-Haenszel test, stratified by disease category (early-stage; locally advanced) 
and hormone receptor status (positive for ER and/or PgR; negative for both) will be used to 
compare the tpCR rate between the two treatment arms.  An unadjusted Fisher exact test result 
will also be provided.  Finally, the difference in tpCR rate and associated 95% CIs will be 
provided with use of the Hauck-Anderson method. 
Determination of Sample Size 
A total of 328 patients will be randomized into the study in a ratio of 2:1 to pertuzumab (Arm A) 
or placebo (Arm B), respectively.  This will provide 85% power to detect an absolute increase in 
tpCR rate of 15% in the pertuzumab arm compared with the placebo arm at a two-sided 
significance level of 5%, assuming the tpCR rate is 20% in the placebo arm. 
Secondary Analyses 
The secondary efficacy outcome measures in this study are tpCR as assessed by the local 
pathologist, bpCR as assessed by the IRC, bpCR as assessed by the local pathologist, clinical 
response, EFS, DFS, and overall survival. 
Safety Analyses 
Safety analyses will be performed on the safety analysis population, which will consist of all 
patients who received at least one dose of study drugs and patients will be grouped by the 
treatment they actually received.  The safety analyses will be performed at the same time as the 
primary efficacy analysis, the final analyses, and when all patients have completed the 
treatment completion or study discontinuation visit. 
Exploratory Analyses 
Exploratory analyses in this study are pharmacokinetic analyses, sensitivity and subgroup 
analyses, biomarker analyses, and anti-therapeutic antibody analyses. 
Interim Analyses 
There is no interim analysis planned for the primary efficacy outcome measure, tpCR.  EFS and 
DFS data will be summarized descriptively at the time of the primary efficacy analysis.  Note 
that a final analysis of EFS, DFS, and overall survival will be performed at the end of the study, 
approximately 5 years after randomization of the last patient. 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
5-FU 
5-fluorouracil 
AJCC 
American Joint Committee on Cancer 
ALND 
axillary lymph node dissection 
ATA 
anti-therapeutic antibody 
AV 
atrioventricular 
bpCR 
breast pathologic complete response 
CBE 
clinical breast examination 
CD8 
cluster of differentiation 8 
CR 
complete response 
Cmax 
maximum concentration 
Cmin 
minimum concentration 
CT 
computed tomography 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
DDI 
drug-drug interaction 
DFS 
disease-free survival 
EBC 
early breast cancer 
EC 
Ethics Committee 
ECD 
extracellular domain 
ECHO 
echocardiography 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EFS 
event-free survival 
EGFR 
epidermal growth factor receptor 
ER 
estrogen receptor 
FEC 
5-fluorouracil, epirubicin, and cyclophosphamide 
G-CSF 
granulocyte colony-stimulating factor 
HER 
human epidermal growth factor receptor 
HR 
hazard ratio 
ICH 
International Conference on Harmonisation 
IHC 
immunohistochemistry 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ISH 
in situ hybridization 


 
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Abbreviation 
Definition 
ITT 
intent to treat 
IV 
intravenous 
IxRS 
interactive voice/Web−based response system 
LVEF 
left ventricular ejection fraction 
LVSD 
left ventricular systolic dysfunction 
MBC 
metastatic breast cancer 
MRI 
magnetic resonance imaging 
MUGA 
multiple-gated acquisition 
NYHA 
New York Heart Association 
ORR 
objective response rate 
pCR 
pathologic complete response 
PD 
progressive disease 
PD-L1 
programmed death−ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PgR 
progesterone receptor 
PK 
pharmacokinetic 
PR 
partial response 
PVC 
polyvinyl chloride 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SLN 
sentinel lymph node 
SLNB 
sentinel lymph node biopsy 
tpCR 
total pathologic complete response 
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. 2008).  In Asia, 528,927 new breast cancer cases 
were diagnosed in 2008 (Ferlay et al. 2008).  In China, incidence of breast cancer is 
increasing with nearly 170,000 new cases reported in 2008 compared with 
126,000 cases in 2002 (Ferlay et al. 2002, 2008).  In addition, in China, breast cancer 
accounts for 16.81% of all female cancers; the incidence rate of female breast cancer 
was 42.55 per 100,000 in 2009 and after standardizing for age in China and the rest of 
the world, these rates were 23.16 per 10,000 and 28.99 per 100,000, respectively 
(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. 2008). 
Overexpression of human epidermal growth factor receptor 2 (HER2, also known as 
erbB2, neu, and p185HER2) or HER2 gene amplification has been observed in 
approximately 10%−34% of invasive human breast cancer (Ross 2009).  In China, the 
number of cases that were HER2 positive (2+/3+) was 42.6% (1342 of 3149 cases) as 
detected by fluorescence in situ hybridization and 46.9% (1477 of 3149 cases) by 
immunohistochemistry (IHC; Xiao Hong et al. 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).  Patients with breast cancers that overexpress 
HER2 have been shown to have better outcomes when treated with the monoclonal 
antibody Herceptin® (trastuzumab) with an improvement of 4-year progression-free 
survival (PFS) from 67.1% to 85.3% and absolute survival rate at 4 years from 86.6% to 
91.4% (Slamon et al. 2001; Romond et al. 2005).  Trastuzumab binds to the 
juxtamembrane epitope (domain IV) of the HER2 extracellular domain (ECD) and 
thereby prevents cleavage and signal transduction.  Trastuzumab is registered in many 
countries for the adjuvant treatment of breast cancer. 
1.2 
BACKGROUND ON PERTUZUMAB 
Pertuzumab (rhuMab 2C4) is a humanized monoclonal antibody that is based on the 
human IgG1 framework sequences and consists of two heavy chains (449 amino acid 
residues) and two light chains (214 residues).  Pertuzumab binds to the dimerization 
epitope of the HER2 receptor, and thereby inhibits dimerization of HER2 with HER2 and 
other HER family receptors, which in turn inhibits downstream signaling pathways.  In 
addition to blocking signal transduction, pertuzumab is capable of inducing 
antibody-dependent cell-mediated cytotoxicity.  Pertuzumab and trastuzumab bind to 


 
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distinct epitopes on the HER2 receptor (pertuzumab, subdomain 2; trastuzumab, 
subdomain 4) without competing with each other and have complementary mechanisms 
for disrupting HER2 signaling, which results in augmented anti-proliferative activity 
in vitro and in vivo when administered in combination. 
1.2.1 
Nonclinical Experience with Pertuzumab 
Pertuzumab showed activity in xenograft models of various tumor origins such as breast, 
lung, and prostate cancer.  In addition, pertuzumab demonstrated synergistic anti-tumor 
activity in combination with trastuzumab in HER2-positive breast, lung, and gastric 
cancer xenograft models. 
Teratology findings in the nonclinical reprotoxicity study in cynomolgus monkeys showed 
embryo or fetal losses, low-volume amniotic fluid (oligohydramnios), and microscopic 
evidence of delayed renal development (renal hypoplasia) in all pertuzumab-treated 
groups.  These findings were consistent with evidence that antibodies can be 
transported across the placenta during the period of organogenesis in the cynomolgus 
monkey. 
See the Pertuzumab Investigator's Brochure for details on nonclinical studies. 
1.2.2 
Clinical Experience with Pertuzumab 
1.2.2.1 
Pertuzumab Clinical Efficacy 
HER2-Positive Early-Stage Breast Cancer 
Study WO20697 (NeoSphere) was a Phase II, randomized, multicenter, four-armed 
study to compare the safety and efficacy of trastuzumab + docetaxel (Arm A) versus 
pertuzumab + trastuzumab + docetaxel (Arm B) versus pertuzumab + trastuzumab (Arm C) 
versus pertuzumab + docetaxel (Arm D) in the neoadjuvant setting in patients with locally 
advanced, inflammatory, or early-stage HER2-positive breast cancer.  The study met its 
primary efficacy endpoint and demonstrated a significantly higher breast pathologic 
complete response (bpCR; defined as ypT0/is in accordance with the American Joint 
Committee on Cancer [AJCC] staging system; see Section 3.4.1.2) rate for Arm B of 
45.8% compared with Arm A (29%) and Arm D (24%).  The bpCR rate for Arm C was 
17% and demonstrated that the two antibodies (pertuzumab and trastuzumab) 
administered without chemotherapy are active but significantly less than in combination 
with docetaxel (Arm B).  The total pathologic complete response (tpCR, defined as 
ypT0/is, ypN0) rates were 21.5% for Arm A, 39.3% for Arm B, 11.2% for Arm C, and 
17.7% for Arm D (Gianni et al. 2012). 
A 5-year follow-up analysis was conducted of the prespecified secondary endpoints of 
PFS (defined as the time from randomization to the first documentation of progressive 
disease or death), disease-free survival (DFS; time from the first date of no disease 
[i.e., date of surgery] to the first documentation of progressive disease or death), and 
safety for the overall and adjuvant treatment periods (Gianni et al. 2016). 


 
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The 5-year PFS rates were 81% (95% CI: 71, 87) for Arm A, 86% (95% CI: 77, 91) for 
Arm B, 73% (95% CI: 64, 81) for Arm C, and 73% (95% CI: 63, 81) for Arm D 
(hazard ratio [HR] = 0.69 [95% CI: 0.34, 1.40] Arm B vs. Arm A).  The 5-year PFS rate 
was 85% (95% CI: 76, 91) for patients who achieved a tpCR compared with 76% 
(95% CI: 71, 81) for patients who did not achieve a tpCR (HR = 0.54 [95% CI: 0.29, 
1.00]) in all arms combined.  DFS results were consistent with PFS results 
(Gianni et al. 2016). 
No new or long-term safety concerns were identified after 5 years of follow-up.  
The overall tolerability profile was similar across the treatment arms and consistent 
with the profile that was previously reported for the neoadjuvant period without any 
additional or long-term cardiotoxicity (Gianni et al. 2016). 
Study BO22280 (TRYPHAENA) was a Phase II, randomized, multicenter, 
multinational, three-arm study in patients with locally advanced, operable, 
and inflammatory (T2−4d) HER2-positive breast cancer who were scheduled 
for neoadjuvant therapy.  Patients were treated with one of three treatment 
regimens:  5-fluorouracil (5-FU), epirubicin, and cyclophosphamide 
(FEC) + trastuzumab + pertuzumab followed by docetaxel + trastuzumab + pertuzumab 
(Arm A); FEC followed by docetaxel + trastuzumab + pertuzumab (Arm B); or 
docetaxel + carboplatin + trastuzumab + pertuzumab (Arm C; Schneeweiss et al. 2011). 
All three treatment regimens were active and the majority of patients achieved a bpCR.  
The bpCR (ypT0/is) rates were similar across the treatment arms for the intent-to-treat 
(ITT) population (Arm A: 61.6%; Arm B: 57.3%; and Arm C: 66.2%).  A similar pattern of 
responses was observed when other definitions of pathologic complete response (pCR) 
were used, such as tpCR (see Section 3.4.1.1) or German Breast Group pCR, (defined 
as ypT0, ypN0), except that the pCR rate decreased as the stringency of the increased 
definition (Schneeweiss et al. 2013). 
The results of Study BO22280 demonstrated that neoadjuvant pertuzumab and 
trastuzumab can be administered concurrently or sequentially in combination with 
FEC-docetaxel chemotherapy or concurrently with a carboplatin-based chemotherapy 
regimen without substantial additions to the cardiac toxicity or the adverse event 
burden, or interrupting or delaying the delivery of standard chemotherapy regimens 
with trastuzumab (Schneeweiss et al. 2013). 
In addition, a Phase III, randomized, multicenter, double-blind, placebo-controlled 
comparison (Study BIG 4-11/BO25126/TOC4939g [APHNITY]) of 
chemotherapy + trastuzumab + placebo versus chemotherapy + trastuzumab + pertuzumab 
as adjuvant therapy in patients with operable HER2-positive primary breast cancer is 
ongoing. 


 
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HER2-Positive Metastatic Breast Cancer 
In a Phase III study (Study WO20698/TOC4129g [CLEOPATRA]) of patients 
with previously-untreated HER2-positive metastatic breast cancer (MBC), a 
statistically-significant and clinically-meaningful improvement in PFS was observed in 
patients who were treated with pertuzumab + trastuzumab + docetaxel compared with 
patients who received placebo + trastuzumab + docetaxel.  Median PFS was prolonged 
by 6.1 months and the risk of disease progression or death was reduced by 38% 
(HR = 0.62; p< 0.0001).  Median PFS was 12.4 months in the control group and 
18.5 months in the pertuzumab group.  Secondary endpoints of investigator-assessed 
PFS (HR = 0.65; 95% CI: 0.54, 0.78) and objective response rate (ORR; patients who 
achieve a complete response [CR] or partial response [PR]; 69% vs. 80%; 
95% CI: 4.2, 17.5) all supported the primary endpoint.  At the second interim analysis of 
overall survival, a statistically-significant reduction in the risk of death was demonstrated 
(HR = 0.66; 95% CI: 0.52, 0.84; p = 0.0008).  At the time of the final analysis of OS, the 
median OS for patients in the pertuzumab-combination group was 56.5 months 
(95% CI: 49.3 to NR) compared with 40.8 months (95% CI, 35.8−48.3) for patients in 
the placebo-combination group (HR 0.68; 95% CI, 0.56-0.84; p< 0.001).  The analysis 
was not adjusted for crossover to pertuzumab (Swain et al. 2015).  These study results 
led to the approval of pertuzumab in combination with trastuzumab and docetaxel 
for the first-line treatment of patients with HER2-positive MBC in some countries 
(i.e., United States and within the European Union) and this application is currently 
under review in other countries (Baselga et al. 2012a, 2012b). 
1.2.2.2 
Pertuzumab Clinical Safety 
As of 7 December 2015, an estimated total of 10,215 patients with cancer had been 
treated with pertuzumab in Roche-sponsored studies.  The most commonly reported 
adverse events in patients who received single-agent pertuzumab (n = 386) were 
diarrhea, fatigue, nausea, vomiting, and decreased appetite.  The majority of adverse 
events that were reported were National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE) Version 4.0 Grade 1 or 2 in severity and the proportion 
of patients across the entire pertuzumab program who discontinued study treatment as a 
result of an adverse event was low. 
The combination of pertuzumab, trastuzumab, and chemotherapy has been evaluated in 
multiple studies of patients with HER2-positive breast cancer.  In a Phase II study 
(Study WO20697; NeoSphere) of treatment with neoadjuvant pertuzumab in patients 
with HER2-positive early breast cancer (EBC), the safety analysis for the neoadjuvant 
treatment period showed that the tolerability of pertuzumab + trastuzumab + docetaxel 
was acceptable, acknowledging that only four cycles of therapy were administered.  The 
adverse events that occurred the most frequently in the neoadjuvant period (in at least 
25% of patients in any arm) were alopecia, neutropenia, diarrhea, nausea, fatigue, rash, 
and mucosal inflammation.  Of these events, alopecia and neutropenia were almost 
absent in Arm C (pertuzumab + trastuzumab) and the rates for many other adverse 
events were also reduced in this arm.  The majority of Grade ≥ 3 adverse events were 


 
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blood and lymphatic system disorders (neutropenia, leukopenia, and febrile neutropenia), 
the rates of severe (Grade ≥ 3) neutropenia for trastuzumab + docetaxel and for 
pertuzumab + trastuzumab + docetaxel were 57.0% and 44.9%, respectively, with 
corresponding rates of febrile neutropenia of 7.5% and 8.5%, respectively.  In the 
principal arms of the study (Arm A [trastuzumab + docetaxel] and Arm B 
[pertuzumab + trastuzumab + docetaxel]), there was no substantial difference in the 
occurrence of symptomatic left ventricular systolic dysfunction (LVSD) or decrease in left 
ventricular ejection fraction (LVEF).  The combination of trastuzumab, pertuzumab, and 
docetaxel was generally well tolerated with no new safety signals that were identified 
(Gianni et al. 2012). 
The safety analysis for Study BO22280 showed that the combination of pertuzumab with 
trastuzumab and standard anthracycline-based or non−anthracycline-based 
chemotherapy was generally well tolerated and resulted in no new safety signals.  The 
cardiac safety outcomes were similar across all three arms of the study in both the 
anthracycline-based and non−anthracycline-based regimens.  Nearly all patients 
(96%−100%) had an adverse event (all grades) during the neoadjuvant period.  The 
most common adverse event in the neoadjuvant period was diarrhea (61%−72% of 
patients).  Other common adverse events (> 20% incidence in any arm) included 
alopecia, nausea, neutropenia, vomiting, fatigue, anemia, mucosal inflammation, 
constipation, dyspepsia, leukopenia, decreased appetite, and headache.  Grade ≥ 3 
events were predominately blood and lymphatic system disorders.  Across Arms A, B, 
and C, rates of Grade ≥ 3 neutropenia were seen at 47.2%, 42.7%, and 46.1% and 
febrile neutropenia at 18.1%, 9.3% and 17.1%, respectively, and are consistent with the 
established profiles of the chemotherapy regimens (Schneeweiss et al. 2011). 
In the Phase III study (Study WO20698/TOC4129g) of patients with previously untreated 
HER2-positive MBC, the regimen of pertuzumab + trastuzumab + docetaxel had a 
toxicity profile including cardiac toxicity that was comparable to the regimen of 
placebo + trastuzumab + docetaxel.  The most common adverse events were alopecia 
(an adverse event associated with docetaxel), diarrhea, neutropenia, nausea, fatigue, 
and rash.  Diarrhea, rash, mucosal inflammation, febrile neutropenia, dry skin, and 
pruritus of all grades had an increased incidence of at least 5% in the pertuzumab arm.  
The only Grade ≥ 3 adverse event that occurred at a higher incidence (> 5% difference) 
in the pertuzumab arm than in the placebo arm was febrile neutropenia (13.8% vs. 7.6%, 
respectively; Baselga et al. 2012a). 
Symptomatic Left Ventricular Systolic Dysfunction or Asymptomatic 
Decrease in Left Ventricular Ejection Fraction 
Decreases in LVEF have been reported with drugs that block HER2 activity, including 
pertuzumab.  In Study WO20698/TOC4129g, pertuzumab + trastuzumab + docetaxel was 
not associated with increases in the incidence of symptomatic LVSD or with decreases 
in LVEF compared with placebo + trastuzumab + docetaxel.  However, patients who 


 
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received prior anthracyclines or radiotherapy to the chest area may be at a higher risk of 
decreased LVEF (Portera et al. 2008). 
Pertuzumab has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a 
history of congestive heart failure, decreases in LVEF to < 50% during prior trastuzumab 
adjuvant therapy, or conditions that could impair left ventricular function such as 
uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia that 
requires treatment, or a cumulative prior anthracycline exposure to > 360 mg/m2 of 
doxorubicin or its equivalent. 
Infusion-Associated Reactions, Hypersensitivity Reactions 
(Including Anaphylaxis) 
In single-agent pertuzumab studies, 8 cases (2.1%) of anaphylaxis or hypersensitivity 
(Grades 1−4) were reported.  In Study BO17929, involving patients with MBC who 
received pertuzumab and trastuzumab, the incidence of anaphylaxis and 
hypersensitivity was 4.8%.  All events were Grade 1 or 2 in severity.  In 
Study WO20697, 7%-13% in all treatment arms that included treatment with 
pertuzumab versus 2% in the trastuzumab + docetaxel arm had an event of anaphylaxis 
and/or hypersensitivity.  Of these, 2 patients who received treatment with 
trastuzumab + pertuzumab + docetaxel (Arm B) and 3 patients who received treatment 
with trastuzumab + pertuzumab (Arm C) had a Grade ≥ 3 event. 
In Study WO20698/TOC4129g, 11.3% of patients in the pertuzumab arm had a 
hypersensitivity event (Grades 1−4), compared with 9.3% in the placebo arm.  
Overall, the reactions were mild or moderate in severity and resolved with treatment.  
Eight patients in the pertuzumab arm had a Grade ≥ 3 event.  Most reactions were 
assessed as secondary to docetaxel infusions. 
In the same study, the initial dose of pertuzumab or placebo (Day 1, Cycle 1) was 
administered the day before trastuzumab and docetaxel were administered to allow for 
the evaluation of pertuzumab infusion−associated reactions.  On Day 1, Cycle 1 
(i.e., after pertuzumab only), the overall frequency of infusion-associated reactions was 
9.8% in the placebo arm and 13.2% in the pertuzumab arm with the majority of reactions 
reported as mild or moderate.  The most common infusion-associated reactions (≥ 1.0%) 
in the pertuzumab arm were pyrexia, chills, fatigue, headache, asthenia, 
hypersensitivity, and vomiting.  During Cycle 2 when all drugs were administered on 
the same day, the most common infusion-associated reactions (≥ 1.0%) in the 
pertuzumab arm were fatigue, drug hypersensitivity, dysgeusia, hypersensitivity, 
myalgia, and vomiting. 
1.2.2.3 
Immunogenicity 
The immunogenicity of pertuzumab has been assessed with use of validated bridging 
immunoassay methods that are designed to detect and confirm the presence of 
anti-therapeutic antibodies (ATAs) to pertuzumab.  In Study WO20698/TOC4129g, 


 
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6.7% of patients in the placebo arm and 3.3% of patients in the pertuzumab arm tested 
positive for ATAs at some time during or after receipt of the study treatment.  None of 
the patients who tested positive for ATAs in this study experienced anaphylaxis or 
hypersensitivity reactions that were clearly related to ATAs.  Many of the patients who 
tested positive for ATAs in this study continued to receive study treatment 
(placebo/pertuzumab + trastuzumab + docetaxel), sometimes for prolonged periods after 
ATAs were first detected.  Although 3 patients in the placebo arm and 3 patients in the 
pertuzumab arm with detectable ATAs experienced hypersensitivity reactions, the 
investigator assessed the event to be related to docetaxel for 3 patients (2 patients in the 
placebo arm and 1 patient in the pertuzumab arm) and related to pamidronate in 
1 patient (in the placebo arm).  The reported course for the events that were reported in 
the other 2 patients in the pertuzumab arm suggests that the events were simple 
infusion reactions such as those seen with trastuzumab and other monoclonal antibodies. 
Two of 366 patients (0.5%) who were treated with pertuzumab in the Phase I and II 
studies who had at least one postdose sample available for ATA analysis tested positive 
for ATAs to pertuzumab.  Both patients experienced Grade 3 hypersensitivity reactions 
that precluded further administration of pertuzumab.  A different ATA assay was used in 
these studies and may contribute to the observed differences between Phase III and 
Phase I/II studies. 
Overall, these data show that anaphylaxis or hypersensitivity reactions as a result of 
ATAs have occurred in patients who were treated with pertuzumab, although these 
events were not observed in the pivotal MBC study.  Therefore, the detection of ATAs 
does not necessarily mean that a patient is at a high risk for such reactions or that 
pertuzumab cannot be continued. 
Among the patients with pharmacokinetic (PK) samples that were collected in a 
substudy of Study WO20698/TOC4129g, only 1 of 20 patients in the pertuzumab arm 
tested positive for ATAs to pertuzumab.  This patient had a slightly lower pertuzumab 
trough concentration (40.8 μg/mL) when compared with Day 168 data from 
ATA-negative patients (mean [coefficient of variation %] = 77.8 μg/mL [26.7]).  However, 
the trough concentration was higher than the PK target concentration of 20 μg/mL at all 
timepoints.  Given that only 1 patient tested positive for ATAs to pertuzumab in the 
PK substudy, a definitive conclusion on whether there is any impact of ATAs on the 
pharmacokinetics of pertuzumab and on clinical relevance cannot be drawn. 
1.2.2.4 
Pharmacokinetics of Pertuzumab 
Pharmacokinetics in Monotherapy or Combination 
The pharmacokinetics of pertuzumab administered as a single agent were studied in two 
Phase Ia studies with doses ranging from 0.5 to 25.0 mg/kg and in five Phase II studies 
with a dose of 1050 mg (with no initial loading dose) or an initial loading dose of 840 mg 
followed by a dose of 420 mg.  In all cases, pertuzumab was administered by 
intravenous (IV) infusion every 3 weeks.  Similar PK disposition was observed across 


 
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these seven studies and the pharmacokinetics exhibited a biphasic profile that was 
characterized by a serum clearance of approximately 0.235 L/day, a half-life of 
approximately 18 days, and a volume of distribution approximating serum volume.  
No differences in pharmacokinetics have been observed between Caucasian and Asian 
(mostly Japanese) patients.  Pertuzumab exhibited linear pharmacokinetics for 
doses ≥ 2.0 mg/kg.  With an 840-mg initial loading dose followed by 420-mg doses every 
3 weeks, serum trough concentrations of pertuzumab were ≥ 20 μg/mL⎯the target 
threshold concentration identified in nonclinical xenograft models⎯in > 90% of patients. 
Five Phase Ib/II studies evaluated the pharmacokinetics of pertuzumab in combination 
with different anti-cancer agents (capecitabine, erlotinib, gemcitabine, and docetaxel).  
Four of the five studies had control arms that allowed for a direct assessment of the 
impact of pertuzumab on the pharmacokinetics of other co-administered anti-cancer 
agents.  Results indicate that pertuzumab does not alter the pharmacokinetics of 
capecitabine (and its metabolites, including 5-FU), erlotinib, gemcitabine (and its 
metabolite 2′, 2′ -difluorodeoxyuridine), or docetaxel.  In addition, the pharmacokinetics 
of pertuzumab in combination with other agents were similar to the pharmacokinetics of 
pertuzumab as a single agent and suggest that there were no changes in pertuzumab 
pharmacokinetics in the presence of capecitabine, erlotinib, gemcitabine, or docetaxel.  
The effects of drug-drug interactions (DDIs) between docetaxel, trastuzumab, and 
pertuzumab were investigated in a substudy of the Phase III 
Study WO20698/TOC4129g.  As expected, because pertuzumab and trastuzumab bind 
to distinct epitopes on the HER2 receptor without competing with each other or causing 
steric hindrance of binding, there was no evidence of a DDI between pertuzumab and 
trastuzumab (in the presence of docetaxel).  Further, there was no evidence of a DDI 
between pertuzumab and docetaxel (in the presence of trastuzumab). 
The potential for a PK DDI of pertuzumab (in combination with trastuzumab) on the 
pharmacokinetics of carboplatin is currently being studied in a subset of patients in the 
Phase III Study BIG 4-11/BO25126/TOC4939g. 
Population Pharmacokinetic Analysis 
A comprehensive population PK analysis was performed with use of data from 
481 patients who are enrolled in 12 Phase I, II, and III studies.  A two-compartment 
linear model with first-order elimination from the central compartment describes the 
pharmacokinetics of pertuzumab across the dose range of 2.0−25.0 mg/kg.  In the final 
model, clearance was 0.235 L/day and central compartment volume was 3.11 L.  
The median terminal elimination half-life was 18 days. 
Lean body weight and serum albumin were identified as statistically-significant 
covariates for pertuzumab pharmacokinetics.  No statistically-significant effects of other 
covariates on PK parameters were detected, with the inclusion of demographic variables 
(age, sex, race/ethnicity [Japanese vs. non-Japanese]), laboratory variables related to 
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creatinine clearance), and disease variables (Eastern Cooperative Oncology Group 
[ECOG]/Karnofsky Performance Status, MBC vs. other tumor types, number of 
metastatic sites, liver metastases, and concomitant chemotherapy).  Clearance 
decreased in patients with higher baseline albumin concentrations and increased in 
patients with a greater lean body weight.  However, sensitivity analyses indicated that a 
dose adjustment on the basis of these covariates would not lead to a meaningful 
reduction in PK variability.  Further, a sensitivity analysis was conducted to evaluate the 
impact of baseline body weight on steady-state trough pertuzumab concentrations.  The 
results were then summarized by quartiles of body weight to evaluate the impact of body 
weight on the achievement of the clinical target concentration (steady-state trough 
concentration of ≥ 20 μg/mL in 90% of patients).  The results indicated that the vast 
majority of patients (90% or above) remained above the target across all body weight 
quartiles and supported the validity of the fixed, non−weight-based pertuzumab dosing 
regimen of an 840-mg initial dose followed by 420-mg doses administered every 
3 weeks. 
See the Pertuzumab Investigator's Brochure for details on clinical studies. 
1.3 
BACKGROUND ON TRASTUZUMAB 
Trastuzumab is a recombinant humanized anti-p185HER2 monoclonal antibody that binds 
with high affinity to the HER2 protein.  In most of the world, trastuzumab is licensed in 
combination with docetaxel as a first-line treatment for HER2-positive MBC because a 
significant survival benefit has been demonstrated for the combination compared with 
chemotherapy alone (Slamon et al. 2001; Marty et al. 2005).  On the basis of data from 
Study BO16348 (Piccart-Gebhart et al. 2005), trastuzumab is registered in the 
European Union and many other countries for use after adjuvant chemotherapy.  In 
addition, trastuzumab is approved in the European Union as a neoadjuvant therapy.  
Other data confirm that adjuvant treatment of HER2-positive breast cancer with 
trastuzumab in combination with chemotherapy is associated with significantly improved 
outcomes and that the improvement is possibly greater when trastuzumab is integrated 
with the taxane part of the adjuvant therapy compared with sequential administration 
(Romond et al. 2005; Perez et al. 2009). 
Details on the use of trastuzumab can be found in the Trastuzumab Investigator's 
Brochure and the Herceptin prescribing information. 
1.3.1 
Trastuzumab Safety Data 
Details of the adverse events associated with the clinical use of trastuzumab can be 
found in the Trastuzumab Investigator's Brochure.  To minimize the risk of cardiac 
dysfunction, only patients who have adequate cardiac function (LVEF ≥ 55%) will be 
enrolled in the study.  Patients with particular cardiac risk factors will be excluded. 


 
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1.3.2 
Pharmacokinetics of Trastuzumab 
Analyses in clinical studies showed that trastuzumab has dose-dependent, non-linear 
pharmacokinetics with dose-dependent clearance and half-life.  The volume of 
distribution approximates the serum volume.  At therapeutic doses, the half-life is 
approximately 26−38 days and may persist in the circulatory system for up to 27 weeks 
after the end of treatment. 
Refer to the Trastuzumab Investigator's Brochure for further information. 
1.4 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Pertuzumab has shown activity and a favorable benefit-risk profile in patients whose 
disease progressed after prior HER2-directed therapies for metastatic disease.  
Data from Study WO20697 confirm that both trastuzumab and pertuzumab are active 
against HER2-positive breast cancer when administered with docetaxel and that the 
two antibodies administered together are more active than either one alone when 
administered with docetaxel.  In addition, pertuzumab appears to have a favorable 
benefit-risk profile in patients who have not received prior chemotherapy for metastatic 
disease with inclusion of patients who had previously received trastuzumab in the 
adjuvant setting.  The safety profile of pertuzumab appears to be acceptable in the 
metastatic setting and is currently under evaluation for HER2-positive EBC.  In the 
curative treatment setting, certain acute adverse events or potential chronic organ 
effects (e.g., cardiac) may constitute a specific concern for pertuzumab.  In studies that 
have been conducted to date, there does not appear to be an increased risk for cardiac 
adverse events with pertuzumab compared with other HER2-directed therapies.  
Although initial safety data to date with pertuzumab in previously-untreated patients in 
the neoadjuvant (Gianni et al. 2012) and metastatic settings (Baselga et al. 2012a) 
appear acceptable, the safety monitoring plan for this study includes appropriate 
eligibility criteria, dose modification guidelines, and regular monitoring of accumulating 
patient safety data by the Sponsor’s study team and has been put in place to minimize 
any potential risk in the study patient population. 
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 trastuzumab + pertuzumab + docetaxel compared with 
trastuzumab + placebo + docetaxel as neoadjuvant treatment prior to surgery in 
patients who are chemotherapy-naive with early-stage or locally advanced 
HER2−positive breast cancer as measured by tpCR rate assessed by an 
Independent Review Committee (IRC). 
 


 
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2.1.2 
Secondary Efficacy Objective 
The secondary efficacy objective for this study is to evaluate the efficacy of 
trastuzumab + pertuzumab + docetaxel compared with trastuzumab + placebo + docetaxel 
as neoadjuvant treatment prior to surgery in patients with early-stage or locally advanced 
HER2-positive breast cancer as measured by the following: 
• 
tpCR rate assessed by the local pathologist 
• 
bpCR rate assessed by the IRC 
• 
bpCR rate assessed by the local pathologist 
• 
Clinical response rates during Cycles 1−4 in accordance with Response Evaluation 
Criteria in Solid Tumors (RECIST), Version 1.1 (see Appendix 4) 
• 
Event-free survival (EFS) 
• 
DFS 
• 
Overall survival 
 
2.2 
SAFETY OBJECTIVE 
The safety objective for this study is as follows: 
• 
To evaluate the safety and tolerability of each treatment regimen 
 
2.3 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
• 
To explore relationships between findings from the sentinel lymph node (SLN) 
biopsy tissue sample (if biopsy is performed) and the axillary lymph node dissection 
tissue sample (ALND) obtained during the surgery that is undertaken after 
neoadjuvant treatment 
• 
To characterize the pharmacokinetics of pertuzumab after IV infusion in a subset of 
Chinese patients with early-stage or locally advanced HER2-positive breast cancer 
• 
To analyze biomarkers in tumor tissue taken at baseline or at the time of resection 
(markers analyzed may include but are not limited to HER2/3 mRNA and/or protein, 
PIK3CA, phosphatase and tensin homolog [PTEN], programmed death−ligand 1 
[PD-L1], and cluster of differentiation 8 [CD8]), and serum (e.g., HER ligands and 
HER2 ECD) and evaluate correlations with clinical outcomes and, if applicable, 
safety outcomes 
• 
To analyze the effect of HER2 ECD on pharmacokinetics of pertuzumab 
• 
To analyze the effect of ATAs on pharmacokinetics, safety, and efficacy 
• 
To assess tpCR in relation to clinical response rate, EFS, DFS, and overall survival 
 


 
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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
3.1.1 
Overview of Study Design 
This is an Asia-Pacific regional, randomized, double-blind, Phase III, multicenter study 
to evaluate treatment with trastuzumab + pertuzumab + docetaxel compared with 
trastuzumab + placebo + docetaxel in patients who are chemotherapy-naive with 
early-stage (T2-3, N0-1, M0) or locally advanced (T2-3, N2 or N3, M0; T4, any N, M0) 
HER2-positive breast cancer.  A primary tumor with the longest diameter of > 2 cm is 
required. 
Patients will be randomized in a 2:1 ratio to Arm A or Arm B, respectively, and treated 
every 3 weeks for four cycles prior to surgery as follows: 
• 
Arm A 
Trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for Cycles 2−4) 
Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for Cycles 2−4) 
Docetaxel (75 mg/m2 for Cycles 1−4) 
• 
Arm B 
Trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for Cycles 2−4) 
Placebo (Cycles 1−4) 
Docetaxel (75 mg/m2 for Cycles 1−4) 
 
Approximately 328 eligible patients will be enrolled at approximately 24 sites, resulting in 
approximately 219 patients in Arm A and 109 patients in Arm B.  Randomization will be 
stratified by disease category (early-stage or locally advanced) and hormone-receptor 
status (positive for estrogen receptor [ER] and/or progesterone receptor [PgR] or 
negative for both). 
After completing four cycles of neoadjuvant treatment, all patients who are eligible for 
surgery will undergo surgery and have their pathologic response evaluated.  After 
surgery, patients will receive 500−600 mg/m2 5-FU, 90−120 mg/m2 epirubicin, and 
500−600 mg/m2 FEC every 3 weeks for three cycles (Cycles 5−7).  Patients will then 
continue HER2-targeted therapy in accordance with the initial randomization every 
3 weeks until disease recurrence (as assessed by the investigator) or unacceptable 
toxicity for up to 1 year total (17 cycles with inclusion of four cycles in the neoadjuvant 
setting) as follows: 
• 
Arm A 
Trastuzumab (8-mg/kg loading dose for Cycle 8, followed by 6 mg/kg for 
Cycles 9−20) 
Pertuzumab (840-mg loading dose for Cycle 8, followed by 420 mg for Cycles 9−20) 




 
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long-term safety follow-up.  Patients will be followed for disease recurrence and survival 
or until 5 years after randomization of the last patient. 
Patients will be evaluated for clinical response prior to surgery (i.e., during Cycles 1−4) 
in accordance with RECIST v1.1.  Patients will be evaluated for pathologic response 
after surgery and evaluated for disease recurrence.  The primary efficacy objective will 
be evaluated when all patients who are eligible for surgery have completed their 
surgical treatment with the assessment of pathological response.  Patients will be 
evaluated for safety throughout the study with laboratory tests and adverse event reports.  
Serum samples will be collected from a subset of approximately 50 Chinese patients for 
characterization of pertuzumab pharmacokinetics. 
A schedule of activities is provided in Appendix 1. 
3.1.2 
Independent Review Committee 
An IRC that consists of independent experts who are not involved in the study (including 
approximately three pathologists) will evaluate the pathologic response. 
Details of the composition, roles, and responsibilities of the IRC will be provided in a 
separate charter. 
The IRC will remain blinded to the treatment assignment for the formal efficacy analyses.  
The Sponsor will remain blinded to the IRC assessments. 
3.1.3 
Safety Data Review 
The Sponsor’s study team will review adverse events, serious adverse events, and any 
other safety data in the study on a regularly scheduled basis. 
It is the responsibility of the study team to review accumulating safety data, assess and 
monitor ongoing safety of patients, evaluate potential changes to the clinical study 
protocol, and ultimately safeguard patient safety. 
3.2 
END OF STUDY 
The study will formally end approximately 5 years after the date of randomization of the 
last patient. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Combining Pertuzumab, Trastuzumab, 
and Docetaxel 
The combination of pertuzumab and trastuzumab is scientifically compelling based on 
their complementary modes of action and on the nonclinical data as previously 
described.  There is clinical evidence that the combination is both active and well 
tolerated in carefully selected patients (Walshe et al. 2006; Baselga et al. 2007).  These 
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suggest that such combinations are highly active and associated with encouraging 
tolerability (Pegram et al. 2005).  The magnitude of clinical benefit and the acceptable 
safety profile in this study confirm the positive benefit-risk ratio of pertuzumab 
combined with trastuzumab and docetaxel in patients with HER2-positive metastatic 
or locally recurrent, unresectable breast cancer, including patients from Asia 
(Baselga et al. 2012a).  This level of clinical benefit has exceeded expectation 
(see Section 1.2.2.1).  Docetaxel is an established agent in the therapy of breast 
cancer and registered for use in this indication. 
3.3.2 
Rationale for Neoadjuvant Therapy 
Adjuvant systemic therapies for breast cancer (i.e., drugs to reduce the risk of breast 
cancer recurrence) historically have been administered after definitive breast surgery.  
Preoperative or neoadjuvant systemic chemotherapy that was once reserved for patients 
with locally advanced breast cancer for whom the goal was to render large breast 
cancers operable has become increasingly common.  There are several potential 
rationales for neoadjuvant treatment for early-stage breast cancer.  Giving preoperative 
chemotherapy permits breast conservation in some patients who would otherwise 
require mastectomy and may improve cosmesis in existing candidates for breast 
conservation (Fisher et al. 2002; Alm El-Din and Taghian 2009).  Preoperative therapy 
also enables the oncologist to evaluate tumor response and discontinue ineffective 
therapy or substitute an alternative systemic therapy.  Further, a patient’s response to 
neoadjuvant chemotherapy may provide prognostic information that can supplement 
conventional prognostic data such as initial staging, tumor grade, and receptor status.  
Finally, the neoadjuvant setting provides investigators with the unique opportunity to 
examine modulation of tumor tissue biomarkers from the time of biopsy to the time of 
definitive breast surgery after completion of preoperative systemic therapy in patients 
who have residual disease. 
A meta-analysis of approximately 4000 patients who are enrolled in nine studies of 
neoadjuvant versus adjuvant chemotherapy or endocrine therapy found no evidence that 
sequencing of systemic therapy and surgery alters distant disease recurrence or overall 
survival (Mauri et al. 2005).  Of note, patients who received neoadjuvant therapy 
compared with those who received postoperative adjuvant therapy had an increased risk 
of locoregional recurrence, which has been attributed to the omission of definitive local 
therapy in some of the neoadjuvant studies (Mauri et al. 2005).  Under the assumption 
that definitive local therapy will be provided, preoperative systemic therapy appears to 
be an acceptable alternative to standard postoperative systemic therapy in patients with 
early-stage breast cancer and facilitating the development of new drugs for use in the 
neoadjuvant setting is a worthwhile objective. 
At the completion of the neoadjuvant therapy, patients will undergo surgery.  The 
surgical specimen will be reviewed and the pathologic response to therapy evaluated.  
The desired outcome of the neoadjuvant therapy is pCR.  There is evidence that those 


 
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patients who achieve a pCR have survival advantage (Fisher et al. 1998; Kurosumi 2004; 
Bear et al. 2006; Kaufmann et al. 2006).  The pCR rate is therefore deemed to be a 
suitable primary endpoint in a study on neoadjuvant therapy. 
3.3.3 
Rationale for Adjuvant Therapy 
The combination of pertuzumab and trastuzumab as an adjuvant therapy is scientifically 
compelling based on their complementary mechanisms of action and the available 
nonclinical data as described in Section 1.2.1.  This rationale is supported by the clinical 
data from Studies WO20697, BO17929, and WO20698/TOC4129g (Gelmon et al. 2008; 
Baselga et al. 2009; 2012a). 
After surgery, patients will receive adjuvant chemotherapy in the form of standard FEC 
combination therapy.  Anthracyclines (generally used in combination with 5-FU and 
cyclophosphamide) have a central role in the management of breast cancer 
(Romond et al. 2005; Poole et al. 2006).  Specifically, there might be a particular activity 
associated with the use of anthracyclines in patients whose tumors overexpress 
chromosome 17 because polysomy 17 is associated with overexpression of HER2, 
topoisomerase II (topoisomerase II being the target for anthracyclines), and other 
potentially relevant proteins such as p53 (Bartlett et al. 2008; Gennari et al. 2008).  
There is evidence that the combination of cardiotoxic anthracyclines (such as epirubicin) 
with trastuzumab may be associated with acceptable cardiac tolerability in patients who 
are selected for their good cardiac function (Untch et al. 2004; Buzdar et al. 2005).  It is 
possible that pertuzumab will be equally tolerable when given in combination with 
anthracyclines to similarly selected patients.  However, in the interest of patient safety, 
adjuvant FEC treatment will be separated from neoadjuvant pertuzumab treatment by a 
minimum of 5 weeks. 
The clinical data that pertain to pertuzumab suggest it has a promising benefit-risk profile 
and could be a suitable additional agent for use in early, potentially curable, breast 
cancer. 
3.3.4 
Rationale for Docetaxel Dosage 
Docetaxel at a dose of 100 mg/m2 given every 3 weeks in combination with trastuzumab 
has been associated with a positive benefit-risk ratio compared with docetaxel alone in 
patients with HER2-overexpressing MBC (Marty et al. 2005).  However, based on the 
results from a Phase Ib study (Study BO17021), the maximum tolerated dose of 
docetaxel in combination with pertuzumab is 75 mg/m2.  The benefits and risks 
associated with different docetaxel doses (single agent) have been established in a 
randomized study that suggests that all three doses of docetaxel (60, 75, and 100 mg/m2) 
were active with manageable toxicity.  Depending on the goals of therapy and the 
individual characteristics of the patient, each of the three doses may be appropriate, with 
lower doses having potential utility in patients who are frail or have specific tolerability 
concerns (Harvey et al. 2006).  The rate of febrile neutropenia in Asian patients was 


 
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notably higher than that in the other populations where docetaxel was administered at 
75 mg/m2 and could be escalated to 100 mg/m2 if well tolerated 
(Study WO20698/TOC4129g).  This is consistent with general observations on the 
tolerability of taxanes in such populations (Fujiwara et al. 1999; Sato et al. 2006) and 
with the fact that docetaxel is registered at lower doses in Asian countries than in 
Western countries.  To increase the tolerability of the combined regimen, the dose of 
docetaxel used in this study will be 75 mg/m2. 
3.3.5 
Rationale for Trastuzumab and Pertuzumab Dosages 
Based on the PK data, lack of DDI between trastuzumab and pertuzumab and positive 
clinical data, a pertuzumab loading dose of 840 mg followed by a 420-mg maintenance 
dose every 3 weeks was determined for pertuzumab (see Section 1.2.2.4).  
A trastuzumab loading dose of 8 mg/kg followed by 6 mg/kg every 3 weeks is deemed 
appropriate on the basis of trastuzumab pharmacokinetics (see Section 1.3.2). 
3.3.6 
Rationale for Biomarker Assessments 
The exploratory biomarker analyses in this study will be used to assess the potential 
prognostic and/or predictive value of candidate markers or biomarker panels, improve 
diagnostic tests, improve understanding of breast cancer biology, or discover new 
biomarker profiles that are related to treatment benefit, treatment safety, and/or disease 
characteristics.  The collection of samples for exploratory biomarker research is 
mandatory. 
Biomarkers to be considered for exploratory analyses are: 
• 
Molecules involved in downstream signaling of HER2 
• 
Molecules that belong to a group of related receptor tyrosine kinases that could 
serve as salvage routes for an inhibited HER2 pathway 
• 
Ligands of HER family proteins that induce activation of the HER pathway 
 
Such molecules that are considered for analyses may include but are not limited to 
PTEN, PIK3CA mutations, HER3 and HER2 mRNA, PD-L1, CD8, and other markers 
that are relevant to breast cancer. 
If appropriate, a refinement of the translational research plan may be implemented prior 
to the data cutoff date to take into account emerging data in the literature and allow for 
the latest state-of-the-art technology to be applied. 
3.4 
OUTCOME MEASURES 
3.4.1 
Efficacy Outcome Measures 
3.4.1.1 
Primary Efficacy Outcome Measure 
The primary efficacy outcome measure is tpCR, defined as the absence of any residual 
invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen 
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surgery (i.e., ypT0/is, ypN0 in accordance with the current AJCC staging system) as 
assessed by the IRC (see Appendix 8). 
3.4.1.2 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures are as follows: 
• 
tpCR assessed by a local pathologist 
• 
bpCR defined as the absence of any residual invasive cancer on hematoxylin and 
eosin evaluation of the resected breast specimen after completion of neoadjuvant 
therapy and surgery (i.e., ypT0/is in accordance with the current AJCC staging 
system) as assessed by the IRC 
• 
bpCR assessed by a local pathologist 
• 
Clinical response during Cycles 1−4 in accordance with RECIST v1.1 
• 
EFS defined as time from randomization to the first documentation of one of the 
following events: 
Disease progression (before surgery) as determined by the investigator with 
use of RECIST v1.1 
Any evidence of in situ contralateral disease will not be identified as 
progressive disease (PD) 
Any evidence of invasive contralateral disease will be considered disease 
progression 
Disease recurrence (local, regional, distant, or contralateral) after surgery 
Death from any cause 
• 
DFS defined as the time from the first date of no disease (i.e., date of surgery) to the 
first documentation of one of the following events: 
Disease recurrence (local, regional, distant, or contralateral) after surgery 
Death from any cause 
• 
Overall survival defined as the time from randomization to death from any cause 
 
3.4.2 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Incidence, type, and severity of adverse events and serious adverse events 
• 
Incidence of symptomatic LVSD (heart failure) defined as the occurrence of 
symptomatic LVEF decrease or definite or probable cardiac death 
• 
Incidence of asymptomatic decrease in LVEF defined as an absolute decrease of 
≥ 10 percentage points from baseline to an LVEF of < 50% 
• 
LVEF values over the course of the study 
• 
Laboratory test result abnormalities 
 


 
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3.4.3 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
To explore relationships between pathology findings from the SLN biopsy tissue 
sample, if the biopsy is performed, and the ALND tissue sampled obtained during 
the surgery undertaken after neoadjuvant treatment 
• 
Observed pertuzumab concentrations at all specified PK sampling timepoints 
• 
Observed pertuzumab concentrations compared with concentrations in Caucasian 
patients with HER2-positive breast cancer from other studies 
• 
Observed pertuzumab concentrations during neoadjuvant treatment compared with 
concentrations during adjuvant treatment (postoperative) 
• 
Expression levels or incidence of biomarkers at baseline and in resection specimen 
tissue, especially for patients with residual disease, at the time of surgery (i.e., after 
neoadjuvant treatment) and their relationship to efficacy or safety parameters 
• 
To analyze the effect of HER2 ECD on pharmacokinetics of pertuzumab 
• 
Incidence of ATAs and relationship with PK, safety, and efficacy outcome measures 
• 
tpCR in relation to clinical response, EFS, DFS, and overall survival 
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 328 patients who are chemotherapy-naive with early-stage or locally 
advanced HER2-positive breast cancer will be enrolled in the study. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form 
• 
Age ≥ 18 years 
• 
Breast cancer that meets the following criteria: 
Histologically confirmed invasive breast carcinoma with a primary tumor size of 
> 2 cm by standard local assessment technique 
Stage at presentation:  early-stage (T2-3, N0-1, M0) or locally advanced (T2-3, 
N2 or N3, M0; T4, any N, M0) 
• 
HER2-positive breast cancer confirmed by a Sponsor-designated central laboratory 
and defined as 3+ score by IHC in > 10% of immunoreactive cells or HER2 gene 
amplification (ratio of HER2 gene signals to centromere 17 signals ≥ 2.0) by in situ 
hybridization (ISH) 
A tumor sample that consists of a tumor block or eight unstained, freshly cut 
slides must be available for central laboratory HER2 testing by IHC and ISH.  
Note that up to an additional seven slides are required for exploratory biomarker 
research.  Therefore, 15 slides are requested at screening. 


 
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• 
Known hormone receptor status (ER and PgR) 
• 
ECOG Performance Status ≤ 1 (see Appendix 5) 
• 
Completion of all necessary baseline laboratory and radiologic investigations prior to 
randomization 
• 
Baseline LVEF ≥ 55% measured by echocardiography (ECHO; preferred) or 
multiple-gated acquisition (MUGA) scan 
• 
For women who are not postmenopausal (≥ 12 months of amenorrhea) or surgically 
sterile (absence of ovaries and/or uterus):  agreement to remain abstinent or use 
one highly effective form of non-hormonal contraception or two effective forms of 
non-hormonal contraception during the treatment period and for at least 7 months 
after the last dose of study treatment (see Section 5.1.3) 
• 
For men:  agreement to use reliable and effective contraceptive measures during 
the treatment period and for at least 7 months after the last dose of study treatment 
(see Section 5.1.3) 
• 
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: 
• 
Stage IV (metastatic) breast cancer 
• 
Inflammatory breast cancer 
• 
Previous anti-cancer therapy or radiotherapy for any malignancy 
• 
History of other malignancy within 5 years prior to screening, except for 
appropriately-treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, 
or Stage I uterine cancer 
• 
Concurrent anti-cancer treatment in another investigational study, including 
hormone therapy, bisphosphonate therapy, or immunotherapy 
• 
Major surgical procedure that is unrelated to breast cancer within 4 weeks prior to 
randomization or from which the patient has not fully recovered 
• 
Serious cardiac illness or medical condition including but not limited to the following: 
History of documented heart failure or systolic dysfunction (LVEF < 50%) 
High-risk uncontrolled arrhythmia, such as atrial tachycardia with a heart rate 
> 100 bpm at rest, significant ventricular arrhythmia (e.g., ventricular 
tachycardia), or higher-grade atrioventricular (AV) block (i.e., Mobitz II 
second-degree AV block or third-degree AV block) 
Angina pectoris that requires anti-angina medication 
Clinically-significant valvular heart disease 
Evidence of transmural infarction on ECG 
Poorly-controlled hypertension (systolic blood pressure > 180 mmHg and/or 
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• 
Other concurrent serious diseases that may interfere with planned treatment, 
including severe pulmonary conditions/illness 
• 
Any of the following abnormal laboratory test results immediately prior to 
randomization: 
Total bilirubin > 1.5 × upper limit of normal (ULN) or, for cases of known Gilbert’s 
syndrome, total bilirubin > 2 × ULN 
AST and/or ALT > 1.25 × ULN 
Alkaline phosphatase > 2.5 × ULN 
Serum creatinine > 1.5 × ULN 
Total WBC count < 2500 cells/μL 
Absolute neutrophil count < 1500 cells/μL 
Platelet count < 100,000 cells/μL 
• 
Sensitivity to any of the study medications, any of the ingredients or excipients of 
these medications, or benzyl alcohol 
• 
Pregnant or lactating 
A negative serum pregnancy test result is required for all women who are not 
postmenopausal (≥ 12 months of amenorrhea). 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
After written informed consent has been obtained and eligibility has been established 
and approved, the study site will obtain the patient randomization number and treatment 
assignment from the interactive voice/Web−based response system (IxRS).  Patients 
should receive their first dose of study treatment on the day of randomization, if possible, 
but no later than 5 business days after randomization.  Patients will be randomized in a 
2:1 ratio to one of the two treatment arms (pertuzumab or placebo) with use of the IxRS.  
Patients will be enrolled with a permuted block randomization procedure that uses the 
following stratification factors: 
• 
Disease category:  early-stage (T2-3, N0-1, M0) or locally advanced (T2-3, N2 or N3, 
M0; T4, any N, M0) 
• 
Hormone-receptor status:  positive for ER and/or PgR; negative for both 
 
The investigator and the patient will be blinded to the treatment assignment.  All other 
individuals who are directly involved in this study will remain blinded to the treatment 
assignment until completion of the primary analysis.  Patient treatment assignment will 
not be unblinded until after the final 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. 


 
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If treatment unblinding is necessary for patient management (in the case of a serious 
adverse event), the investigator will be able to break the treatment code by contacting 
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 treatment unblinding (e.g., accidental 
treatment unblinding, treatment unblinding as a result of a serious adverse event). 
Although PK and HER2 ECD samples must also be obtained from patients who are 
randomized to the placebo arm to maintain the blinding to the treatment assignment, 
only the PK and HER2 ECD samples from patients who are treated with pertuzumab 
and enrolled in the PK substudy in China will be tested.  The study personnel that are 
responsible to perform the PK and HER2 ECD assays will be unblinded to a patient’s 
treatment assignment to identify the appropriate PK and HER2 ECD samples to be 
analyzed. 
As per health authority reporting requirements, the Sponsor will break the treatment 
code for all unexpected serious adverse events (see Section 5.7) considered by the 
investigator to be related to study drug. 
4.3 
STUDY TREATMENT 
Eligible patients will be treated with trastuzumab, pertuzumab, and docetaxel (Arm A) or 
trastuzumab, placebo, and docetaxel (Arm B) for four cycles in the neoadjuvant setting.  
After surgery, patients will receive three cycles of FEC chemotherapy.  Patients will then 
continue HER2-targeted therapy that consists of trastuzumab and pertuzumab (Arm A) 
or trastuzumab and placebo (Arm B) until disease recurrence as assessed by the 
investigator or unacceptable toxicity for up to 1 year in total (17 cycles, including 
four cycles in the neoadjuvant setting). 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Trastuzumab 
Trastuzumab (lyophilized formulation) for use in this study will be supplied by the 
Sponsor as a freeze-dried preparation.  All trastuzumab is supplied for IV administration.  
Trastuzumab is formulated in histidine, trehalose, and polysorbate 20.  Vials of 
trastuzumab are shipped with cool packs at a temperature range of 2°C−8°C (36°F−46°F) 
and must be placed in a refrigerator (same temperature range) immediately upon receipt 
to ensure optimal retention of physical and biochemical integrity.  Temperature logs must 
be maintained (in accordance with local pharmacy practice) on the refrigerator to ensure 
proper storage conditions.  Do not use beyond the expiration date stamped on the vial.  
DO NOT FREEZE. 
Trastuzumab may be sensitive to shear-induced stress (e.g., agitation or rapid expulsion 
from a syringe).  DO NOT SHAKE.  Vigorous handling of solutions of trastuzumab 
results in aggregation of the protein and may create cloudy solutions.  Trastuzumab 


 
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should be carefully handled during reconstitution.  Causing excessive foaming during 
reconstitution or shaking the reconstituted trastuzumab may result in problems with the 
amount of trastuzumab that can be withdrawn from the vial. 
The Sponsor will provide trastuzumab to all study sites labeled for investigational use 
only. 
For further details, see the Trastuzumab Investigator's Brochure as well as local 
prescribing information for trastuzumab. 
4.3.1.2 
Pertuzumab and Placebo 
Pertuzumab is provided as a single-use formulation containing 30 mg/mL pertuzumab 
formulated in 20 mM L-histidine-acetate (pH 6.0), 120 mM sucrose, and 
0.02% polysorbate 20.  Each 20-mL vial (14 mL solution per vial) contains approximately 
420 mg of pertuzumab.  Pertuzumab-matching placebo has the identical formulation but 
does not contain the antibody. 
Upon receipt of pertuzumab, vials are to be refrigerated at 2°C−8°C (36°F−46°F) until 
use.  Pertuzumab vials should not be used beyond the expiration date provided by the 
manufacturer.  Because the formulation does not contain a preservative, the vial seal 
may only be punctured once.  Any remaining solution should be discarded.  Vial 
contents should be protected from light and should not be frozen.  The solution of 
pertuzumab for infusion, diluted in polyvinyl chloride (PVC) or non-PVC polyolefin bags 
containing 0.9% Sodium Chloride Injection, USP, may be stored for up to 24 hours prior 
to use.  Diluted pertuzumab has been shown to be stable for up to 24 hours at a 
temperature range of 2°C−25°C (36°F−46°F).  However, since diluted pertuzumab 
contains no preservative, the diluted solution should be stored refrigerated at 2°C−8°C 
(36°F−46°F). 
The Sponsor will provide pertuzumab and placebo to all study sites labeled for 
investigational use only.  Pertuzumab and placebo will be labeled in accordance with the 
regulatory requirements of each country in which this study is being conducted as well 
as the International Conference on Harmonisation (ICH) E6 guideline for Good Clinical 
Practice. 
For further details, see the Pertuzumab Investigator’s Brochure. 
4.3.1.3 
Docetaxel 
Where permitted by regulatory requirements, sites will obtain and utilize commercially 
available docetaxel.  For details on the docetaxel formulation, see the local prescribing 
information for docetaxel. 
4.3.1.4 
FEC Chemotherapy 
For details on the FEC chemotherapy formulations, see the local prescribing information 
for 5-FU, epirubicin, and cyclophosphamide. 


 
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4.3.2 
Dosage, Administration, and Compliance 
Study treatment will be administered in 3-week (21[± 3] days) cycles (with the 
assumption that there is no delay as a result of an adverse event).  Patients will 
complete four cycles of neoadjuvant treatment prior to surgery with treatments 
administered to the two arms in the following order: 
• 
Arm A:  trastuzumab, pertuzumab, and docetaxel 
• 
Arm B:  trastuzumab, placebo, and docetaxel 
 
After surgery, patients will receive three cycles of FEC chemotherapy (Cycles 5−7).  
Patients will then continue HER2-targeted therapy every 3 weeks until disease 
recurrence as assessed by the investigator or unacceptable toxicity for up to 1 year total 
(17 cycles, including four cycles in the neoadjuvant setting) with treatments administered 
to the two arms in the following order: 
• 
Arm A:  trastuzumab and pertuzumab 
• 
Arm B:  trastuzumab and placebo 
 
Further details on dosing, administration, and compliance are provided below. 
4.3.2.1 
Trastuzumab 
Trastuzumab will be administered by IV infusion on Day 1 of each specified 3-week 
cycle, as outlined below. 
• 
Neoadjuvant treatment (prior to surgery) 
Patients in Arms A and B will receive trastuzumab at a loading dose of 8 mg/kg 
for Cycle 1 and a dose of 6 mg/kg for Cycles 2−4.  The initial dose of 
trastuzumab will be administered over 90 (± 10) minutes, and patients will be 
observed for 30 minutes after the infusion.  If the infusion is well tolerated, 
subsequent doses may be administered over 30 (± 10) minutes and patients 
will be observed for 30 minutes after the infusion. 
• 
Adjuvant treatment (after surgery and three cycles of FEC chemotherapy 
[Cycles 5−7]) 
Patients in Arms A and B will receive trastuzumab at a reloading dose of 
8 mg/kg for Cycle 8 and a dose of 6 mg/kg for Cycles 9−20.  If infusions are 
well tolerated during the neoadjuvant treatment period, subsequent infusions 
may be administered over 30 (± 10) minutes and patients will be observed for 
30 minutes after the infusion. 
 
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, β-agonists, 
antihistamines, antipyretics, and corticosteroids may help alleviate symptoms.  All 
infusion-associated symptoms must be resolved before pertuzumab is administered.  
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premedicated with analgesics and antihistamines for subsequent infusions.  Patients 
who experience a Grade 4 allergic reaction or acute respiratory distress syndrome 
should discontinue treatment. 
The amount of trastuzumab administered is calculated in accordance with the patient’s 
actual body weight with no upper limit.  Weight should be recorded at baseline and at 
every scheduled visit.  The amount to be administered must be recalculated if the 
patient’s body 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 the trastuzumab dose in subsequent cycles. 
Dosage modifications are not permitted (except as required because of changes in body 
weight).  Treatment interruption or discontinuation is permitted for toxicity, including 
cardiotoxicity (see Sections 5.1.1 and 5.1.2).  If trastuzumab must be delayed for a day 
or more, all study treatments should be delayed for the same time frame.  If trastuzumab 
is held for more than two cycles or needs to be permanently discontinued, the patient will 
be withdrawn from all study treatment. 
If a patient misses a dose of trastuzumab for any cycle and the time between doses is 
≥ 6 weeks, the patient should receive a reloading dose of 8 mg/kg of trastuzumab.  
Subsequent trastuzumab doses of 6 mg/kg will continue to be administered every 
3 weeks, beginning 3 weeks after the loading dose. 
4.3.2.2 
Pertuzumab and Placebo 
Pertuzumab or matching placebo will be administered by IV infusion on Day 1 of each 
specified 3-week cycle after the trastuzumab infusion observation period as outlined 
below.  Study site staff and the patient will be blinded as to whether pertuzumab or 
matching placebo is administered. 
• 
Neoadjuvant treatment (prior to surgery) 
Patients will receive pertuzumab or placebo at a loading dose of 840 mg for 
Cycle 1 and a dose of 420 mg for Cycles 2−4.  The initial dose of pertuzumab or 
placebo will be administered over 60 (± 10) minutes, and patients will be 
observed for 60 minutes after the infusion.  If the infusion is well tolerated, 
subsequent doses may be administered over 30 (± 10) minutes and patients will 
be observed for 30 minutes after the infusion. 
• 
Adjuvant treatment (after surgery and three cycles of FEC chemotherapy 
[Cycles 5−7]) 
Patients will receive pertuzumab or placebo at a reloading dose of 840 mg for 
Cycle 8 and a dose of 420 mg for Cycles 9−20.  If infusions are well tolerated 
during the neoadjuvant treatment period, subsequent infusions may be 
administered over 30 (± 10) minutes and patients will be observed for 
30 minutes after the infusion. 
 


 
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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, β-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 discontinue treatment. 
Dosage modifications are not permitted.  Treatment interruption or discontinuation is 
permitted for toxicity, including cardiotoxicity (see Sections 5.1.1 and 5.1.2).  If the 
administration of pertuzumab or placebo must be delayed for a day or more, all study 
treatments should be delayed for the same time frame.  If the treatment with pertuzumab 
or placebo is withheld for more than two cycles or needs to be permanently discontinued, 
the patient will be withdrawn from all study treatment. 
If a patient in Arm A misses a dose of pertuzumab for any cycle and the time between 
doses is ≥ 6 weeks, the patient should receive a reloading dose of 840 mg of 
pertuzumab.  Subsequent pertuzumab doses of 420 mg will continue to be administered 
every 3 weeks, beginning 3 weeks after the loading dose. 
4.3.2.3 
Docetaxel 
Patients in Arms A and B will receive docetaxel at a dose of 75 mg/m2 every 3 weeks for 
four cycles (Cycles 1−4).  Docetaxel will be administered by IV infusion on Day 1 of each 
cycle after the pertuzumab infusion observation period.  Patients will be observed closely 
from the start of the infusion for hypersensitivity reactions, which may occur within 
minutes.  Severe hypotension, bronchospasm, or generalized rash/erythema requires 
immediate discontinuation of docetaxel and appropriate treatment.  The infusion may be 
slowed for minor symptoms such as flushing or local cutaneous reactions.  Patients who 
experience severe hypersensitivity reactions should not continue in the study.  
Premedication that consists of an oral corticosteroid such as dexamethasone 16 mg/day 
(may be divided into two 8-mg doses per day) on Day −1, Day 1, and Day 2 may be 
administered if not contraindicated.  Similarly, prophylactic granulocyte 
colony-stimulating factor (G-CSF) may be used to mitigate the risk of hematological 
toxicities. 
The amount of docetaxel that is administered is calculated in accordance with the 
patient’s body surface area.  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.  The amount 
to be administered must be recalculated if the patient’s body weight has increased or 
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> 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 is provided, which may 
be used for the determination of body surface area (see Appendix 7). 
Guidelines for docetaxel dosage modification and treatment interruption or 
discontinuation as a result of toxicity are provided in Section 5.1.2.  If docetaxel must be 
delayed for a day or more, all study treatments should be delayed for the same 
time frame.  If docetaxel is held for more than two cycles or needs to be permanently 
discontinued, the patient will be withdrawn from all study treatment. 
4.3.2.4 
5-Fluorouracil, Epirubicin, and Cyclophosphamide 
Chemotherapy 
After surgery, patients in Arms A and B will receive FEC chemotherapy every 3 weeks 
for three cycles (Cycles 5−7).  The administration of therapy in Cycle 5 should not occur 
until 2 weeks after surgery. 
The amount of each chemotherapy agent that is administered is calculated in 
accordance with the patient’s body surface area.  Weight and height should be recorded 
at baseline and weight should be recorded at every scheduled visit.  The amount to be 
administered must be recalculated if the patient’s body 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 be used as the new baseline to calculate 
the dose in subsequent cycles.  A nomogram is provided, which may be used for the 
determination of body surface area (see Appendix 7). 
Dosage modification and treatment interruption or discontinuation are permitted for 
FEC chemotherapy as indicated in the relevant local label for each agent and will be 
managed in accordance with local practice. 
5-Fluorouracil 
5-FU will be administered at 500−600 mg/m2 on Day 1 of Cycles 5−7.  It may be given as 
an IV bolus or IV infusion in accordance with local policy.  Patients with a body surface 
area of > 2 m2 should receive a dose of 1200 mg. 
Epirubicin 
Epirubicin will be administered at 90−120 mg/m2 on Day 1 of Cycles 5−7.  It may be 
given as an IV bolus or IV infusion in accordance with local policy. 
Cyclophosphamide 
Cyclophosphamide will be administered at 500−600 mg/m2 on Day 1 of Cycles 5−7.  It 
may be given as an IV bolus or IV infusion in accordance with local policy.  Patients with 
a body surface area of > 2 m2 should receive a dose of 1200 mg. 


 
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4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) that are required for completion of this 
study (trastuzumab, pertuzumab, and placebo) will be provided by the Sponsor.  
Depending on local legislation, docetaxel may also be considered an IMP in this study.  
Where permitted by regulatory requirements, sites will obtain and utilize commercially 
available docetaxel.  The study site will acknowledge receipt of IMPs with use of the 
IxRS to confirm the shipment condition and content.  Any damaged shipments will be 
replaced. 
IMPs will either be disposed of at the study site in accordance with 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-Study Access to Pertuzumab 
The Sponsor does not intend to provide pertuzumab or other study interventions to 
patients after conclusion of the study or any earlier patient withdrawal. 
Patients who experience disease progression before the end of neoadjuvant therapy will 
be withdrawn from study treatment and treated as clinically indicated in accordance with 
local practice.  Patients who complete chemotherapy and surgery but then relapse 
(either during or after completion of adjuvant pertuzumab and trastuzumab) will be 
treated as clinically indicated and relevant follow-up information about subsequent 
therapies and outcomes will be collected. 
4.4 
CONCOMITANT THERAPY 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, and nutritional supplements) or therapy used by 
a patient at any time from 7 days prior to randomization to the treatment completion or 
discontinuation visit.  All concomitant medications should be reported to the investigator 
and recorded on the Concomitant Medications electronic Case Report Form (eCRF). 
Any non−protocol-required therapeutic or surgical procedure that occurs during the study 
period is also considered a concomitant therapy and must be recorded.  Information with 
regard to concomitant medications and treatments should include the date, reason, 
description of the medication, treatment or procedure, and any associated clinical 
findings.  Special attention should be paid to reporting any medications associated with 
the treatment of a suspected or confirmed cardiac event, including an asymptomatic 
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4.4.1 
Surgery 
Patients in both cohorts are scheduled to undergo surgery after four cycles of 
neoadjuvant therapy.  Patients may undergo breast-conserving surgery or mastectomy 
in accordance with routine clinical practice. 
Before the initiation of neoadjuvant treatment, the primary tumor site must be physically 
marked per the standard local practice (e.g., skin tattoo or surgical clip) to enable 
appropriate surgical excision in case of tumor regression during neoadjuvant therapy. 
In the event that a biopsy of the sentinel lymph node (SLNB) is performed, it is 
recommended that both dye and isotope be used.  The dye and isotope should not be 
injected into the tumor itself because they may alter the tissue and affect the molecular 
analyses to be performed on the tumor tissue sample. 
Ongoing clinical studies are evaluating the value of SLNB tissue sample and the role of 
axillary radiotherapy as an alternative to axillary dissection and identifying subgroups of 
patients who may be able to omit axillary dissection after a positive SLNB test result.  
Investigators may follow the local common practice or guidelines based on emerging 
data once they have been incorporated into institutional, local, national, or international 
guidelines (e.g., National Comprehensive Cancer Network, European Society for 
Medical Oncology, St. Gallen, or Lisbon Conference). 
4.4.2 
Permitted Therapy 
In general, all medications that are taken by the patient for concomitant diseases should 
continue during the study treatment period.  Any medication that is necessary for the 
supportive management of the patient may be used at the discretion of the investigator. 
Acceptable methods of contraception must be used when the patient is not surgically 
sterilized or does not meet the study definition of postmenopausal (see Section 5.1.3). 
The following treatments are permitted during the study: 
• 
For patients with tumors that are ER and/or PgR positive:  hormonal agents 
(tamoxifen or an aromatase inhibitor for postmenopausal patients; tamoxifen with or 
without ovarian suppression, or aromatase inhibitor with ovarian suppression for 
premenopausal patients) initiated at the end of FEC chemotherapy and 
administered for at least 5 years 
• 
Radiotherapy (administered as clinically indicated at the end of FEC chemotherapy 
and in accordance with local standard practice) 
• 
H1- and H2-receptor antagonists (e.g., diphenhydramine, cimetidine) 
• 
Cardiovascular medications:  angiotensin-converting enzyme inhibitors, angiotensin 
receptor blockers, β-blockers, calcium channel blockers, and diuretics for treatment 
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β-blockers, calcium channel blockers, and digoxin for heart rate control; 
thrombocyte aggregation inhibitors 
• 
Analgesics/anti-inflammatories (e.g., paracetamol/acetaminophen, meperidine, and 
opioids) 
• 
Short-term use of corticosteroids to treat or prevent allergic or infusion reactions 
• 
Anti-emetic treatments (e.g., approved prophylactic serotonin-antagonists and 
benzodiazepines) 
• 
Medication to treat diarrhea (e.g., loperamide) 
• 
Colony-stimulating factors (e.g., G-CSF) 
• 
Vitamin and mineral supplements 
• 
Bisphosphonates (used in accordance with the approved labeled indication and/or 
nationally recognized treatment guidelines) 
• 
Prophylaxis against hepatitis B reactivation (e.g., lamivudine) 
 
All concomitant medications are to be reported through the treatment completion or 
discontinuation visit.  Thereafter, only medications and therapies that are applicable for 
long-term reporting must be reported including the following: 
• 
Breast cancer treatments (e.g., hormone therapy) 
• 
Anti-cancer treatments for recurrence 
• 
Bisphosphonate or denosumab therapy 
• 
Medications related to the treatment of serious adverse events that are applicable 
for long-term reporting 
 
4.4.3 
Prohibited Therapy 
Use of the following therapies is prohibited during the treatment period of the study: 
• 
Anti-cancer therapies other than those administered in this study, including cytotoxic 
chemotherapy, radiotherapy (except for adjuvant radiotherapy for breast cancer 
after completion of chemotherapy), immunotherapy, and biological anti-cancer 
therapy 
• 
Any targeted anti-cancer therapy (e.g., lapatinib, neratinib) 
• 
High doses of systemic corticosteroids, defined as > 20 mg of dexamethasone a day 
(or equivalent) for > 7 consecutive days 
• 
Any investigational agent except for those used for this study 
• 
Herbal remedies initiated for cancer treatment 
Other herbal remedies are discouraged but permitted and must be reported on 
the appropriate eCRF. 
• 
Any oral, injected, or implanted hormonal method of contraception 
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4.5 
STUDY ASSESSMENTS 
All patients will be closely monitored for safety and tolerability during all cycles of therapy.  
Patients should be assessed for toxicity prior to each dose and dosing will occur only if 
the clinical assessment and local laboratory test values are acceptable.  Study treatment 
will be administered in 3-week (21-day) cycles (assuming there is no delay as a result of 
an adverse event). 
4.5.1 
Description of Study Assessments 
4.5.1.1 
Medical History and Demographic Data 
Medical history includes clinically-significant diseases, cancer history (including all prior 
cancer therapies and procedures), and all medications (e.g., prescription drugs, 
over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) 
that are used by the patient within 7 days prior to the screening visit. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.1.2 
Physical Examinations 
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Any abnormality that is 
identified at baseline should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
At subsequent visits (or as clinically indicated), patients will undergo a limited, 
symptom-driven physical examination that focuses on organ systems related to potential 
and ongoing adverse events and is based on the patient’s clinical course during study 
treatment, the patient’s medical history, and/or the known adverse event profiles of the 
study medications.  Changes from baseline abnormalities should be recorded in patient 
notes.  New or worsened clinically-significant abnormalities should be recorded as 
adverse events on the Adverse Event eCRF. 
4.5.1.3 
Vital Signs 
Vital signs will include measurements of temperature, respiratory rate, pulse rate, and 
systolic and diastolic blood pressures while the patient is in a seated position. 
4.5.1.4 
Tumor and Response Evaluations 
The baseline breast tumor must be > 2 cm in diameter for all patients.  Baseline tumor 
assessments will include a breast magnetic resonance imaging (MRI) scan and a clinical 
breast examination (CBE; including breast, axilla, and supraclavicular fossa).  If a 
patient has an allergy to an MRI contrast agent that cannot be managed with 
premedication per standard practice, then an ultrasound or molybdenum target 
mammography may be used.  Disease status should also be evaluated by additional 
conventional methods such as mammogram, ultrasound, computed tomography (CT) 
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absence of radioactive isotopes, an MRI scan (with gadolinium enhancement if required) 
or positron emission tomography (PET) scan is an acceptable form of assessment of the 
skeleton for the presence of bone metastases. 
Prior to neoadjuvant treatment, the tumor must be physically marked per standard local 
practice (e.g., skin tattoo or surgical clip) so that the appropriate excision can be made 
should the patient experience complete clinical regression of the tumor prior to surgery 
(see Appendix 7, Appendix 8, and Appendix 9). 
The axillary lymph nodes should be clinically evaluated at baseline in accordance with 
local practice and the findings should be recorded.  For patients with clinically and/or 
ultrasound-suspicious axillary nodes at baseline, axillary staging should include a 
fine-needle aspiration or core biopsy sample collection performed prior to neoadjuvant 
therapy. 
Surgical management options for axillary lymph nodes include SLNB sample collection 
prior to or after neoadjuvant treatment and ALND tissue collection of Level I and II 
lymphatics at the time of breast surgery.  The choice of the axillary procedure will be 
based on the clinical status of the axilla, T stage, and local practice. 
Patients will be evaluated by CBE during neoadjuvant treatment (Cycles 1−4) and a 
breast MRI scan and CBE will be repeated after completion of treatment in Cycle 4 
(i.e., prior to surgery).  In addition, disease status may be evaluated by additional 
conventional methods per local medical practice. 
Consistency of consecutive CBEs, MRI scans, CT scans, mammograms, or X-rays 
should be ensured during all assessments for each patient with the same technique 
used to evaluate the target lesion throughout the treatment period.  Tumor 
measurements should be made by the same investigator or radiologist for each patient 
during the study to the extent that this is feasible.  In case of clinically-measurable 
superficial (such as skin) lesions, repeated photographs should be used to document the 
tumor response.  These photographs must include a ruler for documentation purposes. 
If the lesion shows clear signs of progression per RECIST v1.1 (see Appendix 4), the 
patient should be removed from study treatment and provided with local 
standard-of-care treatment. 
Discovery of contralateral ductal carcinoma in situ during Cycles 1−4 will not be 
considered PD.  However, invasive contralateral breast carcinoma will be considered PD. 
4.5.1.5 
Laboratory Assessments 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• 
Hematology:  hemoglobin, hematocrit, platelet count, WBC count, and ANC 


 
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• 
Serum chemistry 
Baseline:  sodium, potassium, chloride, bicarbonate, calcium, magnesium, 
glucose, BUN or urea, creatinine, total protein, albumin, alkaline phosphatase, 
ALT, AST, gamma-glutamyl transferase, total bilirubin, and direct bilirubin 
Subsequent timepoints:  potassium, alkaline phosphatase, ALT, AST, total 
bilirubin, and direct bilirubin if total bilirubin is > ULN 
• 
Coagulation:  INR and aPTT 
• 
Pregnancy test 
Women of childbearing potential (including those who have had a tubal ligation) 
will have a serum pregnancy test performed within 7 days prior to 
randomization.  Urine pregnancy tests will be performed within 7 days prior to 
specified subsequent visits (see Appendix 1).  If a urine pregnancy test result is 
positive, it must be confirmed by a serum pregnancy test. 
• 
Urinalysis, which may be performed by dipstick (pH, specific gravity, glucose, protein, 
ketones, blood) and microscopic examination where applicable (e.g., if the 
urinalysis result is positive, then a microscopic examination should be performed; 
sediment, RBCs, WBCs, casts, crystals, epithelial cells, and bacteria) 
 
Samples for the following laboratory tests will be sent to one or several central 
laboratories or to Roche for analysis: 
• 
Mandatory tumor tissue sample obtained at screening for prospective central 
determination of HER2 status by IHC and ISH and exploratory biomarker research: 
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 or HER2 gene 
amplification (ratio of HER2 gene signals to centromere 17 signals ≥ 2.0) by 
ISH prior to randomization.  Paraffin-embedded tumor tissue block or a partial 
block must be obtained.  If sites are unable to send a tissue block because of 
local regulations, at least 15 unstained, freshly cut slides should be sent for 
HER2 testing and exploratory biomarker research (see below).  The slides 
should be cut from consecutive slices from the same block. 
Central laboratory confirmation of a positive HER2 status is required prior to 
randomization.  The outcome of this assessment will be communicated to the 
investigator. 
After completion of HER2 testing for eligibility criteria, patient samples may also 
be tested with other HER2 assays to establish performance characteristics of 
these assays for diagnostic development but if generated, these data will have 
no impact on the study eligibility of the patient.  Additional testing will not be 
performed on patients who failed screening. 
• 
Remaining tumor tissue sample obtained from enrolled patients at screening will 
be used for exploratory research on candidate biomarkers; such analyses may 
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PIK3CA mutation, PTEN, PD-L1, CD8, and other biomarkers that are relevant to 
breast cancer 
• 
Mandatory resection tissue specimen obtained at the time of surgery for 
determination of HER2 status and for assessment of exploratory biomarkers 
A paraffin-embedded resection tissue block or up to 15 unstained, freshly-cut 
slides should be sent.  The slides should be from consecutive slices from the 
same block. 
• 
Serum samples for analysis of ATAs to pertuzumab 
• 
Serum samples for exploratory research on candidate biomarkers; may include but 
will not be limited to the following:  HER ligands and HER2 ECD 
• 
Optional serum samples for analysis of pertuzumab pharmacokinetics, to be 
performed in a subset of approximately 50 patients in each treatment arm 
(see Section 4.5.1.6) 
The Informed Consent Form will contain a separate section that addresses 
optional collection of these samples. 
• 
Optional tumor tissue and/or serum sample collection at the time of disease 
progression or recurrence 
A paraffin-embedded disease progression or recurrence tumor tissue block or 
up to 15 unstained, freshly-cut slides should be sent.  The slides should be 
from consecutive slices from the same block. 
The Informed Consent Form will contain a separate section that addresses 
optional collection of these samples. 
• 
Optional whole blood samples for DNA extraction for clinical genotyping 
The Informed Consent Form will contain a separate section that addresses 
collection of these samples for the Biomarker Sample Repository. 
Data arising from clinical genotyping will be subject to the following 
confidentiality standards:  given the sensitive nature of genetic data, Roche has 
implemented additional processes to ensure patient confidentiality for 
specimens and associated data.  Upon receipt by the Biomarker Sample 
Repository, each specimen is "double-coded" by replacing the patient 
identification number with a new independent number.  Data generated from 
the use of these specimens and all clinical data transferred from the clinical 
database and considered relevant are also labeled with this same independent 
number.  A "linking key" between the patient identification number and this new 
independent number is stored in a secure database system.  Access to the 
linking key is restricted to authorized individuals and is monitored by audit trail.  
Legitimate operational reasons for accessing the linking key are documented in 
a standard operating procedure.  Access to the linking key for any other reason 
requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable. 
 


 
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For sampling procedures, storage conditions, and shipment instructions, see the Sample 
Handling and Logistics Manual. 
Samples listed above will be destroyed at the end of the study, with the following 
exceptions: 
• 
Tissue blocks that are submitted at baseline for eligibility screening and exploratory 
biomarker research will be returned in a batched manner to the sites after all 
patients have completed the neoadjuvant phase of the study.  All other tissue 
blocks that are submitted will be returned to the sites in batches at the latest 
5 years after the last patient in.  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. 
• 
Serum samples for analysis of ATAs to pertuzumab, exploratory research on 
candidate biomarkers, optional serum samples, and optional whole blood samples 
for DNA extraction will be destroyed no later than 5 years after the date of final 
closure of the clinical database. 
 
A patient's withdrawal from the study does not, by itself, constitute withdrawal of 
specimens collected under optional consent.  Likewise, a patient's withdrawal from 
optional sample collection does not constitute withdrawal from the study. 
Clinical responses will be assessed locally and not independently reviewed. 
4.5.1.6 
Pathologic Response Evaluation 
Pathologic response (tpCR and bpCR) will be assessed with use of tumor tissue 
resection specimens that are obtained during surgery.  All response evaluations will be 
assessed locally as outlined in Appendix 7, Appendix 8, and Appendix 9 and 
independently reviewed by an IRC in accordance with guidelines from a pathology 
manual that will be provided in a separate guidance document. 
Copies of the pathology report(s) from the patient's primary (main) surgery must be 
submitted to the Sponsor within 6 weeks after the date of surgery.  If additional 
information on lymph nodes at surgery is present in other reports, these should also be 
submitted to the Sponsor. 
4.5.1.7 
Diagnosis of Relapse or Recurrence 
Recurrent disease includes local, regional, and distant recurrence and contralateral 
breast cancer.  Wherever possible, maintain patients who are diagnosed with in situ 
breast disease or second (non-breast) malignancies in regular follow-up to fully capture 
any subsequent recurrent disease events.  In cases of diagnostic doubt (e.g., ill-defined, 
palpable mass in an irradiated breast), histologic or cytologic confirmation of recurrence 
should be obtained whenever possible. 


 
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Some patients may develop a suspicious recurrence that quickly leads to death without 
the possibility of confirming relapse of disease.  Efforts should be made to obtain an 
autopsy report for these patients. 
The earliest date of diagnosis of recurrent disease should be used and recorded.  This 
should be based on clinical, radiologic, histologic, or cytologic evidence.  The date of 
disease recurrence should be reported as the date of first diagnosis of a lesion (i.e., an 
objective finding) and not the date of the occurrence of the first symptom. 
Report all second primary malignancies whenever they occur during the study.  Patients 
who receive a diagnosis with a second primary malignancy that does not require 
systemic therapy (i.e., chemotherapy, hormonal therapy, targeted therapy, etc.) and with 
no evidence of breast cancer recurrence will remain in the study and should continue 
with the study drug treatment in accordance with the protocol and schedule of activities 
(see Appendix 1) if considered by the investigator to be in the patient’s best interest 
whenever possible. 
The following events are NOT considered recurrent disease but must be recorded: 
• 
Ipsilateral and contralateral lobular carcinoma in situ 
• 
Ipsilateral and contralateral ductal carcinoma in situ 
• 
Carcinoma in situ of the cervix 
• 
Basal or squamous cell carcinoma of the skin 
 
After recurrence, all patients should be followed for survival in accordance with the 
schedule of activities (see Appendix 1).  Related serious adverse events and non-breast 
second primary malignancies (reportable as serious adverse events) should also be 
reported until the end of the study. 
4.5.1.8 
Pharmacokinetic Assessments 
Blood samples for serial measurements of pertuzumab serum concentrations will be 
collected from a subset of 50 Chinese patients (50 will be capped through the IxRS 
system on a first come first serve basis) in accordance with the schedule of activities 
(see Appendix 1).  One 2-mL sample will be collected at each timepoint (see sampling 
schedule in Appendix 2).  The sampling timepoints will allow for an estimation of 
pertuzumab maximum concentration (Cmax) values in Cycles 1, 2, 4, 10, and 15 and 
estimation of minimum concentration (Cmin) values in Cycles 1, 2, 4, 10, and 15 at 
treatment completion or discontinuation (28 days after the last administration of study 
treatment and at 60−90 days after the last administration of study treatment). 
The date and actual start and end times of each pertuzumab infusion and the date and 
actual time of each sample collection should be recorded on the PK sampling form.  Any 
important information with regard to the sample or its collection (e.g., missed or late 
sample, hemolysis) should also be recorded. 


 
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4.5.1.9 
Anti-Therapeutic Antibody Assessments 
The sampling timepoints for the ATA assessment are prior to the first infusion on 
Day 1 of Cycles 4, 10, and 15 and at the treatment completion or discontinuation 
(28 days after last administration of study treatment and at 60−90 days after last 
administration of study treatment; see Appendix 3). 
4.5.1.10 
Cardiac Assessments 
Electrocardiograms 
Single 12-lead ECGs will be performed locally and assessed at the time of screening 
and otherwise as clinically indicated.  The investigator or designee must review, sign, 
and date all ECG tracings.  Paper copies will be kept as part of the patient's permanent 
study file at the site.  For ECG tracings that will fade over time (e.g., ECGs on thermal 
paper), lasting legible copies should be filed together with the original. 
Left Ventricular Ejection Fraction 
LVEF will be assessed by ECHO (preferred) or MUGA scan.  The same method should 
be used throughout the study for each patient and preferably performed and evaluated 
by the same assessor. 
4.5.1.11 
Assessments at Unplanned Visits 
Assessments at any unplanned visits should be performed as clinically indicated. 
4.5.2 
Timing of Study Assessments 
4.5.2.1 
Screening Assessments 
Written informed consent for participation in the study must be obtained before any 
study-specific screening tests or evaluations are performed.  Informed Consent Forms 
for enrolled patients and patients who are not subsequently enrolled will be maintained 
at the study site. 
Screening tests and evaluations will be performed within 28 days prior to enrollment, 
unless otherwise specified.  Local hematology and chemistry assessments that are 
scheduled for Cycle 1, Day 1 must be performed within 7 days prior to randomization. 
The following standard-of-care tests or examinations performed prior to obtaining 
informed consent and within 28 days prior to enrollment do not need to be repeated for 
screening:  bone scan (or MRI or PET scan), mammogram, ultrasound, breast MRI, 
chest X-ray, ECG, or ECHO or MUGA scan.  All screening evaluations must be 
completed and reviewed to confirm that patients meet all eligibility criteria before 
randomization.  The investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
See Appendix 1 for the Schedule of Activities to be performed during screening. 


 
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4.5.2.2 
Assessments during Treatment 
Scheduled study visits are based on a 3-week (21-day) cycle, with Cycle 1 beginning on 
Day 1.  With the exception of Cycle 1, Day 1, all assessments should be performed 
within 3 days of the scheduled visit unless otherwise specified.  Assessments that are 
scheduled on the day of study treatment administration should be performed prior to 
administration of the study treatment unless otherwise specified.  If the timing of a 
protocol-mandated procedure coincides with a holiday or weekend, it should be 
performed on the nearest following date. 
With the exception of Cycle 1, Day 1, local hematology and chemistry assessments 
scheduled for Day 1 of all cycles must be performed within 3 days prior to study 
treatment administration.  Results of local laboratory assessments must be reviewed and 
the review documented prior to study treatment administration. 
See Appendix 1 for the Schedule of Activities to be performed during the treatment 
period. 
4.5.2.3 
Assessments at Treatment Completion or Discontinuation Visit 
Patients may remain on the study treatment until disease progression (in the 
neoadjuvant setting) or disease recurrence (in the adjuvant setting) as assessed by the 
investigator, unacceptable toxicity, or completion of 17 cycles of HER2-targeted therapy.  
Patients who discontinue the study treatment will be asked to return to the clinic 
approximately 28 (± 7) days after administration of the last dose of study treatment for 
the treatment discontinuation visit. 
See Appendix 1 for the Schedule of Activities to be performed at the treatment 
completion or discontinuation visit. 
4.5.2.4 
Follow-Up Assessments 
After the treatment completion or discontinuation visit, adverse events should be 
followed as outlined in Sections 5.5 and 5.6. 
Patients will be followed for survival every 3 months (± 28 days) for the first year and 
then every 6 months (± 28 days) thereafter until disease progression or recurrence or 
until 5 years after randomization of the last patient, whichever occurs first. 
See Appendix 1 for the Schedule of Activities during the follow-up of patients. 
4.6 
PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
The investigator has the right to discontinue a patient from the study treatment or 
withdraw a patient from the study at any time.  In addition, patients have the right to 
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reason.  Reasons for discontinuation of study treatment or withdrawal from the study 
may include but are not limited to: 
• 
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 
 
4.6.1.1 
Discontinuation from Study Treatment 
Patients must discontinue study treatment if they withdraw consent or if they experience 
any of the following: 
• 
Pregnancy 
• 
Disease progression (in the neoadjuvant setting) or disease recurrence (in the 
adjuvant setting) 
• 
Symptomatic LVSD (heart failure) at any point during the study 
• 
Three intermittent dose delays as a result of an asymptomatic decrease in LVEF 
• 
Withhold treatment administration during the study for more than two cycles 
• 
Intercurrent, non−cancer-related illness that prevents continuation of protocol 
therapy or follow-up 
• 
Major protocol violation that may jeopardize the patient’s safety according to the 
Sponsor 
• 
Repeated patient non-compliance with protocol requirements 
• 
Changes in the patient’s condition or study treatment-related toxicity such that 
continued participation in the protocol would compromise the patient’s well-being, in 
the opinion of the investigator 
 
Patients who discontinue study treatment prematurely will be asked to return to the clinic 
for a treatment completion or discontinuation visit (see Section 4.5.2.3) and may 
undergo follow-up assessments (see Section 4.5.2.4).  The primary reason for 
premature study treatment discontinuation should be documented on the appropriate 
eCRF.  Patients who discontinue study treatment prematurely will not be replaced. 
4.6.1.2 
Withdrawal from the Study 
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.  Patients will not be followed for any reason after consent has been 
withdrawn.  Patients who withdraw from the study will not be replaced. 


 
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4.6.2 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for termination 
of the study may include but are not limited to: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the investigator if the study is placed on hold or if the Sponsor 
decides to discontinue the study or development program. 
The Sponsor has the right to replace a site at any time.  Reasons for the replacement of 
a site may include but are not limited to: 
• 
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 the study and all obligations 
have been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
5.1.1 
Management of Risks that are Associated with Pertuzumab and 
Trastuzumab 
Specific instructions for the management of infusion hypersensitivity reactions (including 
anaphylaxis), symptomatic LVSD or asymptomatic decreases in LVEF, and 
HER2-related toxicities are described below. 
5.1.1.1 
Infusion-Associated Reactions, 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 
very shortly after an infusion. 
In general (and in common with other antibody-associated infusion reactions), 
pertuzumab and trastuzumab 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 trastuzumab therapy—the incidence and severity of such reactions are 
similar regardless of prior or concurrent treatment with trastuzumab. 
The administration of pertuzumab and trastuzumab should be performed in a setting with 
emergency equipment and staff who are trained to monitor medical situations and 


 
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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 30 minutes after the first and each subsequent trastuzumab 
infusion.  If the pertuzumab infusion is well tolerated during Cycle 1, the observation time 
can be decreased to 30 minutes for subsequent infusions. 
Infusion of pertuzumab or trastuzumab should be slowed or interrupted if the patient 
experiences infusion-associated symptoms (e.g., fever, chills, headache, fatigue, 
pruritus, nausea, vomiting, and diarrhea).  Supportive care with oxygen, β-agonists, 
antihistamines, antipyretics, and corticosteroids may help alleviate symptoms.  All 
infusion-associated symptoms must be resolved before pertuzumab is administered.  
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 the potential exists for a delayed onset of 
infusion-associated reactions, patients should be instructed to contact the treating 
physician with any concerns. 
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 trastuzumab, because 
each of these antibodies is directed at the HER2 receptor.  A decrease in LVEF has 
been observed in patients who receive pertuzumab; however, the majority of patients 
show improvement or return to baseline function during follow-up (see Section 1.2.2.2). 
All patients will undergo regular LVEF monitoring by ECHO or MUGA.  Monitoring of 
LVEF is required while patients receive pertuzumab or placebo and trastuzumab as well 
as after treatment completion as per the Schedule of Activities (see Appendix 1). 
If symptomatic LVSD symptoms develop, the patient must discontinue all study 
treatment.  Symptomatic LVSD (heart failure) should be treated and monitored in 
accordance with standard medical practice.  These patients should be evaluated by a 
certified cardiologist and the results of this evaluation should be reported on the eCRF. 
If there is a significant asymptomatic decline in LVEF (LVEF decrease of 
≥ 10 percentage points from baseline to an LVEF value of < 50%), the patient must 
discontinue all study treatment.  Figure 2 summarizes the management of study 
treatment for patients who have an asymptomatic decrease in LVEF.  The decision to 
continue or stop the 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 the Continuation or Discontinuation of Study 
Treatment on the Basis of Asymptomatic Decline in LVEF 
 
LVEF = left ventricular ejection fraction. 
Note:  Treatment refers to trastuzumab, pertuzumab or placebo, and (for neoadjuvant therapy) 
docetaxel. 
 
5.1.1.3 
Epidermal Growth Factor Receptor−Related Toxicities 
Although pertuzumab targets HER2, because of its role in heterodimerization with other 
members of the HER family (e.g., epidermal growth factor receptor [EGFR]), it may 
cause toxicities that are associated with the use of EGFR tyrosine kinase inhibitors.  
Diarrhea has been observed in approximately 60% of patients who were treated with 
pertuzumab in Phase II single-agent studies (up to 90% of patients who received 
pertuzumab in combination studies) and was reported as a Grade 1 or 2 in the majority 
of cases.  For patients who experience diarrhea, early intervention with loperamide 
should be recommended and hydration considered. 
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 who received pertuzumab in Phase II 
single-agent studies (up to 40% of patients who received pertuzumab in combination 
studies) and was generally reported as Grade 1 or 2 in severity. 


 
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5.1.2 
Dosage Modification and Treatment Interruption or 
Discontinuation 
5.1.2.1 
Trastuzumab, Pertuzumab or Placebo, and Docetaxel 
Docetaxel dosage modifications should be managed as per local practice.  A stepwise 
dose reduction from 75 to 60 mg/m2 is permitted.  If a further reduction is required, the 
patient will be withdrawn from all study treatment and treated at the discretion of the 
investigator as clinically indicated.  Once a dose reduction has occurred, the patient’s 
dose should not be re-escalated to a higher one.  Docetaxel dose delays will be allowed 
for myelosuppression, hepatic dysfunction, and other dose-limiting toxicities.  If 
docetaxel must be delayed for a day or more, all study treatments should be delayed for 
the same time frame.  If docetaxel is held for more than two cycles or needs to be 
permanently discontinued, the patient will be withdrawn from all study treatment. 
Dosage modifications are not permitted for trastuzumab or pertuzumab.  Actions to be 
taken for toxicities that are related to treatment with trastuzumab or pertuzumab are 
outlined in Table 1.  If trastuzumab or pertuzumab/placebo must be delayed for a day or 
more, all study treatments should be delayed for the same time frame; thus, delays 
provided in Table 1 also apply to docetaxel. 
Table 1 
Actions to be Taken for Toxicities Related to Study Treatment 
Toxicity 
Action 
Neutropenia 
Withhold all study treatment for up to 6 weeks.  If 
recovery to ANC ≥ 1000 cells/μL occurs within 6 weeks, 
resume all treatment.  If recovery to ANC 
≥ 1000 cells/μL does not occur within 6 weeks, 
discontinue all treatment. 
Symptomatic LVSD (heart failure) 
Discontinue all study treatment. 
Asymptomatic decrease in LVEF 
Follow instructions for withholding, 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 
Withhold 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. 


 
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Table 1 
Actions to be Taken for Toxicities Related to Study Treatment 
(cont.) 
Toxicity 
Action 
Recurrence of other 
non-hematologic toxicities a upon 
rechallenge:  Grade 3 or 4 
Discontinue all study treatment. 
LVEF = left ventricular ejection fraction; LVSD = left ventricular systolic dysfunction; 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Notes:  Severity grades for all events are based on NCI CTCAE v4.0, with the exception of 
symptomatic LVSD, which should be graded according to NCI CTCAE v4.0 for “heart failure” 
(Grade 2, 3, 4, or 5) and the New York Heart Association classification (see Appendix 6).  
Study treatment refers to trastuzumab, pertuzumab/placebo, and (for neoadjuvant therapy) 
docetaxel. 
a Includes non-hematologic toxicities not described above (e.g., cardiac toxicities other than 
symptomatic LVSD or asymptomatic decline in LVEF). 
 
5.1.2.2 
5-Fluorouracil, Epirubicin, and Cyclophosphamide 
Chemotherapy 
Dosage modification and treatment interruption or discontinuation are permitted for FEC 
chemotherapy as indicated in the relevant local label for each agent and will be 
managed in accordance with local practice. 
5.1.3 
Pregnancy and Contraception 
Women who are not postmenopausal (< 12 months of amenorrhea) or surgically sterile 
(absence of ovaries and/or uterus) must agree to use one highly effective form of 
non-hormonal contraception or two effective forms of non-hormonal contraception while 
administered the study treatment and for 7 months after the last dose of study treatment.  
Men who participate in the study must agree to use reliable and effective contraceptive 
measures while administered the study treatment and for 7 months after the last dose of 
the study treatment.  Male study participants whose partners are pregnant should use 
condoms for the duration of the pregnancy. 
Methods of birth control that result in a low failure rate (i.e., < 1% per year) when used 
consistently and correctly are considered highly effective forms of contraception.  The 
following non-hormonal methods of contraception are acceptable: 
• 
True abstinence when this is in line with the preferred and usual lifestyle of the 
patient; periodic abstinence (e.g., calendar, ovulation, symptothermal postovulation 
methods) and withdrawal are not acceptable methods of contraception 
• 
Tubal ligation 
• 
Male sterilization (with appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate); for female patients, the vasectomized male partner should 
be the sole partner 
 


 
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Alternatively, two of the following effective forms of contraception may be used instead: 
• 
Placement of non-hormonal intrauterine device or intrauterine system; consideration 
should be given to the type of device being used, as there are higher failure rates 
quoted for certain types (e.g., steel or copper wire) 
• 
Condom with spermicidal foam, gel, film, cream, or suppository 
• 
Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam, gel, film, 
cream, or suppository 
 
The use of barrier contraceptives should always be supplemented with the use of a 
spermicide.  The following should be noted: 
• 
Failure rates indicate that, when used alone, the diaphragm and condom are not 
highly effective forms of contraception.  Therefore, the use of additional spermicides 
does confer additional theoretical contraceptive protection.  However, spermicides 
alone are ineffective to prevent pregnancy when the whole ejaculate is spilled.  
Therefore, spermicides are not a barrier method of contraception and should not be 
used alone. 
 
It should be noted that two forms of effective contraception are required.  
A double-barrier method is acceptable, which is defined as condom and occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam, gel, film, cream, or suppository. 
5.1.4 
Breastfeeding 
It is not known whether trastuzumab or pertuzumab is excreted in human milk.  As 
maternal IgG is excreted in milk and either monoclonal antibody could harm infant 
growth and development, women should be advised to discontinue nursing during 
pertuzumab or trastuzumab therapy and not breastfeed for at least 7 months after the 
last dose of either monoclonal antibody.  Therefore, during the FEC portion of treatment 
(in absence of the antibodies), patients should also not breastfeed during this time 
period. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest; 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. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject who is administered a 


 
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pharmaceutical product regardless of the causal attribution.  Therefore, an adverse 
event can 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 5.3.5.9 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory test result 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 the study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to the assignment of the study treatment (e.g., invasive screening 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10) 
• 
Results in persistent or significant disability or incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• 
Is a congenital anomaly or birth defect in a neonate or infant born to a mother who is 
exposed to the study drug 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical and/or surgical intervention to prevent one of the 
outcomes listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe, or in accordance with 
NCI CTCAE v4.0; see Section 5.3.3); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
that is recorded on the eCRF. 


 
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The investigator must report serious adverse events to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2 for reporting 
instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest must be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).  Adverse events of special interest for this study include: 
• 
Cases of an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined in Section 5.3.5.6 
• 
Suspected transmission of an infectious agent by the study drug as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient who is exposed to a medicinal product.  This term applies 
only when a contamination of the study drug is suspected. 
• 
Asymptomatic decline in LVEF requiring treatment or leading to discontinuation of 
pertuzumab or placebo and trastuzumab 
 
5.3 
METHODS AND TIMING TO CAPTURE AND ASSESS 
SAFETY PARAMETERS 
The investigator is responsible to ensure that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with the instructions provided in this section and Sections 5.4, 5.5, and 5.6. 
For each adverse event that is recorded on the Adverse Event eCRF, the investigator 
will make an assessment of seriousness (see Section 5.2.2 for seriousness criteria), 
severity (see Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of the study drug, 
only serious adverse events that are caused by a protocol-mandated intervention should 
be reported (e.g., serious adverse events related to invasive procedures such as 
biopsies). 
After initiation of the study drug, all adverse events regardless of the relationship to 
the study drug will be reported until 28 days after administration of the last dose of the 


 
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study drug.  After this period, investigators should report any serious adverse events or 
other adverse events of concern that are believed to be related to prior treatment with 
study drug (see Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted to elicit 
adverse event information during all patient evaluation timepoints.  Examples of 
non-directive questions include: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE v4.0 will be used to assess 
adverse event severity.  Use Table 2 to assess the severity for adverse events that are 
not specifically listed in the NCI CTCAE. 
Table 2 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; or limiting self-care activities of 
daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  based on the NCI CTCAE (v4.0), which can be found at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
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 one's 
self, 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 


 
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adverse event is considered 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 (where 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 who receive combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures to Record Adverse Events 
Investigators should use correct medical terminology and concepts when recording 
adverse events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis with a start date that corresponds to the start date 
of the first symptom of the eventual diagnosis. 
Infusion-Associated Reactions 
Adverse events that occur during or on the same day as study drug infusion should be 
captured as a diagnosis of allergic reaction or infusion reaction rather than as individual 
signs and symptoms. 
5.3.5.2 
Adverse Events that Occur Secondary to Other Events 
In general, adverse events that occur 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 adverse events that 


 
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occur 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. 
• 
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 adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear whether the events are associated. 
5.3.5.3 
Persistent, Intermittent, or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity of the event should be recorded and the 
severity should be updated to reflect the most extreme severity any time the event 
worsens.  If the event becomes serious, it should be recorded as a new event on the 
Adverse Event eCRF.  The date that the event became serious should be recorded as 
the resolution date for the initial non-serious event and as the onset date for the new 
serious adverse event. 
An intermittent adverse event is one that starts, stops, and then restarts within a 28-day 
time window.  Such events should be recorded as one event. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Test Values 
Not every laboratory test result abnormality qualifies as an adverse event.  A laboratory 
test result must be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 


 
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• 
Is clinically significant in the investigator’s judgment 
Note:  For oncology studies, certain abnormal values may not qualify as 
adverse events. 
 
It is the investigator’s responsibility to review all laboratory test result findings.  Medical 
and scientific judgment should be exercised in deciding whether an isolated laboratory 
test result abnormality should be classified as an adverse event. 
If a clinically significant laboratory test result abnormality is a sign of a disease or 
syndrome (e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholecystitis), 
only the diagnosis (i.e., cholecystitis) should be recorded on the Adverse Event eCRF. 
If a clinically–significant laboratory test result abnormality is not a sign of a disease or 
syndrome, the abnormality itself should be recorded on the Adverse Event eCRF along 
with a descriptor that indicates if the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory test 
result abnormality can be characterized by a precise clinical term per standard 
definitions, the clinical term should be recorded as the adverse event.  For example, an 
elevated serum potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically-significant laboratory test result 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. 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
 
The investigator is responsible to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 


 
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Observations of the same clinically-significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
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 an indicator of severe liver injury.  Therefore, 
investigators must report as an adverse event the occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory test values should be recorded on the Adverse Event eCRF 
(see Section 5.3.5.1) and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event) either as a serious adverse event or an adverse 
event of special interest (see Section 5.4.2). 
5.3.5.7 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to the progression of breast cancer should be recorded on the 
Study Completion/Early Discontinuation eCRF.  All other deaths that occur during the 
study, regardless of the relationship to the 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.  The term "sudden death" should only be used for the occurrence of an 
abrupt and unexpected death as a result of presumed cardiac causes in a patient with or 
without preexisting heart disease within 1 hour of the onset of acute symptoms or, in the 
case of an unwitnessed death, within 24 hours after the patient was last seen alive and 
stable.  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. 
During the survival follow-up, deaths that are attributed to the progression of breast 
cancer should be recorded on the Study Completion/Early Discontinuation eCRF as well 
as on the Survival eCRF.  


 
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5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., ”more frequent headaches"). 
5.3.5.9 
Lack of Efficacy or Worsening of Breast Cancer 
Events that are clearly consistent with the expected pattern of progression or recurrence 
of the underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression with the use of objective criteria.  If there is any 
uncertainty as to whether an event is the result of disease progression, it should be 
reported as an adverse event. 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Section 5.2.2), except as outlined below. 
The following hospitalization scenarios are not considered serious adverse events: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration) 
• 
Hospitalization for a 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 adverse event 
• 
Hospitalization due solely to the progression of the underlying cancer 
 
5.3.5.11 
Overdoses 
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied.  An overdose or incorrect administration of study drug is not 
an adverse event unless it results in untoward medical effects. 


 
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Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF.  
All adverse events associated with an overdose or incorrect administration of the study 
drug should be recorded on the Adverse Event eCRF.  If the associated adverse event 
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). 
5.3.5.12 
Symptomatic Left Ventricular Systolic Dysfunction and 
Asymptomatic Decrease in Left Ventricular Ejection Fraction 
Symptomatic LVSD (heart failure) should be reported as a serious adverse event.  If the 
diagnosis is symptomatic LVSD, it should be reported as such and not as individual 
signs and symptoms thereof.  Symptomatic LVSD should be graded in accordance with 
the NCI CTCAE v4.0 for "heart failure" (Grade 2, 3, 4, or 5) and the New York Heart 
Association (NYHA) classification (see Appendix 6).  "Left ventricular systolic 
dysfunction" should not be used to describe symptomatic dysfunction as per the 
NCI CTCAE v4.0. 
Symptomatic LVSD that occurs during the study must be reported irrespective of the 
causal relationship and followed until one of the following occurs:  resolution or 
improvement to baseline status, no further improvement can be expected, or death. 
Asymptomatic decrease in LVEF should not be reported as an adverse event since 
LVEF data are collected separately on the eCRF.  Exceptions to this rule are as follows: 
• 
Asymptomatic decrease in LVEF of ≥ 10 percentage points from baseline to an 
LVEF of < 50% must be reported as an adverse event with the term of "ejection 
fraction decreased" as per the NCI CTCAE v4.0. 
• 
Asymptomatic decrease in LVEF that requires treatment or leads to a 
discontinuation of pertuzumab or placebo and trastuzumab must also be reported as 
an adverse event on the eCRF. 
 
Table 3 summarizes the reporting conventions for asymptomatic decrease in LVEF or 
symptomatic LVSD. 


 
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Table 3 
Reporting Conventions for Asymptomatic Decrease in LVEF or 
Symptomatic LVSD 
Observation 
How to Report 
Term to be 
Reported 
Grading 
Asymptomatic decrease in 
LVEF of < 10 percentage 
points from baseline or to 
an LVEF ≥ 50% 
No additional reporting 
required; LVEF results to be 
reported on eCRF 
NA 
NA 
Asymptomatic decrease in 
LVEF of ≥ 10 percentage 
points from baseline to an 
LVEF < 50% 
AE a (eCRF AE eForm) 
"Ejection fraction 
decreased" a 
NCI CTCAE for 
"ejection fraction 
decreased" 
Asymptomatic decrease in 
LVEF requiring treatment or 
leading to discontinuation 
of pertuzumab/placebo and 
trastuzumab 
AE (eCRF AE eForm) and 
Complete SAE form and 
indicate as AESI with 
expedited reporting (see 
Section 5.4.2) 
"Ejection fraction 
decreased" a 
NCI CTCAE for 
"ejection fraction 
decreased" 
Symptomatic LVSD 
(congestive heart failure) 
AE (eCRF AE eForm) and 
SAE (SAE form) with 
expedited reporting (see 
Section 5.4.2) 
"Heart failure" 
NCI CTCAE for "heart 
failure" and NYHA 
class  
AE = adverse event; AESI = adverse event of special interest; eForm = electronic form; eCRF = electronic 
Case Report Form; LVEF = left ventricular ejection fraction; LVSD = left ventricular systolic dysfunction; 
NA = not applicable; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse 
Events; NYHA = New York Heart Association; SAE = serious adverse event. 
Note:  Any symptomatic LVSD event must be reported as "heart failure." 
a Report the status as asymptomatic and provide the LVEF value in the comments field as appropriate.
 
Refer to the algorithm (see Figure 2) when deciding whether to initiate, continue, or 
discontinue anti-HER2 study treatment on the basis of LVEF assessment in 
asymptomatic patients. 
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 study.  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 (see Section 5.4.2 for further details) 
• 
Adverse events of special interest (see Section 5.4.2 for further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 


 
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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 with the inclusion of recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority, Institutional Review Board (IRB), and Ethics 
Committee (EC). 
5.4.1 
Emergency Medical Contacts 
Medical Monitor (Roche Medical Responsible) Contact Information 
Primary Contact 
Medical Monitor: 
, M.D. 
Telephone No.: 
 
Mobile Telephone No.: 
 
Secondary Contact 
Medical Monitor: 
, M.D., Ph.D. 
Telephone No.: 
 
Mobile Telephone No.: 
 
 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
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 
Adverse Events of Special Interest 
5.4.2.1 
Events that Occur prior to Initiation of Study Drug 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events that are caused by a protocol-mandated intervention should be 
reported.  A paper Serious Adverse Event/Adverse Event of Special Interest CRF and 
Fax Coversheet 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) with 
use of the fax numbers provided to investigators (see "Protocol Administrative and 


 
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Contact Information & List of Investigators").  Patients who undergo screening 
procedures but do not enroll in the study will only have serious adverse events recorded 
in the Roche Drug Safety database and not in the study’s clinical database. 
5.4.2.2 
Events that Occur after Initiation of Study Drug 
After initiation of the study drug, serious adverse events and adverse events of special 
interest will be reported until study completion.  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 Serious Adverse 
Event/Adverse Event of Special Interest CRF and Fax Coversheet 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) with use of 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 after study completion are 
provided in Section 5.6. 
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 Clinical Trial Pregnancy Reporting Form should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the pregnancy), either by faxing or by scanning and emailing the form 
using the fax number or email address provided to investigators.  Pregnancy should not 
be recorded on the Adverse Event eCRF.  The investigator should discontinue study 
drug and counsel the patient, discussing the risks of the pregnancy and the possible 
effects on the fetus.  Monitoring of the patient should continue until conclusion of the 
pregnancy.  Any serious adverse events associated with the pregnancy (e.g., an event in 
the fetus, an event in the mother during or after the pregnancy, or a congenital anomaly 
and/or birth defect in the child) should be reported on the Adverse Event eCRF.  
Additional information on any pertuzumab-exposed pregnancy and infant will be 
requested by Roche Drug Safety at specific timepoints (end of the second trimester, 
2 weeks after the expected date of delivery, and at 3, 6, and 12 months after the 
infant’s birth). 
In the event that the EDC system is unavailable, a Pregnancy Report worksheet and 
Pregnancy Fax Coversheet should be completed and faxed to Roche Safety Risk 


 
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Management or its designee immediately (i.e., no more than 24 hours after learning of 
the pregnancy) with use of the fax numbers provided to investigators (see "Protocol 
Administrative and Contact Information & List of Investigators"). 
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 serious adverse event (as the Sponsor considers 
abortions to be medically significant events), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). 
5.4.3.4 
Congenital Anomalies and/or Birth Defects 
Any congenital anomaly and/or birth defect in a child that is born to a female patient or a 
female partner of a male patient who is exposed to the study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events that are considered related to the study drug or 
study-related procedures until a final outcome can be reported. 


 
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During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
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 that are reported during the study should be followed until the pregnancy 
outcome (see Section 5.4.3).  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 serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) to perform an 
independent medical assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
Upon completion of the study, the investigator should instruct each patient to report to 
the investigator any subsequent adverse events that the patient’s personal physician 
believes could be related to prior study drug treatment or study procedures. 
The investigator should notify the Sponsor of any serious adverse event or other 
adverse event of concern that occurs at any time after a patient has discontinued study 
participation if the event is believed to be related to prior study drug treatment or study 
procedures.  The Sponsor should also be notified if the investigator becomes aware of 
the development of cancer or a congenital anomaly and/or birth defect in a 
subsequently-conceived offspring of a patient who participated in this study. 
The investigator should report these events to Roche Safety Risk Management on the 
Adverse Event eCRF.  If the Adverse Event eCRF is no longer available, the investigator 
should report the event directly to Roche Safety Risk Management via telephone 
(see "Protocol Administrative and Contact Information & List of Investigators"). 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 


 
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To determine the reporting requirements for single adverse event cases, the Sponsor 
will assess the expectedness of these events with use of the following reference 
documents: 
• 
Pertuzumab Investigator's Brochure 
• 
Local prescribing information for trastuzumab 
 
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 to upgrade by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
6.1 
DETERMINATION OF SAMPLE SIZE 
A total of 328 patients will be randomized into the study in a ratio of 2:1 to pertuzumab 
(Arm A) or placebo (Arm B), respectively.  This will provide 85% power to detect an 
absolute increase in tpCR rate of 15% in the pertuzumab arm compared with the 
placebo arm at a two-sided significance level of 5%, assuming the tpCR rate is 20% in 
the placebo arm. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Patient enrollment, duration of the follow-up, discontinuation from the study, and the 
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 
Demographic and baseline characteristics such as age, weight, ECOG Performance 
Status, ER and PgR status, HER2 status, and history of breast cancer will be 
summarized by treatment arm. 
Descriptive statistics (mean, median, SD, 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 ITT principle, with patients grouped by the treatment assigned at the time of 
randomization.  For DFS, only patients who undergo surgery will be included in the 
analysis.  For clinical response rates, only patients with measurable disease at baseline 
will be included in the analysis. 


 
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6.4.1 
Primary Efficacy Endpoint 
The primary efficacy outcome measure is tpCR, defined as the absence of any residual 
invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen 
and all sampled ipsilateral lymph nodes after completion of neoadjuvant therapy and 
surgery (i.e., ypT0/is, ypN0 in accordance with the current AJCC staging system) as 
assessed by the IRC.  The primary analysis will be performed when all patients who 
are eligible for surgery have completed their surgical treatment with an assessment of 
pathological response.  The analysis will be based on the ITT population with patients 
grouped by the treatment assigned at the time of randomization.  In the ITT population, 
patients whose tpCR assessment is missing or invalid are counted as not achieving 
tpCR. 
The tpCR rate as assessed by the IRC will be summarized for each treatment arm and 
95% CIs will be calculated with the Clopper-Pearson method.  The two-sided 
Cochran-Mantel-Haenszel test, stratified by disease category (early-stage or locally 
advanced) and hormone receptor status (positive for ER and/or PgR or negative for both) 
will be used to compare the tpCR rate between the two treatment arms.  An unadjusted 
Fisher exact test result will also be provided.  Finally, the difference in tpCR rate and 
associated 95% CIs will be provided with use of the Hauck-Anderson method. 
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy outcome measures in this study are tpCR as assessed by the 
local pathologist, bpCR as assessed by the IRC, bpCR as assessed by the local 
pathologist, clinical response, EFS, DFS, and overall survival. 
6.4.2.1 
Total Pathologic Complete Response Rate as Assessed by the 
Local Pathologist 
tpCR rate as assessed by the local pathologist will be evaluated with methods that are 
similar to those described for the primary efficacy endpoint. 
6.4.2.2 
Breast Pathologic Complete Response Rate as Assessed by 
the Independent Review Committee 
bpCR is defined as the absence of any residual invasive cancer on the hematoxylin and 
eosin evaluation of the resected breast specimen after completion of neoadjuvant 
therapy and surgery (i.e., ypT0/is in accordance with the current AJCC staging system).  
bpCR rate as assessed by the IRC will be evaluated with use of methods that are similar 
to those described for the primary efficacy endpoint. 
6.4.2.3 
Breast Pathologic Complete Response Rate as Assessed by 
the Local Pathologist 
bpCR rate as assessed by the local pathologist will be evaluated with methods that are 
similar to those described for the primary efficacy endpoint. 


 
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6.4.2.4 
Response Rates 
Clinical response rates that include the proportions of patients with a CR, PR, stable 
disease, or PD will be determined by the investigator during Cycles 1−4 (i.e., prior to 
surgery) on the basis of RECIST v1.1.  ORR is defined as the proportion of patients who 
achieve a CR or PR as the best tumor response during the neoadjuvant period.  No 
confirmation is required for objective response.  Only patients with measurable disease 
at baseline will be included in the analysis.  The methods for data analysis are similar to 
those described for the primary efficacy endpoint. 
6.4.2.5 
Event-Free Survival 
EFS is defined as the time from randomization to the first documentation of one of the 
following events: 
• 
Disease progression (before surgery) as determined by the investigator with use of 
RECIST v1.1 
Any evidence of contralateral disease in situ will not be identified as PD. 
• 
Disease recurrence (local, regional, distant, or contralateral) after surgery 
• 
Death from any cause 
 
Patients who have not had an event at the time of the analysis will be censored as of the 
date they were last known to be alive and event free. 
The two-sided log-rank test, stratified by disease category (early-stage or locally 
advanced) and hormone-receptor status (positive for ER and/or PgR or negative for both) 
will be used to make an exploratory comparison of EFS between the two treatment arms.  
The Kaplan-Meier approach will be used to estimate 3-year EFS rates for each 
treatment arm.  The stratified Cox proportional hazards model will be used to estimate 
the HR between the two treatment arms (i.e., the magnitude of treatment effect) and its 
95% CI. 
6.4.2.6 
Disease-Free Survival 
DFS is defined as the time from the first date of no disease (i.e., date of surgery) to the 
first documentation of one of the following events: 
• 
Disease recurrence (local, regional, distant, or contralateral) after surgery 
Any evidence of contralateral disease in situ will not be identified as disease 
recurrence. 
• 
Death from any cause 
 
Only patients who undergo surgery will be included in the analysis.  It is assumed that all 
patients who undergo surgery are disease free and; hence, patients are known to be 
disease free if they have undergone surgery and no recurrence of disease is reported 
thereafter.  Data from patients who have not had an event at the time of the analysis will 
be censored as of the date they were last known to be alive and event free.  The 


 
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methods for data analysis are similar to those described for EFS.  Note that the analysis 
for DFS is exploratory because of the non-randomized patient population. 
6.4.2.7 
Overall Survival 
Overall survival is defined as the time from randomization to death from any cause.  
Data from patients who are alive at the time of the analysis will be censored as of the 
last date they were known to be alive.  The methods for data analysis are similar to 
those described for EFS. 
6.5 
SAFETY ANALYSES 
Safety analyses will be performed on the safety analysis population, which will consist of 
all patients who received at least one dose of study drugs and patients will be grouped 
by the treatment they actually received.  The safety analyses will be performed at the 
same time as the primary efficacy analysis, the final analyses, and when all patients 
have completed the treatment completion or study discontinuation visit. 
6.5.1 
Study Drug Exposure 
The numbers of patients who experience any dose interruption (including dose delays), 
dose modification, and 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 
Safety will be assessed through summaries of adverse events, serious adverse events, 
deaths, and Grade 3 or 4 adverse events.  Verbatim descriptions of adverse events will 
be mapped to MedDRA thesaurus terms.  All adverse events that occur on or after the 
date of the first study drug administration will be summarized by mapped term, 
appropriate thesaurus levels, and toxicity grade based on NCI CTCAE v4.0. 
Deaths that are reported during the study treatment period and those reported during the 
follow-up (after treatment discontinuation) will be summarized by treatment arm. 
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 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. 


 
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6.5.4 
Laboratory Data 
Clinical laboratory tests will be performed at local laboratories.  Changes in laboratory 
data will be summarized by grade with use of the NCI CTCAE v4.0 for each treatment 
arm.  Changes from baseline will be presented in shift tables for selected laboratory test 
result assessments. 
6.6 
EXPLORATORY ANALYSES 
6.6.1 
Exploratory Pharmacokinetic Analyses 
Observed Cmax and Cmin values will be summarized for pertuzumab at each specified 
sampling timepoint.  Descriptive statistics will include mean, median, SD, CI, and range 
of values as appropriate. 
Graphical plots and comparisons of the descriptive statistics will be made between 
observed serum pertuzumab concentrations in this study and observed serum 
pertuzumab concentrations in studies that are not conducted in China. 
Graphical plots and comparisons of the descriptive statistics will be made between 
observed serum pertuzumab concentrations in the neoadjuvant and adjuvant phase in 
this study.  Additionally, observed serum pertuzumab concentrations in this study will 
also be compared with the observed serum pertuzumab concentrations in the adjuvant 
phase of the PK substudy in Chinese patients from Study BIG 4-11/BO25126/TOC4939g. 
In addition, exploratory analyses will be performed to assess any correlation between 
HER2 ECD and the pharmacokinetics of pertuzumab. 
6.6.2 
Sensitivity and Subgroup Analyses 
Sensitivity analyses will be performed for tpCR rate to ascertain whether the magnitude 
of the effectiveness of the addition of pertuzumab might differ by patient subgroups. 
Variables to be considered to define subgroups of interest include stratification factors as 
well as other disease- or patient-related prognostic or predictive factors.  The following 
factors will be examined in preplanned subgroup analyses: 
• 
Menopausal status at randomization  
• 
Tumor size 
• 
Lymph nodes 
• 
Histological grade 
• 
Disease category 
• 
Hormone receptor status (ER, PgR) 
 
Additional factors may also be considered. 


 
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6.6.3 
Biomarker Analyses 
The correlation between baseline molecular biomarkers and efficacy outcomes will be 
evaluated.  Biomarkers may include but are not limited to the status of HER receptors, 
HER ligands, HER2 ECD, and other biomarkers that are relevant for the HER family 
pathway.  Special emphasis will be placed on biomarkers that have shown an 
association with clinical outcome in patients who were treated with pertuzumab in 
previous studies.  Efficacy outcomes that are considered for this analysis may include 
tpCR, EFS, and DFS. 
If possible, biomarker levels at baseline will be compared with biomarker levels in 
samples that are collected at the time of surgery from patients with residual disease. 
6.6.4 
Anti-Therapeutic Antibody Analyses 
To determine whether ATAs to pertuzumab are formed as a result of the administration 
of study treatment, serum samples will be collected to test for the presence of ATAs to 
pertuzumab from all randomized patients at screening and after treatment. 
The impact of ATAs to pertuzumab on pharmacokinetics, safety, and efficacy will be 
further explored in this study. 
6.7 
INTERIM ANALYSES 
There is no interim analysis planned for the primary efficacy outcome measure tpCR.  
EFS and DFS data will be summarized descriptively at the time of the primary efficacy 
analysis.  Note that a final analysis of EFS, DFS, and overall survival will be performed 
at the end of the study approximately 5 years after randomization of the last patient. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for the data management of this study with inclusion of 
quality checking of the data.  Data that are entered manually will be collected via EDC 
with the use of eCRFs.  Sites will be responsible for data entry into the EDC system.  In 
the event of discrepant data, the Sponsor will request data clarification from the sites, 
which the sites will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor with use of 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. 


 
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7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) that are entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include but are not limited to hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical study. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data that 
are 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 with direct access to applicable source documents and reports for study-related 
monitoring, Sponsor audits, and IRB and/or 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 an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 


 
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electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements with regard to computerized systems that 
are used in clinical research.  An acceptable computerized data collection system allows 
for the 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 that pertain 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). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or 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 and/or EC 
submission.  The final IRB- and/or EC-approved consent forms must be provided to the 
Sponsor for health authority submission purposes in accordance with local requirements. 
The Informed Consent Form will contain a separate section that addresses the use of 
the 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.  


 
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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 will 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 and/or EC-approved consent forms must be 
provided to the Sponsor for health authority submission purposes. 
Patients must re-consent to the most current version of the consent forms (or to a 
significant new information and/or findings addendum in accordance with applicable laws 
and IRB and/or EC policy) during their participation in the study.  For any updated or 
revised consent forms, the case history or clinical records for each patient will document 
the informed consent process and that written informed consent was obtained with use 
of the updated and/or 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. 
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 and/or EC by the 
Principal Investigator and reviewed and approved by the IRB and/or EC before the study 
is initiated.  In addition, any patient recruitment materials must be approved by the IRB 
and/or EC. 
The Principal Investigator is responsible to provide written summaries of the status of the 
study to the IRB and/or EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB and/or EC.  Investigators 
are also responsible to promptly inform the IRB and/or EC of any protocol amendments 
(see Section 9.6). 
In addition to the requirements to report all adverse events to the Sponsor, investigators 
must comply with the requirements to report serious adverse events to the local health 
authority, IRB, and EC.  Investigators are responsible to ensure that such reports are 
reviewed and processed in accordance with health authority requirements and the 


 
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policies and procedures established by their IRB and/or 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 datasets that are transmitted to any Sponsor location. 
Patient medical information that is obtained by this study is confidential and may be 
disclosed only to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) that is signed by the 
patient unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare for treatment purposes. 
Given the complexity and exploratory nature of the analyses, data derived from 
exploratory biomarker specimens will generally not be provided to study investigators 
or patients unless required by law.  The aggregate results of any conducted research 
will be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5). 
Data that are generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB and EC for each study site, as 
appropriate. 
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., approximately 
5 years after the date of randomization of the last patient). 
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 and/or EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 


 
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the patient data, which includes an audit trail that contains a complete record of all 
changes to the data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The 
investigator should promptly report any deviations that might have an impact on 
patient safety and data integrity to the Sponsor and to the IRB and/or EC in accordance 
with established IRB and/or EC policies and procedures. 
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 and ECs to inspect facilities and records relevant to this 
study. 
9.4 
ADMINISTRATIVE STRUCTURE 
The overall procedures for quality assurance of clinical study data are described in the 
Roche Standard Operational Procedures. 
Randomization will occur through an IxRS (see Section 4.2).  Central facilities will be 
used for specified laboratory tests.  Accredited local laboratories will be used for routine 
monitoring; local laboratory ranges will be collected. 
Data for this study will be recorded via an EDC system using eCRFs.  In no case is the 
eCRF to be considered as the source data for this study (see Section 7.3). 
An IRC that consists of independent experts who are not involved in the study (including 
approximately three pathologists) will evaluate pathologic response.  The details of the 
composition, roles, and responsibilities of the IRC will be provided in a charter. 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on the study to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Study Information at the following Web site: 
http://www.roche.com/dam/jcr:1c46aa73-cea0-4b9b-8eaa-
e9a788ed021b/en/roche_global_policy_on_sharing_of_clinical_study_informati
on.pdf 
The results of this study may be published or presented at scientific meetings.  For all 
clinical studies conducted in patients that involve an IMP for which a marketing 


 
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authorization application has been filed or approved in any country, the Sponsor aims 
to submit a journal manuscript reporting primary clinical study results within 
6 months after the availability of the respective Clinical Study Report.  In addition, for 
all clinical studies conducted in patients that involve an IMP for which a marketing 
authorization application has been filed or approved in any country, the Sponsor aims 
to publish results from analyses of additional endpoints and exploratory data that are 
clinically meaningful and statistically sound.  
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and provide comments based on information from other studies 
that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support only publication of multicenter studies 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 that originate 
from the use of the 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 and/or EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB and/or EC and regulatory authorities (as locally 
required) before implementation of any changes except for changes that are necessary 
to eliminate an immediate hazard to patients or changes that involve only logistical or 
administrative aspects (e.g., change in Medical Monitor or contact information). 


 
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10. 
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Cancer 2002;95:681–95. 
Fujiwara K, Kohno I, Tanaka K, et al. Phase II dose escalation: a novel approach to 
balancing efficacy and toxicity of anticancer agents. Japanese Docetaxel Ovarian 
Cancer Study Group. Anticancer Res 1999;19:639–44. 
Gelmon KA, Fumoleau P, Verma S, et al. Results of a phase II trial of trastuzumab (H) 
and pertuzumab (P) in patients (pts) with HER2-positive metastatic breast cancer 
(MBC) who had progressed during trastuzumab therapy [abstract]. Proceedings of 
the American Society of Oncology 2008, abstract 1026. 
Gennari A, Sormani MP, Pronzato P, et al. HER2 status and efficacy of adjuvant 
anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl 
Cancer Inst 2008;100:14−20. 
Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and 
trastuzumab in women with locally advanced, inflammatory, or early HER2-positive 
breast cancer (NeoSphere): a randomised multicentre, open-label, Phase 2 trial. 
Lancet Oncol 2012;13:25−32. 
Gianni L, Pienkowski T, Im YH, et al. 5-year analysis of neoadjuvant pertuzumab and 
trastuzumab in patients with locally advanced, inflammatory, or early-stage 
HER2-positive breast cancer (NeoSphere): a multicentre, open-label, Phase 2 
randomised trial. Lancet Oncol 2016:17:791−800. 
Harvey V, Mouridsen H, Semiglazov V, et al. Phase III trial comparing three doses of 
docetaxel for treatment of second-line advanced breast cancer. J Clin Oncol 
2006;24:4963−70. 
Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 
2011;61:69–90. 
Kaufmann M, Hortobagyi GN, Goldhirsch A, et al. Recommendations from an 
international expert panel on the use of neoadjuvant (primary) systemic treatment 
of operable breast cancer: an update. J Clin Oncol 2006;24:1940−9. Erratum in: 
J Clin Oncol 2006;24:3221. 
Kurosumi M. Significance of histological evaluation in primary therapy for breast 
cancer-recent trends in primary modality with pathological complete response 
(pCR) as endpoint. Breast Cancer 2004;11:139−47. 
Marty M, Cognetti F, Maraninchi D, et al. Randomized Phase II trial of the efficacy and 
safety of trastuzumab combined with docetaxel in patients with human epidermal 
growth factor receptor 2–positive metastatic breast cancer administered as 
first-line treatment: the M77001 Study Group. J Clin Oncol 2005;23:4265−74. 


 
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Mauri D, Pavlidis N, Loannidis JP. Neoadjuvant versus adjuvant systemic treatment in 
breast cancer: A meta-analysis. J Natl Cancer Inst 2005;97:188−94. 
Pegram MD, Pietras R, Bajamonde A, et al. Targeted therapy: wave of the future. J Clin 
Oncol 2005;23:1776−81. 
Perez EA, Suman VJ, Davidson NE, et al. Results of chemotherapy alone, with 
sequential or concurrent addition of 52 weeks of trastuzumab in the NCCTG 
N9831 HER2-positive adjuvant breast cancer trial [abstract]. San Antonio Breast 
Cancer Symposium (SABCS), December 2009, abstract 80. 
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant 
chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659−72. 
Poole CJ, Earl HM, Hiller L, et al. Epirubicin and cyclophosphamide, methotrexate and 
fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med 
2006;355:1851−62. 
Portera CC, Walshe JM, Rosing DR, et al. Cardiac toxicity and efficacy of trastuzumab 
combined with pertuzumab in patients with [corrected] human epidermal growth 
factor receptor 2-positive metastatic breast cancer. Clin Cancer Res 
2008;14:2710−6. 
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for 
operable HER2-positive breast cancer. N Engl J Med 2005;353:1673−84. 
Ross JS. Breast cancer biomarkers and HER2 testing after 10 years of anti-HER2 
therapy. Drug News Perspect 2009;22:93−106. 
Sato N, Sano M, Tabei T, et al. Combination docetaxel and trastuzumab treatment for 
patients with HER-2-overexpressing metastatic breast cancer: a multicenter, 
phase-II study. Breast Cancer 2006;13:166−71. 
Schneeweiss A, Chia S, Hickish T, et al. Neoadjuvant pertuzumab and trastuzumab 
concurrent or sequential with an anthracycline-containing or concurrent with an 
anthracycline-free standard regimen: A Randomized phase II study (TRYPHAENA) 
[abstract]. Cancer Res 2011;71:abstract S5–6. 
Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination 
with standard neoadjuvant anthracycline-containing and anthracycline-free 
chemotherapy regimens in patients with HER2-positive early breast cancer: a 
randomized phase III cardiac safety study (TRYPHAENA). Ann Oncol 
2013:24:2278−84. 
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survival with amplification of the HER-2/neu oncogene. Science 1987;235:177−82. 
Slamon DJ, Leyland-Jones B, Shal S, et al. Use of chemotherapy plus monoclonal 
antibody against HER2 for metastatic breast cancer that overexpresses HER2. 
N Engl J Med 2001;344:783−92. 


 
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Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in 
HER-2 positive metastatic breast cancer. N Engl J Med 2015;372:724−34. 
Untch M, Eidtmann H, du Bois A, et al. Cardiac safety of trastuzumab in combination 
with epirubicin and cyclophosphamide in women with metastatic breast cancer 
results of a phase I trial. Eur J Cancer 2004;40:988−97. 
Walshe JM, Denduluri N, Berman AW, et al. A phase II trial with trastuzumab and 
pertuzumab in patients with HER2-overexpressed locally advanced and metastatic 
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HER−2/neu status in human breast cancer patients of mainland China: comparison 
of fluorescence in situ hybridization and immunohistochemistry. China J Lab Med 
2010;33:655. 
 


 
Pertuzumab—F. Hoffmann-La Roche Ltd 
113/Protocol YO28762, Version 4 
Appendix 1  
Schedule of Activities 
Adjuvant Treatment 
Neoadjuvant 
Treatment 
Pre-
Surgery 
Surgery 
FEC 
HER2-Targeted
Treatment 
Completion/ 
Discontinuation a Follow-Up b
Cycle Screening
1
2 
3 
4 
4 
4 
5 c 
6 
7 
8−20 
Day 
−28 
1
1 
1 
1 
22 
22−35 
1 
1 
1 
1 
 
 
Informed consent d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
General medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examination e 
x 
 
 
 
 
 
 
x 
 
 
 
x 
x 
Limited physical examination f 
 
x
x 
x 
x 
 
 
 
x 
x 
x 
 
 
Vital signs g 
x 
x
x 
x 
x 
 
 
x 
x 
x 
x 
x 
 
Weight h 
x 
x
x 
x 
x 
 
 
x 
x 
x 
x 
x 
 
Height h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
Hematology i 
x 
x
x 
x 
x 
 
 
x 
x 
x 
x 
x 
 
Chemistry j 
x 
x
 
 
 
 
 
x 
 
 
 
x 
 
Limited chemistry k 
 
 
x
x 
x 
 
 
 
x 
x 
x 
 
 
INR and aPTT 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
Urinalysis l 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
Pregnancy test m 
x 
 
 
x
 
 
 
 
x 
 
x n 
x 
x n 
Bone scan o 
x p 
 
 
 
 
 
 
 
 
 
 
 
 
Breast MRI scan p 
x 
 
 
 
 
x 
 
 
 
 
 
 
 


 
 
Appendix 1  
Schedule of Activities (cont.)  
Pertuzumab—F. Hoffmann-La Roche Ltd 
114/Protocol YO28762, Version 4 
Adjuvant Treatment 
Neoadjuvant 
Treatment 
Pre-
Surgery 
Surgery 
FEC 
HER2-Targeted
Treatment 
Completion/ 
Discontinuation a Follow-Up b
Cycle Screening
1
2 
3 
4 
4 
4 
5 c 
6 
7 
8−20 
Day 
−28 
1
1 
1 
1 
22 
22−35 
1 
1 
1 
1 
 
 
Mammogram p (and ultrasound as 
per local practice) 
x 
x  
x 
x 
Additional tumor assessments 
 
x q 
Clinical tumor assessment/breast 
examination r 
x 
x
x 
x 
x 
x 
 
x 
x 
x 
x s 
x 
x 
Placement of skin tattoo and/or 
surgical clip at primary tumor site t 
x 
 
Chest X-ray u  
x p 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG v 
x p 
 
 
 
 
 
 
x 
 
 
x w 
x 
 
ECHO or MUGA scan x 
x p 
 
x y
 
x y 
 
 
x z 
 
 
x y, aa 
x bb 
x cc 
Serum PK sample (optional) dd, ee 
 
x
x 
 
x 
 
 
 
 
 
x ff 
x 
x gg 
Serum sample for HER2 ECD, 
HER ligands, and other 
exploratory biomarkers 
(mandatory) ee 
x 
 
 
 
 
 
x hh 
 
 
 
 
 
 
Serum sample for antibodies to 
pertuzumab (mandatory) ee 
x 
 
 
 
x 
 
 
 
 
 
x ff 
x 
x gg 
Whole blood sample for clinical 
genotyping (optional) ii  
x 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Appendix 1  
Schedule of Activities (cont.)  
Pertuzumab—F. Hoffmann-La Roche Ltd 
115/Protocol YO28762, Version 4 
Adjuvant Treatment 
Neoadjuvant 
Treatment 
Pre-
Surgery 
Surgery 
FEC 
HER2-Targeted
Treatment 
Completion/ 
Discontinuation a Follow-Up b
Cycle Screening
1
2 
3 
4 
4 
4 
5 c 
6 
7 
8−20 
Day 
−28 
1
1 
1 
1 
22 
22−35 
1 
1 
1 
1 
 
 
Tumor tissue collection for 
determination of HER2 status jj 
and exploratory biomarkers 
(mandatory)  
x 
 
 
 
 
 
x kk 
 
 
 
 
 
 
Tumor hormone receptor status 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Pathologic response assessment 
 
 
 
 
 
 
x ll 
 
 
 
 
 
 
Tumor tissue and/or serum 
sample collection at the time of 
disease progression or 
recurrence (optional) mm 
 
x 
 
Trastuzumab administration nn 
 
x
x 
x 
x 
 
 
 
 
 
x 
 
 
Pertuzumab or placebo 
administration oo 
 
x
x 
x 
x 
 
 
 
 
 
x 
 
 
Docetaxel administration pp 
 
x
x 
x 
x 
 
 
 
 
 
 
 
 
FEC administration qq 
 
 
 
 
 
 
 
x 
x 
x 
 
 
 
Adverse events rr 
x 
x
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x rr 
Concomitant medications 
x 
x
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Survival follow-up and anti-cancer 
treatments 
 
 
 
 
 
 
 
 
 
 
 
 
x 


 
 
Appendix 1  
Schedule of Activities (cont.)  
Pertuzumab—F. Hoffmann-La Roche Ltd 
116/Protocol YO28762, Version 4 
5-FU = 5-fluorouracil; AE = adverse event; CT = computed tomography; ECD = extracellular domain; ECHO = echocardiogram; ECOG = Eastern 
Cooperative Oncology Group; eCRF = electronic Case Report Form; FEC = 5-fluorouracil, epirubicin, and cyclophosphamide; HER = human 
epidermal growth factor receptor; IHC = immunohistochemistry; IRC = Independent Review Committee; ISU = in situ hybridization; IV = intravenous; 
LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; MUGA = multiple-gated acquisition; PET = positron emission 
tomography; PK = pharmacokinetic; ULN = upper limit of normal. 
Notes:  With the exception of Day 1 of Cycle 1, all visits and assessments should be performed within 3 days of the scheduled visit date, unless 
otherwise specified.  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.  If the timing of a 
protocol-mandated procedure coincides with a holiday or weekend, it should be performed on the nearest following date. 
Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to enrollment may be 
used; such tests do not need to be repeated for screening. 
a The treatment completion/discontinuation visit will optimally be scheduled for 28 (± 7) days after the last dose of study treatment. 
b After treatment completion/discontinuation, follow-up information will be collected every 3 months (± 28 days) for the first year and then every 
6 months (± 28 days) thereafter, until disease progression or recurrence or until 5 years after randomization of the last patient, whichever 
occurs first.  
c Cycle 5 administration should not occur until 2 weeks after surgery. 
d Written informed consent must be obtained before any study-specific screening assessments are performed. 
e Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the General Medical History and 
Baseline Conditions eCRF.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
f Consists of a symptom-driven physical examination that focuses on organ systems related to potential and ongoing adverse events and is 
based on the patient’s clinical course during study treatment, the patient’s medical history, and/or the known adverse event profiles of the study 
medications.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
g Includes temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a seated position.  Vital signs 
should be obtained and reviewed before and after each study treatment administration but are not required to be entered into the eCRF during 
study treatment.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
h Weight is to be measured on Day 1 of each cycle and compared with baseline.  If ± 10% variation occurs, trastuzumab and chemotherapeutic 
doses will be recalculated.  Height is to be measured at baseline and should be remeasured if the investigator thinks it is possible that the 
patient's height may have changed. 
i Includes hemoglobin, hematocrit, platelet count, WBC count, and absolute neutrophil count.  Hematologic evaluations should be completed and 
reviewed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before).  At baseline, hematologic evaluations should be completed 


 
 
Appendix 1  
Schedule of Activities (cont.)  
Pertuzumab—F. Hoffmann-La Roche Ltd 
117/Protocol YO28762, Version 4 
and reviewed within 7 days prior to study drug dosing.  Additional assessments may be performed as clinically indicated.  For AEs associated 
with abnormal laboratory values, assessments should be performed at a minimum weekly until resolution of the AE (Grade ≤ 1 or baseline). 
j Includes sodium, potassium, chloride, bicarbonate, calcium, magnesium, glucose, BUN or urea, creatinine, total protein, albumin, alkaline 
phosphatase, ALT, AST, gamma-glutamyl transferase (GGT), total bilirubin, and direct bilirubin.  At baseline, chemistry evaluations should be 
completed and reviewed within 7 days prior to study drug dosing.  Chemistry evaluations should be completed and reviewed prior to dosing on 
Day 1 of each indicated cycle (or up to 3 days before).  Additional assessments may be performed as clinically indicated.  For AEs associated 
with abnormal laboratory values, assessments should be performed at a minimum weekly until resolution of the AE (Grade ≤ 1 or baseline). 
k Includes potassium, alkaline phosphatase, ALT, AST, total bilirubin, direct bilirubin if total bilirubin is > ULN, and other tests as clinically 
indicated.  Chemistry evaluations should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before). 
l Urinalysis, which may be performed by dipstick (pH, specific gravity, glucose, protein, ketones, and blood) and microscopic examination when 
applicable (e.g., if the urinalysis is positive; sediment, RBCs, WBCs, casts, crystals, epithelial cells, and bacteria). 
m All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test within 7 days prior to 
randomization.  Urine pregnancy tests will be performed within 7 days prior to the specified subsequent visits with results available prior to 
dosing.  If a urine pregnancy test resu is positive, it must be confirmed by a serum pregnancy test. 
n Perform at Cycles 9, 12, 15, and 18, at 3 and 6 months after the last dose of study treatment and as clinically indicated.  A urine β-HCG test 
may be performed at these cycles; however, all positive urine pregnancy test results must be confirmed by a serum β-HCG test. 
o In the absence of radioactive isotopes, an MRI scan (with gadolinium enhancement if required) or PET scan is an acceptable form of 
assessment of the skeleton for the presence of bone metastases. 
p Standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to enrollment do not need to be 
repeated for screening. 
q Additional conventional methods of tumor assessments, such as MRI, CT scans, mammograms, ultrasound, or X-rays, as per local medical 
practice, may be used to evaluate disease status throughout the study. 
r Clinical tumor assessment will be performed as per local medical practice based on the principles of RECIST Version 1.1 criteria.  Perform 
axillary node examination and management per Section 4.4.1 (Axillary Management) at surgery. 
s During the adjuvant treatment period, patients should be assessed for recurrence at least every 3 months (i.e., Cycle 9, Cycle 13, Cycle 17, etc. 
and at the study completion or early termination visit). 
t Prior to neoadjuvant treatment, the tumor must be marked using local standard methods (e.g., skin tattoo or surgical clip) so that the 
appropriate excision can be made should the patient experience complete clinical regression of the tumor prior to surgery (see Appendix 8 for 
more details). 
u If a chest X-ray is not possible, an MRI or PET scan is acceptable. 


 
 
Appendix 1  
Schedule of Activities (cont.)  
Pertuzumab—F. Hoffmann-La Roche Ltd 
118/Protocol YO28762, Version 4 
v Additional ECGs to be performed as clinically indicated. 
w Perform at Cycles 8, 12, 16, and 20 and as clinically indicated. 
x LVEF assessment by ECHO is preferred, but LVEF can also be assessed by MUGA scan. The same method should be used throughout the 
study for each patient and preferably performed and evaluated by the same assessor. 
y Perform between Days 15 and 21 (inclusive) to allow for evaluation of the results before the next treatment cycle (or before surgery). 
z Perform within 7 days prior to Cycle 5 dosing. 
aa Perform at Cycles 8, 11, and 20. 
bb Perform at the treatment completion/discontinuation visit if not performed within the previous 6 weeks. 
cc Perform every 6 months for 2 years after study drug discontinuation, then annually for an additional 2 years.  Report any cardiac events until 
the end of the study. 
dd Samples should be obtained from a subset of approximately 50 patients who are enrolled in sites in China and who have signed the separate 
consent to participate. 
ee Samples should be obtained only from randomized patients and in according with the schedule outlined in Appendix 2 or Appendix 3. 
ff Perform at Cycles 10 and 15, as outlined in Appendix 2 and Appendix 3. 
gg Samples should be obtained 60−90 days after the last dose of study treatment. 
hh Samples to be taken at surgery or 24 hours prior to surgery, as outlined in Appendix 2. 
ii Samples should be obtained only from patients who sign the separate consent to donate samples to the Biomarker Sample Repository. 
jj HER2-positive breast cancer must be confirmed by a Sponsor-designated central laboratory as 3+ score 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 prior to randomization.  Archival tumor 
samples or samples obtained from primary sites are acceptable.  If submission of tumor blocks or partial blocks is not a feasible alternative, 15 
unstained freshly cut slides should be sent.  The slides should be from consecutive slices from the same block. 
kk Samples from surgical resection specimens should be submitted from all patients.  For patients with residual disease, tissue samples obtained 
from resection specimen (blocks preferred) will be collected for exploratory biomarker analyses for patients who achieve pCR the (former) 
tumor bed may be analyzed, if applicable.  Up to 15 slides should be submitted for HER2 assessment and biomarker analysis. 
ll To be assessed locally and independently reviewed by the IRC, using the resected tumor according to guidelines provided in Appendix 7, 
Appendix 8, and Appendix 9. 
mm Samples should be obtained only from patients who sign the separate consent to participate.  Up to 15 slides should be submitted for HER2 
assessment and biomarker analysis. 
nn Patients will receive trastuzumab by IV infusion in 3-week cycles, as neoadjuvant treatment (8 mg/kg loading dose for Cycle 1, followed by 


 
 
Appendix 1  
Schedule of Activities (cont.)  
Pertuzumab—F. Hoffmann-La Roche Ltd 
119/Protocol YO28762, Version 4 
6 mg/kg for Cycles 2−4) and as adjuvant treatment (8-mg/kg loading dose for Cycle 8, followed by 6 mg/kg for Cycles 9−20). 
oo Patients in Arm A will receive pertuzumab by IV infusion in 3-week cycles, as neoadjuvant treatment (840 mg loading dose for Cycle 1, followed 
by 420 mg for Cycles 2−4) and as adjuvant treatment (840-mg loading dose for Cycle 8, followed by 420 mg for Cycles 9−20).  Patients in 
Arm B will receive placebo by IV infusion in 3-week cycles, as neoadjuvant treatment (Cycles 1−4) and as adjuvant treatment (Cycles 8−20). 
pp Patients will receive docetaxel (75 mg/m2) by IV infusion every 3 weeks for Cycles 1−4. 
qq Patients will receive 500−600 mg/m2 5-FU, 90−120 mg/m2 epirubicin, and 500−600 mg/m2 cyclophosphamide by IV infusion every 3 weeks for 
Cycles 5−7. 
rr 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.  After initiation of study drug, all adverse events will be reported until 28 days after the last dose of study drug.  
After this period, investigators should report any serious adverse events or other adverse events of concern that are believed to be related to 
prior treatment with study drug.  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 study-related procedures until a final outcome can be reported.  The 
Sponsor should also be notified if the investigator becomes aware of the development of cancer or a congenital anomaly/birth defect in a 
subsequently conceived offspring of a patient who participated in this study. 
 


 
Pertuzumab—F. Hoffmann-La Roche Ltd 
120/Protocol YO28762, Version 4 
Appendix 2  
Schedule of Biomarker and Pharmacokinetic Activities 
Visit 
Timepoint 
Sample Type 
Baseline (Day −14) 
NA 
HER2 ECD, HER ligands, and 
other biomarkers (serum) 
Prior to the first infusion 
Pertuzumab PK (serum) 
Day 1 of Cycles 1, 2, and 4 
After the last infusion 
Pertuzumab PK (serum) 
Surgery 
At surgery or 24 hours prior 
to surgery 
HER2 ECD, HER ligands, and 
other biomarkers (serum) 
Prior to the first infusion 
Pertuzumab PK (serum) 
Day 1 of Cycles 10 and 15 
After the last infusion 
Pertuzumab PK (serum) 
Treatment completion/ 
discontinuation visit (28 days 
after the last dose of study 
treatment) 
NA  
Pertuzumab PK (serum) 
Follow-up visit (60−90 days 
after the last dose of study 
treatment) 
NA 
Pertuzumab PK (serum) 
ECD = extracellular domain; HER = human epidermal growth factor receptor; NA = not 
applicable; PK = pharmacokinetic. 


 
Pertuzumab—F. Hoffmann-La Roche Ltd 
121/Protocol YO28762, Version 4 
Appendix 3  
Schedule of Anti-Therapeutic Antibody Activities 
Visit 
Timepoint 
Sample Type 
Baseline (Day −14) 
NA 
Pertuzumab ATA (serum) 
Day 1 of Cycle 4  
Prior to the first infusion 
Pertuzumab ATA (serum) 
Day 1 of Cycles 10 and 15 
Prior to the first infusion 
Pertuzumab ATA (serum) 
Treatment completion/ 
discontinuation visit (28 days 
after the last dose of study 
treatment) 
NA  
Pertuzumab ATA (serum) 
Follow-up visit (60−90 days 
after the last dose of study 
treatment) 
NA 
Pertuzumab ATA (serum) 
ATA = anti-therapeutic antibody; NA = not applicable. 


 
Pertuzumab—F. Hoffmann-La Roche Ltd 
122/Protocol YO28762, Version 4 
Appendix 4  
Response Evaluation Criteria in Solid Tumors:  
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 et al. 2009. 
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:  
Modified Excerpt from Original Publication (cont.) 
Pertuzumab—F. Hoffmann-La Roche Ltd 
123/Protocol YO28762, Version 4 
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:  
Modified Excerpt from Original Publication (cont.) 
Pertuzumab—F. Hoffmann-La Roche Ltd 
124/Protocol YO28762, Version 4 
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 be considered measurable only 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:  
Modified Excerpt from Original Publication (cont.) 
Pertuzumab—F. Hoffmann-La Roche Ltd 
125/Protocol YO28762, Version 4 
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:  
Modified Excerpt from Original Publication (cont.) 
Pertuzumab—F. Hoffmann-La Roche Ltd 
126/Protocol YO28762, Version 4 
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 during the study (nadir) with inclusion 
of baseline 
In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. 


 
 
Appendix 4 
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.) 
Pertuzumab—F. Hoffmann-La Roche Ltd 
127/Protocol YO28762, Version 4 
The appearance of one or more new lesions is also considered progression. 
• 
Stable disease (SD):  neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum during the 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 during the study.  This 
means that when lymph nodes are included as target lesions, the sum of lesions may 
not be zero even if CR 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:  
Modified Excerpt from Original Publication (cont.) 
Pertuzumab—F. Hoffmann-La Roche Ltd 
128/Protocol YO28762, Version 4 
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.  Although 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 
• 
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 studies 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 seen, the patient should be considered to have 


 
 
Appendix 4 
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.) 
Pertuzumab—F. Hoffmann-La Roche Ltd 
129/Protocol YO28762, Version 4 
had overall PD at that point.  Although 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 
CR.  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 only non-measurable (therefore non–target) disease, Table 2 is to 
be used. 


 
 
Appendix 4 
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.) 
Pertuzumab—F. Hoffmann-La Roche Ltd 
130/Protocol YO28762, 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; SD = stable disease. 
a "Non-CR/non-PD" is preferred over "SD" for non–target 
disease since SD is increasingly used as an endpoint for 
assessment of efficacy in some studies; thus, assigning 
"SD" 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) 
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 


 
 
Appendix 4 
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.) 
Pertuzumab—F. Hoffmann-La Roche Ltd 
131/Protocol YO28762, Version 4 
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. 
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. 


 
 
Appendix 4 
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.) 
Pertuzumab—F. Hoffmann-La Roche Ltd 
132/Protocol YO28762, Version 4 
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 
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 Table 1, Table 2, and Table 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 CR if the primary 
tumor is still present but not evaluated as a target or non–target lesion. 
 


 
Pertuzumab—F. Hoffmann-La Roche Ltd 
133/Protocol YO28762, Version 4 
Appendix 5  
Eastern Cooperative Oncology Group (ECOG) Performance 
Status Scale 
Grade 
Description 
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 (e.g., light housework or office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up 
and about > 50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or chair > 50% of waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair 
5 
Dead 
 


 
Pertuzumab—F. Hoffmann-La Roche Ltd 
134/Protocol YO28762, Version 4 
Appendix 6  
New York Heart Association Functional Classification System 
for Heart Failure 
Class 
Description 
I 
No limitation of physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, or dyspnea. 
II 
Slight limitation of physical activity.  Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation, or dyspnea. 
III 
Marked limitation of physical activity.  Comfortable at rest, but less than ordinary activity 
causes fatigue, palpitation, or dyspnea. 
IV 
Inability to carry on any physical activity without discomfort. Symptoms of cardiac 
insufficiency at rest.  If any physical activity is undertaken, discomfort is increased. 
Source:  The Criteria Committee of the New York Heart Association. Nomenclature and criteria for 
diagnosis of diseases of the heart and great vessels. 9th ed. Boston, MA: Little, Brown & Co, 
1994:25. 
 
 


 
Pertuzumab—F. Hoffmann-La Roche Ltd 
135/Protocol YO28762, Version 4 
Appendix 7  
Nomogram for 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 = M
0 425xL
0 725+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]
 
 


 
Pertuzumab—F. Hoffmann-La Roche Ltd 
136/Protocol YO28762, Version 4 
Appendix 8  
Standardized Guideline for Surgical Sampling following 
Neoadjuvant Therapy 
DETERMINATION OF LESION (TUMOR OR TUMOR BED) LOCATION 
SAMPLE CATEGORIZATION 
• 
Sample with prespecified positioning is defined as a sample obtained from a lesion 
that has been clearly positioned using skin tattoo or metal clip before neoadjuvant 
therapy 
• 
Sample without prespecified positioning is defined as either a sample from a lesion 
that has prespecified but unqualified positioning or a sample without any positioning 
marker, as follows: 
a) Sample with prespecified but unqualified positioning is defined as a sample 
obtained from a lesion that has not been clearly positioned before neoadjuvant 
therapy but is positioned before surgery 
b) Sample without any positioning marker is defined as a sample obtained from a 
lesion that is clearly positioned neither before neoadjuvant therapy nor before 
surgery 
 
The table below is intended to provide reference for pathologists when determining 
lesion location. 
 
(Modified) Radical Surgery 
Breast-Preserving Surgery 
Prespecified positioning 
• 
Skin tattoo 
• 
Metal clip and others 
Mark corresponding area 
Identify according to surgical 
markers 
Without prespecified 
positioning: 
• 
Positioning before 
surgery only 
• 
No any positioning 
1. Identify quadrant 
according to anatomical 
marker grossly on the 
sample 
2. Look for quadrant where 
the mass is located as 
recorded at clinical 
diagnosis 
3. Identify in that quadrant 
Identify according to surgical 
markers 
 
SURGICAL MARKERS 
• 
Applicable for breast-preserving surgery 
• 
Method:  use markers on two different spots (an example is shown in the figure 
below; positioning should be determined by clinicians and pathologists on a 
case-by-case basis in individual center) 
 




 
 
Appendix 8  
Standardized Guideline for Surgical Sampling following 
Neoadjuvant Therapy (cont.)  
Pertuzumab—F. Hoffmann-La Roche Ltd 
138/Protocol YO28762, Version 4 
1. 
Sample with significant mass:  Make an incision every 1 cm along the long axis 
of the sample and cut it into several blocks of tissue.  At least one piece of 
sample should be obtained from each block.  For example, at least five 
samples must be obtained from a 5-cm tissue. 
a) 
In case of microscopic non-pathologic complete response (pCR), no 
additional sampling is required 
b) 
In case of microscopic pCR, obtain sample from the entire quadrant 
(in case of breast-preserving surgery, obtain sample from the entire 
breast tissue) 
2. 
Sample with insignificant mass but fibrotic tumor bed:  Obtain sample from 
fibrotic tumor bed using methods described above. 
a) 
In case of microscopic non-pCR, no additional sampling is required 
b) 
In case of microscopic pCR, obtain sample from the entire quadrant 
(in case of breast-preserving surgery, obtain sample from the entire 
breast tissue) 
3. 
Sample without significant mass or fibrotic tumor bed:  Obtain sample from the 
entire area beneath the markers (in case of breast-preserving surgery, obtain 
sample from the entire breast tissue).  
 
LYMPH NODES 
• 
Rigorously examine the axillary adipose tissue for lymph nodes. 
• 
Section along the longest axis of the lymph nodes. 
• 
Submit a cross section of the largest dimension for histologic evaluation with 
adjacent connective tissue. 
  
All identified axillary lymph nodes should be sent for histologic examination. 
This sampling guideline is intended to provide standards for postoperative sampling 
procedures following neoadjuvant therapy only. 



SAP_001.pdf: 
 
 
Official Title:  
 
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PLACEBO-
CONTROLLED, PHASE III STUDY TO EVALUATE PERTUZUMAB 
IN COMBINATION WITH DOCETAXEL AND TRASTUZUMAB AS 
NEOADJUVANT THERAPY, AND PERTUZUMAB IN 
COMBINATION WITH TRASTUZUMAB AS ADJUVANT THERAPY 
AFTER SURGERY AND CHEMOTHERAPY IN PATIENTS WITH 
EARLY-STAGE OR LOCALLY ADVANCED HER2-POSITIVE 
BREAST CANCER 
NCT Number: 
NCT02586025 
Document Date: 
STATISTICAL ANALYSIS PLAN 
Version 1: 05 July 2017 
 


Reason for Signing
 
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 
TITLE: 
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PHASE III STUDY TO  
EVALUATE PERTUZUMAB IN COMBINATION WITH 
DOCETAXEL AND TRASTUZUMAB AS  
NEOADJUVANT THERAPY, AND PERTUZUMAB IN  
COMBINATION WITH TRASTUZUMAB AS  
ADJUVANT THERAPY AFTER SURGERY AND  
CHEMOTHERAPY IN PATIENTS WITH  
EARLY-STAGE OR LOCALLY ADVANCED  
HER2-POSITIVE BREAST CANCER 
PROTOCOL NUMBER: 
YO28762 
STUDY DRUG: 
Pertuzumab (RO4368451) 
VERSION NUMBER: 
1 
IND NUMBER: 
 
Eudract Number: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
, Ph.D. 
DATE FINAL: 
See electronic date stamp below 
Statistical Analysis Plan YO28762 
Name
Date and Time
(UTC)
05-Jul-2017 16:30:35
Company Signatory (Clinical)
STATISTICAL ANALYSIS PLAN APPROVAL


Pertuzumab —F. Hoffmann-La Roche Ltd 
2/Statistical Analysis Plan YO28762 
TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 4 
2. 
STUDY DESIGN ........................................................................................... 4 
2.1 
Protocol Synopsis .................................................................... 6 
2.2 
Outcome Measures ................................................................. 6 
2.2.1 
Primary Efficacy Outcome Measures ...................................... 6 
2.2.2 
Secondary Efficacy Outcome Measures .................................. 6 
2.2.3 
Exploratory Efficacy Outcome Measures ................................. 7 
2.2.4 
Safety Outcome Measures ...................................................... 7 
2.3 
Determination of Sample Size ................................................. 8 
2.4 
Interim and Final Analysis Timing ............................................ 8 
3. 
STUDY CONDUCT ....................................................................................... 8 
3.1 
Randomization Issues ............................................................. 8 
3.2 
Independent Review Committee .............................................. 8 
3.3 
Safety Data Review ................................................................. 8 
4. 
STATISTICAL METHODS ............................................................................ 9 
4.1 
Analysis Populations ............................................................... 9 
4.1.1 
Intent-to-Treat Population ........................................................ 9 
4.1.2 
Pharmacokinetic-Evaluable Population ................................... 9 
4.1.3 
Safety Population .................................................................... 9 
4.2 
Definition of Treatment Periods ............................................... 9 
4.2.1 
Neoadjuvant Study Treatment Period ...................................... 9 
4.2.2 
Adjuvant Study Treatment Period .......................................... 10 
4.2.3 
Overall Study Treatment Period ............................................ 10 
4.2.4 
Treatment-Free Follow-Up ..................................................... 10 
4.3 
Analysis of Study Conduct ..................................................... 10 
4.4 
Analysis of Treatment Group Comparability .......................... 10 
4.5 
Efficacy Analysis .................................................................... 11 
4.5.1 
Primary Efficacy Endpoint ...................................................... 11 
4.5.2 
Secondary Efficacy Endpoints ............................................... 11 
4.5.2.1 
Total Pathologic Complete Response Rate as 
Assessed by the Local Pathologist ........................................ 11 


Pertuzumab —F. Hoffmann-La Roche Ltd 
3/Statistical Analysis Plan YO28762 
4.5.2.2 
Breast Pathologic Complete Response Rate as 
Assessed by the Independent Review Committee ................ 12 
4.5.2.3 
Breast Pathologic Complete Response Rate as 
Assessed by the Local Pathologist ........................................ 12 
4.5.2.4 
Response Rates .................................................................... 12 
4.5.2.5 
Event-Free Survival ............................................................... 12 
4.5.2.6 
Disease-Free Survival ........................................................... 13 
4.5.2.7 
Overall Survival ..................................................................... 13 
4.5.3 
Exploratory Efficacy Endpoints .............................................. 13 
4.5.4 
Sensitivity Analyses ............................................................... 13 
4.5.5 
Subgroup Analyses ............................................................... 14 
4.6 
Pharmacokinetic Analyses ..................................................... 14 
4.7 
Safety Analyses ..................................................................... 15 
4.7.1 
Exposure of Study Medication ............................................... 15 
4.7.2 
Adverse Events ..................................................................... 15 
4.7.3 
Cardiac Safety ....................................................................... 15 
4.7.4 
Laboratory Data ..................................................................... 17 
4.7.5 
Vital Signs .............................................................................. 17 
4.8 
Missing Data .......................................................................... 17 
4.9 
Exploratory Analyses ............................................................. 17 
4.9.1 
Biomarker Analyses ............................................................... 17 
4.9.2 
Anti-Therapeutic Antibody Analyses ...................................... 17 
5. 
REFERENCE .............................................................................................. 17 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................... 5 
 
 
LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis ....................................................................... 19 
Appendix 2 
Schedule of Activities .................................................................. 26 


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1. 
BACKGROUND 
This Statistical Analysis Plan (SAP) provides details of the planned analyses and 
statistical methods for Study YO28762, “PEONY”.  
2. 
STUDY DESIGN 
This is an Asia-Pacific regional, randomized, double-blind, Phase III, multicenter study to 
evaluate treatment with trastuzumab + pertuzumab + docetaxel compared with 
trastuzumab + placebo + docetaxel in patients who are chemotherapy-naive with 
early-stage (T2-3, N0-1, M0) or locally advanced (T2-3, N2 or N3, M0; T4, any N, M0) 
human epidermal growth factor receptor 2 (HER2)-positive breast cancer.  A primary 
tumor with the longest diameter of > 2 cm is required. 
Patients will be randomized in a 2:1 ratio to Arm A or Arm B, respectively, and treated 
every 3 weeks for four cycles prior to surgery as follows: 
• 
Arm A 
Trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for Cycles 2−4) 
Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for Cycles 2−4) 
Docetaxel (75 mg/m2 for Cycles 1−4) 
• 
Arm B 
Trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for Cycles 2−4) 
Placebo (Cycles 1−4) 
Docetaxel (75 mg/m2 for Cycles 1−4) 
Approximately 328 eligible patients will be enrolled in mainland China, Korea, Taiwan, 
and Thailand, resulting in approximately 219 patients in Arm A and 109 patients in Arm 
B.  Randomization will be stratified by disease category (early-stage or locally advanced) 
and hormone-receptor status (positive for estrogen receptor [ER] and/or progesterone 
receptor [PgR] or negative for both). 
After completing four cycles of neoadjuvant treatment, all patients who are eligible for 
surgery will undergo surgery and have their pathologic response evaluated.  After 
surgery, patients will receive 500−600 mg/m2 5-fluorouracil (5-FU), 90−120 mg/m2 
epirubicin, and 500−600 mg/m2 cyclophosphamide (FEC) every 3 weeks for three cycles 
(Cycles 5−7).  Patients will then continue HER2-targeted therapy in accordance with the 
initial randomization every 3 weeks until disease recurrence (as assessed by the 
investigator) or unacceptable toxicity for up to 1 year total (17 cycles with inclusion of 
four cycles in the neoadjuvant setting) as follows: 
• Arm A 
Trastuzumab (8-mg/kg loading dose for Cycle 8, followed by 6 mg/kg for Cycles 9−20) 
Pertuzumab (840-mg loading dose for Cycle 8, followed by 420 mg for Cycles 9−20)  


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 Arm B 
Trastuzumab (8-mg/kg loading dose for Cycle 8, followed by 6 mg/kg for Cycles 9−20)  
Placebo (Cycles 8−20) 
For patients with tumors that are ER and/or PgR positive, hormonal agents (tamoxifen or 
an aromatase inhibitor for postmenopausal patients or tamoxifen, with or without ovarian 
suppression, or aromatase inhibitor with ovarian suppression for premenopausal 
patients) should be started at the end of FEC chemotherapy and given for at least 
5 years.  Radiotherapy is to be given as clinically indicated at the end of 
FEC chemotherapy. 
The study design is displayed graphically in Figure 1 . 
Figure 1 Study Schema 
 
FEC  5-fluorouracil, epirubicin, and cyclophosphamide; HER  human epidermal growth factor 
receptor.  
Note: Patients will be followed for disease recurrence and survival or until 5 years after 
randomization of the last patient. 
 
Patients who discontinue neoadjuvant (preoperative) HER2-targeted therapy as a result 
of toxicity and patients who are not eligible for surgery will be managed as per local 
practice.  Patients who discontinue adjuvant (postoperative) chemotherapy as a result of 
chemotherapy-related toxicity will continue with HER2-targeted therapy until they have 
received a total of 17 cycles of treatment.  Approximately 28 days after the last dose of 
study treatment, a final safety assessment will be performed before a patient enters 
long-term safety follow-up.  Patients will be followed for disease recurrence and survival 
or until 5 years after randomization of the last patient. 
Patients are evaluated for clinical response prior to surgery (i.e., during Cycles 1−4) in 
accordance with Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.  
Patients are evaluated for pathologic response after surgery and evaluated for disease 


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recurrence.  The primary efficacy objective will be evaluated when all patients who are 
eligible for surgery have completed their surgical treatment with the assessment of 
pathological response.  Patients are evaluated for safety throughout the study with 
laboratory tests and adverse event reports.  Serum samples are collected from a subset 
of approximately 50 Chinese patients for characterization of pertuzumab 
pharmacokinetics. 
The pathologic response is evaluated by a local pathologist as well as an Independent 
Review Committee (IRC) consisting of three external independent pathologists. 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Activities in Appendix 2. 
2.2 
OUTCOME MEASURES 
2.2.1 
Primary Efficacy Outcome Measures 
The primary efficacy outcome measure is the total pathologic complete response (tpCR), 
defined as the absence of any residual invasive cancer on hematoxylin and eosin 
evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes after 
completion of neoadjuvant therapy and surgery (i.e., ypT0/is, ypN0 in accordance with 
the current American Joint Committee on Cancer [AJCC] staging system) as assessed 
by the IRC. 
2.2.2 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures are as follows: 
• 
tpCR assessed by a local pathologist 
• 
Breast pathologic complete response (bpCR) defined as the absence of any 
residual invasive cancer on hematoxylin and eosin evaluation of the resected breast 
specimen after completion of neoadjuvant therapy and surgery (i.e., ypT0/is in 
accordance with the current AJCC staging system) as assessed by the IRC 
• 
bpCR assessed by a local pathologist 
• 
Clinical response during Cycles 1−4 in accordance with RECIST v1.1 
• 
Event-free survival (EFS) defined as time from randomization to the first 
documentation of one of the following events: 
Disease progression (before surgery) as determined by the investigator with use of 
RECIST v1.1 
Any evidence of in situ contralateral disease will not be identified as progressive 
disease (PD) 
Any evidence of invasive contralateral disease will be considered disease 
progression 
Disease recurrence (local, regional, distant, or contralateral) after surgery 


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Death from any cause 
• 
Disease-free survival (DFS) defined as the time from the first date of no disease (i.e., 
date of surgery) to the first documentation of one of the following events: 
Disease recurrence (local, regional, distant, or contralateral) after surgery 
Death from any cause 
• 
Overall survival (OS) defined as the time from randomization to death from any 
cause. 
 
2.2.3 
Exploratory Efficacy Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
To explore relationships between pathology findings from the sentinel lymph node 
biopsy tissue sample, if the biopsy is performed, and the axillary lymph node 
dissection tissue sampled obtained during the surgery undertaken after neoadjuvant 
treatment 
• 
Observed pertuzumab concentrations at all specified pharmacokinetic (PK) 
sampling timepoints 
• 
Observed pertuzumab concentrations compared with concentrations in patients with 
HER2-positive breast cancer from other studies 
• 
Observed pertuzumab concentrations during neoadjuvant treatment compared with 
concentrations during adjuvant treatment (postoperative) 
• 
Expression levels or incidence of biomarkers at baseline and in resection specimen 
tissue, especially for patients with residual disease, at the time of surgery (i.e., after 
neoadjuvant treatment) and their relationship to efficacy or safety parameters 
• 
To assess the effect of HER2 extracellular domain (ECD) on PK of pertuzumab 
• 
Incidence of anti-therapeutic antibodies (ATAs) and relationship with PK, safety, and 
efficacy outcome measures (as data allow) 
• 
tpCR in relation to clinical response, EFS, DFS, and OS. 
 
2.2.4 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Incidence, type and severity of adverse events (AEs), and serious adverse events 
(SAEs) 
• 
Incidence of symptomatic left ventricular systolic dysfunction (LVSD) (heart failure) 
defined as the occurrence of symptomatic left ventricular ejection fraction (LVEF) 
decrease or definite or probable cardiac death 
• 
Incidence of asymptomatic decrease in LVEF defined as an absolute decrease 
of  ≥ 10 percentage points from baseline to an LVEF of < 50% 
• 
LVEF values over the course of the study 


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• 
Laboratory test result abnormalities. 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
A total of 328 patients have been planned to be randomized into the study in a ratio of 
2:1 to pertuzumab (Arm A) or placebo (Arm B), respectively.  This will provide 85% 
power to detect an absolute increase in tpCR rate of 15% in the pertuzumab arm 
compared with the placebo arm at a two-sided significance level of 5%, assuming the 
tpCR rate is 20% in the placebo arm. 
2.4 
INTERIM AND FINAL ANALYSIS TIMING 
There is no interim analysis planned for the primary efficacy outcome measure tpCR.  
EFS and DFS data will be summarized descriptively at the time of the primary efficacy 
analysis.  Note that a final analysis of EFS, DFS, and OS will be performed at the end of 
the study, approximately 5 years after randomization of the last patient. 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION ISSUES 
Eligible patients are randomized in a 2:1 ratio to one of the two treatment arms 
(pertuzumab or placebo) with use of the interactive voice/web−based response system 
(IxRS).  Patients are enrolled with a permuted block randomization procedure that uses 
the following stratification factors: 
• 
Disease category: early-stage (T2-3, N0-1, M0) or locally advanced (T2-3, N2 or N3, 
M0; T4, any N, M0) 
• 
Hormone-receptor status: positive for ER and/or PgR; negative for both. 
 
3.2 
INDEPENDENT REVIEW COMMITTEE 
An IRC that consists of independent experts who are not involved in the study (including 
three pathologists) is used to evaluate the pathologic response. 
Details of the composition, roles, and responsibilities of the IRC have been provided in 
the IRC charter. 
The IRC remains blinded to the treatment assignment for the formal efficacy analyses. 
The Sponsor remains blinded to the IRC assessments. 
3.3 
SAFETY DATA REVIEW 
The Sponsor’s study team has been reviewing AEs, SAEs, and any other safety data in 
the study on a regularly scheduled basis. 
The study team is responsible for reviewing accumulating safety data, assessing and 
monitoring ongoing safety of patients, evaluating potential changes to the clinical study 
protocol, and ultimately safeguarding patient safety. 


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4. 
STATISTICAL METHODS 
The analyses described in this SAP will supersede those specified in Protocol YO28762 
for the purposes of a regulatory filing. 
4.1 
ANALYSIS POPULATIONS 
4.1.1 
Intent-to-Treat Population 
The intent-to-treat (ITT) population is defined as all randomized patients, whether or not 
the patient received the assigned treatment.  The ITT patients will be analyzed according 
to the treatment assigned at randomization by IxRS. 
4.1.2 
Pharmacokinetic-Evaluable Population  
Pharmacokinetic analyses will be based on PK observations from all patients who 
received pertuzumab treatment with at least one evaluable post-dose PK sample. 
4.1.3 
Safety Population 
The safety population is defined as patients who receive any amount of study treatment.  
Patients who receive any amount of pertuzumab will be analyzed as part of treatment 
Arm A, even if pertuzumab was given in error.  Patients who are randomized to the study 
but who do not receive any study drug will not be included in the safety population. 
4.2 
DEFINITION OF TREATMENT PERIODS 
The concept of the treatment period will be used to define how study data will be 
reported.  For example, typically tables of AEs will be of interest for the period that 
patients are considered to be on study treatment.  This study has a neoadjuvant, 
adjuvant and treatment–free follow up period.  The overall treatment period is defined as 
the combination of neoadjuvant and adjuvant periods.  It will be assumed that patients 
who have not withdrawn from study treatment according to the database are still in the 
treatment period. 
4.2.1 
Neoadjuvant study treatment period 
The neoadjuvant study treatment (or “neoadjuvant treatment”) period begins after 
randomization upon receiving the first dose > 0 of any of the neoadjuvant study 
medications (trastuzumab, pertuzumab, docetaxel), i.e. on Study Day 1.  
It ends either: 
(i). Immediately before receiving the first dose of adjuvant study treatment (see below); 
or 
(ii). 42 days after the last dose > 0 of neoadjuvant study treatment, for patients who 
discontinued without undergoing primary surgery and never start adjuvant study 
treatment; or 


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(iii). 42 days after the last dose > 0 of neoadjuvant study treatment or on the day of 
primary surgery, whichever is later, for patients who undergo primary surgery and 
discontinued without starting adjuvant study treatment; or 
(iv). If a patient has not yet started the adjuvant treatment and has not withdrawn then all 
assessments will be considered neoadjuvant.  In this case the last known date is 
considered as the end date. 
 
4.2.2 
Adjuvant study treatment period 
The adjuvant study treatment (or “adjuvant treatment”) period begins, after primary 
surgery, upon receiving the first dose > 0 of any of the five adjuvant treatments 
(pertuzumab, trastuzumab, 5-Fluorouracil, epirubicin, and cyclophosphamide).  It ends 
42 days after the last dose of adjuvant study treatment upon treatment completion or 
discontinuation.  If there is no evidence of treatment completion or discontinuation, the 
patient is considered on treatment. 
4.2.3 
Overall study treatment period 
The overall study treatment period begins after randomization upon receiving the first 
dose >0 of neo-adjuvant study treatment.  It ends either at the end of the neo-adjuvant 
treatment period as defined in Section 4.2.1, for patients who do not start adjuvant study 
treatment, or at the end of the adjuvant treatment period as defined in Section 4.2.2. 
4.2.4 
Treatment-free follow-up 
The remaining visits after the on-treatment study periods (see Section 4.2.1 and 
Section 4.2.2) will take place every 3 months ( ± 28 days) for 1 year, followed by every 
6 months ( ± 28 days) thereafter, until disease progression or recurrence or until 5 years 
after randomization of the last patient, whichever occurs first.  
The treatment-free follow-up period is defined to start the day after the end of the overall 
study treatment period as defined in Section 4.2.3. 
4.3 
ANALYSIS OF STUDY CONDUCT 
Patient enrollment, duration of the follow-up, and the reasons for discontinuation from 
study periods (neoadjuvant and adjuvant) will be summarized by treatment arm for the 
ITT population.  In addition, major protocol deviations will be summarized by treatment 
arm. 
4.4 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Demographic and baseline characteristics such as age, weight, Eastern Cooperative 
Oncology Group (ECOG) Performance Status, ER and PgR status, HER2 status, and 
history of breast cancer will be summarized by treatment arm. 
Descriptive statistics (mean, SD, median, 25th percentile, 75th percentile, and range) will 
be presented for continuous variables, and proportions will be presented for categorical 
variables. 


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4.5 
EFFICACY ANALYSIS 
The primary and secondary efficacy analyses will include all randomized patients, 
following the ITT principle, with patients grouped by the treatment assigned at the time of 
randomization.  For DFS, only patients who undergo surgery will be included in the 
analysis.  For clinical response rates, only patients with measurable disease at baseline 
will be included in the analysis. 
4.5.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is tpCR, defined as the absence of any residual invasive 
cancer on hematoxylin and eosin evaluation of the resected breast specimen and all 
sampled ipsilateral lymph nodes after completion of neoadjuvant therapy and surgery 
(i.e., ypT0/is, ypN0 in accordance with the current AJCC staging system) as assessed 
by the IRC.  The primary analysis will be performed when all patients who are eligible for 
surgery have completed their surgical treatment with an assessment of pathological 
response.  The analysis will be based on the ITT population with patients grouped by the 
treatment assigned at the time of randomization.  In the ITT population, patients whose 
tpCR assessment is missing or invalid are counted as not achieving tpCR. 
The tpCR rate as assessed by the IRC will be summarized for each treatment arm and 
95% CIs will be calculated with the Clopper-Pearson method.  The two-sided 
Cochran-Mantel-Haenszel test, stratified by disease category (early-stage or locally 
advanced) and hormone receptor status (positive for ER and/or PgR or negative for 
both), will be used to compare the tpCR rate between the two treatment arms. The 
stratification factors will be the same as those used for randomization.  An unadjusted 
Fisher exact test result will also be provided.  Finally, the difference in tpCR rate and 
associated 95% CIs will be provided with use of the Hauck-Anderson method. 
4.5.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints in this study include tpCR as assessed by the local 
pathologist, bpCR as assessed by the IRC, bpCR as assessed by the local pathologist, 
clinical response, EFS, DFS, and OS. 
4.5.2.1 
Total Pathologic Complete Response Rate as Assessed by the 
Local Pathologist 
The tpCR rate as assessed by the local pathologist will be evaluated using the same 
methods as those described for the primary efficacy endpoint. 
4.5.2.2 
Breast Pathologic Complete Response Rate as Assessed by 
the Independent Review Committee 
The bpCR is defined as the absence of any residual invasive cancer on the hematoxylin 
and eosin evaluation of the resected breast specimen after completion of neoadjuvant 
therapy and surgery (i.e., ypT0/is in accordance with the current AJCC staging system). 
bpCR rate as assessed by the IRC will be evaluated using the same methods as those 
described for the primary efficacy endpoint. 


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4.5.2.3 
Breast Pathologic Complete Response Rate as Assessed by 
the Local Pathologist 
The bpCR rate as assessed by the local pathologist will be evaluated using the same 
methods as those described for the primary efficacy endpoint. 
4.5.2.4 
Response Rates 
Clinical response rates that include the proportions of patients with a CR, PR, stable 
disease, or PD will be determined by the investigator during Cycles 1−4 (i.e., prior to 
surgery) on the basis of RECIST v1.1.  Objective response rate is defined as the 
proportion of patients who achieve a CR or PR as the best tumor response during the 
neoadjuvant period.  No confirmation is required for objective response.  Only patients 
with measurable disease at baseline will be included in the analysis.  The methods for 
data analysis are the same as those described for the primary efficacy endpoint. 
4.5.2.5 
Event-Free Survival 
The EFS is defined as the time from randomization to the first documentation of one of 
the following events: 
• 
Disease progression (before surgery) as determined by the investigator with use of 
RECIST v1.1 
Any evidence of contralateral disease in situ will not be identified as PD. 
• 
Disease recurrence (local, regional, distant, or contralateral) after surgery 
• 
Death from any cause. 
 
Patients who have not had an event at the time of the analysis will be censored as of the 
date they were last known to be alive and event free. 
The two-sided log-rank test, stratified by disease category (early-stage or locally 
advanced) and hormone-receptor status (positive for ER and/or PgR or negative for both) 
will be used to make an exploratory comparison of EFS between the two treatment arms. 
The Kaplan-Meier approach will be used to estimate 3-year EFS rates for each 
treatment arm.  The stratified Cox proportional hazards model will be used to estimate 
the HR between the two treatment arms (i.e., the magnitude of treatment effect) and its 
95% CI. 
4.5.2.6 
Disease-Free Survival 
The DFS is defined as the time from the first date of no disease (i.e., date of surgery) to 
the first documentation of one of the following events: 
• 
Disease recurrence (local, regional, distant, or contralateral) after surgery 
Any evidence of contralateral disease in situ will not be identified as disease 
recurrence 
• 
Death from any cause. 


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Only patients who undergo surgery will be included in the analysis.  It is assumed that all 
patients who undergo surgery are disease free. So patients are considered to be 
disease free if they have undergone surgery and no recurrence of disease is reported 
thereafter.  Data from patients who have not had an event at the time of the analysis will 
be censored as of the date they were last known to be alive and event free.  The 
methods for data analysis are the same as those described for EFS.   
4.5.2.7 
Overall Survival 
The OS is defined as the time from randomization to death from any cause.  Data from 
patients who are alive at the time of the analysis will be censored as of the last date they 
were known to be alive.  The methods for data analysis are similar to those described for 
EFS. 
4.5.3 
Exploratory Efficacy Endpoints 
The relationship between IRC-assessed tpCR and other efficacy endpoints, such as 
clinical response, EFS, DFS, and OS may be explored when appropriate.  
4.5.4 
Sensitivity Analyses 
The concordance of pathological responses (tpCR and bpCR) between IRC and 
investigator assessments will be summarized by treatment group. 
For some patients, inconsistent values of stratification factors were entered at 
randomization (i.e., in the IxRS).  The stratified analyses of IRC-assessed tpCR and 
bpCR will be repeated with the values of stratification factors saved in the clinical 
database. 
The primary analysis, comparing tpCR rates among the ITT population, will be repeated 
only for patients who completed the surgery and have a tpCR assessment available. 
The potential impact of herbal remedies on the efficacy, the IRC-assessed tpCR might 
be explored when appropriate. 
4.5.5 
Subgroup Analyses 
Variables to be considered to define subgroups of interest include stratification factors as 
well as other disease-or patient-related prognostic or predictive factors.  The following 
factors will be examined in the subgroup analyses for IRC-assessed tpCR: 
• 
Age ( < 65 vs. ≥ 65) 
• 
Region (Mainland of China vs other) 
• 
Menopausal status at randomization (post-menopausal vs pre-menopausal) 
• 
Primary tumor stage at baseline (T2 vs T3 or larger) 
• 
Lymph nodes status at baseline (positive vs negative) 


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• 
Histological subtype at baseline (ductal vs non-ductal, not including unknown values)  
• 
Disease category at baseline (early-stage vs locally advanced) 
• 
Hormone receptor status at baseline (positive for ER and/or PgR vs negative for 
both) 
• 
HER2 subgroups defined as IHC3+ (regardless of FISH status), IHC2+/FISH+ and 
IHC0/1+/FISH+  
• 
Pathological tumor stage at surgery (T0 or Tis vs T1 or larger)  
• 
Targeted surgery type (breast conserving vs total mastectomy). 
 
The tpCR will be analyzed separately for each subgroup defined by the above variable in 
a similar way as done for the primary analysis, except that unstratified instead of 
stratified Cochran-Mantel-Haenszel test will be performed. 
4.6 
PHARMACOKINETIC ANALYSES 
Pharmacokinetic parameters Cmax and Cmin values will be tabulated and summarized for 
pertuzumab at each specified sampling timepoint.  Descriptive statistics will include 
mean, SD, median, CI, and range of values as appropriate. 
Graphical plots and comparisons of the descriptive statistics will be made between 
observed serum pertuzumab concentrations in this study and observed serum 
pertuzumab concentrations in studies that are not conducted in China. 
Graphical plots and comparisons of the descriptive statistics will be made between 
observed serum pertuzumab PK in the neoadjuvant and adjuvant phase in this study.  
Additionally, observed serum pertuzumab PK in this study will also be compared with the 
observed serum pertuzumab PK in the adjuvant phase of the PK substudy in Chinese 
patients from Study BIG 4-11/BO25126/TOC4939g.  In addition, exploratory analyses 
will be performed to assess any correlation between soluble systemic HER2 ECD and 
the PK of pertuzumab. 
4.7 
SAFETY ANALYSES 
Safety analyses will be performed on the safety analysis population, which will consist of 
all patients who received at least one dose of study drugs and patients will be grouped 
by the treatment they actually received.  The safety analyses will be performed at the 
same time as the primary efficacy analysis, when all patients have completed the 
treatment completion or study discontinuation visit, and at the final analyses. 
4.7.1 
Exposure of Study Medication 
The number of patients who experience any dose interruption (including dose delays), 
dose modification, and dose discontinuation will be summarized by treatment arm. 
Descriptive statistics of total cumulative dose, number of cycles, and patient number at 


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each treatment cycle will be presented for pertuzumab (or placebo), trastuzumab, and 
chemotherapy by treatment period (neoadjuvant and adjuvant, if applicable). 
4.7.2 
Adverse Events 
Verbatim descriptions of AEs will be mapped to MedDRA thesaurus terms and graded 
according to National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) v4.0.  All AEs that occur on or after the date of the first study drug 
administration will be summarized by mapped term, appropriate thesaurus levels, and 
toxicity grade based on NCI CTCAE Version 4.0.  In addition, AEs leading to 
discontinuation of study treatment and AEs observed on the day of and during the 
infusion will be summarized by treatment arm.  The maximum severity recorded for each 
AE will be used in the summaries.  
Deaths reported during the study treatment period and those reported during the 
follow-up period after treatment completion/discontinuation will be summarized by 
treatment arm. 
AE summaries will be presented by treatment period (neoadjuvant, adjuvant, overall and 
follow-up). 
4.7.3 
Cardiac Safety 
The primary cardiac event is defined as heart failure (NYHA III or NYHA IV) and a drop 
in LVEF of at least 10 ejection fraction points from baseline and to below 50%.  
The secondary cardiac event is defined as an asymptomatic or mildly symptomatic 
(NYHA Class II) drop in LVEF by MUGA scan or echocardiogram confirmed by a second 
LVEF assessment within approximately 3 weeks showing also a documented drop.  A 
significant LVEF drop is defined as an absolute decrease of at least 10 points below the 
baseline measurement and to below 50%.  
The assessment of the secondary cardiac endpoint will be based on data from 
randomization until the start of any new therapy for recurrence of disease.  Therefore, 
any asymptomatic or mildly symptomatic (NYHA Class II) significant drop in LVEF 
should be confirmed within approximately 3 weeks, even during follow-up. 
Secondary cardiac events will only be counted for patients with no primary cardiac event. 
Comparison of incidence of each of the primary and secondary cardiac events by arm 
will be made by summarizing the proportions in each arm and the difference in 
proportions with 95% CI using Hauck-Anderson correction. 
The composite primary and secondary cardiac endpoint over time with competing risk of 
non-cardiac death will be compared between treatment groups by Gray’s test 
(Kalbfleisch and Prentice, 2002). 


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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 percentage points 
• 
Absolute value < 50% and decrease from baseline ≥ 10 percentage points. 
 
The number and percentage of patients with symptomatic LVSD (heart failure) at any 
time during the study will be summarized by treatment arm. Symptomatic LVSD (heart 
failure) will be evaluated by the assessment of NCI CTCAE v4.0 and NYHA class 
(NYHA II, III and IV).  
Risk factors for cardiac dysfunction may be investigated as an exploratory analysis. 
Cardiac safety summaries will be presented by treatment period (neoadjuvant, adjuvant, 
overall, and follow-up). 
4.7.4 
Laboratory Data 
Clinical laboratory tests are performed at local laboratories.  Changes in laboratory data 
will be summarized by grade with use of the NCI CTCAE v4.0 for each treatment arm. 
Changes from baseline will be presented in shift tables for selected laboratory test result 
assessments. 
4.7.5 
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. 
ECOG performance status will also be summarized over time. 


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4.8 
MISSING DATA 
Please refer to Section 4.5.1 and 4.5.2 for methods of handling missing data for the 
primary and secondary endpoints. 
4.9 
EXPLORATORY ANALYSES 
4.9.1 
Biomarker Analyses 
The correlation between baseline molecular biomarkers and efficacy outcomes will be 
evaluated.  Biomarkers may include but are not limited to HER2/3 mRNA and/or protein, 
PIK3CA, phosphatase and tensin homolog (PTEN), programmed death−ligand 1 
(PD−L1), and cluster of differentiation 8 (CD8), HER ligands, HER2 extracellular domain 
(ECD), and other markers that are relevant to breast cancer.  Special emphasis will be 
placed on biomarkers that have shown an association with clinical outcome in patients 
who were treated with pertuzumab in previous studies.  Efficacy outcomes that are 
considered for this analysis may include tpCR, EFS, and DFS. 
If possible, biomarker levels at baseline will be compared with biomarker levels in 
samples that are collected at the time of surgery from patients with residual disease.  
4.9.2 
Anti-Therapeutic Antibody Analyses 
To determine whether ATAs to pertuzumab are formed as a result of the administration 
of study treatment, serum samples will be collected to test for the presence of ATAs to 
pertuzumab from all randomized patients at screening and after treatment. 
The impact of ATAs to pertuzumab on pharmacokinetics, safety, and efficacy will be 
further explored in this study (as data allow). 
5. 
REFERENCE 
Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data; 2nd edition, 
Chapter 8, John Wiley & Sons, 2002. 
 


Appendix 1  
Protocol Synopsis 
PROTOCOL SYNOPSIS 
TITLE: 
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PHASE III STUDY EVALUATING 
PERTUZUMAB IN COMBINATION WITH DOCETAXEL AND 
TRASTUZUMAB AS NEOADJUVANT THERAPY, AND 
PERTUZUMAB IN COMBINATION WITH TRASTUZUMAB AS 
ADJUVANT THERAPY FOLLOWING SURGERY AND 
CHEMOTHERAPY IN PATIENTS WITH EARLY-STAGE OR 
LOCALLY ADVANCED HER2-POSITIVE BREAST CANCER 
PROTOCOL NUMBER: 
YO28762 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
Not applicable 
TEST PRODUCT: 
Pertuzumab (RO4368451) 
PHASE: 
III 
INDICATION: 
HER2-positive breast cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Efficacy Objectives 
The primary efficacy objective for this study is as follows: 
• 
To evaluate the efficacy of trastuzumab + pertuzumab + docetaxel compared with 
trastuzumab + placebo + docetaxel as neoadjuvant treatment prior to surgery in patients 
who are chemotherapy-naive with early-stage or locally advanced human epidermal growth 
factor receptor 2 (HER2)−positive breast cancer as measured by total pathologic complete 
response (tpCR) rate as assessed by an Independent Review Committee (IRC) 
The secondary efficacy objectives for this study are to evaluate the efficacy of 
trastuzumab + pertuzumab + docetaxel compared with trastuzumab + placebo + docetaxel 
as neoadjuvant treatment prior to surgery in patients with early-stage or locally advanced 
HER2-positive breast cancer as measured by the following: 
• 
tpCR rate assessed by the local pathologist 
• 
Breast pathologic complete response (bpCR) rate assessed by the IRC 
• 
bpCR rate assessed by the local pathologist 
• 
Clinical response rates during Cycles 1−4 in accordance with Response Evaluation Criteria 
in Solid Tumors (RECIST), Version 1.1 
• 
Event-free survival (EFS) 
• 
Disease-free survival (DFS) 
• 
Overall survival 
 
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Safety Objective 
The safety objective for this study is as follows: 
• 
To evaluate the safety and tolerability of each treatment regimen 
 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To explore relationships between findings from the sentinel lymph node (SLN) biopsy tissue 
samples (if biopsy is performed) and the axillary lymph node dissection (ALND) tissue 
sample from the surgery undertaken after neoadjuvant treatment 
• 
To characterize the pharmacokinetics of pertuzumab after intravenous (IV) infusion in a 
subset of Chinese patients with early-stage or locally advanced HER2-positive breast 
cancer 
• 
To analyze biomarkers in tumor tissue taken at baseline or at the time of resection 
(markers analyzed may include but are not limited to HER2/3 mRNA and/or protein, 
PIK3CA, phosphatase and tensin homolog, programmed death−ligand 1, and cluster of 
differentiation 8), and serum (e.g., HER ligands and HER2 extracellular domain [ECD]) 
and evaluate correlations with clinical outcomes and, if applicable, safety outcomes 
• 
To analyze the effect of HER2 ECD on pharmacokinetics of pertuzumab 
• 
To analyze the effect of anti-therapeutic antibodies (ATAs) on pharmacokinetics, safety, 
and efficacy 
• 
To assess tpCR in relation to clinical response rate, EFS, DFS, and overall survival 
 
Study Design 
Description of Study 
This is an Asia-Pacific regional, randomized, double-blind, Phase III, multicenter study to 
evaluate treatment with trastuzumab + pertuzumab + docetaxel compared with 
trastuzumab + placebo + docetaxel in patients who are chemotherapy-naive with early-stage 
(T2-3, N0-1, M0) or locally advanced (T2-3, N2 or N3, M0; T4, any N, M0) HER2-positive breast 
cancer.  A primary tumor with the longest diameter of > 2 cm is required. 
Patients will be randomized in a 2:1 ratio to Arm A or Arm B, respectively, and treated every 
3 weeks for four cycles prior to surgery as follows: 
• 
Arm A 
Trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for Cycles 2−4) 
Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for Cycles 2−4) 
Docetaxel (75 mg/m2 for Cycles 1−4) 
• 
Arm B 
Trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for Cycles 2−4) 
Placebo (Cycles 1−4) 
Docetaxel (75 mg/m2 for Cycles 1−4) 
 
After completing four cycles of neoadjuvant treatment, all patients who are eligible for surgery 
will undergo surgery and have their pathologic response evaluated.  After surgery, patients will 
receive 500−600 mg/m2 5-fluorouracil (5-FU), 90−120 mg/m2 epirubicin, and 500−600 mg/m2 
cyclophosphamide (FEC) every 3 weeks for three cycles (Cycles 5−7).  Patients will then 
continue HER2-targeted therapy in accordance with the initial randomization every 3 weeks until 
disease recurrence (as assessed by the investigator) or unacceptable toxicity for up to 1 year 
total (17 cycles with inclusion of four cycles in the neoadjuvant setting) as follows: 
• 
Arm A 
Trastuzumab (8-mg/kg loading dose for Cycle 8, followed by 6 mg/kg for Cycles 9−20) 
Pertuzumab (840-mg loading dose for Cycle 8, followed by 420 mg for Cycles 9−20) 


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• 
Arm B 
Trastuzumab (8-mg/kg loading dose for Cycle 8, followed by 6 mg/kg for Cycles 9−20) 
Placebo (Cycles 8−20) 
 
For patients with tumors that are estrogen receptor (ER) and/or progesterone receptor (PgR) 
positive, hormonal agents (tamoxifen or an aromatase inhibitor for postmenopausal patients or 
tamoxifen, with or without ovarian suppression, or aromatase inhibitor with ovarian 
suppression for premenopausal patients) should be started at the end of FEC chemotherapy 
and given for at least 5 years.  Radiotherapy is to be given as clinically indicated at the end of 
FEC chemotherapy. 
Patients who discontinue neoadjuvant (preoperative) HER2-targed therapy as a result of toxicity 
and patients who are not eligible for surgery will be managed as per local practice.  Patients 
who discontinue adjuvant (postoperative) chemotherapy as a result of chemotherapy-related 
toxicity will continue with HER2-targeted therapy until they have received a total of 17 cycles of 
treatment.  Approximately 28 days after the last dose of study treatment, a final safety 
assessment will be performed before a patient enters long-term safety follow up.  Patients will 
be followed for disease recurrence and survival or until 5 years after randomization of the last 
patient. 
Patients will be evaluated for clinical response prior to surgery (i.e., during Cycles 1−4) in 
accordance with RECIST v1.1.  Patients will be evaluated for pathologic response after surgery 
and evaluated for disease recurrence.  The primary efficacy objective will be evaluated when all 
patients who are eligible for surgery have completed their surgical treatment with the 
assessment of pathological response.  Patients will be evaluated for safety throughout the study 
with laboratory tests and adverse event reports.  Serum samples will be collected from a subset 
of approximately 50 Chinese patients for characterization of pertuzumab pharmacokinetics. 
Number of Patients 
Approximately 328 eligible patients will be enrolled at approximately 24 sites, resulting in 
approximately 219 patients in Arm A and 109 patients in Arm B.  Randomization will be stratified 
by disease category (early-stage or locally advanced) and hormone-receptor status (positive for 
ER and/or PgR or negative for both). 
Target Population 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form 
• 
Age ≥ 18 years 
• 
Breast cancer that meets the following criteria: 
Histologically confirmed invasive breast carcinoma with a primary tumor size of > 2 cm 
by standard local assessment technique 
Stage at presentation:  early-stage (T2-3, N0-1, M0) or locally advanced (T2-3, N2 or N3, 
M0; T4, any N, M0) 
• 
HER2-positive breast cancer confirmed by a Sponsor-designated central laboratory and 
defined as 3+ score by immunohistochemistry (IHC) in > 10% of immunoreactive cells or 
HER2 gene amplification (ratio of HER2 gene signals to centromere 17 signals ≥ 2.0) by 
in situ hybridization (ISH) 
A tumor sample that consists of a tumor block or eight unstained, freshly cut slides 
must be available for central laboratory HER2 testing by IHC and ISH.  Note that up to 
an additional seven slides are required for exploratory biomarker research.  Therefore, 
15 slides are requested at screening. 
• 
Known hormone receptor status (ER and PgR) 
• 
Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 
• 
Completion of all necessary baseline laboratory and radiologic investigations prior to 
randomization 
• 
Baseline left ventricular ejection fraction (LVEF) ≥ 55% measured by echocardiography 
(ECHO; preferred) or multiple-gated acquisition (MUGA) scan 


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• 
For women who are not postmenopausal (≥ 12 months of amenorrhea) or surgically sterile 
(absence of ovaries and/or uterus):  agreement to remain abstinent or use one highly 
effective form of non-hormonal contraception or two effective forms of non-hormonal 
contraception during the treatment period and for at least 7 months after the last dose of 
study treatment  
• 
For men:  agreement to use reliable and effective contraceptive measures during the 
treatment period and for at least 7 months after the last dose of study treatment  
• 
Able to comply with the study protocol in the investigator’s judgment 
 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Stage IV (metastatic) breast cancer 
• 
Inflammatory breast cancer 
• 
Previous anti-cancer therapy or radiotherapy for any malignancy 
• 
History of other malignancy within 5 years prior to screening, except for 
appropriately-treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or 
Stage I uterine cancer 
• 
Concurrent anti-cancer treatment in another investigational study, including hormone 
therapy, bisphosphonate therapy, or immunotherapy 
• 
Major surgical procedure that is unrelated to breast cancer within 4 weeks prior to 
randomization or from which the patient has not fully recovered 
• 
Serious cardiac illness or medical condition including but not limited to the following: 
History of documented heart failure or systolic dysfunction (LVEF < 50%) 
High-risk uncontrolled arrhythmia, such as atrial tachycardia with a heart rate 
> 100 bpm at rest, significant ventricular arrhythmia (e.g., ventricular tachycardia), or 
higher-grade atrioventricular (AV) block (i.e., Mobitz II second-degree AV block or 
third-degree AV block) 
Angina pectoris requiring anti-angina medication 
Clinically-significant valvular heart disease 
Evidence of transmural infarction on ECG 
Poorly-controlled hypertension (systolic blood pressure > 180 mmHg and/or diastolic 
blood pressure > 100 mmHg) 
• 
Other concurrent serious diseases that may interfere with planned treatment, including 
severe pulmonary conditions/illness 
• 
Any of the following abnormal laboratory test results immediately prior to randomization: 
Total bilirubin > 1.5 × upper limit of normal (ULN) or, for cases of known Gilbert’s 
syndrome, total bilirubin > 2 × ULN 
AST and/or ALT > 1.25 × ULN 
Alkaline phosphatase > 2.5 × ULN 
Serum creatinine > 1.5 × ULN 
Total WBC count < 2500 cells/µL 
Absolute neutrophil count < 1500 cells/µL 
Platelet count < 100,000 cells/µL 
• 
Sensitivity to any of the study medications, any of the ingredients or excipients of these 
medications, or benzyl alcohol 
• 
Pregnant or lactating 
A negative serum pregnancy test result is required for all women who are not 
postmenopausal (≥ 12 months of amenorrhea). 
 


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Length of Study 
Recruitment is expected to last approximately 13 months.  On the basis of a treatment length of 
17 months for each patient, the analysis of the primary efficacy outcome measure, tpCR, will 
take place approximately 30 months after randomization of the first patient, when all patients 
have completed the treatment completion/discontinuation visit. 
Approximately 28 days after the last dose of study treatment, a final safety assessment will be 
performed before a patient enters long-term safety follow-up.  Patients will be followed for 
disease recurrence and survival or until 5 years after randomization of the last patient. 
End of Study 
The study will formally end approximately 5 years after the date of randomization of the last 
patient. 
Efficacy Outcome Measures 
The primary efficacy outcome measure is tpCR, defined as the absence of any residual invasive 
cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled 
ipsilateral lymph nodes after completion of neoadjuvant therapy and surgery (i.e., ypT0/is, ypN0 
in accordance with the current American Joint Committee on Cancer [AJCC] staging system) as 
assessed by the IRC. 
The secondary efficacy outcome measures are as follows: 
• 
tpCR assessed by local pathologist 
• 
bpCR defined as the absence of any residual invasive cancer on hematoxylin and eosin 
evaluation of the resected breast specimen after completion of neoadjuvant therapy and 
surgery (i.e., ypT0/is in accordance with the current AJCC staging system) as assessed by 
the IRC 
• 
bpCR assessed by local pathologist 
• 
Clinical response during Cycles 1−4, in accordance with RECIST v1.1 
• 
EFS defined as time from randomization to the first documentation of one of the following 
events: 
Disease progression (before surgery) as determined by the investigator with use of 
RECIST v1.1 
Any evidence of in situ contralateral disease will not be identified as progressive 
disease (PD). 
Any evidence of invasive contralateral disease will be considered disease 
progression 
Disease recurrence (local, regional, distant, or contralateral) after surgery 
Death from any cause 
• 
DFS defined as the time from the first date of no disease (i.e., date of surgery) to the first 
documentation of one of the following events: 
Disease recurrence (local, regional, distant, or contralateral) after surgery 
Death from any cause 
• 
Overall survival defined as the time from randomization to death from any cause 
 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Incidence, type, and severity of adverse events and serious adverse events 
• 
Incidence of symptomatic left ventricular systolic dysfunction (heart failure) defined as the 
occurrence of symptomatic LVEF decrease or definite or probable cardiac death 
• 
Incidence of asymptomatic decline in LVEF, defined as an absolute decrease of 
≥ 10 percentage points from baseline to an LVEF of < 50% 
• 
LVEF values over the course of the study 
• 
Laboratory test result abnormalities 


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Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
To explore relationships between pathology findings from the SLN biopsy tissue sample, if 
biopsy is performed, and the ALND tissue sample, from the surgery undertaken after 
neoadjuvant treatment 
• 
Observed pertuzumab concentrations at all specified pharmacokinetic (PK) sampling 
timepoints 
• 
Observed pertuzumab concentrations compared with concentrations in Caucasian patients 
with HER2-positive breast cancer from other studies 
• 
Observed pertuzumab concentrations during neoadjuvant treatment compared with 
concentrations during adjuvant treatment (postoperative) 
• 
Expression levels or incidence of biomarkers at baseline and in resection specimen tissue, 
especially for patients with residual disease, at the time of surgery (i.e., after neoadjuvant 
treatment) and their relationship to efficacy or safety parameters 
• 
To analyze the effect of HER2 ECD on pharmacokinetics of pertuzumab 
• 
Incidence of ATAs and relationship with PK, safety, and efficacy outcome measures 
• 
tpCR in relation to clinical response, EFS, DFS, and overall survival 
 
Investigational Medicinal Products 
Trastuzumab, pertuzumab, and placebo are investigational medicinal products (IMPs) in this 
study.  Depending on local legislation, docetaxel may also be considered an IMP in this study.  
Where permitted by regulatory requirements, sites will obtain and utilize commercially available 
docetaxel.  Treatments will be administered on Day 1 of each specified cycle. 
All patients will receive docetaxel and trastuzumab by intravenous (IV) infusion in 3-week cycles 
as follows: 
• 
Neoadjuvant treatment (prior to surgery) 
Trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for Cycles 2−4) 
Docetaxel (75 mg/m2 for Cycles 1−4) 
• 
Adjuvant treatment (after surgery and three cycles of FEC chemotherapy) 
Trastuzumab (8-mg/kg loading dose for Cycle-8, followed by 6 mg/kg for Cycles 9−20) 
 
Test Product 
Patients in Arm A will receive pertuzumab by IV infusion in 3-week cycles as follows: 
• 
Neoadjuvant treatment (prior to surgery) 
Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for Cycles 2−4) 
• 
Adjuvant treatment (after surgery and three cycles of FEC chemotherapy) 
Pertuzumab (840-mg loading dose for Cycle 8, followed by 420 mg for Cycles 9−20) 
 
Comparator 
Patients in Arm B will receive placebo by IV infusion in 3-week cycles as neoadjuvant treatment 
(Cycles 1−4) and as adjuvant treatment (Cycles 8−20). 
Non-Investigational Medicinal Products 
5-fluorouracil (5-FU), 90−120 mg/m2 epirubicin, and 500−600 mg/m2 cyclophosphamide are 
non-investigational medicinal products (non-IMPs) in this study.  Depending on local legislation, 
docetaxel may also be considered a non-IMP in this study.  After surgery, all patients will 
receive FEC (5-FU 500−600 mg/m2, epirubicin 90−120 mg/m2, and cyclophosphamide 
500−600 mg/m2) by IV infusion every 3 weeks for three cycles (Cycles 5−7).  
FEC chemotherapeutic agents will be administered on Day 1 of each specified cycle. 


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Statistical Methods 
Primary Analysis 
The primary efficacy outcome measure is tpCR, defined as the absence of any residual invasive 
cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled 
ipsilateral lymph nodes after completion of neoadjuvant therapy and surgery (i.e., ypT0/is, ypN0 
in accordance with the current AJCC staging system) as assessed by the IRC.  The primary 
analysis will be performed when all patients who are eligible for surgery have completed their 
surgical treatment with an assessment of pathological response.  The analysis will be based on 
the intent-to-treat (ITT) population with patients grouped by treatment assigned at the time of 
randomization.  In the ITT population, patients whose tpCR assessment is missing or invalid are 
counted as not achieving tpCR. 
The tpCR rate as assessed by the IRC will be summarized for each treatment arm, and 95% 
CIs will be calculated using the Clopper-Pearson method.  The two-sided 
Cochran-Mantel-Haenszel test, stratified by disease category (early-stage; locally advanced) 
and hormone receptor status (positive for ER and/or PgR; negative for both) will be used to 
compare the tpCR rate between the two treatment arms.  An unadjusted Fisher exact test result 
will also be provided.  Finally, the difference in tpCR rate and associated 95% CIs will be 
provided with use of the Hauck-Anderson method. 
Determination of Sample Size 
A total of 328 patients will be randomized into the study in a ratio of 2:1 to pertuzumab (Arm A) 
or placebo (Arm B), respectively.  This will provide 85% power to detect an absolute increase in 
tpCR rate of 15% in the pertuzumab arm compared with the placebo arm at a two-sided 
significance level of 5%, assuming the tpCR rate is 20% in the placebo arm. 
Secondary Analyses 
The secondary efficacy outcome measures in this study are tpCR as assessed by the local 
pathologist, bpCR as assessed by the IRC, bpCR as assessed by the local pathologist, clinical 
response, EFS, DFS, and overall survival. 
Safety Analyses 
Safety analyses will be performed on the safety analysis population, which will consist of all 
patients who received at least one dose of study drugs and patients will be grouped by the 
treatment they actually received.  The safety analyses will be performed at the same time as the 
primary efficacy analysis, the final analyses, and when all patients have completed the 
treatment completion or study discontinuation visit. 
Exploratory Analyses 
Exploratory analyses in this study are pharmacokinetic analyses, sensitivity and subgroup 
analyses, biomarker analyses, and anti-therapeutic antibody analyses. 
Interim Analyses 
There is no interim analysis planned for the primary efficacy outcome measure, tpCR.  EFS and 
DFS data will be summarized descriptively at the time of the primary efficacy analysis.  Note 
that a final analysis of EFS, DFS, and overall survival will be performed at the end of the study, 
approximately 5 years after randomization of the last patient. 


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Appendix 2  
Schedule of Activities 
Cycle Screening
Neoadjuvant 
Treatment 
Pre-
Surgery 
Surgery 
Adjuvant Treatment 
Treatment 
Completion/ 
Discontinuation a Follow-Up b
FEC 
HER2-Targeted
1
2 
3 
4 
4 
4 
5 c 
6 
7 
820 
 
 
Day 
28 
1
1 
1 
1 
22 
2235 
1 
1 
1 
1 
Informed consent d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
General medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examination e 
x 
 
 
 
 
 
 
x 
 
 
 
x 
x 
Limited physical examination f 
 
x
x 
x 
x 
 
 
 
x 
x 
x 
 
 
Vital signs g 
x 
x
x 
x 
x 
 
 
x 
x 
x 
x 
x 
 
Weight h 
x 
x
x 
x 
x 
 
 
x 
x 
x 
x 
x 
 
Height h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
Hematology i 
x 
x
x 
x 
x 
 
 
x 
x 
x 
x 
x 
 
Chemistry j 
x 
x
 
 
 
 
 
x 
 
 
 
x 
 
Limited chemistry k 
 
 
x
x 
x 
 
 
 
x 
x 
x 
 
 
INR and aPTT 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
Urinalysis l 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
Pregnancy test m 
x 
 
 
x
 
 
 
 
x 
 
x n 
x 
x n 
Bone scan o 
x p 
 
 
 
 
 
 
 
 
 
 
 
 
Breast MRI scan p 
x 
 
 
 
 
x 
 
 
 
 
 
 
 


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Cycle Screening 
Neoadjuvant 
Treatment 
Pre-
Surgery 
Surgery 
Adjuvant Treatment 
Treatment 
Completion/ 
Discontinuation a Follow-Up b 
FEC 
HER2-Targeted 
1 
2 
3 
4 
4 
4 
5 c 
6 
7 
8−20 
 
 
Day 
−28 
1 
1 
1 
1 
22 
22−35 
1 
1 
1 
1 
Mammogram p (and ultrasound as 
per local practice) 
x 
x  
x 
x 
Additional tumor assessments 
 
x q 
Clinical tumor assessment/breast 
examination r 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x s 
x 
x 
Placement of skin tattoo and/or 
surgical clip at primary tumor site t 
x 
 
Chest X-ray u  
x p 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG v 
x p 
 
 
 
 
 
 
x 
 
 
x w 
x 
 
ECHO or MUGA scan x 
x p 
 
x y 
 
x y 
 
 
x z 
 
 
x y, aa 
x bb 
x cc 
Serum PK sample (optional) dd, ee 
 
x 
x 
 
x 
 
 
 
 
 
x ff 
x 
x gg 
Serum sample for HER2 ECD, 
HER ligands, and other 
exploratory biomarkers 
(mandatory) ee 
x 
 
 
 
 
 
x hh 
 
 
 
 
 
 
Serum sample for antibodies to 
pertuzumab (mandatory) ee 
x 
 
 
 
x 
 
 
 
 
 
x ff 
x 
x gg 
Whole blood sample for clinical 
genotyping (optional) ii  
x 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor tissue collection for 
determination of HER2 status jj 
and exploratory biomarkers 
(mandatory)  
x 
 
 
 
 
 
x kk 
 
 
 
 
 
 


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Cycle Screening 
Neoadjuvant 
Treatment 
Pre-
Surgery 
Surgery 
Adjuvant Treatment 
Treatment 
Completion/ 
Discontinuation a Follow-Up b 
FEC 
HER2-Targeted 
1 
2 
3 
4 
4 
4 
5 c 
6 
7 
8−20 
 
 
Day 
−28 
1 
1 
1 
1 
22 
22−35 
1 
1 
1 
1 
Tumor hormone receptor status 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Pathologic response assessment 
 
 
 
 
 
 
x ll 
 
 
 
 
 
 
Tumor tissue and/or serum 
sample collection at the time of 
disease progression or 
recurrence (optional) mm 
 
x 
 
Trastuzumab administration nn 
 
x 
x 
x 
x 
 
 
 
 
 
x 
 
 
Pertuzumab or placebo 
administration oo 
 
x 
x 
x 
x 
 
 
 
 
 
x 
 
 
Docetaxel administration pp 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
FEC administration qq 
 
 
 
 
 
 
 
x 
x 
x 
 
 
 
Adverse events rr 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x rr 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Survival follow-up and anti-cancer 
treatments 
 
 
 
 
 
 
 
 
 
 
 
 
x 
1. 
5-FU = 5-fluorouracil; AE = adverse event; CT = computed tomography; ECD = extracellular domain; ECHO = echocardiogram; ECOG = Eastern 
Cooperative Oncology Group; eCRF = electronic Case Report Form; FEC = 5-fluorouracil, epirubicin, and cyclophosphamide; HER = human 
epidermal growth factor receptor; IHC = immunohistochemistry; IRC = Independent Review Committee; ISU = in situ hybridization; IV = intravenous; 
LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; MUGA = multiple-gated acquisition; PET = positron emission 
tomography; PK = pharmacokinetic; ULN = upper limit of normal. 
2. 
Notes:  With the exception of Day 1 of Cycle 1, all visits and assessments should be performed within 3 days of the scheduled visit date, 
unless otherwise specified.  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.  If the timing of a 
protocol-mandated procedure coincides with a holiday or weekend, it should be performed on the nearest following date. 


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3. 
Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to enrollment may 
be used; such tests do not need to be repeated for screening. 
a The treatment completion/discontinuation visit will optimally be scheduled for 28 (± 7) days after the last dose of study treatment. 
b After treatment completion/discontinuation, follow-up information will be collected every 3 months (± 28 days) for the first year and then every 
6 months (± 28 days) thereafter, until disease progression or recurrence or until 5 years after randomization of the last patient, whichever 
occurs first.  
c Cycle 5 administration should not occur until 2 weeks after surgery. 
d Written informed consent must be obtained before any study-specific screening assessments are performed. 
e Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the General Medical History and 
Baseline Conditions eCRF.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
f Consists of a symptom-driven physical examination that focuses on organ systems related to potential and ongoing adverse events and is 
based on the patient’s clinical course during study treatment, the patient’s medical history, and/or the known adverse event profiles of the study 
medications.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
g Includes temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a seated position.  Vital signs 
should be obtained and reviewed before and after each study treatment administration but are not required to be entered into the eCRF during 
study treatment.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
h Weight is to be measured on Day 1 of each cycle and compared with baseline.  If ± 10% variation occurs, trastuzumab and chemotherapeutic 
doses will be recalculated.  Height is to be measured at baseline and should be remeasured if the investigator thinks it is possible that the 
patient's height may have changed. 
i Includes hemoglobin, hematocrit, platelet count, WBC count, and absolute neutrophil count.  Hematologic evaluations should be completed and 
reviewed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before).  At baseline, hematologic evaluations should be completed 
and reviewed within 7 days prior to study drug dosing.  Additional assessments may be performed as clinically indicated.  For AEs associated 
with abnormal laboratory values, assessments should be performed at a minimum weekly until resolution of the AE (Grade ≤ 1 or baseline). 
j Includes sodium, potassium, chloride, bicarbonate, calcium, magnesium, glucose, BUN or urea, creatinine, total protein, albumin, alkaline 
phosphatase, ALT, AST, gamma-glutamyl transferase (GGT), total bilirubin, and direct bilirubin.  At baseline, chemistry evaluations should be 
completed and reviewed within 7 days prior to study drug dosing.  Chemistry evaluations should be completed and reviewed prior to dosing on 
Day 1 of each indicated cycle (or up to 3 days before).  Additional assessments may be performed as clinically indicated.  For AEs associated 
with abnormal laboratory values, assessments should be performed at a minimum weekly until resolution of the AE (Grade ≤ 1 or baseline). 
k Includes potassium, alkaline phosphatase, ALT, AST, total bilirubin, direct bilirubin if total bilirubin is > ULN, and other tests as clinically 
indicated.  Chemistry evaluations should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before). 
l Urinalysis, which may be performed by dipstick (pH, specific gravity, glucose, protein, ketones, and blood) and microscopic examination when 
applicable (e.g., if the urinalysis is positive; sediment, RBCs, WBCs, casts, crystals, epithelial cells, and bacteria). 


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29/Statistical Analysis Plan YO28762 
m All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test within 7 days prior to 
randomization.  Urine pregnancy tests will be performed within 7 days prior to the specified subsequent visits with results available prior to 
dosing.  If a urine pregnancy test resu is positive, it must be confirmed by a serum pregnancy test. 
n Perform at Cycles 9, 12, 15, and 18, at 3 and 6 months after the last dose of study treatment and as clinically indicated.  A urine β-HCG test 
may be performed at these cycles; however, all positive urine pregnancy test results must be confirmed by a serum β-HCG test. 
o In the absence of radioactive isotopes, an MRI scan (with gadolinium enhancement if required) or PET scan is an acceptable form of 
assessment of the skeleton for the presence of bone metastases. 
p Standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to enrollment do not need to be 
repeated for screening. 
q Additional conventional methods of tumor assessments, such as MRI, CT scans, mammograms, ultrasound, or X-rays, as per local medical 
practice, may be used to evaluate disease status throughout the study. 
r Clinical tumor assessment will be performed as per local medical practice based on the principles of RECIST Version 1.1 criteria.  Perform 
axillary node examination and management per Section 4.4.1 (Axillary Management) at surgery. 
s During the adjuvant treatment period, patients should be assessed for recurrence at least every 3 months (i.e., Cycle 9, Cycle 13, Cycle 17, etc. 
and at the study completion or early termination visit). 
t Prior to neoadjuvant treatment, the tumor must be marked using local standard methods (e.g., skin tattoo or surgical clip) so that the 
appropriate excision can be made should the patient experience complete clinical regression of the tumor prior to surgery (see Appendix 8 for 
more details). 
u If a chest X-ray is not possible, an MRI or PET scan is acceptable. 
v Additional ECGs to be performed as clinically indicated. 
w Perform at Cycles 8, 12, 16, and 20 and as clinically indicated. 
x LVEF assessment by ECHO is preferred, but LVEF can also be assessed by MUGA scan. The same method should be used throughout the 
study for each patient and preferably performed and evaluated by the same assessor. 
y Perform between Days 15 and 21 (inclusive) to allow for evaluation of the results before the next treatment cycle (or before surgery). 
z Perform within 7 days prior to Cycle 5 dosing. 
aa Perform at Cycles 8, 11, and 20. 
bb Perform at the treatment completion/discontinuation visit if not performed within the previous 6 weeks. 
cc Perform every 6 months for 2 years after study drug discontinuation, then annually for an additional 2 years.  Report any cardiac events until 
the end of the study. 
dd Samples should be obtained from a subset of approximately 50 patients who are enrolled in sites in China and who have signed the separate 
consent to participate. 
ee Samples should be obtained only from randomized patients and in according with the schedule outlined in Appendix 2 or Appendix 3. 


Pertuzumab —F. Hoffmann-La Roche Ltd 
30/Statistical Analysis Plan YO28762 
ff Perform at Cycles 10 and 15, as outlined in Appendix 2 and Appendix 3. 
gg Samples should be obtained 60−90 days after the last dose of study treatment. 
hh Samples to be taken at surgery or 24 hours prior to surgery, as outlined in Appendix 2. 
ii Samples should be obtained only from patients who sign the separate consent to donate samples to the Biomarker Sample Repository. 
jj HER2-positive breast cancer must be confirmed by a Sponsor-designated central laboratory as 3+ score 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 prior to randomization.  Archival tumor 
samples or samples obtained from primary sites are acceptable.  If submission of tumor blocks or partial blocks is not a feasible alternative, 15 
unstained freshly cut slides should be sent.  The slides should be from consecutive slices from the same block. 
kk Samples from surgical resection specimens should be submitted from all patients.  For patients with residual disease, tissue samples obtained 
from resection specimen (blocks preferred) will be collected for exploratory biomarker analyses for patients who achieve pCR the (former) 
tumor bed may be analyzed, if applicable.  Up to 15 slides should be submitted for HER2 assessment and biomarker analysis. 
ll To be assessed locally and independently reviewed by the IRC, using the resected tumor according to guidelines provided in Appendix 7, 
Appendix 8, and Appendix 9. 
mm Samples should be obtained only from patients who sign the separate consent to participate.  Up to 15 slides should be submitted for HER2 
assessment and biomarker analysis. 
nn Patients will receive trastuzumab by IV infusion in 3-week cycles, as neoadjuvant treatment (8 mg/kg loading dose for Cycle 1, followed by 
6 mg/kg for Cycles 2−4) and as adjuvant treatment (8-mg/kg loading dose for Cycle 8, followed by 6 mg/kg for Cycles 9−20). 
oo Patients in Arm A will receive pertuzumab by IV infusion in 3-week cycles, as neoadjuvant treatment (840 mg loading dose for Cycle 1, followed 
by 420 mg for Cycles 2−4) and as adjuvant treatment (840-mg loading dose for Cycle 8, followed by 420 mg for Cycles 9−20).  Patients in 
Arm B will receive placebo by IV infusion in 3-week cycles, as neoadjuvant treatment (Cycles 1−4) and as adjuvant treatment (Cycles 8−20). 
pp Patients will receive docetaxel (75 mg/m2) by IV infusion every 3 weeks for Cycles 1−4. 
qq Patients will receive 500−600 mg/m2 5-FU, 90−120 mg/m2 epirubicin, and 500−600 mg/m2 cyclophosphamide by IV infusion every 3 weeks for 
Cycles 5−7. 
rr 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.  After initiation of study drug, all adverse events will be reported until 28 days after the last dose of study drug.  
After this period, investigators should report any serious adverse events or other adverse events of concern that are believed to be related to 
prior treatment with study drug.  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 study-related procedures until a final outcome can be reported.  The 
Sponsor should also be notified if the investigator becomes aware of the development of cancer or a congenital anomaly/birth defect in a 
subsequently conceived offspring of a patient who participated in this study.