Conditions: Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1486
Healthy volunteers: no

Brief summary:
This 2-arm, randomized, open-label study will evaluate the efficacy and safety of trastuzumab emtansine versus trastuzumab as adjuvant therapy in patients with HER2-positive breast cancer who have residual tumor present in the breast or axillary lymph nodes following preoperative therapy. Eligible patients will be randomized to receive either trastuzumab emtansine 3.6 mg/kg or trastuzumab 6 mg/kg intravenously every 3 weeks for 14 cycles. Radiotherapy and/or hormone therapy will be given in addition if indicated.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: trastuzumab intervention 2: trastuzumab emtansine
Intervention descriptions: intervention 1: 6 mg/kg intravenously every 3 weeks, 14 cycles intervention 2: 3.6 mg/kg intravenously every 3 weeks, 14 cycles

Protocol document:
Prot_002.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd
Protocol BO27938, Version 7
PROTOCOL
TITLE:
A RANDOMIZED, MULTICENTER, OPEN-LABEL 
PHASE III STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF TRASTUZUMAB EMTANSINE 
VERSUS TRASTUZUMAB AS ADJUVANT 
THERAPY FOR PATIENTS WITH HER2-POSITIVE 
PRIMARY BREAST CANCER WHO HAVE 
RESIDUAL TUMOR PRESENT PATHOLOGICALLY 
IN THE BREAST OR AXILLARY LYMPH NODES 
FOLLOWING PREOPERATIVE THERAPY
PROTOCOL NUMBER:
BO27938
VERSION NUMBER:
7
EUDRACT NUMBER:
2012-002018-37
IND NUMBER:
71,072
NCT NUMBER:
NCT01772472
NSABP/GBG 
PROTOCOL NUMBERS:
NSABP B-50-I/GBG 77
TEST PRODUCT:
Trastuzumab Emtansine (RO5304020)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
APPROVAL DATE:
See electronic date stamp below
 
Company Signatory
Approver's Name
Title
Date and Time (UTC)
18-Jun-2021 13:03:35


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd
2/Protocol BO27938, Version 7
PROTOCOL HISTORY
Protocol
Version
Date Final
7
See electronic date 
stamp on title page
6
13 October 2015
5
9 July 2014
4
28 March 2014
3
6 September 2013
2
3 April 2013
1
19 October 2012


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd
3/Protocol BO27938, Version 7
PROTOCOL AMENDMENT, VERSION 7:  
RATIONALE
Protocol BO27938 has been amended to extend the completion of the study from 
April 2023 to April 2025 to allow for an increased duration of survival follow-up.  
Changes to the protocol are summarized here:

The Medical Monitor information has been updated to reflect a change in personnel
(title pages).

Study TDM4788g/BO22589 has been finalized, so information about median overall 
survival (OS) has been added (Section 1.2.4).

The study completion has been extended from 10 years post-first patient in (FPI) to 
12 years post-FPI.  Scheduled follow-up assessments have been updated to collect 
more OS events (Sections 3.2, 4.5.2.2, 4.5.2.4.1, 4.6.1, 5.3.5.7, 6.1, and 6.9.1; 
footnote "c" in Appendix 1).

Language has been added to allow for vaccination and/or treatment for coronavirus 
disease 2019 (COVID-19) or similar conditions and to record these medications in 
the patient’s medical record (Section 4.4.1).

The patients will have an option for telephone/electronic visits if they cannot attend 
clinic visits (Section 4.5.2.4.1).

The reporting of the term “sudden death” has been updated to also require the 
presumed cause of death (Section 5.3.5.8).

Adverse event reporting for hospitalization has been clarified (Section 5.3.5.11).

Language has been added to clarify that adverse events associated with a special 
situation that also qualify as adverse events of special interest should be reported 
within 24 hours (Section 5.3.5.12).

Language has been added for consistency with Roche's current data retention 
policy and to accommodate more stringent local requirements (if applicable) 
(Section 7.6).

Language has been added to indicate that the study will comply with applicable 
local, regional, and national laws (Section 8.1).

Determination of sample size and interim analyses have been updated to reflect the 
extension of the study. The details of the planned interim and final analyses of OS 
have been updated accordingly. Notably, based on the revised projection for OS 
events, the third interim analysis of OS has been removed (Sections 6.1 and 6.9.1,
Tables 5 and 6).

Based on the extension of the study, the schedule of activities has been revised to 
clarify which assessments are to be performed with respect to disease status and 
survival (footnote "f" in Appendix 1).

In the schedule of activities, assessments of left ventricular ejection fraction and 
mammograms during follow-up have been clarified (footnotes “m” and “w” in 
Appendix 1).


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd
4/Protocol BO27938, Version 7
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.


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
5/Protocol BO27938, Version 7 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12 
PROTOCOL SYNOPSIS .................................................................................... 13 
1. 
BACKGROUND .......................................................................................... 26 
1.1 
Background on Early-Stage HER2-Positive 
Breast Cancer ........................................................................ 26 
1.2 
Background on Trastuzumab Emtansine ............................... 28 
1.2.1 
Study TDM4450g/BO21976 ................................................... 28 
1.2.2 
Study TDM4874g/BO22857 ................................................... 29 
1.2.3 
Study TDM4370g/BO21977 (EMILIA) ................................... 30 
1.2.4 
Study TDM4788g/BO22589 (MARIANNE) ............................ 32 
1.2.5 
Studies TDM4258g and TDM4374g ...................................... 32 
1.3 
Background on Trastuzumab (Herceptin®) ............................ 32 
1.4 
Study Rationale and Benefit Risk Assessment ...................... 32 
2. 
OBJECTIVES .............................................................................................. 33 
2.1 
Primary Efficacy Objective ..................................................... 33 
2.2 
Safety Objective .................................................................... 33 
2.3 
Patient Reported Outcome Objective .................................... 33 
2.4 
Pharmacokinetics Objectives ................................................. 34 
2.5 
Exploratory Objectives ........................................................... 34 
3. 
STUDY DESIGN ......................................................................................... 34 
3.1 
Description of Study .............................................................. 34 
3.1.1 
Overview ................................................................................ 34 
3.1.2 
Data Monitoring Committee ................................................... 35 
3.1.3 
Clinical Events Committee ..................................................... 36 
3.2 
End of Study .......................................................................... 36 
3.3 
Rationale for Study Design .................................................... 36 
3.3.1 
Rationale for Test Product Dosage ........................................ 36 
3.3.2 
Rationale for Patient Population ............................................ 37 
3.3.3 
Rationale for Control Group and Duration of 
Therapy ................................................................................. 37 
3.3.4 
Rationale for Biomarker Assessments ................................... 37 


 
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3.3.5 
Rationale for Pharmacokinetic Assessments ......................... 38 
3.4 
Outcome Measures ............................................................... 38 
3.4.1 
Primary Efficacy Outcome Measure ...................................... 38 
3.4.2 
Secondary Efficacy Outcome Measures ................................ 39 
3.4.3 
Safety Outcome Measures .................................................... 39 
3.4.4 
Patient-Reported Outcome Measures ................................... 39 
3.4.5 
Pharmacokinetic Outcome Measures .................................... 40 
3.4.6 
Exploratory Outcome Measure .............................................. 40 
4. 
MATERIALS AND METHODS .................................................................... 40 
4.1 
Patients .................................................................................. 40 
4.1.1 
Inclusion Criteria .................................................................... 40 
4.1.1.1 
Disease-Specific Inclusion Criteria ........................................ 40 
4.1.1.2 
General Inclusion Criteria ...................................................... 42 
4.1.2 
Exclusion Criteria ................................................................... 43 
4.1.2.1 
Disease-Related Exclusion Criteria ....................................... 43 
4.1.2.2 
General Exclusion Criteria ..................................................... 44 
4.2 
Method of Treatment Assignment and Blinding ..................... 45 
4.3 
Study Treatment .................................................................... 45 
4.3.1 
Formulation, Packaging, and Handling .................................. 45 
4.3.2 
Dosage, Administration, and Compliance .............................. 46 
4.3.2.1 
Trastuzumab Emtansine ........................................................ 46 
4.3.2.2 
Trastuzumab .......................................................................... 46 
4.3.3 
Investigational Medicinal Product Accountability ................... 46 
4.3.3.1 
Post-Trial Access to Trastuzumab Emtansine ....................... 47 
4.4 
Concomitant Therapy and Food ............................................ 47 
4.4.1 
Permitted Therapy ................................................................. 47 
4.4.1.1 
Adjuvant Radiotherapy .......................................................... 48 
4.4.1.2 
Concomitant Hormonal Therapy ............................................ 48 
4.4.2 
Prohibited Therapy ................................................................ 49 
4.5 
Study Assessments ............................................................... 50 
4.5.1 
Description of Study Assessments ........................................ 50 
4.5.1.1 
Medical History and Demographic Data ................................ 50 
4.5.1.2 
Vital Signs .............................................................................. 50 


 
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4.5.1.3 
Physical Examinations ........................................................... 50 
4.5.1.4 
Radiologic Evaluations .......................................................... 51 
4.5.1.5 
Laboratory Assessments ....................................................... 51 
4.5.1.6 
Cardiac Assessments ............................................................ 52 
4.5.1.7 
Patient-Reported Outcomes .................................................. 52 
4.5.1.8 
Mandatory Samples for Determination of Patient 
Eligibility and Exploratory Biomarker Research ..................... 53 
4.5.1.9 
Optional Biomarker Research Samples ................................. 55 
4.5.2 
Timing of Study Assessments ............................................... 58 
4.5.2.1 
Screening and Pretreatment Assessments ............................ 58 
4.5.2.2 
Assessments during Treatment ............................................. 59 
4.5.2.3 
Assessments at Study Treatment 
Completion/Early Termination Visit ........................................ 60 
4.5.2.4 
Follow-Up Assessments ........................................................ 60 
4.6 
Patient, Study, and Site Discontinuation ................................ 64 
4.6.1 
Patient Discontinuation .......................................................... 64 
4.6.1.1 
Discontinuation from Study Drug ........................................... 64 
4.6.1.2 
Withdrawal from Study........................................................... 65 
4.6.2 
Study and Site Discontinuation .............................................. 66 
5. 
ASSESSMENT OF SAFETY ....................................................................... 66 
5.1 
Safety Plan ............................................................................ 66 
5.1.1 
Toxicities Associated with Trastuzumab 
Emtansine .............................................................................. 66 
5.1.1.1 
Cardiotoxicity ......................................................................... 67 
5.1.1.2 
Hematologic Toxicity (Thrombocytopenia and 
Hemorrhage) ......................................................................... 67 
5.1.1.3 
Hepatotoxicity ........................................................................ 68 
5.1.1.4 
Pulmonary Toxicity ................................................................ 69 
5.1.1.5 
Infusion-Related Reactions/Hypersensitivity .......................... 69 
5.1.1.6 
Neurotoxicity .......................................................................... 70 
5.1.1.7 
Extravasation ......................................................................... 70 
5.1.2 
Toxicities Associated with Trastuzumab ................................ 70 
5.1.3 
Management of Specific Adverse Events .............................. 70 
5.2 
Safety Parameters and Definitions ........................................ 77 


 
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5.2.1 
Adverse Events ..................................................................... 77 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ...................................................................... 77 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 78 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 78 
5.3.1 
Adverse Event Reporting Period ........................................... 79 
5.3.2 
Eliciting Adverse Event Information ....................................... 79 
5.3.3 
Assessment of Severity of Adverse Events ........................... 79 
5.3.4 
Assessment of Causality of Adverse Events ......................... 80 
5.3.5 
Procedures for Recording Adverse Events ............................ 81 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 81 
5.3.5.2 
AEs Occurring Secondary to Other Events ............................ 81 
5.3.5.3 
Persistent or Recurrent Adverse Events ................................ 81 
5.3.5.4 
Abnormal Laboratory Values ................................................. 82 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 83 
5.3.5.6 
Hepatotoxicity ........................................................................ 83 
5.3.5.7 
Abnormal Left Ventricular Ejection Fraction ........................... 84 
5.3.5.8 
Deaths ................................................................................... 84 
5.3.5.9 
Preexisting Medical Conditions .............................................. 85 
5.3.5.10 
Lack of Efficacy or Worsening of Breast Cancer ................... 85 
5.3.5.11 
Hospitalization or Prolonged Hospitalization .......................... 85 
5.3.5.12 
Overdoses ............................................................................. 86 
5.3.5.13 
Patient-Reported Outcome Data ........................................... 86 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 86 
5.4.1 
Emergency Medical Contacts ................................................ 87 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest ...................................................................... 87 
5.4.3 
Reporting Requirements for Pregnancies .............................. 87 
5.4.3.1 
Pregnancies in Female Patients ............................................ 87 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................. 88 
5.4.3.3 
Abortions ............................................................................... 88 


 
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5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 88 
5.5 
Follow-Up of Patients after Adverse Events .......................... 88 
5.5.1 
Investigator Follow-Up ........................................................... 88 
5.5.2 
Sponsor Follow-Up ................................................................ 89 
5.6 
Post-Study Adverse Events ................................................... 89 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ................................................................. 89 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 90 
6.1 
Determination of Sample Size ............................................... 90 
6.2 
Summaries of Conduct of Study ............................................ 90 
6.3 
Summaries of Treatment Group Comparability ..................... 90 
6.4 
Efficacy Analyses .................................................................. 91 
6.4.1 
Primary Efficacy Endpoint ...................................................... 91 
6.4.2 
Secondary Efficacy Endpoints ............................................... 91 
6.5 
Safety Analyses ..................................................................... 91 
6.6 
Patient-Reported Outcome Analyses .................................... 92 
6.7 
Pharmacokinetic analyses ..................................................... 93 
6.8 
Exploratory Analyses ............................................................. 93 
6.9 
Interim Analyses .................................................................... 93 
6.9.1 
Interim Efficacy Analyses ....................................................... 93 
6.9.2 
Interim Safety Analyses ......................................................... 95 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 97 
7.1 
Data Quality Assurance ......................................................... 97 
7.2 
Electronic Case Report Forms ............................................... 97 
7.3 
Electronic Patient-Reported Outcome Data ........................... 97 
7.4 
Source Data Documentation .................................................. 98 
7.5 
Use of Computerized Systems .............................................. 98 
7.6 
Retention of Records ............................................................. 99 
8. 
ETHICAL CONSIDERATIONS .................................................................... 99 
8.1 
Compliance with Laws and Regulations ................................ 99 
8.2 
Informed Consent .................................................................. 99 
8.3 
Institutional Review Board or Ethics Committee .................. 100 


 
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8.4 
Confidentiality ...................................................................... 101 
8.5 
Financial Disclosure ............................................................ 101 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 101 
9.1 
Study Documentation .......................................................... 101 
9.2 
Site Inspections ................................................................... 102 
9.3 
Administrative Structure ....................................................... 102 
9.4 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 102 
9.5 
Protocol Amendments ......................................................... 103 
10. REFERENCES ......................................................................................... 104 
 
LIST OF TABLES 
Table 1 
Recommendations for Hormonal Therapy .................................. 49 
Table 2 
Dose Reduction for Trastuzumab Emtansine .............................. 71 
Table 3 
Guidelines for Managing Specific Adverse Events ...................... 72 
Table 4 
Adverse Event Severity Grading Scale ....................................... 80 
Table 5 
Summary of Planned Analyses of Invasive Disease-Free 
Survival ....................................................................................... 94 
Table 6 
Summary of Planned Analyses of Overall Survival ..................... 95 
Table 7 
Probability of Observing > 3% Increase of Death ........................ 96 
Table 8 
Probability of Observing > 3% Increase of Confirmed Hy’s 
Law Cases .................................................................................. 96 
 
 
LIST OF FIGURES 
Figure 1 
Tissue Collection Flow ................................................................ 54 
Figure 2 
Algorithm for Continuation and Discontinuation of Study 
Treatment Based on LVEF Assessment ..................................... 76 


 
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LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments ......................................................... 106 
Appendix 2 
Schedule of Pharmacokinetic Assessments ............................. 111 
Appendix 3 
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire – Core 30 ........................ 112 
Appendix 4 
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire – Breast Cancer 23 ........ 114 
Appendix 5 
EuroQoL EQ-5D ........................................................................ 116 
Appendix 6 
Ventana HER2 IHC Assay ........................................................ 119 
Appendix 7 
Ventana HER2 ISH Assay ........................................................ 120 
Appendix 8 
Guidelines for Liver Biopsy ....................................................... 121 


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd
12/Protocol BO27938, Version 7
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A RANDOMIZED, MULTICENTER, OPEN-LABEL 
PHASE III STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF TRASTUZUMAB EMTANSINE 
VERSUS TRASTUZUMAB AS ADJUVANT 
THERAPY FOR PATIENTS WITH HER2-POSITIVE 
PRIMARY BREAST CANCER WHO HAVE 
RESIDUAL TUMOR PRESENT 
PATHOLOGICALLY IN THE BREAST OR 
AXILLARY LYMPH NODES FOLLOWING 
PREOPERATIVE THERAPY
PROTOCOL NUMBER:
BO27938
VERSION NUMBER:
7
EUDRACT NUMBER:
2012-002018-37
IND NUMBER:
71,072
NSABP/GBG 
PROTOCOL NUMBERS:
NSABP B-50-I/GBG 77
TEST PRODUCT:
Trastuzumab Emtansine (RO5304020)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name (print)
Principal Investigator’s Signature
Date
Please return the original signed form to your local study monitor.  Please retain a copy 
of the signed form for your study files.


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd
13/Protocol BO27938, Version 7
PROTOCOL SYNOPSIS
TITLE:
A RANDOMIZED, MULTICENTER, OPEN-LABEL 
PHASE III STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF TRASTUZUMAB EMTANSINE 
VERSUS TRASTUZUMAB AS ADJUVANT 
THERAPY FOR PATIENTS WITH HER2-POSITIVE 
PRIMARY BREAST CANCER WHO HAVE 
RESIDUAL TUMOR PRESENT PATHOLOGICALLY 
IN THE BREAST OR AXILLARY LYMPH NODES 
FOLLOWING PREOPERATIVE THERAPY
PROTOCOL NUMBER:
BO27938
VERSION NUMBER:
7
EUDRACT NUMBER:
2012-002018-37
IND NUMBER:
71,072
NCT NUMBER:
NCT01772472
NSABP/GBG 
PROTOCOL NUMBERS: NSABP B-50-I/GBG 77
TEST PRODUCT:
Trastuzumab Emtansine (RO5304020)
PHASE:
III
INDICATION:
HER2-positive primary breast cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Primary Efficacy Objective
The primary efficacy objective for this study is as follows:

To compare invasive disease-free survival (IDFS) in patients with residual invasive breast 
cancer after treatment with preoperative chemotherapy and HER2-directed therapy 
including trastuzumab followed by surgery between the 2 treatment arms
The secondary efficacy objective for this study is as follows:

To compare IDFS including second non-breast cancers, disease-free survival (DFS), overall 
survival (OS), and distant recurrence-free interval (DRFI) between the 2 treatment arms
Safety Objectives
The safety objective for this study is as follows:

To compare cardiac safety and overall safety between the 2 treatment arms according to 
the National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE), Version 4.0
Patient Reported Outcome Objectives
The patient-reported outcome (PRO) objective for this study is as follows:


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd
14/Protocol BO27938, Version 7

To compare PROs between the 2 treatment arms using the European Organisation for 
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire – Core 30 
(QLQ-C30) questionnaire and Quality of Life Questionnaire – Breast Cancer (QLQ-BR23) 
module
Pharmacokinetics Objectives
The pharmacokinetics (PK) objectives for this study are as follows:

To characterize the PK of trastuzumab emtansine (including total trastuzumab and DM1) in 
trastuzumab emtansine treated patients 

To characterize the PK of trastuzumab in trastuzumab-treated patients and permit an intra-
study comparison of trastuzumab exposure in the 2 treatment arms

To investigate exposure–effect (efficacy and safety) relationships in this patient population
Exploratory Objectives
The exploratory objectives for this study are as follows:

To assess correlations between biomarker status and efficacy and/or safety

To assess the incidence of anti-therapeutic antibodies (ATAs) and the effect of ATAs on 
PK, safety, and efficacy
Study Design
Description of Study
This is a Phase III, 2-arm, randomized, multicenter, multinational, open-label study in patients 
with HER2-positive primary breast cancer who have received preoperative chemotherapy and 
HER2-directed therapy including trastuzumab followed by surgery, with a finding of residual 
invasive disease in the breast or axillary lymph nodes.
Patients who provide consent will commence a screening period, which will last up to 30 days.  
Informed consent forms may be obtained at any time (including prior to the 30-day screening 
period) but must be obtained prior to the performance of any screening assessments.  Patients 
who have pathologically documented residual invasive disease in either the breast or axillary 
lymph nodes following completion of preoperative therapy (including, but not limited to, at least 
9 weeks of HER2-directed therapy, including trastuzumab, and at least 9 weeks of 
taxane-based chemotherapy (or, if receiving dose-dense chemotherapy regimens, at least 
6-8 weeks of taxane-based therapy and at least 8 weeks of trastuzumab) and at least 16 weeks 
of total systemic treatment in the preoperative setting) will be eligible to participate in the study.  
At the end of the screening period, eligible patients will be randomized in a 1:1 ratio to receive 
open-label study treatment (trastuzumab emtansine 3.6 mg/kg every 3 weeks [q3w] for 
14 cycles or trastuzumab 6 mg/kg q3w for 14 cycles).  Randomization will be stratified by 
clinical stage at presentation (inoperable [Stage T4NxM0 or TxN2–3M0], operable 
[stages T1-3N0-1M0]), hormone receptor status (estrogen receptor [ER] or progesterone 
receptor [PgR] positive, ER and PgR negative), preoperative HER2-directed therapy 
(trastuzumab, trastuzumab plus additional HER2-directed agent[s]), and pathological nodal 
status evaluated after preoperative therapy (node positive, node negative or not done).  Patients 
will be administered radiotherapy and/or hormonal therapy (for patients with hormone 
receptor-positive tumors) in addition to receiving study treatment for 14 cycles if indicated based 
on the following guidelines:

Hormonal therapy (aromatase inhibitor, tamoxifen, etc.) should be initiated in patients with 
hormone receptor-positive disease at presentation.

For patients undergoing breast-conserving surgery, whole breast irradiation is required.  
Primary tumor bed boost may be administered according to local policy.  Regional node 
irradiation is required if the patient presented at initial diagnosis with clinical T3 (except for 
T3N0) or T4 disease and/or with clinical N2 or N3 disease; it is recommended for T3N0 or 
if there is residual disease in lymph nodes.

For post-mastectomy patients, chest wall and regional node irradiation is required if the 
patient presented at initial diagnosis with clinical T3 (except for T3N0) or T4 disease and/or 
with clinical N2 or N3 disease; it is recommended for T3N0 or if there is residual disease in 
lymph nodes.  For post-mastectomy patients who do not meet these criteria, radiotherapy is 
at the discretion of the investigator based on institutional standards.


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The first dose of study treatment will be administered on Day 1 of a 3-week cycle (i.e., dosing 
will be repeated once q3w to complete a maximum of 14 cycles of treatment). Treatment will be 
discontinued prior to 14 cycles in the event of disease recurrence, unacceptable toxicity, or 
study termination by the Sponsor.  Patients who discontinue trastuzumab emtansine may 
complete the duration of their study therapy with trastuzumab, if appropriate based on toxicity 
considerations.  Efficacy, safety, laboratory, and PRO measures will be assessed throughout 
the study, as detailed in the schedule of assessments (see Appendix 1).  PK measures will be 
assessed as specified in the schedule of PK assessments (see Appendix 2).  The primary 
efficacy endpoint is the IDFS and will be measured from the time of randomization until its first 
occurrence.  Following discontinuation or completion of study treatment, all patients will 
continue to be followed for efficacy and safety objectives until the end of the study. 
Number of Patients
A planned total of 1484 patients will be enrolled in the study.  
Target Population
Patients must meet the following criteria for study entry:
1.
HER2-positive breast cancer
HER2-positive status will be based on pretreatment biopsy material and defined as an 
immunohistochemistry (IHC) (Appendix 6) score of 3and/or positive by in situ 
hybridization (ISH) (Appendix 7) prospectively confirmed by a central laboratory prior to 
study enrollment.  ISH positivity is defined as a ratio of 2.0 for the number of HER2 
gene copies to the number of signals for chromosome 17 copies.  Formalin-fixed 
paraffin-embedded tumor tissue block or a partial block must be available for central 
evaluation of HER2 expression.  If sites are unable to send a tissue block due to local 
regulations, at least 8 unstained slides should be sent for HER2 testing, and in addition 
up to 5 slides for exploratory biomarker research.  A central laboratory will perform both 
IHC and ISH assays; however, only one positive result is required for eligibility.  In the 
event that sufficient material from the pretreatment biopsy is not available for 
submission, central HER2 determination for eligibility may be performed on residual 
tumor tissue from the time of definitive surgery.
Patients with synchronous bilateral invasive disease are eligible provided both lesions 
are HER2-positive. 
2.
Histologically confirmed invasive breast carcinoma
3.
Clinical stage at presentation:  T1–4, N0–3, M0 (Note:  Patients with T1a/bN0 tumors will 
not be eligible)
4.
Completion of preoperative systemic chemotherapy and HER-2 directed treatment.  
Systemic therapy must consist of at least 6 cycles of chemotherapy with a total duration at 
least 16 weeks, including at least 9 weeks of trastuzumab and at least 9 weeks of 
taxane-based chemotherapy.  Patients may have received an anthracycline as part of 
preoperative therapy in addition to taxane chemotherapy  
Patients receiving dose-dense chemotherapy regimens are eligible, provided at least 8 
weeks of taxane-based therapy and at least 8 weeks of trastuzumab have been given.  A 
dose-escalated (225 mg/m2 q2w) dose-dense regimen of paclitaxel over 6 weeks is 
allowed.
Patients may have received more than one HER2-directed therapy.  Note:  HER-2 directed 
therapy alone periods will not satisfy the requirements for cycles of preoperative systemic 
chemotherapy.
All systemic chemotherapy should be completed preoperatively. 
5.
Adequate excision:  surgical removal of all clinically evident disease in the breast and lymph 
nodes as follows:
Breast surgery:  total mastectomy with no gross residual disease at the margin of 
resection, or breast-conserving surgery with histologically negative margins of excision
For patients who undergo breast-conserving surgery, the margins of the resected 
specimen must be histologically free of invasive tumor and ductal carcinoma in situ 
(DCIS) as determined by the local pathologist.  If pathologic examination 
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performed to obtain clear margins.  If tumor is still present at the resected margin 
after re-excision(s), the patient must undergo total mastectomy to be eligible.  
Patients with margins positive for lobular carcinoma in situ (LCIS) are eligible without 
additional resection.
Lymph node surgery:
In case of positive results from a fine-needle aspiration, core biopsy, or sentinel 
node biopsy performed prior to preoperative therapy, additional surgical evaluation 
of the axilla following preoperative therapy is required.
If only micrometastases are present in sentinel nodes preoperatively (i.e., if the 
greatest diameter of the nodal metastasis in a sentinel node is 0.2 mm or less), no 
additional surgical evaluation of the axilla is required.
If sentinel node biopsy performed before preoperative therapy was negative, no 
additional surgery evaluation of the axilla is required after preoperative therapy.
If the only sentinel node identified by isotope scan is in the internal mammary chain, 
surgical evaluation of the axilla is recommended.
If sentinel node biopsy performed after preoperative therapy is positive, additional 
surgical evaluation of the axilla is recommended.
If sentinel node evaluation after preoperative therapy is negative, no further 
additional surgical evaluation of the axilla is required.
Axillary dissection without sentinel node evaluation is permitted after preoperative 
therapy.
6.
Pathologic evidence of residual invasive carcinoma in the breast or axillary lymph nodes 
following completion of preoperative therapy.  If invasive disease is present in both breasts, 
residual invasive carcinoma must be present in at least 1 breast or axillary lymph nodes 
postoperatively.
7.
An interval of no more than 12 weeks between the date of primary surgery and the date of 
randomization
8.
Known hormone receptor status
Hormone receptorpositive status can be determined by either known positive ER or 
known positive PgR status; hormone receptornegative status must be determined by 
both known negative ER and known negative PgR.
9.
Signed written informed consent approved by the study site’s Institutional Review Board 
(IRB)/Ethical Committee (EC)
10. Age18 years
11. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
12. Life expectancy6 months 
13. Adequate organ function during screening, defined as:
a.
Absolute neutrophil count1200 cells/mm3
b.
Platelet count100000 cells/mm3
c.
Hemoglobin9.0 g/dL; patients may receive red blood cell transfusions to obtain this 
level
d.
Serum creatinine1.5 upper limit of normal (ULN)
e.
International normalized ratio (INR) and activated partial thromboplastin time 
(aPTT)1.5ULN
f.
Serum aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT)1.5ULN
g.
Serum total bilirubin (TBILI) 1.0ULN (within normal limits), except for patients with 
Gilbert’s syndrome, for whom direct bilirubin should be within the normal range
h.
Serum alkaline phosphatase (ALK) 1.5ULN
i.
Screening left ventricular ejection fraction (LVEF) 50% on echocardiogram (ECHO) or 
multiple-gated acquisition (MUGA) after receiving neoadjuvant chemotherapy and no 
decrease in LVEF by more than 15% absolute points from the pre-chemotherapy LVEF.  


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Or, if pre-chemotherapy LVEF was not assessed, the screening LVEF must be 55% 
after completion of neoadjuvant chemotherapy.
i.
LVEF assessment may be repeated once up to 3 weeks following the initial 
screening assessment to assess eligibility
14. For women who are not postmenopausal (12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  agreement to remain 
abstinent or use single or combined contraceptive methods that result in a failure rate 
of 1% per year during the treatment period and for at least 7 months after the last dose of 
study drug.
a.
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.
Examples of contraceptive methods with a failure rate of 1% per year include tubal 
ligation, male sterilization, hormonal implants, established, proper use of combined oral 
or injected hormonal contraceptives, and certain intrauterine devices.  Alternatively, two 
methods (e.g., two barrier methods such as a condom and a cervical cap) may be 
combined to achieve a failure rate of < 1% per year.  Barrier methods must always be 
supplemented with the use of a spermicide.
b.
Male patients whose partners are pregnant must use condoms or truly refrain from 
sexual activity for the duration of the pregnancy.
15. Negative serum pregnancy test for premenopausal women including women who have had 
a tubal ligation and for women less than 12 months after the onset of menopause
16. Documentation of hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies is 
required:  this includes HB surface antigen (HBsAg) and/or total HB core antibody 
(anti-HBc) in addition to HCV antibody testing.  The most recent serologic testing must have 
occurred within 3 months prior to initiation of neoadjuvant therapy.  If such testing has not 
been done, it must be performed during screening.
Patients who meet any of the following criteria will be excluded from study entry:
1.
Stage IV (metastatic) breast cancer
2.
History of any prior (ipsi- or contralateral) breast cancer except LCIS
3.
Evidence of clinically evident gross residual or recurrent disease following preoperative 
therapy and surgery
4.
An overall response of progressive disease (PD) according to the investigator at the 
conclusion of preoperative systemic therapy
5.
Treatment with any anti-cancer investigational drug within 28 days prior to commencing 
study treatment
6.
History of other malignancy within the last 5 years except for appropriately treated 
carcinoma in situ (CIS) of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, 
or other non-breast malignancies with an outcome similar to those mentioned above
7.
Patients for whom radiotherapy would be recommended for breast cancer treatment but for 
whom it is contraindicated because of medical reasons (e.g., connective tissue disorder or 
prior ipsilateral breast radiation) 
8.
Current NCI CTCAE (Version 4.0) Grade2 peripheral neuropathy
9.
History of exposure to the following cumulative doses of anthracyclines: 
Doxorubicin 240 mg/m2
Epirubicin or Liposomal Doxorubicin-Hydrochloride (Myocet®) 480 mg/m2
For other anthracyclines, exposure equivalent to doxorubicin240 mg/m2
10. Cardiopulmonary dysfunction as defined by any of the following:
History of NCI CTCAE (Version 4.0) Grade3 symptomatic congestive heart failure 
(CHF) or New York Heart Association (NYHA) criteria Class II 


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Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not 
controlled by adequate medication, severe conduction abnormality, or clinically 
significant valvular disease

High-risk uncontrolled arrhythmias:  i.e., atrial tachycardia with a heart rate100/min 
at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade 
AV-block (second degree AV-block Type 2 [Mobitz 2] or third degree AV-block)
Significant symptoms (Grade2) relating to left ventricular dysfunction, cardiac 
arrhythmia, or cardiac ischemia while or since receiving preoperative therapy.
History of a decrease in LVEF to40% with prior trastuzumab treatment (e.g., during 
preoperative therapy)
Uncontrolled hypertension (systolic blood pressure180 mmHg and/or diastolic blood 
pressure100 mmHg)
Evidence of transmural infarction on ECG
Requirement for continuous oxygen therapy
11. Prior treatment with trastuzumab emtansine
12. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary, or metabolic disease; wound healing disorders; ulcers)
13. For female patients, current pregnancy and/or lactation
14. Major surgical procedure unrelated to breast cancer or significant traumatic injury within 
approximately 28 days prior to randomization or anticipation of the need for major surgery 
during the course of study treatment
15. Any known active liver disease, for example, due to HBV, HCV, autoimmune hepatic 
disorders, or sclerosing cholangitis.  Patients who have positive HBV or HCV serologies 
without known active disease must meet the eligibility criteria for ALT, AST, TBILI, INR, 
aPTT, and alkaline phosphatase (ALK) on at least two consecutive occasions, separated by 
at least 1 week, within the 30 day screening period.
16. Concurrent, serious, uncontrolled infections or known infection with HIV
17. History of intolerance, including Grade 3 to 4 infusion reaction or hypersensitivity to 
trastuzumab or murine proteins or any components of the product
18. Active, unresolved infections at screening requiring treatment
19. Assessment by the investigator as being unable or unwilling to comply with the 
requirements of the protocol
Length of Study
The total length of this study will be approximately 12 years from randomization of the first 
patient to completion of the last follow-up assessment of the last patient.  
End of Study
The study will end after the last patient randomized into the study has undergone the last 
follow-up assessment.  To enable long-term follow-up for survival and safety information, the 
last follow-up assessment is scheduled to occur 12 years after the first patient is randomized.


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Primary Efficacy Outcome Measure
The primary efficacy outcome measure is IDFS, defined as the time from randomization until the 
date of the first occurrence of any one of the following events: 

Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving the 
same breast parenchyma as the original primary lesion) 

Ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast cancer 
in the axilla, regional lymph nodes, chest wall and/or skin of the ipsilateral breast) 

Distant recurrence (i.e., evidence of breast cancer in any anatomic site—other than the 
2 above-mentioned sites—that has either been histologically confirmed or clinically 
diagnosed as recurrent invasive breast cancer)

Contralateral invasive breast cancer

Death attributable to any cause including breast cancer, non-breast cancer or unknown 
cause (but cause of death should be specified if at all possible)
Secondary Efficacy Outcome Measures
Secondary efficacy outcome measures include the following:

IDFS including second primary non-breast cancer:  defined the same way as IDFS for the 
primary endpoint but including second primary non-breast invasive cancer as an event (with 
the exception of non-melanoma skin cancers and CIS of any site)

DFS:  defined as the time between randomization and the date of the first occurrence of an 
IDFS event including second primary non-breast cancer event or contralateral or ipsilateral 
DCIS

OS:  defined as the time from randomization to death due to any cause

DRFI:  defined as the time between randomization and the date of distant breast cancer 
recurrence  
Safety Outcome Measures
The safety outcome measures are the following protocol-specific adverse events (AEs):

Incidence, type and severity of all AEs based on NCI CTCAE Version 4.0

Incidence, type, and severity of serious adverse events (SAEs)

Incidence and type of AEs leading to dose discontinuation, modification, or delay

Cause of death on study

Abnormal laboratory values

LVEF decreases

Cardiac events, defined as death from cardiac cause or severe CHF (NYHA Class III or IV) 
with a decrease in LVEF of 10 percentage points from baseline to an LVEF of 50%.
Patient-Reported Outcome Measures
The PRO outcome measures for this study are as follows:

Incidence of treatment-related symptoms and assessment of health-related quality of life 
(HRQOL) as measured using the EORTC QLQ-C30 questionnaire and QLQ-BR23 module

Assessment of health status as measured using the EuroQol EQ-5Dquestionnaire for 
health economic modeling


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Pharmacokinetic Outcome Measures
The PK outcome measures to be assessed in patients receiving trastuzumab emtansine are the 
following:

Observed serum concentrations and relevant PK parameters of trastuzumab emtansine 
(trastuzumab emtansine conjugated) and total trastuzumab (sum of conjugated and 
unconjugated trastuzumab)

Observed plasma concentrations of DM1

Explore relationship between trastuzumab emtansine exposure and efficacy/safety 

Characterize ATA and assess impact of ATA on PK, safety and efficacy. 
Exploratory Outcome Measures
The exploratory outcome measure for this study is as follows:

The relationship between molecular markers and efficacy outcomes
Efficacy outcomes considered for this analysis will include IDFS and OS, as appropriate.
Investigational Medicinal Products
Trastuzumab emtansine is provided as a single-use lyophilized formulation.  The lyophilized 
product should be reconstituted using sterile water for injection (SWFI).  Patients will receive 
trastuzumab emtansine infusions q3w.  Vials should be refrigerated at 2C to 8C (36F to 46F) 
until use.  The vial and the solution of trastuzumab emtansine should not be shaken or frozen.  
Information on the formulation, packaging, handling, and administration of trastuzumab 
emtansine is provided in the trastuzumab emtansine Investigator’s Brochure (IB) and local 
prescribing information.
Information on the formulation, packaging, handling, and administration of trastuzumab is 
provided in the local prescribing information as appropriate.
Accurate records of all investigational medicinal products (IMPs), including trastuzumab 
emtansine and trastuzumab, that are received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
Statistical Methods
Primary Analysis
The primary efficacy variable is IDFS, defined as the time between randomization and date of 
first occurrence of an IDFS event.  Patients who have not had an event will be censored at the 
date they are last known to be alive and event free on or prior to the clinical data cutoff date.
The log-rank test, stratified by the protocol-defined stratification factors (clinical stage at 
presentation [inoperable vs. operable]; hormone receptor status [ER or PgR positive vs. ER and 
PgR negative/unknown]; preoperative HER2-directed therapy [trastuzumab vs. trastuzumab 
plus additional HER2-directed agent(s)]; and pathologic nodal status evaluated after 
preoperative therapy [node positive vs. node negative/not done]), will be used to compare IDFS 
between the 2 treatment arms.  The unstratified log-rank test results will also be provided as a 
sensitivity analysis.  If at the time of analysis it is deemed that the smallest strata per arm 
is 5 patients to conduct robust stratified analyses, unstratified analyses will be used as the 
primary analysis.
Cox proportional hazards model, stratified by the protocol-defined stratification factors, will be 
used to estimate the HR between the 2 treatment arms and its 95% confidence interval (CI).  
The Kaplan-Meier approach will be used to estimate 3-year IDFS rates and corresponding 
95% CIs for each treatment arm.
Determination of Sample Size  
The sample size of the study is primarily driven by the analysis of IDFS.  To detect a hazard 
ratio (HR) of 0.75 in IDFS (a 6.5% improvement in 3-year IDFS from 70% in the control arm to 
76.5% in the trastuzumab emtansine arm), approximately 384 IDFS events will be required to 
achieve 80% power at a 2-sided significance level of 5%.  Approximately 1484 patients will be 
enrolled in the study.


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The study is expected to be fully enrolled around 35 months after the first patient enrolls in the 
study (FPI).  The final IDFS analysis will be performed after approximately 384 events have 
occurred, which is projected to be approximately 107 months from FPI.
With the study sample size of 1484 patients and approximately 12 years of follow-up, this study 
has about 43% power to detect a HR of 0.8 (a 2.8% improvement in 3-year OS from 85% in the 
control arm to 87.8% in the trastuzumab emtansine arm) at a 2-sided significance level of 5%.
Interim Analyses
One interim analysis of IDFS and 2 interim analyses of OS are planned.
The interim efficacy analysis of IDFS is planned after 67% of the targeted IDFS events have 
occurred, which is estimated to be approximately 48 months after the first patient is enrolled in 
the study.  At this interim analysis, IDFS will be tested at the significance level determined using 
the LanDeMets alpha spending function with an O’BrienFleming boundary so that the overall 
2-sided type I error rate will be maintained at the 5% level for the IDFS primary endpoint.  A 
summary of the planed IDFS analyses is shown in the table below:
Analysis of IDFS
No. of events
Efficacy Stopping 
Boundary a
Estimated Timing b
Interim 
257
p0.0124 or observed 
HR0.732
48 months
Final
384
p0.0462 or observed 
HR0.816
107 months
HRhazard ratio; IDFSinvasive disease-free survival.
a p-value will be based on 2-sided stratified log-rank test.
b Time from the enrollment of first patient to data cutoff.
The purpose of the interim analysis is to evaluate whether there is an overwhelming difference 
in the efficacy observed in the trastuzumab emtansine arm compared with the trastuzumab arm 
in terms of IDFS.  If the test is not significant, the study will continue as planned.  If the test is 
significant, the independent Data Monitoring Committee (iDMC) may recommend releasing the 
primary endpoint results before the targeted number of 384 events is reported.  In this latter 
situation, the Sponsor will be unblinded to the study results and a full data package would be 
prepared for discussion with regulatory authorities.  The study will continue until 12 years of 
follow-up and IDFS analysis will be updated when 384 IDFS events have occurred.  
Two formal interim OS analyses and one final OS analysis are planned, as detailed in the table 
below.  The final OS analysis will be performed at the end of 12 years of follow-up.  A survival 
data sweep will be conducted prior to each analysis.
The overall type I error will be controlled at 0.05 for the formal OS interim analyses and final OS 
analysis using the LanDeMets alpha spending function with an O’BrienFleming boundary.  
The boundaries used at each interim and final OS analysis will depend on the timing of the 
analyses and the number of death events actually included in the analyses.


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Analysis Of OS
No. of 
Events
Efficacy Stopping Boundary a
Estimated Timing b
Interim 1 (at interim IDFS)
98
p 0.0005 or observed HR 0.494 
48 months
Interim 2 (at final IDFS)c
183
p 0.0143 or observed HR 0.696
107 months 
Finalc
263
p 0.0456 or observed HR 0.781
144 months
HRhazard ratio; IDFSinvasive disease-free survival; OSoverall survival.
a p-value will be based on 2-sided stratified log-rank test.
b Time from the enrollment of first patient to data cutoff.
c Estimated number of events. Efficacy boundaries will be calculated based on the actual 
number of events at the time of analysis.
An iDMC will monitor accumulating patient safety data at least once approximately every 6 
months until the last patient has completed study treatment.  In addition, data on SAEs and 
deaths will be monitored by the iDMC at least once approximately every 3 months during this 
period.  At each iDMC review, relevant safety information from ongoing trastuzumab emtansine 
studies will be provided to the iDMC.
After the first 600 patients have been randomized and followed up for 3 months (approximately 
21 months after FPI), the iDMC will perform an interim safety analysis regarding death and 
hepatic events.  The Clinical Events Committee will communicate their findings regarding 
cardiac and hepatic events to the iDMC to aid iDMC review.
If an absolute increase of 3% in the percentage of death (from any cause) or in the percentage 
of Hy’s law cases (confirmed by the independent clinical events committee) is observed in the 
trastuzumab emtansine arm compared with the trastuzumab arm, the iDMC will consider 
recommending holding enrollment for further data review, stopping, or modifying the trial.
If an absolute increase of 3% in the percentage of Hy’s law cases (confirmed by the 
independent clinical events committee) is observed in the trastuzumab emtansine arm 
compared with the control arm, the iDMC will consider recommending holding enrollment for 
further data review, stopping, or modifying the trial.
The iDMC will work according to the guidelines defined in the iDMC Charter.  The iDMC Charter 
will contain details regarding the frequency of meetings, guidelines for decision making, and 
process for requesting further information.  The iDMC members will review and sign off on the 
charter before the first review.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AE
adverse event
ALK
alkaline phosphatase
ALT
alanine aminotransferase
anti-HBc
hepatitis B core antibody
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATA
anti-therapeutic antibody
CHF
congestive heart failure
CI
confidence interval
CIS
carcinoma in situ
COVID 19
coronavirus disease 2019
CTCAE
Common Terminology Criteria for Adverse Events
CT
computed tomography
DCIS
ductal carcinoma in situ
DFS
disease-free survival
DRFI
distant recurrence-free interval
EC
Ethics Committee
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EFS
event-free survival
ePRO
electronic patient-reported outcome
EORTC
European Organisation for Research and Treatment of 
Cancer
ER
estrogen receptor
FACT-B
Functional Assessment of Cancer Therapy-Breast
FDA
U.S. Food and Drug Administration
FISH
fluorescence in situ hybridization
FPI
first patient enrolls in the study
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HR
hazard ratio
HRQOL
health-related quality of life


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Abbreviation
Definition
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
iDCC
independent Data Coordinator Center
iDMC
independent Data Monitoring Committee
IDFS
invasive disease-free survival
IHC
immunohistochemistry
IMP
investigational medicinal product
IND
Investigational New Drug (application)
INR
international normalized ratio
IRB
Institutional Review Board
ISH
in situ hybridization
IV
intravenous
IVRS/IWRS
interactive voice response system/interactive Web 
response system
LCIS
lobular carcinoma in situ
LFT
liver function laboratory test
LVEF
left ventricular ejection fraction
LVSD
Left ventricular systolic dysfunction
MBC
metastatic breast cancer
MRI
magnetic resonance imaging
MUGA
multiple-gated acquisition
NCI
National Cancer Institute
NSABP
National Surgical Adjuvant Breast and Bowel Project
NRH
nodular regenerative hyperplasia
NYHA
New York Heart Association
ORR
objective response rate
OS
overall survival
pCR
pathological complete response
PD
progressive disease
PE
polyethylene
PES
polyethersulfone
PET-FDG
positron emission tomography- fluorodeoxyglucose
PFS
progression-free survival
PK
pharmacokinetic
PgR
progesterone receptor
PP
polypropylene
PRO
patient-reported outcome


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Abbreviation
Definition
PVC
polyvinyl chloride
q3w
every 3 weeks
QLQ-C30
Quality of Life QuestionnaireCore 30
QLQ-BR23
Quality of Life QuestionnaireBreast Cancer 13
RCR
Roche Clinical Repository
RT
radiotherapy
SAE
serious adverse event
SWFI
sterile water for injection
TBILI
total bilirubin
TMA
tissue microarray
ULN
upper limit of normal


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1.
BACKGROUND
1.1
BACKGROUND ON EARLY-STAGE HER2-POSITIVE BREAST 
CANCER
The use of adjuvant (postoperative) trastuzumab in HER2-positive early-stage breast 
cancer improves patient outcomes as demonstrated in several large, randomized trials.  
The 3-year disease-free survival (DFS) rate for patients receiving trastuzumab in these 
studies, all of whom had operable disease, was approximately 85% to 90% 
(Romond et al. 2005; Piccart-Gebhart 2005; Slamon et al. 2011).  A variety of 
trastuzumab-based chemotherapy regimens are considered effective for the treatment of 
non-metastatic HER2-positive breast cancer.  These include doxorubicin and 
cyclophosphamide followed by a taxane (docetaxel or paclitaxel) plus trastuzumab 
(AC-TH); docetaxel, carboplatin, and trastuzumab (TCbH); and 5-fluorouracil, epirubicin, 
and cyclophosphamide in sequence with docetaxel plus trastuzumab (FEC-TH or TH-
FEC).  These chemotherapy regimens for early-stage HER2-positive breast cancer 
share in common the following features:  1) at least 6 total cycles of chemotherapy, 2) at 
least 9 weeks of trastuzumab in combination with a taxane, and 3) subsequent 
trastuzumab monotherapy to complete a total of 1 year of adjuvant HER2-directed 
treatment.  U.S. and E.U. labeling for Herceptin® (trastuzumab) recommends a total of 
12 months of treatment (as adjuvant therapy in the United States and as neoadujvant 
and/or adjuvant therapy in the European Union); this is endorsed by local practice 
guidelines (Gnant et al. 2011; NCCN 2011).  Such regimens used in the adjuvant setting 
are also recommended for preoperative (also known as “neoadjuvant”) therapy, as the 
timing of chemotherapy administration in relation to primary surgery does not impact 
survival (Gnant et al. 2011; NCCN 2011).
For patients with operable breast cancer, preoperative therapy has been shown in 
several randomized trials to result in survival outcomes similar to those with adjuvant 
therapy, with the added benefit of improving breast conservation rates 
(Mauri et al. 2005).  In trials of preoperative therapy, it has been consistently 
demonstrated that patients who achieve a pathological complete response (pCR) have 
an improved prognosis compared with those who have residual invasive disease present 
in the surgical specimen after completion of preoperative therapy (non-pCR).  For 
example, in the National Surgical Adjuvant Breast and Bowel Project (NSABP) Studies 
B-18 and B-27, the hazard ratios (HRs) for DFS for patients who achieved a pCR 
compared with those who did not were 0.47 and 0.49, respectively; the HRs for overall 
survival (OS) were 0.32 and 0.36, respectively (Rastogi et al. 2008).  The U.S. Food and 
Drug Administration (FDA) has recently issued draft guidance on the use of pCR as a 
surrogate endpoint to support accelerated approval.  Although there are only limited data 
for preoperative therapy conducted exclusively in patients with HER2-positive breast 
cancer, in general, pCR rates of approximately 40%–60% have been observed, and 
patients who attain a pCR have a more favorable prognosis than those who have 
residual invasive disease (Buzdar et al. 2005; Gianni et al. 2010; Roche data on file; 
Loibl et al. 2011).  For example, the addition of trastuzumab to 24 weeks of sequential 


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paclitaxel-FEC improved pCR from 25% to 66.7% in patients with operable 
HER2-positive breast cancer (Buzdar et al. 2005).  The Neoadjuvant Herceptin(NOAH) 
study randomized patients with locally advanced or inflammatory HER2-positive cancer 
to preoperative chemotherapy with or without trastuzumab (Gianni et al. 2010).  Those 
who achieved a pCR after trastuzumab-containing therapy had a 3-year event-free 
survival (EFS) rate of 78% compared with 58% in patients who did not have a pCR 
(Roche data on file).  In the Taxol® Epirubicin Cyclophosphamide Herceptin Neoadjuvant 
(TECHNO) study, which included patients with either operable or inoperable HER2-
positive breast cancer, pCR following preoperative trastuzumab-based therapy was 
statistically significantly associated with both improved DFS and OS in multivariate 
analyses, and the 3-year DFS rate was approximately 70% for non-pCR patients 
compared with 88% for those attaining pCR (Untch et al. 2011).  A recent meta-analysis 
of neoadjuvant studies affirmed the prognostic import of pCR in 662 HER2-positive 
patients who had received trastuzumab.  With pCR defined as no invasive or non-
invasive residual disease in the breast or lymph nodes, there was a significant benefit in 
OS for attainment of pCR (p0.0001) (Loibl et al. 2011).  Therefore, the absence of pCR 
after appropriate neoadjuvant therapy allows identification of a patient population at 
higher risk of disease recurrence.  This is a clinical setting where the application of more 
effective therapies would have a potentially large absolute impact on patient outcomes 
and can be considered an area of unmet medical need. 
Although it is recognized that patients without pCR after preoperative treatment are at 
increased risk of recurrence, no specific adjuvant regimens are recommended for this 
population.  Additional systemic therapy for non-pCR patients has not been rigorously 
studied or shown to be of benefit.  Therefore, these patients are currently recommended 
to receive the same adjuvant therapies as would be used for any patient with 
HER2-positive breast cancer, regardless of surgical findings 
(NCCN 2011; Gnant et al. 2011).  For example, patients with HER2-positive breast 
cancer are recommended to complete a total of 1 year of trastuzumab treatment.  They 
may also receive post-surgical radiation as part of breast conservation or for the 
presence of other high-risk features.  In addition, those with hormone receptor–positive 
disease are recommended to receive hormonal therapy after surgery.
Various definitions of pCR have been commonly utilized in clinical trials, but all have 
demonstrated prognostic value.  In the earliest studies of preoperative therapy, the 
absence of residual disease in the breast alone was mainly considered.  More recently, 
the status of the axillary lymph nodes has also been considered.  There are conflicting 
data on whether residual in situ disease carries prognostic significance in the absence of 
residual invasive disease.  Thus, a conservative definition of pCR would be the absence 
of residual invasive disease in the breast or axillary lymph nodes.  Attempts have been 
made to further refine prognostic categories for patients whose tumors do not achieve a 
pCR after preoperative treatment.  However, no additional factors have been validated to 
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In summary, preoperative chemotherapy in combination with trastuzumab is a standard 
of care for patients with HER2-positive locally advanced (Stage IIB to IIIC) breast cancer 
or in cases where patients wish to minimize the extent of breast cancer surgery.  
Compared with patients who attain a pCR after preoperative therapy, patients with 
residual disease have a greater risk of recurrence and death.  It is not known whether 
the application of additional non–cross-resistant agents in the adjuvant setting may 
benefit these patients, and there are no approved therapies in this clinical setting.  
Because trastuzumab emtansine has shown activity in patients who have previously 
progressed after chemotherapy and HER2-directed therapy in the metastatic setting, it 
would be reasonable to explore in a clinical study whether there may be a benefit of 
administering trastuzumab emtansine to patients with HER2-positive early breast cancer 
who have not had an optimal response to commonly recommended preoperative therapy 
regimens.
1.2
BACKGROUND ON TRASTUZUMAB EMTANSINE
Trastuzumab emtansine (known as ado-trastuzumab emtansine in the United States) is 
a novel antibody-drug conjugate (ADC), specifically designed for the treatment of 
HER2-positive cancer.  It is composed of the following components:  trastuzumab, a 
humanized antibody directed against the extracellular region of HER2; DM1, an 
ant-microtubule agent derived from maytansine; and succinimidyl 4-[N-maleimidomethyl] 
cyclohexane-1-carboxylate (SMCC), a thioether linker molecule used to conjugate DM1 
to trastuzumab.  Trastuzumab emtansine binds to HER2 with an affinity similar to that of 
unconjugated trastuzumab.  It is hypothesized that after binding to HER2, trastuzumab 
emtansine undergoes receptor-mediated internalization, resulting in intracellular release 
of DM1 and subsequent cell death.  DM1 is an inhibitor of tubulin polymerization; it binds 
to tubulin competitively with vinca alkaloids.
Data from clinical trials of trastuzumab emtansine that are especially relevant to the 
design of the current trial are summarized below.  Please refer to the most recent 
version of the trastuzumab emtansine Investigator’s Brochure (IB) for further information 
on all of the completed and ongoing trastuzumab emtansine studies.
1.2.1
Study TDM4450g/BO21976
Study TDM4450g/BO21976 was a randomized, multicenter, Phase II trial of the efficacy 
and safety of trastuzumab emtansine (3.6 mg/kg intravenous [IV] every 3 weeks [q3w]) 
versus trastuzumab plus docetaxel in patients with metastatic HER2-positive breast 
cancer who have not received prior chemotherapy for metastatic disease.  
The primary endpoints were investigator-assessed progression-free survival (PFS) and 
safety.  The primary PFS analysis took place after 72 investigator-assessed PFS events 
had occurred in the 2 arms combined (data cut:  15 November 2010).  Objective 
response rate (ORR), duration of ORR, and related exploratory assessments and 
patient-reported outcome (PRO) were also analyzed at this time.  The OS and safety 


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analyses were performed approximately 24 months after the last patient was enrolled 
(data cut:  31 August 2011).  A total of 137 patients were enrolled in the study. 
Trastuzumab emtansine demonstrated significant improvement in PFS over trastuzumab 
plus docetaxel as first-line metastatic breast cancer (MBC) therapy.  The median PFS 
was 14.2 months in the trastuzumab emtansine arm compared with 9.2 months in the 
trastuzumab plus docetaxel arm (HR0.59; 95% confidence interval [CI]: 0.364,0.968; 
log-rank p-value0.035), with a median follow-up of approximately 14 months in both 
arms.  The ORR was 58.0% with trastuzumab plus docetaxel and 64.2% with 
trastuzumab emtansine.  Tumor response was more durable with trastuzumab 
emtansine (median duration of response not reached vs. median duration 9.5 months in 
the control arm).  Compliance rate on QOL measures was high (93%) across cycles for 
both treatment arms.  The worsening of the Functional Assessment of Cancer 
Therapy-Breast (FACT-B) Trial Outcome Index scores was delayed in the trastuzumab 
emtansine arm compared with the control arm (7.5 vs. 3.5 months; HR0.58; p0.022).  
Preliminary results indicate that OS results are similar between the arms.  However, OS 
data were not mature (less than 20% of the patients in the study had died at the time of 
the data cut, and the median duration of OS was not reached for either arm).  Results 
were also potentially confounded by crossover as allowed in the protocol.  At the time of 
OS follow-up, there were 35 patients (50%) from the trastuzumab plus docetaxel arm 
who had crossed over to trastuzumab emtansine after documented disease progression.
Grade3 AEs were reported less frequently in the trastuzumab emtansine group 
compared with the trastuzumab plus docetaxel group (46.4% vs. 90.9%), as were AEs 
leading to treatment discontinuations (7.2% vs. 34.8%) and SAEs (20.3% vs. 25.8%).
1.2.2
Study TDM4874g/BO22857
Study TDM4874g/BO22857 was a multicenter, multinational, single-arm Phase II study 
designed to assess the safety and feasibility of administering trastuzumab emtansine 
(3.6 mg/kg IV q3w) after anthracycline-based chemotherapy as adjuvant or preoperative 
therapy for patients with early-stage HER2-positive breast cancer.  Patients must have 
completed an anthracycline-based regimen (FEC or AC) and must have initiated 
treatment with trastuzumab emtansine within 42 days.  The safety objectives of the study 
included the following:  to evaluate the rate of prespecified cardiac events (New York 
Heart Association [NYHA] Class III/IV congestive heart failure [CHF]) following initiation 
of trastuzumab emtansine treatment; to evaluate the safety and feasibility of 
trastuzumab emtansine when given with concurrent radiotherapy (RT), to evaluate the 
feasibility of the planned duration (up to 17 cycles) of treatment with trastuzumab 
emtansine therapy, and to evaluate the safety profile of trastuzumab emtansine in this 
patient population.
A total of 148 patients received trastuzumab emtansine.  No prespecified cardiac events 
occurred (95% CI:
0.00%, 2.45%), and there were no reports of symptomatic left 
ventricular systolic dysfunction or heart failure.  One patient discontinued trastuzumab 


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emtansine because of asymptomatic left ventricular ejection fraction (LVEF) decrease.  
Overall, 122 patients (82.4%) completed the planned duration of trastuzumab emtansine 
treatment with 98 patients (66.2%) completing trastuzumab emtansine treatment without 
dose reduction.  The results of this study indicate that trastuzumab emtansine was well 
tolerated.  Twenty patients (13.5%) had AEs leading to trastuzumab emtansine 
discontinuation.  Eleven of these were laboratory abnormalities requiring discontinuation 
(none were Grade 4), and 9 were due to symptomatic AEs (2 Grade 3 [fatigue, joint 
crepitation]; no Grade 4).  Of the 148 patients, 41.2% experienced a Grade 3 AE
during trastuzumab emtansine treatment; 2.7% had Grade 4 AEs (1 patient each:  febrile 
neutropenia and pancytopenia; atrial fibrillation; decreased platelet count; hypokalemia); 
no deaths occurred.  The adverse events are consistent with the known safety profile of 
trastuzumab emtansine.  Mean LVEF appeared stable throughout the duration of 
trastuzumab emtansine treatment.  There were no cases of portal hypertension/nodular 
regenerative hyperplasia (NRH) reported.  Of the 116 patients receiving RT, 39 received 
it concurrently with trastuzumab emtansine and 77 received it sequentially.  The 
percentage of patients who completed at least 95% of the planned RT dose without 
delays > 5 days was similar with concurrent or sequential treatment (94.7% and 96.1%, 
respectively), and the adverse event profile was similar for concurrent and sequential 
RT.  There was 1 patient with Grade 2 and 1 patient with Grade 3 RT-associated 
pneumonitis in the sequential RT group and 1 patient in the concurrent RT group with 
Grade 2 RT-associated pneumonitis.
Among the 50 patients who were treated with neoadjuvant therapy (AC/FEC followed by 
one or more doses of trastuzumab emtansine) and received surgery, 28 patients (56%) 
achieved pCR with staging ypT0/isN0 (95% CI: 41.3%, 69.6%). In the neoadjuvant 
setting, 2 patients experienced a DFS event after receiving surgery, and 1 additional 
patient discontinued trastuzumab emtansine treatment as a result of disease 
progression prior to surgery.  No patients in the adjuvant setting experienced a DFS 
event though follow-up was limited to no more than 1 year after the last dose of 
trastuzumab emtansine.
1.2.3
Study TDM4370g/BO21977 (EMILIA)
Study TDM4370g/BO21977 is a randomized Phase III study of trastuzumab emtansine 
versus capecitabine and lapatinib for patients with HER2-positive unresectable locally 
advanced or MBC previously treated with trastuzumab and a taxane (n991). Patients 
received trastuzumab emtansine (3.6 mg/kg IV q3w) or capecitabine (1000 mg/m2 PO 
twice daily, Days 1 to 14 q3w)lapatinib (1250 mg PO daily) until progressive disease 
(PD) or unmanageable toxicity. Primary endpoints were PFS by independent review, 
OS, and safety. There was a significant improvement in PFS favoring trastuzumab 
emtansine (HR0.650, p0.0001; median 9.6 vs. 6.4 months). A strong trend in OS 
was observed in favor of the trastuzumab emtansine arm (HR0.621, p0.0005, 
median not reached vs. 23.3 months). Based on the strong clinical benefit observed at 
the time of the primary PFS analysis, the Sponsor planned a second interim analysis for 


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OS (when at least 50% of the target number of 632 events had occurred) to justify 
allowing patients in the control arm of the study access to trastuzumab emtansine and to 
obtain an accurate estimate of the true treatment effect of trastuzumab emtansine on 
OS prior to any confounding effect due to crossover. As of the data cut-off date for this 
analysis (31 July 2012), 331 events, representing 52% of the 632 events targeted for the 
final analysis, had occurred. The co-primary endpoint of OS was met:  OS was 
significantly improved in patients receiving trastuzumab emtansine, with a 31.8% 
reduction in the risk of death associated with trastuzumab emtansine compared with 
lapatinib and capecitabine (HR0.682, 95% CI: 0.548, 0.849; p0.0006; 
(Verma et al. 2012). This result crossed the pre-specified efficacy stopping boundary 
(HR0.727 or p0.0037). These results were consistent with the unstratified log-rank 
test and the stratified and unstratified Wilcoxon tests. The median duration of survival 
was 25.1 months in patients treated with lapatinib plus capecitabine, compared with 30.9 
months in patients treated with trastuzumab emtansine.
As of the clinical cut-off date for the second OS analysis, both the pre-specified 
landmark 1-year and 2-year survival rates, based on Kaplan Meier estimates, 
demonstrated significantly greater benefit for patients receiving trastuzumab emtansine 
(Verma et al. 2012). The estimated pre−specified landmark 1-year survival rate was 
78.4% for lapatinib plus capecitabine versus 85.2% for trastuzumab emtansine 
(difference of 6.8%, 95% CI:  1.79%, 11.82%), and the estimated pre-specified landmark 
2-year survival rate was 51.8% for lapatinib plus capecitabine versus 64.7% for 
trastuzumab emtansine (difference of 12.9%, 95% CI:  4.89%, 20.95%).
The objective response rate was 43.6% for trastuzumab emtansine versus 30.8% for 
capecitabine/lapatinib with the median duration of response being 12.6 months versus 
6.5 months respectively.  Trastuzumab emtansine was well tolerated with no unexpected 
safety signals.  The most common Grade3 AEs for trastuzumab emtansine were:  
thrombocytopenia (12.9% vs. 0.2%), increased AST (4.3% vs. 0.8%), and increased ALT 
(2.9% vs. 1.4%); and for capecitabine/lapatinib were:  diarrhea (20.7% vs. 1.6%), palmar 
plantar erythrodysesthesia (16.4% vs. 0) and vomiting (4.5% vs. 0.8%).  The incidence 
of Grade3 AEs in the trastuzumab emtansine arm was 40.8% versus 57.0% for 
capecitabine/lapatinib.  Median time to symptom progression, as defined by a 5-point 
decrease in the score derived from the trial outcome index-breast (TOI-B) subscale of 
the FACT-B quality of life questionnaire was delayed in female patients receiving 
trastuzumab emtansine compared to those receiving lapatinib plus capecitabine 
(7.1 months for trastuzumab emtansine, compared to 4.6 months:  HR0.796, 95% 
CI0.667-0.951; p0.0121).


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1.2.4
Study TDM4788g/BO22589 (MARIANNE)
Study TDM4788g/BO22589 is a randomized  three arm, Phase III study of trastuzumab 
emtansine combined with pertuzumab versus trastuzumab emtansine combined with 
pertuzumab-placebo (blinded for pertuzumab) versus trastuzumab plus taxane as 
first-line treatment in HER2-positive progressive or recurrent locally advanced or 
metastatic breast cancer patients.  The primary objectives of the study are to compare 
the efficacy (PFS by independent review) and safety across the three arms.  The study
has been finalized with a total of 1095 patients enrolled.  At the time of the primary 
analysis in Study TDM4788g/BO22589 efficacy (PFS by IRF) of trastuzumab emtansine 
with or without pertuzumab was non-inferior to trastuzumabtaxane, however neither of 
the trastuzumab emtansine containing arms showed PFS superiority over 
trastuzumab taxane (Ellis et al. 2015).  Median OS was similar across the three arms 
(Perez et al. 2019 ).  The trastuzumab emtansine-based regimens were better tolerated 
than trastuzumabtaxane (Perez et al. 2019).  
1.2.5
Studies TDM4258g and TDM4374g
The efficacy of trastuzumab emtansine (at a dose of 3.6 mg/kg q3w) was evaluated in 
two completed single-arm Phase II studies, TDM4258g and TDM4374g.  Study 
TDM4258g enrolled patients with HER2-positive MBC who had progressed on previous 
HER2-directed therapy, although patients in study TDM4374g had disease progression 
after at least two HER2-directed therapies (i.e., trastuzumab and lapatinib) in the 
metastatic or locally advanced setting.  In both of these studies, the primary efficacy 
endpoint was objective response as assessed by independent review of tumor 
assessments.  The clinical activity of trastuzumab emtansine was similar in the two
studies, with an objective response rate of 26% in TDM4258g and 32% in TDM4374g.  
1.3
BACKGROUND ON TRASTUZUMAB (HERCEPTIN®)
Trastuzumab is a recombinant humanized anti-p185 HER2 monoclonal antibody that 
binds with high affinity to the HER2 protein.  U.S. and E.U. labeling for Herceptin®
(trastuzumab) recommends a total of 12 months of treatment as adjuvant therapy in the 
United States and as neoadujvant and/or adjuvant therapy in the European Union based 
on the data generated in randomized trials (Piccart-Gebhart 2005; Romond et al. 2005; 
Gianni et al. 2010; Slamon 2011). 
Details on the AEs associated with trastuzumab and clinical use of trastuzumab are to 
be found in the trastuzumab IB and in the Herceptin local prescribing information.
1.4
STUDY RATIONALE AND BENEFIT RISK ASSESSMENT
Breast cancer patients who do not achieve a pCR following preoperative treatment are 
at increased risk of recurrence and breast cancer–related death compared with those 
that do achieve a pCR.  Trastuzumab emtansine has shown activity and a favorable 
benefit-risk profile in patients who have progressed after prior HER2-directed therapies 
for metastatic disease.  In addition, trastuzumab emtansine appears to have a favorable 


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benefit-risk profile in patients who have not received prior chemotherapy for metastatic 
disease, including patients who have previously received trastuzumab in the adjuvant 
setting.  The safety profile of trastuzumab emtansine appears to be acceptable in the 
metastatic setting and is currently under evaluation for early-stage HER2-positive breast 
cancer.  In the curative treatment setting, certain acute AEs or potential chronic organ 
effects (e.g., cardiac and/or hepatic damage) may constitute a specific concern for 
trastuzumab emtansine.  In studies done to date, there does not appear to be an 
increased risk for cardiac AEs with trastuzumab emtansine as compared to other HER2-
directed therapies.  Increases in transaminases are observed with the administration of 
trastuzumab emtansine but the potential for severe acute drug-induced liver injury is not 
clear.  Although initial safety data to date using trastuzumab emtansine in previously 
untreated patients in both the adjuvant (Dang et al. 2012) and metastatic setting (Hurwitz
2011) appears acceptable, a safety monitoring plan for this study including appropriate 
eligibility criteria, dose modification guidelines, and interim safety analyses, as well as 
regular monitoring of accumulating patient safety data by a Data Monitoring Committee 
has been put in place to minimize any potential risk in the trial patient population.
2.
OBJECTIVES
2.1
PRIMARY EFFICACY OBJECTIVE
The primary efficacy objective for this study is as follows:  

To compare invasive disease-free survival (IDFS, Section 3.4.1) in patients with 
residual invasive breast cancer after treatment with preoperative chemotherapy and 
HER2-directed therapy including trastuzumab followed by surgery between the 
2 treatment arms
The secondary efficacy objective for this study is as follows:

To compare IDFS including second non-breast cancers, DFS, OS, and distant 
recurrence-free interval (DRFI) between the 2 treatment arms 
2.2 SAFETY OBJECTIVE
The safety objective for this study is as follows: 

To compare cardiac safety and overall safety between the 2 treatment arms 
according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE), Version 4.0 
2.3 PATIENT REPORTED OUTCOME OBJECTIVE
The PRO objective for this study is as follows:

To compare PROs between the 2 treatment arms using the European Organisation 
for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire –
Core 30 (QLQ-C30) questionnaire and Quality of Life Questionnaire – Breast 
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2.4 PHARMACOKINETICS OBJECTIVES
The pharmacokinetics (PK) objectives for this study are as follows:

To characterize the PK of trastuzumab emtansine (including total trastuzumab and 
DM1) in trastuzumab emtansine treated patients 

To characterize the PK of trastuzumab in trastuzumab-treated patients and permit 
an intra-study comparison of trastuzumab exposure in the 2 treatment arms

To investigate exposure–effect (efficacy and safety) relationships in this patient 
population
2.5 EXPLORATORY OBJECTIVES
The exploratory objectives for this study are as follows:

To assess correlations between biomarker status and efficacy and/or safety

To assess the incidence of anti-therapeutic antibodies (ATAs) and the effect of 
ATAs on PK, safety, and efficacy
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
3.1.1
Overview
Study BO27938 is a Phase III, 2-arm, randomized, multicenter, multinational, open-label 
study in patients with HER2-positive primary breast cancer who have received 
preoperative chemotherapy and HER2-directed therapy including trastuzumab followed 
by surgery, with a finding of residual invasive disease in the breast or axillary lymph 
nodes.
Patients will be randomized to one of the following treatment arms in a 1:1 ratio:
Arm A:  Trastuzumab emtansine 3.6 mg/kg given IV q3w for 14 cycles
Arm B:  Trastuzumab 6 mg/kg given IV q3w for 14 cycles (an 8 mg/kg loading dose 
should be given in cases where there has been an interval greater than 6 weeks 
since the last dose of trastuzumab) 
The study will enroll approximately 1484 patients who have pathologically documented 
residual invasive disease in either the breast or axillary lymph nodes following 
completion of preoperative therapy.  Patients must have completed preoperative 
systemic treatment consisting of at least 6 cycles with a total duration of at least 
16 weeks, including at least 9 weeks of trastuzumab and at least 9 weeks of 
taxane-based chemotherapy (or, if receiving dose-dense chemotherapy regimens, at 
least 6-8 weeks of taxane-based therapy and at least 8 weeks of trastuzumab).  
HER2-directed therapy and chemotherapy may be given concurrently; patients may 
have received more than one HER2-directed therapy.  Patients may have received an 
anthracycline as part of preoperative therapy.


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Patients will receive study treatment for a maximum of 14 cycles; treatment will be 
discontinued prior to 14 cycles in the event of disease recurrence, unacceptable toxicity, 
or study termination by the Sponsor.  Patients who discontinue trastuzumab emtansine 
may complete the duration of their study therapy with trastuzumab if appropriate based 
on toxicity considerations.  Following discontinuation or completion of study treatment, 
patients will continue to be followed for efficacy and safety objectives until the end of the 
study.
Radiotherapy and/or hormonal therapy (for patients with hormone receptor-positive 
tumors) concurrent with study treatment should be administered if indicated based on 
the following guidelines (refer to Section 4.1.1.1 for lymph node surgery requirements):

Hormonal therapy (aromatase inhibitor, tamoxifen, etc.) should be initiated in 
patients with hormone receptor-positive disease at presentation.

For patients undergoing breast-conserving surgery, whole breast irradiation is 
required.  Primary tumor bed boost may be administered according to local policy.  
Regional node irradiation is required if the patient presented at initial diagnosis with 
clinical T3 (except for T3N0) or T4 disease and/or with clinical N2 or N3 disease; it 
is recommended for T3N0 or if there is residual disease in lymph nodes.

For post-mastectomy patients, chest wall and regional node irradiation is required if 
the patient presented at initial diagnosis with clinical T3 (except for T3N0) or T4 
disease and/or with clinical N2 or N3 disease; it is recommended for T3N0 or if there 
is residual disease in lymph nodes.  For post-mastectomy patients who do not meet 
these criteria, radiotherapy is at the discretion of the investigator based on 
institutional standards.
A permuted-block randomization scheme will be used to ensure an approximate 
1:1 allocation of patients to receive trastuzumab emtansine or trastuzumab with respect 
to the following stratification factors:

Clinical stage at presentation:  inoperable (Stage T4NxM0 or TxN2–3M0) versus 
operable (Stages T1-3N0–1M0)

Hormone receptor status:  estrogen receptor (ER) or progesterone receptor (PgR) 
positive versus ER and PgR negative/unknown

Preoperative HER2-directed therapy:  trastuzumab versus trastuzumab plus 
additional HER2-directed agent(s)

Pathologic nodal status evaluated after preoperative therapy:  node positive versus 
node negative/not done
Schedules of assessments are provided in Appendix 1 and Appendix 2.
3.1.2
Data Monitoring Committee
An iDMC will monitor accumulating patient safety data at least once every 6 months until 
the last patient has completed study treatment.  In addition, data on SAEs and deaths 
will be monitored by the iDMC at least once every 3 months during this period.  The 


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iDMC will also assess safety and efficacy as part of the interim efficacy and safety 
analyses.  At each iDMC review, relevant safety information from ongoing trastuzumab 
emtansine studies will be provided to the iDMC.  An independent Data Coordinator 
Center (iDCC) will perform unblinded analyses to support the periodic iDMC review of 
safety data and the interim analysis.  Additional details will be provided in an iDMC 
Charter.
3.1.3
Clinical Events Committee
An independent safety advisory board will adjudicate pre-specified safety events of 
interest (cardiac and hepatic dysfunction events).  A separate charter will outline the 
committee’s composition, meeting timelines, and members’ roles and responsibilities.  
The committee members may review all potential cases of CHF and cardiac death as 
well as all potential cases of hepatic dysfunction and Hy’s law.  Identified cases will be 
forwarded to the iDMC on a regular basis as part of the ongoing safety reviews.
3.2
END OF STUDY
The study will end after the last patient randomized into the study has undergone the last 
follow-up assessment.  To enable long-term follow-up for survival and safety information, 
the last follow-up assessment is scheduled to occur 12 years after the first patient is 
randomized.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Test Product Dosage
In a Phase I study (TDM3569g), the maximum tolerated dose of trastuzumab emtansine 
administered by IV infusion q3w was 3.6 mg/kg.  Clinical activity has been observed at a 
dose of 3.6 mg/kg q3w in studies of single-agent trastuzumab emtansine in both 
pretreated and previously untreated HER2-positive MBC.  In the adjuvant or neoadjuvant 
setting following anthracycline therapy, trastuzumab emtansine 3.6 mg/kg q3w has been 
tolerated as a single agent administered up to 17 cycles without evidence of significant 
cardiac toxicity.  Please refer to the trastuzumab emtansine IB for further information. 
There are 2 approved dose regimens of trastuzumab:  a 4 mg/kg loading dose followed 
by a 2 mg/kg dose every week; and an 8 mg/kg loading dose followed by a 6 mg/kg 
dose q3w.  The half-life of trastuzumab has been determined to be approximately 28.5 
days, which supports a dosing of q3w.  Data to support the q3w regimen are available 
from 2 studies evaluating the safety, tolerability, and PK of trastuzumab administered to 
women with HER2-positive (immunohistochemistry (IHC) 3or FISH) metastatic breast 
cancer and from the 1-year arm of the HERA study (BO16348).  Data from these three 
trials indicate that serum concentrations of trastuzumab increased until steady-state 
trough concentrations (median 47.3 ng/mL, 95% CI 19.6 to 51.2 ng/mL).  The average 
exposure at any time during the treatment is comparable between the 2 treatment 
regimens.


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Please refer to the trastuzumab IB for further information.
3.3.2
Rationale for Patient Population
Preoperative/neoadjuvant systemic therapy has been shown to be equivalent to adjuvant 
therapy in terms of long-term disease outcomes in randomized trials.  It may be utilized 
to improve operability or to shrink tumors to enable breast conservation at the discretion 
of patients and their physicians.  Patients without a pCR following preoperative treatment 
are at increased risk of recurrence and breast cancer–related death compared with 
those that do achieve a pCR.  A number of questions remain regarding treatment 
duration and exactly how to combine HER2-directed therapy with chemotherapy in the 
neoadjuvant setting.  A randomized Phase II study in HER2-positive patients 
demonstrated that the rate of pCR was equivalent using anthracycline and 
non-anthracycline based chemotherapy regimens (Schneeweiss et al. 2011).  In 
addition, the administration of HER2 targeting agents trastuzumab and pertuzumab with 
a taxane for 3 cycles following anthracycline resulted in similar pCR rates to 
administration of 6 cycles of these HER2 targeting agents initially given concurrently with 
anthracycline.  Therefore, patients who have received both anthracycline and non-
anthracycline based neoadjuvant regimens may enroll in this study, with a minimum 
requirement of 9 weeks of exposure to a taxane (6-8 weeks if part of a dose-dense 
regimen) and 9 weeks of trastuzumab (8 weeks if part of a dose-dense regimen) and 6 
cycles of neoadjuvant chemotherapy.
3.3.3
Rationale for Control Group and Duration of Therapy
Although 1 year of trastuzumab therapy is currently recommended for HER2-positive 
patients, both shorter and longer durations of therapy are being investigated in the 
adjuvant setting.  By standardizing the study treatment duration to 14 cycles, given q3w, 
and requiring at least 9 weeks of preoperative trastuzumab, all patients should receive at 
minimum approximately 1 year of HER2-directed therapy, consistent with current 
practice guidelines, as tolerated.
3.3.4
Rationale for Biomarker Assessments
For all patients, IHC and/or in situ hybridization (ISH) assays will be performed for the 
mandatory confirmation of HER2 status.  Other in situ methods or newly available 
diagnostics to evaluate HER2 may be applied as well on these samples.
HER2 signaling is known to be modulated by expression levels of other HER family 
members (e.g., HER1 and HER3) and their ligands, the expression of which may 
correlate with response or resistance to HER2-targeted therapies.  As an exploratory 
objective, the expression of other HER family receptors or ligands and their potential 
impact on clinical efficacy will be assessed in this study, should sufficient material be 
available.  Additional candidate markers of response to trastuzumab emtansine that 
emerge from other clinical or preclinical studies may also be assessed in this study.


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3.3.5
Rationale for Pharmacokinetic Assessments
The rationale for collecting PK samples is to further characterize the PK of trastuzumab 
emtansine, total trastuzumab, and DM1 in trastuzumab emtansine treated patients and 
to establish correlations between drug exposure and measures of both efficacy and 
toxicity in the adjuvant breast cancer setting.  The proposed PK sampling scheme 
should allow for adequate characterization of each analyte for the planned analysis.  Any 
remaining serum/plasma samples may be, at Sponsors discretion and if stability is 
confirmed, used for measurement of trastuzumab emtansine metabolites as an 
exploratory assessment.
Among patients randomized to receive trastuzumab, the rationale for collecting PK 
samples is to assess the PK of trastuzumab in this patient population and the sampling 
scheme will allow an intra-study comparison of trastuzumab exposure in the 2 treatment 
arms.
3.4
OUTCOME MEASURES
3.4.1
Primary Efficacy Outcome Measure
The primary efficacy outcome measure is IDFS, defined as the time from randomization 
until the date of the first occurrence of any one of the following events: 

Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving 
the same breast parenchyma as the original primary lesion) 

Ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast 
cancer in the axilla, regional lymph nodes, chest wall and/or skin of the ipsilateral 
breast) 

Distant recurrence (i.e., evidence of breast cancer in any anatomic site—other than 
the 2 above-mentioned sites—that has either been histologically confirmed or 
clinically diagnosed as recurrent invasive breast cancer)

Contralateral invasive breast cancer

Death attributable to any cause including breast cancer, non-breast cancer or 
unknown cause (but cause of death should be specified if at all possible)


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3.4.2
Secondary Efficacy Outcome Measures
Secondary efficacy outcome measures include the following:

IDFS including second primary non-breast cancer:  defined the same way as IDFS 
for the primary endpoint but including second primary non-breast invasive cancer as 
an event (with the exception of non-melanoma skin cancers and carcinoma in situ 
[CIS] of any site)

DFS:  defined as the time between randomization and the date of the first 
occurrence of an IDFS event including second primary non-breast cancer event or 
contralateral or ipsilateral ductal carcinoma in situ (DCIS)

OS:  defined as the time from randomization to death due to any cause

DRFI:  defined as the time between randomization and the date of distant breast 
cancer recurrence  
3.4.3
Safety Outcome Measures
Clinical and laboratory AEs will be reported according to the NCI CTCAE, Version 4.0.  
LVEF will be assessed using either echocardiogram (ECHO) or multiple-gated 
acquisition (MUGA).
Safety will be measured by determining the incidence, nature, and severity of AEs.  The 
safety outcome measures are the following protocol-specific AEs:

Incidence, type and severity of all AEs based on NCI CTCAE Version 4.0

Incidence, type, and severity of SAEs

Incidence and type of AEs leading to dose discontinuation, modification, or delay

Cause of death on study

Abnormal laboratory values

LVEF decreases

Cardiac events, defined as death from cardiac cause or severe CHF (NYHA Class 
III or IV) with a decrease in LVEF of10 percentage points from baseline to an 
LVEF of50%.
3.4.4
Patient-Reported Outcome Measures
The PRO outcome measures for this study are as follows:

Incidence of treatment-related symptoms and assessment of health-related quality 
of life (HRQOL) as measured using the EORTC QLQ-C30 questionnaire and QLQ-
BR23 module

Assessment of health status as measured using the EuroQol EQ-5Dquestionnaire 
for health economic modeling


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3.4.5
Pharmacokinetic Outcome Measures
The PK outcome measures to be assessed in patients receiving trastuzumab emtansine 
are the following:

Observed serum concentrations and relevant PK parameters of trastuzumab 
emtansine (trastuzumab emtansine conjugated) and total trastuzumab (sum of 
conjugated and unconjugated trastuzumab)

Observed plasma concentrations of DM1

Explore relationship between trastuzumab emtansine exposure and efficacy/safety 

Characterize ATA and assess impact of ATA on PK, safety and efficacy. 
3.4.6
Exploratory Outcome Measure
The exploratory outcome measure for this study is as follows:

The relationship between molecular markers and efficacy outcomes
Efficacy outcomes considered for this analysis will include IDFS and OS, as appropriate.
4.
MATERIALS AND METHODS
4.1
PATIENTS
The patient population for this study will include patients with primary non-metastatic 
HER2-positive breast cancer (see Section 4.1.1.1 for definition). 
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry: 
4.1.1.1
Disease-Specific Inclusion Criteria
1.
HER2-positive breast cancer
HER2-positive status will be based on pretreatment biopsy material and defined 
as an immunohistochemistry (IHC) (Appendix 6) score of 3and/or positive by 
in situ hybridization (ISH) (Appendix 7) prospectively confirmed by a central 
laboratory prior to study enrollment.  ISH positivity is defined as a ratio of2.0 
for the number of HER2 gene copies to the number of signals for chromosome 
17 copies.  Formalin-fixed paraffin-embedded tumor tissue block or a partial 
block must be available for central evaluation of HER2 expression.  If sites are 
unable to send a tissue block due to local regulations, at least 8 unstained 
slides should be sent for HER2 testing, and in addition up to 5 slides for 
exploratory biomarker research.  A central laboratory will perform both IHC and 
ISH assays; however, only one positive result is required for eligibility.  In the 
event that sufficient material from the pretreatment biopsy is not available for 
submission, central HER2 determination for eligibility may be performed on 
residual tumor tissue from the time of definitive surgery.
Patients with synchronous bilateral invasive disease are eligible provided both 
lesions are HER2-positive. 


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2.
Histologically confirmed invasive breast carcinoma
3.
Clinical stage at presentation:  T1–4, N0–3, M0 (Note:  Patients with T1a/bN0 
tumors will not be eligible)
4.
Completion of preoperative systemic chemotherapy and HER2-directed treatment. 
Systemic therapy must consist of at least 6 cycles of chemotherapy, with a total 
duration at least 16 weeks, including at least 9 weeks of trastuzumab and at least 
9 weeks of taxane-based chemotherapy. Patients may have received an 
anthracycline as part of preoperative therapy in addition to taxane chemotherapy.
Patients receiving dose-dense chemotherapy regimens are eligible, provided at 
least 8 weeks of taxane-based therapy and at least 8 weeks of trastuzumab have 
been given.  A dose-escalated (225 mg/m2 q2w) dose-dense regimen of paclitaxel 
over 6 weeks is allowed.
Patients may have received more than one HER2-directed therapy.  Note: 
HER2-directed therapy alone periods will not satisfy the requirement for cycles of 
preoperative systemic chemotherapy.
All systemic chemotherapy should be completed preoperatively.
5.
Adequate excision:  surgical removal of all clinically evident disease in the breast 
and lymph nodes as follows:
Breast surgery:  total mastectomy with no gross residual disease at the margin 
of resection, or breast-conserving surgery with histologically negative margins 
of excision
For patients who undergo breast-conserving surgery, the margins of the 
resected specimen must be histologically free of invasive tumor and DCIS 
as determined by the local pathologist.  If pathologic examination 
demonstrates tumor at the line of resection, additional operative 
procedures may be performed to obtain clear margins.  If tumor is still 
present at the resected margin after re-excision(s), the patient must 
undergo total mastectomy to be eligible.  Patients with margins positive for 
lobular carcinoma in situ (LCIS) are eligible without additional resection.
Lymph node surgery:
In case of positive results from a fine-needle aspiration, core biopsy, or 
sentinel node biopsy performed prior to preoperative therapy, additional 
surgical evaluation of the axilla following preoperative therapy is required.
If only micrometastases are present in sentinel nodes preoperatively (i.e., if 
the greatest diameter of the nodal metastasis in a sentinel node is 0.2 mm 
or less), no additional surgical evaluation of the axilla is required.
If sentinel node biopsy performed before preoperative therapy was 
negative, no additional surgery evaluation of the axilla is required after 
preoperative therapy.
If the only sentinel node identified by isotope scan is in the internal 
mammary chain, surgical evaluation of the axilla is recommended.


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If sentinel node biopsy performed after preoperative therapy is positive, 
additional surgical evaluation of the axilla is recommended.
If sentinel node evaluation after preoperative therapy is negative, no further 
additional surgical evaluation of the axilla is required.
Axillary dissection without sentinel node evaluation is permitted after 
preoperative therapy.
6.
Pathologic evidence of residual invasive carcinoma in the breast or axillary lymph 
nodes following completion of preoperative therapy.  If invasive disease is present in 
both breasts, residual invasive carcinoma must be present in at least 1 breast or 
axillary lymph node postoperatively.
7.
An interval of no more than 12 weeks between the date of primary surgery and the 
date of randomization
8.
Known hormone receptor status 
Hormone receptorpositive status can be determined by either known positive ER or 
known positive PgR status; hormone receptornegative status must be determined 
by both known negative ER and known negative PgR.
4.1.1.2
General Inclusion Criteria
9.
Signed written informed consent approved by the study site’s Institutional Review 
Board (IRB)/Ethical Committee (EC)
10. Age18 years
11. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
12. Life expectancy6 months 
13. Adequate organ function during screening, defined as:
a. Absolute neutrophil count1200 cells/mm3
b. Platelet count100000 cells/mm3
c.
Hemoglobin9.0 g/dL; patients may receive red blood cell transfusions to 
obtain this level
d. Serum creatinine1.5upper limit of normal (ULN)
e. International normalized ratio (INR) and activated partial thromboplastin 
time (aPTT)1.5ULN
f.
Serum AST and ALT1.5ULN
g. Serum total bilirubin (TBILI)1.0ULN (within normal limits), except for 
patients with Gilbert’s syndrome, for whom direct bilirubin should be 
within the normal range
h. Serum alkaline phosphatase (ALK)1.5ULN
i.
Screening LVEF50% on ECHO or MUGA after receiving neoadjuvant 
chemotherapy and no decrease in LVEF by more than 15% absolute 
points from the pre-chemotherapy LVEF.  Or, if pre-chemotherapy LVEF 


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was not assessed, the screening LVEF must be 55% after completion 
of neoadjuvant chemotherapy.
i.
LVEF assessment may be repeated once up to 3 weeks following the 
initial screening assessment to assess eligibility.
14. For women who are not postmenopausal (12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  agreement to 
remain abstinent or use single or combined contraceptive methods that result in a 
failure rate of 1% per year during the treatment period and for at least 7 months 
after the last dose of study drug.
a. Abstinence is only acceptable if it is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception.
Examples of contraceptive methods with a failure rate of 1% per year 
include tubal ligation, male sterilization, hormonal implants, established, 
proper use of combined oral or injected hormonal contraceptives, and 
certain intrauterine devices.  Alternatively, two methods (e.g., two barrier 
methods such as a condom and a cervical cap) may be combined to 
achieve a failure rate of < 1% per year.  Barrier methods must always be 
supplemented with the use of a spermicide.
b. Male patients whose partners are pregnant must use condoms or truly 
refrain from sexual activity for the duration of the pregnancy.
15. Negative serum pregnancy test for premenopausal women including women who 
have had a tubal ligation and for women less than 12 months after the onset of 
menopause
16. Documentation of hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies is 
required:  this includes HB surface antigen (HBsAg) and/or total HB core antibody 
(anti-HBc) in addition to HCV antibody testing.  The most recent serologic testing 
must have occurred within 3 months prior to initiation of neoadjuvant therapy.  If 
such testing has not been done, it must be performed during screening.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry.
4.1.2.1
Disease-Related Exclusion Criteria
1.
Stage IV (metastatic) breast cancer
2.
History of any prior (ipsi- or contralateral) breast cancer except lobular CIS
3.
Evidence of clinically evident gross residual or recurrent disease following 
preoperative therapy and surgery
4.
An overall response of PD according to the investigator at the conclusion of
preoperative systemic therapy
5.
Treatment with any anti-cancer investigational drug within 28 days prior to 
commencing study treatment


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6.
History of other malignancy within the last 5 years except for appropriately treated 
CIS of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other 
non-breast malignancies with an outcome similar to those mentioned above
7.
Patients for whom radiotherapy would be recommended for breast cancer treatment 
but for whom it is contraindicated because of medical reasons (e.g., connective 
tissue disorder or prior ipsilateral breast radiation) 
8.
Current NCI CTCAE (Version 4.0) Grade2 peripheral neuropathy
9.
History of exposure to the following cumulative doses of anthracyclines: 
Doxorubicin240 mg/m2
Epirubicin or Liposomal Doxorubicin-Hydrochloride (Myocet®) 480 mg/m2
For other anthracyclines, exposure equivalent to doxorubicin240 mg/m2
10. Cardiopulmonary dysfunction as defined by any of the following:
History of NCI CTCAE (Version 4.0) Grade3 symptomatic CHF or NYHA 
criteria ClassII
Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia 
not controlled by adequate medication, severe conduction abnormality, or 
clinically significant valvular disease

High-risk uncontrolled arrhythmias:  i.e., atrial tachycardia with a heart 
rate100/min at rest, significant ventricular arrhythmia (ventricular 
tachycardia) or higher-grade AV-block (second degree AV-block Type 2 
[Mobitz 2] or third degree AV-block)
Significant symptoms (Grade2) relating to left ventricular dysfunction, cardiac 
arrhythmia, or cardiac ischemia while or since receiving preoperative therapy.
History of a decrease in LVEF to40% with prior trastuzumab treatment (e.g., 
during preoperative therapy)
Uncontrolled hypertension (systolic blood pressure180 mmHg and/or diastolic 
blood pressure100 mmHg)
Evidence of transmural infarction on ECG
Requirement for continuous oxygen therapy
11. Prior treatment with trastuzumab emtansine
4.1.2.2
General Exclusion Criteria
12. Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, or metabolic disease; wound-healing disorders; ulcers)
13. For female patients, current pregnancy and/or lactation
14. Major surgical procedure unrelated to breast cancer or significant traumatic injury 
within approximately 28 days prior to randomization or anticipation of the need for 
major surgery during the course of study treatment
15. Any known active liver disease, for example, disease due to HBV, HCV, 
autoimmune hepatic disorders, or sclerosing cholangitis.  Patients who have positive 


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HBV or HCV serologies without known active disease must meet the eligibility 
criteria for ALT, AST, TBILI, INR, aPTT, and alkaline phosphatase (ALK) on at least 
two consecutive occasions, separated by at least 1 week, within the 30 day 
screening period.
16. Concurrent, serious, uncontrolled infections or known infection with HIV
17. History of intolerance, including Grade 3 to 4 infusion reaction or hypersensitivity to 
trastuzumab or murine proteins or any components of the product
18. Active, unresolved infections at screening requiring treatment
19. Assessment by the investigator as being unable or unwilling to comply with the 
requirements of the protocol
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
After written informed consent has been obtained and eligibility has been established 
and approved, the study site will obtain the patient randomization number and treatment 
assignment from the interactive voice response system/interactive web response system
(IVRS/IWRS).  Patients should receive their first dose of study treatment the day of 
randomization if possible, but no later than 5 business days after randomization.  
Patients will be randomized in a 1:1 ratio by a permuted block randomization scheme to 
one of the 2 treatment arms (trastuzumab or trastuzumab emtansine) through use of the 
IVRS/IWRS.
Randomization will be stratified by the stratification factors:

Clinical stage at presentation:  inoperable (Stage T4NxM0 or TxN2–3M0) versus 
operable (Stages T1-3N0 to 1M0)

Hormone receptor status:  ER or PgR positive versus ER and PgR 
negative/unknown

Preoperative HER2-directed therapy:  trastuzumab versus trastuzumab plus 
additional HER2-directed agent(s)

Pathologic nodal status evaluated after preoperative therapy:  node positive versus 
node negative/not done
4.3
STUDY TREATMENT
4.3.1
Formulation, Packaging, and Handling
For further details regarding trastuzumab emtansine, see the IB and local prescribing 
information. For trastuzumab, see the local prescribing information as appropriate.
Please note that both the trastuzumab 150 mg vial and the trastuzumab emtansine 
160 mg vial are available in 20 mL vials and contain a lyophilized product.  Both require 
reconstitution with sterile water for injection (SWFI).  The two vials are similar in 
appearance, and it is important to check the box and vial labels to ensure that the 
product being administered is consistent with what has been assigned to the patient.


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4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Trastuzumab Emtansine
Trastuzumab emtansine will be administered on Day 1 of a 3-week cycle q3w at a dose 
of 3.6 mg/kg IV.  If the timing coincides with a holiday that precludes administration, 
administration should be performed within 5 business days following the scheduled date.  
The total dose will be calculated based on the patient’s weight on Day 1 of (or up to 
3 days before) each cycle with no upper limit.  Changes in weight of10% from baseline 
do not require dose recalculation. 
Trastuzumab emtansine doses may be reduced to as low as 2.4 mg/kg, according to the 
dose-modification guidelines (see Table 2 in Section 5.1.3).  Dose delays of up to 
42 days from the last administered dose are permitted.  
The first infusion of trastuzumab emtansine will be administered over 90 minutes 
(10 minutes).  Infusions may be slowed or interrupted for patients experiencing 
infusion-associated symptoms.  Vital signs must be assessed before and after dose 
administration.  Following the initial dose, patients will be observed for at least 
90 minutes for fever, chills, or other infusion-associated symptoms.  If prior infusions 
were well tolerated (without any signs or symptoms of infusion reactions), subsequent 
doses of trastuzumab emtansine may be administered over 30 minutes (10 minutes), 
with a minimum 30-minute observation period after infusion.  Local health authority 
guidelines must be followed with regard to further observation and monitoring, if 
applicable.  Premedication for nausea and infusion reactions (e.g., acetaminophen or 
other analgesics, antihistamines such as diphenhydramine, or corticosteroids) may be 
given at the investigator’s discretion.
4.3.2.2
Trastuzumab
Trastuzumab will be administered on Day 1 of a 3-week cycle at a maintenance dose of 
6 mg/kg IV.  A loading dose of 8 mg/kg is required if6 weeks have elapsed since the 
prior dose of trastuzumab.  If the timing coincides with a holiday that precludes 
administration, administration should be performed within 5 business days following the 
scheduled date.  
Infusion of trastuzumab should be performed in accordance with local guidelines and/or 
prescribing information.
4.3.3
Investigational Medicinal Product Accountability
All investigational medicinal products (IMPs) required for completion of this study will be 
provided by the Sponsor.  Trastuzumab emtansine is the IMP in this study.  Depending 
on local legislation, trastuzumab may also be considered an IMP in this study.  Where 
permitted by regulatory requirements, sites will obtain and utilize commercially available 
trastuzumab.


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The investigational site will acknowledge receipt of IMPs, using the IVRS/IWRS to 
confirm the shipment condition and content.  Any damaged shipments 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 upon by the 
Sponsor.  The site must obtain written authorization from the Sponsor before any IMP is 
destroyed, and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.3.1
Post-Trial Access to Trastuzumab Emtansine
The Sponsor does not intend to provide trastuzumab emtansine or other study 
interventions to patients after conclusion of the study or any earlier patient withdrawal.
4.4
CONCOMITANT THERAPY AND FOOD
4.4.1
Permitted Therapy
Concomitant therapy and premedication are defined as non-IMPs.
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal/homeopathic remedies, nutritional supplements) or therapy used by a 
patient at any time from 7 days prior to randomization to the study completion/early 
termination visit.
All concomitant medications (within 7 days prior to randomization) and prior treatments 
for breast cancer must be reported in the electronic case report form (eCRF), including 
the following:

All systemic therapies for breast cancer (drug name, dose, schedule, and duration), 
including chemotherapy, biologic therapy (antibody and small molecule therapies), 
or hormonal therapy (including ovarian ablation and drug induced ovarian 
suppression)

Date and extent of primary surgery, as applicable

Any locoregional radiation therapy (extent or volume and total dose)

Bisphosphonate or denosumab therapy (to be used in accordance with the 
approved labeled indication and/or nationally recognized treatment 
guidelines)
All concomitant medications are to be reported until the end of study treatment visit.  
Thereafter, only medications and therapies applicable for long-term reporting must be 
reported, including the following:

Breast cancer treatments (e.g., hormone therapy)

Anticancer treatments for recurrence


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
Bisphosphonate or denosumab therapy

Medications related to the treatment of SAEs that are applicable for long-term 
reporting
Patients on anti-coagulant treatment should have their platelet count monitored closely 
during treatment with trastuzumab emtansine.  
Any medication that is necessary for the supportive management of the patient may be 
used at the discretion of the investigator.  This includes vaccination and/or treatment 
for coronavirus disease 2019 (COVID-19) or similar conditions.  Recording these 
medications or events if experienced by the patient onto eCRFs is not required; 
however, they should be documented in the patient’s medical record.
4.4.1.1
Adjuvant Radiotherapy
Concomitant adjuvant radiotherapy includes the following:

For patients undergoing breast-conserving surgery, whole breast irradiation is 
required.  Primary tumor bed boost may be administered according to local policy.  
Regional node irradiation is required if the patient presented with clinical T3 (except 
for T3N0) or T4 disease and/or with clinical N2 or N3 disease; it is recommended for 
T3N0 or if there is residual disease in lymph nodes.

For post-mastectomy patients, chest wall and regional node irradiation is required if 
the patient presented with clinical T3 (except for T3N0) or T4 disease and/or with 
clinical N2 or N3 disease; it is recommended for T3N0 or if there is residual disease 
in lymph nodes.  For post-mastectomy patients who do not meet these criteria, 
radiotherapy is at the discretion of the investigator based on institutional standards.
Radiotherapy should be initiated within 60 days of surgery in the absence of 
complications requiring delay.  When indicated, it is recommended that radiotherapy is 
given concurrently with study therapy.  Plans for reconstructive surgery should take into 
consideration the protocol therapy.
Dose fractionation of adjuvant whole breast, chest wall and regional node radiotherapy 
may be done according to local institutional guidelines.
4.4.1.2
Concomitant Hormonal Therapy
Concomitant hormonal therapy may be administered according to the following 
recommendations.
Female patients must be classified according to one of the following menopausal status 
definitions on the basis of their pre-chemotherapy status:

Premenopausal
12 months since last menstrual period AND no prior bilateral ovariectomy AND not 
receiving estrogen replacement OR biochemical evidence of premenopausal status, 
according to local policies


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
Postmenopausal
12 months since last menstrual period with no prior hysterectomy OR prior 
bilateral ovariectomy OR biochemical evidence of postmenopausal status, 
according to local policies
Female patients should be treated according to local guidelines.  A minimum of 5 years 
of hormonal therapy should be planned.
NOTE:  Endocrine therapy in male patients is to be given according to local guidelines.
Table 1
Recommendations for Hormonal Therapy
Clinical Scenario
Hormonal Therapy
Hormone receptor negative a
Not permitted
Hormone receptor positive b (premenopausal)
Tamoxifen for 5-10 years with or without 
ovarian suppression as per local policy
Hormone receptor positive b (postmenopausal)
Aromatase inhibitor for 5 years, OR
Aromatase inhibitor for 2-3 years, followed by 
tamoxifen to complete a total of 5-10 years, OR
Tamoxifen for 2-3 years, followed by 
aromatase inhibitor to complete a total of 5 
years, OR
Tamoxifen for 5-10 years, OR
Tamoxifen for 5 years, followed by aromatase 
inhibitor for 5 years
ERestrogen receptor; PgRprogesterone receptor.
a Hormone receptor “positive” is defined as positive for ER and/or PgR based on the 
preoperative or postoperative tumor pathology.  The investigator may decide treatment policy 
according to local laboratory receptor status.
b Patients who are initially premenopausal may become postmenopausal over the course of 
the study, in which case hormonal therapy can be adjusted according to local policy.
4.4.2
Prohibited Therapy
Explicitly prohibited therapies prior to disease recurrence include the following:
–
Anticancer therapies other than those administered in this study, including cytotoxic 
chemotherapy, radiotherapy (except for adjuvant radiotherapy for breast cancer 
after completion of chemotherapy), immunotherapy, and biological or targeted (e.g., 
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–
Any investigational agent, except those used for this study
Concomitant use of strong CYP3A4/5 inhibitors (such as ketoconazole and 
itraconazole) with trastuzumab emtansine should be avoided.  An alternate medication 
with no or minimal potential to inhibit CYP3A4/5 should be considered.  If a strong 
CYP3A4/5 inhibitor is co-administered with trastuzumab emtansine, patients should be 
closely monitored for adverse reactions.  Excessive alcohol intake should be avoided 
(occasional to moderate use is permitted).
4.5
STUDY ASSESSMENTS
All patients will be closely monitored for safety and tolerability during all cycles of 
therapy.  Patients should be assessed for toxicity prior to each dose; dosing will occur 
only if the clinical assessment and local laboratory test values are acceptable.  Study 
treatment will be administered in 21-day cycles if no additional time is required for 
reversal of toxicity.
If the timing of a protocol-mandated procedure coincides with a holiday and/or weekend 
that precludes performance of the procedure within the allotted window, the procedure 
should be performed on the nearest following date.  Study assessments are outlined in 
this section and in Appendix 1 and Appendix 2.
4.5.1
Description of Study Assessments
4.5.1.1
Medical History and Demographic Data
Medical history includes clinically significant diseases, cancer history (including all prior 
cancer therapies and procedures), and all medications (e.g., prescription drugs, 
over-the-counter drugs, herbal/homeopathic remedies, nutritional supplements) used by 
the patient within 7 days prior to the screening visit.  Demographic data will include age, 
sex, and self-reported race/ethnicity.
4.5.1.2
Vital Signs
Vital signs will include measurements of respiratory rate (if obtained as part of standard 
of care), pulse rate, and systolic and diastolic blood pressures while the patient is in a 
seated position, as well as weight and temperature.
4.5.1.3
Physical Examinations
A complete physical examination should include, at the minimum, the evaluation of 
bilateral breast, chest wall, and regional lymph nodes and of the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal (including an evaluation for 
the presence of hepatomegaly), and neurological systems.  Any abnormality identified at 
baseline should be recorded on the General Medical History and Baseline Conditions 
eCRF.
Limited, symptom-directed physical examinations may be performed as indicated in the 
schedule of assessment.  Changes from baseline abnormalities should be recorded in 


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patient notes.  New or worsened abnormalities should be recorded as AEs on the AE 
eCRF.
4.5.1.4
Radiologic Evaluations
Reports of most recent bilateral mammograms and/or magnetic resonance imaging
(MRI) scans performed within 1 year prior to enrollment must be available.  
Mammograms of any remaining breast tissue should be performed at least annually 
during follow-up.  Bone scan, computed tomography (CT), MRI, and/or positron emission 
tomography- fluorodeoxyglucose (PET-FDG) scans may be performed as clinically 
indicated according to the investigator.
4.5.1.5
Laboratory Assessments
Samples for the following laboratory tests will be sent to the study site’s local laboratory 
for analysis according to the Schedule of Assessments:
–
Hematology (hemoglobin, hematocrit, platelet count, WBC count, and absolute 
neutrophil count
–
Serum chemistry
At baseline:  sodium, potassium, chloride, bicarbonate, BUN or urea, creatinine, 
glucose, TBILI (and direct bilirubin when TBILIULN), albumin, total protein, 
ALT, AST, and ALK
At subsequent timepoints:  potassium, TBILI (and direct bilirubin when 
TBILIULN), ALT, AST, ALK, and other studies when clinically indicated
–
Pregnancy test
All women of childbearing potential (including those who have had a tubal 
ligation) will have a serum pregnancy test at screening.  Urine pregnancy tests 
will be performed at specified subsequent visits.  If a urine pregnancy test is 
positive, it must be confirmed by a serum pregnancy test.
–
INR and aPTT at screening; otherwise, as clinically indicated
Samples for the following laboratory tests will be sent to one or several central 
laboratories or to Roche for analysis.  Instruction manuals and supply kits will be 
provided for all central laboratory assessments.
–
Prospective central testing for HER2-positive status by IHC and ISH
Central laboratory confirmation of a positive HER2 status is required prior to 
randomization to the study (see Section 4.1.1.1).  The outcome of this 
assessment will be communicated to the investigator
After completion of HER2 testing for eligibility criteria applying prespecified 
HER2 tests, patient samples may also be tested with other HER2 assays to 
establish performance characteristics of these assays for diagnostic 
development.  Testing could be performed on all screened patients 
(screen-failed and enrolled).  These testing data will have no impact on 


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eligibility and testing will be performed only after eligibility is established for 
each patient.
–
Assessment of potential predictive candidate markers involving alterations to 
molecules relating to HER2 signaling; assessment of the mechanism of action of 
trastuzumab emtansine or trastuzumab, breast cancer biology, or both; assessment 
of the association of candidate markers with the safety profile of trastuzumab 
emtansine; or the improvement of diagnostic methods
For these assessments, tumor blocks will be mandatorily obtained from the 
resection specimen after preoperative treatment and collected.
–
Analysis of serum, plasma, and whole blood samples collected as part of the 
optional biomarker program 
–
Antitrastuzumab emtansine antibody and anti-trastuzumab antibody in 
approximately 50% of the patients in each treatment arm, respectively
–
Analysis of serum and plasma samples for trastuzumab emtansine and trastuzumab 
PK in approximately 50% of the patients in each treatment arm, respectively
4.5.1.6
Cardiac Assessments
4.5.1.6.1
Electrocardiograms
Single 12-lead ECGs will be collected locally and assessed at screening and otherwise 
as clinically indicated.
For safety monitoring purposes, any abnormalities on any of the ECGs will be 
documented on the eCRF.  The investigator or designee must review, sign, and date all 
ECG tracings.  Paper copies will be kept as part of the patient’s permanent study file at 
the site.  For ECG tracings that will fade over time (e.g., ECGs on thermal paper), lasting 
legible copies should be filed together with the original.
4.5.1.6.2
Left Ventricular Ejection Fraction
LVEF will be assessed by ECHO or MUGA.  The same modality should be used 
throughout the study for each patient.  Results of ECHO/MUGA performed prior to 
commencement and immediately after completion of preoperative therapy will also be 
collected in the eCRF.
4.5.1.7
Patient-Reported Outcomes
PRO data will be elicited from the patients in this study to more fully characterize the 
clinical profile of trastuzumab emtansine.  The PRO instruments, translated as required 
into the local language, will be distributed by the investigational site staff and completed 
in their entirety by patients.  To ensure instrument validity and that data standards meet 
health authority requirements, the PRO questionnaires (the EORTC QLQ-C30, the 
EORTC QLQ-BR23 breast cancer module, and the EuroQol EQ-5D) should be 
self-administered at the investigational site prior to the completion of other study 
assessments and the administration of study treatment.  The questionnaires are to be 


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administered at screening, during treatment, and every 6 months for 1 year after the 
study completion visit, as described in the Schedule of Assessments.
The EORTC QLQ-C30 is a validated and reliable self-report measure (Aaronson et al.
1993; Sprangers et al. 1996) that consists of 30 questions that assess five aspects of 
patient functioning (physical, emotional, role, cognitive, and social); three symptom 
scales (fatigue; nausea, vomiting, and pain; and the global health/quality of life) and six 
single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties).  Scale scores can be obtained for the multi-item scales.  The QLQ-BR23 
breast cancer module is meant for use among patients varying in disease stage and 
treatment modality (Sprangers et al. 1996).  The module comprises 23 questions 
assessing disease symptoms, side effects of treatment (surgery, chemotherapy, 
radiotherapy, and hormonal treatment), body image, sexual functioning, and future 
perspective.  The breast cancer module incorporates five multiple-item scales to assess 
systemic therapy side effects, arm symptoms, breast symptoms, body image, and sexual 
functioning.  In addition, single items assess sexual enjoyment, hair loss, and future 
perspective.  The QLQ-C30 and QLQ-BR23 take 10 to 15 minutes to complete (see 
Appendix 3 and Appendix 4, respectively).
The EuroQol EQ-5D questionnaire is a generic, preference-based health utility measure 
with questions about mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression that are used to build a composite of the patient’s health status.  The 
EQ-5D questionnaire will be utilized in this study for economic modeling 
(see Appendix 5).
4.5.1.8
Mandatory Samples for Determination of Patient Eligibility and 
Exploratory Biomarker Research
Tumor samples in the form of a formalin-fixed paraffin-embedded tumor block or partial 
block obtained from the pretreatment primary tumor (biopsy material) are required for 
study enrollment and must be submitted to the central pathology laboratory for 
assessment of HER2 status by IHC and ISH.  If local regulations prevent the site from 
sending a (partial) biopsy block, a minimum of 8 slides should be sent for HER2 testing 
and additional 5 slides for exploratory biomarker analysis.  If sufficient material from the 
pretreatment biopsy is not available for submission, the central pathology laboratory may 
use residual tumor tissue obtained at the time of definitive surgery to assess HER2 
status.  Pathology reports should be included with shipments of the blocks or slides.
If enough tissue (block, partial block, or slides) is available after eligibility HER2 testing, 
samples will also be used for exploratory biomarker research (see below).  
It is also mandatory to send a (partial) tissue block from the surgical specimen for 
exploratory biomarker research, as further outlined below.  If sites are not able to send a 
tissue block due to local regulations, a minimum of 25 slides should be sent.  


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Alternatively, 15 slides could be sent along with a biopsy core from the surgical 
specimen when the tissue block cannot be sent.
The pre-treatment biopsy specimen will be used for exploratory biomarker research to 
determine whether changes in biomarker profiles may characterize potential resistance 
mechanisms.  Furthermore, both tissue samples collected (pre-treatment biopsy core 
and resection specimen) will be used to assess potential predictive candidate 
biomarkers involving alterations to molecules relating to HER2 signaling; to assess the 
mechanism of action of treatment, breast cancer biology, or both; to assess association 
of candidate biomarkers with safety profile of treatment; or to improve diagnostic 
methods.  Examples of such markers are phosphatase and tensin homolog (PTEN), 
phosphoinositide 3-kinases (PI3K), and HER family receptors by protein or messenger 
RNA expression.  Tissue may also be used for central testing of Ki67 and ER/PgR 
staining.  The final set of markers will be defined based on emerging data from the 
trastuzumab emtansine development program and/or literature data.  Such biomarker 
research may methodically include assessment of protein expression (e.g., by IHC) and 
assessment of tumor DNA to explore non-inherited markers and assessment of tumor 
RNA.  Remaining sample materials after the completion of the initial biomarker 
assessments (e.g., aliquots of tumor RNA or DNA) may be used for re-testing, 
developing and validating diagnostic assays, or for further assessment of expanded 
marker panels.  Figure 1 shows the tissue collection flow.
Figure 1
Tissue Collection Flow
HER2human epidermal growth factor receptor 2.
TMA tissue microarray


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When the final set of markers has been defined, approximately at the time of primary 
analysis, baseline samples and recurrence samples will be analyzed for these 
biomarkers.  Tissue blocks will also be used for tissue microarray (TMA) construction.  
Tissue blocks and TMAs will be stored at a study’s central biological samples repository 
for up to 15 years after the date of final closure of the associated clinical database.  If 
local regulations prevent storage of blocks for this duration, slides for biomarker 
analyses will be cut from the block and the blocks will be sent back to the sites.  In case 
partial blocks or slides are sent, tissue blocks will not be returned.  The implementation 
and use of the study repository specimens is governed by the Study Steering 
Committee, with guidance from a dedicated translational advisory committee to ensure 
the appropriate use of the study specimens.  All biomarker specimens will be retained for 
new research related to this study and/or disease in accordance with the 
recommendations and approval of the Study Steering Committee.
For sampling procedures, storage conditions, and shipment instructions, see the Sample 
Handling and Logistics Manual. 
4.5.1.9
Optional Biomarker Research Samples
The blood samples collected will be used to identify biomarkers that may be predictive of 
response or toxicity to treatment and/or prognostic for breast cancer.  Since the 
knowledge of new markers that may correlate with disease activity and the efficacy or 
safety of the treatment is evolving, the analytes may change during the course of the 
study and may include determination of additional markers of tumorogenesis pathways 
and mechanisms of response to anti-HER2 therapies.  The collected blood samples may 
also be used to develop and validate diagnostic assays and allow the generation of 
statistically meaningful biomarker data.  Remaining sample materials after the 
completion of the initial biomarker assessments may be used for re-testing, developing 
and validating diagnostic assays, or for further assessment of expanded marker panels.  
Samples will be stored at a study’s central biological samples repository for up to 15 
years after database closure.  For sampling procedures and shipment see instructions in 
the Sample Collection, Handling and Logistics Manual.
Specimens for biomarker research will be collected from patients who give specific 
consent to participate in this optional research.  These optional biomarker specimens will 
be used to achieve the following objectives:

To study the association of biomarkers with efficacy, AEs, or other effects 
associated with medicinal products

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 
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The specimens in the study repository will be made available for future biomarker 
research towards further understanding of treatment with trastuzumab emtansine or 
trastuzumab of breast cancer, related diseases and AEs, and for the development of 
potential associated diagnostic assays.  Patients must consent to this optional program 
and long-term storage of their blood samples in this study repository.  The 
implementation and use of the study repository specimens is governed by the Study 
Steering Committee, with guidance from a dedicated translational advisory committee to 
ensure the appropriate use of the study specimens.  All biomarker specimens will be 
retained for new research related to this study and/or disease in accordance with the 
recommendations and approval of the Study Steering Committee.
Approval by the Institutional Review Board or Ethics Committee
Sampling for the Optional Biomarker Research is contingent upon the review and 
approval of the exploratory research and this portion of the Informed Consent Form by 
each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for the optional biomarker research sampling, this section of the 
protocol will not be applicable at that site.
Sample Collection for Optional Biomarker Research
The following samples will be collected for identification of dynamic (non-inherited) 
biomarkers:

Plasma samples
For patients who consented to optional biomarker program, blood for plasma 
and serum isolation will be obtained at baseline, during treatment, at the end of 
treatment and at disease recurrence, as described in the schedule of 
assessments (Appendix 1).
If patients are prematurely withdrawn from study treatment without recurrence, 
biomarker sample should be taken as well at the study drug completion visit 
and at disease recurrence.
The following sample will be collected for identification of genetic (inherited) biomarkers:

Blood sample for genetic analysis
For patients who consented to optional biomarker program, blood 
(approximately 6 mL in K3 EDTA) for DNA isolation will be collected at baseline 
as shown in the schedule of assessments.  If, however, the genetic blood 
sample is not collected during the scheduled visit, it may be collected at any 
time (after randomization) during the conduct of the clinical study.  The sample 
may be processed using techniques such as kinetic polymerase chain reaction 
(PCR) and DNA sequencing.
For all samples, dates of consent and specimen collection should be recorded on the 
associated biomarker page of the eCRF.  For sampling procedures, storage conditions, 
and shipment instructions, see the Sample Handling and Logistics Manual.


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The dynamic biomarker specimens will be subject to the confidentiality standards 
described Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below. 
Confidentiality
Given the sensitive nature of genetic data, additional processes to ensure patient 
confidentiality for DNA biomarker specimens has been implemented.  Upon receipt by 
the study biomarker repository, each specimen is "double-coded" by replacing the 
patient identification number with a new independent number.  Data generated from the 
use of these specimens and all clinical data transferred from the clinical database and 
considered relevant are also labeled with this same independent number.  A "linking 
key" between the patient identification number and this new independent number is 
stored in a secure database system.  Access to the linking key is restricted to authorized 
individuals and is monitored by audit trail.  Legitimate operational reasons for accessing 
the linking key are documented in a standard operating procedure.
Data generated from optional biomarker specimens must be available for inspection 
upon request by representatives of national and local health authorities, and study 
monitors, representatives, and collaborators, as appropriate.
Patient medical information associated with biomarker specimens is confidential and 
may only be disclosed to third parties as permitted by the Informed Consent Form (or 
separate authorization for use and disclosure of personal health information) signed by 
the patient, unless permitted or required by law.
Data derived from biomarker specimen analysis (except HER2 status) on individual 
patients will generally not be provided to study investigators.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the biomarker data will become and remain the exclusive and unburdened 
property of Roche, except where agreed otherwise.
Consent to Participate in the Optional Biomarker Research Program
The Informed Consent Form will contain a separate section that addresses participation 
in the optional biomarker program.  The investigator or authorized designee will explain 
to each patient the objectives, methods, and potential hazards of participation in this 
program.  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 biomarker specimens.  Patients who decline to participate will check a 
“no” box in the appropriate section and will not provide a separate signature.


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The investigator should document whether or not the patient has given consent to 
participate by completing the Optional Biomarker Research Sample Informed Consent 
eCRF.
In the event of a participant's death or loss of competence, the participant's specimens 
and data will continue to be used as part of the optional biomarker research.
A separate, specific signature is not required for the following mandatory samples:

Tumor tissue collection for HER2 testing and biomarker analysis (pretreatment 
biopsy tissue sample and surgical tissue sample)
Withdrawal from the Optional Biomarker Research Program
Patients who give consent to provide optional biomarker specimens have the right to 
withdraw their specimens from the Optional Research Program at any time for any 
reason.  If a patient wishes to withdraw consent to the testing of his or her specimens, 
the investigator must inform the Medical Monitor in writing of the patient's wishes using 
the Biomarker Repository Subject Withdrawal Form and, if the trial is ongoing, must 
enter the date of withdrawal on the Optional Biomarker 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 BO27938 
does not, by itself, constitute withdrawal of specimens from the Optional Research 
Program.  Likewise, a patient's withdrawal from the Optional Research Program does 
not constitute withdrawal from Study BO27938.
Monitoring and Oversight
Optional Biomarker Research 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.  Study monitors and auditors will have direct 
access to appropriate parts of records relating to patient participation in the Optional 
Biomarker Research program for the purposes of verifying the data provided to Sponsor.  
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 optional 
biomarker samples.
4.5.2
Timing of Study Assessments
4.5.2.1
Screening and Pretreatment Assessments
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site.  Screening tests and evaluations will be performed within 
30 days prior to enrollment unless otherwise specified.  Results of standard-of-care tests 
or examinations performed prior to obtaining informed consent and within 30 days prior 


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to enrollment may be used; such tests do not need to be repeated for screening.  All 
screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before randomization.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Local HER2 test information, baseline demographic, and disease-related characteristic 
data for all screened patients may be collected in order to support registration of a 
companion diagnostic assay for determination of HER2 status.
Pretreatment tests and evaluations will be performed within 7 days prior to enrollment 
after confirmation of other eligibility criteria, unless otherwise specified.
Please see Appendix 1 for the schedule of screening and pretreatment assessments.
4.5.2.2
Assessments during Treatment
All patients will have a limited physical examination and be assessed for AEs and 
concomitant medications q3w for 14 cycles and will be assessed for disease recurrence 
every 3 months according to the schedule of assessments regardless of whether the 
patient completes or prematurely discontinues study therapy (trastuzumab emtansine or 
trastuzumab).  Patients will be followed for disease-free status and survival according to 
the schedule of assessments for approximately 12 years from the date of randomization
of the first patient.
Scheduled study visits are based on a 21-day (3-week) cycle, with Cycle 1 beginning at 
Day 1.  All visits must occur within5 business days from the scheduled date, unless 
otherwise noted in the schedule of assessments.  All assessments will be performed on 
the day of the specified visit unless a time window is specified.  Assessments scheduled 
on the day of study treatment administration should be performed prior to study 
treatment administration unless otherwise noted.  If the timing of a protocol-mandated 
procedure coincides with a holiday and/or weekend, it should be performed on the 
nearest following date.
Local laboratory assessments scheduled for Day 1 of all cycles must be performed 
within 72 hours prior to study treatment administration unless otherwise specified.  
Results of local laboratory assessments must be reviewed and the review documented 
prior to study treatment administration.
Please see Appendix 1 for the schedule of assessments performed during the treatment 
period.  Please see Appendix 2 for the schedule of assessments for PK and ATA 
determination.


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4.5.2.3
Assessments at Study Treatment Completion/Early 
Termination Visit
Patients may remain on study treatment until disease recurrence as assessed by the 
investigator, unmanageable toxicity, completion of study treatment, or study termination 
by the Sponsor.  Patients who discontinue study treatment will be asked to return to the 
clinic approximately 30 days (7 days) after the last study treatment administration for 
the study treatment discontinuation visit.
Please see Appendix 1 for the schedule of assessments performed at the study 
treatment completion/early termination visit.
4.5.2.4
Follow-Up Assessments
4.5.2.4.1
Scheduled Follow-up Assessments
The follow-up period begins from the date of the study treatment completion/early 
termination visit.  Visit windows are28 days for quarterly and semiannual assessments 
and42 days for annual assessments.
After the study treatment completion/early termination visit, AEs should be followed as 
outlined in Section 5.5 and Section 5.6.
All patients must be followed up for approximately 12 years from the date of 
randomization of the first patient (or until sites are notified that the study is closed by the 
Sponsor) according to the Schedule of Assessments, even if the assigned treatment is 
discontinued permanently.
The schedule of follow-up visits and tests for this study is the minimum required; 
investigators may see their patients more frequently according to their routine practice.  
Follow-up assessments may be conducted via telephone, text, or email messaging or 
video calls if the patients cannot attend the clinic for scheduled appointments,
addressing the following topics:

General well-being assessments
–
Unexplained weight loss or fatigue

Symptom-directed assessments 
–
Tenderness in breast or axilla 
–
Unusual headaches
–
Vision changes
–
Nausea
–
Shortness of breath
–
Extremity swelling
–
Changes in bowel habits
–
Abdominal pain


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–
Bone pain
–
Any unexplained pain
If recurrence is suspected, a patient clinic visit is recommended for a more complete 
assessment.  Annual mammograms and LVEF assessments should be conducted at first 
available opportunity after the scheduled timepoint.  In the unlikely event that there are 
any study medication-related AEs, record the event on the AE eCRF.
Please record any visits, assessments, and diagnoses in the patient charts and on the 
appropriate eCRFs.
In cases of disease recurrence, diagnosed at any time during the study, patients will be 
out of the study schedule and will be followed up once a year (starting 1 year after first 
relapse) for approximately 12 years from the date of randomization of the first patient for 
survival (or until sites are notified that the study is closed by the Sponsor), and new 
relapse events as per secondary endpoints.
Please see Appendix 1 for the schedule of follow-up assessments.
4.5.2.4.2
Follow-up and Confirmation of Disease Recurrence
The diagnosis of a breast cancer recurrence or second primary tumor should be 
confirmed histologically whenever possible.  Some patients may have a suspicious 
recurrence that leads to death quite quickly without the possibility of confirming relapse 
of disease.  Efforts should be made to obtain an autopsy report in such cases.  The 
earliest date of diagnosis of recurrent disease should be used and recorded.  This date 
should be based on objective clinical, radiological, histological or cytological evidence.
If a biopsy is collected as part of routine medical practice at first relapse/recurrence, a 
tissue block or up to five unstained slides should be sent for biomarker analysis in order 
to gain better understanding of resistance mechanisms.  If optional consent was given 
for the Optional Biomarker Program, a sample should also be collected at this time for 
analysis.
Recurrent disease includes local, regional, or distant recurrence and contralateral breast 
cancer.  Patients who have a diagnosis of in situ breast disease or second (non-breast) 
malignancies should be maintained on a regular follow-up schedule wherever possible in 
order to fully capture any subsequent recurrent disease events. The definitions of and 
procedures for confirming disease recurrence, death, and other noteworthy events on 
follow-up are given below:
a)
Local invasive recurrence
Ipsilateral breast after previous lumpectomy
Defined as evidence of invasive tumor (except DCIS and LCIS) in the 
ipsilateral breast after lumpectomy.  Patients who develop clinical evidence 


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of tumor recurrence in the remainder of the ipsilateral breast should have a 
biopsy of the suspicious lesion to confirm the diagnosis.
Confirmed by positive histology or cytology
Ipsilateral after previous mastectomy
Defined as evidence of invasive tumor in any soft tissue or skin of the 
ipsilateral chest wall.  This includes the area bounded by the midline of the 
sternum, extending superiorly to the clavicle, and inferiorly to the costal 
margin.  Soft tissue recurrences in this area extending into the bony chest 
wall or across the midline will be considered as evidence of local 
recurrence.
Confirmed by positive histology or cytology
b)
Regional recurrence
Defined as the development of tumor in the ipsilateral internal mammary lymph 
nodes, ipsilateral axillary lymph nodes, or supraclavicular lymph nodes as well 
as extranodal soft tissue of the ipsilateral axilla.  Regional recurrence does not 
include tumor in the opposite breast.
Confirmed by positive histology or cytology, or radiologic evidence (especially in 
case of PET activity or visible internal mammary lymph nodes on CT or MRI if 
no biopsy was performed)
c)
Distant recurrence
Defined as evidence of tumor in all areas, with the exception of those described 
in a) and b) above
Confirmed by the following criteria:
–
Skin, subcutaneous tissue, and lymph nodes (other than local or regional)
Positive cytology, aspirate or biopsy, OR
Radiological (CT scan, MRI, PET, or ultrasound) evidence of 
metastatic disease
–
Bone
X-ray, CT scan, or MRI evidence of lytic or blastic lesions consistent 
with bone metastasis, OR
Bone scan (requires additional radiological investigation, alone not 
acceptable in case of diagnostic doubt), OR
Biopsy proof of bone metastases or cytology
–
Bone marrow
Positive cytology or histology or MRI scan
–
Lung
Radiologic evidence of multiple pulmonary nodules consistent with 
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Positive cytology or histology (practically rarely performed with the 
exception of solitary nodules)
NOTE:  For solitary lung lesions, cytological or histological 
confirmation should be obtained in case of diagnostic doubt.  Proof of 
neoplastic pleural effusions should be established by cytology or 
pleural biopsy.
–
Liver
Radiologic evidence consistent with liver metastases, OR
Liver biopsy or fine needle aspiration
NOTE:  If radiological findings are not definitive (especially with solitary 
liver nodules), a liver biopsy is recommended; however, if a biopsy is 
not performed, serial scans should be obtained if possible to document 
stability or progression.
–
Central nervous system
Positive MRI or CT scan, usually in a patient with neurologic 
symptoms, OR
Biopsy or cytology (e.g., for a diagnosis of meningeal involvement).  
However, meningeal involvement may also be diagnosed by CT scan 
or MRI and depending from the general status of the patient additional 
investigations (including cytology of the cerebrospinal fluid).
d)
Contralateral invasive breast cancer
Confirmed by positive cytology or histology
e)
Second primary malignancy (breast or other cancer)
Any positive diagnosis of a second (non-breast) primary cancer other than 
basal or squamous cell carcinoma of the skin, or CIS of the cervix will be 
considered an event in the analysis of the IDFS including second primary non-
breast cancer endpoint; however, they will not be included in the IDFS primary 
endpoint.
LCIS and DCIS of the breast and myelodysplastic syndrome are not considered 
progression events.  The diagnosis of a second primary cancer must be 
confirmed histologically.
All second primary malignancies are to be reported whenever they occur during 
the study.
NOTE:  Patients diagnosed with a second primary malignancy not requiring 
systemic therapy (i.e., chemotherapy, hormonal therapy, targeted therapy, etc) 
and with no evidence of breast cancer recurrence will remain on study and 
should continue with study drug treatment according to the protocol and 
schedule of assessment, if considered by the investigator to be in the patient’
s best interest, whenever possible.
f)
Death without recurrence


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Any death occurring without prior breast cancer recurrence or second (non-
breast) malignancy is considered an event for the following endpoints:  IDFS 
including second primary non-breast cancer, DFS, and OS.
g)
Other noteworthy events
The following events should be recorded on the follow-up eCRF:
Ipsilateral and contralateral LCIS
Ipsilateral and contralateral DCIS
NOTE:  These events are not considered recurrent disease, but must be 
recorded. 
4.6
PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
The investigator has the right to discontinue a patient from study drug or withdraw a 
patient from the study at any time.  In addition, patients have the right to voluntarily 
discontinue study drug or withdraw from the study at any time for any reason.  Reasons 
for discontinuation of study drug or 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

Completion of all assessments including 12 years of follow-up 

The study is closed by the Sponsor
4.6.1.1
Discontinuation from Study Drug
Patients must discontinue study drug if they experience any of the following:

Pregnancy

Disease recurrence

Symptomatic CHF at any point in the study

Two consecutive or three intermittent dose delays due to asymptomatic decrease in 
LVEF

Inability to receive trastuzumab emtansine after 2 dose reductions of trastuzumab 
emtansine due to toxicity

Hold on drug administration for42 days from last dose due to toxicity

Unacceptable toxicity

Intercurrent, non−cancer-related illness that prevents continuation of protocol 
therapy or follow-up

Major protocol violation that may jeopardize the patient’s safety according to the 
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
Repeated patient noncompliance with protocol requirements

Changes in the patient’s condition or study drug−related toxicity such that in the 
opinion of the investigator continued participation in the protocol would compromise 
the patient’s well-being

Withdrawal of patient consent
Patients who discontinue study drug prematurely will be asked to return to the clinic for a 
study treatment completion/early termination visit (see Section 4.5.2.3) and may undergo 
follow-up assessments (see Section 4.5.2.4).  The primary reason for premature study 
drug discontinuation should be documented on the appropriate eCRF.  Patients who 
discontinue study drug prematurely will not be replaced.
Patients who discontinue trastuzumab emtansine prior to completion of 14 cycles of 
study therapy may continue treatment with trastuzumab so as to complete 14 cycles of 
HER2-directed study treatment.  For example, if a patient receives 7 cycles of 
trastuzumab emtansine, then the patient could, if otherwise clinically appropriate 
according to the protocol safety plan and investigator judgment, receive up to 7 cycles of 
trastuzumab.  Patients who discontinue trastuzumab emtansine because of toxicity that 
may be attributed to the trastuzumab component (e.g., hypersensitivity, cardiac toxicity, 
pneumonitis) may not continue to receive trastuzumab after discontinuation of 
trastuzumab emtansine.
4.6.1.2
Withdrawal from Study
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  Patients will not be followed for any reason after consent has been 
withdrawn.  Patients who withdraw from the study will not be replaced.
Withdrawal from entire study
Should a patient decide to withdraw from the study, all efforts will be made to complete 
and report the observations for that patient as thoroughly as possible.  No further data 
will be collected after the date of the patient’s withdrawal from study.  The investigator 
should contact the patient or a legally authorized relative by telephone or through a 
personal visit to establish as completely as possible the reason for the withdrawal.  A 
complete final evaluation at the time of the patient’s withdrawal should be made, along 
with an explanation of why the patient is withdrawing from the study.
Partial withdrawal from study
All of the above provisions regarding withdrawal from the entire study are applicable to 
partial withdrawal from the study, except that the patient must agree to be contacted for 
further information on recurrence as per the primary study endpoint and survival status.  
Whenever possible, information on recurrence should be documented through review of 
medical records as well as patient contact.  It should be documented in both the medical 
records and the eCRF that the patient agreed to be contacted for information on survival 


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despite the patient’s withdrawal of informed consent.  If possible, it is preferable to also 
collect adverse event and concomitant medication information during follow-up with 
these patients per Section 4.5.2.4 .
In the case of patients who do not show up for scheduled visits, site staff should make 
several attempts (i.e., at least three attempts within a reasonable period of time after a 
missed visit) to contact these patients for follow-up information.  The collection of 
follow-up data is extremely important for the reliable estimation of study endpoints.
If a patient is lost to follow-up, contact will initially be attempted through the trial research 
nurse and the lead investigator at each study site.  If these attempts are unsuccessful, 
the patient’s physician will be contacted and asked to contact the patient or the patient’s 
family and provide follow-up information to the recruiting study site.
Only after sufficient unsuccessful attempts at contact have been made may a patient be 
declared “lost to follow-up.”
4.6.2
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsor will notify the investigator if the study is placed on hold, or if the Sponsor 
decides to discontinue the study or development program.
The Sponsor has the right to replace a site at any time.  Reasons for replacing a site 
may include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
5.1.1
Toxicities Associated with Trastuzumab Emtansine
The safety plan for patients in this study is based on the known nonclinical toxicities of 
trastuzumab emtansine, clinical experience with this molecule in completed and ongoing 
studies, and clinical toxicities related to its components (trastuzumab and maytansine, 
the parent drug of DM1).  The anticipated important safety risks and potential safety 


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risks of trastuzumab emtansine are outlined below and detailed in the IB.  Please refer to 
the IB for a complete summary of safety.  Risk management guidance to avoid or 
minimize such anticipated toxicities, is detailed herein (Table 2) as well as in the IB.
The iDMC will meet to review AEs on a regularly scheduled basis.
5.1.1.1
Cardiotoxicity
Patients treated with trastuzumab emtansine are at increased risk of developing left 
ventricular dysfunction.  LVEF40% has been observed in patients treated with 
trastuzumab emtansine.  Patients without significant cardiac history and with an 
LVEF50% determined by ECHO or MUGA scan are eligible for study participation.  
LVEF will be monitored at screening and regularly throughout the study until the 
assessment at the safety follow-up visit.  Patients with symptomatic cardiac dysfunction 
will be discontinued from study treatment.  Asymptomatic declines in LVEF will be 
handled as per the algorithm shown in Figure 2.
5.1.1.2
Hematologic Toxicity (Thrombocytopenia and Hemorrhage)
Thrombocytopenia, or decreased platelet count, was reported in patients in clinical trials 
of trastuzumab emtansine.  The majority of these patients had Grade 1 or 2 events 
(50,000/mm3), with the nadir occurring by Day 8 and generally improving to Grade 0 or 
1 (75,000/mm3) by the next scheduled dose.  In clinical trials, the incidence and 
severity of thrombocytopenia were higher in Asian patients.  Cases of bleeding events 
with a fatal outcome have been observed.  Severe cases of hemorrhagic events, 
including CNS hemorrhage, have been reported in clinical trials with trastuzumab 
emtansine; these events were independent of ethnicity.  In some of the cases, the 
patients were also receiving anti-coagulation therapy. There was no clear correlation 
between the severity of thrombocytopenia and severe hemorrhagic events; however, the 
need for use of platelet transfusions has been reported.
Patients on anti-coagulant treatment have to be monitored closely during treatment with 
trastuzumab emtansine.  Platelet counts will be monitored prior to each trastuzumab 
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5.1.1.3
Hepatotoxicity
Hepatotoxicity, predominantly in the form of asymptomatic increases in the 
concentrations of serum transaminases (Grade 14 transaminitis), has been observed 
in patients while on treatment with trastuzumab emtansine in clinical trials.  
Transaminase elevations were generally transient.  The incidence of increased AST was 
substantially higher than that for ALT.  A cumulative effect of trastuzumab emtansine on 
transaminases has been observed; the majority of patients with elevated transaminases 
improved to Grade 1 or normal within 30 days of the last dose of trastuzumab 
emtansine.
Rare cases of severe hepatotoxicity, including death due to drug-induced liver injury and 
associated hepatic encephalopathy, have been observed in patients treated with 
trastuzumab emtansine.  Although there is evidence of drug-induced liver toxicity in 
patients treated with trastuzumab emtansine, its potential to cause acute severe liver 
injury with clinically meaningful changes in liver function is unclear as the observed 
cases were confounded by concomitant medications with known hepatotoxic potential 
and/or underlying conditions.  Nevertheless, a contributory role of trastuzumab 
emtansine in these cases cannot be excluded.  Therefore, acute severe liver injury (Hy’s 
law) remains an important potential risk with trastuzumab emtansine.  A Hy’s law case 
has the following components:

Aminotransferase enzymes are greater than 3ULN with concurrent elevation of 
serum total bilirubin to2ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase).

No other reason can be found to explain the combination of increased 
aminotransferases and serum total bilirubin, such as viral hepatitis A, B, or C; 
preexisting or acute liver disease; or another drug capable of causing the observed 
injury.

The finding should be serious as shown by gross jaundice, clinical disability, or need 
for hospital care and should be at least probably drug-induced (by trastuzumab 
emtansine).
Trastuzumab emtansine treatment in patients with serum transaminases3ULN and 
concomitant total bilirubin2ULN should be permanently discontinued.
Patients must have adequate and stable liver function:  hepatic transaminases 
(AST/ALT) and total bilirubin must be within acceptable range, as defined in the protocol, 
within 4 weeks prior to the first dose of trastuzumab emtansine.  Liver function will be 
monitored prior to each trastuzumab emtansine dose.  Cases of nodular regenerative 
hyperplasia (NRH) of the liver have been identified from liver biopsies in patients treated 
with trastuzumab emtansine and presenting with signs and symptoms of portal 
hypertension.  NRH is a rare liver condition characterized by widespread benign 
transformation of hepatic parenchyma into small regenerative nodules; NRH may lead to 
non-cirrhotic portal hypertension and also may be fatal.  NRH should be considered in 


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patients who develop clinical symptoms of portal hypertension and/or a cirrhosis-like 
pattern seen on CT scan of the liver but with normal transaminases and no other 
manifestations of cirrhosis or liver failure following long-term treatment with trastuzumab 
emtansine.  Diagnosis of NRH can only be confirmed by histopathology.
Upon diagnosis of NRH, trastuzumab emtansine treatment must be permanently 
discontinued.
5.1.1.4
Pulmonary Toxicity
Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute 
respiratory distress syndrome or fatal outcome, have been reported in clinical trials with 
trastuzumab emtansine.  Signs and symptoms include dyspnea, cough, fatigue, and 
pulmonary infiltrates. These events may or may not occur as sequelae of infusion 
reactions.  Patients with dyspnea at rest as a result of complications of advanced 
malignancy and comorbidities may be at increased risk of pulmonary events.  Treatment 
has included administration of steroids and oxygen, as well as study drug 
discontinuation.  Upon diagnosis of drug-related ILD/pneumonitis, trastuzumab 
emtansine treatment has to be permanently discontinued.
5.1.1.5
Infusion-Related Reactions/Hypersensitivity
Infusion-related reactions ([IRR] anaphylactoid/cytokine release reactions) and 
hypersensitivity (anaphylactic/allergic reactions) may occur with the administration of 
monoclonal antibodies and have been reported with trastuzumab emtansine.  Treatment 
with trastuzumab emtansine has not been studied in patients who had trastuzumab 
permanently discontinued due to an IRR/hypersensitivity; treatment with trastuzumab 
emtansine is not recommended for these patients.  
IRRs, characterized by one or more of the following symptoms:  flushing, chills, pyrexia, 
dyspnea, hypotension, wheezing, bronchospasm, and tachycardia-have been reported 
in clinical trials of trastuzumab emtansine.  In general, these symptoms were not severe.  
In most patients, these reactions resolved over the course of several hours to a day after 
the infusion was terminated.  Trastuzumab emtansine treatment should be interrupted in 
patients with severe IRRs.  Trastuzumab emtansine treatment should be permanently 
discontinued in the event of a life threatening IRR. Patients should be observed closely 
for hypersensitivity.  Serious, allergic/anaphylactic-like reactions have been observed in 
clinical trials with treatment of trastuzumab emtansine.  Administration of trastuzumab 
emtansine will be performed in a setting with access to emergency facilities and staff 
who are trained to monitor and respond to medical emergencies.  Patients will be 
observed closely for infusion-related/hypersensitivity reactions during and after each 
trastuzumab emtansine infusion for a minimum of 90 minutes after the first infusion and 
for a minimum of 30 minutes after subsequent infusions in the absence of 
infusion-related AEs.  Pre-medication is allowed according to standard practice 
guidelines.  In the event of a true hypersensitivity reaction (where severity of reaction 


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increases with subsequent infusions), trastuzumab emtansine treatment must be 
permanently discontinued.
5.1.1.6
Neurotoxicity
Peripheral neuropathy, mainly Grade 1 and predominantly sensory, has been reported in 
clinical trials of trastuzumab emtansine.  Treatment with trastuzumab emtansine should 
be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy 
until symptoms resolve or improve toGrade 2.  Patients should be examined for signs 
of peripheral neuropathy prior to each dose of trastuzumab emtansine.  Patients who 
experience Grade3 neurotoxicity in the form of peripheral neuropathy that does not 
resolve to Grade2 within 42 days after last dose received will be discontinued from 
study treatment.
5.1.1.7
Extravasation
In trastuzumab emtansine clinical studies, reactions secondary to extravasation have 
been observed.  These reactions were usually mild and comprised erythema, 
tenderness, skin irritation, pain, or swelling at the infusion site.  Rare reports of more 
severe events, such as cellulitis, pain (tenderness and burning sensation), and skin 
irritation, have been received as part of the continuing surveillance of trastuzumab 
emtansine safety.  These reactions have been observed more frequently within 24 hours 
of infusion.  Specific treatment for trastuzumab emtansine extravasation is unknown at 
this time.  The infusion site should be closely monitored for possible subcutaneous 
infiltration during drug administration.
5.1.2
Toxicities Associated with Trastuzumab
The anticipated safety risks and potential safety risks of trastuzumab are detailed in the 
local prescribing information.
5.1.3
Management of Specific Adverse Events
Guidelines for managing specific AEs are provided in Table 3.  For AEs not listed in 
Table 3, the following guidance should be used:  for Grade 3 non-hematologic AEs not 
adequately managed by standard medical intervention or for any Grade 4 non-
hematologic AE, study treatment should be held until recovery to Grade1.  A maximum 
dose delay of 42 days from the last administered dose of study drug will be allowed for 
recovery.  After appropriate recovery, trastuzumab emtansine may be resumed with one 
dose level reduction (e.g., trastuzumab emtansine reduced from 3.6 mg/kg to 3 mg/kg or 
from 3 mg/kg to 2.4 mg/kg).  Dose reduction levels for trastuzumab emtansine are 
shown in Table 2.  For patients who have an event while being treated with trastuzumab 
emtansine 2.4 mg/kg, study treatment will be discontinued.  The dose of trastuzumab 
emtansine, once reduced, may not be re-escalated.  There are no dose reductions for 
control arm therapy (trastuzumab).
Patients who discontinue trastuzumab emtansine may complete the duration of their 
intended study treatment up to 14 cycles of HER2-directed therapy with trastuzumab if 


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appropriate based on toxicity considerations and investigator discretion.  Patients who 
discontinue trastuzumab emtansine for cardiac toxicity, or other toxicity that may be 
attributed to the trastuzumab component (e.g., hypersensitivity, pneumonitis) may not 
continue on trastuzumab after discontinuation of trastuzumab emtansine.
Table 2
Dose Reduction for Trastuzumab Emtansine
Dose Level
Dose
0
3.6 mg/kg
-1
3.0 mg/kg
-2
2.4 mg/kg
Indication for further dose reduction
Off study treatment


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Table 3
Guidelines for Managing Specific Adverse Events
Event
Action to Be Taken
Infusion reactions (caused by cytokine 
release)/Hypersensitivity (allergic 
reactions)
Life threatening infusion-related 
reaction/Hypersensitivity (allergic 
reaction)
Stop infusion, study treatment permanently discontinued.
Supportive care with oxygen, -agonists, antihistamines, antipyretics, or corticosteroids may be used, 
as appropriate, at the investigator's discretion.
Patients should be monitored until complete resolution of symptoms.
Infusion-related or clinically 
significant hypotension
Stop infusion.  Administer supportive care with oxygen, -agonists, antihistamines, antipyretics, or 
corticosteroids, as appropriate, at the investigator’s discretion.  Monitor patients until complete resolution 
of symptoms.  May re-treat at investigator’s discretion.  In the event of a true hypersensitivity reaction (in 
which severity of reaction increases with subsequent infusions), trastuzumab emtansine treatment must 
be permanently discontinued.
Infusion-related symptoms 
(e.g., chills, fever)
Decrease infusion rate by 50% or interrupt infusion for patients who experience any other infusion-related 
symptoms (e.g., chills, fever).
When symptoms have completely resolved, infusion may be restarted at50% of prior rate and increased 
in 50% increments every 30 minutes as tolerated.  Infusions may be restarted at the full rate at the next 
cycle, with appropriate monitoring.
Supportive care with oxygen, -agonists, antihistamines, antipyretics, or corticosteroids may be used as 
appropriate at the investigator's discretion.
Premedication with corticosteroids, antihistamines, and antipyretics may be used before subsequent 
infusions at the investigator’s discretion.
Patients should be monitored until complete resolution of symptoms.
Hematologic toxicity
Grade3 hematologic toxicity 
(other than thrombocytopenia)
Withhold study treatment until recovery toGrade 1.  Weekly CBC assessments should 
be done until recovery, or as medically indicated.
A maximum dose delay of 42 days from the last administered dose to Grade1 or baseline will be 
allowed; otherwise, patients must be discontinued from study treatment.


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Table 3
Guidelines for Managing Specific Adverse Events (cont.)
Event
Action to Be Taken
Grade 2 or 3 
thrombocytopenia on day of 
scheduled treatment
Assess platelet counts weekly or as medically indicated until recovery.  Hold trastuzumab emtansine 
treatment until Grade 1.  Resume treatment without dose reduction.  If a patient requires 2 delays due to 
thrombocytopenia, consider reducing dose by one level.
Grade 4 thrombocytopenia 
at any time
Assess platelet counts weekly or as medically indicated until recovery.  Hold trastuzumab emtansine until 
Grade 1, then resume with one dose level reduction (i.e., from 3.6 mg/kg to 3 mg/kg or from 3 mg/kg to 
2.4 mg/kg) in subsequent cycles.  If event occurs with 2.4 mg/kg dose, discontinue study treatment.
Hepatotoxicity
ALT
For a Grade 2-3 ALT increase that occurs on the laboratory evaluation for cycle Day 1 or the planned day of 
dosing, hold trastuzumab emtansine until ALT recovers toGrade 1.  Resume with dose reduction by one 
level for Grade 2 or 3 elevations.  Grade 2-3 ALT elevations that are noted between cycles do not require 
dose delay or reduction unless ALT remains elevated (Grade 2) at the time of planned dosing.
For Grade 4 ALT increase, discontinue trastuzumab emtansine.  Repeat lab evaluation (within 24 hours) may 
be done to exclude lab error prior to discontinuing study treatment.
AST
For Grade 2 AST increase on the laboratory evaluation for cycle Day 1 or the planned day of dosing, hold 
trastuzumab emtansine until AST recovers toGrade 1.  Resume without dose reduction when recovered.
For Grade 3 AST increase on the laboratory evaluation for cycle Day 1 or the planned day of dosing, hold 
trastuzumab emtansine until AST recovers toGrade 1.  Resume with dose reduction by one level when 
recovered.
For Grade 4 AST increase, discontinue trastuzumab emtansine.  Repeat lab evaluation (within 24 hours) may 
be done to exclude lab error prior to discontinuing study treatment.


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Table 3
Guidelines for Managing Specific Adverse Events (cont.)
Event
Action to Be Taken
TBILI 
For TBILI1.0ULN to2.0ULN that occurs on the laboratory evaluation for cycle Day 1 or the day of 
planned dosing, hold trastuzumab emtansine until TBILI recovers to1.0ULN (or direct bilirubin recovers 
to1.0ULN for patients with Gilbert’s syndrome).  For TBILI elevations 1.0ULN to2.0ULN, resume 
when recovered with a one level dose reduction.
For TBILI2ULN at any time (or direct bilirubin2ULN for Gilbert’s syndrome), discontinue 
trastuzumab emtansine and report the event as an SAE (if applicable) or non-serious expedited AE (if 
applicable).
Assess AST, ALT, and TBILI weekly or as medically indicated until recovery.  Allow a maximum dose delay 
of 42 days from the last administered dose to recovery as described above or otherwise discontinue study 
treatment.  
Nodular Regenerative Hyperplasia
For any clinical signs of liver dysfunction, discontinue trastuzumab emtansine and have the patient 
evaluated by a hepatologist.  If there are signs of portal hypertension (e.g., ascites and/or varices) and a 
cirrhosis-like pattern is seen on CT scan of the liver, the possibility of NRH should be considered.  For liver 
biopsy guidelines, please see Appendix 8.  Trastuzumab emtansine should be discontinued in the event of 
a diagnosis of NRH.
Neurotoxicity
Grade3 peripheral 
neuropathy
Discontinue trastuzumab emtansine if event does not resolve to Grade2 or baseline value within 42 days 
after the last administered dose.
Cardiotoxicity
LVSD
Refer to Figure 2 for the algorithm for continuation and discontinuation of study treatment on the basis of 
asymptomatic LVEF assessment.
Grade 34 LVSD or Grade 34 
heart failure
Discontinue study treatment.
Grade 2 heart failure 
accompanied by LVEF 45%
Discontinue study treatment.


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Table 3
Guidelines for Managing Specific Adverse Events (cont.)
Event
Action to Be Taken
Interstitial lung disease
Grade 3-4 pneumonitis
Discontinue study treatment regardless of attribution
Grade 1-2 pneumonitis
Discontinue study treatment if not radiotherapy-related.  For symptomatic (Grade 2) radiotherapy-related 
pneumonitis, discontinue if not resolving with standard treatment (e.g., steroids).  Relationship to 
radiotherapy should be determined on the basis of timing and location of radiographic abnormalities 
relative to the radiation treatment.
Upon diagnosis of drug-related ILD/pneumonitis, trastuzumab emtansine treatment has to be permanently 
discontinued.  Patients discontinued from trastuzumab emtansine for pneumonitis may not continue study 
treatment with trastuzumab.
Radiotherapy-related skin toxicity
Grade3-4
Do not administer study treatment until recovery to Grade1.
AEadverse event; CBCcomplete blood count; ILD interstitial lung disease; LVEF left ventricular ejection fraction; LVSDleft ventricular 
systolic dysfunction; NRHnodular regenerative hyperplasia; SAEserious adverse event; ULN upper limit of normal. 




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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording AEs, including serious 
adverse events (SAEs) and non-serious AEs of special interest; measurement of 
protocol-specified safety laboratory assessments; measurement of protocol-specified 
vital signs; and other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an AE is any untoward 
medical occurrence in a clinical investigation subject administered a pharmaceutical 
product, regardless of causal attribution.  An AE can therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

AEs that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., screening invasive procedures such as 
biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
An SAE is any AE that meets any of the following criteria:

Fatal (i.e., the AE actually causes or leads to death)

Life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death)
This does not include any AE that had it occurred in a more severe form or was 
allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions)


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
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an AE (rated as mild, moderate, or severe, or according to NCI CTCAE criteria; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings).
Severity and seriousness need to be independently assessed for each AE recorded on 
the eCRF.
Serious AEs are required to be reported by the investigator to the Sponsor within 24 
hours after learning of the event (see Section 5.4.2 for reporting instructions).
5.2.3
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor)
Non-serious AEs of special interest are required to be reported by the investigator to the 
Sponsor within 24 hours after learning of the event (see Section 5.4.2 for reporting 
instructions).  AEs of special interest for this study include the following:

Cases of increased serum ALT and/or AST in combination with either an increased 
serum TBILI or clinical jaundice, as defined in Section 5.3.5.6

Suspected transmission of an infectious agent by the study drug where any 
organism, virus, or infectious particle (e.g., prion protein transmitting, transmissible 
spongiform encephalopathy), pathogenic or non pathogenic, is considered an 
infectious agent.  A transmission of an infectious agent may be suspected from 
clinical symptoms or laboratory findings indicating an infection in a patient exposed 
to a medicinal product.  This term ONLY applies when a contamination of the study 
drug is suspected, NOT for infections supported by the mode of action (e.g., 
immunosuppression). 
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all AEs (see Section 5.2.1 for definition) 
are recorded on the AE eCRF and reported to the Sponsor in accordance with 
instructions provided in this section and in Section 5.4 through Section 5.6.
For each AE recorded on the AE eCRF, the investigator will make an assessment of 
seriousness (see Section 5.2.2 for seriousness criteria), severity (see Section 5.3.3), and 
causality (see Section 5.3.4).  


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5.3.1
Adverse Event Reporting Period
Investigators will seek information on AEs at each patient contact.  All AEs, whether 
reported by the patient or noted by study personnel, will be recorded in the patient’s 
medical record and on the AE eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
SAEs caused by a protocol-mandated intervention should be reported (e.g., SAEs 
related to invasive procedures such as biopsies).
After initiation of study drug, all AEs, regardless of relationship to study drug, will be 
reported until 30 days after the last dose of study drug.  After this period, investigators 
should report any deaths, SAEs, or other AEs of concern that are believed to be related 
to prior treatment with study drug or study procedures (see Section 5.6).   
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all patient evaluation time points.  Examples of non-directive questions 
include the following:
“How have you felt since your last clinic visit?”
“Have you had any new or changed health problems since you were last here?” 
5.3.3
Assessment of Severity of Adverse Events
The AE severity grading scale for the NCI CTCAE Version 4.0 will be used for assessing 
AE severity.  Table 4 will be used for assessing severity for AEs that are not specifically 
listed in the NCI CTCAE.


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Table 4
Adverse Event Severity Grading Scale
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the NCI CTCAE, Version 4.0, which can be found at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as an SAE (see 
Section 5.4.2 for reporting instructions), per the definition of SAE in Section 5.2.2.
d Grade 4 and 5 events must be reported as SAEs (see Section 5.4.2 for reporting 
instructions), per the definition of SAE in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an AE is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 


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5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording AEs on 
the AE eCRF.  Avoid colloquialisms and abbreviations.
Only one AE term should be recorded in the event field on the AE eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the AE 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 AE eCRF.  If a diagnosis is 
subsequently established, all previously reported AEs based on signs and symptoms 
should be nullified and replaced by one AE report based on the single diagnosis, with a 
starting date that corresponds to the starting date of the first symptom of the eventual 
diagnosis.
5.3.5.2
AEs Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events.  However, medically significant AEs occurring secondary to 
an initiating event that are separated in time should be recorded as independent events 
on the AE eCRF.  For example: 

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by a mild, non-serious infection, only neutropenia 
should be reported on the eCRF.

If neutropenia is accompanied by a severe or serious infection, both events should 
be reported separately on the eCRF.
All AEs should be recorded separately on the AE eCRF if it is unclear as to whether the 
events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation time points.  Such events should only be recorded once on the AE eCRF.  
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to reflect the most extreme severity any time the event worsens.  If the event becomes 
serious, the AE eCRF should be updated to reflect this.
A recurrent AE is one that resolves between patient evaluation time points and 
subsequently recurs.  Each recurrence of an AE should be recorded separately on the 
AE eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an AE.  A laboratory test result should be
reported as an AE if it meets any of the following criteria:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Clinically significant in the investigator’s judgment 
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 AE.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALK and bilirubin 5 times the ULN associated with cholecystitis), only the diagnosis 
(i.e., cholecystitis) should be recorded on the AE eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the AE 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 AE.  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 not be repeatedly recorded on the AE eCRF, unless the etiology changes.  The 
initial severity of the event should be recorded, and the severity or seriousness should 
be updated any time the event worsens.


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5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an AE.  A vital sign result should be reported 
as an AE if it meets any of the following criteria:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an AE.
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 
AE eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the AE eCRF, unless the etiology changes.  The 
initial severity of the event should be recorded, and the severity or seriousness should 
be updated any time the event worsens.
5.3.5.6
Hepatotoxicity
The finding of an increased serum ALT or AST (3ULN) in combination with either an 
increased serum TBILI (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  
Therefore, investigators must report as an AE the occurrence of either of the following:

Treatment-emergent serum ALT or AST3ULN in combination with serum 
TBILI2ULN

Treatment-emergent serum ALT or AST3ULN in combination with clinical 
jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the AE eCRF (see Section 5.3.5.1) and 
reported to the Sponsor within 24 hours after learning of the event, either as a SAE or a 
non-serious AE of special interest (see Section 5.4.2).
NRH, whether or not accompanied by liver laboratory abnormalities, should be reported 
to the Sponsor as a SAE.


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5.3.5.7
Abnormal Left Ventricular Ejection Fraction 
Symptomatic left ventricular systolic dysfunction (otherwise referred to as heart failure) 
should be reported as an SAE if the event fulfills SAE criteria from Section 5.2.2.  If the 
diagnosis is heart failure it should be reported as such and not as individual signs and 
symptoms thereof.
Heart failure should be graded according to NCI-CTCAE v 4.0 for "heart failure" 
(Grade 2, 3, 4 or 5) and in addition according to the NYHA classification.
Heart failure occurring during the study and up to 12 years after last administration of 
study drug must be reported irrespective of causal relationship and followed until one of 
the following occurs:  resolution or improvement to baseline status, no further 
improvement can be expected, or death.
Asymptomatic Left Ventricular Systolic Dysfunction
Asymptomatic declines in LVEF should generally not be reported as AEs since LVEF 
data are collected separately in the eCRF.  Exceptions to this rule are as follows:

An asymptomatic decline in LVEF10 percentage-points from baseline to an 
LVEF50% must be reported as an AE with the term of ‘ejection fraction decreased’ 
as per NCI-CTCAE v4.0 and, in addition, a comment in the AE comments field 
should confirm that this was asymptomatic.

An asymptomatic decline in LVEF requiring treatment delay or leading to 
discontinuation of trastuzumab emtansine or trastuzumab must also be reported.
5.3.5.8
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol-
specified AE reporting period (see Section 5.3.1) that are attributed by the investigator 
solely to recurrence or progression of breast cancer should be recorded only on the 
Study Completion/Discontinuation eCRF.  All other on-study deaths, regardless of 
relationship to study drug, must be recorded on the AE eCRF and immediately reported 
to the Sponsor (see Section 5.4.2).  An independent monitoring committee will monitor 
the frequency of deaths from all causes.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the AE eCRF.  Generally, only one such event should be reported.    If the 
cause of death is unknown and cannot be ascertained at the time of reporting, 
“unexplained death” should be recorded on the AE eCRF.  If the cause of death later 
becomes available (e.g., after autopsy), “unexplained death” should be replaced by the 
established cause of death.  The term “sudden death” should not be used unless 
combined with the presumed cause of death (e.g., “sudden cardiac death”).


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During post-study treatment survival follow-up, deaths attributed to recurrence or 
progression of breast cancer should be recorded only on the Survival eCRF. 
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study.  When recording such 
events on the AE eCRF, it is important to convey the concept that the preexisting 
condition has changed by including applicable descriptors (e.g., “more frequent 
headaches”).
5.3.5.10
Lack of Efficacy or Worsening of Breast Cancer
Events that are clearly consistent with the expected pattern of recurrence or progression 
of the underlying disease should not be recorded as AEs.  These data will be captured 
as efficacy assessment data only.  In most cases, the expected pattern of recurrence or 
progression will be based on radiologic and biopsy criteria.  In rare cases, the 
determination of clinical progression will be based on symptomatic deterioration.  
However, every effort should be made to document recurrence or progression using 
objective criteria.  If there is any uncertainty as to whether an event is due to disease 
recurrence or progression, it should be reported as an AE.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as a SAE (per the definition of SAE in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a SAE:  

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not suffered an AE

Hospitalization due solely to recurrence or progression of the underlying cancer


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5.3.5.12
Overdoses
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied.  An overdose or incorrect administration of study drug is not 
an AE unless it results in untoward medical effects.  
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF.
All AEs associated with an overdose or incorrect administration of study drug should be 
recorded on the AE eCRF.  If the associated AE fulfills serious criteria or qualifies as an 
adverse event of special interest, the event should be reported to the Sponsor within 24 
hours after learning of the event (see Section 5.4.2).
5.3.5.13
Patient-Reported Outcome Data
AE reports will not be derived from PRO data.  However, if any patient responses 
suggestive of a possible AE are identified during site review of the PRO questionnaires, 
site staff will alert the investigator, who will determine if the criteria for an AE have been 
met and will document the outcome of this assessment in the patient's medical record 
per site practice.  If the event meets the criteria for an AE, it will be reported on the AE 
eCRF.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
The investigator must report the following events to the Sponsor within 24 hours after 
learning of the event, regardless of relationship to study drug:

SAEs

Non-serious AEs of special interest (refer to Section 5.2.3)

Pregnancies
The investigator must report new significant follow-up information for these events to the 
Sponsor within 24 hours after becoming aware of the information.  New significant 
information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious AEs to the 
local health authority and IRB/EC.


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5.4.1
Emergency Medical Contacts
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk and 
Medical Monitor contact information will be distributed to all investigators (see "Protocol 
Administrative and Contact Information & List of Investigators"). 
5.4.2
Reporting Requirements for Serious Adverse Events and Non-
Serious Adverse Events of Special Interest
For reports of SAEs and non-serious AEs of special interest, investigators should record 
all case details that can be gathered within 24 hours on the AE eCRF and submit the 
report via the electronic data capture (EDC) system.  A report will be generated and sent 
to Roche Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, a paper SAE/Non-Serious AE of 
Special Interest CRF and Fax Coversheet should be completed and faxed to Roche 
Safety Risk Management or its designee within 24 hours after learning of the event, 
using the fax numbers provided to investigators (see "Protocol Administrative and 
Contact Information & List of Investigators").  Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system.  
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 final
dose of study drug.  A Pregnancy Report eCRF should be completed by the investigator 
within 24 hours after learning of the pregnancy and submitted via the EDC system.  A 
pregnancy report will automatically be generated and sent to Roche Safety Risk 
Management.  Pregnancy should not be recorded on the AE eCRF.  The investigator 
should 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.
Additional information on any trastuzumab emtansine-exposed pregnancy and infant will 
be requested by Roche Drug Safety at specific time points (i.e., after having received the 
initial report, 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 the event that the EDC system is unavailable, a Pregnancy Report worksheet and 
Pregnancy Fax Coversheet should be completed and faxed to Roche Safety Risk 
Management or its designee within 24 hours after learning of the pregnancy, using the 


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fax numbers provided to investigators (see "Protocol Administrative and Contact 
Information & List of Investigators").
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
7 months after the final dose of study drug.  A Pregnancy Report eCRF should be 
completed by the investigator within 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.
Male patients whose partners are pregnant must use condoms or truly refrain from 
sexual activity for the duration of the pregnancy.
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1.
5.4.3.3
Abortions
Any spontaneous abortion should be classified as a serious AE (as the Sponsor 
considers spontaneous abortions to be medically significant events), recorded on the AE 
eCRF, and reported to the Sponsor within 24 hours after learning of the event (see 
Section 5.4.2).
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient exposed to study drug should be classified as a SAE, recorded on the 
AE eCRF, and reported to the Sponsor within 24 hours after learning of the event (see 
Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the investigator, the patient is lost to follow up, 
or the patient withdraws consent.  Every effort should be made to follow all serious AEs 
considered to be related to study drug or trial-related procedures until a final outcome 
can be reported.


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During the study period, resolution of AEs (with dates) should be documented on the AE 
eCRF and in the patient’s medical record to facilitate source data verification.  If, after 
follow-up, return to baseline status or stabilization cannot be established, an explanation 
should be recorded on the AE eCRF. 
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 5.4.3.1.
5.5.2
Sponsor Follow-Up
For SAEs, non-serious AEs 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.  Pathologic material, if already obtained to 
evaluate the event, may be requested for review by the clinical events committee.
5.6
POST-STUDY ADVERSE EVENTS
At the study treatment completion/early termination visit, the investigator should instruct 
each patient to report to the investigator any subsequent AEs that the patient’s personal 
physician believes could be related to prior study drug treatment or study procedures.  
The investigator should notify the Sponsor of any death, SAE, or other AE of concern 
occurring at any time after a patient has discontinued study treatment or study 
participation if the event is believed to be related to prior study drug treatment or study 
procedures.  The Sponsor should also be notified if the investigator becomes aware of 
the development of cancer or a congenital anomaly/birth defect in a subsequently 
conceived offspring of a patient that participated in this study.
The investigator should report these events to Roche Safety Risk Management on the 
AE eCRF.  If the AE eCRF is no longer available, the investigator should report the 
event directly to Roche Safety Risk Management via telephone (see "Protocol 
Administrative and Contact Information & List of Investigators").
During post-study treatment survival follow-up, deaths attributed to recurrence or 
progression of breast cancer should be recorded only on the Survival eCRF.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the IB as a reference.


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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.
A DMC will monitor the incidence of these expected events during the study.  An 
aggregate report of any clinically relevant imbalances that do not favor the test product 
will be submitted to health authorities.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
6.1
DETERMINATION OF SAMPLE SIZE
The sample size of the study is primarily driven by the analysis of IDFS.  To detect a HR 
of 0.75 in IDFS (a 6.5% improvement in 3-year IDFS from 70% in the control arm to 
76.5% in the trastuzumab emtansine arm), approximately 384 IDFS events will be 
required to achieve 80% power at a 2-sided significance level of 5%.  Approximately 
1484 patients will be enrolled in the study.
The study is expected to be fully enrolled around 35 months after the first patient enrolls 
in the study (FPI).  The final IDFS analysis will be performed after approximately 
384 events have occurred, which is projected to be approximately 107 months from FPI.
With the study sample size of 1484 patients and approximately 12 years of follow-up 
from FPI, this study has about 43% power to detect an HR of 0.8 (a 2.8% improvement 
in 3-year OS from 85% in the control arm to 87.8% in the trastuzumab emtansine arm) at 
a 2-sided significance level of 5%.
6.2
SUMMARIES OF CONDUCT OF STUDY
Patient enrollment will be tabulated by study site for each treatment arm.  Patient 
disposition and reasons for discontinuations will be summarized by treatment arm for all 
randomized patients.  Compliance with protocol-specified schedule of disease status 
clinical assessments will also be summarized by treatment arm.  In addition, protocol 
and eligibility violations will be summarized by treatment arm.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
The evaluation of treatment group comparability between the 2 treatment arms will 
include summaries of demographics and baseline characteristics, including age, sex, 
race, breast cancer characteristics, medical history, and prior cancer treatment.  
Descriptive statistics (mean, median, standard deviation, 25th percentile, 75th percentile, 
and range) will be presented for continuous variables, and proportions will be presented 
for categorical variables.


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6.4
EFFICACY ANALYSES
The randomized patient population will form the basis for all efficacy analyses.  In all 
efficacy analyses, following the intent-to-treat principle, patients will be included in the 
treatment group to which they are randomized by the IVRS/IWRS.
6.4.1
Primary Efficacy Endpoint
The primary efficacy variable is IDFS, defined as the time between randomization and 
date of first occurrence of an IDFS event (as described in Section 3.4.1).  Patients who 
have not had an event will be censored at the date they are last known to be alive and 
event free on or prior to the clinical data cutoff date.
The log-rank test, stratified by the protocol-defined stratification factors (clinical stage at 
presentation [inoperable vs. operable]; hormone receptor status [ER or PgR positive vs. 
ER and PgR negative/unknown]; preoperative HER2-directed therapy [trastuzumab vs. 
trastuzumab plus additional HER2-directed agent(s)]; and pathologic nodal status 
evaluated after preoperative therapy [node positive vs. node negative/not done]), will be 
used to compare IDFS between the 2 treatment arms.  The unstratified log-rank test 
results will also be provided as a sensitivity analysis.  If at the time of analysis it is 
deemed that the smallest strata per arm is5 patients to conduct robust stratified 
analyses, unstratified analyses will be used as the primary analysis.  Cox proportional 
hazards model, stratified by the protocol-defined stratification factors, will be used to 
estimate the HR between the 2 treatment arms and its 95% CI.  The Kaplan-Meier 
approach will be used to estimate 3-year IDFS rates and corresponding 95% CIs for 
each treatment arm.
6.4.2
Secondary Efficacy Endpoints
Secondary endpoints include IDFS including second primary non-breast cancer; DFS, 
OS, and DRFI (as defined in Section 3.4.2).  Patients who have not had an event will be 
censored at the date that they are last known to be event free on or prior to the clinical 
data cutoff date.
Secondary endpoints will be analyzed in a similar manner as the primary endpoint to 
estimate 3-year event rates (and 5-year survival rate for OS) for each treatment arm and 
the HR between the 2 treatment arms with 95% CI.
A testing hierarchy will be used to control the overall type I error rate at 5%.  If the 
primary endpoint IDFS reaches statistical significance, the formal hypothesis testing of 
OS will be performed.  More details of OS interim analyses are specified in Section 6.9.
6.5
SAFETY ANALYSES
Patients who receive any amount of study treatment will be included in the safety 
analyses.  Safety results will be summarized based on the treatment patients actually 


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receive.  Specifically, a patient will be included in the trastuzumab emtansine arm in 
safety analyses if the patient receives any trastuzumab emtansine.
The safety of trastuzumab emtansine will be assessed through treatment exposure, 
summaries of AEs, SAEs, cardiac-specific AEs, LVEF measurements, and laboratory 
test results (including thrombocytopenia and transaminases).
Study treatment exposure, such as treatment duration, number of cycles, dose intensity, 
and dose modification (including dose delay, dose reduction, etc.) will be summarized for 
each treatment arm with descriptive statistics.  Reasons for treatment discontinuation will 
also be summarized. 
Verbatim descriptions of AEs will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms and graded according to the NCI CTCAE, 
Version 4.0.  All AEs, SAEs, AEs leading to death, and AEs leading to study treatment 
discontinuation, occurring on or after the first dose of study treatment (i.e., treatment-
emergent AEs), will be summarized by NCI CTCAE grade.  For repeated events of 
varying severity in an individual patient, the highest grade will be used in the summaries.  
Deaths and causes of death will be summarized.
Laboratory toxicities will be summarized by NCI CTCAE grade for each treatment arm 
with shift tables.
Incidence of cardiac events, defined as death from cardiac cause or severe CHF (NYHA 
Class III or IV) with a decrease in LVEF of 10 percentage points or more from baseline 
to an LVEF of50%, will be summarized by treatment arm.  Other cardiac-related 
events (e.g., any symptomatic CHF associated with a 10% drop in LVEF to50%; 
asymptomatic declines in LVEF requiring dose delay) will also be summarized.  Change 
in LVEF over time will be summarized by treatment arm.
Incidence of hepatotoxicity events will be summarized by treatment arm.  Additional 
analyses of liver function laboratory tests (LFTs) will also be performed. 
For patients who continue on trastuzumab after discontinuation of trastuzumab 
emtansine due to toxicity before 14 cycles, exploratory safety analyses will be 
performed.  Summary of trastuzumab exposure, SAEs, cardiac-specific AEs, and NCI 
CTCAE Grade 3 or above AEs will be provided.  Other exploratory safety analyses 
differentiating 2 treatment phases for these patients will be performed as appropriate.
6.6
PATIENT-REPORTED OUTCOME ANALYSES
HRQOL data will be captured using the following questionnaires:  the EORTC QLQ-C30, 
the breast cancer module QLQ-BR23, and the EQ-5D.


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Summary statistics (mean, standard deviation, median, 25th and 75th percentiles, and 
range) of absolute scores of the QLQ-C30 and QLQ-BR23 scales and their changes from 
baseline will be summarized at each assessment time point for the 2 treatment arms.  
Only patients with a baseline assessment and at least one post-baseline assessment will 
be included in this analysis.  Repeated-measures mixed-effects models will be used to 
explore the treatment effect changes over time and treatment-by-time interaction.
The EuroQol EQ-5D is a five-item questionnaire with three categories (no problem, 
moderate problem, severe problems).  Scoring and analysis will be reported in a 
separate document.  The EQ-5D data analysis will be performed to support 
reimbursement dossiers and will not be included in the clinical study report (CSR).
6.7
PHARMACOKINETIC ANALYSES
Blood and serum samples for measurement of trastuzumab emtansine, total 
trastuzumab, and DM1 will be obtained from patients randomized to the trastuzumab 
emtansine arm.  Individual and mean trastuzumab emtansine and total trastuzumab 
serum levels and DM1 plasma concentrations versus time data will be plotted, tabulated, 
and summarized (e.g., mean, standard deviation, coefficient of variation, median, 
minimum, maximum, and range).  Interpatient variability and drug accumulation after 
multiple dosing will be evaluated.  Compartmental, noncompartmental, and/or population 
approaches will be considered as appropriate.  Additional PK analyses and exposure-
efficacy and exposure-safety (ALT/AST, platelet, etc.) analyses will be conducted in 
conjunction with analyses of data from other studies, as appropriate.  Any remaining 
plasma samples may be used for measurement of trastuzumab emtansine metabolites 
as an exploratory assessment, and the results will be plotted, tabulated, and 
summarized.
Blood and serum samples for measurement of trastuzumab will be obtained from 
patients randomized to the trastuzumab arm.  Individual and mean trastuzumab serum 
concentrations versus time data will be plotted, tabulated, and summarized (e.g., mean, 
standard deviation, coefficient of variation, median, minimum, maximum, and range).
6.8
EXPLORATORY ANALYSES
Exploratory analyses will be performed to explore the correlation between biomarker, 
ATA, and clinical outcomes as appropriate.
6.9
INTERIM ANALYSES
6.9.1
Interim Efficacy Analyses
One interim analysis of IDFS and two interim analyses of OS are planned.
The interim efficacy analysis of IDFS is planned after 67% of the targeted IDFS events 
have occurred, which is estimated to be approximately 48 months after the first patient is 
enrolled in the study.  If the accrual rate or event rate are different from expected, the 


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timing of the interim analysis may be delayed such that the interim analysis will only take 
place after all patients have enrolled and have completed treatment.
At this interim analysis, IDFS will be tested at the significance level determined using the 
LanDeMets alpha spending function with an O’BrienFleming boundary so that the 
overall 2-sided type I error rate will be maintained at the 5% level for the IDFS primary 
endpoint.
Table 5 presents a summary of the planned IDFS analyses, the efficacy stopping 
boundary, and the estimated timing of these analyses.
Table 5
Summary of Planned Analyses of Invasive Disease-Free Survival
Analysis of IDFS
No. of events
Efficacy Stopping 
Boundary a
Estimated Timing b
Interim 
257
p0.0124 or observed 
HR0.732
48 months
Final
384
p0.0462 or observed 
HR0.816
107 months
HRhazard ratio; IDFSinvasive disease-free survival.
a p-value will be based on 2-sided stratified log-rank test.
b Time from the enrollment of first patient to data cutoff.
The interim analysis will be performed by the iDCC statistician and the results will be 
presented to the iDMC by the iDCC statistician.
The purpose of the interim analysis is to evaluate whether there is an overwhelming 
difference in the efficacy observed in the trastuzumab emtansine arm compared with the 
trastuzumab arm in terms of IDFS.  If the test is not significant, the study will continue as 
planned.  If the test is significant, the iDMC may recommend releasing the primary 
endpoint results before the targeted number of 384 events is reported.  In this latter 
situation, the Sponsor will be unblinded to the study results and a full data package 
would be prepared for discussion with regulatory authorities.  The study will continue 
until 12 years of follow-up and IDFS analysis will be updated when 384 IDFS events 
have occurred.  Two formal interim OS analyses and one final OS analysis are planned:  
the first OS interim analysis will be performed at the time of the interim IDFS analysis 
(approximately 48 months from FPI) if the interim IDFS analysis crosses the boundary; 
the second interim OS analysis will be performed at the time of the final IDFS analysis 
(approximately 107 months from FPI; in the case where the interim IDFS analysis 
crosses the boundary, the second OS interim analysis will be performed when 384 IDFS 
events have occurred).  The final OS analysis will be performed at the end of 12 years of 
follow-up.  The Sponsor will perform these analyses.  A survival data sweep will be 
conducted prior to each analysis.


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The overall type I error will be controlled at 0.05 for the formal OS interim analyses and 
final OS analysis using the LanDeMets alpha spending function with an 
O’BrienFleming boundary.  The boundaries used at each interim and final OS analysis 
will depend on the timing of the analyses and the number of death events actually 
included in the analyses.
Table 6 presents a summary of the planned OS analyses, the efficacy stopping 
boundary, and the estimated timing of these analyses.
Table 6
Summary of Planned Analyses of Overall Survival
Analysis Of OS
No. of 
Events
Efficacy Stopping Boundary a
Estimated Timing b
Interim 1 (at interim IDFS)
98
p 0.0005 or observed HR 0.494 
48 months
Interim 2 (at final IDFS)c
183
p 0.0143 or observed HR 0.696
107 months 
Finalc
263
p 0.0456 or observed HR 0.781
144 months
HRhazard ratio; IDFSinvasive disease-free survival; OSoverall survival.
a p-value will be based on 2-sided stratified log-rank test.
b Time from the enrollment of first patient to data cutoff.
c Estimated number of events. Efficacy boundaries will be calculated based on the actual 
number of events at the time of analysis.
6.9.2
Interim Safety Analyses
An iDMC will monitor accumulating patient safety data at least once approximately every 
6 months until the last patient has completed study treatment.  In addition, data on SAEs 
and deaths will be monitored by the iDMC at least once approximately every 3 months 
during this period.  At each iDMC review, relevant safety information from ongoing 
trastuzumab emtansine studies will be provided to the iDMC.
After the first 600 patients have been randomized and followed up for 3 months 
(approximately 21 months after FPI), the iDMC will perform an interim safety analysis 
regarding death and hepatic events.  The Clinical Events Committee will communicate 
their findings regarding cardiac and hepatic events to the iDMC to aid iDMC review.
If an absolute increase of3% in the percentage of death (from any cause) is observed 
in the trastuzumab emtansine arm compared with the trastuzumab arm, the iDMC will 
consider recommending holding enrollment for further data review, stopping, or 
modifying the trial.
If the true difference in the percentage of death is3% (e.g., 2% vs. 6%) then there is 
approximately 70% chance of observing an absolute difference of3% at the interim 
with 600 patients. Table 7 presents the probability of observing more than 3% increase 
in the percentage of death in trastuzumab emtansine arm compared with the 
trastuzumab arm with different assumption on the percentage of death in 2 arms.


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Table 7
Probability of Observing3% Increase of Death
Percentage of death
Probability of observing3% increase
Trastuzumab
(N300)
Trastuzumab emtansine
(N300)
2%
2%
0.00
2%
3%
0.05
2%
4%
0.20
2%
5%
0.45
2%
6%
0.70
If an absolute increase of3% in the percentage of Hy’s law cases (confirmed by the 
independent clinical events committee) is observed in the trastuzumab emtansine arm 
compared with the control arm, the iDMC will consider recommending holding enrollment 
for further data review, stopping, or modifying the trial.
If the true difference in the percentage of confirmed Hy’s law cases is3% (e.g., 0.33% 
vs. 3.67%) then there is approximately 54% chance of observing an absolute difference 
of 3% at the interim with 600 patients. Table 8 presents the probability of 
observing 3% increase in the percentage of Hy’s law cases in the trastuzumab 
emtansine arm compared with the trastuzumab arm with different assumptions on the 
number of Hy’s law cases in 2 arms.
Table 8
Probability of Observing3% Increase of Confirmed Hy’s Law 
Cases
Number of confirmed Hy’s law cases (%)
Probability of observing3% increase
Trastuzumab
(N300)
Trastuzumab emtansine
(N300)
1 (0.33%)
4 (1.33%)
<0.01
1 (0.33%)
6 (2%)
0.05
1 (0.33%)
8 (2.67%)
0.19
1 (0.33%)
10 (3.33%)
0.43
1 (0.33%)
11 (3.67%)
0.54
1 (0.33%)
12 (4%)
0.66
The iDMC will work according to the guidelines defined in the iDMC Charter.  The iDMC 
Charter will contain details regarding the frequency of meetings, guidelines for decision 
making, and process for requesting further information.  The iDMC members will review 
and sign off on the charter before the first review.


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7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will supply electronic eCRF specifications for this study.  An academic
research organization (NSABP) will be responsible for data management of this study, 
including quality checking of the data.  Data entered manually will be collected via EDC 
using eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event 
of discrepant data, the NSABP will request data clarification from the sites, which the 
sites will resolve electronically in the EDC system.
The NSABP will produce a Data Quality Plan that describes the quality checking to be 
performed on the data. 
The Sponsor will perform oversight of the data management of this study, including 
approval of the NSABP’s data management plans and specifications.  Data will be 
transferred electronically from the NSABP 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 NSABP and records retention for the study data 
will be consistent with the NSABP’s standard procedures.
Electronic patient-reported outcome (ePRO) data will be collected electronically.  The 
device is designed for entry of data in a way that is attributable, secure, and accurate, in 
compliance with FDA regulations for electronic records (21 CFR Part 11).  The ePRO 
device data are available for view access only via secure access.  Only identified and 
trained users may view the data, and their actions become part of the audit trail.  
The Sponsor will have view access only.  System backups for data stored by the 
Sponsor and records retention for the study data will be consistent with the Sponsor’s 
standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS
eCRFs are to be completed using the NSABP-designated EDC system.  Sites will 
receive training and a 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.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
PRO data will be collected electronically.  The data will be transmitted electronically to a 
centralized database at the ePRO vendor.  The data can be reviewed by site staff via 
secure access to a web server.  Once the study is complete, the ePRO data, audit trail, 


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and trial and system documentation will be archived.  The investigator will receive 
patient data for the site in both human- and machine-readable formats on an archival-
quality compact disc that must be kept with the study records as source data.  
Acknowledgement of receipt of the compact disc is required.  In addition, the Sponsor 
will receive all patient data in a machine-readable format on a compact disc.
7.4
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, PROs, 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 7.6.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The investigational site must also allow 
inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
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.


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7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO 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.
The Sponsor will retain study data for 25 years after the final Clinical Study Report 
has been completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
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 EU/EEA will comply 
with the EU Clinical Trial Directive (2001/20/EC) and applicable local, regional, and 
national laws.
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the “Consent Forms”) before IRB/EC 
submission.  The final IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Patients will be told that they are free to refuse to participate and may 


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withdraw their specimens at any time and for any reason during the storage period.  A 
separate, specific signature will be required to document a patient's agreement to allow 
any remaining specimens to be used for exploratory research.  Patients who decline to 
participate will check a “no” box in the appropriate section and 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.
For sites in the United States, 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 
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 


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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 AEs to the Sponsor, investigators must 
comply with requirements for reporting SAEs 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 only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. 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., last patient, last 
visit).
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 


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amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, which includes an audit trail containing a complete record of all changes 
to data.
9.2
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.
9.3
ADMINISTRATIVE STRUCTURE
This study will have a Steering Committee (SC) that will provide guidance on the 
protocol and study design and the statistical analysis plan and will provide guidance on 
review of any relevant study-related documents or procedures in order to be confident 
that the data will be collected in a timely fashion and will be accurate and complete.  A 
separate SC charter will outline the committee’s composition, meeting timelines, and 
members’ roles and responsibilities.  Additionally, the SC will be kept apprised of all 
relevant efficacy and safety data from this and related clinical trials.
In addition, the study will have an iDMC and clinical events committee.
9.4
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
prior to submission.  This allows the Sponsor to protect proprietary information and to 
provide comments based on information from other studies that may not yet be available 
to the investigator.
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.


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9.5
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  The Sponsor is responsible 
for promptly informing the IRB/EC of any amendments to the protocol.  Approval must be 
obtained from the IRB/EC before implementation of any changes, except for changes 
necessary to eliminate an immediate hazard to patients or changes that involve logistical 
or administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
REFERENCES
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research 
and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in 
international clinical trials in oncology. J Natl Cancer Inst 1993;85:365–376.
Buzdar AU, Ibrahim NK, Francis D, et al. Significantly higher pathologic complete 
remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and 
epirubicin chemotherapy: results of a randomized trial in human epidermal growth 
factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005;23:3676–
3685.
Dang, C, Gianni, L, Romieu, G, et al. Cardiac Safety Data From a Phase 2 Study of 
Trastuzumab Emtansine (T-DM1) Following the Completion of Anthracycline-
Based Chemotherapy as Adjuvant or Neoadjuvant Therapy for Early-Stage HER2-
Positive Breast Cancer. ASCO 2012 abstract.
Ellis P, Barrios C, Eiermann W et al. Phase III, randomized study of trastuzumab 
emtansine (T-DM1) + pertuzumab (P) vs trastuzumab + taxane (HT) for first-line 
treatment of HER2-positive MBC:  Primary results from the MARIANNE study. 
ASCO 2015 abstract.
Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with 
trastuzumab versus neoadjuvant chemotherapy alone in patients with HER2-
positive locally advanced breast cancer (the NOAH trial): a randomized controlled 
superiority trial with a parallel HER2-negative cohort. Lancet. 2010;375:377–384.
Gnant M, Harbeck N, Thomssen C. St. Gallen 2011: summary of the consensus 
discussion. Breast Care (Basel). 2011;6:136–141. Epub 2011 Apr 29.
Hurwitz, S, Dirix, L, Kocsis, J, et al. Trastuzumab emtansine (T-DM1) versus 
trastuzumab and docetaxel in previously untreated HER2-positive metastatic 
breast cancer (MBC): primary results of a randomized multicenter, open-label 
phase II study. ESMO, 2011.
Loibl, S, von Minckwitz, G, Blohmer, J, et al. Comparison of survival according to 
pathologic complete response (pCR) in patients with HER2-positive breast cancer 
receiving neoadjuvant chemotherapy with and without trastuzumab compared to 
patients with HER2-negative tumors. San Antonio Breast Cancer Symposium. Dec 
2011.
Mauri D, Pavlidis N, Ioannidis J. Neoadjuvant versus adjuvant systemic treatment in 
breast cancer: a meta-analysis. J Natl Cancer Inst. 2005;97:188–194.
[NCCN] National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines 
in Oncology: Breast Cancer. Version 2.2011. Available at www.nccn.org.


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Perez EA, Barrios C, Eiermann W, et al. Trastuzumab emtansine with or without 
pertuzumab versus trastuzumab with taxane for human epidermal growth factor 
receptor 2-positive advanced breast cancer: Final results from MARIANNE. 
Cancer. 2019;125:3974-84.
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant 
chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659-
1672.
Rastogi P, Anderson S, Bear H, et al. Preoperative chemotherapy: updates of National 
Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 
2008;26:778–785.
Romond E, Perez E, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for 
operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673–1684.
Schneeweiss, A, Chia, S, Hickish, T, et al. Neoadjuvant pertuzumab and trastuzumab 
concurrent or sequential with an anthracycline-containing or concurrent with an 
anthracycline-free standard regimen: a randomized phase ii study (TRYPHAENA). 
San Antonio Breast Cancer Symposium. December 2011.
Slamon, D, Eiermann, W., Robert, N, et al. Adjuvant trastuzumab in HER2-positive 
breast cancer. N Engl J Med. 2011; 365:1273-1283.
Sprangers MA, Groenvold M, Arraras JI, et al. The European Organization for Research 
and Treatment of Cancer breast cancer-specific quality-of-life questionnaire 
module: first results from a three-country field study. J Clin Oncol. 1996;14:2756–
2768.
Untch M, Fasching P, Konecny G, et al. Pathological complete response after 
neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in HER2-
overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG 
study groups. J Clin Oncol. 2011; 29:3351-57.
Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced 
breast cancer. N Engl J Med. 2012; 367:1783-179.


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Appendix 1 Schedule of Assessments
Screening a
Cycles 1 and 2
Cycles 3–14
Study Drug 
Completion Visit b
Survival 
Follow-Up c 
Day
–30 to –1
1
14–21
1
14–21
Informed consent a
x
Assignment of patient numbers through IVRS/IWRS
x
Tumor tissue submission for HER2 determination and 
exploratory biomarkers (mandatory) 
x d
x d
Blood sample for plasma/serum biomarker analyses 
(optional)
x e
x e
x e
x e
Whole blood sample for genetic analyses (optional)
x e
Medical history and demographics 
x
Disease status assessments f
x
x f
Complete physical examination 
x
x f
Limited physical examination g
x
x
x
Height h
x
Vital signs i
x
x
x
x
ECOG performance status
x
x
Concomitant/follow-up medication reporting
x j
x
x
x
x f, z
AE reporting k
x l
x
x
x
x
12-lead ECG 
x
ECHO/MUGA m
x
x m
x m
x m
x m
HBV and HVC serologyn
x


Appendix 1 Schedule of Assessments (cont.)
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd
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Screening a
Cycles 1 and 2
Cycles 3–14
Study Drug 
Completion Visit b
Survival 
Follow-Up c 
Day
–30 to –1
1
14–21
1
14–21
Hematology o
x p
x q
x q
x
x r
Biochemistry s
x p
x q
x q
xt
xr
PK samples (serum and plasma)  
See Appendix 2 for 
details
ATA assessment u
x u
x u
x u
x u
INR/aPTT
x p
As clinically indicated
Pregnancy test v
x
x v
x
x
Bilateral mammogram
x (within 
1 year)
x w
Patient-reported outcome assessment x
x
x x
x
x
Arm B:  trastuzumab administration y
x
x
Arm A:  trastuzumab emtansine administration y
x
x
AEadverse event; ALKalkaline phosphatase; ALT alanine aminotransferase; aPTT activated partial thromboplastin time; AST aspartate 
aminotransferase; ATAanti-therapeutic antibody; CT computed tomography; ECG electrocardiogram; ECHO echocardiogram; 
ECOGEastern Cooperative Oncology Group; eCRFelectronic Case Report Form; HBVhepatitis B virus; HCVhepatitis C virus; INRinternational 
normalized ratio; IVRS/IWRSinteractive voice response system/interactive web response system; MRI magnetic resonance imaging;
MUGAmultiple-gated acquisition; PKpharmacokinetics; TBILItotal bilirubin.
NOTE:  Unscheduled visits may be conducted at any time for studies that may include hematology, biochemistry, INR/aPTT, ECG, ECHO/MUGA, 
or disease assessment.
a Informed consent may be obtained at any time (including prior to the 30-day screening period) but must be obtained prior to the performance of 
any screening assessments.  Results of screening tests or examinations performed as standard of care prior to obtaining informed consent and 
within 30 days prior to randomization may be used rather than repeating required tests. 
b Performed within approximately 30 days after the last dose of study treatment.


Appendix 1 Schedule of Assessments (cont.)
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c The follow-up period begins from the date of the study drug completion/early termination visit with a duration of up to 12 years from the date of 
randomization of the first patient.  Visit windows are 28 days for quarterly and semiannual assessments and 42 days for annual 
assessments.
d Tumor tissue samples (formalin-fixed paraffin-embedded [FFPE] material) obtained for HER2 testing from the primary site before preoperative 
therapy, or if not possible, from the surgical specimen along with the pathology reports.  Paraffin-embedded tumor tissue blocks or partial blocks 
from pretreatment material must be obtained from the preoperative biopsy in addition to the surgical specimen.  If sites are unable to send tissue 
blocks due to local regulations, at least 8 unstained slides should be sent, and in addition, up to 5 slides for exploratory biomarker research from 
the preoperative biopsy and 25 slides must be submitted for exploratory biomarker analysis from the surgical specimen.  Alternatively, 15 slides 
could be sent along with a biopsy core from the surgical specimen.  If a biopsy is collected as part of routine medical practice at 
relapse/recurrence, a tissue block or up to five unstained slides should be sent for biomarker analysis in order to gain better understanding of 
resistance mechanisms.
e If optional consent was given, serum and plasma samples will be collected for exploratory biomarker analyses and/or for long-term storage in the 
study’s central biomarker repository for future biomarker analyses.  Serum and plasma samples should be drawn at C1D1 baseline, C1D8, C4, 
C8, and C12, as well as at the study drug completion/early termination visit and at time of relapse/recurrence.  The whole blood sample for 
genetic analyses should be drawn at C1D1 but can be drawn during study execution if forgotten at baseline.
f
Disease status based on all available clinical assessments should be documented from the date of randomization at the following timepoints: 
every 3 months during study treatment and up to 2 years, every 6 months from 3 to 5 years, and annually thereafter through to 03 April 2023.  
Whenever possible, disease recurrence should be confirmed pathologically.  In cases of disease recurrence diagnosed at any time during the 
study, patients will be followed once a year (starting 1 year after first relapse) until 03 April 2023 for anti-cancer medications and new relapse 
events.  All patients still in the study will be followed with at least annual contact (virtual, telephone, or in-person) for survival until 03
April 2025, a 2-year extension.  Disease status assessment in the extension period (April 2023 – April 2025) is not mandatory but can be 
recorded on unscheduled survival follow-up visit CRFs if performed as part of standard of care.
g Limited symptom-directed physical exam focusing on organ systems related to a potential AE based on patient’s interim medical history and/or 
existing AE profiles of the study drugs.  Disease status based on all available clinical assessments should be documented every 3 months during 
study treatment.
h Height to be obtained at screening or at Cycle 1 Day 1 only.
i
Vital signs should be obtained and reviewed but, aside from weight, are not required to be entered into the eCRF.  Abnormal vital signs at any 
time during the course of study treatment should be recorded as AEs or SAEs if clinically significant.
j
Record all prior anti-cancer therapies and concomitant medications.


Appendix 1 Schedule of Assessments (cont.)
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k Patients will be followed for new or worsening AEs for 30 days following the last infusion of study drug or until the early termination visit, until 
treatment related AEs resolve or stabilize, or until the initiation of another anti-cancer therapy, whichever occurs first.  After 30 days following last 
study treatment administration, the investigator should continue to follow all unresolved study-related AEs and SAEs until their resolution or 
stabilization, the patient is lost to follow-up, or it is determined that the study treatment or participation is not the cause of the AE/SAE.  The 
investigator should notify the Sponsor of any death, SAE, or other AE of concern occurring at any time after a patient has discontinued study 
treatment or study participation if the event is believed to be related to prior study drug treatment or study procedures.  
l
During screening, only SAEs considered related to protocol-mandated procedures will be collected.
m Cardiac monitoring (ECHO/MUGA) will be performed in all patients enrolled in the study.  ECHO is the preferred method.  The same method 
used for a given patient at screening should be used throughout the study.  ECHO/MUGA should be obtained during the last week (Days 14–21) 
of C2, and every 4 cycles thereafter (C6, C10, C14).  ECHO/MUGA should be obtained at the study drug completion/early termination visit if not 
performed within the previous 6 weeks and at 3, 6, 12, 18, 24, 36, 48, and 60 months.  Cardiac monitoring should continue to be performed in 
all patients according to the schedule above.  For patients who have not had a recurrence, record the assessment(s) on a Survival Follow-Up 
eCRF.  For patients who have had a recurrence, even if receiving treatment for the recurrence, the assessment should be performed annually 
and recorded on a Post-Recurrence Survival Follow-Up eCRF.
n Documentation of HBV and HCV serologies is required:  this includes HB surface antigen (HBsAg) and/or total HB core antibody (anti-HBc) in 
addition to HCV antibody testing.  The most recent serologic testing must have occurred within 3 months prior to initiation of neoadjuvant 
therapy.  If such testing has not been done, it must be performed during screening.
o Hematologic assessments include hemoglobin (Hb), hematocrit, platelet count, and WBC, including determination of absolute neutrophil count 
(ANC). 
p Screening:  to be performed within 7 days prior to randomization. Screening laboratory assessments may be done on the day of randomization 
and their results may be used for randomization visit purposes.
q Cycle 1 Day 1 hematology and biochemistry assessments are not mandatory if the screening assessment was conducted within 7 days prior to 
randomization.  Scheduled for Day 1 of Cycle 2 and beyond:  to be performed within 72 hours preceding administration of study treatment; 
results must be reviewed and documented prior to administration of study treatment.
r
CBC and platelet counts, TBILI, ALT, AST, and ALK will be measured every 3 months during the follow-up period for 1 year after the study drug 
completion/early termination visit.  If platelet counts are decreased or if TBILI, ALT, AST, or ALK are elevated, testing should continue per 
Footnote t.


Appendix 1 Schedule of Assessments (cont.)
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s Biochemistry assessments at baseline include sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (BUN) or urea, creatinine, 
total and direct bilirubin, total protein, albumin, ALT, AST, and ALK.  Patients who have positive HBV or HCV serology without known active 
disease must meet the eligibility criteria for ALT, AST, TBILI, INR, aPTT, and ALK on at least two consecutive occasions, separated by at least 1 
week, within the 30 day screening period.  Further assessment of disease activity may be done per standard local practice, e.g., PCR. 
Assessments at each treatment and at study discontinuation include potassium, TBILI (and direct bilirubin when TBILIULN), ALT, AST, and 
ALK; other assessments may be obtained as clinically indicated.
t
The investigator should follow each elevated liver test finding at least monthly until the event has resolved to baseline, the event is assessed as 
stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  
u To be assessed in approximately 50% of patients from each treatment arm at the following timepoints:  pre-dose Cycle 1, Day 1 and Cycle 4, 
Day 1, study treatment termination, and at 3-4 months after the last study treatment. (See Appendix 2 for additional details.)
v Serum -HCG test must be performed during screening.  Urine -HCG test may be performed at subsequent time points for women of 
childbearing potential (including pre-menopausal women who have had a tubal ligation) and for women not meeting the definition of 
postmenopausal.  For all other women, documentation must be present in medical history confirming that the patient is not of childbearing 
potential.  Urine pregnancy tests in women of childbearing potential in all treatment arms every 3 cycles and at 3 and 6 months after the study
drug completion visit.  All positive urine pregnancy tests must be confirmed by a serum -HCG test.
w Mammograms of any remaining breast tissue should be performed at least annually. Mammograms and/or other relevant imaging, such as CT 
or MRI scans of the breast as determined by clinical practice, should continue to be performed in all patients at least annually.  Each 
recurrence should be documented, including type of recurrence and method of diagnosis (including imaging), either on a Survival Follow-Up 
eCRF if the patient has not yet had a recurrence or on a Post-Recurrence Survival Follow-Up eCRF if a recurrence has already been recorded.
x Patient-reported outcome (PRO) questionnaires should be completed before or upon arrival at the study site before any study-specific 
procedures are performed, and before the patient sees the physician, during screening, at Cycles 5 and 11, at the study drug completion visit, 
and every 6 months in follow-up for 12 months after the study drug completion visit.
y If the timing coincides with a holiday that precludes administration, administration should be performed within 5 business days following 
randomization for Cycle 1 and within 5 business days of the scheduled date for subsequent cycles.  Patients who discontinue trastuzumab 
emtansine may complete the duration of their study therapy with trastuzumab, if appropriate, based on toxicity considerations.  If so, they should 
perform the scheduled assessments as indicated for the study treatment period.
z Medications related to the treatment of SAEs are to be reported during the follow-up period, as well as ongoing or new breast cancer treatments 
(e.g., hormone therapy), anticancer treatments for recurrence, and bisphosphonate or denosumab therapy.


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Appendix 2 Schedule of Pharmacokinetic Assessments
PK and ATA Assessments for Trastuzumab Emtansine- and 
Trastuzumab-Treated Patients a
Study Visit
Time
Sample Acquisition
Cycle 1, Day 1 and 
Cycle 4, Day 1
Pre-trastuzumab 
emtansine infusion
Serum sample for trastuzumab emtansine 
and total trastuzumab
Plasma sample for DM1 b
Serum sample for anti-trastuzumab 
emtansine antibody (ATA)
Cycle 1, Day 1 and 
Cycle 4, Day 1
15-30 min 
post-trastuzumab 
emtansine infusion
Serum sample for trastuzumab emtansine 
and total trastuzumab
Plasma sample for DM1 b
Cycle 1, Day 1 and 
Cycle 4, Day 1
2 hours (15 min) 
post-trastuzumab 
emtansine infusion
Serum sample for trastuzumab emtansine
Plasma sample for DM1 b
Cycle 2, Day 1 and 
Cycle 5, Day 1
Pre-trastuzumab 
emtansine infusion
Serum sample for trastuzumab emtansine
Study Treatment 
Termination
Any point during 
study visit
Serum sample for trastuzumab emtansine
Serum sample for anti-trastuzumab 
emtansine antibody (ATA)
3-4 months after last 
dose of trastuzumab 
emtansine
Any point during 
study visit
Serum sample for anti-trastuzumab 
emtansine antibody (ATA)
Cycle 1, Day 1 and 
Cycle 4, Day 1
Pre-trastuzumab 
infusion
Serum sample for trastuzumab
Serum sample for anti-trastuzumab antibody 
(ATA)
Cycle 1, Day 1 and 
Cycle 4, Day 1
15-30 min 
post-trastuzumab 
infusion
Serum sample for trastuzumab
Study Drug 
Termination
Any point during 
study visit
Serum sample for trastuzumab
Serum sample for anti-trastuzumab antibody 
(ATA)
3-4 months after last 
dose of trastuzumab
Any point during 
study visit
Serum sample for anti-trastuzumab antibody 
(ATA)
Note:  Samples for PK analyses should be obtained from the arm not used for the infusion of 
study drug.  If taking PK samples from the opposite arm is not possible (e.g., due to surgery), PK 
samples should be taken from an alternative site on the arm used for the infusion of study drug.  
The PK samples should not be taken from the same site as the infusion of study drug. 
a Samples collected in approximately 50% of trastuzumab emtansine-treated patients and 50% 
of trastuzumab-treated patients.
b Any remaining plasma samples after DM1 analysis may be used for measurement of 
trastuzumab emtansine metabolites (e.g., MCC-DM1, Lys-MCC-DM1) as an exploratory 
assessment (if stability acceptable and at discretion of sponsor).


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Appendix 3 European Organisation for Research and Treatment 
of Cancer Quality of Life Questionnaire – Core 30


Appendix 3 European Organisation for Research and Treatment 
of Cancer Quality of Life Questionnaire – Core 30 (cont.)
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd
113/Protocol BO27938, Version 7


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd
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Appendix 4 European Organisation for Research and Treatment 
of Cancer Quality of Life Questionnaire – Breast Cancer 23


Appendix 4 European Organisation for Research and Treatment 
of Cancer Quality of Life Questionnaire – Breast Cancer 23
(cont.)
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd
115/Protocol BO27938, Version 7


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd
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Appendix 5 EuroQoL EQ-5D


Appendix 5 EuroQoL EQ-5D (cont.)
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd
117/Protocol BO27938, Version 7


Appendix 5 EuroQoL EQ-5D (cont.)
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd
118/Protocol BO27938, Version 7


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd
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Appendix 6
Ventana HER2 IHC Assay
OVERVIEW
The PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody (PATHWAY 
HER2 [4B5]) is a rabbit monoclonal antibody intended for laboratory use for the semi-
quantitative detection of HER2 antigen in sections of formalin-fixed, paraffin- embedded 
breast cancer tissue to determine tumor HER2 IHC status and to select HER2-positive 
patients for enrollment in study BO27938.  The 4B5 IHC assay is currently being 
developed by Ventana Medical Systems as a companion diagnostic to trastuzumab 
emtansine (T-DM1) and will be used for investigational purposes only.
DEVICE DESCRIPTION
The PATHWAY HER2 (4B5) IHC assay is an automated immunohistochemical staining 
assay system comprising a pre-dilute, ready-to-use rabbit monoclonal primary antibody 
(clone 4B5) directed against the internal domain of HER2, the BenchMark ULTRA 
automated slide staining platform, and ultraView™ universal DAB detection kit.  The 
reagents and the IHC procedure are optimized for use on the BenchMark ULTRA 
automated slide stainer, utilizing VSS software (Ventana System Software).  Details of 
the staining protocol and scoring criteria can be found in the instruction for use and 
interpretation guide published by Ventana.


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Appendix 7
Ventana HER2 ISH Assay
OVERVIEW
The INFORM HER2 Dual ISH DNA Probe Cocktail is intended to determine the ratio of 
the HER2 gene to chromosome 17 using two-color chromogenic ISH in formalin-fixed, 
paraffin-embedded human breast cancer tissue to determine tumor HER2 gene status 
and select HER2-positive patients for enrollment in study BO27938.  The INFORM 
HER2 Dual ISH DNA Probe Cocktail is currently being developed by Ventana Medical 
Systems as a companion diagnostic to trastuzumab emtansine (T-DM1) and will be used 
for investigational purposes only.
DEVICE DESCRIPTION
The Ventana INFORM HER2 Dual ISH assay consists of a dinitrophenyl (DNP)-labeled 
double stranded probe that targets the HER2 gene region of chromosome 17 and a 
digoxigenin (DIG)-labeled double stranded probe that hybridizes to repetitive sequences 
in the centromeric region of chromosome 17 (INFORM Chromosome 17 probe).  The 
probes are packaged as a mixture and require the use of Ventana’s ultraView™ SISH 
DNP Detection Kit, ultraView Red DIG Detection Kit, and other accessory reagents to 
stain routinely processed formalin-fixed paraffin-embedded tissue sections on Ventana 
automated slide stainer instruments.


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Appendix 8
Guidelines for Liver Biopsy
As nodular regenerative hyperplasia (NRH) can be a very subtle diagnosis to make on 
liver biopsy, every attempt should be made to maximize the amount of tissue obtained.  
A minimum size of an 18 gauge needle and percutaneous biopsies of at least 1.5 cm in 
length are recommended if clinically appropriate.  In order to diagnose NRH, reticulin 
and trichrome stains are necessary.
Smaller biopsies obtained via a transjugular approach as well as smaller biopsy gun 
needle biopsies are discouraged.  Small wedge biopsies should also be discouraged.

SAP_003.pdf: 
 
Official Title: 
A Randomized, Multicenter, Open Label Phase III Study to Evaluate 
the Efficacy and Safety of Trastuzumab Emtansine Versus 
Trastuzumab as Adjuvant Therapy for Patients with HER2-POSITIVE 
Primary Breast Cancer who have Residual Tumor Present 
Pathologically in the Breast or Axillary Lymph Nodes Following 
Preoperative Therapy 
NCT Number: 
NCT01772472 
Document Date: 
SAP Version 3: 20-June-2023 
 
 
 


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL 
SPONSOR: 
LEGAL REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd 
Grenzacherstrasse 124 
4070 Basel, Switzerland 
APPROVAL DATE: 
See electronic date stamp on the final page of this 
document.  
CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BO27938
STATISTICAL ANALYSIS PLAN 
STUDY TITLE: 
A RANDOMIZED, MULTICENTER, OPEN LABEL PHASE 
III STUDY TO EVALUATE THE EFFICACY AND SAFETY 
OF TRASTUZUMAB EMTANSINE VERSUS 
TRASTUZUMAB AS ADJUVANT THERAPY FOR 
PATIENTS WITH HER2-POSITIVE PRIMARY BREAST 
CANCER WHO HAVE RESIDUAL TUMOR PRESENT 
PATHOLOGICALLY IN THE BREAST OR AXILLARY 
LYMPH NODES FOLLOWING PREOPERATIVE 
THERAPY 
STUDY NUMBER: 
BO27938 
STUDY NAME:  
KATHERINE 
VERSION NUMBER: 
3 
ROCHE COMPOUND(S): Trastuzumab Emtansine (RO5304020) 
EUDRACT NUMBER: 
2012-002018-37 
IND NUMBER: 
71,072 
NCT NUMBER: 
NCT01772472 
PLAN PREPARED BY: 
, PhD 


 
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STATISTICAL ANALYSIS PLAN VERSION HISTORY 
SAP Version 
Approval Date 
Based on Protocol  
(Version, Approval Date) 
3 
See electronic date stamp 
on the final page of this 
document. 
Version 7, 18 June 2021 
2 
1 November 2012 
Version 1, 19 October 2012 
1 
28 June 2012 
 
 


 
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STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE 
Statistical Analysis Plan (SAP) BO27938 has been amended to align with the protocol 
amendment version 7. 
Key changes to the SAP, along with the rationale(s) for each change, are summarized 
below. 
Sections 
Description of Change 
Rationale for Change 
2.2; 2.3; 4.10.1 
The study completion has been 
extended from 10 years post-first 
patient in (FPI) to 12 years post-FPI. 
extension of the study. The details of 
the planned interim and final analyses 
of OS have been updated accordingly. 
Notably, based on the revised 
projection for OS events, the third 
interim analysis of OS has been 
removed 
Determination of sample size 
and interim analyses have 
been updated to reflect the 
extension of the study and to 
align with the revised 
projection for OS events as 
detailed in Protocol BO27938 
version 7. 
 
Additional minor changes have been made throughout to improve clarity and 
consistency. 


 
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TABLE OF CONTENTS 
 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE ............................. 3 
1. 
BACKGROUND .............................................................................. 7 
2. 
STUDY DESIGN ............................................................................. 7 
2.1 
Protocol Synopsis ...................................................................... 8 
2.2 
Determination of Sample Size ................................................... 8 
2.3 
Analysis Timing .......................................................................... 8 
3. 
STUDY CONDUCT ......................................................................... 9 
3.1 
Randomization Issues ............................................................... 9 
3.2 
Data Monitoring Committee ....................................................... 9 
3.3 
Clinical Events Committee ....................................................... 10 
4. 
STATISTICAL METHODS ............................................................ 10 
4.1 
Analysis Populations ................................................................ 10 
4.2 
Analysis of Study Conduct ....................................................... 10 
4.3 
Analysis of Treatment Group Comparability ............................ 10 
4.4 
Efficacy Analysis ...................................................................... 11 
4.4.1 
Primary Efficacy Endpoint ........................................................ 11 
4.4.2 
Secondary Efficacy Endpoints ................................................. 11 
4.4.3 
Exploratory Efficacy Endpoints ................................................ 12 
4.4.4 
Sensitivity Analyses ................................................................. 12 
4.4.5 
Subgroup Analyses .................................................................. 12 
4.5 
Patient-Reported Outcome Analysis ........................................ 13 
4.6 
Pharmacokinetic and Pharmacodynamic Analyses ................. 14 
4.7 
Safety Analyses ....................................................................... 14 
4.7.1 
Study Treatment Exposure ...................................................... 14 
4.7.2 
Adverse Events ........................................................................ 14 
4.7.3 
Laboratory Data ....................................................................... 15 
4.7.4 
Cardiac Safety ......................................................................... 15 
4.7.5 
Liver Safety .............................................................................. 15 




 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Description 
AE 
adverse event 
ATA 
anti-therapeutic antibody 
CHR 
congestive heart failure 
CI 
confidence interval 
CIS 
carcinoma in situ 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCIS 
ductal carcinoma in situ 
DFS 
disease-free survival 
DRFI 
distant recurrence-free interval 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ePRO 
electronic patient-reported outcome 
EORTC 
European Organisation for Research and Treatment of Cancer 
ER 
estrogen receptor 
FDA 
Food and Drug Administration 
FPI 
first patient enrolls in the study 
HR 
hazard ratio 
HRQOL 
health-related quality of life 
ICH 
International Conference on Harmonisation 
iDCC 
independent Data Coordinator Center 
IDFS 
invasive disease-free survival 
iDMC 
independent Data Monitoring Committee 
IVRS/IWRS 
interactive voice response system/interactive web response system 
LCIS 
lobular carcinoma in situ 
LFT 
liver function laboratory test  
LVEF 
left ventricular ejection fraction 
MUGA 
multiple-gated acquisition 
NCI 
National Cancer Institute 
NSABP 
National Surgical Adjuvant Breast and Bowel Project 


 
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1. 
BACKGROUND 
The use of adjuvant trastuzumab in HER2-positive early-stage breast cancer improves 
patient outcomes as demonstrated in several large, randomized trials.   
Preoperative chemotherapy in combination with trastuzumab is a standard of care for 
patients with HER2-positive locally advanced (Stage IIB to IIIC) breast cancer or in 
cases where patients wish to minimize the extent of breast cancer surgery. Compared 
with patients who attain a pathologic complete response (pCR) after preoperative 
therapy, patients with residual disease have a greater risk of recurrence and death. It is 
not known whether the application of additional non–cross-resistant agents in the 
adjuvant setting may benefit these patients, and there are no approved therapies for this 
specific clinical setting.   
Trastuzumab emtansine has shown positive benefit − risk in patients who have 
previously progressed after chemotherapy and HER2-directed therapy. Study BO27938 
is designed to evaluate the efficacy and safety of trastuzumab emtansine in patients with 
HER2-positive breast cancer who have not had pCR to commonly recommended 
preoperative therapy regimens.   
This document describes the Statistical Analysis Plan (SAP) for the Phase III 
randomized Study BO27938. 
The analyses described in this SAP will supersede those specified in Protocol BO27938 
for the purposes of a regulatory filing. 
2. 
STUDY DESIGN 
Study BO27938 is a prospective, two-arm, randomized, multicenter, multinational, open 
label Phase III study evaluating the efficacy and safety of trastuzumab emtansine in 
patients with HER2-positive primary breast cancer who have received preoperative 
chemotherapy and HER2-directed therapy, followed by surgery, with a finding of residual 
invasive disease in the breast or axillary lymph nodes.   
The trial will recruit approximately 1484 patients from approximately 400 sites worldwide. 
Only patients with centrally confirmed HER2-positive disease will be enrolled into this 
study. Patients will be randomized in a 1:1 ratio to either trastuzumab emtansine 
3.6 mg/kg every 3 weeks (q3w) or trastuzumab 6 mg/kg q3w (an 8 mg/kg loading dose 
should be given if it has been more than 6 weeks since the last dose of trastuzumab). 
Study treatment will continue for 14 cycles, unless any of the following occurs: disease 
relapse, unacceptable toxicity, initiation of another anti-cancer therapy, or patient 
decision to discontinue study treatment. Patients who discontinue trastuzumab 
emtansine due to toxicity before 14 cycles may complete the duration of their study 
therapy with trastuzumab if appropriate based on toxicity considerations. Following 
discontinuation of study treatment, patients will be followed for invasive disease-free 


 
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survival (IDFS) events and survival. Patients in either treatment arm will be allowed to 
receive standard radiotherapy and/or hormonal therapy (for patients with hormonal 
positive disease) during the study as clinically indicated.   
The primary efficacy endpoint of this Phase III study is IDFS, defined as the time 
between randomization and date of first occurrence of an IDFS event. Secondary 
endpoints include IDFS including second primary non-breast cancer, disease-free 
survival (DFS), overall survival (OS), and distant recurrence-free interval (DRFI). In 
addition, cardiac safety, liver safety, overall safety and patient-reported outcomes 
(PROs) of trastuzumab emtansine compared with control arm will also be evaluated.  
2.1 
PROTOCOL SYNOPSIS 
The protocol synopsis is in Appendix 1. For additional details, see the schedule of 
activities in Appendix 2.   
2.2 
DETERMINATION OF SAMPLE SIZE 
The sample size of the study is primarily driven by the analysis of IDFS. To detect a 
hazard ratio (HR) of 0.75 in IDFS (a 6.5% improvement in 3-year IDFS from 70% in the 
control arm to 76.5% in the trastuzumab emtansine arm), approximately 384 IDFS 
events will be required to achieve 80% power at a two-sided significance level of 5%. 
Approximately 1484 patients will be enrolled in the study.   
With the study sample size of 1484 patients and approximately 12 years of follow-up 
from the date of randomization of the first patient, this study has approximately 43% 
power to detect a HR of 0.8 in OS (a 2.8% improvement in 3-year OS from 85% in the 
control arm to 87.8% in the trastuzumab emtansine arm) at a two-sided significance 
level of 5%.   
The sample size estimation was performed using East→ Version 5.2 software (Cytel, Inc., 
Cambridge, MA). 
2.3 
ANALYSIS TIMING 
The study is expected to be fully enrolled around 35 months after the first patient enrolls 
in the study (FPI).   
The interim efficacy analysis of IDFS is planned after 67% of the targeted IDFS events 
have occurred, which is estimated to be approximately 48 months after the first patient is 
enrolled in the study. If the accrual rate or event rate are different from expected, the 
timing of the interim analysis may be delayed such that the interim analysis will only take 
place after all patients have enrolled and have completed treatment. The final IDFS 
analysis will be performed after approximately 384 events have occurred, which is 
projected to be approximately 107 months from FPI. Additional details are provided in 
Section 4.10.1.   


 
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Two formal interim OS analyses and one final OS analysis are planned: the first OS 
interim analysis will be performed at the time of the interim IDFS analysis (approximately 
48 months from FPI) if the interim IDFS analysis crosses the boundary; the second 
interim OS analysis will be performed at the time of the final IDFS analysis when 384 
IDFS events have occurred (approximately 107 months from FPI) in the case where the 
interim IDFS analysis crosses the boundary. The final OS analysis will be performed at 
the end of 12 years of follow-up from the date of randomization of the first patient. 
Additional details are provided in Section 4.10.1.   
One safety interim analysis regarding death and hepatic events is planned after 600 
patients have been randomized and followed for 3 months (approximately 21 months 
from FPI). Additional details are provided in Section 4.10.2.  
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION ISSUES 
Eligible patients will be randomized in a 1:1 ratio by a permuted block randomization 
scheme to one of the two treatment arms (trastuzumab or trastuzumab emtansine) 
through use of the interactive voice response system/interactive web response system 
(IVRS/IWRS).   
Randomization will be stratified by the stratification factors:   
 
Clinical stage at presentation:  inoperable (Stage T4NxM0 or TxN2–3M0) versus 
operable (Stages T1-3N0–1M0) 
 
Hormone receptor status:  estrogen receptor (ER) or progesterone receptor (PR) 
positive versus ER and PR negative/unknown 
 
Preoperative HER2-directed therapy:  trastuzumab versus trastuzumab plus 
additional HER2-directed agent(s)  
 
Pathologic nodal status evaluated after preoperative therapy:  node positive versus 
node negative/not done  
 
3.2 
DATA MONITORING COMMITTEE 
An independent Data Monitoring Committee (iDMC) will monitor accumulating safety 
data every 6 months. In addition, the iDMC will review data on deaths and serious 
adverse events (SAEs) every 3 months. The iDMC will also assess safety and efficacy 
as part of the interim efficacy and safety analyses. At each iDMC review, relevant safety 
information from ongoing trastuzumab emtansine studies will be provided to the iDMC. 
An independent Data Coordinator Center (iDCC) will perform unblinded analyses to 
support the periodic iDMC review of safety data. Additional details will be provided in the 
iDMC Charter.  


 
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3.3 
CLINICAL EVENTS COMMITTEE 
An independent safety advisory board will adjudicate prespecified safety events of 
interest (cardiac and hepatic dysfunction events). Additional details will be provided in 
the Clinical Events Committee Charter. An independent safety advisory board will 
adjudicate prespecified safety events of interest (cardiac and hepatic dysfunction 
events). Additional details will be provided in the Clinical Events Committee Charter.   
4. 
STATISTICAL METHODS 
4.1 
ANALYSIS POPULATIONS 
Two analysis populations will be used for the analysis of data from this study:  the 
randomized patient population and the safety-evaluable population. All patients who are 
randomized to the study will be included in the randomized patient population, 
regardless of whether they receive any study treatment; and the safety-evaluable 
population will include all randomized patients who receive any amount of study 
treatment.   
Analyses of demographics and other baseline information will be based on the 
randomized patient population, and per treatment assigned by the IVRS/IWRS.  
The randomized patient population will form the basis for all efficacy analyses. In all 
efficacy analyses, following the intent-to-treat principle, patients will be included in the 
treatment group to which they were randomized by the IVRS/IWRS.   
The safety-evaluable population will form the basis for all safety analyses. Safety 
analyses will be based on actual treatment received. Specifically, a patient will be 
included in the trastuzumab emtansine arm in safety analyses if the patient receives any 
trastuzumab emtansine, regardless of the initial treatment assignment by IVRS/IWRS.  
4.2 
ANALYSIS OF STUDY CONDUCT 
Patient enrollment will be tabulated by study site for each treatment arm. Patient 
disposition and reasons for discontinuations will be summarized by treatment arm for all 
randomized patients. Compliance with protocol-specified schedule of disease status 
clinical assessments will also be summarized by treatment arm. In addition, protocol 
deviations and eligibility violations will be summarized by treatment arm.   
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
The evaluation of treatment group comparability between the two treatment arms will 
include summaries of demographics and baseline characteristics, including age, sex, 
race, breast cancer characteristics, medical history, and prior cancer treatment. 
Descriptive statistics (mean, median, standard deviation, 25th percentile, 75th percentile, 
and range) will be presented for continuous variables, and proportions will be presented 
for categorical variables.  


 
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4.4 
EFFICACY ANALYSIS 
4.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is IDFS, defined as the time between randomization and 
date of first occurrence of any one of the following events:  
 
Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving 
the same breast parenchyma as the original primary lesion) 
 
Ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast 
cancer in the axilla, regional lymph nodes, chest wall and/or skin of the ipsilateral 
breast)   
 
Distant recurrence (i.e., evidence of breast cancer in any anatomic site—other than 
the two above mentioned sites—that has either been histologically confirmed or 
clinically diagnosed as recurrent invasive breast cancer)   
 
Contralateral invasive breast cancer  
 
Death attributable to any cause including breast cancer, non-breast cancer or 
unknown cause (but cause of death should be specified if at all possible)  
 
Patients who have not had an event will be censored at the date they are last known to 
be alive and event free on or prior to the clinical data cutoff date.   
The log-rank test, stratified by the protocol-defined stratification factors (clinical stage at 
presentation [inoperable vs. operable]; hormone receptor status [ER or PR positive vs. 
ER and PR negative/unknown]; preoperative HER2-directed therapy: [trastuzumab vs. 
trastuzumab plus additional HER2-directed agent(s)]; and pathologic nodal status 
evaluated after preoperative therapy [node positive vs. node negative/not done]), will be 
used to compare IDFS between the two treatment arms. The unstratified log-rank test 
results will also be provided as a sensitivity analysis. If, at the time of analysis, it is 
deemed that the smallest stratum is  5 patients in either arm and so robust stratified 
analyses cannot be conducted, the unstratified analysis will be used as the primary 
analysis. Cox proportional hazards model, stratified by the protocol-defined stratification 
factors, will be used to estimate the HR between the two treatment arms and its 95% 
confidence interval (CI). The Kaplan−Meier approach will be used to estimate 3-year 
IDFS rates and corresponding 95% CIs for each treatment arm.   
4.4.2 
Secondary Efficacy Endpoints 
Secondary efficacy outcome measures include the following:   
 
IDFS:  including second primary non-breast cancer: defined the same way as IDFS 
for the primary endpoint but including second primary non breast invasive cancer as 
an event (with the exception of non-melanoma skin cancers and carcinoma in situ 
[CIS] of any site)   
 
DFS:  defined as the time between randomization and the date of the first 
occurrence of an invasive disease-free survival event including second primary non-
breast cancer event or contralateral or ipsilateral ductal carcinoma in situ (DCIS)   


 
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 
OS:  defined as the time from randomization to death due to any cause  
 
DRFI:  defined as the time between randomization and the date of distant breast 
cancer recurrence   
 
Patients who have not had an event will be censored at the date that they are last known 
to be event free on or prior to the clinical data cutoff date.   
Secondary endpoints will be analyzed in a similar manner as the primary endpoint to 
estimate 3-year event rates (and 5-year survival rate for OS) for each treatment arm and 
the HR between the two treatment arms with 95% CI.  
A testing hierarchy will be used to control the overall type I error rate at 5%. If the 
primary endpoint IDFS reaches statistical significance, the formal hypothesis testing of 
OS will be performed. More details of OS interim analyses are specified in 
Section 4.10.1.   
4.4.3 
Exploratory Efficacy Endpoints 
Exploratory analyses will be performed to explore the correlation between biomarker, 
anti-therapeutic antibody (ATA) and clinical outcomes as appropriate.   
4.4.4 
Sensitivity Analyses 
Alternative definitions of IDFS include: IDFS including second primary non-breast 
cancer; and DFS (including second primary non-breast cancer event or contralateral or 
ipsilateral ductal CIS). Both of these two definitions are secondary endpoints of the 
study, and they serve as sensitivity analyses for the primary analysis of IDFS.   
Additional sensitivity analyses to assess the robustness of the primary endpoint IDFS 
include the following:   
 
Censoring patients at the time they begin a new anti-cancer therapy before 
experiencing an IDFS event. This includes patients who continue on trastuzumab 
after discontinuation of trastuzumab emtansine before 14 cycles without 
experiencing an IDFS event. For these patients, data will be censored at the time of 
initiation of trastuzumab treatment.   
 
Censoring patients at the time they discontinue study treatment due to any reason 
before experiencing an IDFS event. This includes for patients who continue on 
trastuzumab after discontinuation of trastuzumab emtansine before 14 cycles 
without experiencing an IDFS event. For these patients, data will be censored at the 
time of last trastuzumab emtansine treatment.   
 
4.4.5 
Subgroup Analyses 
Subgroup analyses of IDFS and OS will be performed based on age, race, stratification 
factors, and other potential baseline prognostic factors as appropriate.   


 
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4.5 
PATIENT-REPORTED OUTCOME ANALYSIS 
The patient-reported outcomes of health-related quality of life (HRQOL) and breast 
cancer specific and treatment-related symptoms will be assessed using the Quality of 
Life QuestionnaireCore 30 (QLQC30), and its corresponding module for breast 
cancer, Quality of Life QuestionnaireBreast Cancer 13 (QLQBR23) developed by the 
European Organization for the Research and Treatment of Cancer (EORTC). The 
EORTC QLQ-C30 and the QLQ-BR23 are both validated and reliable self-report 
measures (Aaronson et al. 1993; Fayers et al. 1999). The EORTC QLQ-C30 consists of 
30 questions which assess five functional domains (physical, role, cognitive, emotional, 
and social), a global health status/quality of life scale, three symptom scales (fatigue, 
pain, nausea, and vomiting), five single items (dyspnea, appetite loss, sleep disturbance, 
constipation, and diarrhea), and a perceived financial impact of the disease item. The 
QLQ-BR23 includes questions assessing breast cancer-associated symptoms, side 
effects of treatment, arm symptoms, and upset by hair loss, and functions of body 
image, sexual functioning, sexual enjoyment, and future perspective. In total there are 
5 functional and 10 symptoms subscales for the QLQ-C30 and 3 symptom and 
3 functioning subscales for QLQ-BR23. The EuroQol EQ-5D is a five-item questionnaire 
assessing self-care, usual activities, pain and anxiety/depression with three response 
categories (no problem, moderate problem, and severe problems). The visual analog 
scale (VAS) scale associated with the EuroQol EQ-5D will not be used in this study.  
Summary of the compliance rate will be provided at each assessment time point as 
specified in the protocol by treatment arm. Compliance rate is defined as the ratio of 
number of patients with completed assessments (i.e., at least 1 item has been 
answered) and the total number of eligible patients at that time point according to 
protocol specified assessment schedule.   
For the QLQ-C30 and QLQ-BR23 questionnaires, if more than 50% of the constituent 
items are completed, a pro-rated score will be computed consistent with the scoring 
manuals and validation papers (Fayers et al. 1999). For subscales with less than 50% of 
the items completed, the subscale will be considered to be missing.   
Summary statistics (mean, standard deviation, median, 25th and 75th percentiles, and 
range) of absolute scores and change from baseline scores of the QLQ-C30 and QLQ-
BR23 subscales will be summarized at each assessment time point for the two treatment 
arms. Only patients with a baseline assessment and at least one post-baseline 
assessment will be included in this analysis.   
Repeated measures mixed-effects models will be performed on each subscale to 
explore the impact of treatment on patients over time. Each model will have an intercept 
term, a linear time trend term, a term for treatment group, and a term for treatment-by-
time interaction. Covariates will be added as appropriate. Only patients with a baseline 
assessment and at least 1 post-baseline assessment will be included in this analysis.  


 
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The EQ-5D data analysis will be performed to support reimbursement dossiers and will 
not be included in the clinical study report.   
4.6 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Blood and serum samples for measurement of trastuzumab emtansine, total 
trastuzumab, and DM1 will be obtained from patients randomized to the trastuzumab 
emtansine arm. Individual and mean trastuzumab emtansine and total trastuzumab 
serum levels and DM1 plasma concentrations versus time data will be plotted, tabulated, 
and summarized (e.g., mean, standard deviation, coefficient of variation, median, 
minimum, maximum, and range). Inter-patient variability and drug accumulation after 
multiple dosing will be evaluated. Compartmental, noncompartmental, and/or population 
approaches will be considered as appropriate. Additional pharmacokinetic and 
pharmacodynamic analyses and exposure-efficacy and toxicity (alanine 
aminotransferase [ALT]/serum aspartate aminotransferase [AST], platelets, etc.) 
analyses will be conducted in conjunction with data from other studies, as appropriate. 
Any remaining plasma samples may be used for measurement of trastuzumab 
emtansine metabolites as an exploratory assessment and will be plotted, tabulated, and 
summarized.   
Blood and serum samples for measurement of trastuzumab will be obtained from 
patients randomized to the trastuzumab arm. Individual and mean trastuzumab serum 
concentrations versus time data will be plotted, tabulated, and summarized (e.g., mean, 
standard deviation, coefficient of variation, median, minimum, maximum, and range).  
4.7 
SAFETY ANALYSES 
Safety analyses will be performed on the treated population, which is defined as patients 
who receive any amount of study treatment and will be based on the treatment they 
actually receive. Specifically, a patient will be included in the trastuzumab emtansine 
arm in safety analyses if the patient receives any trastuzumab emtansine, regardless of 
the initial treatment assignment by IVRS/IWRS.   
4.7.1 
Study Treatment Exposure 
Study treatment exposure, such as treatment duration, number of cycles, dose intensity, 
and dose modification (including dose delay, dose reduction etc.) will be summarized for 
each treatment arm with descriptive statistics. Reasons for treatment discontinuation will 
also be summarized.   
4.7.2 
Adverse Events 
Verbatim descriptions of adverse events (AEs) will be mapped to Medical Dictionary for 
Regulatory Activities (MedDRA) thesaurus terms and graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
Version 4.0. All AEs, SAEs, AEs leading to death, and AEs leading to study treatment 
discontinuation, occurring on or after the first dose of study treatment (i.e., treatment-


 
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emergent AE), will be summarized by NCI CTCAE grade. For repeated events of varying 
severity in an individual patient, the highest grade will be used in the summaries. Deaths 
and causes of death will be summarized.   
Subgroup analyses of AEs based on age, and race will also be provided.   
4.7.3 
Laboratory Data 
Laboratory toxicities will be summarized by NCI CTCAE grade for each treatment arm 
with shift tables.   
4.7.4 
Cardiac Safety 
Incidence of cardiac events, defined as death from cardiac cause or severe congestive 
heart failure (New York Heart Association [NYHA] Class III or IV) with a decrease in left 
ventricular ejection fraction (LVEF) of 10 percentage points or more from baseline to an 
LVEF of < 50%, will be summarized by treatment arm. Other cardiac-related events 
(e.g., any symptomatic congestive heart failure [CHF] associated with a 10% drop in 
LVEF to   50%; asymptomatic declines in LVEF requiring dose delay) will also be 
summarized. Change in LVEF over time will be summarized by treatment arm.   
4.7.5 
Liver Safety 
Incidence of hepatotoxicity events will be summarized by treatment arm. Analyses of 
liver function laboratory test (LFT) results will include the following:   
 
Shift in NCI CTCAE grade from baseline to worst post-baseline level in ALT, AST, 
total bilirubin (TBILI), and alkaline phosphatase (ALK)  
 
Summary of number/percentage of patients with AST, ALT, TBILI, and ALK 
elevation by NCI CTCAE grade and by treatment cycle  
 
Scatterplots of worst LFT value (AST vs. ALT, ALT vs. TBILI, AST vs. TBILI) relative 
to upper limit normal (ULN)  
 
Kaplan−Meier plots of time to first ALT  3  ULN, first ALT  5  ULN, and first 
ALT  8  ULN events  
 
Patient LFT profiles (including ALT, AST, TBILI, and ALK) over time points for 
patients satisfying one of the following two conditions:   
– 
TBILI elevation  2  ULN within 21 days after AST/ALT elevation   3  ULN  
– 
ALT elevation  8  ULN  
 
4.8 
EXPLORATORY SAFETY ANALYSES 
For patients who continue on trastuzumab after discontinuation of trastuzumab 
emtansine due to toxicity before 14 cycles, exploratory safety analyses will be 
performed. Summary of trastuzumab exposure, SAEs, cardiac-specific AEs, and NCI 
CTCAE Grade 3 or above AEs will be provided. Other exploratory safety analyses 
differentiating two treatment phases for these patients will be performed as appropriate.  


 
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4.9 
MISSING DATA 
For the analyses of IDFS, IDFS including second primary non-breast cancer, DFS and 
DRFI, data for patients who do not experience an event will be censored at the date they 
are last known to be alive and event free. Data for patients who are randomized without 
any post-baseline assessments will be censored at the date of randomization plus one 
day. For the analysis of OS, data for patients who are alive at the time of the data cutoff 
will be censored at the last date they were known to be alive. Data for patients who are 
randomized without any post-baseline information will be censored at the date of 
randomization plus one day.   
For the QLQ-C30 and QLQ-BR23 questionnaires, if less than 50% of the constituent 
items of a subscale are completed, data for the subscale will be considered to be 
missing. No imputation will be performed.   
4.10 
INTERIM ANALYSES 
4.10.1 
Interim Efficacy Analyses 
One interim analysis of IDFS and two interim analyses of OS are planned.   
The interim efficacy analysis of IDFS is planned after 67% of the targeted IDFS events 
have occurred, which is estimated to be approximately 48 months after the first patient is 
enrolled in the study. If the accrual rate or event rate are different from expected, the 
timing of the interim analysis may be delayed such that the interim analysis will only take 
place after all patients have enrolled and have completed treatment.   
At this interim analysis, IDFS will be tested at the significance level determined using the 
Lan−DeMets alpha spending function with an O’Brien−Fleming boundary so that the 
overall two-sided type I error rate will be maintained at the 5% level for the IDFS primary 
endpoint.   
Table 1 presents a summary of the planned IDFS analyses, the efficacy stopping 
boundary, and the estimated timing of these analyses.   
Table 1 
Summary of Planned Analyses of Invasive Disease-Free Survival 
Analysis of IDFS 
No. of events 
Efficacy Stopping 
Boundary a 
Estimated Timing b 
Interim 
257 
p  0.0124 or observed 
HR  0.732 
48 months 
Final 
384 
p  0.0462 or observed 
HR  0.816 
107 months 
HR  hazard ratio; IDFS  invasive disease-free survival. 
a 
p-value will be based on two-sided stratified log-rank test. 
b 
Time from the enrollment of first patient to data cutoff. 
  


 
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The interim analysis will be performed by the iDCC statistician and the results will be 
presented to the iDMC by the iDCC statistician.   
The purpose of the interim analysis is to evaluate whether there is an overwhelming 
difference in the efficacy observed in the trastuzumab emtansine arm compared with the 
trastuzumab arm in terms of IDFS. If the test is not significant, the study will continue as 
planned. If the test is significant, the iDMC may recommend releasing the primary 
endpoint results before the targeted number of 384 events is reported. In this latter 
situation, the Sponsor will be unblinded to the study results and a full data package 
would be prepared for discussion with regulatory authorities. The study will continue until 
12 years of follow-up from the date of randomization of the first patient and IDFS 
analysis will be updated when 384 IDFS events have occurred.   
Two formal interim OS analyses and one final OS analysis are planned: the first OS 
interim analysis will be performed at the time of the interim IDFS analysis (approximately 
48 months from FPI) if the interim IDFS analysis crosses the boundary; the second 
interim OS analysis will be performed at the time of the final IDFS analysis when 384 
IDFS events have occurred (approximately 107 months from FPI) in the case where the 
interim IDFS analysis crosses the boundary. The final OS analysis will be performed at 
the end of 12 years of follow-up from the date of randomization of the first patient. The 
Sponsor will perform these analyses. A survival data sweep will be conducted prior to 
each analysis.   
The overall type I error will be controlled at 0.05 for the formal OS interim analyses and 
final OS analysis using the Lan−DeMets alpha spending function with an 
O’Brien−Fleming boundary. The boundaries used at each interim and final OS analysis 
will depend on the timing of the analyses and the number of death events actually 
included in the analyses.   
Table 2 presents a summary of the planned OS analyses, the efficacy stopping 
boundary, and the estimated timing of these analyses.   


 
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Table 2 
Summary of Planned Analyses of Overall Survival 
Analysis of OS 
No. of 
Events 
Efficacy Stopping Boundary a 
Estimated Timing b 
Interim 1 (at interim IDFS) 
150 
p  0.0005 or observed HR   0.494 
48 months 
Interim 2 (at final IDFS) c 
206 
p  0.0143 or observed HR   0.696 
107 months 
Final 
367 
p  0.0456 or observed HR   0.781 
144 months 
HR  hazard ratio; IDFS  invasive disease-free survival; OS  overall survival. 
a 
p-value will be based on two-sided stratified log-rank test 
b 
Time from the enrollment of first patient to data cutoff. 
c 
Estimated number of events. Efficacy boundaries will be calculated based on the actual 
number of events at the time of analysis. 
  
4.10.2 
Interim Safety Analyses 
An iDMC will monitor accumulating patient safety data at least once every 6 months until 
the last patient has completed study treatment. In addition, data on serious AEs and 
deaths will be monitored by the iDMC at least once every 3 months during this period.  
At each iDMC review, relevant safety information from ongoing trastuzumab emtansine 
studies will be provided to the iDMC.   
After the first 600 patients have been randomized and followed for 3 months 
(approximately 21 months after FPI), the iDMC will perform an interim safety analysis 
regarding death and hepatic events. The Clinical Events Committee will communicate 
their findings regarding hepatic events to the iDMC to aid iDMC review.   
If an absolute increase of > 3% in the percentage of death (from any cause) is observed 
in trastuzumab emtansine arm compared with the trastuzumab arm, the iDMC will 
consider recommending holding enrollment for further data review, stopping or modifying 
the trial.   
If the true difference in the percentage of death is > 3% (e.g., 2% vs. 6%) then there is 
approximately 70% chance of observing an absolute difference of > 3% at the interim 
with 600 patients. Table 3 presents the probability of observing more than 3% increase 
in the percentage of death in trastuzumab emtansine arm compared with the 
trastuzumab arm with different assumption on the percentage of death in 2 arms.  


 
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Table 3 
Probability of Observing  3% Increase of Death 
Percentage of death 
Probability of observing   3% increase 
Trastuzumab (N  300) 
Trastuzumab emtansine 
(N  300) 
2% 
2% 
0.00 
2% 
3% 
0.05 
2% 
4% 
0.20 
2% 
5% 
0.45 
2% 
6% 
0.70 
  
If an absolute increase of > 3% in the percentage of Hy’s law cases (confirmed by the 
independent clinical events committee) is observed in trastuzumab emtansine arm 
compared with the control arm, the iDMC will consider recommending holding enrollment 
for further data review, stopping or modifying the trial.   
If the true difference in the percentage of confirmed Hy’s law cases is > 3% (e.g., 0.33% 
vs. 3.67%) then there is approximately 54% chance of observing an absolute difference 
of > 3% at the interim with 600 patients. Table 4 presents the probability of observing 
more than 3% increase in the percentage of Hy’s law cases in trastuzumab emtansine 
arm compared with the trastuzumab arm with different assumption on the number of 
Hy’s law cases in two arms.  
Table 4 
Probability of Observing >3% Increase of Confirmed Hy’s Law 
Cases 
Number of confirmed Hy’s law cases (%) 
Probability of observing   3% increase 
Trastuzumab (N  300) 
Trastuzumab emtansine 
(N  300) 
1 (0.33%) 
4 (1.33%) 
 0.01 
1 (0.33%) 
6 (2%) 
0.05 
1 (0.33%) 
8 (2.67%) 
0.19 
1 (0.33%) 
10 (3.33%) 
0.43 
1 (0.33%) 
11 (3.67%) 
0.54 
1 (0.33%) 
12 (4%) 
0.66 
  
The iDMC will work according to the guidelines defined in the iDMC Charter. The iDMC 
Charter will contain details regarding frequency of meetings, guidelines for decision 
making and process for requesting further information. The iDMC members will review 
and sign off the charter before the first review.   


 
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5. 
REFERENCES 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for 
Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use 
in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365–6.   
Fayers PM, Aaronson NK, Bjordal K, Curran D, Groenvold M on behalf of the 
EORTC Quality of Life Study Group. The EORTC QLQ-C30 Scoring Manual 
(2nd Edition). Published by: European Organization for Research and 
Treatment of Cancer, Brussels 1999.   


Appendix 1  
Study BO27938 Protocol Synopsis 
PROTOCOL SYNOPSIS 
TITLE: 
A RANDOMIZED, MULTICENTER, OPEN-LABEL 
PHASE III STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF TRASTUZUMAB EMTANSINE VERSUS 
TRASTUZUMAB AS ADJUVANT THERAPY FOR 
PATIENTS WITH HER2-POSITIVE PRIMARY BREAST 
CANCER WHO HAVE RESIDUAL TUMOR PRESENT 
PATHOLOGICALLY IN THE BREAST OR AXILLARY 
LYMPH NODES FOLLOWING PREOPERATIVE 
THERAPY 
PROTOCOL NUMBER: 
BO27938 
VERSION NUMBER: 
7 
EUDRACT NUMBER: 
2012-002018-37 
IND NUMBER: 
71,072 
NCT NUMBER: 
NCT01772472 
NSABP/GBG PROTOCOL 
NUMBERS: 
NSABP B-50-I/GBG 77 
TEST PRODUCT: 
Trastuzumab Emtansine (RO5304020) 
PHASE: 
III 
INDICATION: 
HER2-positive primary breast cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES 
PRIMARY EFFICACY OBJECTIVE 
The primary efficacy objective for this study is as follows: 
 
To compare invasive disease-free survival (IDFS) in patients with residual invasive breast 
cancer after treatment with preoperative chemotherapy and HER2-directed therapy 
including trastuzumab followed by surgery between the 2 treatment arms 
The secondary efficacy objective for this study is as follows: 
 
To compare IDFS including second non-breast cancers, disease-free survival (DFS), overall 
survival (OS), and distant recurrence-free interval (DRFI) between the 2 treatment arms 
SAFETY OBJECTIVES 
The safety objective for this study is as follows: 
 
To compare cardiac safety and overall safety between the 2 treatment arms according to 
the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE), Version 4.0 


 
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PATIENT REPORTED OUTCOME OBJECTIVES 
The patient-reported outcome (PRO) objective for this study is as follows: 
 
To compare PROs between the 2 treatment arms using the European Organisation for 
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire – Core 30 
(QLQ-C30) questionnaire and Quality of Life Questionnaire – Breast Cancer (QLQ-BR23) 
module 
PHARMACOKINETICS OBJECTIVES 
The pharmacokinetics (PK) objectives for this study are as follows: 
 
To characterize the PK of trastuzumab emtansine (including total trastuzumab and DM1) in 
trastuzumab emtansine treated patients  
 
To characterize the PK of trastuzumab in trastuzumab-treated patients and permit an intra-
study comparison of trastuzumab exposure in the 2 treatment arms 
 
To investigate exposure–effect (efficacy and safety) relationships in this patient population 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
 
To assess correlations between biomarker status and efficacy and/or safety 
 
To assess the incidence of anti-therapeutic antibodies (ATAs) and the effect of ATAs on 
PK, safety, and efficacy 
STUDY DESIGN 
DESCRIPTION OF STUDY 
This is a Phase III, 2-arm, randomized, multicenter, multinational, open-label study in patients 
with HER2-positive primary breast cancer who have received preoperative chemotherapy and 
HER2-directed therapy including trastuzumab followed by surgery, with a finding of residual 
invasive disease in the breast or axillary lymph nodes. 
Patients who provide consent will commence a screening period, which will last up to 30 days.  
Informed consent forms may be obtained at any time (including prior to the 30-day screening 
period) but must be obtained prior to the performance of any screening assessments.  Patients 
who have pathologically documented residual invasive disease in either the breast or axillary 
lymph nodes following completion of preoperative therapy (including, but not limited to, at least 
9 weeks of HER2-directed therapy, including trastuzumab, and at least 9 weeks of 
taxane-based chemotherapy (or, if receiving dose-dense chemotherapy regimens, at least 
6-8 weeks of taxane-based therapy and at least 8 weeks of trastuzumab) and at least 16 weeks 
of total systemic treatment in the preoperative setting) will be eligible to participate in the study.   
At the end of the screening period, eligible patients will be randomized in a 1:1 ratio to receive 
open-label study treatment (trastuzumab emtansine 3.6 mg/kg every 3 weeks [q3w] for 
14 cycles or trastuzumab 6 mg/kg q3w for 14 cycles).  Randomization will be stratified by 
clinical stage at presentation (inoperable [Stage T4NxM0 or TxN2–3M0], operable 
[stages T1-3N0-1M0]), hormone receptor status (estrogen receptor [ER] or progesterone 
receptor [PgR] positive, ER and PgR negative), preoperative HER2-directed therapy 
(trastuzumab, trastuzumab plus additional HER2-directed agent[s]), and pathological nodal 
status evaluated after preoperative therapy (node positive, node negative or not done).  Patients 
will be administered radiotherapy and/or hormonal therapy (for patients with hormone 
receptor-positive tumors) in addition to receiving study treatment for 14 cycles if indicated based 
on the following guidelines: 
 
Hormonal therapy (aromatase inhibitor, tamoxifen, etc.) should be initiated in patients with 
hormone receptor-positive disease at presentation. 
 
For patients undergoing breast-conserving surgery, whole breast irradiation is required.  
Primary tumor bed boost may be administered according to local policy.  Regional node 
irradiation is required if the patient presented at initial diagnosis with clinical T3 (except for 
T3N0) or T4 disease and/or with clinical N2 or N3 disease; it is recommended for T3N0 or  
if there is residual disease in lymph nodes. 


 
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 
For post-mastectomy patients, chest wall and regional node irradiation is required if the 
patient presented at initial diagnosis with clinical T3 (except for T3N0) or T4 disease and/or 
with clinical N2 or N3 disease; it is recommended for T3N0 or if there is residual disease in 
lymph nodes.  For post-mastectomy patients who do not meet these criteria, radiotherapy is 
at the discretion of the investigator based on institutional standards. 
The first dose of study treatment will be administered on Day 1 of a 3-week cycle (i.e., dosing 
will be repeated once q3w to complete a maximum of 14 cycles of treatment).  Treatment will be 
discontinued prior to 14 cycles in the event of disease recurrence, unacceptable toxicity, or 
study termination by the Sponsor.  Patients who discontinue trastuzumab emtansine may 
complete the duration of their study therapy with trastuzumab, if appropriate based on toxicity 
considerations.  Efficacy, safety, laboratory, and PRO measures will be assessed throughout 
the study, as detailed in the schedule of assessments (see Appendix 1).  PK measures will be 
assessed as specified in the schedule of PK assessments (see Appendix 2).  The primary 
efficacy endpoint is the IDFS and will be measured from the time of randomization until its first 
occurrence.  Following discontinuation or completion of study treatment, all patients will 
continue to be followed for efficacy and safety objectives until the end of the study.  
NUMBER OF PATIENTS 
A planned total of 1484 patients will be enrolled in the study.   
TARGET POPULATION 
Patients must meet the following criteria for study entry: 
1. HER2-positive breast cancer 
HER2-positive status will be based on pretreatment biopsy material and defined as an 
immunohistochemistry (IHC) (Appendix 6) score of 3  and/or positive by in situ 
hybridization (ISH) (Appendix 7) prospectively confirmed by a central laboratory prior to 
study enrollment.  ISH positivity is defined as a ratio of  2.0 for the number of HER2 
gene copies to the number of signals for chromosome 17 copies.  Formalin-fixed 
paraffin-embedded tumor tissue block or a partial block must be available for central 
evaluation of HER2 expression.  If sites are unable to send a tissue block due to local 
regulations, at least 8 unstained slides should be sent for HER2 testing, and in addition 
up to 5 slides for exploratory biomarker research.  A central laboratory will perform both 
IHC and ISH assays; however, only one positive result is required for eligibility.  In the 
event that sufficient material from the pretreatment biopsy is not available for 
submission, central HER2 determination for eligibility may be performed on residual 
tumor tissue from the time of definitive surgery. 
Patients with synchronous bilateral invasive disease are eligible provided both lesions 
are HER2-positive.  
2. Histologically confirmed invasive breast carcinoma 
3. Clinical stage at presentation:  T1–4, N0–3, M0 (Note:  Patients with T1a/bN0 tumors will 
not be eligible) 
4. Completion of preoperative systemic chemotherapy and HER-2 directed treatment.  
Systemic therapy must consist of at least 6 cycles of chemotherapy with a total duration at 
least 16 weeks, including at least 9 weeks of trastuzumab and at least 9 weeks of 
taxane-based chemotherapy.  Patients may have received an anthracycline as part of 
preoperative therapy in addition to taxane chemotherapy   
Patients receiving dose-dense chemotherapy regimens are eligible, provided at least 8 
weeks of taxane-based therapy and at least 8 weeks of trastuzumab have been given.  A 
dose-escalated (225 mg/m2 q2w) dose-dense regimen of paclitaxel over 6 weeks is 
allowed. 
Patients may have received more than one HER2-directed therapy.  Note:  HER-2 directed 
therapy alone periods will not satisfy the requirements for cycles of preoperative systemic 
chemotherapy. 
All systemic chemotherapy should be completed preoperatively.  
5. Adequate excision:  surgical removal of all clinically evident disease in the breast and lymph 
nodes as follows: 


 
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Breast surgery:  total mastectomy with no gross residual disease at the margin of 
resection, or breast-conserving surgery with histologically negative margins of excision 
For patients who undergo breast-conserving surgery, the margins of the resected 
specimen must be histologically free of invasive tumor and ductal carcinoma in situ 
(DCIS) as determined by the local pathologist.  If pathologic examination 
demonstrates tumor at the line of resection, additional operative procedures may be 
performed to obtain clear margins.  If tumor is still present at the resected margin 
after re-excision(s), the patient must undergo total mastectomy to be eligible.  
Patients with margins positive for lobular carcinoma in situ (LCIS) are eligible without 
additional resection.  
Lymph node surgery: 
In case of positive results from a fine-needle aspiration, core biopsy, or sentinel 
node biopsy performed prior to preoperative therapy, additional surgical evaluation 
of the axilla following preoperative therapy is required. 
If only micrometastases are present in sentinel nodes preoperatively (i.e., if the 
greatest diameter of the nodal metastasis in a sentinel node is 0.2 mm or less), no 
additional surgical evaluation of the axilla is required. 
If sentinel node biopsy performed before preoperative therapy was negative, no 
additional surgery evaluation of the axilla is required after preoperative therapy. 
If the only sentinel node identified by isotope scan is in the internal mammary chain, 
surgical evaluation of the axilla is recommended. 
If sentinel node biopsy performed after preoperative therapy is positive, additional 
surgical evaluation of the axilla is recommended. 
If sentinel node evaluation after preoperative therapy is negative, no further 
additional surgical evaluation of the axilla is required. 
Axillary dissection without sentinel node evaluation is permitted after preoperative 
therapy. 
6. Pathologic evidence of residual invasive carcinoma in the breast or axillary lymph nodes 
following completion of preoperative therapy.  If invasive disease is present in both breasts, 
residual invasive carcinoma must be present in at least 1 breast or axillary lymph nodes 
postoperatively. 
7. An interval of no more than 12 weeks between the date of primary surgery and the date of 
randomization 
8. Known hormone receptor status 
Hormone receptorpositive status can be determined by either known positive ER or 
known positive PgR status; hormone receptornegative status must be determined by 
both known negative ER and known negative PgR. 
9. Signed written informed consent approved by the study site’s Institutional Review Board 
(IRB)/Ethical Committee (EC) 
10. Age  18 years 
11. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
12. Life expectancy  6 months  
13. Adequate organ function during screening, defined as: 
a. Absolute neutrophil count  1200 cells/mm3 
b. Platelet count  100000 cells/mm3 
c. Hemoglobin  9.0 g/dL; patients may receive red blood cell transfusions to obtain this 
level 
d. Serum creatinine  1.5  upper limit of normal (ULN) 
e. International normalized ratio (INR) and activated partial thromboplastin time 
(aPTT)  1.5  ULN 
f. 
Serum aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT)  1.5  ULN 


 
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g. Serum total bilirubin (TBILI)  1.0  ULN (within normal limits), except for patients with 
Gilbert’s syndrome, for whom direct bilirubin should be within the normal range 
h. Serum alkaline phosphatase (ALK)  1.5  ULN 
i. 
Screening left ventricular ejection fraction (LVEF)  50% on echocardiogram (ECHO) or 
multiple-gated acquisition (MUGA) after receiving neoadjuvant chemotherapy and no 
decrease in LVEF by more than 15% absolute points from the pre-chemotherapy LVEF.  
Or, if pre-chemotherapy LVEF was not assessed, the screening LVEF must be  55% 
after completion of neoadjuvant chemotherapy. 
i. 
LVEF assessment may be repeated once up to 3 weeks following the initial 
screening assessment to assess eligibility 
14. For women who are not postmenopausal ( 12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  agreement to remain 
abstinent or use single or combined contraceptive methods that result in a failure rate 
of   1% per year during the treatment period and for at least 7 months after the last dose of 
study drug. 
a. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
Examples of contraceptive methods with a failure rate of   1% per year include tubal 
ligation, male sterilization, hormonal implants, established, proper use of combined oral 
or injected hormonal contraceptives, and certain intrauterine devices.  Alternatively, two 
methods (e.g., two barrier methods such as a condom and a cervical cap) may be 
combined to achieve a failure rate of < 1% per year.  Barrier methods must always be 
supplemented with the use of a spermicide. 
b. Male patients whose partners are pregnant must use condoms or truly refrain from 
sexual activity for the duration of the pregnancy. 
15. Negative serum pregnancy test for premenopausal women including women who have had 
a tubal ligation and for women less than 12 months after the onset of menopause 
16. Documentation of hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies is 
required:  this includes HB surface antigen (HBsAg) and/or total HB core antibody 
(anti-HBc) in addition to HCV antibody testing.  The most recent serologic testing must have 
occurred within 3 months prior to initiation of neoadjuvant therapy.  If such testing has not 
been done, it must be performed during screening. 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Stage IV (metastatic) breast cancer 
2. History of any prior (ipsi- or contralateral) breast cancer except LCIS 
3. Evidence of clinically evident gross residual or recurrent disease following preoperative 
therapy and surgery 
4. An overall response of progressive disease (PD) according to the investigator at the 
conclusion of preoperative systemic therapy 
5. Treatment with any anti-cancer investigational drug within 28 days prior to commencing 
study treatment 
6. History of other malignancy within the last 5 years except for appropriately treated 
carcinoma in situ (CIS) of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, 
or other non-breast malignancies with an outcome similar to those mentioned above 
7. Patients for whom radiotherapy would be recommended for breast cancer treatment but for 
whom it is contraindicated because of medical reasons (e.g., connective tissue disorder or 
prior ipsilateral breast radiation)  
8. Current NCI CTCAE (Version 4.0) Grade  2 peripheral neuropathy 
9. History of exposure to the following cumulative doses of anthracyclines:  
Doxorubicin  240 mg/m2 
Epirubicin or Liposomal Doxorubicin-Hydrochloride (Myocet®)  480 mg/m2 
For other anthracyclines, exposure equivalent to doxorubicin  240 mg/m2 


 
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10. Cardiopulmonary dysfunction as defined by any of the following: 
History of NCI CTCAE (Version 4.0) Grade  3 symptomatic congestive heart failure 
(CHF) or New York Heart Association (NYHA) criteria Class  II Angina pectoris requiring 
anti-anginal medication, serious cardiac arrhythmia not controlled by adequate 
medication, severe conduction abnormality, or clinically significant valvular disease 
 
High-risk uncontrolled arrhythmias:  i.e., atrial tachycardia with a heart rate  100/min 
at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade 
AV-block (second degree AV-block Type 2 [Mobitz 2] or third degree AV-block) 
Significant symptoms (Grade  2) relating to left ventricular dysfunction, cardiac 
arrhythmia, or cardiac ischemia while or since receiving preoperative therapy. 
History of a decrease in LVEF to  40% with prior trastuzumab treatment (e.g., during 
preoperative therapy) 
Uncontrolled hypertension (systolic blood pressure  180 mmHg and/or diastolic blood 
pressure  100 mmHg) 
Evidence of transmural infarction on ECG 
Requirement for continuous oxygen therapy 
11. Prior treatment with trastuzumab emtansine 
12. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary, or metabolic disease; wound healing disorders; ulcers) 
13. For female patients, current pregnancy and/or lactation 
14. Major surgical procedure unrelated to breast cancer or significant traumatic injury within 
approximately 28 days prior to randomization or anticipation of the need for major surgery 
during the course of study treatment 
15. Any known active liver disease, for example, due to HBV, HCV, autoimmune hepatic 
disorders, or sclerosing cholangitis.  Patients who have positive HBV or HCV serologies 
without known active disease must meet the eligibility criteria for ALT, AST, TBILI, INR, 
aPTT, and alkaline phosphatase (ALK) on at least two consecutive occasions, separated by 
at least 1 week, within the 30 day screening period. 
16. Concurrent, serious, uncontrolled infections or known infection with HIV 
17. History of intolerance, including Grade 3 to 4 infusion reaction or hypersensitivity to 
trastuzumab or murine proteins or any components of the product 
18. Active, unresolved infections at screening requiring treatment 
19. Assessment by the investigator as being unable or unwilling to comply with the 
requirements of the protocol 
LENGTH OF STUDY 
The total length of this study will be approximately 12 years from randomization of the first 
patient to completion of the last follow-up assessment of the last patient.   
END OF STUDY 
The study will end after the last patient randomized into the study has undergone the last 
follow-up assessment.  To enable long-term follow-up for survival and safety information, the 
last follow-up assessment is scheduled to occur 12 years after the first patient is randomized. 


 
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PRIMARY EFFICACY OUTCOME MEASURE 
The primary efficacy outcome measure is IDFS, defined as the time from randomization until the 
date of the first occurrence of any one of the following events:  
 
Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving the 
same breast parenchyma as the original primary lesion)  
 
Ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast cancer 
in the axilla, regional lymph nodes, chest wall and/or skin of the ipsilateral breast)  
 
Distant recurrence (i.e., evidence of breast cancer in any anatomic site—other than the 
2 above-mentioned sites—that has either been histologically confirmed or clinically 
diagnosed as recurrent invasive breast cancer) 
 
Contralateral invasive breast cancer 
 
Death attributable to any cause including breast cancer, non-breast cancer or unknown 
cause (but cause of death should be specified if at all possible) 
SECONDARY EFFICACY OUTCOME MEASURES 
Secondary efficacy outcome measures include the following: 
 
IDFS including second primary non-breast cancer:  defined the same way as IDFS for the 
primary endpoint but including second primary non-breast invasive cancer as an event (with 
the exception of non-melanoma skin cancers and CIS of any site) 
 
DFS:  defined as the time between randomization and the date of the first occurrence of an 
IDFS event including second primary non-breast cancer event or contralateral or ipsilateral 
DCIS 
 
OS:  defined as the time from randomization to death due to any cause 
 
DRFI:  defined as the time between randomization and the date of distant breast cancer 
recurrence   
SAFETY OUTCOME MEASURES 
The safety outcome measures are the following protocol-specific adverse events (AEs): 
 
Incidence, type and severity of all AEs based on NCI CTCAE Version 4.0 
 
Incidence, type, and severity of serious adverse events (SAEs) 
 
Incidence and type of AEs leading to dose discontinuation, modification, or delay 
 
Cause of death on study 
 
Abnormal laboratory values 
 
LVEF decreases 
 
Cardiac events, defined as death from cardiac cause or severe CHF (NYHA Class III or IV) 
with a decrease in LVEF of  10 percentage points from baseline to an LVEF of  50%. 
PATIENT-REPORTED OUTCOME MEASURES 
The PRO outcome measures for this study are as follows: 
 
Incidence of treatment-related symptoms and assessment of health-related quality of life 
(HRQOL) as measured using the EORTC QLQ-C30 questionnaire and QLQ-BR23 module 
 
Assessment of health status as measured using the EuroQol EQ-5D questionnaire for 
health economic modeling 


 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BO27938 
28 
PHARMACOKINETIC OUTCOME MEASURES 
The PK outcome measures to be assessed in patients receiving trastuzumab emtansine are the 
following: 
 
Observed serum concentrations and relevant PK parameters of trastuzumab emtansine 
(trastuzumab emtansine conjugated) and total trastuzumab (sum of conjugated and 
unconjugated trastuzumab) 
 
Observed plasma concentrations of DM1 
 
Explore relationship between trastuzumab emtansine exposure and efficacy/safety  
 
Characterize ATA and assess impact of ATA on PK, safety and efficacy.  
EXPLORATORY OUTCOME MEASURES 
The exploratory outcome measure for this study is as follows: 
 
The relationship between molecular markers and efficacy outcomes 
Efficacy outcomes considered for this analysis will include IDFS and OS, as appropriate. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
Trastuzumab emtansine is provided as a single-use lyophilized formulation.  The lyophilized 
product should be reconstituted using sterile water for injection (SWFI).  Patients will receive 
trastuzumab emtansine infusions q3w.  Vials should be refrigerated at 2C to 8C (36F to 46F) 
until use.  The vial and the solution of trastuzumab emtansine should not be shaken or frozen.  
Information on the formulation, packaging, handling, and administration of trastuzumab 
emtansine is provided in the trastuzumab emtansine Investigator’s Brochure (IB) and local 
prescribing information. 
Information on the formulation, packaging, handling, and administration of trastuzumab is 
provided in the local prescribing information as appropriate. 
Accurate records of all investigational medicinal products (IMPs), including trastuzumab 
emtansine and trastuzumab, that are received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log. 
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The primary efficacy variable is IDFS, defined as the time between randomization and date of 
first occurrence of an IDFS event.  Patients who have not had an event will be censored at the 
date they are last known to be alive and event free on or prior to the clinical data cutoff date. 
The log-rank test, stratified by the protocol-defined stratification factors (clinical stage at 
presentation [inoperable vs. operable]; hormone receptor status [ER or PgR positive vs. ER and 
PgR negative/unknown]; preoperative HER2-directed therapy [trastuzumab vs. trastuzumab 
plus additional HER2-directed agent(s)]; and pathologic nodal status evaluated after 
preoperative therapy [node positive vs. node negative/not done]), will be used to compare IDFS 
between the 2 treatment arms.  The unstratified log-rank test results will also be provided as a 
sensitivity analysis.  If at the time of analysis it is deemed that the smallest strata per arm 
is  5 patients to conduct robust stratified analyses, unstratified analyses will be used as the 
primary analysis. 
Cox proportional hazards model, stratified by the protocol-defined stratification factors, will be 
used to estimate the HR between the 2 treatment arms and its 95% confidence interval (CI).  
The Kaplan-Meier approach will be used to estimate 3-year IDFS rates and corresponding 
95% CIs for each treatment arm. 
DETERMINATION OF SAMPLE SIZE   
The sample size of the study is primarily driven by the analysis of IDFS.  To detect a hazard 
ratio (HR) of 0.75 in IDFS (a 6.5% improvement in 3-year IDFS from 70% in the control arm to 
76.5% in the trastuzumab emtansine arm), approximately 384 IDFS events will be required to 
achieve 80% power at a 2-sided significance level of 5%.  Approximately 1484 patients will be 
enrolled in the study. 


 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BO27938 
29 
The study is expected to be fully enrolled around 35 months after the first patient enrolls in the 
study (FPI).  The final IDFS analysis will be performed after approximately 384 events have 
occurred, which is projected to be approximately 107 months from FPI. 
With the study sample size of 1484 patients and approximately 12 years of follow-up, this study 
has about 43% power to detect a HR of 0.8 (a 2.8% improvement in 3-year OS from 85% in the 
control arm to 87.8% in the trastuzumab emtansine arm) at a 2-sided significance level of 5%. 
INTERIM ANALYSES 
One interim analysis of IDFS and 2 interim analyses of OS are planned. 
The interim efficacy analysis of IDFS is planned after 67% of the targeted IDFS events have 
occurred, which is estimated to be approximately 48 months after the first patient is enrolled in 
the study.  At this interim analysis, IDFS will be tested at the significance level determined using 
the LanDeMets alpha spending function with an O’BrienFleming boundary so that the overall 
2-sided type I error rate will be maintained at the 5% level for the IDFS primary endpoint.  A 
summary of the planed IDFS analyses is shown in the table below: 
 
Analysis of IDFS 
No. of events 
Efficacy Stopping 
Boundary a 
Estimated Timing b 
Interim  
257 
p  0.0124 or observed 
HR  0.732 
48 months 
Final 
384 
p  0.0462 or observed 
HR  0.816 
107 months 
HR  hazard ratio; IDFS  invasive disease-free survival. 
a p-value will be based on 2-sided stratified log-rank test. 
b Time from the enrollment of first patient to data cutoff. 
 
The purpose of the interim analysis is to evaluate whether there is an overwhelming difference 
in the efficacy observed in the trastuzumab emtansine arm compared with the trastuzumab arm 
in terms of IDFS.  If the test is not significant, the study will continue as planned.  If the test is 
significant, the independent Data Monitoring Committee (iDMC) may recommend releasing the 
primary endpoint results before the targeted number of 384 events is reported.  In this latter 
situation, the Sponsor will be unblinded to the study results and a full data package would be 
prepared for discussion with regulatory authorities.  The study will continue until 12 years of 
follow-up and IDFS analysis will be updated when 384 IDFS events have occurred.   
Two formal interim OS analyses and one final OS analysis are planned, as detailed in the table 
below.  The final OS analysis will be performed at the end of 12 years of follow-up.  A survival 
data sweep will be conducted prior to each analysis. 
The overall type I error will be controlled at 0.05 for the formal OS interim analyses and final OS 
analysis using the LanDeMets alpha spending function with an O’BrienFleming boundary.  
The boundaries used at each interim and final OS analysis will depend on the timing of the 
analyses and the number of death events actually included in the analyses. 
 


 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BO27938 
30 
Analysis Of OS 
No. of 
Events 
Efficacy Stopping Boundary a 
Estimated Timing b 
Interim 1 (at interim IDFS) 
98 
p  0.0005 or observed HR  0.494  
48 months 
Interim 2 (at final IDFS)c 
183 
p  0.0143 or observed HR  0.696 
107 months  
Finalc 
263 
p  0.0456 or observed HR  0.781 
144 months 
HR  hazard ratio; IDFS  invasive disease-free survival; OS  overall survival. 
a p-value will be based on 2-sided stratified log-rank test. 
b Time from the enrollment of first patient to data cutoff. 
c Estimated number of events. Efficacy boundaries will be calculated based on the actual 
number of events at the time of analysis. 
 
An iDMC will monitor accumulating patient safety data at least once approximately every 6 
months until the last patient has completed study treatment.  In addition, data on SAEs and 
deaths will be monitored by the iDMC at least once approximately every 3 months during this 
period.  At each iDMC review, relevant safety information from ongoing trastuzumab emtansine 
studies will be provided to the iDMC. 
After the first 600 patients have been randomized and followed up for 3 months (approximately 
21 months after FPI), the iDMC will perform an interim safety analysis regarding death and 
hepatic events.  The Clinical Events Committee will communicate their findings regarding 
cardiac and hepatic events to the iDMC to aid iDMC review. 
If an absolute increase of  3% in the percentage of death (from any cause) or in the percentage 
of Hy’s law cases (confirmed by the independent clinical events committee) is observed in the 
trastuzumab emtansine arm compared with the trastuzumab arm, the iDMC will consider 
recommending holding enrollment for further data review, stopping, or modifying the trial. 
If an absolute increase of  3% in the percentage of Hy’s law cases (confirmed by the 
independent clinical events committee) is observed in the trastuzumab emtansine arm 
compared with the control arm, the iDMC will consider recommending holding enrollment for 
further data review, stopping, or modifying the trial. 
The iDMC will work according to the guidelines defined in the iDMC Charter.  The iDMC Charter 
will contain details regarding the frequency of meetings, guidelines for decision making, and 
process for requesting further information.  The iDMC members will review and sign off on the 
charter before the first review. 
 


 
 
Appendix 2 Schedule of Activities 
 
 
Screening a 
Cycles 1 and 2 
Cycles 3–14 
Study Drug 
Completion Visit b 
Survival 
Follow-Up c  
Day 
–30 to –1 
1 
14–21 
1 
14–21 
 
 
Informed consent a 
x 
 
 
 
 
 
 
Assignment of patient numbers through IVRS/IWRS 
x 
 
 
 
 
 
 
Tumor tissue submission for HER2 determination and 
exploratory biomarkers (mandatory)  
x d 
 
 
 
 
 
x d 
Blood sample for plasma/serum biomarker analyses 
(optional) 
 
x e 
 
x e 
 
x e 
x e 
Whole blood sample for genetic analyses (optional) 
 
x e 
 
 
 
 
 
Medical history and demographics  
x 
 
 
 
 
 
 
Disease status assessments f 
 
x 
x f 
Complete physical examination  
x 
 
 
 
 
 
x f 
Limited physical examination g 
 
x 
 
x 
 
x 
 
Height h 
x 
 
 
 
 
 
 
Vital signs i 
x 
x 
 
x 
 
x 
 
ECOG performance status 
x 
 
 
 
 
x 
 
Concomitant/follow-up medication reporting 
x j 
x 
 
x 
 
x 
x f, z 
AE reporting k 
x l 
x 
 
x 
 
x 
x 
12-lead ECG  
x 
 
 
 
 
 
 
ECHO/MUGA m 
x 
 
x m 
 
x m 
x m 
x m 
HBV and HVC serologyn 
x 
 
 
 
 
 
 


Appendix 2:  Schedule of Activities (cont.) 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan BO29743 
32
 
 
Screening a 
Cycles 1 and 2 
Cycles 3–14 
Study Drug 
Completion Visit b 
Survival 
Follow-Up c  
Day 
–30 to –1 
1 
14–21 
1 
14–21 
 
 
Hematology o 
x p 
x q 
 
x q 
 
x 
x r 
Biochemistry s 
x p 
x q 
 
x q 
 
xt 
xr 
PK samples (serum and plasma)   
 
 
See Appendix 2 for 
details 
 
 
 
 
ATA assessment u 
 
x u 
 
x u 
 
x u 
x u 
INR/aPTT 
x p 
As clinically indicated 
Pregnancy test v 
x 
 
 
x v 
 
x 
x 
Bilateral mammogram 
x (within 
1 year) 
 
 
 
 
 
x w 
Patient-reported outcome assessment x 
x 
 
 
x x 
 
x 
x 
Arm B:  trastuzumab administration y 
 
x 
 
x 
 
 
 
Arm A:  trastuzumab emtansine administration y 
 
x 
 
x 
 
 
 
AE  adverse event; ALK  alkaline phosphatase; ALT  alanine aminotransferase; aPTT  activated partial thromboplastin time; AST  aspartate 
aminotransferase; ATA  anti-therapeutic antibody; CT  computed tomography; ECG  electrocardiogram; ECHO  echocardiogram; 
ECOG  Eastern Cooperative Oncology Group; eCRF  electronic Case Report Form; HBV  hepatitis B virus; HCV  hepatitis C virus; INR  international 
normalized ratio; IVRS/IWRS  interactive voice response system/interactive web response system; MRI  magnetic resonance imaging; 
MUGA  multiple-gated acquisition; PK  pharmacokinetics; TBILI  total bilirubin. 
NOTE:  Unscheduled visits may be conducted at any time for studies that may include hematology, biochemistry, INR/aPTT, ECG, ECHO/MUGA, 
or disease assessment. 
a Informed consent may be obtained at any time (including prior to the 30-day screening period) but must be obtained prior to the performance of 
any screening assessments.  Results of screening tests or examinations performed as standard of care prior to obtaining informed consent and 
within 30 days prior to randomization may be used rather than repeating required tests.  
b Performed within approximately 30 days after the last dose of study treatment. 
c The follow-up period begins from the date of the study drug completion/early termination visit with a duration of up to 12 years from the date of 
randomization of the first patient.  Visit windows are  28 days for quarterly and semiannual assessments and  42 days for annual 
assessments. 


Appendix 2:  Schedule of Activities (cont.) 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan BO29743 
33
d Tumor tissue samples (formalin-fixed paraffin-embedded [FFPE] material) obtained for HER2 testing from the primary site before preoperative 
therapy, or if not possible, from the surgical specimen along with the pathology reports.  Paraffin-embedded tumor tissue blocks or partial blocks 
from pretreatment material must be obtained from the preoperative biopsy in addition to the surgical specimen.  If sites are unable to send tissue 
blocks due to local regulations, at least 8 unstained slides should be sent, and in addition, up to 5 slides for exploratory biomarker research from 
the preoperative biopsy and 25 slides must be submitted for exploratory biomarker analysis from the surgical specimen.  Alternatively, 15 slides 
could be sent along with a biopsy core from the surgical specimen.  If a biopsy is collected as part of routine medical practice at 
relapse/recurrence, a tissue block or up to five unstained slides should be sent for biomarker analysis in order to gain better understanding of 
resistance mechanisms. 
e If optional consent was given, serum and plasma samples will be collected for exploratory biomarker analyses and/or for long-term storage in the 
study’s central biomarker repository for future biomarker analyses.  Serum and plasma samples should be drawn at C1D1 baseline, C1D8, C4, 
C8, and C12, as well as at the study drug completion/early termination visit and at time of relapse/recurrence.  The whole blood sample for 
genetic analyses should be drawn at C1D1 but can be drawn during study execution if forgotten at baseline. 
f Disease status based on all available clinical assessments should be documented from the date of randomization at the following timepoints: 
every 3 months during study treatment and up to 2 years, every 6 months from 3 to 5 years, and annually thereafter through to 03 April 2023.  
Whenever possible, disease recurrence should be confirmed pathologically.  In cases of disease recurrence diagnosed at any time during the 
study, patients will be followed once a year (starting 1 year after first relapse) until 03 April 2023 for anti-cancer medications and new relapse 
events.  All patients still in the study will be followed with at least annual contact (virtual, telephone, or in -person) for survival until 03 
April 2025, a 2-year extension.   Disease status assessment in the extension period (April 2023 – April 2025) is not mandatory but can be 
recorded on unscheduled survival follow-up visit CRFs if performed as part of standard of care. 
g Limited symptom-directed physical exam focusing on organ systems related to a potential AE based on patient’s interim medical history and/or 
existing AE profiles of the study drugs.  Disease status based on all available clinical assessments should be documented every 3 months during 
study treatment. 
h Height to be obtained at screening or at Cycle 1 Day 1 only. 
i Vital signs should be obtained and reviewed but, aside from weight, are not required to be entered into the eCRF.  Abnormal vital signs at any 
time during the course of study treatment should be recorded as AEs or SAEs if clinically significant. 
j Record all prior anti-cancer therapies and concomitant medications. 
k Patients will be followed for new or worsening AEs for 30 days following the last infusion of study drug or until the early termination visit, until 
treatment related AEs resolve or stabilize, or until the initiation of another anti-cancer therapy, whichever occurs first.  After 30 days following last 
study treatment administration, the investigator should continue to follow all unresolved study-related AEs and SAEs until their resolution or 
stabilization, the patient is lost to follow-up, or it is determined that the study treatment or participation is not the cause of the AE/SAE.  The 
investigator should notify the Sponsor of any death, SAE, or other AE of concern occurring at any time after a patient has discontinued study 
treatment or study participation if the event is believed to be related to prior study drug treatment or study procedures.   
l During screening, only SAEs considered related to protocol-mandated procedures will be collected. 


Appendix 2:  Schedule of Activities (cont.) 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan BO29743 
34
m Cardiac monitoring (ECHO/MUGA) will be performed in all patients enrolled in the study.  ECHO is the preferred method.  The same method 
used for a given patient at screening should be used throughout the study.  ECHO/MUGA should be obtained during the last week (Days 14–21) 
of C2, and every 4 cycles thereafter (C6, C10, C14).  ECHO/MUGA should be obtained at the study drug completion/early termination visit if not 
performed within the previous 6 weeks and at 3, 6, 12, 18, 24, 36, 48, and 60 months.  Cardiac monitoring should continue to be performed in all 
patients according to the schedule above.  For patients who have not had a recurrence, record the assessment(s) on a Survival Follow-Up 
eCRF.  For patients who have had a recurrence, even if receiving treatment for the recurrence, the assessment should be performed annually 
and recorded on a Post-Recurrence Survival Follow-Up eCRF. 
n Documentation of HBV and HCV serologies is required:  this includes HB surface antigen (HBsAg) and/or total HB core antibody (anti-HBc) in 
addition to HCV antibody testing.  The most recent serologic testing must have occurred within 3 months prior to initiation of neoadjuvant 
therapy.  If such testing has not been done, it must be performed during screening. 
o Hematologic assessments include hemoglobin (Hb), hematocrit, platelet count, and WBC, including determination of absolute neutrophil count 
(ANC).  
p Screening:  to be performed within 7 days prior to randomization.  Screening laboratory assessments may be done on the day of randomization 
and their results may be used for randomization visit purposes. 
q Cycle 1 Day 1 hematology and biochemistry assessments are not mandatory if the screening assessment was conducted within 7 days prior to 
randomization.  Scheduled for Day 1 of Cycle 2 and beyond:  to be performed within 72 hours preceding administration of study treatment; 
results must be reviewed and documented prior to administration of study treatment. 
r CBC and platelet counts, TBILI, ALT, AST, and ALK will be measured every 3 months during the follow-up period for 1 year after the study drug 
completion/early termination visit.  If platelet counts are decreased or if TBILI, ALT, AST, or ALK are elevated, testing should continue per 
Footnote t. 
s Biochemistry assessments at baseline include sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (BUN) or urea, creatinine, 
total and direct bilirubin, total protein, albumin, ALT, AST, and ALK.  Patients who have positive HBV or HCV serology without known active 
disease must meet the eligibility criteria for ALT, AST, TBILI, INR, aPTT, and ALK on at least two consecutive occasions, separated by at least 1 
week, within the 30 day screening period.  Further assessment of disease activity may be done per standard local practice, e.g., PCR.  
Assessments at each treatment and at study discontinuation include potassium, TBILI (and direct bilirubin when TBILI  ULN), ALT, AST, and 
ALK; other assessments may be obtained as clinically indicated. 
t The investigator should follow each elevated liver test finding at least monthly until the event has resolved to baseline, the event is assessed as 
stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.   
u To be assessed in approximately 50% of patients from each treatment arm at the following timepoints:  pre-dose Cycle 1, Day 1 and Cycle 4, 
Day 1, study treatment termination, and at 3-4 months after the last study treatment. (See Appendix 2 for additional details.) 


Appendix 2:  Schedule of Activities (cont.) 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan BO29743 
35
v Serum -HCG test must be performed during screening.  Urine -HCG test may be performed at subsequent time points for women of 
childbearing potential (including pre-menopausal women who have had a tubal ligation) and for women not meeting the definition of 
postmenopausal.  For all other women, documentation must be present in medical history confirming that the patient is not of childbearing 
potential.  Urine pregnancy tests in women of childbearing potential in all treatment arms every 3 cycles and at 3 and 6 months after the study 
drug completion visit.  All positive urine pregnancy tests must be confirmed by a serum -HCG test. 
w Mammograms of any remaining breast tissue should be performed at least annually.  Mammograms and/or other relevant imaging, such as CT 
or MRI scans of the breast as determined by clinical practice, should continue to be performed in all patients at least annually.  Each recurrence 
should be documented, including type of recurrence and method of diagnosis (including imaging), either on a Survival Follow-Up eCRF if the 
patient has not yet had a recurrence or on a Post-Recurrence Survival Follow-Up eCRF if a recurrence has already been recorded. 
x Patient-reported outcome (PRO) questionnaires should be completed before or upon arrival at the study site before any study-specific 
procedures are performed, and before the patient sees the physician, during screening, at Cycles 5 and 11, at the study drug completion visit, 
and every 6 months in follow-up for 12 months after the study drug completion visit. 
y If the timing coincides with a holiday that precludes administration, administration should be performed within 5 business days following 
randomization for Cycle 1 and within 5 business days of the scheduled date for subsequent cycles.  Patients who discontinue trastuzumab 
emtansine may complete the duration of their study therapy with trastuzumab, if appropriate, based on toxicity considerations.  If so, they should 
perform the scheduled assessments as indicated for the study treatment period. 
z Medications related to the treatment of SAEs are to be reported during the follow-up period, as well as ongoing or new breast cancer treatments 
(e.g., hormone therapy), anticancer treatments for recurrence, and bisphosphonate or denosumab therapy. 


 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BO29743 
36 
Appendix 3 Schedule of Pharmacokinetic and 
Pharmacodynamic Assessments 
PK and ATA Assessments for Trastuzumab Emtansine- and Trastuzumab-Treated 
Patients a 
Study Visit 
Time 
Sample Acquisition 
Cycle 1, Day 1 and 
Cycle 4, Day 1 
Pre-trastuzumab 
emtansine infusion 
 Serum sample for trastuzumab emtansine 
and total trastuzumab 
 Plasma sample for DM1 b 
 Serum sample for anti-trastuzumab 
emtansine antibody (ATA) 
Cycle 1, Day 1 and 
Cycle 4, Day 1 
15-30 min 
post-trastuzumab 
emtansine infusion 
 Serum sample for trastuzumab emtansine 
and total trastuzumab 
 Plasma sample for DM1 b 
Cycle 1, Day 1 and 
Cycle 4, Day 1 
2 hours ( 15 min) 
post-trastuzumab 
emtansine infusion 
 Serum sample for trastuzumab emtansine 
 Plasma sample for DM1 b 
Cycle 2, Day 1 and 
Cycle 5, Day 1 
Pre-trastuzumab 
emtansine infusion 
 Serum sample for trastuzumab emtansine 
Study Treatment 
Termination 
Any point during 
study visit 
 Serum sample for trastuzumab emtansine 
 Serum sample for anti-trastuzumab 
emtansine antibody (ATA) 
3-4 months after last 
dose of trastuzumab 
emtansine 
Any point during 
study visit 
 Serum sample for anti-trastuzumab 
emtansine antibody (ATA) 
Cycle 1, Day 1 and 
Cycle 4, Day 1 
Pre-trastuzumab 
infusion 
 Serum sample for trastuzumab 
 Serum sample for anti-trastuzumab antibody 
(ATA) 
Cycle 1, Day 1 and 
Cycle 4, Day 1 
15-30 min 
post-trastuzumab 
infusion 
 Serum sample for trastuzumab 
Study Drug 
Termination 
Any point during 
study visit 
 Serum sample for trastuzumab 
 Serum sample for anti-trastuzumab antibody 
(ATA) 
3-4 months after last 
dose of trastuzumab 
Any point during 
study visit 
 Serum sample for anti-trastuzumab antibody 
(ATA) 
Note:  Samples for PK analyses should be obtained from the arm not used for the infusion of 
study drug.  If taking PK samples from the opposite arm is not possible (e.g., due to surgery), PK 
samples should be taken from an alternative site on the arm used for the infusion of study drug.  
The PK samples should not be taken from the same site as the infusion of study drug.  
a Samples collected in approximately 50% of trastuzumab emtansine-treated patients and 50% 
of trastuzumab-treated patients. 
b Any remaining plasma samples after DM1 analysis may be used for measurement of 
trastuzumab emtansine metabolites (e.g., MCC-DM1, Lys-MCC-DM1) as an exploratory 
assessment (if stability acceptable and at discretion of sponsor). 
 


Signature Page for Statistical Analysis Plan - BO27938 - v3 - Published
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