Clinical trial NCT01702571
Conditions: Breast Cancer
Sponsor: Hoffmann-La Roche
Start date: 2012-11-27; Completion date: 2020-07-31
Enrollment: 2185 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This two-cohort, open-label, multicenter study will assess the safety, efficacy and tolerability of trastuzumab emtansine in participants with HER2-positive locally advanced breast cancer (LABC) or metastatic breast cancer (mBC) who have received prior anti-HER2 and chemotherapy-based treatment. Participants in Cohort 1 will be drawn from the general participant population; Cohort 2 will include only Asian participants.

Detailed description:

Arms: arm 1: This cohort will enroll all participants with HER2-positive, unresectable, LABC or mBC who have received prior anti-HER2 and chemotherapy treatment and have progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants will receive trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression. arm 2: This cohort will enroll Asian race participants with HER2-positive, unresectable, LABC or mBC who have received prior anti-HER2 and chemotherapy treatment and have progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants will receive trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.
Interventions: intervention 1: Trastuzumab Emtansine
Intervention descriptions: intervention 1: Participants will receive trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) intravenously on Day 1 of a 3-week cycle every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.

Protocol documents:
Prot_000.pdf: 
Official Title: 
A Two-Cohort, Open-Label, Multicenter, Study of Trastuzumab 
Emtansine (T-DM1) in HER2 Positive Locally Advanced or 
Metastatic Breast Cancer Patients Who Have Received Prior Anti-
HER2 and Chemotherapy-Based Treatment 
NCT Number: 
NCT01702571 
Document Date: 
Protocol Version 6: 18-July-2019 


FINAL PROTOCOL APPROVAL 
 
Name 
 
 
 
 
 
 
 
 
 
Date and signature 
CONFIDENTIAL STATEMENT 
 
The information contained in this document, especially any unpublished data, is the property of 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 MO28231, Version 6 
1 
 
PROTOCOL 
TITLE: 
A TWO-COHORT, OPEN-LABEL, MULTICENTER, STUDY OF 
TRASTUZUMAB EMTANSINE (T-DM1) IN HER2 POSITIVE 
LOCALLY ADVANCED OR METASTATIC BREAST CANCER 
PATIENTS WHO HAVE RECEIVED PRIOR ANTI-HER2 AND 
CHEMOTHERAPY-BASED TREATMENT  
PROTOCOL NUMBER: MO28231 
VERSION NUMBER: 6 
EUDRACT NUMBER: 
2012-001628-37 
 
 
TEST PRODUCT: 
Trastuzumab emtansine (RO5304020) 
MEDICAL MONITOR: 
, MD 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
See electronic date stamp below 
 
 
 
15-Jul-2019 10:15:57
Company Signatory
18-Jul-2019 21:45:46
Title
Approver's Name
EU QPPV
Date and Time (UTC)


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Protocol MO28231, Version 6 
2 
 
PROTOCOL AMENDMENT, VERSION 6 
RATIONALE 
Protocol MO28231 has been amended to include the following changes as 
outlined below, along with the rationale for the change. Newly inserted text 
are indicated in italics within the document. 
• Clarification about post-trial access to extension study has been 
provided in Synopsis, Sections 3.2, and 4.2.4. It is specified that, due 
to delay in activation of sites in China for the extension study BO25430, 
Chinese patients currently under trastuzumab emtansine treatment will 
continue to receive treatment under MO28231 protocol until 31 Dec 
2019. After this date, or any earlier if site activation allows, these 
patients will be transferred to and treated under Kadcyla extension 
study protocol, BO25430. 
• Following sections have been updated to reflect clarifications provided 
in the notes to file after protocol version 5: Synopsis, Sections 4.1.1, 
4.4.2.3, 4.4.2.4, and Appendix 1 
• Sections 4.3.1 and 4.3.2 were updated with clarifications regarding 
Chinese traditional medicines following the note to file after protocol 
version 5. 
• The following sections were updated to reflect the revised pregnancy 
and post-study adverse event reporting language following the notes to 
file after protocol version 5: Sections 5.4.3.1 and 5.6 
• Minor administrative changes to update the names of protocol 
signatories. 


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Protocol MO28231, Version 6 
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TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................... 9 
PROTOCOL SYNOPSIS .................................................................................... 10 
1. 
BACKGROUND .......................................................................................... 21 
1.1 
HER2-positive, Metastatic Breast Cancer .............................. 21 
1.2 
Background on Trastuzumab Emtansine ............................... 22 
1.2.1.1 Study TDM3569g ................................................................. 24 
1.2.1.2 Study TDM4258g ................................................................. 24 
1.2.1.3 Study TDM4374g ................................................................. 25 
1.2.1.4 Study BO21976 .................................................................... 26 
1.2.1.5 Study TDM4688g ................................................................. 26 
1.2.1.6 Study BO21977 (EMILIA) ..................................................... 27 
1.2.1.7 Study BO25734 (TH3RESA) ................................................ 28 
1.2.1.8 Pharmacokinetics ................................................................. 28 
1.3 
Study Rationale and Benefit–Risk 
Assessment ........................................................................... 30 
2. 
OBJECTIVES .............................................................................................. 31 
2.1 
Primary Objective .................................................................. 31 
2.2 
Secondary Objectives ............................................................ 31 
2.3 
Pharmacoeconomics Outcome Objective .............................. 31 
3. 
STUDY DESIGN ......................................................................................... 32 
3.1 
Description of Study .............................................................. 32 
3.1.1 
Overview ................................................................................ 32 
3.1.2 
Independent Data Monitoring Committee .............................. 34 
3.1.3 
Steering Committee ............................................................... 34 
3.2 
End of Study .......................................................................... 34 
3.3 
Rationale for Study Design .................................................... 34 
3.3.1 
Rationale for Test Product Dosage ........................................ 35 
3.3.2 
Rationale for Continued Dosing ............................................. 35 
3.3.3 
Rationale for Patient Population ............................................ 35 
3.4 
Outcome Measures ............................................................... 36 
3.4.1 
Safety Outcome Measures .................................................... 36 
3.4.2 
Efficacy Outcome Measures .................................................. 37 


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3.4.3 
Pharmacoeconomics Outcome Measures ............................. 37 
4. 
MATERIALS AND METHODS .................................................................... 37 
4.1 
Patients .................................................................................. 37 
4.1.1 
Inclusion Criteria .................................................................... 37 
4.1.2 
Exclusion Criteria ................................................................... 38 
4.2 
Study Treatment .................................................................... 39 
4.2.1 
Formulation, Packaging, and Handling .................................. 39 
4.2.1.1 Trastuzumab Emtansine ...................................................... 39 
4.2.2 
Dosage and Administration .................................................... 41 
4.2.2.1 Trastuzumab Emtansine ...................................................... 41 
4.2.3 
Investigational Medicinal Product 
Accountability ........................................................................................... 41 
4.2.4 
Post-Trial Access to Extension Study .................................... 42 
4.3 
Concomitant Therapy ............................................................ 42 
4.3.1 
Permitted Therapy ................................................................. 42 
4.3.2 
Prohibited Therapy ................................................................ 43 
4.4 
Study Assessments ............................................................... 44 
4.4.1 
Description of Study Assessments ........................................ 44 
4.4.1.1 Medical History and Demographic Data ............................... 44 
4.4.1.2 Vital Signs ............................................................................ 44 
4.4.1.3 Physical Examinations ......................................................... 44 
4.4.1.4 Tumor and Response Evaluations ....................................... 45 
4.4.1.5 Scheduling of Tumor Assessments ...................................... 45 
4.4.1.6 LVEF Assessment ................................................................ 46 
4.4.1.7 ECOG Performance Status .................................................. 46 
4.4.1.8 Laboratory Assessments ...................................................... 46 
4.4.1.9 Electrocardiograms .............................................................. 47 
4.4.1.10 Pharmacoeconomics Evaluation ........................................ 47 
4.4.2 
Timing of Study Assessments ............................................... 47 
4.4.2.1 Screening and Pretreatment Assessments .......................... 47 
4.4.2.2 Assessments during Treatment ............................................ 48 
4.4.2.3 Assessments at Safety Follow-up Visit ................................. 48 
4.4.2.4 Follow-Up Assessments ....................................................... 48 
4.4.2.5 Assessments at Unplanned Visits ........................................ 49 
4.5 
Patient, Study, and Site Discontinuation ................................ 49 


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4.5.1 
Patient Discontinuation .......................................................... 49 
4.5.1.1 Discontinuation from Study Drug .......................................... 49 
4.5.1.2 Withdrawal from Study ......................................................... 49 
4.5.2 
Study and Site Discontinuation .............................................. 50 
5. 
ASSESSMENT OF SAFETY ....................................................................... 50 
5.1 
Safety Plan ............................................................................ 50 
5.1.1 
Cardiotoxicity ......................................................................... 51 
5.1.2 
Hematologic Toxicity (Thrombocytopenia) ............................. 51 
5.1.3 
Hepatotoxicity ........................................................................ 52 
5.1.4 
Pulmonary Toxicity ................................................................ 53 
5.1.5 
Infusion-related Reactions/Hypersensitivity ........................... 53 
5.1.6 
Neurotoxicity .......................................................................... 54 
5.1.7 
Extravasation ......................................................................... 54 
5.1.8 
Trastuzumab Emtansine Dose Modification .......................... 54 
5.1.8.1 Trastuzumab Emtansine Dose Modification 
for Thrombocytopenia ......................................................................... 55 
5.1.8.2 Trastuzumab Emtansine Dose Modification 
for Hepatotoxicity ................................................................................ 56 
5.1.8.2.1 Concurrent elevations of ALT/AST and 
Bilirubin Meeting Hy’s Law laboratory Criteria ............................... 56 
5.1.8.2.2 Nodular Regenerative Hyperplasia 
(NRH) 
 ..................................................................................... 56 
5.1.8.2.3 Transaminase Elevations or Bilirubin 
Elevation Requiring Dose Adjustment ........................................... 56 
5.1.8.3 Trastuzumab Emtansine Dose Modification 
for Neurotoxicity.................................................................................. 57 
5.1.8.4 Trastuzumab Emtansine Dose Modification 
for Cardiotoxicity ................................................................................. 57 
5.1.8.5 Trastuzumab Emtansine Dose Modification 
for Infusion-Related Reactions, Hypersensitivity 
Reactions ........................................................................................... 58 
5.1.8.6 Trastuzumab Emtansine Dose Modification 
for Pulmonary Toxicity ........................................................................ 59 
5.1.8.7 Trastuzumab Emtansine Dose Modification 
for Extravasation ................................................................................. 59 
5.2 
Safety Parameters and Definitions ........................................ 60 
5.2.1 
Adverse Events ..................................................................... 60 


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
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5.2.2 
Serious Adverse Events (Immediately 
Reportable to the Sponsor) ...................................................................... 60 
5.2.3 
Protocol-Defined Events of Special 
Interest/Non-Serious Expedited Adverse Events ..................................... 61 
5.2.4 
Pregnancy and Contraception ............................................... 62 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 64 
5.3.1 
Adverse Event Reporting Period ........................................... 64 
5.3.2 
Eliciting Adverse Event Information ....................................... 64 
5.3.3 
Assessment of Severity of Adverse Events ........................... 65 
5.3.4 
Assessment of Causality of Adverse Events ......................... 65 
5.3.5 
Procedures for Recording Adverse Events ............................ 67 
5.3.5.1 Diagnosis versus Signs and Symptoms ............................... 67 
5.3.5.2 Adverse Events Occurring Secondary to 
Other Events ...................................................................................... 67 
5.3.5.3 Persistent or Recurrent Adverse Events .............................. 67 
5.3.5.4 Abnormal Laboratory Values ................................................ 68 
5.3.5.5 Deaths .................................................................................. 68 
5.3.5.6 Pre-existing Medical Conditions ........................................... 69 
5.3.5.7 Lack of Efficacy or Worsening of Breast 
Cancer  ............................................................................................. 69 
5.3.5.8 Hospitalization or Prolonged Hospitalization ........................ 69 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 70 
5.4.1 
Emergency Medical Contacts ................................................ 70 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of Special 
Interest 
 .............................................................................................. 71 
5.4.3 
Reporting Requirements for Pregnancies .............................. 71 
5.4.3.1 Pregnancies in Female Patients ........................................... 71 
5.4.3.2 Pregnancies in Female Partners of Male 
Patients  ............................................................................................. 71 
5.4.3.3 Abortions .............................................................................. 72 
5.4.3.4 Congenital Anomalies/Birth Defects ..................................... 72 
5.5 
Follow-Up of Patients after Adverse Events .......................... 72 
5.5.1 
Investigator Follow-Up ........................................................... 72 
5.5.2 
Sponsor Follow-Up ................................................................ 73 
5.6 
Post-Study Adverse Events ................................................... 73 


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
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5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ................................................................. 73 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 73 
6.1 
Determination of Sample Size ............................................... 74 
6.2 
Summaries of Treatment Group Comparability ..................... 76 
6.2.1 
Primary Efficacy Endpoint ...................................................... 76 
6.2.2 
Secondary Efficacy Endpoints ............................................... 76 
6.3 
Safety Analyses ..................................................................... 77 
6.4 
Pharmacoeconomics Analyses .............................................. 78 
6.5 
Interim Analyses .................................................................... 78 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 79 
7.1 
Data Quality Assurance ......................................................... 79 
7.2 
Electronic Case Report Forms ............................................... 79 
7.3 
Source Data Documentation .................................................. 80 
7.4 
Use of Computerized Systems .............................................. 80 
7.5 
Retention of Records ............................................................. 81 
8. 
ETHICAL CONSIDERATIONS .................................................................... 81 
8.1 
Compliance with Laws and Regulations ................................ 81 
8.2 
Informed Consent .................................................................. 81 
8.3 
Institutional Review Board or 
Ethics Committee .................................................................. 82 
8.4 
Confidentiality ........................................................................ 83 
8.5 
Financial Disclosure .............................................................. 83 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 83 
9.1 
Study Documentation ............................................................ 83 
9.2 
Site Inspections ..................................................................... 83 
9.3 
Administrative Structure ......................................................... 84 
9.4 
Publication of Data and Protection of Trade 
Secrets .................................................................................. 84 
9.5 
Protocol Amendments ........................................................... 84 
10. REFERENCES ........................................................................................... 85 
 


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
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LIST OF TABLES 
Table 1 
Cycle 1 Mean (SD) Pharmacokinetic Parameters for 
Trastuzumab Emtansine Following Trastuzumab 
Emtansine Administration Every Three Weeks and 
Weekly in Study TDM3569g ........................................................ 29 
Table 2 
Dose Reduction for Trastuzumab Emtansine .............................. 55 
Table 3 
Trastuzumab Emtansine Dose Modification: Total Serum 
Bilirubin ....................................................................................... 56 
Table 4 
Trastuzumab Emtansine Dose Modification: Serum ALT 
or AST ......................................................................................... 57 
Table 5 
Adverse Event Severity Grading Scale ....................................... 65 
Table 6 
Guidance for Causal Attribution of Adverse Event/Serious 
Adverse Event ............................................................................. 66 
Table 7 
Cohort 1: Clopper-Pearson 95% Confidence Intervals for 
the incidence of AEs Grade ≥ 3 based on 2000 patients ............ 74 
Table 8 
Cohort 2: Clopper-Pearson 95% Confidence Intervals for 
the incidence Grade ≥ 3 thrombocytopenia based on 220 
Asian patients ............................................................................. 75 
Table 9 
Clopper-Pearson 95% Confidence Intervals for the 
incidence of Grade ≥ 3 AEs based on 2220 patients .................. 75 
 
LIST OF FIGURES 
Figure 1 
Molecular Structure of Trastuzumab Emtansine ......................... 23 
Figure 2 
Study Design ............................................................................... 33 
Figure 3 
Algorithm for Continuation and Discontinuation of 
Trastuzumab Emtansine Based on Left Ventricular 
Ejection Fraction Assessments in Patients ................................. 58 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments ..................................................... 87 
Appendix 2 
Response Evaluation Criteria in Solid Tumors 
(RECIST): Modified Excerpt from Original Publication ................................ 92 
Appendix 3 
Instructions for Scans in the Event of Isotope 
Shortage 
 ............................................................................................ 105 
Appendix 4 
ECOG Performance Status ................................................. 106 
 


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Protocol MO28231, Version 6 
9 
 
PROTOCOL ACCEPTANCE FORM 
TITLE: 
A TWO-COHORT, OPEN-LABEL, MULTICENTER, STUDY OF 
TRASTUZUMAB EMTANSINE (T-DM1) IN HER2-POSITIVE 
LOCALLY ADVANCED OR METASTATIC BREAST CANCER 
PATIENTS WHO HAVE RECEIVED PRIOR ANTI-HER2 AND 
CHEMOTHERAPY-BASED TREATMENT   
PROTOCOL NUMBER: MO28231 
VERSION NUMBER: 6 
EUDRACT NUMBER: 
2012-001628-37 
 
 
TEST PRODUCT: 
Trastuzumab emtansine (RO5304020) 
MEDICAL MONITOR: 
, MD 
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 a copy of the form as instructed by your local study monitor. 
Please retain the original for your study files. 
 


 
 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Protocol MO28231, Version 6 
10 
 
PROTOCOL SYNOPSIS 
TITLE: 
A TWO-COHORT, OPEN-LABEL, MULTICENTER, STUDY OF 
TRASTUZUMAB EMTANSINE (T-DM1) IN HER2-POSITIVE 
LOCALLY ADVANCED OR METASTATIC BREAST CANCER 
PATIENTS WHO HAVE RECEIVED PRIOR ANTI-HER2 AND 
CHEMOTHERAPY-BASED TREATMENT  
PROTOCOL NUMBER: 
MO28231 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2012-001628-37 
 
 
TEST PRODUCT: 
Trastuzumab emtansine (RO5304020) 
PHASE: 
IIIb 
INDICATION: 
HER2-positive metastatic breast cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Primary Objective 
• 
To evaluate the safety and tolerability of trastuzumab emtansine. 
Secondary Objectives 
• 
Progression Free Survival (PFS) 
• 
Overall Survival (OS) 
• 
Overall Response Rate (ORR) 
• 
Clinical Benefit Rate (CBR) 
• 
Duration of Response (DoR) 
• 
Time to Response (TTR) 
Pharmacoeconomics Outcome Objective 
• 
Health Resource Utilization 
Study Design 
Description of Study 
Two-cohort, open-label, international, multicenter, Phase IIIb study (see Figure 2 in the 
protocol). 
• 
Cohort 1 (approximately 2000 patients) 
• 
Cohort 2 (approximately 220 patients) will include only patients of Asian race 
Enrollment into Cohort 2 will begin around the end of enrollment into Cohort 1. 
 
Number of Patients 
Approximately 2220 patients will be enrolled into this study, approximately 2000 patients in 
Cohort 1 and 220 patients in Cohort 2. 
Target Population 
This study will enroll patients with human epidermal growth factor receptor 2 (HER2) 
positive, unresectable, locally advanced breast cancer (LABC) or metastatic breast cancer 
(mBC) who have previously received prior anti-HER2 and chemotherapy treatment and 
have progressed on or after the most recent treatment for LABC or mBC, or within 6 months 
of completing adjuvant therapy. 


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Protocol MO28231, Version 6 
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Patients must meet the following criteria for study entry according to the timing specified 
in the schedule of assessments (see Appendix 1): 
1.
HER2-positive disease determined locally i.e., immunohistochemistry (IHC) 3 + and/or
gene-amplified by in situ hybridization (ISH) as per institutional practice (however, both
tests should be performed wherever possible and only one positive result is required
for eligibility)
2.
Histologically or cytologically confirmed invasive breast cancer (BC)
3.
Prior treatment for BC in the adjuvant, unresectable, locally advanced or metastatic
setting must include both chemotherapy, alone or in combination with another agent,
and an anti-HER2 agent, alone or in combination with another agent (complementary
hormonal therapy is allowed)
4.
Documented progression of incurable, unresectable, locally advanced, or mBC, defined
by the investigator: progression must occur during or after most recent treatment for
locally advanced/mBC or within 6 months of completing adjuvant therapy
5.
Measurable and/or non-measurable disease
6.
Signed written informed consent approved by the institution’s independent Ethics
Committee (EC)
7.
Age ≥ 18 years
8.
Left ventricular ejection fraction (LVEF) ≥ 50% by either echocardiogram (ECHO) or
multiple-gated acquisition scan (MUGA)
9.
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
10. Adequate organ function:
•
Absolute neutrophil count > 1,500 cells/mm3
•
Platelet count > 100,000 cells/mm3
•
Hemoglobin > 9.0 g/dL. Patients are allowed to be transfused red blood cells to this
level
•
Albumin ≥ 2.5 g/dL
•
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) serum glutamic oxaloacetic
transaminase (SGOT) or aspartate aminotransferase (AST), serum glutamic
pyruvic transaminase (SGPT) or alanine aminotransferase (ALT), and alkaline
phosphatase ≤ 2.5 x ULN with the following exception: Patients with bone
metastases: alkaline phosphatase ≤ 5 x ULN
•
Creatinine clearance (CL) > 50 mL/min based on Cockroft-Gault glomerular
filtration rate (GFR) estimation: (140 – Age) x (weight in kg) x (0.85 if female)/(72 x
serum creatinine)
•
International normalized ratio (INR) < 1.5 (unless on therapeutic anti-coagulation)
11. For women of childbearing potential and men with partners of childbearing potential,
agreement by the patient and/or partner to use a highly effective non-hormonal form of
contraception such as surgical sterilization or two effective forms of non-hormonal
contraception (see Section 5.2.4 of the protocol)
12. Negative serum pregnancy test for women of childbearing potential (including pre-
menopausal women who have had a tubal ligation) and for all women not meeting the
definition of postmenopausal ( ≥ 12 months of amenorrhea), and who have not
undergone surgical sterilization with a hysterectomy and/or bilateral oophorectomy. For
all other women, documentation must be present in medical history confirming that the
patient is not of childbearing potential (see Section 5.2.4 of the protocol)
13. For Cohort 2, only patients of Asian race will be enrolled
Patients who meet any of the following exclusion criteria will not be eligible for this study. 
Assessments must be performed according to the timing specified in the schedule of 
assessments (see Appendix 1): 
1.
History of treatment with trastuzumab emtansine
2.
Prior enrollment into a clinical study containing trastuzumab emtansine regardless of
having received trastuzumab emtansine or not


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Protocol MO28231, Version 6 
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3.
Peripheral neuropathy of Grade ≥ 3 per National Cancer Institute (NCI) common
terminology criteria for adverse events (CTCAE) Version 4.0
4.
History of other malignancy within the previous 5 years, except for appropriately treated
carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage 1 uterine cancer,
synchronous or previously diagnosed HER2-positive BC
5.
History of receiving any anti-cancer drug/biologic or investigational treatment within 21
days prior to first study treatment except hormone therapy, which can be given up to 7
days prior to first study treatment; recovery of treatment-related toxicity consistent with
other eligibility criteria
6.
History of exposure to the following cumulative doses of anthracyclines:
•
Doxorubicin or liposomal doxorubicin > 500 mg/m2
•
Epirubicin > 900 mg/m2
•
Mitoxantrone > 120 mg/m2
•
If another anthracycline, or more than one anthracycline, has been used, the
cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin
7.
History of radiation therapy within 14 days of first study treatment. The patient must
have recovered from any resulting acute toxicity (to Grade ≤ 1) prior to first study
treatment
8.
Metastatic central nervous system (CNS) disease only
9.
Brain metastases which are symptomatic. NOTE: a 14 day window after end of
radiotherapy must be observed. Patient must not be receiving steroids to control
symptoms
10. History of a decrease in LVEF to < 40% or symptomatic congestive heart failure (CHF)
with previous trastuzumab treatment
11. History of symptomatic CHF (New York Heart Association [NYHA] Classes II−IV) or
serious cardiac arrhythmia requiring treatment
12. History of myocardial infarction or unstable angina within 6 months of first study
treatment
13. Current dyspnea at rest due to complications of advanced malignancy or requirement
for continuous oxygen therapy
14. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular,
pulmonary, or metabolic disease)
15. Pregnancy or lactation
16. Currently known active infection with HIV, hepatitis B virus, or hepatitis C virus
17. History of intolerance (such as Grade 3−4 infusion reaction) or hypersensitivity to
trastuzumab or murine proteins or any component of the product
18. Assessed by the investigator to be unable or unwilling to comply with the requirements
of the protocol throughout
Length of Study 
Cohort 1 
Last Patient Last Visit (LPLV) for Cohort 1 will be approximately 4 years after enrollment of 
the first patient into Cohort 1. Enrollment is estimated to take 2 years and there will be 2 
years of follow-up after the last patient has been enrolled into Cohort 1. Patients will receive 
study medication until unacceptable toxicity, withdrawal of consent, disease progression, 
death, or up to a maximum of 2 years after the last patient has been enrolled into Cohort 1, 
whichever occurs first.  
Cohort 2 
LPLV for Cohort 2 and global End of Study will be also 4 years after enrollment of the first 
patient into Cohort 2. Enrollment is estimated to take 2 years and there will be 2 years of 
follow-up after the last patient has been enrolled into Cohort 2. Patients will receive study 
medication until unacceptable toxicity, withdrawal of consent, disease progression, death, or 
up to a maximum of 2 years after the last patient has been enrolled into Cohort 2, whichever 
occurs first. Patients who are under trastuzumab emtansine treatment as of the date of 
version 6 of this protocol will continue under MO28231 protocol until 31 Dec 2019. After this 
date, or earlier if site activation in China allows, these patients will be transferred to and 
treated under the Kadcyla extension study protocol, BO25430. 


 
 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
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Overview of Cohort 1 and 2 
Enrollment into Cohort 2 will begin around the end of enrollment into Cohort 1. Therefore, 
the entire length of the study (covering enrollment and follow-up period) is estimated to be 6 
years.     
End of Study 
Last patient, last visit (LPLV) as per definition is the last data collection point, which can be 
a clinic visit or a laboratory sample (see above Length of Study). 
Safety Outcome Measures 
• 
Incidence, nature and severity by NCI CTCAE version 4.0 of adverse events (AEs) and 
serious AEs (SAEs), including AEs Grade 3 or higher for hepatic events, allergic 
reactions, thrombocytopenia, hemorrhage events, and also all other AEs Grade 3 or 
higher related to trastuzumab emtansine. Pneumonitis events of all grades will be 
analyzed. 
• 
Incidence of CHF 
• 
Cases of drug-induced liver injury meeting Hy’s law criteria 
• 
LVEF decrease over the course of the study as measured by ECHO or MUGA 
• 
Laboratory test abnormalities 
• 
Premature withdrawal from study and study medication 
• 
Exposure to study medication 
Efficacy Outcome Measures 
• 
Efficacy will be assessed according to response evaluation criteria for solid tumors 
(RECIST) v1.1 as per investigator assessment 
• 
Parameters measured will be: PFS, OS, ORR, CBR, DoR, and TTR 
Pharmacoeconomics Outcome Measures 
The resource expenditure due to hospitalizations that are not study-defined evaluations 
while on study treatment will be evaluated. The number of hospital visits, number of days 
admitted, and type of visits (emergency department versus inpatient care) will be collected. 
The reason for admission (disease progression versus AE) will also be assessed. 
Investigational Medicinal Product 
Test Product 
Trastuzumab emtansine will be administered intravenously every 3 weeks at a dose of 
3.6 mg/kg over approximately 90 minutes for the first dose and 30 (±10) minutes for 
subsequent doses. 
The total trastuzumab emtansine dose will be calculated based on the patient’s weight up to 
28 days before each cycle with no upper limit. If within these 28 days a patient experiences 
a severe weight loss, the dose will be recalculated accordingly. 
Patients will receive study medication until unacceptable toxicity, withdrawal of consent, 
disease progression, death, or up to a maximum of 2 years after the last patient has been 
enrolled into the trial, whichever occurs first.  
Patients who have not progressed at the end of the trial will be offered the following options 
to continue with treatment: 
• 
Patients in countries in which trastuzumab emtansine is approved and reimbursed for 
this indication at the study end, may continue treatment outside this study in accordance 
with local labeling and reimbursement. 
• 
Patients in countries in which trastuzumab emtansine is not approved and/or not 
reimbursed for this indication or local regulations do not allow patients to receive 
continued treatment in this way, will be offered the possibility to continue treatment in an 
extension study. 
Non-Investigational Medicinal Product 
Not applicable 


 
 
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Statistical Methods 
Analysis populations 
All safety and efficacy summaries will be presented for each cohort separately and for the 
pooled analysis of Cohorts 1 and 2.  
Two Safety populations will be defined; Safety population 1 and Safety population 2, which 
will be used to summarize safety variables.  
Safety population 1 will include all patients who have received at least one dose of study 
medication in Cohort 1 while Safety population 2 will include all patients who received at 
least one dose of study medication in Cohort 2.  
Pooled analysis for safety will be performed on the Safety population that includes all 
patients in Safety population 1 and Safety population 2. 
The efficacy variables will be summarized for the intent-to-treat (ITT) population 1 and ITT 
population 2. ITT1 will include all patients enrolled in Cohort 1, while ITT2 will include all 
patients in Cohort 2. 
Pooled analysis for efficacy will be performed on the ITT population that includes ITT1 and 
ITT2.  
Primary Analysis 
The primary endpoint of Cohort 1, Cohort 2 and the pooled analysis of Cohorts 1 and 2 will 
be AEs Grade ≥ 3, specifically, hepatic events, allergic reactions, thrombocytopenia, 
hemorrhage events and all Grade ≥ 3 AEs related to trastuzumab emtansine. Pneumonitis 
events of all grades will be analyzed.  
In addition, AEs leading to treatment interruption and discontinuation, SAEs, cause of death, 
incidence of CHF, premature discontinuation from study and treatment, laboratory 
parameters and exposure to study drug will be secondary safety variables.  
Safety will be assessed through summaries of AEs, SAEs, deaths, and changes in 
laboratory test results. 
There are no formal statistical hypothesis tests to be performed. There are no adjustments 
for multiplicity of endpoints or within-subgroup comparisons. 
Efficacy is the secondary endpoint. Efficacy endpoints will be: PFS, OS, ORR, CBR, DoR, 
and TTR. 
Safety Data Analysis 
Summaries of safety data described below will be performed for Cohort 1, Cohort 2, and the 
pooled analysis. 
All AEs will be assessed according to the NCI CTCAE v 4.0 grading system. The analysis of 
AEs will focus on treatment-emergent AEs i.e., AEs occurring on the day of or after first 
administration of study drug. Non-treatment-emergent AEs (i.e., those occurring before 
commencement of study medication) will only be listed. 
AEs will be summarized according to the primary system-organ class (SOC) and within 
each SOC, by Medical Dictionary for Regulatory Activities (MedDRA) preferred term. Based 
on the safety profile of trastuzumab emtansine, time to onset of the first episode of each AE 
described in Section 5 will also be summarized via Kaplan-Meier (KM) estimates. Additional 
summaries by frequency tables will also be provided for these AEs. Pneumonitis events of 
all grades will be analyzed. 
AEs Grade 3 or higher for hepatic events, allergic reactions, thrombocytopenia, hemorrhage 
events, and also all other AEs Grade 3 or higher, AEs leading to treatment interruption and 
discontinuation, pneumonitis of all grades, and SAEs will be analyzed in a similar way to all 
AEs.  
Cause of death will also be summarized and listed. 
The number of patients prematurely discontinued from the treatment with corresponding 
reason for discontinuation will be summarized and listed. The discontinuation from study will 
be also summarized and listed. 
Descriptive statistics will be presented for cumulative study medication doses and duration 
of exposure. 
LVEF over time will be analyzed using descriptive statistics for continuous variable and 
presented graphically over time with associated 95% confidence interval (CI). 


 
 
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Laboratory parameters, hematology, and serum biochemistry will be presented in shift 
tables of NCI CTCAE version 4.0 grade at baseline versus worst grade during treatment 
period. The summary of laboratory parameters presented by means, standard deviation, 
minimum, and maximum will also be presented. The selected laboratory parameters will be 
graphically presented over time. 
Efficacy Analyses 
Summaries of efficacy will be performed for Cohort 1, Cohort 2 and the pooled analysis. 
Estimates for the survivor function for PFS, OS, DoR and TTR will be obtained by the KM 
approach. 
The analysis of ORR is based on the best (confirmed) overall response (BOR). The BOR 
will be assessed by the number and proportion of responders and non-responders, together 
with two-sided 95% CIs. Only patients with measurable disease at baseline will be included 
in the analysis of the BOR. Patients without a post-baseline tumor assessment will be 
considered to be non-responders.  
Logistic analysis will be performed for BOR rate to assess the influence of baseline 
covariates, e.g., age (> 65, ≤ 65), ECOG 0–1 versus ECOG 2 in an exploratory manner.  
In addition to these predictor factors, for the pooled analysis of Cohorts 1 and 2, a further 
factor will be added: region (Asian versus non-Asian regions).  
More details will be specified in the statistical analysis plan. 
CBR will be summarized in a similar way to BOR. 
Exploratory Analyses 
The following subgroup analyses will be performed for both cohorts and pooled across 
cohorts: 
• 
AST or ALT increases that are > 3 × ULN and total bilirubin > 2 × ULN except in 
patients with documented Gilbert syndrome 
• 
Country 
• 
Race 
• 
Region (Asia versus non-Asia regions) 
• 
Age (> 65, ≤ 65) 
• 
Age (>75, ≤75) 
• 
ECOG 0–1 versus ECOG 2 
Other Analyses 
Baseline and disease characteristics such as demographics, medical history, etc. will be 
summarized by descriptive statistics (frequency tables for categorical variables and mean, 
median, range, standard deviation, and 25th-75th quartiles for the continuous variables).  
Pharmacoeconomics: the resource expenditure due to hospitalizations that are not study-
defined evaluations while on study treatment will be also evaluated and summarized. 
Determination of Sample Size 
A sample size of approximately 2000 patients is planned for Cohort 1 of this study. For the 
purpose of the estimation of sample size, the incidence of AEs of Grade 3 or higher related 
to trastuzumab emtansine was chosen as a safety endpoint of primary interest. 
If the observed incidence of AEs Grade ≥ 3 related to trastuzumab emtansine e.g., hepatic 
events, pneumonitis, thrombocytopenia or allergic reactions is between 5% and 10% (Study 
TDM4450g/BO21976), the precision for the estimation of the incidence of AE is presented in 
the table below by 95% Clopper-Pearson CIs. 


 
 
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Cohort 1: Clopper-Pearson 95% Confidence Intervals for the incidence of AEs Grade ≥ 3 based 
on 2000 patients  
Number of AEs/observed AE incidence 
95% Clopper-Pearson CI 
20 (1%) 
0.6% - 1.5% 
40 (2%) 
1.4% - 2.7% 
60 (3%) 
2.3% - 3.8% 
80 (4%) 
3.2% - 5% 
100 (5%) 
4.1% - 6% 
120 (6%) 
5% - 7.1% 
140 (7%) 
5.9% - 8.2% 
160 (8%) 
6.8% - 9.3% 
180 (9%) 
7.8% - 10.3% 
200 (10%) 
8.7% - 11.4% 
 
For the purpose of the sample size estimate of Cohort 2, the incidence of Grade ≥ 3 
thrombocytopenia in Asian patients was chosen as a safety endpoint of primary interest. 
This is based on the pooled analysis of various trials TDM4370g/BO21977, 
TDM4450g/BO21976, TDM4373g/BO22495, TDM4374g, TDM4258g, TDM4688g, 
TDM3569g and TDM4529g/BO25430, and the results of a subset of 99 Asian patients (see 
the trastuzumab emtansine Investigator’s Brochure).   
If the observed incidence of Grade ≥ 3 thrombocytopenia in Asian patients is between 30% 
and 55%, the precision for the estimation of the incidence of AEs is presented in the table 
below by 95% Clopper-Pearson CIs. 
 
Cohort 2: Clopper-Pearson 95% Confidence Intervals for the incidence Grade ≥ 3 
thrombocytopenia based on 220 Asian patients 
Number of AEs/observed AE incidence 
95% Clopper-Pearson CI 
2 (1%) 
0.1% - 3.6% 
10 (5%) 
2.4% - 9% 
20 (10%) 
6.2% - 15% 
60 (30%) 
23.7% - 36.9% 
70 (35%) 
28.4% - 42% 
80 (40%) 
33.2% - 47.1% 
90 (45%) 
38% - 52.2% 
100 (50%) 
42.9% - 57.1% 
110 (55%) 
47.8% - 62% 
 
The sample size of approximately 2220 patients is planned for the pooled analysis of 
Cohorts 1 and 2.  


 
 
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Clopper-Pearson 95% Confidence Intervals for the incidence of AEs Grade ≥ 3 based on 2220 
patients 
Number of AEs/observed AE incidence 
95% Clopper-Pearson CI 
22 (1%) 
0.6% - 1.5% 
44 (2%) 
1.5% - 2.7% 
66 (3%) 
2.3% - 3.8% 
88 (4%) 
3.2% - 4.9% 
110 (5%) 
4.1% - 6% 
132 (6%) 
5% - 7.1% 
154 (7%) 
6% - 8.1% 
176 (8%) 
6.9% - 9.2% 
198 (9%) 
7.8% - 10.3% 
220 (10%) 
8.8% - 11.3% 
Interim Analyses 
Cohort 1, Cohort 2 and pooled analysis of Cohorts 1 and 2 
The final analysis of each cohort will be performed when all patients within the respective 
cohort have been followed up for safety and efficacy for a period of up to 2 years after the 
last patient has been enrolled into the respective cohort, with further review of accumulating 
safety as required (see iDMC charter). The pooled analysis of Cohorts 1 and 2 will be 
conducted in parallel to the final analysis of Cohort 2. 
Cohort 1 
In addition to the final analysis, there will be five interim safety analyses for review by the 
independent Data Monitoring Committee (iDMC): after approximately 50 and 350 patients 
have completed Cycle 1, Day 1 and after approximately 1,000, 1,500, and 2,000 patients 
have completed the first cycle of study medication (Cycle 1, Day 21).  
Cohort 2 
In addition to the final analysis, there will be one interim safety analysis for review by the 
iDMC after approximately 100 patients have completed Cycle 1 (Cycle 1, Day 21).  
In addition to the above interim analyses, there might be additional interim analyses for 
Health Authority purposes (e.g., to support SFDA [China]) after 150 Chinese patients have 
been enrolled and completed Cycle 1 (Cycle 1, Day 21) or by January 2017, whichever 
occurs first. 
 


 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADC 
antibody-drug conjugate 
AE 
adverse event 
ALT 
alanine aminotransferase  
AST 
aspartate aminotransferase 
AUC 
area under the serum concentration-time curve 
BOR 
best overall response  
BUN 
blood urea nitrogen 
BC 
breast cancer 
CBR 
clinical benefit rate 
CHF 
congestive heart failure 
CI 
confidence interval 
CL 
clearance 
Cmax 
maximum concentration 
CNS 
central nervous system 
CR 
complete response 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
common terminology criteria for adverse events 
DoR 
duration of response 
DLT 
dose-limiting toxicity 
DoR 
duration of response 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EEA 
European economic area 
EU 
European Union 
FDA 
Food and Drug Administration 
HER2 
human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
hazard ratio 
ICH 
International Conference on Harmonization 
iDMC 
independent Data Monitoring Committee 
IHC 
Immunohistochemistry 
ILD 
interstitial lung disease 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 


 
 
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INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ISH 
in situ hybridization 
ITT 
Intent-to-treat 
IV 
intravenous 
IxRS 
interactive voice/web recognition system 
KM 
Kaplan-Meier 
LABC 
locally advanced breast cancer 
LVEF 
left ventricular ejection fraction 
LPLV 
last patient, last visit 
mBC 
metastatic breast cancer 
MCC 
maleimidylmethyl cylcohexane-1-carboxylate 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multiple-gated acquisition 
NCI 
National Cancer Institute 
NRH 
nodular regenerative hyperplasia 
NYHA 
New York Heart Association 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression free survival 
PK 
pharmacokinetic 
PR 
partial response 
PRO 
patient-reported outcome 
PVC 
polyvinyl chloride 
QT 
measure between Q wave and T wave in the heart's 
electrical cycle 
QTcF 
heart rate-corrected QT interval using the Fridericia 
formula 
q3w 
every 3 weeks 
qw 
weekly 
RECIST 
response evaluation criteria for solid tumors 
SAE 
serious adverse event 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOC 
system-organ class 
SWFI 
sterile water for injection 


 
 
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t½ 
terminal half-life 
T-DM1 
trastuzumab emtansine 
TTR 
time to response 
ULN 
upper limit of normal 
Vss 
apparent volume of distribution at steady state 
WBC 
white blood cells 
WHO 
World Health Organization 


 
 
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1. 
 BACKGROUND 
1.1 
HER2-POSITIVE, METASTATIC BREAST CANCER 
Breast cancer (BC) is the most common cancer in women worldwide, both in 
the developed and the developing world (WHO, World Health Statistics. 2011), 
with approximately 1.38 million new cases diagnosed in 2008. It is also the 
leading cause of cancer death in females, accounting for 458,400 deaths 
(14% of all cancer deaths) in 2008 (Jemal et al. 2011). Almost 100,000 of 
these BC-related deaths occurred in patients whose tumors overexpressed 
the human epidermal growth factor receptor 2 (HER2). Metastatic breast 
cancer (mBC) is incurable, with the primary goal of treatment to extend life 
and palliate symptoms while preserving quality of life. 
The HER tyrosine kinase receptor family is comprised of four receptors: HER1, 
HER2, HER3, and HER4. These receptors are important mediators of cell 
growth, survival, and differentiation (Sundaresan et al. 1999). Activation of 
HER receptors leads to receptor dimerization and cell signaling through the 
PI3-kinase/AKT pathway for promotion of tumor cell survival and through the 
mitogen-activated protein kinase pathway for cellular proliferation. 
Overexpression of HER2 is observed in approximately 15–20% of human BCs. 
Several lines of scientific and clinical evidence support a direct role for HER2 
overexpression in the aggressive growth and poor clinical outcomes 
associated with these tumors (Slamon et al. 1987). The development of 
trastuzumab in the 1990s provided women with HER2-overexpressing tumors 
with a markedly better outcome than was possible with chemotherapy alone. 
Increases in response rate, response duration, and progression-free survival 
(PFS) were associated with a 5-month survival advantage when trastuzumab 
was given in the first-line metastatic setting, as demonstrated in the initial 
Phase III trial (Slamon et al. 2001). 
For patients with HER2-positive mBC, the combination of trastuzumab and a 
taxane is a globally accepted first-line treatment, based on the survival 
advantage demonstrated in two large pivotal trials (Slamon et al. 2001; Marty 
et al. 2005). However, virtually all patients with HER2-positive mBC develop 
progressive disease (PD) and require additional therapies. Importantly, such 
tumors continue to express high levels of HER2 (Spector et al. 2005), and 
neither the process of internalization nor the level of surface expression is 
altered when HER2 is bound by trastuzumab (Austin et al. 2004). HER2-
directed combination therapy beyond progression for HER2-positive mBC is 
an accepted palliative treatment approach.  
An accepted example of second-line therapy for HER2-positive mBC therapy 
is lapatinib in combination with capecitabine as a treatment for patients who 
have received trastuzumab and a taxane for advanced disease. In a Phase III 
trial involving patients with advanced HER2-positive BC previously treated 
with an anthracycline, a taxane, and trastuzumab, the addition of lapatinib to 
capecitabine resulted in an increased response rate (24% versus 14%) and 


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time to disease progression (6.2 months versus 4.3 months) (Geyer et al. 
2006). 
1.2 
BACKGROUND ON TRASTUZUMAB EMTANSINE 
The study drug, trastuzumab emtansine (also known as T-DM1, see Figure 1) 
is a novel antibody–drug conjugate (ADC) that is specifically designed for the 
treatment of HER2-positive malignancies. Trastuzumab emtansine is 
composed of trastuzumab (Herceptin®), a humanized monoclonal antibody 
directed against the extracellular region of HER2; an average of 3.5 
molecules of DM1 (maytansinoid), an anti-microtubule agent derived from 
maytansine; and the thioether linker maleimidylmethyl cylcohexane-1-
carboxylate (MCC), which is used to conjugate each molecule of DM1 to 
trastuzumab. DM1 is a highly potent drug synthesized from maytansinol that 
binds β–tubulin to inhibit tubulin polymerization. It binds to tubulin 
competitively with vinca alkaloids, but is 20–100 times more potent than 
vincristine in its cytotoxic effect against tumor cell lines. Its parent molecule, 
maytansine, has been studied in approximately 800 cancer patients in the 
1970s and 1980s, with responses seen in patients with breast and lung 
cancer (Junttila et al. 2011; Issell and Crooke 1978). However, because of its 
narrow therapeutic index and the observed gastrointestinal toxicity of the free 
drug, it was not developed further as a therapeutic option (Cassady et al. 
2004; Cabanillas et al. 1979). 
Trastuzumab emtansine and trastuzumab recognize the same epitope on 
HER2 and are binding with a similar affinity. Following antigen specific binding 
of trastuzumab emtansine to HER2, it is hypothesized that the complex of 
receptor and ADC is internalized, where upon DM1-containing catabolites are 
released into the cytosol following proteolytic cleavage of the antibody in 
lysosomes (Erickson et al. 2006). Binding of these DM1-containing species to 
β-tubulin inhibits tubulin polymerization resulting in cell death (Cassady et al. 
2004). 
In addition to targeting delivery of DM1 to HER2-overexpressing tumor cells, 
trastuzumab emtansine retains the anti-tumor activities of trastuzumab, 
including suppression of HER2 signaling pathways that confer a proliferative 
and survival advantage to cells, and the flagging of cells for destruction 
through antibody-dependent cell cytotoxicity (Junttila et al. 2011). 
Completed and ongoing Phase I and II single arm studies of trastuzumab 
emtansine have demonstrated clinical activity. The randomized Phase II study 
BO21976 described in Section 1.2.1.4 showed a significant improvement in 
PFS with a HR 0.59 p=0.0353 and a favorable safety profile compared with 
the standard of care trastuzumab and taxane combination. A Phase III study 
BO21977 (see Section 1.2.1.6) is underway comparing trastuzumab 
emtansine to standard of care HER2-targeted combination therapy 
(capecitabine and lapatinib) for patients with mBC who had received prior 
trastuzumab and taxane therapies. This trial has met its co-primary endpoint 
of improving PFS (by an independent review committee [IRC]) in patients who 
received trastuzumab emtansine compared with those who received the 
combination of lapatinib and capecitabine. 




 
 
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1.2.1.1 
Study TDM3569g  
Study TDM3569g was a Phase I, dose-escalation study that evaluated the 
safety and efficacy of trastuzumab emtansine as a single agent in 52 patients 
with HER2-positive mBC, whose disease progressed on a trastuzumab-
containing chemotherapy regimen. The study was completed on 11 June 
2009, with a total of 52 patients treated; 24 patients received trastuzumab 
emtansine every 3 weeks (q3w); 28 patients received trastuzumab emtansine 
on a weekly schedule. 
On the q3w dosing schedule, DLTs of Grade 4 thrombocytopenia were seen 
in 2 of 3 patients treated at 4.8 mg/kg. Therefore, 3.6 mg/kg was determined 
to be the maximum tolerated dose (MTD) of trastuzumab emtansine given 
q3w, and the cohort was expanded to 15 patients. On the basis of these data, 
the recommended dose schedule for the Phase II studies was 3.6 mg/kg q3w. 
Treatment with trastuzumab emtansine was well tolerated, and toxicity was 
generally mild, reversible, and non-cumulative. No drug-related cardiac 
toxicity was noted. 
Trastuzumab emtansine administration demonstrated considerable activity in 
this Phase I study. The confirmed overall response rate (ORR) in patients with 
measurable disease at the 3.6 mg/kg q3w schedule was 44% (4 of 9 patients), 
as assessed by investigators. The median PFS among the 15 patients 
receiving 3.6 mg/kg q3w was 10.4 months. 
1.2.1.2 
Study TDM4258g 
Study TDM4258g was a Phase II study that evaluated the safety and efficacy 
of trastuzumab emtansine administered at a dose of 3.6 mg/kg (intravenous 
[IV]) q3w in patients with HER2-positive mBC who had progressed on 
previous HER2 directed therapy and conventional chemotherapy. 
The primary objectives for this study were: 1) to assess the ORR (by 
independent radiologic review) associated with trastuzumab emtansine 
3.6 mg/kg IV q3w, and 2) to characterize the safety and tolerability of 
trastuzumab emtansine at this dose. 
The study was activated on 20 July 2007, and enrollment was completed 
(n = 112) on 31 July 2008. The final analysis of ORR was performed with a 
data cut-off date of 25 June 2009, 11 months after the last patient was 
enrolled. The reported ORR in all patients was 37.5% (95% confidence 
interval [CI], 28.6%, 46.6%) by investigator assessment and 25.9% (95% CI, 
18.4%, 34.4%) by IRC. The clinical benefit rate ([CBR] defined as complete 
response [CR], partial response [PR], or stable disease for >6 months) was 
46.3% by investigator assessment and 39.3% by independent review. The 
median PFS was 4.6 months as assessed by both the investigators and the 
IRC. In the subset of patients whose archival primary tumors were 
retrospectively confirmed to be HER2-positive (74 of 95 patients with 
submitted tumor samples), the ORR was 33.8% by independent review and 
47.3% based on investigator assessment. 


 
 
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The most common AEs (occurring in ≥20% of patients) were fatigue (65.2%), 
nausea (50.9%), headache (40.2%), epistaxis (35.7%), pyrexia (34.8%), 
constipation (30.4%), cough (27.7%), hypokalemia (26.8%), diarrhea (25.9%), 
vomiting (24.1%), arthralgia (22.3%), pain in extremity (22.3%), anemia 
(20.5%), and dyspnea (20.5%). Most of these AEs were Grade 1–2. The three 
most common Grade 3–4 AEs observed in this trial were hypokalemia (8.9%), 
thrombocytopenia (8.0%), and fatigue (4.5%). There was one reported Grade 
5 event in a patient who died of respiratory failure attributed by the 
investigator to underlying disease. No Grade ≥3 left ventricular systolic 
dysfunction events (symptomatic congestive heart failure [CHF] and/or left 
ventricular ejection fraction [LVEF] of <40%) were observed. 
1.2.1.3 
Study TDM4374g 
Study TDM4374g was a Phase II, single arm study of trastuzumab emtansine 
administered at 3.6 mg/kg by IV infusion q3w to patients with HER2-positive 
mBC. Patients must have received an anthracycline, trastuzumab, a taxane, 
lapatinib, and capecitabine given in the neo-adjuvant, adjuvant, or metastatic 
setting or as treatment for locally advanced disease. Patients must have been 
treated with two HER2-directed therapies in the metastatic or locally 
advanced setting and have progressed on their most recent treatment. 
The primary objectives of this study were: 1) to assess the ORR as assessed 
by an independent review using the modified Response Evaluation Criteria for 
Solid Tumors (RECIST; v. 1.0, and 2) to characterize the safety and 
tolerability of this trastuzumab emtansine regimen in the aforementioned 
patient population. The study was activated on 2 May 2008, and enrollment 
was complete on 2 April 2009. A total of 110 patients were enrolled and 
treated in the study. 
An efficacy analysis (data cut-off date: 21 June 2010) with a median follow-up 
of 17.4 months demonstrated an ORR (complete and PR of 34.5% (95% CI: 
26.1–43.9%; 38 of 110 patients) by Independent Review Facility and 32.7% 
(95% CI: 24.1–42.1%; 36 patients) by investigator assessment. The CBR was 
48.2% by independent review and 46.4% by investigator assessment. The 
median duration of response (DoR) and PFS by independent review were 7.2 
months and 6.9 months, respectively. In the subset of patients whose archival 
primary tumors were retrospectively confirmed to be HER2-positive (80 of 95 
patients with submitted tumor samples), the ORR was 41.3% by independent 
review and 40.0% based on investigator assessment. 
The most common AEs (occurring in ≥20% of patients) were fatigue (61.8%), 
thrombocytopenia (38.2%), nausea (37.3%), increased AST (26.4%), 
constipation (23.6%), pyrexia (22.7%), epistaxis (22.7%), headache (21.8%), 
hypokalemia (20.9%), decreased appetite (20.9%), dry mouth (20.0%), and 
anemia (20.0%). Most of these AEs were Grade 1–2. Fifty-two patients 
(47.3%) experienced at least one Grade ≥3 AE, the most common being 
thrombocytopenia (9.1%) and fatigue (4.5%). SAEs were recorded by 28 
patients (25.5%), the most common being cellulitis (3.6%), pyrexia (2.7%), 
and pneumonia (2.7%). One patient recorded a Grade 5 AE of hepatic 
dysfunction, which was recorded as possibly related to trastuzumab 


 
 
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emtansine. The patient had pre-existing non-alcoholic fatty liver disease as 
well as multiple other co-morbidities, including renal insufficiency. 
1.2.1.4 
Study BO21976 
This was a randomized, multicenter, Phase II study of the efficacy and safety 
of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with 
metastatic HER2-positive BC who had not received prior chemotherapy for 
metastatic disease. This study completed enrollment in December 2009 
(n = 137). The primary objectives were to assess the efficacy of trastuzumab 
emtansine compared with the combination of trastuzumab and docetaxel, as 
measured by PFS based on investigator tumor assessments, and to 
characterize the safety of trastuzumab emtansine compared with the 
combination of trastuzumab and docetaxel in this population. Secondary 
endpoints included ORR, survival, and DoR. 
The data cut-off date was 15 November 2010. Seventy patients were 
randomized to the control arm and 67 patients to the trastuzumab emtansine 
arm. The median duration of follow-up was 13.5 months for the control arm 
and 13.8 months for the trastuzumab emtansine arm. 
PFS was 14.2 months in the trastuzumab emtansine arm versus 9.2 months 
in the trastuzumab plus docetaxel arm. The hazard ratio (HR) for PFS was 
0.594 (95% CI: 0.364–0.968; p = 0.0353). The ORR in the trastuzumab 
emtansine arm was 64.2% (95% CI: 51.8–74.8%) compared with 58.0% (95% 
CI: 45.5–69.2%) in the control arm (based on 69 evaluable patients). The 
CBR was 74.6% (95% CI: 63.2–84.2%) in the trastuzumab emtansine arm 
versus 81.2% (95% CI: 70.7–89.1%) in the trastuzumab plus docetaxel arm 
(based on 69 evaluable patients). Based on safety data analyzed at the data 
cut-off date, single-agent trastuzumab emtansine appears to have a favorable 
overall safety profile compared with trastuzumab and docetaxel in first-line 
mBC. The incidence of Grade ≥3 AEs in the control arm (89.4%; n = 66) was 
nearly twice that of trastuzumab emtansine (46.4%; n = 69). The rates of 
SAEs for both arms were similar (control arm 25.8% versus trastuzumab 
emtansine 18.8%). One patient in the trastuzumab emtansine group died as a 
result of an AE (sudden death). This patient was randomized to receive 
trastuzumab plus docetaxel but mistakenly received a single dose of 6 mg/kg 
trastuzumab emtansine instead of 6 mg/kg trastuzumab. One patient in the 
trastuzumab plus docetaxel group died due to cardiopulmonary failure. With 
respect to cardiotoxicity, based on local assessments of LVEF, trastuzumab 
emtansine was not associated with an increase in cardiotoxicity compared 
with trastuzumab plus docetaxel. 
1.2.1.5 
Study TDM4688g 
The effect of trastuzumab emtansine (3.6 mg/kg q3w) on the QT interval in 
patients with HER2-positive recurrent locally advanced BC or mBC was 
evaluated in Study TDM4688g. Trastuzumab emtansine had no meaningful 
effect on the corrected QT interval in these patients. At Cycle 1, Day 1, 15 
minutes post-infusion, the baseline-adjusted mean heart rate-corrected QT 
interval using the Fridericia formula (QTcF) increased by 1.2 ms. By 60 


 
 
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minutes post-infusion, the baseline-adjusted mean QTcF interval decreased 
by 1.0 ms, and by Day 8 of Cycle 1, the baseline-adjusted mean QTcF 
interval decreased by 4.0 ms. By Cycle 3 Day 1, prior to trastuzumab 
emtansine infusion, the mean QTcF interval had reverted back to baseline. 
Following the third infusion of trastuzumab emtansine, the baseline-adjusted 
average QTcF interval at both the 15-minute and the 60-minute post-infusion 
time points was increased by an average of 4.7 ms. No patient exhibited an 
average change in QTcF interval from baseline exceeding 30 ms at any of the 
protocol-specified time points. 
The relationship between trastuzumab emtansine pharmacokinetic (PK) and 
electrocardiogram (ECG) data was also assessed. While there appears to be 
a trend between trastuzumab emtansine drug concentration and its effect on 
QT interval, at the observed concentration ranges of trastuzumab emtansine, 
DM1, and total trastuzumab, there is reasonable assurance that the true 
increase in mean baseline-adjusted average QTcF does not exceed 5 ms. 
Moreover, because trastuzumab emtansine, total trastuzumab, and DM1 
achieve steady-state levels by Cycle 3, the likelihood of progressively longer 
QTcF with repeated trastuzumab emtansine dosing is low. 
In this study, ORR of 25.5% (95% CI: 15.2–38.5%) was assessed by the 
investigator; no independent review was performed in this study. The CBR 
was 39.2% (95% CI: 25.8–53.1%), and the median PFS was 4.3 months (95% 
CI: 4.0–6.7). 
1.2.1.6 
Study BO21977 (EMILIA) 
Roche has conducted a randomized, open-label Phase III trial (BO21977) of 
single-agent trastuzumab emtansine versus lapatinib and capecitabine in 
HER2-positive locally advanced unresectable BC or mBC patients who have 
received a prior taxane and trastuzumab therapy and have documented 
disease progression. 991 patients have been enrolled. 
Patients were randomized in a 1:1 ratio to trastuzumab emtansine or 
capecitabine plus lapatinib.  
Trastuzumab emtansine was administered at 3.6 mg/kg IV every 3 weeks. 
The control arm treatment is capecitabine at 1,000 mg/m2 as oral doses twice 
daily on Days 1–14 of a 21-day cycle plus oral lapatinib 1,250 mg/day given 
as continuous dosing. Study treatment was discontinued based on disease 
progression (as assessed by the investigator), unmanageable toxicity or study 
termination by the Sponsor. 
This study of trastuzumab emtansine met both primary efficacy endpoints of 
PFS by independent review and OS in patients with mBC previously treated 
with a taxane and trastuzumab (Herceptin).  
PFS and OS were investigated as co-primary endpoints in this study with PFS 
based on modified RECIST (Therasse et al. 2000) and conducted by the IRC. 
An additional tumor assessment of PFS was performed after investigator-
documented disease progression. Furthermore ORR, DoR, and CBR were 


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included, on the basis of both investigator and independent review of tumor 
assessments, as key secondary endpoints. 
Patients in the trastuzumab emtansine arm had a median PFS of 9.6 months 
vs. 6.4 months for patients in the control arm of lapatinib + capecitabine 
(HR=0.65; 95% CI: 0.55–0.77; P < 0.001).  A consistent PFS benefit with 
T-DM1 vs. lapatinib + capecitabine was seen in all clinically relevant 
subgroups. Patients in the trastuzumab emtansine arm had a median OS of 
30.9 months vs. 25.1 months for patients in the control arm of 
lapatinib + capecitabine (HR=0.68; 95% CI: 0.55–0.85; P < 0.001).
Based on safety data analyzed at the data cutoff date, single-agent 
trastuzumab emtansine appears to have a favorable overall safety profile 
compared with lapatinib and capecitabine in mBC. The incidence of Grade ≥3 
AEs in the control arm (56.9%; n = 488) was 278 compared with that of 
trastuzumab emtansine (40.8%; n = 490), which was 200. No new safety 
signals were seen with trastuzumab emtansine. 
It was concluded that overall trastuzumab emtansine demonstrated improved 
efficacy over capecitabine and lapatinib and that there is no concern 
regarding the clinical safety of trastuzumab emtansine based on the currently 
available data (Verma et al. 2012). 
1.2.1.7 
Study BO25734 (TH3RESA) 
Preliminary results from a randomized, two-arm, open-label Phase III study of 
trastuzumab emtansine compared with treatment of physician’s choice in 
patients with mBC or unresectable local advanced/recurrent HER2-positive 
BC have shown that treatment with trastuzumab emtansine resulted in a 
statistically significant improvement in PFS and fewer AEs of Grade 3 or 
higher severity in patients who had previously been treated with at least two 
HER2-directed regimens. The median PFS, as of the cutoff of 11 February 
2013, was 6.2 months for patients treated with trastuzumab emtansine vs. 3.3 
months (HR: 0.528 [0.422, 0.661]; p < 0.001) for patients who received 
treatment of physician’s choice (Wildiers et al. 2013). 
1.2.1.8 
Pharmacokinetics 
The PK of trastuzumab emtansine and its analytes (total trastuzumab and 
DM1) were characterized in one Phase I study (TDM3569g) and three 
Phase II studies (TDM4258g, TDM4374g, and TDM4688g).  
For study TDM3569g, the final PK parameter estimates based on 
non-compartmental PK analysis for q3w and weekly regimens of trastuzumab 
emtansine administration are presented in Table 1. 


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Table 1 Cycle 1 Mean (SD) Pharmacokinetic Parameters for 
Trastuzumab Emtansine Following Trastuzumab Emtansine 
Administration Every Three Weeks and Weekly in Study 
TDM3569g 
Dose 
(mg/kg) 
No. of 
Patients 
Cmax 
(μg/mL) 
AUCinf 
(day μg/mL) 
t1/2
(day) 
V 
(mL/kg) 
CL 
(mL/day/kg) 
Every 3 Week Dosing 
0.3 
3 
9.6 (1.7) 
14.5 (3.4) 
1.3 (0.2) 
35.7 (7.5) 
21.1 (4.5) 
0.6 
1 
13.3 
24.5 
1.3 
43.8 
24.5 
1.2 
1 
20.3 
42.9 
1.3 
51.8 
27.8 
2.4 
1 
76.3 
330.0 
2.2 
30.7 
7.2 
3.6 
15 
76.2 (19.1) 300.3 (65.8) 
3.1 (0.7) 
58.4 (12.4) 
12.7 (3.6) 
4.8 
3 
130.3 (7.8) 673.0 (12.2) 
4.1 (0.7) 
41.2 (6.2) 
7.1 (0.1) 
Weekly Dosing 
1.2 
3 
29.6 (5.7) 
76.2 (10.4) 
2.3 (0.6) 
47.5 (6.0) 
15.9 (2.4) 
1.6 
3 
34.3 (4.8) 
130.3 (39.7) 
3.4 (0.8) 
59.8 (16.6) 
13.0 (3.4) 
2.0 
3 
48.0 (9.6) 
175.0 (41.0) 
3.1 (0.3) 
51.0 (8.1) 
11.8 (2.4) 
2.4 
16 
54.8 (12.6) 198.5 (54.5) 
3.3 (1.1) 
55.4 (13.0) 
13.1 (4.1) 
2.9 
3 
78.1 (33.9) 212.0 (39.0) 
2.9 (0.5) 
57.7 (2.2) 
14.0 (2.6) 
AUCinf = area under the serum concentration-time curve from time 0 extrapolated to infinity; 
Cmax = maximum serum concentration; CL = clearance; t1/2 = terminal half-life; V = volume of 
distribution; SD = standard deviation. 
Trastuzumab emtansine was administered from 0.3–4.8 mg/kg once q3w 
(n = 25) and from 1.2–2.9 mg/kg once weekly ([qw], n = 28) in the Phase I 
study TDM3569g, which enrolled patients with mBC (Krop et al. 2010; 
Beeram et al. 2012). The MTD of trastuzumab emtansine were 3.6 mg/kg q3w 
and 2.4 mg/kg qw. The ORR among women with HER2-positive mBC was 
similar with either 3.6 mg/kg q3w or 2.4 mg/kg qw. Dose intensity, defined as 
percentage of the planned trastuzumab emtansine dose that was actually 
received, was higher with the 3.6 mg/kg q3w regimen (median 99.7%, range 
88%–106%) than with the 2.4 mg/kg qw schedule (median 82%, range 54%–
101%). However, since the PK of trastuzumab emtansine is linear at 
doses ≥2.4 mg/kg, an almost 2-fold higher cumulative dose can be 
administered within a 21 day cycle with a 2.4 mg/kg qw regimen compared 
with 3.6 mg/kg q3w. 
Based on a population PK analysis, trastuzumab emtansine has a consistent 
PK profile with low inter-individual variability (21–48%) in PK parameters 
among patients with mBC. Greater baseline tumor burden and lower serum 
albumin levels, potential indicators of disease severity, resulted in small 
increases (< 13%) in trastuzumab emtansine clearance (CL). However, 
trastuzumab emtansine PK was not affected by baseline residual trastuzumab 
(from prior treatment) or by differences in serum concentrations of HER2 
extracellular domain (Gupta et al. 2011, Girish et al. 2012). The population PK 


 
 
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results will be updated following the availability of data from study BO21977, 
and other studies. 
To date, no significant correlations have been observed between efficacy (as 
measured by overall response; RECIST, v1.0) and trastuzumab emtansine 
exposure (area under the concentration time-curve [AUC], maximum 
concentration [Cmax]) after 3.6 mg/kg q3w trastuzumab emtansine dosing 
across the Phase II studies (TDM4258g and TDM4374g). Trastuzumab 
emtansine exposures were similar among patients with an objective tumor 
response, stable disease, or PD. This effect appears to be consistent 
regardless of Caucasian or Asian heritage (Girish et al. 2012). Similarly, no 
obvious relationships were observed between trastuzumab emtansine 
exposure and platelet count or serum concentrations of ALT or AST during 
the course of trastuzumab emtansine treatment across the studies at the dose 
of 3.6 mg/kg q3w (to be updated following the availability of data from study 
BO21977). 
An aggregate PK assessment of trastuzumab emtansine was done with 
samples from studies TDM3569g, TDM4258g, TDM4374g, and TDM4688g 
(Girish et al. 2012). PK parameters for trastuzumab emtansine, total 
trastuzumab, and DM1 were consistent across the four studies at Cycle 1 and 
steady state. Trastuzumab emtansine PK was not affected by residual 
trastuzumab from prior therapy or circulating extracellular domain of HER2. 
No significant correlations were observed between trastuzumab emtansine 
exposure and efficacy, thrombocytopenia, or increased concentrations of 
transaminases. Across the four studies, the incidence of anti-therapeutic 
antibodies to trastuzumab emtansine was low and detected in 4.5% (13/286) 
of evaluable patients receiving trastuzumab emtansine q3w. 
The PK profile (i.e., Cmax, AUC, terminal half-life [t½], apparent volume of 
distribution at steady state [Vss], and CL) of single-agent trastuzumab 
emtansine (3.6 mg/kg q3w) is predictable, well characterized, and unaffected 
by circulating levels of HER2 extracellular domain or residual trastuzumab. 
Trastuzumab emtansine exposure does not correlate with clinical responses 
or key AEs. 
1.3 
STUDY RATIONALE AND BENEFIT–RISK 
ASSESSMENT 
At present, mBC remains an incurable disease. The primary goals of 
treatment are maximizing the patient’s survival and preserving quality of life. 
Treatment options for patients with mBC have become more numerous, with 
the option to use sequential single agents or combination regimens. Additional 
considerations to use therapies directed to specific molecular subtypes of BC 
also serve to maximize the benefit for an individual patient. 
Trastuzumab emtansine is a novel agent that has demonstrated efficacy in 
the treatment of HER2-positive mBC. 
In study TDM4450g/BO21976, trastuzumab emtansine has shown a 
significant difference in PFS in favor of trastuzumab emtansine versus the 


 
 
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current standard of care of trastuzumab and taxane (see Section 1.2.1.4) with 
a favorable safety profile. 
Study TDM4370g/BO21977 met its co-primary endpoint of improving PFS in 
patients who received trastuzumab emtansine (by IRC) and OS compared 
with those who received the combination of lapatinib and capecitabine. The 
safety profile of trastuzumab emtansine was consistent with that seen in 
previous studies (see Section 1.2.1.6).  
An integrated safety analysis of trials TDM4370g/BO21977, 
TDM4450g/BO21976, TDM4373g/BO22495, TDM4374g, TDM4258g, 
TDM4688g, TDM3569g and TDM4529g/BO25430 demonstrated that in 
884 patients who received trastuzumab emtansine, the most commonly 
reported AEs (i.e. fatigue [46.3%], nausea [42.9%], thrombocytopenia [29.3%], 
headache [29.2%], and constipation [26.4%]) and the most common Grade 3–
4 AEs (i.e. thrombocytopenia [11.7%] and increased aspartate 
aminotransferase serum concentration [4.3%]) were typically asymptomatic 
and manageable (see the Investigator’s Brochure).  
In this new study, the safety and tolerability of trastuzumab emtansine will be 
explored further to gain better understanding of the safety profile of 
trastuzumab emtansine. 
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to evaluate the safety and tolerability of 
trastuzumab emtansine.  
2.2 
SECONDARY OBJECTIVES 
The secondary objectives of this study are: 
• 
Progression-Free Survival (PFS) 
• 
Overall Survival (OS) 
• 
Overall Response Rate (ORR) = partial response (PR) + complete 
response (CR) 
• 
Clinical Benefit Rate (CBR) 
• 
Duration of Response (DoR) 
• 
Time to Response (TTR)  
2.3 
PHARMACOECONOMICS OUTCOME OBJECTIVE 
The pharmacoeconomics outcome objective for this study is as follows: 
• 
To evaluate the resource expenditures, while on study treatment, due to 
hospitalizations that are not study-defined evaluations. The number of 
hospital visits, number of days admitted, and type of visits (emergency 
department versus inpatient care) will be recorded 


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3.
STUDY DESIGN
3.1 
DESCRIPTION OF STUDY
3.1.1 
OVERVIEW
This study is a two-cohort, open-label, international, multicenter Phase IIIb 
study to evaluate the safety and tolerability of trastuzumab emtansine. 
This study will enroll patients with HER2-positive, unresectable, locally 
advanced BC (LABC) or mBC who have previously received prior anti-HER2 
and chemotherapy treatment and have progressed on or after the most recent 
treatment for LABC or mBC, or within 6 months of completing adjuvant 
therapy. 
Approximately 2220 patients will be enrolled into the study. 
•
Cohort 1 (approximately 2000 patients)
•
Cohort 2 (will include approximately 220 patients only of Asian race)
Overview of Cohort 1 and 2 
Enrollment into Cohort 2 will begin around the end of enrollment into Cohort 1. 
Therefore, the entire length of the study (covering enrollment and follow-up 
period) is estimated to be 6 years. 
Patients who have not progressed at the end of the trial will be offered options 
to continue with trastuzumab emtansine treatment, see Section 4.2.4.  
The study design is presented in Figure 2. The schedule of assessments is 
provided in Appendix 1. 
All patients will be followed up for survival every 6 months (± 14 working days) 
until death, loss to follow-up or withdrawal of consent until study closure. 
Patients who discontinue study treatment for reasons other than disease 
progression will continue to undergo tumor assessments every 3-6 months 
until study closure. 


 
 
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Figure 2 Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
Male or female HER2-
positive LABC or mBC 
patients  
• 
prior anti-HER2 
agent and 
chemotherapy 
• 
progression on most 
recent metastatic 
treatment or within 6 
months of completing 
adjuvant therapy 
Trastuzumab Emtansine 
Enrollment 
3.6 mg/kg administered intravenously every 3 weeks. 
Patients will receive study medication until unacceptable toxicity, withdrawal of 
consent, disease progression, death, or up to a maximum of 2 years after the last 
patient has been enrolled into Cohort 1, whichever occurs first. 
Cohort 2: 220 patients 
only of Asian race 
Cohort 1: 2000 patients 
Trastuzumab Emtansine 
 
 
 
Patients will receive study medication until unacceptable toxicity, withdrawal of consent, 
disease progression, death, or up to a maximum of 2 years after the last patient has been 
enrolled into Cohort 2, whichever occurs first. 
3.6 mg/kg administered intravenously every 3 weeks. 


 
 
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3.1.2 
INDEPENDENT DATA MONITORING COMMITTEE 
An independent data monitoring committee (iDMC) will review the safety data 
after approximately 50 patients have received at least one dose of study 
medication, with further review of accumulating safety data as required. Data 
will also be reviewed after each interim analysis (see Section 6.5). See the 
iDMC charter for further information.  
3.1.3 
STEERING COMMITTEE  
A Steering Committee has been established for this study. It is composed of 
investigators participating in the study, and the Sponsor’s representatives. 
See Steering Committee charter for further information. 
3.2 
END OF STUDY 
The End of Study is defined as the date when the last patient, last visit (LPLV) 
occurs. This will be the last data collection point, which can be a clinic visit or 
a laboratory sample.  
Cohort 1 
LPLV for Cohort 1 will be approximately 4 years after enrollment of the first 
patient into Cohort 1. Enrollment is estimated to take 2 years and there will be 
2 years of follow-up after the last patient has been enrolled into Cohort 1. 
Patients will receive study medication until unacceptable toxicity, withdrawal 
of consent, disease progression, death, or up to a maximum of 2 years after 
the last patient has been enrolled into Cohort 1, whichever occurs first.  
Cohort 2 
LPLV for Cohort 2 and global End of Study will be 4 years after enrollment of 
the first patient into Cohort 2. Enrollment is estimated to take 2 years and 
there will be 2 years of follow-up after the last patient has been enrolled into 
Cohort 2. Patients will receive study medication until unacceptable toxicity, 
withdrawal of consent, disease progression, death, or up to a maximum of 
2 years after the last patient has been enrolled into Cohort 2, whichever 
occurs first. Patients who are under trastuzumab emtansine treatment as of 
the date of version 6 of this protocol will continue under MO28231 protocol 
until 31 Dec 2019. After this date, or earlier if site activation in China allows, 
these patients will be transferred to and treated under the Kadcyla extension 
study protocol, BO25430. 
3.3 
RATIONALE FOR STUDY DESIGN 
In this two-cohort, open-label, multicenter study, the safety and tolerability of 
trastuzumab emtansine will be explored further to gain better understanding of 
the safety profile of trastuzumab emtansine. 
The study design employs standard methods for Phase IIIb safety studies in 
patients with cancer. 


 
 
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The primary objective is to assess the safety and tolerability of trastuzumab 
emtansine in patients with HER2-positive mBC. Good efficacy and a 
manageable safety profile have been demonstrated in clinical trials of 
trastuzumab emtansine in this patient population. As this is a safety study, all 
patients will receive active treatment. 
The ongoing study has been amended to add a second cohort to further 
explore the higher incidence of thrombocytopenia in the Asian population. The 
second cohort will enrich the total Asian population for the study. A two-cohort 
approach also allows for analysis of the initial population of the study before 
the end of the study. 
Safety will be carefully evaluated, and the type of data collected and the 
frequency with which patients are monitored will ensure the safety of the 
patients at all times, as well as fulfilling international regulatory requirements. 
3.3.1 
RATIONALE FOR TEST PRODUCT DOSAGE 
Trastuzumab emtansine will be administered intravenously q3w at a dose of 
3.6 mg/kg over approximately 90 minutes for the first dose and 30 (±10) 
minutes for subsequent doses. The total trastuzumab emtansine dose will be 
calculated based on the patient’s weight on Day 1 (or up to 28 days before) of 
each cycle with no upper limit. 
In Study TDM3569g, the MTD of trastuzumab emtansine administered by IV 
infusion q3w was 3.6 mg/kg. As described in Section 1.2, clinical activity has 
been observed at a dose of 3.6 mg/kg q3w in two Phase II studies of 
single-agent trastuzumab emtansine in patients with advanced heavily 
pretreated HER2-positive mBC (protocols TDM4258g and TDM4374g) and in 
patients who had not received prior chemotherapy for metastatic disease 
(protocol TDM4450g and the Phase III study BO21977). 
Thus, the trastuzumab emtansine dose of 3.6 mg/kg given every 3 weeks has 
been selected for testing in this study. 
3.3.2 
RATIONALE FOR CONTINUED DOSING 
In the Phase I (TDM3569g) and Phase II (TDM4258g) studies of trastuzumab 
emtansine, 4 patients have received more than 12 months of treatment with 
trastuzumab emtansine at the MTD (3.6 mg/kg) on a q3w schedule, with 
1 patient remaining on treatment for nearly 24 months. The reason for 
treatment discontinuation in these patients was due to disease progression 
and not toxicity. Patients who meet the criteria for ongoing clinical benefit will 
be allowed to continue study treatment in the absence of disease progression 
or unacceptable toxicity.  
3.3.3 
RATIONALE FOR PATIENT POPULATION 
Nonclinical studies indicate that the sensitivity of cancer cells to trastuzumab 
emtansine requires HER2 overexpression, and measurement of such 
expression is a standard of care in determining eligibility for trastuzumab 


 
 
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therapy (see the Herceptin Package Insert). Measurement of HER2 gene 
amplification has traditionally been performed using immunohistochemistry 
(IHC) measurement. HER2 gene amplification determined by in situ 
hybridization (ISH) has also proven to be a reliable method for demonstrating 
HER2-positive status (Press et al. 2005). Patients with incurable mBC whose 
tumors are positive for HER2 overexpression represent the patient population 
eligible for study enrollment. This study will explore the safety of trastuzumab 
emtansine using a two-cohort approach. The second cohort will only recruit 
patients who are of Asian race. A higher incidence of Grade ≥ 3 AEs has been 
observed in Asian patients treated with trastuzumab emtansine compared 
with Caucasian patients (63.6% versus 41.6%). These data were obtained 
from 99 Asian patients who were included in a pooled analysis of 884 patients 
with HER2-positive mBC who received treatment with trastuzumab emtansine 
3.6 mg/kg as single agent every 3 weeks (see the Investigator’s Brochure). 
The higher incidence of ≥ Grade 3 AEs observed was largely driven by the 
increased rates of Grade ≥ 3 thrombocytopenia in Asian patients. Enrollment 
into Cohort 2 will around the end of enrollment into Cohort 1.  
3.4 
OUTCOME MEASURES  
3.4.1 
SAFETY OUTCOME MEASURES 
The primary objective of this study is to evaluate the safety and tolerability of 
trastuzumab emtansine. 
The safety outcome measures for this study are as follows: 
• 
Incidence, nature and severity by National Cancer Institute (NCI) common 
terminology criteria for adverse events (CTCAE) version 4.0 of AEs and 
SAEs, including AEs Grade 3 or higher for hepatic events, allergic 
reactions, thrombocytopenia, hemorrhage events, and also all other AEs 
Grade 3 or higher related to trastuzumab emtansine. Pneumonitis of all 
grades will be analyzed. 
• 
Incidence of congestive heart failure (CHF) 
• 
Cases of drug-induced liver injury meeting Hy’s law criteria 
• 
Left ventricular ejection fraction (LVEF) decrease over the course of the 
study as measured by echocardiogram (ECHO) or multiple-gated 
acquisition scan (MUGA) 
• 
Laboratory test abnormalities 
• 
Premature withdrawal from study and study medication 
• 
Exposure to study medication 


 
 
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3.4.2 
EFFICACY OUTCOME MEASURES 
A secondary objective of this study is to evaluate efficacy of trastuzumab 
emtansine treatment, assessed according to response evaluation criteria for 
solid tumors (RECIST) v1.1 as per investigator assessment. 
The efficacy outcome measures for this study are as follows: 
• 
Progression-Free Survival (PFS) 
• 
Overall Survival (OS) 
• 
Overall Response Rate (ORR) = partial response (PR) + complete 
response (CR) 
• 
Clinical Benefit Rate (CBR) 
• 
Duration of Response (DoR) 
• 
Time to Response (TTR)  
3.4.3 
PHARMACOECONOMICS OUTCOME MEASURES 
The pharmacoeconomics outcomes defined in Section 2.3 will be measured. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
This study will enroll patients with HER2-positive, unresectable, LABC or mBC 
who have previously received prior anti-HER2 and chemotherapy treatment 
and have progressed on or after the most recent treatment of LABC or mBC, 
or within 6 months of completing adjuvant therapy. 
4.1.1 
INCLUSION CRITERIA 
1. HER2-positive disease determined locally i.e., IHC 3 + and/or gene-
amplified by ISH as per institutional practice (however, both tests should 
be performed wherever possible and only one positive result is required 
for eligibility) 
2. Histologically or cytologically confirmed invasive BC 
3. Prior treatment for BC in the adjuvant, unresectable, locally advanced or 
metastatic setting must include both chemotherapy, alone or in 
combination with another agent, and an anti-HER2 agent, alone or in 
combination with another agent (complementary hormonal therapy is 
allowed)  
4. Documented progression of incurable, unresectable, locally advanced, or 
mBC, defined by the investigator: progression must occur during or after 
most recent treatment for locally advanced/mBC or within 6 months of 
completing adjuvant therapy 
5. Measurable and/or non-measurable disease 
6. Signed written informed consent approved by the institution’s independent 
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7. Age ≥ 18 years 
8. LVEF ≥ 50% by either ECHO or MUGA 
9. ECOG performance status of 0, 1 or 2 
10. Adequate organ function:  
• 
Absolute neutrophil count > 1,500 cells/mm3 
• 
Platelet count > 100,000 cells/mm3 
• 
Hemoglobin > 9.0 g/dL. Patients are allowed to be transfused red 
blood cells to this level 
• 
Albumin ≥ 2.5 g/dL 
• 
Total bilirubin ≤ 1.5 × ULN) SGOT or AST, SGPT or ALT, and alkaline 
phosphatase ≤ 2.5 x ULN with the following exception: Patients with 
bone metastases: alkaline phosphatase ≤ 5 x ULN 
• 
Creatinine CL > 50 mL/min based on Cockroft-Gault glomerular 
filtration rate (GFR) estimation: (140 − Age) x (weight in kg) x (0.85 if 
female)/(72 x serum creatinine) 
• 
International normalized ratio (INR) < 1.5 (unless on therapeutic anti-
coagulation) 
11. For women of childbearing potential and men with partners of childbearing 
potential, agreement by the patient and/or partner to use a highly effective 
non-hormonal form of contraception such as surgical sterilization or two 
effective forms of non-hormonal contraception (see Section 5.2.4) 
12. Negative serum pregnancy test for women of childbearing potential 
(including pre-menopausal women who have had a tubal ligation) and for 
all women not meeting the definition of postmenopausal ( ≥ 12 months of 
amenorrhea), and who have not undergone surgical sterilization with a 
hysterectomy and/or bilateral oophorectomy. For all other women, 
documentation must be present in medical history confirming that the 
patient is not of childbearing potential (see Section 5.2.4) 
13.  For Cohort 2, only patients of Asian race will be enrolled 
4.1.2 
EXCLUSION CRITERIA 
1. History of treatment with trastuzumab emtansine 
2. Prior enrollment into a clinical study containing trastuzumab emtansine 
regardless of having received trastuzumab emtansine or not 
3. Peripheral neuropathy of Grade ≥ 3 per NCI CTCAE version 4.0 
4. History of other malignancy within the previous 5 years, except for 
appropriately treated carcinoma in situ of the cervix, non-melanoma skin 
carcinoma, Stage 1 uterine cancer, synchronous or previously diagnosed 
HER2-positive BC 
5. History of receiving any anti-cancer drug/biologic or investigational 
treatment within 21 days prior to first study treatment except hormone 
therapy, which can be given up to 7 days prior to first study treatment; 


 
 
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recovery of treatment-related toxicity consistent with other eligibility 
criteria 
6. History of exposure to the following cumulative doses of anthracyclines: 
• 
Doxorubicin or liposomal doxorubicin > 500 mg/m2 
• 
Epirubicin > 900 mg/m2 
• 
Mitoxantrone > 120 mg/m2  
• 
If another anthracycline, or more than one anthracycline, has been 
used, the cumulative dose must not exceed the equivalent of 500 
mg/m2 doxorubicin 
7. History of radiation therapy within 14 days of first study treatment. The 
patient must have recovered from any resulting acute toxicity (to Grade ≤ 
1) prior to first study treatment 
8. Metastatic central nervous system (CNS) disease only 
9. Brain metastases which are symptomatic. NOTE: a 14 day window after 
end of radiotherapy must be observed. Patient must not be receiving 
steroids to control symptoms 
10. History of a decrease in LVEF to < 40% or symptomatic CHF with 
previous trastuzumab treatment 
11. History of symptomatic CHF (New York Heart Association [NYHA] 
Classes II−IV) or serious cardiac arrhythmia requiring treatment 
12. History of myocardial infarction or unstable angina within 6 months of first 
study treatment 
13. Current dyspnea at rest due to complications of advanced malignancy or 
requirement for continuous oxygen therapy 
14. Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, or metabolic disease) 
15. Pregnancy or lactation 
16. Currently known active infection with HIV, hepatitis B virus, or hepatitis C 
virus 
17. History of intolerance (such as Grade 3−4 infusion reaction) or 
hypersensitivity to trastuzumab or murine proteins or any component of 
the product 
18. Assessed by the investigator to be unable or unwilling to comply with the 
requirements of the protocol throughout 
4.2 
STUDY TREATMENT  
4.2.1 
FORMULATION, PACKAGING, AND HANDLING 
4.2.1.1 
Trastuzumab Emtansine  
Trastuzumab emtansine is provided as a single-use, lyophilized formulation in 
a colorless 20 mL Type I glass vial containing 160 mg of trastuzumab 


 
 
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emtansine closed by means of a FluroTec coated stopper and an overseal 
with flip-off cap. Upon receipt of trastuzumab emtansine, vials should be 
refrigerated at 2–8°C (36–46°F) until use. THE VIAL MUST NOT BE FROZEN 
OR SHAKEN. Trastuzumab emtansine must be stored in the original carton to 
protect it from light. Do not use the product beyond the expiration date 
provided by the manufacturer. The reconstituted product contains no 
preservative and is intended for single use only. Any remaining medication 
should be discarded. 
All vials of trastuzumab emtansine should be handled by appropriately trained 
site staff wearing gloves and using appropriate procedures in place at the 
clinical site for preparation of chemotherapeutic drugs. Vials should be 
visually inspected upon receipt to ensure that they are intact without exterior 
contamination. Discard any cracked vials and report vials with surface 
contamination to the clinical site manager for assessment. 
The lyophilized product should be reconstituted using Sterile Water for 
Injection (SWFI). Using a new syringe, 8 mL SWFI should be added to the vial 
and the vial swirled gently until the product is completely dissolved. The vial 
should not be shaken. The resulting product contains 20 mg/mL trastuzumab 
emtansine, 10 mM sodium succinate, pH 5.0, 60 mg/mL sucrose, and 0.02% 
(w/v) polysorbate 20. Each 20 mL vial contains enough trastuzumab 
emtansine to allow delivery of 160 mg trastuzumab emtansine. The 
reconstituted product contains no preservative and is intended for single use 
only. 
The vial should be inspected to ensure the reconstituted product is a clear 
colorless solution, and is free of particulates before proceeding. Drug from 
any vial that appears abnormal upon inspection should not be administered to 
patients. Using a new syringe, the indicated volume of trastuzumab emtansine 
solution should be removed from the vial(s) and added to the IV bag 
containing at least 250 mL of 0.45% sodium chloride (preferred) or 0.9% 
sodium chloride injection and gently inverted to mix the solution. A 0.22 
micron non-protein adsorptive polyethersulfone in-line filter is recommended 
when using 0.45% sodium chloride and required when using 0.9% sodium 
chloride injection. The solution of trastuzumab emtansine should not be 
shaken. 
The solution of trastuzumab emtansine for infusion should be used 
immediately. If not used immediately, storage times should not be longer than 
24 hours at 2–8°C (36–46°F) for solutions of trastuzumab emtansine diluted in 
polyvinyl chloride (PVC) or latex free PVC-free polyolefin, polypropylene, or 
polyethylene bags containing 0.45% or 0.9% Sodium Chloride for injection. 
For additional details, please refer to the current version of the trastuzumab 
emtansine Investigator’s Brochure. 


 
 
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4.2.2 
DOSAGE AND ADMINISTRATION 
4.2.2.1 
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 unless dose reductions or dose delays are required. 
The total dose will be calculated based on the patient’s weight up to 28 days 
before each cycle with no upper limit. If within these 28 days the patient 
experiences a severe weight loss, the dose should be recalculated 
accordingly. 
If the timing of trastuzumab emtansine coincides with a holiday that precludes 
the procedure, the procedure should be performed within 3 working days of 
the scheduled date and, when possible, on the earliest following date, with 
subsequent protocol-specified procedures rescheduled accordingly. 
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 
minutes observation period following infusion. Local health authority 
guidelines must be followed with regard to further observation and monitoring, 
if applicable. 
Patients will receive study medication until unacceptable toxicity, withdrawal 
of consent, disease progression, death, or up to a maximum of 2 years after 
last patient has been enrolled into the trial, whichever occurs first. Patients 
who have not progressed at the end of the trial will be offered options to 
continue with trastuzumab emtansine treatment, see Section 4.2.4. 
Guidelines for dosage modification and treatment interruption or 
discontinuation are provided in Section 5.1.8. 
4.2.3 
INVESTIGATIONAL MEDICINAL PRODUCT ACCOUNTABILITY 
The investigational medicinal product (IMP) required for completion of this 
study (trastuzumab emtansine) will be provided by the Sponsor. The 
investigational site will acknowledge receipt of IMPs, using the interactive 
voice/web recognition system (IxRS) to confirm the shipment condition and 
content. Any damaged shipments will be replaced.  
The IMP 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 
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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. 
4.2.4 
POST-TRIAL ACCESS TO EXTENSION STUDY  
The study will be concluded after the last patient has been followed up for 
2 years after last patient has been enrolled. 
Patients who have not progressed at the end of the trial will be offered the 
following options to continue with treatment: 
• 
Patients in countries in which trastuzumab emtansine is approved and 
reimbursed for this indication at the study end, may continue treatment 
outside this study in accordance with local labeling and reimbursement. 
• 
Patients in countries in which trastuzumab emtansine is not approved 
and/or not reimbursed for this indication or local regulations do not allow 
patients to receive continued treatment in this way, will be offered the 
possibility to continue treatment in an extension study (BO25430).  
Since there is a delay in activation of sites in China for BO25430 as of the 
date of version 6 of this protocol, patients who are under trastuzumab 
emtansine treatment will continue under MO28231 protocol until 31 Dec 2019. 
After this date, or earlier if site activation allows, these patients will be 
transferred to and treated under the Kadcyla extension study protocol, 
BO25430.In case a patient decides to withdraw from the study, no post-trial 
access will be granted. Currently, the Sponsor does not have any plans to 
provide other study interventions to patients after conclusion of the study or 
any earlier patient withdrawal. 
4.3 
CONCOMITANT THERAPY 
4.3.1 
PERMITTED THERAPY  
Concomitant therapy and premedication are defined as non-IMP. 
Concomitant therapy includes any medication (e.g., prescription drugs, 
over-the-counter drugs, herbal/homeopathic remedies, nutritional 
supplements) used by a patient between the 14 days preceding first treatment 
and the safety follow-up visit. Afterwards, only anti-cancer therapies will be 
recorded on the Concomitant Medications electronic Case Report Form 
(eCRF), as part of the survival follow-up period. 
Premedication is allowed according to standard practice guidelines. 
No premedication for the first infusion of trastuzumab emtansine is required; 
however, premedication is allowed at the investigator’s discretion. 
Concomitant use of erythropoiesis-stimulating agents is allowed if clinically 
indicated in accordance with local prescribing guidelines. 
Palliative radiotherapy may be permitted to treat pre-existing bone metastases 
or to treat brain metastases (for patients who have disease control outside of 
the brain). Radiotherapy should be finished at least 7 days before resuming 


 
 
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administration of trastuzumab emtansine and all toxicities need to have 
resolved. If not, the cycle may be delayed for up to 42 days. Please contact 
the Medical Monitor for approval. If the Medical Monitor cannot be reached 
because of time zone differences, radiotherapy may be administered, but the 
Medical Monitor should still be informed. 
Other medications considered necessary for the patient’s safety and wellbeing 
may be given at the discretion of the investigator. Use of bisphosphonates or 
denosumab is permitted for the control of bone pain, prevention and/or 
treatment of bony metastases, and treatment of osteoporosis. If 
bisphosphonates are required for the treatment of symptomatic malignancy-
associated hypercalcemia, tumor assessments should be performed to 
assess for potential disease progression. Premedication for nausea and 
infusion reactions (e.g., acetaminophen or other analgesics, antihistamines 
such as diphenhydramine, or corticosteroids) may also be given at the 
investigator’s discretion. 
Any Chinese traditional medicines that could potentially negatively impacting 
the liver functions are not permitted. However, any Chinese traditional 
medicines having a liver protective action would be considered acceptable, at 
the investigator’s discretion. It will be the investigator’s responsibility to verify 
whether a specific Chinese medication could potentially affect liver function. 
4.3.2 
PROHIBITED THERAPY 
Use of the therapies described below is prohibited during the study prior to 
discontinuation of study treatment (collectively, these will be referred to as 
non-protocol therapy). 
Any therapies intended for the treatment of cancer, other than trastuzumab 
emtansine, whether they are approved by national health authorities or 
experimental, including cytotoxic chemotherapy, immunotherapy, hormonal 
therapy (other than megestrol acetate), and biologic or targeted agents (other 
than granulocyte colony-stimulating factor and erythropoiesis-stimulating 
agents), are prohibited. The use of Chinese traditional medicines in case 
when they have no anti-cancer activity are allowed at the investigator’s 
discretion. 
Radiotherapy for unequivocal disease progression is not permitted while on 
study treatment, with the exception of new brain metastases or isolated 
progression of previously treated brain lesions. Patients who have disease 
control outside of the brain, defined as continued PR or CR of any duration, or 
stable disease for ≥ 4 months, but who have developed brain metastases that 
are treatable with radiation will be allowed to continue to receive study therapy 
until they either experience systemic progression of their disease and/or 
further progression in the brain that cannot be treated with additional radiation. 
Radiotherapy should be finished at least 7 days before resuming 
administration of trastuzumab emtansine and all toxicities need to have 
resolved. The Medical Monitor should be informed before a decision is made 
to resume study treatment after radiotherapy for brain metastases. 


 
 
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Patients with thrombocytopenia and on anti-coagulant treatment must be 
monitored closely during treatment with trastuzumab emtansine. Platelet 
counts will be monitored prior to each trastuzumab emtansine dose. 
4.4 
STUDY ASSESSMENTS  
4.4.1 
DESCRIPTION OF STUDY ASSESSMENTS 
All patients will be closely monitored for safety and tolerability during all cycles 
of therapy and at the safety follow-up visit: 
• 
Trastuzumab emtansine will be administered in 21-day cycles. Dose 
delays and dose reductions will be allowed for trastuzumab emtansine as 
outlined in Section 5.1.8 
• 
Visits will be based on a 21-day cycle. Study assessments are outlined in 
this section and in Appendix 1. 
4.4.1.1 
Medical History and Demographic Data 
Medical history includes previous clinically significant diseases, surgeries, 
cancer history (including prior cancer therapies and procedures), smoking 
history, use of alcohol and drugs of abuse, and all medications 
(e.g., prescription drugs, over-the-counter drugs, herbal/homeopathic 
remedies, nutritional supplements) used by the patient within 14 days prior to 
the screening visit. 
Demographic data will include age, sex, and self-reported ethnicity. 
4.4.1.2 
Vital Signs 
Abnormal or significant changes to vital signs (e.g., pulse rate, body 
temperature or blood pressure) from baseline should be recorded as AEs, if 
appropriate. 
4.4.1.3 
Physical Examinations 
A complete physical examination should include an evaluation of the head, 
eye, ear, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological 
systems. Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF. Height and weight 
should be recorded. 
At subsequent visits, limited, symptom-directed physical examinations should 
be performed. Changes from baseline abnormalities should be recorded in 
patient notes. New or worsened abnormalities should be recorded as AEs on 
the Adverse Event eCRF. 
As part of tumor assessment, physical examinations should also include the 
evaluation of the presence and degree of enlarged lymph nodes, 
hepatomegaly, and splenomegaly. 


 
 
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4.4.1.4 
Tumor and Response Evaluations 
Measurable and unmeasurable disease must be documented at screening 
and re-assessed at each subsequent tumor evaluation. Tumor assessments 
with computed tomography (CT) or magnetic resonance imaging (MRI) scans 
with contrast of the chest, abdomen, and pelvis are to be performed as 
described in Appendix 1 (Schedule of Assessment). CT or MRI of the brain 
and baseline radioisotope bone scan must be obtained at screening. If an 
isotope-based scan was performed ≥ 28 days but ≤ 60 days prior to first 
treatment the bone scan does not need to be repeated and non-isotopic 
radiographic modalities should be utilized to document the extent of bony 
metastatic disease. Tumor assessments should include an evaluation of all 
known and/or suspected sites of disease, whenever possible. Patients should 
have lesions selected that can be evaluated at every tumor assessment. The 
same radiographic procedure used at screening must be used throughout the 
study for the same patient (e.g., the same contrast protocol for CT scans). 
Response assessments will be assessed by the investigator, based on 
physical examinations, CT or MRI scans, and bone scans using RECIST v. 
1.1 (Appendix 2). In the event a positron emission tomography (PET)/CT 
scanner is used for tumor assessments, the CT portion of the PET/CT must 
meet criteria for diagnostic quality. For patients who continue study treatment 
after isolated brain progression, the frequency of follow-up scans is at the 
discretion of the investigator. 
At the investigator’s discretion, CT scans, MRI scans, and/or bone scans may 
be obtained at any time when clinically indicated or if PD is suspected. If a 
bone scan cannot be performed during the course of the study because of the 
unavailability of the Tc-99m isotope, the investigator may choose an 
alternative imaging modality (Appendix 3). 
Radiographic imaging should always be performed rather than clinical 
examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical examination. In applying RECIST, documentation by 
color photography including a ruler to estimate the size of the lesion is 
recommended. 
4.4.1.5 
Scheduling of Tumor Assessments 
Baseline total tumor burden must be assessed within a maximum of 28 days 
before first dose of study drug treatment. Post-baseline assessments are to 
be performed every 12 weeks, taking Day 1 of Cycle 1 as reference. If there is 
suspicion of disease progression based on clinical or laboratory findings 
before the next scheduled assessment, an unscheduled assessment should 
be performed. 
After Cycle 1, Day 1, all tumor assessments should be performed ± 12 weeks 
+/- 5 working days of the scheduled visit, regardless of any delays in 
treatment or other assessments. If a patient inadvertently misses a prescribed 
tumor evaluation or a technical error prevents the evaluation, the patient may 
continue treatment until the next scheduled assessment, unless signs of 
clinical progression are present. The schedule of assessments is provided in 


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Appendix 1 and is independent from drug administration (i.e., assessments 
should not be delayed in case of delayed drug administration). 
After disease progression, assessments are no longer required to evaluate 
new lesions, non-target lesions, and target lesions. 
4.4.1.6 
LVEF Assessment 
LVEF assessments will be performed within 28 days of enrollment, on Day 21 
(or -7 days) of the cycle for Cycle 1, on Day 21 (or -7 days) of Cycle 3 and 
every third cycle thereafter, by either ECHO or MUGA scan (with ECHO as 
the preferred method). Patients will be reassessed with the same technique 
used for baseline cardiac evaluation throughout the study and, to the extent 
possible, will be obtained at the same institution for an individual patient. If 
treatment is delayed for any reason, LVEF assessments can be postponed to 
allow them to be performed within 7 days prior to the next treatment 
administration. 
ECHO is the preferred modality because of the global technetium (Tc-99m) 
shortage (see Section 4.4.1.4 and Appendix 3). The same method used at 
screening should be used throughout the study. 
4.4.1.7 
ECOG Performance Status 
Performance status will be measured using the ECOG performance status 
scale (see Appendix 4). 
It is recommended, where possible, that a patient’s performance status will be 
assessed by the same person throughout the study. 
Performance status will be assessed according to the schedule of 
assessments (see Appendix 1). 
4.4.1.8 
Laboratory Assessments 
Samples for HER2 testing, hematology, biochemistry, urinalysis, and INR 
assessments, coagulation, and pregnancy testing will be analyzed at the 
study site’s local laboratory. 
Laboratory assessments will include the following: 
•
Hematology (hemoglobin, hematocrit, red blood cell count, platelet count,
white blood cell count with differential [including neutrophils, lymphocytes,
monocytes, eosinophils and basophils])
•
Serum chemistry (sodium, potassium, chloride, calcium, magnesium,
glucose, blood urea nitrogen [BUN], creatinine, uric acid, total protein,
albumin, alkaline phosphatase, ALT [SGPT], AST [SGOT], gamma-
glutamyl transferase, lactate dehydrogenase, total bilirubin and direct
bilirubin where total bilirubin > ULN)
•
INR
•
Urinalysis (includes specific gravity, pH, protein, glucose, blood, ketones,
and bilirubin)


 
 
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• 
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. Testing should be performed at a local laboratory within 
7 days prior to the first administration of study medication (Cycle 1, Day 1). 
For all other women, documentation must be present in medical history 
confirming that the patient is not of childbearing potential. Urine 
pregnancy test in women of childbearing potential must be performed 
every 3 cycles and at 3- and 6- months after the safety follow-up visit. All 
positive urine pregnancy tests must be confirmed by a serum β-HCG test. 
4.4.1.9 
Electrocardiograms 
A 12-lead ECG should be obtained at baseline and be printed and kept with 
the patient’s record. 
4.4.1.10 
Pharmacoeconomics Evaluation  
To evaluate pharmacoeconomics outcomes (see in Sections 2.3 and 3.4.3), 
the number of hospital visits, number of days admitted, and type of visits 
(emergency department versus inpatient care) will be entered in the eCRF. 
4.4.2 
TIMING OF STUDY ASSESSMENTS 
4.4.2.1 
Screening and Pretreatment Assessments 
Written informed consent for participation in the study must be obtained 
before performing any study-specific screening tests or evaluations. Once the 
patient has signed the informed consent form, the investigator (or his 
designee) will call the IxRS to obtain the screening number for the patient 
prior to Cycle 1, Day 1. Informed consent forms for enrolled patients and for 
patients who are not subsequently enrolled will be maintained at the study site. 
The IxRS will be available, 24 hours a day, 7 days a week. Detailed 
instructions regarding the IxRS will be provided to each study center. The 
screening numbers are to be allocated according to the specification 
document agreed with the IxRS provider. 
Screening tests and evaluations will be performed according to the schedule 
of assessments (see Appendix 1) prior to first administration of study 
medication (dosing), after confirmation of other eligibility criteria, unless the 
procedures have already been conducted during the defined time period (see 
Appendix 1) as part of the patient’s routine clinical care. Patient must have 
stable liver tests prior to the first dose of study drug. 
All screening evaluations must be completed and reviewed to confirm that 
patients meet all eligibility criteria before enrollment. 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. 
HER2-positive status on fixed blocks from the primary tumor (and/or 
metastatic site, if primary tumor not available) will be assessed locally by IHC 


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and/or ISH according to institutional criteria. These two different tests should 
be performed wherever possible. 
Results from archival tissue are acceptable. 
See Appendix 1 for the schedule of screening assessments. 
4.4.2.2 
Assessments during Treatment 
During the treatment period, a window of ± 3 working days will apply to all 
visits and assessments, unless otherwise specified (see Appendix 1). This 
window of ± 3 working days also applies for the study treatment administration 
at each cycle. Assessments scheduled on the day of study treatment 
administration should be performed prior to administration of study treatment, 
unless otherwise noted in the Schedule of Assessments. 
Please see Section 4.4.1.5 (Scheduling of Tumor Assessment) and 
Appendix 1 for the schedule of assessments performed during the treatment 
period. 
4.4.2.3 
Assessments at Safety Follow-up Visit 
Patients will receive study medication until unacceptable toxicity, withdrawal 
of consent, disease progression, or death, whichever occurs first.  
All patients will continue to be followed up every 6 months (± 14 working days, 
except for pregnancy test, which is at 3 and 6 months after safety follow-up 
visit) for 2 years after the last patient is enrolled, unless they have been lost to 
follow-up, withdrawn consent, or died (whichever occurs first). 
Patients who discontinue from study treatment will be asked to return to the 
clinic 28-42 days after the last dose of study drug for the safety follow-up visit. 
The visit at which response assessment shows PD may be used as the safety 
follow-up visit.  
See Appendix 1 for the schedule of assessments performed at the safety 
follow-up visit. 
4.4.2.4 
Follow-Up Assessments 
After the safety follow-up visit, AEs should be followed as outlined in  
Sections 5.5 and 5.6. 
All patients will be followed up for survival every 6 months (± 14 working days; 
except for pregnancy test, which is at 3 and 6 months after the safety follow-
up visit) until death, loss to follow-up, or withdrawal of consent or study 
closure. Patients who discontinue study treatment for reasons other than 
disease progression will continue to undergo tumor assessments every 3-6 
months until disease progression occurs. If assessments cannot be done at 
survival visits, the study site is permitted to collect survival information by 
phone call. After disease progression, patients will be followed up for survival 
every 6 months (± 14 working days) until death, loss to follow-up, withdrawal 
of consent, or study closure (whichever occurs first). Assessments are no 


 
 
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longer required to evaluate new lesions, non-target lesions, and target lesions. 
However a visit to collect survival information is still required. If a visit cannot 
be done, the study site is permitted to collect survival information by phone 
call.  
See Appendix 1 for the schedule of follow-up assessments. 
4.4.2.5 
Assessments at Unplanned Visits 
In case unplanned visits are required, eCRF pages will be available to report 
the information collected during those visits. 
4.5 
PATIENT, STUDY, AND SITE DISCONTINUATION 
4.5.1 
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 
• 
Noncompliance 
• 
Disease progression 
Patients who discontinue from study treatment prematurely for any of the 
above reasons except withdrawal of consent will continue to be followed 
according to Section 4.4.2.4 “Follow-Up assessments”. The primary reason 
for discontinuation must be recorded on the appropriate eCRF page. 
4.5.1.1 
Discontinuation from Study Drug 
Details of discontinuation due to toxicity are given in Section 5.1. 
Patients who discontinue study drug prematurely will be asked to return to the 
clinic for a safety follow-up visit (see Section 5.5), and may undergo follow-up 
assessments (see Section 5.6). 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. 
4.5.1.2 
Withdrawal from Study 
Patients have the right to withdraw from the study at any time for any reason. 
The investigator also has the right to withdraw patients from the study in the 
event of intercurrent illness, AEs, treatment failure after a prescribed 
procedure, protocol violation, cure, administrative reasons, or for other 
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Should a patient decide to withdraw, all efforts will be made to complete and 
report the observations as thoroughly as possible. 
The investigator should contact the patient or a responsible 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 with an explanation of why the patient is 
withdrawing from the study. If the reason for removal of a patient from the 
study is an AE, the principal specific event will be recorded on the Adverse 
Event eCRF. 
In the case that the patient decides to prematurely discontinue study 
treatment (“refuses treatment”), he/she should be asked if he/she can still be 
contacted for further information. The outcome of that discussion should be 
documented in the medical records. 
4.5.2 
STUDY AND SITE DISCONTINUATION 
The global End of Study is considered as the date of LPLV, this is defined as 
the last data collection point, which can be a clinic visit or a laboratory sample. 
The last clinic visit is defined as the safety follow-up for the last mBC patient, 
which will happen, at the latest, 2 years after the last patient has been 
enrolled into Cohort 2 of the trial. 
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 Harmonization (ICH) 
guidelines for Good Clinical Practice 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Overall safety will be assessed on an ongoing basis during the conduct of the 
study. The iDMC will monitor cumulative safety data as required (see iDMC 
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monitored by the Steering Committee (see Steering Committee charter and 
Section 3.1.3). 
The safety plan for patients having trastuzumab emtansine treatment is based 
on 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). Some of 
the important safety risks anticipated with this treatment as well as measures 
intended to avoid or minimize such toxicities are outlined below. Please refer 
to the trastuzumab emtansine Investigator’s Brochure for the most recent 
comprehensive information on the safety profile of trastuzumab emtansine. 
Trastuzumab emtansine dose modifications are described in Section 5.1.8. 
5.1.1 
CARDIOTOXICITY 
Patients treated with trastuzumab emtansine are at increased risk of 
developing left ventricular dysfunction. Left ventricular ejection fraction 
(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 LVEF declines will be handled as per the algorithm shown in 
Figure 3. Treatment with trastuzumab emtansine has not been studied in 
patients with LVEF < 50%. 
5.1.2 
HEMATOLOGIC TOXICITY (THROMBOCYTOPENIA) 
Thrombocytopenia, or decreased platelet counts, 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. 
Severe cases of both non-fatal and fatal hemorrhagic events, including CNS 
hemorrhage, have been reported in clinical trials with trastuzumab emtansine; 
these events were independent of the patients’ ethnicity. In some of the 
observed cases, the patients were also receiving anti-coagulation therapy. 
There was no clear correlation between the severity of thrombocytopenia and 
severe hemorrhagic events. The need for platelet transfusions has been 
reported. 
Patients with thrombocytopenia and on anti-coagulant treatment have to be 
monitored closely during treatment with trastuzumab emtansine. Platelet 
counts will be monitored prior to each trastuzumab emtansine dose. 
Use of erythropoiesis-stimulating agents will be allowed as consistent with 
prescribing guidelines. Transfusion of red blood cells and/or platelets will be 
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5.1.3 
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. The proportion of 
patients with Grade 1 or 2 increases in transaminases increased with 
successive cycles, suggesting a modest cumulative effect of trastuzumab 
emtansine on transaminases; however, no increase over time in the 
proportion of Grade 3 abnormalities was observed. Patients with elevated 
transaminases improved to Grade 1 or normal within 30 days of the last dose 
of trastuzumab emtansine in the majority of the patients. 
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. Some of the observed cases of 
acute liver injury may have been confounded by concomitant medications with 
known hepatotoxic potential and/or underlying conditions. An acute severe 
liver injury (Hy’s law) case has the following components: 
• Aminotransferase enzymes (ALT/AST) 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, pre-existing 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, need for hospital care, and 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. 
Trastuzumab emtansine is currently being studied in patients with HER2-
positive mBC with serum transaminases > 2.5 × ULN or total 
bilirubin > 1.5 × ULN prior to initiation of treatment (Study BO25499). 
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 was 
also observed in one fatal case of hepatic failure. 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 
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NRH should be considered in 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. Upon 
diagnosis of NRH, trastuzumab emtansine treatment must be permanently 
discontinued. 
5.1.4 
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. Treatment has included 
administration of steroids and oxygen, and study drug discontinuation. 
Patients with dyspnea at rest due to complications of advanced malignancy 
and comorbidities may be at increased risk of pulmonary events.  
Treatment with trastuzumab emtansine has to be permanently discontinued in 
patients who are diagnosed with ILD or pneumonitis. 
5.1.5 
INFUSION-RELATED REACTIONS/HYPERSENSITIVITY 
Infusion-related reactions characterized by one or more of the following 
symptoms, flushing, chills, pyrexia, dyspnea, hypotension, wheezing, 
bronchospasm, and tachycardia may occur with the administration of 
monoclonal antibodies and have been reported with 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. Patients should be observed closely for infusion-related 
reactions, especially during the first infusion. 
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 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. Premedication is allowed 
according to standard practice guidelines. In the event of a true 
hypersensitivity reaction (in which severity of reaction increases with 
subsequent infusions), trastuzumab emtansine treatment must be 
permanently discontinued. Patients who experience a Grade ≥ 3 allergic 
reaction or acute respiratory distress syndrome will be discontinued from 
study treatment. 


 
 
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5.1.6 
NEUROTOXICITY 
DM1, an anti-microtubule agent, can potentially cause peripheral neuropathy. 
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. 
5.1.7 
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. 
5.1.8 
TRASTUZUMAB EMTANSINE DOSE MODIFICATION 
Patients should be assessed for toxicity prior to each dose; dosing will occur 
only if the clinical assessment and laboratory test values are acceptable.  
Dose delays and reductions are designed to maximize treatment for those 
who derive clinical benefit from treatment while ensuring patient safety. 
Dose delays for trastuzumab emtansine−related toxicity other than the ones 
specified below (i.e., infusion reactions, hematologic toxicity, hepatotoxicity, 
neurotoxicity, cardiotoxicity, and ILD or pneumonitis) are as follows: 
• 
If significant trastuzumab emtansine–related toxicities (other than infusion 
reactions, thrombocytopenia, hepatotoxicity, neurotoxicity, cardiotoxicity, 
and ILD or pneumonitis) have not recovered to Grade 1 or baseline, the 
next scheduled dose may be delayed for up to 42 days from the last dose 
received. “Significant” and “related” will be based on the judgment of the 
investigator (in consultation with the Sponsor’s Medical Monitor or 
designee when appropriate). For example, alopecia even if considered 
related would most likely not be considered to be significant. Fatigue may 
or may not be considered either related or significant. 
• 
In general, when the significant and related toxicity (or any other toxicity 
that the investigator chooses to delay dosing for) resolves to Grade 1 or 
baseline, the patient may resume trastuzumab emtansine if the delay has 
not exceeded 42 days from the last received dose. Patients should be 
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resumes, the patient may receive trastuzumab emtansine either at the 
same dose level as before or at one dose level lower (see Table 2), at the 
discretion of the investigator. Subsequent cycles should remain q3w, and 
patients should be assessed for toxicity. 
• 
If a patient requires a dose reduction, dosing will be reduced by one dose 
level, per Table 2. No dose re-escalation will be allowed. 
• 
If a toxicity does not resolve within 42 days from the last dose received, 
the patient will be discontinued from study treatment and will be followed 
for disease progression and survival outcome as described in Section 5.5. 
• 
Patients who experience a Grade 3 or 4 hematologic event should be 
checked at least weekly for recovery. If values do not recover to baseline 
or Grade ≤ 1 within 42 days from the last dose received, the patient will be 
discontinued from study treatment. 
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 
Protocol requirements for specific toxicities are outlined below. 
5.1.8.1 
Trastuzumab Emtansine Dose Modification for 
Thrombocytopenia 
Platelet counts should be obtained no less frequently than weekly to evaluate 
recovery whenever any of the events listed below occurs. If platelet counts do 
not recover to Grade ≤ 1 within 42 days from the last dose received, the 
patient will be discontinued from study treatment.  
No re-escalation of the trastuzumab emtansine dose is allowed. 
Note: although complete blood counts with platelets are required within 72 
hours prior to study treatment administration at each cycle, the investigator 
may monitor platelet counts (or any other laboratory test) more frequently as 
clinically indicated. 
In the event of decreased platelet count to Grade 3 (< 50,000/mm3), do not 
administer trastuzumab emtansine until platelet counts recover to Grade 1 
(≥ 75,000/mm3) then treat at the same dose level. 
Patients receiving trastuzumab emtansine who experience a first Grade 4 
thrombocytopenia event may, after adequate recovery to a platelet count of 
Grade ≤ 1 or baseline, continue treatment with trastuzumab emtansine at a 
dose of 3 mg/kg in subsequent treatment cycles. Patients at the 3 mg/kg dose 
level who experience a Grade 4 thrombocytopenia event may, after adequate 
recovery as defined above, continue treatment with trastuzumab emtansine at 
a dose of 2.4 mg/kg in subsequent treatment cycles. Patients who experience 


 
 
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a Grade 4 thrombocytopenia event at the 2.4 mg/kg dose level will be 
discontinued from study treatment. A dose delay of up to 42 days from the 
patient’s last dose received is permitted.   
5.1.8.2 
Trastuzumab Emtansine Dose Modification for 
Hepatotoxicity 
5.1.8.2.1 
Concurrent elevations of ALT/AST and Bilirubin Meeting 
Hy’s Law laboratory Criteria 
Regardless of dose level, trastuzumab emtansine must be permanently 
discontinued in patients with ALT and/or AST > 3 × ULN and concurrent 
increase of total bilirubin to > 2 × ULN. All relevant hepatic laboratory tests 
performed (including AST, ALT, total bilirubin, alkaline phosphatase, INR, and 
albumin) will be entered into the clinical database. 
5.1.8.2.2 
Nodular Regenerative Hyperplasia (NRH) 
Trastuzumab emtansine must be permanently discontinued in patients who 
are diagnosed with NRH. 
5.1.8.2.3 
Transaminase Elevations or Bilirubin Elevation Requiring 
Dose Adjustment 
Liver function should be stable before the first dose of trastuzumab emtansine 
and monitored at least prior to each infusion. Patients who experience a 
Grade 3 elevation of liver function should be checked twice weekly for the 
recovery of total bilirubin and/or transaminases.  If a patient’s transaminases 
and/or total bilirubin do not recover as per Table 3 and Table 4, within 42 days 
from the patient’s last dose received, the patient will be discontinued from 
study treatment. 
No re-escalation of the trastuzumab emtansine dose is allowed. 
Table 3 and Table 4 describe the dose modification guidelines for increases in 
serum bilirubin and transaminases, respectively.  
Table 3 Trastuzumab Emtansine Dose Modification: Total Serum 
Bilirubin 
Grade 2 
(> 1.5 to ≤ 3 × the ULN)  
Grade 3 
(> 3 to ≤ 10 × the ULN) 
Grade 4 
(> 10 × the ULN) 
Do not administer T-DM1 until 
total bilirubin recovers to 
Grade ≤ 1, and then treat at the 
same dose level. 
 
Do not administer T-DM1 until 
total bilirubin recovers to Grade 
≤ 1 and then reduce one dose 
level.  
Discontinue T-DM1. 
T-DM1 = trastuzumab emtansine; ULN = upper limit of normal.  
Note: A maximum of two trastuzumab emtansine dose reductions is allowed. A patient 
requiring more than two dose reductions must discontinue study treatment. 
 


 
 
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Table 4 Trastuzumab Emtansine Dose Modification: Serum ALT or AST 
 
Grade 2 
(> 3 to ≤ 5 × the ULN) 
Grade 3 
(> 5 to ≤ 20 × the ULN) 
Grade 4 
(> 20 × the ULN) 
Treat at the same dose level. 
 
Do not administer T-DM1 until 
AST/ALT recovers to Grade ≤ 
1, and then reduce one dose 
level. 
Discontinue T-DM1. 
ALT = alanine transaminase; AST = aspartate transaminase; T-DM1 = trastuzumab 
emtansine; ULN = upper limit of normal.  
Note: A maximum of two trastuzumab emtansine dose reductions is allowed. A patient 
requiring more than two dose reductions must discontinue study treatment. 
 
5.1.8.3 
Trastuzumab Emtansine Dose Modification for Neurotoxicity 
Patients receiving trastuzumab emtansine who experience Grade 3 or 4 
peripheral neuropathy that does not resolve to Grade ≤ 2 within 42 days after 
the last dose received will be discontinued from study treatment. 
5.1.8.4 
Trastuzumab Emtansine Dose Modification for 
Cardiotoxicity 
Patients without significant cardiac history and with a baseline LVEF ≥ 50% as 
determined by ECHO or MUGA scan are eligible for study participation. LVEF 
will be monitored on Day 21 of the cycle for Cycle 1, Cycle 3 and every third 
cycle thereafter until the assessment at the safety follow-up visit.  
Figure 3 summarizes the management of trastuzumab emtansine on the basis 
of measured LVEF and changes in LVEF from baseline in patients. If the 
LVEF is reported as a range, the median of the range should be taken. If an 
investigator is concerned that an AE may be related to cardiac dysfunction, an 
additional LVEF measurement may be performed. Trastuzumab emtansine 
will be discontinued in any patient who develops symptomatic CHF. CHF 
should be treated and monitored according to standard medical practice. 


 
 
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Figure 3 Algorithm for Continuation and Discontinuation of 
Trastuzumab Emtansine Based on Left Ventricular Ejection 
Fraction Assessments in Patients 
 
LVEF = left ventricular ejection fraction. 
Note: LVEF assessment results must be reviewed before the next scheduled trastuzumab 
emtansine infusion. 
a LVEF can be repeated within 21 days, and trastuzumab emtansine should be discontinued 
if LVEF < 40% is confirmed. Trastuzumab emtansine should be held while the repeat LVEF 
is obtained. 
b After a second consecutive confirmatory result, trastuzumab emtansine should be 
discontinued if the LVEF is confirmed to be ≥ 10% points below baseline or if medical 
management was required to correct the LVEF. 
 
The decision to stop or continue trastuzumab emtansine should be based on 
the algorithm shown in Figure 3. Trastuzumab emtansine must be 
discontinued in all patients for whom a confirmed drop of LVEF to below 40% 
is documented (with a repeat assessment within 21 days). For patients whose 
LVEF drops to values between 40% and 45% with an absolute decrease in 
LVEF of ≥ 10% points from baseline, trastuzumab emtansine should be held. 
For these patients, the LVEF should be repeated in 21 days, and trastuzumab 
emtansine should be discontinued if the LVEF has not recovered to within 
10% absolute difference below baseline. If clinically significant cardiac 
dysfunction or cardiac failure develops or persists or if significant medical 
management is required to maintain ejection fraction, the patient should be 
discontinued from study treatment. 
5.1.8.5 
Trastuzumab Emtansine Dose Modification for Infusion-
Related Reactions, Hypersensitivity Reactions 
Trastuzumab emtansine treatment should be interrupted in patients with 
severe infusion-related reactions. Trastuzumab emtansine treatment should 


 
 
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be permanently discontinued in the event of life-threatening infusion-related 
reactions. 
Infusion of trastuzumab emtansine should be interrupted for patients who 
develop dyspnea or clinically significant hypotension.  
The infusion should be slowed to ≤ 50% or interrupted for patients who 
experience any other infusion-related symptoms. When the patient’s 
symptoms have completely resolved, the infusion may be continued at ≤ 50% 
of the rate prior to the reaction and increased in 50% increments every 
30 minutes as tolerated. Infusions may be restarted at the full rate during 
the next cycle.  
Patients who experience trastuzumab emtansine infusion-related temperature 
elevations to > 38.5°C and/or other infusion-related symptoms may be treated 
symptomatically with acetaminophen and/or diphenhydramine hydrochloride.  
Serious infusion-related events manifested by dyspnea, hypotension, 
wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 
respiratory distress should be managed with supportive care such as oxygen, 
beta agonists, antihistamines, antipyretics, or corticosteroids at the 
investigator's discretion. Premedication with corticosteroids, antihistamines, 
and antipyretics may be used before subsequent infusions of trastuzumab 
emtansine at the investigator’s discretion. Patients should be monitored until 
complete resolution of symptoms. Patients who experience a Grade ≥ 3 
hypersensitivity reaction or acute respiratory distress syndrome will be 
discontinued from the study. 
Patients who experience a severe delayed infusion reaction will be 
discontinued from study treatment.   
5.1.8.6 
Trastuzumab Emtansine Dose Modification for Pulmonary 
Toxicity 
Cases of ILD including pneumonitis (including severe, life-threatening cases) 
and some leading to acute respiratory distress syndrome or fatal outcome has 
been rarely reported with trastuzumab emtansine. Treatment with 
trastuzumab emtansine has to be permanently discontinued in patients who 
are diagnosed with ILD or pneumonitis.  
5.1.8.7 
Trastuzumab Emtansine Dose Modification for 
Extravasation 
During clinical development of T-DM1, reactions secondary to extravasation 
have been observed. These reactions were usually mild and comprised of 
erythema, tenderness, skin irritation, pain or swelling at the infusion site. 
Although T-DM1 is not considered as a vesicant, close monitoring of the 
infusion site for possible subcutaneous infiltration during drug administration is 
recommended. 


 
 
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5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, including 
SAEs and non-serious AEs of special interest (AESIs; see Section 5.2.3 for 
details); 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 5.3.5.7 
• 
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) 
A 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 occurred in a more severe 
form or had been allowed to continue and might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.8) 
• 
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. 
SAEs are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions). 
5.2.3 
PROTOCOL-DEFINED EVENTS OF SPECIAL INTEREST/NON-
SERIOUS EXPEDITED ADVERSE EVENTS 
Non-serious AESIs are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours) after learning of the event 
(see Section 5.4.2 for reporting instructions).  
AESIs for this study include the following: 
•
Potential drug-induced liver injury
•
Suspected transmission of an infectious agent by the study drug
Potential drug-induced liver injury: 
Any potential case of drug-induced liver injury as assessed by laboratory 
criteria for Hy’s law will be considered as a protocol-defined event of special 
interest and will need to be reported to the Sponsor expeditiously. The 
following laboratory abnormalities define potential Hy’s law cases: 
•
AST and/or ALT elevations that are > 3 × ULN
•
Concurrent elevation of total bilirubin > 2 × ULN (or clinical jaundice if total
bilirubin measures are not available), except in patients with documented
Gilbert’s syndrome. For patients with Gilbert’s syndrome, elevation of
direct bilirubin > 2 × ULN should be used instead.
Suspected transmission of an infectious agent by the study drug: 
•
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


 
 
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applies when a contamination of the study drug is suspected, NOT for 
infections supported by the mode of action, e.g., immunosuppression. 
5.2.4 
PREGNANCY AND CONTRACEPTION 
ICH M3 guidance requires precautions to be taken to minimize risk to fetus or 
embryo when including women of childbearing potential in clinical studies. 
These precautions include the use of highly effective contraceptive measures, 
excluding pregnancy at baseline (serum test), continued pregnancy 
monitoring, and continued pregnancy testing for up to 6 months after the 
safety follow-up visit (follow-up period based on PK considerations). 
Trastuzumab, a component of trastuzumab emtansine, can cause fetal harm 
when administered to a pregnant woman; post-marketing case reports 
indicate that its use during pregnancy increases the risk for oligohydramnios 
during the second and third trimester. Trastuzumab has also been associated 
with fetal pulmonary hypoplasia, skeletal abnormalities, and neonatal death 
(see the Herceptin® Package Insert). There are no clinical studies of 
trastuzumab in pregnant women. Immunoglobulin G (IgG) is known to cross 
the placental barrier. 
Therefore, trastuzumab emtansine should be not used during pregnancy. 
Women of childbearing potential (who have not undergone surgical 
sterilization with a hysterectomy and/or bilateral oophorectomy) and men with 
partners of childbearing potential must agree to use a highly effective non-
hormonal form of contraception or two effective forms of non-hormonal 
contraception by the patient and/or partner.  
Methods of birth control which result in a low failure rate (i.e., < 1% per year) 
when used consistently and correctly are considered highly effective forms of 
contraception. The use of the following non-hormonal methods of 
contraception is acceptable: 
• 
True abstinence, when this is the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, and symptothermal 
post ovulation methods) and withdrawal are not acceptable methods of 
contraception 
• 
Male sterilization (with appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate). For female patients, the vasectomized 
male partner should be the sole partner 
Alternatively, use of two of the following effective forms of contraception is 
acceptable: 
• 
Placement of intrauterine device (IUD) or intrauterine system (IUS). 
Consideration should be given to the type of device being used, as there 
are higher failure rates for certain types (e.g., steel or copper wire) 
• 
Condom with spermicidal foam/gel/film/cream/suppository 
• 
Occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository 


 
 
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The use of barrier contraceptives should always be supplemented with the 
use of a spermicide. The following should be noted: 
• 
Failure rates indicate that, when used alone, the diaphragm and condom 
are not highly effective forms of contraception. Therefore, the use of 
additional spermicides does confer additional theoretical contraceptive 
protection 
• 
However, spermicides alone are ineffective at preventing pregnancy when 
the whole ejaculate is spilled. Therefore, spermicides are not a barrier 
method of contraception and should not be used alone 
It should be noted that two forms of effective contraception are required. A 
double barrier method, defined as condom and occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, is 
acceptable. 
Contraception is not a requirement in the case of any of the following: 
• 
The female patient or female partner of a male patient is considered not to 
be of childbearing potential: if she is postmenopausal, defined by 
amenorrhea of ≥ 12 months duration in a woman > 45 years old; or is ≥ 40 
years of age and has had amenorrhea of ≥ 24 months duration; or has 
undergone surgical sterilization (hysterectomy and/or bilateral 
oophorectomy) 
• 
The male patient or male partner of a female patient is surgically sterilized 
For male patients with a female partner of childbearing potential, cooperation 
of female partner is required (i.e., use of two forms of contraception as stated 
above) during the study and for at least 7 months following the last dose of 
study treatment when a highly effective form of contraception is not 
appropriate. 
Based on PK considerations, contraception must continue for the duration of 
study treatment and for at least 7 months after the last dose of study 
treatment. 
A female patient who becomes pregnant during the study must be instructed 
to stop taking the study medication and immediately inform the investigator. 
The investigator should report all pregnancies within 24 hours to the Sponsor 
including the partners of male patients. The investigator should counsel the 
patient/partner, and discuss the risks of continuing with the pregnancy and the 
possible effects on the fetus. Monitoring of the patient/partner should continue 
until conclusion of the pregnancy. Pregnancies occurring up to 7 months after 
the completion of study medication must also be reported to the investigator. 
Please refer to Section 5.4.3 for reporting procedures. 
It is not known whether trastuzumab or trastuzumab emtansine are excreted 
in human milk. Maternal IgG is excreted in milk and any of these monoclonal 
antibodies could harm infant growth and development; therefore, women 
should be advised to discontinue nursing during trastuzumab emtansine 
therapy and not to breastfeed for at least 7 months following the last dose of 
either study drug. 


 
 
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Experimental studies have reported that IgGs are present in both the pre-
ejaculate and the seminal plasma (Moldoveanu et al. 2005). To date, there 
have been no clinical studies to assess the IgG profile in the pre-ejaculate and 
seminal plasma in male patients receiving trastuzumab or trastuzumab 
emtansine. Therefore, as a precaution male patients with female partners of 
childbearing potential are required to use highly effective form of 
contraception or use two forms of contraception as outlined above. Similarly, 
vaginal absorption of trastuzumab emtansine is unknown and therefore male 
patients with pregnant partners are required to use condoms for the duration 
of the pregnancy, and then revert to contraceptive methods as outlined above. 
This is to ensure that the fetus is not exposed to the study medication through 
vaginal absorption. In addition, sperm or blood donation should not occur for 
at least 7 months after the last dose of study treatment. 
5.3 
METHODS AND TIMING FOR CAPTURING AND 
ASSESSING SAFETY PARAMETERS 
The investigator is responsible for ensuring that all AEs (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the 
Sponsor in accordance with instructions provided in this section and in 
Sections 5.4, 5.5, and 5.6.  
For each AE recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), 
severity (see Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1 
ADVERSE EVENT REPORTING PERIOD 
Investigators will seek information on AEs at each patient contact. All AEs, 
whether reported by the patient or noted by study personnel, will be recorded 
in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study 
drug, only SAEs caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be 
reported (see Section 5.4.2 for instructions for reporting SAEs). 
After initiation of study drug, all AEs, regardless of relationship to study 
drug, will be reported until 28 days after the last dose of study drug. After this 
period, the investigator is not required to actively monitor patients for AEs; 
however, the Sponsor should be notified if the investigator becomes aware of 
any poststudy SAEs or non-serious AESIs (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?” 


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“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 (v4.0) will be used for 
assessing AE severity Table 5. 
Table 5 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 livinga 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily livingb,c 
4 
Life-threatening consequences or urgent intervention indicatedd 
5 
Death related to adverse eventd 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note: Based on the NCI CTCAE (v4.0), which can be found at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE 4.03 2010-06-14 QuickReference 8.5x11.pdf 
a 
Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a 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 study drugs, 
indicating "yes" or "no" accordingly. To ensure consistency of causality 
assessments, investigators should apply the general guidelines outlined in 
Table 6. 


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Table 6 Guidance for Causal Attribution of Adverse Event/Serious 
Adverse Event 
Is the AE/SAE suspected to be caused by the investigational product based on facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the AE and 
administration of the investigational product, and the AE cannot be readily explained 
by the patient’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
AE follows a known pattern of response to the investigational product; and/or the AE 
abates or resolves upon discontinuation of the investigational product or dose 
reduction and, if applicable, reappears upon re-challenge. 
Investigators should apply facts, evidence, or rationales based on scientific 
principles and clinical judgment to support a causal/contributory association 
with an investigational product. 
NO 
AEs will be considered related, unless they fulfill the criteria as specified below. 
Evidence exists that the AE has an etiology other than the investigational product 
(e.g., pre-existing medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the AE has no plausible temporal relationship to 
administration of the investigational product (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
Note: The investigator’s assessment of causality for individual AE reports is part of the 
study documentation process. Regardless of the “Yes” or “No” causality assessment 
for individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities. Attribution of 
SAEs will be reviewed on an ongoing basis, and may be changed as additional 
clinical data emerges (e.g., reversibility of AE, new clinical findings in patient 
with AE, effects of retreatment, AEs in other patients). 
In addition to assessing causality with respect to study drugs, investigators 
should also assess whether other factors (e.g., disease under study, 
concurrent illness, concomitant medication, or study procedure) may have 
caused the event, using similar guidance. 
The investigator’s assessment of causality for individual AE reports is part of 
the study documentation process. Regardless of the “Yes” or “No” causality 
assessment for individual AE reports, the Sponsor will promptly evaluate all 
reported SAEs against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators and 
applicable regulatory authorities. 
For patients receiving combination therapy, causality will be assessed 
individually for each protocol-mandated therapy. 


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5.3.5 
PROCEDURES FOR RECORDING ADVERSE EVENTS 
Investigators should use correct medical terminology/concepts when 
recording AEs on the Adverse Event eCRF. Avoid colloquialisms and 
abbreviations. 
Only one AE term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
Infusion-Related Reactions 
AEs that occur during or within 24 hours after study drug infusion should be 
captured as individual signs and symptoms rather than a diagnosis of allergic 
reaction or infusion reaction. 
Other Adverse Events 
For AEs other than infusion-related reactions, a diagnosis (if known) should 
be recorded on the Adverse Event eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, 
asterixis, and elevated transaminases). However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or 
syndrome at the time of reporting, each individual event should be recorded 
on the Adverse Event eCRF. If a diagnosis is subsequently established, all 
previously reported AEs based on signs and symptoms should be nullified 
and replaced by one AE report based on the single diagnosis, with a starting 
date that corresponds to the starting date of the first symptom of the eventual 
diagnosis. 
5.3.5.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause. For example, if 
severe diarrhea is known to have resulted in dehydration, it is sufficient to 
record only diarrhea as an AE or SAE on the eCRF.  
However, medically significant AEs occurring secondary to an initiating event 
that are separated in time should be recorded as independent events on the 
eCRF. For example, if a severe gastrointestinal hemorrhage leads to renal 
failure, both events should be recorded separately on the eCRF. 
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 Adverse Event eCRF. The initial severity of the event should be recorded, 
and the severity should be updated to reflect the most extreme severity any 
time the event worsens. If the event becomes serious, the Adverse Event 
eCRF should be updated to reflect this. 


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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 Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities that require active 
management will be recorded as AEs or SAEs on the eCRF (e.g., 
abnormalities that require study drug dose modification, discontinuation of 
study treatment, more frequent follow-up assessments, further diagnostic 
investigation, etc.) 
If the clinically significant laboratory abnormality is a sign of a disease or 
syndrome (e.g., alkaline phosphatase and bilirubin 5 × ULN of normal 
associated with cholecystitis), only the diagnosis (e.g., cholecystitis) needs to 
be recorded on the AE eCRF. 
Any potential case of Drug-Induced Liver Damage as assessed by laboratory 
criteria for Hy’s Law should be reported to the Sponsor expeditiously (see 
Section 5.4 for reporting instructions), irrespective of regulatory seriousness 
criteria or causality. The Medical Monitor should be contacted in the event of a 
potential case of Hy’s Law as assessed by laboratory criteria before 
continuing study treatment. 
The following laboratory abnormalities define potential Hy’s Law cases: 
•
AST or ALT increases that are > 3 × ULN
•
Concurrent increases of total bilirubin > 2 × ULN (or clinical jaundice if
total bilirubin measures are not available), except in patients with
documented Gilbert syndrome. For patients with Gilbert’s syndrome,
elevation of direct bilirubin > 2 × the ULN should be used instead.
If the clinically significant laboratory abnormality is not a sign of a disease or 
syndrome, the abnormality itself should be recorded as an AE or SAE on the 
eCRF. If the laboratory abnormality can be characterized by a precise clinical 
term, the clinical term should be recorded as the AE or SAE. 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 as AEs or SAEs on the eCRF, 
unless their severity, seriousness or etiology changes. 
5.3.5.5 
Deaths 
Deaths that occur during the protocol-specified AE reporting period (see 
Section 5.3.1) that are attributed by the investigator solely to progression of 
BC should be recorded only on the Study Completion/Early Discontinuation 
eCRF. All other on-study deaths, regardless of relationship to study drug, 
must be recorded on the Adverse Event eCRF and immediately reported to 
the Sponsor (see Section 5.4.2). The iDMC will monitor the frequency of 
deaths from all causes. 


 
 
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Death should be considered an outcome and not a distinct event. The event 
or condition that caused or contributed to the fatal outcome should be 
recorded as the single medical concept on the Adverse Event eCRF. 
Generally, only one such event should be reported. The term “sudden 
death” should only be used for the occurrence of an abrupt and unexpected 
death due to presumed cardiac causes in a patient with or without pre-existing 
heart disease, within 1 hour of the onset of acute symptoms or, in the case of 
an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable. If the cause of death is unknown and cannot be ascertained at the 
time of reporting, “unexplained death” should be recorded on the Adverse 
Event eCRF. If the cause of death later becomes available (e.g., after 
autopsy), “unexplained death” should be replaced by the established cause of 
death. 
During post-study survival follow-up (i.e., follow-up post-progression or 
post-AEs requiring discontinuation until study site closure or loss to follow-up), 
deaths attributed to progression of BC should be recorded only on the 
Survival eCRF.  
5.3.5.6 
Pre-existing Medical Conditions 
A pre-existing 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 pre-existing medical condition should be recorded as an AE only if the 
frequency, severity, or character of the condition worsens during the study. 
When recording such events on the Adverse Event eCRF, it is important to 
convey the concept that the pre-existing condition has changed by including 
applicable descriptors (e.g., “more frequent headaches”). 
5.3.5.7 
Lack of Efficacy or Worsening of Breast Cancer 
Events that are clearly consistent with the expected pattern of progression of 
the underlying disease should not be recorded as AEs. These data will be 
captured as efficacy assessment data only. In most cases, the expected 
pattern of progression will be based on RECIST. In rare cases, the 
determination of clinical progression will be based on symptomatic 
deterioration. However, every effort should be made to document progression 
using objective criteria. If there is any uncertainty as to whether an event is 
due to disease progression, it should be reported as an AE. 
5.3.5.8 
Hospitalization or Prolonged Hospitalization 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as a SAE unless specifically instructed otherwise in 
this protocol. 
There are some hospitalization scenarios that do not require reporting as an 
SAE when there is no occurrence of an AE. These scenarios include a 
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• 
Perform an efficacy measurement for the study 
• 
Undergo a diagnostic or elective surgical procedure for a pre-existing 
medical condition that has not changed 
• 
Receive scheduled therapy for the target disease of the study 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take 
appropriate measures to address potential new risks in a clinical trial. The 
investigator must report such events to the Sponsor immediately; under no 
circumstances should reporting take place more than 24 hours after the 
investigator learns of the event. The following is a list of events that the 
investigator must report to the Sponsor within 24 hours after learning of the 
event, regardless of relationship to study drug: 
• 
SAEs 
• 
Non-serious AESIs 
• 
Pregnancies 
The investigator must report new significant follow-up information for these 
events to the Sponsor immediately (i.e., no more than 24 hours after 
becoming aware of the information). New significant information includes the 
following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
Investigators must also comply with local requirements for reporting SAEs to 
the local health authority and Institutional Review Board/Ethics Committee 
(IRB/EC). 
5.4.1 
EMERGENCY MEDICAL CONTACTS 
MEDICAL MONITOR (THE SPONSOR MEDICAL RESPONSIBLE) 
CONTACT INFORMATION  
To ensure the safety of study patients, an Emergency Medical Call Center 
Help Desk will access the Sponsor Medical Emergency List, escalate 
emergency medical calls, provide medical translation service (if necessary), 
connect the investigator with a Sponsor 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 and List of Investigators"). 


 
 
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5.4.2 
REPORTING REQUIREMENTS FOR SERIOUS ADVERSE 
EVENTS AND NON-SERIOUS ADVERSE EVENTS OF SPECIAL 
INTEREST 
For reports of SAEs and non-serious AESIs, investigators should record all 
case details that can be gathered within 24 hours on the Adverse Event eCRF 
and submit the report expeditiously via the electronic data capture (EDC) 
system. An expedited report will be generated and sent to the Sponsor 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 the Sponsor 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 last 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 the Sponsor Safety Risk Management. 
Pregnancy should not be recorded on the Adverse Event eCRF. The 
investigator should have the patient discontinue study drug and counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the 
fetus. Sponsor will collect additional follow-up information using the dedicated 
Pregnancy Report Form at the end of the second trimester, after delivery, and 
at 3, 6, and 12 months of the infant’s life on all pregnancy reports received by 
the Sponsor from any source (clinical study and spontaneous reports) or 
identified in the literature by the Sponsor. Also, Sponsor may send follow-up 
queries asking for further information, if required for a comprehensive 
assessment of the case. 
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 fax numbers provided to investigators (see 
"Protocol Administrative and Contact Information & List of Investigators"). 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to 
immediately inform the investigator if their partner becomes pregnant during 
the study or within 7 months after the last dose of study drug. A Pregnancy 
Report eCRF should be completed by the investigator within 24 hours after 


 
 
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learning of the pregnancy and submitted via the EDC system. Attempts 
should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study drug. The 
pregnant partner will need to sign an Authorization for Use and Disclosure of 
Pregnancy Health Information to allow for follow-up on her pregnancy. Once 
the authorization has been signed, the investigator will update the Pregnancy 
Report eCRF with additional information on the course and outcome of the 
pregnancy. An investigator who is contacted by the male patient or his 
pregnant partner may provide information on the risks of the pregnancy and 
the possible effects on the fetus, to support an informed decision in 
cooperation with the treating physician and/or obstetrician. 
In the event that the EDC system is unavailable, follow reporting instructions 
provided in Section 5.4.3.1. 
5.4.3.3 
Abortions 
Any spontaneous abortion should be classified as a SAE (as the Sponsor 
considers spontaneous abortions to be medically significant events), recorded 
on the Adverse Event 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 Adverse Event 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 SAEs considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of AEs (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate 
source data verification. If, after follow-up, return to baseline status or 
stabilization cannot be established, an explanation should be recorded on the 
Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy 
outcome. If the EDC system is not available at the time of pregnancy outcome, 
follow reporting instructions provided in Section 5.4.3.1. 


 
 
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5.5.2 
SPONSOR FOLLOW-UP 
For SAEs, non-serious AESIs, and pregnancies, the Sponsor or a designee 
may follow-up by telephone, fax, electronic mail, and/or a monitoring visit to 
obtain additional case details and outcome information (e.g., from hospital 
discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
 
The Sponsor should be notified if the investigator becomes aware of any SAE 
that occurs after the end of the AE reporting period (defined as 28 days [see 
Section 5.3.1] after the last dose of study drug), if the event is believed to be 
related to prior study drug treatment. 
The investigator should report these events directly to Roche or its designee 
using the eCRF, if still available. If the eCRF is no longer available, then these 
events should be reported by either faxing or scanning and emailing the 
Serious Adverse Event/Adverse Event of Special Interest Reporting Form 
using the fax number or email address provided to investigators.  
5.7 
EXPEDITED REPORTING TO HEALTH 
AUTHORITIES, INVESTIGATORS, INSTITUTIONAL 
REVIEW BOARDS, AND ETHICS COMMITTEES 
To determine reporting requirements for single AE cases, the Sponsor will 
assess the expectedness of these events using the trastuzumab emtansine 
Investigator's Brochure. 
The Sponsor will compare the severity of each event and the cumulative 
event frequency reported for the study with the severity and frequency 
reported in the applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of 
causality and seriousness, with allowance for upgrading by the Sponsor as 
needed. 
The Sponsor will promptly evaluate all reported SAEs against cumulative 
product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
PLAN 
The final analysis will be performed when all patients have been followed up 
for safety and efficacy for up to a period of 2 years after the last patient has 
been enrolled in Cohort 2 of the trial (i.e., after LPLV as in Section 3.2).  
There are no formal statistical hypothesis tests to be performed. There are no 
adjustments for multiplicity of endpoints or within-subgroups comparisons. 


 
 
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Analysis populations: Cohort 1 data will be analyzed after 2 years follow-up 
after last patient is enrolled and prior to Cohort 2.  
6.1 
DETERMINATION OF SAMPLE SIZE 
A sample size of approximately 2000 patients is planned for Cohort 1. For the 
purpose of the estimation of sample size, the incidence of AEs of Grade 3 or 
higher related to trastuzumab emtansine was chosen as a safety endpoint of 
primary interest. 
If the observed incidence of AEs Grade ≥ 3 related to trastuzumab emtansine 
e.g., hepatic events, pneumonitis, thrombocytopenia or allergic reactions is 
between 5% and 10% (Study TDM4450g/BO21976), the precision for the 
estimation of the incidence of AE is presented in the table below by 95% 
Clopper-Pearson CIs. 
Table 7 Cohort 1: Clopper-Pearson 95% Confidence Intervals for the 
incidence of AEs Grade ≥ 3 based on 2000 patients 
Number of AEs/observed AE incidence 
95% Clopper-Pearson CI 
20 (1%) 
0.6% - 1.5% 
40 (2%) 
1.4% - 2.7% 
60 (3%) 
2.3% - 3.8% 
80 (4%) 
3.2% - 5% 
100 (5%) 
4.1% - 6% 
120 (6%) 
5% - 7.1% 
140 (7%) 
5.9% - 8.2% 
160 (8%) 
6.8% - 9.3% 
180 (9%) 
7.8% - 10.3% 
200 (10%) 
8.7% - 11.4% 
 
For the purpose of the sample size estimate of Cohort 2, the incidence of 
Grade ≥ 3 thrombocytopenia in Asian patients was chosen as a safety 
endpoint of primary interest. 
This is based on the pooled analysis of trials TDM4370g/BO21977, 
TDM4450g/BO21976, TDM4373g/BO22495, TDM4374g, TDM4258g, 
TDM4688g, TDM3569g and TDM4529g/BO25430, and the results of a subset 
of 99 Asian patients (see the trastuzumab emtansine Investigator’s Brochure).   
If the observed incidence of Grade ≥ 3 thrombocytopenia in Asian patients is 
between 30% and 55%, the precision for the estimation of the incidence of 
AEs is presented in the table below by 95% Clopper-Pearson CIs. 


 
 
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Table 8 Cohort 2: Clopper-Pearson 95% Confidence Intervals for the 
incidence Grade ≥ 3 thrombocytopenia based on 220 Asian 
patients 
Number of AEs/observed AE incidence 
95% Clopper-Pearson CIs 
2 (1%) 
0.1% - 3.6% 
10 (5%) 
2.4% - 9% 
20 (10%) 
6.2% - 15% 
60 (30%) 
23.7% - 36.9% 
70 (35%) 
28.4% - 42% 
80 (40%) 
33.2% - 47.1% 
90 (45%) 
38% - 52.2% 
100 (50%) 
42.9% - 57.1% 
110 (55%) 
47.8% - 62% 
 
The sample size of approximately 2220 patients is planned for the pooled 
analysis of Cohorts 1 and 2.  
Table 9 Clopper-Pearson 95% Confidence Intervals for the incidence of 
Grade ≥ 3 AEs based on 2220 patients 
Number of AEs/observed AE incidence 
95% Clopper-Pearson CI 
22 (1%) 
0.6% - 1.5% 
44 (2%) 
1.5% - 2.7% 
66 (3%) 
2.3% - 3.8% 
88 (4%) 
3.2% - 4.9% 
110 (5%) 
4.1% - 6% 
132 (6%) 
5% - 7.1% 
154 (7%) 
6% - 8.1% 
176 (8%) 
6.9% - 9.2% 
198 (9%) 
7.8% - 10.3% 
220 (10%) 
8.8% - 11.3% 
 
Summaries of Conduct  
This is a safety study with the safety populations being the main analysis 
populations. Per-protocol (PP) population will not be defined; however major 
protocol violations will be summarized and defined. A median time to 
treatment and median time to follow-up/study will be estimated. 
Two Safety populations will be defined; Safety population 1 and Safety 
population 2, which will be used to summarize safety variables.  


 
 
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Safety population 1 will include all patients who have received at least one 
dose of study medication in Cohort 1 while Safety population 2 will include all 
patients who received at least one dose of study medication in Cohort 2.  
Pooled analysis for safety will be performed on the Safety population that 
includes all patients in Safety population 1 and Safety population 2. 
6.2 
SUMMARIES OF TREATMENT GROUP 
COMPARABILITY 
This study includes only one treatment arm, hence treatment comparability is 
not applicable. 
All safety and efficacy summaries will be presented for each cohort separately, 
and for the pooled analysis of Cohorts 1 and 2. The pooled analysis of 
Cohorts 1 and 2 will be conducted in parallel to the final analysis of Cohort 2. 
Baseline and disease characteristics such as demographics, medical history, 
etc. will be summarized by descriptive statistics (frequency tables for 
categorical variables and mean, median, range, standard deviation [SD], and 
25th-75th quartiles for the continuous variables). 
6.2.1 
PRIMARY EFFICACY ENDPOINT 
This is a safety study; therefore the primary objective of this study is the 
safety parameters. 
6.2.2 
SECONDARY EFFICACY ENDPOINTS 
The efficacy variables will be summarized for the intent-to-treat (ITT) 
population 1 and ITT population 2. ITT1 will include all patients enrolled in 
Cohort 1, while ITT2 will include all patients in Cohort 2. 
Pooled analysis for efficacy will be performed on the ITT population that 
includes ITT1 and ITT2. 
PFS is defined as the time from the date of enrollment until the first 
documented progression of disease or death from any cause, whichever 
occurs first. Patients with no PFS events will be censored at the time of the 
last evaluable tumor assessment. Patients with no tumor assessment after the 
baseline visit will be censored at the time of enrollment plus one day. 
OS is defined as the time from the date of enrollment until the date of death, 
regardless of the cause of death. Patients who were alive at the time of the 
final analysis will be censored at the date of the last follow-up assessment. 
The overall response will be estimated via best (confirmed) overall response 
(BOR) as assessed by investigators. The BOR is defined as the best 
response recorded from the start of this study (date of enrollment) until 
disease progression/recurrence or death from any cause. To be assigned a 
status of PR or CR, i.e., to be a responder, changes in tumor measurements 
must be confirmed by repeat assessments that should be performed no less 
than 4 weeks after the criteria for response are first met, i.e., patients need to 


AEs will be summarized according to the primary system-organ class (SOC) 
and within each SOC, by the Medical Dictionary for Regulatory Activities 
(MedDRA) preferred term. Based on the safety profile of trastuzumab 
emtansine, time to onset of the first episode of each AE described in  
Section 5 will also be summarized via KM estimates. Additional summaries 
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have two consecutive assessments of PR or CR. This status will be assessed 
only for patients with measurable disease at baseline. Patients with non-
measurable disease at baseline will be assessed for the time-to-event 
endpoints (e.g., PFS, OS, etc). 
Logistic analysis will be performed for BOR rate to assess the influence of 
baseline covariates, e.g., age (> 65, ≤ 65), ECOG 0–1 versus ECOG 2 in an 
exploratory manner.  
In addition to these predictor factors, for the pooled analysis of Cohort 1 and 2, 
a further factor will be added: region (Asian versus non-Asian regions). 
CBR includes patients whose best (confirmed) response was PR or CR or 
stable disease that lasts at least 6 months. 
DoR is defined as the period from the date of initial confirmed PR or CR until 
the date of PD or death from any cause. Patients with no documented 
progression after CR or PR will be censored at the last date at which they are 
known to have had the CR or PR, respectively. The method for handling 
censoring is the same as described for the PFS. Only patients with BOR of 
CR or PR (i.e., responders) will be included in the analysis of DoR. 
TTR: time from enrolment to first documentation of confirmed PR or CR 
(whichever occurs first). Patients who do not have a confirmed response are 
censored at the date of the last tumor assessment. 
The number and proportions of responders and non-responders together with 
two-sided, 95% Clopper-Pearson CIs will be presented. 
The analysis of ORR is based on the BOR. The BOR will be assessed by the 
number and proportion of responders and non-responders, together with two-
sided 95% CIs. Patients without a post-baseline tumor assessment will be 
considered to be non-responders. More details will be specified in the 
statistical analysis plan. 
 Estimates for the survivor function for PFS, OS, DoR and TTR will be 
obtained by the Kaplan-Meier (KM) approach. 
6.3 
SAFETY ANALYSES 
Summaries for safety data described below will be performed for Cohort 1, 
Cohort 2, and the pooled analysis. 
All AEs will be assessed according to the NCI CTCAE v 4.0 grading system. 
The analysis of AEs will focus on treatment-emergent AEs i.e., AEs occurring 
on the day of or after first administration of study drug. Non-treatment-
emergent AEs (i.e., those occurring before commencement of study 
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frequency tables will also be provided for these AEs. Pneumonitis events of all 
grades will be analyzed. 
The primary endpoint in this study will be AEs Grade 3 or higher for hepatic 
events, allergic reactions, thrombocytopenia, hemorrhage events, also all 
other AEs Grade 3 or higher related to trastuzumab emtansine, and 
pneumonitis of all grades. AEs leading to treatment interruption and 
discontinuation, and SAEs will be analyzed in a similar way to all AEs. Cause 
of death will also be summarized and listed. 
The number of patients prematurely discontinued from the treatment with 
corresponding reason for discontinuation will be summarized and listed. The 
discontinuation from study will be also summarized and listed. 
Descriptive statistics will be presented for cumulative study medication doses 
and duration of exposure. 
LVEF over time will be analyzed using descriptive statistics for continuous 
variable and presented graphically over time with associated 95% CI. 
Laboratory parameters, hematology, and serum biochemistry will be 
presented in shift tables of NCI CTCAE version 4.0 grade at baseline versus 
worst grade during treatment period. The summary of laboratory parameters 
presented by means, SD, minimum, and maximum will also be presented. 
The selected laboratory parameters will be graphically presented over time. 
Exploratory Analyses 
The following subgroup analyses will be performed for both cohorts and 
pooled across cohorts: 
• 
AST or ALT increases that are > 3 × ULN and total bilirubin > 2 × ULN 
except in patients with documented Gilbert’s syndrome 
• 
Country 
• 
Race 
• 
Region (Asian versus non-Asian regions) 
• 
Age (> 65, ≤ 65) 
• 
Age (>75, ≤75) 
• 
ECOG 0–1 versus ECOG 2 
6.4 
PHARMACOECONOMICS ANALYSES 
The resource expenditure due to hospitalizations that are not study-defined 
evaluations while on study treatment will be evaluated. The number of 
hospital visits, number of days admitted, and type of visits (emergency 
department versus inpatient care) will be collected (see Section 2.3). The 
reason for admission (disease progression versus AE) will also be assessed. 
6.5 
INTERIM ANALYSES 
Cohort 1 


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In addition to the final analysis, there will be five safety interim analyses for 
review by the iDMC: after approximately 50 and 350 patients have completed 
Cycle 1, Day 1 and after approximately 1,000, 1,500, and 2,000 patients have 
completed the first cycle of study medication (Cycle 1, Day 21), with further 
review of accumulating safety data as required (see iDMC charter and  
Section 3.1.2). 
Cohort 2 
In addition to the final analysis, there will be one interim safety analysis for 
review by the iDMC after approximately 100 patients have completed Cycle 1 
(Cycle 1, Day 21).   
In addition to the above interim analyses, there may be additional interim 
analyses for Health Authority purposes (e.g., to support SFDA [China]) after 
150 Chinese patients have been enrolled and completed Cycle 1 (Cycle 1, 
Day 21) or by January 2017, whichever occurs first. 
Final Analysis 
The final analysis will be performed when all patients have been followed up 
for safety and efficacy for a period of up to 2 years after the last patient has 
been enrolled in Cohort 2 of the trial (i.e., as in Section 3.2).  
7.
DATA COLLECTION AND MANAGEMENT
7.1 
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including 
quality checking of the data. Data entered manually will be collected via EDC 
using eCRFs. The sites will be responsible for data entry into the EDC system. 
In the event of discrepant data, the Sponsor will request data clarification from 
the sites, which the sites will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that 
describes the quality checking to be performed on the data. Electronic data 
will be sent directly to the Sponsor, using the Sponsor’s standard procedures 
to handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s 
audit trail. System backups for data stored by the Sponsor and records 
retention for the study data will be consistent with the Sponsor’s standard 
procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed using a Sponsor-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. 


 
 
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All eCRFs should be completed by designated, trained site staff. eCRFs 
should be reviewed and electronically signed and dated by the investigator or 
a designee. 
At the end of the study, the investigator will receive patient data for his or her 
site in a readable format on a compact disc that must be kept with the study 
records. Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized 
site personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are 
recorded and documented for the first time. They include, but are not limited 
to, hospital records, clinical and office charts, laboratory notes, memoranda, 
patient-reported outcomes (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 7.5. 
To facilitate source data verification, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and 
reports for trial-related monitoring, Sponsor audits, and IRB/EC review. The 
investigational site must also allow inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into 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 (for clinical research purposes) would be one that (1) 
allows data entry only by authorized individuals; (2) prevents the deletion or 
alteration of previously entered data and provides an audit trail for such data 
changes (e.g., modification of file); (3) protects the database from tampering; 
and (4) ensures data preservation. 


 
 
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In collaboration with the study monitor, the Sponsor’s Quality Assurance 
group may assist in assessing whether electronic records generated from 
computerized medical record systems used at investigational sites can serve 
as source documents for the purposes of this protocol. 
If a site’s computerized medical record system is not adequately validated for 
the purposes of clinical research (as opposed to general clinical practice), 
applicable hardcopy source documents must be maintained to ensure that 
critical protocol data entered into the eCRFs can be verified. 
7.5 
RETENTION OF RECORDS 
U.S. FDA regulations (21 Code of Federal Regulations §312.62[c]) and the 
ICH Guideline for GCP (see Section 4.9 of the ICH Guideline) require that 
records and documents pertaining to the conduct of this study and the 
distribution of investigational drug, including eCRFs, consent forms, laboratory 
test results, and medication inventory records, must be retained by the 
Principal Investigator for 2 years after the last marketing application approval 
in an ICH region or after at least 2 years have elapsed since formal 
discontinuation of clinical development of the investigational product. All state 
and local laws for retention of records also apply. 
No records should be disposed of without the written approval of the Sponsor. 
Written notification should be provided to the Sponsor for transfer of any 
records to another party or moving them to another location. 
For studies conducted outside the United States under a U.S. Investigational 
New Drug application (IND), the Principal Investigator must comply with the 
record retention requirements set forth in the U.S. FDA IND regulations and 
the relevant national and 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 
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. 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). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form 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 Sample Informed Consent Forms or any alternate consent 


 
 
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forms proposed by the site 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 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. 
A copy of each signed Consent Form must be provided to the patient or the 
patient’s legally authorized representative. If applicable, it will be provided in a 
certified translation of the local language. 
All signed and dated Consent Forms must remain in each patient’s study file 
and must be available for verification by study Monitors at any time. 
The Informed Consent Form should be revised whenever there are changes 
to procedures outlined in the informed consent or when new information 
becomes available that may affect the willingness of the patient to participate. 
For any updated or revised Consent Forms, the case history for each patient 
shall document the informed consent process and that written informed 
consent was obtained for the updated/revised Consent Form for continued 
participation in the study. The final revised IRB/EC-approved Informed 
Consent Form must be provided to the Sponsor for regulatory purposes. 
If the site uses a separate Authorization Form for patient authorization to use 
and disclose personal health information under the U.S. Health Insurance 
Portability and Accountability Act (HIPAA) regulations, the review, approval, 
and other processes outlined above apply except that IRB/EC 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 enrollment materials must 
be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of 
the status of the study to the IRB/EC annually or more frequently in 
accordance with the requirements, policies, and procedures established by 
the IRB/EC. Investigators are also responsible for promptly informing the 
IRB/EC of any protocol amendments (see Section 9.5). 
In addition to the requirements to report protocol-defined AEs to the Sponsor, 
investigators are required to promptly report to their respective IRB/EC all 
unanticipated problems involving risk to human patients. Some IRBs/ECs may 
want prompt notification of all SAEs, whereas others require notification only 
about events that are serious, assessed to be related to study treatment, and 


 
 
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are unexpected. 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 regulatory requirements and with 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., LPLV). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the 
conduct of the study to be fully documented, including but not limited to the 
protocol, protocol amendments, Informed Consent Forms, and documentation 
of IRB/EC and governmental approval. In addition, at the end of the study, the 
investigator will receive the patient data, which includes an audit trail 
containing a complete record of all changes to data. 
9.2 
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 


 
 
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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 
The study will have an iDMC, Steering Committee, IxRS, eCRF, and will be 
conducted by a contract research organization (CRO) together with the 
Sponsor. Assessment of laboratory test results will be performed locally. 
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. 
9.5 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor. Protocol 
amendments will be submitted to the IRB/EC and to regulatory authorities in 
accordance with local regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as 
locally required) before implementation of any changes, except for changes 
necessary to eliminate an immediate hazard to patients or changes that 
involve logistical or administrative aspects only (e.g., change in Medical 
Monitor or contact information). 


 
 
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10. 
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HER2-positive advanced breast cancer. N Engl J Med. 2006; 355:2733–
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8. Girish S, Gupta M, Wang B, et al. Clinical pharmacology of trastuzumab 
emtansine (T-DM1): an antibody–drug conjugate in development for the 
treatment of HER2-positive cancer. Cancer Chemother Pharmacol. 2012; 
69:1229–40. 
9. Gupta M, LoRusso PM, Wang B, et al. Clinical implications of 
pathophysiological and demographic covariates on the population 
pharmacokinetics of trastuzumab-DM1, a HER2-targeted antibody–drug 
conjugate, in patients with HER2-positive metastatic breast cancer. J Clin 
Pharmacol. 2012; 52:691–703. 
10. Issell BF, Crooke ST. Maytansine. Cancer Treat Rev. 1978; 5:199–207. 
11. Jemal A, Bray F, Center MM, et al. Global Cancer Statistics. CA Cancer J 
Clin. 2011; 61:69–90. 
12. Junttila TT, Li G, Parsons K, et al. Trastuzumab-DM1 (T-DM1) retains all 
the mechanisms of action of trastuzumab and efficiently inhibits growth of 
lapatinib insensitive breast cancer. Breast Cancer Res Treat 2011; 
128:347–56. 


 
 
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13. Krop IE, Beeram M, Modi S, et al. Phase I study of trastuzumab-DM1, an 
HER2 antibody-drug conjugate, given every three weeks to patients with 
HER2-positive metastatic breast cancer. J. Clin Oncol 2010; 28:2698–
2704. 
14. Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the 
efficacy and safety of trastuzumab combined with docetaxel in patients 
with human epidermal growth factor receptor 2-positive metastatic breast 
cancer administered as first-line treatment: the M77001 study group. J 
Clin Oncol. 2005; 23:4265–74. 
15. Moldoveanu Z, Huang W-Q, Kulhavy R, et al. Human male genital tract 
secretions: both mucosal and systemic immune compartments contribute 
to the humoral immunity. J Immunol 2005; 175:4127–36. 
16. Press MF, Sauter G, Bernstein L, et al. Diagnostic evaluation of HER-2 as 
a molecular target: an assessment of accuracy and reproducibility of 
laboratory testing in large, prospective, randomized clinical trials. Clin 
Cancer Res. 2005; 11:6598–607. 
17. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer; correlation 
of relapse and survival with amplification of the HER2/neo oncogene. 
Science 1987; 235:177–82. 
18. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a 
monoclonal antibody against HER2 for metastatic breast cancer that 
overexpresses HER2. N Engl J Med. 2001; 344:783–92. 
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validation studies on tumour assessment. Eur J Cancer. 2000; 42:1031–
39. 
22. Tjulandin S, Makhson A, Gligorov J, et al. First results of a Phase II study 
of Bevacizumab in combination with trastuzumab and capecitabine as 
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23. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-
positive advanced breast cancer. N Engl J Med. 2012;367:1783–91. 
24. Wildiers H, et al. T-DM1 for HER2-positive metastatic breast cancer 
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abstract #LBA15- 
25. WHO, World Health Statistics 2011. 
 


 
 
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Appendix 1 Schedule of Assessments 
 
 
Screening 
Treatment Period 
(all visits within  
± 3 days of scheduled 
treatment day) 
Post-treatment Follow-up  
 
Day -28 to 
Day 1 
Day 1 of each  
Treatment Cycle 
Safety Follow-up Visit 
(28–42 days after last 
dose) 
Follow-up until Study 
Closure2 
(every 3–6 months) 
Informed Consent 
Xa 
 
 
 
HER2 Status 
Xb 
 
 
 
Medical History and Demographics 
X 
 
 
 
Complete Physical Examination 
X 
 
 
 
Limited Physical Examinationc 
 
X 
X 
 
Height and Weightd 
X 
X 
X 
 
Vital Signse 
X 
X 
X 
 
ECOG Performance Status 
X 
X 
X 
 
Concomitant Medication Reporting 
Xf 
Ongoing 
Xf 
Adverse Event Reporting 
Xg 
Ongoing 
Xh 
12-lead ECG 
X 
 
 
 
ECHO/MUGAi 
Xi 
Xi 
Xi 
 
Tumor Assessmentsj 
X 
Every 12 weeks 
X 
X 
Brain CT or MRIk 
X 
At the discretion of the investigator, if clinically indicated, until disease progression 


 
 
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Appendix 1 Schedule of Assessments (cont.) 
 
 
 
Screening 
Treatment Period 
(all visits within  
± 3 days of scheduled 
treatment day) 
Post-treatment Follow-up  
 
Day -28 to 
Day 1 
Day 1 of each  
Treatment Cycle 
Safety Follow-up Visit 
(28–42 days after last 
dose) 
Follow-up until Study 
Closure2 
(every 3–6 months) 
Bone Scan/Imagingl 
X 
As clinically indicated or to confirm a response, until disease progression 
Hematologym 
X1 
Xn 
X 
 
Biochemistryo 
X1 
Xn 
X 
 
Urinalysisp 
X1 
As clinically indicated 
X 
 
INR 
X1 
As clinically indicated, e.g. for 
patients receiving anti-
coagulation therapy 
X 
 
Pregnancy Testq 
X 
Every 3 cycles 
X 
Xq 
Assessment of Patient Hospitalizations 
and/or Hospital Visits 
 
X 
X 
 
Administration of Trastuzumab Emtansine 
 
Xr 
 
 
 


 
 
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Appendix 1 Schedule of Assessments (cont.) 
 
AE = Adverse Event; CT = Computed Tomography; ECG = Electrocardiogram; ECHO = Echocardiogram; ECOG = Eastern Cooperative Oncology Group; D = 
Day; HER2 = human epidermal growth factor receptor 2; INR = International Normalized Ratio; MRI = Magnetic Resonance Imaging; MUGA = Multiple-Gated 
Acquisition; PD = Progressive Disease; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, version 1.1; SAE = Serious Adverse Event.  
 
1. 
NOTE: Local laboratory (hematology, biochemistry, urinalysis, and INR assessments) at Screening: to be performed within 14 days prior to first study 
treatment. Screening laboratory assessments may be done on the day of first study treatment (Cycle 1, Day 1).  
2. 
All patients will be followed up for survival every 6 months (± 14 working days; except for pregnancy test which is at 3 and 6 months after safety follow-up 
visit) until death, loss to follow-up, withdrawal of consent, or study closure . Patients who discontinue study treatment for reasons other than disease 
progression will continue to undergo tumor assessments every 3-6 months until disease progression occurs. If assessments cannot be done at survival 
visits, the study site is permitted to collect survival information by phone call. After disease progression, patients will be followed up for survival every 6 
months (± 14 working days) until death, loss to follow-up, withdrawal of consent, or study closure (whichever occurs first). 
a) 
Informed consent may be obtained at any time (including prior to the 28-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 28 days 
prior to first study treatment may be used rather than repeating required tests. 
b) 
HER2 positivity is defined as IHC 3+ or gene amplification by ISH, it will be performed locally.  
c) 
Defined as a directed physical rather than thorough examination of all body systems. For example if a patient presents with a symptom, there should be a 
more comprehensive assessment of the affected body system.  
d) 
Height to be obtained at screening or at Cycle 1, Day 1 only. 
e) 
Vital signs should be obtained and reviewed but 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. 
f) 
Record all prior investigational, anti-cancer therapies and concomitant medications within 28 days prior to first study treatment. At follow-up, assessment 
of anti-cancer therapies only. 
g) 
During screening, only SAEs considered related to protocol-mandated procedures will be collected. 


 
 
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Appendix 1 Schedule of Assessments (cont.) 
 
h) 
Patients will be followed for new or worsening AEs for 28 days following the last infusion of study drug, until treatment-related AEs resolve or stabilize, or 
until the initiation of another anti-cancer therapy, whichever occurs first, and until disease progresses for tumor assessments. After 28 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 until it is determined that the study treatment or participation is not the cause of the AE/SAE. Additionally, patients will be 
contacted regarding the occurrence of any new SAE considered to be treatment-related at 60 and 90 days following the last study treatment 
administration or until initiation of another anti-cancer therapy, whichever occurs first.  
i) 
Cardiac monitoring (ECHO/MUGA) will be performed in all patients enrolled in the study. Assessments will occur during the screening period, and on Day 
21 (or -7 days) of the cycle for Cycle 1, Cycle 3 and every third cycle thereafter. ECHO or MUGA will be performed following study treatment 
discontinuation only if the most recent follow-up ECHO/MUGA was performed ≥ 28 days after last study treatment administration or if no post-treatment 
evaluation was performed. The same imaging technique should be used per patient throughout the study. Results must be reviewed and documented 
prior to administration of study treatment. If treatment is delayed for any reason, LVEF assessments can be postponed to allow them to be performed 
within 7 days prior to the next treatment administration. 
j) 
From Cycle 1, Day 1 onwards, tumor assessments, including a CT or MRI with contrast of the chest, abdomen, and pelvis should be performed according 
to the indicated schedule (± 5 working days), regardless of any delays in treatment or other assessments. Tumor assessments obtained within 28 days 
prior to first study treatment may be used for screening purposes. Tumor response must be assessed through physical examination and imaged-based 
evaluation using RECIST version 1.1. Assessments should include an evaluation of all sites of disease. In cases where there is suspicion of progression 
before the next scheduled assessment, an unscheduled assessment should be performed. The same radiographic procedure used to define measurable 
disease sites at baseline must be used throughout the study for the same patient, e.g. the same contrast protocol for CT scans. For patients who 
discontinue study treatment for reasons other than PD, continued tumor assessments according to the protocol every 3-6 months. After disease 
progression, assessments are no longer required to evaluate new lesions, non-target lesions, and target lesions. 
k) 
Patients with isolated brain metastases may continue study treatment if they demonstrate clinical benefit (CR or PR of any duration or SD ≥ 4 months) as 
detailed in Section 4.4.1.4. A brain MRI or CT should be performed along with regularly scheduled tumor assessments in these instances. 
l) 
An isotope bone scan and/or other radiographic modalities (as a consequence of the anticipated Tc-99 shortage), will be performed at screening and 
should be repeated in the event of clinical suspicion of progression of existing bone lesions and/or the development of new bone lesions. If an isotope-


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based scan was performed >28 days but ≤ 60 days prior to first study treatment, non-isotopic radiographic modalities should be utilized to document the 
extent of bony metastatic disease. Refer to Appendix 3 for additional details. 
m)
Hematologic assessments include Hemoglobin (Hb), hematocrit, red blood cell count, platelet count, and white blood cells (WBC) with differential
(including neutrophils, lymphocytes, monocytes, eosinophils and basophils).
n)
Scheduled for Day 1 of Cycle 1 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.
o)
Biochemistry assessments include: sodium, potassium, chloride, calcium, magnesium, glucose, BUN, creatinine, uric acid, total protein, albumin, alkaline
phosphatase, ALT (SGPT), AST (SGOT), gamma-glutamyl transferase, lactate dehydrogenase, total bilirubin (and direct bilirubin where total bilirubin >
ULN).
p)
Includes specific gravity, pH, protein, glucose, blood, ketones and bilirubin.
q)
Serum β-HCG test must be performed during screening. Urine β-HCG test must 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 (refer to   
Section 5.2.4). Testing should be performed at a local laboratory within 7 days prior to the first administration of study medication (Cycle 1, Day1). For all 
other women, documentation must be present in medical history confirming that the patient is not of childbearing potential. Urine pregnancy test in 
women of childbearing potential must be performed every 3 cycles and at 3- and 6- months after the safety follow-up visit. All positive urine pregnancy 
tests must be confirmed by a serum β-HCG test. Contraception should be used for 7 months after the last dose of study medication.
r)
The initial dose of trastuzumab emtansine will be administered over 90 minutes if well tolerated subsequent infusions may be administered over 30 (±10)
min.


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


 
 
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c. Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy 
require particular comment, as outlined below. 
Bone Lesions: 
• 
Bone scan, positron emission tomography (PET) scan, or plain films are 
not considered adequate imaging techniques for measuring bone lesions. 
However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• 
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft 
tissue components, that can be evaluated by cross-sectional imaging 
techniques such as CT or MRI can be considered as measurable lesions 
if the soft tissue component meets the definition of measurability 
described above. 
• 
Blastic bone lesions are non-measurable. 
Cystic Lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor 
non-measurable) since they are, by definition, simple cysts. 
• 
Cystic lesions thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability 
described above. However, if non-cystic lesions are present in the same 
patient, these are preferred for selection as target lesions. 
Lesions with Prior Local Treatment: 
• 
Tumor lesions situated in a previously irradiated area, or in an area 
subjected to other loco-regional therapy, are usually not considered 
measurable unless there has been demonstrated progression in the 
lesion. Study protocols should detail the conditions under which such 
lesions would be considered measurable. 
Target Lesions: Specifications by Methods of Measurements  
a. Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if 
clinically assessed. All baseline evaluations should be performed as close as 


 
 
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possible to the treatment start and never more than 4 weeks before the 
beginning of the treatment. 
b. Method of Assessment 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the 
study. Imaging-based evaluation should always be the preferred option. 
Clinical Lesions. Clinical lesions will only be considered measurable when 
they are superficial and ≥ 10 mm in diameter as assessed using calipers (e.g., 
skin nodules). For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is suggested. 
Chest X-Ray. Chest CT is preferred over chest X-ray, particularly when 
progression is an important endpoint, since CT is more sensitive than X-ray, 
particularly in identifying new lesions. However, lesions on chest X-ray may 
be considered measurable if they are clearly defined and surrounded by 
aerated lung. 
CT, MRI. CT is the best currently available and reproducible method to 
measure lesions selected for response assessment. This guideline has 
defined measurability of lesions on CT scan based on the assumption that CT 
slice thickness is 5 mm or less. When CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable.  
If prior to enrollment it is known that a patient is unable to undergo CT scans 
with intravenous (IV) contrast because of allergy or renal insufficiency, the 
decision as to whether a non-contrast CT or MRI (without IV contrast) will be 
used to evaluate the patient at baseline and during the study should be guided 
by the tumor type under investigation and the anatomic location of the disease. 
For patients who develop contraindications to contrast after baseline contrast 
CT is done, the decision as to whether non-contrast CT or MRI (enhanced or 
non-enhanced) will be performed should also be based on the tumor type and 
the anatomic location of the disease, and should be optimized to allow for 
comparison with the prior studies if possible. Each case should be discussed 
with the radiologist to determine if  
substitution of these other approaches is possible and, if not, the patient should 
be considered not evaluable from that point forward. Care must be taken in 
measurement of target lesions on a different modality and interpretation of non-
target disease or new lesions, since the same lesion may appear to have a 
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Ultrasound. Ultrasound is not useful in assessment of lesion size and should 
not be used as a method of measurement. 
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology. The 
utilization of these techniques for objective tumor evaluation cannot generally 
be advised. 
Tumor Response Evaluation 
Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to 
estimate the overall tumor burden at baseline and use this as a comparator 
for subsequent measurements. Measurable disease is defined by the 
presence of at least one measurable lesion, as detailed above. 
Baseline Documentation of Target and Non-Target Lesions 
When more than one measurable lesion is present at baseline, all lesions up 
to a maximum of five lesions total (and a maximum of two lesions per organ) 
representative of all involved organs should be identified as target lesions and 
will be recorded and measured at baseline. This means that, for instances in 
which patients have only one or two organ sites involved, a maximum of two 
lesions (one site) and four lesions (two sites), respectively, will be recorded. 
Other lesions (albeit measurable) in those organs will be recorded as non-
measurable lesions (even if the size is > 10 mm by CT scan).  
Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and be representative of all involved organs, but in addition 
should lend themselves to reproducible repeated measurements. It may be 
the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement, in which circumstance the next largest lesion that 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical 
structures that may be visible by imaging even if not involved by tumor. As 
noted above, pathological nodes that are defined as measurable and may be 
identified as  
target lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan. 
Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if 
a node is involved by solid tumor. Nodal size is normally reported as two 
dimensions in the plane in which the image is obtained (for CT this is almost 
always the axial plane; for MRI the plane of acquisition may be axial, sagittal, 
or coronal). The smaller of these measures is the short axis. For example, an 
abdominal node that is reported as being 20 mm × 30 mm has a short axis of 


 
 
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20 mm and qualifies as a malignant, measurable node. In this example, 20 
mm should be recorded as the node measurement. All other pathological 
nodes (those with short axis ≥ 10 mm but < 15 mm) should be considered 
non-target lesions. Nodes that have a short axis of < 10 mm are considered 
non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline 
sum of diameters. If lymph nodes are to be included in the sum, then, as 
noted above, only the short axis is added into the sum. The baseline sum of 
diameters will be used as a reference to further characterize any objective 
tumor regression in the measurable dimension of the disease. 
All other lesions (or sites of disease), including pathological lymph nodes, 
should be identified as non-target lesions and should also be recorded at 
baseline. Measurements are not required and these lesions should be 
followed as “present,” “absent,” or in rare cases “unequivocal progression.” 
In addition, it is possible to record multiple non-target lesions involving the 
same organ as a single item on the Case Report Form (CRF) (e.g., “multiple 
enlarged pelvic lymph nodes” or “multiple liver metastases”). 
Response Criteria 
a. Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective 
tumor response for target lesions. 
• 
Complete response (CR): Disappearance of all target lesions 
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to < 10 mm. 
 
• 
Partial response (PR): At least a 30% decrease in the sum of diameters of 
target lesions, taking as reference the baseline sum of diameters 


 
 
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• 
Progressive disease (PD): At least a 20% increase in the sum of 
diameters of target lesions, taking as reference the smallest sum on study 
(nadir), including baseline 
In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. 
The appearance of one or more new lesions is also considered 
progression. 
• 
Stable disease: Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study 
b. Special Notes on the Assessment of Target Lesions 
Lymph Nodes. Lymph nodes identified as target lesions should always have 
the actual short axis measurement recorded (measured in the same 
anatomical plane as the baseline examination), even if the nodes regress to < 
10 mm on study. This means that when lymph nodes are included as target 
lesions, the sum of lesions may not be zero even if CR criteria are met, since 
a normal lymph node is defined as having a short axis of <10 mm. 
Target Lesions That Become Too Small to Measure. During the study, all 
lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very 
small (e.g., 2 mm). However, sometimes lesions or lymph nodes that are 
recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may 
report them as being too small to measure. When this occurs, it is important 
that a value be recorded on the CRF, as follows: 
• 
If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. 
• 
If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned and BML 
(below measurable limit) should be ticked. (Note: It is less likely that this 
rule will be used for lymph nodes since they usually have a definable size 
when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and BML should also be ticked). 


 
 
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To reiterate, however, if the radiologist is able to provide an actual measure, that 
should be recorded, even if it is below 5 mm, and in that case BML should not be 
ticked. 
Lesions That Split or Coalesce on Treatment. When non-nodal lesions 
fragment, the longest diameters of the fragmented portions should be added 
together to calculate the target lesion sum. Similarly, as lesions coalesce, a 
plane between them may be maintained that would aid in obtaining maximal 
diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest 
diameter in this instance should be the maximum longest diameter for the 
coalesced lesion. 
c. Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the 
tumor response for the group of non-target lesions. While some non-target 
lesions may actually be measurable, they need not be measured and instead 
should be assessed only qualitatively at the time points specified in the 
protocol. 
• 
CR: Disappearance of all non-target lesions and (if applicable) 
normalization of tumor marker level 
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
• 
Non-CR/Non-PD: Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
• 
PD: Unequivocal progression of existing non-target lesions 
The appearance of one or more new lesions is also considered 
progression. 
d. Special Notes on Assessment of Progression of Non-Target Disease 
When the Patient Also Has Measurable Disease. In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be 
an overall level of substantial worsening in non-target disease in a magnitude 
that, even in the presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A 
modest increase in the size of one or more non-target lesions is usually not 


 
 
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sufficient to qualify for unequivocal progression status. The designation of 
overall progression solely on the basis of change in non-target disease in the 
face of SD or PR of target disease will therefore be extremely rare. 
When the Patient Has Only Non-Measurable Disease. This circumstance 
arises in some Phase III trials when it is not a criterion of study entry to have 
measurable disease. The same general concepts apply here as noted above; 
however, in this instance there is no measurable disease assessment to 
factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by 
definition: if all lesions are truly non-measurable), a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if 
the increase in overall disease burden based on the change in non-
measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease, that is, an increase in tumor 
burden representing an additional 73% increase in volume (which is 
equivalent to a 20% increase in diameter in a measurable lesion). Examples 
include an increase in a pleural effusion from “trace” to “large” or an increase 
in lymphangitic disease from localized to widespread, or may be described in 
protocols as “sufficient to require a change in therapy.” If unequivocal 
progression is seen, the patient should be considered to have had overall PD 
at that point. While it would be ideal to have objective criteria to apply to non-
measurable disease, the very nature of that disease makes it impossible to do 
so; therefore, the increase must be substantial. 
e. New Lesions 
The appearance of new malignant lesions denotes disease progression; 
therefore, some comments on detection of new lesions are important. There 
are no specific criteria for the identification of new radiographic lesions; 
however, the finding of a new lesion should be unequivocal, that is, not 
attributable to differences in scanning technique, change in imaging modality,  
or findings thought to represent something other than tumor (for example, 
some “new” bone lesions may be simply healing or flare of pre-existing 
lesions). This is particularly important when the patient’s baseline lesions 
show PR or CR. For example, necrosis of a liver lesion may be reported on a 
CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not 
scanned at baseline is considered a new lesion and will indicate disease 
progression. 
If a new lesion is equivocal, for example because of its small size, continued 
therapy and follow-up evaluation will clarify if it represents truly new disease. 


 
 
Appendix 2 Response Evaluation Criteria in Solid Tumors 
(RECIST): Modified Excerpt from Original Publication (cont.)  
 
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If repeat scans confirm there is definitely a new lesion, then progression 
should be declared using the date of the initial scan. 
Evaluation of Response 
a. Time point Response (Overall Response) 
It is assumed that at each protocol-specified time point, a response 
assessment occurs. Table 1 provides a summary of the overall response 
status calculation at each time point for patients who have measurable 
disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, 
Table 2 is to be used. 


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


 
 
Appendix 2 Response Evaluation Criteria in Solid Tumors 
(RECIST): Modified Excerpt from Original Publication (cont.)  
 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
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be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response. This would be most likely to 
happen in the case of PD. For example, if a patient had a baseline sum of 50 
mm with three measured lesions and during the study only two lesions were 
assessed, but those gave a sum of 80 mm, the patient will have achieved PD 
status, regardless of the contribution of the missing lesion.  
If one or more target lesions were not assessed either because the scan was not 
done or the scan could not be assessed because of poor image quality or 
obstructed view, the response for target lesions should be “unable to assess” 
since the patient is not evaluable. Similarly, if one or more non-target lesions are 
not assessed, the response for non-target lesions should be “unable to assess” 
except where there is clear progression. Overall response would be “unable to 
assess” if either the target response or the non-target response is “unable to 
assess” except where this is clear evidence of progression, as this equates with 
the case being not evaluable at that time point. 
 


 
 
Appendix 2 Response Evaluation Criteria in Solid Tumors 
(RECIST): Modified Excerpt from Original Publication (cont.)  
 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
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Table 3 Best Overall Response When Confirmation Is Required 
Overall Response at First 
Time point 
Overall Response at 
Subsequent Time point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR a 
CR 
SD 
SD, provided minimum 
duration for SD was met; 
otherwise, PD 
CR 
PD 
SD, provided minimum 
duration for SD was met; 
otherwise, PD 
CR 
NE 
SD, provided minimum 
duration for SD was met; 
otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD, provided minimum 
duration for SD was met; 
otherwise, PD 
PR 
NE 
SD, provided minimum 
duration for SD was met; 
otherwise, NE 
NE 
NE 
NE 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
SD = stable disease. 
a If a CR is truly met at the first time point, any disease seen at a subsequent time point, 
even disease meeting PR criteria relative to baseline, qualifies as PD at that point (since 
disease must have reappeared after CR). Best response would depend on whether the 
minimum duration for SD was met. However, sometimes CR may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had 
PR, not CR, at the first time point. Under these circumstances, the original CR should be 
changed to PR and the best response is PR. 
 
c. Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes 
decrease to “normal” size (< 10 mm), they may still have a measurement 
reported on scans. This measurement should be recorded even though the 
nodes are normal in order not to overstate progression should it be based on 
increase in size of the nodes. As noted earlier, this means that patients with 
CR may not have a total sum of “zero” on the CRF. 


 
 
Appendix 2 Response Evaluation Criteria in Solid Tumors 
(RECIST): Modified Excerpt from Original Publication (cont.)  
 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
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Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time 
should be reported as “symptomatic deterioration.” Every effort should be 
made to document objective progression even after discontinuation of 
treatment. Symptomatic deterioration is not a descriptor of an objective 
response; it is a reason for stopping study therapy. The objective response 
status of such patients is to be determined by evaluation of target and non-
target disease as shown in Table 1, Table 2, and Table 3. 
For equivocal findings of progression (e.g., very small and uncertain new 
lesions; cystic changes or necrosis in existing lesions), treatment may 
continue until the next scheduled assessment. If at the next scheduled 
assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
In studies for which patients with advanced disease are eligible (i.e., primary 
disease still or partially present), the primary tumor should also be captured 
as a target or non-target lesion, as appropriate. This is to avoid an incorrect 
assessment of CR if the primary tumor is still present but not evaluated as a 
target or non-target lesion. 
 


 
 
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Appendix 3 Instructions for Scans in the Event of Isotope 
Shortage 
Two key suppliers of Tc-99m generators (Chalk River Reactor, Canada and 
High Flux Reactor, the Netherlands) are expected to close. Supplies from 
other reactor sources will be unable to meet the expected world-wide patient-
care needs. As a result, significant shortages of Tc-99m are expected, and 
the instructions listed below should be followed: 
• 
ECHO will be the preferred imaging modality over MUGA scans to 
evaluate cardiac function. 
• 
Tc-99m bone scans should be obtained as part of the baseline tumor 
assessment in all patients and should be repeated to confirm a CR or if 
progression of existing bone lesions and/or the development of new bone 
lesions is clinically suspected. 
• 
If a bone scan cannot be performed at baseline or if the investigator 
suspects that a bone scan may not be able to be repeated during the 
course of the study because of the Tc-99m shortage, the investigator may 
choose F-18 NaF or FDG-PET scan as an alternative. 
• 
If bone lesions are selected as index non-target lesions, they must be 
apparent on baseline CT scans or other radiographic modalities (e.g., 
skeletal X-rays that can be repeated in subsequent tumor assessments). 
Additional scans may be obtained to follow clinically important bone 
lesions if not visualized on the chest, abdomen, or pelvic CT scan. 
These measures are intended to ensure that the same method of assessment 
and the same imaging technique is used throughout the study for each patient. 
If there is a question regarding the choice of alternatives in the event that a 
standard bone scan cannot be obtained during screening and/or during the 
study, please contact the Medical Monitor. 
 


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

SAP_001.pdf: 
Official Title: 
A Two-Cohort, Open-Label, Multicenter, Study of Trastuzumab 
Emtansine (T-DM1) in HER2 Positive Locally Advanced or Metastatic 
Breast Cancer Patients Who Have Received Prior Anti-HER2 and 
Chemotherapy-Based Treatment 
NCT Number: 
NCT01702571 
Document Date: 
SAP Version 2: 02-February-2020 


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Statistical Analysis Plan
F. HOFFMANN-LA ROCHE LTD
Protocol: MO28231
Treatment: Trastuzumab emtansine (RO5304020)
A TWO-COHORT, OPEN-LABEL, MULTICENTER, STUDY OF TRASTUZUMAB
EMTANSINE (T-DM1) IN HER2 POSITIVE LOCALLY ADVANCED OR
METASTATIC BREAST CANCER PATIENTS WHO HAVE RECEIVED PRIOR
ANTI-HER2 AND CHEMOTHERAPY-BASED TREATMENT
Author(s):
Document Status:
Version 2, Final
Version Dates:
Version 2, Draft 1: 14Oct2019
Version 2, Final: 02Feb2020
Pages:
50
STATEMENT OF CONFIDENTIALITY
The information contained in this document, especially unpublished data, is the property of F.
Hoffmann-La Roche Ltd (or under its control), and therefore provided to you in confidence for
review by you and/or your staff. It is understood that this information will not be disclosed to
others without written authorization from Roche.


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Contents
ABBREVIATIONS..................................................................................................................4
1
INTRODUCTION............................................................................................................6
2
STUDY OBJECTIVES AND ENDPOINTS..................................................................8
2.1
OBJECTIVES ................................................................................................................8
2.1.1
Primary Objective..................................................................................................8
2.1.2
Secondary Objective ..............................................................................................8
2.1.3
Exploratory objective.............................................................................................8
2.1.4
Pharmacoeconomics outcome objective................................................................8
2.2
ENDPOINTS .................................................................................................................8
2.2.1
Primary endpoint ...................................................................................................8
2.2.2
Secondary endpoints..............................................................................................8
2.2.2.1
Secondary safety endpoints............................................................................8
2.2.2.2
Secondary efficacy endpoints ........................................................................9
2.2.2.3
Exploratory efficacy endpoints......................................................................9
2.2.2.4
Pharmacoeconomic endpoints .......................................................................9
3
STUDY DESIGN..............................................................................................................9
3.1
DISCUSSION OF STUDY DESIGN...................................................................................9
3.2
STUDY TREATMENT..................................................................................................10
3.3
STUDY SCHEDULE.....................................................................................................11
3.4
CONCOMITANT MEDICATION....................................................................................16
3.5
STUDY ANALYSIS POPULATIONS...............................................................................16
3.5.1
Safety Population.................................................................................................17
3.5.2
ITT Population.....................................................................................................17
3.5.3
Subgroups ............................................................................................................17
3.6
WITHDRAWN SUBJECTS ............................................................................................18
3.7
RANDOMIZATION......................................................................................................19
3.8
BLINDING..................................................................................................................19
3.9
SAMPLE SIZE.............................................................................................................19
4
STATISTICAL METHODOLOGY.............................................................................21
4.1
PLANNED ANALYSES ................................................................................................21
4.2
INTERIM ANALYSIS PLAN .........................................................................................22
4.3
DISPOSITION OF SUBJECTS ........................................................................................23
4.4
BASELINE AND DEMOGRAPHIC CHARACTERISTICS ...................................................23
4.5
EXPOSURE.................................................................................................................24
4.6
CONCOMITANT MEDICATION....................................................................................24
4.7
EFFICACY ANALYSIS.................................................................................................25
4.7.1
Progression free survival.....................................................................................25
4.7.2
Overall survival ...................................................................................................25
4.7.3
Best overall response and overall response rate.................................................26
4.7.4
Duration of response............................................................................................29
4.7.5
Time to response ..................................................................................................29
4.7.6
Clinical benefit rate .............................................................................................30
4.7.7
Lesions count .......................................................................................................30
4.7.7.1
Target lesions...............................................................................................30
4.7.7.2
New lesions and Non target lesions.............................................................30


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4.7.8
Time to progression .............................................................................................30
4.8
SAFETY ANALYSIS....................................................................................................30
4.8.1
General consideration .........................................................................................30
4.8.2
Primary endpoint .................................................................................................32
4.8.3
Secondary endpoints............................................................................................32
4.8.3.1
Adverse events of special interest................................................................32
4.8.3.2
Other adverse events of interest...................................................................33
4.8.3.3
Summary of all adverse events ....................................................................34
4.8.4
Laboratory findings .............................................................................................35
4.8.5
LVEF....................................................................................................................36
4.8.6
ECG......................................................................................................................36
4.8.7
Weight ..................................................................................................................37
4.8.8
ECOG...................................................................................................................37
4.8.9
Physical Examinations.........................................................................................37
4.8.10
Assessments of hospitalizations .......................................................................37
4.9
ADJUSTMENT FOR COVARIATES................................................................................37
4.9.1
Centre effects .......................................................................................................37
4.10
PROTOCOL VIOLATIONS............................................................................................37
4.10.1
Violation criteria..............................................................................................37
4.11
MISSING VALUES – MISSING VISITS .........................................................................38
4.12
DEVIATIONS FROM SAP............................................................................................38
4.13
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL ...................38
4.14
ALGORITHMS/SAS CODES........................................................................................39
5
TABLES AND LISTINGS ............................................................................................40
5.1
TABLE FORMAT ........................................................................................................40
5.2
CONVENTIONS ..........................................................................................................40
5.3
TABLES.....................................................................................................................41
5.3.1
Section 14.1: Demographic and Baseline............................................................41
5.3.2
Section 14.2: Efficacy ..........................................................................................42
5.3.3
Section 14.3: Safety..............................................................................................43
5.3.3.1
Primary endpoint..........................................................................................43
5.3.3.2
Secondary endpoints....................................................................................43
5.3.3.3
Laboratory results ........................................................................................47
5.3.3.4
ECG..............................................................................................................47
5.3.3.5
ECOG...........................................................................................................47
5.3.3.6
LVEF............................................................................................................47
5.3.3.7
Hospitalizations............................................................................................47
5.3.3.8
Weight..........................................................................................................47
5.4
LISTINGS...................................................................................................................48
5.5
FIGURES....................................................................................................................49
5.6
APPENDICES..............................................................................................................50
5.7
REFERENCES .............................................................................................................50


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Abbreviations
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALT (SGPT)
Alanine Aminotransferase
aPTT
Activated Partial Thromboplastin Time
AST (SGOT)
Aspartate Aminotransferase
BC
Breast Cancer
BOR
Best Overall Response
bpm
Beats Per Minute
BUN
Blood Urea Nitrogen
CBR
Clinical Benefit Rate
CHF
Congestive Heart Failure
CI
Confidence Interval
CR
Complete Response
CRF
Case Report Form
CT
Computed Tomography
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria For Adverse Events
DoR
Duration of Response
DRM
Data Review Meeting
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
FDA
Food and Drug Administration
G-GT
Gamma-Glutamyl Transpeptidase
HER2
Human Epidermal growth factor Receptor 2
ICU
Intensive Care Unit
iDMC
Independent Data Monitoring Committee
INR
International Normalized Ratio
ISR
Injection Site Reaction
ITT
Intent-To-Treat
KM
Kaplan Meier
kg
Kilogram
LABC
Locally Advanced Breast Cancer
LDH
Lactate Dehydrogenase
LPLV
Last Patient Last Visit
LVEF
Left Ventricular Ejection Fraction
Max
Maximum
MedDRA
Medical Dictionary For Regulatory Activities
mBC
Metastatic Breast Cancer
mg
Milligram
Min
Minimum
MRI
Magnetic Resonance Imaging
MUGA
Multiple-Gated Acquisition
NCI
National Cancer Institute
NRH
Nodular Regenerative Hyperplasia
ORR
Overall Response Rate


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OS
Overall Survival
PFS
Progression Free Survival
PR
Partial Response
PTT
Partial Thromboplastin Time
q3w
every 3 weeks
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
T-DM1
Trastuzumab Emtansine
TTP
Time To Progression
TTR
Time To Response
ULN
Upper Limit of Normal
WBC
White Blood Cell Count


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1
Introduction
This document presents the statistical analysis plan (SAP) for F. Hoffmann-La Roche Ltd,
Protocol No. MO28231: A two-cohort, open-label, multicenter, study of trastuzumab
emtansine (T-DM1) in HER2 positive locally advanced or metastatic breast cancer (BC)
patients who have received prior anti-HER2 and chemotherapy-based treatment.
This analysis plan is based on the final protocol, dated 12 June 2012; incorporating
Amendment 1, dated 22 June 2012; Amendment 2, dated 21 August 2012; Amendment 3,
dated 11 February 2013; Amendment 4, dated 30 May 2013; and Amendment 5, dated
31 January 2014; and Amendment 6, dated 18th July 2019.
The final analysis of each cohort will be performed when all patients within the respective
cohort have been followed up for safety and efficacy for a period of up to 2 years after the
last patient has been enrolled into Cohort 2 of the trial. The analysis of Cohort 1 will be
conducted and then combined for the pooled analysis of Cohorts 1 and 2. This pooled
analysis will be conducted in parallel to the final analysis of Cohort 2.
In addition to the final analysis, there were seven interim safety analyses in the Cohort 1 for
review by the independent Data Monitoring Committee (iDMC): after approximately 50 and
350 patients have completed Cycle 1, Day 1 and after approximately 1000, 1500 and 2000
patients have completed the first cycle of study medication (Cycle 1, Day 21), and two which
were approximately every 6 months thereafter, as per the iDMC charter.
In addition to the final analysis, there will be one interim safety analysis in Cohort 2 for
review by the iDMC after approximately 100 patients have completed Cycle 1 (Cycle 1,
Day 21).
Also, there might be additional interim analyses for Health Authority purposes (e.g., to
support the China Food and Drug Administration [CFDA] [China]) after 150 Chinese patients
have been enrolled and completed Cycle 1 (Cycle 1, Day 21) or by January 2017, whichever
occurs first.
This SAP provides the description of the analysis for the final analyses.




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2
Study Objectives and Endpoints
2.1
Objectives
2.1.1 Primary Objective
-
The primary objective of this study is to evaluate the safety and tolerability of
trastuzumab emtansine.
2.1.2 Secondary Objective
-
The secondary objectives of the study include the evaluation of the following
parameters:

Progression free survival (PFS)

Overall survival (OS)

Overall response rate (ORR) = partial response (PR) + complete response (CR)

Clinical benefit rate (CBR)

Duration of response (DoR)

Time to Response (TTR)
2.1.3 Exploratory objective
-
The exploratory objective of the study includes the evaluation of the following
parameters:

Time to Progression (TTP)
2.1.4 Pharmacoeconomics outcome objective
-
The pharmacoeconomics outcome objective for this study is of health resource
utilization and will be as follows:

To evaluate the resource expenditures, while on study treatment, due to
hospitalizations that are not study-defined evaluations. The number of hospital
visits and type of visits (Intensive Care Unit [ICU] versus other) will be recorded,
as detailed in Section 4.13.
2.2
Endpoints
2.2.1 Primary endpoint
The primary endpoint in this study is the incidence of AEs Grade 3 or higher specifically for
hepatic events, allergic reactions, thrombocytopenia, hemorrhage events, also all other AEs
Grade 3 or higher related to trastuzumab emtansine, and pneumonitis of all grades.
2.2.2 Secondary endpoints
2.2.2.1
Secondary safety endpoints
All AEs of primary interest that constitute the primary endpoint will be analyzed separately
as secondary safety endpoints:
-
AEs Grade 3 or higher for hepatic events,
-
AEs Grade 3 or higher for allergic reactions,
-
AEs Grade 3 or higher for thrombocytopenia,
-
AEs Grade 3 or higher for hemorrhage events,
-
AEs Grade 3 or higher related to trastuzumab emtansine,
-
pneumonitis of all grades


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Adverse events of special interest (AESIs) for this study include the following:
-
Potential drug-induced liver injury
-
Suspected transmission of an infectious agent by the study drug
In addition, AEs leading to treatment interruption and discontinuation, related and unrelated
SAEs, cause of death, peripheral neuropathy, left ventricular dysfunction disorders, incidence
of CHF, infusion-related reaction/hypersensitivity, premature discontinuation from study and
treatment, laboratory test abnormalities, left ventricular ejection fraction (LVEF) decrease
over the course of the study as measured by echocardiogram (ECHO) or multiple-gated
acquisition scan (MUGA) and exposure to study drug, will be analyzed as secondary safety
endpoints.
All the AEs or safety parameters that are not mentioned above will be also analyzed to
respond to the primary objective.
2.2.2.2
Secondary efficacy endpoints
The secondary efficacy endpoints of this study are as follows:

Progression Free Survival (PFS)

Overall Survival (OS)

Overall Response Rate (ORR) = PR + CR

Clinical Benefit Rate (CBR)

Duration of Response (DoR)

Time to Response (TTR)
2.2.2.3
Exploratory efficacy endpoints
The exploratory efficacy endpoint of this study is as follows:

Time to Progression (TTP)
2.2.2.4
Pharmacoeconomic endpoints
The pharmacoeconomic endpoints of this study are as follows:

Number of hospital visits

Type of visits (ICU versus other)
3
Study Design
3.1
Discussion of Study Design
This study is a two-cohort, open-label, international, multicenter Phase IIIb study to evaluate
the safety and tolerability of trastuzumab emtansine.
This study will enroll patients with HER2-positive, unresectable, locally advanced breast
cancer (LABC) or metastatic breast cancer (mBC) who have previously received prior
anti-HER2 and chemotherapy treatment and have progressed on or after the most recent
treatment for LABC or mBC, or within 6 months of completing adjuvant therapy.


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Approximately 2220 patients will be enrolled into the study.

Cohort 1 (approximately 2000 patients)

Cohort 2 (will include approximately 220 patients only of Asian race)
Enrollment into Cohort 2 will begin around the end of enrollment into Cohort 1. Therefore,
the entire length of the study (covering enrollment and follow-up period) is estimated to be
6 years. Patients who have not progressed at the end of the trial will be offered options to
continue with trastuzumab emtansine treatment.
All patients will be followed up for survival every 6 months (± 14 working days) until death,
loss to follow-up or withdrawal of consent until study closure. Patients who discontinue study
treatment for reasons other than disease progression will continue to undergo tumor
assessments every 3-6 months until study closure.
The schedule of assessments is presented in Section 3.3, Table 1.
3.2
Study Treatment
Trastuzumab emtansine will be administered on Day 1 of a 3-week cycle; every 3 weeks
(q3w) at a dose of 3.6 mg/kg IV unless dose reductions or dose delays are required. The total
dose will be calculated based on the patient’s weight up to 28 days before each cycle with no
upper limit. If within these 28 days, the patient experiences a severe weight loss, the dose
should be recalculated accordingly.
If the timing of trastuzumab emtansine coincides with a holiday that precludes the procedure,
the procedure should be performed within 3 business days of the scheduled date and, when
possible, on the earliest following date, with subsequent protocol-specified procedures
rescheduled accordingly.
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 60 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 minutes observation period
following infusion. Local health authority guidelines must be followed with regard to further
observation and monitoring, if applicable.
Patients will receive study medication until unacceptable toxicity, withdrawal of consent,
disease progression, death, or up to a maximum of 2 years after last patient first visit,
whichever occurs first. Patients who have not progressed at the end of the trial will be offered
options to continue with trastuzumab emtansine treatment.


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3.3
Study Schedule
Table 1: Schedule of Assessments
Screening
Treatment Period
(all visits within
± 3 days of scheduled treatment
day)
Post-treatment Follow-up
Day -28 to
Day 1
Day 1 of each
Treatment Cycle
Safety Follow-up Visit
(28–42 days after last
dose)
Follow-up until Study
Closure2
(every 3–6 months)
Informed Consent
Xa
HER2 Status
Xb
Medical History and Demographics
X
Complete Physical Examination
X
Limited Physical Examinationc
X
X
Height and Weightd
X
X
X
Vital Signse
X
X
X
ECOG Performance Status
X
X
X
Concomitant Medication Reporting
Xf
Ongoing
Xf
Adverse Event Reporting
Xg
Ongoing
Xh
12-lead ECG
X
ECHO/MUGAi
Xi
Xi
Xi
Tumor Assessmentsj
X
Every 12 weeks
X
X
Brain CT or MRIk
X
At the discretion of the investigator, if clinically indicated, until disease progression


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Table 1: Schedule of Assessments (Continued)
Screening
Treatment Period
(all visits within
± 3 days of scheduled treatment
day)
Post-treatment Follow-up
Day -28 to
Day 1
Day 1 of each
Treatment Cycle
Safety Follow-up Visit
(28–42 days after last
dose)
Follow-up until Study
Closure2
(every 3–6 months)
Bone Scan/Imagingl
X
As clinically indicated or to confirm a response, until disease progression
Hematologym
X1
Xn
X
Biochemistryo
X1
Xn
X
Urinalysisp
X1
As clinically indicated
X
INR
X1
As clinically indicated, e.g. for
patients receiving anti-
coagulation therapy
X
Pregnancy Testq
X
Every 3 cycles
X
Xq
Assessment of Patient Hospitalizations and/or
Hospital Visits
X
X
Administration of Trastuzumab Emtansine
Xr


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Table 1 Schedule of Assessments (Continued)
AE = Adverse Event; CT = Computed Tomography; ECG = Electrocardiogram; ECHO = Echocardiogram; ECOG = Eastern Cooperative Oncology Group; D = Day; HER2 =
human epidermal growth factor receptor 2; INR = International Normalized Ratio; MRI = Magnetic Resonance Imaging; MUGA = Multiple-Gated Acquisition; PD =
Progressive Disease; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, version 1.1; SAE = Serious Adverse Event.
–
NOTE: Local laboratory (hematology, biochemistry, urinalysis, and INR assessments) at Screening: to be performed within 14 days prior to first study treatment.
Screening laboratory assessments may be done on the day of first study treatment (Cycle 1, Day 1).
–
All patients will be followed up for survival every 6 months (± 14 working days; except for pregnancy test which is at 3 and 6 months after safety follow-up visit) until
death, loss to follow-up, or withdrawal of consent until study closure and until disease progression and/or until a new anti-cancer treatment is initiated (whichever occurs
first). Patients who discontinue study treatment for reasons other than disease progression will continue to undergo tumor assessments every 3-6 months. If assessments
cannot be done at survival visits, the study site is permitted to collect survival information by phone call. Patients will also be followed for subsequent anti-cancer
therapies (not all concomitant medications).
a)
Informed consent may be obtained at any time (including prior to the 28-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 28 days prior to first study treatment
may be used rather than repeating required tests.
b)
HER2 positivity is defined as IHC 3+ or gene amplification by ISH, it will be performed locally.
c)
Defined as a directed physical rather than thorough examination of all body systems. For example if a patient presents with a symptom, there should be a more
comprehensive assessment of the affected body system.
d)
Height to be obtained at screening or at Cycle 1, Day 1 only.
e)
Vital signs should be obtained and reviewed but 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.
f)
Record all prior investigational, anti-cancer therapies and concomitant medications within 28 days prior to first study treatment. At follow-up, assessment of anti-cancer
therapies only.
g)
During screening, only SAEs considered related to protocol-mandated procedures will be collected.


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Table 1 Schedule of Assessments (Continued)
h)
Patients will be followed for new or worsening AEs for 28 days following the last infusion of study drug, until treatment-related AEs resolve or stabilize, or until the
initiation of another anti-cancer therapy, whichever occurs first, and until disease progresses for tumor assessments. After 28 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 until it is determined that the study treatment or participation is not the cause of the AE/SAE. Additionally, patients will be contacted regarding the occurrence of any
new SAE considered to be treatment-related at 60 and 90 days following the last study treatment administration or until initiation of another anti-cancer therapy,
whichever occurs first.
i)
Cardiac monitoring (ECHO/MUGA) will be performed in all patients enrolled in the study. Assessments will occur during the screening period, and on Day 21 (or -7
days) of the cycle for Cycle 1, Cycle 3 and every third cycle thereafter. ECHO or MUGA will be performed following study treatment discontinuation only if the most
recent follow-up ECHO/MUGA was performed ≥ 28 days after last study treatment administration or if no post-treatment evaluation was performed. The same imaging 
technique should be used per patient throughout the study. Results must be reviewed and documented prior to administration of study treatment. If treatment is delayed
for any reason, LVEF assessments can be postponed to allow them to be performed within 7 days prior to the next treatment administration.
j)
From Cycle 1, Day 1 onwards, tumor assessments, including a CT or MRI with contrast of the chest, abdomen, and pelvis should be performed according to the indicated
schedule (± 5 working days), regardless of any delays in treatment or other assessments. Tumor assessments obtained within 28 days prior to first study treatment may be
used for screening purposes. Tumor response must be assessed through physical examination and imaged-based evaluation using RECIST version 1.1. Assessments
should include an evaluation of all sites of disease. In cases where there is suspicion of progression before the next scheduled assessment, an unscheduled assessment
should be performed. The same radiographic procedure used to define measurable disease sites at baseline must be used throughout the study for the same patient, e.g. the
same contrast protocol for CT scans. For patients who discontinue study treatment for reasons other than PD, continued tumor assessments according to the protocol
every 3-6 months. After disease progression, assessments are no longer required to evaluate new lesions, non-target lesions, and target lesions.
k)
Patients with isolated brain metastases may continue study treatment if they demonstrate clinical benefit (CR or PR of any duration or SD ≥ 4 months) as detailed in 
Section 4.4.1.4 of the protocol. A brain MRI or CT should be performed along with regularly scheduled tumor assessments in these instances.
l)
An isotope bone scan and/or other radiographic modalities (as a consequence of the anticipated Tc-99 shortage), will be performed at screening and should be repeated in
the event of clinical suspicion of progression of existing bone lesions and/or the development of new bone lesions. If an isotope-based scan was performed >28 days but
≤ 60 days prior to first study treatment, non-isotopic radiographic modalities should be utilized to document the extent of bony metastatic disease. Refer to Appendix 3 
for additional details.


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Table 1 Schedule of Assessments (Continued)
m)
Hematologic assessments include Hemoglobin (Hb), hematocrit, red blood cell count, platelet count, and white blood cells (WBC) with differential (including
neutrophils, lymphocytes, monocytes, eosinophils and basophils).
n)
Scheduled for Day 1 of Cycle 1 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.
o)
Biochemistry assessments include: sodium, potassium, chloride, calcium, magnesium, glucose, BUN, creatinine, uric acid, total protein, albumin, alkaline phosphatase,
ALT (SGPT), AST (SGOT), gamma-glutamyl transferase, lactate dehydrogenase, total bilirubin (and direct bilirubin where total bilirubin > ULN).
p)
Includes specific gravity, pH, protein, glucose, blood, ketones and bilirubin.
q)
Serum β-HCG test must be performed during screening. Urine β-HCG test must 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 (refer to Section 5.2.4). Testing should be performed
at a local laboratory within 7 days prior to the first administration of study medication (Cycle 1, Day1). For all other women, documentation must be present in medical
history confirming that the patient is not of childbearing potential. Urine pregnancy test in women of childbearing potential must be performed every 3 cycles and at 3-
and 6- months after the safety follow-up visit. All positive urine pregnancy tests must be confirmed by a serum β-HCG test. Contraception should be used for 7 months 
after the last dose of study medication.
r)
The initial dose of trastuzumab emtansine will be administered over 90 minutes if well tolerated subsequent infusions may be administered over 30 (±10) min.


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3.4
Concomitant Medication
Concomitant therapy and premedication are defined as non-investigational medicinal
products.
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter
drugs, herbal/homeopathic remedies, nutritional supplements) used by a patient between the
28 days preceding first treatment and the safety follow-up visit (28 – 42 days after last dose).
Afterwards, only anti-cancer therapies will be recorded on the Concomitant Medications
electronic Case Report Form (eCRF), as part of the survival follow-up period.
Premedication is allowed according to standard practice guidelines. No premedication for the
first infusion of trastuzumab emtansine is required; however, premedication is allowed at the
investigator’s discretion. Concomitant use of erythropoiesis-stimulating agents is allowed if
clinically indicated in accordance with local prescribing guidelines.
Palliative radiotherapy may be permitted to treat pre-existing painful bone metastases or to
treat brain metastases (for patients who have disease control outside of the brain).
Radiotherapy should be finished at least 7 days before resuming administration of
trastuzumab emtansine and all toxicities need to have resolved. If not, the cycle may be
delayed for up to 42 days.
Other medications considered necessary for the patient’s safety and well-being may be given
at the discretion of the investigator. Use of bisphosphonates or denosumab is permitted for
the control of bone pain, prevention and/or treatment of bony metastases, and treatment of
osteoporosis. If bisphosphonates are required for the treatment of symptomatic malignancy-
associated hypercalcemia, tumor assessments should be performed to assess for potential
disease progression. Premedication for nausea and infusion reactions (e.g., acetaminophen or
other analgesics, antihistamines such as diphenhydramine, or corticosteroids) may also be
given at the investigator’s discretion.
Any Chinese traditional medicines that could potentially negatively impacting the liver
functions are not permitted. However, any Chinese traditional medicines having a liver
protective action would be considered acceptable, at the investigator’s discretion. It will be
the investigator’s responsibility to verify whether a specific Chinese medication could
potentially affect liver function.
Prohibited Therapy
The medications and or therapies described below are prohibited during the study prior to
discontinuation of study treatment.
Any therapies intended for the treatment of cancer, other than trastuzumab emtansine,
whether they are approved by national health authorities or experimental, including cytotoxic
chemotherapy, immunotherapy, hormonal therapy (other than megestrol acetate), and
biologic or targeted agents (other than granulocyte colony-stimulating factor and
erythropoiesis stimulating agents), are prohibited. The use of Chinese traditional medicines in
case when they have no anti-cancer activity are allowed at the investigator’s discretion.
Radiotherapy for unequivocal disease progression is not permitted while on study treatment,
with the exception of new brain metastases or isolated progression of previously treated brain
lesions. Patients who have disease control outside of the brain, defined as continued PR or
CR of any duration, or SD for ≥3 months, but who have developed brain metastases that are 
treatable with radiation will be allowed to continue to receive study therapy until they either
experience systemic progression of their disease and/or further progression in the brain that


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cannot be treated with additional radiation. Radiotherapy should be finished at least 7 days
before resuming administration of trastuzumab emtansine and all toxicities need to have
resolved. Patients with thrombocytopenia and on anti-coagulant treatment must be monitored
closely during treatment with trastuzumab emtansine. Platelet counts will be monitored prior
to each trastuzumab emtansine dose.
3.5
Study Analysis Populations
There will be 2 analysis populations (Safety and Intent-to-Treat (ITT)) defined for the study
analyses. The Safety and ITT populations are described below.
This is a safety study with the safety populations being the main analysis populations.
Per-protocol (PP) population will not be defined; however major protocol violations will be
summarized and defined.
3.5.1 Safety Population
The safety population includes all patients who have received at least one dose of study
medication. Two safety populations will be defined: Safety Population 1 will include all
patients enrolled in Cohort 1, while Safety Population 2 will include all patients in Cohort 2.
Safety Population 1 and Safety Population 2 will be used to summarize safety variables for
Cohort 1 and Cohort 2, respectively.
Pooled analysis for safety will be performed on the Safety Population that includes all
patients in Safety Population 1 and Safety Population 2.
3.5.2 ITT Population
The ITT population includes all patients enrolled to the study (with informed consent signed
and enrolled for the study). Two ITT populations will be defined: ITT Population 1 will
include all patients enrolled in Cohort 1, while ITT Population 2 will include all patients in
Cohort 2.
ITT Population 1 and ITT Population 2 will be used to summarize efficacy variables for
Cohort 1 and Cohort 2, respectively.
Pooled analysis for efficacy will be performed on the ITT Population that includes all patients
in ITT Population 1 and ITT Population 2.
3.5.3 Subgroups
The following subgroup analyses will be performed for both cohorts and pooled across
cohorts for safety analyses:

AST or ALT increases that are > 3 × ULN and total bilirubin > 2 × ULN except in
patients with documented Gilbert’s syndrome

Country; see below for more details.

Race (Asian, non-Asian, NA or Unknown)

Age (≤65, 66-74, ≥75) 

ECOG 0–1 versus ECOG ≥ 2 


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Country has been replaced by pooled countries for safety reporting. Singular countries will
still be used for patient disposition. The regrouped countries are given as follows:
Asia: Hong Kong, Korea, Taiwan, China and United Arab Emirates (UAE)
North America: Canada
South America: Argentina, Brazil, Dominican Republic, Ecuador, Guatemala, Mexico,
Panama, Peru and Venezuela
Europe : Austria, Belgium, Bulgaria, Croatia, Denmark, Estonia, Finland, France, Germany,
Greece, Hungary, Iceland, Ireland, Italy, Luxembourg, Netherlands, Norway, Poland,
Portugal, Slovakia, Slovenia, Spain, Sweden, Turkey and UK
Australia: Australia
Analyses on the subgroups of patients for whom non-validated tests were used, will be
performed for demography, HER2 status, baseline characteristics and AEs (including most
common AEs, SAEs and AEs leading to discontinuation). In addition, Kaplan-Meier
estimates will be calculated for PFS and OS, as well as the BOR, in this subgroup.
The subgroup comprised patients who had either:

a non-validated IHC test result and no ISH test performed

or a non-validated ISH test result and no IHC test performed

or a non-validated IHC test result and a non-validated ISH test result
3.6
Withdrawn Subjects
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

Noncompliance

Disease progression
In addition, patients must permanently discontinue study drug if they experience any of the
following:

Clinical signs and symptoms suggesting CHF.

Dyspnea or clinically significant hypotension (defined per investigator discretion).

Symptomatic left ventricular dysfunction (NCI-CTCAE version 4.0 Grade 3 or 4)
with a drop in LVEF consistent with cardiac failure.

Pregnancy.

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. 


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
Patients who experience Grade > 3 elevation of liver function which does not recover
within 42 days

Trastuzumab emtansine treatment in patients with serum transaminases 3 ULN
and concomitant total bilirubin 2 ULN

Patients who are diagnosed with NRH (Nodular Regenerative Hyperplasia)

Patients who are diagnosed with ILD or pneumonitis

Patients who experience a Grade 3 allergic reaction or acute respiratory distress
syndrome
Patients who discontinue study drug prematurely will be asked to return to the clinic for a
safety follow-up visit, and may undergo follow-up assessments.
The primary reason for discontinuation of study drug and/or withdrawal from the study will
be recorded on the appropriate eCRF pages.
The following reasons will be collected:

Adverse event/Unacceptable toxicity

Death

Lost to follow-up

Lack of compliance

Withdrew consent

Investigator's decision

Trial terminated by Sponsor

Completed treatment per protocol

Disease Progression

Other
Patients who discontinue study drug prematurely will not be replaced.
3.7
Randomization
N/A
3.8
Blinding
N/A
3.9
Sample Size
A sample size of approximately 2000 patients is planned for Cohort 1. For the purpose of the
estimation of sample size, the incidence of AEs of Grade 3 or higher related to trastuzumab
emtansine was chosen as a safety endpoint of primary interest. If the observed incidence of
AEs Grade ≥ 3 related to trastuzumab emtansine e.g., hepatic events, pneumonitis, 
thrombocytopenia or allergic reactions is between 5% and 10% (Study
TDM4450g/BO21976), the precision for the estimation of the incidence of AE is presented in
Table 2 by 95% Clopper-Pearson Confidence Intervals (CIs).


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Table 2 Cohort 1: Clopper-Pearson 95% Confidence Intervals for the Incidence of AEs
Grade ≥ 3 Based on 2000 Patients 
Number of AEs/observed AE
incidence
95% Clopper-Pearson CI
20 (1%)
0.6% - 1.5%
40 (2%)
1.4% - 2.7%
60 (3%)
2.3% - 3.8%
80 (4%)
3.2% - 5%
100 (5%)
4.1% - 6%
120 (6%)
5% - 7.1%
140 (7%)
5.9% - 8.2%
160 (8%)
6.8% - 9.3%
180 (9%)
7.8% - 10.3%
200 (10%)
8.7% - 11.4%
For the purpose of the sample size estimate of Cohort 2, the incidence of Grade ≥ 3 
thrombocytopenia in Asian patients was chosen as a safety endpoint of primary interest.
This is based on the pooled analysis of trials: TDM4370g/BO21977, TDM4450g/BO21976,
TDM4373g/BO22495, TDM4374g, TDM4258g, TDM4688g, TDM3569g and
TDM4529g/BO25430, and the results of a subset of 99 Asian patients (see the trastuzumab
emtansine Investigator’s Brochure).
If the observed incidence of Grade ≥ 3 thrombocytopenia in Asian patients is between 30% 
and 55%, the precision for the estimation of the incidence of AEs is presented in Table 3 by
95% Clopper-Pearson CIs.
Table 3 Cohort 2: Clopper-Pearson 95% Confidence Intervals for the Incidence of
Grade ≥ 3 Thrombocytopenia Based on 220 Asian Patients 
Number of AEs/observed AE
incidence
95% Clopper-Pearson CIs
2 (1%)
0.1% - 3.6%
10 (5%)
2.4% - 9%
20 (10%)
6.2% - 15%
60 (30%)
23.7% - 36.9%
70 (35%)
28.4% - 42%
80 (40%)
33.2% - 47.1%
90 (45%)
38% - 52.2%
100 (50%)
42.9% - 57.1%
110 (55%)
47.8% - 62%


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The sample size of approximately 2220 patients is planned for the pooled analysis of
Cohorts 1 and 2. Table 4 shows the precision for the estimation of the incidence of AEs.
Table 4
Clopper-Pearson 95% Confidence Intervals for the Incidence of Grade
≥ 3 AEs based on 2220 patients 
Number of AEs/observed AE
incidence
95% Clopper-Pearson CI
22 (1%)
0.6% - 1.5%
44 (2%)
1.5% - 2.7%
66 (3%)
2.3% - 3.8%
88 (4%)
3.2% - 4.9%
110 (5%)
4.1% - 6%
132 (6%)
5% - 7.1%
154 (7%)
6% - 8.1%
176 (8%)
6.9% - 9.2%
198 (9%)
7.8% - 10.3%
220 (10%)
8.8% - 11.3%
4
Statistical Methodology
4.1
Planned Analyses
This study includes only one treatment arm; hence treatment comparability is not applicable.
All safety and efficacy summaries will be presented for each cohort separately, and for the
pooled analysis of Cohorts 1 and 2. The analysis of Cohort 1 will be conducted and then the
pooled analysis of Cohorts 1 and 2 will be conducted in parallel to the final analysis of
Cohort 2.
Safety Population 1 and Safety Population 2 will be used to summarize safety variables for
Cohort 1 and Cohort 2, respectively.
Pooled analysis for safety will be performed on the safety population that includes all patients
in Safety Population 1 and Safety Population 2.
The following subgroup analyses will be performed on Safety Population 1, Safety
Population 2 and the overall safety population (pooled analysis) for all safety analyses:
-
AST or ALT increases that are > 3 × ULN and total bilirubin > 2 × ULN except in
patients with documented Gilbert’s syndrome
-
Country
-
Race (Asian, non-Asian, NA or Unknown)
-
Age (≤65, 66-74, ≥75) 
-
ECOG 0–1 versus ECOG ≥ 2 
Country has been replaced by pooled countries for safety reporting. The regrouped countries
are given as follows:
-
Asia: Hong Kong, Korea, Taiwan, China and UAE


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-
North America: Canada
-
South America: Argentina, Brazil, Dominican Republic, Ecuador, Guatemala,
Mexico, Panama, Peru and Venezuela
-
Europe: Austria, Belgium, Bulgaria, Croatia, Denmark, Estonia, Finland, France,
Germany, Greece, Hungary, Iceland, Ireland, Italy, Luxembourg, Netherlands,
Norway, Poland, Portugal, Slovakia, Slovenia, Spain, Sweden, Turkey and UK
-
Australia: Australia
ITT Population 1 and ITT Population 2 will be used to summarize efficacy variables for
Cohort 1 and Cohort 2, respectively.
Pooled analysis for efficacy will be performed on the ITT population that includes all patients
in ITT Population 1 and ITT Population 2.
Demography and baseline characteristic summaries will be presented for both the safety and
ITT populations (Populations 1, 2 and pooled). Summary statistics will be presented for
continuous variables, by way of n, mean, standard deviation (SD), median, minimum and
maximum and by way of group frequencies and percentages for categories of categorical
variables. Baseline and disease characteristics that are continuous variables will also present
the first and third quartiles. Percentages will be calculated using the total subjects.
There are no formal statistical hypothesis tests to be performed. There are no adjustments for
multiplicity of endpoints or within-subgroups comparisons.
Notes:

Baseline is defined as the last value recorded prior to first dose of study drug (except
for the laboratory data, where a value recorded the date of first dose of study drug and
corresponding to screening visit will be also considered as baseline).

Where a change from baseline is presented, results for baseline are those recorded
immediately prior to treatment. Where this value is missing or unavailable, then the
next available preceding result will be used.

All data will be listed.

Listings will be provided for 11 patients in China who continued study treatment after
clinical data cutoff pending delayed entry into a rollover study (per Protocol
Amendment 5). These listings will contain additional data from these patients’ visits
after 10th July 2019 (protocol LPLV) until their actual last visit.
4.2
Interim Analysis Plan
In addition to the final analysis, for Cohort 1 there will be seven safety interim analyses for
review by the iDMC: after approximately 50 and 350 patients have completed Cycle 1, Day 1
and after approximately 1,000, 1,500, and 2,000 patients have completed the first cycle of
study medication (Cycle 1, Day 21), and two which were approximately at 6 and 12 months
thereafter, as per the iDMC charter. For Cohort 2, there will be one interim safety analysis
for review by the iDMC after approximately 100 patients have completed Cycle 1 (Cycle 1,
Day 21).
As discussed and agreed with the iDMC members, the following has approach will be
implemented.


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1)
The 100th patient enrolled and dosed should occur at the same time as the DBL
2)
To allow for programing and data cleaning activities, the iDMC review was moved
by 4 months.
In addition to the above interim analyses, there may be additional interim analyses for Health
Authority purposes (e.g., to support CFDA [China]) after 150 Chinese patients have been
enrolled and completed Cycle 1 (Cycle 1, Day 21) or by January 2017, whichever occurs
first.
The description of the analyses required for the iDMC is presented in the iDMC charter.
The final analysis of each cohort will be performed when all patients within the respective
cohort have been followed up for safety and efficacy for a period of up to 2 years after the
last patient has been enrolled in Cohort 2 of the trial.
4.3
Disposition of Subjects
The number of screened patients (enrolled, inform consent form signed) and eligible patients
will be presented.
The number of patients eligible for the study, number and percentage, in each analysis
population will be presented. It should be noted that for this study the patients eligible for the
study correspond to the ITT population.
The number of patients who completed treatment (Yes/No), in follow-up (Yes/No),
completed study (Yes/No) and the reasons for discontinuation of treatment and
discontinuation from study will be presented for each analysis population.
The number of patients by country and pooled country will also be presented.
The summary of patients receiving the study drug at each cycle will be presented graphically.
4.4
Baseline and Demographic Characteristics
All baseline and demographic characteristics will be summarized for the safety population,
and repeated for ITT population. Included will be age, age in classes([<65 and ≥ 65],  [<75 
and ≥75], [≤65, 66-74, ≥ 75] , [18-64, 65-74, ≥ 75] and [18-64, 65-84, ≥ 85] years old), 
gender, race, self-reported ethnicity, country of the site in which the patient was screened,
female reproductive status, height, weight, ECOG status, smoking history, alcohol and drug
abuse, human epidermal growth factor receptor 2 (HER2) test results, ongoing and all
medical history, cancer history, tumor assessments at baseline, previous cancer therapy and
surgery, neoadjuvant treatment, adjuvant treatment, locally advanced /metastatic treatment,
visceral disease at screening and location of metastasis at diagnosis.
Notes:

Age will be as reported on the eCRF at screening and will not be derived.

Medical history will be coded according to the latest version of the Medical
Dictionary for Regulatory Activities (MedDRA). At the time of the pooled analyses
the MedDRA version will be different from the MedDRA version used at the Cohort
1 analyses. For the pooled analyses the latest version of MedDRA will be used for all
patients.

Ongoing medical history is defined as histories marked as ongoing at time of
screening.


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
All medical histories are all medical histories recorded in the eCRF
4.5
Exposure
Summaries of study treatment exposure will be presented for the safety population, and
repeated for ITT population.
The total number of cycles received will be summarized both by descriptive statistics and by
presenting the number and percentage of patients in each cohort.
Study drug administration details will be summarized by descriptive statistics and will
include the duration of exposure, the number and percentage of patients with missed doses,
doses reduced and doses interrupted, and the cumulative doses received.
Missed Dose is identified from the following question in the CRF –‘Was the study
medication administered at this visit?’
Number of Doses Reduced is derived from planned and received dose. If received dose is less
than planned dose then this is considered as dose reduced.
Dose Interruption is when the infusion is interrupted, taken from the ‘Was infusion
interrupted?’ in the CRF
The duration of exposure and duration of follow-up will be displayed.
Duration of exposure (months) will be derived as follows:
((Date of last administration – Date of first administration) + 1)/ 30.4375
Duration of follow-up (months) is the duration the patient is in the study and will be derived
as follows:
((Date of end of study – Date of inclusion) + 1)/ 30.4375
Cumulative doses received (mg/kg) will be calculated over all received infusions, according
to received dose (in mg) divided by patient’s body weight at each dose.
4.6
Concomitant Medication
Summaries of prior and concomitant medications will be presented for the safety population.
Prior medications are those that stopped before exposure to study drug; concomitant
medications are all those taken during the study, including those started before (28 days) but
ongoing at first dose of study drug.
Incidence of prior medications and concomitant medications will be presented in a listing
separately by indication (pre-existing condition, prophylaxis, and adverse event) therapeutic
area and preferred drug name.
Where a medication end date is partially or fully missing, and it is unclear as to whether the
medication is prior or concomitant, it will be assumed that it is concomitant.
Medications are coded using the latest version of the World Health Organization (WHO)
Drug dictionary, by ATC Class and Preferred Drug Name.
Previous anti-cancer therapy refers to previous systemic therapies; chemotherapy, targeted
therapy, anti-estrogen therapy and radiotherapy.
The number of patients with anti-tumor therapy will be summarized, as well as the number of
patients having received each type of anti-cancer therapy, and the number of lines of
metastatic treatment received.


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A table per type of anti-cancer therapy will also be provided, describing the number of
patients who received the anti-cancer treatment in each setting (neo-adjuvant, adjuvant setting
etc), the reason for discontinuation of previous treatment, and the product received.
4.7
Efficacy Analysis
The efficacy variables will be summarized for ITT Population 1 and ITT Population 2, for
Cohort 1 and Cohort 2, respectively.
Pooled analysis for efficacy will be performed on the ITT population that includes all patients
from ITT Population 1 and ITT Population 2.
No formal hypothesis testing is planned.
4.7.1 Progression free survival
PFS is defined as the time from the date of first dose until the first documented progression of
disease or death from any cause (event), whichever occurs first. Patients with no PFS events
will be censored at the time of the last evaluable tumor assessment. Patients with no tumor
assessment after the baseline visit will be censored at the time of first dosing plus one day.
The progression of disease as assessed by investigators will be taken for the analysis.
Time to event will be calculated in months as follows:
PFS (months) = ((date of event – date of first dosing) + 1)/ 30.4375
Kaplan-Meier (KM) estimates of the median time to event and the corresponding two-sided
95% CI will be presented along with the estimates for the 1st and 3rd quartiles and the
associated ranges (minimum, maximum). The estimate of the survivor function (probability
of event) will be displayed graphically using a KM curve and listed along with the associated
95% CI; the log-log transformation is applied to the survivor function to obtain the CIs. PFS
will be assessed for patients with either measurable or non-measurable disease at baseline.
Progression free survival rates at Week 12, and at 12-week intervals thereafter will be
estimated and presented along with the corresponding two-sided 95% CI. The final analysis
will take place 2 years after the last patient has been enrolled in the trial.
PFS outputs (i.e. table and KM figure) will be presented stratified by Previous Lines of
Treatment and prior treatment with pertuzumab.
4.7.2 Overall survival
OS is defined as the time from the date of first dosing until the date of death, regardless of the
cause of death. Patients who were alive at the time of the final analysis will be censored at the
date of the last follow-up assessment.
Time to event will be calculated in months as follows:
OS (months) = ((date of event – date of first dosing) + 1) /30.4375
Overall survival will be assessed for patients with either measurable or non-measurable
disease at baseline and analyzed and presented as described for PFS.


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OS outputs will be presented stratified by Previous Lines of Treatment and prior treatment
with Pertuzumab.
4.7.3 Best overall response and overall response rate
Overall response will be estimated via best (confirmed) overall response (BOR) as assessed
by investigators. The BOR is defined as the best response recorded from the start of first
dosing (date of first dosing) until disease progression/recurrence or death from any cause. To
be assigned a status of PR or CR, i.e.to be a responder, changes in tumor measurements must
be confirmed by repeat assessments that should be performed no less than 4 weeks after the
criteria for response are first met, i.e., patients need to have two consecutive assessments of
PR or CR. This status will be assessed only for patients with measurable disease at baseline.
Patients with non-measurable disease at baseline will be assessed for the time-to-event
endpoints (e.g., PFS, OS, etc).
Response as assessed by investigators will follow the RECIST version 1.1 criteria described
in Table 5 and Table 6 below:


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Table 5
Time point Response: Patients with Target Lesions (with or without Non-
Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall
Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all
evaluated
No
PR
SD
Non-PD or not all
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CR complete response; NE not evaluable; PD progressive disease;
PR partial response; SD stable disease.
Table 6
Time point Response: Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CR complete response; NE not evaluable; PD progressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease
since stable disease is increasingly used as an endpoint for assessment of
efficacy in some trials; thus, assigning “stable disease” when no lesions can
be measured is not advised.
The best confirmed overall response (BOR) will be computed in Table 7 (RECIST V1.1):


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Table 7
Best Overall Response When Confirmation Is Required
Overall Response at
First Time point
Overall Response at
Subsequent Time point
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR a
CR
SD
SD, provided minimum
durationMD for SD was met;
otherwise, PD
CR
PD
SD, provided minimum
durationMD for SD was met;
otherwise, PD
CR
NE
SD, provided minimum
durationMD for SD was met;
otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD, provided minimum
duration for SD was met;
otherwise, PD
PR
NE
SD, provided minimum
duration for SD was met;
otherwise, NE
NE
NE
NE
CR complete response; NE not evaluable; PD progressive disease; PR partial
response; SD stable disease.
a If a CR is truly met at the first time point, any disease seen at a subsequent time
point, even disease meeting PR criteria relative to baseline, qualifies as PD at that
point (since disease must have reappeared after CR). Best response would depend on
whether the minimum duration for SD was met. However, sometimes CR may be
claimed when subsequent scans suggest small lesions were likely still present and in
fact the patient had PR, not CR, at the first time point. Under these circumstances,
the original CR should be changed to PR and the best response is PR.
MD Minimum duration = 6 weeks (42 days)
The analysis of overall response rate (ORR) is based on the best (confirmed) overall response
(BOR). In the case of SD, measurements must have met the SD criteria at least once after
study entry at a minimum interval equal to 6 weeks.
The BOR will be assessed by the number and proportion of responders and non-responders
together with two-sided 95% Clopper-Pearson CIs. Only patients with measurable disease at
baseline will be included in the analysis of the BOR. Patients without a post-baseline tumor
assessment will be considered to be non-responders. To assess the influence of baseline
covariates, e.g. age groups (≤ 65 vs. >65) (≤65, 66-74, ≥75), ECOG 0-1 versus ECOG ≥ 2, a 
logistic regression analysis will be conducted for BOR as a univariate analysis, followed by a
multiple regression analysis. The list of covariates to be included in this analysis was set
before database lock for Cohort 1, during the pre-database lock dry-run review of outputs (on
mature data): pooled countries, age groups (≤65 vs. >65, and ≤65, 66-74, ≥75), organs 
involved in target lesions (≤3 vs. >3 organs involved), hormone positivity, drug interruption 


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vs no drug interruption, dose reduction vs. no dose reduction, missing dose vs. no missing
dose, histology grade at diagnosis Grade 3 vs. Grades 1,2, unknown, missing, aggressiveness
of the disease using TNM [Tx-T0-T1-T2 vs T3-T4 (best case scenario) , T0-T1-T2 vs Tx-T3-
T4 (worst case scenario), N0, NX versus N1, N2, N3 (best case) and N0 vs. N1, N2, N3, NX
(worst case), N1, N2, N3 vs. N0 (Nx excluded), M0, MX vs. M1 (best case) and M0 vs M1,
MX (worst case), M0 vs. M1 (Mx excluded) ; the selection of the variables in case of
significance in the univariate model will be based on the Akaike criteria in the multivariate
model], visceral vs. non-visceral, currently in 2nd line of treatment vs. currently in 3rd or
later line of treatment, prior treatment with pertuzumab vs. no prior exposure to pertuzumab.
In addition to these predictor factors, for the pooled analysis of Cohort 1 and 2, a further
factor will be added: region (Asian versus non-Asian regions).
A univariate analysis will be performed for each covariate. The number of patients included
in the analysis, the odds ratio of each covariate, the corresponding two-sided 95% Wald CI
and the p-values (Wald test) for the covariate will be presented in a summary table. In this
univariate model, the null hypothesis of the Wald test will be: “the covariate has no influence
on the BOR”.
Further exploratory analysis will be performed. All covariates which are significant at the
0.20 level in the univariate analysis will be included in a multiple regression model
(interaction will not be included), then backwards selection at the 5% level will be performed
to obtain a final model. The number of patients included in the analysis and the odds ratio for
each of the covariates included in the final model will be estimated and presented in a
summary table, including the corresponding two-sided 95% Wald CI and the p-value (Wald
test). In the multivariate model, the null hypothesis of the Wald test will be: “the covariate
has no influence on the BOR when adjusting for other covariates in the model”.
4.7.4 Duration of response
DoR is defined as the period from the date of initial confirmed PR or CR (whichever occurs
first) until the date of PD or death from any cause. DoR will be calculated in days as follows:
DoR (months) = ((Date of PD or death – Date of first confirmed PR or CR) + 1) /30.4375
Patients with no documented progression or death after CR or PR will be censored at the last
date at which they are known to have had the CR or PR, respectively. The method for
handling censoring is the same as described for the PFS. Only patients with BOR of CR or
PR (i.e., responders) will be included in the analysis of DoR. The analysis and presentation of
DoR will be as described for PFS.
4.7.5 Time to response
Time to (confirmed) response (TTR) is defined as the time from first dose to first
documentation of confirmed PR or CR (whichever occurs first). TTR will be calculated in
days as follows:
TTR (months) = ((Date of first response assessment of confirmed PR or CR - Date of first
dosing) + 1) /30.4375
Patients who do not have a confirmed response will be censored at the date of the last tumor
assessment.
To be assigned a status of PR or CR, i.e., to be a responder, changes in tumor measurements
must be confirmed by repeat assessments that should be performed no less than 4 weeks after


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the criteria for response are first met, i.e., patients need to have two consecutive assessments
of PR or CR. This status will be assessed only for patients with measurable disease at
baseline.
The analysis and presentation of TTR will be as described for PFS.
4.7.6 Clinical benefit rate
CBR includes patients whose best (confirmed) response was PR, CR or SD that lasted at least
6 months. The number and proportions of responders and non-responders together with two-
sided, 95% Clopper-Pearson CIs will be presented. This status will be assessed only for
patients with measurable disease at baseline.
CBR will be summarized in a similar way to the ORR as assessed by BOR.
4.7.7 Lesions count
4.7.7.1
Target lesions
Target lesions will be identified at the Screening visit. A maximum of 5 target lesions may
be identified, with no more than 2 target lesions per organ. The size of each target lesion and
the sum of diameters of all target lesions will be recorded.
The sum of diameters of the target lesions (in mm) will be summarized by visit including
change from baseline (Screening visit) and change from lowest measurement of their size.
4.7.7.2
New lesions and Non target lesions
The number of new lesions will be recorded for each organ site. The number and percentage
of patients with new lesions will be presented at each visit.
Non target lesions will be identified at baseline (Screening visit). The number of non-target
lesions (multiple or single) will be recorded for each organ site. At the post baseline visits the
non-target lesions will be recorded for each organ site.
4.7.8 Time to progression
Time to progression (TTP) is defined as the time from first dose to the first documented
progression of disease
TTP (months) = ((Date of progression of disease - Date of first dosing) + 1) /30.4375
4.8
Safety Analysis
4.8.1 General consideration
The safety variables will be summarized for Safety Population 1 and Safety Population 2, for
Cohort 1 and Cohort 2, respectively.
Pooled analysis for safety will be performed on the safety population that includes all patients
in Safety Population 1 and Safety Population 2.


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The following subgroup analyses will be performed on Safety Population 1, Safety
Population 2 and the overall safety population (pooled analysis) for all safety analyses:
-
AST or ALT increases that are > 3 × ULN and total bilirubin > 2 × ULN except in
patients with documented Gilbert’s syndrome
-
Country
-
Race (Asian, non-Asian, NA or Unknown)
-
Age (≤65, 66-74, ≥75) 
-
ECOG 0–1 versus ECOG ≥ 2 
Country has been replaced by pooled countries for safety reporting, see section 3.5.3
All AEs and laboratory variables will be assessed according to the National Cancer Institute
Common Terminology Criteria for AEs (NCI CTC-AE) version 4.0 or later version grading
system.
Prior to initiation of study drug, only SAEs caused by a protocol-mandated intervention will
be reported (e.g., SAEs related to invasive procedures such as biopsies, discontinuation of
medicines etc.). After initiation of study drug, all AEs and SAEs, regardless of relationship to
study drug, will be reported until 28 days after the last dose of study drug. After this period,
investigator is not required to actively monitor patients for AEs; however, the Sponsor should
be notified if the investigator becomes aware of any post study SAEs or non-serious AESIs.
Only treatment emergent AEs (starting on the day of or after the first administration of
trastuzumab) will be included in the summary tables. Non-treatment emergent events
(starting prior to first administration of trastuzumab) will be listed only. Where an AE start
date is partially or fully missing, and it is unclear as to whether the AE is treatment emergent,
it will be assumed to be treatment emergent. Time to onset of AE will be calculated as
follows:
(start date of AE – date of first study treatment) + 1.
If start date of AE was before study treatment administration, then time to onset of AE will be
calculated as:
Date of assessment/event – Date of first study treatment
Imputation of Adverse Event Onset Date
For AEs, a missing or incomplete onset date will be imputed according to the following
conventions:
If an onset date is missing or only the year is known, the imputed onset date will be the date
of first dose of study treatment.
If only the month and year is known for onset date, the surrogate onset date will be set to the
first day of that month and then the following rules applied:
1. If the month and year of the onset date is prior to the month and year of the first dose
of study treatment, then the surrogate onset date will be the imputed onset date.
2. If the month and year of the onset date is on or after the month and year of the first
dose of study treatment, then the imputed onset date will be the latest of the following
non-missing dates:
-
Date of first dose of study treatment


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-
Surrogate onset date
If the imputed onset date of an adverse event is after the complete end date, the imputed onset
date will be the same as the complete adverse event end date.
For the adverse events statistical analysis “related” refers to those events for which there is a
reasonable suspected causal relationship to the study drug, or with an unknown relationship.
Adverse events will be coded using MedDRA dictionary. It is likely that at the time of the
pooled analyses the MedDRA version will be different from the MedDRA version used at the
Cohort 1 analyses. For the pooled analyses the latest version of MedDRA will be used.
4.8.2 Primary endpoint
The primary endpoint in this study is AEs Grade 3 or higher for hepatic events, allergic
reactions, thrombocytopenia, hemorrhage events, also all other AEs Grade 3 or higher related
to trastuzumab emtansine, and pneumonitis of all grades.
The primary endpoint will be computed for each patient, as the experience of at least:
-
an AE Grade 3 or higher for hepatic events,
-
an AE Grade 3 or higher for allergic reactions,
-
an AE Grade 3 or higher for thrombocytopenia,
-
an AE Grade 3 or higher for hemorrhage events,
-
an AE Grade 3 or higher related to trastuzumab emtansine,
-
or pneumonitis events of all grades
The incidence of the primary endpoint during the study will be provided in terms of number
of patients and percentage with 95% Clopper-Pearson CI.
4.8.3 Secondary endpoints
4.8.3.1
Adverse events of special interest
Adverse events of special interest (AESIs) for this study include the following:
-
Potential drug-induced liver injury
-
Suspected transmission of an infectious agent by the study drug
Potential drug-induced liver injury:
Any potential case of drug-induced liver injury as assessed by laboratory criteria for Hy’s law
(according to laboratory results, not from the AE form), will be considered as a protocol-
defined event of special interest and needs to be reported to the Sponsor expeditiously. The
following laboratory abnormalities define potential Hy’s law cases:
-
AST and/or ALT elevations that are > 3 × ULN
and


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-
Concurrent elevation of total bilirubin > 2 × ULN (or clinical jaundice if total bilirubin
measures are not available), except in patients with documented Gilbert’s syndrome.
For patients with Gilbert’s syndrome, elevation of direct bilirubin > 2 × ULN should
be used instead.
Potential cases of drug-induced liver injury reported by the investigators were recorded as
adverse events and were considered to be related to the study drug. These cases will be
summarized.
In addition, potential drug-induced liver injury will be computed from the laboratory data and
adverse events (clinical jaundice events) collected for the study, and summarized.
Suspected transmission of an infectious agent by the study drug will be analyzed:
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.
Information on suspected transmission of an infectious agent by the study drug is taken from
the AE form.
The incidence of each AESI for patients experiencing at least one AESI, will be provided in
term of number and percentage, with 95% Clopper-Pearson confidence interval.
AESIs will be displayed as, potential drug-induced liver injury reported by the investigators,
calculated potential drug-induced liver injury and suspected transmission of an infectious
agent by the study drug (reported by the investigator).
4.8.3.2
Other adverse events of interest
Other adverse events of interest (included in the safety plan, but not mentioned as adverse
events of primary interest or adverse events of special interest) include the following:
-
Hepatic events all grades
-
Allergic reactions all grades
-
Thrombocytopenia all grades
-
Hemorrhage events all grades
-
Pneumonitis Grade 3 and above
-
Peripheral neuropathy (neurotoxicity)
-
Cardiac dysfunction (cardiotoxicity)
Incidence of each Other AE of Interest will be provided in term of number and percentage,
with 95% Clopper-Pearson CI, of patients experiencing the AE at least once.


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4.8.3.3
Summary of all adverse events
AEs and SAEs, related and unrelated, will be summarized separately by presenting the
number and percentage of patients having any events, events leading to discontinuation of
study drug, events leading to interruption of study drug, events by CTC grade, and
relationship.
Summary tables by system organ class (SOC) and preferred term (PT) of the number and
percentage of patients having events including number of events will be presented for:

All AEs

Related AEs

All SAEs

Related SAEs

AEs leading to study drug discontinuation

AEs leading to study drug interruption

AEs of all NCI-CTCAE Grades

AEs NCI-CTCAE Grade 3 and above

AE of NCI-CTCAE Grades 1, 2, 3 and 4 – Hepatoxicity / Hematoxicity

AEs by maximum CTC grade

SAEs by maximum CTC grade

AEs of primary interest (i.e. primary endpoint; AEs Grade 3 and above for hepatic
events, allergic reactions, thrombocytopenia, hemorrhage events, AEs Grade 3 or
higher related to trastuzumab emtansine, and pneumonitis all grades). Pneumonitis
will be given overall and by grade

AEs of special interest all grades, overall and by grade

AEs of special interest Grade 3 and above

Hepatic events all grades, overall and by grade

Allergic reactions all grades, overall and by grade

Thrombocytopenia all grades, overall and by grade

Hemorrhage events all grades, overall and by grade

Pneumonitis Grade 3 and above

Peripheral neuropathy all grades, overall and by grade

Peripheral neuropathy Grade 3 and above

Cardiac dysfunction disorders all grades, overall and by grade

Cardiac dysfunction disorders Grade 3 and above
If a patient experiences the same adverse event at more than one CTC grade level, or with
more than one relationship to study drug, the most severe rating or the stronger causal


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relationship to study drug will be given precedence. Any missing CTC grade, causality, or
outcome will not be imputed, but will be classed as unknown.
In addition, analysis of incidence and time to onset will be provided for the following AEs:
AEs leading to treatment interruption and discontinuation, SAEs, hepatic events, allergic
reactions, thrombocytopenia, hemorrhage events all grades, pneumonitis Grade 3 and above,
AESIs Grade 3 and above, peripheral neuropathy all grades and Grade 3 and above, left
ventricular dysfunction disorders all grades and Grade 3 and above, CHF all grades and
Grade 3 and above, and Infusion-Related Reaction/Hypersensitivity all grades and Grade 3
and above.
The incidence AEs for patients experiencing at least one AE, will be provided in term of
number and percentage, with 95% Clopper-Pearson confidence interval.
A summary of deaths will be presented, tabulating the number and percentage of patients by
primary cause of death, and underlying cause of death.
4.8.3.3.1 Subsets
The most frequent MedDRA preferred terms (≥ 5% patients in the total column) and system 
organ class will be presented. All other information collected (e.g. action taken) will be listed
as appropriate.
4.8.4 Laboratory findings
Samples for hematology and biochemistry are scheduled at Screening, and on Day 1 (within
72 hours preceding administration of study treatment) of each treatment cycle and at the
safety follow-up visit 28-42 days after last study treatment. Samples for urinalysis are
scheduled at screening and safety follow-up visit and as clinically indicated during the
treatment period.
Results from the following laboratory parameters will be converted to standard international
units and summarized:
Hematology:
Hemoglobin (Hb), hematocrit, red blood cell count, platelet count, and white blood cells
(WBC) with differential (including neutrophils, leukocytes, lymphocytes, monocytes,
eosinophils and basophils).
Shift table for the any incidence of Hemorrhage adverse events and any incidence of
Thrombocytopenia (lab results - platelet grade 3 or 4) by maximum grade will be presented.
Biochemistry:
Sodium, potassium, chloride, calcium, magnesium, glucose, blood urea nitrogen (BUN),
creatinine, uric acid, total protein, albumin, alkaline phosphatase, ALT (SGPT), AST
(SGOT), gamma glutamyl transferase, lactate dehydrogenase, total bilirubin (and direct
bilirubin where total bilirubin > ULN).
Urinalysis:


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Specific gravity, pH, protein, glucose, blood, ketones and bilirubin.
Hematology, biochemistry and continuous urinalysis laboratory values and changes from
Baseline to each visit (where they are planned to be evaluated) will be summarized.
Categorical urinalysis values will be presented by the number and percentage of patients
within each category.
The graphical presentation of the mean value and 95% CI of selected laboratory parameters:
AST, ALT, alkaline phosphatase, total bilirubin will be displayed.
Shift tables for the hematology and biochemistry laboratory parameters comparing NCI-CTC
grade at baseline versus worst grade during the trastuzumab treatment period will be
presented.
High and/or low grade values will be presented as applicable. Hematology and biochemistry
laboratory parameters will also be presented by toxicity grade.
Notes:

All results outside predefined normal ranges will be flagged in the data listings.

Repeat laboratory results within a visit will replace the original value. Unscheduled
results will be listed only.
Any other laboratory results will be listed only.
4.8.5 LVEF
LVEF observations are recorded at Screening and on Day 21 (or -7 days) of Cycle 1, Cycle 3
and every third cycle thereafter and at the Safety follow-up visit.
LVEF will be summarized over time using descriptive statistics. LVEF will also be
summarized by number and percentage of patients for LVEF values ≥50% and <50%.  LVEF 
will also be summarized by number and percentage of patients within the following
categories by cycle and by worst (lowest) on treatment value.
LVEF ≥ 50% and a 10% drop from baseline 
LVEF 45% – 49% and a 10% drop from baseline
LVEF 40% – 44% and a 10% drop from baseline
LVEF ≤ 39% and a 20% drop from baseline 
Mean LVEF values with associated 95% CIs will be presented graphically with line graphs
over time.
LVEF will be summarized over time using descriptive statistics.
4.8.6 ECG
ECG findings (normal, abnormal) and heart rate (bpm) are recorded and a 12-lead ECG
examination performed at Screening. ECG findings and heart rate will be summarized as part
of the baseline characteristics.


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4.8.7 Weight
Weight (kg) is measured for all patients at Screening, at each treatment cycle and at the safety
follow-up visit. Weight will be summarized over time using descriptive statistics.
4.8.8 ECOG
ECOG performance status will be recorded at Screening, at each treatment cycle and at the
safety follow-up visit. ECOG performance status will be summarized by cycle presenting the
number and percentage of patients in each grade.
ECOG performance status (Grade 0 - Grade 5) will be summarized by over time by
presenting the number and percentage of patients in each grade.
4.8.9 Physical Examinations
A complete physical examination will be performed at Screening. A limited physical
examination will also be performed at each treatment cycle and the safety follow-up visit
recording any changes from the general physical exam performed at screening.
Physical examination results will be listed only.
4.8.10 Assessments of hospitalizations
The number of hospital visits, number of days admitted, and type of visits (emergency
department versus inpatient care) will be recorded.
4.9
Adjustment for Covariates
4.9.1 Centre effects
This is a multi-center, international trial. Patients from all centers will be pooled.
4.10 Protocol Violations
No per-protocol population is defined but protocol violations will be identified.
Major protocol violations will be summarized in the Clinical Study Report (CSR).
The data will be provided by Roche Data Management from the Procedural Document
Management System (PDMS).
A list of patients with important violations will be agreed upon and will be documented in the
“Analysis Set Specifications” document.
4.10.1 Violation criteria
Where possible the PDMS will be used to identify violations from the protocol, otherwise
protocol violations are to be identified programmatically. In general, the violations will be
considered according to the following general categories:

Non-compliance with inclusion criteria (Section 4.1.1 of the protocol)

Non-compliance with exclusion criteria (Section 4.1.2 of the protocol)

Unauthorized concomitant therapy


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
Non-compliance with study treatment

Subjects who did not take at least 6 doses of study medication over the 12 week study
period (evaluable subject)

Other, e.g. consent not signed
Note: Other reasons for violations may be added to this list.
4.11 Missing Values – Missing Visits
Unless otherwise specified, missing values will not be replaced.
4.12 Deviations from SAP
The SAP will be finalized before the database lock and changes from the final SAP will be
described in the clinical study report with rationale provided by the Statistician.
4.13 Changes in Conduct or Planned Analyses from the Protocol
A change in the conduct or planned analyses (Section 2.3 of the protocol; ‘the
pharmacoeconomics outcome objective’) is as follows:

To evaluate the resource expenditures, while on study treatment, due to hospitalizations
that are not study-defined evaluations. The number of hospital visits, number of days
admitted and type of visits (emergency department versus inpatient care) will be recorded
Has been changed in the SAP to:

To evaluate the resource expenditures, while on study treatment, due to hospitalizations
that are not study-defined evaluations. The number of hospital visits and type of visits
(ICU versus other) will be recorded.
A change in the Section 6.3 Safety Analyses of the protocol:

Based on the safety profile of trastuzumab emtansine, time to onset of the first
episode of each AE is described in Section 5 will also be summarized via KM
estimates.
Has been removed from the SAP. Indeed, KM outputs for ‘Time to onset of AE’ events will
not be produced since during the pre-database lock dry-run review of outputs (on mature
data) it was observed that there were insufficient events to determine estimates for the KM
median (and CIs).
A change in the safety analyses (Section 6.3 of the protocol, exploratory analyses):

Subgroup analyses Age (>65, ≤65) 

Subgroup analyses Age (>75, ≤75) 

Region (Asian versus non-Asian regions)
Subgroup analyses age (>65, ≤65) and age (>75, ≤75) have been removed from the SAP  
and replaced by the subgroup Age (≤65, 66-74, ≥75).  


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An analyses on the subgroups of patients for whom non-validated tests were used has been
added in this SAP that was not mentioned in the protocol (Section 6.3 of the protocol,
exploratory analyses).
An exploratory efficacy endpoint has been added in this SAP that was not mentioned in the
protocol (Section 6.2 of the protocol, Summaries of treatment group comparability): a section
2.2.3 Exploratory efficacy endpoints has been added in this SAP, with the time to progression
(TTP) as an exploratory endpoint.
4.14 Algorithms/SAS Codes

Tables that need descriptive statistics – continuous variables:
PROC UNIVARIATE DATA=DSET NOPRINT;
VAR VAR1 VAR2 VAR3 … VARN;
BY BYVAR; (optional)
OUTPUT OUT=OUTNAME
N=N MEAN=MEAN MIN=MIN MAX=MAX MEDIAN=MEDIAN STD=STD;
RUN;

Tables that need frequency counts:
PROC FREQ DATA=DSET NOPRINT;
BY BYVAR; (optional)
TABLES VAR1*VAR2;
OUTPUT OUT=OUTNAME;
RUN;

Tables that need exact or asymptotic 95% CIs between groups for proportions:
PROC FREQ DATA=DSET;
BY BYVAR; (optional)
TABLES VAR1 * VAR2 / measures riskdiff alpha=0.05;
EXACT MEASURES;
RUN;
Notes: 1 Estimates are computed for 2x2 tables only
2 This code also gives exact 95% CIs within group for binomial proportions

Tables that need 95% CIs within group for binomial proportions:
PROC FREQ DATA=DSET;
BY BYVAR; (optional)
TABLES VAR1;
EXACT BINOMIAL;
RUN;

Tables that need life table with estimates of survival, with CIs and log rank test:
PROC LIFETEST DATA=DSET
OUTSURV=LIFE
METHOD=KM
CONFTYPE=LOGLOG
PLOTS=(s,ls,lls);
TIME duration*censor (0 or 1);
ID patient;
RUN;


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
Tables that require logistic regression, including 95% CIs:
PROC LOGISTIC DATA= dset descending;
CLASS variables/param=ref ref=FIRST;
MODEL ‘Responses’ = variables ;
WHERE wherever; (optional)
BY byvar; (optional)
RUN;
Notes: (Treatment order: 1= responder, 2= non-responder)
5
Tables and Listings
5.1
Table Format
All output will be produced using SAS version 9.1.3 or a later version.
In the top left portion of each table/listing, a table/listing number followed by the title of the
table/listing will be presented. After the title line, optional sub-title or population information
can be presented. Horizontal lines will appear before and after the column heading of the
table/listing. Footnotes will be put under the main body of text at the bottom of the page.
The sponsor name, protocol number, programmers User ID, status of the table/listing (i.e.
draft or final) and SAS program name will appear bottom left in a string and the page number
will appear on the bottom right corner of each table/listing. The date and time of creation of
table/listing will appear bottom left under the sponsor name. The source listing number will
appear bottom left.
A landscape layout is proposed for both table and listing presentations.
The left and right margins of all tables and listings will be a minimum of 2.1 cm from the left
and 1.9 cm from the right. The top and bottom margins will be a minimum 2.92cm. Header
and footer will be both 1.27 cm.
There is no special requirement of font type and size, but an 8-point font size for tables and
7or 8-point for listings is proposed using Courier New font. A maximum SAS line size=141
and page size=44 for 8-point font size, and line size=161 and page size=50 for 7-point will be
used so as to fit on both UK and US paper sizes.
In a listing, in the case that a subject’s record has been continued to the next page, an
appropriate identification (e.g., the subject ID number) must be presented at the beginning of
that page.
5.2
Conventions
Unless otherwise specified, in summary tables of continuous variables, the minimum and
maximum values will be displayed to the same number of decimal places as the raw data, the
mean and median will be presented to one extra decimal place compared to the raw data, and
the standard deviation will be displayed to two extra decimal places compared to the raw
data. Wherever possible data will be decimal aligned.
Unless otherwise specified frequency tabulations will be presented by number and
percentage, where the percentage is presented in brackets to 1 decimal place.
P-values, if applicable, will be presented to 3 decimal places. If a p-value is less than 0.05 but
is greater than or equal to 0.01, then an asterisk (*) will be added next to this value. If a p-


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value is less than 0.01 but is greater than or equal to 0.001, then two asterisks (**) will be
added next to this value. Finally, if the p-value is less than 0.001 then three asterisks (***)
will be added next to this value and it will be presented as <0.001. If the rounded result is a
value of 1.000, it will be displayed as >0.999. Any date information in the listing will use the
date9. format, for example, 07MAY2002. In the listing, a unit associated with a variable will
be presented only once within parentheses either below or next to that variable in the heading
portion. If a parameter has multiple units, each unit will be displayed only once, as
applicable.
All tables will have their source listing referenced in a footnote. Listings should be sorted by
treatment group, subject and visit and have the source data received by data management
referenced in a footnote. All tables and listings will be converted into Microsoft Word
documents and collated into two complete documents.
5.3
Tables
In the following table titles list, the population or set of patients indicated in brackets applies
for:
- Enrolled Patients Cohort 1, Cohort 2 and pooled cohorts
– Safety/ITT Population 1, 2 and overall (pooled)
For safety subgroup analysis, Tables and Figures to be performed for each subgroup are
flagged with an asterisk (*)
(Patients with potential drug-induced liver injury (calculated) – Safety population/ Safety
Population 1, 2)
(Pooled countries - Safety population/ Safety population 1, 2)
(Race with Asian / non-Asian/ NA or Unknown - Safety population/ Safety population 1, 2)
(Patients with age ≤65, 66-74, ≥75 - Safety population/ Safety population 1, 2) 
(Patients with ECOG 0–1, ≥ 2 - Safety population/ Safety population 1, 2) 
For safety subgroup analysis, Tables to be performed only on patients with potential drug-
induced liver injury (calculated) are flagged with #.
For safety subgroup analysis, Tables not to be performed on patients with ECOG group are
flagged with +.
For safety subgroup analysis, Tables not to be performed on patients with age ≤65, 66-74, 
≥75 group are flagged with ~. 
5.3.1 Section 14.1: Demographic and Baseline
Table 14.1.1.1*
Patient Disposition (Enrolled Patients)
Table 14.1.1.2
Patient Disposition by Country and Pooled Country (Safety
Populations)
Table 14.1.2.1
Major Protocol Violations (Safety Populations)
Table 14.1.3.1*
Demographics (Safety Populations)
Table 14.1.3.2
Demographics (ITT Populations)
Table 14.1.3.3
Demographics - Unvalidated HER2 (Safety Populations)
Table 14.1.4.1*
Baseline Characteristics (Safety Populations)
Table 14.1.4.2
Baseline Characteristics (ITT Populations)
Table 14.1.4.3
Baseline Characteristics - Unvalidated HER2 (Safety Populations)
Table 14.1.5.1*
HER2 Status (Safety Populations)
Table 14.1.5.2
HER2 Status - Unvalidated HER2 (Safety Populations)


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Table 14.1.6*
Previous Breast Cancer History (Safety Populations)
Table 14.1.7.1
Ongoing Medical History (Safety Populations)
Table 14.1.7.2
All Medical History (Safety Populations)
Table 14.1.8.1*
Previous Anti-Cancer Therapy (Safety Populations)
Table 14.1.8.2*
Previous Anti-Cancer Therapy: Chemotherapy (Safety
Populations)
Table 14.1.8.3*
Previous Anti-Cancer Therapy: Targeted Therapy (Safety
Populations)
Table 14.1.8.4*
Previous Anti-Cancer Therapy: Anti-Estrogen (Safety Populations)
Table 14.1.8.5*
Previous Anti-Cancer Therapy: Radiotherapy (Safety Populations)
Table 14.1.8.6*
Previous Cancer Surgery (Safety Populations)
Table 14.1.9.1
Prior Medications (Safety Populations)
Table 14.1.9.2
Concomitant Medications (Safety Populations)
Table 14.1.10.1*
Study Drug Exposure – Number of Cycles (Safety Populations)
Table 14.1.10.2*
Study Drug Exposure – Duration, Missed Doses, Doses Reduced
and Interruptions, and the Cumulative Doses Received (Safety
Populations)
Table 14.1.11
HER2 testing (Safety Populations)
5.3.2 Section 14.2: Efficacy
Table 14.2.1.1.1*
Progression Free Survival (ITT Populations)
Table 14.2.1.1.2*
Progression Free Survival by Previous Lines of Treatment (ITT
Populations)
Table 14.2.1.1.3
Progression Free Survival by Prior Pertuzumab (ITT
Populations)
Table 14.2.1.1.4
Progression Free Survival - Unvalidated HER2 (ITT
Populations)
Table 14.2.1.2.1
Progression Free Survival Rates (ITT Populations)
Table 14.2.1.2.2
Progression Free Survival Rates - Unvalidated HER2 (ITT
Populations)
Table 14.2.1.3
Time to Progression (ITT Populations)
Table 14.2.2.1.1*
Overall Survival – Time to Death (ITT Populations)
Table 14.2.2.1.2*
Overall Survival – Time to Death by Previous Lines of
Treatment (ITT Populations)
Table 14.2.2.1.3
Overall Survival – Time to Death by Prior Pertuzumab (ITT
Populations)
Table 14.2.2.1.4
Overall Survival – Time to Death - Unvalidated HER2 (ITT
Populations)
Table 14.2.2.2.1
Overall Survival Rates (ITT Populations)
Table 14.2.2.2.2
Overall Survival Rates - Unvalidated HER2 (ITT Populations)
Table 14.2.3.1.1*
Best Overall Response (ITT Populations)
Table 14.2.3.1.2
Best Overall Response - Unvalidated HER2 (ITT Populations)
Table 14.2.3.2.1
Best Overall Response: Logistic Regression univariate analysis
results (ITT Populations)
Table 14.2.3.2.2
Best Overall Response: Logistic Regression multivariate
analysis results (ITT Populations)
Table 14.2.3.3
Overall Response by Cycle (ITT Populations)
Table 14.2.4.1
Duration of Response (ITT Populations - Patients with
Measurable Disease)


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Table 14.2.4.2
Duration of Response Rates (ITT Populations - Patients with
Measurable Disease)
Table 14.2.5.1
Time to Response (ITT Populations - Patients with Measurable
Disease)
Table 14.2.5.2
Time to Response Rates (ITT Populations - Patients with
Measurable Disease)
Table 14.2.5.3
Time to Response - Responders (ITT Populations - Patients
with Measurable Disease)
Table 14.2.5.4
Time to Response Rates - Responders (ITT Populations -
Patients with Measurable Disease)
Table 14.2.6
Clinical Benefit Rate (ITT Populations)
Table 14.2.7.1
Sum of diameters: Target Lesions (ITT Populations)
Table 14.2.7.2
Lesion Counts: New Target Lesions (ITT Populations)
5.3.3 Section 14.3: Safety
5.3.3.1
Primary endpoint
Table 14.3.1.1*
Primary Endpoint – Incidence and 95% Clopper-Pearson CI (Safety
Populations)
5.3.3.2
Secondary endpoints
5.3.3.2.1 Adverse Events of primary interest
Table 14.3.1.2.1#
Adverse events of primary interest – Hepatic events Grade 3 or higher –
Incidence and 95% Clopper-Pearson CI (Safety Populations)
Table 14.3.1.2.2#
Adverse events of primary interest – Hepatic events Grade 3 or higher By
System Organ Class and Preferred Term (Safety Populations)
Table 14.3.1.2.3#
Adverse events of primary interest – Hepatic events Grade 3 or higher By
System Organ Class, Preferred Term and Grade (Safety Populations)
Table 14.3.1.2.4
Adverse events of primary interest – Allergic reactions Grade 3 or higher –
Incidence and 95% Clopper-Pearson CI (Safety Populations)
Table 14.3.1.2.5
Adverse events of primary interest – Allergic reactions Grade 3 or higher
By System Organ Class and Preferred Term (Safety Populations)
Table 14.3.1.2.6
Adverse events of primary interest – Allergic reactions Grade 3 or higher
By System Organ Class, Preferred Term and Grade (Safety Populations)
Table 14.3.1.2.7
Adverse events of primary interest – Thrombocytopenia Grade 3 or higher
– Incidence and 95% Clopper-Pearson CI (Safety Populations)
Table 14.3.1.2.8
Adverse events of primary interest – Thrombocytopenia Grade 3 or higher
By System Organ Class and Preferred Term (Safety Populations)
Table 14.3.1.2.9
Adverse events of primary interest – Thrombocytopenia Grade 3 or higher
By System Organ Class, Preferred Term and Grade (Safety Populations)
Table 14.3.1.2.10#
Adverse events of primary interest – Hemorrhage events Grade 3 or higher
– Incidence and 95% Clopper-Pearson CI (Safety Populations)
Table 14.3.1.2.11#
Adverse events of primary interest – Hemorrhage events Grade 3 or higher
By System Organ Class and Preferred Term (Safety Populations)
Table 14.3.1.2.12#
Adverse events of primary interest – Hemorrhage events Grade 3 or higher
By System Organ Class, Preferred Term and Grade (Safety Populations)
Table 14.3.1.2.13#
Adverse events of primary interest – Related to trastuzumab emtansine
Grade 3 or higher – Incidence and 95% Clopper-Pearson CI (Safety


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Populations)
Table 14.3.1.2.14#
Adverse events of primary interest – Related to trastuzumab emtansine
Grade 3 or higher By System Organ Class and Preferred Term (Safety
Populations)
Table 14.3.1.2.15#
Adverse events of primary interest – Related to trastuzumab emtansine
Grade 3 or higher By System Organ Class, Preferred Term and Grade
(Safety Populations)
Table 14.3.1.2.16
Adverse events of primary interest – Pneumonitis of all grades – Incidence
and 95% Clopper-Pearson CI (Safety Populations)
Table 14.3.1.2.17
Adverse events of primary interest – Pneumonitis of all grades By System
Organ Class and Preferred Term (Safety Populations)
Table 14.3.1.2.18
Adverse events of primary interest – Pneumonitis of all grades By System
Organ Class, Preferred Term and Grade (Safety Populations)
5.3.3.2.2 Adverse Events of special interest
Table 14.3.1.3.1#
Adverse events of special interest – Potential drug-induced liver injury
(investigator reported) – Incidence and 95% Clopper-Pearson CI (Safety
Populations)
Table 14.3.1.3.2#
Adverse events of special interest – Potential drug-induced liver injury
(investigator reported) By System Organ Class and Preferred Term
(Safety Populations)
Table 14.3.1.3.3#
Adverse events of special interest – Potential drug-induced liver injury
(investigator reported) By System Organ Class, Preferred Term and Grade
(Safety Populations)
Table 14.3.1.3.4#
Adverse events of special interest – Potential drug-induced liver injury
(investigator reported) grade 3 and above – Incidence and 95% Clopper-
Pearson CI (Safety Populations)
Table 14.3.1.3.5#
Adverse events of special interest – Potential drug-induced liver injury
(investigator reported) grade 3 and above By System Organ Class and
Preferred Term (Safety Populations)
Table 14.3.1.3.6#
Adverse events of special interest – Potential drug-induced liver injury
(investigator reported) grade 3 and above By System Organ, Preferred
Term and Grade (Safety Populations)
Table 14.3.1.3.7#
Adverse events of special interest – Concurrent elevation of ALT/AST
and bilirubin meeting Hy’s Law laboratory criteria – Incidence and 95%
Clopper-Pearson CI (Safety Populations)
Table 14.3.1.3.8#
Adverse events of special interest – Concurrent elevation of ALT/AST
and bilirubin meeting Hy’s Law laboratory criteria By System Organ
Class and Preferred Term (Safety Populations)
Table 14.3.1.3.9#
Adverse events of special interest – Concurrent elevation of ALT/AST
and bilirubin meeting Hy’s Law laboratory criteria By System Organ
Class, Preferred Term and Grade (Safety Populations)
Table 14.3.1.3.10
Adverse events of special interest – Suspected transmission of an
infectious agent by the study drug – Incidence and 95% Clopper-Pearson
CI (Safety Populations)
Table 14.3.1.3.11
Adverse events of special interest – Suspected transmission of an
infectious agent by the study drug By System Organ Class and Preferred
Term (Safety Populations)


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Table 14.3.1.3.12
Adverse events of primary interest – Suspected transmission of an
infectious agent by the study drug By System Organ, Preferred Term and
Grade (Safety Populations)
Table 14.3.1.3.13
Adverse events of special interest – Suspected transmission of an
infectious agent by the study drug grade 3 and above – Incidence and
95% Clopper-Pearson CI (Safety Populations)
Table 14.3.1.3.14
Adverse events of special interest – Suspected transmission of an
infectious agent by the study drug grade 3 and above By System Organ
Class and Preferred Term (Safety Populations)
Table 14.3.1.3.15
Adverse events of special interest – Suspected transmission of an
infectious agent by the study drug grade 3 and above By System Organ
Class, Preferred Term and Grade (Safety Populations)
5.3.3.2.3 Other Adverse Events of interest
Table 14.3.1.4.1#
Other Adverse events of interest – Hepatic events all grades – Incidence
and 95% Clopper-Pearson CI (Safety Populations)
Table 14.3.1.4.2#
Other Adverse events of interest – Hepatic events all grades By System
Organ Class and Preferred Term (Safety Populations)
Table 14.3.1.4.3#
Other Adverse events of interest – Hepatic events all grades By System
Organ Class, Preferred Term and Grade (Safety Populations)
Table 14.3.1.4.4
Other Adverse events of interest – Allergic reactions all grades –
Incidence and 95% Clopper-Pearson CI (Safety Populations)
Table 14.3.1.4.5
Other Adverse events of interest – Allergic reactions all grades By
System Organ Class and Preferred Term (Safety Populations)
Table 14.3.1.4.6
Other Adverse events of interest – Allergic reactions all grades By
System Organ Class, Preferred Term and Grade (Safety Populations)
Table 14.3.1.4.7
Other Adverse events of interest – Thrombocytopenia all grades –
Incidence and 95% Clopper-Pearson CI (Safety Populations)
Table 14.3.1.4.8
Other Adverse events of interest – Thrombocytopenia all grades By
System Organ Class and Preferred Term (Safety Populations)
Table 14.3.1.4.9
Other Adverse events of interest – Thrombocytopenia all grades By
System Organ Class, Preferred Term and Grade (Safety Populations)
Table 14.3.1.4.10#
Other Adverse events of interest – Hemorrhage events all grades –
Incidence and 95% Clopper-Pearson CI (Safety Populations)
Table 14.3.1.4.11#
Other Adverse events of interest – Hemorrhage events all grades By
System Organ Class and Preferred Term (Safety Populations)
Table 14.3.1.4.12#
Other Adverse events of interest – Hemorrhage events all grades By
System Organ Class, Preferred Term and Grade (Safety Populations)
Table 14.3.1.4.13
Other Adverse events of interest – Pneumonitis grade 3 and above –
Incidence and 95% Clopper-Pearson CI (Safety Populations)
Table 14.3.1.4.14
Other Adverse events of interest – Pneumonitis grade 3 and above By
System Organ Class and Preferred Term (Safety Populations)
Table 14.3.1.4.15
Other Adverse events of interest – Pneumonitis grade 3 and above By
System Organ Class, Preferred Term and Grade (Safety Populations)
Table 14.3.1.4.16
Other Adverse events of interest – Peripheral neuropathy (Neurotoxicity)
– Incidence and 95% Clopper-Pearson CI (Safety Populations)
Table 14.3.1.4.17
Other Adverse events of interest – Peripheral neuropathy (Neurotoxicity)
By System Organ Class and Preferred Term (Safety Populations)


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Table 14.3.1.4.18
Other Adverse events of interest – Peripheral neuropathy (Neurotoxicity)
By System Organ Class, Preferred Term and Grade (Safety Populations)
Table 14.3.1.4.19
Other Adverse events of interest – Cardic dysfunction (Cardiotoxicity) –
Incidence and 95% Clopper-Pearson CI (Safety Populations)
Table 14.3.1.4.20
Other Adverse events of interest – Cardic dysfunction (Cardiotoxicity)
By System Organ Class and Preferred Term (Safety Populations)
Table 14.3.1.4.21
Other Adverse events of interest – Cardic dysfunction (Cardiotoxicity)
By System Organ Class, Preferred Term and Grade (Safety Populations)
5.3.3.2.4 Summary of all Adverse Events
Table 14.3.1.5.1*
Cause of Death (Safety Populations)
Table 14.3.1.5.2.1*
Summary of Adverse Events (Safety Populations)
Table 14.3.1.5.2.2
Summary of Adverse Events - Unvalidated HER2 (Safety Populations)
Table 14.3.1.5.3.1*
Summary of Serious Adverse Events (Safety Populations)
Table 14.3.1.5.3.2
Summary of Serious Adverse Events - Unvalidated HER2 (Safety
Populations)
Table 14.3.1.5.4.1* 
Most Frequent Adverse Events By Preferred Term ( ≥ 5% Patients) 
(Safety Populations)
Table 14.3.1.5.4.2
Most Frequent Adverse Events By Preferred Term - Unvalidated HER2
( ≥ 5% Patients) (Safety Populations)
Table 14.3.1.5.4.3* 
Most Frequent Non-Serious Adverse Events By Preferred Term ( ≥ 5% 
Patients) (Safety Populations)
Table 14.3.1.5.5*+
Adverse Events By System Organ Class and Preferred Term (Safety
Populations)
Table 14.3.1.5.6*+
Adverse Events By System Organ Class, Preferred Term and ECOG
Status (Safety Populations)
Table 14.3.1.5.7*
Serious Adverse Events by System Organ Class and Preferred Term
(Safety Populations)
Table 14.3.1.5.8*
Related Adverse Events by System Organ Class and Preferred Term
(Safety Populations)
Table 14.3.1.5.9*
Adverse Events of Special Interest for Analysis by System Organ Class
and Preferred Term (Safety Populations)
Table 14.3.1.5.10.1*
Adverse Events Leading to Study Drug Discontinuation By System
Organ Class And Preferred Term (Safety Populations)
Table 14.3.1.5.10.2
Adverse Events Leading to Study Drug Discontinuation By System
Organ Class And Preferred Term - Unvalidated HER2 (Safety
Populations)
Table 14.3.1.5.11*
Adverse Events Leading to Study Drug Interruption by System Organ
Class And Preferred Term (Safety Populations)
Table 14.3.1.5.12.1*~
Adverse Events of all NCI-CTCAE Grades by System Organ Class
and Preferred Term (Safety Populations)
Table 14.3.1.5.12.2
Adverse Events of all NCI-CTCAE Grades by System Organ Class
and Preferred Term - Unvalidated HER2 (Safety Populations)
Table 14.3.1.5.13.1
Adverse Events of all NCI-CTCAE Grades by System Organ Class,
Preferred Term and Age Group <65 years (Safety Populations)
Table 14.3.1.5.13.2
Adverse Events of all NCI-CTCAE Grades by System Organ Class,
Preferred Term and Age Group ≥65 years (Safety Populations)
Table 14.3.1.5.13.3
Adverse Events of all NCI-CTCAE Grades by System Organ Class,


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Preferred Term and Age Group 65 - 74 years (Safety Populations)
Table 14.3.1.5.13.4
Adverse Events of all NCI-CTCAE Grades by System Organ Class,
Preferred Term and Age Group ≥75 years (Safety Populations)
Table 14.3.1.5.14*
Adverse Events of all NCI-CTCAE Grades by System Organ Class,
Preferred Term and Relationship (Safety Populations)
Table 14.3.1.5.15*
Adverse Events of NCI-CTCAE Grades 1, 2, 3 and 4 –
Hepatoxicity/Hematoxicity (Safety Populations)
Table 14.3.1.5.16*
Adverse Events by System Organ Class, Preferred Term and Maximum
CTC Grade (Safety Populations)
Table 14.3.1.5.17.1*
Serious Adverse Events by System Organ Class, Preferred Term and
Maximum CTC Grade (Safety Populations)
Table 14.3.1.5.17.2
Serious Adverse Events by System Organ Class, Preferred Term and
Maximum CTC Grade - Unvalidated HER2 (Safety Populations)
5.3.3.3
Laboratory results
Table 14.3.5.1
Laboratory Parameter Results – Hematology Observed Values and
Change from Baseline (Safety Populations)
Table 14.3.5.2
Shift Table of Laboratory Parameter NCI CTC Toxicity Grades –
Hematology (Safety Populations)
Table 14.3.5.3
Laboratory Parameter Results – Biochemistry Observed Values and
Change from Baseline (Safety Populations)
Table 14.3.5.4
Shift Table of Laboratory Parameter NCI CTC Toxicity Grades –
Biochemistry (Safety Populations)
Table 14.3.5.5
Laboratory results – Urinalysis (continuous) (Safety Populations)
Table 14.3.5.6
Laboratory results – Urinalysis (categorical) (Safety Populations)
Table 14.3.5.7
Any Incidence of Haemorrhage Adverse Events and Any Incidence of
Thrombocytopenia (Lab Results - Platelet Grade 3 or 4)
5.3.3.4
ECG
Table 14.3.6.1
Summary of 12-Lead ECG at Baseline (Safety Populations)
5.3.3.5
ECOG
Table 14.3.6.2
Summary of ECOG (Safety Populations)
5.3.3.6
LVEF
Table 14.3.6.3.1
Summary of Left Ventricular Ejection Fraction (%) by Visit (Safety
Populations)
Table 14.3.6.3.2
Summary of Left Ventricular Ejection Fraction (%) Worst on Treatment
Value (Safety Populations)
5.3.3.7
Hospitalizations
Table 14.3.6.4
Assessment of Hospitalizations (Safety Populations)
5.3.3.8
Weight
Table 14.3.6.5
Weight over time (Safety Populations)


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5.4
Listings
Listings indicated with an # will be repeated for 11 patients in China who are still on study
treatment and are waiting for rollover study. These listings will contain additional data from
these patients visits after 10th July 2019 (LPLV) until their last visit.
Listing 16.2.1.1#
Patient Disposition (End of Treatment)
Listing 16.2.1.2#
Patient Disposition (End of Study)
Listing 16.2.2.1
Inclusion Criteria Questions
Listing 16.2.2.2
Inclusion Criteria – Patient Responses
Listing 16.2.2.3
Exclusion Criteria Questions
Listing 16.2.2.4
Exclusion Criteria – Patient Responses
Listing 16.2.2.5
Patient Eligibility
Listing 16.2.3.1
Analysis Sets and Protocol Violations
Listing 16.2.4.1
Patient Demography and Informed Consent
Listing 16.2.4.2
HER-2 Status
Listing 16.2.4.3
Medical History
Listing 16.2.4.4.1
Cancer History
Listing 16.2.4.4.2
Cancer History Current Status
Listing 16.2.4.5.1
Previous Cancer Treatment: Neo-Adjuvant Treatment
Listing 16.2.4.5.2
Previous Cancer Treatment: Chemotherapy in a Neo-Adjuvant Setting
Listing 16.2.4.5.3
Previous Cancer Treatment: Targeted Therapy in a Neo-Adjuvant
Setting
Listing 16.2.4.5.4
Previous Cancer Treatment: Anti-Estrogen Therapy in a Neo-Adjuvant
Setting
Listing 16.2.4.5.5
Previous Cancer Treatment: Radiotherapy in a Neo-Adjuvant Setting
Listing 16.2.4.6
Previous Cancer Surgery
Listing 16.2.4.7.1
Previous Cancer Treatment: Adjuvant Treatment
Listing 16.2.4.7.2
Previous Cancer Treatment: Chemotherapy in an Adjuvant Setting
Listing 16.2.4.7.3
Previous Cancer Treatment: Targeted Therapy in an Adjuvant Setting
Listing 16.2.4.7.4
Previous Cancer Treatment: Anti-Estrogen in an Adjuvant Setting
Listing 16.2.4.7.5
Previous Cancer Treatment: Radiotherapy in an Adjuvant Setting
Listing 16.2.4.8.1
Previous Cancer Treatment: Locally Advanced/Metastatic Treatment
Listing 16.2.4.8.2
Previous Cancer Treatment: Chemotherapy in a Metastatic Setting
Listing 16.2.4.8.3
Previous Cancer Treatment: Targeted Therapy in a Metastatic Setting
Listing 16.2.4.8.4
Previous Cancer Treatment: Anti-Estrogen Therapy in a Metastatic
Setting
Listing 16.2.4.8.5
Previous Cancer Treatment: Radiotherapy in a Metastatic Setting
Listing 16.2.4.9
Prior Medications
Listing 16.2.4.10#
Concomitant Medications
Listing 16.2.5.1.1#
Study Drug Administration
Listing 16.2.5.1.2#
Study Drug Administration – Missed Doses, Modifications and
Interruptions
Listing 16.2.5.1.3#
Study Drug Administration and Exposure – Derived Data
Listing 16.2.5.2#
Cycle Dates
Listing 16.2.6.1
Baseline Summary Lesions
Listing 16.2.6.2#
Tumor Assessments - RECIST
Listing 16.2.6.3
Progression Free Survival
Listing 16.2.6.4
Overall Survival
Listing 16.2.6.5
Best Overall Response
Listing 16.2.6.6
Disease Progression – Safety Follow up


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Listing 16.2.6.7
Brain CT or MRI and Bone Scan/Imaging
Listing 16.2.6.8#
Deaths on Study
Listing 16.2.7.1#
Adverse Events
Listing 16.2.7.2
Serious Adverse Events
Listing 16.2.7.3
Related Adverse Events
Listing 16.2.7.4
Adverse Events Leading to Treatment Discontinuation of Study Drug
Listing 16.2.7.5
Adverse Events Leading to Study Drug Interruption
Listing 16.2.7.6
Adverse Events NCI-CTC Grade 3 or Higher
Listing 16.2.7.7
Adverse Events – Primary endpoint
Listing 16.2.7.8
Adverse Events – Adverse events of special interest
Listing 16.2.7.9
Adverse Events of Special Interest – Hy’s Law
Listing 16.2.7.10
Adverse Events – Other Adverse events of interest
Listing 16.2.7.11
Adverse Events Leading to Discontinuation from Study Drug Due to
LVEF Decrease or Drug Induced Liver Dysfunction
Listing 16.2.7.12
Adverse Events Leading to Death
Listing 16.2.8.1#
Laboratory Results – Hematology
Listing 16.2.8.2#
Laboratory Results – Biochemistry
Listing 16.2.8.3#
Laboratory Results - Urinalysis
Listing 16.2.8.4#
INR/aPPT values
Listing 16.2.9.1#
Weight
Listing 16.2.9.2#
12-Lead ECG
Listing 16.2.9.3#
Left Ventricular Ejection Fraction
Listing 16.2.9.4
Left Ventricular Ejection Fraction – Worst on Treatment Value
Listing 16.2.9.5
ECOG Grade Definitions
Listing 16.2.9.6#
ECOG Performance Status
Listing 16.2.9.7#
Physical Examination
Listing 16.2.9.8
Serum Pregnancy Test
Listing 16.2.9.9
Urine Pregnancy Test
Listing 16.2.9.10#
Assessment of Hospitalizations
Listing 16.2.9.11#
Unscheduled Assessments
5.5
Figures
Figure 14.2.1*
Percentage of Patients Receiving Study Drug by Cycle
Figure 14.2.2
Left Ventricular Ejection Fraction – Mean Values Over Time
Figure 14.2.3.1
AST - Mean Values Over Time
Figure 14.2.3.2
ALT - Mean Values Over Time
Figure 14.2.3.3
Total Bilirubin - Mean Values Over Time
Figure 14.2.4.1*
Kaplan Meier Curve of Progression Free Survival, ITT
populations
Figure 14.2.4.2*
Kaplan Meier Curve of Progression Free Survival by Previous
Lines of Treatment, ITT populations
Figure 14.2.4.3
Kaplan Meier Curve of Progression Free Survival by Prior
Pertuzumab, ITT populations
Figure 14.2.4.4
Kaplan Meier Curve of Progression Free Survival -
Unvalidated HER2, ITT populations
Figure 14.2.5.1*
Kaplan Meier Curve of Overall Survival, ITT populations
Figure 14.2.5.2*
Kaplan Meier Curve of Overall Survival by Previous Lines of
Treatment, ITT populations
Figure 14.2.5.3
Kaplan Meier Curve of Overall Survival by Prior Pertuzumab,
ITT populations


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Figure 14.2.5.4*
Kaplan Meier Curve of Overall Survival - Unvalidated HER2,
ITT populations
Figure 14.2.6
Kaplan Meier Curve of Duration of Response, ITT populations
Figure 14.2.7
Kaplan Meier Curve of Time to Response, ITT populations
5.6
Appendices
Appendix 1
Raw SAS Statistical Output for primary criterion and for modelling
(variable selection for BOR analysis) only.
5.7
References
- ICH E3, Structure and Content of Clinical Study Reports, November 1995;
- ICH E9, Statistical Principles for Clinical Trials, February 1998
- Investigator’s Brochure, Trastuzumab Emtansine, December 2012