Conditions: Metastatic Breast Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 40
Healthy volunteers: no

Brief summary:
This study will examine the safety and efficacy of pertuzumab in combination with high-dose trastuzumab in adult participants with HER2-positive MBC with CNS metastases and disease progression in the brain following radiotherapy.

Detailed description:

Arms:
arm 1: Participants with CNS metastases secondary to HER2-positive MBC will receive pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination.

Interventions: intervention 1: Pertuzumab intervention 2: Trastuzumab
Intervention descriptions: intervention 1: Participants will receive 840 milligrams (mg) loading dose of pertuzumab, followed every 3 weeks thereafter by a dose of 420 mg via intravenous (IV) infusion until disease progression, unacceptable toxicity, withdrawal of consent, or study termination. intervention 2: Participants will receive trastuzumab at a dose of 6 milligrams per kilogram (mg/kg) of body weight once weekly via IV infusion until disease progression, unacceptable toxicity, withdrawal of consent, or study termination.

Protocol document:
Prot_000.pdf: 
 
Official Title: 
 
AN OPEN-LABEL, SINGLE-ARM, PHASE II STUDY OF 
PERTUZUMAB WITH HIGH-DOSE TRASTUZUMAB FOR THE 
TREATMENT OF CENTRAL NERVOUS SYSTEM PROGRESSION 
POST-RADIOTHERAPY IN PATIENTS WITH HER2-POSITIVE 
METASTATIC BREAST CANCER (PATRICIA) 
NCT Number: 
NCT02536339 
Document Date: 
Protocol Version 3: 29-October-2018 
 
 


PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (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 Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered.
Pertuzumab and Trastuzumab —Genentech, Inc.
Protocol ML29366, Version 3
PROTOCOL
TITLE:
AN OPEN-LABEL, SINGLE-ARM, PHASE II STUDY 
OF PERTUZUMAB WITH HIGH-DOSE 
TRASTUZUMAB FOR THE TREATMENT OF 
CENTRAL NERVOUS SYSTEM PROGRESSION 
POST-RADIOTHERAPY IN PATIENTS WITH 
HER2-POSITIVE METASTATIC BREAST CANCER 
(PATRICIA)
PROTOCOL NUMBER:
ML29366
VERSION NUMBER:
3
EUDRACT NUMBER:
Not applicable
IND NUMBER:
4517
TEST PRODUCT:
Pertuzumab (RO4368451), Trastuzumab (RO0452317)
MEDICAL MONITOR:
 Pharm.D.
SPONSOR:
Genentech, Inc.
DATE FINAL:
Version 1:  29 April 2015
DATE AMENDED:
Version 2:  16 August 2016
Version 3:  See electronic date stamp below
 
29-Oct-2018 00:56:38
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Pertuzumab and Trastuzumab—Genentech, Inc. 
2/ Protocol ML29366, Version 3 
 
PROTOCOL AMENDMENT, VERSION 3: 
RATIONALE 
The ML29366 protocol is being amended to shorten the survival follow-up period from 
24 months to 12 months and to shorten the safety follow-up after treatment 
discontinuation from 6 months to 1 month; as the median survival observed in this 
patient population is less than 24 months.  Three patients remain on study and continue 
to receive treatment. 
Changes to the protocol, along with a rationale for each change, are summarized below: 
 
In Section 3.2, the end of study definition has been revised as patients will be 
followed for 12, not 24, months after treatment discontinuation. 
 
In Section 4.5.5, language has been revised to reflect that patients will be followed 
for 12, not 24, months after treatment discontinuation. 
 
In Section 4.6.2.2, language has been revised to reflect that all patients will be 
followed for a minimum of 12, not 24, months from the date of the last dose of study 
drug or until death, whichever occurs first. 
 
In Section 5.1.2, language has been revised to reflect that patients will be followed 
for 12, not 24, months after treatment discontinuation. 
 
In Section 5.7, the Perjeta USPI and Herceptin USPI have been removed as the 
Investigators Brochure is the appropriate single reference document to determine 
reporting requirements for single adverse event cases. 
 
In Section 6.9, the language has been revised to reflect that the primary efficacy 
analysis will be performed when all enrolled patients have been followed for 
approximately 1 month after the last patient has disease progression or early 
discontinuation or has been at least 6 months on treatment, whichever occurs first. 
 
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. 


Pertuzumab and Trastuzumab—Genentech, Inc.
3/ Protocol ML29366, Version 3
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM ............................................ 9
PROTOCOL SYNOPSIS .................................................................................... 10
1.
BACKGROUND .......................................................................................... 18
1.1
Background on HER2-Positive Central Nervous 
System Metastases ............................................................... 18
1.2
Background on Pertuzumab .................................................. 19
1.3
Background on Trastuzumab................................................. 20
1.4
Study Rationale and Benefit-Risk Assessment...................... 21
2.
OBJECTIVES.............................................................................................. 24
2.1
Efficacy Objectives ................................................................ 24
2.2
Safety Objective .................................................................... 24
2.3
Pharmacokinetic Objective .................................................... 24
2.4
Patient-Reported Outcome Objectives .................................. 24
2.5
Exploratory Objectives........................................................... 24
3.
STUDY DESIGN......................................................................................... 25
3.1
Description of Study .............................................................. 25
3.2
End of Study.......................................................................... 26
3.3
Rationale for Study Design.................................................... 26
3.3.1
Rationale for Pertuzumab and Trastuzumab 
Dose and Schedule ............................................................... 26
3.4
Outcome Measures ............................................................... 27
3.4.1
Primary Efficacy Outcome Measure ...................................... 27
3.4.2
Secondary Efficacy Outcome Measures................................ 27
3.4.3
Safety Outcome Measures .................................................... 27
3.4.4
Pharmacokinetic Outcome Measure...................................... 28
3.4.5
Patient-Reported Outcome Measure ..................................... 28
3.4.6
Exploratory Outcome Measures ............................................ 28
4.
MATERIALS AND METHODS .................................................................... 28
4.1
Patients.................................................................................. 28
4.1.1
Inclusion Criteria.................................................................... 28


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4.1.2
Exclusion Criteria................................................................... 29
4.2
Method of Treatment Assignment.......................................... 30
4.3
Study Treatment.................................................................... 31
4.3.1
Formulation, Packaging, and Handling.................................. 31
4.3.1.1
Pertuzumab (Perjeta)............................................................. 31
4.3.1.2
Trastuzumab (Herceptin)....................................................... 31
4.3.2
Dosage and Administration.................................................... 32
4.3.2.1
Pertuzumab ........................................................................... 32
4.3.2.2
Trastuzumab.......................................................................... 33
4.3.3
Investigational Medicinal Product Accountability ................... 34
4.3.4
Post-Trial Access to Pertuzumab and 
Trastuzumab.......................................................................... 34
4.4
Concomitant Therapy ............................................................ 35
4.4.1
Permitted Therapy................................................................. 35
4.4.2
Prohibited Therapy ................................................................ 35
4.5
Study Assessments ............................................................... 36
4.5.1
Informed Consent Forms and Screening Log........................ 36
4.5.2
Medical History and Demographic Data ................................ 36
4.5.3
Physical Examinations........................................................... 36
4.5.4
Vital Signs, Weight, and Height ............................................. 37
4.5.5
LVEF Evaluations.................................................................. 37
4.5.6
Performance Status............................................................... 37
4.5.7
Tumor and Response Evaluations......................................... 37
4.5.7.1
Scheduling of Tumor Assessments ....................................... 37
4.5.8
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 38
4.5.8.1
Pharmacokinetic Assessments.............................................. 39
4.5.9
Patient-Reported Outcomes .................................................. 40
4.5.10
Samples for Roche Clinical Repository.................................. 40
4.5.10.1
Overview of the Roche Clinical Repository............................ 41
4.5.10.2
Sample Collection.................................................................. 41
4.5.10.3
Confidentiality........................................................................ 41
4.5.10.4
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 42


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4.5.10.5
Withdrawal from the Roche Clinical Repository..................... 42
4.5.10.6
Monitoring and Oversight....................................................... 43
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 43
4.6.1
Patient Discontinuation.......................................................... 43
4.6.2
Study Treatment Discontinuation........................................... 43
4.6.2.1
Progression-Free Survival Follow-Up .................................... 44
4.6.2.2
Survival and LVEF Follow-Up................................................ 44
4.6.3
Study and Site Discontinuation.............................................. 44
5.
ASSESSMENT OF SAFETY....................................................................... 45
5.1
Safety Plan ............................................................................ 45
5.1.1
General Safety Monitoring..................................................... 45
5.1.2
Cardiac Safety....................................................................... 46
5.1.3
Management of Specific Adverse Events .............................. 47
5.1.3.1
Pertuzumab and Trastuzumab .............................................. 47
5.2
Safety Parameters and Definitions ........................................ 49
5.2.1
Adverse Events ..................................................................... 50
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 50
5.2.3
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 51
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 52
5.3.1
Adverse Event Reporting Period ........................................... 52
5.3.2
Eliciting Adverse Event Information....................................... 52
5.3.3
Assessment of Severity of Adverse Events ........................... 52
5.3.4
Assessment of Causality of Adverse Events ......................... 53
5.3.5
Procedures for Recording Adverse Events............................ 54
5.3.5.1
Infusion-Related Reactions.................................................... 54
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 54
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 55
5.3.5.4
Persistent or Recurrent Adverse Events................................ 55
5.3.5.5
Abnormal Laboratory Values ................................................. 55


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5.3.5.6
Abnormal Vital Sign Values ................................................... 56
5.3.5.7
Abnormal Liver Function Tests.............................................. 57
5.3.5.8
Deaths ................................................................................... 57
5.3.5.9
Preexisting Medical Conditions.............................................. 58
5.3.5.10
Lack of Efficacy or Worsening of Central Nervous 
System Metastases ............................................................... 58
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 58
5.3.5.12
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 59
5.3.5.13
Patient-Reported Outcome Data ........................................... 59
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 59
5.4.1
Emergency Medical Contacts................................................ 60
5.4.2
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 60
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 60
5.4.2.2
Events That Occur after Study Drug Initiation........................ 60
5.4.3
Reporting Requirements for Pregnancies.............................. 61
5.4.3.1
Pregnancies in Female Patients............................................ 61
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 61
5.4.3.3
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 61
5.5
Follow-Up of Patients after Adverse Events .......................... 62
5.5.1
Investigator Follow-Up........................................................... 62
5.5.2
Sponsor Follow-Up ................................................................ 62
5.6
Post-Study Adverse Events................................................... 62
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 63
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 63
6.1
Determination of Sample Size ............................................... 63
6.2
Summaries of Conduct of Study............................................ 65
6.3
Summaries of Treatment Group Comparability ..................... 65
6.4
Efficacy Analyses .................................................................. 65


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6.4.1
Primary Efficacy Endpoint...................................................... 65
6.4.2
Secondary Efficacy Endpoints............................................... 65
6.5
Safety Analysis...................................................................... 66
6.6
Pharmacokinetic Analyses..................................................... 66
6.7
Patient-Reported Outcome Analyses .................................... 67
6.8
Interim Analysis ..................................................................... 67
6.8.1
Planned Interim Analysis ....................................................... 67
6.9
Final Analysis ........................................................................ 68
7.
DATA COLLECTION AND MANAGEMENT ............................................... 68
7.1
Data Quality Assurance......................................................... 68
7.2
Electronic Case Report Forms............................................... 69
7.3
Source Data Documentation.................................................. 69
7.4
Use of Computerized Systems .............................................. 70
7.5
Retention of Records............................................................. 70
8.
ETHICAL CONSIDERATIONS.................................................................... 70
8.1
Compliance with Laws and Regulations ................................ 70
8.2
Informed Consent.................................................................. 70
8.3
Institutional Review Board or Ethics Committee.................... 71
8.4
Confidentiality........................................................................ 72
8.5
Financial Disclosure .............................................................. 72
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 73
9.1
Study Documentation ............................................................ 73
9.2
Protocol Deviations................................................................ 73
9.3
Site Inspections ..................................................................... 73
9.4
Administrative Structure......................................................... 73
9.5
Publication of Data and Protection of Trade 
Secrets .................................................................................. 73
9.6
Protocol Amendments ........................................................... 74
10. REFERENCES ........................................................................................... 75


Pertuzumab and Trastuzumab—Genentech, Inc.
8/ Protocol ML29366, Version 3
LIST OF TABLES
Table 1
Actions to be Taken in Case of Pertuzumab- and 
Trastuzumab-Related Toxicity .................................................... 48
Table 2
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 53
Table 3
Causal Attribution Guidance ....................................................... 54
Table 4
Estimated Confidence Intervals for Additional Assumed 
Objective Response Rates.......................................................... 64
Table 5
Probability of Adverse Events ..................................................... 64
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 26
LIST OF APPENDICES
Appendix 1
Schedule of Assessments........................................................... 78
Appendix 2
Schedule of Assessments for Scans........................................... 83
Appendix 3
Schedule of Pertuzumab and Trastuzumab Pharmacokinetic 
Assessments............................................................................... 84
Appendix 4
Response Assessment in Neuro-Oncology-Brain Metastases 
(RANO-BM) Criteria:  Modified Excerpt from Original 
Publication .................................................................................. 85
Appendix 5
Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1):  Modified Excerpt from Original Publication ....... 91
Appendix 6
Asymptomatic Decline in LVEF:  Algorithm for Continuation 
and Discontinuation of Pertuzumab and Trastuzumab Based 
on LVEF Assessments.............................................................. 103
Appendix 7
New York Heart Association Classification of Functional 
Cardiac Capacity....................................................................... 104
Appendix 8
Eastern Cooperative Oncology Group (ECOG) Performance 
Status Scale.............................................................................. 105
Appendix 9
Left Ventricular Systolic Dysfunction Grading ........................... 106
Appendix 10
Reporting Conventions for Left Ventricular Systolic 
Dysfunction/Heart Failure ......................................................... 107
Appendix 11
M.D. Anderson Symptom Inventory-Brain Tumor
(MDASI-BT) .............................................................................. 108


Pertuzumab and Trastuzumab—Genentech, Inc.
9/ Protocol ML29366, Version 3
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
AN OPEN-LABEL, SINGLE-ARM, PHASE II STUDY 
OF PERTUZUMAB WITH HIGH-DOSE 
TRASTUZUMAB FOR THE TREATMENT OF 
CENTRAL NERVOUS SYSTEM PROGRESSION 
POST-RADIOTHERAPY IN PATIENTS WITH 
HER2-POSITIVE METASTATIC BREAST CANCER 
(PATRICIA)
PROTOCOL NUMBER:
ML29366
VERSION NUMBER:
3
EUDRACT NUMBER:
Not applicable
IND NUMBER:
4517
TEST PRODUCT:
Pertuzumab (RO4368451), trastuzumab (RO0452317)
MEDICAL MONITOR:
, Pharm.D.
SPONSOR:
Genentech, Inc.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by the CRO.


Pertuzumab and Trastuzumab—Genentech, Inc.
10/ Protocol ML29366, Version 3
PROTOCOL SYNOPSIS
TITLE:
AN OPEN-LABEL, SINGLE-ARM, PHASE II STUDY OF 
PERTUZUMAB WITH HIGH-DOSE TRASTUZUMAB FOR THE 
TREATMENT OF CENTRAL NERVOUS SYSTEM PROGRESSION 
POST-RADIOTHERAPY IN PATIENTS WITH HER2-POSITIVE 
METASTATIC BREAST CANCER (PATRICIA)
PROTOCOL NUMBER:
ML29366
VERSION NUMBER:
3
EUDRACT NUMBER:
Not applicable
IND NUMBER:
4517
TEST PRODUCT:
Pertuzumab (RO4368451), trastuzumab (RO0452317)
PHASE:
Phase II
INDICATION:
HER2-positive MBC with CNS metastases
SPONSOR:
Genentech, Inc.
Objectives
Efficacy Objectives
The primary efficacy objective for this study is as follows:

To evaluate the efficacy of the study combination of pertuzumab with high-dose 
trastuzumab for the treatment of central nervous system (CNS) progression 
post-radiotherapy in patients with human epidermal growth factor receptor-2 
(HER2)-positive metastatic breast cancer (MBC), as measured by objective response rate 
(ORR) in the CNS
The secondary efficacy objective for this study is as follows:

To evaluate the efficacy of pertuzumab with high-dose trastuzumab for these same patients, 
as measured by duration of response (DOR) in the CNS, clinical benefit rate (CBR) for the 
CNS, progression-free survival (PFS) in the CNS, PFS (CNS or non-CNS), and overall 
survival (OS)
Safety Objective
The safety objective for this study is as follows:

To evaluate the safety of the study dose of pertuzumab (loading dose of 840 mg 
intravenous [IV] followed every 3 weeks thereafter by a dose of 420 mg IV) and high-dose 
trastuzumab (6 mg/kg IV weekly) for the treatment of patients with HER2-positive MBC with 
CNS progression post-radiotherapy
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is as follows:

To characterize the serum pharmacokinetics of pertuzumab (loading dose of 840 mg IV 
followed every 3 weeks thereafter by a dose of 420 mg IV) and high-dose trastuzumab 
(6 mg/kg IV weekly) for the treatment of patients with HER2-positive MBC with CNS 
progression post-radiotherapy


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Patient-Reported Outcome Objectives
The patient-reported outcome (PRO) objectives for this study are as follows:

To evaluate the impact of treatment with pertuzumab and high-dose trastuzumab in patients 
with HER2-positive MBC with CNS progression post-radiotherapy on PROs, as measured 
by the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT) assessment 

To evaluate the relationship of ORRs with PRO endpoints, as measured by the MDASI-BT
Exploratory Objectives
The exploratory objectives for this study are as follows:

To perform an exploratory analysis of the relationship between pertuzumab and high-dose 
trastuzumab exposure and efficacy and safety endpoints

To collect (optional) tissue samples and plasma, which will be banked for future biomarker 
analysis
Study Design
Description of Study
This is a U.S.-based, Phase II, open-label, single-arm study designed to examine the safety and 
efficacy of pertuzumab (loading dose of 840 mg IV followed every 3 weeks thereafter by a dose 
of 420 mg IV) and high-dose trastuzumab (6 mg/kg IV weekly) administered to patients with 
HER2-positive, MBC-related CNS metastases (parenchymal) that have disease progression in 
the brain following radiotherapy (stereotactic radiosurgery [SRS] or whole brain radiotherapy 
[WBRT]).  No changes will be made to the patient’s current treatment (e.g., chemotherapy, 
hormonal therapy) for systemic disease in order to optimize the ability to detect any incremental 
benefits provided by the combination of pertuzumab and high-dose trastuzumab (see 
Section 4.3.1.1 for dosing information).  The following exceptions, however, will be made:  

Patients receiving treatment with ado-trastuzumab emtansine (also known as T-DM1 or 
Kadcyla)
–
Ado-trastuzumab emtansine will be discontinued 3 weeks prior to initiation of 
pertuzumab with high-dose trastuzumab. 

Patients receiving treatment with lapatinib
–
Lapatinib will be discontinued 1 week prior to initiation of pertuzumab with high-dose 
trastuzumab.
Patients may remain on study treatment until disease progression within the CNS or systemic 
progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, 
whichever occurs first.
Overall safety will be assessed on an ongoing basis during the conduct of the study. 
Number of Patients
Approximately 40 patients will be enrolled in the study.
Target Population
Patients with HER2-positive MBC with documented CNS progression of disease 
post-radiotherapy (WBRT/SRS) and stable systemic disease will be enrolled in the study.  
Inclusion Criteria
Patients must meet the following criteria for study entry:

Able and willing to provide written informed consent

Able and willing to comply with the study protocol

Age 18 years

Pathologically confirmed HER2-positive MBC by local laboratory with the following 
requirements:
–
HER2 overexpressed or amplified (immunohistochemistry of 3or HER2 gene 
amplification by in situ hybridization with a ratio of HER2-gene signals to centromere 
17 signals 2.0 or average HER2 copy number 6.0 signals/cells) 


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
Unequivocal evidence of new and/or progressive brain metastases after completion of 
WBRT or SRS

Completed previous SRS or WBRT 60 days

At least one measurable CNS metastasis (lesion 10 mm per Response Assessment in 
Neuro-Oncology-Brain Metastases [RANO-BM] criteria)

Confirmed tumor assessment demonstrating stable measureable/non-measureable 
systemic disease

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

LVEF 50% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 
28 days before Day 1 of study

Adequate bone marrow function, as indicated by the following:
–
ANC 1500/L
–
Platelets 75,000/L
–
Hemoglobin 9 g/dL

Adequate renal function, as indicated by creatinine 1.5 upper limit of normal (ULN)

Adequate liver function, as indicated by bilirubin 1.5 ULN
–
AST and ALT 2.5 ULN unless related to primary disease; up to 5ULN if liver 
metastases are present

Life expectancy12 weeks

Female patients of childbearing potential, including those who have had tubal ligation, and 
women 12 months after the onset of menopause, even if they have undergone surgical 
sterilization, must have a negative serum pregnancy test 7 days prior to initiation of study 
drug (with result available prior to dosing).

Female patients of childbearing potential (who are not postmenopausal 12 months of 
non-therapy-induced amenorrhea or surgically sterile [absence of ovaries and/or uterus]) 
and male patients with female partners of childbearing potential must agree to use one 
highly effective or two effective methods of non-hormonal contraception, as specified in the 
protocol, during their participation in the study and for at least 7 months after last dose of 
study drug.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Progression of systemic disease at time of screening

Leptomeningeal disease (LMD)
–
LMD is a clinical diagnosis, defined as positive cerebrospinal fluid (CSF) cytology 
and/or unequivocal radiological or clinical evidence of clinically significant 
leptomeningeal involvement
–
Patients with leptomeningeal symptoms would be considered to have LMD even in the 
absence of positive CSF cytology, unless a parenchymal lesion can adequately explain 
the neurological deficit
–
Patients who are asymptomatic or with nonspecific leptomeningeal enhancement would 
not be considered to have LMD. However, if there is clinical or radiographic suspicion 
of LMD, CSF confirmation to rule out LMD is at the investigator’s discretion.

History of intolerance (Grade 3) or hypersensitivity to trastuzumab or pertuzumab

Current use or history of receiving a non-approved, investigational treatment within 21 days 
prior to study enrollment

Current use of anthracyclines

Patients unwilling to discontinue ado-trastuzumab emtansine or lapatinib therapy

Active infection

Pregnant or lactating women


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–
Women who are not postmenopausal (12 months of non-therapy-induced 
amenorrhea) or surgically sterile must have a negative serum pregnancy test 
result 7 days prior to initiation of study drug.

History of significant cardiac disease, cardiac risk factors, uncontrolled arrhythmias, or 
uncontrolled hypertension

Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs, resulting in 
dyspnea at rest

History of other malignancy within the last 5 years, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or 
other cancers with a similar outcome as those mentioned
Length of Study
The total length of this study will be from screening of the first patient to completion of the last 
follow-up assessment of the last patient, which is estimated to occur approximately 3 years after 
the first patient is screened.
End of Study
The study will end when all patients have been followed for 12 months after the treatment
discontinuation visit (inclusive of the safety and survival follow-up periods), unless they have 
been lost to follow-up, withdrawn consent, or died, or if the study is prematurely terminated by 
the Sponsor, whichever occurs first.
Outcome Measures
Primary Efficacy Outcome Measure
The primary efficacy outcome measure for this study is as follows:

Objective response rate (ORR) in the CNS (assessed per RANO-BM criteria; see 
Appendix 4).  Objective response is defined as complete response (CR) or partial response 
(PR).
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures for this study are as follows:

DOR in the CNS, CBR for the CNS, PFS in the CNS, PFS (CNS or non-CNS), and OS
–
Tumor response in CNS will be assessed per RANO-BM criteria (see Appendix 4).  
–
Non-CNS tumor response will be assessed by Response Evaluation Criteria in Solid 
Tumors, Version 1.1 (RECIST v1.1; see Appendix 5).
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence and severity of all non-serious and serious adverse events

Incidence and severity of Grade 3 adverse events and serious adverse events

Incidence of adverse events leading to discontinuation or interruption of pertuzumab alone 
or the combination of pertuzumab and trastuzumab

Cause of death while on study

Incidence and severity of cardiac events, as assessed by the investigator using National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI 
CTCAE v4.0) and New York Heart Association (NYHA) classification for congestive heart 
failure (CHF; see Appendix 7) 

Characterization of changes in left ventricular ejection fraction (LVEF) and changes in LVEF 
from baseline over the course of the study (see Appendix 6)

Clinically significant laboratory test abnormalities


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Pharmacokinetic Outcome Measures
The PK outcome measures for this study are as follows:

Observed serum concentrations for pertuzumab and trastuzumab at the following 
timepoints: 
–
Week 1, Day 1 (1 sample pre-dose and 1 sample within 30 minutes after completion
of both infusions [maximum concentration (Cmax)]) (total of 2 samples)
–
Week 4, Day 1 (pre-dose [trough])
–
Week 10, Day 1 (pre-dose [trough])
–
Week 16, Day 1 (1 sample pre-dose and 1 sample within 30 minutes after 
completion of both infusions [Cmax])  (total of 2 samples)
Patient-Reported Outcome Measure
The PRO outcome measures for this study is as follows:

Scores from the MDASI-BT assessment
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:

To explore the relationship between pertuzumab and high-dose trastuzumab exposure and 
efficacy and safety endpoints

Collection of (optional) tissue and plasma samples
Investigational Medicinal Products
Study treatment is defined as systemic, biologic agent for the treatment of CNS metastases due 
to HER2-positive breast cancer.  Pertuzumab and trastuzumab are considered investigational 
medicinal products (IMPs) in this study.
Any background systemic agents for the management of disease (i.e., chemotherapy, hormone 
therapy) are considered non-IMPs in this study.
Test Product (Investigational Drugs)
Pertuzumab will be administered at a dose of 840 mg administered as a 60-minute IV infusion 
with an observation period of 60 minutes (loading dose), followed every 3 weeks thereafter by a 
dose of 420 mg administered over a period of 30 60 minutes with an observation period of 
30 60 minutes.  For patients already receiving pertuzumab as part of their ongoing systemic 
therapy, no loading dose is required in the case of an interval 6 weeks between the last dose 
of pertuzumab and the first administration of on-study pertuzumab.   
High-dose trastuzumab will be administered at a dose of 6 mg/kg weekly, infused intravenously 
over 30 90 minutes.  No loading dose is required.  Trastuzumab-naïve patients should receive 
their first dose over 90 minutes.  Patients who are actively receiving trastuzumab prior to 
enrollment will have a dose increase to 6 mg/kg IV weekly.  The dose of trastuzumab will be 
based on the patient’s actual body weight measured at baseline.  The dose need not be 
recalculated unless body weight has changed by10% from baseline.    
Non-Investigational Medicinal Products
For non-IMPs, refer to local prescribing information/institutional guidelines for detailed 
guidelines on administration, premedications, and dose delays/reductions for toxicities.
Statistical Methods
Efficacy Analyses
The primary efficacy endpoint is ORR in the CNS per RANO-BM criteria.  To evaluate the ORR, 
two sets of analyses will be performed:  one is based on the efficacy-evaluable population and 
the other is based on the safety population.  The efficacy-evaluable population is the primary 
population for ORR in CNS.  Any patient without sufficient data to determine response (e.g., 
non-evaluable patients) will be classified as a non-responder.  The estimate of the ORR with 95% 
Clopper-Pearson exact confidence interval (CI) will be presented.  Responses to study 
treatment will be based on investigator assessments. 
Secondary efficacy endpoints include DOR in the CNS, CBR for the CNS, PFS in the CNS, PFS 
(CNS or non-CNS), and OS.  The Kaplan-Meier approach will be used to estimate the 


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distribution of DOR, PFS, and OS.  The 95% CI for the median time to event will be calculated 
using the Brookmeyer and Crowley method.
Determination of Sample Size  
The emphasis of this study is estimation of the ORR with a given precision, rather than 
hypothesis testing.  ORRs of 20% or higher will be deemed clinically significant because no 
other therapeutic options are available for this patient population. 
With 35 evaluable patients, and assuming that the study treatment is expected to lead to an 
ORR in CNS of 20% (7 patients), the 95% CI around the estimated ORR will be 8.4%36.9%.  
Interim Analysis
An interim analysis will be performed when 15 patients are enrolled and have the following:  
1) at least two LVEF measurements (at Week 6 and Week 12), 2) two cycles (3-week cycle) of 
study drug, and 3) two response measurements for review.  Complete guidelines to assist in 
decision-making will be described in the Steering Committee charter.  For this interim analysis, 
the safety endpoints will be of primary consideration.  Efficacy endpoints will also be examined 
to identify potential treatment non-benefits. 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AC
anthracycline plus cyclophosphamide
BBB
blood-brain barrier
CBR
clinical benefit rate
CHF
congestive heart failure
Cmax
concentration maximum
Cmin
concentration minimum
CNS
central nervous system
CR
complete response
CRO
contract research organization
CSF
cerebrospinal fluid
CT
computed tomography
D5W
dextrose (5%) in water
DOR
duration of response
EC
Ethics Committee
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
FDA
U.S. Food and Drug Administration
HER2
human epidermal growth factor receptor-2
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Conference on Harmonisation
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (application)
IRB
Institutional Review Board
IRF
independent review facility
IRR
infusion-related reaction
IUD
intrauterine device
IV
intravenous
IXRS
interactive voice/web response system
LPLV
last patient, last visit
LVEF
left ventricular ejection fraction
LVSD
left ventricular systolic dysfunction


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MBC
metastatic breast cancer
MDASI-BT
M.D. Anderson Symptom Inventory-Brain Tumor
MRI
magnetic resonance imaging
MUGA
multigated acquisition
NCCN
National Comprehensive Cancer Network
NCI CTCAE
National Cancer Institute Common Terminology Criteria 
for Adverse Events
NYHA
New York Heart Association
ORR
objective response rate
OS
overall survival
PET-CT
positron-emission tomography CT
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PRO
patient-reported outcome
RANO-BM
Response Assessment in Neuro-Oncology-Brain 
Metastases
RCR
Roche Clinical Repository
RECIST
Response Evaluation Criteria in Solid Tumors
SRS
stereotactic radiosurgery
ULN
upper limit of normal
USPI
U.S. Package Insert
WBRT
whole-brain radiation therapy


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1.
BACKGROUND
1.1
BACKGROUND ON HER2-POSITIVE CENTRAL NERVOUS 
SYSTEM METASTASES
Breast cancer is the second most prevalent malignancy metastasizing to the central 
nervous system (CNS), accounting for 20% of cases observed in cancer care (Boogerd 
et al. 1993). The incidence of clinically evident brain metastasis in patients with 
metastatic breast cancer (MBC) is estimated to be between 10% and 30% (Pivot et al. 
2015). Patients who develop metastatic CNS disease have a poor prognosis and 
associated neurological complications that often lead to significant morbidity and 
mortality. The management of intracranial metastases from breast cancer has become 
a vital component of disease control, and increasingly patients are progressing in the 
CNS after radiotherapy, at which point the standard options become quite limited.
Human epidermal growth factor receptor-2 (HER2) is a member of the erb-B epidermal 
growth factor receptor tyrosine kinase family, and is overexpressed in 18%20% of 
human breast cancers (Altaha et al. 2005; Stemmler et al. 2006; Yau et al. 2006; Pinder 
et al. 2007). Clinically, its overexpression is an independent adverse prognostic factor 
and is associated with an aggressive clinical course and poor survival in breast cancer 
patients. Advancements in HER2-targeted therapies have altered the natural landscape 
of HER2-positive breast cancer and improved systemic control and overall survival. 
The incidence of CNS metastases (24%48%) is higher in HER2-positive MBC patients 
than reported for other cancers  (Altaha et al. 2005; Stemmler et al. 2006; Yau et al. 
2006; Pinder et al. 2007).  In an analysis of 10 adjuvant trials examining the sites of 
metastases in 9524 patients with early stage breast cancers treated without 
anthracyclines, taxanes, or trastuzumab in the pre-trastuzumab era, the 10-year 
incidence of CNS relapse at any time was almost double in patients with HER2-positive 
disease compared to those with HER2-negative breast cancer (6.8% versus 3.5%; 
p0.01) (Pestalozzi et al. 2006). In the epidemiological registHER (registry of 
HER2-positive patients) study of 1023 patients with newly diagnosed HER2-positive 
MBC, 37% of patients had a diagnosis of CNS metastases at a 29-month median 
follow-up (Brufsky et al. 2011). Of these, 7% had intracranial involvement at the time of 
their MBC diagnosis and 30% as a subsequent site of disease progression. Patients are 
not actively screened for CNS involvement. The actual incidence of CNS metastases 
may be greater than observed in retrospective studies. The CEREBEL trial compared 
the incidence of the CNS as the site of first relapse in patients with HER2-positive MBC 
treated with trastuzumab plus capecitabine to the incidence in patients treated with 
lapatinib plus capecitabine. At screening, asymptomatic CNS metastases were 
identified in 20% of the patients (Pivot et al. 2015).
In older studies, the one-year survival rate in patients with CNS metastases was 20% 
(Pestalozzi 2009).  However, patients with HER2-positive brain metastases often live 


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longer, and in some multicenter series, median survival after a brain metastasis 
diagnosis is now in the range of 2 years in HER2-positive patients (Sperduto et al. 2012).   
1.2
BACKGROUND ON PERTUZUMAB
Pertuzumab (Perjeta), a humanized monoclonal antibody to the HER2 receptor, blocks 
ligand-dependent heterodimerization of HER2 with other HER family members. This 
results in the inhibition of ligand-initiated intracellular signaling.  In addition, pertuzumab
mediates antibody-dependent cellular cytotoxicity.
Pertuzumab has been shown in nonclinical settings to have superior anti-tumor effects 
when combined with trastuzumab than when used as monotherapy.
Trastuzumab and pertuzumab monoclonal antibodies bind to distinct epitopes on the 
HER2 receptor without competing with each other, resulting in distinctive mechanisms 
for disrupting HER2 signaling.  These mechanisms are complementary and result in 
augmented therapeutic efficacy when pertuzumab and trastuzumab are given in 
combination.  Pertuzumab binds to an epitope within subdomain 2 of HER2, whereas 
the epitope for trastuzumab is localized to subdomain 4 (Cho et al. 2003; Franklin et al. 
2004).  Pertuzumab acts by blocking dimerization of HER2 with other HER family 
members, thereby inhibiting ligand-initiated intracellular signaling through two major 
signaling pathways, MAPK and PI3K.  Inhibition of these pathways can result in growth 
arrest and apoptosis (Hanahan and Weinberg 2000).  In comparison, trastuzumab binds 
to the juxtamembrane epitope (subdomain 4), preventing cleavage and ligand 
independent signal transduction.  Both antibodies are also capable of activating 
antibody-dependent, cell-mediated cytotoxicity (Spector and Blackwell 2009).
In the Phase III, pivotal study WO20698/TOC4129g (CLEOPATRA; N808) in patients 
with previously untreated HER2-positive MBC, a statistically significant and clinically 
meaningful improvement in progression-free survival (PFS), based on tumor 
assessments by an independent review facility (IRF), was observed in patients treated 
with pertuzumab, trastuzumab, and docetaxel (n406) compared with those receiving 
placebo, trastuzumab, and docetaxel (n402).  PFS was prolonged at the median by 
6.1 months, and the risk of disease progression or death was reduced by 38% (hazard 
ratio [HR]:  0.62; 95% confidence interval [CI]:  0.51, 0.75; p0.0001) with an 
improvement in median PFS from 12.4 months to 18.5 months.  Results of the 
investigator-assessed PFS analysis (HR:  0.65 [0.54, 0.78]; p0.0001; median 12.4 vs. 
18.5 months, respectively) were consistent with those observed for IRF-assessed PFS.  
A second interim analysis of overall survival (OS; performed one year after the primary 
analysis of efficacy) crossed the predefined stopping boundary for statistical significance 
(p 0.0138), demonstrating that treatment with pertuzumab, trastuzumab, and docetaxel 
significantly improved OS when compared with the placebo arm (HR:  0.66; 95% CI:  
0.52, 0.84; p 0.0008).  The updated analysis of investigator-assessed PFS 
demonstrated that the PFS benefit observed at the primary analysis was maintained 
after an additional year of follow-up.  The HR of 0.69 and the increase in median PFS of 


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6.3 months (from 12.4 months in the placebo arm to 18.7 months in the treatment arm) 
were highly consistent with those from the first analysis of investigator-assessed PFS 
and consequently also with the primary IRF analysis (Swain et al. 2013). 
Based on these data, pertuzumab was approved by the FDA for use in 
HER2-overexpressing MBC in combination with trastuzumab and docetaxel for first-line 
treatment metastatic disease.
Pertuzumab is also currently approved in the early breast cancer setting.  
See the pertuzumab Investigator's Brochure for additional information.
1.3
BACKGROUND ON TRASTUZUMAB
Trastuzumab (Herceptin) is a recombinant monoclonal antibody that binds specifically 
and with high affinity to the extracellular domain of HER2. Trastuzumab has been
shown to inhibit the proliferation of human tumor cells overexpressing HER2 both in vitro 
and in vivo.
The clinical benefit of trastuzumab in women with MBC has been demonstrated in two 
pivotal studies. 
A Phase II trial (H0649g) assessed the activity of single-agent trastuzumab in 
222 women with HER2-overexpressing MBC with progressive disease after one or more 
chemotherapy regimens (Cobleigh et al. 1999). An independent response evaluation 
committee identified 8 complete and 26 partial responses, for an objective response rate 
of 15% in the intent-to-treat population (95% CI: 11% to 21%). The median duration of 
response was 9.1 months, and the median duration of survival was 13 months. The 
most common adverse events, which occurred in approximately 40% of patients, were 
mild to moderate infusion-associated fever and/or chills.  The most clinically significant 
event was cardiac dysfunction, which occurred in 4.7% of patients.
An open-label, randomized, Phase III study (H0648g) in 469 patients with HER2-positive 
MBC was conducted to evaluate the efficacy of trastuzumab in combination with 
chemotherapy as first-line treatment. Patients who were anthracycline-naïve were 
randomized to receive either anthracycline plus cyclophosphamide (AC) or trastuzumab
plus AC. Patients who had received prior anthracyclines in the adjuvant setting were 
randomized to receive either paclitaxel or trastuzumab plus paclitaxel. As determined by 
an independent response evaluation committee, trastuzumab prolonged median time to 
disease progression from 4.6 months to 7.4 months (p0.001), improved the overall 
response rate (complete and partial responses) from 32% to 50% (p0.001), and 
increased median duration of response from 6.1 to 9.1 months (p0.001). Compared to 
chemotherapy alone, the addition of trastuzumab significantly lowered the incidence of 
death at one year from 33% to 22% (p0.008) and increased median overall survival 24% 
from 20.3 months to 25.1 months (p0.046) (Slamon et al. 2001). The observed 


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survival advantage remained despite crossover of 66% of patients initially randomized to 
chemotherapy alone who elected to receive trastuzumab upon disease progression 
(Tripathy et al. 2000). Fever/chills were observed with the initial trastuzumab infusion in 
approximately 25% of patients. Class III or IV cardiac dysfunction was observed in 16% 
of the trastuzumabAC subgroup; increasing age was an associated risk factor for the 
development of cardiotoxicity in this treatment cohort (Slamon et al. 2001). 
Based on these data, trastuzumab was approved by the U.S. Food and Drug 
Administration (FDA) for use in HER2-overexpressing MBC in combination with 
paclitaxel for first-line treatment and as a single agent for patients failing prior 
chemotherapy for metastatic disease. 
Trastuzumab is also currently approved in the early breast cancer setting.  
See the trastuzumab Investigator's Brochure for additional information.
1.4
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
The incidence of CNS disease in HER2-positive MBC is close to 50%. Tumors 
overexpressing HER2 may have a predilection for brain metastases. Kallioniemi and 
colleagues (1991) demonstrated that HER2-positive disease is associated with a 
different pattern of metastatic spread, and those with overexpression of the HER2 gene 
metastasized three times more often (p0.0002) to the brain.  HER2 overexpression 
has shown to be a predictive factor for CNS metastases in advanced breast cancer 
(Miller at al. 2003).
Improvements in extra-cranial control with HER2-directed therapy may be a contributing 
factor to the observed increased risk of brain metastases as site of first relapse reported 
in multiple studies. A systematic review of trastuzumab-containing regimens from early 
breast cancer examined data from five randomized clinical trials (B-31, FinHer, HERA, 
N9831, and PACS-04).  This analysis reported an increased risk of brain metastases as 
the site of first relapse in patients treated with trastuzumab (risk ratio: 1.75, 90% CI: 
1.292.38; p0.002) compared to trastuzumab-naïve patients in the control arms, 
73/3120 patients and 50/3761 patients, respectively (Moja et al. 2012). In a 
population-based registry study of 1458 patients with early stage breast cancer, CNS as 
the site of first recurrence was documented for 0.6% of patients with HER2-negative 
disease and for 4% and 1.2% of patients with HER2-positive disease who had and had 
not received adjuvant trastuzumab, respectively. Time to CNS as first recurrence from 
diagnosis, however, was significantly prolonged in patients with HER2-positive disease 
who received adjuvant (20.3 months) compared with patients with HER2-negative 
disease (19.8 months) and those with HER2-positive disease who did not receive 
trastuzumab (10.3 months) (p0.018) (Musolino et al. 2011).
Multiple retrospective studies have reported an OS benefit in patients with CNS 
metastases treated with trastuzumab.  Dawood et al. (2008) reported findings 


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demonstrating that patients with HER2-negative disease and patients with 
HER2-positive disease who had never received trastuzumab had an increased hazard of 
death compared with patients with HER2-positive disease who had received 
trastuzumab before or at the time of CNS metastases diagnosis.  The prospective 
observational registHER trial demonstrated continuation of trastuzumab after intracranial 
metastases to be associated with improved survival. The median survival for patients 
who received trastuzumab subsequent to CNS diagnosis was 17.5 months compared 
with 3.7 months for patients who did not (Brufsky et al. 2011). Results from the Phase III 
CLEOPATRA trial in HER2-positive, first-line MBC demonstrated significant 
improvements in PFS and OS with pertuzumab in combination with trastuzumab and 
docetaxel over placebo, trastuzumab, and docetaxel. A subsequent exploratory 
analyses of the incidence and time to development of CNS metastases in patients from 
CLEOPATRA suggest that pertuzumab added to trastuzumab and docetaxel delays the 
onset of CNS disease compared with the control arm, as well as an OS trend in favor of 
pertuzumab combined with trastuzumab and docetaxel in patients who developed CNS 
metastases as the first site of disease progression (Swain et al. 2014).
The standard of care for the treatment of CNS metastasis consists of local modalities 
and includes surgery, whole brain radiotherapy (WBRT), and stereotactic radiosurgery 
(SRS). These approaches can reduce tumor burden and palliate neurological symptoms
but are often associated with neurocognitive and other morbidities. Current American 
Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network 
(NCCN) recommendations for the systemic management of HER2-positive breast 
cancer are limited and based on low-level evidence. 
CNS response to existing systemic anticancer therapies at standard dosages has been 
disappointing, in part due to the limited capacity of many of these drugs to cross the 
blood–brain barrier (BBB) effectively and the therapeutic concentration limitations 
resulting from active drug efflux proteins such as P-glycoprotein (Pgp), which are 
present in high concentrations in the luminal membranes of brain endothelium (Régina 
et al. 2001). Large monoclonal antibodies in particular are not believed to cross an 
intact BBB.  However, the BBB may be subject to increased permeability/disruption 
associated with radiation effects and tumor invasion. The influence of WBRT on 
monoclonal antibody uptake in the brain was examined in a pilot study in patients with 
HER2-positive breast cancer-related brain metastases. This study demonstrated 
increased trastuzumab uptake after WBRT; the median serum cerebrospinal fluid
trastuzumab concentration ratios were 420:1 and 76:1 pre- and post-WBRT (Stemmler 
et al. 2007). A study using positron electron tomography imaging demonstrated CNS 
penetration by 89Zr-trastuzumab in patients with MBC with an 18-fold higher uptake in 
brain tumors than in normal brain tissue (Dijkers et al. 2010).
Multiple studies have demonstrated in both retrospective and prospective observational 
data that patients treated with trastuzumab prior to the development of CNS metastases 
and/or after CNS metastases have improved survival outcomes. Incremental increases 


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in uptake of trastuzumab have been observed with standard systemic dosing when the 
BBB is disrupted by associated radiation effects and/or tumor invasion (Dijkers et al. 
2010). Subtherapeutic trastuzumab levels achieved in the CNS may be related to 
insufficient dosing as opposed to the inability of trastuzumab to cross the BBB. 
Phillips et al. (unpublished Genentech internal data) evaluated the relationship between 
dose-response in brain graft experiments in murine models.  When evaluated in brain 
graft experiments, 4D5 (a murine equivalent of trastuzumab) doses up to three times the 
effective dose used in mammary grafts were required to achieve efficacy in brain grafts.  
These data suggest that an increased dose of trastuzumab could lead to improved 
efficacy against metastases in the CNS for HER2-positive MBC patients.  Higher 
trastuzumab dosages have not been associated with increased cardiotoxicity or adverse 
events as observed in a Phase I study (8 patients received 500 mg intravenously every 
week for 8 weeks), and data from two Phase II studies (Vogel et al. 2002; Leyland-Jones 
et al. 2010) where patients received two (N57) and three times (N47) the standard 
dose. 
The impact of a more comprehensive blockade of cell signaling associated with the 
addition of pertuzumab to trastuzumab has been demonstrated in the nonclinical and 
clinical settings. The combination of pertuzumab and trastuzumab with docetaxel 
demonstrated statistically significant and clinically meaningful improvements in 
outcomes (PFS and OS) without an observed increase in cardiotoxicity compared with 
trastuzumab and docetaxel in a pivotal, Phase III, randomized, controlled trial 
(CLEOPATRA; Perjeta U.S. Package Insert [USPI]). Pertuzumab and trastuzumab
combinations are the current standard of care in first-line HER2-positive MBC.  Data 
from CLEOPATRA also suggest that the addition of pertuzumab to trastuzumab and 
chemotherapy delays the onset of CNS disease compared with trastuzumab and 
chemotherapy alone (15 months vs. 11.9 months; hazard ratio:  0.58; 95% CI: 
0.390.85; p0.0049), demonstrating that the two agents in combination may have 
improved activity in the CNS (Swain et al. 2014).
Currently, there is no clear standard of care that addresses recurring or multiple 
intracranial metastases in HER2-positive MBC. CNS metastasis is a stipulated 
exclusion criterion in most clinical trials of systemic therapies, and clinical data reporting 
the efficacy of systemic therapy for breast cancer brain metastases are limited. CNS 
response to existing systemic anticancer therapies at standard dosages has been 
disappointing, necessitating clinical investigations examining alternative dosing of 
efficacious therapies in patients with HER2-positive MBC with CNS progression 
post-radiotherapy. 
This study will examine the safety and efficacy of pertuzumab (loading dose of 840 mg 
intravenous [IV] followed every 3 weeks thereafter by a dose of 420 mg IV) in 
combination with high-dose trastuzumab (6 mg/kg IV weekly) in patients with 


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HER2-positive MBC with CNS metastases that have disease progression in the brain 
following radiotherapy.
2.
OBJECTIVES
2.1
EFFICACY OBJECTIVES
The primary efficacy objective for this study is as follows:

To evaluate the efficacy of the study combination of pertuzumab with high-dose 
trastuzumab for the treatment of CNS progression post-radiotherapy in patients with 
HER2-positive MBC, as measured by objective response rate (ORR) in the CNS
The secondary efficacy objective for this study is as follows:

To evaluate the efficacy of pertuzumab with high-dose trastuzumab for these same 
patients, as measured by duration of response (DOR) in the CNS, clinical benefit 
rate (CBR) for the CNS, PFS in the CNS, PFS (CNS or non-CNS), and OS
2.2
SAFETY OBJECTIVE
The safety objective for this study is as follows:

To evaluate the safety of the study dose of pertuzumab (loading dose of 840 mg IV 
followed every 3 weeks thereafter by a dose of 420 mg IV) and high-dose 
trastuzumab (6 mg/kg IV weekly) for the treatment of patients with HER2-positive
MBC with CNS progression post-radiotherapy
2.3
PHARMACOKINETIC OBJECTIVE
The pharmacokinetic (PK) objective for this study is as follows:

To characterize the serum pharmacokinetics of pertuzumab (loading dose of 
840 mg IV followed every 3 weeks thereafter by a dose of 420 mg IV) and high-dose 
trastuzumab (6 mg/kg IV weekly) for the treatment of patients with HER2-positive 
MBC with CNS progression post-radiotherapy
2.4
PATIENT-REPORTED OUTCOME OBJECTIVES
The patient-reported outcome (PRO) objectives for this study are as follows:

To evaluate the impact of treatment with pertuzumab and high-dose trastuzumab in 
patients with HER2-positive MBC with CNS progression post-radiotherapy on PROs, 
as measured by the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT) 
assessment

To evaluate the relationship of ORRs with PRO endpoints, as measured by the 
MDASI-BT
2.5
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are as follows:

To perform an exploratory analysis of the relationship between pertuzumab and 
trastuzumab exposure and efficacy and safety endpoints


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
To collect (optional) tissue samples and plasma, which will be banked for future 
biomarker analysis
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
This is a U.S.-based, Phase II, open-label, single-arm study designed to examine the 
safety and efficacy of pertuzumab (loading dose of 840 mg IV followed every 3 weeks 
thereafter by a dose of 420 mg IV) and high-dose trastuzumab (6 mg/kg IV weekly) 
administered to patients with HER2-positive, MBC-related CNS metastases
(parenchymal) that have disease progression in the brain following radiotherapy (SRS or 
WBRT).  No changes will be made to the patient’s current treatment (e.g., chemotherapy, 
hormonal therapy) for systemic disease in order to optimize the ability to detect any 
incremental benefits provided by the combination of pertuzumab and high-dose 
trastuzumab (see Section 4.3.1.1 for dosing information).  The following exceptions, 
however, will be made:
1.
Patients receiving treatment with ado-trastuzumab emtansine (also known as 
T-DM1 or Kadcyla)
–
Ado-trastuzumab emtansine will be discontinued 3 weeks prior to initiation of 
pertuzumab with high-dose trastuzumab.
2.
Patients receiving treatment with lapatinib
–
Lapatinib will be discontinued 1 week prior to initiation of pertuzumab with 
high-dose trastuzumab.
Patients may remain on study treatment until disease progression within the CNS or 
systemic progression, unacceptable toxicity, withdrawal of consent, or study termination 
by the Sponsor, whichever occurs first.
Overall safety will be assessed on an ongoing basis during the conduct of the study. 
The study schema is presented in Figure 1. The schedule of assessments is provided in 
Appendix 1. 


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Figure 1
Study Schema
BCbreast cancer; CBRclinical benefit rate; CNScentral nervous system; DORduration of 
response; HER2human epidermal growth factor receptor-2; ORRobjective response rate; 
OSoverall survival; PDprogressive disease; PFSprogression-free survival; 
SRSstereotactic radiosurgery; WBRTwhole-brain radiation therapy.
3.2
END OF STUDY
The study will end when all patients have been followed for 12 months after the
treatment discontinuation visit (inclusive of the safety and survival follow-up periods), 
unless they have been lost to follow-up, withdrawn consent, or died, or if the study is 
prematurely terminated by the Sponsor, whichever occurs first.
At this time, the study will end and no further data will be collected in the clinical 
database for this study.  The end of study is defined as the last patient last visit (LPLV) 
at the end of the follow-up period.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Pertuzumab and Trastuzumab Dose and 
Schedule
Currently, there is no clear standard of care that addresses recurring or multiple 
intracranial metastases post-radiotherapy in HER2-positive MBC. Despite incremental 
increases in uptake of trastuzumab observed with standard systemic dosing when the 
BBB is disrupted, subtherapeutic levels are achieved in the CNS. Brain graft 
experiments with 4D5 (a murine equivalent of trastuzumab) demonstrated that doses up 
to three times the effective dose used in mammary grafts were required to achieve 
efficacy in brain grafts. 
Eligibility:

Metastatic HER2+ BC

Previous treatment (WBRT/SRS) for 
brain metastases with development 
of new and/or progressive 
measurable lesion 

Stable systemic disease
N40
Pertuzumab
(loading dose of 840 mg 
IV followed Q3W by 
420 mg IV)

High-dose Trastuzumab
(6 mg/kg IV weekly) 

Continuation of ongoing 
systemic treatment
Treat to PD 
(at least 20%
increase in 
sum of 
diameters of 
target 
lesions) or 
unacceptable 
toxicity

Primary efficacy endpoint:  ORR in the CNS

Secondary efficacy endpoint:  DOR in the CNS, CBR for the CNS, PFS in the CNS, PFS (CNS or 
non-CNS), and OS

Safety endpoint:  Safety of pertuzumab and trastuzumabfor the treatment of HER2-positive MBC 
with CNS progression post-radiotherapy


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The impact of a more comprehensive blockade of cell signaling associated with the 
addition of pertuzumab to trastuzumab has been demonstrated in the nonclinical and 
clinical settings, and may translate in to improved CNS activity. This study will examine 
the safety and efficacy of pertuzumab (loading dose of 840 mg IV followed every 
3 weeks thereafter by a dose of 420 mg IV) in combination with high-dose trastuzumab
(6 mg/kg IV weekly) in patients with HER2-positive MBC with CNS metastases that have 
disease progression in the brain following radiotherapy.  Treatment will continue until 
disease progression in the CNS or systemic progression, unacceptable toxicity, 
withdrawal of consent, or study termination by the Sponsor (see Section 1.3).
3.4
OUTCOME MEASURES 
3.4.1
Primary Efficacy Outcome Measure
The primary efficacy outcome measure for this study is as follows:

ORR in the CNS (assessed per Response Assessment in Neuro-Oncology-Brain 
Metastases [RANO-BM] criteria; see Appendix 4).  Objective response is defined as 
complete response (CR) or partial response (PR).
3.4.2
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures for this study are as follows:

DOR in the CNS, CBR for the CNS, PFS in the CNS, PFS (CNS or non-CNS), and 
OS
– Tumor response in CNS will be assessed per RANO-BM criteria (see 
Appendix 4).  
– Non-CNS tumor response will be assessed by Response Evaluation Criteria in 
Solid Tumors, Version 1.1 (RECIST v1.1; see Appendix 5).
3.4.3
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence and severity of all non-serious and serious adverse events

Incidence and severity of Grade3 adverse events and serious adverse events

Incidence of adverse events leading to discontinuation or interruption of pertuzumab
alone or the combination of pertuzumab and trastuzumab

Cause of death while on study

Incidence and severity of cardiac events, as assessed by the investigator using 
National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 4.0 (NCI CTCAE v4.0) and New York Heart Association (NYHA) 
classification for congestive heart failure (CHF; see Appendix 7) 

Characterization of changes in left ventricular ejection fraction (LVEF) and changes 
in LVEF from baseline over the course of the study (see Appendix 6)

Clinically significant laboratory test abnormalities


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3.4.4
Pharmacokinetic Outcome Measure
The PK outcome measure for this study is as follows:

Observed serum concentrations for pertuzumab and trastuzumab at the following 
timepoints: 
–
Week 1, Day 1 (1 sample pre-dose and 1 sample within 30 minutes after 
completion of both infusions [maximum concentration (Cmax)]) (total of 
2 samples)
–
Week 4, Day 1 (pre-dose [trough])
–
Week 10, Day 1 (pre-dose [trough])
–
Week 16, Day 1 (1 sample pre-dose and at 1 sample within 30 minutes after 
completion of both infusions [Cmax]) (total of 2 samples)
3.4.5
Patient-Reported Outcome Measure
The PRO outcome measure for this study is as follows:

Scores from the MDASI-BT assessment
3.4.6
Exploratory Outcome Measures
The exploratory outcome measures for this study are follows:

To explore the relationship between pertuzumab and high-dose trastuzumab
exposure and efficacy and safety endpoints

Collection of (optional) tissue and plasma samples
4.
MATERIALS AND METHODS
4.1
PATIENTS
Patients with HER2-positive MBC with documented CNS progression of disease 
post-radiotherapy and stable systemic disease will be enrolled in the study.  Written 
informed consent will be obtained before initiation of any study-specific, non-standard of 
care procedures.  Unless otherwise noted, screening evaluations may be performed at 
any time within 28 days prior to Day 1 (time of the first study treatment), per the 
schedule of assessments in Appendix 1.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Able and willing to provide written informed consent

Able and willing to comply with the study protocol

Age 18 years


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
Pathologically confirmed HER2-positive MBC by local laboratory with the following 
requirements:
–
HER2 overexpressed or amplified (immunohistochemistry of 3or HER2 gene 
amplification by in situ hybridization with a ratio of HER2-gene signals to 
centromere 17 signals 2.0 or average HER2 copy number 6.0 signals/cells)

Unequivocal evidence of new and/or progressive brain metastases after completion 
of WBRT or SRS

Completed previous SRS or WBRT60 days

At least one measurable CNS metastasis (lesion10 mm per RANO-BM criteria)

Confirmed tumor assessment demonstrating stablesystemic disease

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

LVEF50% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan 
within 28 days before Day 1 of study

Adequate bone marrow function, as indicated by the following:
–
ANC1500/L
–
Platelets75,000/L
–
Hemoglobin9 g/dL

Adequate renal function, as indicated by creatinine1.5upper limit of normal (ULN)

Adequate liver function, as indicated by bilirubin1.5ULN
–
AST and ALT2.5ULN unless related to primary disease; up to 5ULN if 
liver metastases are present

Life expectancy12 weeks

Female patients of childbearing potential, including those who have had tubal 
ligation, and women12 months after the onset of menopause, even if they have 
undergone surgical sterilization, must have a negative serum pregnancy 
test 7 days prior to initiation of study drug (with result available prior to dosing).

Female patients of childbearing potential (who are not postmenopausal 12 months 
of non-therapy-induced amenorrhea or surgically sterile [absence of ovaries and/or 
uterus]) and male patients with female partners of childbearing potential must agree 
to use one highly effective or two effective methods of non-hormonal contraception, 
as specified in the protocol, during their participation in the study and for at least 
7 months after last dose of study drug.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Progression of systemic disease at time of screening

Leptomeningeal disease (LMD)


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–
LMD is a clinical diagnosis, defined as positive cerebrospinal fluid (CSF) 
cytology and/or unequivocal radiological or clinical evidence of clinically 
significant leptomeningeal involvement
–
Patients with leptomeningeal symptoms would be considered to have LMD 
even in the absence of positive CSF cytology, unless a parenchymal lesion can 
adequately explain the neurological deficit
–
Patients who are asymptomatic or with nonspecific leptomeningeal 
enhancement would not be considered to have LMD. However, if there is 
clinical or radiographic suspicion of LMD, CSF confirmation to rule out LMD is 
at the investigator’s discretion.

History of intolerance (Grade 3) or hypersensitivity to trastuzumab or pertuzumab

Current use or history of receiving a non-approved, investigational treatment within 
21 days prior to study enrollment

Current use of anthracyclines

Patients unwilling to discontinue ado-trastuzumab emtansine or lapatinib therapy

Active infection

Pregnant or lactating women
–
Women who are not postmenopausal (12 months of non-therapy-induced 
amenorrhea) or surgically sterile must have a negative serum pregnancy test 
result7 days prior to initiation of study drug.

History of significant cardiac disease, cardiac risk factors, uncontrolled arrhythmias, 
or uncontrolled hypertension

Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs, 
resulting in dyspnea at rest

History of other malignancy within the last 5 years, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine 
cancer, or other cancers with a similar outcome as those mentioned
4.2
METHOD OF TREATMENT ASSIGNMENT
This is an open-label, Phase II, single-arm study. Randomization will not be performed.  
Once a patient’s eligibility has been confirmed by the investigator, the study staff must 
ensure the patient is registered via the interactive voice/web response system (IXRS) to 
obtain a unique enrollment identification number prior to initiation of study treatment.  A 
patient number will not be re-used if the patient leaves the study.  
Under no circumstances will patients who enroll in this study and complete treatment as 
specified be permitted to re-enroll in the study.  A Patient Enrollment and Identification 
Code List must be maintained by the Principal Investigator.


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4.3
STUDY TREATMENT 
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Pertuzumab (Perjeta)
Pertuzumab drug product for IV administration is provided as a single-use 
formulation containing 30 mg/mL pertuzumab in 20 mM L-histidine acetate (pH 6.0), 
120 mM sucrose, and 0.02% polysorbate 20.  Each 20-mL vial contains 420 mg of 
pertuzumab (14.0 mL/vial).  Pertuzumab does not contain any antimicrobial preservative.  
Therefore, care must be taken to ensure the sterility of the prepared solution for infusion 
and should be prepared by a healthcare professional using aseptic technique.  A 
14 mL of pertuzumab liquid concentrate should be withdrawn from the vial and 
diluted into a 250 mL PVC or non-PVC polyolefin infusion bag of 0.9% sodium 
chloride solution for infusion.
For information on the formulation, packaging, and handling of pertuzumab, see the 
Perjeta Investigator's Brochure.
Incompatibilities
No incompatibilities between pertuzumab and polyvinylchloride, polyethylene, or 
non-PVC polyolefin bags have been observed.  Dextrose (5%) in water (D5W) solution 
should not be used to dilute pertuzumab since it has been shown to be chemically and 
physically unstable in such solutions (dilute formulations of pertuzumab liquid 
formulations in D5W IV bags did not maintain stable pH after storage at room 
temperature [27°C33°C] for 24 hours followed by 24 hours at refrigerator temperature 
[2°C8°C]).
Pertuzumab should not be mixed or diluted with other drugs unless stated in the 
clinical protocol and supported with compatibility data.
4.3.1.2
Trastuzumab (Herceptin)
Trastuzumab is supplied for use as a freeze-dried preparation at a nominal content of
440 mg per vial for parenteral administration.  The drug is formulated in 
histidine/histidine-HCl, ,-trehalose dihydrate, and polysorbate 20.
For IV administration, each vial of trastuzumab is reconstituted with 20 mL of 
bacteriostatic water for injection (BWFI; containing 1.1% benzyl alcohol), which is 
supplied with each vial.  When reconstituted, this results in a 21 mg/mL solution of 
trastuzumab.  This vial configuration and formulation is designed for multiple use and 
must be used within 28 days after reconstitution when stored at 2C to 8C.  Each vial 
should be used for multiple doses for the same patient only.  For patients who are 
sensitive to benzyl alcohol, trastuzumab may be reconstituted in 20 mL sterile water for 
injection (SWFI) for immediate use.  The appropriate dose of trastuzumab should be 
withdrawn from the vial using aseptic techniques and added to 250 mL 0.9% sodium 
chloride for injection for subsequent patient administration.


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For information on the formulation, packaging, and handling of trastuzumab, see the 
Herceptin Investigator's Brochure.
Incompatibilities
No incompatibilities between trastuzumab and polyvinylchloride, polyolefin, or 
polypropylene bags have been observed.  Dextrose 5% solution should not be used 
because it causes aggregation of the protein.  Trastuzumab should not be mixed or 
diluted with other drugs.
4.3.2
Dosage and Administration
Pertuzumab and trastuzumab may be given in any order.  Other systemic therapy should 
be administered after pertuzumab and trastuzumab.
4.3.2.1
Pertuzumab
The loading dose of pertuzumab will be 840 mg administered as a 60-minute IV infusion 
with an observation period of 60 minutes, followed every 3 weeks thereafter by a dose of 
420 mg administered over a period of 3060 minutes with an observation period of 
3060 minutes.  For patients already receiving pertuzumab as part of their ongoing 
systemic therapy, no loading dose is required in the case of an interval6 weeks 
between last dose of pertuzumab and the first administration of on-study pertuzumab.
Left Ventricular Ejection Fraction
Assess LVEF as per the algorithm for continuation and discontinuation of trastuzumab
and pertuzumab based on LVEF assessments in Appendix 6.
Infusion-Related Reactions 
Like other monoclonal antibodies, pertuzumab has been associated with infusion-related 
reactions (IRRs), such as chills, diarrhea, fatigue, headache, nausea, and pyrexia. The 
infusion rate of pertuzumab may be slowed or interrupted and appropriate medical 
therapies should be administered if the patient develops a significant IRR.  Patients 
should be evaluated and carefully monitored until complete resolution of signs and 
symptoms. 
Hypersensitivity Reactions/Anaphylaxis 
The infusion should be discontinued immediately if the patient experiences a serious 
hypersensitivity reaction.
4.3.2.1.1
Dose Modifications
Dose reductions are not allowed for pertuzumab in this study. 
4.3.2.1.2
Delayed or Missed Doses
For delayed or missed doses, if the time between two sequential infusions is less than 
6 weeks, the 420-mg dose of pertuzumab should be administered.  Do not wait until the 
next planned dose.  If the time between two sequential infusions is 6 weeks or more, the 
loading dose of 840 mg pertuzumab should be re-administered as a 60-minute IV 


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infusion followed every 3 weeks thereafter by a dose of 420 mg administered as an IV 
infusion over 3060 minutes. 
4.3.2.1.3
Treatment Discontinuations
If a patient experiences an adverse event deemed associated with high-dose 
trastuzumab that requires trastuzumab discontinuation, pertuzumab should also be 
discontinued.
Additional information and guidelines on treatment interruption or discontinuation are 
provided in the Perjeta USPI.
4.3.2.2
Trastuzumab
High-dose trastuzumab will be administered at a dose of 6 mg/kg weekly, infused 
intravenously over 3090 minutes.  No loading dose is required.  Trastuzumab-naïve 
patients should receive their first dose over 90 minutes.  Patients who are actively 
receiving trastuzumab prior to enrollment will have a dose increase to 6 mg/kg IV weekly.  
The dose of trastuzumab will be based on the patient’s actual body weight measured at 
baseline.  The dose need not be recalculated unless the body weight has changed 
by10% from baseline.  
Weekly doses may be administered 2 days (no less than 5 days apart).
Left Ventricular Ejection Fraction
Assess LVEF as per the algorithm for continuation and discontinuation of pertuzumab
and trastuzumab based on LVEF assessments in Appendix 6
Infusion-Related Reactions 
Additional guidelines for treatment interruption or discontinuation related to IRRs are 
provided in the Herceptin USPI .
4.3.2.2.1
Dose Modifications
Dose reductions are not allowed for trastuzumab in this study. 
4.3.2.2.2
Delayed or Missed Doses
If a patient misses a dose of trastuzumab, then the study dose of 6 mg/kg IV should be 
administered as soon as possible.  Do not wait until the next planned cycle.  Subsequent 
trastuzumab IV maintenance doses of 6 mg/kg should be administered 7 days later 
according to the dosing schedule.
4.3.2.2.3
Treatment Discontinuations
If a patient experiences an adverse event deemed associated with high-dose 
trastuzumab that requires trastuzumab discontinuation, pertuzumab should also be 
discontinued.  However, if a patient experiences a pertuzumab-associated adverse 
event requiring pertuzumab discontinuation, high-dose trastuzumab may be continued.


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Guidelines for treatment interruption or discontinuation are provided in the Herceptin 
USPI.
4.3.3
Investigational Medicinal Product Accountability
Pertuzumab and trastuzumab, the investigational medicinal products (IMPs) required for 
completion of this study, will be provided by the Sponsor.  The study site will 
acknowledge receipt of IMPs, using the IXRS to confirm the shipment condition and 
content.  Any damaged shipments must be reported and will be replaced. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed 
or returned, and IMP destruction or return must be documented on the appropriate form.
Accurate records of all IMPs received, dispensed, destroyed, or returned must be 
recorded on the Drug Inventory Log.
4.3.4
Post-Trial Access to Pertuzumab and Trastuzumab
The Sponsor will offer post-trial access to the study drugs (pertuzumab and trastuzumab) 
free of charge to eligible patients in accordance with the Roche Global Policy on 
Continued Access to Investigational Medicinal Product, as outlined below.  
A patient will be eligible to receive study drug after completing the study if all of the 
following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being 

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them
A patient will not be eligible to receive study drug after completing the study if any of the 
following conditions are met:

The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for CNS metastases from HER2-positive breast 
cancer

The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for CNS metastases from HER2-positive breast cancer

Provision of study drug is not permitted under the laws and regulations of the 
patient's country


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The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
4.4.1
Permitted Therapy
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to screening to the study completion/discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications electronic Case Report Form (eCRF).
The following treatments are permitted throughout the duration of the study treatment
phase and during follow-up:

Current anti-cancer therapy and associated pre-medications that the patient is 
receiving for HER2-positive MBC resulting in stable systemic disease except 
ado-trastuzumab emtansine, which must be discontinued 3 weeks before the 
initiation of study treatment, or lapatinib, which must be discontinued 1 week before 
the initiation of study treatment

Standard therapies for preexisting medical conditions unless listed as prohibited 
therapy in Section 4.4.1.  Any medication intended solely for supportive care (e.g., 
analgesics, anti-diarrheals, anti-depressants) may be used at the investigator’s 
discretion. 

Local radiation therapy outside of the CNS for palliation of symptoms is allowed.

Corticosteroids for treatment of CNS edema are allowed.  Increasing doses of 
steroids alone will not be taken into account in determining CNS progression in the 
absence of persistent clinical deterioration (see RANO-BM criteria, Appendix 4).

Hematopoietic growth factors (e.g., granulocyte-colony stimulating factor [G-CSF], 
granulocyte macrophage colony stimulating factor) may be used at investigator’s 
discretion for the primary prophylaxis and/or management of treatment-emergent 
neutropenia and/or for secondary prophylaxis per NCCN guidelines or local 
standard practice.

Bisphosphonate or denosumab therapy (to be used in accordance with the 
approved labeled indication and/or nationally recognized treatment guidelines)
4.4.2
Prohibited Therapy
Use of the following therapies is prohibited during the study and for at least 21 days prior 
to initiation of study treatment, unless otherwise specified below:

A non-approved, investigational therapy

Ado-trastuzumab emtansine

Lapatinib (must be discontinued 1 week before initiation of study treatment)


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
Anthracyclines

Any newly initiated anti-cancer therapies other than those administered in this study, 
including cytotoxic chemotherapy, immunotherapy, and biological or targeted (e.g., 
lapatinib, neratinib) anti-cancer therapy

Any systemically active oral, injected, or implanted hormonal method of 
contraception except for progesterone coated intrauterine devices (IUDs) that had 
been previously implanted

Estrogen-replacement therapy
4.5
STUDY ASSESSMENTS 
Please see Appendix 1 for the schedule of assessments performed during the study.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Original signed Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment/registration via IXRS.  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.  Enrollment will be 
tracked via registration of patients in the IXRS.  Re-screening of patients is permitted on 
a case-by-case basis, to be determined by the Medical Monitor.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, and cancer history 
(including prior cancer therapies and procedures). Demographic data will include age, 
sex, and self-reported race/ethnicity.
4.5.3
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, and neurological systems.  Any abnormality identified at baseline should 
be recorded on the General Medical History and Baseline Conditions eCRF.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF.  Neurological status should be 
performed as part of these exams.


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As part of tumor assessment, physical examinations should also include the evaluation 
of the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly.
4.5.4
Vital Signs, Weight, and Height
Vital signs will include measurements of heart rate, systolic and diastolic blood 
pressures while the patient is in a seated position, respiratory rate, and temperature. 
Vital signs and weight will be assessed before treatment on Day 1 of every cycle.  
Weight changes of 10% would require the dose of trastuzumab to be adjusted.  Height 
will be collected at screening.
4.5.5
LVEF Evaluations
LVEF evaluations will be assessed at Screening, 6 and 12 weeks (after Cycle 1, Day 1), 
followed by LVEF evaluations every 3 months during the treatment period.  LVEF 
evaluations will also be conducted every 6 months during the survival follow-up period
(12 months after the treatment discontinuation visit).  Measurements will be done by
either ECHO or MUGA scan (with ECHO as the preferred method). Patients should be 
reassessed with the same technique used for baseline cardiac evaluation throughout the 
study.
4.5.6
Performance Status
Performance status will be measured using the ECOG Performance Status scale at 
screening (see Appendix 8).
4.5.7
Tumor and Response Evaluations
Tumor response for CNS disease will be assessed by the investigator according to 
RANO-BM criteria (see Appendix 4).  Tumor response of the brain will be evaluated by 
magnetic resonance imaging (MRI).  Progression of systemic disease will be assessed 
according to RECIST v1.1 (see Appendix 5).  Systemic evaluations of chest, abdomen, 
pelvis (and neck, if clinically indicated) will be measured using computed tomography 
(CT), MRI, or positron-emission tomography CT (PET-CT).  (Use of spiral CT or MRI is 
required for baseline lesions 20 mm and must be documented in medical records and 
used consistently throughout the study.)  The same assessment modality must be used 
throughout the study.  All tumor measurement data and CNS response data must be 
documented on the appropriate eCRF.
The use of oral and intravenous contrast, etc., should, as long as it is clinically possible, 
be kept consistent.  Tumor measurements should be made by the same 
investigator/radiologist for each patient during the study to the extent that it is feasible. 
4.5.7.1
Scheduling of Tumor Assessments
Baseline total tumor burden must be assessed at screening (within a maximum of 
28 days before first dose of study drug).  


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Brain Metastases
All target and non-target CNS disease must be documented at screening and 
reassessed at each subsequent tumor evaluation.  T1-weighted perfusion MRI will be 
used to evaluate changes in brain metastases that indicate treatment effects.  
Post-baseline MRI of the brain will be conducted every 6 weeks 2, followed by every 
8 weeks 2, then every 12 weeks until progression.  If there is suspicion of disease 
progression based on clinical or laboratory findings before the next scheduled 
assessment, an unscheduled assessment should be performed.  An additional 
assessment may be conducted at the treatment discontinuation visit.  For further details, 
see the schedule of assessments in Appendix 1.
Response for brain metastases will be assessed by the investigator, based on MRIs of 
the brain, physical examinations, routine neurological examinations, and corticosteroid 
dosing using RANO-BM criteria (see Appendix 4).  An objective response (CR, PR) and 
progressive disease in the CNS should be confirmed by repeat assessments 46 weeks 
after initial finding or at the next scheduled tumor assessment if it is to occur 46 weeks 
after the initial response.  
Other Sites (non-CNS) of Disease
Tumor response of systemic disease will be measured using CT, MRI, or PET-CT of the 
chest, abdomen, and pelvis (and neck, if clinically indicated).  Assessments will be 
performed every 8 weeks for the first 16 weeks, followed by assessments every 
12 weeks.  For patients with no evidence of systemic disease at baseline, additional 
systemic tumor assessments (chest, abdomen, and pelvis) will be performed every 
8 weeks for the first 16 weeks, followed by systemic assessments every 12 weeks.  All 
other known sites of disease must be documented at screening and reassessed at each 
subsequent tumor evaluation.  
Disease progression will be assessed by the investigator on the basis of physical 
examinations and scans using RECIST v1.1 (see Appendix 5).  The same radiographic 
procedure used to assess disease sites at screening should be used throughout the 
study (e.g., the same contrast protocol for CT scans).
4.5.8
Laboratory, Biomarker, and Other Biological Samples
Hematology and chemistry testing must be done during screening and every 6 weeks
within 3 days (with results available) prior to the administration of study drug.  
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology (hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
percent and absolute differential count [neutrophils, bands, eosinophils, 
lymphocytes, monocytes, basophils, and other cells])


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
Serum chemistries (sodium, potassium, chloride, bicarbonate, glucose, BUN, 
creatinine, calcium, total bilirubin, total protein, albumin, ALT, AST, alkaline 
phosphatase, and LDH)

Pregnancy test
–
All women of childbearing potential (including those who have had a tubal 
ligation and women12 months after the onset of menopause, even if they 
have undergone surgical sterilization) will have a serum pregnancy test at 
screening within 7 days before the first dose of study drug (with results 
available prior to dosing).  Urine pregnancy tests will be performed at specified 
subsequent visits within 7 days before every 3rd pertuzumab cycle and at the 
treatment discontinuation visit.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test.  During the treatment period, pregnancy 
test results must be available prior to administration of study drug.
The following samples will be sent to the Sponsor or a central laboratory for analysis:

PK assays
–
Serum pertuzumab and trastuzumab concentrations will be determined using 
validated assays.

Optional samples for the Roche Clinical Repository (RCR; see Section 4.5.9)
–
Plasma (at screening and treatment discontinuation)
–
Tissue from primary tumor or metastatic site (at screening)
For sampling procedures, storage conditions, and shipment instructions, see the 
Laboratory Manual.
4.5.8.1
Pharmacokinetic Assessments
Blood samples for serial measurements of pertuzumab and trastuzumab serum 
concentrations will be collected from all patients, according to the schedule in 
Appendix 3.
On specified days of study drug administration, two pre-infusion PK samples should be 
drawn 04 hours before the start of the infusions, and two post-infusion PK samples 
should be drawn 030 minutes after the end of the infusions, unless otherwise specified.  
Two separate 2-mL blood samples will be collected (one sample for each analyte,
pertuzumab and trastuzumab) at each timepoint as follows:
1.
Week 1, Day 1 (1 sample pre-dose [22 mL; trough] and 1 sample within 30 
minutes after completion of both infusions [22 mL; Cmax]) (total of 2 samples)
2.
Week 4, Day 1 (pre-dose [22 mL; trough])
3.
Week 10, Day 1 (pre-dose [22 mL; trough])
4.
Week 16, Day 1 (1 sample pre-dose [22 mL; trough] and 1 sample within 30 
minutes after completion of both infusions [22 mL; Cmax]) (total of 2 samples)


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Each blood sample will be 2 mL in volume, totaling 24 mL for PK sampling in each 
patient over approximately 16 weeks. 
The date and actual start and end times of infusion, and the date and actual time of each 
sample collection, should be recorded in the PK sampling form.  Any important 
information concerning the sample or its collection (e.g., missed or late sample, 
hemolysis, etc.) should also be recorded.  Instructions for the processing and labeling of 
all PK samples, as well as shipping instructions, are provided in the Laboratory Manual.  
PK samples will be destroyed no later than 15 years after the date of final closure of the 
associated clinical database. 
4.5.9
Patient-Reported Outcomes
PROs will be collected in this study via paper questionnaire to evaluate the impact of 
treatment on the symptom severity and symptom interference with daily life, due to CNS 
metastases, as measured by the MDASI-BT assessment from the patient’s perspective.  
To ensure instrument validity and data standards, the instrument will be completed 
directly by the patient and will be administered to patients at the study site prior to any 
study procedures and prior to receiving treatment.  The PRO questionnaire will be 
administered at baseline (Day 1 prior to study treatment), at every brain MRI visit, every 
6 weeks 2, followed by every 8 weeks 2, then every 12 weeks until progression.  The 
MDASI-BT will also be administered at treatment discontinuation visit.  
The MDASI-BT includes 13 core symptom items, 9 brain tumor-specific items, and 
6 interference with life items.  The 9 brain tumor-specific items are:  weakness on one 
side of the body, difficulty understanding, difficulty speaking, seizures, difficulty 
concentrating, vision, change in appearance, change in bowel patterns, and irritability.  
See Appendix 11 for a sample of the PRO to be used in this study.
Adverse event reports will not be derived from PRO data by the Sponsor.  However, any 
PRO responses suggestive of a possible adverse event that are identified during site 
review of the PRO data should be reported as outlined in Section 5.3.5.11.
4.5.10
Samples for Roche Clinical Repository
Genentech is a member of the Roche group and participates in the collection and/or 
submission of biological samples to the RCR or designated repository vendor.  
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the RCR portion of the Informed Consent Form by each site's 
Institutional Review Board or Ethics Committee (IRB/EC) and, if applicable, an 
appropriate regulatory body.  If a site is not granted the necessary approval for RCR
sampling, this section of the protocol will not be applicable at that site.


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4.5.10.1
Overview of the Roche Clinical Repository
The RCR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection and analysis of RCR specimens will 
facilitate the rational design of new pharmaceutical agents and the development of 
diagnostic tests, which may allow for individualized drug therapy for patients in the future.
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.10.2
Sample Collection
The following optional samples will be collected for research purposes, including but not 
limited to research on dynamic (non-inherited) biomarkers related to HER2-positive 
breast cancer:

Plasma (at screening and treatment discontinuation)

Tissue from primary tumor or metastatic site (at screening)
For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the Laboratory Manual.  
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.2.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below.  
4.5.10.3
Confidentiality
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 


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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.
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate.
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise.
4.5.10.4
Consent to Participate in the Roche Clinical Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF.
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research.
4.5.10.5
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 


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consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the RCR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RCR Research 
Sample Withdrawal of Informed Consent eCRF.  The patient will be provided with 
instructions on how to withdraw consent after the trial is closed.  A patient's withdrawal 
from Study ML29366 does not, by itself, constitute withdrawal of specimens from the 
RCR.  Likewise, a patient's withdrawal from the RCR does not constitute withdrawal from 
Study ML29366.
4.5.10.6
Monitoring and Oversight
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples.
4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Premature termination of the study by the Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced.
4.6.2
Study Treatment Discontinuation
Patients must discontinue study treatment if they experience any of the following:

Pregnancy

Disease progression in the CNS or systemic progression

Initiation of a non-protocol-specified anti-cancer treatment 


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
Unacceptable toxicity

Withdrawal of consent

Investigator discretion 
Patients who discontinue from study treatment will be asked to return to the clinic within 
30 days of the last infusion of trastuzumab for a treatment completion visit.  The visit at 
which a response assessment showed disease progression may be used as the 
treatment completion visit.  
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
4.6.2.1
Progression-Free Survival Follow-Up
Patients who discontinue study treatment prematurely (i.e., without disease progression) 
will be followed for the assessments listed below as per standard of care until disease 
progression: 

MRIs of brain 

Assessments of the chest, abdomen, and pelvis (only scans that were abnormal at 
baseline need to be repeated)
The patient’s physician will be contacted to collect follow-up information.  
4.6.2.2
Survival and LVEF Follow-Up
All patients will be followed for a minimum of 12 months from the date of the last dose of
study drug or until death, whichever occurs first, for the assessments listed below:

Survival (every 3 months)

LVEF (every 6 months)
Survival information may be gathered either by phone or by clinic visit.
4.6.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of 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 Sponsor decides to discontinue the study.  
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment


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
Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice

No study activity (i.e., all patients have completed and all obligations have been 
fulfilled)
5.
ASSESSMENT OF SAFETY 
5.1
SAFETY PLAN
Safety evaluations will consist of medical interviews, recording of adverse events of all 
grades of severity, physical examinations, cardiac assessments (ECHO/MUGA scans), 
electrocardiograms [ECGs] as clinically indicated, and laboratory measurements 
(hematology, chemistry, and pregnancy test). 
Patients will be evaluated for adverse events (all grades according to NCI CTCAE v4.0), 
serious adverse events, and any adverse events requiring treatment interruption or 
discontinuation (for pertuzumab and/or trastuzumab).  Patients who, at time of CNS or 
systemic progression, have an ongoing adverse event leading to treatment 
discontinuation will be followed until the event resolves, the investigator assesses the 
event as stable, the patient has withdrawn consent, the patient is lost to follow-up, or the 
patient starts a different anti-tumor therapy.
5.1.1
General Safety Monitoring
This study will employ an Internal Monitoring Committee (IMC) with an external Steering 
Committee.  The purpose of the IMC and Steering Committee will be to make 
recommendations regarding study conduct on the basis of trial safety and efficacy data 
to ensure patient safety while receiving study treatment.  The IMC will include a Sponsor 
Medical Monitor, Drug Safety Scientist, Biostatistician, and Statistical Programmer.  The 
Steering Committee will include three external disease-state experts. 
Grade 4 and 5 adverse events assessed as not related to pertuzumab or trastuzumab
will be reviewed to verify their attribution and to monitor the emergence of a previously 
unrecognized treatment-related adverse event/safety signals. 
In addition to the monthly assessment of the incidence and nature of adverse events, 
serious adverse events, and laboratory abnormalities by the Medical Monitor, the IMC 
will meet every 6 months or earlier, if needed, based on unexpected safety signals.  The 
IMC will review all potential cases of left ventricular systolic dysfunction (LVSD),
including CHF. In addition, the IMC will monitor data on serious adverse events at least 
once every 3 months. 
The IMC and Steering Committee may make recommendations regarding study conduct 
including, but not limited to, the following:  performing additional safety analyses, 


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amending the study protocol, holding patient enrollment pending further safety 
evaluations, holding/discontinuing study treatment, or terminating the study.  Complete 
details of the IMC and Steering Committee will be described in the Steering Committee 
charter.
5.1.2
Cardiac Safety
All patients must have a baseline LVEF50%.  LVEF evaluations will be assessed at 
Screening, 6 weeks and 12 weeks (after Cycle 1, Day 1), followed by LVEF evaluations 
every 3 months during the treatment period.  LVEF evaluations will also be conducted 
every 6 months during the survival follow-up period (12 months after the treatment
discontinuation visit).  Measurements will be done by either ECHO or MUGA scan (with 
ECHO as the preferred method).  Patients should be reassessed with the same 
technique used for baseline cardiac evaluation throughout the study.  Study treatment 
will be adjusted if necessary according to the algorithm described in Appendix 6.
If an investigator is concerned that an adverse event may be related to cardiac 
dysfunction, an additional LVEF measurement should be performed.  Study treatment 
will be discontinued permanently in any patient who develops clinical signs and 
symptoms suggesting symptomatic CHF, with the diagnosis confirmed by a suggestive 
chest X-ray and a drop in LVEF by ECHO or MUGA.  CHF should be treated and 
monitored according to standard medical practice.
At present, there are inadequate data available to assess the prognostic significance of 
asymptomatic drops of LVEF.  Study treatment must be held in all patients for whom a 
drop of LVEF to 40% or 40%45% with a 10%-point or greater drop below baseline.  If 
this value is confirmed or LVEF has not recovered to 45% or 40%45% and LESS 
than 10% below baseline with a repeat assessment within 3 weeks of the first 
assessment, using the same assessment method, study drug must be discontinued (see 
Appendix 6).
Patients who resume therapy will resume pertuzumab at the study dose of 420 mg every 
3 weeks (840 mg loading dose of pertuzumab required if study drug is held 6 weeks) 
and trastuzumab at the study dose of 6 mg/kg weekly.  Patients will be allowed to hold 
and resume therapy for a maximum of three times, after which the study drug must be 
discontinued.
The incidence of CHF will also be recorded throughout the study.
See Appendix 7 for details of NYHA classification, Appendix 9 for LVSD according to 
NCI CTCAE v4.0 grading, and Appendix 10 for reporting conventions for LVSD/heart 
failure.


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5.1.3
Management of Specific Adverse Events
5.1.3.1
Pertuzumab and Trastuzumab
Administration of trastuzumab may be delayed to assess or treat adverse events, such 
as changes in LVEF, as shown in Appendix 6.
Since pertuzumab is also associated with a risk for cardiac dysfunction, the 
management of cardiac safety for patients receiving both drugs in the study, as outlined 
in the next section, applies to both drugs.  
For additional information regarding adverse events, see the Perjeta USPI and/or the 
Herceptin USPI.


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Table 1
Actions to be Taken in Case of Pertuzumab- and Trastuzumab-
Related Toxicity
Toxicity Related to Study Treatment
Action
1. Non-hematological, Grade 1 or 2 
(NCI CTCAE v4.0; excluding cardiaca) toxicity
Continue study treatment. 
2. Non-hematological, Grade 3 or 4 
(NCI CTCAE v4.0; excluding cardiaca) toxicity
Hold study treatment (all medication in the cycle) 
until recovery to Grade 2.
Toxicity resolved to Grade 1 within a maximum 
of 2 weeks calculated from last administration:  
resume study treatment.
Toxicity did not resolve to Grade 2 within a 
maximum of 2 weeks calculated from last 
administration:  discontinue the related study 
medication (pertuzumab or trastuzumab) 
permanently.  Continue treatment as deemed 
suitable by the local investigator.
3. Recurrence of non-hematological, Grade 3 
or 4 (NCI CTCAE v4.0; excluding cardiaca) 
toxicity upon rechallenge
Discontinue the related study medication 
(pertuzumab or trastuzumab) permanently.  
Continue treatment as deemed suitable by the 
local investigator.
4. Cardiac toxicity (asymptomatic drop in LVEF 
or symptomatic CHF)
Study treatment (all medication in the cycle) to be 
held, continued, or resumed according to the 
algorithm in Appendix 6.
Related study medication (pertuzumab or 
trastuzumab) to be discontinued permanently in 
case of symptomatic CHF (refer to 
Management of Symptomatic Cardiac 
Changes).
5. Cardiac toxicity (NCI CTCAE or other 
cardiac toxicities not covered by the treatment 
algorithm in Appendix 6
Actions must follow rules 1 to 3 for 
non-hematological toxicities.
6. Hematological toxicityneutropenia
Hold study treatment (all medication in the cycle) 
until neutrophils 1.5109/L.
CHFcongestive heart failure; LVEFleft ventricular ejection fraction; NCI CTCAENational 
Cancer Institute Common Terminology Criteria for Adverse Events; NYHANew York Heart 
Association.
a Severity corresponding to NYHA classification (see Appendix 7). 
Management of Cardiac Safety.  All patients must have a baseline evaluation of 
cardiac function including a measurement of LVEF by either ECHO or MUGA scan prior 
to study entry.  Only patients with LVEF of 50% should be entered into this study.  
While receiving treatment, all patients will have regular monitoring of LVEF with ECHO 
or MUGA (at screening, 6 weeks and 12 weeks [after Cycle1, Day 1], followed by LVEF 
evaluations every 3 months or as clinically indicated). 


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During the course of therapy with pertuzumab and trastuzumab, patients should be 
monitored for signs and symptoms of heart failure (i.e., dyspnea, tachycardia, new 
unexplained cough, neck vein distention, cardiomegaly, hepatomegaly, paroxysmal 
nocturnal dyspnea, orthopnea, peripheral edema, and rapid unexplained weight gain).  
The diagnosis must be confirmed using the same method used to measure LVEF at 
baseline (either ECHO or MUGA).
Management of Symptomatic Cardiac Changes.  Patients who develop signs and 
symptoms of heart failure NCI CTCAE v4.0 Grade 2, 3, or 4 should have pertuzumab
and trastuzumab held and should receive treatment for heart failure as prescribed by the 
Heart Failure Society of American (HFSA 2010; e.g., ACE inhibitors, angiotensin-II 
receptor blockers, -blockers, diuretics, and cardiac glycosides, as needed).  
Consideration should be given to obtaining a cardiac consultation.  LVEF should be 
reassessed after 3 weeks (using the same method of measurement).
If the symptoms of heart failure resolve with treatment, and cardiac function (as 
measured by ECHO or MUGA) improves, pertuzumab and trastuzumab may be 
restarted after discussion with the patient concerning the risks and benefits of continued 
therapy.  If the patient is benefiting clinically from HER2-targeted study treatment, the 
benefit of continued treatment may outweigh the risk of cardiac dysfunction.  If 
pertuzumab and trastuzumab are restarted, continued surveillance with noninvasive 
measures of LVEF (ECHO or MUGA) will continue per protocol. 
Management of Asymptomatic Decreases in LVEF.  If routine LVEF measurements 
document asymptomatic LVEF decreases during treatment, patient management should 
follow guidelines outlined in Appendix 6.
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, performing
protocol-specified safety laboratory assessments, performing protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.3.5.13.


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5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding),
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

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 5.3.5.8

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
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/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE


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criteria; see Section 5.3.2); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4 for 
reporting instructions).
5.2.3
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor)
Non-serious adverse events of special interest are required to be reported by the 
investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4 for reporting instructions).  Adverse events of special interest for 
this study include the following:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.5)

Suspected transmission of an infectious agent by the study drug, as defined below
–
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

Congestive heart failure
Note:  In general, asymptomatic declines in LVEF should not be reported as adverse 
events since LVEF data are collected separately in the eCRF.  Exceptions to this rule 
are as follows:

An asymptomatic decline in LVEF to a value 10 percentage points below baseline or 
lower, and45% must be reported as an adverse event

An asymptomatic decline in LVEF that requires treatment or that leads to 
discontinuation of study treatment must be reported in an expedited manner by 
using the Serious Adverse Event form and classifying the event as a Non-Serious 
Event of Special Interest
In both cases, it should be reported as “left ventricular systolic dysfunction” and graded 
according to NCI CTCAE v4.0.


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5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in 
Section 5.3.5.13Section 5.5.2.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.1 for seriousness criteria), severity (see 
Section 5.3.2), and causality (see Section 5.3.3).  
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 study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.1 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported until 30 days after the last dose of study drug.  After this period, 
the investigator is not required to actively monitor patients for adverse events; however, 
the Sponsor should report any serious adverse events that are believed to be related to 
prior study drug treatment (see Section 5.5.2).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 2 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 2
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.1 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.1.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.1 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.1.
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 or 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration (see also 
Table 3):

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event


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Table 3
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study drug administration 
should be captured as individual signs and symptoms on the Adverse Event eCRF 
rather than an overall diagnosis (e.g., record dyspnea and hypotension as separate 
events rather than a diagnosis of infusion-related reaction).
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than infusion-related reactions (see Section 5.3.5), a diagnosis 
(if known) should be recorded on the Adverse Event eCRF rather than individual signs 
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, 
and elevated transaminases).  However, if a constellation of signs and/or symptoms 
cannot be medically characterized as a single diagnosis or syndrome at the time of 
reporting, each individual event should be recorded on the Adverse Event eCRF.  If a 
diagnosis is subsequently established, all previously reported adverse events based on 
signs and symptoms should be nullified and replaced by one adverse event report based 
on the single diagnosis, with a starting date that corresponds to the starting date of the 
first symptom of the eventual diagnosis.


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5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.1 for reporting instructions).  The Adverse Event eCRF should be updated by 
changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)


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
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
–
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (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 only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3 baseline value in combination with total 
bilirubin 2 ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3 baseline value in combination with clinical 
jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 5.4.1).
5.3.5.8
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3) that are attributed by 
the investigator solely to progression of disease (progression of CNS or systemic 
disease) should be recorded only on the Study Completion/Early Discontinuation eCRF.  
All other on-study deaths, regardless of relationship to study drug, must be recorded on 
the Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.1).
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 be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after 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 survival follow-up, deaths attributed to progression of HER2-positive MBC should 
be recorded only on the Survival eCRF.


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5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Central Nervous System
Metastases
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RANO-BM criteria.  In rare cases, the determination of 
clinical progression will be based on symptomatic deterioration.  However, every effort 
should be made to document progression through use of objective criteria.  If there is 
any uncertainty as to whether an event is due to disease progression, it should be 
reported as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.1), except as outlined 
below.  
The following hospitalization scenarios are not considered to be 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 experienced an adverse event


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The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead:

Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available
5.3.5.12
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.1).
No safety data related to overdosing of pertuzumab or trastuzumab are available.  
5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (see Section 5.4.1 for further details)

Non-serious adverse events of special interest (see Section 5.4.1 for further details)

Pregnancies (see Section 5.4.2.2 for further details)
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


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
Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
Genentech Medical Monitor contact information:
Medical Monitor:
, Pharm.D.
Telephone No.:
 (
; cell)
Alternatively, please contact the CRO Clinical Lead.
5.4.2
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and non-serious adverse events of 
special interest will be reported until 30 calendar days after the last dose of study drug.  
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the electronic data capture (EDC) system.  A report will be generated and sent to 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.  
Instructions for reporting post-study adverse events are provided in Section 5.6


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5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 7 months after the last 
dose of study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Safety Risk Management.  Pregnancy should not be recorded on the Adverse Event 
eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  
In the event that the EDC system is unavailable, the Clinical Trial Pregnancy Reporting 
Form provided to investigators should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Once the EDC system is available, all information will 
need to be entered and submitted via the EDC system.
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 5.3.5.
5.4.3.3
Congenital Anomalies/Birth Defects and Abortions
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 


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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 5.4.1).  Any abortion should be reported in the same fashion (as the Sponsor 
considers abortions to be medically significant).
Additional information on any pertuzumab- or trastuzumab-exposed pregnancy and 
infant will be requested by Roche Drug Safety at specific timepoints (i.e., after having 
received the initial report during the first trimester, at the end of the second trimester, 2 
weeks after the expected date of delivery, and at 3, 6, and 12 months of the infant’s life).  
In case of a report of a congenital abnormality, a guided questionnaire will be sent out by 
Roche Drug Safety.
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 considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.
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) in order to 
perform an independent medical assessment of the reported case.
5.6
POST-STUDY ADVERSE EVENTS
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
30 days after the last dose of study drug), if the event is believed to be related to prior 
study drug treatment.  
The investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of 


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Special Interest Reporting Form using the fax number or email address provided to 
investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all 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.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Perjeta Investigator’s Brochure

Herceptin Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Two analysis populations are defined for this study:

Efficacy-evaluable population:  includes all treated patients who have at least one 
follow-up CNS tumor assessment or who die without follow-up tumor assessment 
within 30 days from the last dose of study drug  

Safety population:  includes all patients receiving any dose of study drugs
Details of the analyses will be provided in the Statistical Analysis Plan.
6.1
DETERMINATION OF SAMPLE SIZE
The emphasis of this study is estimation of the ORR with a given precision, rather than 
hypothesis testing.  ORRs of 20% or higher will be deemed clinically significant because 
no other therapeutic options are available for this patient population. 
With 35 evaluable patients, and assuming that the study treatment is expected to lead to 
an ORR in CNS of 20% (7 patients), the 95% CI around the estimated ORR will be 
8.4%36.9%.  
Table 4 below shows the estimated CIs for additional assumed ORRs.  The final sample 
size will be approximately 40 patients, allowing for dropouts and loss to follow-up.  


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Table 4
Estimated Confidence Intervals for Additional Assumed 
Objective Response Rates
N
Number of Patients 
who Achieve CNS 
ORR
Rate
Lower Bound
Exact 95% CI
Upper Bound
Exact 95% CI
Half-Width of CI
35
1
2.86
0.07%
14.92%
7.43%
35
2
5.71
0.70%
19.16%
9.23%
35
3
8.57
1.80%
23.06%
10.63%
35
4
11.43
3.20%
26.74%
11.77%
35
5
14.29
4.81%
30.26%
12.73%
35
6
17.14
6.56%
33.65%
13.55%
35
7
20.00
8.44%
36.94%
14.25%
35
8
22.86
10.42%
40.14%
14.86%
35
9
25.71
12.49%
43.26%
15.39%
35
10
28.57
14.64%
46.30%
15.83%
CIconfidence interval; CNScentral nervous system; ORRobjective response rate.
CI based on Clopper Pearson method.
Table 5 below contains the probabilities of a particular adverse event occurring with a 
sample size of 40.  The range of adverse event rates includes published cardiac event 
rates in metastatic patients receiving trastuzumab in combination with chemotherapy 
(Telli et al. 2007).
Table 5
Probability of Adverse Events
Incidence of Adverse 
Event
Probability of at Least One 
Adverse Event Occurring
Probability of at Least Two 
Adverse Events Occurring
1.00%
0.33
0.06
2.00%
0.55
0.19
3.00%
0.70
0.34
4.00%
0.80
0.48
5.00%
0.87
0.60
8.00%
0.96
0.84
10.00%
0.99
0.92
13.00%
1.00
0.97
16.00%
1.00
0.99
27.00%
1.00
1.00


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6.2
SUMMARIES OF CONDUCT OF STUDY
Patient enrollment, duration of follow-up, and discontinuation from the study and 
discontinuation reasons will be summarized for all enrolled patients.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Patients will not be randomized in this study; all enrolled patients will receive study 
medication.  
Demographic characteristics, medical history, baseline disease characteristics, patient 
treatment history, and current and previous brain MBC treatment will be summarized.
Descriptive statistics (mean, median, standard deviation, 25 h percentile, 75th percentile, 
and range) will be presented for continuous variables, such as age and time since 
metastatic diagnosis.
Frequency counts will be presented for categorical variables such as sex, race, age 
category, ECOG Performance Status, number of prior chemotherapy agents, and prior 
brain radiation therapy type.
Enrolled patients who are later found to be ineligible will be discontinued from the study 
and the reason for discontinuation will be recorded on the CRF.
6.4
EFFICACY ANALYSES
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is ORR in the CNS per RANO-BM criteria.  To evaluate 
the ORR, two sets of analyses will be performed:  one is based on the efficacy-evaluable 
population and the other is based on the safety population.  The efficacy-evaluable 
population is the primary population for ORR in CNS.  Any patient without sufficient data 
to determine response (e.g., non-evaluable patients) will be classified as a 
non-responder.  The estimate of the ORR with 95% Clopper-Pearson exact CI will be 
presented.
Responses to study treatment will be based on investigator assessments. 
6.4.2
Secondary Efficacy Endpoints
Secondary efficacy endpoints include DOR in the CNS, CBR for the CNS, PFS in the 
CNS, PFS (CNS or non-CNS), and OS.

Among patients with an objective response, DOR will be defined as the time from 
documentation of the first CR or PR to the time of disease progression, relapse, or 
death from any cause.  If a patient does not experience death or disease 
progression before the end of the study, DOR will be censored on the last date the 
patient is known to be progression free. 


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
CBR (CNS), defined as a combination of CR, PR, or stable disease6 months in 
CNS, will be estimated.  A 95% Clopper-Pearson exact CI for CBR will be presented.  

PFS in the CNS, defined as the time from the date of enrollment to disease 
progression in the CNS or death from any cause, will be calculated.  If no 
progressive disease in the CNS and no death occurs, PFS (CNS) will be censored 
on the date of the last CNS tumor assessment.  If a post-baseline assessment is not 
available, PFS (CNS) will be censored on Day 1.    

PFS (CNS or systemic), defined as the time from the date of enrollment to disease 
progression in the CNS or systemically, or death from any cause, will be calculated.  
If no progressive disease in the CNS or systemically and no death occurs, PFS will 
be censored on the date of the last CNS or systemic tumor assessment, whichever 
occurs first.  If a post-baseline assessment is not available, PFS will be censored on 
Day 1.  Progression will be recorded as the first documented progression in the 
CNS (for PFS CNS) or as the first documented progression at any site (for CNS or 
systemic disease PFS).  

OS is defined as the period from the date of enrollment until the date of death from 
any cause.  If no death occurs, OS will be censored on the last date the patient is 
known to be alive.
The Kaplan-Meier approach will be used to estimate the distribution of DOR, PFS, and 
OS.  The 95% CI for the median time to event will be calculated using the Brookmeyer 
and Crowley method.
6.5
SAFETY ANALYSIS
All patients who receive any amount of either study drug will be included in the safety 
analysis.
Exposure will be described by a summary of number of doses received, length of 
therapy, number of patients experiencing dose interruptions, and dose discontinuation 
for reasons other than disease progression.
Adverse events will be mapped to Medical Dictionary for Regulatory Activities (MedDRA)
terms and will be graded according to NCI CTCAE v4.0.  Serious adverse events and 
non-serious adverse events of special interest, pregnancies, and serious adverse events 
considered related to a protocol-mandated procedure during screening will also be 
summarized separately by mapped terms. 
NCI CTCAE v4.0 severity grade, study treatment discontinuations, and deaths will be 
summarized as well.  Laboratory results will be summarized by using NCI CTCAE v4.0 
grade.
6.6
PHARMACOKINETIC ANALYSES
Observed Cmax and minimum concentration (Cmin) values of pertuzumab and 
trastuzumab will be summarized at each specified sampling timepoint.  Descriptive 


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statistics will be captured and compared, as appropriate, including means, medians, 
standard deviations, and ranges of values as appropriate.  All patients who have 
measurable concentrations will be included in the PK analysis unless there are major 
protocol deviations or if information impacting PK evaluation (e.g., exact blood sampling 
time, labeling error, technical failure in sample analysis) are unavailable.
All pertuzumab and trastuzumab concentration data will be reported, but observed Cmin 
values measured on days other than those scheduled, and similar outlier values that do 
not allow comparability with data from other patients, may be excluded from the 
analyses.
Relationships between observed and/or population model-predicted PK and safety, and 
between PK and efficacy, will also be examined as part of the exploratory analyses.
6.7
PATIENT-REPORTED OUTCOME ANALYSES
PROs will be collected in this study to evaluate the impact of treatment on the CNS 
metastases (MDASI-BT assessment per the patient’s perspective).  The instrument will 
be completed directly by the patient and will be administered to patients upon arrival for 
their visit prior to receiving treatment or brain MRI procedure, every 6 weeks 2, followed 
by every 8 weeks 2, then every 12 weeks until progression.
MDASI-BT
Symptom Severity Score:  A component score for the MDASI-BT symptom severity 
scale will be calculated by averaging of the 22 items.  A prorated total score will be 
derived when patients score at least 12 of the 22. The score will be considered missing 
if less than 12 items are not completed.
Symptom Interference Score:  The mean of the interference items will be calculated to 
represent overall symptom distress.  A prorated total score will be derived when patients 
score at least 4 of the 6 items on a given administration. The score will be considered 
missing If less than 4 items are not completed.
Further details on the change from baseline analyses, as well as the time to symptom 
deterioration analyses based on the MDASI-BT scores, will be provided in the Statistical 
Analysis Plan.  Further exploratory analyses will be conducted on the association of 
PRO scores (neurologic symptom deterioration) with response to therapy or with PFS.
6.8
INTERIM ANALYSIS
6.8.1
Planned Interim Analysis
An interim analysis will be performed when 15 patients are enrolled and have the 
following:  1) at least two LVEF measurements (at Week 6 and Week 12), 2) two cycles 
(3-week cycle) of study drug, and 3) two response measurements for review.  Complete 
guidelines to assist in decision-making will be described in the Steering Committee


 
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charter.  For this interim analysis, the safety endpoints will be of primary consideration.  
Efficacy endpoints will also be examined to identify potential treatment non-benefits.  
Accrual will be suspended and the study will be stopped if it is confirmed that the 
following scenarios have occurred:  
 
Two or more CHF events considered related to pertuzumab or trastuzumab in the 
first 15 patients treated 
 
None of the 15 patients with objective response or stable disease in the CNS  
 
With this stopping rule (zero objective responses or stable disease in the CNS out of 
15 efficacy-evaluable patients), the probabilities of stopping the study are 1.3%, 3.5%, 
8.7%, 20.6%, and 46.3% when the true ORRs in the CNS are 25%, 20%, 15%, 10%, 
and 5%, respectively.  
6.9 
FINAL ANALYSIS 
Primary efficacy analysis will be performed when all enrolled patients have been 
followed for approximately 1 month after the last patient has disease progression or early 
discontinuation or has been at least 6 months on treatment, whichever occurs first.  Follow-up 
data analysis will be performed when all the follow-up data are entered into the EDC 
system (or clinical database). 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will supply eCRF specifications for this study.  A contract research 
organization (CRO) will be responsible for data management of this study, including 
quality checking of the data.  Data entered manually will be collected via EDC through 
use of eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event 
of discrepant data, the CRO will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data.  Both CRF and non-CRF data will be sent directly to the CRO, 
using the Sponsor’s standard procedures to handle and process the electronic transfer 
of these data. 
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO’s data management plans and specifications.  Data will be 
periodically transferred electronically from the CRO to the Sponsor, and the Sponsor’s 
standard procedures will be used 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 at the CRO and records retention for the study data will 
be consistent with the CRO’s standard procedures. 


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Data from paper PRO questionnaires will be entered into the EDC system by site staff.
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) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.4.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.


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7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, PRO data, 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).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union (E.U.) 
or European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Home Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 


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before IRB/EC submission.  The final IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
Each Consent Form may also include patient authorization to allow use and disclosure 
of personal health information in compliance with the U.S. Health Insurance Portability 
and Accountability Act of 1996 (HIPAA).  If the site utilizes a separate Authorization 
Form for patient authorization for use and disclosure of personal health information 
under the HIPAA regulations, the review, approval, and other processes outlined above 
apply except that IRB review and approval may not be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 


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Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.5).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/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., LPLV).


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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
Genentech, Inc., a member of the Roche group, will sponsor this study.  A clinical 
research organization will provide clinical operations, data management, IXRS, day-to-
day clinical science monitoring, and statistical programming.  Approximately 20 study 
centers in the U.S. will participate in the study to enroll approximately 40 patients.
Electronic data capture will be utilized for this study.  An IXRS will be used to assign 
patient numbers.  A central laboratory will be used to manage and analyze laboratory 
samples for PK and biological samples.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, 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 Trials Data at the following Web site:
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf


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The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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on overall survival. Ann Oncol 2003;14:10721077.
Moja L, Tagliabue L, Balduzzi S, et al. Trastuzumab containing regimens for early breast 
cancer. Cochrane Database Syst Rev 2012:CD006243.


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Musolino A, Ciccolallo L, Panebianco M, et al. Multifactorial central nervous system 
recurrence susceptibility in patients with HER2-positive breast cancer:
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Cancer 2011;117:18371846.
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2009;20:803805.
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Appendix 1
Schedule of Assessments
Assessments
Screening
Study Treatment Period
Treatment 
Discontinuation a
Q3 Month
Survival 
Follow-Up
(15 days)
Every Week Until 
Progression
(2 days)
Every 3 Weeks 
Until Progression
(2 days)
Every 4 Weeks 
Until Progression
(2 days)
Every 8 Weeks 
Until Progression
(2 days)
Day
Day 28 to 
Day 1
Day 1
Day 1
Day 1
Day 1
Within 30 Days 
after Last Dose
Written informed 
consent b
x
Medical history and 
demographic data c
x
Physical examination d
x
x
Vital signs, height, and 
weight e
x e
x
Concomitant 
medications f
x
x
x
LVEF monitoring g
x
See footnote g
x g
ECOG Performance 
Status
x
Tumor Response and Evaluations
MRI brain h
x
See footnote h
CT, MRI, PET-CT of 
chest, abdomen, 
pelvis (and neck, if 
clinically indicated) i
x
x 
Laboratory, Biomarker, and Other Biological Sample Evaluations 
Hematology j
x
See footnote j
Chemistry k
x
See footnote k
Pregnancy test l
x
See footnote l
x


Appendix 1
Schedule of Assessments (cont.)
Pertuzumab and Trastuzumab—Genentech, Inc.
79/ Protocol ML29366, Version 3
Assessments
Screening
Study Treatment Period
Treatment 
Discontinuation a
Q3 Month
Survival 
Follow-Up
(15 days)
Every Week Until 
Progression
(2 days)
Every 3 Weeks 
Until Progression
(2 days)
Every 4 Weeks 
Until Progression
(2 days)
Every 8 Weeks 
Until Progression
(2 days)
Day
Day 28 to 
Day 1
Day 1
Day 1
Day 1
Day 1
Within 30 Days 
after Last Dose
Laboratory, Biomarker, and Other Biological Sample Evaluations (cont.)
Serum pertuzumab
and trastuzumab
levels m
See footnote m
Optional biomarker 
plasma sample n
x
x 
Optional archival 
tumor sample o
x
Patient-Reported Outcomes
MDASI-BT p
x
x
x
Treatment
Administration of 
pertuzumab q
x
Administration of 
trastuzumab r
x
Adverse events s
x
x
x
Survival status t
x
Cmaxmaximum concentration; CNScentral nervous system; CRcomplete response; CT computed tomography; ECOG Eastern Cooperative 
Oncology Group; eCRFelectronic case report form; LVEF left ventricular ejection fraction; MDASI-BT M.D. Anderson Symptom Inventory-Brain Tumor; 
MRImagnetic resonance imaging; PET-CTposition-emission tomography CT; PFSprogression-free survival; PRpartial response; PRO patient-
reported outcome.


Appendix 1
Schedule of Assessments (cont.)
Pertuzumab and Trastuzumab—Genentech, Inc.
80/ Protocol ML29366, Version 3
a Patients who experience clinical benefit (stable disease, PR, or CR) may continue to receive treatment with pertuzumab and trastuzumab on study until 
disease progression (in the CNS or systemically) or intolerable toxicity.  Patients who discontinue from study treatment will be asked to return to the 
clinic within 30 days of the last infusion of study treatment for a treatment completion visit.  The visit at which a response assessment showed disease 
progression may be used as the treatment completion visit.
b Written informed consent for participation in the study must be obtained before performing any study-specific screening tests or evaluations, and may 
be obtained more than 28 days before initiation of study treatment (Day 1).
c Medical history includes clinically significant diseases, surgeries, and cancer history (including prior cancer therapies and procedures). Demographic 
data will include age, sex, and self-reported race/ethnicity.
d A complete physical examination will be performed at baseline.  Physical examination includes evaluation of the head, eyes, ears, nose, and throat; and 
the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems.  Record abnormalities observed at baseline 
on the General Medical History and Baseline Conditions eCRF.  At subsequent visits (Day 1 of each 3-week cycle or as clinically indicated), limited, 
symptom-directed physical examinations should be performed (record changes in patient notes).  Neurological status should be performed as part of 
these examinations.  As part of tumor assessment, physical examinations should also include the evaluation of the presence and degree of enlarged 
lymph nodes, hepatomegaly, and splenomegaly.  Record new or worsened clinically significant abnormalities as adverse events on the Adverse Event 
eCRF.
e Vital sign assessments include measurements of heart rate, systolic and diastolic blood pressures while the patient is in a seated position, respiratory 
rate, and temperature.  Vital signs and weight will be assessed before treatment on Day 1 of every 3-week cycle.  Record abnormalities on the Adverse 
Event eCRF. Height and weight will be measured at screening.  Weight changes of 10% would require the dose of trastuzumab to be adjusted.  
f
Concomitant medication includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional 
supplements) used by a patient from 7 days prior to screening to the study completion/discontinuation visit.  All such medications should be reported to 
the investigator and recorded on the Concomitant Medications eCRF.  
g LVEF evaluations will be assessed at Screening, 6 and 12 weeks (after Cycle 1, Day 1), followed by LVEF evaluations every 3 months during the 
treatment period.  LVEF evaluations will also be conducted every 6 months during the survival follow-up period (12 months after the treatment 
discontinuation visit).  
h All target and non-target CNS disease must be documented at screening and reassessed at each subsequent tumor evaluation.  T1-weighted perfusion 
MRI will be used to evaluate changes in brain metastases that indicate treatment effects.  Post-baseline MRI of the brain will be conducted every 6 
weeks 2, followed by every 8 weeks 2, then every 12 weeks until progression.  If there is suspicion of disease progression based on clinical or 
laboratory findings before the next scheduled assessment, an unscheduled assessment should be performed.  An additional assessment may be 
conducted at the treatment discontinuation visit.  An objective response (CR, PR) in the CNS should be confirmed by repeat assessments 4 6 weeks 
after initial finding or at the next scheduled tumor assessment if it is to occur 4 6 weeks after the initial response.


Appendix 1
Schedule of Assessments (cont.)
Pertuzumab and Trastuzumab—Genentech, Inc.
81/ Protocol ML29366, Version 3
i
Tumor response of systemic disease will be measured using CT, MRI, or PET-CT of the chest, abdomen, pelvis (and neck, if clinically indicated).  
Assessments will be performed every 8 weeks for the first 16 weeks, then every 12 weeks.  For patients with no evidence of systemic disease at 
baseline, additional systemic tumor assessments (chest, abdomen, and pelvis) will be performed every 8 weeks for the first 16 weeks, followed by 
systemic assessments every 12 weeks.  All other known sites of disease must be documented at screening and reassessed at each subsequent tumor 
evaluation.  
j
Hematology testing must be done during screening and every 6 weeks within 3 days (with results available) prior to the administration of study drug.  
Hematology testing includes:  hemoglobin, hematocrit, platelet count, RBC count, WBC count, and percent and absolute differential count (neutrophils, 
bands, eosinophils, lymphocytes, monocytes, basophils, and other cells).
k Chemistry testing must be done during screening and every 6 weeks within 3 days (with results available) prior to the administration of study drug.  
Chemistry testing includes:  sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, total bilirubin, total protein, albumin, ALT, 
AST, alkaline phosphatase, and LDH.
l
All women of childbearing potential (including those who have had a tubal ligation and women 12 months after the onset of menopause, even if they 
have undergone surgical sterilization) will have a serum pregnancy test at screening within 7 days before the first dose of study drug (with results 
available prior to dosing).  Urine pregnancy tests will be performed at specified subsequent visits within 7 days before every 3rd pertuzumab cycle and 
at the treatment discontinuation visit.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  During the treatment period, 
pregnancy test results must be available prior to administration of study drug.  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.  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.  
m On specified days of study drug administration, pre-infusion PK samples should be drawn 0 4 hours before the start of the first infusion and 
post-infusion PK samples should be drawn 0 30 minutes after the end of the infusions, unless otherwise specified.  Two separate 2-mL blood samples 
will be collected (one sample for each analyte, pertuzumab and trastuzumab) at each timepoint as follows:  Week 1, Day 1 (1 sample pre-dose and 1 
sample within 30 minutes after completion of both infusions [Cmax]) (total of 2 samples); Week 4, Day 1 (pre-dose [trough]); Week 10, Day 1 (pre-
dose [trough]); Week 16, Day 1 (1 sample pre-dose and 1 sample within 30 minutes after completion of both infusions [Cmax]) (total of 2 
samples).  Each blood sample will be 2 mL in volume, totaling 24 mL for PK sampling in each patient over approximately 16 weeks. 
n Two optional exploratory biomarker plasma samples may be taken.
o Tissue from primary tumor or metastatic site.
p The PRO questionnaire will be administered at baseline (Day 1 prior to study treatment), every 6 weeks2, followed by every 8 weeks 2, then every 12 
weeks until progression. 


Appendix 1
Schedule of Assessments (cont.)
Pertuzumab and Trastuzumab—Genentech, Inc.
82/ Protocol ML29366, Version 3
q A loading dose of pertuzumab will be given on Day 1 on study.  Subsequent pertuzumab doses will be given every 3 weeks. However, for patients 
already receiving pertuzumab as part of their ongoing systemic therapy, no loading dose is required in the case of an interval 6 weeks between last 
dose of pertuzumab and the first administration of on-study pertuzumab.
r Safety assessments should be performed and results reviewed prior to administration of trastuzumab.  Note:  Weight changes 10% require the dose 
of trastuzumab to be recalculated.  Weekly doses should be no less than 5 days apart.
s After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated intervention 
should be reported (see Section 5.4 ).  After initiation of study drug, serious adverse events and non-serious adverse events of special interest will be 
reported until 30 calendar days after the last dose of study drug.  LVEF events will be reported for 2 years after the last dose of study drug.   
t
For PFS survival follow-up, patients who discontinue study treatment will be followed per standard of care, including MRIs of the brain and assessments 
of the chest, abdomen, and pelvis (only scans that were abnormal at baseline need to be repeated).  For survival and LVEF follow-up, all patients will 
be followed for a minimum of 12 months from the date of the last dose of study drug or until death, whichever occurs first, every 3 months for survival 
and every 6 months for LVEF.  


Pertuzumab and Trastuzumab—Genentech, Inc.
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Appendix 2
Schedule of Assessments for Scans
Assessments
Screening
Day 28 
to Day 1
Week 
6
Week 
8
Week
12
Week 
16
Week 
20
Week 
24
Week 
28
Week 32 & 
Every 8 
Weeks until 
Progression
Week 36 & 
Every 12 
Weeks until 
Progression
Week 40 & 
Every 12 
Weeks until 
Progression
Treatment 
Discont-
inuation
Within 30 
Days after 
Last Dose
Q3 Month 
Survival 
Follow-Up
(15 days)
MRI brain a
X
X
X
X
X
X
X
Scans of chest, 
abdomen & pelvis 
(neck if clinically 
indicated) b
X
X
X
X
X
LVEF monitoring c
X
X
X
X
X
X
CNScentral nervous system; CRcomplete response; CT computed tomography; LVEFleft ventricular ejection fraction; MRImagnetic resonance 
imaging; PET-CTpositron-emission tomography CT.
a All target and non-target CNS disease must be documented at screening and reassessed at each subsequent tumor evaluation.  T1-weighted 
perfusion MRI will be used to evaluate changes in brain metastases that indicate treatment effects.  Post-baseline MRI of the brain will be conducted 
every 6 weeks 2, followed by every 8 weeks 2, then every 12 weeks until progression.  If there is suspicion of disease progression based on clinical 
or laboratory findings before the next scheduled assessment, an unscheduled assessment should be performed.  An additional assessment may be 
conducted at the treatment discontinuation visit.  An objective response (CR, PR) and progressive disease in the CNS should be confirmed by repeat 
assessments 4 6 weeks after initial finding or at the next scheduled tumor assessment if it is to occur 4 6 weeks after the initial response.
b Tumor response of systemic disease will be measured using CT, MRI, or PET-CT of the chest, abdomen, pelvis (and neck, if clinically indicated).  
Assessments will be performed every 8 weeks for the first 16 weeks, then every 12 weeks.  For patients with no evidence of systemic disease at 
baseline, additional systemic tumor assessments (chest, abdomen, and pelvis) will be performed every 8 weeks for the first 16 weeks, followed by 
systemic assessments every 12 weeks.  All other known sites of disease must be documented at screening and reassessed at each subsequent 
tumor evaluation.
c LVEF evaluations will be assessed at Screening, 6 and 12 weeks (after Cycle 1, Day 1), followed by LVEF evaluations every 3 months during the 
treatment period.  LVEF evaluations will also be conducted every 6 months during the survival follow-up period (12 months after the treatment 
discontinuation visit).


Pertuzumab and Trastuzumab—Genentech, Inc.
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Appendix 3
Schedule of Pertuzumab and Trastuzumab Pharmacokinetic 
Assessments
Visit
Timepoint
Sample Types
Week 1, Day 1
Pre-dose (trough)
PK trastuzumab, PK 
pertuzumab (serum)
Post-infusions (Cmax)
PK trastuzumab, PK 
pertuzumab (serum)
Week 4, Day 1
Pre-dose (trough)
PK trastuzumab, PK 
pertuzumab (serum)
Week 10, Day 1
Pre-dose (trough)
PK trastuzumab, PK 
pertuzumab (serum)
Week 16, Day 1
Pre-dose (trough)
PK trastuzumab, PK 
pertuzumab (serum)
Post-infusions (Cmax)
PK trastuzumab, PK 
pertuzumab (serum)
Cmaxmaximum concentration; PKpharmacokinetic.
At each timepoint, 22 mL samples will be collected, totaling 24 mL for PK 
sampling in each patient over approximately 16 weeks.
Pre-dose samples can be collected up to 4 hours prior to infusion.  Post-infusion 
samples can be collected within 30 minutes after completion of both infusions.


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Appendix 4
Response Assessment in Neuro-Oncology-Brain Metastases 
(RANO-BM) Criteria:  Modified Excerpt from Original Publication
Definitions
Definition of Measurable Disease: Measurable disease is defined as a contrast 
enhancing lesion that can be accurately measured in at least one dimension with a 
minimum size of 10 mm, visible on two or more axial slices that are preferably5 mm 
apart with 0-mm skip (and ideally1.5 mm apart with 0-mm skip). In addition, although 
the longest diameter in the plane of measurement is to be recorded, the diameter 
perpendicular to the longest diameter in the plane of measurement should be at least 
5 mm for the lesion to be considered measurable. In the event the MRI is performed 
with thicker slices, the size of the measurable lesion at baseline should be at least two 
times the slice thickness. If there are interslice gaps, this also needs to be considered in 
determining the minimum size of measurable lesions at baseline. Measurement of 
tumor around a cyst or surgical cavity represents a particularly difficult challenge. In 
general, such lesions should be considered non-measurable unless there is a nodular 
component measuring10 mm in longest diameter and5 mm in the perpendicular 
plane. The cystic or surgical cavity should not be measured in determining response 
(Figure 1 in the original publication).  
Definition of Non-measurable Disease: All other lesions, including lesions with longest 
dimension10 mm, lesions with borders that cannot be reproducibly measured, dural 
metastases, bony skull metastases, cystic-only lesions, and leptomeningeal disease.
Specifications of Methods of Measurement
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 follow-up. It is important to use imaging techniques that are consistent across all 
imaging timepoints in order to ensure that the assessment of interval appearance or 
disappearance of lesions or of change in size is not affected by scan parameters such 
as slice thickness. Use of thin section imaging (for example, Appendix A of the original 
publication) is particularly important when evaluating lesions10 mm in LD and/or small 
changes in lesion size.
Imaging Modality: Gadolinium-enhanced MRI is the best currently available, sensitive, 
and reproducible method to measure CNS lesions selected for response assessment.  
Suggested brain MRI specifications are detailed in Appendix A of the original publication.
A sum of the diameters for all target lesions will be calculated and reported as the 
baseline sum of longest diameters (sum LD). All other CNS lesions should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not 


Appendix 4
Response Assessment in Neuro-Oncology-Brain Metastases 
(RANO-BM) Criteria:  Modified Excerpt from Original Publication 
(cont.)
Pertuzumab and Trastuzumab—Genentech, Inc.
86/ Protocol ML29366, Version 3
required and these lesions should be followed as ‘present’, ‘absent’, or ‘unequivocal 
progression’.  
Definition of Best Overall CNS Response
Best overall CNS response represents a composite of radiographic CNS target and 
non-target response (see definitions above), corticosteroid use, and clinical status. In 
non-randomized trials where CNS response is the primary endpoint, confirmation of PR 
or CR at least 4 weeks later is required to deem either one the best overall response. 
At each protocol-specified timepoint, a response assessment should occur and CNS 
assessments should be coincident with extra-CNS assessment. Table 1 shows the 
additional corticosteroid and clinical status requirements to deem a PR or CR.
Evaluation of Target Lesions
Complete response (CR): Disappearance of all CNS target lesions sustained for at 
least 4 weeks; no new lesions; no corticosteroids; stable or improved clinically. 
Partial response (PR): At least a 30% decrease in the sum LD of CNS target lesions, 
taking as reference the baseline sum LD sustained for at least 4 weeks; no new lesions; 
stable to decreased corticosteroid dose; stable or improved clinically. 
Progressive disease (PD): At least a 20% increase in the sum LD of CNS target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, at least one 
lesion must increase by an absolute value of5 mm to be 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 LD while on study.
Evaluation of Non-Target Lesions
Non-target lesions should be assessed qualitatively at each of the timepoints specified in 
the protocol.
CR: Requires all of the following: disappearance of all enhancing CNS non-target 
lesions, no new CNS lesions.
Non-CR/Non-PD: Persistence of one or more non-target CNS lesion(s).


Appendix 4
Response Assessment in Neuro-Oncology-Brain Metastases 
(RANO-BM) Criteria:  Modified Excerpt from Original Publication 
(cont.)
Pertuzumab and Trastuzumab—Genentech, Inc.
87/ Protocol ML29366, Version 3
PD: Any of the following: unequivocal progression of existing enhancing non-target CNS 
lesions, new lesion(s) (except while on immunotherapy-based treatment), or unequivocal 
progression of existing tumor-related non-enhancing (T2/FLAIR) CNS lesions. In the 
case of immunotherapy-based treatment, new lesions alone may not constitute 
progressive disease (see “Guidance in the case of new lesion(s) while on 
immunotherapy” below).
Special Notes on the Assessment of Target and Non-Target CNS Lesions:
a)
Target lesions that become too small to measure: While on study, all CNS target 
lesions should have their actual measurement recorded, even when very small (e.g., 
2 mm).  If the lesion disappears, the value should be recorded as 0 mm. However, 
if the lesion is sufficiently small (but still present) that the radiologist does not feel 
comfortable assigning an exact measure, a default value of 5 mm should be 
recorded on the case report form. 
b)
Lesions that coalesce on treatment: As lesions coalesce, a plane between them 
may be maintained that would aid in obtaining maximum LD 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 LD for the 
‘coalesced’ lesion.    
c)
Definition of new lesion(s): The finding of a new CNS lesion should be unequivocal 
and not due to technique or slice variation. A new lesion is one that was not present 
on prior scans. If the MRI is obtained with1.5 mm slice thickness, then the new 
lesion should also be visible in axial, coronal, and sagittal reconstructions of 1.5 
mm projections. If a new lesion is equivocal, for example because of its small size 
(i.e.,5 mm), continued therapy may be considered, 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 
showing the new lesion. In the case of immunotherapy, new lesions alone may not 
constitute progressive disease (see “Guidance in the case of new lesion(s) while on 
immunotherapy” below).
d)
Definition of Unequivocal Progression of Non-Target Lesion(s): When the patient 
also has measurable disease, to achieve ‘unequivocal progression’ on the basis of 
non-target disease alone, there must be an overall level of substantial worsening in 
non-target disease such that, even in the presence of SD or PR in target disease, 
the overall tumor burden has increased sufficiently to merit discontinuation of 
therapy.  When the patient has only non-measurable disease, there must be an 
overall level of substantial worsening to merit discontinuation of therapy.


Appendix 4
Response Assessment in Neuro-Oncology-Brain Metastases 
(RANO-BM) Criteria:  Modified Excerpt from Original Publication 
(cont.)
Pertuzumab and Trastuzumab—Genentech, Inc.
88/ Protocol ML29366, Version 3
e)
Guidance in the Case of Uncertain Attribution of Radiographic Findings and/or 
Equivocal Cases: The RANO-BM group acknowledges that in the case of patients 
followed after SRS or during immunotherapy-based approaches, there may be 
radiographic evidence of enlargement of target and non-target lesions which may 
not necessarily represent tumor progression. If there is evidence of radiographic 
progression but there is clinical evidence supporting the possibility that the 
radiological changes are due to treatment effect (and not to progression of cancer), 
additional evidence is required to distinguish true progression versus treatment 
effect as standard MRI alone is not sufficient. The methods used to distinguish 
between the two entities should be specified prospectively in the clinical protocol. 
Patients may be continued on protocol therapy pending further investigation with 
one or more of the following options: (1) Repeat the scan at the next protocol 
scheduled evaluation or sooner, and generally within ~6 weeks.  An investigator 
may choose a shorter time interval in the case of progressive symptoms or other 
clinically concerning findings.  If there is continued increase in enhancement 
concerning for tumor growth, then this may be consistent with radiographic 
progression and the patient should be taken off study (Figure 2 in the original 
publication). If the lesion is stable or decreased in size, then this may be consistent 
with treatment effect and the patient may remain on study (Figure 3 in the original 
publication). For patients with equivocal results even on the next restaging scan, 
the scan may be repeated again at a subsequent protocol scheduled evaluation or 
sooner although surgery and/or use of an advanced imaging modality (in the case of 
SRS) are strongly encouraged. (2) Surgical pathology obtained via biopsy or 
resection. (3) For SRS treated lesions, an advanced imaging modality such as 
perfusion MR imaging, MR spectroscopy, or 18FLT or 18FDG positron emission 
tomography (PET) may be used as additional evidence of tumor progression or 
treatment effect/radionecrosis. Upon review of the literature and extensive 
discussions by the Working Group, we were not able to conclude that any one 
modality or approach can be recommended across all patients to distinguish 
between radiation necrosis versus true progression, as the literature is not 
sufficiently robust, and recommend clinical judgment and involvement of a 
multidisciplinary team.  We recognize this is less than satisfactory and agree that 
developing more sensitive and specific methods for distinguishing between 
treatment effect and tumor progression are needed.  We should also note that these 
advanced imaging modalities have not been extensively studied with regards to 
immunotherapy-based approaches and therefore are cannot be recommended for 
distinguishing tumor progression versus immune-related changes at this time. 
Regardless of the additional testing obtained, if subsequent testing demonstrates 
that progression has occurred, the date of progression should be recorded as the 
date of the scan at which this issue was first raised. Patients may also have an 
equivocal finding on a scan (for example, a small lesion that is not clearly new). It is 


Appendix 4
Response Assessment in Neuro-Oncology-Brain Metastases 
(RANO-BM) Criteria:  Modified Excerpt from Original Publication 
(cont.)
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permissible to continue treatment until the next protocol scheduled evaluation. If the 
subsequent evaluation demonstrates that progression has indeed occurred, the date 
of progression should be recorded as the date of the initial scan where progression 
was suspected. 
f)
Guidance in the Case of New Lesion(s) while on Immunotherapy: For patients 
receiving immunotherapy-based approaches, an initial increase in the number and 
size of metastases may be followed by radiographic stabilization or regression. This 
may be related to the mechanism of action for immunotherapy, including immune 
infiltrates as well as the time required for development of an effective immune 
response. Thus, progressive disease will be defined not solely by the appearance 
of new lesions but by at least a 20% increase in the sum of the LD of CNS target 
lesions and the new lesion(s); or unequivocal progression of existing enhancing 
non-target CNS lesions; or unequivocal progression of existing non-enhancing 
(T2/FLAIR) CNS lesions; or clinical decline related to tumor. If immune-related 
radiographic changes are suspected, we advise not changing treatment until a short 
interval scan is obtained. If the subsequent evaluation confirms that progression 
has indeed occurred, the date of progression should be recorded as the date of the 
initial scan where progression was suspected.
Notes Regarding Corticosteroid Use and Clinical Deterioration:
a)
An increase in corticosteroid dose alone, in the absence of clinical deterioration 
related to tumor, will not be used as a sole determinant of progression. Patients 
with stable imaging studies whose corticosteroid dose was increased for reasons 
other than clinical deterioration related to tumor do not qualify for stable disease or 
progression. They should be observed closely. If their corticosteroid dose can be 
reduced back to baseline, they will be considered as having stable disease; if further 
clinical deterioration related to tumor becomes apparent, they will be considered to 
have progression.  
b)
The definition of clinical deterioration is left to the discretion of the treating physician, 
but it is recommended that a decline in the KPS from 100 or 90 to 70 or less, a 
decline in KPS of at least 20 points from 80 or less, or a decline in KPS from any 
baseline to 50 or less, for at least 7 days, be considered neurologic deterioration 
unless attributable to comorbid events, treatment-related toxicity, or changes in 
corticosteroid dose. 


Appendix 4
Response Assessment in Neuro-Oncology-Brain Metastases 
(RANO-BM) Criteria:  Modified Excerpt from Original Publication 
(cont.)
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Table 1
Summary of the Proposed RANO Response Criteria for CNS Metastases
Criterion
CR
PR
SD
PD
Target lesions
None
30% decrease 
in sum LD 
relative to
baseline
30% decrease 
relative to baseline 
but20% increase in 
sum LD relative to 
nadir
20% increase 
in sum LD 
relative to nadir*
Non-target 
lesions
None
Stable or 
improved
Stable or improved
Unequivocal PD*
New lesion(s)**
None
None
None
Present*
Corticosteroids
None
Stable or 
decreased
Stable or decreased
NA
Clinical status
Stable or 
improved
Stable or 
improved
Stable or improved
Worse*
Requirement 
for response
All
All
All
Any
Abbreviations: CNScentral nervous system; CRcomplete response; LDlongest 
dimension; NAnot applicable; PDprogressive disease; PRpartial response; 
RANOResponse Assessment in Neuro-Oncology; SDstable disease.
*Progression occurs when this criterion is met. 
**New lesionnew lesion not present on prior scans and visible in at least 2 projections.  
If a new lesion is equivocal, for example because of its small size, continued therapy 
may be considered, 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 showing the new lesion. For immunotherapy-
based approaches, new lesions alone to do not define progression (See “Guidance in 
the Case of New Lesion(s) while on Immunotherapy”).
Increase in corticosteroids alone will not be taken into account in determining 
progression in the absence of persistent clinical deterioration.


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Appendix 5
Response Evaluation Criteria in Solid Tumors, Version 1.1
(RECIST v1.1):  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.
a.
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).  In addition, lymph nodes in 
the pelvis must measure 2 cm in greatest diameter to be considered target lesions.  
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.
b.
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 
                                           
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847.
2 For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made.


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(RECIST v1.1):  Modified Excerpt from Original Publication (cont.)
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mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
c.
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 malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered 
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.
TARGET LESIONS:  SPECIFICATIONS BY METHODS OF MEASUREMENTS
a.
Measurement of Lesions
All measurements should be recorded in metric notation, with use of 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 treatment.


Appendix 5
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(RECIST v1.1):  Modified Excerpt from Original Publication (cont.)
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b.
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 that includes 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 on the basis of 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 whether 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 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.


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(RECIST v1.1):  Modified Excerpt from Original Publication (cont.)
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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 whether a node is involved by solid tumor.  Nodal size is 
normally 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.


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(RECIST v1.1):  Modified Excerpt from Original Publication (cont.)
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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
a.
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.

Complete response (CR):  Disappearance of all target lesions
–
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to 10 mm.

Partial response (PR):  At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters

Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (nadir), including baseline
–
In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.
–
The appearance of one or more new lesions is also considered progression.

Stable disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study
b.
Special Notes on the Assessment of Target Lesions
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to 10 mm on study.  This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero 


Appendix 5
Response Evaluation Criteria in Solid Tumors, Version 1.1
(RECIST v1.1):  Modified Excerpt from Original Publication (cont.)
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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 below measurable limit (BML) 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 is 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.
c.
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.  Whereas 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.

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).


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(RECIST v1.1):  Modified Excerpt from Original Publication (cont.)
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
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.
d.
Special Notes on Assessment of Progression of Non-Target Disease
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease in a magnitude that, even in the 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest increase in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have measurable disease.  
The same general concepts apply here as noted above; however, in this instance, 
there is no measurable disease assessment to factor into the interpretation of an 
increase in non-measurable disease burden.  Because worsening in non-target disease 
cannot be easily quantified (by definition:  if all lesions are truly non-measurable), 
a useful test that can be applied when assessing patients for unequivocal progression is 
to consider whether 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 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.
Bone Only Disease:  Since bone lesions are not considered measurable, patients with 
bone only disease will be evaluated for progression only.  Progression is defined as the 
appearance of new lytic lesions or other new bone destruction thought to be related to 
cancer by X-ray, MRI, or CT scan or a bone event requiring intervention (surgery) if not 


Appendix 5
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(RECIST v1.1):  Modified Excerpt from Original Publication (cont.)
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associated with trauma or other obvious cause.  Changes in bone scan or 18F-sodium 
fluoride (NaF) PET scan should not be used to define progression.  Any changes in bone 
imaging should be evaluated radiographically by CT scan, MRI, or X-ray to ascertain the 
presence of bone destruction versus a healing reaction.  The appearance of new lesions 
on bone scan or 18F-NaF PET scan may constitute progressive disease if associated 
with clinical symptoms suggestive of disease progression.  The occurrence of a 
pathologic fracture at a site previously recognized bone disease may constitute 
progressive disease if not associated with trauma or other obvious cause.  Bone pain 
requiring radiation will constitute progressive disease.  Increase in pain at a site of 
previously recognized bone disease may constitute progressive disease if it is persistent 
and not associated with other obvious cause.
e.
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 
(e.g., some “new” bone lesions may be simply healing or flare of preexisting lesions).  
This is particularly important when the patient’s baseline lesions show PR 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 whether 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
a.
Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.


Appendix 5
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(RECIST v1.1):  Modified Excerpt from Original Publication (cont.)
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Table 1
Timepoint Response:  Patients with Target Lesions
(with or without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CR complete response; NE not evaluable; PD progressive disease; PR partial response; 
SD stable disease.
Table 2
Timepoint Response:  Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CR complete response; NE not evaluable; PD progressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease, since stable 
disease is increasingly used as an endpoint for assessment of efficacy in some trials; thus, 
assigning “stable disease” when no lesions can be measured is not advised.
b.
Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements is 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 
measured lesions and during the study only two lesions were assessed but those gave a 


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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, since this equates with the case being not evaluable at that timepoint.


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Table 3
Best Overall Response When Confirmation Is Required
Overall Response 
at First Timepoint
Overall Response at 
Subsequent Timepoint
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR a
CR
SD
SD, provided minimum duration for SD was met;
otherwise, PD
CR
PD
SD, provided minimum duration for SD was met; 
otherwise, PD
CR
NE
SD, provided minimum duration for SD was met; 
otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD, provided minimum duration for SD was met; 
otherwise, PD
PR
NE
SD, provided minimum duration for SD was met; 
otherwise, NE
NE
NE
NE
CR complete response; NE not evaluable; PD progressive disease; PR partial response; 
SD stable disease.
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, even 
disease meeting PR criteria relative to baseline, qualifies as PD at that point (since disease 
must have reappeared after CR).  Best response would depend on whether the minimum 
duration for SD was met.  However, sometimes CR may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the patient had PR, not CR, at the first 
timepoint.  Under these circumstances, the original CR should be changed to PR, and the best 
response is PR.
c.
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 


Appendix 5
Response Evaluation Criteria in Solid Tumors, Version 1.1
(RECIST v1.1):  Modified Excerpt from Original Publication (cont.)
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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 (e.g., 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. 




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Appendix 7
New York Heart Association Classification of Functional 
Cardiac Capacity
Class
I
No limitation:  Ordinary physical activity does not cause undue fatigue, dyspnea, or 
palpitation.
II
Slight limitation of physical activity:  Such patients are comfortable at rest.  Ordinary 
physical activity results in fatigue, palpitations, dyspnea, or angina.
III
Marked limitation of physical activity:  Although patients are comfortable at rest, less 
than ordinary physical activity will lead to symptoms.
IV
Inability to carry on physical activity without discomfort:  Symptoms of congestive 
heart failure are present even at rest.  With any physical activity, increased 
discomfort is experienced.
From:  Criteria Committee, New York Heart Association, Inc. Diseases of the heart and blood 
vessels.  Nomenclature and criteria for diagnosis. 6th ed. Boston, Little, Brown and Co, 1964:114.


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Appendix 8
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


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Appendix 9
Left Ventricular Systolic Dysfunction Grading
NCI CTCAE 
Grade
Left Ventricular Systolic Dysfunction Severity
1

2

3
Symptomatic due to drop in ejection fraction responsive to intervention
4
Refractory or poorly controlled heart failure due to drop in ejection fraction; 
intervention such as ventricular assist device, intravenous vasopressor 
support, or heart transplant indicated
5
Death
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v 4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm
LVSD Definition:  A disorder characterized by failure of the left ventricle to produce adequate 
output despite an increase in distending pressure and in end-diastolic volume.  Clinical 
manifestations may include dyspnea, orthopnea, and other signs and symptoms of pulmonary 
congestion and edema.


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Appendix 10
Reporting Conventions for Left Ventricular Systolic 
Dysfunction/Heart Failure
Observation
How to Report
Term to be 
Reported
Grading
Asymptomatic decline in 
LVEF 10% points from 
baseline or tan an 
LVEF 45%
No additional reporting 
required, LVEF results to be 
reported on eCRF
N/A
N/A
Asymptomatic decline in 
LVEF10% points from 
baseline or tan an 
LVEF45%
AE (eCRF)
“Ejection fraction 
decreased” a
NCI CTCAE for 
“ejection fraction 
decreased”
Asymptomatic decline in 
LVEFrequiring treatment or 
leading to discontinuation of 
pertuzumab and trastuzumab
AE (eCRF) and on-serious 
AESI (reported on an SAE 
form)
“Ejection fraction 
decreased” a
NCI CTCAE for 
“ejection fraction 
decreased”
Heart failure/CHF 
(symptomatic LVSD)
AE (eCRF) and SAE (SAE 
form)
“Heart failure”
NCI CTCAE for 
“heart failure” and 
NYHA Class
AEadverse event; CHFcongestive heart failure; eCRFelectronic Case Report Form; LVEFleft 
ventricular ejection fraction; LVSDleft ventricular systolic dysfunction; N/A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 “asymptomatic” and the LVEF value in the comments field as appropriate.


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Appendix 11
M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT)
The MDASI-BT consists of 28 items and is a multi-symptom measure of cancer-related 
symptoms (Cleeland et al. 2000) that are sensitive to disease and treatment changes.  
The MDASI-BT is composed of the symptom severity scale and the symptom 
interference scale. In the symptom severity scale, patients rate the severity of their 
symptoms in the last 24 hours on 010 numeric scales, ranging from “not present” to 
“as bad as you can imagine.” In the symptom interference scale, patients rate 
interference with daily activities caused by their symptoms on 010 numeric scales 
ranging from “did not interfere” to “interfered completely.”  This instrument is brief, takes 
less than five minutes to complete, is easily understood and validated in the cancer 
population (Cleeland 2008). 


Appendix 11
M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT)
(cont.)
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Appendix 11
M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT)
(cont.)
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SAP_001.pdf: 
 
Official Title: 
 
AN OPEN-LABEL, SINGLE-ARM, PHASE II STUDY OF 
PERTUZUMAB WITH HIGH-DOSE TRASTUZUMAB FOR THE 
TREATMENT OF CENTRAL NERVOUS SYSTEM PROGRESSION 
POST-RADIOTHERAPY IN PATIENTS WITH HER2-POSITIVE 
METASTATIC BREAST CANCER (PATRICIA) 
NCT Number: 
NCT02536339 
Document Date: 
SAP Version 1: 29-April-2019 
 
 


Confidential 
This is a Genentech, Inc. document that contains confidential information.  Nothing herein is to be 
disclosed without written consent from Genentech, Inc. 
 
Study ML29366 
1/34 
Statistical Analysis Plan, Version Final Draft 
 
Date: 2019-04-29 
 
STATISTICAL ANALYSIS PLAN 
TITLE: 
AN OPEN-LABEL, SINGLE-ARM, PHASE II 
STUDY OF PERTUZUMAB WITH HIGH-DOSE 
TRASTUZUMAB FOR THE TREATMENT OF 
CENTRAL NERVOUS SYSTEM PROGRESSION 
POST-RADIOTHERAPY IN PATIENTS WITH 
HER2-POSITIVE METASTATIC BREAST CANCER 
(PATRICIA) 
PROTOCOL NUMBER: 
ML29366 
STUDY DRUG: 
Pertuzumab (RO4368451), Trastuzumab (RO0452317) 
IND NUMBER: 
4517 
SPONSOR: 
Genentech, Inc. 
1 DNA Way 
South San Francisco, CA 94080 
PLAN PREPARED BY: 
, Ph.D. 
. 
 
 
VERSION: 
Final Draft 
DATE FINAL: 
29APR2019 


Table of Contents 
 
Page 
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Statistical Analysis Plan, Version Final Draft 
 
Date: 2019-04-29 
1. 
BACKGROUND ...............................................................................4 
2. 
STUDY DESIGN ..............................................................................5 
2.1 
Protocol Synopsis (including Schedule of Assessment) ........6 
2.2 
Outcome Measures ..............................................................7 
2.2.1 
Primary Efficacy Outcome Measures .....................7 
2.2.2 
Secondary Efficacy Outcome Measures .................7 
2.2.3 
Safety Outcome Measures .....................................7 
2.2.4 
Pharmacokinetic Outcome Measures .....................8 
2.2.5 
Patient-Reported Outcome Measures ....................8 
2.2.6 
EXPLORATORY OUTCOME Measures .................8 
2.3 
Determination of Sample Size ..............................................8 
3. 
STUDY CONDUCT ........................................................................ 10 
3.1 
Randomization Issues ........................................................ 10 
3.2 
Data Monitoring .................................................................. 10 
4. 
STATISTICAL METHODS .............................................................. 10 
4.1 
Analysis Populations........................................................... 10 
4.1.1 
Intent-to-Treat Population..................................... 10 
4.1.2 
Efficacy Evaluable Population .............................. 10 
4.1.3 
Pharmacokinetic Evaluable Population ................ 11 
4.1.4 
Patient-Reported Outcomes Evaluable 
Population ............................................................ 11 
4.1.5 
Safety Population ................................................. 11 
4.2 
Analysis of Study Conduct .................................................. 11 
4.3 
Analysis of Treatment Group Comparability ........................ 11 
4.4 
Efficacy Analyses ............................................................... 12 
4.4.1 
Primary Efficacy Endpoint(s) ................................ 12 
4.4.2 
Secondary Efficacy Endpoints .............................. 12 
4.4.3 
Sensitivity Analyses ............................................. 14 
4.4.4 
Subgroup Analyses .............................................. 14 
4.4.5 
Exploratory Analyses ........................................... 14 
4.5 
Safety Analyses .................................................................. 14 
4.5.1 
Exposure of Study Medication .............................. 15 
4.5.2 
Adverse Events .................................................... 15 
4.5.3 
Laboratory Data ................................................... 17 
4.5.4 
Vital Signs ............................................................ 17 
4.5.5 
Electrocardiogram ................................................ 17 
4.5.6 
LVEF Evaluations ................................................ 17 


Table of Contents 
 
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4.6 
Pharmacokinetic Analyses .................................................. 18 
4.7 
Patient Report Outcomes Analyses .................................... 18 
4.8 
Handling of Dropouts, Missing/Incomplete Data, or 
Outliers ............................................................................... 18 
4.9 
Interim Analyses and/or Safety Reviews ............................. 19 
5. 
REFERENCES .............................................................................. 20 
6. 
APPENDICES ................................................................................ 21 
6.1 
APPENDIX A: Schedule of Assessments ........................... 21 
6.2 
APPENDIX B: SCHEDULE OF ASSESSMENTS FOR 
SCANS ............................................................................... 26 
6.3 
APPENDIX C: SCHEDULE OF Pertuzumab and 
Trastuzumab Pharmacokinetic Assessments...................... 29 
6.4 
APPENDIX D: Statistical Methods Requiring Input ............. 30 
6.5 
APPENDIX E: Documentation of Additional Analyses 
Performed after Database Lock .......................................... 31 
6.6 
APPENDIX F: Data Handling Rules .................................... 32 
6.6.1 
NCI CTCAE V4.0 Grades for Laboratory 
Parameters .......................................................... 32 
6.6.2 
MDASI-BT Scoring Algorithm ............................... 34 
6.7 
APPEDNDIX G: Programming Codes for Statistical 
Analysis .............................................................................. 35 
 
 


 
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1. 
BACKGROUND 
Breast cancer is the second most prevalent malignancy metastasizing to the central nervous 
system (CNS), accounting for 20% of cases observed in cancer care (Boogerd et al. 1993). 
The incidence of clinically evident brain metastasis in patients with metastatic breast cancer 
(MBC) is estimated to be between 10% and 30% (Pivot et al. 2015). Patients who develop 
metastatic CNS disease have a poor prognosis and associated neurological complications that 
often lead to significant morbidity and mortality. The management of intracranial metastases 
from breast cancer has become a vital component of disease control, and increasingly patients 
are progressing in the CNS after radiotherapy, at which point the standard options become 
quite limited. 
Human epidermal growth factor receptor-2 (HER2) is a member of the erb-B epidermal growth 
factor receptor tyrosine kinase family, and is overexpressed in 18%− 20% of human breast 
cancers (Altaha et al. 2005; Stemmler et al. 2006; Yau et al. 2006; Pinder et al. 2007). 
Clinically, its overexpression is an independent adverse prognostic factor and is associated 
with an aggressive clinical course and poor survival in breast cancer patients. Advancements 
in HER2-targeted therapies have altered the natural landscape of HER2-positive breast cancer 
and improved systemic control and overall survival. 
The incidence of CNS metastases (24% −48%) is higher in HER2-positive MBC patients than 
reported for other cancers (Altaha et al. 2005; Stemmler et al. 2006; Yau et al. 2006; Pinder et 
al. 2007). In an analysis of 10 adjuvant trials examining the sites of metastases in 9524 
patients with early stage breast cancers treated without anthracyclines, taxanes, or 
trastuzumab in the pre-trastuzumab era, the 10-year incidence of CNS relapse at any time was 
almost double in patients with HER2-positive disease compared to those with HER2-negative 
breast cancer (6.8% versus 3.5%; p < 0.01) (Pestalozzi et al. 2006). In the epidemiological 
registHER (registry of HER2-positive patients) study of 1023 patients with newly diagnosed 
HER2-positive MBC, 37% of patients had a diagnosis of CNS metastases at a 29-month 
median follow-up (Brufsky et al. 2011). Of these, 7% had intracranial involvement at the time of 
their MBC diagnosis and 30% as a subsequent site of disease progression. Patients are not 
actively screened for CNS involvement. The actual incidence of CNS metastases may be 
greater than observed in retrospective studies. The CEREBEL trial compared the incidence of 
the CNS as the site of first relapse in patients with HER2-positive MBC treated with 
trastuzumab plus capecitabine to the incidence in patients treated with lapatinib plus 
capecitabine. At screening, asymptomatic CNS metastases were identified in 20% of the 
patients (Pivot et al. 2015). In older studies, the one-year survival rate in patients with CNS 
metastases was 20% (Pestalozzi 2009). However, patients with HER2-positive brain 
metastases often live longer, and in some multicenter series, median survival after a brain 
metastasis diagnosis is now in the range of 2 years in HER2-positive patients (Sperduto et al. 
2012). 


 
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2. 
STUDY DESIGN 
This is a U.S.-based, Phase II, open-label, single-arm study designed to examine the safety 
and efficacy of pertuzumab (loading dose of 840 mg IV followed every 3 weeks thereafter by a 
dose of 420 mg IV) and high-dose trastuzumab (6 mg/kg IV weekly) administered to patients 
with HER2-positive, MBC-related CNS metastases (parenchymal) that have disease 
progression in the brain following radiotherapy (SRS or WBRT). No changes will be made to 
the patient’s current treatment (e.g., chemotherapy, hormonal therapy) for systemic disease in 
order to optimize the ability to detect any incremental benefits provided by the combination of 
pertuzumab and high-dose trastuzumab (see Section 4.3.1.1 in the protocol for dosing 
information). The following exceptions, however, will be made: 
1. Patients receiving treatment with ado-trastuzumab emtansine (also known as T-DM1 or 
Kadcyla®) 
– Ado-trastuzumab emtansine will be discontinued 3 weeks prior to initiation of pertuzumab 
with high-dose trastuzumab. 
2. Patients receiving treatment with lapatinib 
– Lapatinib will be discontinued 1 week prior to initiation of pertuzumab with high-dose 
trastuzumab. 
Patients may remain on study treatment until disease progression within the CNS or systemic 
progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, 
whichever occurs first. 
Overall safety will be assessed on an ongoing basis during the conduct of the study. The study 
schema is presented in Figure 1. The schedule of assessments is provided in Appendix A. 


 
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Figure 1 Study Schema 
 
BC  breast cancer; CBR  clinical benefit rate; CNS  central nervous system; DOR  duration of 
response; HER2  human epidermal growth factor receptor-2; ORR  objective response rate; 
OS  overall survival; PD  progressive disease; PFS  progression-free survival; SRS  stereotactic 
radiosurgery; WBRT  whole-brain radiation therapy. 
 
The study will end when all patients have been followed for 12 months after the treatment 
discontinuation visit (inclusive of the safety and survival follow-up periods), unless they have 
been lost to follow-up, withdrawn consent, or died, or if the study is prematurely terminated by 
the Sponsor, whichever occurs first. 
At this time, the study will end and no further data will be collected in the clinical database for 
this study. The end of study is defined as the last patient last visit (LPLV) at the end of the 
follow-up period. 
Final Analysis 
The study Primary efficacy analysis will be performed when all enrolled patients have been 
followed for approximately 1 month after the last patient has disease progression or early 
discontinuation or has been at least 6 months on treatment, whichever occurs first. Follow-up 
data analysis will be performed when all the follow-up data are entered into the EDC 
system (or clinical database). 
 
2.1 
PROTOCOL SYNOPSIS (INCLUDING SCHEDULE OF ASSESSMENT) 
Refer to the protocol for the protocol synopsis. See Appendix A for the schedule of 
assessments and Appendix B for the schedule of assessments for scans.  
Eligibility: 
 
Metastatic HER2+ BC 
 
Previous treatment (WBRT/SRS) for 
brain metastases with development 
of new and/or progressive 
measurable lesion  
 
Stable systemic disease 
N  40 
Pertuzumab  
(loading dose of 840 mg 
IV followed Q3W by 
420 mg IV) 
 
High-dose Trastuzumab  
(6 mg/kg IV weekly)   
  
 Continuation of ongoing 
systemic treatment 
Treat to PD 
(at least 20% 
increase in 
sum of 
diameters of 
target 
lesions) or 
unacceptable 
toxicity 
 
Primary efficacy endpoint:  ORR in the CNS  
 
Secondary efficacy endpoint:  DOR in the CNS, CBR for the CNS, PFS in the CNS, PFS (CNS or 
non-CNS), and OS 
 
Safety endpoint:  Safety of pertuzumab and trastuzumab for the treatment of HER2-positive MBC 
with CNS progression post-radiotherapy 


 
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2.2 
OUTCOME MEASURES 
2.2.1 
PRIMARY EFFICACY OUTCOME MEASURES 
The primary efficacy outcome measure for this study is as follows: 
 
Objective response rate (ORR) in the CNS (assessed per Response Assessment in 
Neuro-Oncology-Brain Metastases [RANO-BM] criteria; see Appendix 4 in the 
protocol). Objective response is defined as complete response (CR) or partial response 
(PR). 
2.2.2 
SECONDARY EFFICACY OUTCOME MEASURES 
The secondary efficacy outcome measures for this study are as follows: 
 
Duration of response (DOR) in the CNS, clinical benefit rate (CBR) for the CNS, 
progression free survival (PFS) in the CNS, PFS (CNS or non-CNS), and overall 
survival (OS) 
– Tumor response in CNS will be assessed per RANO-BM criteria (see Appendix 4 in 
the protocol). 
– Non-CNS tumor response will be assessed by Response Evaluation Criteria in Solid 
Tumors, Version 1.1 (RECIST v1.1; see Appendix 5 in the protocol). 
2.2.3 
SAFETY OUTCOME MEASURES 
The safety outcome measures for this study are as follows: 
 
Incidence and severity of all non-serious and serious adverse events 
 
Incidence and severity of Grade ≥ 3 adverse events and serious adverse events 
 
Incidence of adverse events leading to discontinuation or interruption of pertuzumab 
alone or the combination of pertuzumab and trastuzumab 
 
Cause of death while on study 
 
Incidence and severity of cardiac events, as assessed by the investigator using 
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 
4.0 (NCI CTCAE v4.0) and New York Heart Association (NYHA) classification for 
congestive heart failure (CHF; see Appendix 7 in the protocol)  
 
Characterization of changes in left ventricular ejection fraction (LVEF) and changes in 
LVEF from baseline over the course of the study (see Appendix 6 in the protocol) 
 
Clinically significant laboratory test abnormalities 
 


 
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2.2.4 
PHARMACOKINETIC OUTCOME MEASURES 
Blood samples for measurements of pertuzumab and trastuzumab serum concentrations will 
be collected from patients according to the schedule below: 
– Week 1, Day 1 (pre-dose and at 30 minutes after the end of the infusions [maximum 
concentration (Cmax)]) 
– Week 4, Day 1 (pre-dose [trough]) 
– Week 10, Day 1 (pre-dose [trough]) 
– Week 16, Day 1 (pre-dose and at 30 minutes after the end of the infusions [Cmax]) 
2.2.5 
PATIENT-REPORTED OUTCOME MEASURES 
The PRO outcome measure for this study is as follows: 
 
Scores from the MDASI-BT assessment 
2.2.6 
EXPLORATORY OUTCOME MEASURES 
To explore the relationship between pertuzumab and high-dose trastuzumab exposure 
expressed as PK paramters and efficacy and safety endpoints. 
2.3 
DETERMINATION OF SAMPLE SIZE 
The emphasis of this study is estimation of the ORR with a given precision, rather than 
hypothesis testing. ORRs of 20% or higher will be deemed clinically significant because no 
other therapeutic options are available for this patient population. 
With 35 evaluable patients, and assuming that the study treatment is expected to lead to an 
ORR in CNS of 20% (7 patients), the 95% CI around the estimated ORR will be 8.4%−36.9%. 
Table 1 below shows the estimated CIs for additional assumed ORRs. The final sample size 
will be approximately 40 patients, allowing for dropouts and loss to follow-up. 


 
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Table 1 
Estimated Confidence Intervals for Additional Assumed Objective 
Response Rates 
N 
Number of Patients 
who Achieve CNS 
ORR 
Rate 
Lower Bound 
Exact 95% CI 
Upper Bound 
Exact 95% CI 
Half-Width of CI 
35 
1 
2.86 
0.07% 
14.92% 
7.43% 
35 
2 
5.71 
0.70% 
19.16% 
9.23% 
35 
3 
8.57 
1.80% 
23.06% 
10.63% 
35 
4 
11.43 
3.20% 
26.74% 
11.77% 
35 
5 
14.29 
4.81% 
30.26% 
12.73% 
35 
6 
17.14 
6.56% 
33.65% 
13.55% 
35 
7 
20.00 
8.44% 
36.94% 
14.25% 
35 
8 
22.86 
10.42% 
40.14% 
14.86% 
35 
9 
25.71 
12.49% 
43.26% 
15.39% 
35 
10 
28.57 
14.64% 
46.30% 
15.83% 
CI  confidence interval; CNS  central nervous system; ORR  objective response rate. 
CI based on Clopper Pearson method. 
 
Table 2 below contains the probabilities of a particular adverse event occurring with a sample 
size of 40.  The range of adverse event rates includes published cardiac event rates in 
metastatic patients receiving trastuzumab in combination with chemotherapy (Telli et al. 2007). 
Table 2 
Probability of Adverse Events 
Incidence of Adverse 
Event 
Probability of at Least One 
Adverse Event Occurring 
Probability of at Least Two 
Adverse Events Occurring 
1.00% 
0.33 
0.06 
2.00% 
0.55 
0.19 
3.00% 
0.70 
0.34 
4.00% 
0.80 
0.48 
5.00% 
0.87 
0.60 
8.00% 
0.96 
0.84 
10.00% 
0.99 
0.92 
13.00% 
1.00 
0.97 
16.00% 
1.00 
0.99 
27.00% 
1.00 
1.00 
 


 
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3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION ISSUES 
This is an open-label, single arm study. There is no randomization in the study. 
3.2 
DATA MONITORING 
The Genentech team will monitor study data and will consult with an external Steering 
Committee. The purpose of the Genentech Study Team and Steering Committee will be to 
make recommendations regarding study conduct on the basis of trial safety and efficacy data 
to ensure patient safety while receiving study treatment. The Genentech team will include the 
CMM, MSDs, LSR, Drug Safety Scientist, Biostatistician, and Statistical Programmer. The 
Steering Committee will include at least 3 external disease-state experts and is governed by 
the Steering Committee Charter. 
 
4. 
STATISTICAL METHODS 
Demographic characteristics, medical history, baseline disease characteristics, patient 
treatment history, and current and previous brain MBC treatment will be summarized on the 
ITT population. 
Descriptive statistics (mean, median, standard deviation, 25th percentile, 75th percentile, and 
range) will be presented for continuous variables, such as age and time since metastatic 
diagnosis. Frequency counts and percentage will be presented for categorical variables such 
as sex, race, age category, ECOG Performance Status, number of prior chemotherapy agents, 
and prior brain radiation therapy type. 
No formal statistical hypotheses will be tested in the study. 
4.1 
ANALYSIS POPULATIONS 
The analysis populations are defined below.  
4.1.1 
INTENT-TO-TREAT POPULATION 
Intent-to-Treat (ITT) population includes all enrolled patients in the study, regardless of 
whether they are exposed to study drugs (Pertuzumab or Trastuzumab). 
4.1.2 
EFFICACY EVALUABLE POPULATION 
Efficacy evaluable population includes all patients in the ITT population who received any dose 
of Pertuzumab or Trastuzumab and had at least one follow-up CNS tumor assessment or who 
received any dose of Pertuzumab or Trastuzumab, but die without follow-up tumor assessment 
within 30 days from the last dose of study drug. 


 
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This will be the population used for efficacy analyses unless otherwise noted. 
4.1.3 
PHARMACOKINETIC EVALUABLE POPULATION 
Pharmacokinetic evaluable population includes all patients in the ITT population who received 
any dose of Pertuzumab or Trastuzumab and had at least one PK assessment unless there 
are major protocol deviations or if information impacting PK evaluation (e.g., exact blood 
sampling time, labeling error, technical failure in sample analysis) are unavailable. 
4.1.4 
PATIENT-REPORTED OUTCOMES EVALUABLE POPULATION 
Patient-reported outcomes evaluable population includes all patients in the ITT population who 
received any dose of Pertuzumab or Trastuzumab and had both a non-missing baseline and at 
least one post-baseline PRO assessment. Summary statistics of the symptom severity score 
and symptom interference score will be presented at each scheduled visit, and the change 
from baseline scores will be presented at each post-baseline visit.  
4.1.5 
SAFETY POPULATION 
Safety population includes all patients in the ITT population who received any dose of 
Pertuzumab or Trastuzumab. 
4.2 
ANALYSIS OF STUDY CONDUCT 
The number of enrolled patients will be tabulated by study site and overall. Analysis 
populations, patient disposition, primary reason for premature discontinuation, and protocol 
violations (including inclusion/exclusion criteria not met), and duration of follow-up will be 
tabulated for all patients enrolled. Eligibility, protocol violations, and premature discontinuations 
will be presented in data listings. 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
This is a single-arm study and therefore no treatment group comparisons will be performed. 
Demographic and baseline characteristics, such as age, sex, reproductive status, ethnicity, 
race, age category, height, weight, BMI, ECOG score, time from metastatic diagnosis to the 
first dose of study drug, time from metastatic diagnosis to CNS diagnosis, time from CNS 
metastases to the first dose of study drug, number of prior chemotherapy agents, and prior 
brain radiation therapy type will be summarized using mean, median, standard deviation, 25th 
percentile, 75th percentile, and range for continuous variables and using counts and 
percentages for categorical variables. Individual patient demographic and baseline 
characteristics will also be presented in a data listing. 


 
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Verbatim description of each medical history will be classified into standardized medical 
terminology using the Medical Dictionary for Regulatory Activities (MedDRA, the most current 
version). The number (percentage) of patients in the ITT population reporting any medical 
condition will be summarized by SOC and preferred term. Subject data listings of general 
medical history, cardiac history, breast cancer history, prior EBC surgery, non-breast cancer 
related surgery and procedures history, EBC and MBC systemic treatment history will be 
presented. 
All verbatim terms for medications recorded in the CRF will be coded by Genentech/Roche and 
assigned a preferred term and an anatomic therapeutic class (ATC) term using International 
Non-proprietary Name (INN) drug terms and procedures. Medications with (1) start date on or 
after the first dose of study drug up to 30 days after the last dose of study drug or (2) start date 
before the first dose of study drug and stop date on or after the first dose of study drug or 
ongoing are considered as concomitant medications. Medications with stop date before the 
first dose of study drug are considered as prior medications. Concomitant medications and 
prior medications will be summarized separately, based on the ITT population, with number 
(percentage) of patients in each ATC class and preferred drug name. Prior and concomitant 
medications will also be presented in a data listing. Listings of concomitant corticosteroids, 
screening systemic status, CNS treatment history, prior and on-study breast cancer 
radiotherapy, and on-study MBC systemic treatment will also be presented. 
Patient treatment history, and current/previous brain MBC treatment will be summarized in 
separated tables. 
4.4 
EFFICACY ANALYSES 
4.4.1 
PRIMARY EFFICACY ENDPOINT(S) 
The primary efficacy endpoint is ORR (confirmed CR or confirmed PR) in the CNS per RANO-
BM criteria. To evaluate the ORR, two sets of analyses will be performed: one is based on the 
efficacy-evaluable population and the other is based on the safety population. The efficacy-
evaluable population is the primary population for the ORR in CNS. Any patient without 
sufficient data to determine response (e.g., non-evaluable patients) will be classified as a non-
responder. The estimate of the ORR with 95% Clopper-Pearson exact CI will be presented. 
Water fall plot of the percent change in the total sum of target lesion diameter will be 
presented.  
Responses to study treatment will be based on investigator assessments. 
4.4.2 
SECONDARY EFFICACY ENDPOINTS 
Secondary efficacy endpoints include DOR in the CNS, CBR for the CNS, PFS in the CNS, 
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used to estimate the distribution of DOR, PFS, and OS. The 95% CI for the median time to 
event will be calculated using the Brookmeyer and Crowley method. 
4.4.2.1 
Duration of Response 
Among patients with an objective response, duration of response will be defined as the time 
from documentation of the first CR or PR to the time of disease progression, relapse, or death 
from any cause. If a patient does not experience death, relapse, or disease progression before 
the end of the study, duration of response will be censored on the last date the patient is 
known to be progression free. 
Median duration of response and the corresponding 95% CI will be presented. Minimum, the 
first quartile, the third quartile, and maximum of the duration of response will also be 
presented. Swimmer plot of the duration of response will be presented for subjects with 
objective response.  
4.4.2.2 
Clinical Benenfit Rate 
CBR (CNS), defined as a combination of confirmed CR, confirmed PR, or stable disease (≥ 4 
months and ≥ 6 months, respectively) in CNS, will be calculated. A 95% Clopper-Pearson 
exact CI for CBR will be presented. Note that duration of CBR will be calculated with SD in ≥ 4 
and ≥ 6 months, respectively. Swimmer plot of the duration of response will be presented for 
subjects with clinical benefit. 
4.4.2.3 
Progression-Free Survival in the CNS 
PFS (CNS), defined as the time from the date of first dose to disease progression in the CNS 
or death from any cause, will be calculated. If no progressive disease in the CNS and no death 
occurs, PFS (CNS) will be censored on the date of the last CNS tumor assessment. If a post-
baseline assessment is not available, PFS (CNS) will be censored on Day 1. Median PFS 
(CNS) and the corresponding 95% CI will be presented. Minimum, the first quartile, the third 
quartile, and maximum of the duration of response will also be presented. 
 
4.4.2.4 
Progression-Free Survival in the Systemic 
PFS (systemic), defined as the time from the date of first dose  to disease progression in the 
systemic or death from any cause, will be calculated. If no progressive disease in the systemic 
and no death occurs, PFS (systemic) will be censored on the date of the last systemic tumor 
assessment. If a post-baseline assessment is not available, PFS (systemic) will be censored 
on Day 1. Median PFS (systemic) and the corresponding 95% CI will be presented. Minimum, 
the first quartile, the third quartile, and maximum of the duration of response will also be 
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4.4.2.5 
Progression-Free Survival (CNS or Systemic) 
PFS (CNS or systemic), defined as the time from the date of first dose to disease progression 
in the CNS or systemically, or death from any cause, will be calculated. If no progressive 
disease in the CNS or systemically and no death occurs, PFS will be censored on the date of 
the last CNS or systemic tumor assessment, whichever occurs first. If a post-baseline 
assessment is not available, PFS will be censored on Day 1. Median PFS (CNS or systemic) 
and the corresponding 95% CI will be presented. Minimum, the first quartile, the third quartile, 
and maximum of the duration of response will also be presented. 
4.4.2.6 
Overall Survival 
OS is defined as the period from the date of first dose  until the date of death from any cause. 
If no death occurs, OS will be censored on the last date the patient is known to be alive. 
Median OS and the corresponding 95% CI will be presented. Minimum, the first quartile, the 
third quartile, and maximum of the OS will also be presented. 
4.4.3 
SENSITIVITY ANALYSES 
Sensitivity analysis is currently not planned. 
4.4.4 
SUBGROUP ANALYSES 
 Subgroup analysis is currently not planned. 
4.4.5 
EXPLORATORY ANALYSES 
Analyses will be conducted to explore the relationship between Pertuzumab / Trastuzumab 
exposure and PK parameters and efficacy / safety endpoints. 
4.5 
SAFETY ANALYSES 
Safety analyses will be performed on the safety population. Baseline value is defined as the 
last observation prior to the initiation of study drug. 
Due to unscheduled laboratory or other safety assessments, the safety analyses will use the 
actual visit dates and the time windows shown below to define the visit cycles. Time window for 
screening (baseline) is defined from study day -28 up to study day -1. For post baseline visits, 
the time windows are generated in such a way that the windows are not overlapping. If more 
than one assessment is measured within the same visit window, the assessment closest to the 
scheduled day in the specific visit window will be used for the analysis for that visit. Abnormal 
values may have to be reported as Adverse Event. For all safety analyses, Day 1 is defined as 
the day on which the patient receives the first dose of study drug. 




 
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AEs will also be graded using National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) version 4.0. 
All AEs occurring on or after Day 1 of study treatment until 30 days after the last dose of study 
treatment (i.e., treatment-emergent adverse events (TEAEs)) will be summarized by System 
Organ Classes, preferred terms, and NCI CTCAE grade. In the AE summaries, a patient 
having the same event more than once will be counted only once for that event type. For AEs 
of varying severity, the highest (worst) grade will be used in the summaries. AEs related to 
study drug are those suspected to be caused by Pertuzumab or Trastuzumab. Missing severity 
or relationship to study drug will be imputed as described in section 4.8. 
Summaries of the following AEs will be provided: 
1. Overall summary of TEAEs 
2. Death and cause of death 
3. TEAEs by NCI CTCAE grade 
4. TEAEs related to study drug by NCI CTCAE grade 
5. Serious TEAEs by NCI CTCAE grade 
6. Serious TEAEs related to study drug by NCI CTCAE grade 
7. TEAEs with incidence rate ≥ 5% 
8. TEAEs related to study drug with incidence rate ≥ 5% 
9. TEAEs with Grade 3 and above 
10. TEAEs related to study drug with Grade 3 and above 
11. TEAEs leading to any study drug discontinuation 
12. TEAEs leading to Pertuzumab only discontinuation 
13. TEAEs leading to Pertuzumab infusion delay, slow down, or interruption 
14. TEAEs leading to Trastuzumab dose modification 
15. TEAEs of special interest (defined below) 
16. TEAEs of special interest related to study drug 
17. Time to the first incidence of TEAEs of special interest 
The following AEs are considered of special interest (AESIs): 
 
an elevated ALT or AST (> 3 × baseline value) in combination with either an elevated 
total bilirubin (> 2 × ULN) or clinical jaundice 
 
Suspected transmission of an infectious agent by the study drug (to be defined) 
 
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 
An asymptomatic decline in LVEF (a value 10 percentage points below baseline or 
lower, and < 45%) that requires treatment or that leads to discontinuation of study 
treatment 
Overall summary of TEAEs will be presented for number of deaths, patients with any TEAE, 
serious TEAE, TEAE with severity Grade 3 or higher, TEAE of special interest, infusion related 
reaction, TEAE leading to interruption of any study drug, and TEAE leading to withdrawal of 
any study drug. All AEs of special interest will be summarized in another table. A separate 
table will summarize number and percentage of death and cause of death. 
All recorded AEs, SAEs, AEs leading to study drug discontinuation, deaths, and supplemental 
data for AEs of special interest will be presented in data listings. A glossary of AE verbatim 
terms and preferred terms will also be provided. 
4.5.3 
LABORATORY DATA 
The incidence of NCI CTCAE, v4.0, Grade 3 and 4 hematology and serum chemistry 
abnormalities will be summarized at each protocol-specified collection timepoint for each 
parameter. Refer to Appendix F, Section 6.6.1 for the NCI CTCAE V4.0 Grades for laboratory 
paramaters. 
Laboratory data (hematology and serum chemistry) will also be presented in data listings. 
Patients who became pregnant during the study period will be listed separately. 
4.5.4 
VITAL SIGNS 
Vital signs assessments will be performed before treatment on Day 1 of every 3-week cycle. 
Descriptive statistics for vital signs parameters (i.e. heart rate, systolic and diastolic BP, 
respiratory rate, and temperature) at each cycle and changes from baseline (Cycle 1 Day 1) to 
each following cycle will be presented. 
Vital signs data will also be presented in data listing. 
4.5.5 
ELECTROCARDIOGRAM 
ECG data will be presented in data listing. 
4.5.6 
LVEF EVALUATIONS 
LVEF evaluations will be assessed at Screening, 6 and 12 weeks (after Cycle 1, Day 1), 
followed by LVEF evaluations every 3 months during the treatment period. LVEF evaluations 
will also be conducted every 6 months during the survival follow-up period (12 months after the 
treatment discontinuation visit). 
 
LVEF results and  interpretations will be summarized at each scheduled visit. The 
corresponding LVEF data will be presented in data listing. 
 


 
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4.6 
PHARMACOKINETIC ANALYSES 
Observed Cmax and minimum concentration (Cmin) values of pertuzumab and trastuzumab will 
be summarized at each specified sampling timepoint. Summary statistics, including arithmetic 
mean, geometric mean, median, standard deviation, and range, and coefficient of variation, will 
be presented for the PK-evaluable population. 
All pertuzumab and trastuzumab concentration data will be reported, but observed Cmin values 
measured on days other than those scheduled, and similar outlier values that do not allow 
comparability with data from other patients, may be excluded from the analyses. 
Relationships between observed and/or population model-predicted PK and safety, and 
between PK and efficacy, will also be examined as part of the exploratory analyses. 
4.7 
PATIENT REPORT OUTCOMES ANALYSES 
The MDASI-BT consists of 28 items and is a multi-symptom measure of cancer-related 
symptoms (Cleeland et al. 2000) that are sensitive to disease and treatment changes. The 
MDASI-BT is composed of the symptom severity scale and the symptom interference scale. In 
the symptom severity scale, patients rate the severity of their symptoms in the last 24 hours on 
0 − 10 numeric scales, ranging from “not present” to “as bad as you can imagine.” In the 
symptom interference scale, patients rate interference with daily activities caused by their 
symptoms on 0 − 10 numeric scales ranging from “did not interfere” to “interfered completely.” 
For details of the scoring algorithm, please refer to Appendix F, Section 6.6.2. 
For each individual item and each scale, the data and their change from baseline values will be 
summarized descriptively at each protocol-specified timepoint. Data listings of individual scores 
and scale scores will also be presented. 
To explore the relationship of ORR with PRO endpoints, subjects will be divided into two 
groups by symptom severity scale score, one group with score <= median and the other group 
with score > median. Similarly, subjects will be divided into two groups by symptom 
interference scale. ORR and the corresponding 95% CI will be presented. 
4.8 
HANDLING OF DROPOUTS, MISSING/INCOMPLETE DATA, OR OUTLIERS 
No imputation will be performed for missing efficacy data. 
AEs with missing relationship to study drug will be counted as 'Related', and AEs with missing 
CTCAE grade will be imputed as grade 3. Incomplete onset dates for AEs and concomitant 
medications will be imputed according to the following rules:  
 
In case the day is missing this will be replaced by the 1st of the month.  
 
In case of missing day and month this will be replaced by the January 1st. 


 
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If the imputation of the onset date leads to AEs or concomitant medications occurring before 
treatment start, the start date will be set to treatment start date.  
Incomplete end dates will be imputed according to the following rules: 
 
In case the day is missing this will be replaced by the last day of the month.  
 
In case of missing day and month this will be imputed as December 31st.  
If the imputation of the end date leads to AEs or concomitant medications ending after date of 
last contact, the end date will be set to date of last contact. 
4.9 
INTERIM ANALYSES AND/OR SAFETY REVIEWS 
An interim analysis will be performed when 15 patients are enrolled and have the following: 1) 
at least two LVEF measurements (at Week 6 and Week 12), 2) two cycles (3-week cycle) of 
study drug, and 3) two response measurements for review. For this interim analysis, the safety 
endpoints will be of primary consideration. Overall summary of TEAEs, TEAEs and serious 
TEAEs by NCI CTCAE grade, TEAEs with Grade 3 and above, TEAEs lead to any study drug 
discontinuation, summary of the incidence of NCI CTCAE, v4.0, Grade 3 and 4 Lab results, 
summary of vital signs and ECG will be reviewed. Efficacy endpoints (ORR, DOR, PFS in CNS 
per RANO-BM criteria) will also be examined to identify potential treatment non-benefits. 
Complete details of the data outputs will be described in the Steering Committee charter. In 
addition, summary of all AEs, AEs and serious AEs by NCI CTCAE grade, AEs with Grade 3 
and above, AEs lead to any study drug discontinuation will also be presented. 
Accrual will be suspended and the study will be stopped if it is confirmed that the following 
scenarios have occurred: 
 
Two or more CHF events considered related to pertuzumab or trastuzumab in the first 
15 patients treated 
 
None of the 15 patients with objective response or stable disease in the CNS 
With this stopping rule (zero objective responses or stable disease in the CNS out of 15 
efficacy-evaluable patients), the probabilities of stopping the study are 1.3%, 3.5%, 8.7%, 
20.6%, and 46.3% when the true ORRs in the CNS are 25%, 20%, 15%, 10%, and 5%, 
respectively. 


 
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5. 
REFERENCES 
Brookmeyer, R. and Crowley, J. (1982). “A Confidence Interval for the Median Survival Time,” 
Biometrics, 38, 29–41. 
 
Clopper, C.; Pearson, E. S. (1934). "The use of confidence or fiducial limits illustrated in the 
case of the binomial". Biometrika 26: 404–413. 
 
Kaplan, E. L.; Meier, P. (1958). "Nonparametric estimation from incomplete observations". J. 
Amer. Statist. Assn. 53 (282): 457–481. 
 
National Institute of Health. (2010, June 14). Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03. Retrieved from National Cancer Institute: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 


 
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6. 
APPENDICES 
6.1 
APPENDIX A: SCHEDULE OF ASSESSMENTS 
Assessments 
Screening  
Study Treatment Period 
Treatment 
Discontinuation 
a 
Q3 Month 
Survival 
Follow-Up 
( 15 days) 
Every Week Until 
Progression 
( 2 days) 
Every 3 Weeks 
Until Progression 
( 2 days) 
Every 4 Weeks 
Until Progression 
( 2 days) 
Every 8 Weeks 
Until Progression 
( 2 days) 
Day 
Day   28 to 
Day   1 
Day 1 
Day 1 
Day 1 
Day 1 
Within 30 Days 
after Last Dose 
 
Written informed consent b 
x 
 
 
 
 
 
 
Medical history and 
demographic data c 
x 
 
 
 
 
 
 
Physical examination d 
x 
 
x 
 
 
 
 
Vital signs, height, and 
weight e 
x e 
x 
x 
x 
x 
 
 
Concomitant medications f 
x 
x 
 
 
 
x 
 
LVEF monitoring g 
x 
See footnote g 
x g 
ECOG Performance 
Status 
x 
 
 
 
 
 
 
Tumor Response and Evaluations 
MRI brain h 
x  
See footnote h 
 
CT, MRI, PET-CT of 
chest, abdomen, pelvis 
(and neck, if clinically  
indicated) i 
x 
 
 
 
x  
 
 
Laboratory, Biomarker, and Other Biological Sample Evaluations  
Hematology j 
x 
See footnote j 
 
 
Chemistry k 
x 
See footnote k 
 
 
 


 
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Assessments 
Screening  
Study Treatment Period 
Treatment 
Discontinuation 
a 
Q3 Month 
Survival 
Follow-Up 
( 15 days) 
Every Week Until 
Progression 
( 2 days) 
Every 3 Weeks 
Until Progression 
( 2 days) 
Every 4 Weeks 
Until Progression 
( 2 days) 
Every 8 Weeks 
Until Progression 
( 2 days) 
Day 
Day   28 to 
Day   1 
Day 1 
Day 1 
Day 1 
Day 1 
Within 30 Days 
after Last Dose 
 
Pregnancy test l 
x 
See footnote l 
x 
 
Serum pertuzumab and 
trastuzumab levels m 
See footnote m 
Optional biomarker 
plasma sample n 
x  
 
 
 
 
x  
 
Optional archival tumor 
sample o 
x  
 
 
 
 
 
 
Patient-Reported Outcomes 
MDASI-BT p 
x 
 
 
 
x  
x 
 
Treatment 
Administration of 
pertuzumab 
 
 
x 
 
 
 
 
Administration of 
trastuzumab q 
 
x 
 
 
 
 
 
 


 
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Assessments 
Screening  
Study Treatment Period 
Treatment 
Discontinuation 
a 
Q3 Month 
Survival 
Follow-Up 
( 15 days) 
Every Week Until 
Progression 
( 2 days) 
Every 3 Weeks 
Until Progression 
( 2 days) 
Every 4 Weeks 
Until Progression 
( 2 days) 
 
Day 
Day   28 
to Day   1 
Day 1 
Day 1 
Day 1 
Day 1 
Within 30 Days 
after Last Dose 
 
Adverse events r 
x 
x 
 
 
 
x 
 
Survival status s 
 
 
 
 
 
 
x 


 
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Cmax  maximum concentration; CNS  central nervous system; CR  complete response; CT  computed tomography; ECOG  Eastern Cooperative Oncology 
Group; eCRF  electronic case report form; LVEF  left ventricular ejection fraction; MDASI-BT  M.D. Anderson Symptom Inventory-Brain Tumor; 
MRI  magnetic resonance imaging; PET-CT  position-emission tomography CT; PFS  progression-free survival; PR  partial response; PRO  patient-
reported outcome. 
a Patients who experience clinical benefit (stable disease, PR, or CR) may continue to receive treatment with pertuzumab and trastuzumab on study until 
disease progression (in the CNS or systemically) or intolerable toxicity.  Patients who discontinue from study treatment will be asked to return to the clinic 
within 30 days of the last infusion of study treatment for a treatment completion visit.  The visit at which a response assessment showed disease progression 
may be used as the treatment completion visit. 
b Written informed consent for participation in the study must be obtained before performing any study-specific screening tests or evaluations, and may be 
obtained more than 28 days before initiation of study treatment (Day 1). 
c Medical history includes clinically significant diseases, surgeries, and cancer history (including prior cancer therapies and procedures).  Demographic data 
will include age, sex, and self-reported race/ethnicity. 
d A complete physical examination will be performed at baseline.  Physical examination includes evaluation of the head, eyes, ears, nose, and throat; and the 
cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems.  Record abnormalities observed at baseline on the 
General Medical History and Baseline Conditions eCRF.  At subsequent visits (Day 1 of each 3-week cycle or as clinically indicated), limited, symptom-
directed physical examinations should be performed (record changes in patient notes).  Neurological status should be performed as part of these 
examinations.  As part of tumor assessment, physical examinations should also include the evaluation of the presence and degree of enlarged lymph nodes, 
hepatomegaly, and splenomegaly.  Record new or worsened clinically significant abnormalities as adverse events on the Adverse Event eCRF. 
e Vital sign assessments include measurements of heart rate, systolic and diastolic blood pressures while the patient is in a seated position, respiratory rate, 
and temperature.  Vital signs and weight will be assessed before treatment on Day 1 of every cycle.  Record abnormalities on the Adverse Event eCRF.  
Height and weight will be measured at screening.  Weight changes of   10% would require the dose of trastuzumab to be adjusted.   
f Concomitant medication includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) 
used by a patient from 7 days prior to screening to the study completion/discontinuation visit.  All such medications should be reported to the investigator 
and recorded on the Concomitant Medications eCRF.   
g LVEF evaluations will be assessed at Screening, 6 and 12 weeks (after Cycle 1, Day 1), followed by LVEF evaluations every 3 months during the treatment 
period.  LVEF evaluations will also be conducted every 6 months during the survival follow-up period (12 months after the treatment discontinuation visit).   
h All target and non-target CNS disease must be documented at screening and reassessed at each subsequent tumor evaluation.  T1-weighted perfusion MRI 
will be used to evaluate changes in brain metastases that indicate treatment effects.  Post-baseline MRI of the brain will be conducted every 6 weeks  2 
followed by every 8 weeks  2 then every 12 weeks until progression.  If there is suspicion of disease progression based on clinical or laboratory findings 
before the next scheduled assessment, an unscheduled assessment should be performed.  An additional assessment may be conducted at the treatment 
discontinuation visit.  An objective response (CR, PR) in the CNS should be confirmed by repeat assessments 4  6 weeks after initial finding or at the next 
scheduled tumor assessment if it is to occur 4  6 weeks after the initial response. 
i Tumor response of systemic disease will be measured using CT, MRI, or PET-CT of the chest, abdomen, pelvis (and neck, if clinically indicated).  
Assessments will be performed every 8 weeks.  For patients with no evidence of systemic disease at baseline, additional systemic tumor assessments 


 
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(chest, abdomen, and pelvis) will be performed every 8 weeks for the first 16 weeks, followed by systemic assessments every 16 weeks.  All other known 
sites of disease must be documented at screening and reassessed at each subsequent tumor evaluation.   
j Hematology testing must be done during screening and every 6 weeks within  3 days (with results available) prior to the administration of study drug.  
Hematology testing includes:  hemoglobin, hematocrit, platelet count, RBC count, WBC count, and percent and absolute differential count (neutrophils, 
bands, eosinophils, lymphocytes, monocytes, basophils, and other cells). 
k Chemistry testing must be done during screening and every 6 weeks within  3 days (with results available) prior to the administration of study drug.  
Chemistry testing includes:  sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, magnesium, phosphorus, total and direct bilirubin, 
total protein, albumin, ALT, AST, and alkaline phosphatase, LDH, and uric acid. 
l All women of childbearing potential (including those who have had a tubal ligation and women  12 months after the onset of menopause unless they have 
undergone surgical sterilization) will have a serum pregnancy test at screening within 7 days before the first dose of study drug (with results available prior to 
dosing).  Urine pregnancy tests will be performed at specified subsequent visits prior to every 3rd pertuzumab cycle ( 7days) and at the treatment 
discontinuation visit.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  During the treatment period, pregnancy test 
results must be available prior to administration of study drug.  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.  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.   
m On specified days of study drug administration, pre-infusion PK samples should be drawn 0  4 hours before the start of the first infusion and post-infusion 
PK samples should be drawn 0  30 minutes after the end of the infusions, unless otherwise specified.  Two separate 2-mL blood samples will be collected 
(one sample for each analyte, pertuzumab and trastuzumab) at each timepoint as follows:  Week 1, Day 1 (pre-dose and at 30 minutes after the end of the 
infusions [Cmax]); Week 4, Day 1 (pre-dose [trough]); Week 10, Day 1 (pre-dose [trough]); Week 16, Day 1 (pre-dose and at 30 minutes after the end of the 
infusions [Cmax]).  Each blood sample will be 2 mL in volume, totaling 24 mL for PK sampling in each patient over approximately 16 weeks.   
n Two optional exploratory biomarker plasma samples may be taken. 
o Tissue from primary tumor or metastatic site. 
p The PRO questionnaire will be administered at baseline (Day 1 prior to study treatment), every 4 weeks for the first 16 weeks, and every 8 weeks thereafter 
while the patient is receiving study treatment.  
q Safety assessments should be performed and results reviewed prior to administration of trastuzumab.  Note:  Weight changes  10% require the dose of 
trastuzumab to be recalculated.  Weekly doses should be no less than 5 days apart. 
r  After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated intervention 
should be reported (see Section 5.4).  After initiation of study drug, serious adverse events and non-serious adverse events of special interest will be 
reported until 30 calendar days after the last dose of study drug.  LVEF events will be reported for 2 years after the last dose of study drug.    
s For PFS survival follow-up, patients who discontinue study treatment will be followed per standard of care, including MRIs of the brain and assessments of 
the chest, abdomen, and pelvis (only scans that were abnormal at baseline need to be repeated).  For survival and LVEF follow-up, all patients will be 
followed for a minimum of 12 months from the date of the last dose of study drug or until death, whichever occurs first, every 3 months for survival and every 
6 months for LVEF.   


 
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6.2 
APPENDIX B: SCHEDULE OF ASSESSMENTS FOR SCANS 


 
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Assessments 
Screening 
Week 
6 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
28 
Week 32 & 
Every 8 
Weeks until 
Progression 
Week 36 & 
Every 12 
Weeks until 
Progression 
Week 40 & 
Every 12 
Weeks until 
Progression 
Treatment 
Discont-
inuation 
Q3 
Month 
Survival 
Follow-
Up 
( 15 
days) 
Day   28 
to Day   1 
 
 
 
 
 
 
 
 
 
 
Within 30 
Days after 
Last Dose 
 
MRI brain a  
X 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
 
Scans of 
chest, 
abdomen & 
pelvis (neck if 
clinically 
indicated) b  
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
LVEF 
monitoring c 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
CNS  central nervous system; CR  complete response; CT  computed tomography; LVEF  left ventricular ejection fraction; MRI  magnetic resonance 
imaging; PET-CT  positron-emission tomography CT. 
a All target and non-target CNS disease must be documented at screening and reassessed at each subsequent tumor evaluation.  T1-weighted perfusion MRI 
will be used to evaluate changes in brain metastases that indicate treatment effects.  Post-baseline MRI of the brain will be conducted every 6 weeks  2 
followed by every 8 weeks 2 then every 12 weeks until progression.  If there is suspicion of disease progression based on clinical or laboratory findings 
before the next scheduled assessment, an unscheduled assessment should be performed.  An additional assessment may be conducted at the treatment 
discontinuation visit.  An objective response (CR, PR) in the CNS should be confirmed by repeat assessments 4  6 weeks after initial finding or at the next 
scheduled tumor assessment if it is to occur 4  6 weeks after the initial response. 
b Tumor response of systemic disease will be measured using CT, MRI, or PET-CT of the chest, abdomen, pelvis (and neck, if clinically indicated).  
Assessments will be performed every 8 weeks.  For patients with no evidence of systemic disease at baseline, additional systemic tumor assessments 
(chest, abdomen, and pelvis) will be performed every 8 weeks for the first 16 weeks, followed by systemic assessments every 16 weeks.  All other known 
sites of disease must be documented at screening and reassessed at each subsequent tumor evaluation. 
c LVEF evaluations will be assessed at Screening, 6 and 12 weeks (after Cycle 1, Day 1), followed by LVEF evaluations every 3 months during the treatment 
period.  LVEF evaluations will also be conducted every 6 months during the survival follow-up period (12 months after the treatment discontinuation visit). 


 
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6.3 
APPENDIX C: SCHEDULE OF PERTUZUMAB AND TRASTUZUMAB 
PHARMACOKINETIC ASSESSMENTS 
 
Visit 
Timepoint 
Sample Types 
Week 1, Day 1 
Pre-dose (trough) 
PK trastuzumab, PK 
pertuzumab (serum) 
Post-infusions (Cmax) 
PK trastuzumab, PK 
pertuzumab (serum) 
Week 4, Day 1 
Pre-dose (trough) 
PK trastuzumab, PK 
pertuzumab (serum) 
Week 10, Day 1 
Pre-dose (trough) 
PK trastuzumab, PK 
pertuzumab (serum) 
Week 16, Day 1 
Pre-dose (trough) 
PK trastuzumab, PK 
pertuzumab (serum) 
Post-infusions (Cmax) 
PK trastuzumab, PK 
pertuzumab (serum) 
Cmax  maximum concentration; PK  pharmacokinetic. 
At each timepoint, 2  2 mL samples will be collected, totaling 24 mL for PK 
sampling in each patient over approximately 16 weeks. 
Pre-dose samples can be collected up to 4 hours prior to infusion.  Post-infusion 
samples can be collected up to 30 minutes after end of infusion. 
 
 


 
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6.4 
APPENDIX D: STATISTICAL METHODS REQUIRING INPUT 
 There is no statistical method requiring input. 
 
 


 
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6.5 
APPENDIX E: DOCUMENTATION OF ADDITIONAL ANALYSES 
PERFORMED AFTER DATABASE LOCK 
There are no additional analyses planned at this point. 
 
 


 
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6.6 
APPENDIX F: DATA HANDLING RULES 
6.6.1 
NCI CTCAE V4.0 GRADES FOR LABORATORY PARAMETERS 
Panel: Chemistry 
Lab Test 
Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Alkaline 
Phosphatase 
U/L 
(ULN, 2.5*ULN] 
(2.5*ULN, 5*ULN] 
(5*ULN, 20*ULN] 
>20*ULN 
ALT (increased) 
U/L 
(ULN, 3.0*ULN] 
(3.0*ULN, 5.0*ULN] 
(5*ULN, 20*ULN]; 
>20*ULN 
AST (increased) 
U/L 
(ULN, 3.0*ULN] 
(3.0*ULN, 5.0*ULN] 
(5*ULN, 20*ULN]; 
>20*ULN 
Bilirubin 
umol/L 
(ULN, 1.5*ULN] 
(1.5*ULN, 3*ULN] 
(3*ULN, 10*ULN] 
>10*ULN 
Calcium high 
(Hypercalcemia)  
mmol/L 
(ULN, 2.9] 
(2.9, 3.1] 
(3.1, 3.4] 
>3.4 
Calcium low 
(Hypocalcemia)  
mmol/L 
[2.0, LLN) 
[1.75, 2.0) 
[1.5, 1.75) ; 
hospitalization 
indicated 
[0, 1.5); life 
threatening 
consequences 
Creatinine 
(increased) 
umol/L 
(1 – 
1.5*baseline]; 
(ULN, 1.5*ULN] 
(1.5 – 3.0* baseline]; 
(1.5*ULN, 3*ULN] 
>3.0*baseline; 
(3*ULN, 6*ULN] 
>6*ULN 
Glucose high 
(hyperglycemia) 
mmol/L 
(ULN, 8.9] 
(8.9, 13.9] 
(13.9, 27.8] ; 
hospitalization 
indicated 
>27.8; life 
threatening 
consequences 
Glucose low 
(hypoglycemia) 
mmol/L 
[3.0, LLN) 
[2.2, 3.0) 
[1.7, 2.2) 
[0, 1.7); life 
threatening 
consequences; 
seizures 
Magnesium high 
(Hypermagnesemia) 
mmol/L 
(ULN, 1.23] 
UNDEFINED 
(1.23, 3.30] 
>3.30; life 
threatening 
consequences 
Magnesium low 
(Hypomagnesemia) 
mmol/L 
[0.5, LLN) 
[0.4, 0.5) 
[0.3, 0.4) 
[0, 0.3); life 
threatening 
consequences 
Phosphate 
(hypophosphatemia) 
mmol/L 
[0.8, LLN) 
[0.6, 0.8) 
[0.3, 0.6) 
[0, 0.3); life-
threatening 
consequences 
Potassium high 
(hyperkalemia)  
mmol/L 
(ULN, 5.5] 
(5.5, 6]  
(6, 7]; hospitalization 
indicated 
>7; life-threatening 
consequences 
Potassium low 
(hypokalemia)  
mmol/L 
[3, LLN) 
[3, LLN); symptomatic; 
intervention indicated 
[2.5, 3) ; 
hospitalization 
indicated 
[0, 2.5); life-
threatening 
consequences 
Sodium high 
(hypernatraemia) 
mmol/L 
(ULN, 150] 
(150, 155] 
(155, 160]; 
hospitalization 
indicated 
>160; life-
threatening 
consequences 
Sodium low 
(hyponatraemia) 
mmol/L 
[130, LLN) 
UNDEFINED 
[120, 130) 
[0, 120); life-
threatening 
consequences 
 
 


 
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Panel: Hematology 
Lab Test 
Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin (decreased) 
g/L 
[100, LLN) 
[80, 100) 
[0, 80); transfusion 
indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Platelet count (decreased) 
10^9/L 
[75, LLN) 
[50, 75) 
[25, 50) 
[0, 25) 
WBC (decreased) 
10^9/L 
[3, LLN) 
[2, 3) 
[1, 2) 
[0, 1) 
Lymphocytes (decreased) 
10^9/L 
[0.8, LLN)  
[0.5, 0.8) 
[0.2, 0.5) 
[0, 0.2) 
Neutrophil count (decreased) 
10^9/L 
[1.5, LLN) 
[1, 1.5) 
[0.5, 1) 
[0, 0.5) 
 
Reference:  (National Institute of Health, 2010) 


 
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6.6.2 
MDASI-BT SCORING ALGORITHM 
Symptom Severity Score: The MDASI-BT symptom severity scale score will be calculated by 
(total scores of non-missing items)/(number of non-missing items), if patients answer at least 12 
of the 22 severity scale items. The score will be considered missing if less than 12 items are 
completed. 
 
Symptom Interference Score: The MDASI-BT symptom interference scale score will be 
calculated by (total scores of non-missing items)/(number of non-missing items), if patients 
answer at least 4 of the 6 interference scale items. The score will be considered missing If less 
than 4 items are completed.