Conditions: Breast Cancer Gastric Cancer
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 182
Healthy volunteers: no

Brief summary:
This multicenter study will assess the maximum tolerated dose (MTD) of capecitabine in combination with Kadcyla (trastuzumab emtansine) in participants with HER2-positive mBC or HER2-positive LA/mGC using a Phase 1 design, followed by a randomized, open-label Phase 2 part to explore the efficacy and safety of the combination of Kadcyla and capecitabine compared with Kadcyla alone in participants with mBC. The anticipated time on study treatment is until disease progression, intolerable toxicity, withdrawal of consent, or study end.

Detailed description:

Arms:
arm 1: In Phase 1, Cohort 1 participants (with mBC) will receive trastuzumab emtansine (T-DM1) at a dose of 3.6 milligrams per kilogram (mg/kg) via intravenous (IV) infusion (on Day 1 \[on Day 2 for Cycle 1\] of each 21-day cycle) along with capecitabine at de-escalating dose levels (starting from 750 milligrams per meter squared \[mg/m\^2\]) via tablet orally twice daily on Days 1-14 of each 21-day cycle until unacceptable toxicity, withdrawal of consent, disease progression (PD), death, or study end. arm 2: In Phase 1, Cohort 2 participants (with LA/mGC) will receive trastuzumab emtansine at a dose of 2.4 mg/kg via IV infusion on Day 1 (on Day 2 of first week) of every week along with capecitabine at MTD (determined in Cohort 1) via tablet orally twice daily on Days 1-14 followed by a 7-day rest period, in each 21-day cycle until unacceptable toxicity, withdrawal of consent, PD, death, or study end. arm 3: In Phase 2, participants (with mBC) who will be randomized to this group, will receive trastuzumab emtansine at a dose of 3.6 mg/kg via IV infusion on Day 1 of each 21-day cycle along with capecitabine at MTD via tablet orally twice daily on Days 1-14 of each 21-day cycle until unacceptable toxicity, withdrawal of consent, PD, death, or study end. arm 4: In Phase 2, participants (with mBC) who will be randomized to this group, will receive trastuzumab emtansine at a dose of 3.6 mg/kg via IV infusion on Day 1 of each 21-day cycle until investigator-assessed PD, unacceptable toxicity, withdrawal of consent, death, or study end.

Interventions: intervention 1: Capecitabine intervention 2: Trastuzumab emtansine (T-DM1) intervention 3: Trastuzumab emtansine (T-DM1) intervention 4: Capecitabine
Intervention descriptions: intervention 1: Capecitabine will be administered at de-escalating doses (starting from 750 mg/m\^2) to determine the MTD. intervention 2: Trastuzumab emtansine will be administered at a dose of 3.6 mg/kg via IV infusion every 3 weeks. intervention 3: Trastuzumab emtansine will be administered at a dose of 2.4 mg/kg via IV infusion every week. intervention 4: Capecitabine will be administered at the MTD determined in Cohort 1.

Protocol document:
Prot_000.pdf: 
 
Official Title: 
Phase I Study of the Combination of Trastuzumab Emtansine (T-
DM1) and Capecitabine in HER2-Positive Metastatic Breast 
Cancer and HER2-Positive Locally Advanced/Metastatic Gastric 
Cancer Patients, Followed by a Randomized, Open-Label Phase 
II Study of Trastuzumab Emtansine and Capecitabine Versus 
Trastuzumab Emtansine Alone in HER2-Positive Metastatic 
Breast Cancer 
NCT Number: 
NCT01702558 
Document Dates: 
Protocol Amendment Version 4: 23-Mar-2016 
Protocol Amendment Version 3: 30-Jun-2014 
Protocol Amendment Version 2: 03-Sep-2013 
Protocol Version 1: 02-Jul-2012 
 
 
 


 
 
13.1.1 
Protocol and Protocol Amendments 
 
The following documents are included in this appendix: 
 
Protocol 
 
 
 
 
Version 1 
 
02 Jul 2012 
Protocol 
 
 
 
 
Version 2 
 
03 Sep 2013 
Note to File for Version 2 
 
 
Note to File 
 
22 Oct 2013 
 
Protocol 
 
 
 
 
Version 3 
 
30 Jun 2014 
Protocol 
 
 
 
 
Version 4 
 
23 Mar 2016 
 
Protocol Amendment Version 2 
 
Final Version  
03 Sep 2013 
Protocol Amendment Version 3 
 
Final Version  
30 Jun 2014 
Protocol Amendment Version 4 
 
Final Version  
23 Mar 2016 
 
 
 
 
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TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................... 9 
PROTOCOL SYNOPSIS .................................................................................... 10 
1. 
BACKGROUND .......................................................................................... 24 
1.1 
Background on Disease......................................................... 24 
1.1.1 
HER2-Positive Breast Cancer, Metastatic 
Breast Cancer ........................................................................ 24 
1.1.2 
HER2-Positive Locally Advanced or 
Metastatic Gastric Cancer ..................................................... 25 
1.2 
Background on Study Drugs .................................................. 26 
1.2.1 
Trastuzumab Emtansine ........................................................ 26 
1.2.1.1 
Study TDM3569g ................................................................... 28 
1.2.1.2 
Study TDM4258g ................................................................... 28 
1.2.1.3 
Study TDM4374g ................................................................... 29 
1.2.1.4 
Study TDM4450g ................................................................... 30 
1.2.1.5 
Study TDM4688g ................................................................... 30 
1.2.1.6 
Phase III Study TDM4370g .................................................... 31 
1.2.1.7 
Pharmacokinetics .................................................................. 32 
1.2.2 
Capecitabine .......................................................................... 34 
1.2.2.1 
Study BO18255: Capecitabine and 
Trastuzumab in mGC............................................................. 34 
1.2.3 
Preclinical Data of the Combination of 
Trastuzumab Emtansine and a 
Fluoropyrimidine .................................................................... 35 
1.3 
Study Rationale and Benefit-Risk Assessment ...................... 37 
1.3.1 
For mBC ................................................................................ 37 
1.3.2 
For mGC ................................................................................ 38 
2. 
OBJECTIVES .............................................................................................. 39 
2.1 
Phase I: MTD Finding of Trastzumab 
Emtansine and Capecitabine in mBC .................................... 39 
2.1.1 
Primary Objective .................................................................. 39 
2.1.2 
Secondary Objectives ............................................................ 39 
2.2 
Phase II: Exploration of Efficacy in mBC 
Patients .................................................................................. 39 
2.2.1 
Primary Objective .................................................................. 39 
2.2.2 
Secondary Objectives ............................................................ 39 
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2.3 
Phase I: MTD Finding of Trastzumab 
Emtansine and Capecitabine in MGC .................................... 39 
2.3.1 
Primary Objective .................................................................. 39 
2.3.2 
Secondary Objectives ............................................................ 40 
3. 
STUDY DESIGN ......................................................................................... 40 
3.1 
Description of Study .............................................................. 40 
3.1.1 
Overview of Study Design ..................................................... 40 
3.1.1.1 
Overview of Phase I Design in mBC Patients ........................ 43 
3.1.1.2 
Overview of Phase II: Exploration of Efficacy 
in mBC Patients ..................................................................... 45 
3.1.1.3 
Overview of Phase I Design in mGC Patients ....................... 45 
3.1.1.4 
Considerations for all Patients Treated in the 
Study ..................................................................................... 46 
3.1.1.5 
Number of Patients ................................................................ 46 
3.1.1.6 
Number of Centers ................................................................ 46 
3.1.2 
Steering Committee ............................................................... 46 
3.2 
End of Study .......................................................................... 47 
3.3 
Rationale For Study Design ................................................... 47 
3.3.1 
Rationale for Patient Group Selection ................................... 47 
3.3.1.1 
Rationale for Phase I ............................................................. 47 
3.3.1.2 
Rationale for Phase II ............................................................ 47 
3.3.2 
Rationale For Investigational Medicinal Dose 
Selection ................................................................................ 47 
3.3.2.1 
In mBC Patients ..................................................................... 47 
3.3.2.2 
In mGC Patients .................................................................... 48 
3.3.2.3 
Rationale for Duration of 
Treatment .............................................................................. 48 
3.3.3 
Pharmacokinetic Sampling 
Rationale ............................................................................... 48 
3.4 
Outcome Measures ............................................................... 49 
3.4.1 
Phase I: mBC ........................................................................ 49 
3.4.1.1 
Primary Efficacy Outcome Measure ...................................... 49 
3.4.1.2 
Secondary Efficacy Outcome Measure.................................. 49 
3.4.1.3 
Primary Safety Outcome Measure ......................................... 49 
3.4.1.4 
Secondary Safety Outcome Measures .................................. 49 
3.4.1.5 
Pharmacokinetic Outcome Measures .................................... 49 
3.4.2 
Phase II: Exploration of Efficacy: mBC .................................. 49 
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3.4.2.1 
Primary Efficacy Outcome Measure ...................................... 49 
3.4.2.2 
Secondary Efficacy Outcome Measures ................................ 50 
3.4.2.3 
Primary Safety Outcome Measure ......................................... 50 
3.4.2.4 
Secondary Safety Outcome Measures .................................. 50 
3.4.2.5 
Pharmacokinetic Outcome Measures .................................... 50 
3.4.3 
Phase I: mGC ........................................................................ 50 
3.4.3.1 
Primary Efficacy Outcome Measure ...................................... 50 
3.4.3.2 
Secondary Efficacy Outcome Measure.................................. 51 
3.4.3.3 
Primary Safety Outcome Measure ......................................... 51 
3.4.3.4 
Secondary Safety Outcome Measures .................................. 51 
3.4.3.5 
Pharmacokinetic Outcome Measures .................................... 51 
4. 
MATERIALS AND METHODS .................................................................... 51 
4.1 
Patients .................................................................................. 51 
4.1.1 
mBC Patients ......................................................................... 51 
4.1.2 
mGC Patients ........................................................................ 52 
4.1.3 
Inclusion Criteria .................................................................... 52 
4.1.3.1 
For mBC Patients .................................................................. 52 
4.1.3.2 
For mGC Patients: ................................................................. 53 
4.1.4 
Exclusion Criteria ................................................................... 54 
4.1.4.1 
For mBC Patients: ................................................................. 54 
4.1.4.2 
For mGC Patients: ................................................................. 56 
4.2 
Study Treatment .................................................................... 58 
4.2.1 
Formulation, Packaging, and Handling .................................. 58 
4.2.1.1 
Trastuzumab Emtansine ........................................................ 58 
4.2.1.2 
Capecitabine .......................................................................... 59 
4.2.2 
Dosage and Administration .................................................... 59 
4.2.2.1 
For mBC Patients .................................................................. 59 
4.2.2.2 
For mGC Patients .................................................................. 60 
4.2.3 
Investigational Medicinal Product 
Accountability ........................................................................ 60 
4.2.4 
Post-trial Access to Extension Study ..................................... 61 
4.3 
Concomitant And Excluded Therapies .................................. 61 
4.3.1 
Permitted Therapy ................................................................. 61 
4.3.2 
Prohibited Therapy ................................................................ 61 
4.4 
Study Assessments ............................................................... 62 
4.4.1 
Description of Study Assessments ........................................ 62 
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4.4.1.1 
Medical History and Demographic Data ................................ 62 
4.4.1.2 
Vital Signs .............................................................................. 63 
4.4.1.3 
Physical Examinations ........................................................... 63 
4.4.1.4 
Tumor and Response Evaluations ......................................... 63 
4.4.1.5 
Laboratory Assessments ....................................................... 64 
4.4.1.6 
Electrocardiograms ................................................................ 64 
4.4.1.7 
ECHO/MUGA ........................................................................ 65 
4.4.2 
Timing of Study Assessments ............................................... 65 
4.4.2.1 
Screening and Pretreatment Assessments............................ 65 
4.4.2.2 
Assessments During Treatment ............................................ 65 
4.4.2.3 
Assessments at Study Completion/Early 
Termination Visit .................................................................... 66 
4.4.2.4 
Follow-Up Assessments ........................................................ 66 
4.4.2.5 
Assessments at Unplanned Visits ......................................... 67 
4.5 
Patient, Study, and Site Discontinuation ................................ 67 
4.5.1 
Patient Discontinuation .......................................................... 67 
4.5.2 
Study Discontinuation ............................................................ 67 
5. 
ASSESSMENT OF SAFETY ....................................................................... 68 
5.1 
Safety Plan ............................................................................ 68 
5.1.1 
Risks Associated with Trastuzumab 
Emtansine .............................................................................. 68 
5.1.2 
Risks Associated with Capecitabine ...................................... 70 
5.1.3 
Trastuzumab Emtansine and Capecitabine 
Combination: ......................................................................... 70 
5.1.4 
Definition of Dose Limiting Toxicity ........................................ 70 
5.1.5 
Management of Specific Adverse Events .............................. 71 
5.1.5.1 
Trastuzumab Emtansine Dosage Modification ...................... 71 
5.1.5.2 
Capecitabine Dosage Modification ........................................ 77 
5.2 
Safety Parameters and Definitions ........................................ 77 
5.2.1 
Adverse Events ..................................................................... 77 
5.2.2 
Serious Adverse Events (Immediately 
Reportable to the Sponsor) .................................................... 78 
5.2.3 
Protocol-Defined Events of Special 
Interest/Non-Serious Expedited Adverse 
Events.................................................................................... 79 
5.2.4 
Pregnancy and Contraception ............................................... 79 
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5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 81 
5.3.1 
Adverse Event Reporting Period ........................................... 81 
5.3.2 
Eliciting Adverse Event Information ....................................... 82 
5.3.3 
Assessment of Severity of Adverse Events ........................... 82 
5.3.4 
Assessment of Causality of Adverse Events ......................... 83 
5.3.5 
Procedures for Recording Adverse Events ............................ 84 
5.3.5.1 
Diagnosis Versus Signs and Symptoms ................................ 85 
5.3.5.2 
Adverse Events Occurring Secondary to other 
Events.................................................................................... 85 
5.3.5.3 
Persistent or Recurrent Adverse Events ................................ 85 
5.3.5.4 
Abnormal Laboratory Values ................................................. 85 
5.3.5.5 
Deaths ................................................................................... 86 
5.3.5.6 
Pre-Existing Medical Conditions ............................................ 86 
5.3.5.7 
Lack of Efficacy or Clinical Worsening ................................... 87 
5.3.5.8 
Hospitalization or Prolonged Hospitalization .......................... 87 
5.4 
Immediate Reporting Requirements from 
Investigator to the Sponsor .................................................... 87 
5.4.1 
Emergency Medical Contacts ................................................ 88 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest ...................................................................... 88 
5.4.3 
Reporting Requirements for Pregnancies .............................. 88 
5.4.3.1 
Pregnancies in Female Patients ............................................ 88 
5.4.3.2 
Pregnancies in Female Partners of Male 
Patients .................................................................................. 89 
5.4.3.3 
Abortions ............................................................................... 89 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 89 
5.5 
Follow-Up of Patients after Adverse Events .......................... 89 
5.5.1 
Investigator Follow-Up ........................................................... 89 
5.5.2 
Sponsor Follow-Up ................................................................ 90 
5.6 
Post-Study Adverse Events ................................................... 90 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees .......................................................... 90 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 91 
6.1 
Determination of Sample Size ............................................... 91 
6.2 
Summaries of Conduct of Study ............................................ 92 
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6.3 
Summaries of Treatment Group Comparability ..................... 93 
6.4 
Efficacy Analyses .................................................................. 93 
6.4.1 
Primary Efficacy Endpoint ...................................................... 94 
6.4.2 
Secondary Efficacy Endpoints ............................................... 94 
6.5 
Safety Analyses ..................................................................... 96 
6.6 
Pharmacodynamic Analyses ................................................. 97 
6.7 
Pharmacokinetic Analyses ..................................................... 97 
6.8 
Exploratory Analyses ............................................................. 98 
6.9 
Interim Analyses .................................................................... 98 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 98 
7.1 
Data Quality Assurance ......................................................... 98 
7.2 
Electronic Case Report Forms ............................................... 99 
7.3 
Source Data Documentation .................................................. 99 
7.4 
Use of Computerized Systems .............................................. 99 
7.5 
Retention of Records ........................................................... 100 
8. 
ETHICAL CONSIDERATIONS .................................................................. 100 
8.1 
Compliance with Laws and Regulations .............................. 100 
8.2 
Informed Consent ................................................................ 101 
8.3 
Institutional Review Board or 
Ethics Committee ................................................................ 101 
8.4 
Confidentiality ...................................................................... 102 
8.5 
Financial Disclosure ............................................................ 102 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 102 
9.1 
Study Documentation .......................................................... 102 
9.2 
Site Inspections ................................................................... 103 
9.3 
Administrative Structure....................................................... 103 
9.4 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 103 
9.5 
Protocol Amendments ......................................................... 103 
10. REFERENCES ......................................................................................... 105 
 
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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 ........................................................ 33 
Table 2 
Dose Reductions for Trastuzumab Emtansine (mBC 
Patients) ...................................................................................... 72 
Table 3 
Dose Reductions for Trastuzumab Emtansine (mGC 
Patients) ...................................................................................... 72 
Table 4 
Trastuzumab Emtansine Dose Modification: Total Serum 
Bilirubin ....................................................................................... 74 
Table 5 
 Trastuzumab Emtansine Dose Modification: Serum ALT 
or AST ......................................................................................... 74 
Table 6 
Adverse Event Severity Grading Scale ....................................... 83 
Table 7 
Guidance for Causal Attribution of Adverse Event/Serious 
Adverse Event ............................................................................. 84 
Table 8 
Sample Size Estimation for Phase II ........................................... 92 
 
 
LIST OF FIGURES 
Figure 1 
Molecular Structure of Trastuzumab Emtansine ......................... 27 
Figure 2 
MMTV HER2 Fo5 Mammary Tumor Transplants ........................ 36 
Figure 3 
Anti-tumor Activity of Trastuzumab Emtansine in 
Combination with Capecitabine in NCI-N87 ................................ 37 
Figure 4 
Overview of Study Design ........................................................... 42 
Figure 5 
 Overview of Phase I Dose Finding Study Design ...................... 43 
Figure 6 
Algorithm for Continuation and Discontinuation of 
Trastuzumab Emtansine Based on Left Ventricular 
Ejection Fraction Assessments in Patients ................................. 76 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments ......................................................... 109 
Appendix 2 
Pharmacokinetic Sampling for Phase I, Metastatic 
Breast and Gastric Cancer Patients .......................................... 118 
Appendix 3 
Response Evaluation Criteria in Solid Tumors 
(RECIST):  Modified Excerpt from Original 
Publication ................................................................................. 120 
Appendix 4 
Instructions for Scans in the Event of Isotope 
Shortage .................................................................................... 132 
Appendix 5 
New York Heart Association Classification of 
Functional Cardiac Capacity...................................................... 133 
 
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PROTOCOL ACCEPTANCE FORM 
TITLE: 
PHASE I FOLLOWED BY PHASE II STUDY OF THE COMBINATION 
OF TRASTUZUMAB EMTANSINE (T-DM1) AND CAPECITABINE IN 
HER2-POSITIVE METASTATIC BREAST CANCER AND HER2-
POSITIVE LOCALLY ADVANCED OR METASTATIC GASTRIC 
CANCER PATIENTS 
PROTOCOL NUMBER: MO28230 
VERSION NUMBER: 1 
EUDRACT NUMBER: 
2012-001547-46 
 
 
TEST PRODUCT: 
Trastuzumab emtansine (RO5304020) 
MEDICAL MONITOR: 
 
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 to the contact provided below. Please retain 
the original for your study files. 
 
 
 
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Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Protocol MO28230, Version 1 
10 
PROTOCOL SYNOPSIS 
TITLE: 
PHASE I FOLLOWED BY PHASE II STUDY OF THE COMBINATION OF 
TRASTUZUMAB EMTANSINE (T-DM1) AND CAPECITABINE IN HER2-POSITIVE 
METASTATIC BREAST CANCER AND HER2-POSITIVE LOCALLY ADVANCED 
OR METASTATIC GASTRIC CANCER PATIENTS 
PROTOCOL NUMBER: 
MO28230 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
2012-001547-46 
 
 
TEST PRODUCT: 
Trastuzumab emtansine (RO5304020) 
PHASE: 
I/II 
INDICATION: 
HER2-positive metastatic breast and locally advanced or metastatic 
gastric cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Phase I: Maximum Tolerated Dose Finding of Trastzumab Emtansine and 
Capecitabine in Metastatic Breast Cancer 
Primary Objective 
 
To determine the Maximum Tolerated Dose (MTD) of the combination of trastuzumab 
emtansine and capecitabine in metastatic breast cancer (mBC) patients 
Secondary Objectives 
 
Pharmacokinetics (PK) of trastuzumab emtansine and metabolites and capecitabine 
 
Safety of the combination of trastuzumab emtansine and capecitabine 
 
Overall Response Rate (ORR) 
Phase II: Exploration of Efficacy: mBC 
Primary Objective: 
 
ORR by investigator assessment  
Secondary Objectives 
 
Safety profile of the combination at the dose established during Phase I 
 
Time to response (TTR)  
 
Duration of response (DoR) 
 
Time to progression (TTP)  
 
Time to treatment failure (TTF)  
 
Progression free survival (PFS)  
 
Clinical benefit rate (CBR) 
 
Overall survival (OS) 
Phase I: MTD Finding of Trastzumab Emtansine and Capecitabine in Metastatic 
Gastric Cancer 
Primary Objective 
 
To determine the MTD of the combination of trastuzumab emtansine and capecitabine 
in metastatic gastric cancer (mGC) patients 
Secondary Objectives 
 
PK of trastuzumab emtansine and metabolites and capecitabine 
 
Safety of the combination of trastuzumab emtansine and capecitabine 
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 
Overall Response Rate (ORR) 
Study Design 
Description of Study 
This is an international, multicenter study. 
The study is designed to determine the MTD of capecitabine in combination with 
trastuzumab emtansine in HER2-positive mBC and locally advanced or mGC patients, using 
a Phase I design, followed by a Phase II single arm study to explore the efficacy of the 
combination in mBC patients. There will be no exploration of efficacy in the mGC cohort. 
Results from the Phase I in mGC will be used as supporting information for future studies in 
the indication (see Figure 4 in the protocol). 
Cohort 1 (mBC) and Cohort 2 (mGC) will open sequentially during Phase I. 
Phase I: MTD Finding, Cohort 1: mBC 
Cohort 1 will open first with a 3 by 3 classical design. Cohort 1 will enroll patients with 
HER2-positive mBC. The dose tested of trastuzumab emtansine remains fixed at 3.6 mg/kg 
every 3 weeks and 3 dose levels of capecitabine administered twice daily on days 1 to 14 in 
cycles of 3 weeks will be tested. All patients will be treated until disease progression, 
intolerable toxicity, withdrawn consent, or death. All patients will be followed-up intolerable 
toxicity, withdrawn consent, death or up to a maximum of 2 years after the last patient was 
enrolled in the Phase II part of the study, whichever occurs first. 
The rules for dose escalation are presented below.  
If Dose level 1 is too toxic (dose limiting toxicity [DLT] >1/3 or >1/6) the combination may be 
considered unfeasible, recruitment will be closed and no other cohort will open. Patients 
who at that point experience response as per Response Evaluation Criteria for Solid Tumors 
(RECIST) will be offered the possibility to continue on trastuzumab emtansine as a single 
agent. 
Dose Levels Explored in Phase I, Cohort 1: 
Dose level 1: 750 mg/m2 capecitabine twice daily (bid) + 3.6 mg/kg every three weeks (q3w) 
trastuzumab emtansine 
Dose level 2: 850 mg/m2 capecitabine bid + 3.6 mg/kg q3w trastuzumab emtansine 
Dose level 3: 1000 mg/m2 capecitabine bid + 3.6 mg/kg q3w trastuzumab emtansine 
Phase II: Exploration of Efficacy, Cohort 1: mBC 
Phase II will be conducted in mBC patients only. 
Once the MTD in Cohort 1 is established, recruitment into this cohort will be extended to a 
total of 110 HER2-positive mBC patients for the Phase II part. Patients, who are on the MTD 
established in the Phase I part of the study, must re-consent to be enrolled into Phase II. 
Patients will be treated until disease progression, intolerable toxicity withdrawn consent, or 
death. If capecitabine needs to be discontinued for any reason, trastuzumab emtansine may 
continue, and the patient will remain evaluable in the study. In case of discontinuation of 
trastuzumab emtansine, patients will be withdrawn from the study. 
All patients will be followed up until disease progression, intolerable toxicity, withdrawn 
consent, death or up to a maximum of 2 years after the last patient was enrolled in the 
Phase II part of the study, whichever occurs first. Patients who have not progressed at that 
point in time may be enrolled into an extension study. 
Phase I: MTD Finding, Cohort 2: mGC 
Once the capecitabine MTD dose is established for Cohort 1, Cohort 2 will open, with a 3 by 
3 classical design to enroll HER2-positive mGC patients. Trastuzumab emtansine will be 
administered weekly at the dose of 2.4 mg/kg and capecitabine will start at the MTD dose 
defined in Cohort 1, capecitabine dose level may be de-escalated. 
All patients will be treated until disease progression, intolerable toxicity, withdrawn consent, 
or death. All patients will be followed-up until intolerable toxicity, withdrawn consent, death 
or up to a maximum of 2 years after the last patient was enrolled in the Phase II part of the 
study, whichever occurs first. 
The dose levels for capecitabine will be the same as described in Cohort 1. Guidelines for 
dose escalation and de-escalation are as follows: 
If MTD is defined at Dose Level 1 of 750 mg/m2 bid: 
 
Escalation will be to Dose Level 2 of 850 mg/m2 bid. 
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 
De-escalation: if Dose Level 1 is not tolerated (>1/3 or >1/6 DLT), the combination will 
be considered not feasible. 
If MTD defined at Dose Level 2 of 850 mg/m2 bid: 
 
Escalation will be to Dose Level 3 of 1000 mg/m2 bid 
 
De-escalation will be to Dose Level 1 of 750 mg/m2 bid 
If MTD defined at Dose Level 3 of 1000 mg/m2 bid 
 
Escalation: There will be no escalation, MTD will be defined at Dose Level 3 
 
De-escalation will be to Dose Level 2 of 850 mg/m2 bid 
Number of Patients 
Phase I: mBC 
3 to 18 patients may be enrolled. 
Phase II: mBC 
Cohort 1 will be expanded to enroll 110 patients in total. 
Phase I: mGC 
3 to 18 patients may be enrolled. 
Target Population 
Phase I, Cohort 1: mBC 
HER2-positive mBC patients will be enrolled. 
Patients must have received at least one treatment regimen which includes a chemotherapy 
and trastuzumab agent. 
Phase II, Cohort 1: mBC 
HER2-positive mBC patients will be enrolled. 
Patients must have received at least one treatment regimen which includes a chemotherapy 
and trastuzumab agent. 
Phase I, Cohort 2: mGC 
HER2-positive advanced mGC patients will be enrolled. 
Patients must not have received prior chemotherapy for advanced/metastatic disease. 
Inclusion Criteria: 
For mBC Patients: 
1. Age ≥ 18 years old 
2. Signed informed consent prior to any study specific procedure 
3. Able and willing to comply with protocol 
4. 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 
5. 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 or two effective forms of non-hormonal contraception and to continue its 
use for the duration of study treatment and for 6 months after the last dose of study 
treatment (see Section 5.2.4 in the protocol) 
6. ECOG performance status of 0, 1, or 2 
7. Blood: 
a) Platelet count > 100,000 cells/mm3 
b) International normalized ratio (INR) < 1.5 × the upper limit of normal (ULN) 
c) Absolute neutrophil count (ANC) > 1500 cells/mm3 
d) Hemoglobin > 9.0 g/dL. Patients are allowed to have received transfusion to achieve 
this level. 
8. Liver function: 
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a) Total bilirubin ≤ 1.5 × ULN except in patients with previously documented Gilbert’s 
syndrome in which case total bilirubin ≤ 3 mg/dL is acceptable 
b) Serum glutamic oxaloacetic transaminase (SGOT)/AST and serum glutamic pyruvic 
transaminase (SGPT)/alanine transaminase (ALT) ≤ 2.5 × the ULN 
c) Alkaline phosphatase ≤ 2.5 × the ULN. Patients with hepatic and/or bone metastases: 
alkaline phosphatase ≤ 5 × the ULN 
9. Renal function: 
a) Serum creatinine of < 177 µmol/L or calculated creatinine clearance (CL) > 50 mL/min. 
If urine dipstick for proteinuria is ≥ 2+ at baseline, the patient must undergo 24 hour 
urine collection and demonstrate ≤ 1 g of protein/24 hours 
10. Cardiac function: 
a) Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) or multiple 
gated acquisition (scan) (MUGA) 
11. Histologically or cytologically confirmed breast cancer 
12. HER2-positive disease immunohistochemistry (IHC) 3+ or in situ hybridization (ISH) 
positive 
13. Tumor block available or 15 slides for retrospective central confirmation of HER2-
positivity (central confirmation not necessary for enrolment) 
14. mBC with at least one measurable lesion according to RECIST 
15. Disease progression on at least one regimen containing trastuzumab and 
chemotherapy 
16. Patients must have recovered from previous treatments 
For mGC Patients: 
1. Age  ≥ 18 years old 
2. Signed informed consent prior to any study specific procedure 
3. Able and willing to comply with protocol 
4. 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 
5. 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 or two effective forms of non-hormonal contraception and to continue its 
use for the duration of study treatment and for 6 months after the last dose of study 
treatment (see Section 5.2.4 in the protocol) 
6. ECOG performance status of 0, 1, or 2 
7. Blood: 
a) Platelet count > 100,000 cells/mm3 
b) INR < 1.5 × the ULN 
c) ANC > 1500 cells/mm3 
d) Hemoglobin > 9.0 g/dL. Patients are allowed to have received transfusion to achieve 
this level. 
8. Liver function: 
a) Total bilirubin ≤ 1.5 × ULN except in patients with previously documented Gilbert’s 
syndrome in which case total bilirubin ≤ 3 mg/dL is acceptable 
b) SGOT/AST and SGPT/ALT ≤ 2.5 × the ULN 
c) Alkaline phosphatase ≤ 2.5 × the ULN. Patients with hepatic and/or bone metastases: 
alkaline phosphatase ≤ 5 × the ULN 
9. Renal function: 
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a) Serum creatinine of < 177 µmol/L or calculated creatinine CL > 50 mL/min. If urine 
dipstick for proteinuria is ≥ 2+ at baseline, the patient must undergo 24 hour urine 
collection and demonstrate ≤ 1 g of protein/24 hours 
10. Cardiac function: 
a) LVEF ≥ 50% by ECHO or MUGA 
11. Histologically or cytologically confirmed GC 
12. HER2-positive tumor (primary tumor or metastatic lesion), defined as either IHC 3+ 
alone or IHC 2+ in combination with ISH+, prospectively confirmed by a Sponsor-
designated central laboratory prior to enrollment. ISH positivity is defined as a ratio 
of ≥ 2.0 for the number of HER2 gene copies to the number of signals for CEP17. 
a) Archival tumor samples obtained from primary or metastatic sites are acceptable. 
b) Invasive tumor for central confirmation of HER2 status is required. 
c) A formalin-fixed paraffin-embedded (FFPE) tissue block with at least 5 mm of invasive 
tumor for central confirmation is preferred. 
If FFPE tissue blocks (or partial block) are unavailable due to country or site regulations, 
a minimum of 8 freshly cut unstained slides MUST be available for central review of 
HER2 status. 
13. Inoperable locally advanced or mGC 
Exclusion Criteria: 
For mBC Patients: 
1. Prior treatments before first study treatment: 
a) Investigational therapy within ≤ 28 days or 5 half lives, whatever is longest 
b) Hormonal therapy within 14 days 
c) Trastuzumab within 21 days 
2. Prior enrollment in a trastuzumab emtansine−containing study, regardless of whether 
the patient received prior trastuzumab emtansine 
3. Prior treatment with capecitabine 
4. History of severe and unexpected reactions to fluoropyrimidine or with known 
hypersensitivity to fluorouracil 
5. Related capecitabine contraindications: 
a) Treatment with sorivudine or its chemically related analogues, such as brivudine 
b) Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or 
glucose-galactose malabsorption 
6. History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity to 
trastuzumab or murine proteins 
7. History of exposure to the following cumulative doses of anthracyclines: 
a) Doxorubicin or liposomal doxorubicin > 360 mg/m2 
b) Epirubicin > 900 mg/m2 
c) Mitoxantrone > 120 mg/m2 
d) If another anthracycline, or more than one anthracycline, has been used, the cumulative 
dose must not exceed the equivalent of 360 mg/m2 doxorubicin. 
8. Brain metastases that are symptomatic, or require any radiation, surgery, or steroid 
therapy to control their symptoms within 28 days of first study drug administration 
9. Current peripheral neuropathy of Grade ≥ 3 per the NCI CTCAE, v4.0 
10. History of other malignancy within the last 5 years, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, 
or other cancers with a similar outcome as those mentioned above 
11. Current unstable ventricular arrhythmia requiring treatment 
12. History of symptomatic congestive heart failure (CHF) (New York Heart Association 
[NYHA] Classes II−IV) 
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13. History of myocardial infarction or unstable angina within 6 months prior to first study 
drug administration 
14. History of a decrease in LVEF to < 40% or symptomatic CHF with previous trastuzumab 
treatment 
15. Severe dyspnea at rest due to complications of advanced malignancy or requiring 
current continuous oxygen therapy 
16. Clinically significant malabsorption syndrome or inability to take oral medication 
17. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary, or metabolic disease) 
18. Major surgical procedure or significant traumatic injury within 28 days before enrollment 
or anticipation of the need for major surgery during the course of study treatment 
19. Current pregnancy or lactation 
20. Current known active infection with HIV, hepatitis B, and/or hepatitis C virus 
a) For patients who are known carriers of hepatitis B virus (HBV), active hepatitis B 
infection must be ruled out based on negative serologic testing and/or determination of 
HBV DNA viral load per local guidelines 
21. Lapatinib ≤ 14 days before first study drug administration 
22. Previous radiotherapy for the treatment of unresectable, locally advanced/recurrent or 
mBC is not allowed if: 
a) The last fraction of radiotherapy has been administered within 14 days prior to first 
study drug administration 
b) More than 25% of marrow-bearing bone has been irradiated 
c) The patient has not recovered from any resulting acute toxicity to Grade ≤ 1 prior to first 
study drug administration 
For mGC Patients: 
1. Prior treatments before first study treatment: 
a) Investigational therapy within ≤ 28 days or 5 half lives, whatever is longest 
b) Hormonal therapy within 14 days 
c) Trastuzumab within 21 days 
2. Prior enrollment in a trastuzumab emtansine−containing study, regardless of whether 
the patient received prior trastuzumab emtansine 
3. Prior treatment with capecitabine 
4. History of severe and unexpected reactions to fluoropyrimidine or with known 
hypersensitivity to fluorouracil 
5. Related capecitabine contraindications: 
a) Treatment with sorivudine or its chemically related analogues, such as brivudine 
b) Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or 
glucose-galactose malabsorption 
6. History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity to 
trastuzumab or murine proteins 
7. History of exposure to the following cumulative doses of anthracyclines: 
a) Doxorubicin or liposomal doxorubicin > 360 mg/m2 
b) Epirubicin > 900 mg/m2 
c) Mitoxantrone > 120 mg/m2 
d) If another anthracycline, or more than one anthracycline, has been used, the cumulative 
dose must not exceed the equivalent of 360 mg/m2 doxorubicin. 
8. Brain metastases that are symptomatic, or require any radiation, surgery, or steroid 
therapy to control their symptoms within 28 days of first study drug administration 
9. Current peripheral neuropathy of Grade ≥ 3 per the NCI CTCAE, v4.0 
10. History of other malignancy within the last 5 years, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, 
or other cancers with a similar outcome as those mentioned above 
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11. Current unstable ventricular arrhythmia requiring treatment 
12. History of symptomatic CHF (NYHA Classes II−IV) 
13. History of myocardial infarction or unstable angina within 6 months prior to first study 
drug administration 
14. History of a decrease in LVEF to < 40% or symptomatic CHF with previous trastuzumab 
treatment 
15. Severe dyspnea at rest due to complications of advanced malignancy or requiring 
current continuous oxygen therapy 
16. Clinically significant malabsorption syndrome or inability to take oral medication 
17. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary, or metabolic disease) 
18. Major surgical procedure or significant traumatic injury within 28 days before enrollment 
or anticipation of the need for major surgery during the course of study treatment 
19. Current pregnancy or lactation 
20. Current known active infection with HIV, hepatitis B, and/or hepatitis C virus 
a) For patients who are known carriers of HBV, active hepatitis B infection must be ruled 
out based on negative serologic testing and/or determination of HBV DNA viral load per 
local guidelines 
21. Previous chemotherapy for advanced/metastatic disease 
a) Prior adjuvant/neoadjuvant therapy is allowed if at least 6 months has elapsed between 
completion of adjuvant/neoadjuvant therapy and enrolment into the study 
Length of Study 
The duration of the study is estimated to be approximately 4 years. Recruitment is estimated 
to be 2 years for dose finding and the Phase II exploration of efficacy. All patients will be 
followed up until intolerable toxicity, withdrawn consent, death or up to a maximum of 2 
years after the last patient was enrolled in the Phase II part of the study whichever occurs 
first. In case that Dose Level 1 is too toxic, the study may be terminated prematurely. 
End of Study 
Last Patient Last Visit (LPLV) as per definition is the last data collection point that can be 
either a clinic visit or a lab sample (see above length of study). 
Efficacy Outcome Measures 
Efficacy will be evaluated as per RECIST. 
 
Best overall response rate (BORR) 
 
Duration of response (DoR) 
 
Time to response (TTR) 
 
Time to progression (TTP) 
 
Time to treatment failure (TTF) 
 
Progression free survival (PFS) 
 
Clinical benefit rate (CBR) 
 
Overall survival (OS) 
Safety Outcome Measures 
 
Incidence and severity by NCI CTCAE version 4.0 of adverse events (AEs) and serious 
adverse events (SAEs) 
 
Cases and causes of death 
 
Laboratory parameters 
 
Left ventricular ejection fraction (LVEF) 
 
Treatment exposure 
Pharmacodynamic Outcome Measures 
Hospital visit parameters. 
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Pharmacokinetic Outcome Measures 
PK will be evaluated during Phase I for both trastuzumab emtansine and capecitabine (see 
Appendix 1, Schedule of Assessment in the protocol) 
Investigational Medicinal Products 
For mBC Patients: 
Trastuzumab emtansine will be administered every 3 weeks at a dose of 3.6 mg/kg IV. 
The total trastuzumab emtansine dose will be calculated based on the patient’s weight on 
Day 1 of (or up to 3 days before) each cycle with no upper limit. 
Capecitabine will be administered twice a day, orally for 14 days followed by a 7-day rest 
period at the dose levels 1–3 described in the ‘Trial Design’ section. 
Capecitabine tablets should be swallowed with water within 30 minutes after a meal. 
For mGC Patients: 
Trastuzumab emtansine will be administered on Day 1 of a weekly cycle at the dose of 2.4 
mg/kg IV. 
The total trastuzumab emtansine dose will be calculated based on the patient’s weight on 
Day 1 of (or up to 3 days before) each cycle with no upper limit. 
Capecitabine will be administered twice a day, orally for 14 days followed by a 7-day rest 
period at the dose levels 1–3 described in the ‘Trial Design’ section. 
Capecitabine tablets should be swallowed with water within 30 minutes after a meal. 
Non-Investigational Medicinal Products 
Not applicable. 
Statistical Analysis 
The study will include two phases and 2 cohorts: 
Phase I, Cohort 1: mBC Dose Finding Cohort 
Phase II, Cohort 1: mBC Exploration of Efficacy Cohort 
Phase I, Cohort 2: mGC Dose Fining Cohort 
During Phase I, the primary objective is reaching the MTD and establishing a safety profile. 
There is no formal efficacy interim analysis. 
Corresponding analyses as described in the protocol will be performed when all data for 
both cohorts and study phases are collected and cleaned 
Analysis of primary and secondary endpoints: 
Analysis Populations: 
Phase I: MTD Finding: mBC Patients: 
The main analysis population will be the safety population including all patients in this cohort 
who received at least one dose of study medication (trastuzumab emtansine and 
capecitabine) during this phase. 
Phase II: Exploration of Efficacy: mBC Patients 
The main analysis population for the efficacy analysis will be the intent-to-treat population 
(ITT) including all new patients enrolled in Phase II and patients from Cohort 1 who 
achieved the MTD level. The per-protocol (PP) population will include all ITT patients who 
have at least one post-baseline tumor assessment during the Phase II and no major 
protocol violations which will be defined in the statistical analysis plan. Safety parameters 
will be summarized for the safety population that includes all patients who received at least 
one dose of study medication in this part of the study. 
Phase I: MTD Finding, mGC Patients: 
The main analysis population will be the safety population including all patients in this cohort 
who received at least one dose of study medication (trastuzumab emtansine and 
capecitabine) during this phase. 
Efficacy Endpoints: 
Phase I: MTD Finding, mBC 
The primary objectives are reaching the MTD and establishing a safety profile. 
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ORR, as a main efficacy endpoint, will be assessed via BORR. The BOR is defined as the 
best response recorded from the date when the MTD is achieved until disease 
progression/recurrence (or death). The number of patients is very small in this part of the 
study. Therefore, all analyses will be descriptive. 
Due to the small number of patients and the design of this part of the study, no secondary 
efficacy endpoints will be investigated. 
Phase II: Exploration of Efficacy: mBC 
The primary efficacy endpoint for Phase II is the BOR as assessed by investigators. The 
BOR is defined as the best response recorded from the start of this Phase II until disease 
progression/recurrence (or death) or for patients who were involved in Phase I of the study: 
the best response from the date of the MTD reached until disease progression/recurrence or 
death. To be assigned a status of partial response (PR) or complete response (CR), i.e. to 
be a responder, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 28 days 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). 
The number and proportions of responders and non-responders together with two-sided, 
95% Clopper-Pearson confidence intervals will be presented. CBR will be summarized in a 
similar way. 
The secondary endpoints for Phase II will be: 
 
Time to response (TTR) 
 
Duration of response (DoR) 
 
Time to progression (TTP) 
 
Time to treatment failure (TTF) 
 
Progression free survival (PFS) 
 
Clinical benefit rate (CBR) 
 
Overall survival (OS) 
Estimates for the survivor function for the time-to-event variable such as TTR, DoR, TTP, 
TTF, PFS, and OS, will be obtained by using the Kaplan-Meier approach. CBR will be 
summarized in a similar way to the primary efficacy endpoint, BOR. 
Phase I: MTD Finding: mGC 
The primary objectives are reaching the MTD and establishing a safety profile. 
Efficacy endpoints will be analysed in a similar way to Phase I: mBC. 
Safety Endpoints 
Phase I: MTD Finding: mBC 
Safety parameters for this study part will be summarized by treatment dose. The summaries 
of AEs, SAEs, AEs that cause discontinuation from the study treatment will be analyzed in a 
similar way to AEs in Phase II. The summaries will include all patients who received at least 
one dose of study medication. 
The incidence of AEs and SAEs will be summarized according to the primary system-organ 
class (SOC) and within each SOC, by MedDRA preferred term. Patients who died will be 
listed together with the cause of death. 
Laboratory parameters, hematology and biochemistry, will be presented in shift tables of 
NCI-CTC grade at baseline versus worst grade during treatment for Phase I, Cohort 1, and 
overall. 
LVEF will be summarized over time by means of mean, median and range (minimum and 
maximum) and will be presented graphically. Vital signs will be analyzed in a similar way. 
Other safety variables, such as exposure to study medication, concomitant medications and 
physical examinations will be analyzed in a similar way. The exposure of study medication 
will be summarized by frequency tables. 
ECOG performance status will be summarized over time and the percentage of patients in 
different categories will be presented by bar charts at different time points. 
Phase II: Exploration of Efficacy: mBC 
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Safety endpoints during Phase II will be assessed via: total AEs, AEs Grade ≥ 3, SAEs, 
premature withdrawal from study and study medication, laboratory parameters, LVEF, 
exposure to study medication, concomitant medications, vital signs, ECOG performance 
status, and physical examination. 
The incidence of AEs and SAEs will be summarized according to the primary system-organ 
class (SOC) and within each SOC, by MedDRA preferred term. Patients who died will be 
listed together with the cause of death. 
Laboratory parameters, hematology and biochemistry, will be presented in shift tables of 
NCI-CTC grade at baseline versus worst grade during treatment for Phase II, Cohort 1 and 
overall. 
LVEF will be summarized over time by means of mean, median and range (minimum and 
maximum) and will be presented graphically. Vital signs will be analyzed in a similar way. 
Other safety variables, such as exposure to study medication, concomitant medications and 
physical examinations will be analyzed in a similar way. The exposure of study medication 
will be summarized by frequency tables. 
ECOG performance status will be summarized over time and the percentage of patients in 
different categories will be presented by bar charts at different time points. 
Phase I: MTD Finding: mGC 
Safety parameters will be summarized in a similar way to Phase I: mBC. 
Pharmacokinetic Analysis 
The following pharmacokinetic parameters of trastuzumab emtansine and capecitabine (not 
limited to these listed) will be determined only in the Phase I part of the study in 
all patients who receive study treatment using either non-compartmental and/or population 
methods, if data allow: 
 
Serum concentrations of trastuzumab emtansine (conjugate) and total trastuzumab 
 
Plasma concentrations of DM1, capecitabine and its active metabolite 5-fluorouracil (5-
FU) 
 
Total exposure (AUC)  
 
Cmax  
 
Clearance (CL)  
 
Volume of distribution (Vd)  
 
Terminal half-life (T1/2) 
All PK parameters will be listed and tabulated by treatment dose and by Cohort. Descriptive 
summary statistics including arithmetic mean, geometric mean (e.g. AUC and Cmax), median, 
range, standard deviation (SD) and coefficient of variation will be presented for each Cohort. 
Nonlinear mixed effects modeling will be also used but details will be presented in the 
statistical anal analysis plan. 
Exploratory Analyses 
Subgroup analysis for BOR, safety (AEs, SAEs and AE with Grade ≥ 3) in Phase II will be 
presented for: elderly versus younger patients, patients with ECOG 0–1 versus ECOG 2. 
More details will be presented in the statistical analysis plan. 
Pharmaceconomic Endpoint 
The number of hospital visits, number of days admitted, and type of visits (emergency 
department versus inpatient care) will be collected and compared. The reason for admission 
(disease progression versus AE) will also be assessed. 
Determination of Sample Size 
Sample Size for Phase I: MTD Finding: mBC 
This part will be based on a classical 3 by 3 Phase I design. From 3 to 18 patients might be 
enrolled in Cohort 1. There is no formal sample size estimation for this part. 
Sample Size for Phase II: Exploration of Efficacy: mBC 
Assuming a preferable BORR of 75% to 80% in Cohort 1 (mBC patients) and aiming for a 
precision of 8-10%, lower limit of 95% confidence interval of at least 65%, a total of 100 
patients would need to be evaluable for Cohort 1. 
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Table 1: Sample Size Estimation 
Total number of patients is 100 (Phase II) 
Number of Patients/ Response 
95% Clopper-Pearson 
Confidence Intervals 
75 patients (75%) 
65% - 83 % 
80 patients (80%) 
71% - 87% 
 
 
Total number of patients adjusted for 10% withdrawal rate is 
110 patients 
For example, the observed BOR of 75% could be estimated to be within 65% and 83% with 
a probability of 95% (Clopper-Pearson exact confidence intervals). Adjusting for a 
withdrawal rate of approximately 10%, 110 patients will be enrolled in this phase. 
The BOR rate of 75% is chosen based on the previously published data with trastuzumab 
and capecitabine (see protocol for reference) 
The estimation of Sample Size is performed by Nquery and SAS programs. 
Sample Size for Phase I: MTD Finding: mGC 
This part will be based on a classical 3 by 3 Phase I design. From 3 to 18 patients might be 
enrolled in Cohort 2. There is no formal sample size estimation for this part. 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADL 
activities of daily living 
AE 
adverse event 
ADC 
antibody-drug conjugate 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ARDS 
acute respiratory distress syndrome 
AST 
aspartate transaminase 
AUC 
area under the serum concentration-time curve 
BC 
breast cancer 
bid 
twice daily 
BML 
below measurable limit 
BOR 
best overall response 
BORR 
best overall response rate 
BUN 
blood urea nitrogen 
CBR 
clinical benefit rate 
CHF 
congestive heart failure 
CI 
confidence interval 
CL 
clearance 
Cmax 
maximum concentration 
CR 
complete response 
CRO 
contract research organization 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose limiting toxicity 
DoR 
duration of response 
DPD 
dihydropyrimidine dehydrogenase 
5`DFUR 
5’-deoxy-5-fluorouridine 
5`FU 
5-fluoruracil 
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 
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FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
GC 
gastric cancer 
GCP 
Good Clinical Practice 
GEJ 
gastroesophageal junction 
HER2 
human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
hazard ratio 
HIV 
human influenza virus 
ICH 
International Conference on Harmonisation 
IHC 
immunohistochemistry 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
IxRS 
interactive voice/web recognition system 
LVEF 
left ventricular ejection fraction 
mBC 
metastatic breast cancer 
mGC 
metastatic gastric cancer 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multiple-gated acquisition (scan) 
NCI 
National Cancer Institute 
NE 
not evaluable 
ORR 
overall response rate 
OS 
overall survival 
PD 
pharmacodynamic/progressive disease 
PET 
positron emission tomography 
PFS 
progression free survival 
PK 
pharmacokinetic 
PP 
per-protocol 
PR 
partial response 
QTcF 
heart rate-corrected QT interval using the Fridericia 
formula 
q3w 
every 3 weeks 
qw 
weekly 
RECIST 
Response Evaluation Criteria for Solid Tumors 
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SAE 
serious adverse event 
SGOT 
serum glutamic oxaloacetic transaminase 
SD 
standard deviation 
SGPT 
serum glutamic pyruvic transaminase 
SWFI 
sterile water for injection 
T1/2 
terminal half-life 
TTF 
time to treatment failure 
TTP 
time to progression 
TTR 
time to response 
ULN 
upper limit of normal 
V 
volume of distribution 
WBC 
white blood cells 
WHO 
World Health Organization 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON DISEASE 
1.1.1 
HER2-POSITIVE BREAST CANCER, 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 
human epidermal growth factor receptor 2 (HER2) receptors. 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 
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capecitabine resulted in an increased response rate (24% versus 14%) and 
time to disease progression (6.2 months versus 4.3 months) (Geyer et al. 
2006). 
Capecitabine (Xeloda®) in combination with docetaxel for treatment of patients 
with locally advanced or mBC after failure of cytotoxic chemotherapy, 
including an anthracycline was studied in a multicenter, randomized, 
controlled Phase III clinical trial (SO14999). In this trial, 255 patients were 
randomized to treatment with capecitabine (1250 mg/m2 twice daily (bid) for 2 
weeks followed by a 1-week rest period) and docetaxel (75 mg/m2 as a 1-hour 
intravenous [IV] infusion every 3 weeks). A total of 256 patients were 
randomized to treatment with docetaxel alone (100 mg/m2 as a 1-hour IV 
infusion every 3 weeks). Survival was superior in the capecibabine plus 
docetaxel combination arm (p = 0.0126). Median survival was 442 days 
(capecitabine plus docetaxel) versus 352 days (docetaxel alone). The overall 
objective response rates in the all-randomized population (investigator 
assessment) were 41.6% (capecitabine plus docetaxel) versus 29.7% 
(docetaxel alone); p = 0.0058. Time to progression (TTP) of disease or 
number of deaths was superior in the capecitabine plus docetaxel 
combination arm (p < 0.0001). The median TTP was 186 days (capecitabine 
plus docetaxel) versus 128 days (docetaxel alone). 
Two multicenter Phase II clinical trials were conducted to determine the use of 
capecitabine monotherapy for treatment of patients with locally advanced or 
mBC after failure of a taxane and an anthracycline-containing chemotherapy 
regimen or for whom further anthracycline therapy is not indicated. In these 
trials, a total of 236 patients were treated with capecitabine (1250 mg/m2 bid 
for 2 weeks followed by 1-week rest period). The overall objective response 
rates (investigator assessment) were 20% (first trial) and 25% (second trial). 
The median TTP was 93 and 98 days. Median survival was 384 and 373 days 
(Blum et al. 1999; Blum et al. 2001). 
1.1.2 
HER2-POSITIVE LOCALLY ADVANCED OR METASTATIC 
GASTRIC CANCER 
Gastric cancer (GC) remains one of the most common malignancies in the 
world with an estimated 989,600 new cases in 2008 (Jemal et al. 2011). GC 
also continues to be a deadly disease; it is the second leading cause of 
cancer-related death accounting for 738,000 deaths (9.7% of all cancer 
deaths) worldwide in 2008 (Ferlay et al. 2010). The only potentially curative 
treatment for GC is complete resection of localized disease. The overall 5-
year survival for all cases, regardless of initial stage at diagnosis, is less than 
25% (Catalano et al. 2005; Faivre et al. 1998; Parkin et al. 2005; Power et al. 
2010). Among patients with localized disease who undergo curative surgery, 
approximately 40–60% will have disease recurrence. Patients with 
unresectable disease due to locally advanced growth or metastatic spread 
have the poorest prognosis, with an overall 5-year survival in the range of 3–
15% (De Vivo et al. 2000; Ries et al. 2008; Power et al. 2010).  
Whereas HER2 overexpression is associated with a poor prognosis in BC, the 
prognostic significance of HER2 overexpression in GC is not fully defined. 
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Studies of HER2 positivity rates in GC have shown a broad variation of HER2 
positivity ranging from 6.8–34.0% for immunohistochemistry (IHC) and 7.1–
42.6% for fluorescence in situ hybridization (FISH) techniques (Hofmann et al. 
2008; Tanner et al. 2005). In a recent study, HER2 positivity was shown in 
17% of resected esophageal adenocarcinomas and was significantly 
associated with lower tumor grade, less invasiveness, fewer malignant nodes, 
and the presence of adjacent Barrett's esophagus (Yoon et al. 2012). 
In the ToGA trial (study BO18255), a global, Phase III study of trastuzumab 
plus chemotherapy as first-line treatment for advanced HER2-positive GC, an 
overall HER2-positivity rate of 22.1% was observed (810/3667 evaluable 
samples), which is comparable to BC. A higher HER2-positivity rate was seen 
in adenocarcinoma of the gastroesophageal junction (GEJ) than in the 
stomach (33.2% versus 20.9%), and intestinal type GCs showed a 
significantly higher HER2-positivity rate than diffuse or mixed-type tumors 
(intestinal: 32.2%, diffuse: 6.1%, mixed: 20.4%) (Albarello et al. 2011; Bang et 
al. 2010).  
In the ToGA trial (study BO18255), the addition of trastuzumab to 
chemotherapy (capecitabine or fluorouracil combined with cisplatin) for the 
treatment of patients with HER2-positive (defined as IHC 3+ or FISH positive), 
inoperable, locally advanced or recurrent and/or metastatic adenocarcinoma 
of the stomach or GEJ resulted in an increase in the median overall survival 
([OS]; 13.8 months versus 11.1 months, hazard ratio [HR] 0.74, p = 0.0046), 
objective response rate (47% versus 35%), PFS (6.7 versus 5.5 months), and 
TTP (7.1 versus 5.6 months) compared with chemotherapy alone (Bang et al. 
2010). 
1.2 
BACKGROUND ON STUDY DRUGS  
1.2.1 
TRASTUZUMAB EMTANSINE 
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, 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, 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, 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). 
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trastuzumab emtansine Investigator’s Brochure for further information on all of 
the completed and ongoing trastuzumab emtansine studies. 
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 (qw) schedule. 
On the q3w dosing schedule, dose limiting toxicities 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. On the qw schedule, 2.4 mg/kg was 
identified as the MTD (Krop et al. 2008). 
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 (IV) q3w in 
HER2-positive mBC patients 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 Independent Review Committee (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 
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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. 
The most common adverse events (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 dyspnoea (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 neoadjuvant, 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 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 was 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 aspartate 
transaminase (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%). Serious 
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AEs 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 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 TDM4450g 
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 breast cancer 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. 
As of 15 November 2010, the PFS was 14.2 months in the trastuzumab 
emtansine arm versus 9.2 months in the trastuzumab plus docetaxel arm. The 
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 serious AEs 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 breast cancer or mBC 
was evaluated in study TDM4688g, and had no meaningful effect on the 
corrected QT interval in these patients. At Cycle 1 Day 1, 15 minutes post-
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infusion, the baseline-adjusted average heart rate-corrected QT interval using 
the Fridericia formula (QTcF) increased by 1.2 ms on average. By 60 minutes 
post-infusion, the baseline-adjusted average QTcF interval decreased by 1.0 
ms on average, and by Day 8 of Cycle 1, the baseline-adjusted average QTcF 
interval decreased by 4.0 ms on average. By Cycle 3 Day 1, prior to 
trastuzumab emtansine infusion, the average QTcF interval had reverted back 
to baseline on average. 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, an 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 
Phase III Study TDM4370g 
Roche is conducting a randomized, open-label Phase III trial (TDM4370g) 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. The study is ongoing, enrollment is completed, and 991 
patients have been enrolled. 
Patients are randomized in a 1:1 ratio to trastuzumab emtansine or 
capecitabine plus lapatinib. 
Trastuzumab emtansine is administered at 3.6 mg/kg IV every three weeks. 
The control arm treatment is capecitabine at 1000 mg/m2 as oral doses bid on 
Days 1–14 of a q3w cycle plus oral lapatinib 1250 mg/day given as 
continuous dosing. Study treatment is discontinued based on disease 
progression (as assessed by the investigator), unmanageable toxicity or study 
termination by Roche/Genentech. 
PFS and OS are 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 is performed after investigator-
documented disease progression. Furthermore ORR, DoR, and CBR are 
included, on the basis of both investigator and independent review of tumor 
assessments, as key secondary endpoints. 
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This trial has met its co-primary endpoint of improving PFS (by independent 
review committee) compared to those who received the combination of 
lapatinib and capecitabine. 
PFS was 9.6 months in the trastuzumab emtansine arm versus 6.4 months in 
the lapatinib and capecitabine arm. OS has not yet been reached in the 
trastuzumab emtansine arm while in the control arm the OS was 23.3 months. 
The HR for PFS was 0.650 (95% CI: 0.55, 0.77; p = 0.0001). The ORR in the 
trastuzumab emtansine arm was 43.6% (95% CI: 38.6, 48.6) compared with 
30.8% (95% CI: 26.3, 35.7) in the control arm (based on 786 evaluable 
patients). 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; that of trastuzumab 
emtansine (40.8%; n = 490) was 200. The rates of SAEs for both arms were 
similar (control arm 18% versus trastuzumab emtansine 15.5%). 
It is concluded that overall, there is no concern regarding the clinical safety of 
trastuzumab emtansine based on the currently available data. 
1.2.1.7 
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 qw 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; SD = standard deviation; 
T1/2 = terminal half-life; V = volume of distribution. 
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 q3w cycle with a 2.4 mg/kg qw regimen 
compared to 3.6 mg/kg q3w (Krop et al. 2009, Krop et al 2010). 
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). 
An aggregate PK assessment of trastuzumab emtansine was done with 
samples from studies TDM3569g, TDM4258g, TDM4374g, and TDM4688g 
(Girish et al. 2012; Igawa 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 
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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., maximum concentration [Cmax], area under the serum 
concentration-time curve [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. Weekly administration of trastuzumab emtansine in study 
TDM3568g at a dose of 2.4 mg/kg showed consistent PK data with the q3w 
dosing schedule (Krop et al. 2008). 
1.2.2 
CAPECITABINE 
Capecitabine (Xeloda®) is a fluoropyrimidine carbamate with antineoplastic 
activity. It is an orally administered systemic prodrug of 5’-deoxy-5-
fluorouridine (5’-DFUR) which is converted to 5-fluorouracil in the tumor, 
where it inhibits DNA synthesis and slows down tumor tissue growth. It has 
been evaluated in clinical trials in combination with docetaxel and as 
monotherapy in BC (Geyer et al. 2006; Wardley et al. 2006; von Minckwitz et 
al. 2011). Please see the national Xeloda® prescribing information or 
Investigator brochure for more information. 
1.2.2.1 
Study BO18255: Capecitabine and Trastuzumab in mGC 
Recently, a global phase III study (ToGA trial, BO18255) of trastuzumab plus 
chemotherapy as first-line treatment for advanced HER2-positive GC was 
conducted in 584 patients previously untreated for HER2-positive inoperable 
locally advanced or recurrent and/or metastatic adenocarcinoma of the 
stomach or GEJ. Patients received either capecitabine or fluorouracil 
combined with cisplatin or the same chemotherapy in combination with 
trastuzumab. The primary study endpoint was OS, defined as the time from 
the date of randomization to the date of death from any cause. At the time of 
the analysis a total of 349 randomized patients had died: 182/290 patients 
(62.8%) in the control arm and 167/294 patients (56.8%) in the treatment arm. 
The majority of the deaths were due to events related to the underlying cancer 
(Bang et al. 2010). 
Most patients enrolled in the study were male (76%); 52.9% were Asian and 
37.7% were white. The primary tumor site was the stomach for 81.8% of 
patients, with the others having GEJ tumors. The addition of trastuzumab to 
chemotherapy resulted in an increase in median OS from 11.1 months to 13.8 
months (HR 0.74, p = 0.0046). Objective response rate (47% versus 35%), 
PFS (6.7 versus 5.5 months), and TTP (7.1 versus 5.6 months) were also 
significantly increased with the addition of trastuzumab to chemotherapy 
compared to chemotherapy alone. 
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With regard to OS, a treatment effect could not be excluded in any predefined 
subgroup, including primary tumor site, histologic subtype, method of 
determining HER2-positivity, performance status, chemotherapy regimen, age, 
gender, and region of enrollment. A multivariate analysis for OS showed a 
consistent result, with an adjusted HR of 0.72 (p = 0.0036); variables found to 
influence primary outcome included Eastern Cooperative Oncology Group 
(ECOG) performance status (0 or 1 versus 2), prior gastrectomy, and Asian 
region of enrollment (data on file). A multivariate analysis of OS for patients 
enrolled in Japan, from which the bulk of Asian patients were enrolled, 
demonstrated a HR of 0.68. This was consistent with the overall study results 
(Sawaki et al. 2011). 
A pre-planned subgroup analysis by IHC score indicated that positive 
treatment effects are greater in tumors with higher levels of HER2 expression. 
Among patients whose tumors had these higher levels of HER2 expression, 
the median OS was 11.8 months versus 16 months (HR 0.65; 95% CI 0.51–
0.83) and median PFS was 5.5 months versus 7.6 months (HR 0.64; 95 % CI 
0.51–0.79) for chemotherapy versus chemotherapy plus trastuzumab 
respectively. For OS, the HR was 0.75 (95% CI 0.51–1.11) in the IHC 
2 + /FISH + group and 0.58 (95% CI 0.41–0.81) in the IHC 3+/FISH+ group 
(Bang et al. 2010). 
The addition of trastuzumab to chemotherapy did not result in an increased 
incidence of severe (Grade 3–4) or fatal (Grade 5) AEs. There were no 
additional significant safety issues with trastuzumab used in the treatment of 
advanced GC over and above those observed when it was used to BC. Taken 
together, the results of the ToGA trial (BO18255) not only demonstrate the 
role of HER2 suppression in the treatment of HER2-positive GC but also show 
that HER2-directed therapies can be added to conventional chemotherapy 
regimens without substantial increases in toxic side effects. 
1.2.3 
PRECLINICAL DATA OF THE COMBINATION OF 
TRASTUZUMAB EMTANSINE AND A FLUOROPYRIMIDINE 
In breast cancer preclinical models an additive anti-tumor activity was 
observed with combinations of trastuzumab emtansine and 5FU (see Figure 2, 
[Lewis Phillips et al. 2008]). In GC models a similar additive effect was 
observed with trastuzumab emtansine and capecitabine (see Figure 3, [data 
on file]). 
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Figure 2 MMTV HER2 Fo5 Mammary Tumor Transplants 
 
T-DM1 = trastuzumab emtansine; 5-FU = 5-fluoruracil 
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In study TDM4450g, trastuzumab emtansine as a single agent showed a 
significant increase in PFS compared to the current standard of care of 
trastuzumab and a taxane (see Section 1.2.1.4), together with a favorable 
safety profile. 
The Phase III, TDM4370g trial met its co-primary endpoint of improving PFS 
(by IRC) compared to those who received the combination of lapatinib and 
capecitabine (see Section 1.2.1.6). 
Based on the mentioned studies, the combination of trastuzumab emtansine 
and capecitabine could provide the potential for enhanced anti-tumor efficacy 
in mBC, compared to single agent trastuzumab emtansine or trastuzumab in 
combination with chemotherarapy. 
Furthermore, preclinical data suggest that the combination of trastuzumab 
emtansine and capecitabine has an additive effect (see Section 1.2.3). 
Approximately 2000 patients with breast cancer have been treated in 
trastuzumab emtansine clinical trials with an acceptable safety profile and a 
positive risk-benefit ratio. A safety monitoring is in place to avoid potential 
overlapping toxicities. A broad development program is in place to seek 
approval for indications for mBC. Capecitabine in combination with anti-HER2 
agent is a proven efficacious regimen with a well established safety profile in 
mBC. Trastuzumab emtansine and capecitabine have no known significant 
overlapping toxicities. Therefore, exploring the benefit of combination therapy 
of trastzumab emtansine and capecitabine in mBC patients seems justified. 
1.3.2 
FOR MGC 
As for mBC, the primary goal of treatment for metastatic gastric cancer (mGC) 
is the maximizing of the patient’s survival and quality of life. 
HER2-positive gastric tumors have shown to benefit from anti-HER2 therapy. 
Regimens using the combination of anti-HER2 agents and chemotherapy 
have demonstrated higher efficacy than single agent therapy. As a 
consequence several different combination therapies have been approved for 
HER2-positive mGC treatment in most countries and are considered the 
current standard of care. 
In HER2-positive mGC, the ToGA study (BO18255) has proven that the 
combination of chemotherapy and trastuzumab significantly improves OS (see 
Section 1.2.2.1) in this population. Fluropyrimidine based therapies 
(capecitabine, 5-fluorouracil) are the standard of care in mGC in general and 
were also the most frequent combination agents used in the ToGA trial 
(BO18255) (see Section 3.3.2). 
Furthermore, preclinical data suggest that the combination of trastuzumab 
emtansine and capecitabine has an additive effect (see Section 1.2.3). 
A development program for trastuzumab emtansine is in place to seek 
approval for mGC indications. Capecitabine in combination with anti-HER2 
agent is a proven efficacious regimen with a well established safety profile in 
mGC. Trastuzumab emtansine and capecitabine might have overlapping 
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toxicities and therefore a safety monitoring is in place to avoid exposing 
patients to harm. Therefore, exploring the benefit of combination therapy of 
trastzumab emtansine and capecitabine in mGC patients seems justified. 
2. 
OBJECTIVES 
2.1 
PHASE I: MTD FINDING OF TRASTZUMAB 
EMTANSINE AND CAPECITABINE IN MBC 
2.1.1 
PRIMARY OBJECTIVE 
 
To determine the MTD of the combination of trastuzumab emtansine and 
capecitabine in mBC patients 
2.1.2 
SECONDARY OBJECTIVES 
 
Pharmacokinetics of trastuzumab emtansine and metabolites and 
capecitabine 
 
Safety of the combination of trastuzumab emtansine and capecitabine 
 
Overall response rate (ORR) 
2.2 
PHASE II: EXPLORATION OF EFFICACY IN MBC 
PATIENTS 
2.2.1 
PRIMARY OBJECTIVE 
 
ORR by investigator assessment 
2.2.2 
SECONDARY OBJECTIVES 
 
Safety profile of the combination at the dose established during Phase I 
 
Time to response (TTR)  
 
Duration of response (DoR) 
 
Time to progression (TTP) 
 
Time to treatment failure (TTF) 
 
Progression free survival (PFS) 
 
Clinical benefit rate (CBR) 
 
Overall survival (OS) 
2.3 
PHASE I: MTD FINDING OF TRASTZUMAB 
EMTANSINE AND CAPECITABINE IN MGC 
2.3.1 
PRIMARY OBJECTIVE 
 
To determine the MTD of the combination of trastuzumab emtansine and 
capecitabine in mGC patients 
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2.3.2 
SECONDARY OBJECTIVES 
 
Pharmacokinetics of trastuzumab emtansine and metabolites and 
capecitabine 
 
Safety of the combination of trastuzumab emtansine and capecitabine 
 
Overall response rate (ORR) 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is an international, multicenter Phase I/II dose finding study of two dosing 
schedules of trastuzumab emtansine and capecitabine combination therapy in 
HER2-positive mBC and locally advanced or mGC patients. The study is 
designed to determine the MTD of capecitabine in combination with 
trastuzumab emtansine in a Phase I study in both mBC and locally advanced 
or mGC patients. The MTD will also be assessed for anti-tumor effects 
(exploration of efficacy) in a Phase II, single arm study in the mBC cohort. 
There will be no exploration of efficacy in the mGC cohort. 
3.1.1 
OVERVIEW OF STUDY DESIGN 
Overview of Study Design 
The study is designed to determine the MTD of capecitabine in combination 
with trastuzumab emtansine, in HER2-positive mBC and locally advanced or 
mGC patients, using a Phase I design, followed by a Phase II single arm 
study to explore the efficacy of the combination in mBC patients. There will be 
no exploration of efficacy in the mGC cohort. Results from the Phase I in 
mGC will be used as supporting information for future studies in the indication. 
Cohort 1 for mBC patients will open first and MTD will be established. Once 
MTD is established, both Phase II for mBC patients and Cohort 2 for mGC 
patients will open. 
An overview of the study design is depicted in Figure 4. 
Duration of Treatment and Patient Follow-up 
Length of treatment: All patients will be treated until disease progression, 
intolerable toxicity, withdrawal of consent, or death. 
Patient follow-up: All patients from both cohorts will be followed up until 
intolerable toxicity, withdrawn consent, death or up to a maximum of 2 years 
after the last patient was enrolled in the Phase II part of the study, whichever 
occurs first. 
Duration of Study, Data Base Closure and Data Reporting 
The duration of the study is estimated to be approximately 4 years. 
Recruitment is estimated to be 2 years for dose finding and the Phase II/ 
Exploration of Efficacy. The study will end after the follow-up period was 
completed, as defined above. Last patient last visit (LPLV) is defined as the 
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last data collection point that can be either a clinic visit or a lab sample. At that 
time point, the database will be closed. 
In the case that in Cohort 1 the dose level 1 is too toxic (>1/3 or >1/6 of dose 
limiting toxicity [DLT]), the combination may be considered unfeasible. 
Enrollment will be closed and no other cohort will be opened. Patients, who at 
that point, experience response as per RECIST will be offered the possibility 
to continue on trastuzumab emtansine as a single agent. 
Data may be reported at the end of each cohort i.e. once the MTD for Cohort 
1 has been defined and the dose for Phase II/Exploration of Efficacy has been 
selected. The latest point to write the Clinical Study Report (CSR) will be one 
year after database closure. 
Treatment of Patients after Database Closure 
If at the moment of study closure there are patients who have not progressed 
and are still receiving study treatment, they will be offered the possibility to 
continue treatment by enrolling in an extension study. 
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Figure 4 Overview of Study Design 
 
 
COHORT 1 mBC 
 
COHORT 2 mGC 
Phase I 
Dose Finding 
 
 
n = ~3–18 
3 by 3 classical design 
T-DM1: 3.6 mg/kg q3w 
Capecitabine: 1–3 dose levels1 
 
 
 
n = ~3–18 
3 by 3 classical design 
T-DM1: 2.4 mg/kg qw 
Capecitabine: 1–3 dose 
levels1,3 
 
 
 
Phase II 
Exploration 
of Efficacy 
 
 
n=1104 
Single arm 
TDM-1: 3.6 mg/kg q3w 
Capecitabine: MTD defined 
 
 
 
1 Capecitabine doses are administered daily on days 1 to 14 of the 3-week cycles  
2 The MTD defined in mBC Phase I will be implemented in mBC Phase II and mGC Phase I 
3 Cohort 2 will open to recruit mGC patients once the MTD is defined in Phase I for mBC 
patients 
4 Patients on MTD in Phase I must re-consent, recruitment will be extended to 110 mBC 
patients 
mBC = metastatic breast cancer; mGC = metastatic gastric cancer; MTD = maximum 
tolerated dose; q3w = every 3 weeks; qw = weekly; T-DM1 = trastuzumab emtansine 
 
A schedule of assessments is provided in Appendix 1. 
MTD defined2 
MTD defined2 
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3.1.1.1 
Overview of Phase I Design in mBC Patients 
An overview of the Phase I study design is depicted in Figure 5. 
Figure 5  Overview of Phase I Dose Finding Study Design 
0 DLT 
1/3 DLT 
>1 DLT 
STOP 
MTD1 Previous level 
1/6 DLT 
Escalate Dose level X+1 
n=3 
Dose level X 
n=3 
Expand (+3) 
N=6 
>1/6 DLT 
STOP 
MTD Previous level 
1 If Dose level 1 is too toxic (>1/3 or >1/6 DLT), the study will be terminated. 
DLT = dose limiting toxicity; MTD = maximum tolerated dose 
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Determination of the Maximum Tolerated Dose in mBC Patients 
The trial will first investigate the feasibility of the combination of capecitabine 
and trastuzumab emtansine q3w in one cohort up to 18 patients, by escalating 
the dose of capecitabine from 750 mg/m2 bid to 1000 mg/m2 bid on days 1 to 
14 in cycles of 3 weeks with a 3 by 3 classical Phase I design. Cohort 1 will 
open first and enroll patients with HER2-positive mBC. 
Enrollment into Cohort 1 
Dose finding in mBC patients (Phase I) 
According to the 3 by 3 classical study design, Cohort 1 will start with the 
enrollment of 3 patients at dose level 1. Patients will be evaluated for DLTs as 
specified in DLT definition (see Section 5.1.4). The dose tested of 
trastuzumab emtansine will remain fixed at 3.6 mg/kg q3w and 3 dose levels 
of capecitabine administered bid on days 1 to 14 in 3-week cycles will be 
tested. 
The following doses will be explored in Cohort 1: 
 
Dose level 1: 750 mg/m2 capecitabine bid plus 3.6 mg/kg q3w 
trastuzumab emtansine 
 
Dose level 2: 850 mg/m2 capecitabine bid plus 3.6 mg/kg q3w 
trastuzumab emtansine 
 
Dose level 3: 1000 mg/m2 capecitabine bid plus 3.6 mg/kg q3w 
trastuzumab emtansine 
If dose level 1 is found to be too toxic (DLT >1/3 or >1/6), the enrollment will 
be closed and the study will be terminated. The following escalation rules will 
be applied during the dose finding treatment phase: 
 
Step 1: Three patients will be enrolled at dose level 1 
 
Step 2: The toxicity of dose level 1 will be monitored and the following 
actions taken: 
a) If none of these three patients (0/3) experiences a DLT, escalation to 
dose level 2 will occur 
b) If one of the initial three patients (1/3) experiences a DLT, an additional 
three patients should be enrolled and treated at the same dose, i.e. 
dose level 1 
c) If no more patients experience a DLT (1/6), escalation to the next dose 
level will occur 
d) If one or more patients experience a DLT (>1/6), the MTD will be 
established as the immediate inferior dose level or the study may be 
terminated if it happens at dose level 1. 
 
Step 3: Step 2 should be repeated until the MTD is reached 
 
If the last dose exceeds the MTD, de-escalation to the previous dose 
should occur. This dose should be defined as MTD if 6 or more patients 
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have been safely treated at this dose level and no more than 1/6 of the 
patients experienced a DLT at that dose level. 
 
If only 3 patients have been treated at this dose level, then 3 more 
patients will be treated and observed at this level in order to achieve at 
least 6 patients treated at the same dose level. 
 
In order to define the dose for the Phase II/exploration of efficacy part of 
the study, the Steering Committee will evaluate not only the DLTs during 
Cycle 1 but also all available safety information during the subsequent 
cycles. The dose level considered optimal by the Steering Committee will 
be the dose level selected to move forward with in the Phase II and mGC 
parts of the study. 
Once the appropriate dose of study medication is established, the other 
cohorts will open as per Figure 4. 
3.1.1.2 
Overview of Phase II: Exploration of Efficacy in mBC 
Patients 
Once the Steering Committee has defined the MTD to treat patients in Phase 
II, additional 90–100 mBC patients will be enrolled. 
Only the mBC patients who have received the MTD dose from Phase I will 
continue with the Phase II part of the study to assess efficacy and safety of 
this treatment combination of capecitabine and trastuzumab emtansine. 
See Section 3.1.1 for further information. 
3.1.1.3 
Overview of Phase I Design in mGC Patients 
Determination of MTD in mGC patients 
Cohort 2 will open when the capecitabine MTD is established for Cohort 1 and 
enroll HER2-positive locally advanced and mGC patients. Trastuzumab 
emtansine will be administered qw at the fixed dose of 2.4 mg/kg and 
capecitabine will be started at the MTD defined for mBC patients in Cohort 1. 
See Section 3.1.1 for further information. 
Enrollment into Cohort 2 
Cohort 2 will open with a 3 by 3 classical design to investigate the feasibility of 
combination therapy of capecitabine and trastuzumab emtansine in Cohort 2 
(enrolling up to 18 mGC patients) by escalating or de-escalating the dose of 
capecitabine starting from the MTD determined in Cohort 1. In case the MTD 
was not established or the enrollment was stopped for Cohort 1, enrollment 
into Cohort 2 will not take place.  
The dose levels for escalation or de-escalation of capecitabine will be the 
same as described for Cohort 1: 
a) If the MTD in Cohort 1 was defined at dose level 1 of 750 mg/m2 bid 
o 
If dose level 1 is tolerated, doses should be escalated to dose level 2 
of 850 mg/m2 bid 
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o 
If dose level 1 is not tolerated (>1/3 or >1/6 DLT), the combination will 
be considered not feasible and Cohort 2 will be terminated 
b) If the MTD in Cohort 1 was defined at dose level 2 of 850 mg/m2 bid 
o 
If dose level 2 is tolerated, doses should be escalated to dose level 3 
of 1000 mg/m2 bid 
o 
If dose level 2 is not tolerated, doses should be de-escalated to dose 
level 1 of 750 mg/m2 bid 
c) If the MTD in Cohort 1 was defined at dose level 3 of 1000 mg/m2 bid 
oIf dose level 3 is tolerated, no escalation will be done and the MTD will 
be defined at dose level 3 
oIf dose level 3 is not tolerated, doses should be de-escalated to dose 
level 2 of 850 mg/m2 bid 
3.1.1.4 
Considerations for all Patients Treated in the Study 
Safety data will be reviewed on an ongoing basis (i.e. real time safety 
monitoring) by the Steering Committee. The preliminary safety review will be 
based on the safety information (DLTs, dose delays, dose reductions and 
Grade 3–5 events) observed during the first cycle in at least 3 patients. 
3.1.1.5 
Number of Patients 
Overall, it is anticipated that the maximum number of patients enrolled into the 
study will be 140 patients. 
Phase I: mBC 
From 3–18 patients will be enrolled into Cohort 1 to determine the MTD of 
capecitabine in combination with trastuzumab emtansine in mBC patients. 
Phase II: Exploration of Efficacy in mBC 
For this part of the study, Cohort 1 will be expanded to 110 mBC patients. 
Phase I: mGC 
After the MTD in Cohort 1 has been established, 3–18 patients will be enrolled 
into Cohort 2 to determine the MTD of capecitabine in combination with 
trastuzumab emtansine in mGC patients. 
3.1.1.6 
Number of Centers 
This is a multicenter, international study. 
3.1.2 
STEERING COMMITTEE 
A Steering Committee has been established for this study. Initially, it is 
composed of the investigators participating in the Phase I Cohort 1 part of the 
study and one medical representative and one statistician of the Sponsor. The 
study design and DLT has been developed by the Steering Committee. See 
Steering Committee Charter for further information. 
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3.2 
END OF STUDY 
End of study is defined as LPLV at the end of the follow-up period as defined 
in Section 3.1.1. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
RATIONALE FOR PATIENT GROUP SELECTION 
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 
therapy (see the Herceptin® national prescribing information). Measurement of 
HER2 gene amplification has traditionally been performed using IHC 
measurement. HER2 gene amplification determined by FISH has also proven 
to be a reliable method for demonstrating HER2-positive status (Press et al. 
2005). 
This study will enroll patients diagnosed with the disease to which the 
combination is intended. The combination of anti-HER2 agent and 
capecitabine has shown to be efficacious in both mBC (von Minckwitz et al. 
2011; Geyer et al. 2006) and mGC (Bang et al. 2010), and capecitabine is a 
standard of care treatment for both diseases. Both diseases have been shown 
to benefit from anti-HER2 treatment; therefore, all patients must be diagnosed 
with HER2-positive disease. Patients with incurable mBC and locally 
advanced or mGC whose tumors are positive for HER2 overexpression 
represent the patient population eligible for study enrollment. 
3.3.1.1 
Rationale for Phase I 
The study design of 3 by 3 Phase I is well established and well known method 
for Phase I studies. PK parameters will be collected and analyzed in order to 
investigate the PK interaction of the drugs under investigation. Since both 
agents are administered at efficacious doses, the risk of enrolling patients at 
the sub-optimal doses is minimal. 
3.3.1.2 
Rationale for Phase II 
Phase II is designed to provide an estimation of the treatment effect of the 
combination at the selected MTD. In addition, it will provide important 
information on the longer term safety of the combination. 
3.3.2 
RATIONALE FOR INVESTIGATIONAL MEDICINAL DOSE 
SELECTION 
3.3.2.1 
In mBC Patients 
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 
pre-treated HER2-positive mBC (protocol TDM4258g and protocol TDM4374g) 
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and in patients who had not received prior chemotherapy for metastatic 
disease (TDM4450g). 
Capecitabine doses have been selected as being in the range of efficacious 
doses for single agent or combination use. The dose of 750 mg/m2 bid was 
considered the minimum efficacious dose. The maximum dose of 1000 mg/m2 
bid is the currently approved dose of capecitabine (please see the current 
national prescribing information of Xeloda®). 
3.3.2.2 
In mGC Patients 
In the ToGA study (BO18255: trastuzumab in combination with chemotherapy 
in mGC), patients with higher drug exposure had a greater benefit compared 
to those with lower exposure (Yang et al. 2011). As a consequence, a 
randomized, open label, multicenter Phase IIIb study comparing two 
trastuzumab dosing regimens, each in combination with cisplatin/capecitabine 
chemotherapy, as first line therapy in patients with HER2-positive metastatic 
gastric or gastro-esophageal junction adenocarcinoma is being conducted 
(Study BO27798). 
In TDM3569g (see Section 1.2.1.1), the qw administration of 2.4 mg/kg of 
trastuzumab emtansine resulted in higher exposure (see Section 1.2.1.7) 
(Krop et al. 2008). Therefore, this dose may result in larger clinical benefit for 
mGC patients. Trastuzumab emtansine at 2.4 mg/kg qw is being tested in the 
BO27952 study.  
In Cohort 2, the starting dose of capecitabine will be the MTD from Cohort 1 
(mBC) in order to minimize the exposure of patients to sub-optimal treatment. 
The dose of capectiabine can be de-escalated if needed. 
3.3.2.3 
Rationale for Duration of Treatment 
Treatment will be given until disease progression or unacceptable toxicity (see 
Section 3.1.1 for full information). As of 1 January 2010, of 237 patients 
enrolled in studies TDM3569g, TDM4258g, and TDM4374g receiving 
trastuzumab emtansine at 3.6 mg/kg, approximately 30% have tolerated more 
than 12 cycles, with 14.8% having received more than 17 cycles. 
Twenty patients (8.4%) have discontinued trastuzumab emtansine due to AEs 
and 24 patients (10.1%) required dose reductions in trastuzumab emtansine 
because of AEs. In the absence of intolerable toxicity, patients with mBC are 
generally treated until disease progression. 
Capecitabine will be given until disease progression, as per Xeloda® national 
prescribing information. 
3.3.3 
PHARMACOKINETIC SAMPLING RATIONALE 
The PK sampling rationale is to characterize the pharmacokinetics of 
trastuzumab emtansine, total trastuzumab, and DM1, to assess potential 
drug-drug interaction when trastuzumab emtansine is given in combination 
with capecitabine, and to explore potential correlations between drug 
exposure and measures of both efficacy (ORR) and toxicity (ALT/AST, 
platelets, etc.), if data allow. 
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3.4 
OUTCOME MEASURES 
3.4.1 
PHASE I: MBC 
3.4.1.1 
Primary Efficacy Outcome Measure 
The main objective for Phase I is to determine the MTD of capecitabine when 
combined with trastuzumab emtansine. 
3.4.1.2 
Secondary Efficacy Outcome Measure 
The secondary outcome is ORR, based on best overall response rate (BORR) 
as per RECIST v.1.1; based on investigator assessment. 
3.4.1.3 
Primary Safety Outcome Measure 
The primary outcome measure is to establish MTD. 
3.4.1.4 
Secondary Safety Outcome Measures 
Safety endpoints will be summarized for both treatment phases: dose finding 
and exploration of efficacy. Again, the summary of safety endpoints will be 
presented for each cohort: 
 
Incidence, nature and severity of AEs, as per NCI CTCAE v. 4.0 
 
Incidence, nature, and severity of serious AEs 
 
Incidence and nature of AEs equal or higher than Grade 3 
 
Premature withdrawal from study and study medication 
 
Abnormal laboratory values 
 
LVEF 
 
Exposure to study medication 
 
Concomitant medications and physical examination 
3.4.1.5 
Pharmacokinetic Outcome Measures 
The PK outcome measures to be assessed in patients receiving trastuzumab 
emtansine and capecitabine will include: 
 
Serum concentrations of trastuzumab emtansine (conjugated drug) and 
total trastuzumab (free and conjugated to DM1) 
 
Plasma concentration of DM1 
 
Plasma concentration of capecitabine and its active metabolite 5-
fluorouracil (5-FU) 
3.4.2 
PHASE II: EXPLORATION OF EFFICACY: MBC 
3.4.2.1 
Primary Efficacy Outcome Measure 
The primary outcome measure is ORR, based on best overall response (BOR) 
(defined as the best response recorded from the start of treatment until 
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disease progression/recurrence or death; or for newly enrolled patients the 
best response from the start of Phase II until disease progression or death) by 
investigator assessment; as per RECIST v.1.1 Appendix 3. 
3.4.2.2 
Secondary Efficacy Outcome Measures 
Secondary outcomes include: 
 
Time to response (TTR) 
 
Duration of response (DoR) 
 
Time to progression (TTP) 
 
Time to treatment failure (TTF) 
 
Progression free survival (PFS) 
 
Clinical benefit rate (CBR) 
 
Overall survival (OS) 
3.4.2.3 
Primary Safety Outcome Measure 
A primary safety outcome is defined only for Phase I. 
3.4.2.4 
Secondary Safety Outcome Measures 
Safety endpoints will be summarized for both treatment phases: dose finding 
and exploration of efficacy. Again, the summary of safety endpoints will be 
presented for each cohort: 
 
Incidence, nature and severity of AEs, as per NCI CTCAE v. 4.0 
 
Incidence, nature, and severity of serious AEs 
 
Incidence and nature of AEs equal or higher than Grade 3 
 
Premature withdrawal from study and study medication 
 
Abnormal laboratory values 
 
LVEF 
 
Exposure to study medication 
 
Concomitant medications and physical examination 
3.4.2.5 
Pharmacokinetic Outcome Measures 
Not applicable for Phase II. 
3.4.3 
PHASE I: MGC 
3.4.3.1 
Primary Efficacy Outcome Measure 
The main objective for Phase I is to determine the MTD of capecitabine when 
combined with trastuzumab emtansine. 
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3.4.3.2 
Secondary Efficacy Outcome Measure 
The secondary outcome is ORR, based on BORR as per RECIST v.1.1; 
based on investigator assessment. 
3.4.3.3 
Primary Safety Outcome Measure 
 
The primary outcome measure is to establish MTD 
3.4.3.4 
Secondary Safety Outcome Measures 
Safety endpoints will be summarized for both treatment phases: dose finding 
and exploration of efficacy. Again, the summary of safety endpoints will be 
presented for each cohort: 
 
Incidence, nature and severity of AEs, as per NCI CTCAE v. 4.0 
 
Incidence, nature, and severity of serious AEs 
 
Incidence and nature of AEs equal or higher than Grade 3 
 
Premature withdrawal from study and study medication 
 
Abnormal laboratory values 
 
LVEF 
 
Exposure to study medication 
 
Concomitant medications and physical examination 
3.4.3.5 
Pharmacokinetic Outcome Measures 
The PK outcome measures to be assessed in patients receiving trastuzumab 
emtansine and capecitabine will include: 
 
Serum concentrations of trastuzumab emtansine (conjugated drug) and 
total trastuzumab (free and conjugated to DM1) 
 
Plasma concentration of DM1 
 
Plasma concentration of capecitabine and its active metabolite 5-
fluorouracil (5-FU) 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
4.1.1 
MBC PATIENTS 
This study will enroll HER2-positive BC patients with histologically or 
cytologically confirmed metastatic disease which are amenable for 
combination treatment with trastuzumab emtansine and capecitabine. 
Metastatic BC patients must have received at least one treatment regimen 
which includes a chemotherapy and trastuzumab agent. Only patients whose 
HER2 tumor status was locally scored as IHC 3+ or ISH positive will be 
permitted for both study parts (Phase I and II). 
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4.1.2 
MGC PATIENTS 
This study will enroll HER2-positive GC patients with histologically or 
cytologically confirmed inoperable locally advanced or metastatic disease 
which are amendable for combination treatment with trastuzumab emtansine 
and capecitabine. 
Metastatic GC patients must have not received prior chemotherapy for 
advanced/metastatic disease, and only patients with HER2-positive primary 
tumor or metastasis as assessed by central laboratory will be allowed to enroll 
in dose finding part for this disease in this study. 
4.1.3 
INCLUSION CRITERIA 
4.1.3.1 
For mBC Patients 
Patients must meet the following criteria for study entry: 
1. Age ≥ 18 years old 
2. Signed informed consent prior to any study specific procedure 
3. Able and willing to comply with protocol 
4. 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 
5.  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 or two effective forms of non-
hormonal contraception and to continue its use for the duration of study 
treatment and for 6 months after the last dose of study treatment (see 
Section 5.2.4) 
6. ECOG performance status of 0, 1, or 2 
7. Blood: 
a) Platelet count > 100,000 cells/mm3 
b) International normalized ratio (INR) < 1.5 × the upper limit of normal 
(ULN) 
c) Absolute neutrophil count (ANC) > 1500 cells/mm3 
d) Hemoglobin > 9.0 g/dL. Patients are allowed to have received 
transfusion to achieve this level. 
8. Liver function: 
a) Total bilirubin ≤ 1.5 × ULN except in patients with previously 
documented Gilbert’s syndrome in which case total bilirubin ≤ 3 mg/dL 
is acceptable 
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b) Serum glutamic oxaloacetic transaminase (SGOT)/AST and serum 
glutamic pyruvic transaminase (SGPT)/alanine transaminase 
(ALT) ≤ 2.5 × the ULN 
c) Alkaline phosphatase ≤ 2.5 × the ULN. Patients with hepatic and/or 
bone metastases: alkaline phosphatase ≤ 5 × the ULN 
9. Renal function: 
a) Serum creatinine of < 177 µmol/L or calculated creatinine CL > 50 
mL/min. I urine dipstick for proteinuria is ≥ 2+ at baseline, the patient 
must undergo 24 hour urine collection and demonstrate ≤ 1 g of 
protein/24 hours 
10. Cardiac function: 
a) LVEF ≥ 50% by echocardiogram (ECHO) or multiple-gated acquisition 
(scan) (MUGA) 
11. Histologically or cytologically confirmed breast cancer 
12. HER2-positive disease IHC 3+ or ISH positive 
13. Tumor block available or 15 slides for retrospective central confirmation of 
HER2-positivity (central confirmation not necessary for enrolment) 
14. Metastatic breast cancer (mBC) with at least one measurable lesion 
according to RECIST 
15. Disease progression on at least one regimen containing trastuzumab and 
chemotherapy 
16. Patients must have recovered from previous treatments 
4.1.3.2 
For mGC Patients: 
Patients must meet the following criteria for study entry: 
1. Age ≥ 18 years old 
2. Signed informed consent prior to any study specific procedure 
3. Able and willing to comply with protocol 
4. 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 
5.  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 or two effective forms of non-
hormonal contraception and to continue its use for the duration of study 
treatment and for 6 months after the last dose of study treatment (see 
Section 5.2.4) 
6. ECOG performance status of 0, 1, or 2 
7. Blood: 
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a) 
Platelet count > 100,000 cells/mm3 
b) INR < 1.5 × the ULN 
c) ANC > 1500 cells/mm3 
d) Hemoglobin > 9.0 g/dL. Patients are allowed to have received 
transfusion to achieve this level. 
8. Liver function: 
a)  Total bilirubin ≤ 1.5 × ULN except in patients with previously 
documented Gilbert’s syndrome in which case total bilirubin ≤ 3 mg/dL 
is acceptable 
b) SGOT/AST and serum glutamic pyruvic transaminase 
(SGPT)/ALT ≤ 2.5 × the ULN 
c) Alkaline phosphatase ≤ 2.5 × the ULN. Patients with hepatic and/or 
bone metastases: alkaline phosphatase ≤ 5 × the ULN 
9. Renal function: 
a) Serum creatinine of < 177 µmol/L or calculated creatinine CL > 50 
mL/min. I urine dipstick for proteinuria is ≥ 2+ at baseline,  the patient 
must undergo 24 hour urine collection and demonstrate ≤ 1 g of 
protein/24 hours 
10. Cardiac function: 
a) LVEF ≥ 50% by ECHO or MUGA 
11. Histologically or cytologically confirmed GC 
12. HER2-positive tumor (primary tumor or metastatic lesion), defined as 
either IHC 3+ alone or IHC 2+ in combination with ISH+, prospectively 
confirmed by a Sponsor-designated central laboratory prior to 
enrollment. ISH positivity is defined as a ratio of ≥ 2.0 for the number of 
HER2 gene copies to the number of signals for CEP17. 
a) Archival tumor samples obtained from primary or metastatic sites are 
acceptable. 
b) Invasive tumor for central confirmation of HER2 status is required. 
c) A formalin-fixed paraffin-embedded (FFPE) tissue block with at least 
5 mm of invasive tumor for central confirmation is preferred. 
If FFPE tissue blocks (or partial block) are unavailable due to country or 
site regulations, a minimum of 8 freshly cut unstained slides MUST be 
available for central review of HER2 status. 
13. Inoperable locally advanced or mGC 
4.1.4 
EXCLUSION CRITERIA 
4.1.4.1 
For mBC Patients: 
1. Prior treatments before first study treatment: 
a) Investigational therapy within ≤ 28 days or 5 half lives, whatever is 
longest 
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b)  Hormonal therapy within 14 days 
c) Trastuzumab within 21 days 
2. Prior enrollment in a trastuzumab emtansine−containing study, regardless 
of whether the patient received prior trastuzumab emtansine 
3. Prior treatment with capecitabine 
4. History of severe and unexpected reactions to fluoropyrimidine or with 
known hypersensitivity to fluorouracil 
5. Related capecitabine contraindications: 
a)Treatment with sorivudine or its chemically related analogues, such as 
brivudine 
b)Rare hereditary problems of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactose malabsorption 
6. History of intolerance (including Grade 3 or 4 infusion reaction) or 
hypersensitivity to trastuzumab or murine proteins 
7. History of exposure to the following cumulative doses of anthracyclines: 
a) Doxorubicin or liposomal doxorubicin > 360 mg/m2 
b)  Epirubicin > 900 mg/m2 
c) Mitoxantrone > 120 mg/m2 
d) If another anthracycline, or more than one anthracycline, has been 
used, the cumulative dose must not exceed the equivalent of 360 
mg/m2 doxorubicin. 
8. Brain metastases that are symptomatic, or require any radiation, surgery, 
or steroid therapy to control their symptoms within 28 days of first study 
drug administration 
9. Current peripheral neuropathy of Grade ≥ 3 per the NCI CTCAE, v4.0 
10. History of other malignancy within the last 5 years, except for 
appropriately treated carcinoma in situ of the cervix, non-melanoma skin 
carcinoma, Stage I uterine cancer, or other cancers with a similar 
outcome as those mentioned above 
11. Current unstable ventricular arrhythmia requiring treatment 
12. History of symptomatic CHF (New York Heart Association [NYHA] 
Classes II−IV) 
13. History of myocardial infarction or unstable angina within 6 months prior to 
first study drug administration 
14. History of a decrease in LVEF to < 40% or symptomatic CHF with 
previous trastuzumab treatment 
15. Severe dyspnea at rest due to complications of advanced malignancy or 
requiring current continuous oxygen therapy 
16. Clinically significant malabsorption syndrome or inability to take oral 
medication 
17. Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, or metabolic disease) 
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18. Major surgical procedure or significant traumatic injury within 28 days 
before enrollment or anticipation of the need for major surgery during the 
course of study treatment 
19. Current pregnancy or lactation 
20. Current known active infection with human influenca virus (HIV), hepatitis 
B, and/or hepatitis C virus 
a) For patients who are known carriers of hepatitis B virus (HBV), active 
hepatitis B infection must be ruled out based on negative serologic 
testing and/or determination of HBV DNA viral load per local guidelines 
21.  Lapatinib ≤ 14 days before first study drug administration 
22. Previous radiotherapy for the treatment of unresectable, locally 
advanced/recurrent or mBC is not allowed if: 
a) The last fraction of radiotherapy has been administered within 14 days 
prior to first study drug administration. 
b) More than 25% of marrow-bearing bone has been irradiated. 
c) The patient has not recovered from any resulting acute toxicity to 
Grade ≤ 1 prior to first study drug administration. 
4.1.4.2 
For mGC Patients: 
1. Prior treatments before first study treatment: 
a) Investigational therapy within ≤ 28 days or 5 half lives, whatever is 
longest 
b)  Hormonal therapy within 14 days 
c) Trastuzumab within 21 days 
2. Prior enrollment in a trastuzumab emtansine−containing study, regardless 
of whether the patient received prior trastuzumab emtansine 
3. Prior treatment with capecitabine 
4. History of severe and unexpected reactions to fluoropyrimidine or with 
known hypersensitivity to fluorouracil 
5. Related capecitabine contraindications: 
a) Treatment with sorivudine or its chemically related analogues, such as 
brivudine 
b) Rare hereditary problems of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactose malabsorption 
6. History of intolerance (including Grade 3 or 4 infusion reaction) or 
hypersensitivity to trastuzumab or murine proteins 
7. History of exposure to the following cumulative doses of anthracyclines: 
a) Doxorubicin or liposomal doxorubicin > 360 mg/m2 
b)  Epirubicin > 900 mg/m2 
c) Mitoxantrone > 120 mg/m2 
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d) If another anthracycline, or more than one anthracycline, has been 
used, the cumulative dose must not exceed the equivalent of 360 
mg/m2 doxorubicin. 
8. Brain metastases that are symptomatic, or require any radiation, surgery, 
or steroid therapy to control their symptoms within 28 days of first study 
drug administration 
9. Current peripheral neuropathy of Grade ≥ 3 per the NCI CTCAE, v4.0 
10. History of other malignancy within the last 5 years, except for 
appropriately treated carcinoma in situ of the cervix, non-melanoma skin 
carcinoma, Stage I uterine cancer, or other cancers with a similar 
outcome as those mentioned above 
11. Current unstable ventricular arrhythmia requiring treatment 
12. History of symptomatic CHF (New York Heart Association [NYHA] 
Classes II−IV) 
13. History of myocardial infarction or unstable angina within 6 months prior to 
first study drug administration 
14. History of a decrease in LVEF to < 40% or symptomatic CHF with 
previous trastuzumab treatment 
15. Severe dyspnea at rest due to complications of advanced malignancy or 
requiring current continuous oxygen therapy 
16. Clinically significant malabsorption syndrome or inability to take oral 
medication 
17. Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, or metabolic disease) 
18. Major surgical procedure or significant traumatic injury within 28 days 
before enrollment or anticipation of the need for major surgery during the 
course of study treatment 
19. Current pregnancy or lactation 
20. Current known active infection with HIV, hepatitis B, and/or hepatitis C 
virus 
a) For patients who are known carriers of hepatitis B virus (HBV), active 
hepatitis B infection must be ruled out based on negative serologic 
testing and/or determination of HBV DNA viral load per local guidelines 
21. Previous chemotherapy for advanced/metastatic disease 
a) Prior adjuvant/neoadjuvant therapy is allowed if at least 6 months has 
elapsed between completion of adjuvant/neoadjuvant therapy and 
enrolment into the study 
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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 
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. 
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For additional details, please refer to the current version of the trastuzumab 
emtansine Investigator’s Brochure. 
4.2.1.2 
Capecitabine 
The following information has been obtained from the Xeloda® EU Summary 
of Product Characteristics and U.S. Xeloda® Package Insert. 
Capecitabine is available as biconvex, oblong, film-coated tablets, available 
as follows: 
 
150 mg tablets: color, light peach; engraving, XELODA on one side, 150 
on the other; packs of 60 
 
500 mg tablets: color, peach; engraving, XELODA on one side, 500 on 
the other; packs of 120 
Capecitabine tablets should not be stored above 30°C. 
4.2.2 
DOSAGE AND ADMINISTRATION 
4.2.2.1 
For mBC Patients 
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 (see Appendix 1). The total dose will be calculated 
based on the patients weight on Day 1 (or up to 3 days before) of each cycle 
with no upper limit. 
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 
minute observation period following infusion. Local health authority guidelines 
must be followed with regard to further observation and monitoring, if 
applicable. 
Pre-medication for nausea and infusion reactions (e.g., acetaminophen or 
other analgesics, antihistamines such as diphenhydramine, or corticosteroids) 
may be given at the investigator’s discretion. 
Capecitabine 
Capecitabine will be administered twice a day, orally for 14 days followed by a 
7-day rest period at the dose levels 1–3 described in the “study design” 
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Section 3.1.1. Capecitabine tablets should be swallowed with water within 30 
minutes after a meal. 
If a dose is missed, the patient should skip that dose. The patient should not 
double the dose during the next administration. 
For Phase II, guidelines for dosage modification and treatment interruption or 
discontinuation are provided in Section 5.1. For this part of the study, the MTD 
from Phase I will be used as a starting dose. 
4.2.2.2 
For mGC Patients 
Trastuzumab Emtansine 
Trastuzumab emtansine will be administered on Day 1 of a qw cycle qw at a 
dose of 2.4 mg/kg IV (see Appendix 1). The total dose will be calculated 
based on the patients weight on Day 1 (or up to 3 days before) of each cycle 
with no upper limit. 
Administration time and observation period will be performed as described in 
Section 4.2.2.1 for trastuzumab emtansine. 
Guidelines regarding timing delays and infusion times are the same as for 
mBC patients, as is the accepted pre-medication. 
Capecitabine 
Capecitabine will be administered twice a day, orally, for 14 days followed by 
a 7-day rest period at the dose level that was determined during the dose 
finding part of the study in mBC patients as the MTD in Cohort 1. 
Capecitabine tablets should be swallowed with water within 30 minutes after a 
meal. 
If a dose is missed, the patient should skip that dose. The patient should not 
double the dose the next administration. 
Guidelines for dosage modification and treatment interruption or 
discontinuation are provided in Section 5.1. 
4.2.3 
INVESTIGATIONAL MEDICINAL PRODUCT ACCOUNTABILITY 
All investigational medicinal products (IMPs) required for completion of this 
study (trastuzumab emtansine and capecitabine) 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. 
IMPs will either be disposed of at the study site according to the study site’s 
institutional standard operating procedure or returned to the Sponsor with the 
appropriate documentation. The site's method of IMP destruction must be 
agreed upon by the Sponsor. The site must obtain written authorization from 
the Sponsor before any IMP is destroyed, and IMP destruction must be 
documented on the appropriate form. 
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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 
Post-trial access of trastuzumab emtansine and capecitabine will be 
performed as described in Section 3.1.1, Treatment of Patients and Database 
Closure. 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 AND EXCLUDED THERAPIES 
4.3.1 
PERMITTED THERAPY 
Concomitant therapy and pre-medication are defined as non-IMPs. 
Concomitant therapy includes any prescription medication, over-the-counter 
preparation, or herbal therapy between the 14 days preceding first treatment 
and the Study Treatment Discontinuation Visit. Afterwards, only anti-cancer 
therapies will be collected as part of the survival follow-up period. 
Pre-medication is allowed according to standard practice guidelines. 
No pre-medication for the first infusion of trastuzumab emtansine is required; 
however, pre-medication 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). 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 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. 
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 
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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. 
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 cannot be treated with additional radiation. 
Patients must not miss more than one cycle of study treatment for the 
treatment of their brain metastases and must have an ECOG performance 
status of 0, 1 or 2 to continue on therapy. The Medical Monitor should be 
informed before a decision is made to resume study treatment after 
radiotherapy for brain metastases. 
4.4 
STUDY ASSESSMENTS 
All patients will be closely monitored for safety and tolerability during all cycles 
of therapy and at the safety follow-up visit: 
 
Visits will be based on a q3w cycle for mBC 
 
Visits will be based on a qw cycle for mGC 
Study assessments are outlined in this section and in Appendix 1. 
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 Study Treatment Discontinuation Visit. Patients should 
be assessed for toxicity prior to each dose; dosing will occur only if the clinical 
assessment and local laboratory test values are acceptable. Trastuzumab 
emtansine will be administered either in q3w cycles (mBC patients) or qw 
cycles (mGC patients) if no additional time is required for reversal of toxicity. 
Dose delays and dose reductions will be allowed for trastuzumab emtansine 
as outlined in Section 5.1.5. 
If the timing of a protocol-mandated procedure coincides with a holiday and/or 
weekend that precludes the procedure within the allotted window, the 
procedure should be performed on the nearest following date (i.e. within 3 
business days). 
4.4.1.1 
Medical History and Demographic Data 
Medical history includes 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. 
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Demographic data will include age, sex, and self-reported race/ethnicity. 
4.4.1.2 
Vital Signs 
Vital signs will include measurements of weight, respiratory rate, heart rate, 
blood pressure, and temperature. Abnormal or significant changes to vital 
signs from baseline should be recorded as AEs, if appropriate. 
4.4.1.3 
Physical Examinations 
A complete physical examination should include the evaluation of head, eye, 
ear, nose, and throat; cardiovascular; dermatological; musculoskeletal; 
respiratory; gastrointestinal; and neurological systems. Changes from 
baseline abnormalities should be recorded at each subsequent physical 
examination. New or worsened abnormalities should be recorded as AEs if 
appropriate. 
As part of tumor assessment, physical examinations should also include the 
evaluation of the presence and degree of enlarged lymph nodes, 
hepatomegaly, and splenomegaly. 
Limited physical examinations will be symptom-directed. 
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 
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 (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 (see Appendix 3). 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. Please consult the 
Imaging Manual for guidelines on performing a diagnostic quality (optimized) 
CT exam. 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 
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unavailability of the Tc-99m isotope, the investigator may choose an 
alternative imaging modality (see Appendix 4). 
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 
Laboratory Assessments 
For mBC Patients: 
Local Laboratory Assessments: 
 
Hematology, biochemistry, coagulation, urinalysis, and pregnancy testing 
 
Prospective HER2 status. Patients will be enrolled based on local results 
Central Laboratory Assessments: 
 
Retrospective HER2 status 
 
PK assays: 
– 
Serum trastuzumab emtansine concentration and total trastuzumab using 
a validated immunoassay 
– 
Serum capeciatbine and 5 follow-up PK samples 
– 
Plasma concentration of DM1 using a validated liquid chromatography 
electrospray tandem mass spectrometry (LC-MS/MS) method 
For mGC Patients: 
Local Laboratory Assessments: 
 
Hematology, biochemistry, coagulation, urinalysis, and pregnancy testing 
Central Laboratory Assessments: 
 
Prospective HER2 status. Patients will be enrolled based on central 
results 
 
PK assays: 
– 
Serum trastuzumab emtansine concentration and total trastuzumab using 
a validated immunoassay 
– 
Serum capeciatbine and 5 follow-up PK samples 
– 
Plasma concentration of DM1 using a validated liquid chromatography 
electrospray tandem mass spectrometry (LC-MS/MS) method 
4.4.1.6 
Electrocardiograms 
A 12-lead ECG should be obtained at baseline and be printed and kept with 
the patient’s record. 
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4.4.1.7 
ECHO/MUGA 
ECHO is the preferred modality because of the global technetium (Tc-99m) 
shortage (see Appendix 4). The same method used at screening should be 
used throughout the study. 
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. Informed 
Consent Forms for enrolled patients and for patients who are not 
subsequently enrolled will be maintained at the study site. 
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. 
Results of standard of care tests or examinations performed prior to obtaining 
informed consent and within 28 days prior to study start may be used; such 
tests do not need to be repeated for screening. 
All screening evaluations must be completed and reviewed to confirm that 
patients meet all eligibility criteria before study start. 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. 
Patients who are on the MTD dose established in Cohort 1 must re-consent to 
be enrolled into Phase II. 
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. 
Please see Appendix 1 for the schedule of screening assessments. 
4.4.2.2 
Assessments During Treatment 
For mBC Patients 
Scheduled study visits are based on a q3w cycle, with Cycle 1 beginning at 
Day 1. All visits must occur within ± 3 business days from the scheduled date, 
unless otherwise noted in the schedule of assessments. All assessments will 
be performed on the day of the specified visit unless a time window is 
specified. Assessments scheduled on the day of study treatment 
administration should be performed prior to study treatment administration 
unless otherwise noted. If the timing of a protocol-mandated procedure 
coincides with a holiday and/or weekend, it should be performed on the 
nearest following date (i.e. within 3 business days). 
Local laboratory assessments scheduled for Day 1 of all cycles must be 
performed within 72 hours prior to study treatment administration unless 
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otherwise specified. Results of local laboratory assessments must be 
reviewed and the review documented prior to study treatment administration. 
Please see Appendix 1 for the schedule of treatment period assessments. 
For mGC patients: 
Scheduled study visits are based on a qw cycle, with Cycle 1 beginning at 
Day 1. All visits must occur within ± 3 business days from the scheduled date, 
unless otherwise noted in the schedule of assessments. All assessments will 
be performed on the day of the specified visit unless a time window is 
specified. Assessments scheduled on the day of study treatment 
administration should be performed prior to study treatment administration 
unless otherwise noted. If the timing of a protocol-mandated procedure 
coincides with a holiday and/or weekend, it should be performed on the 
nearest following date (i.e. within 3 business days). 
Local laboratory assessments scheduled for Day 1 of all cycles must be 
performed within 72 hours prior to study treatment administration unless 
otherwise specified. Results of local laboratory assessments must be 
reviewed and the review documented prior to study treatment administration. 
Please see Appendix 1 for the schedule of treatment period assessments. 
4.4.2.3 
Assessments at Study Completion/Early Termination Visit 
Patients may remain on study treatment until disease progression as 
assessed by the investigator, intolerable toxicity or the patient wishes to 
withdraw from study treatment. Patients who discontinue study treatment will 
be asked to return to the clinic approximately 28–42 days after the last study 
treatment administration, for the safety follow-up visit. 
Please see Appendix 1 for assessments to be performed at the safety follow-
up visit. 
4.4.2.4 
Follow-Up Assessments 
After the Study Treatment Discontinuation Visit, all patients (regardless of 
reason for discontinuation) will have anti-cancer therapies recorded and will 
be followed for all unresolved study-related AEs and serious adverse events 
(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. 
Patients who discontinue study drugs for any reason other than disease 
progression or withdrawal of consent (e.g., an AE) will continue to be followed 
until the development of disease progression, consent withdrawal, lost to 
follow-up or beginning of another anti-cancer therapy. 
After the study completion/early termination visit, AEs should be followed as 
outlined in Section 5.5 and 5.6. 
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Please see Appendix 1 for the schedule of follow-up assessments. 
4.4.2.5 
Assessments at Unplanned Visits 
In case unplanned visits are required, electronic Case Report Form (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 
Patients have the right to withdraw from the study at any time for any reason. 
The investigator has the right to discontinue a patient from study treatment or 
from the study for any medical condition that the investigator determines may 
jeopardize the patient’s safety if he or she continues in the study, for reasons 
of noncompliance (e.g., missed doses, visits), if the patient becomes pregnant, 
or if the investigator determines it is in the best interest of the patient. 
Patients must be withdrawn from study treatment if they experience any of the 
following: 
 
Pregnancy 
 
Disease progression defined using RECIST v. 1.1 Appendix 3. The 
exception to this is patients who develop isolated progression in the brain 
as described in Appendix 3 
 
Unacceptable toxicity because of the trastuzumab emtansine dose as 
specified in Section 5.1 
 
Unacceptable toxicity because of the capecitabine dose as specified in 
Section 5.1 
Other reasons for patient discontinuation may include, but are not limited to, 
the following: 
 
Noncompliance 
 
Investigator decision based on the patient’s best interest 
 
Patient decision 
Patients who discontinue from study treatment prematurely for any of the 
above reasons 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. 
4.5.2 
STUDY DISCONTINUATION 
Section 3.1.1 describes the end of study definition and discontinuation of 
study. Prior to that, 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 
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 
Data recording is inaccurate or incomplete 
5. 
ASSESSMENT OF SAFETY 
Overall safety will be assessed on an ongoing basis during the conduct of the 
study. 
5.1 
SAFETY PLAN 
The safety plan for patients receiving trastuzumab emtansine is based on the 
toxicities of trastuzumab emtansine observed in nonclinical studies; the 
toxicities related to its components (trastuzumab and maytansine, the parent 
drug of DM1) observed in clinical studies; and the clinical experience with this 
molecule in completed and ongoing studies. Please refer to the trastuzumab 
emtansine and capecitabine (Xeloda®) Investigator`s Brochures for the most 
recent information. 
All patients will be monitored closely for toxicity. The potential safety issues 
anticipated in this trial, as well as measures intended to avoid or minimize 
such toxicities, are outlined in the following sections. 
5.1.1 
RISKS ASSOCIATED WITH TRASTUZUMAB EMTANSINE 
Trastuzumab emtansine dose modifications are described in Section 5.1.5.1. 
The following summarizes the experience with trastuzumab emtansine in 
multiple breast cancer studies to date. Trastuzumab emtansine has 
demonstrated a favorable toxicity and tolerability profile to date across 
multiple studies. Please refer to the Investigator’s Brochure for further 
information. 
Reversible thrombocytopenia has been commonly observed in completed and 
ongoing studies with trastuzumab emtansine. Most events were Grade 1–2; 
Grade 3–4 thrombocytopenia has been observed less commonly. The 
incidence of Grade 1 thrombocytopenia gradually increased over successive 
cycles; however, there was no increase in the proportion of Grade ≥ 3 
abnormalities. The number of patients who experienced platelet count 
recovery to normal levels by Day 1 of the subsequent cycle decreased with 
successive cycles, suggesting a modest cumulative effect of trastuzumab 
emtansine on platelet count. There was no clear association between 
thrombocytopenia and severe hemorrhagic events; however, the use of 
platelet transfusions has been reported. 
Transient and reversible increases in serum AST and ALT have been 
observed across the trastuzumab emtansine studies. Grade 1–2 events have 
been observed frequently; Grade 3–4 events have been observed much less 
commonly. The incidence of increased AST was substantially higher than that 
for ALT. Increases in AST and ALT were commonly observed by Day 8 of 
each cycle and generally returned to baseline by Day 21. The proportion of 
patients with Grade 1–2 increases in transaminases increased with 
successive cycles; however, no increase in the proportion of Grade 3 
abnormalities over time was observed. To date, there have been no cases 
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meeting Hy’s Law criteria for drug-induced liver injury. Although significant 
hepatotoxicity has rarely been seen in clinical trials with trastuzumab 
emtansine to date, the relationship to trastuzumab emtansine has not been 
established. Nevertheless, severe liver injury remains an important potential 
risk. 
Infusion-related reactions are known to occur with the administration of 
monoclonal antibodies and have been reported with trastuzumab emtansine. 
Infusion reaction AEs occurred rarely and were mostly Grade 1–2. Non-
specific symptoms that occurred on the first day of trastuzumab emtansine 
infusion that could be associated with an infusion reaction included fatigue, 
nausea, chills, pyrexia, and, less commonly, headache, hypertension, 
vomiting, and cough. 
Pneumonitis has been rarely reported with trastuzumab emtansine. Signs, 
symptoms, and clinical findings include dyspnea, cough, fatigue, and 
pulmonary infiltrates. There were no fatalities among the cases of pneumonitis 
reported with trastuzumab emtansine. 
In clinical trials with trastuzumab emtansine, peripheral neuropathy has been 
reported, mainly as Grade 1 toxicity. Hypokalemia and decreases in serum 
potassium have been reported in completed and ongoing studies with 
trastuzumab emtansine. Most of these AEs were Grade 1–2. 
Although significant cardiac events have been infrequent in clinical trials with 
trastuzumab emtansine to date, severe cardiotoxicity remains an important 
potential risk. Treatment with trastuzumab, a component of trastuzumab 
emtansine, has resulted in subclinical and clinical cardiac failure manifesting 
as CHF, decreased LVEF, and cardiac death. The incidence and severity of 
cardiac dysfunction was highest in patients who received trastuzumab 
concurrently with anthracycline-containing chemotherapy regimens. 
Cardiotoxicity, manifesting as a decline in LVEF or CHF, is being closely 
monitored in the trastuzumab development program. Across studies 
TDM4258g, TDM4374g, and TDM4688g, approximately 273 patients were 
treated, and a total of 8 patients recorded an asymptomatic decrease in 
baseline LVEF of at least 10%, concomitant with an LVEF < 50%. Two 
patients had trastuzumab emtasine treatment withdrawn because of 
decreased LVEF. Rare cases of Grade 3 cardiac dysrhythmias have been 
reported among patients receiving trastuzumab emtansine, although a direct 
relationship to study drug remains unclear. 
Importantly, preliminary evaluations of safety in the randomized study 
TDM4450g suggest that the safety and tolerability of trastuzumab emtansine 
compared favorably with that of trastuzumab plus docetaxel, with the overall 
incidence of Grade ≥ 3 AEs favoring the trastuzumab emtansine arm (46.4% 
vs. 89.4%) (data on file). 
Full details regarding the clinical safety of trastuzumab emtansine are 
presented in Sections 5 and 6 of the Investigator’s Brochure. 
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5.1.2 
RISKS ASSOCIATED WITH CAPECITABINE 
Capecitabine dose modifications will be done according to Section 3.1.1, 
study design. 
Patients treated with capecitabine should be carefully monitored for toxicity. 
Most AEs are reversible and do not require permanent discontinuation of 
therapy (please refer to the Xeloda® Investigator`s Brochure for more 
information). 
The spectrum of cardiotoxicity observed with capecitabine is similar to that of 
other fluorinated pyrimidines. This includes myocardial infarction, angina, 
dysrhythmias, cardiac arrest, cardiac failure and electrocardiographic changes. 
These AEs may be more common in patients with a prior history of coronary 
artery disease. 
DPD deficiency, a rarely, unexpected, severe toxicity (e.g. stomatitis, diarrhea, 
neutropenia and neurotoxicity) associated with 5-FU has been attributed to a 
deficiency of dihydropyrimidine dehydrogenase (DPD) activity. Therefore, a 
link between decreased levels of DPD and increased, potentially fatal toxic 
effects of 5-FU cannot be excluded. 
Capecitabine can induce hand–foot syndrome (palmar-plantar 
erythrodysesthesia or chemotherapy-induced acral erythema), which is a 
cutaneous toxicity. For patients receiving capecitabine monotherapy in the 
metastatic setting, the median time to onset was 79 days (range 11 to 360 
days), with a severity range of Grades 1 to 3. Grade 1 hand-foot syndrome is 
defined by numbness, dysesthesia/paresthesia, tingling or erythema of the 
hands and/or feet and/or discomfort which does not disrupt normal activities. 
Grade 2 is defined as painful erythema and swelling of the hands and/or feet 
and/or discomfort affecting the patient’s activities of daily living (ADL). Grade 
3 is defined as moist desquamation, ulceration, blistering or severe pain of the 
hands and/or feet and/or severe discomfort that causes the patient to be 
unable to work or perform ADL. If Grade 2 or 3 hand-foot syndrome occurs, 
administration of capecitabine should be interrupted until the event resolves or 
decreases in intensity to Grade 1. Following Grade 3 hand-foot syndrome, 
subsequent doses of capecitabine should be decreased. 
Capecitabine can induce hyperbilirubinemia. Administration of capecitabine 
should be interrupted if treatment-related elevations in bilirubin of > 3.0 × ULN 
or treatment-related elevations in hepatic aminotransferases (ALT, AST) 
of > 2.5 × ULN occur. Treatment may be resumed when bilirubin decreases 
to ≤ 3.0 × ULN or hepatic aminotransferases decrease to ≤ 2.5 x ULN.  
5.1.3 
TRASTUZUMAB EMTANSINE AND CAPECITABINE 
COMBINATION: 
DLTs for the combination of trastuzumab emtansine and capecitabine will be 
observed during Cycle 1 (Day 1–21) of this study. 
5.1.4 
DEFINITION OF DOSE LIMITING TOXICITY 
DLT toxicities will be observed during Cycle 1 (Day 1–21). 
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Definition of DLT: 
Hematologic 
1. Uncomplicated thrombocytopenia Grade 4 which does not recover 
to ≥ 75.000/Ml before Day 21 
2. Thrombocytopenia (any grade) complicated with clinically significant 
bleeding requiring medical intervention such as: platelet transfusion, 
cauterization, patients with epistaxis Grade 1 or 2 may have cauterization 
and this should not be consider as DLT etc. 
3. Neutropenia Grade 4 lasting > 7 consecutive days 
4. Febrile neutropenia with an ANC of < 1000 
Non-hematologic 
5. Diarrhea Grade ≥ 3 which does not decrease to ≤ Grade 2 after 24 hours 
of starting recommended anti-diarrheal treatment in absence of DPD 
deficiency 
6. Hand-foot syndrome Grade ≥ 3 in absence of DPD deficiency 
7. Any other treatment-related toxicity ≥ Grade 3 prohibiting the start of the 
2nd cycle on day 22 (3 weeks cycle length plus 1 day) 
8. Grade 2 toxicity requiring interruption of treatment for > 7 days 
NOTE: Patients experiencing ≥ Grade 3 hand-foot syndrome or diarrhea or 
mucositis or Febrile neutropenia with ANC < 500 during Cycle 1 must be 
tested for DPD deficiency (central lab will be appointed). 
NOTE TO point 7, if a Grade 2 event requires a dose delay, it will not be 
considered as DLT. 
5.1.5 
MANAGEMENT OF SPECIFIC ADVERSE EVENTS 
5.1.5.1 
Trastuzumab Emtansine Dosage 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, thrombocytopenia, hepatotoxicity, 
neurotoxicity, and cardiotoxicity) are as follows: 
 
If significant trastuzumab emtansine related toxicities (other than infusion 
reactions, thrombocytopenia, hepatotoxicity, neurotoxicity, and 
cardiotoxicity) 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 
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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 
reevaluated qw during the delay, whenever possible. If dosing resumes, 
the patient may receive trastuzumab emtansine either at the same dose 
level as before or at one dose level lower than the previous dose (see 
Table 2 and Table 3), at the discretion of the investigator. Subsequent 
cycles should remain the same (q3w or qw), 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 or Table 3. No dose re-escalation will be allowed. 
 
If 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. 
 
Patients who experience a Grade 3 or 4 hematologic event should be 
checked at least qw 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 Reductions for Trastuzumab Emtansine (mBC Patients) 
Dose Level 
q3w Schedule 
0 
3.6 mg/kg 
 - 1 
3.0 mg/kg 
 - 2 
2.4 mg/kg 
Indication for 
further dose 
reduction 
Off study treatment 
q3w = every 3 weeks 
Table 3 Dose Reductions for Trastuzumab Emtansine (mGC Patients) 
Dose Level 
qw Schedule 
0 
2.4 mg/kg 
 - 1 
2 mg/kg 
 - 2 
Off study 
Indication for 
further dose 
reduction 
Off study 
qw = weekly 
Protocol requirements for specific toxicities are outlined below. 
Trastuzumab Emtansine Dose Modification for Thrombocytopenia 
Patients receiving trastuzumab emtansine who experience any of the 
following events listed below, after adequate recovery to a platelet count of 
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Grade ≤ 1 ( ≥ 75,000/μL), may continue treatment with trastuzumab 
emtansine at one dose level reduction in subsequent treatment cycles (see 
Table 2 and Table 3). 
Grade 4 Thrombocytopenia: 
Hold study drug until platelet count qualifies for Grade ≤ 1 (≥ 75,000 μL). 
 
Platelets < 10,000 cells/mm3 for any duration 
 
Platelets ≥ 10,000 cells/mm3 but < 25,000 cells/mm3 for more than 7 days 
Grade 3 Thrombocytopenia: 
Hold study drug until platelet count qualifies for Grade ≤ 1 ( ≥ 75,000 μL). 
 
Trastuzumab emtansine 2.4 mg/mg/week dosing 
– Platelets must be ≥ 75,000 μL on day of treatment. 
 
Trastuzumab emtansine 3.6 mg/kg/q3w dosing: 
– Platelets must be ≥ 75,000 μL on day of treatment. 
Patients on Anticoagulation Therapy: 
Hold study drug until platelet count qualifies for Grade ≤ 1 (≥ 75,000 μL). 
 
For platelet count of Grade ≥ 3 (< 50,000 cells/μL) of any duration 
Patients who experience any of these toxicities should be reassessed at least 
qw for recovery. 
Trastuzumab Emtansine Dose Modification for Hepatotoxicity 
Table 4 and Table 5 describe the dose modification guidelines for increases in 
serum bilirubin and transaminases, respectively. Patients who develop a 
Grade 4 serum total bilirubin increase or a Grade 4 ALT and/or AST increase 
must discontinue study treatment permanently. Patients should be checked 
assessed at least qw for the recovery of total bilirubin and/or ALT and/or AST. 
If total bilirubin and/or ALT and/or AST do not recover to baseline or 
Grade ≤ 1 (total bilirubin) or Grade ≤ 2 (ALT and/or AST) within 42 days after 
the last dose received, the patient must discontinue study treatment. Please 
see Section 5.2.3 and Table 4 and Table 5 for further information. 
No re-escalation of the trastuzumab emtansine dose is allowed. 
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Table 4 Trastuzumab Emtansine Dose Modification: Total Serum 
Bilirubin 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Up to 
1.5 × ULN 
 > 1.5–3 × ULN 
 ≥ 3–10 × ULN 
 ≥ 10 × ULN 
T-DM1 
action 
Treat without 
dose reduction 
or delay 
Hold a dose; reduce one 
dose level when 
recovered to Grade ≤ 1.  
Discontinue b if 
> 2 × ULN and occurs 
concurrent c with ALT 
and/or AST elevation 
> 3 × ULN 
Hold a dose; reduce 
one dose level when 
recovered to 
Grade ≤ 1.  
Discontinue b if occurs 
concurrent c with ALT 
and/or AST elevation 
> 3 × ULN 
Discontinue. 
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. 
a A dose delay of up to 42 days after the last received dose is permitted for patients on a 
q3w schedule or 28 days for patients on a weekly schedule. 
b Unless a decision is made to hold then continue trastuzumab emtansine treatment based 
on the results of further evaluation of the situation and agreement by the investigator and 
the Sponsor. See also Section 5.2.3 
c Within 21 days. 
Table 5  Trastuzumab Emtansine Dose Modification: Serum ALT or AST 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Up to 
3 × ULN 
 > 3–5 × ULN 
 ≥ 5–20 × ULN 
 ≥ 20 × ULN 
T-
DM1 
action 
Treat without 
dose 
reduction or 
delay 
Treat without dose 
reduction or delay. 
Discontinue b if 
occurs concurrent c 
with total bilirubin 
> 2 × ULN or clinical 
jaundice 
Hold a dose; reduce one 
dose level when recovered 
to Grade ≤ 2.  Discontinue 
b if occurs concurrent c with 
total bilirubin > 2 × ULN or 
clinical jaundice 
Discontinue 
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. 
a A dose delay of up to 42 days after the last received dose is permitted for patients on a 
q3w schedule or 28 days for patients on a weekly schedule. 
b Unless a decision is made to hold then continue trastuzumab emtansine treatment based 
on the results of further evaluation of the situation and agreement by the investigator and 
the Sponsor.  See also Section 5.2.3 
c Within 21 days. 
Trastuzumab Emtansine Dose Modification for Neurotoxicity 
DM1, an anti-microtubule agent, can potentially cause peripheral neuropathy. 
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. 
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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. 
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. 
Ejection fractions will be monitored according to the schedules of assessment 
in Appendix 1. 
Figure 6 summarizes the management of trastuzumab emtansine on the basis 
of measured LVEF and changes in LVEF from baseline. 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. 
The decision to stop or continue trastuzumab emtansine should be based on 
the algorithm shown in Figure 6. 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. 
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Figure 6 Algorithm for Continuation and Discontinuation of 
Trastuzumab Emtansine Based on Left Ventricular Ejection 
Fraction Assessments in Patients 
 
CHF = congestive heart failure; 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. 
 
Trastuzumab Emtansine Dose Modification/Management for Infusion 
Reactions 
No pre-medication for the first infusion of trastuzumab emtansine is required; 
however, pre-medication is allowed at the investigator’s discretion. Patients 
who experience trastuzumab emtansine infusion-related temperature 
elevations of > 38.5°C or other minor infusion-related symptoms may be 
treated symptomatically with acetaminophen and/or H1 and H2 receptor 
antagonists (e.g., diphenhydramine and ranitidine, respectively). Serious 
infusion-related events (Grade ≥ 3 allergic reaction or acute respiratory 
distress syndrome [ARDS]) manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory 
distress should be managed with supportive therapies as clinically indicated 
according to standard clinical practice. Patients who experience a Grade ≥ 3 
allergic reaction or ARDS will be discontinued from study treatment. Patients 
who have infusion-related symptoms, such as chills or fever, may have the 
infusion rate decreased by 50% or interrupted. When symptoms have 
resolved, the infusion may be restarted at ≤ 50% of the prior rate and 
increased in 50% increments every 30 minutes as tolerated. Pre-medication 
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may be used before subsequent infusions at the investigator’s discretion. 
Patients should be monitored until complete resolution of symptoms. 
5.1.5.2 
Capecitabine Dosage Modification 
Phase I: mBC Patients 
Capecitabine dose modifications during Phase I will be performed according 
to the description in Section 3.1.1, study design for mBC patients. 
Phase II: Exploration of Efficacy: mBC 
During Phase II, capecitabine will be modified as per the Xeloda® 
Investigator`s Brochure (or SMPC). 
Phase I: mGC Patients 
Capecitabine dose modifications during Phase I will be performed according 
to the description in Section 3.1.1, study design for mGC patients. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording protocol-defined 
AEs and SAEs; measurement of protocol-specified hematology, clinical 
chemistry, and urinalysis variables; measurement of protocol-specified vital 
signs; and other protocol-specified tests that are deemed critical to the safety 
evaluation of the study drug(s). 
The Sponsor or its designee is responsible for reporting relevant SAEs to the 
Competent Authority, other applicable regulatory authorities, and participating 
investigators, in accordance with International Conference on Harmonisation 
(ICH) guidelines, Food and Drug Administration (FDA) regulations, European 
Clinical Trials Directive (Directive 2001/20/EC), and/or local regulatory 
requirements. 
The Sponsor or its designee is responsible for reporting unexpected fatal or 
life-threatening events associated with the use of the study drug to the 
regulatory agencies and competent authorities by telephone or fax within 7 
calendar days after being notified of the event. The Sponsor or its designee 
will report other relevant SAEs associated with the use of the study 
medication to the appropriate competent authorities (according to local 
guidelines), investigators, and central Institutional Review Boards/Ethics 
Committees (IRBs/ECs) by a written safety report within 15 calendar days of 
notification. 
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: 
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 
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 it occurred in a more severe form 
or was allowed to continue might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.8) 
 
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) 
 
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). 
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5.2.3 
PROTOCOL-DEFINED EVENTS OF SPECIAL INTEREST/NON-
SERIOUS EXPEDITED ADVERSE EVENTS 
Non-serious AEs of special interest are required to be reported by the 
investigator to the Sponsor immediately (i.e., no more than 24 hours) after 
learning of the event (see Section 5.4.2 for reporting instructions). AEs of 
special interest for this study include the following: 
 
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 or ALT elevations that are > 3 × the ULN 
Concurrent elevation (within 21 days of AST and/or ALT elevations) of 
total bilirubin > 2 × the ULN, except in patients with documented Gilbert 
syndrome 
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 following last 
dose of study drug (follow-up period based on PK considerations). 
Trastuzumab, a component of trastuzumab emtansine, can cause fetal harm 
when administered to a pregnant woman; postmarketing 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. IgGs are 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 
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 
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 
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 6 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 6 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 
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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 6 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 6 months following the last dose of 
either study drug. 
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 6 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 AE 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 AE eCRF, the investigator will make an 
assessment of seriousness (see Section 5.2.2, for seriousness criteria), 
severity (see Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
ADVERSE EVENT REPORTING PERIOD 
Investigators will seek information on AEs at each patient contact. All AEs, 
whether reported by the patient or noted by study personnel, will be recorded 
in the patient’s medical record and on the AE eCRF. 
After informed consent has been obtained but prior to initiation of study drug, 
only SAEs caused by a protocol-mandated intervention should be reported 
(e.g., SAEs related to invasive procedures such as biopsies, medication 
washout, or no treatment run-in). 
After initiation of study treatment, all AEs, regardless of relationship to study 
drug, will be reported until 30 days after the last administration of study drug 
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or study discontinuation/termination, whichever is later. After this period, 
investigators should report any deaths, SAEs, or other AEs of concern that 
are believed to be related to prior treatment with study drug (see Section 5.6). 
5.3.2 
ELICITING ADVERSE EVENT INFORMATION 
A consistent methodology of non-directive questioning should be adopted for 
eliciting AE information at all patient evaluation time points. Examples of 
non-directive questions include the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last 
here?” 
5.3.3 
ASSESSMENT OF SEVERITY OF ADVERSE EVENTS 
The AE grading (severity) scale found in the NCI CTCAE (v. 4.0) will be used 
for assessing AE severity (see Table 6). 
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Table 6 Adverse Event Severity Grading Scale 
 
Grade 
Severity 
Alternate Description a 
1 
Mild (apply event-specific 
NCI CTCAE grading criteria) 
Asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated 
2 
Moderate (apply event-specific  
NCI CTCAE grading criteria) 
Minimal, local or noninvasive intervention 
indicated; limiting age-appropriate instrumental 
ADLb 
3 
Severe (apply event-specific  
NCI CTCAE grading criteria) 
Severe or medically significant but 
not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; 
disabling; limiting self-care ADLc 
4 
Very severe, life-threatening,  
or disabling (apply event-specific 
NCI CTCAE grading criteria) 
Life-threatening consequences; 
urgent intervention indicated 
5 
Death related to AE 
 
ADL = activities of daily living; AE = adverse event; CTCAE = Common Terminology Criteria for 
Adverse Events; NCI = National Cancer Institute. 
The NCI CTCAE v4.0 can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
Note: Regardless of severity, some events may also meet regulatory seriousness criteria. Refer 
to definition of a serious AE (see Section 5.2.2). 
a Use these alternative definitions for Grade 1, 2, 3, and 4 events when the observed or 
reported AE is not in the NCI CTCAE listing. 
b Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
c Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
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 7. 
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Table 7 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 serious AEs 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. 
5.3.5 
PROCEDURES FOR RECORDING ADVERSE EVENTS 
Investigators should use correct medical terminology/concepts when 
recording AEs on the AE eCRF. Avoid colloquialisms and abbreviations. 
There is one eCRF page for recording AEs or SAEs. 
Only one AE term should be recorded in the event field on the AE eCRF. 
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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 AE eCRF rather than individual signs and symptoms (e.g., 
record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or 
syndrome at the time of reporting, each individual event should be recorded 
on the AE eCRF. If a diagnosis is subsequently established, all previously 
reported AEs based on signs and symptoms should be nullified and replaced 
by one AE report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis. 
5.3.5.2 
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 AE 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 AE eCRF should be 
updated to reflect this. 
A recurrent AE is one that resolves between patient evaluation time points 
and subsequently recurs. Each recurrence of an AE should be recorded 
separately on the AE eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
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.). 
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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. 
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 
mBC or mGC 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 AE eCRF and immediately reported to 
the Sponsor (see Section 5.4.2). An independent monitoring committee will 
monitor the frequency of death from all causes. 
Death should be considered an outcome and not a distinct event. The event 
or condition that caused or contributed to the fatal outcome should be 
recorded as the single medical concept on the AE eCRF. Generally, only one 
such event should be reported. If the cause of death is unknown and cannot 
be ascertained at the time of reporting, “unexplained death” should be 
recorded on the AE eCRF. If the cause of death later becomes available (e.g., 
after autopsy), “unexplained death” should be replaced by the established 
cause of death.  
During post-study survival follow-up, deaths attributed to progression of mBC 
or mGC 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 start of this study. 
Such conditions should be recorded on the Medical and Surgical History 
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 AE eCRF, it is important to convey the 
concept that the pre-existing condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”). 
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5.3.5.7 
Lack of Efficacy or Clinical Worsening 
Events that are clearly consistent with the expected pattern of progression of 
mBC or mGC 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 the RECIST criteria. 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 
planned hospitalization or prolonged hospitalization to: 
 
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 THE SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take 
appropriate measures to address potential new risks in a clinical trial. The 
investigator must report such events to the Sponsor immediately; under no 
circumstances should reporting take place more than 24 hours after the 
investigator learns of the event. The following is a list of events that the 
investigator must report to the Sponsor within 24 hours after learning of the 
event, regardless of relationship to study drug: 
 
Serious adverse events (SAEs) 
 
Non-serious AEs of special interest 
 
Pregnancies 
The investigator must report new significant follow-up information for these 
events to the Sponsor immediately (i.e., no more than 24 hours) after 
becoming aware of the information. New significant information includes the 
following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event’s outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
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Investigators must also comply with local requirements for reporting SAEs to 
the local health authority and IRB/EC. 
5.4.1 
EMERGENCY MEDICAL CONTACTS 
MEDICAL MONITOR (SPONSOR’S 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"). 
5.4.2 
REPORTING REQUIREMENTS FOR SERIOUS ADVERSE 
EVENTS AND NON-SERIOUS ADVERSE EVENTS OF SPECIAL 
INTEREST 
For reports of SAEs and non-serious AEs of special interest, investigators 
should record all case details that can be gathered immediately (i.e., no more 
than 24 hours) on the AE eCRF and submit the report via the electronic data 
capture (EDC) system. A report will be generated and sent to 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 immediately 
(i.e., no more than 24 hours) after learning of the event, using the fax 
numbers provided to investigators (see "Protocol Administrative and Contact 
Information & List of Investigators"). Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system. 
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 6 
months after the last dose of study drug. A Pregnancy Report eCRF should 
be completed by the investigator immediately (i.e., no more than 24 hours) 
after learning of the pregnancy and submitted via the EDC system. A 
Pregnancy Report will automatically be generated and sent to the Sponsor 
Safety Risk Management. Pregnancy should not be recorded on the AE eCRF. 
The investigator should have the patient discontinue the study drug and 
discuss with the patient the risks of the pregnancy and the possible effects on 
the fetus. Monitoring of the patient should continue until conclusion of the 
pregnancy. 
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In the event that the EDC system is unavailable, a Pregnancy Report 
worksheet and Pregnancy Fax Coversheet should be completed and faxed to 
the Sponsor Safety Risk Management or its designee immediately (i.e., no 
more than 24 hours) after learning of the pregnancy, using the fax numbers 
provided to investigators (see "Protocol Administrative and Contact 
Information & List of Investigators"). 
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 6 months after the last dose of study drug. A Pregnancy 
Report eCRF should be completed by the investigator immediately (i.e., no 
more than 24 hours) after learning of the pregnancy and submitted via the 
EDC system. Attempts should be made to collect and report details of the 
course and outcome of any pregnancy in the partner of a male patient 
exposed to study drug. The pregnant partner will need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow 
for follow-up on her pregnancy. Once the authorization has been signed, the 
investigator will update the Pregnancy Report eCRF with additional 
information on the course and outcome of the pregnancy. An investigator who 
is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, 
to support an informed decision in cooperation with the treating physician 
and/or obstetrician. 
In the event that the EDC system is unavailable, follow reporting instructions 
provided in Section 5.4.3.1. 
5.4.3.3 
Abortions 
Any spontaneous abortion should be classified as an SAE (as the Sponsor 
considers spontaneous abortions to be medically significant events), recorded 
on the AE eCRF, and reported to the Sponsor immediately (i.e., no more than 
24 hours) after learning of the event (see Section 5.4.2). 
5.4.3.4 
Congenital Anomalies/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 
an SAE, recorded on the AE eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours) after learning of the event (see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER 
ADVERSE EVENTS 
5.5.1 
INVESTIGATOR FOLLOW-UP 
The investigator should follow all unresolved AEs and until the events are 
resolved or stabilized, the patient is lost to follow-up, or it has been determined 
that the study treatment or participation is not the cause of the AE/SAE. 
Resolution of AEs and SAEs (with dates) should be documented on the AE 
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eCRF and in the patient’s medical record to facilitate source data verification 
(SDV). 
All pregnancies reported during the study should be followed until pregnancy 
outcome. If the EDC system is not available at the time of pregnancy outcome, 
follow reporting instructions provided in Section 5.4.3.1. 
5.5.2 
SPONSOR FOLLOW-UP 
For SAEs, non-serious AEs of special interest, and pregnancies, the Sponsor 
or a designee may follow-up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information 
(e.g., from hospital discharge summaries, consultant reports, autopsy reports) 
in order to perform an independent medical assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
At the last scheduled visit, the investigator should instruct each patient to 
report to the investigator any subsequent AEs that the patient’s personal 
physician believes could be related to prior study drug treatment. 
The investigator should notify the Sponsor of any death, SAE or other AE of 
concern occurring at any time after a patient has discontinued study 
participation if the event is believed to be related to prior study drug treatment 
or study procedures. The Sponsor should also be notified if the investigator 
becomes aware of the development of cancer or a congenital anomaly/birth 
defect in a subsequently conceived offspring of a patient that participated in 
this study. 
The investigator should report these events to the Sponsor Safety Risk 
Management on the AE eCRF. If the AE eCRF is no longer available, the 
investigator should report the event directly to Roche/Genentech Safety Risk 
Management via telephone via phone at +1-888-835-2555. 
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 following reference 
documents: 
 
Trastuzumab emtansine and capecitabine Investigator's Brochures 
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 Steering Committee will closely monitor the incidence of these expected 
events during the study. An aggregate report of any clinically relevant 
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imbalances that do not favor the test product will be submitted to health 
authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
PLAN 
Phase I: mBC Patients: 
Enrollment into Cohort 1, HER2-positive mBC patients, will open first. 
Enrolled patients will receive study drug until Investigator-assessed disease 
progression, unacceptable toxicities, patient consent withdrawal, death, 
reasons deemed by the treating physician or study termination by the Sponsor. 
Phase II: Exploration of Efficacy: mBC Patients 
Phase II will include only Cohort 1, i.e. mBC patients. Patients in Cohort 1, 
who achieved MTD level will continue with the Phase II part to be assessed 
for efficacy and safety. Additional patients will be enrolled in this phase in 
order to achieve the required sample size for this part of the study. 
Enrolled patients will receive study drug until Investigator-assessed disease 
progression, unacceptable toxicities, patient consent withdrawal, death, 
reasons deemed by the treating physician or study termination by the Sponsor. 
The final analysis of Phase II part of this study for ORR will be performed at 
the end of study (defined in Section 3.2). 
Phase I: mGC Patients: 
Once MTD is established for Cohort 1, enrollment of HER2-positive and 
locally advanced or mGC patients into Cohort 2 will be opened. 
Enrolled patients will receive study drug until Investigator-assessed disease 
progression, unacceptable toxicities, patient consent withdrawal, death, 
reasons deemed by the treating physician or study termination by the Sponsor. 
6.1 
DETERMINATION OF SAMPLE SIZE 
Sample Size for Phase I: mBC 
This part will be based on a classical 3 by 3 Phase I design. From 3 to 18 
patients might be enrolled into Cohort 1. There is no formal sample size 
estimation for this part. 
Sample Size for Phase II: Exploration of Efficacy: mBC 
Assuming a preferable BORR rate of 75% to 80% in Cohort 1 (mBC patients) 
and aiming for a precision of 8-10%, lower limit of 95% confidence interval of 
at least 65%, a total of 100 patients would need to be evaluable for Cohort 1. 
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Table 8 Sample Size Estimation for Phase II 
Total number of patients is 100 (Phase II) 
Number of Patients/ 
Response 
95% Clopper-Pearson 
Confidence Intervals 
75 patients (75%) 
65–83% 
80 patients (80%) 
71–87% 
Total number of patients adjusted for 10% withdrawal rate is 
110 patients 
For example, the observed BOR of 75% could be estimated to be within 65% 
and 83% with a probability of 95% (Clopper-Pearson exact confidence 
intervals). Adjusting for a withdrawal rate of approximately 10%, 110 patients 
will be enrolled in this phase. Patients from the Phase I (Cohort 1), who 
received the same dose of study medication during Phase I as chosen dose 
during Phase II, will contribute to the sample size of 110 patients. 
The BOR rate of 75% was chosen based on previously published data for 
trastuzumab and capecitabine (Tjulandin et al. 2011). 
The estimation of sample size was performed by Nquery and SAS programs. 
Sample Size for Phase I: mGC 
This part will be based on a classical 3 by 3 Phase I design. From 3 to 18 
patients might be enrolled into Cohort 2. There is no formal sample size 
estimation for this part. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Phase I: mBC Patients 
Due to a small sample size, per-protocol (PP) population will not be defined 
for the Phase I Cohort 1, however major protocol violations will be 
summarized for this phase. A median follow-up will be estimated for Phase I, 
Cohort 1. 
Phase II: Exploration of Efficacy: mBC Patients 
For Phase II, Cohort 1, the PP population will be defined (Section 6.4). A 
median follow-up will be estimated for Phase II, Cohort 1. 
Phase I: mGC Patients 
Due to a small sample size, PP population will not be defined for the Phase I 
Cohort 2, however major protocol violations will be summarized for this phase. 
A median follow-up will be estimated for Phase I, Cohort 2. 
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6.3 
SUMMARIES OF TREATMENT GROUP 
COMPARABILITY 
Phase I: mBC 
As Phase I is the Dose Finding part of the study, there are no treatment group 
comparisons for this part of the study. 
Demographics, medical history and baseline characteristics will be 
summarized. Continuous variable will be summarized by means of median, 
mean, standard deviation, 25th and 75th percentiles and range while 
categorical variables by the number and percentage of patients in each 
category. 
Phase II: mBC 
Phase II includes only Cohort 1, hence treatment comparability is also not 
applicable for this part. 
Demographics, medical history and baseline characteristics will be 
summarized. Continuous variable will be summarized by means of median, 
mean, standard deviation, 25th and 75th percentiles and range while 
categorical variables by the number and percentage of patients in each 
category. 
Phase I: mGC 
As Phase I is the Dose Finding part of the study, there are no treatment group 
comparisons for this part of the study.  
Demographics, medical history and baseline characteristics will be 
summarized. Continuous variable will be summarized by means of median, 
mean, standard deviation, 25th and 75th percentiles and range while 
categorical variables by the number and percentage of patients in each 
category. 
6.4 
EFFICACY ANALYSES 
Phase I: mBC 
The main analysis population will be the safety population including all 
patients who received at least one dose of study medication (trastuzumab 
emtansine and capecitabine). 
Phase II: Exploration of Efficacy: mBC 
The main analysis population for the efficacy analysis will be the intent-to-treat 
population (ITT) including all new patients enrolled in Phase II and patients 
from Cohort 1 who achieved the MTD level. The PP population will include all 
ITT patients who have at least one post-baseline tumor assessment during 
the Phase II and no major protocol violations which will be defined in the 
statistical analysis plan. 
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Phase I: mGC 
The main analysis population will be the safety population including all 
patients who received at least one dose of study medication (trastuzumab 
emtansine and capecitabine). 
6.4.1 
PRIMARY EFFICACY ENDPOINT 
Phase I: mBC Patients 
The primary objectives are reaching the MTD and establishing a safety profile. 
ORR, as a main efficacy endpoint, will be assessed via BORR. The BOR is 
defined as the best response recorded from the date when the MTD is 
achieved until disease progression/recurrence (or death). The number of 
patients is very small in this part of the study. Therefore, all analyses will be 
descriptive. 
Phase II: Exploration of Efficacy: mBC Patients 
The primary efficacy endpoint for Phase II is the BOR as assessed by 
investigators. The BOR is defined as the best response recorded from the 
start of this Phase II until disease progression/recurrence (or death) or for 
patients who were involved in Phase I of the study: the best response from 
the date of the MTD reached until disease progression/recurrence or death. 
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 28 days 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). 
The number and proportions of responders and non-responders together with 
two-sided, 95% Clopper-Pearson confidence intervals will be presented. 
Phase I: mGC Patients 
The primary objectives are reaching the MTD and establishing a safety profile. 
ORR, as a main efficacy endpoint, will be assessed via BORR. The BOR is 
defined as the best response recorded from the date when the MTD is 
achieved until disease progression/recurrence (or death). The number of 
patients is very small in this part of the study. Therefore, all analyses will be 
descriptive. 
6.4.2 
SECONDARY EFFICACY ENDPOINTS 
Phase I: mBC 
Due to the small number of patients and the design of this part of the study, 
no secondary efficacy endpoints will be investigated. 
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Phase II: Exploration of Efficacy: mBC 
The secondary endpoints for Phase II will be: 
 
Time to response (TTR) 
 
Duration of response (DoR) 
 
Time to progression (TTP) 
 
Time to treatment failure (TTF) 
 
Progression free survival (PFS) 
 
Clinical benefit rate (CBR) 
 
Overall survival (OS) 
TTR is defined as the time from enrollment to first documentation of confirmed 
PR or CR (whichever occurs first). Patients who do not have a confirmed 
response will be censored at the date of the last tumor assessment. 
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 below. Only patients with 
BOR of CR or PR (i.e. responders) will be included in the analysis of DoR. 
For patients with a BOR of CR or PR, TTR is defined as the time from the 
date of enrollment into Cohort 1 to the date of first CR or PR. The censoring 
rules will be similar to those of the PFS. 
TTP is defined as time from enrollment into Cohort 1 to the first occurrence of 
PD. Patients who have not progressed at the time of study completion 
(including patients who have died before PD) or who are lost to follow-up are 
censored at the date of the last tumor assessment. 
TTF is defined from enrollment into Cohort 1 until TTF, for example, to 
disease progression, death, withdrawal due to AE or lab abnormality, or 
refusal of treatment. Patients who do not experience any of the above events 
while on study will be censored on the day of their last tumor assessment. For 
patients who were already in Phase I, the start date will be date of first study 
medication that was chosen for Phase II. 
PFS is defined as the time from enrolment into Cohort 1 until the first 
documented progression of disease or death from any cause, whichever 
occurs first. For patients who were already enrolled in Cohort 1 during Phase 
1, the time to PFS will be defined from the start date of study medication that 
was chosen for Phase II. 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 at the time of Phase II will be censored at 
the time of enrolment plus 1 day. 
Clinical benefit response includes patients whose best (confirmed) response 
was PR or CR or stable disease that lasts at least 6 months. 
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OS is defined as the time from the date of enrollment into Cohort 1 until the 
date of death, regardless of the cause of death. For patients who were 
already in Phase I, same rule as for PFS will be applied. Patients who were 
alive at the time of the analysis will be censored at the date of the last follow-
up assessment. 
Estimates for the survivor function for the time-to-event variable such as TTR, 
DoR, TTP, TTF, PFS, and OS, will be obtained by using the Kaplan-Meier 
approach. CBR will be summarized in a similar way to the primary efficacy 
endpoint, BOR. 
Phase I: mGC 
Due to the small number of patients and the design of this part of the study, 
no secondary efficacy endpoints will be investigated. 
6.5 
SAFETY ANALYSES 
Safety Population Phase I: mBC 
The safety population (SP) Phase I, mBC will include all patients who 
received at least one dose of study medication during Phase I. Safety 
endpoints will be summarized for this part of the study and presented. 
Safety parameters will be analysed in a similar way to safety parameters in 
Phase I: mGC. 
Phase II: Exploration of Efficacy: mBC 
The SP Phase II, mBC will include all patients who received at least one dose 
of study medication during Phase II. Safety endpoints will be summarized for 
this part of the study and presented. 
Safety endpoints during Phase II will be assessed via: total AEs, AEs 
Grade ≥ 3, SAEs, premature withdrawal from study and study medication, 
laboratory parameters, LVEF, exposure to study medication, concomitant 
medications, vital signs, ECOG performance status, and physical examination. 
The incidence of AEs and SAEs will be summarized according to the primary 
system-organ class (SOC) and within each SOC, by MedDRA preferred term. 
Patients who died will be listed together with the cause of death. 
Laboratory parameters, hematology and biochemistry, will be presented in 
shift tables of NCI-CTC grade at baseline versus worst grade during treatment 
for Cohort 1, Phase II and overall. 
LVEF will be summarized over time by means of mean, median and range 
(minimum and maximum) and will be presented graphically. Vital signs will be 
analyzed in a similar way. 
Other safety variables, such as exposure to study medication, concomitant 
medications and physical examinations will be analyzed in a similar way. The 
exposure of study medication will be summarized by frequency tables. 
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ECOG performance status will be summarized over time and the percentage 
of patients in different categories will be presented by bar charts at different 
time points. 
Safety Population Phase I: mGC 
The SP Phase I, mGC will include all patients who received at least one dose 
of study medication during Phase I. Safety endpoints will be summarized for 
this part of the study and presented. 
Safety parameters for this part of the study will be summarized by treatment 
dose. The summaries of AEs, SAEs, AEs that cause discontinuation from the 
study treatment will be analyzed in a similar way to AEs in Phase II. 
The incidence of AEs and SAEs will be summarized according to the primary 
system-organ class (SOC) and within each SOC, by MedDRA preferred term. 
Patients who died will be listed together with the cause of death. 
Laboratory parameters, hematology and biochemistry, will be presented in 
shift tables of NCI-CTC grade at baseline versus worst grade during treatment 
for Cohort 2, Phase I and overall. 
LVEF will be summarized over time by means of mean, median and range 
(minimum and maximum) and will be presented graphically. Vital signs will be 
analyzed in a similar way. 
Other safety variables, such as exposure to study medication, concomitant 
medications and physical examinations will be analyzed in a similar way. The 
exposure of study medication will be summarized by frequency tables. 
ECOG performance status will be summarized over time and the percentage 
of patients in different categories will be presented by bar charts at different 
time points. 
6.6 
PHARMACODYNAMIC ANALYSES 
No pharmacodynamic analyses are planned for this study. 
6.7 
PHARMACOKINETIC ANALYSES 
For Phase I only (mBC and mGC Patients): 
The following PK parameters of trastuzumab emtansine and capecitabine (not 
limited to these listed) will be determined only in the Phase I part of the study 
for Cohort 1 and Cohort 2 in all patients who receive study treatment using 
either non-compartmental and/or population methods, if data allow: 
 
Serum concentrations of trastuzumab emtansine (conjugate) and total 
trastuzumab 
 
Plasma concentrations of DM1, capecitabine and its active metabolite 5-
fluorouracil (5-FU) 
 
Total exposure (AUC)  
 
Cmax 
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 
Clearance (CL) 
 
Volume of distribution (Vd) 
 
Terminal half-life (T1/2) 
The pharmacokinetics of trastuzumab emtansine, total trastuzumab and DM1 
will be compared with historical single agent PK data to evaluate the potential 
effect of capecitabine on the PK of trastuzumab emtansine and related 
analytes. The PK of capecitabine and its active metabolite 5-FU in cycle 1 (in 
the absence of trastuzumab emtansine) will be compared with the PK of cycle 
2 (in the presence of trastuzumab emtansine) to evaluate the potential effect 
of trastuzumab emtansine on the PK of capecitabine and 5-FU. 
All PK parameters will be listed and tabulated by treatment dose and by 
Cohort. Descriptive summary statistics including arithmetic mean, geometric 
mean (e.g. AUC and Cmax), median, range, SD and coefficient of variation will 
be presented for each cohort. Nonlinear mixed effects modeling will be also 
used but details will be presented in the statistical analysis plan. 
6.8 
EXPLORATORY ANALYSES 
For Phase II: Exploration of Efficacy in mBC Patients only: 
Subgroup analysis for BOR, safety (AEs, SAEs and AE with Grade ≥ 3) in 
Phase II will be presented for: elderly versus younger patients, and patients 
with ECOG 0–1 versus ECOG 2. More details about subgroups will be 
provideded in the statistical analysis plan. 
Pharmacoeconomic Endpoint: 
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. 
6.9 
INTERIM ANALYSES 
There is no formal efficacy interim analysis. 
The design of this study includes: Phase I, Phase II and different cohorts. 
Corresponding analyses as described in the protocol will be performed when 
all data for particular cohort and study phase are collected and cleaned. 
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. 
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The Sponsor will produce an EDC Study Specification document that 
describes the quality checking to be performed on the data. Central laboratory 
data and other 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 have access to a manual for appropriate eCRF 
completion. eCRFs will be submitted electronically to the Sponsor and should 
be handled in accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff. eCRFs 
should be reviewed and electronically signed and dated by the investigator or 
a designee. 
At the end of the study, the investigator will receive patient data for his or her 
site in a readable format on a compact disc that must be kept with the study 
records. Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing SDV to confirm that critical protocol data 
(i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are 
recorded and documented for the first time. They include, but are not limited 
to, hospital records, clinical and office charts, laboratory notes, memoranda, 
patient-reported outcomes, evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies of transcriptions 
that are certified after verification as being accurate and complete, microfiche, 
photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Source documents that are required to verify the validity and completeness of 
data entered into the eCRFs must not be obliterated or destroyed. 
To facilitate SDV, the investigators and institutions must provide the Sponsor 
with 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), 
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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. 
In collaboration with the study monitor, 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 Good Clinical Practice (GCP) (see Section 4.9 of the 
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 
GCP and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever 
affords the greater protection to the individual. The study will comply with the 
requirements of the ICH E2A guideline (Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting). Studies conducted in the 
United States or under a U.S. Investigational New Drug (IND) application will 
comply with U.S. FDA regulations and applicable local, state, and federal laws. 
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Studies conducted in the European Union (EU)/European economic area 
(EEA) will comply with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
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 Form or any alternate Consent 
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 Form 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/IEC 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 
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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. 
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 
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, 
the 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. 
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 
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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 
investigator will permit national and local health authorities, the 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 a Steering Committee, central laboratory, IxRS, eCRF, 
and will be conducted by a contract research organization (CRO) together 
with the Sponsor. 
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 the Sponsor 
personnel exceeded that of conventional monitoring will be considered as a 
joint publication by the investigator and the appropriate the 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 
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necessary to eliminate an immediate hazard to patients or changes that 
involve logistical or administrative aspects only (e.g., change in Medical 
Monitor or contact information). 
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10. 
REFERENCES 
1. Albarello, L, Pecciarini, L, & Doglioni, C (2011). HER2 testing in gastric 
cancer. Advances in anatomic pathology 2011; 18:53–59. 
2. Austin CD, De Mazière AM, Pisacane PI, et al. Endocytosis and sorting of 
ErbB2 and the site of action of cancer therapeutics trastuzumab and 
geldanamycin. Mol Biol Cell 2004; 15:5268-5282. 
3. Bang YJ, van Cutsem E, Feyereislova A, et al. Trastuzumab in 
combination with chemotherapy versus chemotherapy alone for treatment 
of HER2-positive advanced gastric or gastro-oesophageal junction cancer 
(ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010; 
376:687–697. 
4. Blum JL, Dieras V, Lo Russo PM, et al. Multicenter, phase II study of oral 
capecitabine in taxane-pretreated metastatic breast carcinoma patients. 
Cancer 2001; 92:1759–1768. 
5. Blum JL, Jones SE, Buzdar AU, et al. Multicenter phase II study of 
capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 
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6. Cabanillas F, Chan KK, Floss HG, et al. Results of a phase II study of 
maytansine in patients with breast carcinoma and melanoma. Cancer 
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7. Cassady JM, Chan KK, Floss HG, et al. Recent developments in the 
maytansinoid antitumor agents. Chem Pharm Bull (Tokyo) 2004; 52:1–26. 
8. Catalano V, Labianca R, Beretta GD, et al. Gastric cancer. Crit Rev Oncol 
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9. Igawa Y, Matsubara M, Matsunaga K et al. Pharmacokinetic (PK) and 
pharmacodynamic (PD) analysis of trastuzumab emtansine (T-DM1) in 
Japanese patients with advanced or recurrent HER2-positive breast 
cancer (JO22591): Comparison with Western patients. ASCPT 2012. 
10. De Vivo R, Pignata S, Palaia R, et al. The role of chemotherapy in the 
management of gastric cancer. J Clin Gastroenterol. 2000; 30:364–371. 
11. Erickson HK, Park PU, Widdison WC, et al. Antibody-maytansinoid 
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degradation and linker-dependent intracellular processing. Cancer Res. 
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12. Faivre J, Forman D, Esteve J, et al. Survival of patients with oesophageal 
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13. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer 
in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127:2893–917. 
14. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for 
HER2-positive advanced breast cancer. N Engl J Med. 2006; 355:2733–
43. 
15. Girish S, Gupta M, Wang B, et al. Clinical pharmacology of trastuzumab 
emtansine (T-DM1): an antibody–drug conjugate in development for the 
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treatment of HER2-positive cancer. Cancer Chemother Pharmacol. 2012; 
69:1229–40. 
16. 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 
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17. Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system 
for gastric cancer: results from a validation study. Histopathology 2008; 
52:797–805. 
18. Issell BF, Crooke ST. Maytansine. Cancer Treat Rev. 1978; 5:199–207. 
19. Jemal A, Bray F, Center MM, et al. Global Cancer Statistics. CA Cancer J 
Clin. 2011; 61:69–90. 
20. 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. 
21. 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-
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22. Krop IE, Mita M, Burris HA, et al. A Phase I Study of Weekly Dosing of 
Trastuzumab-DM1 (T-DM1) in Patients with Advanced HER 2-Positive 
Breast Cancer. Clin Oncol 2008; 26:suppl.abstract:1029. 
23. Krop IE, Mita M, Burris HA, et al. A phase I study of weekly dosing of 
trastuzumab-DM1 (T-DM1) in patients with advanced HER2+ breast 
cancer. (SABCS 2008) Cancer Res 2009; 69:suppl1:3136. 
24. Lewis Phillips G, Fields CT, Crocker L, et al. Potent anti-tumor activity of 
trastuzumab-DM1 antibody conjugate in combination with cytotoxic 
chemotherapeutic agents, antibodies or small molecule kinase inhibitors. 
AACR 2008; poster#2133. 
25. 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. 
26. 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. 
27. Parkin DM, Bray F, Ferlay J, et al. Global Cancer Statistics 2002. CA 
Cancer J Clin. 2005; 55:74–108. 
28. Power DG, Kelsen DP, Shah MA. Power Advanced gastric cancer--slow 
but steady progress. Cancer Treat Rev. 2010; 36:384-92. 
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29. 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. 
30. Ries LAG, Melbert D, Krapcho M, et al (eds). SEER Cancer Statistics 
Review 1975 2005. Bethesda (MD): National Cancer Institute, 
2008;http://seer.cancer.gov/csr/1975 2005 
31. Sawaki A, Ohashi Y, Omuro Y, et al. Efficacy of trastuzumab in Japanese 
patients with HER2-positive advanced gastric or gastroesophageal 
junction cancer: a subgroup analysis of the Trastuzumab for Gastric 
Cancer (ToGA) study. Gastric Cancer 2011; epub ahead of print. DOI: 
10.1007/s10120-011-0118-1. 
32. Shen B-Q, Bumbaca D, Saad O, et al. Metabolic Fate and 
Pharmacokinetic Characterization of Trastuzumab Emtansine (T-DM1): 
An Emphasis on Preclinical and Clinical Catabolism. ASCPT 2011. 
33. 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; 235:177–182. 
34. 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. 
35. Spector NL, Xia W, Burris H 3rd, et al. Study of the biologic effects of 
lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on 
tumor growth and survival pathways in patients with advanced 
malignancies. J Clin Oncol. 2005; 23:2502–12. 
36. Sundaresan S, Penuel E, Sliwkowski MX. The biology of human 
epidermal growth factor receptor 2. Curr Oncol Rep. 1999;1:16–22. 
37. Tanner M, Hollmen M, Junttila TT, et al. Amplification of HER2 in gastric 
cancer—association with topoisomerase IIa gene amplification, intestinal 
type, poor prognosis and sensitivity to trastuzumab. Annals Oncol. 2005; 
16: 273–278. 
38. Therasse P, Eisenhauer EA, Verwij J. RECIST revisited: a review of 
validation studies on tumour assessment. Eur J Cancer. 2000; 42:1031–
1039. 
39. Tjulandin S, Makhson A, Gligorov J, et al. First results of a Phase II study 
of Bevacizumab in combination with trastuzumab and capecitabine as 
first-line treatment of HER2-positive LR/MBC. ASCO 2011; Poster#571. 
40. von Minckwitz G, Schwedler K, Schmidt M, et al. Trastuzumab beyond 
progression: overall survival analysis of the GBG 26/BIG 3-05 phase III 
study in HER2-positive breast cancer. Eur J Cancer 2011; 47:2273–81. 
41. Yang J, Wang Y, Zhao H, et al. Combination of exposure-response and 
case-control analyses in regulatory decision making. J Clin Oncol 2011; 
29: suppl; 4087. 
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42. Yoon HH, Shi Q, Sukov WR, et al. Association of HER2/ErbB2 expression 
and gene amplification with pathologic features and prognosis in 
esophageal adenocarcinomas. Clin Cancer Res. 2012; 18:546-54. 
43. Wardley A, et al. Trastuzumab plus docetaxel with or without capecitabine 
in patients with HER2-positive advanced/metastatic breast cancer: first 
efficacy results from the Phase II MO16419 (CHAT) Study. SABCS 2006; 
Abstract# 2063. 
44. WHO, World Health Statistics 2011. 
 
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Appendix 1 
Schedule of Assessments 
Table 1Schedule of assessments for mBC patients (Phase I and II, Cohort 1) 
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 onwards 
Safety 
Follow-Up 
Visit 
Safety  
Follow-Up2 
Day 
-28 to -1 
1 
8 
15 
1 
8 
15 
1 
8 
15 
28-42 days 
after last 
dose 
every 6 
months 
Informed Consent 
Xa 
 
 
 
 
 
 
 
 
 
 
 
HER2 Status  
Xb 
 
 
 
 
 
 
 
 
 
 
 
Medical History and Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination  
X 
 
 
 
 
 
 
 
 
 
 
 
Limited Physical Examinationc 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Height and Weightd 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Vital Signse 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
ECOG Performance Status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Concomitant Medication Reporting 
Xf 
X 
Ongoing 
 
Adverse Event Reporting 
Xg 
Ongoing 
X 
  Xh 
12-lead ECG  
X  
 
 
 
 
 
 
 
 
 
 
 
ECHO/MUGAi 
Xi 
 
 
Xi   
 
 
Xi 
 
 
Xi 
Xi   
 
Tumor Assessmentsj 
X 
At cycle 3 (9 weeks after C1 D1), and then every 4th cycle (12 weeks there-after, 
regardless of dose delay or early discontinuation, until disease progression or study 
termination) 
X 
X 
Brain CT or MRIk 
X 
At the discretion of the investigator, if clinically indicated, until disease progression 
Bone Scan/Imagingl 
X 
As clinically indicated 
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Schedule of Assessments (cont.) 
Table 1Schedule of assessments for mBC patients (Phase I and II, Cohort 1) (cont.) 
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 onwards 
Safety 
Follow-Up 
Visit 
Safety 
Follow-Up2  
Day 
-28 to -1 
1  
8 
15 
1  
8 
15 
1  
8 
15 
28-42 days 
after last 
dose 
every 6 
months 
Hematologym 
X  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
 
 
X 
 
Biochemistryo 
X  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
 
 
X 
 
Urinalysisp 
X  
As clinically indicated 
X 
 
INR/aPTT 
X  
As clinically indicated, e.g. for patients receiving anticoagulation therapy 
X 
 
Pregnancy Testq 
X  
 
 
 
 
 
X q 
 
 
X q 
X  
X 
PK/PD Samples (see Appendix 2)r 
 
Xr 
 
 
Xr 
 
 
 
 
 
 
 
Assessment of Patient 
Hospitalizations and/or Hospital 
Visits 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Administration of trastuzumab 
emtansine 
 
D 2s 
 
 
D 1s 
 
 
D 1s 
 
 
 
 
Administration of capecitabine 
 
D 1–14 
 
D 1–14 
 
D 1–14 
 
 
 
Overall survival 
X 
X 
X 
X 
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AE = Adverse Event; aPTT = Activated Partial Thromboplastin Time; CT = Computed Tomography; ECHO = Echocardiogram; ECOG = Eastern Cooperative 
Oncology Group; D= Day; 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, INR and aPTT assessments) at Screening: to be performed within 14 days prior to first 
treatment. Screening laboratory assessments may be done on the same day of first study treatment (Cycle1 Day1). 
2.All patients will be followed up every 6 months (except for pregnancy every 3 months) until disease progression or study closure, whichever occurs first. 
Patients who discontinue study treatment for reasons other than disease progression will continue to undergo tumor assessments every 3–6 months. 
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. Patients who are on the MTD dose established in Cohort 1 must re-consent to 
be enrolled into Phase II. 
b)HER2-positivity is defined as IHC 3+ or gene amplification by ISH. It will be performed locally for mBC patients.  
c)Limited symptom-directed physical examination. 
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. 
g)During screening, only SAEs considered related to protocol-mandated procedures will be collected. 
h)Patients will be followed for new or worsening AEs for 28 days following the last infusion of study drug or until the early termination visit, until treatment-
related AEs resolve or stabilize, or until the initiation of another anti-cancer therapy, whichever occurs first. After 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 15-
21 of 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. 
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j)Tumor assessments (± 5 business days), including a CT or MRI with contrast of the chest, abdomen, and pelvis should be performed according to the 
indicated schedule. 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, e.g. the same contrast protocol for 
CT scans. For patients who discontinue study treatment for reasons other than disease progression, continued tumor assessments according to the protocol 
schedule of assessments is required. 
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 and in Appendix 3. 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 study treatment, non-isotopic radiographic modalities should be utilized to document the extent of bony 
metastatic disease. Refer to Appendix 4 in the protocol 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)Assessments should be performed at screening, on Day 1, 8 and 15 of Cycles 1–3, on Day 1 of all subsequent cycles, and weekly following any 
hematologic AE. If capecitabine is discontinued due to toxicity, assessments should be performed weekly (minimum) until resolution of the AE (Grade  1/ 
baseline), and on Day 1 of subsequent cycles thereafter. All assessments should 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, blood urea nitrogen (BUN)/urea, creatinine, uric acid, total 
protein, albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), G-GT, LDH, total bilirubin (and direct bilirubin where total bilirubin > ULN). 
p)Includes specific gravity, pH, protein, glucose, blood, ketones and bilirubin. 
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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. 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 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. 
r)Pharmacokinetic assessments will be performed during the dose finding period of the study only (see Appendix 2). 
s)Trastuzumab emtansine will be administered on Day 1 of each 3 weekly cycle for all mBC patients in Cohort 1 and Phase II period of the study except in the 
first cycle where trastzumab emtansine will be given on DAY 2 (to allow PK sampling). 
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Schedule of Assessments (cont.) 
Table 2Schedule of assessments for mGC patients (Phase I, Cohort 2) 
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 onwards 
Safety 
Follow-Up 
Visit 
Safety 
Follow-Up2  
Day 
-28 to -1 
1 
8 
15 
1 
8 
15 
1 
8 
15 
28-42 days 
after last 
dose 
every 6 
months 
Informed Consent 
Xa 
 
 
 
 
 
 
 
 
 
 
 
HER2 Status  
Xb 
 
 
 
 
 
 
 
 
 
 
 
Medical History and Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination  
X 
 
 
 
 
 
 
 
 
 
 
 
Limited Physical Examinationc 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Height and Weightd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signse 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
ECOG Performance Status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Concomitant Medication Reporting 
Xf 
X 
Ongoing 
 
Adverse Event Reporting 
Xg 
Ongoing 
X 
Xh 
12-lead ECG  
X  
 
 
 
 
 
 
 
 
 
 
 
ECHO/MUGAi 
Xi 
 
 
Xi   
 
 
Xi 
 
 
Xi 
Xi   
 
Tumor Assessmentsj 
X 
At 9 weeks after C1D1, and every 12 weeks thereafter, regardless of dose delay or early 
discontinuation, until disease progression or study termination 
X 
 
Brain CT or MRIk 
X 
At the discretion of the investigator, if clinically indicated, until disease progression 
Bone Scan/Imagingl 
X 
As clinically indicated 
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Schedule of Assessments (cont.) 
Table 2Schedule of assessments for mGC patients (Phase I, Cohort 2) (cont.) 
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 onwards 
Safety 
Follow-Up 
Visit 
Safety 
Follow-Up3  
Day 
-28 to -1 
1  
8 
15 
1  
8 
15 
1  
8 
15 
28-42 days 
after last 
dose 
every 6 
months 
Hematologym 
X  
Xn 
Xn  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
X 
 
Biochemistryo 
X  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
X 
 
Urinalysisp 
X  
As clinically indicated 
X 
 
INR/aPTT 
X  
As clinically indicated, e.g. for patients receiving anticoagulation therapy 
X 
 
Pregnancy Testq 
X  
 
 
 
 
 
Xq 
 
 
Xq 
X 
X 
PK/PD Samples (see Appendix 2) 
 
X 
 
 
X 
 
 
 
 
 
 
 
Assessment of Patient 
Hospitalizations and/or Hospital 
Visits 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Administration of trastuzumab 
emtansine 
 
D 2r 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Administration of capecitabine 
 
D 1–14 
 
D 1–14 
 
D 1–14 
 
 
 
Overall survival 
X 
X 
X 
X 
AE = Adverse Event; aPTT = Activated Partial Thromboplastin Time; CT = Computed Tomography; ECHO = Echocardiogram; ECOG = Eastern Cooperative 
Oncology Group; D= Day; 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 
 
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Appendix 1 
Schedule of Assessments (cont.) 
1.NOTE: Local laboratory (hematology, biochemistry, urinalysis, INR and aPTT assessments) at Screening: to be performed within 14 days prior to first study 
treatment. Screening laboratory assessments may be done on the same day of first study treatment (Cycle1 Day1) visit. 
2.All patients will be followed up every 6 months (except for pregnancy which is every 3 months) until disease progression or study closure, whichever occurs 
first. Patients who discontinue study treatment for reasons other than disease progression will continue to undergo tumor assessments every 3-6 months. 
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+ alone or IHC 2+ in combination with gene amplification by ISH. For mGC patients enrolled into Cohort 2, central 
confirmation of HER2 status is required. 
c)Limited symptom-directed physical examination. 
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 fist study treatment. 
g)During screening, only SAEs considered related to protocol-mandated procedures will be collected. 
h)Patients will be followed for new or worsening AEs for 28 days following the last infusion of study drug or until the early termination visit, until treatment-
related AEs resolve or stabilize, or until the initiation of another anti-cancer therapy, whichever occurs first. After 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 Days 
15–21, 30–42 and 9 weeks 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. 
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j)Tumor assessments (± 5 business days), including a CT or MRI with contrast of the chest, abdomen, and pelvis should be performed according to the 
indicated schedule. 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, e.g. the same contrast protocol for 
CT scans. For patients who discontinue study treatment for reasons other than disease progression, continued tumor assessments according to the protocol 
schedule of assessments is required. 
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 and in Appendix 3. 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 4 in the protocol for additional details. 
m)Hematologic assessments include Hemoglobin (Hb), hematocrit, red blood cell count, platelet count, and WBC with differential (including neutrophils, 
lymphocytes, monocytes, eosinophils and basophils). 
n)Assessments should be performed at screening, on Day 1, 8 and 15 of all cycles. All assessments should 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/urea, creatinine, uric acid, total protein, albumin, 
alkaline phosphatase, ALT (SGPT), AST (SGOT), G-GT, LDH, total bilirubin (and direct bilirubin where total bilirubin > ULN). 
p)Includes specific gravity, pH, protein, glucose, blood, ketones and bilirubin. 
q)Serum -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. 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 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. 
r)Trastuzumab emtansine will be administered on Day 1 of each weekly cycle for all patients enrolled in Cohort 2 (A&B) except in the first cycle where 
trastzumab emtansine will be given on DAY 2 (to allow drug interaction assessment). 
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Appendix 2 
Pharmacokinetic Sampling for Phase I, Metastatic Breast and 
Gastric Cancer Patients 
 
Trastuzumab 
emtansine, total 
trastuzumab and DM1 
PK samples 
Capecitabine and 5-FU 
PK samples 
Cycle 1 Day 1 
 
 
Pre capecitabine dose 
 
x 
30 min post capecitabine dosing 
 
x 
60 min post capecitabine dosing 
 
x 
1.5 hours post capecitabine 
dosing 
 
x 
2 hours post capecitabine 
dosing 
 
x 
2.5 hours post capecitabine 
dosing 
 
x 
4 hours post capecitabine 
dosing 
 
x 
6 hours post capecitabine 
dosing 
 
x 
Cycle 1 Day 2 
 
 
Pre trastzumab emtansine dose 
x 
 
15-30 minutes after end of 
trastuzumab emtansine infusion 
x 
 
Cycle 2 Day 1 
 
 
Pre trastuzumab emtansine or 
capecitabine dose 
x 
x 
30 min post capecitabine dosing 
 
x 
60 min post capecitabine dosing 
 
x 
1.5 hours post capecitabine 
dosing 
 
x 
15-30 min after end of 
trastuzumab emtansine infusion 
x 
 
2 hours post capecitabine 
dosing 
 
x 
2.5 hours post capecitabine 
dosing 
 
x 
4 hours post capecitabine 
dosing 
 
x 
 
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Pharmacokinetic Sampling for Phase I, Metastatic Breast and 
Gastric Cancer Patients (cont.) 
 
Trastuzumab 
emtansine, total 
trastuzumab and DM1 
PK samples 
Capecitabine and 5-FU 
PK samples 
6 hours post capecitabine 
dosing 
 
x 
Cycle 3 
 
 
Pre trastuzumab emtansine 
dose 
x 
 
PK = pharmacokinetic; 5-FU = 5-fluoruracil 
 
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Appendix 3 
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 CT or magnetic resonance imaging (MRI) scan (CT/MRI scan 
slice thickness/interval no greater than 5 mm) 
 
10-mm caliper measurement by clinical examination (lesions that cannot 
be accurately measured with calipers should be recorded as non-
measurable) 
 
20 mm by chest X-ray 
Malignant Lymph Nodes. To be considered pathologically enlarged and 
measurable, a lymph node must be  15 mm in the short axis when assessed 
by CT scan (CT scan slice thickness recommended to be no greater than 5 
mm). At baseline and follow-up, only the short axis will be measured and 
followed.  See also notes below on “Baseline Documentation of Target and 
Non-Target Lesions” for information on lymph node measurement. 
                                            
 
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228–47. 
2 For consistency within this document, the section numbers and cross-references to other  
sections within the article have been deleted and minor formatting changes have been made. 
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Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.) 
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. 
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, 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. 
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Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.) 
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 
possible to the treatment start and never more than 28 days 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 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 
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Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.) 
be taken in measurement of target lesions on a different modality and 
interpretation of non-target disease or new lesions, since the same lesion may 
appear to have a different size using a new modality. 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should 
not be used as a method of measurement. 
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology. The 
utilization of these techniques for objective tumor evaluation cannot generally 
be advised. 
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 
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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 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 
 
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 
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In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. 
The appearance of one or more new lesions is also considered 
progression. 
 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
on study 
b. Special Notes on the Assessment of Target Lesions 
Lymph Nodes. Lymph nodes identified as target lesions should always have 
the actual short axis measurement recorded (measured in the same 
anatomical plane as the baseline examination), even if the nodes regress 
to < 10 mm on study. This means that when lymph nodes are included as 
target lesions, the sum of lesions may not be zero even if CR criteria are met, 
since a normal lymph node is defined as having a short axis of < 10 mm. 
Target Lesions That Become too Small to Measure. During the study, all 
lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very 
small (e.g., 2 mm). However, sometimes lesions or lymph nodes that are 
recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may 
report them as being too small to measure. When this occurs, it is important 
that a value be recorded on the CRF, as follows: 
 
If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. 
 
If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned and below 
measuralble limit (BML) should be ticked. (Note: It is less likely that this 
rule will be used for lymph nodes since they usually have a definable size 
when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and BML should also be ticked). 
To reiterate, however, if the radiologist is able to provide an actual measure, that 
should be recorded, even if it is below 5 mm, and in that case BML should not be 
ticked. 
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions 
fragment, the longest diameters of the fragmented portions should be added  
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Modified Excerpt from Original Publication (cont.) 
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. 
 
Complete response (CR): Disappearance of all non-target lesions and 
(if applicable) normalization of tumor marker level 
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
 
Non-CR/Non-PD: Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
 
Progressive disease (PD): Unequivocal progression of existing non-target 
lesions 
The appearance of one or more new lesions is also considered 
progression. 
d. Special Notes on Assessment of Progression of Non-Target Disease 
When the Patient Also Has Measurable Disease. In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be 
an overall level of substantial worsening in non-target disease in a magnitude 
that, even in the presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A 
modest increase in the size of one or more non-target lesions is usually not 
sufficient to qualify for unequivocal progression status. The designation of 
overall progression solely on the basis of change in non-target disease in the 
face of SD or PR of target disease will therefore be extremely rare. 
When the Patient Has Only Non-Measurable Disease. This circumstance 
arises in some Phase III trials when it is not a criterion of study entry to have 
measurable disease. The same general concepts apply here as noted above; 
however, in this instance there is no measurable disease assessment to 
factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by 
definition: if all lesions are truly non-measurable), a useful test that can be  
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Modified Excerpt from Original Publication (cont.) 
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 partial or CR. For example, necrosis of a liver lesion may be reported on 
a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not 
scanned at baseline is considered a new lesion and will indicate disease 
progression. 
If a new lesion is equivocal, for example because of its small size, continued 
therapy and follow-up evaluation will clarify if it represents truly new disease. 
If repeat scans confirm there is definitely a new lesion, then progression 
should be declared using the date of the initial scan. 
Evaluation of Response 
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. 
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Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.) 
When patients have non-measurable (therefore non-target) disease only, 
Table 2 is to be used. 
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. 
 
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Modified Excerpt from Original Publication (cont.) 
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 
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. 
c. Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes 
decrease to “normal” size (10 mm), they may still have a measurement 
reported on scans. This measurement should be recorded even though the 
nodes are normal in order not to overstate progression should it be based on 
increase in size of the nodes. As noted earlier, this means that patients with 
CR may not have a total sum of “zero” on the CRF. 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time 
should be reported as “symptomatic deterioration.” Every effort should be 
made to document objective progression even after discontinuation of 
treatment. Symptomatic deterioration is not a 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, Table 3. 
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Modified Excerpt from Original Publication (cont.) 
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. 
 
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Appendix 3 
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.) 
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 4 
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. eSupplies 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 5 
New York Heart Association Classification of Functional 
Cardiac Capacity 
Class 
 
I 
No limitation: Ordinary physical activity does not cause undue fatigue, 
dyspnea, or palpitation. 
II 
Slight limitation of physical activity: Such patients are comfortable at rest.  
Ordinary physical activity results in fatigue, palpitations, dyspnea, or angina. 
III 
Marked limitation of physical activity: Although patients are comfortable at 
rest, less than ordinary physical activity will lead to symptoms. 
IV 
Inability to carry on physical activity without discomfort: Symptoms of 
congestive heart failure are present even at rest. With any physical activity, 
increased discomfort is experienced. 
From: Criteria Committee, New York Heart Association, Inc. Diseases of the heart 
and blood vessels. Nomenclature and criteria for diagnosis. 6th ed. Boston, Little, 
Brown and Co, 1964:114. 
 
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TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................. 10 
PROTOCOL SYNOPSIS .................................................................................... 11 
1. 
BACKGROUND .......................................................................................... 27 
1.1 
Background on Disease......................................................... 27 
1.1.1 
HER2-Positive Breast Cancer, Metastatic 
Breast Cancer ....................................................................... 27 
1.1.2 
HER2-Positive Locally Advanced or 
Metastatic Gastric Cancer ..................................................... 28 
1.2 
Background on Study Drugs .................................................. 29 
1.2.1 
Trastuzumab Emtansine ........................................................ 29 
1.2.1.1 Study TDM3569g ................................................................. 31 
1.2.1.2 Study TDM4258g ................................................................. 31 
1.2.1.3 Study TDM4374g ................................................................. 32 
1.2.1.4 Study TDM4450g ................................................................. 33 
1.2.1.5 Study TDM4688g ................................................................. 34 
1.2.1.6 Phase III Study TDM4370g .................................................. 34 
1.2.1.7 Pharmacokinetics ................................................................. 35 
1.2.2 
Capecitabine .......................................................................... 37 
1.2.2.1 Study BO18255: Capecitabine and 
Trastuzumab in mGC ........................................................... 37 
1.2.3 
Preclinical Data of the Combination of Trastuzumab 
Emtansine and a Fluoropyrimidine ........................................ 38 
1.3 
Study Rationale and Risk-Benefit Assessment ...................... 40 
1.3.1 
For mBC ................................................................................ 40 
1.3.2 
For mGC ................................................................................ 41 
2. 
OBJECTIVES .............................................................................................. 41 
2.1 
Phase I: MTD Finding of Trastuzumab 
Emtansine and Capecitabine in mBC .................................... 41 
2.1.1 
Primary Objective .................................................................. 41 
2.1.2 
Secondary Objectives ............................................................ 41 
2.2 
Randomized Phase II: Exploration of Efficacy 
and Safety in mBC ................................................................. 42 
2.2.1 
Primary Objective .................................................................. 42 
2.2.2 
Secondary Objectives ............................................................ 42 
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2.3 
Phase I: MTD Finding of Trastuzumab 
Emtansine and Capecitabine in MGC .................................... 42 
2.3.1 
Primary Objective .................................................................. 42 
2.3.2 
Secondary Objectives ............................................................ 42 
3. 
STUDY DESIGN ......................................................................................... 42 
3.1 
Description of Study .............................................................. 42 
3.1.1 
Overview of Study Design ..................................................... 43 
3.1.1.1 Overview of Phase I Design in Patients with mBC ............... 44 
3.1.1.2 Overview of Phase II: Exploration of Efficacy 
and Safety in Patients with mBC .......................................... 47 
3.1.1.3 Overview of Phase I Design in mGC Patients ...................... 47 
3.1.1.4 Number of Patients ............................................................... 48 
3.1.1.5 Number of Centers ............................................................... 48 
3.1.2 
Steering Committee ............................................................... 48 
3.1.3 
Independent Data Monitoring Committee .............................. 49 
3.2 
End of Study .......................................................................... 49 
3.3 
Rationale for Study Design .................................................... 49 
3.3.1 
Rationale for Patient Group Selection ................................... 49 
3.3.1.1 Rationale for Phase I ............................................................ 49 
3.3.1.2 Rationale for Randomized Phase II ...................................... 50 
3.3.2 
Rationale for Investigational Medicinal Dose 
Selection................................................................................ 51 
3.3.2.1 In Patients with mBC ............................................................ 51 
3.3.2.2 In Patients with mGC ............................................................ 51 
3.3.2.3 Rationale for Duration of Treatment ..................................... 51 
3.3.3 
Pharmacokinetic Sampling Rationale .................................... 52 
3.4 
Outcome Measures ............................................................... 52 
3.4.1 
Phase I: mBC ........................................................................ 52 
3.4.1.1 Primary Efficacy Outcome Measure ..................................... 52 
3.4.1.2 Secondary Efficacy Outcome Measure ................................ 52 
3.4.1.3 Primary Safety Outcome Measure ....................................... 52 
3.4.1.4 Secondary Safety Outcome Measures ................................. 52 
3.4.1.5 Pharmacokinetic Outcome Measures ................................... 52 
3.4.2 
Randomized Phase II: Exploration of Efficacy 
and Safety in mBC ................................................................ 53 
3.4.2.1 Primary Efficacy Outcome Measure ..................................... 53 
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3.4.2.2 Secondary Efficacy Outcome Measures .............................. 53 
3.4.2.3 Primary Safety Outcome Measure ....................................... 53 
3.4.2.4 Secondary Safety Outcome Measures ................................. 53 
3.4.2.5 Pharmacokinetic Outcome Measures ................................... 54 
3.4.3 
Phase I: mGC ........................................................................ 54 
3.4.3.1 Primary Efficacy Outcome Measure ..................................... 54 
3.4.3.2 Secondary Efficacy Outcome Measure ................................ 54 
3.4.3.3 Primary Safety Outcome Measure ....................................... 54 
3.4.3.4 Secondary Safety Outcome Measures ................................. 54 
3.4.3.5 Pharmacokinetic Outcome Measures ................................... 54 
4. 
MATERIALS AND METHODS .................................................................... 55 
4.1 
Patients .................................................................................. 55 
4.1.1 
Patients with mBC ................................................................. 55 
4.1.2 
mGC Patients ........................................................................ 55 
4.1.3 
Inclusion Criteria .................................................................... 55 
4.1.3.1 For Patients with mBC .......................................................... 55 
4.1.3.2 For Patients with mGC ......................................................... 56 
4.1.4 
Exclusion Criteria ................................................................... 58 
4.1.4.1 For Patients with mBC .......................................................... 58 
4.1.4.2 For Patients with mGC ......................................................... 59 
4.1.5 
Patient Replacement Policy ................................................... 61 
4.2 
Method of Treatment Assignment .......................................... 61 
4.3 
Study Treatment .................................................................... 61 
4.3.1 
Formulation, Packaging, and Handling .................................. 61 
4.3.1.1 Trastuzumab Emtansine ...................................................... 61 
4.3.1.2 Capecitabine ........................................................................ 62 
4.3.2 
Dosage and Administration .................................................... 63 
4.3.2.1 For Patients with mBC .......................................................... 63 
4.3.2.2 For Patients with mGC ......................................................... 64 
4.3.3 
Investigational Medicinal Product 
Accountability ........................................................................ 64 
4.3.4 
Post-trial Access to Extension Study ..................................... 64 
4.4 
Concomitant And Excluded Therapies .................................. 65 
4.4.1 
Permitted Therapy ................................................................. 65 
4.4.2 
Prohibited Therapy ................................................................ 65 
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4.5 
Study Assessments ............................................................... 66 
4.5.1 
Description of Study Assessments ........................................ 66 
4.5.1.1 Medical History and Demographic Data ............................... 66 
4.5.1.2 Vital Signs ............................................................................ 66 
4.5.1.3 Physical Examinations ......................................................... 67 
4.5.1.4 Tumor and Response Evaluations ....................................... 67 
4.5.1.5 Laboratory Assessments ...................................................... 68 
4.5.1.6 Electrocardiograms .............................................................. 68 
4.5.1.7 ECOG Performance Status .................................................. 68 
4.5.1.8 ECHO/MUGA ....................................................................... 69 
4.5.2 
Timing of Study Assessments ............................................... 69 
4.5.2.1 Screening and Pretreatment Assessments .......................... 69 
4.5.2.2 Assessments during Treatment ............................................ 70 
4.5.2.3 Assessments at Study Completion/Early 
Termination Visit .................................................................. 70 
4.5.2.4 Follow-up Assessments ....................................................... 71 
4.5.2.5 Assessments at Unplanned Visits ........................................ 71 
4.6 
Patient, Study, and Site Discontinuation ................................ 71 
4.6.1 
Patient Discontinuation .......................................................... 71 
4.6.2 
Study Discontinuation ............................................................ 72 
5. 
ASSESSMENT OF SAFETY ....................................................................... 72 
5.1 
Safety Plan ............................................................................ 72 
5.1.1 
Risks Associated with Trastuzumab Emtansine .................... 72 
5.1.1.1 Cardiotoxicity ........................................................................ 72 
5.1.1.2 Hematologic Toxicity (Thrombocytopenia) ........................... 73 
5.1.1.3 Hepatotoxicity ....................................................................... 73 
5.1.1.4 Pulmonary Toxicity ............................................................... 74 
5.1.1.5 Infusion-related Reactions/Hypersensitivity .......................... 75 
5.1.1.6 Neurotoxicity ........................................................................ 75 
5.1.1.7 Extravasation ....................................................................... 75 
5.1.1.8 Trastuzumab Emtansine Dose Modification ......................... 76 
5.1.2 
Risks Associated with Capecitabine ...................................... 76 
5.1.3 
Risks Associated with Trastuzumab 
Emtansine and Capecitabine Combination ........................... 76 
5.1.4 
Definition of Dose-limiting Toxicity ......................................... 77 
5.1.5 
Management of Specific Adverse Events .............................. 78 
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5.1.5.1 Trastuzumab Emtansine Dose Modification ......................... 78 
5.1.5.1.1 Trastuzumab Emtansine Dose 
Modification for Thrombocytopenia .............................. 79 
5.1.5.1.2 Trastuzumab Emtansine Dose 
Modification for Hepatotoxicity ..................................... 80 
5.1.5.1.2.1 Concurrent elevations of ALT/AST and bilirubin 
meeting Hy’s Law laboratory criteria .......................... 80 
5.1.5.1.2.2 Nodular regenerative hyperplasia (NRH) .................... 80 
5.1.5.1.2.3 Transaminase elevations or bilirubin elevation 
requiring dose adjustment .......................................... 80 
5.1.5.1.3 Trastuzumab Emtansine Dose 
Modification for Neurotoxicity ....................................... 81 
5.1.5.1.4 Trastuzumab Emtansine Dose 
Modification for Cardiotoxicity ...................................... 81 
5.1.5.1.5 Trastuzumab Emtansine Dose 
Modification/Management for Infusion-related 
Reactions, Hypersensitivity Reactions ......................... 83 
5.1.5.1.6 Trastuzumab Emtansine Dose 
Modification for Pulmonary Toxicity ............................. 84 
5.1.5.1.7 Trastuzumab Emtansine Dose Modification 
for Extravasation .......................................................... 84 
5.1.5.2 Capecitabine Dosage Modification ....................................... 84 
5.2 
Safety Parameters and Definitions ........................................ 85 
5.2.1 
Adverse Events ..................................................................... 85 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ...................................................................... 86 
5.2.3 
Protocol-defined Events of Special Interest/Non-Serious 
Expedited Adverse Events .................................................... 86 
5.2.4 
Pregnancy and Contraception ............................................... 87 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 89 
5.3.1 
Adverse Event Reporting Period ........................................... 89 
5.3.2 
Eliciting Adverse Event Information ....................................... 90 
5.3.3 
Assessment of Severity of Adverse Events ........................... 90 
5.3.4 
Assessment of Causality of Adverse Events ......................... 91 
5.3.5 
Procedures for Recording Adverse Events ............................ 92 
5.3.5.1 Diagnosis versus Signs and Symptoms ............................... 93 
5.3.5.2 Adverse Events Occurring Secondary to 
Other Events ........................................................................ 93 
5.3.5.3 Persistent or Recurrent Adverse Events .............................. 93 
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5.3.5.4 Abnormal Laboratory Values ................................................ 94 
5.3.5.5 Deaths .................................................................................. 94 
5.3.5.6 Pre-Existing Medical Conditions ........................................... 94 
5.3.5.7 Lack of Efficacy or Clinical Worsening ................................. 95 
5.3.5.8 Hospitalization or Prolonged Hospitalization ........................ 95 
5.4 
Immediate Reporting Requirements from 
Investigator to the Sponsor .................................................... 95 
5.4.1 
Emergency Medical Contacts ................................................ 96 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-serious Adverse Events of 
Special Interest ...................................................................... 96 
5.4.3 
Reporting Requirements for Pregnancies .............................. 96 
5.4.3.1 Pregnancies in Female Patients ........................................... 96 
5.4.3.2 
Pregnancies in Female Partners of Male 
Patients ................................................................................ 97 
5.4.3.3 Abortions .............................................................................. 97 
5.4.3.4 Congenital Anomalies/Birth Defects ..................................... 97 
5.5 
Follow-up of Patients after Adverse Events ........................... 98 
5.5.1 
Investigator Follow-up............................................................ 98 
5.5.2 
Sponsor Follow-up ................................................................. 98 
5.6 
Post-study Adverse Events .................................................... 98 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ................................................................. 98 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 99 
6.1 
Determination of Sample Size ............................................... 99 
6.2 
Summaries of Conduct of Study .......................................... 101 
6.3 
Summaries of Treatment Group Comparability ................... 102 
6.4 
Efficacy Analyses ................................................................ 103 
6.4.1 
Primary Efficacy Endpoint .................................................... 103 
6.4.2 
Secondary Efficacy Endpoints ............................................. 104 
6.5 
Safety Analyses ................................................................... 105 
6.6 
Pharmacodynamic Analyses ............................................... 107 
6.7 
Pharmacokinetic Analyses ................................................... 107 
6.8 
Exploratory Analyses ........................................................... 108 
6.9 
Interim Analyses .................................................................. 108 
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7. 
DATA COLLECTION AND MANAGEMENT ............................................. 109 
7.1 
Data Quality Assurance ....................................................... 109 
7.2 
Electronic Case Report Forms ............................................. 109 
7.3 
Source Data Documentation ................................................ 110 
7.4 
Use of Computerized Systems ............................................ 110 
7.5 
Retention of Records ........................................................... 110 
8. 
ETHICAL CONSIDERATIONS .................................................................. 111 
8.1 
Compliance with Laws and Regulations .............................. 111 
8.2 
Informed Consent ................................................................ 111 
8.3 
Institutional Review Board or Ethics Committee .................. 112 
8.4 
Confidentiality ...................................................................... 112 
8.5 
Financial Disclosure ............................................................ 113 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 113 
9.1 
Study Documentation .......................................................... 113 
9.2 
Site Inspections ................................................................... 113 
9.3 
Administrative Structure....................................................... 113 
9.4 
Publication of Data and Protection of Trade Secrets ........... 113 
9.5 
Protocol Amendments ......................................................... 114 
10. REFERENCES ......................................................................................... 115 
 
 
LIST OF TABLES 
Table 1 
Cycle 1 Mean (s.d.) Pharmacokinetic Parameters for 
Trastuzumab Emtansine Following Trastuzumab 
Emtansine Administration Every 3 Weeks and Weekly in 
Study TDM3569g ........................................................................ 36 
Table 2 
Dose Reduction for Trastuzumab Emtansine  (Patients 
with mBC) ................................................................................... 79 
Table 3 
Dose Reductions for Trastuzumab Emtansine  (Patients 
with mGC) ................................................................................... 79 
Table 4 
Trastuzumab Emtansine Dose Modification: Total Serum 
Bilirubin ....................................................................................... 81 
Table 5 
Trastuzumab Emtansine Dose Modification: Serum ALT 
or AST ......................................................................................... 81 
Table 6 
Adverse Event Severity Grading Scale ....................................... 91 
Table 7 
Guidance for Causal Attribution of Adverse Event/Serious 
Adverse Event ............................................................................. 92 
Table 8 
Sample Size Based on BOR ..................................................... 100 
 
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LIST OF FIGURES 
Figure 1 
Molecular Structure of Trastuzumab Emtansine ......................... 30 
Figure 2 
MMTV HER2 Fo5 Mammary Tumor Transplants ........................ 39 
Figure 3 
Anti-tumor Activity of Trastuzumab Emtansine in 
Combination with Capecitabine in NCI-N87 ................................ 39 
Figure 4 
Overview of Study Design ........................................................... 44 
Figure 5 
Overview of Phase I Dose Finding Study Design ........................ 45 
Figure 6 
Algorithm for Continuation and Discontinuation of 
Trastuzumab Emtansine Based on Left Ventricular 
Ejection Fraction Assessments in Patients ................................. 83 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments ......................................................... 119 
Appendix 2 
Pharmacokinetic Sampling for Phase I, Metastatic 
Breast and Gastric Cancer Patients .......................................... 128 
Appendix 3 
Response Evaluation Criteria in Solid Tumors 
(RECIST): Modified Excerpt from Original Publication .............. 130 
Appendix 4 
Instructions for Scans in the Event of Isotope Shortage ............ 142 
Appendix 5 
New York Heart Association Classification of 
Functional Cardiac Capacity...................................................... 143 
 Appendix 6     ECOG Performance Status ........................................................ 144
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PROTOCOL ACCEPTANCE FORM 
TITLE: 
PHASE I STUDY OF THE COMBINATION OF TRASTUZUMAB 
EMTANSINE (T-DM1) AND CAPECITABINE IN HER2-POSITIVE 
METASTATIC BREAST CANCER AND HER2-POSITIVE LOCALLY 
ADVANCED OR METASTATIC GASTRIC CANCER PATIENTS, 
FOLLOWED BY A RANDOMIZED, OPEN-LABEL PHASE II STUDY 
OF T-DM1 AND CAPECITABINE VERSUS T-DM1 ALONE IN HER2-
POSITIVE METASTATIC BREAST CANCER 
PROTOCOL NUMBER: MO28230 
VERSION NUMBER: 2 
EUDRACT NUMBER: 
2012-001547-46 
 
 
IND NUMBER 
To be determined 
TEST PRODUCT: 
Trastuzumab emtansine (RO5304020) 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return the signed original of this form {as instructed by XX [e.g., your 
local study monitor, the CRO]} [or] {to the contact provided below}. Please retain 
a copy for your study files. 
{Name}  
{Address} 
 
 
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PROTOCOL SYNOPSIS 
TITLE: 
PHASE I STUDY OF THE COMBINATION OF TRASTUZUMAB EMTANSINE  
(T-DM1) AND CAPECITABINE IN HER2-POSITIVE METASTATIC BREAST 
CANCER AND HER2-POSITIVE LOCALLY ADVANCED OR METASTATIC 
GASTRIC CANCER PATIENTS, FOLLOWED BY A RANDOMIZED, OPEN-LABEL 
PHASE II STUDY OF T-DM1 AND CAPECITABINE VERSUS T-DM1 ALONE IN 
HER2-POSITIVE METASTATIC BREAST CANCER 
PROTOCOL NUMBER: 
MO28230 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2012-001547-46 
 
 
TEST PRODUCT: 
Trastuzumab emtansine (RO5304020) 
PHASE: 
I/II 
INDICATION: 
HER2-positive metastatic breast and locally advanced or metastatic 
gastric cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Phase I: Maximum Tolerated Dose Finding of Trastuzumab Emtansine and 
Capecitabine in Metastatic Breast Cancer 
Primary Objective 
• 
To determine the maximum tolerated dose (MTD) of the combination of trastuzumab 
emtansine and capecitabine in metastatic breast cancer (mBC) patients 
Secondary Objectives 
• 
Pharmacokinetics (PK) of trastuzumab emtansine and metabolites and capecitabine 
• 
Safety of the combination of trastuzumab emtansine and capecitabine 
• 
Overall response rate (ORR) 
Randomized Phase II: Exploration of Efficacy and Safety in mBC 
Primary Objective 
• 
To explore the efficacy of the combination of trastuzumab emtansine and capecitabine 
compared with trastuzumab emtansine in mBC patients, as measured by ORR by 
Response Evaluation Criteria for Solid Tumors (RECIST) v.1.1 per investigator local 
assessment  
Secondary Objectives 
• 
Safety profile of the combination of trastuzumab emtansine and capecitabine compared 
with trastuzumab emtansine 
• 
To explore the efficacy of the combination of trastuzumab emtansine and capecitabine 
compared with trastuzumab emtansine in mBC patients, as measured by: 
• Time to response (TTR)  
• Duration of response (DoR) 
• Time to progression (TTP)  
• Time to treatment failure (TTF)  
• Progression-free survival (PFS)  
• Clinical benefit rate (CBR) 
• Overall survival (OS) 
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Phase I: MTD Finding of Trastuzumab Emtansine and Capecitabine in Metastatic 
Gastric Cancer 
Primary Objective 
• 
To determine the MTD of the combination of trastuzumab emtansine and capecitabine 
in metastatic gastric cancer (mGC) patients 
Secondary Objectives 
• 
PK of trastuzumab emtansine and metabolites and capecitabine 
• 
Safety of the combination of trastuzumab emtansine and capecitabine 
• 
ORR 
Study Design 
Description of Study 
This is an international, multicenter study. 
The study is designed to determine the MTD of capecitabine in combination with 
trastuzumab emtansine in human epidermal growth factor receptor 2 (HER2)-positive mBC 
and locally advanced or mGC patients using a Phase I design, followed by a randomized, 
open-label Phase II study to explore the efficacy and safety of the combination of 
trastuzumab emtansine and capecitabine compared with trastuzumab emtansine in mBC 
patients. Results from the Phase I in mGC will be used as supporting information for future 
studies in the indication (see Figure 4 in the protocol). 
Phase I: MTD Finding, Cohort 1: mBC 
Cohort 1 will open first with a 3 plus 3 classical design. Cohort 1 will enroll patients with 
HER2-positive mBC. The dose tested of trastuzumab emtansine remains fixed at 3.6 mg/kg 
every 3 weeks (q3w) and 3 dose levels of capecitabine administered twice daily (bid) on 
Days 1 to 14 in cycles of 3 weeks will be tested. All patients will be treated until disease 
progression, intolerable toxicity, withdrawn consent, or death. All patients will be followed-up 
until withdrawn consent, death, or up to a maximum of 2 years after the last patient was 
randomized in the Phase II part of the study, whichever occurs first. 
Dose Levels Explored in Phase I, Cohort 1  
Dose Level 1: 750 mg/m2 capecitabine bid + 3.6 mg/kg q3w trastuzumab emtansine 
Dose Level -1: 700 mg/m2 capecitabine bid + 3.6 mg/kg q3w trastuzumab emtansine 
Dose Level -2: 650 mg/m2 capecitabine bid + 3.6 mg/kg q3w trastuzumab emtansine 
The rules for determining the MTD are presented below.  
If Dose Level 1 is proved too toxic (dose-limiting toxicity [DLT] > 1/3 or > 1/6), the dose will 
be de-escalated to one dose level below (Dose Level -1)  
If Dose Level -1 is well tolerated (DLT ≤ 1/6), this dose will be considered the MTD and, 
following the independent Data Monitoring Committee (IDMC) agreement, will be further 
explored in the Randomized Phase II part of the study. If Dose Level -1 is too toxic 
(DLT >1/6), the dose will be de-escalated to Dose Level -2. 
If Dose Level -2 is well tolerated (DLT ≤ 1/6), this dose will be considered the MTD and, 
following iDMC approval, will be further explored in the Randomized Phase II part of the 
study. However, if Dose Level -2 is too toxic (DLT > 1/6), the combination may be 
considered unfeasible, recruitment will be closed and neither the Randomized Phase II nor 
mGC cohort will be opened. Patients who, at that point, experience response as per 
RECIST v.1.1 will be offered the possibility to continue on trastuzumab emtansine as a 
single agent, or with the combination, based on risk-benefit balance and agreement with the 
Steering Committee (SC).  
Randomized Phase II: Exploration of Efficacy and Safety in mBC 
Phase II will be conducted in mBC patients only. This part of the study will explore the 
efficacy and safety of the combination treatment of T-DM1 and capecitabine, at the 
established MTD, compared with T-DM1 alone in mBC patients. 
Once the MTD in Cohort 1 is established, additional 117 HER2-positive mBC patients will be 
randomized into the Phase II part of the study. Patients in the Phase I part of the study will 
not contribute to the Phase II part of the study; however, they will be followed-up until end of 
study (EOS). 
Patients will be treated until disease progression/recurrence, intolerable toxicity, withdrawn 
consent, or death. If capecitabine needs to be discontinued for any reason, trastuzumab 
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emtansine may continue, and the patient will be followed-up until EOS. In case of 
discontinuation of trastuzumab emtansine, patients will be followed-up until EOS. 
All patients will be followed-up until withdrawn consent, death, or up to a maximum of 2 
years after the last patient was randomized in the Phase II part of the study, whichever 
occurs first. 
Phase I: MTD Finding, Cohort 2: mGC 
Once the capecitabine MTD dose is established in Cohort 1, Cohort 2 will open, with a 3 
plus 3 classical design to enroll HER2-positive mGC patients. Trastuzumab emtansine will 
be administered weekly at the dose of 2.4 mg/kg and capecitabine will start at the MTD 
dose defined in Cohort 1; capecitabine dose level may be de-escalated. 
All patients will be treated until disease progression, intolerable toxicity, withdrawn consent, 
or death. All patients will be followed-up until withdrawn consent, death, or up to a maximum 
of 2 years after the last patient was randomized in the Phase II part of the study, whichever 
occurs first. 
The dose levels for capecitabine will be the same as described in Cohort 1, except for Dose 
Level 1, which will not be explored in mGC patients. Guidelines for dose escalation and de-
escalation are as follows: 
If the MTD established in Cohort 1 is defined at Dose Level -1: 
• 
This will be the starting dose in Cohort 2. If Dose Level -1 is well tolerated (DLT ≤ 1/6), 
this dose will be established as the MTD for mGC  
• 
De-escalation: if Dose Level -1 is not tolerated in Cohort 2 (> 1/6 DLT), de-escalation 
will be to Dose Level -2 
If the MTD established in Cohort 1 is defined at Dose Level -2: 
• 
This will be the starting dose in Cohort 2. If Dose Level -2 is well tolerated (DLT ≤ 1/6), 
this dose will be established as the MTD for mGC  
• 
De-escalation: if Dose Level -2 is not tolerated in Cohort 2 (> 1/6 DLT), the combination 
will be considered not feasible for mGC and Cohort 2 will be terminated. Patients who, 
at that point, experience response as per RECIST v.1.1 will be offered the possibility to 
continue on trastuzumab emtansine as a single agent, or with the combination, based 
on risk-benefit balance and agreement with the SC 
Number of Patients 
Phase I, Cohort 1: mBC 
A minimum of 6 and up to 18 patients will be enrolled. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
Exploration of efficacy and safety in mBC will be based on 117 randomized patients in total. 
Phase I, Cohort 2: mGC 
A total of 3 to 12 patients will be enrolled. 
Target Population 
Phase I, Cohort 1: mBC 
HER2-positive mBC patients will be enrolled. 
The patient’s HER2 status will be considered positive if the local institution or reference lab 
reported Grade 3+ staining intensity (on a scale of 0 to 3) by means of immunohisto-
chemistry (IHC) or fluorescent in situ hybridization (FISH). 
The HER2 status will be retrospectively confirmed by IHC and/or FISH in a central 
laboratory using archival paraffin-embedded tumor tissue. Patients must have metastatic 
disease and/or locally recurrent disease not amenable to resection. Retrospective central 
confirmation will not impact the treatment decisions or primary endpoint of Phase I and will 
be used to validate efficacy analyses in Phase I. 
Patients must have received at least one treatment regimen, which includes a 
chemotherapy agent and trastuzumab. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
HER2-positive mBC patients will be randomized to one of the treatment groups receiving 
either the combination of trastuzumab emtansine (T-DM1) with capecitabine or T-DM1 
alone. Retrospective central confirmation will be used to censor the efficacy population for 
the Randomized Phase II part of the study. 
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Patients must have received at least one treatment regimen, which includes a 
chemotherapy agent and trastuzumab. 
Phase I, Cohort 2: mGC 
HER2-positive locally advanced or mGC patients will be enrolled. 
Patients must not have received prior chemotherapy for advanced/metastatic disease. 
 
Inclusion Criteria: 
For mBC Patients: 
1. Age ≥ 18 years old. 
2. Signed informed consent prior to any study specific procedure. 
3. Able and willing to comply with protocol. 
4. 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. 
5. 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 or two effective forms of non-hormonal contraception and to continue its 
use for the duration of study treatment and for 6 months after the last dose of study 
treatment (see Section 5.2.4 in the protocol). 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 
7. Blood: 
a) Platelet count > 100,000 cells/mm3 
b) International normalized ratio (INR) < 1.5 
c) Absolute neutrophil count (ANC) > 1,500 cells/mm3 
d) Hemoglobin > 9.0 g/dL. Patients are allowed to have received transfusion to 
achieve this level. 
8. Liver function: 
a) Total bilirubin ≤ 1.5 × the upper limit of normal (ULN).  
b) Serum glutamic oxaloacetic transaminase (SGOT)/aspartate transaminase (AST) 
and serum glutamic pyruvic transaminase (SGPT)/alanine transaminase 
(ALT) ≤ 2.5 × the ULN. 
c) Alkaline phosphatase ≤ 2.5 × the ULN. Patients with hepatic and/or bone 
metastases: alkaline phosphatase ≤ 5 × the ULN. 
d) Evidence of stable liver function during the month prior to enrollment with liver 
function tests’ (LFTs) fluctuations not exceeding 2.5 × ULN (for AST, ALT) and 
1.5 × ULN (for total bilirubin). Patients with bone metastases: AST and ALT ≤ 5.0 x 
ULN. 
9. Renal function: 
a) Serum creatinine of < 177 µmol/L or calculated creatinine clearance (CL)  
> 50 mL/min. If urine dipstick for proteinuria is ≥ 2+ at baseline, the patient must 
undergo 24-hour urine collection and demonstrate ≤ 1 g of protein/24 hours. 
10. Cardiac function: 
a) Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) or 
multiple-gated acquisition (scan) (MUGA). 
11. Histologically or cytologically confirmed breast cancer. 
12. HER2-positive disease IHC 3+ or in situ hybridization (ISH) positive. 
13. Tumor block or 15 slides available for retrospective central confirmation of HER2-
positivity (central confirmation not necessary for enrollment).  
14. mBC with at least one measurable lesion according to RECIST v.1.1. 
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15. Disease progression on at least one regimen containing trastuzumab and 
chemotherapy. 
16. Patients must have recovered from previous treatments 
For mGC Patients: 
1. Age ≥ 18 years old. 
2. Signed informed consent prior to any study specific procedure. 
3. Able and willing to comply with protocol. 
4. 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. 
5. 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 or two effective forms of non-hormonal contraception and to continue its 
use for the duration of study treatment and for 6 months after the last dose of study 
treatment (see Section 5.2.4 in the protocol). 
6. ECOG performance status of 0, 1, or 2. 
7. Blood: 
a) Platelet count > 100,000 cells/mm3. 
b) INR < 1.5.  
c) ANC > 1,500 cells/mm3. 
d) Hemoglobin > 9.0 g/dL. Patients are allowed to have received transfusion to 
achieve this level. 
8. Liver function: 
a) Total bilirubin ≤ 1.5 × ULN.  
b) SGOT/AST and SGPT/ALT ≤ 2.5 × the ULN. 
c) Alkaline phosphatase ≤ 2.5 × the ULN. Patients with hepatic and/or bone 
metastases: alkaline phosphatase ≤ 5 × the ULN. 
d) Evidence of stable liver function during the month prior to enrollment with LFTs 
fluctuations not exceeding 2.5 × ULN (for AST, ALT) and 1.5 × ULN (for total 
bilirubin). Patients with bone metastases: AST and ALT ≤ 5.0 x ULN. 
9. Renal function: 
a) Serum creatinine of < 177 µmol/L or calculated creatinine CL > 50 mL/min. If urine 
dipstick for proteinuria is ≥ 2+ at baseline, the patient must undergo 24-hour urine 
collection and demonstrate ≤ 1 g of protein/24 hours. 
10. Cardiac function: 
a) LVEF ≥ 50% by ECHO or MUGA. 
11. Histologically or cytologically confirmed mGC or locally advanced gastric cancer. 
12. HER2-positive tumor (primary tumor or metastatic lesion), defined as either IHC 3+ 
alone or IHC 2+ in combination with ISH+, prospectively confirmed by a Sponsor-
designated central laboratory prior to enrollment. ISH positivity is defined as a ratio 
of ≥ 2.0 for the number of HER2 gene copies to the number of signals for CEP17. 
a) Archival tumor samples obtained from primary or metastatic sites are acceptable. 
b) Invasive tumor for central confirmation of HER2 status is required. 
c) A formalin-fixed paraffin-embedded (FFPE) tissue block with at least 5 mm of 
invasive tumor for central confirmation is preferred. If FFPE tissue blocks (or partial 
block) are unavailable due to country or site regulations, a minimum of 8 freshly cut 
unstained slides MUST be available for central review of HER2 status. 
13. Inoperable locally advanced or mGC. 
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Exclusion Criteria: 
For mBC Patients: 
1. Prior treatments before first study treatment: 
a) Investigational therapy within ≤ 28 days or 5 half-lives, whatever is longest. 
b) Hormonal therapy within 14 days. 
c) Trastuzumab within 21 days. 
2. Prior enrollment in a trastuzumab emtansine−containing study, regardless of whether 
the patient received prior trastuzumab emtansine. 
3. Prior treatment with capecitabine. 
4. History of severe and unexpected reactions to fluoropyrimidine or with known 
hypersensitivity to fluorouracil. 
5. Related capecitabine contraindications: 
a) Treatment with sorivudine or its chemically-related analogues, such as brivudine. 
b) Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or 
glucose-galactose malabsorption. 
6. History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity to 
trastuzumab or murine proteins or any component of the product. 
7. History of exposure to the following cumulative doses of anthracyclines: 
a) Doxorubicin or liposomal doxorubicin > 500 mg/m2. 
b) Epirubicin > 900 mg/m2. 
c) Mitoxantrone > 120 mg/m2 
d) If another anthracycline, or more than one anthracycline, has been used, the 
cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin. 
8. Brain metastases that are symptomatic, or require any radiation, surgery, or steroid 
therapy to control their symptoms within 28 days of first study drug administration. 
9. Current peripheral neuropathy of Grade ≥ 3 per the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) v.4.0. 
10. History of other malignancy within the last 5 years, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, 
or other cancers with a similar outcome as those mentioned above. 
11. Current unstable ventricular arrhythmia requiring treatment. 
12. History of symptomatic congestive heart failure (CHF) (New York Heart Association 
[NYHA] Classes II−IV). 
13. History of myocardial infarction or unstable angina within 6 months prior to first study 
drug administration. 
14. History of a decrease in LVEF to < 40% or symptomatic CHF with previous trastuzumab 
treatment. 
15. Severe dyspnea at rest due to complications of advanced malignancy or requiring 
current continuous oxygen therapy. 
16. Clinically significant malabsorption syndrome or inability to take oral medication 
17. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary, or metabolic disease). 
18. Major surgical procedure or significant traumatic injury within 28 days before enrollment 
or anticipation of the need for major surgery during the course of study treatment. 
19. Current pregnancy or lactation. 
20. Current known active infection with human immunodeficiency virus (HIV), hepatitis B, 
and/or hepatitis C virus (HBV/HCV). 
a) For patients who are known carriers of HBV, active hepatitis B infection must be 
ruled out based on negative serologic testing and/or determination of HBV 
deoxyribonucleic acid (DNA) viral load per local guidelines. 
21. Lapatinib ≤ 14 days before first study drug administration. 
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22. Previous radiotherapy for the treatment of unresectable, locally advanced/recurrent or 
mBC is not allowed if: 
a) The last fraction of radiotherapy has been administered within 14 days prior to first 
study drug administration. 
b) More than 25% of marrow-bearing bone has been irradiated. 
c) The patient has not recovered from any resulting acute toxicity to Grade ≤ 1 prior to 
first study drug administration. 
23. No signs and symptoms suggestive that the patient has dihydropyrimidine 
dehydrogenase (DPD) deficiency. 
For mGC Patients: 
1. Prior treatments before first study treatment: 
a) Investigational therapy within ≤ 28 days or 5 half-lives, whatever is longest. 
b) Hormonal therapy within 14 days. 
c) Trastuzumab within 21 days. 
2. Prior enrollment in a trastuzumab emtansine−containing study, regardless of whether 
the patient received prior trastuzumab emtansine. 
3. Prior treatment with capecitabine. 
4. History of severe and unexpected reactions to fluoropyrimidine or with known 
hypersensitivity to fluorouracil. 
5. Related capecitabine contraindications: 
a) Treatment with sorivudine or its chemically-related analogues, such as brivudine. 
b) Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or 
glucose-galactose malabsorption. 
6. History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity to 
trastuzumab or murine proteins or any component of the product. 
7. History of exposure to the following cumulative doses of anthracyclines: 
a) Doxorubicin or liposomal doxorubicin > 500 mg/m2. 
b) Epirubicin > 900 mg/m2. 
c) Mitoxantrone > 120 mg/m2. 
d) If another anthracycline, or more than one anthracycline, has been used, the 
cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin. 
8. Brain metastases that are symptomatic, or require any radiation, surgery, or steroid 
therapy to control their symptoms within 28 days of first study drug administration. 
9. Current peripheral neuropathy of Grade ≥ 3 per the NCI CTCAE, v4.0. 
10. History of other malignancy within the last 5 years, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, 
or other cancers with a similar outcome as those mentioned above. 
11. Current unstable ventricular arrhythmia requiring treatment. 
12. History of symptomatic CHF (NYHA Classes II−IV). 
13. History of myocardial infarction or unstable angina within 6 months prior to first study 
drug administration. 
14. History of a decrease in LVEF to < 40% or symptomatic CHF with previous trastuzumab 
treatment. 
15. Severe dyspnea at rest due to complications of advanced malignancy or requiring 
current continuous oxygen therapy. 
16. Clinically significant malabsorption syndrome or inability to take oral medication 
17. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary, or metabolic disease) 
18. Major surgical procedure or significant traumatic injury within 28 days before enrollment 
or anticipation of the need for major surgery during the course of study treatment 
19. Current pregnancy or lactation 
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20. Current known active infection with HIV, HBV, and/or HCV 
a) For patients who are known carriers of HBV, active hepatitis B infection must be 
ruled out based on negative serologic testing and/or determination of HBV DNA 
viral load per local guidelines 
21. Previous chemotherapy for advanced/metastatic disease 
a) Prior adjuvant/neoadjuvant therapy is allowed if at least 6 months has elapsed 
between completion of adjuvant/neoadjuvant therapy and enrollment into the study 
22. No signs and symptoms suggestive that the patient has DPD deficiency 
23. Lapatinib ≤ 14 days before first study drug administration 
Length of Study 
The duration of the study is estimated to be approximately 4 years. Recruitment is estimated 
to be 2 years for Dose Finding and the Phase II/Exploration of Efficacy and Safety. All 
patients will be followed-up until withdrawn consent, death or up to a maximum of 2 years 
after the last patient was randomized in the Phase II part of the study, whichever occurs first. 
In case Dose Level -2 is too toxic, the study may be terminated prematurely. Patients who, 
at that point, experience response as per RECIST v.1.1 will be offered the possibility to 
continue on trastuzumab emtansine as a single agent, or with the combination, based on 
risk-benefit balance and agreement with the SC. 
End of Study 
Last patient last visit (LPLV) as per definition is the last data collection point that can be 
either a clinic visit or a laboratory sample (see above length of study). 
Efficacy Outcome Measures 
Efficacy will be evaluated as per RECIST v.1.1. 
• 
Best overall response (BOR) rate  
• 
DoR 
• 
TTR 
• 
TTP 
• 
TTF 
• 
PFS 
• 
CBR 
• 
OS 
Safety Outcome Measures 
• 
DLT assessment 
• 
Incidence and severity by NCI CTCAE version 4.0 of adverse events (AEs), serious 
adverse events (SAEs), AEs that cause discontinuation from the study treatment, and 
AEs of special interest (AESIs) 
• 
Fatal cases and causes of death 
• 
Laboratory parameters 
• 
LVEF 
• 
Treatment exposure 
Pharmacodynamic Outcome Measures 
Hospital visit parameters. 
Pharmacokinetic Outcome Measures 
PK will be evaluated during Phase I for both trastuzumab emtansine and capecitabine (see 
Appendix 1, Schedule of Assessment in the protocol). In addition, PK samples may be 
taken ad hoc, in case of SAE or unexpected toxicities, which may be suggestive of potential 
drug-drug interaction. 
Investigational Medicinal Products 
For mBC Patients: 
Trastuzumab emtansine will be administered q3w at a dose of 3.6 mg/kg intravenous (IV). 
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The total trastuzumab emtansine dose will be calculated based on the patient’s weight on 
Day 1 of (or up to 3 days before) each cycle with no upper limit. 
Capecitabine will be administered twice a day, orally for 14 days followed by a 7-day rest 
period at the Dose Levels 1 to -2 described in the ‘Trial Design’ section. 
Capecitabine tablets should be swallowed with water within 30 minutes after a meal. 
Rounding of capecitabine dose, based on 150 mg and 500 mg tablet strength will be 
allowed to the nearest target dose, based on patient body surface area (BSA).  
For mGC Patients: 
Trastuzumab emtansine will be administered on Day 1 of a weekly cycle at the dose of 
2.4 mg/kg IV. 
The total trastuzumab emtansine dose will be calculated based on the patient’s weight on 
Day 1 of (or up to 3 days before) each cycle with no upper limit. 
Capecitabine will be administered twice a day, orally for 14 days followed by a 7-day rest 
period at the Dose Levels -1 to -2 described in the ‘Trial Design’ section. 
Capecitabine tablets should be swallowed with water within 30 minutes after a meal. 
Non-Investigational Medicinal Products 
Not applicable. 
Statistical Analysis 
The study will include 2 phases and 2 cohorts: 
• 
Phase I, Cohort 1: mBC Dose Finding Cohort 
• 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
• 
Phase I, Cohort 2: mGC Dose Finding Cohort 
There is no formal efficacy interim analysis. However, an independent data monitoring 
committee (IDMC) will advise whether the Randomized Phase II part of the study can 
commence. The IDMC will also monitor safety outcomes after 20 and 60 patients have 
received at least 3 cycles of treatment (Cycle 3 Day 1) in the Randomized Phase II part of 
the study. Afterwards, the IDMC will monitor accumulating patient safety data every 6 
months during the Randomized Phase II of the study or as requested. 
Efficacy data will only be provided if required by the IDMC to estimate the risk-benefit 
balance for the patients. Further details on the function and logistics of the IDMC will be 
provided in the IDMC Charter. 
Corresponding analyses as described in the protocol will be performed when all data for 
both study phases are collected and cleaned. 
Analysis of primary and secondary endpoints: 
Analysis Populations: 
Phase I, Cohort 1: MTD Finding: mBC Patients 
The main analysis population for DLT assessment is the DLT evaluable population, which is 
defined as all enrolled and treated patients who have not experienced any major protocol 
violations (including violations of the inclusion and exclusion criteria) and have completed 
Cycle 1.  
The safety population (SP) will include all patients who received at least one dose of study 
medication during Phase I. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
The main analysis population for the efficacy analysis will be the intent-to-treat (ITT) 
population, which will include all patients randomized in the Phase II part of the study. The 
per-protocol (PP) population will include all ITT patients who have at least one post-baseline 
tumor assessment during the Phase II part of the study and no major protocol violations, 
which will be defined in the statistical analysis plan (SAP). 
The SP will include all patients who received at least one dose of study medication during 
the Randomized Phase II part of the study.  
Phase I, Cohort 2: MTD Finding, mGC Patients 
The main analysis population for DLT assessment is the DLT evaluable population, which is 
defined as all enrolled and treated patients who have not experienced any major protocol 
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violation (including violation of the inclusion and exclusion criteria) and have completed 
Cycle 1.  
The SP will include all patients who received at least one dose of study medication during 
Phase I. 
Efficacy Endpoints:  
Phase I, Cohort 1: MTD Finding, mBC 
The primary objectives are reaching the MTD and establishing a safety profile. 
ORR, as a main efficacy endpoint, will be assessed via BOR rate. The BOR is defined as 
the best response recorded from the date of enrollment until disease 
progression/recurrence, death, withdrawal of consent or EOS, whichever occurs first. The 
number of patients is very small in this part of the study. Therefore, all analyses will be 
descriptive. 
Due to the small number of patients and the design of this part of the study, no secondary 
efficacy endpoints will be investigated. 
Randomized Phase II: Exploration of Efficacy in mBC  
The primary efficacy endpoint for the Phase II part of the study is the ORR, as assessed via 
BOR. The BOR is defined as the best response recorded from the start or randomization 
into the Phase II part of the study and until disease progression or recurrence, death, 
withdrawal of consent or EOS, whichever occurs first. To be assigned a status of partial 
response (PR) or complete response (CR), i.e., to be a responder, changes in tumor 
measurements must be confirmed by repeated assessments performed no less than 28 
days after the response criteria are first met, i.e., patients need to have two consecutive 
assessments of PR or CR.  
The emphasis of the exploratory Randomized Phase II part of the study will not be formal 
statistical hypothesis testing but the estimation of: 
• 
The BOR rate with corresponding 95% confidence intervals (CIs) for each treatment 
group. The justification of the sample size is based on considerations regarding the 
width of 95% CIs for each treatment group estimate (precision of the corresponding 
estimate). 
• 
The treatment effect (between treatment groups comparison) with corresponding 95% 
CIs.  
The number and proportions of responders and non-responders (based on BOR) together 
with the two-sided 95% Clopper-Pearson CIs will be presented for each treatment group. 
The difference in BOR between treatment groups will be displayed with associated 95% CIs 
using the Hauck-Anderson approach.  
The secondary endpoints for the Phase II part of the study will be: 
• 
TTR 
• 
DoR 
• 
TTP 
• 
TTF 
• 
PFS 
• 
CBR 
• 
OS 
Estimates for the survivor function of both treatment groups for TTR, DoR, TTP, TTF, PFS 
and OS will be obtained by using the Kaplan-Meier method. Hazard ratios and associated 
95% CIs will be estimated from non-stratified and stratified (based on the stratification factor) 
Cox regression models. 
Clinical benefit response will include patients whose best (confirmed) response was PR or 
CR, or stable disease (SD) that lasted at least 6 months. CBR will be summarized in a 
similar way to the primary efficacy endpoint, ORR, as assessed by BOR.  
Phase I, Cohort 2: MTD Finding: mGC 
The primary objectives are reaching the MTD and establishing a safety profile. 
Efficacy endpoints will be analyzed in a similar way to Phase I, Cohort 1: mBC. 
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Safety Endpoints: 
Phase I, Cohort 1: MTD Finding: mBC 
The number and proportion of patients with DLTs will be used as the primary measure for 
the MTD determination. The definition of DLTs is presented in Section 5.1.4. DLTs for this 
part of the study will be summarized by treatment dose. 
Safety parameters for this study part will be summarized by treatment dose. The summaries 
of AEs, SAEs, AEs that cause discontinuation from the study treatment, and AESIs (as 
described in Section 5) will be analyzed in a similar way to AEs in Phase II. The summaries 
will include all patients who received at least one dose of study medication. 
The incidence of AEs and SAEs will be summarized according to the primary system-organ 
class (SOC) and within each SOC, by Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term. Patients who died will be listed together with the cause of death. 
Laboratory parameters, hematology and biochemistry will be presented in shift tables of 
NCI-CTC grade at baseline versus worst grade during treatment for Phase I, Cohort 1, and 
overall. 
LVEF will be summarized over time by means of mean, median and range (minimum and 
maximum) and will be presented graphically. Vital signs will be analyzed in a similar way. 
Other safety variables, such as exposure to study medication, concomitant medications, and 
physical examinations will be analyzed in a similar way. The exposure of study medication 
will be summarized by frequency tables. 
ECOG performance status will be summarized over time and the percentage of patients in 
different categories will be presented by bar charts at different time points. 
Randomized Phase II: Exploration of Safety in mBC  
Safety endpoints will be summarized by treatment group. 
Safety endpoints during the Randomized Phase II part of the study will be assessed via: 
total AEs, AEs Grade ≥ 3, SAEs, premature withdrawal from study medication, AESIs, 
laboratory parameters, LVEF, exposure to study medication, concomitant medications, vital 
signs, ECOG performance status, and physical examination. 
The incidence of AEs and SAEs will be summarized according to the primary SOC and 
within each SOC, by MedDRA preferred term. Time to onset of the first episode of AESI will 
also be summarized via Kaplan-Meier method. Patients who died will be listed together with 
the cause of death. 
Laboratory parameters, hematology and biochemistry will be presented in shift tables of 
NCI-CTC grade at baseline versus worst grade during treatment for the Randomized 
Phase II part of the study. 
LVEF will be summarized over time by means of mean, median and range (minimum and 
maximum) and will be presented graphically. Vital signs will be analyzed in a similar way. 
Other safety variables, such as exposure to study medication, concomitant medications, and 
physical examinations will be analyzed in a similar way. The exposure of study medication 
will be summarized by frequency tables. 
ECOG performance status will be summarized over time and the percentage of patients in 
different categories will be presented by bar charts at different time points. 
Phase I, Cohort 2: MTD Finding: mGC 
The number and the proportion of patients with DLTs will be used as the primary measure 
for the MTD determination. The definition of DLTs is presented in Section 5.1.4. DLTs for 
this part of the study will be summarized by treatment dose. 
Safety parameters will be summarized in a similar way to Phase I, Cohort 1: mBC. 
Pharmacokinetic Analysis 
The following PK parameters of trastuzumab emtansine and capecitabine (not limited to 
these listed) will be determined only in the Phase I part of the study in all patients who 
receive study treatment using either non-compartmental and/or population methods, if data 
allow: 
• 
Serum concentrations of trastuzumab emtansine (conjugate) and total trastuzumab 
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• 
Plasma concentrations of DM1, capecitabine and its active metabolite 5-fluorouracil (5-
FU) 
• 
Total exposure (area under the serum concentration-time curve [AUC])  
• 
Maximum concentration (Cmax)  
• 
CL  
• 
Volume of distribution (Vd) 
• 
Terminal half-life (T1/2) 
All PK parameters will be listed and tabulated by treatment dose and by Cohort. Descriptive 
summary statistics including arithmetic mean, geometric mean (e.g., AUC and Cmax), 
median, range, standard deviation (s.d.), and coefficient of variation will be presented for 
each Cohort. Nonlinear mixed effects modeling will be also used but details will be 
presented in the SAP. 
Exploratory Analyses 
For all patients a retrospective central confirmation of the HER2 status will be done. Further  
exploratory analysis for HER2-positive patients (based on central confirmation) will be 
done for selected endpoints, e.g. BOR and safety (AEs, SAEs, AEs with Grade ≥ 3, and 
AESIs). 
Subgroup analysis for BOR, safety (AEs, SAEs, AEs with Grade ≥ 3, and AESIs) in the 
Randomized Phase II part of the study will be presented for both treatment groups: elderly 
versus younger patients, patients with ECOG 0–1 versus ECOG 2. More details will be 
presented in the SAP. 
Pharmacoeconomic Endpoint 
The number of hospital visits, number of days admitted, and type of visits (emergency 
department versus inpatient care) will be collected and compared. The reason for admission 
(disease progression versus AE) will also be assessed. 
Determination of Sample Size 
Sample Size for Phase I: MTD Finding: mBC 
This part will be based on a classical 3 plus 3 Phase I design. A minimum of 6 and up to 
18 patients will be enrolled in Cohort 1. There is no formal sample size estimation for this 
part. 
Sample Size for Randomized Phase II: Exploration of Efficacy and Safety in mBC 
Approximately 117 patients (78 patients in the combination of T-DM1 and capecitabine 
respective 39 patients in T-DM1 treatment group), including a 10% withdrawal rate, will be 
randomized with a 2:1 ratio to the combination of T-DM1 and capecitabine or T-DM1. 
Point estimates and 95% Clopper-Pearson exact CIs are tabulated for a range of possible 
BOR outcomes for both treatment groups: 
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Table 1: Sample Size Estimation (2:1 randomization) 
Sample size based on BOR  
 
N (T-DM1 and capecitabine)* = 70 patients* 
BOR rate [%] 
95% CI (within treatment group) [%] 
57.5 
(45.1–69.2) 
60.0 
(47.6–71.5) 
62.5 
(50.1–73.8) 
65.0 
(52.7–76.0) 
67.5 
(55.2–78.2) 
 
N (T-DM1) = 35 patients* 
BOR rate [%] 
95% CI (within treatment group) [%] 
37.0 
(21.4–54.9) 
40.0 
(23.9–57.9) 
43.0 
(26.4–60.8) 
46.0 
(29.1–63.6) 
49.0 
(31.8–66.4) 
 
* N = Number of patients without adjustment for withdrawal; CI = confidence interval  
N (T-DM1 and capecitabine) / N (T-DM1) = 2 
 
Expected BOR rate for patients who received trastuzumab emtansine of 43.6% (95% CI: 
38.6% – 48.6%) was chosen based on previously published data for trastuzumab emtansine 
(see Section 6.1 of the main body of the protocol for reference). 
The precision for the BOR estimate of the combination of T-DM1 and capecitabine is 
approximately 12%, e.g. BOR of 60%, 95% CI of (47.6%, 71.5%). Due to the lower sample 
size of the treatment group T-DM1, the corresponding precision for the BOR estimate is 
increased to 18%, e.g. BOR of 46%, 95% CI of (29.1%, 63.6%) 
A 2:1 randomization will be applied to allow more patients being exposed to the combination 
of T-DM1 and capecitabine. This will enable a more thorough assessment of the 
corresponding safety profile. 
Stratification Factors 
The following stratification factor will be implemented in the Randomized Phase II part of the 
study: 
• 
Number of prior lines of treatment for metastatic disease (1 or >1; excluding single-
agent hormones). 
A treatment line is defined as any treatment regime given to patient from treatment initiation 
until confirmed disease progression. 
Sample Size for Phase I, Cohort 2: MTD Finding: mGC 
This part will be based on a classical 3 plus 3 Phase I design. From 3 to 12 patients might 
be enrolled in Cohort 2. There is no formal sample size estimation for this part. 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADL 
activities of daily living 
AE 
AESI 
adverse event 
adverse event of special interest 
ADC 
antibody-drug conjugate 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ARDS 
acute respiratory distress syndrome 
AST 
aspartate transaminase 
AUC 
area under the serum concentration-time curve 
BC 
breast cancer 
bid 
twice daily 
BML 
below measurable limit 
BOR 
BSA 
best overall response 
body surface area 
BUN 
blood urea nitrogen 
CBR 
clinical benefit rate 
CHF 
congestive heart failure 
CI 
confidence interval 
CL 
clearance 
Cmax 
maximum concentration 
CR 
complete response 
CRO 
contract research organization 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
DNA 
dose-limiting toxicity 
deoxyribonucleic acid 
DoR 
duration of response 
DPD 
dihydropyrimidine dehydrogenase 
5-DFUR 
5’-deoxy-5-fluorouridine 
5-FU 
5-fluoruracil 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
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EEA 
European economic area 
EU 
European Union 
FDA 
FFPE 
Food and Drug Administration 
formalin-fixed paraffin-embedded 
FISH 
fluorescence in situ hybridization 
GC 
gastric cancer 
GCP 
Good Clinical Practice 
GEJ 
HBV 
HCV 
gastroesophageal junction 
hepatitis B virus 
hepatitis C virus 
HER2 
human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
hazard ratio 
HIV 
human immunodeficiency virus 
ICH 
IDMC 
International Conference on Harmonisation 
independent data monitoring committee 
IHC 
ILD 
immunohistochemistry 
interstitial lung disease 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IRB 
ISH 
Institutional Review Board 
in situ hybridization 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
IxRS 
LC-MS/MS 
 
LFT 
LPLV 
interactive voice/web recognition system 
liquid chromatography electrospray tandem mass 
spectrometry 
liver function test 
last patient last visit 
LVEF 
left ventricular ejection fraction 
mBC 
metastatic breast cancer 
mGC 
metastatic gastric cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multiple-gated acquisition (scan) 
N 
number of patients 
NCI 
National Cancer Institute 
NE 
not evaluable 
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NRH 
NYHA 
nodular regenerative hyperplasia 
New York Heart Association 
ORR 
overall response rate 
OS 
overall survival 
PD 
pharmacodynamic/progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PP 
per-protocol 
PR 
PVC 
partial response 
polyvinyl chloride 
QTcF 
heart rate-corrected QT interval using the Fridericia 
formula 
q3w 
every 3 weeks 
qw 
weekly 
RECIST 
Response Evaluation Criteria for Solid Tumors 
SAE 
SAP 
serious adverse event 
statistical analysis plan 
SGOT 
serum glutamic oxaloacetic transaminase 
SC 
Steering Committee 
s.d. 
standard deviation 
SD 
SDV 
stable disease 
source data verification 
SGPT 
serum glutamic pyruvic transaminase 
SOC 
SP 
system-organ class 
safety population 
SWFI 
sterile water for injection 
T1/2 
terminal half-life 
TTF 
time to treatment failure 
TTP 
time to progression 
TTR 
time to response 
ULN 
upper limit of normal 
Vd 
volume of distribution 
WBC 
white blood cells 
WHO 
World Health Organization 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON DISEASE 
1.1.1 
HER2-POSITIVE BREAST CANCER, 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 
human epidermal growth factor receptor 2 (HER2) receptors. 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 
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with an anthracycline, a taxane, and trastuzumab, the addition of lapatinib to 
capecitabine resulted in an increased response rate (24% versus 14%) and 
time to disease progression (6.2 months versus 4.3 months) (Geyer et al. 
2006). 
Capecitabine (Xeloda®) in combination with docetaxel for treatment of patients 
with locally advanced or mBC after failure of cytotoxic chemotherapy, 
including an anthracycline was studied in a multicenter, randomized, 
controlled Phase III clinical trial (SO14999). In this trial, 255 patients were 
randomized to treatment with capecitabine (1,250 mg/m2 twice daily [bid] for 2 
weeks followed by a 1-week rest period) and docetaxel (75 mg/m2 as a 1-hour 
intravenous [IV] infusion every 3 weeks [q3w]). A total of 256 patients were 
randomized to treatment with docetaxel alone (100 mg/m2 as a 1-hour IV 
infusion q3w). Survival was superior in the capecitabine plus docetaxel 
combination arm (p = 0.0126). Median survival was 442 days (capecitabine 
plus docetaxel) versus 352 days (docetaxel alone). The overall objective 
response rates in the all-randomized population (investigator assessment) 
were 41.6% (capecitabine plus docetaxel) versus 29.7% (docetaxel alone); 
p = 0.0058. Time to progression (TTP) of disease or number of deaths was 
superior in the capecitabine plus docetaxel combination arm (p < 0.0001). The 
median TTP was 186 days (capecitabine plus docetaxel) versus 128 days 
(docetaxel alone). 
Two multicenter Phase II clinical trials were conducted to determine the use of 
capecitabine monotherapy for treatment of patients with locally advanced or 
mBC after failure of a taxane and an anthracycline-containing chemotherapy 
regimen or for whom further anthracycline therapy is not indicated. In these 
trials, a total of 236 patients were treated with capecitabine (1,250 mg/m2 bid 
for 2 weeks followed by 1-week rest period). The overall objective response 
rates (investigator assessment) were 20% (first trial) and 25% (second trial). 
The median TTP was 93 and 98 days. Median survival was 384 and 373 days 
(Blum et al. 1999; Blum et al. 2001). 
1.1.2 
HER2-POSITIVE LOCALLY ADVANCED OR METASTATIC 
GASTRIC CANCER 
Gastric cancer (GC) remains one of the most common malignancies in the 
world with an estimated 989,600 new cases in 2008 (Jemal et al. 2011). GC 
also continues to be a deadly disease; it is the second leading cause of 
cancer-related death accounting for 738,000 deaths (9.7% of all cancer 
deaths) worldwide in 2008 (Ferlay et al. 2010). The only potentially curative 
treatment for GC is complete resection of localized disease. The overall 5-
year survival for all cases, regardless of initial stage at diagnosis, is less than 
25% (Catalano et al. 2005; Faivre et al. 1998; Parkin et al. 2005; Power et al. 
2010). Among patients with localized disease who undergo curative surgery, 
approximately 40–60% will have disease recurrence. Patients with 
unresectable disease due to locally advanced growth or metastatic spread 
have the poorest prognosis, with an overall 5-year survival in the range of 3% 
to 15% (De Vivo et al. 2000; Ries et al. 2008; Power et al. 2010).  
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Whereas HER2 overexpression is associated with a poor prognosis in BC, the 
prognostic significance of HER2 overexpression in GC is not fully defined. 
Studies of HER2 positivity rates in GC have shown a broad variation of HER2 
positivity ranging from 6.8% to 34.0% for immunohistochemistry (IHC) and 
7.1% to 42.6% for fluorescence in situ hybridization (FISH) techniques 
(Hofmann et al. 2008; Tanner et al. 2005). In a recent study, HER2 positivity 
was shown in 17% of resected esophageal adenocarcinomas and was 
significantly associated with lower tumor grade, less invasiveness, fewer 
malignant nodes, and the presence of adjacent Barrett's esophagus (Yoon et 
al. 2012). 
In the ToGA trial (study BO18255), a global, Phase III study of trastuzumab 
plus chemotherapy as first-line treatment for advanced HER2-positive GC, an 
overall HER2-positivity rate of 22.1% was observed (810/3667 evaluable 
samples), which is comparable to BC. A higher HER2-positivity rate was seen 
in adenocarcinoma of the gastroesophageal junction (GEJ) than in the 
stomach (33.2% versus 20.9%), and intestinal type GCs showed a 
significantly higher HER2-positivity rate than diffuse or mixed-type tumors 
(intestinal: 32.2%, diffuse: 6.1%, mixed: 20.4%; Albarello et al. 2011; Bang et 
al. 2010).  
In the ToGA trial, the addition of trastuzumab to chemotherapy (capecitabine 
or fluorouracil combined with cisplatin) for the treatment of patients with 
HER2-positive (defined as IHC 3+ or FISH positive), inoperable, locally 
advanced or recurrent and/or metastatic adenocarcinoma of the stomach or 
GEJ resulted in an increase in the median overall survival (OS; 13.8 months 
versus 11.1 months, hazard ratio [HR] 0.74, p = 0.0046), objective response 
rate (47% versus 35%), PFS (6.7 versus 5.5 months), and TTP (7.1 versus 
5.6 months) compared with chemotherapy alone (Bang et al. 2010). 
1.2 
BACKGROUND ON STUDY DRUGS  
1.2.1 
TRASTUZUMAB EMTANSINE 
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, 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, 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, Crooke 1978). 
However, because of its narrow therapeutic index and the observed 
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Data from clinical trials of trastuzumab emtansine that are relevant to the 
design of the current trial are summarized below. Please refer to the 
trastuzumab emtansine Investigator’s Brochure for further information on all of 
the completed and ongoing trastuzumab emtansine studies. 
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 q3w; 28 patients received trastuzumab emtansine on a weekly (qw) 
schedule. 
On the q3w dosing schedule, dose-limiting toxicities 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. On the qw schedule, 2.4 mg/kg was 
identified as the MTD (Krop et al. 2008). 
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 (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 Independent Review Board (IRB). The clinical benefit rate 
(CBR; defined as complete response [CR], partial response [PR], or stable 
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disease [SD] 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 IRB. 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. 
The most common adverse events (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 neoadjuvant, 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 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 was 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 aspartate 
transaminase (AST, 26.4%), constipation (23.6%), pyrexia (22.7%), epistaxis 
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(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%). Serious 
AEs (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 emtansine. The patient had pre-existing non-alcoholic fatty 
liver disease as well as multiple other comorbidities, including renal 
insufficiency. 
1.2.1.4 
Study TDM4450g 
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. 
As of 15 November 2010, the PFS was 14.2 months in the trastuzumab 
emtansine arm versus 9.2 months in the trastuzumab plus docetaxel arm. The 
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. 
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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, and 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 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 mean QTcF interval at both the 
15 minute and the 60 minute post-infusion time points was increased by 4.7 
ms. No patient exhibited a mean 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, an 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 
Phase III Study TDM4370g 
Roche is conducting a randomized, open-label Phase III trial (TDM4370g) of 
single-agent trastuzumab emtansine versus lapatinib and capecitabine in 
patients with HER2-positive locally advanced unresectable BC or mBC who 
have received a prior taxane and trastuzumab therapy and have documented 
disease progression. The study is ongoing, enrollment is completed, and 991 
patients have been enrolled. 
Patients are randomized in a 1:1 ratio to trastuzumab emtansine or 
capecitabine plus lapatinib. 
Trastuzumab emtansine is administered at 3.6 mg/kg IV q3w. The control arm 
treatment is capecitabine at 1,000 mg/m2 as oral doses bid on Days 1–14 of a 
q3w cycle plus oral lapatinib 1,250 mg/day given as continuous dosing. Study 
treatment is discontinued based on disease progression (as assessed by the 
investigator), unmanageable toxicity, or study termination by 
Roche/Genentech. 
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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 are investigated as co-primary endpoints in this study with PFS 
based on modified RECIST (Therasse et al. 2000) and conducted by the IRB. 
An additional tumor assessment of PFS is performed after investigator-
documented disease progression. Furthermore ORR, DoR, and CBR are 
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 
versus 6.4 months for patients in the control arm of lapatinib + capecitabine 
(HR = 0.65; 95% CI: 0.55–0.77; p < 0.001, log-rank test). Patients in the 
trastuzumab emtansine arm had a median OS of 30.9 months versus 25.1 
months for patients in the control arm of lapatinib + capecitabine (HR = 0.68; 
95% CI: 0.55–0.85; p < 0.001, log-rank test). The ORR in the trastuzumab 
emtansine arm was 43.6% (95% CI: 38.6%–48.6%) compared with 30.8% 
(95% CI: 26.3%–35.7%) in the control arm (based on 786 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 lapatinib and capecitabine in mBC. The incidence of Grade ≥ 3 
AEs in the control arm (56.9%; n = 488) was 278; that of trastuzumab 
emtansine (40.8%; n = 490) was 200. The rates of SAEs for both arms were 
similar (control arm 18% versus trastuzumab emtansine 15.5%). 
It was concluded that overall, there is no concern regarding the clinical safety 
of trastuzumab emtansine for the patient population that was studied, based 
on the currently available data (Verma et al. 2012). 
1.2.1.7 
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 qw regimens of trastuzumab 
emtansine administration are presented in Table 1. 
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Table 1 Cycle 1 Mean (s.d.) Pharmacokinetic Parameters for 
Trastuzumab Emtansine Following Trastuzumab Emtansine 
Administration Every 3 Weeks and Weekly in Study TDM3569g 
Dose 
(mg/kg) 
No. of 
Patients 
Cmax 
(μg/mL) 
AUCinf 
(day μg/mL) 
T1/2 
(day) 
Vd 
(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; s.d. = standard deviation; 
T1/2 = terminal half-life; Vd = volume of distribution. 
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 q3w cycle with a 2.4 mg/kg qw regimen 
compared with 3.6 mg/kg q3w (Krop et al. 2009, Krop et al. 2010). 
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). 
An aggregate PK assessment of trastuzumab emtansine was performed with 
samples from studies TDM3569g, TDM4258g, TDM4374g, and TDM4688g 
(Girish et al. 2012; Igawa 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 
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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., maximum concentration [Cmax], area under the serum 
concentration-time curve [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. Weekly administration of trastuzumab emtansine in study 
TDM3568g at a dose of 2.4 mg/kg showed consistent PK data with the q3w 
dosing schedule (Krop et al. 2008). 
1.2.2 
CAPECITABINE 
Capecitabine (Xeloda®) is a fluoropyrimidine carbamate with antineoplastic 
activity. It is an orally administered systemic prodrug of 5’-deoxy-5-
fluorouridine (5’-DFUR), which is converted to 5-fluorouracil (5-FU) in the 
tumor, where it inhibits DNA synthesis and slows down tumor tissue growth. It 
has been evaluated in clinical trials in combination with docetaxel and as 
monotherapy in BC (Geyer et al. 2006; Wardley et al. 2006; von Minckwitz et 
al. 2011). Please see the national Xeloda® prescribing information or 
Investigator brochure for more information. 
1.2.2.1 
Study BO18255: Capecitabine and Trastuzumab in mGC 
Recently, a global Phase III study (ToGA trial, BO18255) of trastuzumab plus 
chemotherapy as first-line treatment for advanced HER2-positive GC was 
conducted in 584 patients previously untreated for HER2-positive inoperable 
locally advanced or recurrent and/or metastatic adenocarcinoma of the 
stomach or GEJ. Patients received either capecitabine or fluorouracil 
combined with cisplatin or the same chemotherapy in combination with 
trastuzumab. The primary study endpoint was OS, defined as the time from 
the date of randomization to the date of death from any cause. At the time of 
the analysis a total of 349 randomized patients had died: 182/290 patients 
(62.8%) in the control arm and 167/294 patients (56.8%) in the treatment arm. 
The majority of the deaths were due to events related to the underlying cancer 
(Bang et al. 2010). 
Most patients enrolled in the study were male (76%); 52.9% were Asian and 
37.7% were white. The primary tumor site was the stomach for 81.8% of 
patients, with the others having GEJ tumors. The addition of trastuzumab to 
chemotherapy resulted in an increase in median OS from 11.1 months to 13.8 
months (HR 0.74, p = 0.0046). Objective response rate (47% versus 35%), 
PFS (6.7 versus 5.5 months), and TTP (7.1 versus 5.6 months) were also 
significantly increased with the addition of trastuzumab to chemotherapy 
compared with chemotherapy alone. 
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With regard to OS, a treatment effect could not be excluded in any predefined 
subgroup, including primary tumor site, histologic subtype, method of 
determining HER2-positivity, performance status, chemotherapy regimen, age, 
gender, and region of enrollment. A multivariate analysis for OS showed a 
consistent result, with an adjusted HR of 0.72 (p = 0.0036); variables found to 
influence primary outcome included Eastern Cooperative Oncology Group 
(ECOG) performance status (0 or 1 versus 2), prior gastrectomy, and Asian 
region of enrollment (data on file). A multivariate analysis of OS for patients 
enrolled in Japan, from which the bulk of Asian patients were enrolled, 
demonstrated a HR of 0.68. This was consistent with the overall study results 
(Sawaki et al. 2012). 
A pre-planned subgroup analysis by IHC score indicated that positive 
treatment effects are greater in tumors with higher levels of HER2 expression. 
Among patients whose tumors had these higher levels of HER2 expression, 
the median OS was 11.8 months versus 16 months (HR = 0.65; 95% CI: 
0.51–0.83) and median PFS was 5.5 months versus 7.6 months (HR = 0.64; 
95 % CI: 0.51–0.79) for chemotherapy versus chemotherapy plus 
trastuzumab respectively. For OS, the HR was 0.75 (95% CI: 0.51–1.11) in 
the IHC 2 + /FISH + group and 0.58 (95% CI: 0.41–0.81) in the IHC 3+/FISH+ 
group (Bang et al. 2010). 
The addition of trastuzumab to chemotherapy did not result in an increased 
incidence of severe (Grade 3–4) or fatal (Grade 5) AEs. There were no 
additional significant safety issues with trastuzumab used in the treatment of 
advanced GC over and above those observed when it was used to BC. Taken 
together, the results of the ToGA trial (BO18255) not only demonstrate the 
role of HER2 suppression in the treatment of HER2-positive GC but also show 
that HER2-directed therapies can be added to conventional chemotherapy 
regimens without substantial increases in toxic side effects. 
1.2.3 
PRECLINICAL DATA OF THE COMBINATION OF 
TRASTUZUMAB EMTANSINE AND A FLUOROPYRIMIDINE 
In BC preclinical models an additive anti-tumor activity was observed with 
combinations of trastuzumab emtansine and 5-FU (see Figure 2, [Lewis 
Phillips et al. 2008]). In GC models a similar additive effect was observed with 
trastuzumab emtansine and capecitabine (see Figure 3, [data on file]). 
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1.3 
STUDY RATIONALE AND RISK-BENEFIT 
ASSESSMENT 
1.3.1 
FOR MBC 
At present, mBC remains an incurable disease. The primary goal of treatment 
is maximizing the patient’s survival and quality of life. 
HER2-positive breast tumors have shown to benefit from anti-HER2 therapy. 
Regimens using the combination of anti-HER2 agents and chemotherapy 
have demonstrated higher efficacy than single-agent therapy. As a 
consequence several different combination therapies have been approved for 
HER2-positive mBC treatment in most countries and are considered the 
current standard of care. 
The combination of capecitabine with anti-HER2 therapies has demonstrated 
to be beneficial for patients with mBC. The combination of capecitabine and 
lapatinib is approved in the United States since March 2007 for the treatment 
of patients with HER2-positive mBC who have previously received an 
anthracycline, a taxane, and trastuzumab. In June 2008, the European 
Commission granted conditional marketing authorization for lapatinib in 
combination with capecitabine for the treatment of patients with HER2-positive 
advanced or mBC who have previously received and progressed on an 
anthracycline, a taxane, and trastuzumab in the metastatic setting. The 
combination of capecitabine and trastuzumab has demonstrated significant 
efficacy benefit when compared with capecitabine alone (von Minckwitz et al. 
2011). 
In study TDM4450g, trastuzumab emtansine as a single agent showed a 
significant increase in PFS compared with the current standard of care of 
trastuzumab and a taxane (see Section 1.2.1.4), together with a favorable 
safety profile. 
The Phase III, TDM4370g trial met its co-primary endpoint of improving PFS 
(by IRB) and OS compared with those who received the combination of 
lapatinib and capecitabine (see Section 1.2.1.6). 
Based on the mentioned studies, the combination of trastuzumab emtansine 
and capecitabine could provide the potential for enhanced anti-tumor efficacy 
in mBC, compared with single-agent trastuzumab emtansine or trastuzumab 
in combination with chemotherapy. 
Furthermore, preclinical data suggest that the combination of trastuzumab 
emtansine and capecitabine has an additive effect (see Section 1.2.3). 
Approximately 2,000 patients with BC have been treated in trastuzumab 
emtansine clinical trials with an acceptable safety profile and a positive risk-
benefit ratio. A broad development program is in place to seek approval for 
indications for mBC. Capecitabine in combination with anti-HER2 agent is a 
proven efficacious regimen with a well-established safety profile in mBC. 
Trastuzumab emtansine and capecitabine have no known significant 
overlapping toxicities. As a part of the Phase I conduct, regular teleconference 
calls with the investigators will be held to discuss the study treatment risk-
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benefit profile for each patient. An IDMC will be established with the main 
responsibility to assess the risk-benefit for the Phase II part of the study. 
Therefore, exploring the benefit of combination therapy of trastuzumab 
emtansine and capecitabine in patients with mBC seems justified.  
1.3.2 
FOR MGC 
As for mBC, the primary goal of treatment for metastatic gastric cancer (mGC) 
is the maximizing of the patient’s survival and quality of life. 
HER2-positive gastric tumors have shown to benefit from anti-HER2 therapy. 
Regimens using the combination of anti-HER2 agents and chemotherapy 
have demonstrated higher efficacy than single-agent therapy. As a 
consequence several different combination therapies have been approved for 
HER2-positive mGC treatment in most countries and are considered the 
current standard of care. 
In HER2-positive mGC, the ToGA study (BO18255) has proven that the 
combination of chemotherapy and trastuzumab significantly improves OS (see 
Section 1.2.2.1) in this population. Fluoropyrimidine-based therapies 
(capecitabine, 5-FU) are the standard of care in mGC in general and were 
also the most frequent combination agents used in the ToGA trial (BO18255; 
see Section 1.2.2.1). 
Furthermore, preclinical data suggest that the combination of trastuzumab 
emtansine and capecitabine has an additive effect (see Section 1.2.3). 
A development program for trastuzumab emtansine is in place to seek 
approval for mGC indications. Capecitabine in combination with anti-HER2 
agent is a proven efficacious regimen with a well-established safety profile in 
mGC. Trastuzumab emtansine and capecitabine might have overlapping 
toxicities and therefore a safety monitoring is in place to avoid exposing 
patients to harm. Therefore, exploring the benefit of combination therapy of 
trastuzumab emtansine and capecitabine in patients with mGC seems 
justified. Results from the Phase I part of the study in mGC will be used as 
supporting information for future studies in the indication. 
2. 
OBJECTIVES 
2.1 
PHASE I: MTD FINDING OF TRASTUZUMAB 
EMTANSINE AND CAPECITABINE IN MBC 
2.1.1 
PRIMARY OBJECTIVE 
• 
To determine the MTD of the combination of trastuzumab emtansine and 
capecitabine in patients with mBC  
2.1.2 
SECONDARY OBJECTIVES 
• 
PK of trastuzumab emtansine and metabolites and capecitabine 
• 
Safety of the combination of trastuzumab emtansine and capecitabine 
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• 
ORR 
2.2 
RANDOMIZED PHASE II: EXPLORATION OF 
EFFICACY AND SAFETY IN MBC  
2.2.1 
PRIMARY OBJECTIVE 
To explore the efficacy of the combination of trastuzumab emtansine and 
capecitabine compared with trastuzumab emtansine in patients with mBC, as 
measured by ORR by RECIST v.1.1 per investigator local assessment 
2.2.2 
SECONDARY OBJECTIVES 
Safety profile of the combination of trastuzumab emtansine and capecitabine 
compared with trastuzumab emtansine 
To explore the efficacy of the combination of trastuzumab emtansine and 
capecitabine compared with trastuzumab emtansine in patients with mBC, as 
measured by: 
• 
Time to response (TTR)  
• 
DoR 
• 
TTP 
• 
Time to treatment failure (TTF) 
• 
PFS 
• 
CBR 
• 
OS 
2.3 
PHASE I: MTD FINDING OF TRASTUZUMAB 
EMTANSINE AND CAPECITABINE IN MGC 
2.3.1 
PRIMARY OBJECTIVE 
To determine the MTD of the combination of trastuzumab emtansine and 
capecitabine in patients with mGC  
2.3.2 
SECONDARY OBJECTIVES 
• 
PK of trastuzumab emtansine and metabolites and capecitabine 
• 
Safety of the combination of trastuzumab emtansine and capecitabine 
• 
ORR 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is an international, multicenter Phase I/II dose finding study of two dosing 
schedules of trastuzumab emtansine and capecitabine combination therapy in 
HER2-positive mBC and locally advanced or patients with mGC.  
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The study is designed to determine the MTD of capecitabine in combination 
with trastuzumab emtansine in a Phase I study in patients with mBC and 
locally advanced or mGC. The efficacy and safety of the combination in 
patients with mBC will also be explored in a randomized, open-label Phase II 
part of the study.  
3.1.1 
OVERVIEW OF STUDY DESIGN 
Overview of Study Design 
The study is designed to determine the MTD of capecitabine in combination 
with trastuzumab emtansine in patients with HER2-positive mBC and locally 
advanced or mGC, using a Phase I design, followed by a randomized, open-
label Phase II part of the study to explore the efficacy and safety of the 
combination in patients with mBC. There will be no exploration of efficacy in 
the mGC cohort. Results from the Phase I in mGC will be used as supporting 
information for future studies in the indication. 
Cohort 1 for patients with mBC will open first and MTD will be established. 
Once MTD is established, both randomized Phase II for patients with mBC 
and Cohort 2 for patients with mGC will open. 
An overview of the study design is depicted in Figure 4. 
Duration of Treatment and Patient Follow-up 
Length of treatment: All patients will be treated until disease progression, 
intolerable toxicity, withdrawal of consent, or death. 
Patient follow-up: All patients will be followed-up until withdrawn consent, 
death, or up to a maximum of 2 years after the last patient was randomized in 
the Randomized Phase II part of the study, whichever occurs first. 
Duration of Study, Database Closure and Data Reporting 
The duration of the study is estimated to be approximately 4 years. 
Recruitment is estimated to be 2 years for the Dose Finding and the 
Phase II/Exploration of Efficacy and Safety. The study will end after the follow-
up period is completed, as defined above. Last patient last visit (LPLV) is 
defined as the last data collection point that can be either a clinic visit or a 
laboratory sample. At that time point, the database will be closed. 
In the case that in Cohort 1 the Dose Level -2 is too toxic (> 1/6 of dose-
limiting toxicity [DLT]), the combination may be considered unfeasible, 
recruitment will be closed and neither the Randomized Phase II nor mGC 
cohort will be opened. Patients who, at that point, experience response as per 
RECIST v.1.1 will be offered the possibility to continue on trastuzumab 
emtansine as a single agent, or with the combination, based on risk-benefit 
balance and agreement with the Steering Committee (SC). 
Data may be reported at the end of each cohort i.e., once the MTD for 
Cohort 1 for mBC has been defined and the dose for Phase II/Exploration of 
Efficacy and Safety has been selected. The latest point to write the Clinical 
Study Report (CSR) will be 1 year after database closure. 
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Dose Level -2: 650 mg/m2 capecitabine bid plus 3.6 mg/kg q3w trastuzumab 
emtansine 
If Dose Level -2 is found to be too toxic (DLT > 1/6), the combination may be 
considered unfeasible, the recruitment will be closed and neither the 
Randomized Phase II nor mGC cohort will be opened. Patients who, at that 
point, experience response as per RECIST v.1.1 will be offered the possibility 
to continue on trastuzumab emtansine as a single agent, or with the 
combination, based on risk-benefit balance and agreement with the SC. 
The following MTD determining rules will be applied during the Dose Finding 
treatment phase: 
• 
Step 1: Three patients will be enrolled at Dose Level 1 
• 
Step 2: The toxicity of Dose Level 1 will be monitored and the following 
actions taken: 
a) If none of these 3 patients (0/3) experiences a DLT, the MTD will be 
established as the current dose level and will need to be confirmed in 3 
more patients (to achieve ≤ 1/6 DLT at the current dose level) 
b) If 1 of the initial 3 patients (1/3) experiences a DLT, additional 3 
patients should be enrolled and treated at the same dose, i.e., Dose 
Level 1 
c) If no more patients experience a DLT (1/6), the MTD will be established 
as the current dose level 
d) If 1 or more patients experience a DLT (> 1/6), the dose will be de-
escalated to the next lower dose level. If no more than 1 patient 
experiences a DLT (≤ 1/6) after dose de-escalation, the dose will be 
considered the MTD and, following iDMC agreement, will be further 
explored in the Randomized Phase II part of the study. Dose 
re-escalation will not be allowed. If 2 or more patients experience DLT 
(> 1/6) after dose de-escalation, de-escalation should continue to the 
next lower dose level. Based on the DLT findings, the next dose level 
may be considered the MTD and, following iDMC agreement, be 
further explored in the Randomized Phase II part of the study or the 
study may be terminated if > 1/6 DLTs occur at Dose Level -2 
In order to define the dose for the Randomized Phase II/Exploration of 
Efficacy and Safety part of the study, not only the DLTs during Cycle 1 will be 
evaluated but also all available safety information during the subsequent 
cycles. The dose level considered optimal will be the dose level selected to 
move forward with in the Phase II and mGC parts of the study. 
Once the appropriate dose of study medication is established, the 
Randomized Phase II part of the study and Phase I, Cohort 2 will open as per 
Figure 4. 
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3.1.1.2 
Overview of Phase II: Exploration of Efficacy and Safety in 
Patients with mBC  
This part of the study will explore the efficacy and safety of the combination 
treatment of T-DM1 and capecitabine, at the established MTD, compared with 
T-DM1 alone in mBC patients. 
Once the MTD has been defined to treat patients in Phase II, approximately 
117 additional patients with mBC will be randomized into the Phase II part of 
the study. Patients in the Phase I part of the study will not contribute to the 
Phase II part of the study; however, they will be followed-up until end of study 
(EOS). 
Patients will be treated until disease progression/recurrence, intolerable 
toxicity, withdrawn consent, or death. If capecitabine needs to be discontinued 
for any reason, trastuzumab emtansine may continue, and the patient will be 
followed-up until EOS. In case of discontinuation of trastuzumab emtansine, 
patients will be followed-up until EOS. 
All patients will be followed-up until withdrawn consent, death, or up to a 
maximum of 2 years after the last patient was randomized in the Phase II part 
of the study, whichever occurs first. 
See Section 3.1.1 for further information. 
3.1.1.3 
Overview of Phase I Design in mGC Patients 
Determination of MTD in Patients with mGC  
Cohort 2 will open when the capecitabine MTD is established for Cohort 1 and 
enroll patients with HER2-positive locally advanced and mGC. Trastuzumab 
emtansine will be administered qw at the fixed dose of 2.4 mg/kg and 
capecitabine will be started at the MTD defined for patients with mBC in 
Cohort 1. See Section 3.1.1 for further information. 
Enrollment into Cohort 2 
Cohort 2 will open with a 3 plus 3 classical design to investigate the feasibility 
of combination therapy of capecitabine and trastuzumab emtansine in 
Cohort 2 (enrolling up to 12 patients with mGC) by de-escalating the dose of 
capecitabine starting from the MTD determined in Cohort 1. In case the MTD 
was not established or the enrollment was stopped for Cohort 1, enrollment 
into Cohort 2 will not take place.  
The dose levels for de-escalation of capecitabine will be the same as 
described for Cohort 1, except for Dose Level 1, which will not be explored in 
patients with mGC (see also Section 3.3.2.1). 
If the MTD established in Cohort 1 is defined at Dose Level -1: 
• 
This will be the starting dose in Cohort 2.  If Dose Level -1 is well tolerated 
(DLT ≤ 1/6), this dose will be established as the MTD for mGC. 
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• 
De-escalation: if Dose Level -1 is not tolerated in Cohort 2 (> 1/6 DLT), 
de-escalation will be to Dose Level -2. 
If the MTD established in Cohort 1 is defined at Dose Level -2: 
• 
This will be the starting dose in Cohort 2. If Dose Level -2 is well tolerated 
(DLT ≤ 1/6), this dose will be established as the MTD for mGC. 
• 
De-escalation: if Dose Level -2 is not tolerated in Cohort 2 (> 1/6 DLT), 
the combination will be considered not feasible in mGC and Cohort 2 will 
be terminated. Patients who, at that point, experience response as per 
RECIST v.1.1 will be offered the possibility to continue on trastuzumab 
emtansine as a single agent, or with the combination, based on risk-
benefit balance and agreement with the SC 
3.1.1.4 
Number of Patients 
Overall, it is anticipated that the maximum number of patients enrolled into the 
study will be approximately 147 patients. 
Phase I, Cohort 1: mBC 
From a minimum of 6 to 18 patients will be enrolled into Cohort 1 to determine 
the MTD of capecitabine in combination with trastuzumab emtansine in 
patients with mBC. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
For this part of the study, a total of approximately 117 patients with mBC will 
be randomized. 
Phase I, Cohort 2: mGC 
After the MTD in Cohort 1 has been established, 3–12 patients will be enrolled 
into Cohort 2 to determine the MTD of capecitabine in combination with 
trastuzumab emtansine in patients with mGC. 
3.1.1.5 
Number of Centers 
This is a multicenter, international study. 
3.1.2 
STEERING COMMITTEE 
A SC has been established for this study. Initially, it is composed of the 
investigators participating in the Phase I, Cohort 1 part of the study and one 
medical representative and one statistician of the Sponsor. The study design 
and DLT has been developed by the SC. See SC Charter for further 
information. 
The SC will collectively review the status of the ongoing patients on a regular 
basis. The SC will also review in due course all available efficacy data and PK 
information to ensure that safety information is in the context of risk-benefit 
and that dosing is also related to exposure to the drug.  
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The SC will adjudicate in cases of DLTs that are not covered by the existing 
DLT criteria. 
3.1.3 
INDEPENDENT DATA MONITORING COMMITTEE 
An independent data monitoring committee (IDMC) will be established for the 
Randomized Phase II part of the study. The IDMC will review the safety 
outcomes for patients enrolled in Phase I, Cohort 1 and advise whether the 
Randomized Phase II part of the study can commence. The IDMC will also 
monitor safety outcomes after 20 and 60 patients have received at least 3 
cycles (Cycle 3 Day 1) of treatment in the Phase II part of the study. 
Afterwards, the IDMC will monitor accumulating patient safety data every 6 
months during the Randomized Phase II of the study or as requested. 
3.2 
END OF STUDY 
End of study (EOS) is defined as LPLV at the end of the follow-up period, as 
defined in Section 3.1.1. This will be the last data collection point, which can 
be a clinic visit or a laboratory sample. LPLV is expected to occur 
approximately 2 years after the last patient has been enrolled into the trial. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
RATIONALE FOR PATIENT GROUP SELECTION 
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 
therapy (see the Herceptin® national prescribing information). Measurement of 
HER2 gene amplification has traditionally been performed using IHC 
measurement. HER2 gene amplification determined by FISH has also proven 
to be a reliable method for demonstrating HER2-positive status (Press et al. 
2005). 
This study will enroll patients diagnosed with the disease, to which the 
combination is intended. The combination of anti-HER2 agent and 
capecitabine has shown to be efficacious in both mBC (von Minckwitz et al. 
2011; Geyer et al. 2006) and mGC (Bang et al. 2010), and capecitabine is a 
standard of care treatment for both diseases. Both diseases have been shown 
to benefit from anti-HER2 treatment; therefore, all patients must be diagnosed 
with HER2-positive disease. Patients with incurable mBC and locally 
advanced or mGC, whose tumors are positive for HER2 overexpression, 
represent the patient population eligible for study enrollment. 
3.3.1.1 
Rationale for Phase I 
The study design of 3 plus 3 Phase I is a well-established and well-known 
method for Phase I studies. PK parameters will be collected and analyzed in 
order to investigate the PK interaction of the drugs under investigation. Since 
both agents are administered at efficacious doses, the risk of enrolling 
patients at the sub-optimal doses is minimal. 
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Following review of preliminary data from Cohort 1 of this study by the SC for 
patients enrolled to receive 750 mg/m2 capecitabine, where 2 DLTs were 
observed in 6 evaluable patients, it was decided not to explore dose levels of 
capecitabine higher than 750 mg/m2. According to the investigator 
assessment and the SC recommendation, the available evidence shows an 
acceptable positive risk-benefit in all 7 patients treated at Dose Level 1.  
As of 7 August 2013, five patients remain on treatment, with a follow-up 
period of 4 to 8 months. Of the two patients who have discontinued treatment, 
one patient’s disease has progressed, and the other discontinuation was 
based on the investigator’s decision, following the central confirmation, that 
the patient’s disease was HER2-negative. Considering the available safety 
data for all patients (maximum number of cycles is 12), the combination of 
capecitabine and T-DM1 is well tolerated, except for increases in 
transaminases and hand-foot syndrome. Dose modifications of T-DM1 and/or 
capecitabine have allowed those patients to continue on treatment. Of note, 
no SAE has been reported in 6 patients. Latest tumor response data show 2 
patients with PR and 4 patients with SD. Any required dose modifications 
(dose reductions) are allowed for each individual drug as described in 
Sections 5.1.5.1 and 5.1.5.2 and are in line with the trastuzumab emtansine 
Investigator’s Brochure and Xeloda® Summary of Product Characteristics.  
The combination of T-DM1 and capecitabine will be evaluated with a de-
escalation study design. Patients who are currently receiving the combination 
of T-DM1 and capecitabine 750 mg/m2 can continue to receive the dose as 
per protocol until there is no longer evidence of positive risk-benefit as per 
investigator assessment and SC endorsement. 
3.3.1.2 
Rationale for Randomized Phase II 
Randomized Phase II part of the study is designed to provide an estimation of 
the treatment effect of the combination, at the selected MTD, compared with 
T-DM1 alone. 
The patient data will be stratified by previous anti-cancer treatment (excluding 
single-agent hormones) for the treatment of metastatic disease (1 or >1prior 
lines of treatment). The stratified data will be compared with data from 
historical studies of single-agent trastuzumab emtansine in similar patient 
populations. This will allow a more robust evaluation of the added treatment 
effect of Xeloda® within the combination treatment. 
A 2:1 randomization will be applied to allow more patients being exposed to 
the combination of T-DM1 and capecitabine. This will enable a more thorough 
assessment of the corresponding safety profile. 
In addition, it will provide important information on the longer-term safety of 
the combination. 
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3.3.2 
RATIONALE FOR INVESTIGATIONAL MEDICINAL DOSE 
SELECTION 
3.3.2.1 
In Patients with mBC 
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 
pre-treated HER2-positive mBC (protocol TDM4258g and protocol TDM4374g) 
and in patients who had not received prior chemotherapy for metastatic 
disease (TDM4450g). 
Capecitabine doses have been selected as being in the range of efficacious 
doses for single-agent or combination use. The doses selected are within the 
dosing range included in the Xeloda® Summary of Product Characteristics 
(SmPC) and therefore are considered to be efficacious.  
3.3.2.2 
In Patients with mGC 
In the ToGA study (BO18255: trastuzumab in combination with chemotherapy 
in mGC), patients with higher drug exposure had a greater benefit compared 
with those with lower exposure (Yang et al. 2011). As a consequence, a 
randomized, open-label, multicenter Phase IIIb study comparing two 
trastuzumab dosing regimens, each in combination with cisplatin/capecitabine 
chemotherapy, as first-line therapy in patients with HER2-positive metastatic 
gastric or GEJ adenocarcinoma is being conducted (Study BO27798). 
In TDM3569g (see Section 1.2.1.1), the qw administration of 2.4 mg/kg of 
trastuzumab emtansine resulted in higher exposure (see Section 1.2.1.7) 
(Krop et al. 2008). Therefore, this dose may result in larger clinical benefit for 
patients with mGC. Trastuzumab emtansine at 2.4 mg/kg qw is being tested in 
the BO27952 study.  
In Cohort 2, the starting dose of capecitabine will be the MTD from Cohort 1 
(mBC) in order to minimize the exposure of patients to sub-optimal treatment. 
The dose of capecitabine can be de-escalated if needed. 
3.3.2.3 
Rationale for Duration of Treatment 
Treatment will be given until disease progression or unacceptable toxicity (see 
Section 3.1.1 for full information). As of 1 January 2010, of 237 patients 
enrolled in studies TDM3569g, TDM4258g, and TDM4374g receiving 
trastuzumab emtansine at 3.6 mg/kg, approximately 30% have tolerated more 
than 12 cycles, with 14.8% having received more than 17 cycles. Twenty 
patients (8.4%) have discontinued trastuzumab emtansine due to AEs and 24 
patients (10.1%) required dose reductions in trastuzumab emtansine because 
of AEs. In the absence of intolerable toxicity, patients with mBC are generally 
treated until disease progression. 
Capecitabine will be given until disease progression, as per Xeloda® national 
prescribing information. 
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3.3.3 
PHARMACOKINETIC SAMPLING RATIONALE 
The PK sampling rationale is to characterize the PK of trastuzumab 
emtansine, total trastuzumab, and DM1, to assess potential drug-drug 
interaction when trastuzumab emtansine is given in combination with 
capecitabine, and to explore potential correlations between drug exposure 
and measures of both efficacy (ORR) and toxicity (alanine transaminase 
[ALT]/AST, platelets, etc.), if data allow. 
3.4 
OUTCOME MEASURES 
3.4.1 
PHASE I: MBC 
3.4.1.1 
Primary Efficacy Outcome Measure 
The main objective for Phase I is to determine the MTD of capecitabine when 
combined with trastuzumab emtansine. 
3.4.1.2 
Secondary Efficacy Outcome Measure 
The secondary outcome is ORR, based on best overall response (BOR) rate 
as per RECIST v.1.1; per investigator local assessment. 
3.4.1.3 
Primary Safety Outcome Measure 
The primary safety outcome measure is to establish the MTD. The number 
and the proportion of patients with DLTs will be used as the primary measure 
for the MTD determination and will be summarized for each treatment dosage. 
3.4.1.4 
Secondary Safety Outcome Measures 
Safety endpoints will be summarized for each treatment dosage: 
• 
Incidence, nature, and severity of AEs, as per National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) v. 4.0 
• 
Incidence, nature, and severity of SAEs, as per NCI CTCAE v. 4.0 
• 
Incidence and nature of AEs equal or higher than Grade 3 
• 
Incidence, nature, and severity of AEs of special interest (AESIs), as per 
NCI CTCAE v. 4.0 
• 
Premature withdrawal from study medication 
• 
Abnormal laboratory values 
• 
LVEF 
• 
Exposure to study medication 
• 
Concomitant medications and physical examination 
3.4.1.5 
Pharmacokinetic Outcome Measures 
The PK outcome measures to be assessed in patients receiving trastuzumab 
emtansine and capecitabine will include: 
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• 
Serum concentrations of trastuzumab emtansine (conjugated drug) and 
total trastuzumab (free and conjugated to DM1) 
• 
Plasma concentration of DM1 
• 
Plasma concentration of capecitabine and its active metabolite 5-FU 
3.4.2 
RANDOMIZED PHASE II: EXPLORATION OF EFFICACY AND 
SAFETY IN MBC 
The primary and secondary efficacy outcome measures will be presented for 
each treatment group.  
3.4.2.1 
Primary Efficacy Outcome Measure 
The primary outcome measure is ORR by investigator assessment, based on 
BOR (defined as the best response recorded from the start or randomization 
into Phase II part of the study and until disease progression or recurrence, 
death, withdrawal of consent, or EOS, whichever occurs first) as per RECIST 
v.1.1 provided in Appendix 3. 
3.4.2.2 
Secondary Efficacy Outcome Measures 
Secondary outcomes include: 
• 
TTR 
• 
DoR 
• 
TTP 
• 
TTF 
• 
PFS 
• 
CBR 
• 
OS 
3.4.2.3 
Primary Safety Outcome Measure 
A primary safety outcome is defined only for Phase I, and will be presented for 
both treatment groups.  
3.4.2.4 
Secondary Safety Outcome Measures 
Again, the summary of safety endpoints will be presented for each treatment 
group: 
• 
Incidence, nature, and severity of AEs, as per NCI CTCAE v. 4.0 
• 
Incidence, nature, and severity of SAEs, as per NCI CTCAE v. 4.0 
• 
Incidence and nature of AEs equal or higher than Grade 3 
• 
Incidence, nature, and severity of AESIs, as per NCI CTCAE v. 4.0 
• 
Premature withdrawal from study medication 
• 
Abnormal laboratory values 
• 
LVEF 
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• 
Exposure to study medication 
• 
Concomitant medications and physical examination 
3.4.2.5 
Pharmacokinetic Outcome Measures 
Not applicable for Phase II. 
3.4.3 
PHASE I: MGC 
3.4.3.1 
Primary Efficacy Outcome Measure 
The main objective for Phase I is to determine the MTD of capecitabine when 
combined with trastuzumab emtansine. 
3.4.3.2 
Secondary Efficacy Outcome Measure 
The secondary outcome is ORR, based on BOR rate as per RECIST v.1.1; 
based on investigator assessment. 
3.4.3.3 
Primary Safety Outcome Measure 
The primary outcome measure is to establish MTD. The number and the 
proportion of patients with DLTs will be used as the primary measure for the 
MTD determination and will be summarized for each treatment dosage. 
3.4.3.4 
Secondary Safety Outcome Measures 
Safety endpoints will be summarized for both treatment phases: Dose Finding 
and Exploration of Efficacy. Again, the summary of safety endpoints will be 
presented for each treatment dosage: 
• 
Incidence, nature, and severity of AEs, as per NCI CTCAE v. 4.0 
• 
Incidence, nature, and severity of SAEs, as per NCI CTCAE v. 4.0 
• 
Incidence and nature of AEs equal or higher than Grade 3 
• 
Incidence, nature, and severity of AESIs, as per NCI CTCAE v. 4.0 
• 
Fatal cases and causes of death 
• 
Laboratory parameters 
• 
LVEF 
• 
Treatment exposure 
3.4.3.5 
Pharmacokinetic Outcome Measures 
The PK outcome measures to be assessed in patients receiving trastuzumab 
emtansine and capecitabine will include: 
• 
Serum concentrations of trastuzumab emtansine (conjugated drug) and 
total trastuzumab (free and conjugated to DM1) 
• 
Plasma concentration of DM1 
• 
Plasma concentration of capecitabine and its active metabolite 5-FU 
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4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
4.1.1 
PATIENTS WITH MBC  
This study will enroll patients with HER2-positive BC with histologically or 
cytologically confirmed metastatic disease, which are amenable for 
combination treatment with trastuzumab emtansine and capecitabine. 
Patients with mBC must have received at least one treatment regimen, which 
includes a chemotherapy and trastuzumab agent. Only patients whose HER2 
tumor status was locally scored as IHC 3+ or ISH positive will be permitted for 
both study parts (Phase I and II). 
4.1.2 
MGC PATIENTS 
This study will enroll patients with HER2-positive GC with histologically or 
cytologically confirmed inoperable locally advanced or metastatic disease, 
which are amendable for combination treatment with trastuzumab emtansine 
and capecitabine. 
Patients with mGC must have not received prior chemotherapy for 
advanced/metastatic disease, and only patients with HER2-positive primary 
tumor or metastasis as assessed by central laboratory will be allowed to enroll 
in the Dose Finding part for this disease in this study. 
4.1.3 
INCLUSION CRITERIA 
4.1.3.1 
For Patients with mBC 
Patients must meet the following criteria for study entry: 
1. Age ≥ 18 years old 
2. Signed informed consent prior to any study specific procedure 
3. Able and willing to comply with protocol 
4. 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. 
5.  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 or two effective forms of non-
hormonal contraception and to continue its use for the duration of study 
treatment and for 6 months after the last dose of study treatment (see 
Section 5.2.4). 
6. ECOG performance status of 0, 1, or 2 
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7. Blood: 
a) Platelet count > 100,000 cells/mm3 
b) International normalized ratio (INR) < 1.5  
c) Absolute neutrophil count (ANC) > 1,500 cells/mm3 
d) Hemoglobin > 9.0 g/dL. Patients are allowed to have received 
transfusion to achieve this level. 
8. Liver function: 
a)  Total bilirubin ≤ 1.5 × upper limit of normal (ULN)  
b) Serum glutamic oxaloacetic transaminase (SGOT)/AST and serum 
glutamic pyruvic transaminase (SGPT)/ALT ≤ 2.5 × the ULN 
c) Alkaline phosphatase ≤ 2.5 × the ULN. Patients with hepatic and/or 
bone metastases: alkaline phosphatase ≤ 5 × the ULN 
d) Evidence of stable liver function during the month prior to enrollment 
with liver function tests’ (LFTs) fluctuations not exceeding 2.5 x ULN 
(for AST, ALT) and 1.5 x ULN (for total bilirubin). Patients with bone 
metastases: AST and ALT ≤ 5.0 x ULN 
9. Renal function: 
a) Serum creatinine of < 177 µmol/L or calculated creatinine CL > 50 
mL/min. I urine dipstick for proteinuria is ≥ 2+ at baseline, the patient 
must undergo 24-hour urine collection and demonstrate ≤ 1 g of 
protein/24 hours 
10. Cardiac function: 
a) LVEF ≥ 50% by echocardiogram (ECHO) or multiple-gated acquisition 
(scan) (MUGA) 
11. Histologically or cytologically confirmed BC 
12. HER2-positive disease IHC 3+ or ISH positive 
13. Tumor block or 15 slides available for retrospective central confirmation of 
HER2-positivity (central confirmation not necessary for enrollment).  
14. mBC with at least one measurable lesion according to RECIST v.1.1 
15. Disease progression on at least one regimen containing trastuzumab and 
chemotherapy 
16. Patients must have recovered from previous treatments 
4.1.3.2 
For Patients with mGC 
Patients must meet the following criteria for study entry: 
1. Age ≥ 18 years old 
2. Signed informed consent prior to any study specific procedure 
3. Able and willing to comply with protocol 
4. 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 
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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 
5.  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 or two effective forms of non-
hormonal contraception and to continue its use for the duration of study 
treatment and for 6 months after the last dose of study treatment (see 
Section 5.2.4) 
6. ECOG performance status of 0, 1, or 2 
7. Blood: 
a) Platelet count > 100,000 cells/mm3 
b) INR < 1.5  
c) ANC > 1,500 cells/mm3 
d) Hemoglobin > 9.0 g/dL. Patients are allowed to have received 
transfusion to achieve this level. 
8. Liver function: 
a) Total bilirubin ≤ 1.5 × ULN  
b) SGOT/AST and serum glutamic pyruvic transaminase 
(SGPT)/ALT ≤ 2.5 × the ULN 
c) Alkaline phosphatase ≤ 2.5 × the ULN. Patients with hepatic and/or 
bone metastases: alkaline phosphatase ≤ 5 × the ULN 
d) Evidence of stable liver function in the month prior to enrollment with 
LFTs fluctuations not exceeding 2.5 x ULN (for AST, ALT) and 1.5 x 
ULN (for total bilirubin). Patients with bone metastases: AST and ALT 
≤ 5.0 x ULN 
9. Renal function: 
a) Serum creatinine of < 177 µmol/L or calculated creatinine CL > 50 
mL/min. I urine dipstick for proteinuria is ≥ 2+ at baseline, the patient 
must undergo 24-hour urine collection and demonstrate ≤ 1 g of 
protein/24 hours 
10. Cardiac function: 
a) LVEF ≥ 50% by ECHO or MUGA 
11. Histologically or cytologically confirmed mGC or locally advanced GC 
12. HER2-positive tumor (primary tumor or metastatic lesion), defined as 
either IHC 3+ alone or IHC 2+ in combination with ISH+, prospectively 
confirmed by a Sponsor-designated central laboratory prior to 
enrollment. ISH positivity is defined as a ratio of ≥ 2.0 for the number of 
HER2 gene copies to the number of signals for CEP17. 
a) Archival tumor samples obtained from primary or metastatic sites are 
acceptable. 
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b) Invasive tumor for central confirmation of HER2 status is required. 
c) A formalin-fixed paraffin-embedded (FFPE) tissue block with at least 
5 mm of invasive tumor for central confirmation is preferred. 
If FFPE tissue blocks (or partial block) are unavailable due to country or 
site regulations, a minimum of 8 freshly cut unstained slides MUST be 
available for central review of HER2 status. 
13. Inoperable locally advanced or mGC 
4.1.4 
EXCLUSION CRITERIA 
4.1.4.1 
For Patients with mBC 
1. Prior treatments before first study treatment: 
a) Investigational therapy within ≤ 28 days or 5 half-lives, whatever is 
longest 
b)  Hormonal therapy within 14 days 
c) Trastuzumab within 21 days 
2. Prior enrollment in a trastuzumab emtansine−containing study, regardless 
of whether the patient received prior trastuzumab emtansine 
3. Prior treatment with capecitabine 
4. History of severe and unexpected reactions to fluoropyrimidine or with 
known hypersensitivity to fluorouracil 
5. Related capecitabine contraindications: 
a) Treatment with sorivudine or its chemically-related analogues, such as 
brivudine 
b) Rare hereditary problems of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactose malabsorption 
6. History of intolerance (including Grade 3 or 4 infusion reaction) or 
hypersensitivity to trastuzumab or murine proteins or any component of 
the product 
7. History of exposure to the following cumulative doses of anthracyclines: 
a) Doxorubicin or liposomal doxorubicin > 500 mg/m2 
b)  Epirubicin > 900 mg/m2 
c) Mitoxantrone > 120 mg/m2 
d) If another anthracycline, or more than one anthracycline, has been 
used, the cumulative dose must not exceed the equivalent of 
500 mg/m2 doxorubicin. 
8. Brain metastases that are symptomatic, or require any radiation, surgery, 
or steroid therapy to control their symptoms within 28 days of first study 
drug administration 
9. Current peripheral neuropathy of Grade ≥ 3 per the NCI CTCAE, v. 4.0 
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10. History of other malignancy within the last 5 years, except for 
appropriately treated carcinoma in situ of the cervix, non-melanoma skin 
carcinoma, Stage I uterine cancer, or other cancers with a similar 
outcome as those mentioned above 
11. Current unstable ventricular arrhythmia requiring treatment 
12. History of symptomatic CHF (New York Heart Association [NYHA] 
Classes II−IV) 
13. History of myocardial infarction or unstable angina within 6 months prior to 
first study drug administration 
14. History of a decrease in LVEF to < 40% or symptomatic CHF with 
previous trastuzumab treatment 
15. Severe dyspnea at rest due to complications of advanced malignancy or 
requiring current continuous oxygen therapy 
16. Clinically significant malabsorption syndrome or inability to take oral 
medication 
17. Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, or metabolic disease) 
18. Major surgical procedure or significant traumatic injury within 28 days 
before enrollment or anticipation of the need for major surgery during the 
course of study treatment 
19. Current pregnancy or lactation 
20. Current known active infection with human immunodeficiency virus (HIV), 
hepatitis B and/or hepatitis C virus (HBV/HCV) 
a) For patients who are known carriers of HBV, active hepatitis B infection 
must be ruled out based on negative serologic testing and/or 
determination of HBV DNA viral load per local guidelines 
21.  Lapatinib ≤ 14 days before first study drug administration 
22. Previous radiotherapy for the treatment of unresectable, locally 
advanced/recurrent or mBC is not allowed if: 
a) The last fraction of radiotherapy has been administered within 14 days 
prior to first study drug administration. 
b) More than 25% of marrow-bearing bone has been irradiated. 
c) The patient has not recovered from any resulting acute toxicity to 
Grade ≤ 1 prior to first study drug administration. 
23. No signs and symptoms suggestive that the patient has dihydropyrimidine 
dehydrogenase (DPD) deficiency 
4.1.4.2 
For Patients with mGC 
1. Prior treatments before first study treatment: 
a) Investigational therapy within ≤ 28 days or 5 half-lives, whatever is 
longest 
b)  Hormonal therapy within 14 days 
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c) Trastuzumab within 21 days 
2. Prior enrollment in a trastuzumab emtansine−containing study, regardless 
of whether the patient received prior trastuzumab emtansine 
3. Prior treatment with capecitabine 
4. History of severe and unexpected reactions to fluoropyrimidine or with 
known hypersensitivity to fluorouracil 
5. Related capecitabine contraindications: 
a) Treatment with sorivudine or its chemically-related analogues, such as 
brivudine 
b) Rare hereditary problems of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactose malabsorption 
6. History of intolerance (including Grade 3 or 4 infusion reaction) or 
hypersensitivity to trastuzumab or murine proteins or any component of 
the product 
7. History of exposure to the following cumulative doses of anthracyclines: 
a) Doxorubicin or liposomal doxorubicin > 500 mg/m2 
b)  Epirubicin > 900 mg/m2 
c) Mitoxantrone > 120 mg/m2 
d) If another anthracycline, or more than one anthracycline, has been 
used, the cumulative dose must not exceed the equivalent of 
500 mg/m2 doxorubicin. 
8. Brain metastases that are symptomatic, or require any radiation, surgery, 
or steroid therapy to control their symptoms within 28 days of first study 
drug administration 
9. Current peripheral neuropathy of Grade ≥ 3 per the NCI CTCAE, v. 4.0 
10. History of other malignancy within the last 5 years, except for 
appropriately treated carcinoma in situ of the cervix, non-melanoma skin 
carcinoma, Stage I uterine cancer, or other cancers with a similar 
outcome as those mentioned above 
11. Current unstable ventricular arrhythmia requiring treatment 
12. History of symptomatic CHF (NYHA Classes II−IV) 
13. History of myocardial infarction or unstable angina within 6 months prior to 
first study drug administration 
14. History of a decrease in LVEF to < 40% or symptomatic CHF with 
previous trastuzumab treatment 
15. Severe dyspnea at rest due to complications of advanced malignancy or 
requiring current continuous oxygen therapy 
16. Clinically significant malabsorption syndrome or inability to take oral 
medication 
17. Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, or metabolic disease) 
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18. Major surgical procedure or significant traumatic injury within 28 days 
before enrollment or anticipation of the need for major surgery during the 
course of study treatment 
19. Current pregnancy or lactation 
20. Current known active infection with HIV, HBV, and/or HCV 
a) For patients who are known carriers of HBV, active hepatitis B infection 
must be ruled out based on negative serologic testing and/or 
determination of HBV DNA viral load per local guidelines 
21. Previous chemotherapy for advanced/metastatic disease 
a) Prior adjuvant/neoadjuvant therapy is allowed if at least 6 months has 
elapsed between completion of adjuvant/neoadjuvant therapy and 
enrollment into the study 
22. No signs and symptoms suggestive that the patient has DPD deficiency 
23. Lapatinib ≤ 14 days before first study drug administration 
4.1.5 
PATIENT REPLACEMENT POLICY 
None of the patients in the Phase I part of the study may be replaced unless 
approved by the entire SC. 
4.2 
METHOD OF TREATMENT ASSIGNMENT 
In the Randomized Phase II part of the study, patients will be randomized to 
receive either the combination of T-DM1 and capecitabine or T-DM1 alone. 
The 2:1 randomization ratio will be applied to allow more patients being 
exposed to the combination treatment and to enable a more thorough 
assessment of the corresponding safety profile. 
This is an open-label study; therefore, no blinding will be used. 
4.3 
STUDY TREATMENT 
4.3.1 
FORMULATION, PACKAGING, AND HANDLING 
4.3.1.1 
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 
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 
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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. 
4.3.1.2 
Capecitabine 
The following information has been obtained from the Xeloda® EU SmPC and 
U.S. Xeloda® Package Insert. 
Capecitabine is available as biconvex, oblong, film-coated tablets, available 
as follows: 
• 
150 mg tablets: color, light peach; engraving, XELODA on one side, 150 
on the other; packs of 60 
• 
500 mg tablets: color, peach; engraving, XELODA on one side, 500 on 
the other; packs of 120 
Capecitabine tablets should not be stored above 30°C. 
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4.3.2 
DOSAGE AND ADMINISTRATION 
4.3.2.1 
For Patients with mBC 
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 (see Appendix 1). The total dose will be calculated 
based on the patient’s weight on Day 1 (or up to 3 days before) of each cycle 
with no upper limit. 
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 90 minutes for fever, chills, or other infusion-associated 
symptoms. If prior infusions were well tolerated (without any signs or 
symptoms of infusion reactions), subsequent doses of trastuzumab emtansine 
may be administered over 30 minutes (±10 minutes), with a minimum 30-
minute observation period following infusion. Local health authority guidelines 
must be followed with regard to further observation and monitoring, if 
applicable. 
Pre-medication for nausea and infusion reactions (e.g., acetaminophen or 
other analgesics, antihistamines such as diphenhydramine, or corticosteroids) 
may be given at the investigator’s discretion. 
Capecitabine 
Capecitabine will be administered twice a day, orally for 14 days followed by a 
7-day rest period at the Dose Levels 1 to -2 described in the “Study Design” 
Section 3.1.1. Capecitabine tablets should be swallowed with water within 30 
minutes after a meal. Capecitabine doses can be delayed for up to 4 hours, 
while keeping the minimal interval of 8 hours between the doses. 
Rounding of the dose, based on 150 and 500 mg strength tablets, will be 
allowed to the nearest dose per patient body surface area (BSA). 
If a dose is missed, the patient should skip that dose. The patient should not 
double the dose during the next administration. 
Guidelines for dosage modification and treatment interruption or 
discontinuation are provided in Section 5.1. For this part of the study, the MTD 
established in Phase I, Cohort 1 will be used as a starting dose. 
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4.3.2.2 
For Patients with mGC 
Trastuzumab Emtansine 
Trastuzumab emtansine will be administered on Day 1 of a qw cycle qw at a 
dose of 2.4 mg/kg IV (see Appendix 1). The total dose will be calculated 
based on the patients weight on Day 1 (or up to 3 days before) of each cycle 
with no upper limit. 
Administration time and observation period will be performed as described in 
Section 4.3.2.1 for trastuzumab emtansine. 
Guidelines regarding timing delays and infusion times are the same as for 
patients with mBC, as is the accepted pre-medication. 
Capecitabine 
Capecitabine will be administered twice a day, orally, for 14 days followed by 
a 7-day rest period at the dose level that was determined during the Dose 
Finding part of the study in patients with mBC as the MTD in Cohort 1. 
Capecitabine tablets should be swallowed with water within 30 minutes after a 
meal. Capecitabine doses can be delayed for up to 4 hours, while keeping the 
minimal interval of 8 hours between the doses. 
If a dose is missed, the patient should skip that dose. The patient should not 
double the dose the next administration. 
Guidelines for dosage modification and treatment interruption or 
discontinuation are provided in Section 5.1. 
4.3.3 
INVESTIGATIONAL MEDICINAL PRODUCT ACCOUNTABILITY 
All investigational medicinal products (IMPs) required for completion of this 
study (trastuzumab emtansine and capecitabine) 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. 
IMPs will either be disposed of at the study site according to the study site’s 
institutional standard operating procedure or returned to the Sponsor with the 
appropriate documentation. The site's method of IMP destruction must be 
agreed upon by the Sponsor. The site must obtain written authorization from 
the Sponsor before any IMP is destroyed, and IMP destruction must be 
documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and 
disposed of by the study site should be recorded on the Drug Inventory Log. 
4.3.4 
POST-TRIAL ACCESS TO EXTENSION STUDY 
Post-trial access of trastuzumab emtansine and capecitabine will be 
performed as described in Section 3.1.1, Treatment of Patients and Database 
Closure. 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 
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provide other study interventions to patients after conclusion of the study or 
any earlier patient withdrawal. 
4.4 
CONCOMITANT AND EXCLUDED THERAPIES 
4.4.1 
PERMITTED THERAPY 
Concomitant therapy and pre-medication are defined as non-IMPs. 
Concomitant therapy includes any prescription medication, over-the-counter 
preparation, or herbal therapy between the 14 days preceding first treatment 
and the Study Treatment Discontinuation Visit. Afterwards, only anti-cancer 
therapies will be collected as part of the survival follow-up period. 
Pre-medication is allowed according to standard practice guidelines. 
No pre-medication for the first infusion of trastuzumab emtansine is required; 
however, pre-medication 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). 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 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. 
4.4.2 
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. 
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 
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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 cannot be treated with additional radiation. 
Patients must not miss more than one cycle of study treatment for the 
treatment of their brain metastases and must have an ECOG performance 
status of 0, 1, or 2 to continue on therapy. The Medical Monitor should be 
informed before a decision is made to resume study treatment after 
radiotherapy for brain metastases. 
4.5 
STUDY ASSESSMENTS 
All patients will be closely monitored for safety and tolerability during all cycles 
of therapy and at the safety follow-up visit: 
• 
Visits will be based on a q3w cycle for mBC 
• 
Visits will be based on a qw cycle for mGC 
Study assessments are outlined in this section and in Appendix 1. 
4.5.1 
DESCRIPTION OF STUDY ASSESSMENTS 
All patients will be closely monitored for safety and tolerability during all cycles 
of therapy and at the Study Treatment Discontinuation Visit. Patients should 
be assessed for toxicity prior to each dose; dosing will occur only if the clinical 
assessment and local laboratory test values are acceptable. Trastuzumab 
emtansine will be administered either in q3w cycles (patients with mBC) or qw 
cycles (patients with mGC) if no additional time is required for reversal of 
toxicity. Dose delays and dose reductions will be allowed for trastuzumab 
emtansine as outlined in Section 5.1.5. 
If the timing of a protocol-mandated procedure coincides with a holiday and/or 
weekend that precludes the procedure within the allotted window, the 
procedure should be performed on the nearest following date (i.e., within 
3 business days). 
4.5.1.1 
Medical History and Demographic Data 
Medical history includes 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 race/ethnicity. 
4.5.1.2 
Vital Signs 
Vital signs will include measurements of weight, respiratory rate, heart rate, 
blood pressure, and temperature. Abnormal or significant changes to vital 
signs from baseline should be recorded as AEs, if appropriate. 
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4.5.1.3 
Physical Examinations 
A complete physical examination should include the evaluation of head, eye, 
ear, nose, and throat; cardiovascular; dermatological; musculoskeletal; 
respiratory; gastrointestinal; and neurological systems. Changes from 
baseline abnormalities should be recorded at each subsequent physical 
examination. New or worsened abnormalities should be recorded as AEs if 
appropriate. 
As part of tumor assessment, physical examinations should also include the 
evaluation of the presence and degree of enlarged lymph nodes, 
hepatomegaly, and splenomegaly. 
Limited physical examinations will be symptom-directed. 
4.5.1.4 
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 
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 (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 (see Appendix 3). 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 (see Appendix 4). 
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. 
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4.5.1.5 
Laboratory Assessments 
For Patients with mBC: 
Local Laboratory Assessments: 
• 
Hematology, biochemistry, coagulation, urinalysis, and pregnancy testing 
• 
Prospective or retrospective HER2 status. Patients will be enrolled based 
on local results. 
Central Laboratory Assessments: 
• 
Retrospective HER2 status. Retrospective central confirmation will not 
impact the treatment decisions or primary endpoint of Phase I, Cohort 1 
and will be used to validate efficacy analyses in Phase I and to censor the 
efficacy population for the Randomized Phase II part of the study 
• 
PK assays: 
– 
Serum trastuzumab emtansine concentration and total trastuzumab using 
a validated immunoassay 
– 
Serum capecitabine and 5-FU PK samples 
– 
Plasma concentration of DM1 using a validated liquid chromatography 
electrospray tandem mass spectrometry (LC-MS/MS) method 
For Patients with mGC: 
Local Laboratory Assessments: 
• 
Hematology, biochemistry, coagulation, urinalysis, and pregnancy testing 
Central Laboratory Assessments: 
• 
Prospective HER2 status. Patients will be enrolled based on the central 
testing results 
• 
PK assays: 
– 
Serum trastuzumab emtansine concentration and total trastuzumab using 
a validated immunoassay 
– 
Serum capecitabine and 5-FU PK samples 
– 
Plasma concentration of DM1 using a validated liquid chromatography 
electrospray tandem mass spectrometry (LC-MS/MS) method 
4.5.1.6 
Electrocardiograms 
A 12-lead ECG should be obtained at baseline and be printed and kept with 
the patient’s record. 
4.5.1.7 
ECOG Performance Status 
Performance status will be measured using the ECOG performance status 
scale (see Appendix 6). 
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It is recommended, where possible, that a patient’s performance status be 
assessed by the same person throughout the study. 
Performance status will be assessed according to the schedule of 
assessments (see Appendix 1) 
4.5.1.8 
ECHO/MUGA 
ECHO is the preferred modality because of the global technetium (Tc-99m) 
shortage (see Appendix 4). The same method used at screening should be 
used throughout the study. 
4.5.2 
TIMING OF STUDY ASSESSMENTS 
4.5.2.1 
Screening and Pretreatment Assessments 
Written informed consent for participation in the study must be obtained 
before performing any study specific screening tests or evaluations. Informed 
Consent Forms for enrolled patients and for patients who are not 
subsequently enrolled will be maintained at the study site. 
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. 
Results of standard of care tests or examinations performed prior to obtaining 
informed consent and within 28 days prior to study start may be used; such 
tests do not need to be repeated for screening. 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 study start. 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. 
Patients in Cohort 1 will not contribute to Phase II; however, they will be 
followed-up until EOS. In Randomized Phase II, patients will be randomized in 
a 2:1 ratio to receive  
T-DM1 or the combination of T-DM1 and capecitabine prior to receiving the 
first dose of study medication. 
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. 
Please see Appendix 1 for the schedule of screening assessments. 
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4.5.2.2 
Assessments during Treatment 
For Patients with mBC 
Scheduled study visits are based on a q3w cycle, with Cycle 1 beginning at 
Day 1. All visits must occur within ± 3 business days from the scheduled date, 
unless otherwise noted in the schedule of assessments. All assessments will 
be performed on the day of the specified visit unless a time window is 
specified. Assessments scheduled on the day of study treatment 
administration should be performed prior to study treatment administration 
unless otherwise noted. If the timing of a protocol-mandated procedure 
coincides with a holiday and/or weekend, it should be performed on the 
nearest following date (i.e., within 3 business days). 
Local laboratory assessments scheduled for Day 1 of all cycles must be 
performed within 72 hours prior to study treatment administration unless 
otherwise specified. Results of local laboratory assessments must be 
reviewed and the review documented prior to study treatment administration. 
Please see Appendix 1 for the schedule of treatment period assessments. 
For Patients with mGC 
Scheduled study visits are based on a qw cycle, with Cycle 1 beginning at 
Day 1. All visits must occur within ± 3 business days from the scheduled date, 
unless otherwise noted in the schedule of assessments. All assessments will 
be performed on the day of the specified visit unless a time window is 
specified. Assessments scheduled on the day of study treatment 
administration should be performed prior to study treatment administration 
unless otherwise noted. If the timing of a protocol-mandated procedure 
coincides with a holiday and/or weekend, it should be performed on the 
nearest following date (i.e., within 3 business days). 
Local laboratory assessments scheduled for Day 1 of all cycles must be 
performed within 72 hours prior to study treatment administration unless 
otherwise specified. Results of local laboratory assessments must be 
reviewed and the review documented prior to study treatment administration. 
Please see Appendix 1 for the schedule of treatment period assessments. 
4.5.2.3 
Assessments at Study Completion/Early Termination Visit 
Patients may remain on study treatment until disease progression as 
assessed by the investigator, intolerable toxicity, or until the patient wishes to 
withdraw from study treatment. Patients who discontinue study treatment will 
be followed-up until EOS and will be asked to return to the clinic 
approximately 28–42 days after the last study treatment administration for the 
safety follow-up visit. 
Please see Appendix 1 for assessments to be performed at the safety follow-
up visit. 
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4.5.2.4 
Follow-up Assessments 
After the Study Treatment Discontinuation Visit, all patients (regardless of 
reason for discontinuation) will have anti-cancer therapies recorded and will 
be followed for 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. 
Patients who discontinue study drugs for any reason other than disease 
progression or withdrawal of consent (e.g., an AE) will continue to be followed 
until the development of disease progression, consent withdrawal, lost to 
follow-up, or beginning of another anti-cancer therapy. 
After the study completion/early termination visit, AEs should be followed as 
outlined in Section 5.5 and 5.6. 
Please see Appendix 1 for the schedule of follow-up assessments. 
4.5.2.5 
Assessments at Unplanned Visits 
In case unplanned visits are required, electronic Case Report Form (eCRF) 
pages will be available to report the information collected during those visits. 
4.6 
PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
PATIENT DISCONTINUATION 
Patients have the right to withdraw from the study at any time for any reason. 
The investigator has the right to discontinue a patient from study treatment or 
from the study for any medical condition that the investigator determines may 
jeopardize the patient’s safety if he or she continues in the study, for reasons 
of non-compliance (e.g., missed doses, visits), if the patient becomes 
pregnant, or if the investigator determines it is in the best interest of the 
patient. 
Patients must be withdrawn from study treatment if they become pregnant or 
experience disease progression defined using RECIST v. 1.1 Appendix 3. The 
exception to this is patients who develop isolated progression in the brain as 
described in Appendix 3. 
Details of discontinuation due to toxicity are given in Section 5.1. 
Other reasons for patient discontinuation may include, but are not limited to, 
the following: 
• 
Pregnancy 
• 
Non-compliance 
• 
Investigator decision based on the patient’s best interest 
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• 
Patient decision 
Patients who discontinue from study treatment prematurely for any of the 
above reasons will continue to be followed according to Section 4.5.2.4 
“Follow-Up Assessments”. The primary reason for discontinuation must be 
recorded on the appropriate eCRF page. 
4.6.2 
STUDY DISCONTINUATION 
Section 3.1.1 describes the EOS definition and discontinuation of study. Prior 
to that, 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 
• 
Data recording is inaccurate or incomplete 
5. 
ASSESSMENT OF SAFETY 
Overall safety will be assessed on an ongoing basis during the conduct of the 
study. 
5.1 
SAFETY PLAN 
The safety plan for patients receiving trastuzumab emtansine is based on the 
toxicities of trastuzumab emtansine observed in nonclinical studies; the 
toxicities related to its components (trastuzumab and maytansine, the parent 
drug of DM1) observed in clinical studies; and the clinical experience with this 
molecule in completed and ongoing studies. Please refer to the trastuzumab 
emtansine and capecitabine (Xeloda®) Investigator`s Brochures for the most 
recent information. 
All patients will be monitored closely for toxicity. The important safety issues 
anticipated in this trial, as well as measures intended to avoid or minimize 
such toxicities, are outlined in the following sections. 
5.1.1 
RISKS ASSOCIATED WITH TRASTUZUMAB EMTANSINE 
Full details regarding the clinical safety of trastuzumab emtansine are 
presented in Sections 5 and 6 of the Investigator’s Brochure. 
5.1.1.1 
Cardiotoxicity 
Patients treated with trastuzumab emtansine are at increased risk of 
developing left ventricular dysfunction. LVEF < 40% has been observed in 
patients treated with trastuzumab emtansine. Patients without significant 
cardiac history and with an LVEF ≥ 50% determined by ECHO or MUGA scan 
are eligible for study participation. LVEF will be monitored at screening and 
regularly throughout the study until the assessment at the safety follow-up 
visit. Patients with symptomatic cardiac dysfunction will be discontinued from 
study treatment. Asymptomatic LVEF declines will be handled as per the 
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algorithm shown in Figure 6. Treatment with trastuzumab emtansine has not 
been studied in patients with LVEF < 50%. 
5.1.1.2 
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 central nervous system 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. 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 
allowed according to and at the discretion of the treating physician. 
5.1.1.3 
Hepatotoxicity 
Hepatotoxicity, predominantly in the form of asymptomatic increases in the 
concentrations of serum transaminases (Grade 1 − 4 transaminitis), has been 
observed in patients while on treatment with trastuzumab emtansine in clinical 
trials. Transaminase elevations were generally transient. The incidence of 
increased AST was substantially higher than that for ALT. 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. While there is evidence of 
drug-induced liver toxicity (predominantly in the form of asymptomatic 
increases in the concentrations of serum transaminases) in patients treated 
with trastuzumab emtansine, its potential to cause acute severe liver injury 
with clinically meaningful changes in liver function is unclear as the observed 
cases of acute liver injury were confounded by concomitant medications with 
known hepatotoxic potential and/or underlying conditions. Nevertheless, a 
contributory role of trastuzumab emtansine in these cases cannot be excluded. 
Therefore, acute severe liver injury (Hy’s law) remains an important potential 
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risk with trastuzumab emtansine. A 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.  
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 
hypertension. Diagnosis of NRH can only be confirmed by histopathology. 
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. 
5.1.1.4 
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. 
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5.1.1.5 
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. Pre-medication 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. 
5.1.1.6 
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. 
5.1.1.7 
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 
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time. The infusion site should be closely monitored for possible subcutaneous 
infiltration during drug administration. 
5.1.1.8 
Trastuzumab Emtansine Dose Modification 
Trastuzumab emtansine dose modifications are described in Section 5.1.5.1. 
5.1.2 
RISKS ASSOCIATED WITH CAPECITABINE 
Patients treated with capecitabine should be carefully monitored for toxicity. 
Most AEs are reversible and do not require permanent discontinuation of 
therapy (please refer to the Xeloda® Investigator`s Brochure for more 
information). 
The spectrum of cardiotoxicity observed with capecitabine is similar to that of 
other fluorinated pyrimidines. This includes myocardial infarction, angina, 
dysrhythmias, cardiac arrest, cardiac failure and electrocardiographic changes. 
These AEs may be more common in patients with a prior history of coronary 
artery disease. 
A rare, unexpected, severe toxicity (e.g. stomatitis, diarrhea, neutropenia, and 
neurotoxicity) associated with 5-FU has been attributed to deficiency of DPD 
activity. Therefore, a link between decreased levels of DPD and increased, 
potentially fatal, toxic effects of 5-FU cannot be excluded. 
Capecitabine can induce hand-foot syndrome (palmar-plantar 
erythrodysesthesia or chemotherapy-induced acral erythema), which is a 
cutaneous toxicity. For patients receiving capecitabine monotherapy in the 
metastatic setting, the median time to onset was 79 days (range 11–360 
days), with a severity range of Grades 1 to 3. Grade 1 hand-foot syndrome is 
defined by numbness, dysesthesia/paresthesia, tingling or erythema of the 
hands and/or feet and/or discomfort which does not disrupt normal activities. 
Grade 2 is defined as painful erythema and swelling of the hands and/or feet 
and/or discomfort affecting the patient’s activities of daily living (ADL). Grade 
3 is defined as moist desquamation, ulceration, blistering or severe pain of the 
hands and/or feet and/or severe discomfort that causes the patient to be 
unable to work or perform ADL. If Grade 2 or 3 hand-foot syndrome occurs, 
administration of capecitabine should be interrupted until the event resolves or 
decreases in intensity to Grade 1. Following Grade 3 hand-foot syndrome, 
subsequent doses of capecitabine should be decreased. 
Capecitabine can induce hyperbilirubinemia. Administration of capecitabine 
should be interrupted if treatment-related elevations in bilirubin of > 3.0 × ULN 
or treatment-related elevations in hepatic aminotransferases (ALT/AST) 
of Grade ≥ 2 occur.  
5.1.3 
RISKS ASSOCIATED WITH TRASTUZUMAB EMTANSINE AND 
CAPECITABINE COMBINATION 
DLTs for the combination of trastuzumab emtansine and capecitabine will be 
observed during Cycle 1 (Day 1–21) of this study. The combination treatment 
must be considered as a new treatment during Cycle 1, and no individual 
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dose reduction will be allowed; the general DLT rules will be used instead. 
Interruptions can be made due to toxicities considered by the investigator to 
be related to capecitabine. Grade 2–4 toxicities should be interrupted until 
resolved to Grade 0–1. For Grade 4 toxicities, consideration to discontinue 
treatment with capecitabine will be made with the adjudication of the SC.  
5.1.4 
DEFINITION OF DOSE-LIMITING TOXICITY 
DLT toxicities will be observed during Cycle 1 (Day 1–21). Please refer to 
Xeloda® SmPC for recommendations on dose reduction. 
Definition of DLT: 
Hematologic 
1. Uncomplicated thrombocytopenia Grade 4 which does not recover 
to ≥ 75,000/Ml before Day 21 
2. Thrombocytopenia (any grade) complicated with clinically significant 
bleeding requiring medical intervention such as: platelet transfusion, 
cauterization, patients with epistaxis Grade 1 or 2 may have cauterization 
and this should not be consider as DLT etc. 
3. Neutropenia Grade 4 lasting > 7 consecutive days 
4. Febrile neutropenia with an ANC of < 1,000 cells/mm3 
Non-hematologic 
5. Diarrhea Grade ≥ 3 which does not decrease to ≤ Grade 2 after 24 hours 
of starting recommended anti-diarrheal treatment 
6. Hand-foot syndrome Grade ≥ 3 
7. Any other treatment-related toxicity ≥ Grade 3 prohibiting the start of the 
2nd cycle on Day 22 (3 weeks cycle length plus 1 day) 
NOTE: If a Grade 2 event requires a dose delay, it will not be considered as 
DLT. However, if the toxicity does not resolve to Grade 1 or baseline by 
Day 42, this requires discontinuation and will be considered as DLT. 
8. Grade 2 toxicity requiring interruption of treatment for > 14 days 
NOTE: Patients experiencing ≥ Grade 3 hand-foot syndrome or diarrhea or 
mucositis or febrile neutropenia with ANC < 500 cells/mm3 during Cycle 1 
must be tested for DPD deficiency (central laboratory will be appointed). The 
SC will adjudicate in cases of DLTs that are not covered by the existing DLT 
criteria. 
9. Having taken < 14 full doses of capecitabine due to toxicity 
10. Patient not able to receive 100% of the dose level going into Cycle 2, 
Day 1 
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5.1.5 
MANAGEMENT OF SPECIFIC ADVERSE EVENTS 
5.1.5.1 
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 those specified 
below (i.e., infusion reactions, thrombocytopenia, hepatotoxicity, neurotoxicity, 
cardiotoxicity, and ILD or pneumonitis) are as follows: 
• 
If significant trastuzumab emtansine-related toxicities (other than infusion 
reactions, thrombocytopenia, hepatotoxicity, neurotoxicity, and 
cardiotoxicity) 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 re-
evaluated qw during the delay, whenever possible. If dosing resumes, the 
patient may receive trastuzumab emtansine either at the same dose level 
as before or at one dose level lower (see Table 2 and Table 3), at the 
discretion of the investigator. Subsequent cycles should remain the same 
(q3w or qw), 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 or Table 3. No dose re-escalation will be allowed. 
• 
If 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. 
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Table 2 Dose Reduction for Trastuzumab Emtansine  
(Patients with mBC) 
Dose Level 
q3w Schedule 
0 
3.6 mg/kg 
 - 1 
3.0 mg/kg 
 - 2 
2.4 mg/kg 
Indication for 
further dose 
reduction 
Off study treatment 
q3w = every 3 weeks 
 
Table 3 Dose Reductions for Trastuzumab Emtansine  
(Patients with mGC) 
Dose Level 
qw Schedule 
0 
2.4 mg/kg 
 - 1 
2.0 mg/kg 
 - 2 
Off study 
Indication for 
further dose 
reduction 
Off study 
qw = weekly 
 
In case of toxicities requiring the discontinuation of T-DM1, the patient will be 
followed-up until the EOS. 
Protocol requirements for specific toxicities are outlined below. 
5.1.5.1.1 
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 
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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 
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.  
5.1.5.1.2 
Trastuzumab Emtansine Dose Modification for 
Hepatotoxicity 
5.1.5.1.2.1 
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, activated 
partial thromboplastin time [aPTT], INR, and albumin) will be entered into the 
clinical database. 
5.1.5.1.2.2 
Nodular regenerative hyperplasia (NRH) 
Trastuzumab emtansine must be permanently discontinued in patients who 
are diagnosed with NRH. 
5.1.5.1.2.3 
Transaminase elevations or bilirubin elevation requiring 
dose adjustment 
Patients who experience a Grade 3 elevation of liver function should be 
checked twice weekly for the recovery of transaminases and/or total bilirubin. 
If a patient’s transaminases and/or total bilirubin do not recover as per Table 4 
and Table 5, 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 4 and Table 5 describe the dose modification guidelines for increases in 
serum bilirubin and transaminases, respectively. 
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Table 4 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. 
 
Table 5 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 ≤ 2, 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. 
5.1.5.1.3 
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. 
5.1.5.1.4 
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. 
Ejection fractions will be monitored during the last week of Cycle 1, Cycle 3 
and every third cycle thereafter until the assessment at the safety follow-up 
visit. 
Figure 6 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 
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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. 
The decision to stop or continue trastuzumab emtansine should be based on 
the algorithm shown in Figure 6. 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. 
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Figure 6 Algorithm for Continuation and Discontinuation of 
Trastuzumab Emtansine Based on Left Ventricular Ejection 
Fraction Assessments in Patients 
 
CHF = congestive heart failure; 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. 
 
5.1.5.1.5 
Trastuzumab Emtansine Dose Modification/Management for 
Infusion-related Reactions, Hypersensitivity Reactions 
Trastuzumab emtansine treatment should be interrupted in patients with 
severe infusion-related reactions. Trastuzumab emtansine treatment should 
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. 
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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. Pre-medication 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. In the event of a true hypersensitivity 
reaction (i.e., if the severity of reaction increases with subsequent infusions), 
trastuzumab emtansine treatment must be permanently discontinued. Patients 
who experience a Grade ≥ 3 hypersensitivity reaction or acute respiratory 
distress syndrome (ARDS) will be discontinued from the study. 
Patients who experience a severe delayed infusion reaction will be 
discontinued from study treatment.  
5.1.5.1.6 
Trastuzumab Emtansine Dose Modification for Pulmonary 
Toxicity 
Cases of ILD, including pneumonitis (including severe, life-threatening cases) 
and some leading to ARDS or fatal outcome have been reported with 
trastuzumab emtansine. Treatment with trastuzumab emtansine has to be 
permanently discontinued in patients who are diagnosed with ILD or 
pneumonitis.  
5.1.5.1.7 
Trastuzumab Emtansine Dose Modification for 
Extravasation 
During the 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. 
5.1.5.2 
Capecitabine Dosage Modification 
Phase I: Patients with mBC 
The dose of capecitabine can be modified if considered appropriate by the 
investigator (please refer to the Xeloda® SmPC for recommendations). 
In case of toxicities requiring the discontinuation of capecitabine, single-agent 
trastuzumab emtansine may be continued in patients with mBC. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
During the Randomized Phase II part of the study, the dose of capecitabine 
will be modified as per the Xeloda® SmPC. 
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In case of toxicities requiring the discontinuation of capecitabine, single-agent 
trastuzumab emtansine may be continued in patients with mBC. 
Phase I: Patients with mGC 
The dose of capecitabine can be modified if considered appropriate by the 
investigator (please refer to Xeloda® SmPC for recommendations). 
In case of toxicities requiring the discontinuation of capecitabine, single-agent 
trastuzumab emtansine may be continued in patients with mGC. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording protocol-defined 
AEs and SAEs; measurement of protocol-specified hematology, clinical 
chemistry, and urinalysis variables; measurement of protocol-specified vital 
signs; and other protocol-specified tests that are deemed critical to the safety 
evaluation of the study drug(s). 
The Sponsor or its designee is responsible for reporting relevant SAEs to the 
Competent Authority, other applicable regulatory authorities, and participating 
investigators, in accordance with International Conference on Harmonisation 
(ICH) guidelines, Food and Drug Administration (FDA) regulations, European 
Clinical Trials Directive (Directive 2001/20/EC), and/or local regulatory 
requirements. 
The Sponsor or its designee is responsible for reporting unexpected fatal or 
life-threatening events associated with the use of the study drug to the 
regulatory agencies and competent authorities by telephone or fax within 7 
calendar days after being notified of the event. The Sponsor or its designee 
will report other relevant SAEs associated with the use of the study 
medication to the appropriate competent authorities (according to local 
guidelines), investigators, and central Institutional Review Boards/Ethics 
Committees (IRBs/ECs) by a written safety report within 15 calendar days of 
notification. 
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 
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• 
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 it occurred in a more severe form 
or was allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.8) 
• 
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) 
• 
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 
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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 with concurrent elevation 
of total bilirubin > 2 × ULN, 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: 
• Defined as any organism, virus, or infectious particle (e.g., prion protein 
transmitting transmissible spongiform encephalopathy), both pathogenic 
and non-pathogenic. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings indicating an 
infection in a patient exposed to a medicinal product. This term ONLY 
applies when a contamination of the study drug is suspected, NOT for 
infections supported by the mode of action, e.g., immunosuppression. 
5.2.4 
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 following last 
dose of study drug (follow-up period based on PK considerations). 
Trastuzumab, a component of trastuzumab emtansine, can cause fetal harm 
when administered to a pregnant woman; postmarketing 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 
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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 
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 6 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 6 months after the last dose of study 
treatment. 
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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 6 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 6 months following the last dose of 
either study drug. 
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 6 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 AE 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 AE eCRF, the investigator will make an 
assessment of seriousness (see Section 5.2.2, for seriousness criteria), 
severity (see Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
ADVERSE EVENT REPORTING PERIOD 
Investigators will seek information on AEs at each patient contact. All AEs, 
whether reported by the patient or noted by study personnel, will be recorded 
in the patient’s medical record and on the AE eCRF. 
After informed consent has been obtained but prior to initiation of study drug, 
only SAEs caused by a protocol-mandated intervention should be reported 
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(e.g., SAEs related to invasive procedures such as biopsies, medication 
washout, or no treatment run-in). 
After initiation of study treatment, all AEs, regardless of relationship to study 
drug, will be reported until 30 days after the last administration of study drug 
or study discontinuation/termination, whichever is later. After this period, all 
SAEs and non-serious AESIs (regardless of causality) occurring to a patient 
after the treatment of that patient has ended should be reported to the 
Sponsor if the investigator becomes aware of them. The investigator is not 
required to actively monitor patients after the study has ended (see Section 
5.6). 
5.3.2 
ELICITING ADVERSE EVENT INFORMATION 
A consistent methodology of non-directive questioning should be adopted for 
eliciting AE information at all patient evaluation time points. Examples of non-
directive questions include the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last 
here?” 
5.3.3 
ASSESSMENT OF SEVERITY OF ADVERSE EVENTS 
The AE grading (severity) scale found in the NCI CTCAE (v. 4.0) will be used 
for assessing AE severity (see Table 6). 
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Table 6 Adverse Event Severity Grading Scale 
 
Grade 
Severity 
Alternate Description a 
1 
Mild (apply event-specific 
NCI CTCAE grading criteria) 
Asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated 
2 
Moderate (apply event-specific  
NCI CTCAE grading criteria) 
Minimal, local or non-invasive intervention 
indicated; limiting age-appropriate instrumental 
ADLb 
3 
Severe (apply event-specific  
NCI CTCAE grading criteria) 
Severe or medically significant but 
not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; 
disabling; limiting self-care ADLc 
4 
Very severe, life-threatening,  
or disabling (apply event-specific 
NCI CTCAE grading criteria) 
Life-threatening consequences; 
urgent intervention indicated 
5 
Death related to AE 
 
ADL = activities of daily living; AE = adverse event; CTCAE = Common Terminology Criteria for 
Adverse Events; NCI = National Cancer Institute. 
The NCI CTCAE v4.0 can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
Note: Regardless of severity, some events may also meet regulatory seriousness criteria. Refer 
to definition of a serious AE (see Section 5.2.2). 
a Use these alternative definitions for Grade 1, 2, 3, and 4 events when the observed or 
reported AE is not in the NCI CTCAE listing. 
b Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
c Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
 
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 7. 
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Table 7 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 serious AEs 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. 
5.3.5 
PROCEDURES FOR RECORDING ADVERSE EVENTS 
Investigators should use correct medical terminology/concepts when 
recording AEs on the AE eCRF. Avoid colloquialisms and abbreviations. 
There is one eCRF page for recording AEs or SAEs. 
Only one AE term should be recorded in the event field on the AE eCRF. 
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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-related reaction. However, a diagnosis has to be captured 
as an AE if signs and symptoms constitute a diagnosis of allergic 
reaction/hypersensitivity or infusion-related reaction and are classified as 
SAEs; all such symptoms have to be described in the narrative (e.g., in the 
Additional Case Details field of the eCRF). 
Other Adverse Events 
For AEs other than infusion-related reactions, a diagnosis (if known) should 
be recorded on the AE eCRF rather than individual signs and symptoms (e.g., 
record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or 
syndrome at the time of reporting, each individual event should be recorded 
on the AE eCRF. If a diagnosis is subsequently established, all previously 
reported AEs based on signs and symptoms should be nullified and replaced 
by one AE report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis. 
5.3.5.2 
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 AE 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 AE eCRF should be 
updated to reflect this. 
A recurrent AE is one that resolves between patient evaluation time points 
and subsequently recurs. Each recurrence of an AE should be recorded 
separately on the AE eCRF. 
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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. 
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 
mBC or mGC 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 AE eCRF and immediately reported to 
the Sponsor (see Section 5.4.2). An independent monitoring committee will 
monitor the frequency of death from all causes. 
Death should be considered an outcome and not a distinct event. The event 
or condition that caused or contributed to the fatal outcome should be 
recorded as the single medical concept on the AE eCRF. Generally, only one 
such event should be reported. If the cause of death is unknown and cannot 
be ascertained at the time of reporting, “unexplained death” should be 
recorded on the AE eCRF. If the cause of death later becomes available (e.g., 
after autopsy), “unexplained death” should be replaced by the established 
cause of death.  
During post-study survival follow-up, deaths attributed to progression of mBC 
or mGC 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 start of this study. 
Such conditions should be recorded on the Medical and Surgical History 
eCRF. 
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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 AE 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 Clinical Worsening 
Events that are clearly consistent with the expected pattern of progression of 
mBC or mGC 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 the RECIST criteria. 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 
planned hospitalization or prolonged hospitalization to: 
• 
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 THE 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: 
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• 
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 (SPONSOR’S 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"). 
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 immediately (i.e., no more than 24 hours) 
on the AE eCRF and submit the report via the electronic data capture (EDC) 
system. A report will be generated and sent to 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 immediately 
(i.e., no more than 24 hours) after learning of the event, using the fax 
numbers provided to investigators (see "Protocol Administrative and Contact 
Information & List of Investigators"). Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system. 
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 6 
months after the last dose of study drug. A Pregnancy Report eCRF should 
be completed by the investigator immediately (i.e., no more than 24 hours) 
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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 AE eCRF. 
The investigator should have the patient discontinue the study drug and 
discuss with the patient the risks of the pregnancy and the possible effects on 
the fetus. Monitoring of the patient should continue until conclusion of the 
pregnancy. 
In the event that the EDC system is unavailable, a Pregnancy Report 
worksheet and Pregnancy Fax Coversheet should be completed and faxed to 
the Sponsor Safety Risk Management or its designee immediately (i.e., no 
more than 24 hours) after learning of the pregnancy, using the fax numbers 
provided to investigators (see "Protocol Administrative and Contact 
Information & List of Investigators"). 
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 6 months after the last dose of study drug. A Pregnancy 
Report eCRF should be completed by the investigator immediately (i.e., no 
more than 24 hours) after learning of the pregnancy and submitted via the 
EDC system. Attempts should be made to collect and report details of the 
course and outcome of any pregnancy in the partner of a male patient 
exposed to study drug. The pregnant partner will need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow 
for follow-up on her pregnancy. Once the authorization has been signed, the 
investigator will update the Pregnancy Report eCRF with additional 
information on the course and outcome of the pregnancy. An investigator who 
is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, 
to support an informed decision in cooperation with the treating physician 
and/or obstetrician. 
In the event that the EDC system is unavailable, follow reporting instructions 
provided in Section 5.4.3.1. 
5.4.3.3 
Abortions 
Any spontaneous abortion should be classified as an SAE (as the Sponsor 
considers spontaneous abortions to be medically significant events), recorded 
on the AE eCRF, and reported to the Sponsor immediately (i.e., no more than 
24 hours) after learning of the event (see Section 5.4.2). 
5.4.3.4 
Congenital Anomalies/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 
an SAE, recorded on the AE eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours) after learning of the event (see Section 5.4.2). 
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5.5 
FOLLOW-UP OF PATIENTS AFTER 
ADVERSE EVENTS 
5.5.1 
INVESTIGATOR FOLLOW-UP 
The investigator should follow all unresolved AEs and until the events are 
resolved or stabilized, the patient is lost to follow-up, or it has been determined 
that the study treatment or participation is not the cause of the AE/SAE. 
Resolution of AEs and SAEs (with dates) should be documented on the AE 
eCRF and in the patient’s medical record to facilitate source data verification 
(SDV). 
All pregnancies reported during the study should be followed until pregnancy 
outcome. If the EDC system is not available at the time of pregnancy outcome, 
follow reporting instructions provided in Section 5.4.3.1. 
5.5.2 
SPONSOR FOLLOW-UP 
For SAEs, non-serious 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 
At the study completion/early termination visit, the investigator should instruct 
each patient to report to the investigator any subsequent AEs that could be 
related or not related to the drug under observation. 
The investigator should notify the Sponsor of any death, SAE or AESI 
occurring at any time after a patient has discontinued study participation. The 
Sponsor should also be notified if the investigator becomes aware of the 
development of cancer or a congenital anomaly/birth defect in a subsequently 
conceived offspring of a patient that participated in this study. 
The investigator does not need to actively monitor patients for AEs once the 
trial has ended. The investigator should report the event directly to Roche 
Safety Risk Management via telephone or via facsimile using the Roche 
Clinical Trial (SAE) Reporting Form. 
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 following reference 
documents: 
• 
Trastuzumab emtansine and capecitabine Investigator's Brochures 
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The Sponsor will compare the severity of each event and the cumulative 
event frequency reported for the study with the severity and frequency 
reported in the applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of 
causality and seriousness, with allowance for upgrading by the Sponsor as 
needed. 
The iDMC will closely monitor the incidence of these expected events during 
the study. An aggregate report of any clinically relevant imbalances that do 
not favor the test product will be submitted to health authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
PLAN 
Phase I: Patients with mBC: 
Enrollment into Cohort 1, patients with HER2-positive mBC, will open first. 
Enrolled patients will receive study drug until Investigator-assessed disease 
progression, unacceptable toxicities, patient consent withdrawal, death, 
reasons deemed by the treating physician, or study termination by the 
Sponsor. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC Patients 
randomized in Phase II will receive study drug until Investigator-assessed 
disease progression, unacceptable toxicities, patient consent withdrawal, 
death, reasons deemed by the treating physician, or study termination by the 
Sponsor. 
The final analysis of Randomized Phase II part of this study for ORR will be 
performed at the EOS (defined in Section 3.2). 
Phase I: Patients with mGC: 
Once MTD is established for Cohort 1, enrollment of patients with HER2-
positive and locally advanced or mGC into Cohort 2 will be opened. 
Enrolled patients will receive study drug until Investigator-assessed disease 
progression, unacceptable toxicities, patient consent withdrawal, death, 
reasons deemed by the treating physician, or study termination by the 
Sponsor. 
6.1 
DETERMINATION OF SAMPLE SIZE 
Sample Size for Phase I: mBC 
This part will be based on a classical 3 plus 3 Phase I design. A minimum of 6 
and up to 18 patients will be enrolled into Cohort 1. There is no formal sample 
size estimation for this part. 
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Sample Size for Randomized Phase II: Exploration of Efficacy and Safety 
in mBC 
Approximately 117 patients (78 patients in the combination of T-DM1 and 
capecitabine respective 39 patients in TDM1 treatment group), including a 
10% withdrawal rate, will be randomized with a 2:1 ratio to the combination of 
T-DM1 and capecitabine or T-DM1.  
Point estimates and 95% Clopper-Pearson exact CIs are tabulated for a range 
of possible BOR outcomes for both treatment groups in Table 8. 
Table 8 Sample Size Based on BOR  
 
N (T-DM1 and capecitabine)* = 70 patients* 
BOR rate [%] 
95% CI (within the treatment group) [%] 
57.5 
 (45.1–69.2) 
60.0 
 (47.6–71.5) 
62.5 
 (50.1–73.8) 
65.0 
 (52.7–76.0) 
67.5 
 (55.2–78.2) 
 
N (T-DM1) = 35 patients* 
BOR rate [%] 
95% CI (within the treatment group) [%] 
37.0 
 (21.4–54.9) 
40.0 
 (23.9–57.9) 
43.0 
 (26.4–60.8) 
46.0 
 (29.1–63.6) 
49.0 
 (31.8–66.4) 
 
* N = Number of patients without adjustment for withdrawal; CI = confidence 
interval  
N (T-DM1 and capecitabine) / N (T-DM1) = 2 
 
Expected BOR rate for patients who received trastuzumab emtansine of 
43.6% (95% CI: 38.6%–48.6%) was chosen based on previously published 
data for T-DM1 in patients with unresectable, locally advanced or mBC 
previously treated with a taxane and trastuzumab (EMILIA study; Verma et al. 
2012). 
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The BOR rates for patients treated with the combination of T-DM1 and 
capecitabine were chosen based on recent results from other combination 
studies of T-DM1 plus chemotherapy or trastuzumab plus capecitabine. 
Response rates were based on those observed in patients with HER2-positive 
mBC in a Phase Ib/IIa study (BP22752) that compared the combination of 
trastuzumab emtansine with docetaxel, with or without pertuzumab (ORR: 
76% [95% CI: 53%–92%]), and also in a Phase II study that compared the 
combination of trastuzumab with docetaxel, with or without capecitabine 
(ORRs: 72.7% [95% CI: 63.4%–80.8%] and 70.5% [95% CI: 61.2%–78.8%]; 
Wardley et al., 2010). 
Increased BOR rates for the combination treatment compared with 
single-agent trastuzumab emtansine are in line with previously published 
results of a randomized Phase III study in patients with locally advanced or 
mBC treated with the combination of trastuzumab with capecitabine versus 
capecitabine alone (ORR: 48.1% versus 27.0%, odds ratio = 2.50, p = 0.0115; 
von Minckwitz et al., 2009). 
The precision for the BOR estimate of the combination of T-DM1 and 
capecitabine is approximately 12%, e.g. BOR of 60%, 95% CI of (47.6%, 
71.5%). Due to the lower sample size of the treatment group T-DM1, the 
corresponding precision for the BOR estimate is increased to 18%, e.g. BOR 
of 46%, 95% CI of (29.1%, 63.6%). 
The 2:1 randomization ratio will be applied to allow more patients being 
exposed to the combination of T-DM1 and capecitabine and to enable a more 
thorough assessment of the corresponding safety profile. 
The estimation of sample size was performed by Nquery® and SAS® 
programs. 
Stratification Factors 
The following stratification factor will be implemented in the Randomized 
Phase II of the trial: 
• 
Number of prior lines of treatment for metastatic disease (1 or >1; 
excluding single-agent hormones) 
A treatment line is any regimen given to patient from treatment initiation until 
confirmed disease progression. 
Sample Size for Phase I: mGC 
This part will be based on a classical 3 plus 3 Phase I design. From 3 to 12 
patients might be enrolled into Cohort 2. There is no formal sample size 
estimation for this part. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Phase I: Patients with mBC 
Due to a small sample size, per-protocol (PP) population will not be defined 
for the Phase I, Cohort 1. 
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Major protocol violations will be summarized by treatment dosage. A median 
follow-up will be estimated for Phase I, Cohort 1. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
For the Randomized Phase II part of the study, a PP population will be 
defined (Section 6.4).  
Patient enrollment, duration of follow-up, discontinuation from study treatment 
and study, and reasons for discontinuation will be summarized by treatment 
group for all randomized patients. In addition, major protocol violations will be 
summarized by treatment arm. 
Phase I: Patients with mGC  
Due to a small sample size, a PP population will not be defined for the 
Phase I, Cohort 2. 
Major protocol violations will be summarized by treatment dosage. A median 
follow-up will be estimated for Phase I, Cohort 2. 
6.3 
SUMMARIES OF TREATMENT GROUP 
COMPARABILITY 
Phase I: mBC 
As Phase I is the Dose Finding part of the study, there are no treatment group 
comparisons for this part of the study. 
Demographics, medical history, and baseline characteristics will be 
summarized. Continuous variables will be summarized by means of median, 
mean, standard deviation, 25th and 75th percentiles and range while 
categorical variables – by the number and percentage of patients for each 
treatment dosage. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
The Randomized Phase II part of the study is designed to explore the efficacy 
and safety of the combination of T-DM1 and capecitabine compared with T-
DM1. 
Demographics, medical history, and baseline characteristics will be 
summarized. Continuous variables will be summarized by means of median, 
mean, standard deviation, 25th and 75th percentiles and range while 
categorical variables – by the number and percentage of patients for each 
treatment group. 
Phase I: mGC 
As Phase I is the Dose Finding part of the study, there are no treatment group 
comparisons for this part of the study.  
Demographics, medical history and baseline characteristics will be 
summarized. Continuous variables will be summarized by means of median, 
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mean, standard deviation, 25th and 75th percentiles and range while 
categorical variables – by the number and percentage for each treatment 
dosage. 
6.4 
EFFICACY ANALYSES 
Phase I, Cohort 1: mBC 
The main analysis population will be the DLT evaluable population as defined 
in Section 6.5. 
Randomized Phase II: Exploration of Efficacy in mBC  
The main analysis population for the efficacy analysis will be the intent-to-treat 
population (ITT), which will include all patients in the Randomized Phase II 
part of the study. The PP population will include all ITT patients who have at 
least one post-baseline tumor assessment during the Phase II and no major 
protocol violations, which will be defined in the statistical analysis plan (SAP). 
Phase I, Cohort 2: mGC 
The main analysis population will be the DLT evaluable population as defined 
in Section 6.5. 
6.4.1 
PRIMARY EFFICACY ENDPOINT 
Phase I, Cohort 1: Patients with mBC  
The primary objectives are reaching the MTD and establishing a safety profile. 
The number and the proportion of patients with DLTs will be used as the 
primary measure for the MTD determination. 
ORR, as a main efficacy endpoint, will be assessed via BOR rate. The BOR is 
defined as the best response recorded from the date of enrollment until 
disease progression/recurrence, death, withdrawal of consent or EOS, 
whichever occurs first. The number of patients is very small in this part of the 
study. Therefore, all analyses will be descriptive. 
Randomized Phase II: Exploration of Efficacy in mBC  
The primary efficacy endpoint for the Randomized Phase II part of the study is 
the ORR as assessed via BOR. The BOR is defined as the best response 
recorded from the start or randomization into the Phase II part of the study 
and until disease progression/recurrence, death, withdrawal of consent or 
EOS, whichever occurs first. 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 28 days after the criteria 
for response are first met, i.e., patients need to have two consecutive 
assessments of PR or CR.  
The emphasis of the exploratory Randomized Phase II part of the study will 
not be formal statistical hypothesis testing but the estimation of: 
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• 
The BOR rate with corresponding 95% CIs for each treatment group. The 
justification of the sample size is based on considerations regarding the 
width of 95% CIs for each treatment group estimate (precision of the 
corresponding estimate). 
• 
The treatment effect (between treatment groups comparison) with 
corresponding 95% CIs.  
The number and proportions of responders and non-responders (based on 
BOR) together with 95% Clopper-Pearson CIs will be presented for each 
treatment group.  
The difference in BOR between treatment groups will be displayed with 
associated 95% CIs using the Hauck-Anderson approach.  
Logistic analysis will be used to assess the influence of the stratification factor 
and baseline covariates in an exploratory manner. 
Phase I, Cohort 2: Patients with mGC 
The primary objectives are reaching the MTD and establishing a safety profile. 
The number and the proportion of patients with DLTs will be used as the 
primary measure for the MTD determination. 
ORR, as a main efficacy endpoint, will be assessed via BOR rate. The BOR is 
defined as the best response recorded from the date of enrollment until 
disease progression/recurrence, death, withdrawal of consent or EOS, 
whichever occurs first. The number of patients is very small in this part of the 
study. Therefore, all analyses will be descriptive. 
6.4.2 
SECONDARY EFFICACY ENDPOINTS 
Phase I, Cohort 1: mBC 
Due to the small number of patients and the design of this part of the study, 
no secondary efficacy endpoints will be investigated. 
Randomized Phase II: Exploration of Efficacy in mBC  
The secondary efficacy endpoints for the Randomized Phase II will be: 
• 
TTR 
• 
DoR 
• 
TTP 
• 
TTF 
• 
PFS 
• 
CBR 
• 
OS 
TTR is defined as the time from randomization to first documentation of 
confirmed PR or CR (whichever occurs first). Patients who do not have a 
confirmed response will be censored at the date of the last tumor assessment. 
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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 below. Only patients with 
BOR of CR or PR (i.e., responders) will be included in the analysis of DoR. 
For patients with a BOR of CR or PR, TTR is defined as the time from 
randomization to the date of first CR or PR. The censoring rules will be similar 
to those of the PFS. 
TTP is defined as time from randomization to the first occurrence of PD. 
Patients who have not progressed at the time of study completion (including 
patients who have died before PD) or who are lost to follow-up are censored 
at the date of the last tumor assessment. 
TTF is defined as time from randomization until treatment failure, e.g., to 
disease progression, death, withdrawal due to AE or laboratory abnormality, 
or refusal of treatment. Patients who do not experience any of the above 
events while on study will be censored on the day of their last tumor 
assessment.  
PFS is defined as time from randomization 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 
at the time of Phase II will be censored at the time of enrollment plus 1 day. 
OS is defined as the time from randomization until the date of death, 
regardless of the cause of death. Patients who were alive at the time of the 
analysis will be censored at the date of the last follow-up assessment.  
Estimates for the survivor function of both treatment groups for TTR, DoR, 
TTP, TTF, and OS will be obtained by using the Kaplan-Meier method. HRs 
and associated 95% CIs will be estimated from non-stratified and stratified 
(based on the stratification factor) Cox regression models. 
Clinical benefit response includes patients whose best (confirmed) response 
was PR, CR or SD that lasted at least 6 months. CBR will be summarized in a 
similar way to the primary efficacy endpoint, ORR as assessed by BOR.  
Phase I, Cohort 2: mGC 
Due to the small number of patients and the design of this part of the study, 
no secondary efficacy endpoints will be investigated. 
6.5 
SAFETY ANALYSES 
Safety Population Phase I, Cohort 1: mBC 
The DLT evaluable population is defined for all enrolled and treated patients 
who have not experienced any major protocol violation (including violation of 
the inclusion and exclusion criteria) and completed Cycle 1.  
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The number and the proportion of patients with DLTs will be used as the 
primary measure for the MTD determination. The definition of DLTs is 
presented in Section 5.1.4. DLTs for this part of the study will be summarized 
by treatment dose. 
The safety population (SP) will include all patients who received at least one 
dose of study medication during Phase I. Safety endpoints will be summarized 
by treatment dosage. 
Safety parameters will be analyzed in a similar way to safety parameters in 
Phase I, Cohort 2: mGC. 
Randomized Phase II: Exploration of Safety in mBC  
The SP will include all patients who received at least one dose of study 
medication during the Randomized Phase II part of the study. Safety 
endpoints will be summarized by treatment group.   
Safety endpoints during Phase II will be assessed via total AEs, AEs 
Grade ≥ 3, SAEs, AESIs (as described in Section 5), premature withdrawal 
from study medication, laboratory parameters, LVEF, exposure to study 
medication, concomitant medications, vital signs, ECOG performance status, 
and physical examination. 
The incidence of AEs and SAEs 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 any AESI 
described in Section 5 will also be summarized via Kaplan-Meier estimates. 
Additional summaries by frequency tables will also be provided for the AESIs. 
Patients who died will be listed together with the cause of death. 
Laboratory parameters, hematology and biochemistry will be presented in 
shift tables of NCI-CTC grade at baseline versus worst grade during treatment 
for the Randomized Phase II part of the study. 
LVEF will be summarized over time by means of mean, median and range 
(minimum and maximum) and will be presented graphically. Vital signs will be 
analyzed in a similar way. 
Other safety variables, such as exposure to study medication, concomitant 
medications and physical examinations, will be analyzed in a similar way. The 
exposure of study medication will be summarized by frequency tables. 
ECOG performance status will be summarized over time and the percentage 
of patients in different categories will be presented by bar charts at different 
time points. 
Safety Population Phase I, Cohort 2: mGC 
The DLT evaluable population is defined for all enrolled and treated patients 
who have not experienced any major protocol violation (including violation of 
the inclusion and exclusion criteria) and have completed Cycle 1.  
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The number and the proportion of patients with DLTs will be used as the 
primary measure for the MTD determination. The definition of DLTs is 
presented in Section 5.1.4. DLTs for this part of the study will be summarized 
by treatment dose. 
The SP will include all patients who received at least one dose of study 
medication during Phase I. Safety endpoints will be summarized by treatment 
dosage. 
Safety parameters for this part of the study will be summarized by treatment 
dose. The summaries of AEs, SAEs, AEs that caused discontinuation from 
the study treatment, and AESIs will be analyzed in a similar way to AEs in 
Phase II. 
The incidence of AEs and SAEs will be summarized according to the primary 
SOC and, within each SOC, by MedDRA preferred term. Based on the safety 
profile of trastuzumab emtansine time to onset of the first episode of any AESI 
described in Section 5 will also be summarized via Kaplan-Meier estimates. 
Additional summaries by frequency tables will also be provided for the AESIs. 
Patients who died will be listed together with the cause of death. 
Laboratory parameters, hematology and biochemistry will be presented in 
shift tables of NCI-CTC grade at baseline versus worst grade during treatment 
for Phase I, Cohort 2, and overall. 
LVEF will be summarized over time by means of mean, median and range 
(minimum and maximum) and will be presented graphically. Vital signs will be 
analyzed in a similar way. 
Other safety variables, such as exposure to study medication, concomitant 
medications and physical examinations will be analyzed in a similar way. The 
exposure of study medication will be summarized by frequency tables. 
ECOG performance status will be summarized over time and the percentage 
of patients in different categories will be presented by bar charts at different 
time points. 
6.6 
PHARMACODYNAMIC ANALYSES 
No pharmacodynamic analyses are planned for this study. 
6.7 
PHARMACOKINETIC ANALYSES 
For Phase I only (Patients with mBC and mGC): 
The following PK parameters of trastuzumab emtansine and capecitabine 
(including but not limited to those listed below) will be determined only in the 
Phase I part of the study for Cohort 1 and Cohort 2 in all patients who receive 
study treatment using either non-compartmental and/or population methods, if 
data allow: 
• 
Serum concentrations of trastuzumab emtansine (conjugate) and total 
trastuzumab 
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• 
Plasma concentrations of DM1, capecitabine and its active metabolite  
5-FU 
• 
Total exposure (e.g., AUC)  
• 
Cmax 
• 
Clearance (CL) 
• 
Vd 
• 
T1/2 
The PK of trastuzumab emtansine, total trastuzumab and DM1 will be 
compared with historical single-agent PK data to evaluate the potential effect 
of capecitabine on the PK of trastuzumab emtansine and related analytes. 
The PK of capecitabine and its active metabolite 5-FU in Cycle 1 (in the 
absence of trastuzumab emtansine) will be compared with the PK of Cycle 2 
(in the presence of trastuzumab emtansine) to evaluate the potential effect of 
trastuzumab emtansine on the PK of capecitabine and 5-FU. 
All PK parameters will be listed and tabulated by treatment dose and by 
Cohort. Descriptive summary statistics including arithmetic mean, geometric 
mean (e.g., AUC and Cmax), median, range, s.d., and coefficient of variation 
will be presented for each cohort. Nonlinear mixed effects modeling will be 
also used but details will be presented in the SAP. 
PK samples can be obtained ad hoc in case of SAE or unexpected toxicities 
which may suggest a potential drug-drug interaction. 
6.8 
EXPLORATORY ANALYSES 
For all patients a retrospective central confirmation of the HER2 status will be 
done. Further exploratory analysis for HER2-positive patients– (based on 
central confirmation) will be done for selected endpoints such as BOR and 
safety endpoints (AEs, SAEs, AEs with Grade ≥ 3 and AESIs). 
For the Randomized Phase II: Exploration of Efficacy and Safety in 
Patients with mBC only: 
Subgroup analysis for BOR, safety endpoints (AEs, SAEs, AEs with 
Grade ≥ 3 and AESIs) in Phase II will be presented for: elderly versus 
younger patients, and patients with ECOG 0–1 versus ECOG 2.  
More details about subgroups will be provided in the SAP. 
Pharmacoeconomic Endpoint: 
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. 
6.9 
INTERIM ANALYSES 
There is no formal efficacy interim analysis.  
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However, an IDMC will advise whether the Randomized Phase II part of the 
study can commence. The IDMC will also monitor safety outcomes after 20 
and 60 patients have received at least 3 cycles (Cycle 3 Day 1) of treatment in 
the Randomized Phase II part of the study. Afterwards, the IDMC will monitor 
accumulating patient safety data every 6 months during the course of the 
Randomized Phase II of the study or as requested. 
Efficacy data will only be provided if required by the IDMC to estimate the risk-
benefit balance for the patients. Further details on the function and logistics of 
the IDMC will be provided in the IDMC Charter. 
The design of this study includes: Phase I, Randomized Phase II and different 
cohorts. Corresponding analyses as described in the protocol will be 
performed when all data for particular cohort and study phase are collected 
and cleaned. 
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. Central laboratory 
data and other 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 have access to a manual for appropriate eCRF 
completion. eCRFs will be submitted electronically to the Sponsor and should 
be handled in accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff. eCRFs 
should be reviewed and electronically signed and dated by the investigator or 
a designee. 
At the end of the study, the investigator will receive patient data for his or her 
site in a readable format on a compact disc that must be kept with the study 
records. Acknowledgment of receipt of the compact disc is required. 
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7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing SDV to confirm that critical protocol data 
(i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are 
recorded and documented for the first time. They include, but are not limited 
to, hospital records, clinical and office charts, laboratory notes, memoranda, 
patient-reported outcomes, evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies of transcriptions 
that are certified after verification as being accurate and complete, microfiche, 
photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Source documents that are required to verify the validity and completeness of 
data entered into the eCRFs must not be obliterated or destroyed. 
To facilitate SDV, the investigators and institutions must provide the Sponsor 
with 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. 
In collaboration with the study monitor, 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 Good Clinical Practice (GCP) (see Section 4.9 of the 
guideline) require that records and documents pertaining to the conduct of this 
study and the distribution of investigational drug, including eCRFs, Consent 
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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 (IND) application, 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 
GCP 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 European Union (EU)/European economic area (EEA) will comply with the 
EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
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 Form or any alternate Consent 
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 Form 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. 
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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/IEC 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. 
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 
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 
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(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, 
the 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. 
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 
investigator will permit national and local health authorities, the 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 a SC, iDMC, central laboratory, IxRS, eCRF, and will be 
conducted by a contract research organization (CRO) together with the 
Sponsor. 
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 
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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 the Sponsor 
personnel exceeded that of conventional monitoring will be considered as a 
joint publication by the investigator and the appropriate the 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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emtansine (T-DM1): an antibody–drug conjugate in development for the 
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treatment of HER2-positive cancer. Cancer Chemother Pharmacol 2012; 
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16. Gupta M, LoRusso PM, Wang B, et al. Clinical implications of 
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17. Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system 
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20. Junttila TT, Li G, Parsons K, et al. Trastuzumab-DM1 (T-DM1) retains all 
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21. Krop IE, Beeram M, Modi S, et al. Phase I study of trastuzumab-DM1, an 
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trastuzumab-DM1 antibody conjugate in combination with cytotoxic 
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AACR 2008; poster#2133. 
25. Marty M, Cognetti F, Maraninchi D, et al. Randomized Phase II trial of the 
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cancer administered as first-line treatment: the M77001 study group. J 
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27. Parkin DM, Bray F, Ferlay J, et al. Global Cancer Statistics 2002. CA 
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28. Power DG, Kelsen DP, Shah MA. Power Advanced gastric cancer--slow 
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29. Press MF, Sauter G, Bernstein L, et al. Diagnostic evaluation of HER-2 as 
a molecular target: an assessment of accuracy and reproducibility of 
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laboratory testing in large, prospective, randomized clinical trials. Clin 
Cancer Res 2005; 11:6598–607. 
30. Ries LAG, Melbert D, Krapcho M, et al (eds). SEER Cancer Statistics 
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31. Sawaki A, Ohashi Y, Omuro Y, et al. Efficacy of trastuzumab in Japanese 
patients with HER2-positive advanced gastric or gastroesophageal 
junction cancer: a subgroup analysis of the Trastuzumab for Gastric 
Cancer (ToGA) study. Gastric Cancer 2012; 15:313–22. 
32. Shen B-Q, Bumbaca D, Saad O, et al. Metabolic Fate and 
Pharmacokinetic Characterization of Trastuzumab Emtansine (T-DM1): 
An Emphasis on Preclinical and Clinical Catabolism. ASCPT 2011. 
33. 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. 
34. 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. 
35. Spector NL, Xia W, Burris H 3rd, et al. Study of the biologic effects of 
lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on 
tumor growth and survival pathways in patients with advanced 
malignancies. J Clin Oncol 2005; 23:2502–12. 
36. Sundaresan S, Penuel E, Sliwkowski MX. The biology of human 
epidermal growth factor receptor 2. Curr Oncol Rep 1999; 1:16–22. 
37. Tanner M, Hollmen M, Junttila TT, et al. Amplification of HER2 in gastric 
cancer—association with topoisomerase IIa gene amplification, intestinal 
type, poor prognosis and sensitivity to trastuzumab. Ann Oncol 2005; 
16:273–8. 
38. Therasse P, Eisenhauer EA, Verwij J. RECIST revisited: a review of 
validation studies on tumour assessment. Eur J Cancer 2000; 42:1031–9. 
39. Tjulandin S, Makhson A, Gligorov J, et al. First results of a Phase II study 
of Bevacizumab in combination with trastuzumab and capecitabine as 
first-line treatment of HER2-positive LR/MBC. ASCO 2011; Poster #571. 
40. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-
positive advanced breast cancer. N Engl J Med 2012; 367:1783–91. 
41. von Minckwitz G, Schwedler K, Schmidt M, et al. Trastuzumab beyond 
progression: overall survival analysis of the GBG 26/BIG 3-05 Phase III 
study in HER2-positive breast cancer. Eur J Cancer 2011; 47:2273–81. 
42. Yang J, Wang Y, Zhao H, et al. Combination of exposure-response and 
case-control analyses in regulatory decision making. J Clin Oncol 2011; 
29: (Suppl); 4087. 
43. Yoon HH, Shi Q, Sukov WR, et al. Association of HER2/ErbB2 expression 
and gene amplification with pathologic features and prognosis in 
esophageal adenocarcinomas. Clin Cancer Res 2012; 18:546–54. 
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44. Wardley A, Anton-Torres A, Pivot X, et al. Trastuzumab plus docetaxel 
with or without capecitabine in patients with HER2-positive 
advanced/metastatic breast cancer: first efficacy results from the Phase II 
MO16419 (CHAT) Study. SABCS 2006; Abstract# 2063. 
45. Wardley A, Pivot X, Morales-Vasquez F, et al. Randomized phase II trial 
of first-line trastuzumab plus docetaxel and capecitabine compared with 
trastuzumab plus docetaxel in HER2-positive metastatic breast cancer. J 
Clin Oncol. 2010; 28:976-83. 
46. World Health Organization, World Health Statistics 2011; 
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Appendix 1 
Schedule of Assessments 
Table 1 
 Schedule of assessments for mBC patients (Phase I, Cohort 1 and Randomized Phase II) 
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 Onwards 
Safety 
Follow-Up 
Visit 
Follow-Up2 
Day 
-28 to -1 
1 
8 
15 
1 
8 
15 
1 
8 
15 
28-42 days 
after last 
dose 
every 3-6 
months 
Informed Consent 
Xa 
 
 
 
 
 
 
 
 
 
 
 
HER2 Status  
Xb 
 
 
 
 
 
 
 
 
 
 
 
Medical History and Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination  
X 
 
 
 
 
 
 
 
 
 
 
 
Limited Physical Examinationc 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Height and Weightd 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Vital Signse 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
ECOG Performance Status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Concomitant Medication Reporting 
Xf 
X 
Ongoing 
 
AE Reporting 
Xg 
Ongoing 
X 
Xh 
12-lead ECG  
X  
 
 
 
 
 
 
 
 
 
 
 
ECHO/MUGAi 
Xi 
 
 
Xi 
 
 
Xi 
 
 
Xi 
Xi 
 
Tumor Assessmentsj 
X 
At Cycle 3 (9 weeks after randomization), and then every 4th cycle (12 weeks thereafter, 
regardless of dose delay or early discontinuation, until disease progression or study 
termination) 
X 
X 
Brain CT or MRIk 
X 
At the discretion of the investigator, if clinically indicated, until disease progression 
Bone Scan/Imagingl 
X 
As clinically indicated 
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Appendix 1 
Schedule of Assessments (cont.) 
Table 1Schedule of assessments for mBC patients (Phase I, Cohort 1 and Randomized Phase II) (cont.) 
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 Onwards 
Safety 
Follow-Up 
Visit 
Follow-Up2  
Day 
-28 to -1 
1  
8 
15 
1  
8 
15 
1  
8 
15 
28-42 days 
after last 
dose 
every 3-6 
months 
Hematologym 
X  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
 
 
X 
 
Biochemistryo 
X  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
 
 
X 
 
Urinalysisp 
X  
As clinically indicated 
X 
 
INR/aPTT 
X  
As clinically indicated, e.g. for patients receiving anticoagulation therapy 
X 
 
Pregnancy Testq 
X  
 
 
 
 
 
X q 
 
 
X q 
X  
X 
PK/PD Samples (see Appendix 2)r 
 
Xr 
 
 
Xr 
 
 
 
 
 
 
 
Assessment of Patient 
Hospitalizations and/or Hospital 
Visits 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Administration of Trastuzumab 
Emtansine 
 
D 2s 
 
 
D 1s 
 
 
D 1s 
 
 
 
 
Administration of Capecitabine 
 
D 1–14 
 
D 1–14 
 
D 1–14 
 
 
 
Overall Survival 
X 
X 
X 
X 
Randomization into the Phase II 
Part of the Study 
Xt 
 
 
 
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Appendix 1 
Schedule of Assessments (cont.) 
AE = Adverse Event; aPTT = Activated Partial Thromboplastin Time; CT = Computed Tomography; ECHO = Echocardiogram; ECOG = Eastern Cooperative 
Oncology Group; D= Day; 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, INR and aPTT assessments) at Screening: to be performed within 14 days prior to first 
treatment. Screening laboratory assessments may be done on the same day of first study treatment (Cycle1 Day1). 
2.All patients will be followed-up every 6 months (except for pregnancy, which is at 3 and 6 months after safety follow-up visit until disease progresses for 
tumor assessment or study closure, whichever occurs first. Patients who discontinue study treatment for reasons other than disease progression will 
continue to undergo tumor assessments every 3–6 months. 
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 for patients with mBC.  
c)Limited symptom-directed physical examination. 
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. 
g)During screening, only SAEs considered related to protocol-mandated procedures will be collected. 
h)Patients will be followed for new or worsening AEs for 28 days following the last infusion of study drug or until the early termination visit, until treatment-
related AEs resolve or stabilize, or until the initiation of another anti-cancer therapy, whichever occurs first. After 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 15-
21 of 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. 
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Appendix 1 
Schedule of Assessments (cont.) 
j)Tumor assessments (± 5 business days), including a CT or MRI with contrast of the chest, abdomen, and pelvis should be performed according to the 
indicated schedule. 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, 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. 
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 4.5.1.4 of the protocol and in Appendix 3. 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 study treatment, non-isotopic radiographic modalities should be utilized to document the extent of bony 
metastatic disease. Refer to Appendix 4 in the protocol 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)Assessments should be performed at screening, on Day 1, 8 and 15 of Cycles 1–3, on Day 1 of all subsequent cycles, and weekly following any 
hematologic AE. If capecitabine is discontinued due to toxicity, assessments should be performed weekly (minimum) until resolution of the AE (Grade ≤ 1/ 
baseline), and on Day 1 of subsequent cycles thereafter. All assessments should 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, blood urea nitrogen (BUN), creatinine, uric acid, total protein, 
albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), G-GT, LDH, total bilirubin (and direct bilirubin where total bilirubin > ULN). 
p)Includes specific gravity, pH, protein, glucose, blood, ketones and bilirubin. 
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Schedule of Assessments (cont.) 
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. 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 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. 
r)Pharmacokinetic assessments will be performed during the Dose Finding part of the study only (see Appendix 2). 
s)Trastuzumab emtansine will be administered on Day 1 of each 3-weekly cycle for all patients with mBC in Cohort 1 and Randomized Phase II period of the 
study except in the first cycle where trastuzumab emtansine will be given on Day 2 (to allow PK sampling). 
t)Patients will be randomized only in the Randomized Phase II part of the study. No blinding will be used, as this is an open-label study. A 2:1 randomization 
ratio will be applied to allow more patients to be exposed to the combination of T-DM1 and capecitabine, and to enable a more thorough assessment of the 
corresponding safety profile. 
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Appendix 1 
Schedule of Assessments (cont.) 
Table 2 Schedule of assessments for patients with mGC (Phase I, Cohort 2) 
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 Onwards 
Safety 
Follow-Up 
Visit 
Follow-Up2  
Day 
-28 to -1 
1 
8 
15 
1 
8 
15 
1 
8 
15 
28–42 days 
after last 
dose 
every 3–6 
months 
Informed Consent 
Xa 
 
 
 
 
 
 
 
 
 
 
 
HER2 Status  
Xb 
 
 
 
 
 
 
 
 
 
 
 
Medical History and Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination  
X 
 
 
 
 
 
 
 
 
 
 
 
Limited Physical Examinationc 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Height and Weightd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signse 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
ECOG Performance Status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Concomitant Medication Reporting 
Xf 
X 
Ongoing 
 
AE Reporting 
Xg 
Ongoing 
X 
Xh 
12-lead ECG  
X  
 
 
 
 
 
 
 
 
 
 
 
ECHO/MUGAi 
Xi 
 
 
Xi 
 
 
Xi 
 
 
Xi 
Xi 
 
Tumor Assessmentsj 
X 
At 9 weeks after C1D1, and every 12 weeks thereafter, regardless of dose delay or early 
discontinuation, until disease progression or study termination 
X 
 
Brain CT or MRIk 
X 
At the discretion of the investigator, if clinically indicated, until disease progression 
Bone Scan/Imagingl 
X 
As clinically indicated 
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Appendix 1 
Schedule of Assessments (cont.) 
Table 2 Schedule of assessments for patients with mGC (Phase I, Cohort 2) (cont.) 
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 Onwards 
Safety 
Follow-Up 
Visit 
Follow-Up3  
Day 
-28 to -1 
1  
8 
15 
1  
8 
15 
1  
8 
15 
28–42 days 
after last 
dose 
every 3–6 
months 
Hematologym 
X  
Xn 
Xn  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
X 
 
Biochemistryo 
X  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
X 
 
Urinalysisp 
X  
As clinically indicated 
X 
 
INR/aPTT 
X  
As clinically indicated, e.g. for patients receiving anticoagulation therapy 
X 
 
Pregnancy Testq 
X  
 
 
 
 
 
Xq 
 
 
Xq 
X 
X 
PK/PD Samples (see Appendix 2) 
 
X 
 
 
X 
 
 
 
 
 
 
 
Assessment of Patient 
Hospitalizations and/or Hospital 
Visits 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Administration of Trastuzumab 
Emtansine 
 
D 2r 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Administration of Capecitabine 
 
D 1–14 
 
D 1–14 
 
D 1–14 
 
 
 
Overall Survival 
X 
X 
X 
X 
AE = Adverse Event; aPTT = Activated Partial Thromboplastin Time; CT = Computed Tomography; ECHO = Echocardiogram; ECOG = Eastern Cooperative 
Oncology Group; D= Day; 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 
 
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Schedule of Assessments (cont.) 
1.NOTE: Local laboratory (hematology, biochemistry, urinalysis, INR and aPTT assessments) at Screening: to be performed within 14 days prior to first study 
treatment. Screening laboratory assessments may be done on the same day of first study treatment (Cycle1 Day1) visit. 
2.All patients will be followed-up every 6 months (except for pregnancy, which is at 3 and 6 months after safety follow-up visit) until disease progresses for 
tumor assessment or study closure, whichever occurs first. Patients who discontinue study treatment for reasons other than disease progression will 
continue to undergo tumor assessments every 3–6 months. 
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+ alone or IHC 2+ in combination with gene amplification by ISH. For patients with mGC enrolled into Cohort 2, central 
confirmation of HER2 status is required. 
c)Limited symptom-directed physical examination. 
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 fist study treatment. 
g)During screening, only SAEs considered related to protocol-mandated procedures will be collected. 
h)Patients will be followed for new or worsening AEs for 28 days following the last infusion of study drug or until the early termination visit, until treatment-
related AEs resolve or stabilize, or until the initiation of another anti-cancer therapy, whichever occurs first. After 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 Days 
15–21, 30–42 and 9 weeks 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. 
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Schedule of Assessments (cont.) 
j)Tumor assessments (± 5 business days), including a CT or MRI with contrast of the chest, abdomen, and pelvis should be performed according to the 
indicated schedule. 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, 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. 
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 4.5.1.4 of the protocol and in Appendix 3. 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 4 in the protocol for additional details. 
m)Hematologic assessments include Hemoglobin (Hb), hematocrit, red blood cell count, platelet count, and WBC with differential (including neutrophils, 
lymphocytes, monocytes, eosinophils and basophils). 
n)Assessments should be performed at screening, on Day 1, 8 and 15 of all cycles. All assessments should 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/urea, creatinine, uric acid, total protein, albumin, 
alkaline phosphatase, ALT (SGPT), AST (SGOT), G-GT, LDH, 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. 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 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. 
r)Trastuzumab emtansine will be administered on Day 1 of each weekly cycle for all patients enrolled in Cohort 2 (A&B) except in the first cycle where 
trastuzumab emtansine will be given on DAY 2 (to allow drug interaction assessment). 
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Appendix 2 
Pharmacokinetic Sampling for Phase I, Metastatic Breast and 
Gastric Cancer Patients 
 
Trastuzumab emtansine 
(T-DM1), total 
trastuzumab and DM1a 
PK samples 
Capecitabine and 5-FU 
PK samples 
Cycle 1 Day 1 
 
 
Pre-capecitabine dose 
 
x 
30 min post capecitabine dosing 
 
x 
60 min post capecitabine dosing 
 
x 
1.5 hours post capecitabine 
dosing 
 
x 
2 hours post capecitabine 
dosing 
 
x 
2.5 hours post capecitabine 
dosing 
 
x 
4 hours post capecitabine 
dosing 
 
x 
6 hours post capecitabine 
dosing 
 
x 
Cycle 1 Day 2 
 
 
Pre-T-DM1 dose 
x 
 
15-30 min after end of  
T-DM1infusion 
x 
 
Pre-capecitabine dose 
 
x 
30 min post capecitabine dosing 
 
x 
2 hours post capecitabine 
dosing 
 
x 
6 hours post capecitabine 
dosing 
 
x 
Cycle 1 Day 3 
 
 
24 hours (± 2 hours) after the 
end of infusion of T-DM1 
x 
 
Cycle 1 Day 8 
 
 
7 days (± 1 day) after the end of 
infusion of T-DM1a 
x 
 
Cycle 2 Day 1 
 
 
Pre- capecitabine and T-DM1 
dosea 
x 
 
15–30 min after end of 
trastuzumab emtansine infusion 
x 
 
30 min post capecitabine dosing 
 
x 
60 min post capecitabine dosing 
 
x 
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1.5 hours post capecitabine 
dosing 
 
x 
2 hours post capecitabine 
dosing 
 
x 
2.5 hours post capecitabine 
dosing 
 
x 
4 hours post capecitabine 
dosing 
 
x 
6 hours post capecitabine 
dosing 
 
x 
Cycle 2 Day 2 
 
 
24 hours (± 2 hours) after the 
end of infusion of T-DM1 
x 
 
Cycle 2 Day 7 
 
 
7 days (± 1 day) after the end of 
infusion of T-DM1a 
x 
 
Cycle 3 
 
 
Pre T-DM1 dose 
x 
 
PK = pharmacokinetic; 5-FU = 5-fluoruracil 
a = Plasma DM1 samples will not be collected at Day 7 post-infusion of T-DM1 neither at  
pre-dose of Cycle 2 and Cycle 3. 
Data from historic studies have determined that results are the lower limit of quantitation. 
 
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Appendix 3 
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 CT or magnetic resonance imaging (MRI) scan (CT/MRI scan 
slice thickness/interval no greater than 5 mm) 
• 
10mm caliper measurement by clinical examination (lesions that cannot 
be accurately measured with calipers should be recorded as non-
measurable) 
• 
20 mm by chest X-ray 
Malignant Lymph Nodes. To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in the short axis when assessed 
by CT scan (CT scan slice thickness recommended to be no greater than 5 
mm). At baseline and follow-up, only the short axis will be measured and 
followed. See also notes below on “Baseline Documentation of Target and 
Non-Target Lesions” for information on lymph node measurement. 
                                            
 
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228–47. 
2 For consistency within this document, the section numbers and cross-references to other  
sections within the article have been deleted and minor formatting changes have been made. 
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Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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. 
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, 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. 
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Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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 
possible to the treatment start and never more than 28 days 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 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 
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Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
be taken in measurement of target lesions on a different modality and 
interpretation of non-target disease or new lesions, since the same lesion may 
appear to have a different size using a new modality. 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should 
not be used as a method of measurement. 
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology. The 
utilization of these techniques for objective tumor evaluation cannot generally 
be advised. 
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 
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Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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 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 
• 
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 
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Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. 
The appearance of one or more new lesions is also considered 
progression. 
• 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
on study 
b. Special Notes on the Assessment of Target Lesions 
Lymph Nodes. Lymph nodes identified as target lesions should always have 
the actual short axis measurement recorded (measured in the same 
anatomical plane as the baseline examination), even if the nodes regress 
to < 10 mm on study. This means that when lymph nodes are included as 
target lesions, the sum of lesions may not be zero even if CR criteria are met, 
since a normal lymph node is defined as having a short axis of < 10 mm. 
Target Lesions That Become Too Small to Measure. During the study, all 
lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very 
small (e.g., 2 mm). However, sometimes lesions or lymph nodes that are 
recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may 
report them as being too small to measure. When this occurs, it is important 
that a value be recorded on the CRF, as follows: 
• 
If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. 
• 
If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned and below 
measurable limit (BML) should be ticked. (Note: It is less likely that this 
rule will be used for lymph nodes since they usually have a definable size 
when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and BML should also be ticked). 
To reiterate, however, if the radiologist is able to provide an actual measure, that 
should be recorded, even if it is below 5 mm, and in that case BML should not be 
ticked. 
Lesions That Split or Coalesce on Treatment. When non-nodal lesions 
fragment, the longest diameters of the fragmented portions should be added  
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Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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. 
• 
Complete response (CR): Disappearance of all non-target lesions and 
(if applicable) normalization of tumor marker level 
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
• 
Non-CR/Non-PD: Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
• 
Progressive disease (PD): Unequivocal progression of existing non-target 
lesions 
The appearance of one or more new lesions is also considered 
progression. 
d. Special Notes on Assessment of Progression of Non-Target Disease 
When the Patient Also Has Measurable Disease. In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be 
an overall level of substantial worsening in non-target disease in a magnitude 
that, even in the presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A 
modest increase in the size of one or more non-target lesions is usually not 
sufficient to qualify for unequivocal progression status. The designation of 
overall progression solely on the basis of change in non-target disease in the 
face of SD or PR of target disease will therefore be extremely rare. 
When the Patient Has Only Non-Measurable Disease. This circumstance 
arises in some Phase III trials when it is not a criterion of study entry to have 
measurable disease. The same general concepts apply here as noted above; 
however, in this instance there is no measurable disease assessment to 
factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by 
definition: if all lesions are truly non-measurable), a useful test that can be  
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Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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 (e.g., 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 partial or CR. 
For example, necrosis of a liver lesion may be reported on a CT scan report 
as a “new” cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not 
scanned at baseline is considered a new lesion and will indicate disease 
progression. 
If a new lesion is equivocal, e.g., because of its small size, continued therapy 
and follow-up evaluation will clarify if it represents truly new disease. If repeat 
scans confirm there is definitely a new lesion, then progression should be 
declared using the date of the initial scan. 
Evaluation of Response 
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. 
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Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
When patients have non-measurable (therefore non-target) disease only, 
Table 2 is to be used. 
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. 
 
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Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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 
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. 
c. Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes 
decrease to “normal” size (<10 mm), they may still have a measurement 
reported on scans. This measurement should be recorded even though the 
nodes are normal in order not to overstate progression should it be based on 
increase in size of the nodes. As noted earlier, this means that patients with 
CR may not have a total sum of “zero” on the CRF. 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time 
should be reported as “symptomatic deterioration.” Every effort should be 
made to document objective progression even after discontinuation of 
treatment. Symptomatic deterioration is not a 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, Table 3. 
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Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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. 
 
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Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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 4 
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 5 
New York Heart Association Classification of Functional 
Cardiac Capacity 
Class 
 
I 
No limitation: Ordinary physical activity does not cause undue fatigue, 
dyspnea, or palpitation. 
II 
Slight limitation of physical activity: Such patients are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitations, dyspnea, or angina. 
III 
Marked limitation of physical activity: Although patients are comfortable at 
rest, less than ordinary physical activity will lead to symptoms. 
IV 
Inability to carry on physical activity without discomfort: Symptoms of 
congestive heart failure are present even at rest. With any physical activity, 
increased discomfort is experienced. 
From: Criteria Committee, New York Heart Association, Inc. Diseases of the heart 
and blood vessels. Nomenclature and criteria for diagnosis. 6th ed. Boston, Little, 
Brown and Co, 1964:114. 
 
 
 
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Appendix 6 
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 
 
– http://www.ecog.org/general/perf_stat.html 
 
 
 
 
 
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TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................. 10 
PROTOCOL SYNOPSIS .................................................................................... 11 
1. 
BACKGROUND .......................................................................................... 28 
1.1 
Background on Disease......................................................... 28 
1.1.1 
HER2-Positive Breast Cancer ............................................... 28 
1.1.2 
HER2-Positive Locally Advanced/Metastatic 
Gastric Cancer ......................................................................................... 29 
1.2 
Background on Study Drugs .................................................. 30 
1.2.1 
Trastuzumab Emtansine ........................................................ 30 
1.2.1.1 Study TDM3569g ................................................................. 31 
1.2.1.2 Study TDM4258g ................................................................. 32 
1.2.1.3 Study TDM4374g ................................................................. 32 
1.2.1.4 Study TDM4450g ................................................................. 33 
1.2.1.5 Study TDM4688g ................................................................. 34 
1.2.1.6 Phase III Study TDM4370g .................................................. 35 
1.2.1.7 Phase III study TDM4997g ................................................... 35 
1.2.1.8 Pharmacokinetics ................................................................. 36 
1.2.2 
Capecitabine .......................................................................... 38 
1.2.2.1 Study BO18255: Capecitabine and 
Trastuzumab in LA/mGC .................................................................... 39 
1.2.3 
Preclinical Data of the Combination of 
Trastuzumab Emtansine and a Fluoropyrimidine ..................................... 40 
1.3 
Study Rationale and Risk-Benefit Assessment ...................... 41 
1.3.1 
For mBC ................................................................................ 41 
1.3.2 
For mGC ................................................................................ 42 
2. 
OBJECTIVES .............................................................................................. 43 
2.1 
Phase I: MTD-Finding of Trastuzumab 
Emtansine and Capecitabine in mBC .................................... 43 
2.1.1 
Primary Objective .................................................................. 43 
2.1.2 
Secondary Objectives ............................................................ 43 
2.2 
Randomized Phase II: Exploration of Efficacy 
and Safety in mBC ................................................................. 43 
2.2.1 
Primary Objective .................................................................. 43 
2.2.2 
Secondary Objectives ............................................................ 43 
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2.3 
Phase I: MTD Finding of Trastuzumab 
Emtansine and Capecitabine in LA/mGC .............................. 44 
2.3.1 
Primary Objective .................................................................. 44 
2.3.2 
Secondary Objectives ............................................................ 44 
3. 
STUDY DESIGN ......................................................................................... 44 
3.1 
Description of Study .............................................................. 44 
3.1.1 
Overview of Study Design ..................................................... 44 
3.1.1.1 Overview of Phase I Design in Patients with 
mBC 
46 
3.1.1.2 Overview of Phase II: Exploration of Efficacy 
and Safety in Patients with mBC ........................................................ 48 
3.1.1.3 Overview of Phase I Design in LA/mGC 
Patients 49 
3.1.1.4 Number of Patients ............................................................... 49 
3.1.1.5 Number of Centers ............................................................... 50 
3.1.2 
Steering Committee ............................................................... 50 
3.1.3 
Independent Data Monitoring Committee .............................. 50 
3.2 
End of Study .......................................................................... 50 
3.3 
Rationale for Study Design .................................................... 50 
3.3.1 
Rationale for Patient Group Selection ................................... 50 
3.3.1.1 Rationale for Phase I ............................................................ 51 
3.3.1.2 Rationale for Randomized Phase II ...................................... 52 
3.3.2 
Rationale for Investigational Medicinal Dose 
Selection 52 
3.3.2.1 In Patients with mBC ............................................................ 52 
3.3.2.2 In Patients with mGC ............................................................ 52 
3.3.2.3 Rationale for Duration of Treatment ..................................... 53 
3.3.3 
Pharmacokinetic Sampling Rationale .................................... 53 
3.4 
Outcome Measures ............................................................... 53 
3.4.1 
Phase I: mBC ........................................................................ 53 
3.4.1.1 Primary Outcome Measure .................................................. 53 
3.4.1.2 Secondary Outcome Measure .............................................. 53 
3.4.1.3 Primary Safety Outcome Measure ....................................... 53 
3.4.1.4 Secondary Safety Outcome Measures ................................. 54 
3.4.1.5 Pharmacokinetic Outcome Measures ................................... 54 
3.4.2 
Randomized Phase II: Exploration of Efficacy 
and Safety in mBC ................................................................................... 54 
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3.4.2.1 Primary Efficacy Outcome Measure ..................................... 54 
3.4.2.2 Secondary Efficacy Outcome Measures .............................. 55 
3.4.2.3 Primary Safety Outcome Measure ....................................... 55 
3.4.2.4 Secondary Safety Outcome Measures ................................. 55 
3.4.2.5 Pharmacokinetic Outcome Measures ................................... 55 
3.4.3 
Phase I: LA/mGC ................................................................... 55 
3.4.3.1 Primary Outcome Measure .................................................. 55 
3.4.3.2 Secondary Efficacy Outcome Measure ................................ 56 
3.4.3.3 Secondary Safety Outcome Measures ................................. 56 
3.4.3.4 Pharmacokinetic Outcome Measures ................................... 56 
4. 
MATERIALS AND METHODS .................................................................... 57 
4.1 
Patients .................................................................................. 57 
4.1.1 
Patients with mBC ................................................................. 57 
4.1.2 
LA/mGC Patients ................................................................... 57 
4.1.3 
Inclusion Criteria .................................................................... 57 
4.1.3.1 For Patients with mBC .......................................................... 57 
4.1.3.2 For Patients with LA/mGC .................................................... 58 
4.1.4 
Exclusion Criteria ................................................................... 60 
4.1.4.1 For Patients with mBC .......................................................... 60 
4.1.4.2 For Patients with LA/mGC .................................................... 62 
4.1.5 
Patient Replacement Policy ................................................... 63 
4.2 
Method of Treatment Assignment .......................................... 63 
4.3 
Study Treatment .................................................................... 63 
4.3.1 
Formulation, Packaging, and Handling .................................. 63 
4.3.1.1 Trastuzumab Emtansine ...................................................... 63 
4.3.1.2 Capecitabine ........................................................................ 64 
4.3.2 
Dosage and Administration .................................................... 65 
4.3.2.1 For Patients with mBC .......................................................... 65 
4.3.2.2 For Patients with LA/mGC .................................................... 66 
4.3.3 
Investigational Medicinal Product 
Accountability ........................................................................................... 66 
4.3.4 
Post-trial Access to Extension Study ..................................... 66 
4.4 
Concomitant And Excluded Therapies .................................. 67 
4.4.1 
Permitted Therapy ................................................................. 67 
4.4.2 
Prohibited Therapy ................................................................ 67 
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4.5 
Study Assessments ............................................................... 68 
4.5.1 
Description of Study Assessments ........................................ 68 
4.5.1.1 Medical History and Demographic Data ............................... 68 
4.5.1.2 Vital Signs ............................................................................ 68 
4.5.1.3 Physical Examinations ......................................................... 69 
4.5.1.4 Tumor and Response Evaluations ....................................... 69 
4.5.1.5 Laboratory Assessments ...................................................... 70 
4.5.1.6 Electrocardiograms .............................................................. 70 
4.5.1.7 ECOG Performance Status .................................................. 70 
4.5.1.8 ECHO/MUGA ....................................................................... 71 
4.5.2 
Timing of Study Assessments ............................................... 71 
4.5.2.1 Screening and Pretreatment Assessments .......................... 71 
4.5.2.2 Assessments during Treatment ............................................ 72 
4.5.2.3 Assessments at Study Completion/Early 
Termination Visit ................................................................................. 72 
4.5.2.4 Follow-up Assessments ....................................................... 73 
4.5.2.5 Assessments at Unplanned Visits ........................................ 73 
4.6 
Patient and STUDY Discontinuation ...................................... 73 
4.6.1 
Patient Discontinuation .......................................................... 73 
4.6.2 
Study Discontinuation ............................................................ 73 
5. 
ASSESSMENT OF SAFETY ....................................................................... 74 
5.1 
Safety Plan ............................................................................ 74 
5.1.1 
Risks Associated with Trastuzumab 
Emtansine 74 
5.1.1.1 Cardiotoxicity ........................................................................ 74 
5.1.1.2 Hematologic Toxicity (Thrombocytopenia) ........................... 74 
5.1.1.3 Hepatotoxicity ....................................................................... 75 
5.1.1.4 Pulmonary Toxicity ............................................................... 76 
5.1.1.5 Infusion-related Reactions/Hypersensitivity .......................... 76 
5.1.1.6 Neurotoxicity ........................................................................ 76 
5.1.1.7 Extravasation ....................................................................... 77 
5.1.1.8 Trastuzumab Emtansine Dose Modification ......................... 77 
5.1.2 
Risks Associated with Capecitabine ...................................... 77 
5.1.3 
Risks Associated with Trastuzumab 
Emtansine and Capecitabine Combination .............................................. 78 
5.1.4 
Definition of Dose-limiting Toxicity ......................................... 78 
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5.1.5 
Management of Specific Adverse Events .............................. 79 
5.1.5.1 Trastuzumab Emtansine Dose Modification ......................... 79 
5.1.5.1.1 Trastuzumab Emtansine Dose 
Modification for Thrombocytopenia ............................................... 80 
5.1.5.1.2 Trastuzumab Emtansine Dose 
Modification for Hepatotoxicity ...................................................... 81 
5.1.5.1.3 Trastuzumab Emtansine Dose 
Modification for Neurotoxicity ........................................................ 82 
5.1.5.1.4 Trastuzumab Emtansine Dose 
Modification for Cardiotoxicity ....................................................... 82 
5.1.5.1.5 Trastuzumab Emtansine Dose 
Modification/Management for Infusion-related 
Reactions, Hypersensitivity Reactions .......................................... 84 
5.1.5.1.6 Trastuzumab Emtansine Dose 
Modification for Pulmonary Toxicity ............................................... 85 
5.1.5.1.7 Trastuzumab Emtansine Dose 
Modification for Extravasation ....................................................... 85 
5.1.5.2 Capecitabine Dosage Modification ....................................... 85 
5.2 
Safety Parameters and Definitions ........................................ 86 
5.2.1 
Adverse Events ..................................................................... 86 
5.2.2 
Serious Adverse Events (Immediately 
Reportable to the Sponsor) ...................................................................... 87 
5.2.3 
Protocol-defined Events of Special 
Interest/Non-Serious Expedited Adverse Events ..................................... 87 
5.2.4 
Pregnancy and Contraception ............................................... 88 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 90 
5.3.1 
Adverse Event Reporting Period ........................................... 91 
5.3.2 
Eliciting Adverse Event Information ....................................... 91 
5.3.3 
Assessment of Severity of Adverse Events ........................... 91 
5.3.4 
Assessment of Causality of Adverse Events ......................... 92 
5.3.5 
Procedures for Recording Adverse Events ............................ 93 
5.3.5.1 Diagnosis versus Signs and Symptoms ............................... 94 
5.3.5.2 Adverse Events Occurring Secondary to 
Other Events ...................................................................................... 94 
5.3.5.3 Persistent or Recurrent Adverse Events .............................. 94 
5.3.5.4 Abnormal Laboratory Values ................................................ 95 
5.3.5.5 Deaths .................................................................................. 95 
5.3.5.6 Pre-Existing Medical Conditions ........................................... 95 
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5.3.5.7 Lack of Efficacy or Clinical Worsening ................................. 96 
5.3.5.8 Hospitalization or Prolonged Hospitalization ........................ 96 
5.4 
Immediate Reporting Requirements from 
Investigator to the Sponsor .................................................... 96 
5.4.1 
Emergency Medical Contacts ................................................ 97 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-serious Adverse Events of Special 
Interest 
97 
5.4.3 
Reporting Requirements for Pregnancies .............................. 97 
5.4.3.1 Pregnancies in Female Patients ........................................... 97 
5.4.3.2 Pregnancies in Female Partners of Male 
Patients 98 
5.4.3.3 Abortions .............................................................................. 98 
5.4.3.4 Congenital Anomalies/Birth Defects ..................................... 98 
5.5 
Follow-up of Patients after Adverse Events ........................... 99 
5.5.1 
Investigator Follow-up............................................................ 99 
5.5.2 
Sponsor Follow-up ................................................................. 99 
5.6 
Post-study Adverse Events .................................................... 99 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ................................................................. 99 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ..................... 100 
6.1 
Determination of Sample Size ............................................. 101 
6.2 
Summaries of Conduct of Study .......................................... 102 
6.3 
Summaries of Treatment Group Comparability ................... 102 
6.4 
Efficacy Analyses ................................................................ 103 
6.4.1 
Primary Efficacy Endpoint .................................................... 103 
6.4.2 
Secondary Efficacy Endpoints ............................................. 105 
6.5 
Safety Analyses ................................................................... 106 
6.6 
Pharmacodynamic Analyses ............................................... 108 
6.7 
Pharmacokinetic Analyses ................................................... 108 
6.8 
Exploratory Analyses ........................................................... 109 
6.9 
Interim Analyses .................................................................. 109 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 110 
7.1 
Data Quality Assurance ....................................................... 110 
7.2 
Electronic Case Report Forms ............................................. 110 
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7.3 
Source Data Documentation ................................................ 110 
7.4 
Use of Computerized Systems ............................................ 111 
7.5 
Retention of Records ........................................................... 111 
8. 
ETHICAL CONSIDERATIONS .................................................................. 112 
8.1 
Compliance with Laws and Regulations .............................. 112 
8.2 
Informed Consent ................................................................ 112 
8.3 
Institutional Review Board or 
Ethics Committee ................................................................ 113 
8.4 
Confidentiality ...................................................................... 113 
8.5 
Financial Disclosure ............................................................ 114 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 114 
9.1 
Study Documentation .......................................................... 114 
9.2 
Site Inspections ................................................................... 114 
9.3 
Administrative Structure....................................................... 114 
9.4 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 114 
9.5 
Protocol Amendments ......................................................... 115 
10. REFERENCES ......................................................................................... 116 
 
 
LIST OF TABLES 
Table 1 
Cycle 1 Mean (s.d.) Pharmacokinetic Parameters for 
Trastuzumab Emtansine Following Trastuzumab 
Emtansine Administration Every 3 Weeks and Weekly in 
Study TDM3569g ........................................................................ 37 
Table 2 
Dose Reduction for Trastuzumab Emtansine  (Patients 
with mBC) ................................................................................... 80 
Table 3 
Dose Reductions for Trastuzumab Emtansine  (Patients 
with mGC) ................................................................................... 80 
Table 4 
Trastuzumab Emtansine Dose Modification: Total Serum 
Bilirubin ....................................................................................... 82 
Table 5 
Trastuzumab Emtansine Dose Modification: Serum ALT 
or AST ......................................................................................... 82 
Table 6 
Adverse Event Severity Grading Scale ....................................... 92 
Table 7 
Guidance for Causal Attribution of Adverse Event/Serious 
Adverse Event ............................................................................. 93 
 
 
LIST OF FIGURES 
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Figure 1 
Molecular Structure of Trastuzumab Emtansine ......................... 30 
Figure 2 
MMTV HER2 Fo5 Mammary Tumor Transplants ........................ 40 
Figure 3 
Anti-tumor Activity of Trastuzumab Emtansine in 
Combination with Capecitabine in NCI-N87 ................................ 41 
Figure 4 
Overview of Study Design ........................................................... 46 
Figure 5 
Overview of Phase I Dose Finding Study Design ........................ 47 
Figure 6 
Algorithm for Continuation and Discontinuation of 
Trastuzumab Emtansine Based on Left Ventricular 
Ejection Fraction Assessments in Patients ................................. 84 
 
 
LIST OF APPENDICES 
Appendix 1 
 Schedule of Assessments .................................................. 120 
Appendix 2 
 Pharmacokinetic Sampling for Phase I, 
Metastatic Breast and Gastric Cancer Patients ......................................... 129 
Appendix 3 
 Response Evaluation Criteria in Solid 
Tumors (RECIST): Modified Excerpt from Original 
Publication 
 ............................................................................................ 131 
Appendix 4 
 Instructions for Scans in the Event of Isotope 
Shortage 
 ............................................................................................ 143 
Appendix 5 
 New York Heart Association Classification of 
Functional Cardiac Capacity ..................................................................... 144 
Appendix 6 
 ECOG Performance Status ................................................ 145 
 
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PROTOCOL ACCEPTANCE FORM 
TITLE: 
PHASE I STUDY OF THE COMBINATION OF TRASTUZUMAB 
EMTANSINE (T-DM1) AND CAPECITABINE IN HER2-POSITIVE 
METASTATIC BREAST CANCER AND HER2-POSITIVE LOCALLY 
ADVANCED OR METASTATIC GASTRIC CANCER PATIENTS, 
FOLLOWED BY A RANDOMIZED, OPEN-LABEL PHASE II STUDY 
OF TRASTUZUMAB EMTANSINE AND CAPECITABINE VERSUS 
TRASTUZUMAB EMTANSINE ALONE IN HER2-POSITIVE 
METASTATIC BREAST CANCER 
PROTOCOL NUMBER: MO28230 
VERSION NUMBER: 3 
EUDRACT NUMBER: 
2012-001547-46 
 
 
TEST PRODUCT: 
Trastuzumab emtansine (RO5304020) 
Capecitabine (RO091978) 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return the signed original of this form {as instructed by XX [e.g., your 
local study monitor, the CRO]} [or] {to the contact provided below}. Please retain 
a copy for your study files. 
{Name}  
{Address} 
 
 
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PROTOCOL SYNOPSIS 
TITLE: 
PHASE I STUDY OF THE COMBINATION OF TRASTUZUMAB EMTANSINE  
(T-DM1) AND CAPECITABINE IN HER2-POSITIVE METASTATIC BREAST 
CANCER AND HER2-POSITIVE LOCALLY ADVANCED/METASTATIC GASTRIC 
CANCER PATIENTS, FOLLOWED BY A RANDOMIZED, OPEN-LABEL PHASE II 
STUDY OF TRASTUZUMAB EMTANSINE AND CAPECITABINE VERSUS 
TRASTUZUMAB EMTANSINE ALONE IN HER2-POSITIVE METASTATIC 
BREAST CANCER 
PROTOCOL NUMBER: 
MO28230 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2012-001547-46 
 
 
TEST PRODUCT: 
Trastuzumab emtansine (RO5304020) 
Capecitabine (RO091978) 
PHASE: 
I/II 
INDICATION: 
HER2-positive metastatic breast cancer or HER2-positive locally 
advanced/metastatic gastric cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Phase I: Maximum Tolerated Dose (MTD) Finding of Trastuzumab Emtansine (T-DM1) 
and Capecitabine in Metastatic Breast Cancer (mBC) 
Primary Objective 
• 
To determine the MTD of the combination of trastuzumab emtansine and capecitabine 
in patients with human epidermal growth factor receptor 2 (HER2)-positive mBC  
Secondary Objectives 
To assess the: 
• 
Pharmacokinetics (PK) of trastuzumab emtansine, capecitabine, and their metabolites  
• 
Safety of the combination of trastuzumab emtansine and capecitabine 
• 
Overall response rate (ORR) 
Randomized Phase II: Exploration of Efficacy and Safety in mBC 
Primary Objective 
• 
To explore the efficacy of the combination of trastuzumab emtansine and capecitabine 
compared with trastuzumab emtansine alone in patients with HER2-positive mBC, as 
measured by ORR by Response Evaluation Criteria for Solid Tumors (RECIST) v.1.1 
per investigator local assessment  
Secondary Objectives 
• 
To assess the safety profile of the combination of trastuzumab emtansine and 
capecitabine compared with trastuzumab emtansine alone 
• 
To explore the efficacy of the combination of trastuzumab emtansine and capecitabine 
compared with trastuzumab emtansine alone in mBC patients, as measured by: 
• Time to response (TTR)  
• Duration of response (DoR) 
• Time to progression (TTP)  
• Time to treatment failure (TTF)  
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• Progression-free survival (PFS)  
• Clinical benefit rate (CBR) 
• Overall survival (OS) 
Phase I: MTD Finding of Trastuzumab Emtansine and Capecitabine in Locally 
Advanced/Metastatic Gastric Cancer (LA/mGC) 
Primary Objective 
• 
To determine the MTD of the combination of trastuzumab emtansine and capecitabine 
in patients with LA/mGC  
Secondary Objectives 
To assess the: 
• 
PK of trastuzumab emtansine, capecitabine, and their metabolites  
• 
Safety of the combination of trastuzumab emtansine and capecitabine 
• 
ORR 
Study Design 
Description of Study 
This is an international, multicenter study. 
The study is designed to determine the MTD of capecitabine in combination with 
trastuzumab emtansine in patients with HER2-positive mBC or LA/mGC using a Phase I 
design, followed by a randomized, open-label Phase II study to explore the efficacy and 
safety of the combination of trastuzumab emtansine and capecitabine compared with 
trastuzumab emtansine alone in HER2-positive mBC. Results from the Phase I study in 
LA/mGC will be used as supporting information for future studies in the indication (see 
Figure 4 in the protocol). 
Phase I: MTD Finding, Cohort 1: mBC 
Cohort 1 used a 3 plus 3 classical design to determine the MTD of capecitabine in 
combination with trastuzumab emtansine. Initially the study had a dose escalation design, 
but following the occurrence of two DLTs at Dose Level 1 (750 mg/m2 capecitabine bid + 3.6 
mg/kg q3w trastuzumab emtansine), the study design was adapted and the dose de-
escalated to 700 mg/m2 capecitabine bid + 3.6 mg/kg q3w trastuzumab emtansine. At this 
Dose Level there were no DLTs and following review of the safety data, the Independent 
Data Monitoring Committee (IDMC) recommended that the study should proceed to explore 
this Dose Level further in the Randomized Phase II part of the study.  
Randomized Phase II: Exploration of Efficacy and Safety in mBC 
Phase II will be conducted in mBC patients only. This part of the study will explore the 
efficacy and safety of the combination treatment of trastuzumab emtansine (T-DM1) and 
capecitabine, at 700 mg/m2 bid (the recommended MTD), compared with trastuzumab 
emtansine alone in patients with mBC. 
Approximately 210 additional patients with HER2-positive mBC will be randomized into the 
Phase II part of the study. Patients in the Phase I part of the study will not contribute to the 
Phase II part of the study; however, they will be followed up until end of study (EOS). 
Phase I: MTD Finding, Cohort 2: LA/mGC 
Cohort 2 will have a 3 plus 3 classical design and enroll patients with HER2-positive 
LA/mGC. Trastuzumab emtansine will be administered weekly at a dose of 2.4 mg/kg and 
capecitabine will start at dose level -1 (700 mg/m2, the MTD defined in Cohort 1), with de-
escalation if required as follows:  
• 
If Dose Level -1 is well tolerated (DLT in ≤ 1/6 patients), this dose will be established as 
the MTD for LA/mGC  
• 
If Dose Level -1 is not tolerated in Cohort 2 (DLT in > 1/6 patients), de-escalation will be 
to Dose Level -2.  
• 
If Dose Level -2 is too toxic, the combination of capecitabine with trastuzumab 
emtansine 2.4 mg/kg every week may be considered unfeasible in LA/mGC, recruitment 
will be terminated and the LA/mGC part will be closed. However, this will have no 
impact on continuation of the Randomized Phase II mBC part. 
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Duration of treatment and follow-up 
All patients will be treated until investigator-assessed disease progression, unacceptable 
toxicity, withdrawal of consent, death, reasons deemed by the treating physician, or study 
termination by the Sponsor. If toxicity is considered by the investigator to be related to only 
one of the two agents, the non-implicated agent can be continued as single-agent therapy.  
All patients will be followed up until withdrawal of consent, death, or for up to a maximum of 
2 years after the last patient was randomized in the Phase II part of the study, whichever 
occurs first. 
Number of Patients 
Phase I, Cohort 1: mBC 
A minimum of 6 and up to 18 patients will be enrolled. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
Exploration of efficacy and safety in mBC will be based on approximately 210 randomized 
patients in total. 
Phase I, Cohort 2: LA/mGC 
A total of 6 to 12 patients will be enrolled. 
Target Population 
Phase I, Cohort 1: mBC 
Patients with HER2-positive mBC will be enrolled. 
The patient’s HER2 status will be considered positive if the local institution or reference lab 
reported immunohistochemistry (IHC) 3+ staining intensity (on a scale of 0 to 3) or in situ 
hybridization (ISH) positive. 
The HER2 status will be retrospectively confirmed by IHC and/or ISH in a central laboratory 
using archival paraffin-embedded tumor tissue. Retrospective central confirmation will not 
affect the treatment decisions or primary endpoint of Phase I and will be used to validate 
efficacy analyses in Phase I. 
Before entering the study, patients must have received at least one prior treatment regimen 
for early or metastatic disease, which included a chemotherapy agent and trastuzumab 
either separately or in combination. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
Patients with HER2-positive mBC will be randomized to receive either the combination of 
trastuzumab emtansine with capecitabine or trastuzumab emtansine alone. Retrospective 
central confirmation will be used to categorize patients for subgroup analyses according to 
central HER2 testing. 
Before entering the study, patients must have received at least one prior treatment regimen 
for early or metastatic disease, which included a chemotherapy agent and trastuzumab 
either separately or in combination. 
Phase I, Cohort 2: LA/mGC 
Patients with centrally confirmed HER2-positive LA/mGC will be enrolled. 
Patients must not have received prior chemotherapy for advanced/metastatic disease. 
 
Inclusion Criteria: 
For mBC Patients: 
1. Male or female. 
2.  Age ≥ 18 years old. 
3. Signed informed consent before any study-specific procedure. 
4. Able and willing to comply with the protocol. 
5. 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 the medical history confirming that 
the patient is not of childbearing potential. 
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6. 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 or two effective forms of non-hormonal contraception and to continue its 
use for the duration of study treatment and for 7 months after the last dose of study 
treatment (see Section 5.2.4 in the protocol). 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 
8. Blood: 
a) Platelet count > 100,000 cells/mm3 
b) International normalized ratio (INR) < 1.5 
c) Absolute neutrophil count (ANC) > 1,500 cells/mm3 
d) Hemoglobin > 9.0 g/dL. Patients are allowed to have received transfusion to 
achieve this level. 
9. Liver function: 
a) Total bilirubin ≤ 1.5 × upper limit of normal (ULN) or direct bilirubin ≤ 1.5 × ULN in 
patients with documented Gilbert’s syndrome.  
b) Serum glutamic oxaloacetic transaminase (SGOT)/aspartate transaminase (AST) 
and serum glutamic pyruvic transaminase (SGPT)/alanine transaminase 
(ALT) ≤ 2.5 × ULN. 
c) Alkaline phosphatase ≤ 2.5 × ULN. In patients with bone metastases: alkaline 
phosphatase ≤ 5 × ULN. 
d) Evidence of stable liver function during the month prior to enrollment with liver 
function test (LFT) fluctuations not exceeding 2.5 × ULN (for AST, ALT) and 
1.5 × ULN (for total bilirubin).  
10. Renal function: 
a) Serum creatinine of < 177 µmol/L or calculated creatinine clearance (CL)  
> 50 mL/min. If urine dipstick for proteinuria is ≥ 2+ at baseline, the patient must 
undergo 24-hour urine collection and demonstrate ≤ 1 g of protein/24 hours. 
11. Cardiac function: 
a) Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) or 
multiple-gated acquisition (MUGA) scan. 
12. Life expectancy ≥12 weeks 
13. Histologically or cytologically confirmed breast cancer. 
14. HER2-positive disease, defined as IHC 3+ or ISH positive. 
15. Tumor block or 8 slides available for retrospective central confirmation of HER2-
positivity (central confirmation not necessary for enrollment).  
16. mBC with at least one measurable lesion according to RECIST v.1.1. 
17. Disease progression on at least one prior regimen containing trastuzumab and 
chemotherapy either separately or in combination. 
18. Patients must have recovered from previous treatments 
For LA/mGC Patients: 
1. Male or female 
2.  Age ≥ 18 years old. 
3. Signed informed consent before any study-specific procedure. 
4. Able and willing to comply with the protocol. 
5. 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 the medical history confirming that 
the patient is not of childbearing potential. 
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6. 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 or two effective forms of non-hormonal contraception and to continue its 
use for the duration of study treatment and for 76 months after the last dose of study 
treatment (see Section 5.2.4 in the protocol). 
7. ECOG performance status of 0, 1, or 2. 
8. Blood: 
a) Platelet count > 100,000 cells/mm3. 
b) INR < 1.5.  
c) ANC > 1,500 cells/mm3. 
d) Hemoglobin > 9.0 g/dL. Patients are allowed to have received transfusion to 
achieve this level. 
9. Liver function: 
a) Total bilirubin ≤ 1.5 × ULN or direct bilirubin ≤ 1.5 × ULN in patients with 
documented Gilbert’s syndrome.  
b) SGOT/AST and SGPT/ALT ≤ 2.5 × ULN. 
c) Alkaline phosphatase ≤ 2.5 × ULN. In patients with bone metastases: alkaline 
phosphatase ≤ 5 × ULN. 
d) Evidence of stable liver function during the month prior to enrollment with LFT 
fluctuations not exceeding 2.5 × ULN (for AST, ALT) and 1.5 × ULN (for total 
bilirubin).  
10. Renal function: 
a) Serum creatinine of < 177 µmol/L or calculated creatinine CL > 50 mL/min. If urine 
dipstick for proteinuria is ≥ 2+ at baseline, the patient must undergo 24-hour urine 
collection and demonstrate ≤ 1 g of protein/24 hours. 
11. Cardiac function: 
a) LVEF ≥ 50% by ECHO or MUGA scan. 
12. Life expectancy ≥12 weeks 
13. Histologically or cytologically confirmed mGC or locally advanced GC. 
14. HER2-positive tumor (primary tumor or metastatic lesion), defined as either IHC 3+ or 
IHC 2+ and ISH+, prospectively confirmed by a Sponsor-designated central laboratory 
prior to enrollment. ISH positivity is defined as a ratio of ≥ 2.0 for the number of HER2 
gene copies to the number of signals for CEP17. 
a) Archival tumor samples obtained from primary or metastatic sites are acceptable. 
b) Invasive tumor for central confirmation of HER2 status is required. 
c) A formalin-fixed paraffin-embedded (FFPE) tissue block with at least 5 mm of 
invasive tumor for central confirmation is preferred. If FFPE tissue blocks (or partial 
block) are unavailable due to country or site regulations, a minimum of 8 freshly cut 
unstained slides MUST be available for central review of HER2 status. 
15. Inoperable LA/mGC. 
Exclusion Criteria: 
For mBC Patients: 
1. Prior treatments before first study treatment: 
a) Investigational therapy within ≤ 28 days or five half-lives, whichever is longer. 
b) Hormonal therapy within 14 days. 
c) Trastuzumab within 21 days. 
2. Prior enrollment in a trastuzumab emtansine-containing study, regardless of whether 
the patient received trastuzumab emtansine. 
3. Prior treatment with capecitabine. 
4. History of severe or unexpected reactions to fluoropyrimidine or known hypersensitivity 
to fluorouracil. 
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5. Related capecitabine contraindications: 
a) Treatment with sorivudine or its chemically-related analogs, such as brivudine. 
b) Rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or 
glucose-galactose malabsorption. 
c)  Signs or symptoms suggesting that the patient has dihydropyrimidine 
dehydrogenase (DPD) deficiency. 
6. History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity to 
trastuzumab or murine proteins or any component of the product. 
7. History of exposure to the following cumulative doses of anthracyclines: 
a) Doxorubicin or liposomal doxorubicin > 500 mg/m2. 
b) Epirubicin > 900 mg/m2. 
c) Mitoxantrone > 120 mg/m2 
d) If another anthracycline, or more than one anthracycline, has been used, the 
cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin. 
8. Brain metastases that are symptomatic, or require any radiation, surgery, or steroid 
therapy to control symptoms within 28 days before first study drug administration. 
9. Current peripheral neuropathy of Grade ≥ 3 according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.0. 
10. History of other malignancy within the last 5 years, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, 
or other cancers with a similar outcome as those mentioned above.  
11. Current unstable ventricular arrhythmia requiring treatment. 
12. History of symptomatic congestive heart failure (CHF) (New York Heart Association 
[NYHA] Classes II−IV). 
13. History of myocardial infarction or unstable angina within 6 months prior to first study 
drug administration. 
14. History of a decrease in LVEF to < 40% or symptomatic CHF with previous trastuzumab 
treatment. 
15. Severe dyspnea at rest due to complications of advanced malignancy or currently 
requiring continuous oxygen therapy. 
16. Clinically significant malabsorption syndrome or inability to take oral medication. 
17. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary, or metabolic disease). 
18. Major surgical procedure or significant traumatic injury within 28 days before enrollment 
or anticipation of the need for major surgery during the course of study treatment. 
19. Current pregnancy or lactation. 
20. Current known active infection with human immunodeficiency virus (HIV), hepatitis B, 
and/or hepatitis C virus (HBV/HCV). 
a) For patients who are known carriers of HBV, active hepatitis B infection must be 
ruled out based on negative serologic testing and/or determination of HBV 
deoxyribonucleic acid (DNA) viral load per local guidelines. 
21. Lapatinib ≤ 14 days before first study drug administration. 
22. Previous radiotherapy for the treatment of mBC is not allowed if: 
a) The last fraction of radiotherapy has been administered within 14 days prior to first 
study drug administration (28 days for patients with radiotherapy to control 
symptoms of brain metastases, see exclusion criterion 8). 
b) More than 25% of marrow-bearing bone has been irradiated. 
c) Any acute toxicity has not resolved to Grade ≤ 1 before first study drug 
administration. 
For LA/mGC Patients: 
1. Prior treatments before first study treatment: 
a) Investigational therapy within ≤ 28 days or 5 half-lives, whichever is longer. 
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b) Hormonal therapy within 14 days. 
c) Trastuzumab within 21 days. 
2. Prior enrollment in a trastuzumab emtansine-containing study, regardless of whether 
the patient received trastuzumab emtansine. 
3. Prior treatment with capecitabine. 
4. History of severe or unexpected reactions to fluoropyrimidine or known hypersensitivity 
to fluorouracil. 
5. Related capecitabine contraindications: 
a) Treatment with sorivudine or its chemically-related analogs, such as brivudine. 
b) Rare hereditary problems of galactose intolerance, Lapp lactase deficiency or 
glucose-galactose malabsorption. 
c)  Signs or symptoms suggesting that the patient has DPD deficiency. 
6. History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity to 
trastuzumab or murine proteins or any component of the product. 
7. History of exposure to the following cumulative doses of anthracyclines: 
a) Doxorubicin or liposomal doxorubicin > 500 mg/m2. 
b) Epirubicin > 900 mg/m2. 
c) Mitoxantrone > 120 mg/m2. 
d) If another anthracycline, or more than one anthracycline, has been used, the 
cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin. 
8. Brain metastases that are symptomatic, or require any radiation, surgery, or steroid 
therapy to control symptoms within 28 days before first study drug administration. 
9. Current peripheral neuropathy of Grade ≥ 3 according to NCI CTCAE, v4.0. 
10. History of other malignancy within the last 5 years, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, 
or other cancers with a similar outcome as those mentioned above. 
11. Current unstable ventricular arrhythmia requiring treatment. 
12. History of symptomatic CHF (NYHA Classes II−IV). 
13. History of myocardial infarction or unstable angina within 6 months prior to first study 
drug administration. 
14. History of a decrease in LVEF to < 40% or symptomatic CHF with previous trastuzumab 
treatment. 
15. Severe dyspnea at rest due to complications of advanced malignancy or currently 
requiring continuous oxygen therapy. 
16. Clinically significant malabsorption syndrome or inability to take oral medication. 
17. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary, or metabolic disease) 
18. Major surgical procedure or significant traumatic injury within 28 days before enrollment 
or anticipation of the need for major surgery during the course of study treatment 
19. Current pregnancy or lactation. 
20. Current known active infection with HIV, HBV, and/or HCV 
a) For patients who are known carriers of HBV, active hepatitis B infection must be 
ruled out based on negative serologic testing and/or determination of HBV DNA 
viral load per local guidelines 
21. Previous chemotherapy for advanced/metastatic disease 
a) Prior adjuvant/neoadjuvant therapy is allowed if at least 6 months has elapsed 
between completion of adjuvant/neoadjuvant therapy and enrollment into the study 
22. Lapatinib ≤ 14 days before first study drug administration 
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Length of Study 
The duration of the study is estimated to be approximately 4 years. Recruitment is estimated 
to last 2 years in total (1 year for MTD Finding, 1 year for the Phase II Exploration of 
Efficacy and Safety in mBC).  
End of Study 
The study will end after the follow-up period has been completed as defined above. Last 
patient last visit (LPLV) is defined as the last data collection point, which can be either a 
clinic visit or a laboratory sample. 
In case Dose Level -2 is too toxic in LA/mGC, the LA/mGC cohort may be terminated 
prematurely. Patients who, at that point, experience response according to RECIST v.1.1 
will be offered the possibility to continue on trastuzumab emtansine as a single agent or with 
capecitabine, based on the risk-benefit balance and agreement with the SC. 
Randomized Phase II Exploration of Efficacy and Safety in mBC: The primary analysis of 
best overall response (BOR) rate will be performed when 70% of the patients have 
experienced a PFS event or at the end of the trial, whichever occurs first. It is estimated that 
70% of patients will have experienced a PFS event approximately 26 months after 
randomization of the first patient. The EOS analysis (approximately 24 months after the last 
patient is randomized) will include an updated analysis of BOR, which will be done in a 
purely exploratory manner.   
 
Efficacy Outcome Measures 
Efficacy will be evaluated according to RECIST v.1.1. 
• 
BOR rate  
• 
TTR 
• 
DoR 
• 
TTP 
• 
TTF 
• 
PFS 
• 
CBR 
• 
OS 
Safety Outcome Measures 
• 
DLT assessment/determination of the MTD of capecitabine when combined with 
trastuzumab emtansine (Phase I only) 
• 
Incidence, nature, and severity by NCI CTCAE v4.0 of adverse events (AEs), serious 
adverse events (SAEs), AEs leading to discontinuation from either component of the 
study treatment, and AEs of special interest (AESIs) 
• 
Fatal AEs and their causes  
• 
Events to monitor 
• 
Laboratory parameters 
• 
LVEF 
• 
Treatment exposure 
• 
Physical examinations 
• 
Vital signs and ECOG performance status 
• 
Premature withdrawal from study medication and/or study 
Pharmacodynamic Outcome Measures 
Hospital visit parameters. 
Pharmacokinetic Outcome Measures 
PK will be evaluated during Phase I for trastuzumab emtansine, capecitabine, and their 
metabolites (see Appendix 1, Schedule of Assessment in the protocol). In addition, PK 
samples may be taken ad hoc, in case of SAEs or unexpected toxicities, which may be 
suggestive of a potential drug-drug interaction. 
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Investigational Medicinal Products 
For mBC Patients: 
Trastuzumab emtansine will be administered q3w at a dose of 3.6 mg/kg intravenous (IV). 
The total trastuzumab emtansine dose will be calculated based on the patient’s weight on 
Day 1 of each cycle (or up to 3 days before) with no upper limit. 
Capecitabine will be administered orally bid for 14 days followed by a 7-day rest period at 
the Dose Levels described in the ‘Trial Design’ section. 
Capecitabine tablets should be swallowed with water within 30 minutes after a meal. 
Rounding of the capecitabine dose, based on 150 mg and 500 mg tablet strength, will be 
allowed to the nearest target dose based on the patient’s body surface area (BSA).  
For LA/mGC Patients: 
Trastuzumab emtansine will be administered on Day 1 of each 1-week cycle at a dose of 
2.4 mg/kg IV. 
The total trastuzumab emtansine dose will be calculated based on the patient’s weight on 
Day 1 of each cycle (or up to 3 days before) with no upper limit. 
Capecitabine will be administered orally bid for 14 days followed by a 7-day rest period at 
the Dose Levels -1 to -2 described in the ‘Trial Design’ section. 
Capecitabine tablets should be swallowed with water within 30 minutes after a meal. 
Non-Investigational Medicinal Products 
Not applicable. 
Statistical Methods 
The study will include 2 phases and 2 cohorts: 
• 
Phase I, Cohort 1: mBC MTD-Finding Cohort 
• 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
• 
Phase I, Cohort 2: LA/mGC MTD-Finding Cohort 
Corresponding analyses as described in the protocol will be performed when all data from 
both study phases are collected and cleaned. 
Randomized Phase II: The primary analysis of BOR will be performed when 70% of the 
patients have experienced a PFS event or at the end of the trial, whichever occurs first. It is 
estimated that 70% of patients will have experienced a PFS event approximately 26 months 
after randomization of the first patient. The EOS analysis (approximately 24 months after the 
last patient is randomized) will include an updated analysis of BOR, which will be done in a 
purely exploratory manner. 
Analysis of primary and secondary endpoints: 
Analysis Populations: 
Phase I, Cohort 1: MTD-Finding: mBC Patients 
The main analysis population for DLT assessment is the DLT-evaluable population, which is 
defined as all enrolled and treated patients who have not experienced any major protocol 
violations (including violations of the inclusion and exclusion criteria) and have completed 
Cycle 1.  
The safety population (SP) will include all patients who received at least one dose of study 
medication (trastuzumab emtansine and/or capecitabine) during Phase I. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
The main analysis population for the efficacy analysis will be the intent-to-treat (ITT) 
population, which will include all patients randomized in the Phase II part of the study. The 
per-protocol (PP) population will include all ITT patients who have at least one post-baseline 
tumor assessment during the Phase II part of the study and no major protocol violations, 
which will be defined in the statistical analysis plan (SAP). 
The SP will include all patients who received at least one dose of study medication during 
the Randomized Phase II part of the study.  
Phase I, Cohort 2: MTD-Finding, LA/mGC Patients 
The main analysis population for DLT assessment is the DLT-evaluable population, which is 
defined as all enrolled and treated patients who have not experienced any major protocol 
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violation (including violation of the inclusion and exclusion criteria) and have completed 
Cycle 1.  
The SP will include all patients who received at least one dose of study medication during 
Phase I. 
Efficacy Endpoints:  
Phase I, Cohort 1: MTD-Finding, mBC 
The primary objectives are defining the MTD and establishing the safety profile of the 
combination regimen. 
ORR, as a main efficacy endpoint, will be assessed via BOR rate. The BOR is defined as 
the best response recorded from the date of enrollment until disease progression, death, 
withdrawal of consent, start of new anticancer treatment, or EOS, whichever occurs first. 
The number of patients is very small in this part of the study. Therefore, all analyses will be 
descriptive. 
Due to the small number of patients and the design of this part of the study, no secondary 
efficacy endpoints will be investigated. 
Randomized Phase II: Exploration of Efficacy in mBC  
The primary efficacy endpoint for the Phase II part of the study is the ORR, assessed via 
the BOR rate. BOR is defined as the best response recorded between randomization into 
the Phase II part of the study and disease progression, death, withdrawal of consent, start 
of new anticancer treatment, or EOS, whichever occurs first. To be assigned a status of 
partial response (PR) or complete response (CR), i.e., to be a responder, changes in tumor 
measurements must be confirmed by repeated assessments performed no less than 28 
days after the response criteria are first met, i.e., patients need to have two consecutive 
assessments of PR or CR.  
The primary hypothesis of interest when comparing ORR – as assessed via BOR - between 
the two treatment groups, combination of trastuzumab emtansine and capecitabine versus 
trastuzumab emtansine alone:  
•  H0: πtrastuzumab emtansine = πtrastuzumab emtansine + capecitabine where πtrastuzumab emtansine is BOR 
in trastuzumab emtansine alone and π trastuzumab emtansine + capecitabine is BOR in trastuzumab 
emtansine + capecitabine 
• 
H1: π trastuzumab emtansine ≠ π trastuzumab emtansine + capecitabine  
The number and proportions of responders and non-responders (based on BOR) together 
with the two-sided 90% Clopper-Pearson confidence intervals (CIs) will be presented for 
each treatment group. The difference in BOR between treatment groups will be displayed 
with associated 90% CIs using the Hauck-Anderson approach and p-value for the Fisher’s 
exact test.  
The secondary endpoints for the Phase II part of the study will be: 
• 
TTR 
• 
DoR 
• 
TTP 
• 
TTF 
• 
PFS 
• 
CBR 
• 
OS 
Estimates for the survivor function of both treatment groups for TTR, DoR, TTP, TTF, PFS 
and OS will be obtained by using the Kaplan-Meier method. Hazard ratios and associated 
90% CIs will be estimated from non-stratified and stratified (based on the stratification factor) 
Cox regression models. 
CBR will include patients whose best (confirmed) response was PR or CR, or stable disease 
(SD) that lasted at least 6 months. CBR will be summarized in a similar way to the primary 
efficacy endpoint, ORR, as assessed by BOR.  
Phase I, Cohort 2: MTD-Finding: LA/mGC 
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The primary objectives are defining the MTD and establishing the safety profile of the 
combination regimen. 
Efficacy endpoints will be analyzed in a similar way to that described for Phase I, Cohort 1 in 
mBC. 
Safety Endpoints: 
Phase I, Cohort 1: MTD-Finding: mBC 
The number and proportion of patients with DLTs will be used as the primary measure for 
the MTD determination. The definition of DLTs is presented in Section 5.1.4. DLTs for this 
part of the study will be summarized by treatment dose. 
Safety parameters for this study part will also be summarized by treatment dose. The 
summaries of AEs, SAEs, AEs that cause discontinuation from the study treatment, AESIs 
(as described in Section 5), and events to monitor will be analyzed in a similar way to AEs in 
Phase II. The summaries will include all patients who received at least one dose of study 
medication. 
The incidence of AEs and SAEs will be summarized according to the primary system-organ 
class (SOC) and within each SOC, by Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term. Patients who died will be listed together with the cause of death. 
Laboratory parameters, hematology and biochemistry will be presented in shift tables of NCI 
CTCAE grade at baseline versus worst grade during treatment for Phase I, Cohort 1. 
LVEF over time will be summarized as mean, median and range (minimum and maximum) 
and will be presented graphically. Vital signs will be analyzed in a similar way. 
Other safety variables, such as exposure to study medication, concomitant medications, and 
physical examinations, will be analyzed in a similar way. Exposure to study medication will 
be summarized by frequency tables. 
ECOG performance status will be summarized over time and the percentage of patients in 
each category will be presented by bar charts at different time points. 
Randomized Phase II: Exploration of Safety in mBC  
Safety endpoints will be summarized by treatment group. 
Safety endpoints during the Randomized Phase II part of the study will be assessed via: 
total AEs, Grade ≥ 3 AEs, SAEs, premature withdrawal from study medication, AESIs, 
events to monitor, laboratory parameters, LVEF, exposure to study medication, concomitant 
medications, vital signs, ECOG performance status, and physical examination. 
The incidence of AEs and SAEs will be summarized according to the primary SOC and 
within each SOC, by MedDRA preferred term. Time to onset of the first episode of AESI will 
also be summarized via Kaplan-Meier method. Patients who died will be listed together with 
the cause of death. 
Laboratory parameters, hematology, and biochemistry will be presented in shift tables of 
NCI CTCAE grade at baseline versus worst grade during treatment in the Randomized 
Phase II part of the study. 
LVEF over time will be summarized as mean, median and range (minimum and maximum) 
and will be presented graphically. Vital signs will be analyzed in a similar way. 
Other safety variables, such as exposure to study medication, concomitant medications, and 
physical examinations, will be analyzed in a similar way. Exposure to study medication will 
be summarized by frequency tables. 
ECOG performance status will be summarized over time and the percentage of patients in 
each category will be presented by bar charts at different time points. 
Phase I, Cohort 2: MTD-Finding: mGC 
The number and the proportion of patients with DLTs will be used as the primary measure 
for the MTD determination. The definition of DLTs is presented in Section 5.1.4. DLTs for 
this part of the study will be summarized by treatment dose. 
Safety parameters will be summarized in a similar way to that described for Phase I, 
Cohort 1 in mBC. 
Pharmacokinetic Analysis 
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The following PK parameters of trastuzumab emtansine and capecitabine (not limited to 
these listed) will be determined only in the Phase I part of the study in all patients who 
receive study treatment using either non-compartmental and/or population methods, if data 
allow: 
• 
Serum concentrations of trastuzumab emtansine (conjugate) and total trastuzumab 
• 
Plasma concentrations of DM1, capecitabine, and its active metabolite 5-fluorouracil (5-
FU) 
• 
Total exposure (area under the serum concentration-time curve [AUC])  
• 
Maximum concentration (Cmax)  
• 
CL  
• 
Volume of distribution (Vd) 
• 
Terminal half-life (T1/2) 
All PK parameters will be listed and tabulated by treatment dose and by Cohort. Descriptive 
summary statistics including arithmetic mean, geometric mean (e.g., AUC and Cmax), 
median, range, standard deviation (s.d.), and coefficient of variation will be presented for 
each Cohort. Nonlinear mixed effects modeling will also be used; details will be presented in 
the SAP. 
Exploratory Analyses 
For all patients with mBC (Phase I, cohort 1; Phase II Exploration of Efficacy and Safety in 
mBC), a retrospective central confirmation of the HER2 status will be done. Further  
exploratory analyses will be done according to centrally confirmed HER2 status for selected 
endpoints, e.g. BOR and safety (AEs, SAEs, Grade ≥ 3 AEs, and AESIs). 
Subgroup analysis for BOR, safety (AEs, SAEs, AEs with Grade ≥ 3, and AESIs) in the 
Randomized Phase II part of the study will be presented for both treatment groups with 
respect to: elderly versus younger patients; patients with ECOG 0–1 versus ECOG 2; and 
patients with ≤1 versus >1 prior treatment line for metastatic disease. More details will be 
presented in the SAP. 
Pharmacoeconomic Endpoint 
The number of hospital visits, number of days admitted, and type of visits (emergency 
department versus inpatient care) will be collected and compared. The reason for admission 
(disease progression versus AE) will also be assessed. 
Determination of Sample Size 
Sample Size for Phase I: MTD-Finding: mBC 
This part will be based on a classical 3 plus 3 Phase I design. A minimum of 6 and up to 
18 patients will be enrolled in Cohort 1. There is no formal sample size estimation for this 
part. 
Sample Size for Randomized Phase II: Exploration of Efficacy and Safety in mBC 
The sample size for the primary endpoint BOR is based on a Fisher’s exact test with an 
alpha level of 5% (one-sided), power of 80% and the clinical assumption of a BOR rate of 
43% with trastuzumab emtansine alone and 62.5% with the combination of trastuzumab 
emtansine and capecitabine. Approximately 210 patients (105 patients in each treatment 
group), including a 15% withdrawal rate, will be randomized with a 1:1 ratio to either 
trastuzumab emtansine alone or the combination of trastuzumab emtansine and 
capecitabine.  
Stratification Factors 
The following stratification factor will be implemented in the Randomized Phase II part of the 
study: 
• 
Number of prior lines of treatment for metastatic disease (≤1 or >1; excluding single-
agent hormones). 
A treatment line is defined as any treatment regimen given to a patient from treatment 
initiation until confirmed disease progression. 
Sample Size for Phase I, Cohort 2: MTD-Finding: LA/mGC 
This part will be based on a classical 3 plus 3 Phase I design. Between 3 and 12 patients 
might be enrolled in Cohort 2. There is no formal sample size estimation for this part. 
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Interim analysis 
There is no formal interim analysis of efficacy.  
An independent data monitoring committee (IDMC) will recommend whether the 
Randomized Phase II part of the study can commence.  
The IDMC will also monitor safety outcomes after 25, 75, and 150 patients have received at 
least 3 cycles of treatment (Cycle 3 Day 21) in the Randomized Phase II part of the study. 
Afterwards, the IDMC will monitor accumulating patient safety data every 6 months during 
the Randomized Phase II part of the study or as requested. 
Efficacy data will be provided only if required by the IDMC to estimate the risk-benefit 
balance for the patients. Further details on the function and logistics of the IDMC will be 
provided in the IDMC Charter. 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADL 
activities of daily living 
ADC 
antibody-drug conjugate 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ARDS 
acute respiratory distress syndrome 
AST 
aspartate transaminase 
AUC 
area under the serum concentration-time curve 
BC 
breast cancer 
bid 
twice daily 
BML 
below measurable limit 
BOR 
BSA 
best overall response 
body surface area 
BUN 
blood urea nitrogen 
CBR 
clinical benefit rate 
CHF 
congestive heart failure 
CI 
confidence interval 
CL 
clearance 
Cmax 
maximum concentration 
CR 
complete response 
CRO 
contract research organization 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose-limiting toxicity 
DM1 
derivative of maytansine 
DoR 
duration of response 
DPD 
dihydropyrimidine dehydrogenase 
5-DFUR 
5’-deoxy-5-fluorouridine 
5-FU 
5-fluorouracil 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
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EEA 
European economic area 
EOS 
end of study 
EU 
European Union 
FDA 
FFPE 
Food and Drug Administration 
formalin-fixed paraffin-embedded 
FISH 
fluorescence in situ hybridization 
GC 
gastric cancer 
GCP 
Good Clinical Practice 
GEJ 
HBV 
HCV 
gastroesophageal junction 
hepatitis B virus 
hepatitis C virus 
HER 
human epidermal growth factor receptor  
HER2 
human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
ICH 
International Conference on Harmonisation 
IDMC 
independent data monitoring committee 
IgG 
immunoglobulin 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISH 
in situ hybridization 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
IxRS 
interactive voice/web recognition system 
LA/mGC 
locally advanced/metastatic gastric cancer 
LC-MS/MS 
liquid chromatography electrospray tandem mass 
spectrometry 
LFT 
liver function test 
LPLV 
last patient last visit 
LVEF 
left ventricular ejection fraction 
mBC 
metastatic breast cancer 
mGC 
metastatic gastric cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
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MTD 
maximum tolerated dose 
MUGA 
multiple-gated acquisition 
N 
number of patients 
NCI 
National Cancer Institute 
NE 
NRH 
NYHA 
not evaluable 
nodular regenerative hyperplasia 
New York Heart Association 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PP 
per-protocol 
PR 
PVC 
partial response 
polyvinyl chloride 
QTcF 
heart rate-corrected QT interval using the Fridericia 
formula 
q3w 
every 3 weeks 
qw 
weekly 
RECIST 
Response Evaluation Criteria for Solid Tumors 
SAE 
SAP 
serious adverse event 
statistical analysis plan 
SGOT 
serum glutamic oxaloacetic transaminase 
SC 
Steering Committee 
s.d. 
standard deviation 
SD 
SDV 
stable disease 
source data verification 
SGPT 
serum glutamic pyruvic transaminase 
SmPC 
Summary of Product Characteristics 
SOC 
SP 
system-organ class 
safety population 
SWFI 
sterile water for injection 
T1/2 
terminal half-life 
TTF 
time to treatment failure 
TTP 
time to progression 
TTR 
time to response 
ULN 
upper limit of normal 
Vd 
volume of distribution 
Vss 
volume of distribution at steady state 
WBC 
white blood cells 
WHO 
World Health Organization 
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5-FU 
5-fluorouracil 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON DISEASE 
1.1.1 
HER2-POSITIVE BREAST CANCER 
Breast cancer (BC) is the most common cancer in women worldwide, both in 
the developed and the developing world1, with an estimated 1.67 million new 
cases diagnosed in 2012. It is also the leading cause of cancer death in 
females in less developed regions, accounting for 324,000 deaths (14.3% of 
all cancer deaths) in 2012, and the second most common cause of cancer 
death in women in more developed regions (198,000 deaths, 15.4%) after 
lung cancer.1 Metastatic breast cancer (mBC) is incurable, with the primary 
goal of treatment to extend life and palliate symptoms while preserving quality 
of life. 
Human epidermal growth factor receptor 2 (HER2) is an important prognostic 
factor in BC and is a key factor influence treatment strategies. The human 
epidermal growth factor receptor (HER) tyrosine kinase receptor family 
comprises four receptors: HER1, HER2, HER3, and HER4. These receptors 
are important mediators of cell growth, survival, and differentiation.2 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.3 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 overall 
response rate (ORR), response duration, and progression-free survival (PFS) 
were associated with a 5-month overall survival (OS) advantage when 
trastuzumab was given in the first-line metastatic setting, as demonstrated in 
the initial Phase III trial.4  
For patients with HER2-positive mBC, the combination of anti-HER2 therapy 
and a taxane is a globally accepted first-line treatment, based on the OS 
advantage demonstrated in three large pivotal trials.4–6 
However, disease progresses in almost all patients with HER2-positive mBC 
and these patients require additional therapies. Importantly, such tumors 
continue to express high levels of HER2,7 and neither the process of 
internalization nor the level of surface expression is altered when HER2 is 
bound by trastuzumab.8  
After progression, the standard strategy is further HER2-directed therapy, 
either continuing trastuzumab with a different chemotherapy agent (eg 
trastuzumab plus capecitabine), or changing to a different HER2-directed 
regimen (eg lapatinib plus capecitabine). In a randomized Phase III trial, 
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GBG26, in patients whose disease had progressed on previous trastuzumab-
containing therapy, the combination of trastuzumab and capecitabine was 
associated with significantly improved time to progression (TTP) (hazard ratio 
[HR] 0.69, median 8.2 versus 5.6 months, respectively) and ORR (48% 
versus 27%) compared with capecitabine alone.9 In another 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 ORR (24% versus 14%) and TTP 
(median 6.2 months versus 4.3 months) compared with capecitabine alone.9   
1.1.2 
HER2-POSITIVE LOCALLY ADVANCED/METASTATIC 
GASTRIC CANCER 
Gastric cancer (GC) remains one of the most common malignancies in the 
world with an estimated 952,000 new cases in 2012.1 GC also continues to be 
a deadly disease; it is the third leading cause of cancer-related death, 
accounting for 723,000 deaths (8.8% of all cancer deaths) worldwide in 2012. 
The only potentially curative treatment for GC is complete resection of 
localized disease. The overall 5-year survival for all cases, regardless of initial 
stage at diagnosis, is less than 25%.11-14 Among patients with localized 
disease who undergo curative surgery, approximately 40–60% will have 
disease recurrence. Patients with unresectable disease due to locally 
advanced growth or metastatic spread have the poorest prognosis, with an 
overall 5-year survival rate in the range of 3% to 15%.11,13,14  
Whereas HER2 overexpression is associated with a poor prognosis in BC, the 
prognostic significance of HER2 overexpression in GC is not fully defined. 
Studies of HER2 positivity rates in GC have shown a broad variation of HER2 
positivity ranging from 6.8% to 34.0% for immunohistochemistry (IHC) and 
7.1% to 42.6% for fluorescence in situ hybridization (FISH) techniques.15,16 In 
a recent study, HER2 positivity was shown in 17% of resected esophageal 
adenocarcinomas and was significantly associated with lower tumor grade, 
less invasiveness, fewer malignant nodes, and the presence of adjacent 
Barrett's esophagus.17 
In the ToGA trial (study BO18255), a global, Phase III study of trastuzumab 
plus chemotherapy as first-line treatment for advanced HER2-positive GC,18 
an overall HER2-positivity rate of 22.1% was observed (810/3667 evaluable 
samples), which is similar to BC. A higher HER2 positivity rate was seen in 
adenocarcinoma of the gastroesophageal junction (GEJ) than in the stomach 
(33.2% versus 20.9%), and intestinal type GCs showed a significantly higher 
HER2 positivity rate than diffuse or mixed-type tumors (intestinal: 32.2%, 
diffuse: 6.1%, mixed: 20.4%).19  
In the ToGA trial, the addition of trastuzumab to chemotherapy (capecitabine 
or fluorouracil combined with cisplatin) for the treatment of patients with 
HER2-positive (defined as IHC 3+ or FISH positive), inoperable, locally 
advanced or recurrent and/or metastatic adenocarcinoma of the stomach or 
GEJ resulted in an increase in OS (median 13.8 months versus 11.1 months, 
HR 0.74, p = 0.0046), ORR (47% versus 35%), PFS (median 6.7 versus 5.5 
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Following antigen-specific binding of trastuzumab emtansine to HER2, the 
complex of receptor and ADC is internalized, whereupon DM1-containing 
catabolites are released into the cytosol following proteolytic cleavage of the 
antibody in lysosomes.24 Binding of these DM1-containing species to β-tubulin 
inhibits tubulin polymerization, resulting in cell death.22 
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.20 
Phase I single-arm studies were conducted to identify the most appropriate 
dosing regimen for further clinical development, and assess the safety of 
trastuzumab emtansine. Low levels of DM1 in systemic circulation supported 
the stability of the linker.25 The studies also provided an indication of clinical 
activity and led to randomized evaluation of single-agent trastuzumab 
emtansine versus other HER2-directed therapy in combination with 
chemotherapy. These trials demonstrated significantly superior PFS and OS 
with trastuzumab emtansine.26–28 
Data from clinical trials of trastuzumab emtansine that are relevant to the 
design of the current trial are summarized below. Please refer to the 
trastuzumab emtansine Investigator’s Brochure for further information on all of 
the completed and ongoing trastuzumab emtansine studies. 
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.29,30 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 (qw) schedule. 
On the q3w dosing schedule, dose-limiting toxicities (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. On the qw schedule, 2.4 mg/kg was 
identified as the MTD. 
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 ORR in patients with measurable disease at 
the 3.6 mg/kg q3w schedule was 44% (4 of 9 patients), as assessed by 
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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 whose disease had progressed 
on previous HER2-directed therapy and conventional chemotherapy.31 
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 independent review. The clinical benefit rate (CBR; defined 
as complete response [CR], partial response [PR], or stable disease [SD] 
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 independent review. 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. 
The most common adverse events (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.32 Patients must have received an anthracycline, trastuzumab, a taxane, 
lapatinib, and capecitabine given in the neoadjuvant, 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 experienced progressive disease (PD) on their 
most recent treatment. 
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The primary objectives of this study were: 1) to assess the ORR as 
determined 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 (CR or PR) of 34.5% (95% CI: 26.1%–
43.9%; 38 of 110 patients) by independent review 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 median PFS by independent review was 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 aspartate 
transaminase (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%). Serious 
AEs (SAEs) were recorded in 28 patients (25.5%), the most common being 
cellulitis (3.6%), pyrexia (2.7%), and pneumonia (2.7%). There was one 
Grade 5 AE (hepatic dysfunction), which was recorded as possibly related to 
trastuzumab emtansine. The patient had pre-existing non-alcoholic fatty liver 
disease as well as multiple other comorbidities, including renal insufficiency. 
1.2.1.4 
Study TDM4450g 
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.26 This study completed enrollment in December 2009 
(n = 137). The co-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, OS, 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. 
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As of 15 November 2010, the median PFS was 14.2 months in the 
trastuzumab emtansine arm versus 9.2 months in the trastuzumab plus 
docetaxel arm. The 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 as first-line therapy for 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.33 No meaningful effect of trastuzumab 
emtansine on the corrected QT interval was seen 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 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 to baseline. 
Following the third infusion of trastuzumab emtansine, the baseline-adjusted 
mean QTcF interval at both the 15-minute and the 60-minute post-infusion 
time points was increased by 4.7 ms. No patient exhibited a mean 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. 
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In this study, the ORR was 25.5% (95% CI: 15.2%–38.5%) as assessed by 
the investigator; no independent review was performed. 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 
Phase III Study TDM4370g 
A randomized, open-label Phase III trial (TDM4370g; EMILIA) compared 
single-agent trastuzumab emtansine versus lapatinib and capecitabine in 
patients with HER2-positive locally advanced unresectable BC or mBC who 
had received a prior taxane and trastuzumab therapy and had documented 
PD.27  
Patients were randomized in a 1:1 ratio to trastuzumab emtansine 3.6 mg/kg 
IV q3w or the combination of oral capecitabine 1,000 mg/m2 twice daily (bid) 
on Days 1–14 q3w plus oral lapatinib 1,250 mg/day given as continuous 
dosing. Treatment was continued until PD (as assessed by the investigator), 
unmanageable toxicity, or study termination. PFS and OS were co-primary 
endpoints, with PFS based on modified RECIST34 and assessed by 
independent review. Key secondary endpoints were ORR, DoR, and CBR, 
determined both by the investigator and by independent review. 
The study demonstrated statistically significant and clinically meaningful 
improvements in both PFS and OS for trastuzumab emtansine compared with 
lapatinib plus capecitabine. Median PFS was 9.6 months in the trastuzumab 
emtansine arm versus 6.4 months in the control arm (HR = 0.65; 95% CI: 
0.55–0.77; p < 0.001, log-rank test). Median OS was 30.9 months versus 25.1 
months, respectively (HR = 0.68; 95% CI: 0.55–0.85; p < 0.001, log-rank test).  
This benefit was supported by consistent improvements in all secondary 
efficacy endpoints, including investigator-assessed PFS, ORR, time to 
treatment failure (TTF), and the patient-reported outcome of time to symptom 
progression. The ORR in the trastuzumab emtansine arm was 43.6% (95% CI: 
38.6%–48.6%) compared with 30.8% (95% CI: 26.3%–35.7%) in the control 
arm (based on 786 evaluable patients). 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; that of trastuzumab emtansine (40.8%; n = 490) 
was 200. The rates of SAEs for both arms were similar (control arm 18% 
versus trastuzumab emtansine 15.5%). 
Based on the results of this phase III trial, both the Food and Drug 
Administration (FDA) in the US and the European Commission in Europe 
approved trastuzumab emtansine for the treatment of HER2-positive mBC 
previously treated with trastuzumab and a taxane.  
1.2.1.7 
Phase III study TDM4997g 
A second open-label randomized Phase III trial (TDM4997g; TH3RESA) 
compared single-agent trastuzumab emtansine versus the investigator’s 
choice of therapy in patients with HER2-positive advanced BC who had 
previously received two or more HER2-directed regimens in the advanced 
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setting, including trastuzumab and lapatinib, and previous taxane therapy in 
any setting.28 A total of 602 patients were randomized in a 2:1 ratio (404 to 
trastuzumab emtansine and 198 to physician’s choice).  
After median follow-up of approximately 7 months in both arms, 219 patients 
(54%) in the trastuzumab emtansine group and 129 (65%) in the physician’s 
choice group had experienced PFS events. PFS was significantly improved 
with trastuzumab emtansine compared with physician’s choice (HR 0.528, 
p<0.0001; median PFS 6.2 months with trastuzumab emtansine versus 3.3 
months in the control arm. The HR for OS at the interim analysis was 0.552 
(95% CI 0.369–0.826) but the stopping boundary was not crossed.  
Grade ≥3 AEs occurred less frequently with trastuzumab emtansine than with 
physician’s choice (32% of patients vs 43%). Grade ≥3 neutropenia, diarrhea, 
and febrile neutropenia were less common with trastuzumab emtansine than 
physician’s choice, whereas grade ≥3 thrombocytopenia (5% vs 2%) was 
more common with trastuzumab emtansine.  
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 qw regimens of trastuzumab 
emtansine administration are presented in Table 1. 
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Table 1 Cycle 1 Mean (s.d.) Pharmacokinetic Parameters for 
Trastuzumab Emtansine Following Trastuzumab Emtansine 
Administration q3w and qw in Study TDM3569g 
 
Dose 
(mg/kg) 
No. of 
Patients 
Cmax 
(μg/mL) 
AUCinf 
(day μg/mL) 
T1/2 
(day) 
Vd 
(mL/kg) 
CL 
(mL/day/kg) 
q3w 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) 
qw 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; s.d. = standard deviation; 
T1/2 = terminal half-life; Vd = volume of distribution. 
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 q3w cycle with a 2.4 mg/kg qw regimen 
compared with 3.6 mg/kg q3w.29,30 
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.35 
An aggregate PK assessment of trastuzumab emtansine was performed with 
samples from studies TDM3569g, TDM4258g, TDM4374g, and 
TDM4688g.36,37 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 
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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., maximum concentration [Cmax], area under the serum 
concentration-time curve [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. Weekly administration of trastuzumab emtansine in study 
TDM3568g at a dose of 2.4 mg/kg showed consistent PK data with the q3w 
dosing schedule.29 
1.2.2 
CAPECITABINE 
Capecitabine (Xeloda®) is a fluoropyrimidine carbamate with antineoplastic 
activity. It is an orally administered systemic prodrug of 5’-deoxy-5-
fluorouridine (5’-DFUR), which is converted to 5-fluorouracil (5-FU) in the 
tumor, where it inhibits DNA synthesis and slows down tumor tissue growth. It 
is approved in combination with docetaxel and as monotherapy in mBC. 
Please see the national Xeloda® prescribing information or Investigator 
brochure for more information. 
The activity of capecitabine as single-agent chemotherapy was initially 
demonstrated in two multicenter Phase II clinical trials (before testing of HER2 
status was standard) in patients with locally advanced or mBC after failure of 
a taxane and an anthracycline-containing chemotherapy regimen or for whom 
further anthracycline therapy was not indicated.38,39 In these trials, a total of 
236 patients were treated with capecitabine (1,250 mg/m2 bid for 2 weeks 
followed by 1-week rest period). The ORRs (investigator assessment) were 
20% (first trial) and 25% (second trial). The median TTP was 3.1 months and 
3.2 months, respectively. Median OS was 12.6 months and 12.3 months, 
respectively. 
The combination of capecitabine and docetaxel was studied as treatment for 
locally advanced or mBC after failure of anthracycline-containing 
chemotherapy in a multicenter randomized controlled Phase III clinical trial 
(SO14999).40 In this trial, 255 patients were randomized to treatment with 
capecitabine (1,250 mg/m2 bid for 2 weeks followed by a 1-week rest period) 
and docetaxel (75 mg/m2 as a 1-hour IV infusion q3w) and 256 patients were 
randomized to treatment with docetaxel alone (100 mg/m2 as a 1-hour IV 
infusion q3w). OS was superior in the capecitabine plus docetaxel 
combination arm (HR 0.775; p = 0.0126). Median OS was 14.5 months 
(capecitabine plus docetaxel) versus 11.5 months (docetaxel alone). The 
ORR in the all-randomized population (investigator assessment) was 41.6% 
(capecitabine plus docetaxel) versus 29.7% (docetaxel alone; p = 0.0058). 
TTP was superior in the capecitabine plus docetaxel combination arm (HR 
0.652; p < 0.0001). The median TTP was 6.1 months (capecitabine plus 
docetaxel) versus 4.2 months (docetaxel alone).  
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This trial led to the randomized Phase II CHAT trial evaluating the addition of 
capecitabine to first-line trastuzumab and docetaxel for locally advanced or 
metastatic HER2-positive mBC.41 PFS was significantly improved with the 
addition of capecitabine (HR 0.72; median 17.9 months versus 12.8 months in 
patients receiving docetaxel and trastuzumab without capecitabine), although 
there was no difference in ORR (71% versus 73%, respectively). 
1.2.2.1 
Study BO18255: Capecitabine and Trastuzumab in LA/mGC 
A global Phase III study (ToGA trial, BO18255) of trastuzumab plus 
chemotherapy as first-line treatment for advanced HER2-positive GC was 
conducted in 584 patients previously untreated for HER2-positive inoperable 
locally advanced or recurrent and/or metastatic adenocarcinoma of the 
stomach or GEJ. Patients received either capecitabine or fluorouracil 
combined with cisplatin or the same chemotherapy in combination with 
trastuzumab. The primary study endpoint was OS, defined as the time from 
the date of randomization to the date of death from any cause. At the time of 
the analysis a total of 349 randomized patients had died: 182/290 patients 
(62.8%) in the control arm and 167/294 patients (56.8%) in the trastuzumab-
containing arm. The majority of the deaths were due to events related to the 
underlying cancer.18 
Most patients enrolled in the study were male (76%); 52.9% were Asian and 
37.7% were white. The primary tumor site was the stomach for 81.8% of 
patients, with the others having GEJ tumors. The addition of trastuzumab to 
chemotherapy resulted in an increase in median OS from 11.1 months to 13.8 
months (HR 0.74, p = 0.0046). ORR (47% versus 35%), PFS (median 6.7 
versus 5.5 months), and TTP (median 7.1 versus 5.6 months) were also 
significantly increased with the addition of trastuzumab to chemotherapy 
compared with chemotherapy alone. 
With regard to OS, a treatment effect could not be excluded in any predefined 
subgroup, including primary tumor site, histologic subtype, method of 
determining HER2-positivity, performance status, chemotherapy regimen, age, 
gender, and region of enrollment. A multivariate analysis for OS showed a 
consistent result, with an adjusted HR of 0.72 (p = 0.0036); variables found to 
influence primary outcome included Eastern Cooperative Oncology Group 
(ECOG) performance status (0 or 1 versus 2), prior gastrectomy, and Asian 
region of enrollment (data on file). A multivariate analysis of OS for patients 
enrolled in Japan, from which the bulk of Asian patients were enrolled, 
demonstrated a HR of 0.68. This was consistent with the overall study 
results.42 
A pre-planned subgroup analysis by IHC score indicated that positive 
treatment effects were greater in tumors with higher levels of HER2 
expression. Among patients whose tumors had these higher levels of HER2 
expression, the median OS was 11.8 months versus 16 months (HR = 0.65; 
95% CI: 0.51–0.83) and median PFS was 5.5 months versus 7.6 months 
(HR = 0.64; 95 % CI: 0.51–0.79) for chemotherapy versus chemotherapy plus 
trastuzumab respectively. For OS, the HR was 0.75 (95% CI: 0.51–1.11) in 
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The Phase III, TDM4370g trial met its co-primary endpoint of improving PFS 
(by independent review) and OS compared with the combination of lapatinib 
and capecitabine (see Section 1.2.1.6).  
Based on the studies mentioned above, the combination of trastuzumab 
emtansine and capecitabine could provide the potential for enhanced anti-
tumor efficacy in mBC compared with single-agent trastuzumab emtansine or 
trastuzumab in combination with chemotherapy. Furthermore, preclinical data 
suggest that the combination of trastuzumab emtansine and capecitabine has 
an additive effect (see Section 1.2.3). 
Approximately 2,000 patients with BC have been treated in trastuzumab 
emtansine clinical trials with an acceptable safety profile and a positive risk-
benefit ratio. A broad development program is in place to seek approval for 
indications for mBC. Capecitabine in combination with an anti-HER2 agent is 
a proven efficacious regimen with a well-established safety profile in mBC. 
Trastuzumab emtansine and capecitabine have no known significant 
overlapping toxicities. As part of the Phase I conduct, regular teleconference 
calls with the investigators will be held to discuss the study treatment risk-
benefit profile for each patient. An Independent Data Monitoring Committee 
(IDMC) will be established with the main responsibility of assessing the risk-
benefit for the Phase II part of the study. Therefore, exploring the benefit of 
combination therapy of trastuzumab emtansine and capecitabine in patients 
with mBC seems justified. 
1.3.2 
FOR MGC 
As for mBC, the primary goal of treatment for metastatic gastric cancer (mGC) 
is to maximize patients’ survival and quality of life. 
In HER2-positive gastric tumors, anti-HER2 therapy has shown benefit. In the 
ToGA study (BO18255), the combination of chemotherapy and trastuzumab 
significantly improved OS versus chemotherapy alone (see Section 1.2.2.1) in 
this population. Fluoropyrimidine-based therapies (capecitabine, 5-FU) are the 
standard of care in mGC in general and were also the most frequent 
combination agents used in the ToGA trial (BO18255; see Section 1.2.2.1).  
Furthermore, preclinical data suggest that the combination of trastuzumab 
emtansine and capecitabine has an additive effect (see Section 1.2.3).  
A development program for trastuzumab emtansine is in place to seek 
approval for mGC indications. Capecitabine in combination with trastuzumab 
is a proven efficacious regimen with a well-established safety profile in mGC. 
Trastuzumab emtansine and capecitabine might have overlapping toxicities 
and therefore safety monitoring is in place to avoid exposing patients to harm. 
Therefore, exploring the benefit of combination therapy of trastuzumab 
emtansine and capecitabine in patients with mGC seems justified. 
In the ToGA study in LA/mGC, trastuzumab exposure was lower than that 
observed in breast cancer studies. Based on this observation, together with 
pharmacokinetic results and findings from a Phase I study in mBC, it was 
considered that a weekly trastuzumab emtansine regimen may provide higher 
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cumulative trastuzumab emtansine exposure than the q3w schedule and was 
therefore chosen for the Phase I, Cohort 2 part of the present study in 
LA/mGC. This approach has subsequently been supported by findings from 
stage I of the adaptive phase II/III BO27952 trial in this setting (see Section 
3.3.2.2). In October 2013, the IDMC for the BO27952 trial recommended 
selection of the weekly 2.4 mg/kg regimen for further evaluation in the phase 
III part of the trial based on pharmacokinetic, safety, and efficacy data 
available at the time. 
Results from the Phase I part of the study in mGC will be used as supporting 
information for future studies in the indication. 
2. 
OBJECTIVES 
2.1 
PHASE I: MTD-FINDING OF TRASTUZUMAB 
EMTANSINE AND CAPECITABINE IN MBC 
2.1.1 
PRIMARY OBJECTIVE 
• 
To determine the MTD of the combination of trastuzumab emtansine and 
capecitabine in patients with HER2-positive mBC  
2.1.2 
SECONDARY OBJECTIVES 
To assess the: 
• 
PK of trastuzumab emtansine, capecitabine and their metabolites  
• 
Safety of the combination of trastuzumab emtansine and capecitabine 
• 
ORR 
2.2 
RANDOMIZED PHASE II: EXPLORATION OF 
EFFICACY AND SAFETY IN MBC  
2.2.1 
PRIMARY OBJECTIVE 
To explore the efficacy of the combination of trastuzumab emtansine and 
capecitabine compared with trastuzumab emtansine alone in patients with 
HER2-positive mBC, as measured by ORR by RECIST v.1.1 per investigator 
local assessment 
2.2.2 
SECONDARY OBJECTIVES 
To assess the safety profile of the combination of trastuzumab emtansine and 
capecitabine compared with trastuzumab emtansine alone 
To explore the efficacy of the combination of trastuzumab emtansine and 
capecitabine compared with trastuzumab emtansine alone in patients with 
HER2-positive mBC, as measured by: 
• 
Time to response (TTR)  
• 
DoR 
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• 
TTP 
• 
TTF 
• 
PFS 
• 
CBR 
• 
OS 
2.3 
PHASE I: MTD FINDING OF TRASTUZUMAB 
EMTANSINE AND CAPECITABINE IN LA/MGC 
2.3.1 
PRIMARY OBJECTIVE 
To determine the MTD of the combination of trastuzumab emtansine and 
capecitabine in patients with LA/mGC  
2.3.2 
SECONDARY OBJECTIVES 
To assess the: 
• 
PK of trastuzumab emtansine, capecitabine, and their metabolites  
• 
Safety of the combination of trastuzumab emtansine and capecitabine 
• 
ORR 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is an international, multicenter Phase I/II dose-finding study of two dosing 
schedules of trastuzumab emtansine and capecitabine combination therapy in 
HER2-positive mBC and LA/mGC.  
The study is designed to determine the MTD of capecitabine in combination 
with trastuzumab emtansine in Phase I studies in patients with HER2-positive 
mBC or LA/mGC.  
The efficacy and safety of the combination in patients with mBC will also be 
explored in a randomized, open-label Phase II part of the study.  
3.1.1 
OVERVIEW OF STUDY DESIGN 
Overview of Study Design 
The study is designed to determine the MTD of capecitabine in combination 
with trastuzumab emtansine in patients with HER2-positive mBC or LA/mGC 
using a Phase I design, followed by a randomized, open-label Phase II part of 
the study to explore the efficacy and safety of the combination in patients with 
HER2-positive mBC. There will be no follow-on randomized exploration of 
efficacy in mGC. Results from the Phase I study in LA/mGC will be used as 
supporting information for future studies in the indication. 
Cohort 1 for patients with mBC will open first and the MTD will be established. 
Once the MTD is defined, both the randomized Phase II trial for patients with 
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HER2-positive mBC and the Phase I Cohort 2 for patients with LA/mGC will 
open. 
An overview of the study design is depicted in Figure 4. 
Duration of Treatment and Patient Follow-up 
Duration of treatment: All patients will be treated until investigator-assessed 
PD, unacceptable toxicity, withdrawal of consent, death, reasons deemed by 
the treating physician, or study termination by the Sponsor. If toxicity is 
considered by the investigator to be related to only one of the two agents, the 
non-implicated agent can be continued as single-agent therapy.   
If at the time of study closure there are patients whose disease has not 
progressed and who are still receiving study treatment, they will be offered the 
possibility to continue treatment by enrolling in an extension study at the 
discretion of the investigator. 
Patient follow-up: All patients will be followed up until withdrawal of consent, 
death, or for up to a maximum of 2 years after the last patient was 
randomized in the Randomized Phase II part of the study, whichever occurs 
first. 
Duration of Study, Database Closure and Data Reporting 
The duration of the study is estimated to be approximately 4 years. 
Recruitment is estimated to last 2 years in total (1 year for the MTD-Finding 
study in mBC and 1 year for the Phase II Exploration of Efficacy and Safety in 
mBC). See Section 3.2 for further details about EOS.  
Specifically in Phase I, cohort 2, if dose level -2 is too toxic in LA/mGC, 
recruitment into the LA/mGC cohort will be closed. See Section 3.1.1.3 for 
details of treatment continuation if patients are still responding to treatment at 
this time.  
Data may be published/presented publicly at the end of each cohort e.g., once 
the MTD for Cohort 1 for mBC has been defined and the dose for Phase II 
Exploration of Efficacy and Safety has been selected, and after the 
prespecified analyses for the Randomized Phase II exploration of efficacy and 
safety in mBC. The Clinical Study Report (CSR) will be finalized/published 
within 1 year after EOS (LPLV). 
 
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Figure 4 Overview of Study Design 
 
 
 
COHORT 1 mBC 
 
COHORT 2 LA/mGC 
Phase I 
Dose Finding 
 
 
 
n = ~6–18 
3 plus 3 classical design 
Trastuzumab emtansine: 3.6 mg/kg 
q3w 
Capecitabine: Dose Levels 1 to -21 
 
 
 
n = ~3–12 
3 plus 3 classical design 
Trastuzumab emtansine: 2.4 
mg/kg qw 
Capecitabine: Dose Levels -1 
to -21,3 
 
 
 
Randomized 
Phase II 
Exploration of 
Efficacy and 
Safety 
 
 
n = 210 
Randomized, open-label with two 
treatment groups4 
Trastuzumab emtansine: 3.6 
mg/kg q3w 
Capecitabine: MTD defined 
 
 
 
1 Capecitabine doses are administered daily on Days 1–14 q3w 
2 The MTD defined in the mBC Phase I study will be implemented in the mBC Randomized 
Phase II and mGC Phase I studies 
3 Cohort 2 will open to recruit patients with LA/mGC using the MTD defined in Phase I for 
patients with mBC. Dose Level 1 will not be explored in Cohort 2 (see also Section 3.3.2.2) 
4 Stratification factor: Number of prior lines of treatment for metastatic disease (≤1 or >1; 
excluding single-agent hormones) 
mBC = metastatic breast cancer; LA/mGC = locally advanced/metastatic gastric cancer; MTD 
= maximum tolerated dose; q3w = every 3 weeks; qw = weekly. 
 
A schedule of assessments is provided in Appendix 1. 
3.1.1.1 
Overview of Phase I Design in Patients with mBC 
An overview of the Phase I study design is depicted in Figure 5. 
MTD defined2 
MTD defined2 
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Dose Level -1: 700 mg/m2 capecitabine bid plus 3.6 mg/kg q3w trastuzumab 
emtansine 
Dose Level -2: 650 mg/m2 capecitabine bid plus 3.6 mg/kg q3w trastuzumab 
emtansine 
The following MTD determining rules will be applied during the MTD-Finding 
treatment phase: 
• 
Step 1: Three patients will be enrolled at Dose Level 1 
• 
Step 2: The toxicity of Dose Level 1 will be monitored and the following 
actions taken: 
a) If none of these 3 patients (0/3) experiences a DLT, the MTD will be 
established as the current dose level and will need to be confirmed in 3 
more patients (to achieve DLTs in ≤ 1/6 patients at that dose level) 
b) If 1 of the initial 3 patients (1/3) experiences a DLT, an additional 3 
patients should be enrolled and treated at the same dose, i.e., Dose 
Level 1 
c) If no additional patients experience a DLT (1/6), the MTD will be 
established as the current dose level 
d) If 1 or more additional patients experience a DLT (> 1/6), the dose will 
be de-escalated to the next lowest dose level. If no more than 1 patient 
experiences a DLT (≤ 1/6) after dose de-escalation, the dose will be 
considered the MTD and, following IDMC recommendation, will be 
further explored in the Randomized Phase II part of the study. Dose 
re-escalation will not be allowed. If 2 or more patients experience a 
DLT (> 1/6) after dose de-escalation, de-escalation should continue to 
the next lowest dose level. Based on the DLT findings, the next dose 
level may be considered the MTD and, following IDMC 
recommendation, be further explored in the Randomized Phase II part 
of the study or the study may be terminated if DLTs occur in > 1/6 
patients at Dose Level -2. 
In order to define the dose for the Randomized Phase II Exploration of 
Efficacy and Safety part of the study, evaluation will include not only the DLTs 
during Cycle 1 but also all available safety information during the subsequent 
cycles. The dose level considered optimal will be the dose level selected to 
proceed to the Phase II and LA/mGC parts of the study. 
Once the appropriate dose of study medication is established, the 
Randomized Phase II part of the study and Phase I, Cohort 2 will open as 
shown in Figure 4. 
3.1.1.2 
Overview of Phase II: Exploration of Efficacy and Safety in 
Patients with mBC  
After review of safety data from Part 1, cohort 1, the IDMC recommended a 
regimen of capecitabine 700 mg/m2 bid days 1–14 in combination with 
trastuzumab emtansine 3.6 mg/kg q3w for further evaluation. The Phase II 
part of the study will explore the efficacy and safety of this recommended 
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regimen compared with trastuzumab emtansine alone in patients with HER2-
positive mBC. See Section 3.1.1 for details of duration of treatment.  
Approximately 210 additional patients with HER2-positive mBC will be 
randomized into the Phase II part of the study. Patients in the Phase I part of 
the study will not contribute to the Phase II part of the study; however, they 
will be followed-up until end of study (EOS). 
 
3.1.1.3 
Overview of Phase I Design in LA/mGC Patients 
Determination of the MTD in Patients with LA/mGC  
Cohort 2 will enroll patients with HER2-positive LA/mGC. Trastuzumab 
emtansine will be administered qw at a fixed dose of 2.4 mg/kg and 
capecitabine will be started at 700 mg/m2 bid, the MTD defined for patients 
with mBC in Cohort 1.  
Enrollment into Cohort 2 
Cohort 2 will open with a 3 plus 3 classical design to investigate the feasibility 
of combination therapy of capecitabine and trastuzumab emtansine in up to 
12 patients with LA/mGC. The capecitabine dose will be de-escalated from 
the starting dose of 700 mg/m2 bid (the MTD recommended in Cohort 1).  
The dose levels for de-escalation of capecitabine will be the same as 
described for Cohort 1, except for Dose Level 1, which will not be explored in 
patients with mGC (see also Section 3.3.2.2). 
If Dose Level -1 (700 mg/m2 bid, the MTD recommended in cohort 1) is well 
tolerated (DLT in ≤ 1/6), this dose will be established as the MTD for LA/mGC. 
• 
If Dose Level -1 is not tolerated in Cohort 2 (DLT in > 1/3 or > 1/6 
patients), de-escalation will be to Dose Level -2. 
• 
If Dose Level -2 is not tolerated in Cohort 2 (DLT in > 1/6), the 
combination will be considered not feasible in LA/mGC and Cohort 2 will 
be terminated. Patients who, at that time, experience response according 
to RECIST v.1.1 will be offered the possibility to continue on trastuzumab 
emtansine as a single agent, or with the combination, based on risk-
benefit balance and agreement with the Steering Committee (SC). 
3.1.1.4 
Number of Patients 
Overall, it is anticipated that the maximum number of patients enrolled into the 
study will be approximately 240. 
Phase I, Cohort 1: mBC 
Between 6 and 18 patients will be enrolled into Cohort 1 to determine the 
MTD of capecitabine in combination with trastuzumab emtansine in patients 
with mBC. 
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Randomized Phase II: Exploration of Efficacy and Safety in mBC  
For this part of the study, a total of approximately 210 patients with mBC will 
be randomized. 
Phase I, Cohort 2: mGC 
After the MTD in Cohort 1 has been established, 3–12 patients will be enrolled 
into Cohort 2 to determine the MTD of capecitabine in combination with 
trastuzumab emtansine in patients with mGC. 
3.1.1.5 
Number of Centers 
This is a multicenter, international study. 
3.1.2 
STEERING COMMITTEE 
A SC has been established for this study. Initially, it is composed of the 
investigators participating in the Phase I, Cohort 1 part of the study and one 
medical representative and one statistician of the Sponsor. The study design 
and DLT definition have been developed by the SC. See the SC Charter for 
further information. 
The SC will collectively review the status of the ongoing patients in Phase I on 
a regular basis. The SC will adjudicate in the event of DLTs that are not 
covered by the existing DLT criteria. 
3.1.3 
INDEPENDENT DATA MONITORING COMMITTEE 
An IDMC will review the safety outcomes for patients enrolled in Phase I, 
Cohort 1 and recommend whether the Randomized Phase II part of the study 
can commence. The IDMC will also monitor safety outcomes after 25, 75, and 
150 patients have received at least 3 cycles (Cycle 3 Day 21) of treatment in 
the Phase II part of the study. Afterwards, the IDMC will monitor accumulating 
patient safety data every 6 months during the Randomized Phase II part of 
the study or as requested. 
3.2 
END OF STUDY 
EOS is defined as the last patient last visit (LPLV) at the end of the follow-up 
period, as defined in Section 3.1.1. This will be the last data collection point, 
which can be a clinic visit or a laboratory sample. LPLV is expected to occur 
approximately 2 years after the last patient has been randomized into the 
Phase II part of the trial. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
RATIONALE FOR PATIENT GROUP SELECTION 
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 
therapy (see the Herceptin® national prescribing information). Measurement of 
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HER2 gene amplification has traditionally been performed using IHC. HER2 
gene amplification determined by ISH has also proven to be a reliable method 
for demonstrating HER2-positive status.44 
This study will enroll patients diagnosed with HER2-positive mBC or LA/mGC. 
Capecitabine is an established chemotherapy for both diseases. In patients 
with HER2-positive mBC or LA/mGC, anti-HER2 therapy has demonstrated 
activity. Furthermore, the combination of anti-HER2 therapy and capecitabine 
has been shown to be efficacious in both mBC9,10 and LA/mGC.18 Eligible 
patients for this study will have incurable mBC or LA/mGC overexpressing 
HER2. 
3.3.1.1 
Rationale for Phase I 
The 3 plus 3 design is a well-established and well-known method for Phase I 
studies. PK parameters will be collected and analyzed to investigate the PK 
interaction of the drugs under investigation.  
The capecitabine dose evaluated in combination with trastuzumab and 
docetaxel in the CHAT trial was 950 mg/m2 bid. However, retrospective 
evaluations and post hoc analyses of early dose reduction suggest that lower 
starting doses of capecitabine offer similar efficacy with better tolerability. 
Therefore the capecitabine starting dose selected in combination with 
trastuzumab emtansine for the MTD-Finding Phase I part of the present study 
was 750 mg/m2 bid, taking into account the aim of maintaining the good 
tolerability of trastuzumab emtansine while benefitting from synergy observed 
between the two agents in nonclinical studies. 
The combination of T-DM1 and capecitabine was evaluated with a de-
escalation study design. Following the emergence of two DLTs (grade 3 
vomiting, grade 3 elevated AST/ALT) at the starting dose of 750 mg/m2 bid 
(days 1–14 q3w) in combination with trastuzumab emtansine 3.6 mg/kg q3w, 
a de-escalated dose cohort was opened to evaluate capecitabine 700 mg/m2 
bid combined with the same dose of trastuzumab emtansine. At this dose no 
DLTs were observed in the six patients treated, and of note, none of the 
patients had experienced grade ≥3 AEs in cycles delivered after the DLT 
evaluation period.45 Following review of safety data from patients treated at 
these two dose levels, the IDMC recommended the regimen of capecitabine 
700 mg/m2 bid combined with trastuzumab emtansine 3.6 mg/kg q3w for the 
phase II exploration of efficacy and safety.  
In the ToGA study in LA/mGC, trastuzumab exposure was lower than that 
observed in breast cancer studies. A weekly trastuzumab emtansine regimen 
may provide higher cumulative trastuzumab emtansine exposure than the 
q3w schedule and was therefore chosen for the Phase I, Cohort 2 part of the 
present study in LA/mGC. This approach has subsequently been supported 
by findings from stage I of the adaptive phase II/III BO27952 trial in this 
setting (see Section 3.3.2.2).  
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3.3.1.2 
Rationale for Randomized Phase II 
The Randomized Phase II part of the study is designed to explore the efficacy 
and safety of the combination recommended following the Phase I MTD-
Finding phase (trastuzumab emtansine 3.6 mg/kg in combination with 
capecitabine 700 mg/m2) compared with trastuzumab emtansine alone.  
3.3.2 
RATIONALE FOR INVESTIGATIONAL MEDICINAL DOSE 
SELECTION 
3.3.2.1 
In Patients with mBC 
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 heavily pre-treated 
HER2-positive mBC (protocol TDM4258g31 and protocol TDM4374g32), in 
patients who had not received prior chemotherapy for metastatic disease 
(TDM4450g26), and subsequently in the randomized phase III trials.27,28 
Capecitabine doses have been selected as being in the range of efficacious 
doses for single-agent or combination use. The doses selected are within the 
dosing range included in the Xeloda® Summary of Product Characteristics 
(SmPC) and therefore are considered to be efficacious.  
3.3.2.2 
In Patients with mGC 
In the ToGA study (BO18255) evaluating trastuzumab in combination with 
chemotherapy for mGC, patients with higher drug exposure had a greater 
benefit than those with lower exposure.46 As a consequence, an ongoing 
randomized, open-label, multicenter Phase IIIb study is comparing two 
trastuzumab dosing regimens, each in combination with cisplatin/capecitabine 
chemotherapy, as first-line therapy in patients with HER2-positive metastatic 
gastric or GEJ adenocarcinoma (Study BO27798). 
In TDM3569g (see Section 1.2.1.1), the qw administration of 2.4 mg/kg of 
trastuzumab emtansine resulted in higher exposure than q3w dosing (see 
Section 1.2.1.8).29,30 Therefore, this dose may result in larger clinical benefit 
for patients with mGC.  
In the ongoing randomized adaptive phase II/III BO27952 trial evaluating 
trastuzumab emtansine versus the investigator’s choice of taxane therapy in 
unrectable LA/mGC, two trastuzumab emtansine regimens were evaluated in 
stage I: 3.6 mg/kg q3w and 2.4 mg/kg qw . In October 2013, the IDMC for the 
BO27952 trial recommended selection of the weekly 2.4 mg/kg regimen for 
further evaluation in the phase III part of the trial based on pharmacokinetic, 
safety, and efficacy data available at the time. This recommendation provides 
further support for using the weekly regimen in Phase I, Cohort 2 of the 
present trial.  
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In Cohort 2, the starting dose of capecitabine will be 700 mg/m2 bid (the MTD 
from Cohort 1 in mBC) in order to minimize the exposure of patients to sub-
optimal treatment. The dose of capecitabine can be de-escalated if needed. 
3.3.2.3 
Rationale for Duration of Treatment 
Treatment will be given until investigator-assessed PD, unacceptable toxicity, 
withdrawal of consent, death, reasons deemed by the treating physician, or 
study termination by the Sponsor (see Section 3.1.1 for full information). As of 
1 January 2010, of 237 patients enrolled in studies TDM3569g, TDM4258g, 
and TDM4374g receiving trastuzumab emtansine at 3.6 mg/kg, approximately 
30% have tolerated more than 12 cycles, with 14.8% having received more 
than 17 cycles. Twenty patients (8.4%) have discontinued trastuzumab 
emtansine due to AEs and 24 patients (10.1%) required dose reductions in 
trastuzumab emtansine because of AEs. In the absence of unacceptable 
toxicity, patients with mBC are generally treated until PD. Further support for 
treatment until PD comes from the EMILIA randomized phase III trial.27 
Among the 490 patients randomized to trastuzumab-emtansine, only 29 (5.9%) 
discontinued because of adverse events.  
Capecitabine will be given until PD, in accordance with Xeloda® national 
prescribing information. 
3.3.3 
PHARMACOKINETIC SAMPLING RATIONALE 
PK is studied only in the Phase I (MTD-Finding) parts (both cohorts 1 and 2). 
The PK sampling rationale is to characterize the PK of trastuzumab 
emtansine and capecitabine and their metabolites, to assess any potential 
drug-drug interaction when trastuzumab emtansine is given in combination 
with capecitabine, and to explore potential correlations between drug 
exposure and measures of both efficacy (ORR) and toxicity (alanine 
transaminase [ALT]/AST, platelets, etc.), if data allow. 
3.4 
OUTCOME MEASURES 
3.4.1 
PHASE I: MBC 
3.4.1.1 
Primary Outcome Measure 
The main objective for Phase I is to determine the MTD of capecitabine when 
combined with trastuzumab emtansine. 
3.4.1.2 
Secondary Outcome Measure 
The secondary outcome is ORR, based on best overall response (BOR) rate 
according to RECIST v.1.1, per investigator local assessment. 
3.4.1.3 
Primary Safety Outcome Measure 
The primary safety outcome measure is to establish the MTD. The number 
and the proportion of patients with DLTs will be used as the primary measure 
for the MTD determination and will be summarized for each treatment dosage. 
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3.4.1.4 
Secondary Safety Outcome Measures 
Safety endpoints will be summarized for each treatment dosage: 
• 
Incidence, nature, and severity of AEs, according to National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
v. 4.0 
• 
Incidence, nature, and severity of SAEs, according to NCI CTCAE v. 4.0 
• 
Incidence and nature of Grade ≥3 AEs  
• 
Incidence, nature, and severity of AEs of special interest (AESIs), 
according to NCI CTCAE v. 4.0 
• 
Fatal AEs and their causes  
• 
Laboratory parameters 
• 
LVEF 
• 
Exposure to study medication 
• 
Physical examination 
• 
Vital signs and ECOG performance status 
• 
Premature withdrawal from study medication and/or study 
3.4.1.5 
Pharmacokinetic Outcome Measures 
The PK outcome measures to be assessed in patients receiving trastuzumab 
emtansine and capecitabine will include: 
• 
Serum concentrations of trastuzumab emtansine (conjugated drug) and 
total trastuzumab (free and conjugated to DM1) 
• 
Plasma concentration of DM1 
• 
Plasma concentration of capecitabine and its active metabolite 5-FU 
• 
Total exposure (e.g., AUC)  
• 
Cmax 
• 
CL 
• 
Vd 
• 
T1/2 
3.4.2 
RANDOMIZED PHASE II: EXPLORATION OF EFFICACY AND 
SAFETY IN MBC 
The primary and secondary efficacy outcome measures will be presented for 
each treatment group.  
3.4.2.1 
Primary Efficacy Outcome Measure 
The primary outcome measure is ORR by investigator assessment, based on 
BOR (defined as the best response recorded from randomization into the 
Phase II part of the study and until PD, death, withdrawal of consent, start of 
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new anticancer treatment, or EOS, whichever occurs first) according to 
RECIST v.1.1 (See Appendix 3). 
3.4.2.2 
Secondary Efficacy Outcome Measures 
Secondary efficacy outcomes include: 
• 
TTR 
• 
DoR 
• 
TTP 
• 
TTF 
• 
PFS 
• 
CBR 
• 
OS 
3.4.2.3 
Primary Safety Outcome Measure 
A primary safety outcome is defined only for Phase I.  
3.4.2.4 
Secondary Safety Outcome Measures 
The summary of safety endpoints will be presented for each treatment group: 
• 
Incidence, nature, and severity of AEs, according to NCI CTCAE v. 4.0 
• 
Incidence, nature, and severity of SAEs, according to NCI CTCAE v. 4.0 
• 
Incidence and nature of Grade ≥3 AEs  
• 
Incidence, nature, and severity of AESIs, according to NCI CTCAE v. 4.0 
• 
Fatal AEs and their causes  
• 
Events to monitor 
• 
Laboratory parameters 
• 
LVEF 
• 
Exposure to study medication 
• 
Physical examination 
• 
Vital signs and ECOG performance status 
• 
Premature withdrawal from study medication and/or study 
3.4.2.5 
Pharmacokinetic Outcome Measures 
Not applicable for Phase II. 
3.4.3 
PHASE I: LA/MGC 
3.4.3.1 
Primary Outcome Measure 
The main objective for Phase I is to determine the MTD of capecitabine when 
combined with trastuzumab emtansine. The number and the proportion of 
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patients with DLTs will be used as the primary measure for the MTD 
determination and will be summarized for each treatment dosage. 
 
3.4.3.2 
Secondary Efficacy Outcome Measure 
The secondary (efficacy) outcome is ORR, based on BOR rate according to 
RECIST v.1.1 according to investigator assessment. 
3.4.3.3 
Secondary Safety Outcome Measures 
Safety endpoints will be summarized for each treatment dosage: 
• 
Incidence, nature, and severity of AEs, according to NCI CTCAE v. 4.0 
• 
Incidence, nature, and severity of SAEs, according to NCI CTCAE v. 4.0 
• 
Incidence and nature of Grade ≥3 AEs  
• 
Incidence, nature, and severity of AESIs, according to NCI CTCAE v. 4.0 
• 
Fatal AEs and their causes  
• 
Events to monitor 
• 
Laboratory parameters 
• 
LVEF 
• 
Exposure to study medication 
• 
Physical examination 
• 
Vital signs and ECOG performance status 
• 
Premature withdrawal from study medication and/or study 
3.4.3.4 
Pharmacokinetic Outcome Measures 
The PK outcome measures to be assessed in patients receiving trastuzumab 
emtansine and capecitabine will include: 
• 
Serum concentrations of trastuzumab emtansine (conjugated drug) and 
total trastuzumab (free and conjugated to DM1) 
• 
Plasma concentration of DM1 
• 
Plasma concentration of capecitabine and its active metabolite 5-FU 
• 
Total exposure (e.g., AUC)  
• 
Cmax 
• 
CL 
• 
Vd 
• 
T1/2 
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4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
4.1.1 
PATIENTS WITH MBC  
This study will enroll patients with HER2-positive BC with histologically or 
cytologically confirmed metastatic disease that is amenable to combination 
treatment with trastuzumab emtansine and capecitabine. 
Patients with mBC must have received at least one prior treatment regimen 
for early or metastatic disease, which included a chemotherapy agent and 
trastuzumab either separately or in combination. In both study parts (Phase I 
and II), only patients whose HER2 tumor status was locally scored as IHC 3+ 
or in situ hybridization (ISH) positive will be eligible. 
4.1.2 
LA/MGC PATIENTS 
This study will enroll patients with HER2-positive GC with histologically or 
cytologically confirmed inoperable LA/mGC that is amenable to combination 
treatment with trastuzumab emtansine and capecitabine. 
Patients with mGC must not have received prior chemotherapy for 
advanced/metastatic disease, and only patients with HER2-positive primary 
tumor or metastasis as assessed by the central laboratory will be allowed to 
enroll in the mGC part of the study. 
4.1.3 
INCLUSION CRITERIA 
4.1.3.1 
For Patients with mBC 
Patients must meet the following criteria for study entry: 
1. Male or female 
2. Age ≥ 18 years old 
3. Signed informed consent before any study-specific procedure 
4. Able and willing to comply with the protocol 
5. 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 the medical history confirming that the 
patient is not of childbearing potential. 
6.  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 or two effective forms of non-
hormonal contraception and to continue its use for the duration of study 
treatment and for 7 months after the last dose of study treatment (see 
Section 5.2.4). 
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7. ECOG performance status of 0, 1, or 2 
8. Blood: 
a) Platelet count > 100,000 cells/mm3 
b) International normalized ratio (INR) < 1.5  
c) Absolute neutrophil count (ANC) > 1,500 cells/mm3 
d) Hemoglobin > 9.0 g/dL. Patients are allowed to have received 
transfusion to achieve this level. 
9. Liver function: 
a)  Total bilirubin ≤ 1.5 × upper limit of normal (ULN) or direct bilirubin ≤1.5 
× ULN in patients with documented Gilbert’s syndrome.  
b) Serum glutamic oxaloacetic transaminase (SGOT)/AST and serum 
glutamic pyruvic transaminase (SGPT)/ALT ≤ 2.5 × ULN 
c) Alkaline phosphatase ≤ 2.5 × ULN. In patients with bone metastases: 
alkaline phosphatase ≤ 5 × ULN 
d) Evidence of stable liver function during the month prior to enrollment 
with liver function test (LFT) fluctuations not exceeding 2.5 x ULN (for 
AST, ALT) and 1.5 x ULN (for total bilirubin).  
10. Renal function: 
a) Serum creatinine of < 177 µmol/L or calculated creatinine CL > 50 
mL/min. If urine dipstick for proteinuria is ≥ 2+ at baseline, the patient 
must undergo 24-hour urine collection and demonstrate ≤ 1 g of 
protein/24 hours 
11. Cardiac function: 
a) LVEF ≥ 50% by echocardiogram (ECHO) or multiple-gated acquisition 
(MUGA) scan 
12. Life expectancy ≥12 weeks 
13. Histologically or cytologically confirmed BC 
14. HER2-positive disease, defined as IHC 3+ or ISH positive 
15. Tumor block or 8 slides available for retrospective central confirmation of 
HER2-positivity (central confirmation not necessary for enrollment).  
16. mBC with at least one measurable lesion according to RECIST v.1.1 
17. Disease progression on at least one prior regimen containing trastuzumab 
and chemotherapy either separately or in combination 
18. Patients must have recovered from previous treatments 
4.1.3.2 
For Patients with LA/mGC 
Patients must meet the following criteria for study entry: 
1.  Male or female 
2.  Age ≥ 18 years old 
3. Signed informed consent before any study-specific procedure 
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4. Able and willing to comply with the protocol 
5. 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 the medical history confirming that the 
patient is not of childbearing potential 
6.  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 or two effective forms of non-
hormonal contraception and to continue its use for the duration of study 
treatment and for 7 months after the last dose of study treatment (see 
Section 5.2.4) 
7. ECOG performance status of 0, 1, or 2 
8. Blood: 
a) Platelet count > 100,000 cells/mm3 
b) INR < 1.5  
c) ANC > 1,500 cells/mm3 
d) Hemoglobin > 9.0 g/dL. Patients are allowed to have received 
transfusion to achieve this level. 
9. Liver function: 
a) Total bilirubin ≤ 1.5 × ULN or direct bilirubin ≤1.5 × ULN in patients with 
documented Gilbert’s syndrome 
b) SGOT/AST and SGPT/ALT ≤ 2.5 × ULN 
c) Alkaline phosphatase ≤ 2.5 × ULN. In patients with bone metastases: 
alkaline phosphatase ≤ 5 × ULN 
d) Evidence of stable liver function in the month prior to enrollment with 
LFT fluctuations not exceeding 2.5 x ULN (for AST, ALT) and 1.5 x 
ULN (for total bilirubin).  
10. Renal function: 
a) Serum creatinine of < 177 µmol/L or calculated creatinine CL > 50 
mL/min. If urine dipstick for proteinuria is ≥ 2+ at baseline, the patient 
must undergo 24-hour urine collection and demonstrate ≤ 1 g of 
protein/24 hours 
11. Cardiac function: 
a) LVEF ≥ 50% by ECHO or MUGA scan 
12. Histologically or cytologically confirmed mGC or locally advanced GC 
13. HER2-positive tumor (primary tumor or metastatic lesion), defined as 
either IHC 3+ or IHC 2+ and ISH+, prospectively confirmed by a Sponsor-
designated central laboratory prior to enrollment. ISH positivity is defined 
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as a ratio of ≥ 2.0 for the number of HER2 gene copies to the number of 
signals for CEP17. 
a) Archival tumor samples obtained from primary or metastatic sites are 
acceptable. 
b) Invasive tumor for central confirmation of HER2 status is required. 
c) A formalin-fixed paraffin-embedded (FFPE) tissue block with at least 
5 mm of invasive tumor for central confirmation is preferred. If FFPE 
tissue blocks (or partial block) are unavailable due to country or site 
regulations, a minimum of 8 freshly cut unstained slides MUST be 
available for central review of HER2 status. 
14.  Inoperable LA/mGC 
4.1.4 
EXCLUSION CRITERIA 
4.1.4.1 
For Patients with mBC 
1. Prior treatments before first study treatment: 
a) Investigational therapy within ≤ 28 days or 5 half-lives, whichever is 
longer 
b)  Hormonal therapy within 14 days 
c) Trastuzumab within 21 days 
2. Prior enrollment in a trastuzumab emtansine-containing study, regardless 
of whether the patient received trastuzumab emtansine 
3. Prior treatment with capecitabine 
4. History of severe and unexpected reactions to fluoropyrimidine or known 
hypersensitivity to fluorouracil 
5. Related capecitabine contraindications: 
a) Treatment with sorivudine or its chemically-related analogues, such as 
brivudine 
b)  Rare hereditary problems of galactose intolerance, Lapp lactase 
deficiency, or glucose-galactose malabsorption 
c) Signs or symptoms suggesting that the patient has DPD deficiency 
6. History of intolerance (including Grade 3 or 4 infusion reaction) or 
hypersensitivity to trastuzumab or murine proteins or any component of 
the product 
7. History of exposure to the following cumulative doses of anthracyclines: 
a) Doxorubicin or liposomal doxorubicin > 500 mg/m2 
b) Epirubicin > 900 mg/m2 
c) Mitoxantrone > 120 mg/m2 
d) If another anthracycline, or more than one anthracycline, has been 
used, the cumulative dose must not exceed the equivalent of 
500 mg/m2 doxorubicin. 
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8. Brain metastases that are symptomatic, or require any radiation, surgery, 
or steroid therapy to control their symptoms within 28 days before first 
study drug administration 
9.  Current peripheral neuropathy of Grade ≥ 3 according to NCI CTCAE, v. 
4.0 
10. History of other malignancy within the last 5 years, except for 
appropriately treated carcinoma in situ of the cervix, non-melanoma skin 
carcinoma, Stage I uterine cancer, or other cancers with a similar 
outcome as those mentioned above.  
11. Current unstable ventricular arrhythmia requiring treatment 
12. History of symptomatic CHF (New York Heart Association [NYHA] 
Classes II−IV) 
13. History of myocardial infarction or unstable angina within 6 months prior to 
first study drug administration 
14. History of a decrease in LVEF to < 40% or symptomatic CHF with 
previous trastuzumab treatment 
15. Severe dyspnea at rest due to complications of advanced malignancy or 
currently requiring continuous oxygen therapy 
16. Clinically significant malabsorption syndrome or inability to take oral 
medication 
17. Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, or metabolic disease) 
18. Major surgical procedure or significant traumatic injury within 28 days 
before enrollment or anticipation of the need for major surgery during the 
course of study treatment 
19. Current pregnancy or lactation 
20. Current known active infection with human immunodeficiency virus (HIV), 
hepatitis B and/or hepatitis C virus (HBV/HCV) 
a) For patients who are known carriers of HBV, active hepatitis B infection 
must be ruled out based on negative serologic testing and/or 
determination of HBV DNA viral load per local guidelines 
21.  Lapatinib ≤ 14 days before first study drug administration 
22. Previous radiotherapy for the treatment of mBC is not allowed if: 
a) The last fraction of radiotherapy has been administered within 14 days 
prior to first study drug administration (28 days for patients with 
radiotherapy to control symptoms of brain metastases, see exclusion 
criterion 8). 
b) More than 25% of marrow-bearing bone has been irradiated. 
c) Any acute toxicity has not resolved to Grade ≤ 1 before first study drug 
administration. 
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4.1.4.2 
For Patients with LA/mGC 
1. 
Prior treatments before first study treatment: 
a) Investigational therapy within ≤ 28 days or 5 half-lives, whichever is 
longer 
b)  Hormonal therapy within 14 days 
c) Trastuzumab within 21 days 
2. Prior enrollment in a trastuzumab emtansine-containing study, regardless 
of whether the patient received prior trastuzumab emtansine 
3. Prior treatment with capecitabine 
4. History of severe or unexpected reactions to fluoropyrimidine or known 
hypersensitivity to fluorouracil 
5. Related capecitabine contraindications: 
a) Treatment with sorivudine or its chemically-related analogs, such as 
brivudine 
b)  Rare hereditary problems of galactose intolerance, Lapp lactase 
deficiency or glucose-galactose malabsorption 
c) Signs or symptoms suggesting that the patient has DPD deficiency 
6. History of intolerance (including Grade 3 or 4 infusion reaction) or 
hypersensitivity to trastuzumab or murine proteins or any component of 
the product 
7. History of exposure to the following cumulative doses of anthracyclines: 
a) Doxorubicin or liposomal doxorubicin > 500 mg/m2 
b)  Epirubicin > 900 mg/m2 
c) Mitoxantrone > 120 mg/m2 
d) If another anthracycline, or more than one anthracycline, has been 
used, the cumulative dose must not exceed the equivalent of 
500 mg/m2 doxorubicin. 
8. Brain metastases that are symptomatic, or require any radiation, surgery, 
or steroid therapy to control symptoms within 28 days before first study 
drug administration 
9. Current peripheral neuropathy of Grade ≥ 3 according to NCI CTCAE, v. 
4.0 
10. History of other malignancy within the last 5 years, except for 
appropriately treated carcinoma in situ of the cervix, non-melanoma skin 
carcinoma, Stage I uterine cancer, or other cancers with a similar 
outcome as those mentioned above 
11. Current unstable ventricular arrhythmia requiring treatment 
12. History of symptomatic CHF (NYHA Classes II−IV) 
13. History of myocardial infarction or unstable angina within 6 months prior to 
first study drug administration 
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14. History of a decrease in LVEF to < 40% or symptomatic CHF with 
previous trastuzumab treatment 
15. Severe dyspnea at rest due to complications of advanced malignancy or 
currently requiring continuous oxygen therapy 
16. Clinically significant malabsorption syndrome or inability to take oral 
medication 
17. Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, or metabolic disease) 
18. Major surgical procedure or significant traumatic injury within 28 days 
before enrollment or anticipation of the need for major surgery during the 
course of study treatment 
19. Current pregnancy or lactation 
20. Current known active infection with HIV, HBV, and/or HCV 
a) For patients who are known carriers of HBV, active hepatitis B infection 
must be ruled out based on negative serologic testing and/or 
determination of HBV DNA viral load per local guidelines 
21. Previous chemotherapy for advanced/metastatic disease 
a) Prior adjuvant/neoadjuvant therapy is allowed if at least 6 months has 
elapsed between completion of adjuvant/neoadjuvant therapy and 
enrollment into the study 
22. Lapatinib ≤ 14 days before first study drug administration 
4.1.5 
PATIENT REPLACEMENT POLICY 
None of the patients in the Phase I part of the study may be replaced unless 
approved by the entire SC. Phase II patients will not be replaced. 
4.2 
METHOD OF TREATMENT ASSIGNMENT 
In the Randomized Phase II part of the study, patients will be randomized to 
receive either the combination of trastuzumab emtansine and capecitabine or 
trastuzumab emtansine alone. Patients are stratified according to the number 
of prior lines of treatment for metastatic disease (≤1 or >1, excluding single-
agent therapy). 
This is an open-label randomized study; therefore, no blinding will be used. 
4.3 
STUDY TREATMENT 
4.3.1 
FORMULATION, PACKAGING, AND HANDLING 
4.3.1.1 
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 
emtansine, closed by means of a FluroTec coated stopper and an overseal 
with flip-off cap. Upon receipt of trastuzumab emtansine, vials should be 
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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. 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. 
4.3.1.2 
Capecitabine 
The following information has been obtained from the Xeloda® European 
Union (EU) SmPC and US Xeloda® Package Insert. 
Capecitabine is available as biconvex, oblong, film-coated tablets, available 
as follows: 
• 
150 mg tablets: color, light peach; engraving, XELODA on one side, 150 
on the other; packs of 60 
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• 
500 mg tablets: color, peach; engraving, XELODA on one side, 500 on 
the other; packs of 120 
Capecitabine tablets should not be stored above 30°C. 
4.3.2 
DOSAGE AND ADMINISTRATION 
4.3.2.1 
For Patients with mBC 
Trastuzumab Emtansine 
Trastuzumab emtansine will be administered on Day 1 q3w at a dose of 3.6 
mg/kg IV (see Appendix 1). The total dose will be calculated based on the 
patient’s weight on Day 1 of each cycle (or up to 3 days before) with no upper 
limit. 
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 90 minutes for fever, chills, or other infusion-associated 
symptoms. If prior infusions were well tolerated (without any signs or 
symptoms of infusion reactions), subsequent doses of trastuzumab emtansine 
may be administered over 30 minutes (±10 minutes), with a minimum 30-
minute observation period following infusion. Local health authority guidelines 
must be followed with regard to further observation and monitoring, if 
applicable. 
Pre-medication for nausea and infusion reactions (e.g., acetaminophen or 
other analgesics, antihistamines such as diphenhydramine, or corticosteroids) 
may be given at the investigator’s discretion. 
Capecitabine 
Capecitabine will be administered twice a day, orally for 14 days followed by a 
7-day rest period at the Dose Levels described in Section 3.1.1. Capecitabine 
tablets should be swallowed with water within 30 minutes after a meal. 
Capecitabine doses can be delayed for up to 4 hours, while keeping the 
minimal interval of 8 hours between the doses. 
Rounding of the dose, based on 150 and 500 mg strength tablets, will be 
allowed to the nearest dose per patient body surface area (BSA). 
If a dose is missed, the patient should skip that dose. The patient should not 
double the dose during the next administration. 
Guidelines for dosage modification and treatment interruption or 
discontinuation are provided in Section 5.1.  
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4.3.2.2 
For Patients with LA/mGC 
Trastuzumab Emtansine 
Trastuzumab emtansine will be administered on Day 1 qw at a dose of 2.4 
mg/kg IV (see Appendix 1). The total dose will be calculated based on the 
patient’s weight on Day 1 of each cycle (or up to 3 days before) with no upper 
limit. 
Administration time and observation period are described in Section 4.3.2.1 
for trastuzumab emtansine. 
Guidelines regarding timing delays and infusion times are the same as for 
patients with mBC, as is the accepted pre-medication. 
Capecitabine 
Capecitabine will be administered at a starting dose of 700 mg/m2 bid, orally, 
for 14 days followed by a 7-day rest period (the dose level determined as the 
MTD in cohort 1, with de-escalation as described in section 3.1.1.3. 
Capecitabine tablets should be swallowed with water within 30 minutes after a 
meal. Capecitabine doses can be delayed for up to 4 hours, while keeping the 
minimal interval of 8 hours between the doses. 
If a dose is missed, the patient should skip that dose. The patient should not 
double the dose at the next administration. 
Guidelines for dosage modification and treatment interruption or 
discontinuation are provided in Section 5.1. 
4.3.3 
INVESTIGATIONAL MEDICINAL PRODUCT ACCOUNTABILITY 
All investigational medicinal products (IMPs) required for completion of this 
study (trastuzumab emtansine and capecitabine) 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. 
IMPs will be either disposed of at the study site according to the study site’s 
institutional standard operating procedure or returned to the Sponsor with the 
appropriate documentation. The site's method of IMP destruction must be 
agreed upon by the Sponsor. The site must obtain written authorization from 
the Sponsor before any IMP is destroyed, and IMP destruction must be 
documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and 
disposed of by the study site should be recorded on the Drug Inventory Log. 
4.3.4 
POST-TRIAL ACCESS TO EXTENSION STUDY 
Post-trial access to trastuzumab emtansine and capecitabine will be 
performed as described in Section 3.1.1, Duration of Treatment and Patient 
Follow-Up. If 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 
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other study interventions to patients after conclusion of the study or any 
earlier patient withdrawal. 
4.4 
CONCOMITANT AND EXCLUDED THERAPIES 
4.4.1 
PERMITTED THERAPY 
Concomitant therapy and pre-medication are defined as non-IMPs. 
Concomitant therapy includes any prescription medication, over-the-counter 
preparation, or herbal therapy between the 14 days preceding first treatment 
and the Study Treatment Discontinuation Visit. Afterwards, only anti-cancer 
therapies will be collected as part of the survival follow-up. 
Pre-medication is allowed according to standard practice guidelines. 
No pre-medication for the first infusion of trastuzumab emtansine is required; 
however, pre-medication 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 is permitted to treat pre-existing painful bone 
metastases or to treat brain metastases (for patients who have disease 
control outside of the brain). 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 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 PD. 
4.4.2 
PROHIBITED THERAPY 
During the study, use of the therapies described below is prohibited until 
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. 
Radiotherapy for unequivocal PD 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 
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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 cannot be treated with additional radiation. Patients must not 
miss more than one cycle of study treatment for the treatment of their brain 
metastases and must have an ECOG performance status of 0, 1, or 2 to 
continue on therapy. The Medical Monitor should be informed before a 
decision is made to resume study treatment after radiotherapy for brain 
metastases. 
4.5 
STUDY ASSESSMENTS 
All patients will be closely monitored for safety and tolerability during all cycles 
of therapy and at the safety follow-up visit: 
• 
Visits will be based on a q3w cycle for mBC 
• 
Visits will be based on a qw cycle for mGC 
Study assessments are outlined in this section and in Appendix 1. 
4.5.1 
DESCRIPTION OF STUDY ASSESSMENTS 
All patients will be closely monitored for safety and tolerability during all cycles 
of therapy and at the Study Treatment Discontinuation Visit. Patients should 
be assessed for toxicity prior to each dose; dosing will occur only if the clinical 
assessment and local laboratory test values are acceptable. Trastuzumab 
emtansine will be administered either in q3w cycles (patients with mBC) or qw 
cycles (patients with mGC) if no additional time is required for resolution of 
toxicity. Dose delays and dose reductions will be allowed for trastuzumab 
emtansine as outlined in Section 5.1.5. 
If the timing of a protocol-mandated procedure coincides with a holiday and/or 
weekend that precludes the procedure within the allotted window, the 
procedure should be performed on the nearest following date (i.e., within 
3 business days). 
4.5.1.1 
Medical History and Demographic Data 
Medical history includes 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 race/ethnicity 
(unless not allowed per local regulations). 
4.5.1.2 
Vital Signs 
Vital signs will include measurements of weight, respiratory rate, heart rate, 
blood pressure, and temperature. Abnormal or significant changes to vital 
signs from baseline should be recorded as AEs, if appropriate. 
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4.5.1.3 
Physical Examinations 
A complete physical examination should include the evaluation of head, eye, 
ear, nose, and throat; cardiovascular; dermatological; musculoskeletal; 
respiratory; gastrointestinal; and neurological systems. Changes from 
baseline abnormalities should be recorded at each subsequent physical 
examination. New or worsened abnormalities should be recorded as AEs if 
appropriate. 
As part of the tumor assessment, physical examinations should also include 
the evaluation of the presence and degree of enlarged lymph nodes, 
hepatomegaly, and splenomegaly. 
Limited physical examinations will be symptom-directed. 
4.5.1.4 
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 
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 (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 (see Appendix 3). 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 (see Appendix 4). 
Radiographic imaging should always be performed rather than clinical 
examination unless the lesion(s) being followed cannot be imaged but is 
assessable by clinical examination. In applying RECIST, documentation by 
color photography including a ruler to estimate the size of the lesion is 
recommended. 
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4.5.1.5 
Laboratory Assessments 
For Patients with mBC: 
Local Laboratory Assessments: 
• 
Hematology, biochemistry, coagulation, urinalysis, and pregnancy testing 
• 
Prospective or retrospective HER2 status. Patients will be enrolled based 
on local results. 
Central Laboratory Assessments: 
• 
Retrospective HER2 status. Retrospective central confirmation will not 
impact the treatment decisions or primary endpoint of Phase I, Cohort 1 
and will be used to validate efficacy analyses in Phase I and to define 
subgroups for efficacy analyses in the Randomized Phase II part of the 
study 
• 
PK assays: 
– 
Serum trastuzumab emtansine concentration and total trastuzumab using 
a validated immunoassay 
– 
Serum capecitabine and 5-FU PK samples 
– 
Plasma concentration of DM1 using a validated liquid chromatography 
electrospray tandem mass spectrometry (LC-MS/MS) method 
For Patients with mGC: 
Local Laboratory Assessments: 
• 
Hematology, biochemistry, coagulation, urinalysis, and pregnancy testing 
Central Laboratory Assessments: 
• 
Prospective HER2 status. Patients will be enrolled based on the central 
testing results 
• 
PK assays: 
– 
Serum trastuzumab emtansine concentration and total trastuzumab using 
a validated immunoassay 
– 
Serum capecitabine and 5-FU PK samples 
– 
Plasma concentration of DM1 using a validated LC-MS/MS method 
4.5.1.6 
Electrocardiograms 
A 12-lead ECG should be obtained at baseline and be printed and kept with 
the patient’s record. 
4.5.1.7 
ECOG Performance Status 
Performance status will be measured using the ECOG performance status 
scale (see Appendix 6). 
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It is recommended, where possible, that a patient’s performance status be 
assessed by the same person throughout the study. 
Performance status will be assessed according to the schedule of 
assessments (see Appendix 1). 
4.5.1.8 
ECHO/MUGA 
ECHO is the preferred modality because of the global technetium (Tc-99m) 
shortage (see Appendix 4). The same method used at screening should be 
used throughout the study. 
4.5.2 
TIMING OF STUDY ASSESSMENTS 
4.5.2.1 
Screening and Pretreatment Assessments 
Written informed consent for participation in the study must be obtained 
before performing any study-specific screening tests or evaluations. Informed 
Consent Forms for enrolled patients and for patients who are not 
subsequently enrolled will be maintained at the study site. 
Once the patient has signed the Informed Consent Form, the investigator (or 
his or her designee) will call the IxRS to obtain the screening number for the 
patient prior to Cycle 1, Day 1. 
Results of standard of care tests or examinations performed prior to obtaining 
informed consent and within 28 days prior to study start may be used; such 
tests do not need to be repeated for screening. Patients must have stable 
LFTs before the first dose of study drug. 
All screening evaluations must be completed and reviewed to confirm that 
patients meet all eligibility criteria before study start. 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. 
Patients in Cohort 1 will not contribute to Phase II; however, they will be 
followed up until EOS. In the Randomized Phase II part, patients will be 
randomized in a 1:1 ratio to receive trastuzumab emtansine alone or the 
combination of trastuzumab emtansine and capecitabine prior to receiving the 
first dose of study medication. 
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. 
Please see Appendix 1 for the schedule of screening assessments. 
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4.5.2.2 
Assessments during Treatment 
For Patients with mBC 
Scheduled study visits are based on a q3w cycle, with Cycle 1 beginning at 
Day 1. All visits must occur within ± 3 business days from the scheduled date, 
unless otherwise noted in the schedule of assessments. All assessments will 
be performed on the day of the specified visit unless a time window is 
specified. Assessments scheduled on the day of study treatment 
administration should be performed prior to study treatment administration 
unless otherwise noted. If the timing of a protocol-mandated procedure 
coincides with a holiday and/or weekend, it should be performed on the 
nearest following date (i.e., within 3 business days). 
Local laboratory assessments scheduled for Day 1 of all cycles must be 
performed within 72 hours prior to study treatment administration unless 
otherwise specified. Results of local laboratory assessments must be 
reviewed and the review documented prior to study treatment administration. 
Please see Appendix 1 for the schedule of treatment period assessments. 
For Patients with mGC 
Scheduled study visits are based on a qw cycle, with Cycle 1 beginning at 
Day 1. All visits must occur within ± 3 business days from the scheduled date, 
unless otherwise noted in the schedule of assessments. All assessments will 
be performed on the day of the specified visit unless a time window is 
specified. Assessments scheduled on the day of study treatment 
administration should be performed prior to study treatment administration 
unless otherwise noted. If the timing of a protocol-mandated procedure 
coincides with a holiday and/or weekend, it should be performed on the 
nearest following date (i.e., within 3 business days). 
Local laboratory assessments scheduled for Day 1 of all cycles must be 
performed within 72 hours prior to study treatment administration unless 
otherwise specified. Results of local laboratory assessments must be 
reviewed and the review documented prior to study treatment administration. 
Please see Appendix 1 for the schedule of treatment period assessments. 
4.5.2.3 
Assessments at Study Completion/Early Termination Visit 
Patients may remain on study treatment until investigator-assessed PD, 
unacceptable toxicity, withdrawal of consent, death, reasons deemed by the 
treating physician, or study termination by the Sponsor. Patients who 
discontinue study treatment will be followed up until EOS and will be asked to 
return to the clinic approximately 28–42 days after the last study treatment 
administration for the safety follow-up visit. 
Please see Appendix 1 for assessments to be performed at the safety follow-
up visit. 
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4.5.2.4 
Follow-up Assessments 
After the Study Treatment Discontinuation Visit, all patients (regardless of 
reason for discontinuation) will have survival status and anti-cancer therapies 
recorded and will be followed for all unresolved study-related AEs and SAEs 
until their resolution or stabilization, the patient is lost to follow-up or dies, 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. 
Patients who discontinue study drugs for any reason other than PD or 
withdrawal of consent (e.g., an AE) will continue to be followed according to 
the tumor assessment schedule until withdrawal of consent, death, or EOS, 
whichever occurs first. 
After the study treatment completion/early termination visit, AEs should be 
followed as outlined in Section 5.5 and 5.6. 
Please see Appendix 1 for the schedule of follow-up assessments. 
4.5.2.5 
Assessments at Unplanned Visits 
In case unplanned visits are required, electronic Case Report Form (eCRF) 
pages will be available to report the information collected during those visits. 
4.6 
PATIENT AND STUDY DISCONTINUATION 
4.6.1 
PATIENT DISCONTINUATION 
Patients have the right to withdraw from the study at any time for any reason. 
The investigator has the right to discontinue a patient from study treatment or 
from the study for any medical condition that the investigator determines may 
jeopardize the patient’s safety if he or she continues in the study, for reasons 
of non-compliance (e.g., missed doses, visits), if the patient becomes 
pregnant, or if the investigator determines it is in the best interest of the 
patient. 
Patients must be withdrawn from study treatment if they become pregnant or 
experience PD defined using RECIST v. 1.1 (Appendix 3). The exception to 
this is patients who develop isolated progression in the brain as described in 
Appendix 3. 
Details of discontinuation due to toxicity are given in Section 5.1. 
Patients who discontinue from study treatment prematurely for any of the 
above reasons will continue to be followed according to Section 4.5.2.4 
“Follow-Up Assessments”. The primary reason for discontinuation must be 
recorded on the appropriate eCRF page. 
4.6.2 
STUDY DISCONTINUATION 
Sections 3.1.1 and 3.2 describe the EOS definition and discontinuation of 
study treatment. Prior to that, the Sponsor has the right to terminate this study 
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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 
• 
Data recording is inaccurate or incomplete. 
5. 
ASSESSMENT OF SAFETY 
Overall safety will be assessed on an ongoing basis during the conduct of the 
study. 
5.1 
SAFETY PLAN 
The safety plan for patients receiving trastuzumab emtansine is based on the 
toxicities of trastuzumab emtansine observed in nonclinical studies; the 
toxicities related to its components (trastuzumab and maytansine, the parent 
drug of DM1) observed in clinical studies; and the clinical experience with this 
molecule in completed and ongoing studies. Please refer to the trastuzumab 
emtansine and capecitabine (Xeloda®) Investigator’s Brochures for the most 
recent information. 
All patients will be monitored closely for toxicity. The important safety issues 
anticipated in this trial, as well as measures intended to avoid or minimize 
such toxicities, are outlined in the following sections. 
5.1.1 
RISKS ASSOCIATED WITH TRASTUZUMAB EMTANSINE 
Full details regarding the clinical safety of trastuzumab emtansine are 
presented in Sections 5 and 6 of the Investigator’s Brochure. 
5.1.1.1 
Cardiotoxicity 
Patients treated with trastuzumab emtansine are at increased risk of 
developing left ventricular dysfunction. LVEF < 40% has been observed in 
patients treated with trastuzumab emtansine. Patients without significant 
cardiac history and with an LVEF ≥ 50% determined by ECHO or MUGA scan 
are eligible for study participation. LVEF will be monitored at screening and 
regularly throughout the study until the assessment at the safety follow-up 
visit. Patients with symptomatic cardiac dysfunction will be discontinued from 
study treatment. Asymptomatic LVEF declines will be handled according to 
the algorithm shown in Figure 6. Treatment with trastuzumab emtansine has 
not been studied in patients with LVEF < 50%. 
5.1.1.2 
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 
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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 central nervous system 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. 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 
allowed according to and at the discretion of the treating physician. 
5.1.1.3 
Hepatotoxicity 
Hepatotoxicity, predominantly in the form of asymptomatic increases in the 
concentrations of serum transaminases (Grade 1−4 transaminitis), has been 
observed in patients while on treatment with trastuzumab emtansine in clinical 
trials. Transaminase elevations were generally transient. A cumulative effect 
of trastuzumab emtansine on transaminases has been observed; elevated 
transaminases improved to Grade 1 or normal within 30 days of the last dose 
of trastuzumab emtansine in the majority of the patients. 
Serious hepatobiliary disorders, including nodular regenerative hyperplasia 
(NRH) of the liver and some resulting in fatal liver failure, have been observed 
in patients treated with trastuzumab emtansine in clinical trials. Some of the 
observed cases may have been confounded by comorbidities and/or 
concomitant medications with known hepatotoxic potential. Liver function 
should be monitored before initiation of treatment and each trastuzumab 
emtansine dose. 
 
Trastuzumab emtansine has not been studied in patients with serum 
transaminases > 2.5 × ULN or total bilirubin > 1.5 × ULN before initiation of 
treatment. Trastuzumab emtansine treatment in patients with serum 
transaminases > 3 × ULN and concomitant total bilirubin > 2 × ULN should be 
permanently discontinued. 
Cases of NRH of the liver have been identified from liver biopsies in patients 
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 
hypertension. Diagnosis of NRH can only be confirmed by histopathology. 
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. 
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5.1.1.4 
Pulmonary Toxicity 
Cases of interstitial lung disease (ILD), including pneumonitis, some leading 
to acute respiratory distress syndrome or fatal outcome, have been reported 
in clinical trials with trastuzumab emtansine. Signs and symptoms include 
dyspnea, cough, fatigue, and pulmonary infiltrates. These events may or may 
not occur as sequelae of infusion reactions. 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. 
5.1.1.5 
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. Pre-medication 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. 
5.1.1.6 
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 
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does not resolve to Grade ≤ 2 within 42 days after last dose received will be 
discontinued from study treatment. 
5.1.1.7 
Extravasation 
In trastuzumab emtansine clinical studies, reactions secondary to 
extravasation have been observed. These reactions were usually mild and 
comprised erythema, tenderness, skin irritation, pain, or swelling at the 
infusion site. Rare reports of more severe events such as cellulitis, pain 
(tenderness and burning sensation), and skin irritation have been received as 
part of the continuing surveillance of trastuzumab emtansine safety. These 
reactions have been observed more frequently within 24 hours of infusion. 
Specific treatment for trastuzumab emtansine extravasation is unknown at this 
time. The infusion site should be closely monitored for possible subcutaneous 
infiltration during drug administration. 
5.1.1.8 
Trastuzumab Emtansine Dose Modification 
Trastuzumab emtansine dose modifications are described in Section 5.1.5.1. 
5.1.2 
RISKS ASSOCIATED WITH CAPECITABINE 
Patients treated with capecitabine should be carefully monitored for toxicity. 
Most AEs are reversible and do not require permanent discontinuation of 
therapy (please refer to the Xeloda® SmPC for more information). 
The spectrum of cardiotoxicity observed with capecitabine is similar to that of 
other fluorinated pyrimidines. This includes myocardial infarction, angina, 
dysrhythmias, cardiac arrest, cardiac failure and electrocardiographic changes. 
These AEs may be more common in patients with a prior history of coronary 
artery disease. 
A rare, unexpected, severe toxicity (e.g. stomatitis, diarrhea, neutropenia, and 
neurotoxicity) associated with 5-FU has been attributed to deficiency of DPD 
activity. Therefore, a link between decreased levels of DPD and increased, 
potentially fatal, toxic effects of 5-FU cannot be excluded. 
Capecitabine can induce hand-foot syndrome (palmar-plantar 
erythrodysesthesia or chemotherapy-induced acral erythema), which is a 
cutaneous toxicity. For patients receiving capecitabine monotherapy in the 
metastatic setting, the median time to onset was 79 days (range 11–360 
days), with a severity range of Grades 1 to 3. Grade 1 hand-foot syndrome is 
defined by numbness, dysesthesia/paresthesia, tingling or erythema of the 
hands and/or feet and/or discomfort which does not disrupt normal activities. 
Grade 2 is defined as painful erythema and swelling of the hands and/or feet 
and/or discomfort affecting the patient’s activities of daily living (ADL). Grade 
3 is defined as moist desquamation, ulceration, blistering or severe pain of the 
hands and/or feet and/or severe discomfort that causes the patient to be 
unable to work or perform ADL. If Grade 2 or 3 hand-foot syndrome occurs, 
administration of capecitabine should be interrupted until the event resolves or 
decreases in intensity to Grade 1. Following Grade 3 hand-foot syndrome, 
subsequent doses of capecitabine should be decreased. 
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Capecitabine can induce hyperbilirubinemia. Administration of capecitabine 
should be interrupted if treatment-related elevations in bilirubin of > 3.0 × ULN 
or treatment-related elevations in hepatic aminotransferases (ALT/AST) 
of Grade ≥ 2 occur.  
Capecitabine can induce severe skin reactions such as Stevens-Johnson 
syndrome and toxic epidermal necrolysis. Capecitbaine should be 
permanently discontinued in patients who experience a severe skin reaction 
during treatment. 
5.1.3 
RISKS ASSOCIATED WITH TRASTUZUMAB EMTANSINE AND 
CAPECITABINE COMBINATION 
The two DLTs observed in Phase I, Cohort 1 (in mBC) were grade 3 vomiting 
in one patient and grade 3 elevated AST and ALT in one patient (see Section 
3.1.1.2). Both patients were treated at dose level 1 (capecitabine 750 mg/m2 
bid, days 1–14) in combination with trastuzumab emtansine 3.6 mg/kg q3w). 
During Phase I in LA/mGC, DLTs for the combination of trastuzumab 
emtansine and capecitabine will be observed during Cycle 1 (Days 1–21) of 
this study. The combination treatment must be considered as a new treatment 
during Cycle 1, and no individual dose reduction will be allowed during Cycle 
1; the general DLT rules will be used instead. Interruptions can be made due 
to toxicities considered by the investigator to be related to capecitabine. 
Grade 2–4 toxicities should be interrupted until resolved to Grade 0–1. For 
Grade 4 toxicities, consideration to discontinue treatment with capecitabine 
will be made with the adjudication of the SC.  
5.1.4 
DEFINITION OF DOSE-LIMITING TOXICITY 
DLTs will be observed during Cycle 1 (Day 1–21). Please refer to the Xeloda® 
SmPC for recommendations on dose reduction in subsequent cycles. 
Definition of DLT: 
Hematologic 
1. Uncomplicated Grade 4 thrombocytopenia that does not recover 
to ≥ 75,000/Ml before Day 21 
2. Thrombocytopenia (any grade) complicated with clinically significant 
bleeding requiring medical intervention, such as platelet transfusion or 
cauterization. However, patients with Grade 1 or 2 epistaxis may have 
cauterization and this should not be considered as a DLT. 
3. Grade 4 neutropenia lasting > 7 consecutive days 
4. Febrile neutropenia with an ANC of < 1,000 cells/mm3 
Non-hematologic 
5. Grade ≥ 3 diarrhea that does not decrease to Grade ≤ 2 after 24 hours 
of starting recommended anti-diarrheal treatment 
6. Grade 3 hand-foot syndrome (Grade 4 not applicable)  
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7. Any other treatment-related toxicity Grade ≥ 3 prohibiting the start of the 
second cycle on Day 22 (3 weeks cycle length plus 1 day) 
NOTE: If a Grade 2 event requires a dose delay, it will not be considered as a 
DLT. However, if the toxicity does not resolve to Grade 1 or baseline by 
Day 42, this requires discontinuation and will be considered as a DLT. 
8. Grade 2 toxicity requiring interruption of treatment for > 14 days 
NOTE: Patients experiencing Grade ≥ 3 hand-foot syndrome, diarrhea, 
mucositis, or febrile neutropenia with ANC < 500 cells/mm3 during Cycle 1 
must be tested for DPD deficiency (a central laboratory will be appointed). 
The SC will adjudicate in cases of DLTs that are not covered by the existing 
DLT criteria. 
9. Having taken < 14 full doses of capecitabine due to toxicity 
10. Patient not able to receive 100% of the dose level going into Cycle 2, 
Day 1 
5.1.5 
MANAGEMENT OF SPECIFIC ADVERSE EVENTS 
5.1.5.1 
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 those specified 
below (i.e., infusion reactions, thrombocytopenia, hepatotoxicity, neurotoxicity, 
cardiotoxicity, and ILD or pneumonitis) are as follows: 
• 
If significant trastuzumab emtansine-related toxicities (other than infusion 
reactions, thrombocytopenia, hepatotoxicity, neurotoxicity, and 
cardiotoxicity) 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 re-
evaluated qw during the delay, whenever possible. If dosing resumes, the 
patient may receive trastuzumab emtansine either at the same dose level 
as before or at one dose level lower (see Table 2 and Table 3), at the 
discretion of the investigator. Subsequent cycles should remain the same 
(q3w or qw), and patients should be assessed for toxicity. 
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• 
If a patient requires a dose reduction, dosing will be reduced by one dose 
level, per Table 2or Table 3. No dose re-escalation will be allowed. 
• 
If 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 
PD 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  
(Patients with mBC) 
 
Dose Level 
q3w Schedule 
0 
3.6 mg/kg 
 - 1 
3.0 mg/kg 
 - 2 
2.4 mg/kg 
Indication for 
further dose 
reduction 
Off study treatment 
q3w = every 3 weeks 
 
Table 3 Dose Reductions for Trastuzumab Emtansine  
(Patients with mGC) 
 
Dose Level 
qw Schedule 
0 
2.4 mg/kg 
 - 1 
2.0 mg/kg 
 - 2 
Off study 
Indication for 
further dose 
reduction 
Off study 
qw = weekly 
 
In case of toxicities requiring the discontinuation of trastuzumab emtansine, 
the patient will be followed-up until the EOS. 
Protocol requirements for specific toxicities are outlined below. 
5.1.5.1.1 
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. 
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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 
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.  
5.1.5.1.2 
Trastuzumab Emtansine Dose Modification for 
Hepatotoxicity 
5.1.5.1.2.1 
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, activated 
partial thromboplastin time [aPTT], INR, and albumin) will be entered into the 
clinical database. 
5.1.5.1.2.2 
Nodular regenerative hyperplasia  
Trastuzumab emtansine must be permanently discontinued in patients who 
are diagnosed with NRH. 
5.1.5.1.2.3 
Transaminase elevations or bilirubin elevation requiring 
dose adjustment 
Patients who experience a Grade 3 elevation of liver function should be 
checked twice weekly for the recovery of transaminases and/or total bilirubin. 
If a patient’s transaminases and/or total bilirubin do not recover according to 
Table 4 and Table 5, 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 4 and Table 5 describe the dose modification guidelines for increases in 
serum bilirubin and transaminases, respectively. 
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Table 4 Trastuzumab Emtansine Dose Modification: Total Serum 
Bilirubin 
 
Grade 2 
(> 1.5 to ≤ 3 × ULN) 
Grade 3 
(> 3 to ≤ 10 × ULN) 
Grade 4 
(> 10 × ULN) 
Do not administer  
trastuzumab emtansine 
until total bilirubin 
recovers to Grade ≤ 1, 
and then treat at the 
same dose level 
Do not administer  
trastuzumab emtansine 
until total bilirubin 
recovers to Grade ≤ 1 
and then reduce one 
dose level 
Discontinue 
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. 
 
Table 5 Trastuzumab Emtansine Dose Modification: Serum ALT or AST 
 
Grade 2 
(> 3 to ≤ 5 × ULN) 
Grade 3 
(> 5 to ≤ 20 × ULN) 
Grade 4 
(> 20 × ULN) 
Treat at the same dose 
level 
 
Do not administer trastuzumab 
emtansine until AST/ALT 
recovers to Grade ≤ 2, and 
then reduce one dose level 
Discontinue 
trastuzumab 
emtansine 
ALT = alanine transaminase; AST = aspartate transaminase; 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. 
5.1.5.1.3 
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. 
5.1.5.1.4 
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. 
Ejection fractions will be monitored during the last week of Cycle 1, Cycle 3 
and every third cycle thereafter until the assessment at the safety follow-up 
visit. 
Figure 6 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 
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will be discontinued in any patient who develops symptomatic CHF. CHF 
should be treated and monitored according to standard medical practice. 
The decision to stop or continue trastuzumab emtansine should be based on 
the algorithm shown in Figure 6. 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. 
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Figure 6 Algorithm for Continuation and Discontinuation of 
Trastuzumab Emtansine Based on Left Ventricular Ejection 
Fraction Assessments in Patients 
 
 
CHF = congestive heart failure; 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. 
 
5.1.5.1.5 
Trastuzumab Emtansine Dose Modification/Management for 
Infusion-related Reactions, Hypersensitivity Reactions 
Trastuzumab emtansine treatment should be interrupted in patients with 
severe infusion-related reactions. Trastuzumab emtansine treatment should 
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. 
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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. Pre-medication 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. In the event of a true hypersensitivity 
reaction (i.e., if the severity of reaction increases with subsequent infusions), 
trastuzumab emtansine treatment must be permanently discontinued. Patients 
who experience a Grade ≥ 3 hypersensitivity reaction or acute respiratory 
distress syndrome (ARDS) will be discontinued from the study. 
Patients who experience a severe delayed infusion reaction will be 
discontinued from study treatment.  
5.1.5.1.6 
Trastuzumab Emtansine Dose Modification for Pulmonary 
Toxicity 
Cases of ILD, including pneumonitis (including severe, life-threatening cases) 
and some leading to ARDS or fatal outcome have been reported with 
trastuzumab emtansine. Treatment with trastuzumab emtansine has to be 
permanently discontinued in patients who are diagnosed with ILD or 
pneumonitis.  
5.1.5.1.7 
Trastuzumab Emtansine Dose Modification for 
Extravasation 
During the clinical development of trastuzumab emtansine, reactions 
secondary to extravasation have been observed. These reactions were 
usually mild and consisted of erythema, tenderness, skin irritation, pain or 
swelling at the infusion site. Although trastuzumab emtansine is not 
considered as a vesicant, close monitoring of the infusion site for possible 
subcutaneous infiltration during drug administration is recommended. 
5.1.5.2 
Capecitabine Dosage Modification 
Phase I: Patients with mBC 
The dose of capecitabine can be modified from Cycle 2 onwards if considered 
appropriate by the investigator (please refer to the Xeloda® SmPC for 
recommendations). 
In case of toxicities requiring the discontinuation of capecitabine, single-agent 
trastuzumab emtansine may be continued in patients with mBC. 
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Randomized Phase II: Exploration of Efficacy and Safety in mBC  
During the Randomized Phase II part of the study, the dose of capecitabine 
will be modified according to the Xeloda® SmPC. 
In case of toxicities requiring the discontinuation of capecitabine, single-agent 
trastuzumab emtansine may be continued in patients with mBC. 
Phase I: Patients with mGC 
The dose of capecitabine can be modified from cycle 2 onwards if considered 
appropriate by the investigator (please refer to Xeloda® SmPC for 
recommendations). 
In case of toxicities requiring the discontinuation of capecitabine, single-agent 
trastuzumab emtansine may be continued (see Section 3.1.1).  
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording protocol-defined 
AEs and SAEs; measurement of protocol-specified hematology, clinical 
chemistry, and urinalysis variables; measurement of protocol-specified vital 
signs; and other protocol-specified tests that are deemed critical to the safety 
evaluation of the study drug(s). 
The Sponsor or its designee is responsible for reporting relevant SAEs to the 
Competent Authority, other applicable regulatory authorities, and participating 
investigators, in accordance with International Conference on Harmonisation 
(ICH) guidelines, FDA regulations, European Clinical Trials Directive 
(Directive 2001/20/EC), and/or local regulatory requirements. 
The Sponsor or its designee is responsible for reporting unexpected fatal or 
life-threatening events associated with the use of the study drug to the 
regulatory agencies and competent authorities by telephone or fax within 7 
calendar days after being notified of the event. The Sponsor or its designee 
will report other relevant SAEs associated with the use of the study 
medication to the appropriate competent authorities (according to local 
guidelines), investigators, and central Institutional Review Boards/Ethics 
Committees (IRBs/ECs) by a written safety report within 15 calendar days of 
notification. 
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 
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• 
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 it occurred in a more severe form 
or was allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.8) 
• 
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) 
• 
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 
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(see Section 5.4.2 for reporting instructions) regardless of the attribution of 
causality. AESIs for this study include the following: 
• 
Potential drug-induced liver injury 
Any case of potential 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 with 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: 
• Defined as any organism, virus, or infectious particle (e.g., prion protein 
transmitting transmissible spongiform encephalopathy), both pathogenic 
and non-pathogenic. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings indicating an 
infection in a patient exposed to a medicinal product. This term ONLY 
applies when a contamination of the study drug is suspected, NOT for 
infections supported by the mode of action, e.g., immunosuppression. 
5.2.4 
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 7 months following last 
dose of study drug (follow-up period based on PK considerations). 
Trastuzumab, a component of trastuzumab emtansine, can cause fetal harm 
when administered to a pregnant woman; postmarketing 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 
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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 
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. 
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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 or partner of a male 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, including the partners of male patients, to the Sponsor within 24 
hours. 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. 
Experimental studies have reported that IgGs are present in both the pre-
ejaculate and the seminal plasma.47 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 AE 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 AE eCRF, the investigator will make an 
assessment of seriousness (see Section 5.2.2, for seriousness criteria), 
severity (see Section 5.3.3), and causality (see Section 5.3.4). 
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5.3.1 
ADVERSE EVENT REPORTING PERIOD 
Investigators will seek information on AEs at each patient contact. All AEs, 
whether reported by the patient or noted by study personnel, will be recorded 
in the patient’s medical record and on the AE eCRF. 
After informed consent has been obtained but prior to initiation of study drug, 
only SAEs caused by a protocol-mandated intervention (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 treatment, all AEs, regardless of relationship to study 
drug, will be reported until 28 days after the last administration of study drug. 
After this period, the investigator is not required to actively monitor for AEs; 
however, the Sponsor should be notified if the investigator becomes aware of 
any poststudy SAEs (see Section 5.6). 
5.3.2 
ELICITING ADVERSE EVENT INFORMATION 
A consistent methodology of non-directive questioning should be adopted for 
eliciting AE information at all patient evaluation time points. Examples of non-
directive questions include the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last 
here?” 
5.3.3 
ASSESSMENT OF SEVERITY OF ADVERSE EVENTS 
The AE grading (severity) scale found in the NCI CTCAE (v. 4.0) will be used 
for assessing AE severity (see Table 6). 
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Table 6 Adverse Event Severity Grading Scale 
 
Grade 
Severity 
Alternate Description a 
1 
Mild (apply event-specific 
NCI CTCAE grading criteria) 
Asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated 
2 
Moderate (apply event-specific  
NCI CTCAE grading criteria) 
Minimal, local or non-invasive intervention 
indicated; limiting age-appropriate instrumental 
ADLb 
3 
Severe (apply event-specific  
NCI CTCAE grading criteria) 
Severe or medically significant but 
not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; 
disabling; limiting self-care ADLc 
4 
Very severe, life-threatening,  
or disabling (apply event-specific 
NCI CTCAE grading criteria) 
Life-threatening consequences; 
urgent intervention indicated 
5 
Death related to AE 
 
ADL = activities of daily living; AE = adverse event; CTCAE = Common Terminology Criteria for 
Adverse Events; NCI = National Cancer Institute. 
The NCI CTCAE v4.0 can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
Note: Regardless of severity, some events may also meet regulatory seriousness criteria. Refer 
to definition of a serious AE (see Section 5.2.2). 
a Use these alternative definitions for Grade 1, 2, 3, and 4 events when the observed or 
reported AE is not in the NCI CTCAE listing. 
b Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
c Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
 
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 7. 
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Table 7 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 serious AEs 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. 
5.3.5 
PROCEDURES FOR RECORDING ADVERSE EVENTS 
Investigators should use correct medical terminology/concepts when 
recording AEs on the AE eCRF. Avoid colloquialisms and abbreviations. 
There is one eCRF page for recording AEs or SAEs. 
Only one AE term should be recorded in the event field on the AE eCRF. 
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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-related reaction. However, a diagnosis has to be captured 
as an AE if signs and symptoms constitute a diagnosis of allergic 
reaction/hypersensitivity or infusion-related reaction and are classified as 
SAEs; all such symptoms have to be described in the narrative (e.g., in the 
Additional Case Details field of the eCRF). 
Other Adverse Events 
For AEs other than infusion-related reactions, a diagnosis (if known) should 
be recorded on the AE eCRF rather than individual signs and symptoms (e.g., 
record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or 
syndrome at the time of reporting, each individual event should be recorded 
on the AE eCRF. If a diagnosis is subsequently established, all previously 
reported AEs based on signs and symptoms should be nullified and replaced 
by one AE report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis. 
5.3.5.2 
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 AE 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 AE eCRF should be 
updated to reflect this. 
A recurrent AE is one that resolves between patient evaluation time points 
and subsequently recurs. Each recurrence of an AE should be recorded 
separately on the AE eCRF. 
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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. 
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 
mBC or mGC 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 AE eCRF and immediately reported to 
the Sponsor (see Section 5.4.2). The IDMC will monitor the frequency of 
death from all causes. 
Death should be considered an outcome and not a distinct event. The event 
or condition that caused or contributed to the fatal outcome should be 
recorded as the single medical concept on the AE eCRF. Generally, only one 
such event should be reported. If the cause of death is unknown and cannot 
be ascertained at the time of reporting, “unexplained death” should be 
recorded on the AE eCRF. If the cause of death later becomes available (e.g., 
after autopsy), “unexplained death” should be replaced by the established 
cause of death.  
During post-study survival follow-up, deaths attributed to progression of mBC 
or LA/mGC 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 start of this study. 
Such conditions should be recorded on the Medical and Surgical History 
eCRF. 
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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 AE 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 Clinical Worsening 
Events that are clearly consistent with the expected pattern of progression of 
mBC or LA/mGC 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 the RECIST criteria. 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 PD, 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 
planned hospitalization or prolonged hospitalization to: 
• 
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 THE 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: 
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• 
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 (SPONSOR’S 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"). 
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 immediately (i.e., no more than 24 hours) 
on the AE eCRF and submit the report via the electronic data capture (EDC) 
system. A report will be generated and sent to 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 immediately 
(i.e., no more than 24 hours) after learning of the event, using the fax 
numbers provided to investigators (see "Protocol Administrative and Contact 
Information & List of Investigators"). Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system. 
5.4.3 
REPORTING REQUIREMENTS FOR PREGNANCIES 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately 
inform the investigator if they become pregnant during the study or within 7 
months after the last dose of study drug. A Pregnancy Report eCRF should 
be completed by the investigator immediately (i.e., no more than 24 hours) 
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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 AE eCRF. 
The investigator should have the patient discontinue the study drug and 
discuss with the patient the risks of the pregnancy and the possible effects on 
the fetus. Monitoring of the patient should continue until conclusion of the 
pregnancy. 
In the event that the EDC system is unavailable, a Pregnancy Report 
worksheet and Pregnancy Fax Coversheet should be completed and faxed to 
the Sponsor Safety Risk Management or its designee immediately (i.e., no 
more than 24 hours) after learning of the pregnancy, using the fax numbers 
provided to investigators (see "Protocol Administrative and Contact 
Information & List of Investigators"). 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to 
immediately inform the investigator if their partner becomes pregnant during 
the study or within 7 months after the last dose of study drug. A Pregnancy 
Report eCRF should be completed by the investigator immediately (i.e., no 
more than 24 hours) after learning of the pregnancy and submitted via the 
EDC system. Attempts should be made to collect and report details of the 
course and outcome of any pregnancy in the partner of a male patient 
exposed to study drug. The pregnant partner will need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow 
for follow-up on her pregnancy. Once the authorization has been signed, the 
investigator will update the Pregnancy Report eCRF with additional 
information on the course and outcome of the pregnancy. An investigator who 
is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, 
to support an informed decision in cooperation with the treating physician 
and/or obstetrician. 
In the event that the EDC system is unavailable, follow reporting instructions 
provided in Section 5.4.3.1. 
5.4.3.3 
Abortions 
Any spontaneous abortion should be classified as an SAE (as the Sponsor 
considers spontaneous abortions to be medically significant events), recorded 
on the AE eCRF, and reported to the Sponsor immediately (i.e., no more than 
24 hours) after learning of the event (see Section 5.4.2). 
5.4.3.4 
Congenital Anomalies/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 
an SAE, recorded on the AE eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours) after learning of the event (see Section 5.4.2). 
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5.5 
FOLLOW-UP OF PATIENTS AFTER 
ADVERSE EVENTS 
5.5.1 
INVESTIGATOR FOLLOW-UP 
The investigator should follow all unresolved AEs and until the events are 
resolved or stabilized, the patient is lost to follow-up, or it has been determined 
that the study treatment or participation is not the cause of the AE/SAE. 
Resolution of AEs and SAEs (with dates) should be documented on the AE 
eCRF and in the patient’s medical record to facilitate source data verification 
(SDV). 
All pregnancies reported during the study should be followed until pregnancy 
outcome. If the EDC system is not available at the time of pregnancy outcome, 
follow reporting instructions provided in Section 5.4.3.1. 
5.5.2 
SPONSOR FOLLOW-UP 
For SAEs, non-serious 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 
At the time of study completion or study discontinuation, the investigator 
should instruct each patient to report to the investigator any subsequent AEs 
that the patient’s physician believes could be related to prior study drug 
treatment or study procedures. 
The investigator is not required to actively monitor patients for AEs after the 
end of the AE reporting period (defined as 28 days after the last dose of study 
drug). However, the Sponsor should be notified if the investigator becomes 
aware of any death or other SAE occurring after the end of the AE reporting 
period, regardless of causality.  
The investigator should report these events directly to Roche Safety Risk 
Management via telephone or via facsimile using the Roche Clinical Trial 
(SAE) Reporting Form. 
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 following reference 
documents: 
• 
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The Sponsor will compare the severity of each event and the cumulative 
event frequency reported for the study with the severity and frequency 
reported in the applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of 
causality and seriousness, with allowance for upgrading by the Sponsor as 
needed. 
The IDMC will closely monitor the incidence of these expected events during 
the study. An aggregate report of any clinically relevant imbalances that do 
not favor the test product will be submitted to health authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
PLAN 
The design of this study includes: Phase I, Randomized Phase II and different 
cohorts. Corresponding analyses as described in the protocol will be 
performed when all data for a particular cohort and study phase are collected 
and cleaned. 
Phase I: Patients with mBC: 
Enrollment into Cohort 1, patients with HER2-positive mBC, will open first. 
Enrolled patients will receive study drug until Investigator-assessed PD, 
unacceptable toxicity, withdrawal of consent, death, reasons deemed by the 
treating physician, or study termination by the Sponsor. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
Patients randomized in Phase II will receive study drug until investigator-
assessed PD, unacceptable toxicity, withdrawal of consent, death, reasons 
deemed by the treating physician, or study termination by the Sponsor. 
The primary analysis of BOR will be performed when 70% of the patients 
have experienced a PFS event or at the end of the trial, whichever comes first. 
It is estimated that 70% of patients will have experienced a PFS event 
approximately 26 months after the randomization of the first patient.  
The EOS analysis will include an updated analysis of BOR, which will be done 
in a purely exploratory manner.   
Phase I: Patients with mGC: 
Once the MTD is established for Cohort 1, enrollment of patients with HER2-
positive and LA/mGC into Cohort 2 will be opened. 
Enrolled patients will receive study drug until investigator-assessed PD, 
unacceptable toxicity, withdrawal of consent, death, reasons deemed by the 
treating physician, or study termination by the Sponsor. 
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6.1 
DETERMINATION OF SAMPLE SIZE 
Sample Size for Phase I: mBC 
This part will be based on a classical 3 plus 3 Phase I design. A minimum of 6 
and up to 18 patients will be enrolled into Cohort 1. There is no formal sample 
size estimation for this part. 
Sample Size for Randomized Phase II: Exploration of Efficacy and Safety 
in mBC 
The sample size for the primary endpoint BOR is based on a Fisher’s exact 
test with an alpha level of 5% (one-sided),48,49 power of 80% and the clinical 
assumption of a BOR rate of 43% with trastuzumab emtansine alone and 
62.5% with the combination of trastuzumab emtansine and capecitabine. 
Approximately 210 patients (105 patients in each treatment group), including 
a 15% withdrawal rate, will be randomized with a 1:1 ratio to trastuzumab 
emtansine alone or the combination of trastuzumab emtansine and 
capecitabine. 
An expected BOR rate of 43.6% (95% CI: 38.6%–48.6%) for patients 
receiving trastuzumab emtansine alone was chosen based on previously 
published data for T-DM1 in patients with unresectable, locally advanced or 
mBC previously treated with a taxane and trastuzumab (EMILIA study).27 
The BOR rates for patients treated with the combination of T-DM1 and 
capecitabine were chosen based on recent results from other combination 
studies of T-DM1 plus chemotherapy or trastuzumab plus capecitabine. 
Response rates were based on those observed in patients with HER2-positive 
mBC in a Phase Ib/IIa study (BP22752) that compared the combination of 
trastuzumab emtansine with docetaxel, with or without pertuzumab (ORR: 
76% [95% CI: 53%–92%]), and also in a Phase II study that compared the 
combination of trastuzumab with docetaxel, with or without capecitabine 
(ORRs: 72.7% [95% CI: 63.4%–80.8%] and 70.5% [95% CI: 61.2%–
78.8%]).41 
Increased BOR rates for the combination treatment compared with 
single-agent trastuzumab emtansine are in line with previously published 
results of a randomized Phase III study in patients with locally advanced or 
mBC treated with the combination of trastuzumab with capecitabine versus 
capecitabine alone (ORR: 48.1% versus 27.0%, odds ratio = 2.50, p = 
0.0115).9 
The estimation of sample size was performed by Nquery® and EAST® 
programs. 
Stratification Factors 
The following stratification factor will be implemented in the Randomized 
Phase II of the study: 
• 
Number of prior lines of treatment for metastatic disease (≤1 or >1; 
excluding single-agent hormones) 
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A treatment line is any regimen given to a patient from treatment initiation until 
confirmed PD. 
Sample Size for Phase I: mGC 
This part will be based on a classical 3 plus 3 Phase I design. From 3 to 12 
patients might be enrolled into Cohort 2. There is no formal sample size 
estimation for this part. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Phase I: Patients with mBC 
Due to the small sample size, per-protocol (PP) population will not be defined 
for the Phase I, Cohort 1. 
Major protocol violations will be summarized by treatment dosage. Median 
follow-up will be estimated for Phase I, Cohort 1. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
For the Randomized Phase II part of the study, a PP population will be 
defined (Section 6.4).  
Patient enrollment, duration of follow-up, discontinuation from study treatment 
and study, and reasons for study discontinuation will be summarized by 
treatment group for all randomized patients. In addition, major protocol 
violations will be summarized by treatment arm. 
Phase I: Patients with LA/mGC  
Due to the small sample size, a PP population will not be defined for the 
Phase I, Cohort 2. 
Major protocol violations will be summarized by treatment dosage. Median 
follow-up will be estimated for Phase I, Cohort 2. 
6.3 
SUMMARIES OF TREATMENT GROUP 
COMPARABILITY 
Phase I: mBC 
As Phase I is the MTD-Finding part of the study, there are no treatment group 
comparisons for this part of the study. 
Demographics, medical history, and baseline characteristics will be 
summarized. Continuous variables will be summarized using median, mean, 
standard deviation, 25th and 75th percentiles and range. Categorical variables 
will be summarized by the number and percentage of patients for each 
treatment dosage. 
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Randomized Phase II: Exploration of Efficacy and Safety in mBC  
The Randomized Phase II part of the study is designed to explore the efficacy 
and safety of the combination of trastuzumab emtansine and capecitabine 
compared with trastuzumab emtansine alone. 
Demographics, medical history, and baseline characteristics will be 
summarized. Continuous variables will be summarized using median, mean, 
standard deviation, 25th and 75th percentiles and range. Categorical variables 
will be summarized by the number and percentage of patients for each 
treatment group. 
Phase I: mGC 
As Phase I is the MTD-Finding part of the study, there are no treatment group 
comparisons for this part of the study.  
Demographics, medical history and baseline characteristics will be 
summarized. Continuous variables will be summarized using median, mean, 
standard deviation, 25th and 75th percentiles and range. Categorical variables 
will be summarized by the number and percentage for each treatment dosage. 
6.4 
EFFICACY ANALYSES 
Phase I, Cohort 1: mBC 
The main analysis population will be the DLT-evaluable population as defined 
in Section 6.5. 
Randomized Phase II: Exploration of Efficacy in mBC  
The main analysis population for the efficacy analysis will be the intent-to-treat 
population (ITT), which will include all patients in the Randomized Phase II 
part of the study. The PP population will include all ITT patients who have at 
least one post-baseline tumor assessment during the Phase II part and no 
major protocol violations, which will be defined in the statistical analysis plan 
(SAP). 
Phase I, Cohort 2: mGC 
The main analysis population will be the DLT-evaluable population as defined 
in Section 6.5. 
6.4.1 
PRIMARY EFFICACY ENDPOINT 
Phase I, Cohort 1: Patients with mBC  
The primary objectives are defining the MTD and establishing the safety 
profile. The number and the proportion of patients with DLTs will be used as 
the primary measure for the MTD determination. 
ORR, as a main efficacy endpoint, will be assessed via BOR rate. The BOR is 
defined as the best response recorded from the date of enrollment until PD, 
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death, withdrawal of consent, start of new anticancer treatment, or EOS, 
whichever occurs first. The number of patients is very small in this part of the 
study. Therefore, all analyses will be descriptive. 
Randomized Phase II: Exploration of Efficacy in mBC  
The primary efficacy endpoint for the Randomized Phase II part of the study is 
the ORR as assessed via BOR. The BOR is defined as the best response 
recorded from the start or randomization into the Phase II part of the study 
and until PD, death, withdrawal of consent, start of new anticancer treatment, 
or EOS, whichever occurs first. 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 28 days after the 
criteria for response are first met, i.e., patients need to have two consecutive 
assessments of PR or CR.  
The primary hypothesis of interest when comparing ORR – as assessed via 
BOR – between the two treatment groups (combination of trastuzumab 
emtansine and capecitabine versus trastuzumab emtansine alone) is:  
• 
H0: πTDM1 = πtrastuzumab emtansine + capecitabine where πtrastuzumab emtansine is 
BOR in TDM1 and π trastuzumab emtansine + capecitabine is BOR in trastuzumab 
emtansine + capecitabine 
• 
H1: π trastuzumab emtansine ≠ π trastuzumab emtansine + capecitabine  
The number and proportions of responders and non-responders (based on 
BOR) together with 90% Clopper-Pearson CIs will be presented for each 
treatment group.  
The difference in BOR between treatment groups will be displayed with 
associated 90% CIs using the Hauck-Anderson approach and p-values for the 
Fisher’s exact test.  
Logistic analysis will be used to assess the influence of the stratification factor 
and baseline covariates in an exploratory manner. 
The primary analysis of BOR will be performed when 70% of the patients 
have experienced a PFS event or at the end of the trial, whichever comes first. 
It is estimated that 70% of patients will have experienced a PFS event 
approximately 26 months after the randomization of the first patient. 
Phase I, Cohort 2: Patients with LA/mGC 
The primary objectives are defining the MTD and establishing the safety 
profile. The number and the proportion of patients with DLTs will be used as 
the primary measure for the MTD determination. 
ORR, as a main efficacy endpoint, will be assessed via BOR rate. The BOR is 
defined as the best response recorded from the date of enrollment until PD, 
death, withdrawal of consent, start of new anticancer treatment, or EOS, 
whichever occurs first. The number of patients is very small in this part of the 
study. Therefore, all analyses will be descriptive. 
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6.4.2 
SECONDARY EFFICACY ENDPOINTS 
Phase I, Cohort 1: mBC 
Due to the small number of patients and the design of this part of the study, 
no secondary efficacy endpoints will be investigated. 
Randomized Phase II: Exploration of Efficacy in mBC  
The secondary efficacy endpoints for the Randomized Phase II will be: 
• 
TTR 
• 
DoR 
• 
TTP 
• 
TTF 
• 
PFS 
• 
CBR 
• 
OS 
TTR is defined as the time from randomization to first documentation of 
confirmed PR or CR (whichever occurs first). Patients who do not have a 
confirmed response will be censored at the date of the last tumor assessment. 
DoR is defined as the period from the date of first recorded 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. The method for handling censoring is the 
same as described for PFS below. Only patients with a BOR of CR or PR (i.e., 
responders) will be included in the analysis of DoR. 
For patients with a BOR of CR or PR, TTR is defined as the time from 
randomization to the date of first CR or PR. The censoring rules will be similar 
to those of the PFS. 
TTP is defined as time from randomization to the first occurrence of PD. 
Patients who have not progressed at the time of study completion (including 
patients who have died before PD) or who are lost to follow-up are censored 
at the date of the last tumor assessment. 
TTF is defined as time from randomization until treatment failure, i.e., to PD, 
death, withdrawal due to AE or laboratory abnormality, or refusal of treatment. 
Patients who do not experience any of the above events while on study will be 
censored on the day of their last tumor assessment.  
PFS is defined as the time from randomization 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 post-baseline tumor assessment will be 
censored at the time of randomization plus 1 day.  
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OS is defined as the time from randomization until the date of death, 
regardless of the cause of death. Patients who are alive at the time of data 
cut-off will be censored at the date of the last follow-up assessment.  
Estimates for the survivor function of both treatment groups for TTR, DoR, 
TTP, TTF, and OS will be obtained by using the Kaplan-Meier method. HRs 
and associated 90% CIs will be estimated from non-stratified and stratified 
(based on the stratification factor) Cox regression models. 
CBR includes patients whose best (confirmed) response was PR, CR or SD 
that lasted at least 6 months. CBR will be summarized in a similar way to the 
primary efficacy endpoint, ORR as assessed by BOR.  
Phase I, Cohort 2: mGC 
Due to the small number of patients and the design of this part of the study, 
no secondary efficacy endpoints will be investigated. 
6.5 
SAFETY ANALYSES 
Safety Population Phase I, Cohort 1: mBC 
The DLT-evaluable population is defined as all enrolled and treated patients 
who have not experienced any major protocol violation (including violation of 
the inclusion and exclusion criteria) and completed Cycle 1.  
The number and the proportion of patients with DLTs will be used as the 
primary measure for the MTD determination. The definition of DLTs is 
presented in Section 5.1.4. DLTs for this part of the study will be summarized 
by treatment dose. 
The safety population (SP) will include all patients who received at least one 
dose of study medication during Phase I. Safety endpoints will be summarized 
by treatment dosage. 
Safety parameters for this part of the study will be summarized by treatment 
dose. The summaries of AEs, SAEs, AEs that caused discontinuation from 
the study treatment and/or study, and AESIs will be analyzed in a similar way 
to AEs in Phase II. 
The incidence of AEs and SAEs will be summarized according to the primary 
SOC and, within each SOC, by MedDRA preferred term. Based on the safety 
profile of trastuzumab emtansine, time to onset of the first episode of any 
AESI described in Section 5 will also be summarized via Kaplan-Meier 
estimates. Additional summaries by frequency tables will also be provided for 
the AESIs. Patients who died will be listed together with the cause of death. 
Laboratory parameters, hematology and biochemistry will be presented in 
shift tables of NCI-CTC grade at baseline versus worst grade during treatment 
for Phase I, Cohort 2, and overall. 
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LVEF will be summarized over time using mean, median and range (minimum 
and maximum) and will be presented graphically. Vital signs will be analyzed 
in a similar way. 
Other safety variables, such as exposure to study medication, concomitant 
medications and physical examinations will be analyzed in a similar way. The 
exposure of study medication will be summarized by frequency tables. 
ECOG performance status will be summarized over time and the percentage 
of patients in different categories will be presented by bar charts at different 
time points. 
 
Randomized Phase II: Exploration of Safety in mBC  
The SP will include all patients who received at least one dose of study 
medication during the Randomized Phase II part of the study. Safety 
endpoints will be summarized by treatment group.   
Safety endpoints during Phase II will be assessed via total AEs, Grade ≥3 
AEs, SAEs, AESIs (as described in Section 5), fatal AEs and their causes, 
events to monitor, premature withdrawal from study medication and/or study, 
laboratory parameters, LVEF, exposure to study medication, concomitant 
medications, vital signs, ECOG performance status, and physical examination. 
The incidence of AEs and SAEs 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 any AESI 
described in Section 5 will also be summarized via Kaplan-Meier estimates. 
Additional summaries by frequency tables will be provided for the AESIs. 
Patients who died will be listed together with the cause of death. 
Laboratory parameters, hematology, and biochemistry will be presented in 
shift tables of NCI-CTCAE grade at baseline versus worst grade during 
treatment for the Randomized Phase II part of the study. 
LVEF will be summarized over time using mean, median and range (minimum 
and maximum) and will be presented graphically. Vital signs will be analyzed 
in a similar way. 
Other safety variables, such as exposure to study medication, concomitant 
medications and physical examinations, will be analyzed in a similar way. The 
exposure to study medication will be summarized by frequency tables. 
ECOG performance status will be summarized over time and the percentage 
of patients in different categories will be presented by bar charts at different 
time points. 
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Safety Population Phase I, Cohort 2: LA/mGC 
The DLT-evaluable population is defined as all enrolled and treated patients 
who have not experienced any major protocol violation (including violation of 
the inclusion and exclusion criteria) and have completed Cycle 1.  
The number and the proportion of patients with DLTs will be used as the 
primary measure for the MTD determination. The definition of DLTs is 
presented in Section 5.1.4. DLTs for this part of the study will be summarized 
by treatment dose. 
The SP will include all patients who received at least one dose of study 
medication during Phase I. Safety endpoints will be summarized by treatment 
dosage. 
Safety parameters will be analyzed in a similar way to safety parameters in 
Phase I, Cohort 1: mBC. 
6.6 
PHARMACODYNAMIC ANALYSES 
No pharmacodynamic analyses are planned for this study. 
6.7 
PHARMACOKINETIC ANALYSES 
For Phase I only (Patients with mBC and LA/mGC): 
The following PK parameters of trastuzumab emtansine, capecitabine and 
their metabolites (including but not limited to those listed below) will be 
determined only in the Phase I part of the study for Cohort 1 and Cohort 2 in 
all patients who receive study treatment using either non-compartmental 
and/or population methods, if data allow: 
• 
Serum concentrations of trastuzumab emtansine (conjugate) and total 
trastuzumab 
• 
Plasma concentrations of DM1, capecitabine and its active metabolite  
5-FU 
• 
Total exposure (e.g., AUC)  
• 
Cmax 
• 
CL 
• 
Vd 
• 
T1/2 
The PK of trastuzumab emtansine, total trastuzumab and DM1 will be 
compared with historical single-agent PK data to evaluate the potential effect 
of capecitabine on the PK of trastuzumab emtansine and related analytes. 
The PK of capecitabine and its active metabolite 5-FU in Cycle 1 (in the 
absence of trastuzumab emtansine) will be compared with the PK of Cycle 2 
(in the presence of trastuzumab emtansine) to evaluate the potential effect of 
trastuzumab emtansine on the PK of capecitabine and 5-FU. 
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All PK parameters will be listed and tabulated by treatment dose and by 
Cohort. Descriptive summary statistics including arithmetic mean, geometric 
mean (e.g., AUC and Cmax), median, range, s.d., and coefficient of variation 
will be presented for each cohort. Nonlinear mixed effects modeling will also 
be used; details will be presented in the SAP. 
PK samples can be obtained ad hoc in case of a SAE or unexpected toxicities 
which may suggest a potential drug-drug interaction. 
6.8 
EXPLORATORY ANALYSES 
For all patients with mBC (Phase I, cohort 1; Phase II Exploration of Efficacy 
and Safety in mBC), a retrospective central confirmation of the HER2 status 
will be done. Further exploratory analysis for HER2-positive patients (based 
on central confirmation) will be done for selected endpoints such as BOR and 
safety endpoints (AEs, SAEs, Grade ≥ 3 AEs, and AESIs). 
For the Randomized Phase II only: Exploration of Efficacy and Safety in 
Patients with mBC: 
Subgroup analysis for BOR, safety endpoints (AEs, SAEs, Grade ≥ 3 AEs, 
and AESIs) in Phase II will be presented for: elderly versus younger patients, 
patients with ECOG 0–1 versus ECOG 2, and patients with ≤ versus >1 prior 
treatment regimen for metastatic disease.  
More details about subgroups will be provided in the SAP. 
Pharmacoeconomic Endpoint: 
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 
(PD versus AE) will also be assessed. 
6.9 
INTERIM ANALYSES 
There is no formal efficacy interim analysis.  
However, an IDMC will recommend whether the Randomized Phase II part of 
the study can commence. The IDMC will also monitor safety outcomes after 
25, 75, and 150 patients have received at least 3 cycles (Cycle 3 Day 1) of 
treatment in the Randomized Phase II part of the study. Afterwards, the IDMC 
will monitor accumulating patient safety data every 6 months during the 
course of the Randomized Phase II of the study or as requested. 
Efficacy data will be provided only if required by the IDMC to estimate the risk-
benefit balance for the patients. Further details on the function and logistics of 
the IDMC will be provided in the IDMC Charter. 
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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. Central laboratory 
data and other 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 have access to a manual for appropriate eCRF 
completion. eCRFs will be submitted electronically to the Sponsor and should 
be handled in accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff. eCRFs 
should be reviewed and electronically signed and dated by the investigator or 
a designee. 
At the end of the study, the investigator will receive patient data for his or her 
site in a readable format on a compact disc that must be kept with the study 
records. Acknowledgment of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing SDV to confirm that critical protocol data 
(i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are 
recorded and documented for the first time. They include, but are not limited 
to, hospital records, clinical and office charts, laboratory notes, memoranda, 
patient-reported outcomes, evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies of transcriptions 
that are certified after verification as being accurate and complete, microfiche, 
photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
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Source documents that are required to verify the validity and completeness of 
data entered into the eCRFs must not be obliterated or destroyed. 
To facilitate SDV, the investigators and institutions must provide the Sponsor 
with 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. 
In collaboration with the study monitor, 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 Good Clinical Practice (GCP) (see Section 4.9 of the 
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 (IND) application, 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. 
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8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for 
GCP 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 European Union (EU)/European economic area (EEA) will comply with the 
EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
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 Form or any alternate Consent 
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 Form 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, 
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and other processes outlined above apply except that IRB/IEC 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. 
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 
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, 
the Sponsor monitors, representatives, and collaborators, and the IRB/EC for 
each study site, as appropriate. 
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8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to 
submit complete and accurate financial certification or disclosure statements 
to the appropriate health authorities. Investigators are responsible for 
providing information on financial interests during the course of the study and 
for 1 year after completion of the study. 
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 
investigator will permit national and local health authorities, the 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 a SC, IDMC, central laboratory, IxRS, eCRF, and will be 
conducted by a contract research organization (CRO) together with the 
Sponsor. 
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. 
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Any formal publication of the study in which contribution the Sponsor 
personnel exceeded that of conventional monitoring will be considered as a 
joint publication by the investigator and the appropriate the 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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22. Cassady JM, Chan KK, Floss HG, et al. Recent developments in the 
maytansinoid antitumor agents. Chem Pharm Bull (Tokyo) 2004; 52:1–
26. 
23. Cabanillas F, Chan KK, Floss HG, et al. Results of a Phase II study of 
maytansine in patients with breast carcinoma and melanoma. Cancer 
Treat Rep 1979; 63:507–9. 
24. Erickson HK, Park PU, Widdison WC, et al. Antibody-maytansinoid 
conjugates are activated in targeted cancer cells by lysosomal 
degradation and linker-dependent intracellular processing. Cancer Res 
2006; 66:4426–33. 
25. Shen B-Q, Bumbaca D, Saad O, et al. Metabolic fate and 
pharmacokinetic characterization of trastuzumab emtansine (T-DM1): An 
emphasis on preclinical and clinical catabolism. ASCPT 2011. 
26. Hurvitz SA, Dirix L, Kocsis J, et al. Phase II randomized study of 
trastuzumab emtansine versus trastuzumab plus docetaxel in patients 
with human epidermal growth factor receptor 2-positive metastatic 
breast cancer. J Clin Oncol 2013;31(9):1157-63. 
27. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-
positive advanced breast cancer. N Engl J Med 2012; 367:1783–91. 
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28. Krop IE, Kim SB, González-Martín A, et al. Trastuzumab emtansine 
versus treatment of physician's choice for pretreated HER2-positive 
advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 
trial. Lancet Oncol 2014;15(7):689-99. 
29. Beeram M, Krop IE, Burris HA, et al. A phase 1 study of weekly dosing 
of trastuzumab emtansine (T-DM1) in patients with advanced human 
epidermal growth factor 2-positive breast cancer. Cancer 
2012;118(23):5733-40.  
30. 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; 
28:2698–704. 
31. Burris HA 3rd, Rugo HS, Vukelja SJ, et al. Phase II study of the antibody 
drug conjugate trastuzumab-DM1 for the treatment of human epidermal 
growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-
directed therapy. J Clin Oncol 2011;29(4):398-405.  
32. Krop IE, LoRusso P, Miller KD, et al. A phase II study of trastuzumab 
emtansine in patients with human epidermal growth factor receptor 2-
positive metastatic breast cancer who were previously treated with 
trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J 
Clin Oncol 2012;30(26):3234-41.  
33. Gupta M, Wang B, Carrothers TJ, et al. Effects of trastuzumab 
emtansine (T-DM1) on QT interval and safety of pertuzumab plus T-DM1 
in patients with previously treated human epidermal growth factor 
receptor 2-positive metastatic breast cancer. Clinical Pharm in Drug Dev 
2013;2:11–24. 
34. Therasse P, Eisenhauer EA, Verwij J. RECIST revisited: a review of 
validation studies on tumour assessment. Eur J Cancer 2000; 42:1031–
9. 
35. 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 2011; 52:691–703. 
36. 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. 
37. Igawa Y, Matsubara M, Matsunaga K, et al. Pharmacokinetic (PK) and 
pharmacodynamic (PD) analysis of trastuzumab emtansine (T-DM1) in 
Japanese patients with advanced or recurrent HER2-positive breast 
cancer (JO22591): Comparison with Western patients. ASCPT 2012. 
38. Blum JL, Dieras V, Lo Russo PM, et al. Multicenter, Phase II study of 
oral capecitabine in taxane-pretreated metastatic breast carcinoma 
patients. Cancer 2001; 92:1759–68. 
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39. Blum JL, Jones SE, Buzdar AU, et al. Multicenter Phase II study of 
capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin 
Oncol 1999; 17:485–93. 
40. O’Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, 
Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van 
Hazel G, Verma S, Leonard R. Superior survival with capecitabine plus 
docetaxel combination therapy in anthracycline-pretreated patients with 
advanced breast cancer: phase III trial results. J Clin Oncol 
2002;20(12):2812-23. 
41. Wardley A, Pivot X, Morales-Vasquez F, et al. Randomized phase II trial 
of first-line trastuzumab plus docetaxel and capecitabine compared with 
trastuzumab plus docetaxel in HER2-positive metastatic breast cancer. J 
Clin Oncol. 2010; 28:976-83. 
42. Sawaki A, Ohashi Y, Omuro Y, et al. Efficacy of trastuzumab in 
Japanese patients with HER2-positive advanced gastric or 
gastroesophageal junction cancer: a subgroup analysis of the 
Trastuzumab for Gastric Cancer (ToGA) study. Gastric Cancer 2012; 
15:313–22. 
43. Lewis Phillips G, Fields CT, Crocker L, et al. Potent anti-tumor activity of 
trastuzumab-DM1 antibody conjugate in combination with cytotoxic 
chemotherapeutic agents, antibodies or small molecule kinase inhibitors. 
AACR 2008; poster#2133. 
44. 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. 
45. Gelmon KA, Vidal M, Sablin M-P, et al. Trastuzumab emtansine (T-DM1) 
plus capecitabine (X) in patients with HER2-positive MBC: MO28230 
TRAX-HER2 phase 1 results. J Clin Oncol 32:5s, 2014 (suppl; abstr 
606). 
46. Yang J, Wang Y, Zhao H, et al. Combination of exposure-response and 
case-control analyses in regulatory decision making. J Clin Oncol 2011; 
29: (Suppl); 4087. 
47. 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. 
48. Rubinstein LV, Korn EL, Freidlin B, et al. Design issues of randomized 
phase II trials and a proposal for phase II screening trials. J Clin Oncol 
2005;23:7199–206.  
49. Ratain MJ, Sargent DJ. Optimising the design of phase II oncology trials: 
the importance of radnomisation. Eur J Cancer 2009;45:275–80. 
 
 
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Appendix 1 
Schedule of Assessments 
Table 1 
 Schedule of assessments for mBC patients (Phase I, Cohort 1 and Randomized Phase II) 
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 Onwards 
Safety 
Follow-Up 
Visit 
Follow-Up2 
Day 
-28 to -1 
1 
8 
15 
1 
8 
15 
1 
8 
15 
28-42 days 
after last 
dose 
every 3-6 
months 
Informed Consent 
Xa 
 
 
 
 
 
 
 
 
 
 
 
HER2 Status  
Xb 
 
 
 
 
 
 
 
 
 
 
 
Medical History and Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination  
X 
 
 
 
 
 
 
 
 
 
 
 
Limited Physical Examinationc 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Height and Weightd 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Vital Signse 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
ECOG Performance Status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Concomitant Medication Reporting 
Xf 
X 
Ongoing 
 
AE Reporting 
Xg 
Ongoing 
X 
Xh 
12-lead ECG  
X  
 
 
 
 
 
 
 
 
 
 
 
ECHO/MUGAi 
Xi 
 
 
Xi 
 
 
Xi 
 
 
Xi 
Xi 
 
Tumor Assessmentsj 
X 
At Cycle 3 (9 weeks after randomization), and then every 4th cycle (12 weeks thereafter, 
regardless of dose delay or early discontinuation) until PD or study termination, 
whichever occurs earlier 
X 
X 
Brain CT or MRIk 
X 
At the discretion of the investigator, if clinically indicated, until PD 
Bone Scan/Imagingl 
X 
As clinically indicated 
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Appendix 1 
Schedule of Assessments (cont.) 
Table 1 
 Schedule of assessments for mBC patients (Phase I, Cohort 1 and Randomized Phase II) (cont.) 
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 Onwards 
Safety 
Follow-Up 
Visit 
Follow-Up2  
Day 
-28 to -1 
1  
8 
15 
1  
8 
15 
1  
8 
15 
28-42 days 
after last 
dose 
every 3-6 
months 
Hematologym 
X  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
 
 
X 
 
Biochemistryo 
X  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
 
 
X 
 
Urinalysisp 
X  
As clinically indicated 
X 
 
INR/aPTT 
X  
As clinically indicated, e.g. for patients receiving anticoagulation therapy 
X 
 
Pregnancy Testq 
X  
 
 
 
 
 
X q 
 
 
X q 
X  
X 
PK Samples (seeAppendix 2)r 
 
Xr 
 
 
Xr 
 
 
 
 
 
 
 
Assessment of Patient 
Hospitalizations and/or Hospital 
Visits 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Administration of Trastuzumab 
Emtansine 
 
D 2s 
 
 
D 1s 
 
 
D 1s 
 
 
 
 
Administration of Capecitabine 
 
D 1–14 
 
D 1–14 
 
D 1–14 
 
 
 
Overall Survival 
 
X 
X 
X 
Randomization into the Phase II 
Part of the Study 
Xt 
 
 
 
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Appendix 1 
Schedule of Assessments (cont.) 
AE = Adverse Event; aPTT = Activated Partial Thromboplastin Time; CT = Computed Tomography; ECHO = Echocardiogram; ECOG = Eastern Cooperative 
Oncology Group; D= Day; 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, INR and aPTT assessments) at Screening: to be performed within 14 days prior to first 
treatment. Screening laboratory assessments may be done on the same day of first study treatment (Cycle1 Day1). 
2.All patients will be followed-up every 6 months (except for pregnancy, which is at 3 and 6 months after safety follow-up visit until disease progresses for 
tumor assessment or study closure, whichever occurs first. Patients who discontinue study treatment for reasons other than PD will continue to undergo 
tumor assessments every 3–6 months. 
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 for patients with mBC.  
c)Limited symptom-directed physical examination. 
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. 
g)During screening, only SAEs considered related to protocol-mandated procedures will be collected. 
h)Patients will be followed for new or worsening AEs for 28 days following the last infusion of study drug or until the early termination visit, until treatment-
related AEs resolve or stabilize, or until the initiation of another anti-cancer therapy, whichever occurs first. After 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, between Days 
15 and 21 in cycles 1 and 3, and between Days 15 and 21 of 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. 
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Appendix 1 
Schedule of Assessments (cont.) 
j)Tumor assessments (± 5 business days), including a CT or MRI with contrast of the chest, abdomen, and pelvis should be performed according to the 
indicated schedule. 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, 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 until PD, withdrawal of consent, or study terminaton (whichever occurs earlier). 
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 4.5.1.4 of the protocol and in Appendix 3. 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 study treatment, non-isotopic radiographic modalities should be utilized to document the extent of bony 
metastatic disease. Refer to Appendix 4 in the protocol 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)Assessments should be performed at screening, on Day 1, 8 and 15 of Cycles 1–3, on Day 1 of all subsequent cycles, and weekly following any 
hematologic AE. If capecitabine is discontinued due to toxicity, assessments should be performed weekly (minimum) until resolution of the AE (Grade ≤ 1/ 
baseline), and on Day 1 of subsequent cycles thereafter. All assessments should 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, blood urea nitrogen (BUN)/urea (mandatory), creatinine, 
uric acid, total protein, albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), G-GT, LDH, total bilirubin (and direct bilirubin where total bilirubin > ULN). 
p)Includes specific gravity, pH, protein, glucose, blood, ketones and bilirubin. 
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Appendix 1 
Schedule of Assessments (cont.) 
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. 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 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. 
r)Pharmacokinetic assessments will be performed during the MTD-Finding part of the study only (see Appendix 2). 
s)Trastuzumab emtansine will be administered on Day 1 of each 3-weekly cycle for all patients with mBC in Cohort 1 and Randomized Phase II period of the 
study except in the first cycle where trastuzumab emtansine will be given on Day 2 (to allow PK sampling). 
t)Patients will be randomized only in the Randomized Phase II part of the study. No blinding will be used, as this is an open-label study. 
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Appendix 1 
Schedule of Assessments (cont.) 
Table 2 Schedule of assessments for patients with LA/mGC (Phase I, Cohort 2) 
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 Onwards 
Safety 
Follow-Up 
Visit 
Follow-Up2  
Day 
-28 to -1 
1 
8 
15 
1 
8 
15 
1 
8 
15 
28–42 days 
after last 
dose 
every 3–6 
months 
Informed Consent 
Xa 
 
 
 
 
 
 
 
 
 
 
 
HER2 Status  
Xb 
 
 
 
 
 
 
 
 
 
 
 
Medical History and Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination  
X 
 
 
 
 
 
 
 
 
 
 
 
Limited Physical Examinationc 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Height and Weightd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signse 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
ECOG Performance Status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Concomitant Medication Reporting 
Xf 
X 
Ongoing 
 
AE Reporting 
Xg 
Ongoing 
X 
Xh 
12-lead ECG  
X  
 
 
 
 
 
 
 
 
 
 
 
ECHO/MUGAi 
Xi 
 
 
Xi 
 
 
Xi 
 
 
Xi 
Xi 
 
Tumor Assessmentsj 
X 
At 9 weeks after C1D1, and every 12 weeks thereafter, regardless of dose delay or early 
discontinuation, until PD or study termination, whichever occurs earliest 
X 
 
Brain CT or MRIk 
X 
At the discretion of the investigator, if clinically indicated, until PD 
Bone Scan/Imagingl 
X 
As clinically indicated 
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Hematologym 
X  
Xn 
Xn  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
X 
 
Biochemistryo 
X  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
X 
 
Urinalysisp 
X  
As clinically indicated 
X 
 
INR/aPTT 
X  
As clinically indicated, e.g. for patients receiving anticoagulation therapy 
X 
 
Pregnancy Testq 
X  
 
 
 
 
 
Xq 
 
 
Xq 
X 
X 
PK/PD Samples (see Appendix 2) 
 
X 
 
 
X 
 
 
 
 
 
 
 
Assessment of Patient 
Hospitalizations and/or Hospital 
Visits 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Administration of Trastuzumab 
Emtansine 
 
D 2r 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Administration of Capecitabine 
 
D 1–14 
 
D 1–14 
 
D 1–14 
 
 
 
Overall Survival 
 
X 
X 
X 
AE = Adverse Event; aPTT = Activated Partial Thromboplastin Time; CT = Computed Tomography; ECHO = Echocardiogram; ECOG = Eastern Cooperative 
Oncology Group; D= Day; 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 
 
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Appendix 1 
Schedule of Assessments (cont.) 
1.NOTE: Local laboratory (hematology, biochemistry, urinalysis, INR and aPTT assessments) at Screening: to be performed within 14 days prior to first study 
treatment. Screening laboratory assessments may be done on the same day of first study treatment (Cycle1 Day1) visit. 
2.All patients will be followed-up every 6 months (except for pregnancy, which is at 3 and 6 months after safety follow-up visit) until disease progresses for 
tumor assessment or study closure, whichever occurs first. Patients who discontinue study treatment for reasons other than PD will continue to undergo 
tumor assessments every 3–6 months. 
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+ alone or IHC 2+ in combination with gene amplification by ISH. For patients with mGC enrolled into Cohort 2, central 
confirmation of HER2 status is required. 
c)Limited symptom-directed physical examination. 
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 fist study treatment. 
g)During screening, only SAEs considered related to protocol-mandated procedures will be collected. 
h)Patients will be followed for new or worsening AEs for 28 days following the last infusion of study drug or until the early termination visit, until treatment-
related AEs resolve or stabilize, or until the initiation of another anti-cancer therapy, whichever occurs first. After 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, between Days 
15 and 21 in cycles 1 and 3, and between Days 15 and 21 of every 3rd 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. 
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Appendix 1 
Schedule of Assessments (cont.) 
j)Tumor assessments (± 5 business days), including a CT or MRI with contrast of the chest, abdomen, and pelvis should be performed according to the 
indicated schedule. 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, e.g. the same contrast protocol for 
CT scans. For patients who discontinue study treatment for reasons other than PD, continue tumor assessments according to the protocol every 3–6 months 
until PD, withdrawal of consent, or study termination (whichever occurs earliest). 
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 4.5.1.4 of the protocol and in Appendix 3. 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 4 in the protocol for additional details. 
m)Hematologic assessments include Hemoglobin (Hb), hematocrit, red blood cell count, platelet count, and WBC with differential (including neutrophils, 
lymphocytes, monocytes, eosinophils and basophils). 
n)Assessments should be performed at screening, on Day 1, 8 and 15 of all cycles. All assessments should 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/urea (mandatory), creatinine, uric acid, total protein, 
albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), G-GT, LDH, 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. 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 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. 
r)Trastuzumab emtansine will be administered on Day 1 of each weekly cycle for all patients enrolled in Cohort 2 (A&B) except in the first cycle where 
trastuzumab emtansine will be given on DAY 2 (to allow drug interaction assessment). 
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Appendix 3 
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 CT or magnetic resonance imaging (MRI) scan (CT/MRI scan 
slice thickness/interval no greater than 5 mm) 
• 
10mm caliper measurement by clinical examination (lesions that cannot 
be accurately measured with calipers should be recorded as non-
measurable) 
• 
20 mm by chest X-ray 
Malignant Lymph Nodes. To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in the short axis when assessed 
by CT scan (CT scan slice thickness recommended to be no greater than 5 
mm). At baseline and follow-up, only the short axis will be measured and 
followed. See also notes below on “Baseline Documentation of Target and 
Non-Target Lesions” for information on lymph node measurement. 
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228–47. 
2 For consistency within this document, the section numbers and cross-references to other  
sections within the article have been deleted and minor formatting changes have been made. 
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Appendix 3 (cont.) 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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. 
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, 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. 
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Appendix 3 (cont.) 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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 
possible to the treatment start and never more than 28 days 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 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 
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Appendix 3 (cont.) 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
be taken in measurement of target lesions on a different modality and 
interpretation of non-target disease or new lesions, since the same lesion may 
appear to have a different size using a new modality. 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should 
not be used as a method of measurement. 
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology. The 
utilization of these techniques for objective tumor evaluation cannot generally 
be advised. 
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 
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Appendix 3 (cont.) 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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 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 
• 
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 
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Appendix 3 (cont.) 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. 
The appearance of one or more new lesions is also considered 
progression. 
• 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
on study 
b. Special Notes on the Assessment of Target Lesions 
Lymph Nodes. Lymph nodes identified as target lesions should always have 
the actual short axis measurement recorded (measured in the same 
anatomical plane as the baseline examination), even if the nodes regress 
to < 10 mm on study. This means that when lymph nodes are included as 
target lesions, the sum of lesions may not be zero even if CR criteria are met, 
since a normal lymph node is defined as having a short axis of < 10 mm. 
Target Lesions That Become Too Small to Measure. During the study, all 
lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very 
small (e.g., 2 mm). However, sometimes lesions or lymph nodes that are 
recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may 
report them as being too small to measure. When this occurs, it is important 
that a value be recorded on the CRF, as follows: 
• 
If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. 
• 
If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned and below 
measurable limit (BML) should be ticked. (Note: It is less likely that this 
rule will be used for lymph nodes since they usually have a definable size 
when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and BML should also be ticked). 
To reiterate, however, if the radiologist is able to provide an actual measure, that 
should be recorded, even if it is below 5 mm, and in that case BML should not be 
ticked. 
Lesions That Split or Coalesce on Treatment. When non-nodal lesions 
fragment, the longest diameters of the fragmented portions should be added  
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Appendix 3 (cont.) 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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. 
• 
Complete response (CR): Disappearance of all non-target lesions and 
(if applicable) normalization of tumor marker level 
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
• 
Non-CR/Non-PD: Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
• 
Progressive disease (PD): Unequivocal progression of existing non-target 
lesions 
The appearance of one or more new lesions is also considered 
progression. 
d. Special Notes on Assessment of Progression of Non-Target Disease 
When the Patient Also Has Measurable Disease. In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be 
an overall level of substantial worsening in non-target disease in a magnitude 
that, even in the presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A 
modest increase in the size of one or more non-target lesions is usually not 
sufficient to qualify for unequivocal progression status. The designation of 
overall progression solely on the basis of change in non-target disease in the 
face of SD or PR of target disease will therefore be extremely rare. 
When the Patient Has Only Non-Measurable Disease. This circumstance 
arises in some Phase III trials when it is not a criterion of study entry to have 
measurable disease. The same general concepts apply here as noted above; 
however, in this instance there is no measurable disease assessment to 
factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by 
definition: if all lesions are truly non-measurable), a useful test that can be  
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Appendix 3 (cont.) 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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 PD; therefore, some 
comments on detection of new lesions are important. There are no specific 
criteria for the identification of new radiographic lesions; however, the finding 
of a new lesion should be unequivocal, that is, not attributable to differences 
in scanning technique, change in imaging modality, or findings thought to 
represent something other than tumor (e.g., some “new” bone lesions may be 
simply healing or flare of pre-existing lesions). This is particularly important 
when the patient’s baseline lesions show partial or CR. For example, necrosis 
of a liver lesion may be reported on a CT scan report as a “new” cystic lesion, 
which it is not. 
A lesion identified during the study in an anatomical location that was not 
scanned at baseline is considered a new lesion and will indicate PD. 
If a new lesion is equivocal, e.g., because of its small size, continued therapy 
and follow-up evaluation will clarify if it represents truly new disease. If repeat 
scans confirm there is definitely a new lesion, then progression should be 
declared using the date of the initial scan. 
Evaluation of Response 
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. 
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Appendix 3 (cont.) 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
When patients have non-measurable (therefore non-target) disease only, 
Table 2 is to be used. 
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. 
 
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Appendix 3 (cont.) 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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 
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. 
c. Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes 
decrease to “normal” size (<10 mm), they may still have a measurement 
reported on scans. This measurement should be recorded even though the 
nodes are normal in order not to overstate progression should it be based on 
increase in size of the nodes. As noted earlier, this means that patients with 
CR may not have a total sum of “zero” on the CRF. 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of PD 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, Table 3. 
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Appendix 3 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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. 
 
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Appendix 3 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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 4 
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 5 
New York Heart Association Classification of Functional 
Cardiac Capacity 
 
Class 
 
I 
No limitation: Ordinary physical activity does not cause undue fatigue, 
dyspnea, or palpitation. 
II 
Slight limitation of physical activity: Such patients are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitations, dyspnea, or angina. 
III 
Marked limitation of physical activity: Although patients are comfortable at 
rest, less than ordinary physical activity will lead to symptoms. 
IV 
Inability to carry on physical activity without discomfort: Symptoms of 
congestive heart failure are present even at rest. With any physical activity, 
increased discomfort is experienced. 
From: Criteria Committee, New York Heart Association, Inc. Diseases of the heart 
and blood vessels. Nomenclature and criteria for diagnosis. 6th ed. Boston, Little, 
Brown and Co, 1964:114. 
 
 
 
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Appendix 6 
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 
 
50. http://www.ecog.org/general/perf_stat.html 
 
 
 
 
 
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TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................. 10 
PROTOCOL SYNOPSIS .................................................................................... 11 
1. 
BACKGROUND .......................................................................................... 28 
1.1 
Background on Disease ......................................................... 28 
1.1.1 
HER2-Positive Breast Cancer ............................................... 28 
1.1.2 
HER2-Positive Locally Advanced/Metastatic 
Gastric Cancer ......................................................................................... 29 
1.2 
Background on Study Drugs .................................................. 30 
1.2.1 
Trastuzumab Emtansine ........................................................ 30 
1.2.1.1 Study TDM3569g ................................................................. 32 
1.2.1.2 Study TDM4258g ................................................................. 32 
1.2.1.3 Study TDM4374g ................................................................. 33 
1.2.1.4 Study TDM4450g ................................................................. 34 
1.2.1.5 Study TDM4688g ................................................................. 35 
1.2.1.6 Phase III Study TDM4370g .................................................. 35 
1.2.1.7 Phase III study TDM4997g ................................................... 36 
1.2.1.8 Pharmacokinetics ................................................................. 37 
1.2.2 
Capecitabine .......................................................................... 38 
1.2.2.1 Study BO18255: Capecitabine and 
Trastuzumab in LA/mGC .................................................................... 39 
1.2.3 
Preclinical Data of the Combination of 
Trastuzumab Emtansine and a Fluoropyrimidine ..................................... 40 
1.3 
Study Rationale and Risk-Benefit Assessment ...................... 42 
1.3.1 
For mBC ................................................................................ 42 
1.3.2 
For mGC ................................................................................ 43 
2. 
OBJECTIVES .............................................................................................. 44 
2.1 
Phase I: MTD-Finding of Trastuzumab 
Emtansine and Capecitabine in mBC .................................... 44 
2.1.1 
Primary Objective .................................................................. 44 
2.1.2 
Secondary Objectives ............................................................ 44 
2.2 
Randomized Phase II: Exploration of Efficacy 
and Safety in mBC ................................................................. 44 
2.2.1 
Primary Objective .................................................................. 44 
2.2.2 
Secondary Objectives ............................................................ 45 
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2.3 
Phase I: MTD Finding of Trastuzumab 
Emtansine and Capecitabine in LA/mGC .............................. 45 
2.3.1 
Primary Objective .................................................................. 45 
2.3.2 
Secondary Objectives ............................................................ 45 
3. 
STUDY DESIGN ......................................................................................... 45 
3.1 
Description of Study .............................................................. 45 
3.1.1 
Overview of Study Design ..................................................... 46 
3.1.1.1 Overview of Phase I Design in Patients with 
mBC 
47 
3.1.1.2 Overview of Phase II: Exploration of Efficacy 
and Safety in Patients with mBC ........................................................ 50 
3.1.1.3 Overview of Phase I Design in LA/mGC 
Patients 50 
3.1.1.4 Number of Patients ............................................................... 51 
3.1.1.5 Number of Centers ............................................................... 51 
3.1.2 
Steering Committee ............................................................... 51 
3.1.3 
Independent Data Monitoring Committee .............................. 51 
3.2 
End of Study .......................................................................... 51 
3.3 
Rationale for Study Design .................................................... 52 
3.3.1 
Rationale for Patient Group Selection ................................... 52 
3.3.1.1 Rationale for Phase I ............................................................ 52 
3.3.1.2 Rationale for Randomized Phase II ...................................... 53 
3.3.2 
Rationale for Investigational Medicinal Dose 
Selection 53 
3.3.2.1 In Patients with mBC ............................................................ 53 
3.3.2.2 In Patients with mGC ............................................................ 53 
3.3.2.3 Rationale for Duration of Treatment ..................................... 54 
3.3.3 
Pharmacokinetic Sampling Rationale .................................... 54 
3.4 
Outcome Measures ............................................................... 55 
3.4.1 
Phase I: mBC ........................................................................ 55 
3.4.1.1 Primary Outcome Measure .................................................. 55 
3.4.1.2 Secondary Outcome Measure .............................................. 55 
3.4.1.3 Primary Safety Outcome Measure ....................................... 55 
3.4.1.4 Secondary Safety Outcome Measures ................................. 55 
3.4.1.5 Pharmacokinetic Outcome Measures ................................... 55 
3.4.2 
Randomized Phase II: Exploration of Efficacy 
and Safety in mBC ................................................................................... 56 
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3.4.2.1 Primary Efficacy Outcome Measure ..................................... 56 
3.4.2.2 Secondary Efficacy Outcome Measures .............................. 56 
3.4.2.3 Primary Safety Outcome Measure ....................................... 56 
3.4.2.4 Secondary Safety Outcome Measures ................................. 56 
3.4.2.5 Pharmacokinetic Outcome Measures ................................... 57 
3.4.3 
Phase I: LA/mGC ................................................................... 57 
3.4.3.1 Primary Outcome Measure .................................................. 57 
3.4.3.2 Secondary Efficacy Outcome Measure ................................ 57 
3.4.3.3 Secondary Safety Outcome Measures ................................. 57 
3.4.3.4 Pharmacokinetic Outcome Measures ................................... 58 
4. 
MATERIALS AND METHODS .................................................................... 58 
4.1 
Patients .................................................................................. 58 
4.1.1 
Patients with mBC ................................................................. 58 
4.1.2 
LA/mGC Patients ................................................................... 58 
4.1.3 
Inclusion Criteria .................................................................... 59 
4.1.3.1 For Patients with mBC .......................................................... 59 
4.1.3.2 For Patients with LA/mGC .................................................... 60 
4.1.4 
Exclusion Criteria ................................................................... 62 
4.1.4.1 For Patients with mBC .......................................................... 62 
4.1.4.2 For Patients with LA/mGC .................................................... 63 
4.1.5 
Patient Replacement Policy ................................................... 65 
4.2 
Method of Treatment Assignment .......................................... 65 
4.3 
Study Treatment .................................................................... 65 
4.3.1 
Formulation, Packaging, and Handling .................................. 65 
4.3.1.1 Trastuzumab Emtansine ...................................................... 65 
4.3.1.2 Capecitabine ........................................................................ 66 
4.3.2 
Dosage and Administration .................................................... 67 
4.3.2.1 For Patients with mBC .......................................................... 67 
4.3.2.2 For Patients with LA/mGC .................................................... 68 
4.3.3 
Investigational Medicinal Product 
Accountability ........................................................................................... 68 
4.3.4 
Post-trial Access to Extension Study ..................................... 68 
4.4 
Concomitant And Excluded Therapies .................................. 69 
4.4.1 
Permitted Therapy ................................................................. 69 
4.4.2 
Prohibited Therapy ................................................................ 69 
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4.5 
Study Assessments ............................................................... 70 
4.5.1 
Description of Study Assessments ........................................ 70 
4.5.1.1 Medical History and Demographic Data ............................... 70 
4.5.1.2 Vital Signs ............................................................................ 71 
4.5.1.3 Physical Examinations ......................................................... 71 
4.5.1.4 Tumor and Response Evaluations ....................................... 71 
4.5.1.5 Laboratory Assessments ...................................................... 72 
4.5.1.6 Electrocardiograms .............................................................. 73 
4.5.1.7 ECOG Performance Status .................................................. 73 
4.5.1.8 ECHO/MUGA ....................................................................... 73 
4.5.2 
Timing of Study Assessments ............................................... 73 
4.5.2.1 Screening and Pretreatment Assessments .......................... 73 
4.5.2.2 Assessments during Treatment ............................................ 74 
4.5.2.3 Assessments at Study Completion/Early 
Termination Visit ................................................................................. 75 
4.5.2.4 Follow-up Assessments ....................................................... 75 
4.5.2.5 Assessments at Unplanned Visits ........................................ 75 
4.6 
Patient and STUDY Discontinuation ...................................... 75 
4.6.1 
Patient Discontinuation .......................................................... 75 
4.6.2 
Study Discontinuation ............................................................ 76 
5. 
ASSESSMENT OF SAFETY ....................................................................... 76 
5.1 
Safety Plan ............................................................................ 76 
5.1.1 
Risks Associated with Trastuzumab 
Emtansine 76 
5.1.1.1 Cardiotoxicity ........................................................................ 77 
5.1.1.2 Hematologic Toxicity (Thrombocytopenia) ........................... 77 
5.1.1.3 Hepatotoxicity ....................................................................... 77 
5.1.1.4 Pulmonary Toxicity ............................................................... 78 
5.1.1.5 Infusion-related Reactions/Hypersensitivity .......................... 78 
5.1.1.6 Neurotoxicity ........................................................................ 79 
5.1.1.7 Extravasation ....................................................................... 79 
5.1.1.8 Trastuzumab Emtansine Dose Modification ......................... 79 
5.1.2 
Risks Associated with Capecitabine ...................................... 79 
5.1.3 
Risks Associated with Trastuzumab 
Emtansine and Capecitabine Combination .............................................. 81 
5.1.4 
Definition of Dose-limiting Toxicity ......................................... 81 
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5.1.5 
Management of Specific Adverse Events .............................. 82 
5.1.5.1 Trastuzumab Emtansine Dose Modification ......................... 82 
5.1.5.1.1 Trastuzumab Emtansine Dose 
Modification for Thrombocytopenia ............................................... 84 
5.1.5.1.2 Trastuzumab Emtansine Dose 
Modification for Hepatotoxicity ...................................................... 85 
5.1.5.1.2.1 
Concurrent elevations of ALT/AST and bilirubin meeting Hy’s 
Law laboratory criteria ............................................................................... 85 
5.1.5.1.2.2 
Nodular regenerative hyperplasia ......................................... 85 
5.1.5.1.2.3 
Transaminase elevations or bilirubin elevation requiring dose 
adjustment 85 
5.1.5.1.3 Trastuzumab Emtansine Dose 
Modification for Neurotoxicity ........................................................ 86 
5.1.5.1.4 Trastuzumab Emtansine Dose 
Modification for Cardiotoxicity ....................................................... 86 
5.1.5.1.5 Trastuzumab Emtansine Dose 
Modification/Management for Infusion-related 
Reactions, Hypersensitivity Reactions .......................................... 87 
5.1.5.1.6 Trastuzumab Emtansine Dose 
Modification for Pulmonary Toxicity ............................................... 88 
5.1.5.1.7 Trastuzumab Emtansine Dose 
Modification for Extravasation ....................................................... 88 
5.1.5.2 Capecitabine Dosage Modification ....................................... 88 
5.2 
Safety Parameters and Definitions ........................................ 89 
5.2.1 
Adverse Events ..................................................................... 89 
5.2.2 
Serious Adverse Events (Immediately 
Reportable to the Sponsor) ...................................................................... 90 
5.2.3 
Protocol-defined Events of Special 
Interest/Non-Serious Expedited Adverse Events ..................................... 91 
5.2.4 
Pregnancy and Contraception ............................................... 91 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 93 
5.3.1 
Adverse Event Reporting Period ........................................... 94 
5.3.2 
Eliciting Adverse Event Information ....................................... 94 
5.3.3 
Assessment of Severity of Adverse Events ........................... 94 
5.3.4 
Assessment of Causality of Adverse Events ......................... 95 
5.3.5 
Procedures for Recording Adverse Events ............................ 96 
5.3.5.1 Diagnosis versus Signs and Symptoms ............................... 97 
5.3.5.2 Adverse Events Occurring Secondary to 
Other Events ...................................................................................... 97 
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5.3.5.3 Persistent or Recurrent Adverse Events .............................. 97 
5.3.5.4 Abnormal Laboratory Values ................................................ 98 
5.3.5.5 Abnormal Vital Sign Values .................................................. 98 
5.3.5.6 Abnormal Liver Function Tests ............................................. 99 
5.3.5.7 Deaths .................................................................................. 99 
5.3.5.8 Pre-Existing Medical Conditions ......................................... 100 
5.3.5.9 Lack of Efficacy or Clinical Worsening ............................... 100 
5.3.5.10 Hospitalization or Prolonged Hospitalization .................... 100 
5.3.5.11 Adverse Events Associated with an 
Overdose or Error in Drug Administration ......................................... 100 
5.4 
Immediate Reporting Requirements from 
Investigator to the Sponsor .................................................. 101 
5.4.1 
Emergency Medical Contacts .............................................. 101 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-serious Adverse Events of Special 
Interest 
101 
5.4.3 
Reporting Requirements for Pregnancies ............................ 102 
5.4.3.1 Pregnancies in Female Patients ......................................... 102 
5.4.3.2 Pregnancies in Female Partners of Male 
Patients 102 
5.4.3.3 Abortions ............................................................................ 103 
5.4.3.4 Congenital Anomalies/Birth Defects ................................... 103 
5.5 
Follow-up of Patients after Adverse Events ......................... 103 
5.5.1 
Investigator Follow-up.......................................................... 103 
5.5.2 
Sponsor Follow-up ............................................................... 104 
5.6 
Post-study Adverse Events .................................................. 104 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ............................................................... 104 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ..................... 105 
6.1 
Determination of Sample Size ............................................. 105 
6.2 
Summaries of Conduct of Study .......................................... 107 
6.3 
Summaries of Treatment Group Comparability ................... 107 
6.4 
Efficacy Analyses ................................................................ 108 
6.4.1 
Primary Efficacy Endpoint .................................................... 108 
6.4.2 
Secondary Efficacy Endpoints ............................................. 110 
6.5 
Safety Analyses ................................................................... 111 
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6.6 
Pharmacodynamic Analyses ............................................... 113 
6.7 
Pharmacokinetic Analyses ................................................... 113 
6.8 
Exploratory Analyses ........................................................... 114 
6.9 
Interim Analyses .................................................................. 114 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 115 
7.1 
Data Quality Assurance ....................................................... 115 
7.2 
Electronic Case Report Forms ............................................. 115 
7.3 
Source Data Documentation ................................................ 115 
7.4 
Use of Computerized Systems ............................................ 116 
7.5 
Retention of Records ........................................................... 116 
8. 
ETHICAL CONSIDERATIONS .................................................................. 117 
8.1 
Compliance with Laws and Regulations .............................. 117 
8.2 
Informed Consent ................................................................ 117 
8.3 
Institutional Review Board or 
Ethics Committee ................................................................ 118 
8.4 
Confidentiality ...................................................................... 118 
8.5 
Financial Disclosure ............................................................ 119 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 119 
9.1 
Study Documentation .......................................................... 119 
9.2 
Site Inspections ................................................................... 119 
9.3 
Administrative Structure ....................................................... 119 
9.4 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 120 
9.5 
Protocol Amendments ......................................................... 120 
10. REFERENCES ......................................................................................... 121 
 
 
LIST OF TABLES 
Table 1 
 Cycle 1 Mean (s.d.) Pharmacokinetic Parameters for 
Trastuzumab Emtansine Following Trastuzumab 
Emtansine Administration q3w and qw in Study 
TDM3569g .................................................................................. 37 
Table 2 
 Dose Reduction for Trastuzumab Emtansine  (Patients 
with mBC) ................................................................................... 83 
Table 3 
Dose Reductions for Trastuzumab Emtansine  (Patients 
with mGC) ................................................................................... 84 
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Table 4 
Trastuzumab Emtansine Dose Modification: Total Serum 
Bilirubin ....................................................................................... 85 
Table 5 
 Trastuzumab Emtansine Dose Modification: Serum ALT 
or AST ......................................................................................... 86 
Table 6 
Adverse Event Severity Grading Scale ....................................... 95 
Table 7 
 Guidance for Causal Attribution of Adverse 
Event/Serious Adverse Event ..................................................... 96 
 
 
LIST OF FIGURES 
Figure 1 
 Molecular Structure of Trastuzumab Emtansine ........................ 31 
Figure 2 
MMTV HER2 Fo5 Mammary Tumor Transplants ........................ 41 
Figure 3 
 Anti-tumor Activity of Trastuzumab Emtansine in 
Combination with Capecitabine in NCI-N87 ................................ 42 
Figure 4 
Overview of Study Design ........................................................... 47 
Figure 5 
Overview of Phase I Dose Finding Study Design ........................ 48 
Figure 6 
Algorithm for Continuation and Discontinuation of 
Trastuzumab Emtansine Based on Left Ventricular 
Ejection Fraction Assessments in Patients ................................. 87 
 
 
LIST OF APPENDICES 
Appendix 1 
 Schedule of Assessments .................................................. 126 
Appendix 2 
 Pharmacokinetic Sampling for Phase I, 
Metastatic Breast and Gastric Cancer Patients ......................................... 136 
Appendix 3 
 Response Evaluation Criteria in Solid Tumors 
(RECIST): Modified Excerpt from Original Publication .............................. 138 
Appendix 4 
 Instructions for Scans in the Event of Isotope 
Shortage 
 ............................................................................................ 150 
Appendix 5 
 New York Heart Association Classification of 
Functional Cardiac Capacity ..................................................................... 15  
Appendix 6 
 ECOG Performance Status ................................................ 152 
 
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PROTOCOL ACCEPTANCE FORM 
TITLE: 
PHASE I STUDY OF THE COMBINATION OF TRASTUZUMAB 
EMTANSINE (T-DM1) AND CAPECITABINE IN HER2-POSITIVE 
METASTATIC BREAST CANCER AND HER2-POSITIVE LOCALLY 
ADVANCED OR METASTATIC GASTRIC CANCER PATIENTS, 
FOLLOWED BY A RANDOMIZED, OPEN-LABEL PHASE II STUDY 
OF TRASTUZUMAB EMTANSINE AND CAPECITABINE VERSUS 
TRASTUZUMAB EMTANSINE ALONE IN HER2-POSITIVE 
METASTATIC BREAST CANCER 
PROTOCOL NUMBER: MO28230 
VERSION NUMBER: 4 
EUDRACT NUMBER: 
2012-001547-46 
 
 
TEST PRODUCT: 
Trastuzumab emtansine (RO5304020) 
Capecitabine (RO091978) 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return the signed original of this form {as instructed by XX [e.g., your 
local study monitor, the CRO]} [or] {to the contact provided below}. Please retain 
a copy for your study files. 
{Name}  
{Address} 
 
 
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PROTOCOL SYNOPSIS 
TITLE: 
PHASE I STUDY OF THE COMBINATION OF TRASTUZUMAB EMTANSINE  
(T-DM1) AND CAPECITABINE IN HER2-POSITIVE METASTATIC BREAST 
CANCER AND HER2-POSITIVE LOCALLY ADVANCED/METASTATIC GASTRIC 
CANCER PATIENTS, FOLLOWED BY A RANDOMIZED, OPEN-LABEL PHASE II 
STUDY OF TRASTUZUMAB EMTANSINE AND CAPECITABINE VERSUS 
TRASTUZUMAB EMTANSINE ALONE IN HER2-POSITIVE METASTATIC 
BREAST CANCER 
PROTOCOL NUMBER: 
MO28230 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2012-001547-46 
 
 
TEST PRODUCT: 
Trastuzumab emtansine (RO5304020) 
Capecitabine (RO091978) 
PHASE: 
I/II 
INDICATION: 
HER2-positive metastatic breast cancer or HER2-positive locally 
advanced/metastatic gastric cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Phase I: Maximum Tolerated Dose (MTD) Finding of Trastuzumab Emtansine (T-DM1) and 
Capecitabine in Metastatic Breast Cancer (mBC) 
Primary Objective 
 
To determine the MTD of the combination of trastuzumab emtansine and capecitabine in 
patients with human epidermal growth factor receptor 2 (HER2)-positive mBC  
Secondary Objectives 
To assess the: 
 
Pharmacokinetics (PK) of trastuzumab emtansine, capecitabine, and their metabolites  
 
Safety of the combination of trastuzumab emtansine and capecitabine 
 
Overall response rate (ORR) 
Randomized Phase II: Exploration of Efficacy and Safety in mBC 
Primary Objective 
 
To explore the efficacy of the combination of trastuzumab emtansine and capecitabine 
compared with trastuzumab emtansine alone in patients with HER2-positive mBC, as 
measured by ORR by Response Evaluation Criteria for Solid Tumors (RECIST) v.1.1 per 
investigator local assessment  
Secondary Objectives 
 
To assess the safety profile of the combination of trastuzumab emtansine and capecitabine 
compared with trastuzumab emtansine alone 
 
To explore the efficacy of the combination of trastuzumab emtansine and capecitabine 
compared with trastuzumab emtansine alone in mBC patients, as measured by: 
 Time to response (TTR)  
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 Duration of response (DoR) 
 Time to progression (TTP)  
 Time to treatment failure (TTF)  
 Progression-free survival (PFS)  
 Clinical benefit rate (CBR) 
 Overall survival (OS) 
Phase I: MTD Finding of Trastuzumab Emtansine and Capecitabine in Locally 
Advanced/Metastatic Gastric Cancer (LA/mGC) 
Primary Objective 
 
To determine the MTD of the combination of trastuzumab emtansine and capecitabine in 
patients with LA/mGC  
Secondary Objectives 
To assess the: 
 
PK of trastuzumab emtansine, capecitabine, and their metabolites  
 
Safety of the combination of trastuzumab emtansine and capecitabine 
 
ORR 
Study Design 
Description of Study 
This is an international, multicenter study. 
The study is designed to determine the MTD of capecitabine in combination with trastuzumab 
emtansine in patients with HER2-positive mBC or LA/mGC using a Phase I design, followed by 
a randomized, open-label Phase II study to explore the efficacy and safety of the combination of 
trastuzumab emtansine and capecitabine compared with trastuzumab emtansine alone in 
HER2-positive mBC. Results from the Phase I study in LA/mGC will be used as supporting 
information for future studies in the indication (see Figure 4 in the protocol). 
Phase I: MTD Finding, Cohort 1: mBC 
Cohort 1 used a 3 plus 3 classical design to determine the MTD of capecitabine in combination 
with trastuzumab emtansine. Initially the study had a dose escalation design, but following the 
occurrence of two DLTs at Dose Level 1 (750 mg/m2 capecitabine bid + 3.6 mg/kg q3w 
trastuzumab emtansine), the study design was adapted and the dose de-escalated to 700 
mg/m2 capecitabine bid + 3.6 mg/kg q3w trastuzumab emtansine. At this Dose Level there were 
no DLTs and following review of the safety data, the Independent Data Monitoring Committee 
(IDMC) recommended that the study should proceed to explore this Dose Level further in the 
Randomized Phase II part of the study.  
Randomized Phase II: Exploration of Efficacy and Safety in mBC 
Phase II will be conducted in mBC patients only. This part of the study will explore the efficacy 
and safety of the combination treatment of trastuzumab emtansine (T-DM1) and capecitabine, 
at 700 mg/m2 bid (the recommended MTD), compared with trastuzumab emtansine alone in 
patients with mBC. 
Approximately 160 additional patients with HER2-positive mBC will be randomized into the 
Phase II part of the study. Patients in the Phase I part of the study will not contribute to the 
Phase II part of the study; however, they will be followed up until end of study (EOS). 
Phase I: MTD Finding, Cohort 2: LA/mGC 
Cohort 2 will have a 3 plus 3 classical design and enroll patients with HER2-positive LA/mGC. 
Trastuzumab emtansine will be administered weekly at a dose of 2.4 mg/kg and capecitabine 
will start at dose level -1 (700 mg/m2, the MTD defined in Cohort 1), with de-escalation if 
required as follows:  
 
If Dose Level -1 is well tolerated (DLT in ≤ 1/6 patients), this dose will be established as the 
MTD for LA/mGC  
 
If Dose Level -1 is not tolerated in Cohort 2 (DLT in > 1/6 patients), de-escalation will be to 
Dose Level -2.  
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 
If Dose Level -2 is too toxic, the combination of capecitabine with trastuzumab emtansine 
2.4 mg/kg every week may be considered unfeasible in LA/mGC, recruitment will be 
terminated and the LA/mGC part will be closed. However, this will have no impact on 
continuation of the Randomized Phase II mBC part. 
Duration of treatment and follow-up 
All patients will be treated until investigator-assessed disease progression, unacceptable 
toxicity, withdrawal of consent, death, reasons deemed by the treating physician, or study 
termination by the Sponsor. In case of toxicities requiring the discontinuation of capecitabine, 
single agent trastuzumab emtansine may be continued. In case of toxicities requiring the 
discontinuation of trastuzumab emtansine, the patient will be followed up until EOS (treatment 
with capecitabine alone is not allowed).  
All patients will be followed up until withdrawal of consent, death, or for up to a maximum of 2 
years after the last patient was randomized in the Phase II part of the study, whichever occurs 
first. 
Number of Patients 
Phase I, Cohort 1: mBC 
A minimum of 6 and up to 18 patients will be enrolled. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
Exploration of efficacy and safety in mBC will be based on approximately 160 randomized 
patients in total. 
Phase I, Cohort 2: LA/mGC 
A total of 6 to 12 patients will be enrolled. 
Target Population 
Phase I, Cohort 1: mBC 
Patients with HER2-positive mBC will be enrolled. 
The patient’s HER2 status will be considered positive if the local institution or reference lab 
reported immunohistochemistry (IHC) 3+ staining intensity (on a scale of 0 to 3) or in situ 
hybridization (ISH) positive. 
The HER2 status will be retrospectively confirmed by IHC and/or ISH in a central laboratory 
using archival paraffin-embedded tumor tissue. Retrospective central confirmation will not affect 
the treatment decisions or primary endpoint of Phase I and will be used to validate efficacy 
analyses in Phase I. 
Before entering the study, patients must have received at least one prior treatment regimen for 
early or metastatic disease, which included a chemotherapy agent and trastuzumab either 
separately or in combination. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
Patients with HER2-positive mBC will be randomized to receive either the combination of 
trastuzumab emtansine with capecitabine or trastuzumab emtansine alone. Retrospective 
central confirmation will be used to categorize patients for subgroup analyses according to 
central HER2 testing. 
Before entering the study, patients must have received at least one prior treatment regimen for 
early or metastatic disease, which included a chemotherapy agent and trastuzumab either 
separately or in combination. 
Phase I, Cohort 2: LA/mGC 
Patients with centrally confirmed HER2-positive LA/mGC will be enrolled. 
Patients must not have received prior chemotherapy for advanced/metastatic disease. 
 
Inclusion Criteria: 
For mBC Patients: 
1. Male or female. 
2.   Age ≥ 18 years old. 
3. Signed informed consent before any study-specific procedure. 
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4. Able and willing to comply with the protocol. 
5. 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 the medical history confirming that the patient is 
not of childbearing potential. 
6. 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 or two effective forms of non-hormonal contraception and to continue its use 
for the duration of study treatment and for 7 months after the last dose of study treatment 
(see Section 5.2.4 in the protocol). 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 
8. Blood: 
a) Platelet count > 100,000 cells/mm3 
b) International normalized ratio (INR) < 1.5 
c) Absolute neutrophil count (ANC) > 1,500 cells/mm3 
d) Hemoglobin > 9.0 g/dL. Patients are allowed to have received transfusion to achieve 
this level. 
9. Liver function: 
a) Total bilirubin ≤ 1.5 × upper limit of normal (ULN) or direct bilirubin ≤ 1.5 × ULN in 
patients with documented Gilbert’s syndrome.  
b) Serum glutamic oxaloacetic transaminase (SGOT)/aspartate transaminase (AST) and 
serum glutamic pyruvic transaminase (SGPT)/alanine transaminase (ALT) ≤ 2.5 × ULN. 
c) Alkaline phosphatase ≤ 2.5 × ULN. In patients with bone metastases: alkaline 
phosphatase ≤ 5 × ULN. 
d) Evidence of stable liver function during the month prior to enrollment with liver function 
test (LFT) fluctuations not exceeding 2.5 × ULN (for AST, ALT) and 1.5 × ULN (for total 
bilirubin).  
10. Renal function: 
a) Serum creatinine of < 177 µmol/L or calculated creatinine clearance (CL)  
> 50 mL/min. If urine dipstick for proteinuria is ≥ 2+ at baseline, the patient must 
undergo 24-hour urine collection and demonstrate ≤ 1 g of protein/24 hours. 
11. Cardiac function: 
a) Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) or multiple-
gated acquisition (MUGA) scan. 
12. Life expectancy ≥12 weeks 
13. Histologically or cytologically confirmed breast cancer. 
14. HER2-positive disease, defined as IHC 3+ or ISH positive. 
15. Tumor block or 8 slides available for retrospective central confirmation of HER2-positivity 
(central confirmation not necessary for enrollment).  
16. mBC with at least one measurable lesion according to RECIST v.1.1. 
17. Disease progression on at least one prior regimen containing trastuzumab and 
chemotherapy either separately or in combination. Patients may be eligible to receive study 
therapy in the first-line setting if trastuzumab and chemotherapy were given in the 
[neo]adjuvant setting. 
18. Patients must have recovered from previous treatments 
For LA/mGC Patients: 
1. Male or female 
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2.    Age ≥ 18 years old. 
3. Signed informed consent before any study-specific procedure. 
4. Able and willing to comply with the protocol. 
5. 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 the medical history confirming that the patient is 
not of childbearing potential. 
6. 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 or two effective forms of non-hormonal contraception and to continue its use 
for the duration of study treatment and for 7months after the last dose of study treatment 
(see Section 5.2.4 in the protocol). 
7. ECOG performance status of 0, 1, or 2. 
8. Blood: 
a) Platelet count > 100,000 cells/mm3. 
b) INR < 1.5.  
c) ANC > 1,500 cells/mm3. 
d) Hemoglobin > 9.0 g/dL. Patients are allowed to have received transfusion to achieve 
this level. 
9. Liver function: 
a) Total bilirubin ≤ 1.5 × ULN or direct bilirubin ≤ 1.5 × ULN in patients with documented 
Gilbert’s syndrome.  
b) SGOT/AST and SGPT/ALT ≤ 2.5 × ULN. 
c) Alkaline phosphatase ≤ 2.5 × ULN. In patients with bone metastases: alkaline 
phosphatase ≤ 5 × ULN. 
d) Evidence of stable liver function during the month prior to enrollment with LFT 
fluctuations not exceeding 2.5 × ULN (for AST, ALT) and 1.5 × ULN (for total bilirubin).  
10. Renal function: 
a) Serum creatinine of < 177 µmol/L or calculated creatinine CL > 50 mL/min. If urine 
dipstick for proteinuria is ≥ 2+ at baseline, the patient must undergo 24-hour urine 
collection and demonstrate ≤ 1 g of protein/24 hours. 
11. Cardiac function: 
a) LVEF ≥ 50% by ECHO or MUGA scan. 
12. Life expectancy ≥2 weeks 
13. Histologically or cytologically confirmed mGC or locally advanced GC. 
14. HER2-positive tumor (primary tumor or metastatic lesion), defined as either IHC 3+ or IHC 
2+ and ISH+, prospectively confirmed by a Sponsor-designated central laboratory prior to 
enrollment. ISH positivity is defined as a ratio of ≥ 2.0 for the number of HER2 gene copies 
to the number of signals for CEP17. 
a) Archival tumor samples obtained from primary or metastatic sites are acceptable. 
b) Invasive tumor for central confirmation of HER2 status is required. 
c) A formalin-fixed paraffin-embedded (FFPE) tissue block with at least 5 mm of invasive 
tumor for central confirmation is preferred. If FFPE tissue blocks (or partial block) are 
unavailable due to country or site regulations, a minimum of 8 freshly cut unstained 
slides MUST be available for central review of HER2 status. 
15. Inoperable LA/mGC. 
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Exclusion Criteria: 
For mBC Patients: 
1. Prior treatments before first study treatment: 
a) Investigational therapy within ≤ 28 days or five half-lives, whichever is longer. 
b) Hormonal therapy within 14 days. 
c) Trastuzumab within 21 days. 
2. Prior treatment with trastuzumab emtansine or prior enrollment in a trastuzumab 
emtansine-containing study, regardless of whether the patient received trastuzumab 
emtansine. 
3. Prior treatment with capecitabine. 
4. History of severe or unexpected reactions to fluoropyrimidine or known hypersensitivity to 
fluorouracil. 
5. Related capecitabine contraindications: 
a) Treatment with sorivudine or its chemically-related analogs, such as brivudine. 
b) Rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or 
glucose-galactose malabsorption. 
c)  Known complete absence of dihydropyrimidine dehydrogenase (DPD) activity. 
6. History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity to 
trastuzumab or murine proteins or any component of the product. 
7. History of exposure to the following cumulative doses of anthracyclines: 
a) Doxorubicin or liposomal doxorubicin > 500 mg/m2. 
b) Epirubicin > 900 mg/m2. 
c) Mitoxantrone > 120 mg/m2 
d) If another anthracycline, or more than one anthracycline, has been used, the 
cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin. 
8. Brain metastases that are symptomatic, or require any radiation, surgery, or steroid therapy 
to control symptoms within 28 days before first study drug administration. 
9. Current peripheral neuropathy of Grade ≥ 3 according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) v.4.0. 
10. History of other malignancy within the last 5 years, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or 
other cancers with a similar outcome as those mentioned above.  
11. Current unstable ventricular arrhythmia requiring treatment. 
12. History of symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] 
Classes II−IV). 
13. History of myocardial infarction or unstable angina within 6 months prior to first study drug 
administration. 
14. History of a decrease in LVEF to < 40% or symptomatic CHF with previous trastuzumab 
treatment. 
15. Severe dyspnea at rest due to complications of advanced malignancy or currently requiring 
continuous oxygen therapy. 
16. Clinically significant malabsorption syndrome or inability to take oral medication. 
17. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary, or metabolic disease). 
18. Major surgical procedure or significant traumatic injury within 28 days before enrollment or 
anticipation of the need for major surgery during the course of study treatment. 
19. Current pregnancy or lactation. 
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20. Current known active infection with human immunodeficiency virus (HIV), hepatitis B, 
and/or hepatitis C virus (HBV/HCV). 
a) For patients who are known carriers of HBV, active hepatitis B infection must be ruled 
out based on negative serologic testing and/or determination of HBV deoxyribonucleic 
acid (DNA) viral load per local guidelines. 
21. Lapatinib ≤ 14 days before first study drug administration. 
22. Previous radiotherapy for the treatment of mBC is not allowed if: 
a) The last fraction of radiotherapy has been administered within 14 days prior to first 
study drug administration (28 days for patients with radiotherapy to control symptoms 
of brain metastases, see exclusion criterion 8). 
b) More than 25% of marrow-bearing bone has been irradiated. 
c) Any acute toxicity has not resolved to Grade ≤ 1 before first study drug administration. 
For LA/mGC Patients: 
1. Prior treatments before first study treatment: 
a) Investigational therapy within ≤ 28 days or 5 half-lives, whichever is longer. 
b) Hormonal therapy within 14 days. 
c) Trastuzumab within 21 days. 
2. Prior treatment with trastuzumab emtansine or prior enrollment in a trastuzumab 
emtansine-containing study, regardless of whether the patient received trastuzumab 
emtansine. 
3. Prior treatment with capecitabine. 
4. History of severe or unexpected reactions to fluoropyrimidine or known hypersensitivity to 
fluorouracil. 
5. Related capecitabine contraindications: 
a) Treatment with sorivudine or its chemically-related analogs, such as brivudine. 
b) Rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-
galactose malabsorption. 
c)  Known complete absence of DPD activity.  
6. History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity to 
trastuzumab or murine proteins or any component of the product. 
7. History of exposure to the following cumulative doses of anthracyclines: 
a) Doxorubicin or liposomal doxorubicin > 500 mg/m2. 
b) Epirubicin > 900 mg/m2. 
c) Mitoxantrone > 120 mg/m2. 
d) If another anthracycline, or more than one anthracycline, has been used, the 
cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin. 
8. Brain metastases that are symptomatic, or require any radiation, surgery, or steroid therapy 
to control symptoms within 28 days before first study drug administration. 
9. Current peripheral neuropathy of Grade ≥ 3 according to NCI CTCAE, v4.0. 
10. History of other malignancy within the last 5 years, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or 
other cancers with a similar outcome as those mentioned above. 
11. Current unstable ventricular arrhythmia requiring treatment. 
12. History of symptomatic CHF (NYHA Classes II−IV). 
13. History of myocardial infarction or unstable angina within 6 months prior to first study drug 
administration. 
14. History of a decrease in LVEF to < 40% or symptomatic CHF with previous trastuzumab 
treatment. 
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15. Severe dyspnea at rest due to complications of advanced malignancy or currently requiring 
continuous oxygen therapy. 
16. Clinically significant malabsorption syndrome or inability to take oral medication. 
17. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary, or metabolic disease) 
18. Major surgical procedure or significant traumatic injury within 28 days before enrollment or 
anticipation of the need for major surgery during the course of study treatment 
19. Current pregnancy or lactation. 
20. Current known active infection with HIV, HBV, and/or HCV 
a) For patients who are known carriers of HBV, active hepatitis B infection must be ruled 
out based on negative serologic testing and/or determination of HBV DNA viral load 
per local guidelines 
21. Previous chemotherapy for advanced/metastatic disease 
a) Prior adjuvant/neoadjuvant therapy is allowed if at least 6 months has elapsed 
between completion of adjuvant/neoadjuvant therapy and enrollment into the study 
22. Lapatinib ≤ 14 days before first study drug administration 
Length of Study 
The duration of the study is estimated to be approximately 4 years. Recruitment is estimated to 
last 2 years in total (1 year for MTD Finding, 1 year for the Phase II Exploration of Efficacy and 
Safety in mBC).  
End of Study 
The study will end after the follow-up period has been completed as defined above. Last patient 
last visit (LPLV) is defined as the last data collection point, which can be either a clinic visit or a 
laboratory sample. 
In case Dose Level -2 is too toxic in LA/mGC, the LA/mGC cohort may be terminated 
prematurely. Patients who, at that point, experience response according to RECIST v.1.1 will be 
offered the possibility to continue on trastuzumab emtansine as a single agent or with 
capecitabine, based on the risk-benefit balance and agreement with the SC. 
Randomized Phase II Exploration of Efficacy and Safety in mBC: The primary analysis of best 
overall response (BOR) rate will be performed when 70% of the patients have experienced a 
PFS event or at the end of the trial, whichever occurs first. It is estimated that 70% of patients 
will have experienced a PFS event approximately 26 months after randomization of the first 
patient. The EOS analysis (approximately 24 months after the last patient is randomized) will 
include an updated analysis of BOR, which will be done in a purely exploratory manner.   
 
Efficacy Outcome Measures 
Efficacy will be evaluated according to RECIST v.1.1. 
 
BOR rate  
 
TTR 
 
DoR 
 
TTP 
 
TTF 
 
PFS 
 
CBR 
 
OS 
Safety Outcome Measures 
 
DLT assessment/determination of the MTD of capecitabine when combined with 
trastuzumab emtansine (Phase I only) 
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 
Incidence, nature, and severity by NCI CTCAE v4.0 of adverse events (AEs), serious 
adverse events (SAEs), AEs leading to discontinuation from either component of the study 
treatment, and AEs of special interest (AESIs) 
 
Fatal AEs and their causes  
 
Events to monitor 
 
Laboratory parameters 
 
LVEF 
 
Treatment exposure 
 
Physical examinations 
 
ECOG performance status 
 
Premature withdrawal from study medication and/or study 
Pharmacodynamic Outcome Measures 
Hospital visit parameters. 
Pharmacokinetic Outcome Measures 
PK will be evaluated during Phase I for trastuzumab emtansine, capecitabine, and their 
metabolites (see Appendix 1, Schedule of Assessment in the protocol). In addition, PK samples 
may be taken ad hoc, in case of SAEs or unexpected toxicities, which may be suggestive of a 
potential drug-drug interaction. 
Investigational Medicinal Products 
For mBC Patients: 
Trastuzumab emtansine will be administered q3w at a dose of 3.6 mg/kg intravenous (IV). 
The total trastuzumab emtansine dose will be calculated based on the patient’s weight on Day  
of each cycle (or up to 3 days before) with no upper limit. 
Capecitabine will be administered orally bid for 14 days followed by a 7-day rest period at the 
Dose Levels described in the ‘Trial Design’ section. 
Capecitabine tablets should be swallowed with water within 30 minutes after a meal. Rounding 
of the capecitabine dose, based on 150 mg and 500 mg tablet strength, will be allowed to the 
nearest target dose based on the patient’s body surface area (BSA).  
For LA/mGC Patients: 
Trastuzumab emtansine will be administered on Day 1 of each 1-week cycle at a dose of 
2.4 mg/kg IV. 
The total trastuzumab emtansine dose will be calculated based on the patient’s weight on Day  
of each cycle (or up to 3 days before) with no upper limit. 
Capecitabine will be administered orally bid for 14 days followed by a 7-day rest period at the 
Dose Levels -1 to -2 described in the ‘Trial Design’ section. 
Capecitabine tablets should be swallowed with water within 30 minutes after a meal. 
Non-Investigational Medicinal Products 
Not applicable. 
Statistical Methods 
The study will include 2 phases and 2 cohorts: 
 
Phase I, Cohort 1: mBC MTD-Finding Cohort 
 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
 
Phase I, Cohort 2: LA/mGC MTD-Finding Cohort 
Corresponding analyses as described in the protocol will be performed when all data from both 
study phases are collected and cleaned. 
Randomized Phase II: The primary analysis of BOR will be performed when 70% of the patients 
have experienced a PFS event or at the end of the trial, whichever occurs first. It is estimated 
that 70% of patients will have experienced a PFS event approximately 26 months after 
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randomization of the first patient. The EOS analysis (approximately 24 months after the last 
patient is randomized) will include an updated analysis of BOR, which will be done in a purely 
exploratory manner. 
Analysis of primary and secondary endpoints: 
Analysis Populations: 
Phase I, Cohort 1: MTD-Finding: mBC Patients 
The main analysis population for DLT assessment is the DLT-evaluable population, which is 
defined as all enrolled and treated patients who have not experienced any major protocol 
violations (including violations of the inclusion and exclusion criteria) and have completed Cycle 
1.  
The safety population (SP) will include all patients who received at least one dose of study 
medication (trastuzumab emtansine and/or capecitabine) during Phase I. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
The main analysis population for the efficacy analysis will be the intent-to-treat (ITT) population, 
which will include all patients randomized in the Phase II part of the study. The per-protocol (PP) 
population will include all ITT patients who have at least one post-baseline tumor assessment 
during the Phase II part of the study and no major protocol violations, which will be defined in 
the statistical analysis plan (SAP). 
The SP will include all patients who received at least one dose of study medication during the 
Randomized Phase II part of the study.  
Phase I, Cohort 2: MTD-Finding, LA/mGC Patients 
The main analysis population for DLT assessment is the DLT-evaluable population, which is 
defined as all enrolled and treated patients who have not experienced any major protocol 
violation (including violation of the inclusion and exclusion criteria) and have completed Cycle 1.  
The SP will include all patients who received at least one dose of study medication during 
Phase I. 
Efficacy Endpoints:  
Phase I, Cohort 1: MTD-Finding, mBC 
The primary objectives are defining the MTD and establishing the safety profile of the 
combination regimen. 
ORR, as a main efficacy endpoint, will be assessed via BOR rate. The BOR is defined as the 
best response recorded from the date of enrollment until disease progression, death, withdrawal 
of consent, start of new anticancer treatment, or EOS, whichever occurs first. The number of 
patients is very small in this part of the study. Therefore, all analyses will be descriptive. 
Due to the small number of patients and the design of this part of the study, no secondary 
efficacy endpoints will be investigated. 
Randomized Phase II: Exploration of Efficacy in mBC  
The primary efficacy endpoint for the Phase II part of the study is the ORR, assessed via the 
BOR rate. BOR is defined as the best response recorded between randomization into the 
Phase II part of the study and disease progression, death, withdrawal of consent, start of new 
anticancer treatment, or EOS, whichever occurs first. To be assigned a status of partial 
response (PR) or complete response (CR), i.e., to be a responder, changes in tumor 
measurements must be confirmed by repeated assessments performed no less than 28 days 
after the response criteria are first met, i.e., patients need to have two consecutive assessments 
of PR or CR.  
The primary hypothesis of interest when comparing ORR – as assessed via BOR - between the 
two treatment groups, combination of trastuzumab emtansine and capecitabine versus 
trastuzumab emtansine alone is:  
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  H0: πtrastuzumab emtansine = πtrastuzumab emtansine + capecitabine where πtrastuzumab emtansine is BOR in 
trastuzumab emtansine alone and 
 trastuzumab emtansine + capecitabine is BOR in trastuzumab 
emtansine + capecitabine 
 
H : 
 trastuzumab emtansine  
 trastuzumab emtansine + capecitabine  
The number and proportions of responders and non-responders (based on BOR) together with 
the two-sided 90% Clopper-Pearson confidence intervals (CIs) will be presented for each 
treatment group. The difference in BOR between treatment groups will be displayed with 
associated 90% CIs using the Hauck-Anderson approach and p-value for the Fisher’s exact test.  
The secondary endpoints for the Phase II part of the study will be: 
 
TTR 
 
DoR 
 
TTP 
 
TTF 
 
PFS 
 
CBR 
 
OS 
Estimates for the survivor function of both treatment groups for TTR, DoR, TTP, TTF, PFS and 
OS will be obtained by using the Kaplan-Meier method. Hazard ratios and associated 90% CIs 
will be estimated from non-stratified and stratified (based on the stratification factor) Cox 
regression models. 
CBR will include patients whose best (confirmed) response was PR or CR, or stable disease 
(SD) that lasted at least 6 months. CBR will be summarized in a similar way to the primary 
efficacy endpoint, ORR, as assessed by BOR.  
Phase I, Cohort 2: MTD-Finding: LA/mGC 
The primary objectives are defining the MTD and establishing the safety profile of the 
combination regimen. 
Efficacy endpoints will be analyzed in a similar way to that described for Phase I, Cohort 1 in 
mBC. 
Safety Endpoints: 
Phase I, Cohort 1: MTD-Finding: mBC 
The number and proportion of patients with DLTs will be used as the primary measure for the 
MTD determination. The definition of DLTs is presented in Section 5.1.4. DLTs for this part of 
the study will be summarized by treatment dose. 
Safety parameters for this study part will also be summarized by treatment dose. The 
summaries of AEs, SAEs, AEs that cause discontinuation from the study treatment, AESIs (as 
described in Section 5), and events to monitor will be analyzed in a similar way to AEs in 
Phase II. The summaries will include all patients who received at least one dose of study 
medication. 
The incidence of AEs and SAEs will be summarized according to the primary system-organ 
class (SOC) and within each SOC, by Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term. Patients who died will be listed together with the cause of death. 
Laboratory parameters, hematology and biochemistry will be presented in shift tables of NCI 
CTCAE grade at baseline versus worst grade during treatment for Phase I, Cohort 1. 
LVEF over time will be summarized as mean, median and range (minimum and maximum) and 
will be presented graphically. 
Other safety variables, such as exposure to study medication, concomitant medications, and 
physical examinations, will be analyzed in a similar way. Exposure to study medication will be 
summarized by frequency tables. 
ECOG performance status will be summarized over time and the percentage of patients in each 
category will be presented by bar charts at different time points. 
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Randomized Phase II: Exploration of Safety in mBC  
Safety endpoints will be summarized by treatment group. 
Safety endpoints during the Randomized Phase II part of the study will be assessed via: total 
AEs, Grade ≥ 3 AEs, SAEs, premature withdrawal from study medication, AESIs, events to 
monitor, laboratory parameters, LVEF, exposure to study medication, concomitant medications, 
ECOG performance status, and physical examination. 
The incidence of AEs and SAEs will be summarized according to the primary SOC and within 
each SOC, by MedDRA preferred term. Time to onset of the first episode of AESI will also be 
summarized via Kaplan-Meier method. Patients who died will be listed together with the cause 
of death. 
Laboratory parameters, hematology, and biochemistry will be presented in shift tables of NCI 
CTCAE grade at baseline versus worst grade during treatment in the Randomized Phase II part 
of the study. 
LVEF over time will be summarized as mean, median and range (minimum and maximum) and 
will be presented graphically. 
Other safety variables, such as exposure to study medication, concomitant medications, and 
physical examinations, will be analyzed in a similar way. Exposure to study medication will be 
summarized by frequency tables. 
ECOG performance status will be summarized over time and the percentage of patients in each 
category will be presented by bar charts at different time points. 
Phase I, Cohort 2: MTD-Finding: mGC 
The number and the proportion of patients with DLTs will be used as the primary measure for 
the MTD determination. The definition of DLTs is presented in Section 5.1.4. DLTs for this part 
of the study will be summarized by treatment dose. 
Safety parameters will be summarized in a similar way to that described for Phase I, Cohort 1 in 
mBC. 
Pharmacokinetic Analysis 
The following PK parameters of trastuzumab emtansine and capecitabine (not limited to these 
listed) will be determined only in the Phase I part of the study in all patients who receive study 
treatment using either non-compartmental and/or population methods, if data allow: 
 
Serum concentrations of trastuzumab emtansine (conjugate) and total trastuzumab 
 
Plasma concentrations of DM1, capecitabine, and its active metabolite 5-fluorouracil (5-FU) 
 
Total exposure (area under the serum concentration-time curve [AUC])  
 
Maximum concentration (Cmax)  
 
CL  
 
Volume of distribution (Vd) 
 
Terminal half-life (T1/2) 
All PK parameters will be listed and tabulated by treatment dose and by Cohort. Descriptive 
summary statistics including arithmetic mean, geometric mean (e.g., AUC and Cmax), median, 
range, standard deviation (s.d.), and coefficient of variation will be presented for each Cohort. 
Nonlinear mixed effects modeling will also be used; details will be presented in the SAP. 
Exploratory Analyses 
For all patients with mBC (Phase I, cohort 1; Phase II Exploration of Efficacy and Safety in 
mBC), a retrospective central confirmation of the HER2 status will be done. Further  
exploratory analyses will be done according to centrally confirmed HER2 status for selected 
endpoints, e.g. BOR and safety (AEs, SAEs, Grade ≥ 3 AEs, and AESIs). 
Subgroup analysis for BOR, safety (AEs, SAEs, AEs with Grade ≥ 3, and AESIs) in the 
Randomized Phase II part of the study will be presented for both treatment groups with respect 
to: elderly versus younger patients; patients with ECOG 0–1 versus ECOG 2; and patients with 
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≤1 versus >1 prior treatment line for metastatic disease. More details will be presented in the 
SAP. 
Pharmacoeconomic Endpoint 
The number of hospital visits, number of days admitted, and type of visits (emergency 
department versus inpatient care) will be collected and compared. The reason for admission 
(disease progression versus AE) will also be assessed. 
Determination of Sample Size 
Sample Size for Phase I: MTD-Finding: mBC 
This part will be based on a classical 3 plus 3 Phase I design. A minimum of 6 and up to 
18 patients will be enrolled in Cohort 1. There is no formal sample size estimation for this part. 
Sample Size for Randomized Phase II: Exploration of Efficacy and Safety in mBC 
The sample size for the primary endpoint BOR is based on a Fisher’s exact test with an alpha 
level of 5% (one-sided), power of 70% and the clinical assumption of a BOR rate of 43% with 
trastuzumab emtansine alone and 62.5% with the combination of trastuzumab emtansine and 
capecitabine. Approximately 160 patients (approximately 80 patients in each treatment group), 
including a 15% withdrawal rate, will be randomized with a 1:1 ratio to either trastuzumab 
emtansine alone or the combination of trastuzumab emtansine and capecitabine.  
Stratification Factors 
The following stratification factor will be implemented in the Randomized Phase II part of the 
study: 
 
Number of prior lines of treatment for metastatic disease (≤1 or >1; excluding single-agent 
hormones). 
A treatment line is defined as any treatment regimen given to a patient from treatment initiation 
until confirmed disease progression. 
Sample Size for Phase I, Cohort 2: MTD-Finding: LA/mGC 
This part will be based on a classical 3 plus 3 Phase I design. Between 3 and 12 patients might 
be enrolled in Cohort 2. There is no formal sample size estimation for this part. 
Interim analysis 
There is no formal interim analysis of efficacy.  
An independent data monitoring committee (IDMC) will recommend whether the Randomized 
Phase II part of the study can commence.  
The IDMC will also monitor safety outcomes after 25, 75, and 150 patients have received at 
least 3 cycles of treatment (Cycle 3 Day 21) in the Randomized Phase II part of the study. 
Afterwards, the IDMC will monitor accumulating patient safety data every 6 months during the 
Randomized Phase II part of the study or as requested. 
Efficacy data will be provided only if required by the IDMC to estimate the risk-benefit balance 
for the patients. Further details on the function and logistics of the IDMC will be provided in the 
IDMC Charter. 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADL 
activities of daily living 
ADC 
antibody-drug conjugate 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ARDS 
acute respiratory distress syndrome 
AST 
aspartate transaminase 
AUC 
area under the serum concentration-time curve 
BC 
breast cancer 
bid 
twice daily 
BML 
below measurable limit 
BOR 
BSA 
best overall response 
body surface area 
BUN 
blood urea nitrogen 
CBR 
clinical benefit rate 
CHF 
congestive heart failure 
CI 
confidence interval 
CL 
clearance 
Cmax 
maximum concentration 
CR 
complete response 
CRO 
contract research organization 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose-limiting toxicity 
DM1 
derivative of maytansine 
DoR 
duration of response 
DPD 
dihydropyrimidine dehydrogenase 
DPYD 
dihydropyrimidine dehydrogenase gene  
5-DFUR 
5’-deoxy-5-fluorouridine 
5-FU 
5-fluorouracil 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
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ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EEA 
European economic area 
EOS 
end of study 
EU 
European Union 
FDA 
FFPE 
Food and Drug Administration 
formalin-fixed paraffin-embedded 
FISH 
fluorescence in situ hybridization 
GC 
gastric cancer 
GCP 
Good Clinical Practice 
GEJ 
HBV 
HCV 
gastroesophageal junction 
hepatitis B virus 
hepatitis C virus 
HER 
human epidermal growth factor receptor  
HER2 
human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
ICH 
International Conference on Harmonisation 
IDMC 
independent data monitoring committee 
IgG 
immunoglobulin 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISH 
in situ hybridization 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
IxRS 
interactive voice/web recognition system 
LA/mGC 
locally advanced/metastatic gastric cancer 
LC-MS/MS 
liquid chromatography electrospray tandem mass 
spectrometry 
LFT 
liver function test 
LPLV 
last patient last visit 
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LVEF 
left ventricular ejection fraction 
mBC 
metastatic breast cancer 
mGC 
metastatic gastric cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multiple-gated acquisition 
N 
number of patients 
NCI 
National Cancer Institute 
NE 
NRH 
NYHA 
not evaluable 
nodular regenerative hyperplasia 
New York Heart Association 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PP 
per-protocol 
PR 
PVC 
partial response 
polyvinyl chloride 
QTcF 
heart rate-corrected QT interval using the Fridericia 
formula 
q3w 
every 3 weeks 
qw 
weekly 
RECIST 
Response Evaluation Criteria for Solid Tumors 
SAE 
SAP 
serious adverse event 
statistical analysis plan 
SGOT 
serum glutamic oxaloacetic transaminase 
SC 
Steering Committee 
s.d. 
standard deviation 
SD 
SDV 
stable disease 
source data verification 
SGPT 
serum glutamic pyruvic transaminase 
SmPC 
Summary of Product Characteristics 
SOC 
SP 
system-organ class 
safety population 
SWFI 
sterile water for injection 
T1/2 
terminal half-life 
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TTF 
time to treatment failure 
TTP 
time to progression 
TTR 
time to response 
ULN 
upper limit of normal 
Vd 
volume of distribution 
Vss 
volume of distribution at steady state 
WBC 
white blood cells 
WHO 
World Health Organization 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON DISEASE 
1.1.1 
HER2-POSITIVE BREAST CANCER 
Breast cancer (BC) is the most common cancer in women worldwide, both in the 
developed and the developing world1, with an estimated 1.67 million new cases 
diagnosed in 2012. It is also the leading cause of cancer death in females in less 
developed regions, accounting for 324,000 deaths (14.3% of all cancer deaths) in 
2012, and the second most common cause of cancer death in women in more 
developed regions (198,000 deaths, 15.4%) after lung cancer.1 Metastatic breast 
cancer (mBC) is incurable, with the primary goal of treatment to extend life and 
palliate symptoms while preserving quality of life. 
Human epidermal growth factor receptor 2 (HER2) is an important prognostic 
factor in BC and is a key factor influence treatment strategies. The human 
epidermal growth factor receptor (HER) tyrosine kinase receptor family 
comprises four receptors: HER1, HER2, HER3, and HER4. These receptors are 
important mediators of cell growth, survival, and differentiation.2 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.3 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 overall response rate (ORR), 
response duration, and progression-free survival (PFS) were associated with a 5-
month overall survival (OS) advantage when trastuzumab was given in the first-
line metastatic setting, as demonstrated in the initial Phase III trial.4  
For patients with HER2-positive mBC, the combination of anti-HER2 therapy and 
a taxane is a globally accepted first-line treatment, based on the OS advantage 
demonstrated in three large pivotal trials.4–6 
However, disease progresses in almost all patients with HER2-positive mBC and 
these patients require additional therapies. Importantly, such tumors continue to 
express high levels of HER2,7 and neither the process of internalization nor the 
level of surface expression is altered when HER2 is bound by trastuzumab.8  
After progression, the standard strategy is further HER2-directed therapy, either 
continuing trastuzumab with a different chemotherapy agent (eg trastuzumab 
plus capecitabine), or changing to a different HER2-directed regimen (eg 
lapatinib plus capecitabine). In a randomized Phase III trial, GBG26, in patients 
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whose disease had progressed on previous trastuzumab-containing therapy, the 
combination of trastuzumab and capecitabine was associated with significantly 
improved time to progression (TTP) (hazard ratio [HR] 0.69, median 8.2 versus 
5.6 months, respectively) and ORR (48% versus 27%) compared with 
capecitabine alone.9 In another 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 
ORR (24% versus 14%) and TTP (median 6.2 months versus 4.3 months) 
compared with capecitabine alone.9   
1.1.2 
HER2-POSITIVE LOCALLY ADVANCED/METASTATIC GASTRIC 
CANCER 
Gastric cancer (GC) remains one of the most common malignancies in the world 
with an estimated 952,000 new cases in 2012.1 GC also continues to be a deadly 
disease; it is the third leading cause of cancer-related death, accounting for 
723,000 deaths (8.8% of all cancer deaths) worldwide in 2012. The only 
potentially curative treatment for GC is complete resection of localized disease. 
The overall 5-year survival for all cases, regardless of initial stage at diagnosis, is 
less than 25%.11-14 Among patients with localized disease who undergo curative 
surgery, approximately 40–60% will have disease recurrence. Patients with 
unresectable disease due to locally advanced growth or metastatic spread have 
the poorest prognosis, with an overall 5-year survival rate in the range of 3% to 
15%.11,13,14  
Whereas HER2 overexpression is associated with a poor prognosis in BC, the 
prognostic significance of HER2 overexpression in GC is not fully defined. 
Studies of HER2 positivity rates in GC have shown a broad variation of HER2 
positivity ranging from 6.8% to 34.0% for immunohistochemistry (IHC) and 7.1% 
to 42.6% for fluorescence in situ hybridization (FISH) techniques.15,16 In a recent 
study, HER2 positivity was shown in 17% of resected esophageal 
adenocarcinomas and was significantly associated with lower tumor grade, less 
invasiveness, fewer malignant nodes, and the presence of adjacent Barrett's 
esophagus.17 
In the ToGA trial (study BO18255), a global, Phase III study of trastuzumab plus 
chemotherapy as first-line treatment for advanced HER2-positive GC,18 an 
overall HER2-positivity rate of 22.1% was observed (810/3667 evaluable 
samples), which is similar to BC. A higher HER2 positivity rate was seen in 
adenocarcinoma of the gastroesophageal junction (GEJ) than in the stomach 
(33.2% versus 20.9%), and intestinal type GCs showed a significantly higher 
HER2 positivity rate than diffuse or mixed-type tumors (intestinal: 32.2%, diffuse: 
6.1%, mixed: 20.4%).19  
In the ToGA trial, the addition of trastuzumab to chemotherapy (capecitabine or 
fluorouracil combined with cisplatin) for the treatment of patients with HER2-
positive (defined as IHC 3+ or FISH positive), inoperable, locally advanced or 
recurrent and/or metastatic adenocarcinoma of the stomach or GEJ resulted in 
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an increase in OS (median 13.8 months versus 11.1 months, HR 0.74, p = 
0.0046), ORR (47% versus 35%), PFS (median 6.7 versus 5.5 months), and TTP 
(median 7.1 versus 5.6 months) compared with chemotherapy alone.18  
1.2 
BACKGROUND ON STUDY DRUGS  
1.2.1 
TRASTUZUMAB EMTANSINE 
Trastuzumab emtansine (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, a humanized monoclonal 
antibody directed against the extracellular region of HER2; an average of 3.5 
molecules of derivative of maytansine (DM1; maytansinoid), an anti-microtubule 
agent; and the thioether linker maleimidylmethyl cylcohexane-1-carboxylate, 
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, was studied in approximately 800 cancer 
patients in the 1970s and 1980s, with responses seen in patients with breast and 
lung cancers.20,21 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.22,23 
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Data from clinical trials of trastuzumab emtansine that are relevant to the design 
of the current trial are summarized below. Please refer to the trastuzumab 
emtansine Investigator’s Brochure for further information on all of the completed 
and ongoing trastuzumab emtansine studies. 
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.29,30 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 (qw) 
schedule. 
On the q3w dosing schedule, dose-limiting toxicities (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. On the qw schedule, 2.4 mg/kg was identified as the 
MTD. 
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 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 whose disease had progressed on 
previous HER2-directed therapy and conventional chemotherapy.31 
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%–
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46.6%) by investigator assessment and 25.9% (95% CI: 18.4%–34.4%) by 
independent review. The clinical benefit rate (CBR; defined as complete 
response [CR], partial response [PR], or stable disease [SD] 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 
independent review. 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. 
The most common adverse events (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.32 Patients must have received an anthracycline, trastuzumab, a taxane, 
lapatinib, and capecitabine given in the neoadjuvant, 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 experienced progressive disease (PD) on their most recent 
treatment. 
The primary objectives of this study were: 1) to assess the ORR as determined 
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 (CR or PR) of 34.5% (95% CI: 26.1%–43.9%; 
38 of 110 patients) by independent review 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 median PFS by independent review was 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 
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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 aspartate transaminase 
(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%). Serious AEs (SAEs) were 
recorded in 28 patients (25.5%), the most common being cellulitis (3.6%), pyrexia 
(2.7%), and pneumonia (2.7%). There was one Grade 5 AE (hepatic dysfunction), 
which was recorded as possibly related to trastuzumab emtansine. The patient 
had pre-existing non-alcoholic fatty liver disease as well as multiple other 
comorbidities, including renal insufficiency. 
1.2.1.4 
Study TDM4450g 
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.26 This study completed enrollment in December 2009 
(n = 137). The co-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, OS, 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. 
As of 15 November 2010, the median PFS was 14.2 months in the trastuzumab 
emtansine arm versus 9.2 months in the trastuzumab plus docetaxel arm. The 
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 as first-
line therapy for 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 
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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.33 No meaningful effect of trastuzumab emtansine 
on the corrected QT interval was seen 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 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 to baseline. Following the third infusion of 
trastuzumab emtansine, the baseline-adjusted mean QTcF interval at both the 
15-minute and the 60-minute post-infusion time points was increased by 4.7 ms. 
No patient exhibited a mean 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, the ORR was 25.5% (95% CI: 15.2%–38.5%) as assessed by the 
investigator; no independent review was performed. 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 
Phase III Study TDM4370g 
A randomized, open-label Phase III trial (TDM4370g; EMILIA) compared single-
agent trastuzumab emtansine versus lapatinib and capecitabine in patients with 
HER2-positive locally advanced unresectable BC or mBC who had received a 
prior taxane and trastuzumab therapy and had documented PD.27  
Patients were randomized in a 1:1 ratio to trastuzumab emtansine 3.6 mg/kg IV 
q3w or the combination of oral capecitabine 1,000 mg/m2 twice daily (bid) on 
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Days 1–14 q3w plus oral lapatinib 1,250 mg/day given as continuous dosing. 
Treatment was continued until PD (as assessed by the investigator), 
unmanageable toxicity, or study termination. PFS and OS were co-primary 
endpoints, with PFS based on modified RECIST34 and assessed by independent 
review. Key secondary endpoints were ORR, DoR, and CBR, determined both by 
the investigator and by independent review. 
The study demonstrated statistically significant and clinically meaningful 
improvements in both PFS and OS for trastuzumab emtansine compared with 
lapatinib plus capecitabine. Median PFS was 9.6 months in the trastuzumab 
emtansine arm versus 6.4 months in the control arm (HR = 0.65; 95% CI: 0.55–
0.77; p < 0.001, log-rank test). Median OS was 30.9 months versus 25.1 months, 
respectively (HR = 0.68; 95% CI: 0.55–0.85; p < 0.001, log-rank test).  
This benefit was supported by consistent improvements in all secondary efficacy 
endpoints, including investigator-assessed PFS, ORR, time to treatment failure 
(TTF), and the patient-reported outcome of time to symptom progression. The 
ORR in the trastuzumab emtansine arm was 43.6% (95% CI: 38.6%–48.6%) 
compared with 30.8% (95% CI: 26.3%–35.7%) in the control arm (based on 786 
evaluable patients). 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; 
that of trastuzumab emtansine (40.8%; n = 490) was 200. The rates of SAEs for 
both arms were similar (control arm 18% versus trastuzumab emtansine 15.5%). 
Based on the results of this phase III trial, both the Food and Drug Administration 
(FDA) in the US and the European Commission in Europe approved trastuzumab 
emtansine for the treatment of HER2-positive mBC previously treated with 
trastuzumab and a taxane.  
1.2.1.7 
Phase III study TDM4997g 
A second open-label randomized Phase III trial (TDM4997g; TH3RESA) 
compared single-agent trastuzumab emtansine versus the investigator’s choice 
of therapy in patients with HER2-positive advanced BC who had previously 
received two or more HER2-directed regimens in the advanced setting, including 
trastuzumab and lapatinib, and previous taxane therapy in any setting.28 A total 
of 602 patients were randomized in a 2:1 ratio (404 to trastuzumab emtansine 
and 
8 to physician’s choice).  
After median follow-up of approximately 7 months in both arms, 219 patients 
(54%) in the trastuzumab emtansine group and 2  (65
) in the physician’s 
choice group had experienced PFS events. PFS was significantly improved with 
trastuzumab emtansine compared with physician’s choice (HR 0.528, p<0.0001; 
median PFS 6.2 months with trastuzumab emtansine versus 3.3 months in the 
control arm. The HR for OS at the interim analysis was 0.552 (95% CI 0.369–
0.826) but the stopping boundary was not crossed.  
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Grade ≥3 AEs occurred less frequently with trastuzumab emtansine than with 
physician’s choice (32
 of patients vs 43
). Grade ≥3 neutropenia, diarrhea, 
and febrile neutropenia were less common with trastuzumab emtansine than 
physician’s choice, whereas grade ≥3 thrombocytopenia (5% vs 2%) was more 
common with trastuzumab emtansine.  
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 qw regimens of trastuzumab emtansine 
administration are presented in Table 1. 
Table 1 Cycle 1 Mean (s.d.) Pharmacokinetic Parameters for Trastuzumab 
Emtansine Following Trastuzumab Emtansine Administration q3w 
and qw in Study TDM3569g 
 
Dose 
(mg/kg) 
No. of 
Patients 
Cmax 
(μg/mL) 
AUCinf 
(day μg/mL) 
T1/2 
(day) 
Vd 
(mL/kg) 
CL 
(mL/day/kg) 
q3w 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) 
qw 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; s.d. = standard deviation; 
T1/2 = terminal half-life; Vd = volume of distribution. 
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 
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administered within a q3w cycle with a 2.4 mg/kg qw regimen compared with 3.6 
mg/kg q3w.29,30 
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.35 
An aggregate PK assessment of trastuzumab emtansine was performed with 
samples from studies TDM3569g, TDM4258g, TDM4374g, and TDM4688g.36,37 
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., maximum concentration [Cmax], area under the serum 
concentration-time curve [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. 
Weekly administration of trastuzumab emtansine in study TDM3568g at a dose 
of 2.4 mg/kg showed consistent PK data with the q3w dosing schedule.29 
1.2.2 
CAPECITABINE 
Capecitabine (Xeloda®) is a fluoropyrimidine carbamate with antineoplastic 
activity. It is an orally administered systemic prodrug of 5’-deoxy-5-fluorouridine 
(5’-DFUR), which is converted to 5-fluorouracil (5-FU) in the tumor, where it 
inhibits DNA synthesis and slows down tumor tissue growth. It is approved in 
combination with docetaxel and as monotherapy in mBC. Please see the national 
Xeloda® prescribing information or Investigator brochure for more information. 
The activity of capecitabine as single-agent chemotherapy was initially 
demonstrated in two multicenter Phase II clinical trials (before testing of HER2 
status was standard) in patients with locally advanced or mBC after failure of a 
taxane and an anthracycline-containing chemotherapy regimen or for whom 
further anthracycline therapy was not indicated.38,39 In these trials, a total of 236 
patients were treated with capecitabine (1,250 mg/m2 bid for 2 weeks followed by 
1-week rest period). The ORRs (investigator assessment) were 20% (first trial) 
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and 25% (second trial). The median TTP was 3.1 months and 3.2 months, 
respectively. Median OS was 12.6 months and 12.3 months, respectively. 
The combination of capecitabine and docetaxel was studied as treatment for 
locally advanced or mBC after failure of anthracycline-containing chemotherapy 
in a multicenter randomized controlled Phase III clinical trial (SO14999).40 In this 
trial, 255 patients were randomized to treatment with capecitabine (1,250 mg/m2 
bid for 2 weeks followed by a 1-week rest period) and docetaxel (75 mg/m2 as a 
1-hour IV infusion q3w) and 256 patients were randomized to treatment with 
docetaxel alone (100 mg/m2 as a 1-hour IV infusion q3w). OS was superior in the 
capecitabine plus docetaxel combination arm (HR 0.775; p = 0.0126). Median 
OS was 14.5 months (capecitabine plus docetaxel) versus 11.5 months 
(docetaxel alone). The ORR in the all-randomized population (investigator 
assessment) was 41.6% (capecitabine plus docetaxel) versus 29.7% (docetaxel 
alone; p = 0.0058). TTP was superior in the capecitabine plus docetaxel 
combination arm (HR 0.652; p < 0.0001). The median TTP was 6.1 months 
(capecitabine plus docetaxel) versus 4.2 months (docetaxel alone).  
This trial led to the randomized Phase II CHAT trial evaluating the addition of 
capecitabine to first-line trastuzumab and docetaxel for locally advanced or 
metastatic HER2-positive mBC.41 PFS was significantly improved with the 
addition of capecitabine (HR 0.72; median 17.9 months versus 12.8 months in 
patients receiving docetaxel and trastuzumab without capecitabine), although 
there was no difference in ORR (71% versus 73%, respectively). 
1.2.2.1 
Study BO18255: Capecitabine and Trastuzumab in LA/mGC 
A global Phase III study (ToGA trial, BO18255) of trastuzumab plus 
chemotherapy as first-line treatment for advanced HER2-positive GC was 
conducted in 584 patients previously untreated for HER2-positive inoperable 
locally advanced or recurrent and/or metastatic adenocarcinoma of the stomach 
or GEJ. Patients received either capecitabine or fluorouracil combined with 
cisplatin or the same chemotherapy in combination with trastuzumab. The 
primary study endpoint was OS, defined as the time from the date of 
randomization to the date of death from any cause. At the time of the analysis a 
total of 349 randomized patients had died: 182/290 patients (62.8%) in the 
control arm and 167/294 patients (56.8%) in the trastuzumab-containing arm. 
The majority of the deaths were due to events related to the underlying cancer.18 
Most patients enrolled in the study were male (76%); 52.9% were Asian and 
37.7% were white. The primary tumor site was the stomach for 81.8% of patients, 
with the others having GEJ tumors. The addition of trastuzumab to chemotherapy 
resulted in an increase in median OS from 11.1 months to 13.8 months (HR 0.74, 
p = 0.0046). ORR (47% versus 35%), PFS (median 6.7 versus 5.5 months), and 
TTP (median 7.1 versus 5.6 months) were also significantly increased with the 
addition of trastuzumab to chemotherapy compared with chemotherapy alone. 
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With regard to OS, a treatment effect could not be excluded in any predefined 
subgroup, including primary tumor site, histologic subtype, method of determining 
HER2-positivity, performance status, chemotherapy regimen, age, gender, and 
region of enrollment. A multivariate analysis for OS showed a consistent result, 
with an adjusted HR of 0.72 (p = 0.0036); variables found to influence primary 
outcome included Eastern Cooperative Oncology Group (ECOG) performance 
status (0 or 1 versus 2), prior gastrectomy, and Asian region of enrollment (data 
on file). A multivariate analysis of OS for patients enrolled in Japan, from which 
the bulk of Asian patients were enrolled, demonstrated a HR of 0.68. This was 
consistent with the overall study results.42 
A pre-planned subgroup analysis by IHC score indicated that positive treatment 
effects were greater in tumors with higher levels of HER2 expression. Among 
patients whose tumors had these higher levels of HER2 expression, the median 
OS was 11.8 months versus 16 months (HR = 0.65; 95% CI: 0.51–0.83) and 
median PFS was 5.5 months versus 7.6 months (HR = 0.64; 95 % CI: 0.51–0.79) 
for chemotherapy versus chemotherapy plus trastuzumab respectively. For OS, 
the HR was 0.75 (95% CI: 0.51–1.11) in the IHC 2+/FISH+ group and 0.58 (95% 
CI: 0.41–0.81) in the IHC 3+/FISH+ group.18 
The addition of trastuzumab to chemotherapy did not result in an increased 
incidence of severe (Grade 3/4) or fatal AEs. There were no additional significant 
safety issues with trastuzumab used in the treatment of advanced GC over and 
above those observed when it was used in BC. Taken together, the results of the 
ToGA trial (BO18255) not only demonstrate the role of HER2 suppression in the 
treatment of HER2-positive GC but also show that HER2-directed therapies can 
be added to conventional chemotherapy regimens without substantial increases 
in side effects. 
1.2.3 
PRECLINICAL DATA OF THE COMBINATION OF TRASTUZUMAB 
EMTANSINE AND A FLUOROPYRIMIDINE 
In preclinical BC models, additive anti-tumor activity was observed with 
combinations of trastuzumab emtansine and 5-FU (seeFigure 2).43 In GC models 
a similar additive effect was observed with trastuzumab emtansine and 
capecitabine (see Figure 3 [data on file]). 
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Figure 2 MMTV HER2 Fo5 Mammary Tumor Transplants 
 
T-DM1 = trastuzumab emtansine; 5-FU = 5-fluorouracil 
 
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and trastuzumab in the metastatic setting. The combination of capecitabine and 
trastuzumab has demonstrated significant efficacy benefit when compared with 
capecitabine alone.9  
The Phase III, TDM4370g trial met its co-primary endpoint of improving PFS (by 
independent review) and OS compared with the combination of lapatinib and 
capecitabine (see Section 1.2.1.6).  
Based on the studies mentioned above, the combination of trastuzumab 
emtansine and capecitabine could provide the potential for enhanced anti-tumor 
efficacy in mBC compared with single-agent trastuzumab emtansine or 
trastuzumab in combination with chemotherapy. Furthermore, preclinical data 
suggest that the combination of trastuzumab emtansine and capecitabine has an 
additive effect (see Section 1.2.3). 
Approximately 2,000 patients with BC have been treated in trastuzumab 
emtansine clinical trials with an acceptable safety profile and a positive risk-
benefit ratio. A broad development program is in place to seek approval for 
indications for mBC. Capecitabine in combination with an anti-HER2 agent is a 
proven efficacious regimen with a well-established safety profile in mBC. 
Trastuzumab emtansine and capecitabine have no known significant overlapping 
toxicities. As part of the Phase I conduct, regular teleconference calls with the 
investigators will be held to discuss the study treatment risk-benefit profile for 
each patient. An Independent Data Monitoring Committee (IDMC) will be 
established with the main responsibility of assessing the risk-benefit for the 
Phase II part of the study. Therefore, exploring the benefit of combination therapy 
of trastuzumab emtansine and capecitabine in patients with mBC seems justified. 
1.3.2 
FOR MGC 
As for mBC, the primary goal of treatment for metastatic gastric cancer (mGC) is 
to maximize patients’ survival and quality of life. 
In HER2-positive gastric tumors, anti-HER2 therapy has shown benefit. In the 
ToGA study (BO18255), the combination of chemotherapy and trastuzumab 
significantly improved OS versus chemotherapy alone (see Section 1.2.2.1) in 
this population. Fluoropyrimidine-based therapies (capecitabine, 5-FU) are the 
standard of care in mGC in general and were also the most frequent combination 
agents used in the ToGA trial (BO18255; see Section 1.2.2.1).  
Furthermore, preclinical data suggest that the combination of trastuzumab 
emtansine and capecitabine has an additive effect (see Section 1.2.3).  
A development program for trastuzumab emtansine is in place to seek approval 
for mGC indications. Capecitabine in combination with trastuzumab is a proven 
efficacious regimen with a well-established safety profile in mGC. Trastuzumab 
emtansine and capecitabine might have overlapping toxicities and therefore 
safety monitoring is in place to avoid exposing patients to harm. Therefore, 
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exploring the benefit of combination therapy of trastuzumab emtansine and 
capecitabine in patients with mGC seems justified. 
In the ToGA study in LA/mGC, trastuzumab exposure was lower than that 
observed in breast cancer studies. Based on this observation, together with 
pharmacokinetic results and findings from a Phase I study in mBC, it was 
considered that a weekly trastuzumab emtansine regimen may provide higher 
cumulative trastuzumab emtansine exposure than the q3w schedule and was 
therefore chosen for the Phase I, Cohort 2 part of the present study in LA/mGC. 
This approach has subsequently been supported by findings from stage I of the 
adaptive phase II/III BO27952 trial in this setting (see Section 3.3.2.2). In October 
2013, the IDMC for the BO27952 trial recommended selection of the weekly 2.4 
mg/kg regimen for further evaluation in the phase III part of the trial based on 
pharmacokinetic, safety, and efficacy data available at the time. 
Results from the Phase I part of the study in mGC will be used as supporting 
information for future studies in the indication. 
2. 
OBJECTIVES 
2.1 
PHASE I: MTD-FINDING OF TRASTUZUMAB 
EMTANSINE AND CAPECITABINE IN MBC 
2.1.1 
PRIMARY OBJECTIVE 
 
To determine the MTD of the combination of trastuzumab emtansine and 
capecitabine in patients with HER2-positive mBC  
2.1.2 
SECONDARY OBJECTIVES 
To assess the: 
 
PK of trastuzumab emtansine, capecitabine and their metabolites  
 
Safety of the combination of trastuzumab emtansine and capecitabine 
 
ORR 
2.2 
RANDOMIZED PHASE II: EXPLORATION OF 
EFFICACY AND SAFETY IN MBC  
2.2.1 
PRIMARY OBJECTIVE 
To explore the efficacy of the combination of trastuzumab emtansine and 
capecitabine compared with trastuzumab emtansine alone in patients with HER2-
positive mBC, as measured by ORR by RECIST v.1.1 per investigator local 
assessment 
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2.2.2 
SECONDARY OBJECTIVES 
To assess the safety profile of the combination of trastuzumab emtansine and 
capecitabine compared with trastuzumab emtansine alone 
To explore the efficacy of the combination of trastuzumab emtansine and 
capecitabine compared with trastuzumab emtansine alone in patients with HER2-
positive mBC, as measured by: 
 
Time to response (TTR)  
 
DoR 
 
TTP 
 
TTF 
 
PFS 
 
CBR 
 
OS 
2.3 
PHASE I: MTD FINDING OF TRASTUZUMAB 
EMTANSINE AND CAPECITABINE IN LA/MGC 
2.3.1 
PRIMARY OBJECTIVE 
To determine the MTD of the combination of trastuzumab emtansine and 
capecitabine in patients with LA/mGC  
2.3.2 
SECONDARY OBJECTIVES 
To assess the: 
 
PK of trastuzumab emtansine, capecitabine, and their metabolites  
 
Safety of the combination of trastuzumab emtansine and capecitabine 
 
ORR 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is an international, multicenter Phase I/II dose-finding study of two dosing 
schedules of trastuzumab emtansine and capecitabine combination therapy in 
HER2-positive mBC and LA/mGC.  
The study is designed to determine the MTD of capecitabine in combination with 
trastuzumab emtansine in Phase I studies in patients with HER2-positive mBC or 
LA/mGC.  
The efficacy and safety of the combination in patients with mBC will also be 
explored in a randomized, open-label Phase II part of the study.  
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3.1.1 
OVERVIEW OF STUDY DESIGN 
Overview of Study Design 
The study is designed to determine the MTD of capecitabine in combination with 
trastuzumab emtansine in patients with HER2-positive mBC or LA/mGC using a 
Phase I design, followed by a randomized, open-label Phase II part of the study 
to explore the efficacy and safety of the combination in patients with HER2-
positive mBC. There will be no follow-on randomized exploration of efficacy in 
mGC. Results from the Phase I study in LA/mGC will be used as supporting 
information for future studies in the indication. 
Cohort 1 for patients with mBC will open first and the MTD will be established. 
Once the MTD is defined, both the randomized Phase II trial for patients with 
HER2-positive mBC and the Phase I Cohort 2 for patients with LA/mGC will open. 
An overview of the study design is depicted in Figure 4. 
Duration of Treatment and Patient Follow-up 
Duration of treatment: All patients will be treated until investigator-assessed PD, 
unacceptable toxicity, withdrawal of consent, death, reasons deemed by the 
treating physician, or study termination by the Sponsor. In case of toxicities 
requiring the discontinuation of capecitabine, single agent trastuzumab 
emtansine may be continued. In case of toxicities requiring the discontinuation of 
trastuzumab emtansine, the patient will be followed up until EOS (treatment with 
capecitabine alone is not allowed).  
If at the time of study closure there are patients whose disease has not 
progressed and who are still receiving study treatment, they will be offered the 
possibility to continue treatment by enrolling in an extension study at the 
discretion of the investigator. 
Patient follow-up: All patients will be followed up until withdrawal of consent, 
death, or for up to a maximum of 2 years after the last patient was randomized in 
the Randomized Phase II part of the study, whichever occurs first. 
Duration of Study, Database Closure and Data Reporting 
The duration of the study is estimated to be approximately 4 years. Recruitment 
is estimated to last 2 years in total (1 year for the MTD-Finding study in mBC and 
1 year for the Phase II Exploration of Efficacy and Safety in mBC). See Section 
3.2 for further details about EOS.  
Specifically in Phase I, cohort 2, if dose level -2 is too toxic in LA/mGC, 
recruitment into the LA/mGC cohort will be closed. See Section 3.1.1.3 for details 
of treatment continuation if patients are still responding to treatment at this time.  
Data may be published/presented publicly at the end of each cohort e.g., once 
the MTD for Cohort 1 for mBC has been defined and the dose for Phase II 
Exploration of Efficacy and Safety has been selected, and after the prespecified 
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analyses for the Randomized Phase II exploration of efficacy and safety in mBC. 
The Clinical Study Report (CSR) will be finalized/published within 1 year after 
EOS (LPLV). 
 
Figure 4 Overview of Study Design 
 
 
 
COHORT 1 mBC 
 
COHORT 2 LA/mGC 
Phase I 
Dose Finding 
 
 
 
n = ~6–18 
3 plus 3 classical design 
Trastuzumab emtansine: 3.6 mg/kg 
q3w 
Capecitabine: Dose Levels 1 to -21 
 
 
 
n = ~3–12 
3 plus 3 classical design 
Trastuzumab emtansine: 2.4 
mg/kg qw 
Capecitabine: Dose Levels -1 to 
-21,3 
 
 
 
Randomized 
Phase II 
Exploration of 
Efficacy and 
Safety 
 
 
n = ~160  
Randomized, open-label with two 
treatment groups4 
Trastuzumab emtansine: 3.6 mg/kg 
q3w 
Capecitabine: MTD defined 
 
 
 
1 Capecitabine doses are administered daily on Days 1–14 q3w 
2 The MTD defined in the mBC Phase I study will be implemented in the mBC Randomized 
Phase II and mGC Phase I studies 
3 Cohort 2 will open to recruit patients with LA/mGC using the MTD defined in Phase I for patients 
with mBC. Dose Level 1 will not be explored in Cohort 2 (see also Section 3.3.2.2) 
4 Stratification factor: Number of prior lines of treatment for metastatic disease (≤1 or >1; 
excluding single-agent hormones) 
mBC = metastatic breast cancer; LA/mGC = locally advanced/metastatic gastric cancer; MTD = 
maximum tolerated dose; q3w = every 3 weeks; qw = weekly. 
 
A schedule of assessments is provided in Appendix 1. 
3.1.1.1 
Overview of Phase I Design in Patients with mBC 
An overview of the Phase I study design is depicted in Figure 5. 
MTD defined2 
MTD defined2 
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Figure 5 Overview of Phase I Dose Finding Study Design 
 
Determination of the MTD in Patients with mBC  
The trial will first investigate the feasibility of the combination of capecitabine and 
trastuzumab emtansine q3w in one cohort of up to 18 patients, by de-escalating 
the dose of capecitabine from 750 mg/m2 bid to 650 mg/m2 bid on Days 1 to 14 
q3w with a 3 plus 3 classical Phase I design. Cohort 1 will open first and enroll 
patients with HER2-positive mBC. 
Enrollment into Cohort 1 
MTD-finding in patients with mBC (Phase I) 
According to the 3 plus 3 classical study design, Cohort 1 will start with the 
enrollment of 3 patients at Dose Level 1. Patients will be evaluated for DLTs as 
specified in the DLT definition (see Section 5.1.4). The dose of trastuzumab 
emtansine is fixed at 3.6 mg/kg q3w. Three dose levels of capecitabine 
administered bid on Days 1 to 14 q3w will be tested. 
The following doses will be explored in Cohort 1: 
Dose Level X 
N=3 
DLT in 1/3 
DLT in >1/3 
Expand/confirm (+3 patients) 
N=6 
DLT in 0/3  
DLT in ≤1/6 
De-escalate to Dose Level ( −)1 
N=3 
or 
STOP2 
Open the Randomized 
Phase II part 
MTD = Current level 
DLT in >1/6 
1 Repeat with the new dose level until the MTD is established 
2 If Dose Level -2 is too toxic (DLT in > 1/6 patients), the study will be 
terminated. 
DLT = dose-limiting toxicity; MTD = maximum tolerated dose 
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Dose Level 1: 750 mg/m2 capecitabine bid plus 3.6 mg/kg q3w trastuzumab 
emtansine 
Dose Level -1: 700 mg/m2 capecitabine bid plus 3.6 mg/kg q3w trastuzumab 
emtansine 
Dose Level -2: 650 mg/m2 capecitabine bid plus 3.6 mg/kg q3w trastuzumab 
emtansine 
The following MTD determining rules will be applied during the MTD-Finding 
treatment phase: 
 
Step 1: Three patients will be enrolled at Dose Level 1 
 
Step 2: The toxicity of Dose Level 1 will be monitored and the following 
actions taken: 
a) If none of these 3 patients (0/3) experiences a DLT, the MTD will be 
established as the current dose level and will need to be confirmed in 3 
more patients (to achieve DLTs in ≤ 1/6 patients at that dose level) 
b) If 1 of the initial 3 patients (1/3) experiences a DLT, an additional 3 
patients should be enrolled and treated at the same dose, i.e., Dose Level 
1 
c) If no additional patients experience a DLT (1/6), the MTD will be 
established as the current dose level 
d) If 1 or more additional patients experience a DLT (> 1/6), the dose will be 
de-escalated to the next lowest dose level. If no more than 1 patient 
experiences a DLT (≤ 1/6) after dose de-escalation, the dose will be 
considered the MTD and, following IDMC recommendation, will be further 
explored in the Randomized Phase II part of the study. Dose re-escalation 
will not be allowed. If 2 or more patients experience a DLT (> 1/6) after 
dose de-escalation, de-escalation should continue to the next lowest dose 
level. Based on the DLT findings, the next dose level may be considered 
the MTD and, following IDMC recommendation, be further explored in the 
Randomized Phase II part of the study or the study may be terminated 
if DLTs occur in > 1/6 patients at Dose Level -2. 
 In order to define the dose for the Randomized Phase II Exploration of Efficacy 
and Safety part of the study, evaluation will include not only the DLTs during 
Cycle 1 but also all available safety information during the subsequent cycles. 
The dose level considered optimal will be the dose level selected to proceed to 
the Phase II and LA/mGC parts of the study. 
Once the appropriate dose of study medication is established, the Randomized 
Phase II part of the study and Phase I, Cohort 2 will open as shown in Figure 4. 
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3.1.1.2 
Overview of Phase II: Exploration of Efficacy and Safety in 
Patients with mBC  
After review of safety data from Part 1, cohort 1, the IDMC recommended a 
regimen of capecitabine 700 mg/m2 bid days 1–14 in combination with 
trastuzumab emtansine 3.6 mg/kg q3w for further evaluation. The Phase II part of 
the study will explore the efficacy and safety of this recommended regimen 
compared with trastuzumab emtansine alone in patients with HER2-positive mBC. 
See Section 3.1.1 for details of duration of treatment.  
Approximately 160 additional patients with HER2-positive mBC will be 
randomized into the Phase II part of the study. Patients in the Phase I part of the 
study will not contribute to the Phase II part of the study; however, they will be 
followed-up until end of study (EOS). 
 
3.1.1.3 
Overview of Phase I Design in LA/mGC Patients 
Determination of the MTD in Patients with LA/mGC  
Cohort 2 will enroll patients with HER2-positive LA/mGC. Trastuzumab 
emtansine will be administered qw at a fixed dose of 2.4 mg/kg and capecitabine 
will be started at 700 mg/m2 bid, the MTD defined for patients with mBC in 
Cohort 1.  
Enrollment into Cohort 2 
Cohort 2 will open with a 3 plus 3 classical design to investigate the feasibility of 
combination therapy of capecitabine and trastuzumab emtansine in up to 12 
patients with LA/mGC. The capecitabine dose will be de-escalated from the 
starting dose of 700 mg/m2 bid (the MTD recommended in Cohort 1).  
The dose levels for de-escalation of capecitabine will be the same as described 
for Cohort 1, except for Dose Level 1, which will not be explored in patients with 
mGC (see also Section 3.3.2.2). 
If Dose Level -1 (700 mg/m2 bid, the MTD recommended in cohort 1) is well 
tolerated (DLT in ≤ 1/6), this dose will be established as the MTD for LA/mGC. 
 
If Dose Level -1 is not tolerated in Cohort 2 (DLT in > 1/3 or > 1/6 patients), 
de-escalation will be to Dose Level -2. 
 
If Dose Level -2 is not tolerated in Cohort 2 (DLT in > 1/6), the combination 
will be considered not feasible in LA/mGC and Cohort 2 will be terminated. 
Patients who, at that time, experience response according to RECIST v.1.1 
will be offered the possibility to continue on trastuzumab emtansine as a 
single agent, or with the combination, based on risk-benefit balance and 
agreement with the Steering Committee (SC). 
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3.1.1.4 
Number of Patients 
Overall, it is anticipated that the maximum number of patients enrolled into the 
study will be approximately 190. 
Phase I, Cohort 1: mBC 
Between 6 and 18 patients will be enrolled into Cohort 1 to determine the MTD of 
capecitabine in combination with trastuzumab emtansine in patients with mBC. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
For this part of the study, a total of approximately 160 patients with mBC will be 
randomized. 
Phase I, Cohort 2: mGC 
After the MTD in Cohort 1 has been established, 3–12 patients will be enrolled 
into Cohort 2 to determine the MTD of capecitabine in combination with 
trastuzumab emtansine in patients with mGC. 
3.1.1.5 
Number of Centers 
This is a multicenter, international study. 
3.1.2 
STEERING COMMITTEE 
A SC has been established for this study. Initially, it is composed of the 
investigators participating in the Phase I, Cohort 1 part of the study and one 
medical representative and one statistician of the Sponsor. The study design and 
DLT definition have been developed by the SC. See the SC Charter for further 
information. 
The SC will collectively review the status of the ongoing patients in Phase I on a 
regular basis. The SC will adjudicate in the event of DLTs that are not covered by 
the existing DLT criteria. 
3.1.3 
INDEPENDENT DATA MONITORING COMMITTEE 
An IDMC will review the safety outcomes for patients enrolled in Phase I, Cohort 
1 and recommend whether the Randomized Phase II part of the study can 
commence. The IDMC will also monitor safety outcomes after 25, 75, and 150 
patients have received at least 3 cycles (Cycle 3 Day 21) of treatment in the 
Phase II part of the study. Afterwards, the IDMC will monitor accumulating patient 
safety data every 6 months during the Randomized Phase II part of the study or 
as requested. 
3.2 
END OF STUDY 
EOS is defined as the last patient last visit (LPLV) at the end of the follow-up 
period, as defined in Section 3.1.1. This will be the last data collection point, 
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which can be a clinic visit or a laboratory sample. LPLV is expected to occur 
approximately 2 years after the last patient has been randomized into the Phase 
II part of the trial. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
RATIONALE FOR PATIENT GROUP SELECTION 
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 therapy (see the 
Herceptin® national prescribing information). Measurement of HER2 gene 
amplification has traditionally been performed using IHC. HER2 gene 
amplification determined by ISH has also proven to be a reliable method for 
demonstrating HER2-positive status.44 
This study will enroll patients diagnosed with HER2-positive mBC or LA/mGC. 
Capecitabine is an established chemotherapy for both diseases. In patients with 
HER2-positive mBC or LA/mGC, anti-HER2 therapy has demonstrated activity. 
Furthermore, the combination of anti-HER2 therapy and capecitabine has been 
shown to be efficacious in both mBC9,10 and LA/mGC.18 Eligible patients for this 
study will have incurable mBC or LA/mGC overexpressing HER2. 
3.3.1.1 
Rationale for Phase I 
The 3 plus 3 design is a well-established and well-known method for Phase I 
studies. PK parameters will be collected and analyzed to investigate the PK 
interaction of the drugs under investigation.  
The capecitabine dose evaluated in combination with trastuzumab and docetaxel 
in the CHAT trial was 950 mg/m2 bid. However, retrospective evaluations and 
post hoc analyses of early dose reduction suggest that lower starting doses of 
capecitabine offer similar efficacy with better tolerability. Therefore the 
capecitabine starting dose selected in combination with trastuzumab emtansine 
for the MTD-Finding Phase I part of the present study was 750 mg/m2 bid, taking 
into account the aim of maintaining the good tolerability of trastuzumab 
emtansine while benefitting from synergy observed between the two agents in 
nonclinical studies. 
The combination of T-DM1 and capecitabine was evaluated with a de-escalation 
study design. Following the emergence of two DLTs (grade 3 vomiting, grade 3 
elevated AST/ALT) at the starting dose of 750 mg/m2 bid (days 1–14 q3w) in 
combination with trastuzumab emtansine 3.6 mg/kg q3w, a de-escalated dose 
cohort was opened to evaluate capecitabine 700 mg/m2 bid combined with the 
same dose of trastuzumab emtansine. At this dose no DLTs were observed in 
the six patients treated, and of note, none of the patients had experienced grade 
≥3 AEs in cycles delivered after the DLT evaluation period.45 Following review of 
safety data from patients treated at these two dose levels, the IDMC 
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recommended the regimen of capecitabine 700 mg/m2 bid combined with 
trastuzumab emtansine 3.6 mg/kg q3w for the phase II exploration of efficacy 
and safety.  
In the ToGA study in LA/mGC, trastuzumab exposure was lower than that 
observed in breast cancer studies. A weekly trastuzumab emtansine regimen 
may provide higher cumulative trastuzumab emtansine exposure than the q3w 
schedule and was therefore chosen for the Phase I, Cohort 2 part of the present 
study in LA/mGC. This approach has subsequently been supported by findings 
from stage I of the adaptive phase II/III BO27952 trial in this setting (see Section 
3.3.2.2).  
3.3.1.2 
Rationale for Randomized Phase II 
The Randomized Phase II part of the study is designed to explore the efficacy 
and safety of the combination recommended following the Phase I MTD-Finding 
phase (trastuzumab emtansine 3.6 mg/kg in combination with capecitabine 700 
mg/m2) compared with trastuzumab emtansine alone.  
3.3.2 
RATIONALE FOR INVESTIGATIONAL MEDICINAL DOSE 
SELECTION 
3.3.2.1 
In Patients with mBC 
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 heavily pre-treated HER2-
positive mBC (protocol TDM4258g31 and protocol TDM4374g32), in patients who 
had not received prior chemotherapy for metastatic disease (TDM4450g26), and 
subsequently in the randomized phase III trials.27,28 
Capecitabine doses have been selected as being in the range of efficacious 
doses for single-agent or combination use. The doses selected are within the 
dosing range included in the Xeloda® Summary of Product Characteristics 
(SmPC) and therefore are considered to be efficacious.  
3.3.2.2 
In Patients with mGC 
In the ToGA study (BO18255) evaluating trastuzumab in combination with 
chemotherapy for mGC, patients with higher drug exposure had a greater benefit 
than those with lower exposure.46 As a consequence, an ongoing randomized, 
open-label, multicenter Phase IIIb study is comparing two trastuzumab dosing 
regimens, each in combination with cisplatin/capecitabine chemotherapy, as first-
line therapy in patients with HER2-positive metastatic gastric or GEJ 
adenocarcinoma (Study BO27798). 
In TDM3569g (see Section 1.2.1.1), the qw administration of 2.4 mg/kg of 
trastuzumab emtansine resulted in higher exposure than q3w dosing (see 
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Section 1.2.1.8).29,30 Therefore, this dose may result in larger clinical benefit for 
patients with mGC.  
In the ongoing randomized adaptive phase II/III BO27952 trial evaluating 
trastuzumab emtansine versus the investigator’s choice of taxane therapy in 
unrectable LA/mGC, two trastuzumab emtansine regimens were evaluated in 
stage I: 3.6 mg/kg q3w and 2.4 mg/kg qw. In October 2013, the IDMC for the 
BO27952 trial recommended selection of the weekly 2.4 mg/kg regimen for 
further evaluation in the phase III part of the trial based on pharmacokinetic, 
safety, and efficacy data available at the time. This recommendation provides 
further support for using the weekly regimen in Phase I, Cohort 2 of the present 
trial.  
In Cohort 2, the starting dose of capecitabine will be 700 mg/m2 bid (the MTD 
from Cohort 1 in mBC) in order to minimize the exposure of patients to sub-
optimal treatment. The dose of capecitabine can be de-escalated if needed. 
3.3.2.3 
Rationale for Duration of Treatment 
Treatment will be given until investigator-assessed PD, unacceptable toxicity, 
withdrawal of consent, death, reasons deemed by the treating physician, or study 
termination by the Sponsor (see Section 3.1.1 for full information). As of 1 
January 2010, of 237 patients enrolled in studies TDM3569g, TDM4258g, and 
TDM4374g receiving trastuzumab emtansine at 3.6 mg/kg, approximately 30% 
have tolerated more than 12 cycles, with 14.8% having received more than 
17 cycles. Twenty patients (8.4%) have discontinued trastuzumab emtansine due 
to AEs and 24 patients (10.1%) required dose reductions in trastuzumab 
emtansine because of AEs. In the absence of unacceptable toxicity, patients with 
mBC are generally treated until PD. Further support for treatment until PD comes 
from the EMILIA randomized phase III trial.27 Among the 490 patients 
randomized to trastuzumab-emtansine, only 29 (5.9%) discontinued because of 
adverse events.  
Capecitabine will be given until PD, in accordance with Xeloda® national 
prescribing information. 
3.3.3 
PHARMACOKINETIC SAMPLING RATIONALE 
PK is studied only in the Phase I (MTD-Finding) parts (both cohorts 1 and 2). The 
PK sampling rationale is to characterize the PK of trastuzumab emtansine and 
capecitabine and their metabolites, to assess any potential drug-drug interaction 
when trastuzumab emtansine is given in combination with capecitabine, and to 
explore potential correlations between drug exposure and measures of both 
efficacy (ORR) and toxicity (alanine transaminase [ALT]/AST, platelets, etc.), if 
data allow. 
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3.4 
OUTCOME MEASURES 
3.4.1 
PHASE I: MBC 
3.4.1.1 
Primary Outcome Measure 
The main objective for Phase I is to determine the MTD of capecitabine when 
combined with trastuzumab emtansine. 
3.4.1.2 
Secondary Outcome Measure 
The secondary outcome is ORR, based on best overall response (BOR) rate 
according to RECIST v.1.1, per investigator local assessment. 
3.4.1.3 
Primary Safety Outcome Measure 
The primary safety outcome measure is to establish the MTD. The number and 
the proportion of patients with DLTs will be used as the primary measure for the 
MTD determination and will be summarized for each treatment dosage. 
3.4.1.4 
Secondary Safety Outcome Measures 
Safety endpoints will be summarized for each treatment dosage: 
 
Incidence, nature, and severity of AEs, according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) v. 4.0 
 
Incidence, nature, and severity of SAEs, according to NCI CTCAE v. 4.0 
 
Incidence and nature of Grade ≥3 AEs  
 
Incidence, nature, and severity of AEs of special interest (AESIs), according 
to NCI CTCAE v. 4.0 
 
Fatal AEs and their causes  
 
Laboratory parameters 
 
LVEF 
 
Exposure to study medication 
 
Physical examination 
 
ECOG performance status 
 
Premature withdrawal from study medication and/or study 
3.4.1.5 
Pharmacokinetic Outcome Measures 
The PK outcome measures to be assessed in patients receiving trastuzumab 
emtansine and capecitabine will include: 
 
Serum concentrations of trastuzumab emtansine (conjugated drug) and total 
trastuzumab (free and conjugated to DM1) 
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 
Plasma concentration of DM1 
 
Plasma concentration of capecitabine and its active metabolite 5-FU 
 
Total exposure (e.g., AUC)  
 
Cmax 
 
CL 
 
Vd 
 
T1/2 
3.4.2 
RANDOMIZED PHASE II: EXPLORATION OF EFFICACY AND 
SAFETY IN MBC 
The primary and secondary efficacy outcome measures will be presented for 
each treatment group.  
3.4.2.1 
Primary Efficacy Outcome Measure 
The primary outcome measure is ORR by investigator assessment, based on 
BOR (defined as the best response recorded from randomization into the Phase 
II part of the study and until PD, death, withdrawal of consent, start of new 
anticancer treatment, or EOS, whichever occurs first) according to RECIST v.1.1 
(See Appendix 3). 
3.4.2.2 
Secondary Efficacy Outcome Measures 
Secondary efficacy outcomes include: 
 
TTR 
 
DoR 
 
TTP 
 
TTF 
 
PFS 
 
CBR 
 
OS 
3.4.2.3 
Primary Safety Outcome Measure 
A primary safety outcome is defined only for Phase I.  
3.4.2.4 
Secondary Safety Outcome Measures 
The summary of safety endpoints will be presented for each treatment group: 
 
Incidence, nature, and severity of AEs, according to NCI CTCAE v. 4.0 
 
Incidence, nature, and severity of SAEs, according to NCI CTCAE v. 4.0 
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 
Incidence and nature of Grade ≥3 AEs  
 
Incidence, nature, and severity of AESIs, according to NCI CTCAE v. 4.0 
 
Fatal AEs and their causes  
 
Events to monitor 
 
Laboratory parameters 
 
LVEF 
 
Exposure to study medication 
 
Physical examination 
 
ECOG performance status 
 
Premature withdrawal from study medication and/or study 
3.4.2.5 
Pharmacokinetic Outcome Measures 
Not applicable for Phase II. 
3.4.3 
PHASE I: LA/MGC 
3.4.3.1 
Primary Outcome Measure 
The main objective for Phase I is to determine the MTD of capecitabine when 
combined with trastuzumab emtansine. The number and the proportion of 
patients with DLTs will be used as the primary measure for the MTD 
determination and will be summarized for each treatment dosage. 
 
3.4.3.2 
Secondary Efficacy Outcome Measure 
The secondary (efficacy) outcome is ORR, based on BOR rate according to 
RECIST v.1.1 according to investigator assessment. 
3.4.3.3 
Secondary Safety Outcome Measures 
Safety endpoints will be summarized for each treatment dosage: 
 
Incidence, nature, and severity of AEs, according to NCI CTCAE v. 4.0 
 
Incidence, nature, and severity of SAEs, according to NCI CTCAE v. 4.0 
 
Incidence and nature of Grade ≥3 AEs  
 
Incidence, nature, and severity of AESIs, according to NCI CTCAE v. 4.0 
 
Fatal AEs and their causes  
 
Events to monitor 
 
Laboratory parameters 
 
LVEF 
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 
Exposure to study medication 
 
Physical examination 
 
ECOG performance status 
 
Premature withdrawal from study medication and/or study 
3.4.3.4 
Pharmacokinetic Outcome Measures 
The PK outcome measures to be assessed in patients receiving trastuzumab 
emtansine and capecitabine will include: 
 
Serum concentrations of trastuzumab emtansine (conjugated drug) and total 
trastuzumab (free and conjugated to DM1) 
 
Plasma concentration of DM1 
 
Plasma concentration of capecitabine and its active metabolite 5-FU 
 
Total exposure (e.g., AUC)  
 
Cmax 
 
CL 
 
Vd 
 
T1/2 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
4.1.1 
PATIENTS WITH MBC  
This study will enroll patients with HER2-positive BC with histologically or 
cytologically confirmed metastatic disease that is amenable to combination 
treatment with trastuzumab emtansine and capecitabine. 
Patients with mBC must have received at least one prior treatment regimen for 
early or metastatic disease, which included a chemotherapy agent and 
trastuzumab either separately or in combination. In both study parts (Phase I and 
II), only patients whose HER2 tumor status was locally scored as IHC 3+ or in 
situ hybridization (ISH) positive will be eligible. 
4.1.2 
LA/MGC PATIENTS 
This study will enroll patients with HER2-positive GC with histologically or 
cytologically confirmed inoperable LA/mGC that is amenable to combination 
treatment with trastuzumab emtansine and capecitabine. 
Patients with mGC must not have received prior chemotherapy for 
advanced/metastatic disease, and only patients with HER2-positive primary 
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tumor or metastasis as assessed by the central laboratory will be allowed to 
enroll in the mGC part of the study. 
4.1.3 
INCLUSION CRITERIA 
4.1.3.1 
For Patients with mBC 
Patients must meet the following criteria for study entry: 
1. Male or female 
2. Age ≥ 18 years old 
3. Signed informed consent before any study-specific procedure 
4. Able and willing to comply with the protocol 
5. 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 the medical history confirming that the 
patient is not of childbearing potential. 
6.  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 or two effective forms of non-hormonal 
contraception and to continue its use for the duration of study treatment and 
for 7 months after the last dose of study treatment (see Section 5.2.4). 
7. ECOG performance status of 0, 1, or 2 
8. Blood: 
a) Platelet count > 100,000 cells/mm3 
b) International normalized ratio (INR) < 1.5  
c) Absolute neutrophil count (ANC) > 1,500 cells/mm3 
d) Hemoglobin > 9.0 g/dL. Patients are allowed to have received transfusion 
to achieve this level. 
9. Liver function: 
a)  Total bilirubin ≤ 1.5 × upper limit of normal (ULN) or direct bilirubin ≤1.5 
× ULN in patients with documented Gilbert’s syndrome.  
b) Serum glutamic oxaloacetic transaminase (SGOT)/AST and serum 
glutamic pyruvic transaminase (SGPT)/ALT ≤ 2.5 × ULN 
c) Alkaline phosphatase ≤ 2.5 × ULN. In patients with bone metastases: 
alkaline phosphatase ≤ 5 × ULN 
d) Evidence of stable liver function during the month prior to enrollment with 
liver function test (LFT) fluctuations not exceeding 2.5 x ULN (for AST, 
ALT) and 1.5 x ULN (for total bilirubin).  
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10. Renal function: 
a) Serum creatinine of < 177 µmol/L or calculated creatinine CL > 50 mL/min. 
If urine dipstick for proteinuria is ≥ 2+ at baseline, the patient must 
undergo 24-hour urine collection and demonstrate ≤ 1 g of protein/24 
hours 
11. Cardiac function: 
a) LVEF ≥ 50% by echocardiogram (ECHO) or multiple-gated acquisition 
(MUGA) scan 
12.  Life expectancy ≥2 weeks 
13. Histologically or cytologically confirmed BC 
14. HER2-positive disease, defined as IHC 3+ or ISH positive 
15. Tumor block or 8 slides available for retrospective central confirmation of 
HER2-positivity (central confirmation not necessary for enrollment).  
16. mBC with at least one measurable lesion according to RECIST v.1.1 
17. Disease progression on at least one prior regimen containing trastuzumab 
and chemotherapy either separately or in combination. Patients may be 
eligible to receive study therapy in the first-line setting if trastuzumab and 
chemotherapy were given in the [neo]adjuvant setting. 
18. Patients must have recovered from previous treatments 
4.1.3.2 
For Patients with LA/mGC 
Patients must meet the following criteria for study entry: 
1.   Male or female 
2.   Age ≥ 18 years old 
3. Signed informed consent before any study-specific procedure 
4. Able and willing to comply with the protocol 
5. 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 the medical history confirming that the 
patient is not of childbearing potential 
6.  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 or two effective forms of non-hormonal 
contraception and to continue its use for the duration of study treatment and 
for 7 months after the last dose of study treatment (see Section 5.2.4) 
7. ECOG performance status of 0, 1, or 2 
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8. Blood: 
a) Platelet count > 100,000 cells/mm3 
b) INR < 1.5  
c) ANC > 1,500 cells/mm3 
d) Hemoglobin > 9.0 g/dL. Patients are allowed to have received transfusion 
to achieve this level. 
9. Liver function: 
a) Total bilirubin ≤ 1.5 × ULN or direct bilirubin ≤1.5 × ULN in patients with 
documented Gilbert’s syndrome 
b) SGOT/AST and SGPT/ALT ≤ 2.5 × ULN 
c) Alkaline phosphatase ≤ 2.5 × ULN. In patients with bone metastases: 
alkaline phosphatase ≤ 5 × ULN 
d) Evidence of stable liver function in the month prior to enrollment with LFT 
fluctuations not exceeding 2.5 x ULN (for AST, ALT) and 1.5 x ULN (for 
total bilirubin).  
10. Renal function: 
a) Serum creatinine of < 177 µmol/L or calculated creatinine CL > 50 mL/min. 
If urine dipstick for proteinuria is ≥ 2+ at baseline, the patient must 
undergo 24-hour urine collection and demonstrate ≤ 1 g of protein/24 
hours 
11. Cardiac function: 
a) LVEF ≥ 50% by ECHO or MUGA scan 
12.  Life expectancy ≥2 weeks 
13. Histologically or cytologically confirmed mGC or locally advanced GC 
14. HER2-positive tumor (primary tumor or metastatic lesion), defined as either 
IHC 3+ or IHC 2+ and ISH+, prospectively confirmed by a Sponsor-
designated central laboratory prior to enrollment. ISH positivity is defined as 
a ratio of ≥ 2.0 for the number of HER2 gene copies to the number of signals 
for CEP17. 
a) Archival tumor samples obtained from primary or metastatic sites are 
acceptable. 
b) Invasive tumor for central confirmation of HER2 status is required. 
c) A formalin-fixed paraffin-embedded (FFPE) tissue block with at least 5 mm 
of invasive tumor for central confirmation is preferred. If FFPE tissue 
blocks (or partial block) are unavailable due to country or site regulations, 
a minimum of 8 freshly cut unstained slides MUST be available for central 
review of HER2 status. 
15. Inoperable LA/mGC 
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4.1.4 
EXCLUSION CRITERIA 
4.1.4.1 
For Patients with mBC 
1. Prior treatments before first study treatment: 
a) Investigational therapy within ≤ 28 days or 5 half-lives, whichever is longer 
b)  Hormonal therapy within 14 days 
c) Trastuzumab within 21 days 
2. Prior treatment with trastuzumab emtansine or prior enrollment in a 
trastuzumab emtansine-containing study, regardless of whether the patient 
received trastuzumab emtansine 
3. Prior treatment with capecitabine 
4. History of severe and unexpected reactions to fluoropyrimidine or known 
hypersensitivity to fluorouracil 
5. Related capecitabine contraindications: 
a) Treatment with sorivudine or its chemically-related analogues, such as 
brivudine 
b)  Rare hereditary problems of galactose intolerance, Lapp lactase 
deficiency, or glucose-galactose malabsorption 
c) Known complete absence of DPD activity.  
6. History of intolerance (including Grade 3 or 4 infusion reaction) or 
hypersensitivity to trastuzumab or murine proteins or any component of the 
product 
7. History of exposure to the following cumulative doses of anthracyclines: 
a) Doxorubicin or liposomal doxorubicin > 500 mg/m2 
b) Epirubicin > 900 mg/m2 
c) Mitoxantrone > 120 mg/m2 
d) If another anthracycline, or more than one anthracycline, has been used, 
the cumulative dose must not exceed the equivalent of 500 mg/m2 
doxorubicin. 
8. Brain metastases that are symptomatic, or require any radiation, surgery, or 
steroid therapy to control their symptoms within 28 days before first study 
drug administration 
9. Current peripheral neuropathy of Grade ≥ 3 according to NCI CTCAE, v. 4.0 
10. History of other malignancy within the last 5 years, except for appropriately 
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage 
I uterine cancer, or other cancers with a similar outcome as those mentioned 
above.  
11. Current unstable ventricular arrhythmia requiring treatment 
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12. History of symptomatic CHF (New York Heart Association [NYHA] Classes 
II−IV) 
13. History of myocardial infarction or unstable angina within 6 months prior to 
first study drug administration 
14. History of a decrease in LVEF to < 40% or symptomatic CHF with previous 
trastuzumab treatment 
15. Severe dyspnea at rest due to complications of advanced malignancy or 
currently requiring continuous oxygen therapy 
16. Clinically significant malabsorption syndrome or inability to take oral 
medication 
17. Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, or metabolic disease) 
18. Major surgical procedure or significant traumatic injury within 28 days before 
enrollment or anticipation of the need for major surgery during the course of 
study treatment 
19. Current pregnancy or lactation 
20. Current known active infection with human immunodeficiency virus (HIV), 
hepatitis B and/or hepatitis C virus (HBV/HCV) 
a) For patients who are known carriers of HBV, active hepatitis B infection 
must be ruled out based on negative serologic testing and/or 
determination of HBV DNA viral load per local guidelines 
21.  Lapatinib ≤ 14 days before first study drug administration 
22. Previous radiotherapy for the treatment of mBC is not allowed if: 
a) The last fraction of radiotherapy has been administered within 14 days 
prior to first study drug administration (28 days for patients with 
radiotherapy to control symptoms of brain metastases, see exclusion 
criterion 8). 
b) More than 25% of marrow-bearing bone has been irradiated. 
c) Any acute toxicity has not resolved to Grade ≤ 1 before first study drug 
administration. 
4.1.4.2 
For Patients with LA/mGC 
1. Prior treatments before first study treatment: 
a) Investigational therapy within ≤ 28 days or 5 half-lives, whichever is longer 
b)  Hormonal therapy within 14 days 
c) Trastuzumab within 21 days 
2. Prior treatment with trastuzumab emtansine or prior enrollment in a 
trastuzumab emtansine-containing study, regardless of whether the patient 
received prior trastuzumab emtansine 
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3. Prior treatment with capecitabine 
4. History of severe or unexpected reactions to fluoropyrimidine or known 
hypersensitivity to fluorouracil 
5. Related capecitabine contraindications: 
a) Treatment with sorivudine or its chemically-related analogs, such as 
brivudine 
b)  Rare hereditary problems of galactose intolerance, Lapp lactase 
deficiency or glucose-galactose malabsorption 
c) Known complete absence of DPD activity. 
6. History of intolerance (including Grade 3 or 4 infusion reaction) or 
hypersensitivity to trastuzumab or murine proteins or any component of the 
product 
7. History of exposure to the following cumulative doses of anthracyclines: 
a) Doxorubicin or liposomal doxorubicin > 500 mg/m2 
b)  Epirubicin > 900 mg/m2 
c) Mitoxantrone > 120 mg/m2 
d) If another anthracycline, or more than one anthracycline, has been used, 
the cumulative dose must not exceed the equivalent of 500 mg/m2 
doxorubicin. 
8. Brain metastases that are symptomatic, or require any radiation, surgery, or 
steroid therapy to control symptoms within 28 days before first study drug 
administration 
9.  Current peripheral neuropathy of Grade ≥ 3 according to NCI CTCAE, v. 4.0 
10. History of other malignancy within the last 5 years, except for appropriately 
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage 
I uterine cancer, or other cancers with a similar outcome as those mentioned 
above 
11. Current unstable ventricular arrhythmia requiring treatment 
12. History of symptomatic CHF (NYHA Classes II−IV) 
13. History of myocardial infarction or unstable angina within 6 months prior to 
first study drug administration 
14. History of a decrease in LVEF to < 40% or symptomatic CHF with previous 
trastuzumab treatment 
15. Severe dyspnea at rest due to complications of advanced malignancy or 
currently requiring continuous oxygen therapy 
16. Clinically significant malabsorption syndrome or inability to take oral 
medication 
17. Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, or metabolic disease) 
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18. Major surgical procedure or significant traumatic injury within 28 days before 
enrollment or anticipation of the need for major surgery during the course of 
study treatment 
19. Current pregnancy or lactation 
20. Current known active infection with HIV, HBV, and/or HCV 
a) For patients who are known carriers of HBV, active hepatitis B infection 
must be ruled out based on negative serologic testing and/or 
determination of HBV DNA viral load per local guidelines 
21. Previous chemotherapy for advanced/metastatic disease 
a) Prior adjuvant/neoadjuvant therapy is allowed if at least 6 months has 
elapsed between completion of adjuvant/neoadjuvant therapy and 
enrollment into the study 
22. Lapatinib ≤ 14 days before first study drug administration 
4.1.5 
PATIENT REPLACEMENT POLICY 
None of the patients in the Phase I part of the study may be replaced unless 
approved by the entire SC. Phase II patients will not be replaced. 
4.2 
METHOD OF TREATMENT ASSIGNMENT 
In the Randomized Phase II part of the study, patients will be randomized to 
receive either the combination of trastuzumab emtansine and capecitabine or 
trastuzumab emtansine alone. Patients are stratified according to the number of 
prior lines of treatment for metastatic disease (≤ or > , excluding single-agent 
therapy). 
This is an open-label randomized study; therefore, no blinding will be used. 
4.3 
STUDY TREATMENT 
4.3.1 
FORMULATION, PACKAGING, AND HANDLING 
4.3.1.1 
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 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. 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 
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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. 
4.3.1.2 
Capecitabine 
The following information has been obtained from the Xeloda® European Union 
(EU) SmPC and US Xeloda® Package Insert. 
Capecitabine is available as biconvex, oblong, film-coated tablets, available as 
follows: 
 
150 mg tablets: color, light peach; engraving, XELODA on one side, 150 on 
the other; packs of 60 
 
500 mg tablets: color, peach; engraving, XELODA on one side, 500 on the 
other; packs of 120 
Capecitabine tablets should not be stored above 30°C. 
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4.3.2 
DOSAGE AND ADMINISTRATION 
4.3.2.1 
For Patients with mBC 
Trastuzumab Emtansine 
Trastuzumab emtansine will be administered on Day 1 q3w at a dose of 3.6 
mg/kg IV (see Appendix 1). The total dose will be calculated based on the 
patient’s weight on Day 1 of each cycle (or up to 3 days before) with no upper 
limit. 
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 90 minutes for fever, chills, or other infusion-associated symptoms. If prior 
infusions were well tolerated (without any signs or symptoms of infusion 
reactions), subsequent doses of trastuzumab emtansine may be administered 
over 30 minutes (±10 minutes), with a minimum 30-minute observation period 
following infusion. Local health authority guidelines must be followed with regard 
to further observation and monitoring, if applicable. 
Pre-medication for nausea and infusion reactions (e.g., acetaminophen or other 
analgesics, antihistamines such as diphenhydramine, or corticosteroids) may be 
given at the investigator’s discretion. 
Capecitabine 
Capecitabine will be administered twice a day, orally for 14 days followed by a 7-
day rest period at the Dose Levels described in Section 3.1.1. Capecitabine 
tablets should be swallowed with water within 30 minutes after a meal. 
Capecitabine doses can be delayed for up to 4 hours, while keeping the minimal 
interval of 8 hours between the doses. 
Rounding of the dose, based on 150 and 500 mg strength tablets, will be allowed 
to the nearest dose per patient body surface area (BSA). 
If a dose is missed, the patient should skip that dose. The patient should not 
double the dose during the next administration. 
Guidelines for dosage modification and treatment interruption or discontinuation 
are provided in Section 5.1.  
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4.3.2.2 
For Patients with LA/mGC 
Trastuzumab Emtansine 
Trastuzumab emtansine will be administered on Day 1 qw at a dose of 2.4 mg/kg 
IV (see Appendix 1). The total dose will be calculated based on the patient’s 
weight on Day 1 of each cycle (or up to 3 days before) with no upper limit. 
Administration time and observation period are described in Section 4.3.2.1 for 
trastuzumab emtansine. 
Guidelines regarding timing delays and infusion times are the same as for 
patients with mBC, as is the accepted pre-medication. 
Capecitabine 
Capecitabine will be administered at a starting dose of 700 mg/m2 bid, orally, for 
14 days followed by a 7-day rest period (the dose level determined as the MTD in 
cohort 1, with de-escalation as described in section 3.1.1.3. Capecitabine tablets 
should be swallowed with water within 30 minutes after a meal. Capecitabine 
doses can be delayed for up to 4 hours, while keeping the minimal interval of 8 
hours between the doses. 
If a dose is missed, the patient should skip that dose. The patient should not 
double the dose at the next administration. 
Guidelines for dosage modification and treatment interruption or discontinuation 
are provided in Section 5.1. 
4.3.3 
INVESTIGATIONAL MEDICINAL PRODUCT ACCOUNTABILITY 
All investigational medicinal products (IMPs) required for completion of this study 
(trastuzumab emtansine and capecitabine) 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. 
IMPs will be either disposed of at the study site according to the study site’s 
institutional standard operating procedure or returned to the Sponsor with the 
appropriate documentation. The site's method of IMP destruction must be agreed 
upon by the Sponsor. The site must obtain written authorization from the Sponsor 
before any IMP is destroyed, and IMP destruction must be documented on the 
appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and 
disposed of by the study site should be recorded on the Drug Inventory Log. 
4.3.4 
POST-TRIAL ACCESS TO EXTENSION STUDY 
Post-trial access to trastuzumab emtansine and capecitabine will be performed 
as described in Section 3.1.1, Duration of Treatment and Patient Follow-Up. If a 
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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. 
4.4 
CONCOMITANT AND EXCLUDED THERAPIES 
4.4.1 
PERMITTED THERAPY 
Concomitant therapy and pre-medication are defined as non-IMPs. 
Concomitant therapy includes any prescription medication, over-the-counter 
preparation, or herbal therapy between the 14 days preceding first treatment and 
the Study Treatment Discontinuation Visit. Afterwards, only anti-cancer therapies 
will be collected as part of the survival follow-up. 
Pre-medication is allowed according to standard practice guidelines. 
No pre-medication for the first infusion of trastuzumab emtansine is required; 
however, pre-medication 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 is permitted to treat pre-existing painful bone metastases 
or to treat brain metastases (for patients who have disease control outside of the 
brain). 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 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 PD. 
4.4.2 
PROHIBITED THERAPY 
During the study, use of the therapies described below is prohibited until 
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. 
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Radiotherapy for unequivocal PD 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 cannot be 
treated with additional radiation. Patients must not miss more than one cycle of 
study treatment for the treatment of their brain metastases and must have an 
ECOG performance status of 0, 1, or 2 to continue on therapy. The Medical 
Monitor should be informed before a decision is made to resume study treatment 
after radiotherapy for brain metastases. 
4.5 
STUDY ASSESSMENTS 
All patients will be closely monitored for safety and tolerability during all cycles of 
therapy and at the safety follow-up visit: 
 
Visits will be based on a q3w cycle for mBC 
 
Visits will be based on a qw cycle for mGC 
Study assessments are outlined in this section and in Appendix 1. 
4.5.1 
DESCRIPTION OF STUDY ASSESSMENTS 
All patients will be closely monitored for safety and tolerability during all cycles of 
therapy and at the Study Treatment Discontinuation Visit. Patients should be 
assessed for toxicity prior to each dose; dosing will occur only if the clinical 
assessment and local laboratory test values are acceptable. Trastuzumab 
emtansine will be administered either in q3w cycles (patients with mBC) or qw 
cycles (patients with mGC) if no additional time is required for resolution of 
toxicity. Dose delays and dose reductions will be allowed for trastuzumab 
emtansine as outlined in Section 5.1.5. 
If the timing of a protocol-mandated procedure coincides with a holiday and/or 
weekend that precludes the procedure within the allotted window, the procedure 
should be performed on the nearest following date (i.e., within 3 business days). 
4.5.1.1 
Medical History and Demographic Data 
Medical history includes 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 race/ethnicity (unless 
not allowed per local regulations). 
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4.5.1.2 
Vital Signs 
Vital signs will include measurements of weight, respiratory rate, heart rate, blood 
pressure, and temperature. Abnormal or significant changes to vital signs from 
baseline should be recorded as AEs, if appropriate. 
4.5.1.3 
Physical Examinations 
A complete physical examination should include the evaluation of head, eye, ear, 
nose, and throat; cardiovascular; dermatological; musculoskeletal; respiratory; 
gastrointestinal; and neurological systems. Changes from baseline abnormalities 
should be recorded at each subsequent physical examination. New or worsened 
abnormalities should be recorded as AEs if appropriate. 
As part of the tumor assessment, physical examinations should also include the 
evaluation of the presence and degree of enlarged lymph nodes, hepatomegaly, 
and splenomegaly. 
Limited physical examinations will be symptom-directed. 
4.5.1.4 
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 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 (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 (see 
Appendix 3). 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 (see Appendix 4). 
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Radiographic imaging should always be performed rather than clinical 
examination unless the lesion(s) being followed cannot be imaged but is 
assessable by clinical examination. In applying RECIST, documentation by color 
photography including a ruler to estimate the size of the lesion is recommended. 
4.5.1.5 
Laboratory Assessments 
For Patients with mBC: 
Local Laboratory Assessments: 
 
Hematology, biochemistry, coagulation, urinalysis, and pregnancy testing 
 
Prospective or retrospective HER2 status. Patients will be enrolled based on 
local results. 
Central Laboratory Assessments: 
 
Retrospective HER2 status. Retrospective central confirmation will not 
impact the treatment decisions or primary endpoint of Phase I, Cohort 1 and 
will be used to validate efficacy analyses in Phase I and to define subgroups 
for efficacy analyses in the Randomized Phase II part of the study 
 
PK assays: 
– 
Serum trastuzumab emtansine concentration and total trastuzumab using a 
validated immunoassay 
– 
Serum capecitabine and 5-FU PK samples 
– 
Plasma concentration of DM1 using a validated liquid chromatography 
electrospray tandem mass spectrometry (LC-MS/MS) method 
For Patients with mGC: 
Local Laboratory Assessments: 
 
Hematology, biochemistry, coagulation, urinalysis, and pregnancy testing 
Central Laboratory Assessments: 
 
Prospective HER2 status. Patients will be enrolled based on the central 
testing results 
 
PK assays: 
– 
Serum trastuzumab emtansine concentration and total trastuzumab using a 
validated immunoassay 
– 
Serum capecitabine and 5-FU PK samples 
– 
Plasma concentration of DM1 using a validated LC-MS/MS method 
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4.5.1.6 
Electrocardiograms 
A 12-lead ECG should be obtained at baseline and be printed and kept with the 
patient’s record. 
4.5.1.7 
ECOG Performance Status 
Performance status will be measured using the ECOG performance status scale 
(see Appendix 6). 
It is recommended, where possible, that a patient’s performance status be 
assessed by the same person throughout the study. 
Performance status will be assessed according to the schedule of assessments 
(see Appendix 1). 
4.5.1.8 
ECHO/MUGA 
ECHO is the preferred modality because of the global technetium (Tc-99m) 
shortage (see Appendix 4). The same method used at screening should be used 
throughout the study. 
4.5.2 
TIMING OF STUDY ASSESSMENTS 
4.5.2.1 
Screening and Pretreatment Assessments 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations. Informed Consent 
Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site. 
Once the patient has signed the Informed Consent Form, the investigator (or his 
or her designee) will call the IxRS to obtain the screening number for the patient 
prior to Cycle 1, Day 1. 
Results of standard of care tests or examinations performed prior to obtaining 
informed consent and within 28 days prior to study start may be used; such tests 
do not need to be repeated for screening. Patients must have stable LFTs before 
the first dose of study drug. 
All screening evaluations must be completed and reviewed to confirm that 
patients meet all eligibility criteria before study start. 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. 
Patients in Cohort 1 will not contribute to Phase II; however, they will be followed 
up until EOS. In the Randomized Phase II part, patients will be randomized in a 
1:1 ratio to receive trastuzumab emtansine alone or the combination of 
trastuzumab emtansine and capecitabine prior to receiving the first dose of study 
medication. 
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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. 
Please see Appendix 1 for the schedule of screening assessments. 
4.5.2.2 
Assessments during Treatment 
For Patients with mBC 
Scheduled study visits are based on a q3w cycle, with Cycle 1 beginning at Day 
1. All visits must occur within ± 3 business days from the scheduled date, unless 
otherwise noted in the schedule of assessments. All assessments will be 
performed on the day of the specified visit unless a time window is specified. 
Assessments scheduled on the day of study treatment administration should be 
performed prior to study treatment administration unless otherwise noted. If the 
timing of a protocol-mandated procedure coincides with a holiday and/or 
weekend, it should be performed on the nearest following date (i.e., within 3 
business days). 
Local laboratory assessments scheduled for Day 1 of all cycles must be 
performed within 72 hours prior to study treatment administration unless 
otherwise specified. Results of local laboratory assessments must be reviewed 
and the review documented prior to study treatment administration. 
Please see Appendix 1 for the schedule of treatment period assessments. 
For Patients with mGC 
Scheduled study visits are based on a qw cycle, with Cycle 1 beginning at Day 1. 
All visits must occur within ± 3 business days from the scheduled date, unless 
otherwise noted in the schedule of assessments. All assessments will be 
performed on the day of the specified visit unless a time window is specified. 
Assessments scheduled on the day of study treatment administration should be 
performed prior to study treatment administration unless otherwise noted. If the 
timing of a protocol-mandated procedure coincides with a holiday and/or 
weekend, it should be performed on the nearest following date (i.e., within 3 
business days). 
Local laboratory assessments scheduled for Day 1 of all cycles must be 
performed within 72 hours prior to study treatment administration unless 
otherwise specified. Results of local laboratory assessments must be reviewed 
and the review documented prior to study treatment administration. 
Please see Appendix 1 for the schedule of treatment period assessments. 
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4.5.2.3 
Assessments at Study Completion/Early Termination Visit 
Patients may remain on study treatment until investigator-assessed PD, 
unacceptable toxicity, withdrawal of consent, death, reasons deemed by the 
treating physician, or study termination by the Sponsor. Patients who discontinue 
study treatment will be followed up until EOS and will be asked to return to the 
clinic approximately 28–42 days after the last study treatment administration for 
the safety follow-up visit. 
Please see Appendix 1 for assessments to be performed at the safety follow-up 
visit. 
4.5.2.4 
Follow-up Assessments 
After the Study Treatment Discontinuation Visit, all patients (regardless of reason 
for discontinuation) will have survival status and anti-cancer therapies recorded 
and will be followed for all unresolved study-related AEs and SAEs until their 
resolution or stabilization, the patient is lost to follow-up or dies, 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. 
Patients who discontinue study drugs for any reason other than PD or withdrawal 
of consent (e.g., an AE) will continue to be followed according to the tumor 
assessment schedule until withdrawal of consent, death, or EOS, whichever 
occurs first. 
After the study treatment completion/early termination visit, AEs should be 
followed as outlined in Section 5.5 and 5.6. 
Please see Appendix 1 for the schedule of follow-up assessments. 
4.5.2.5 
Assessments at Unplanned Visits 
In case unplanned visits are required, electronic Case Report Form (eCRF) 
pages will be available to report the information collected during those visits. 
4.6 
PATIENT AND STUDY DISCONTINUATION 
4.6.1 
PATIENT DISCONTINUATION 
Patients have the right to withdraw from the study at any time for any reason. 
The investigator has the right to discontinue a patient from study treatment or 
from the study for any medical condition that the investigator determines may 
jeopardize the patient’s safety if he or she continues in the study, for reasons of 
non-compliance (e.g., missed doses, visits), if the patient becomes pregnant, or if 
the investigator determines it is in the best interest of the patient. 
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Patients must be withdrawn from study treatment if they become pregnant or 
experience PD defined using RECIST v. 1.1 (Appendix 3). The exception to this 
is patients who develop isolated progression in the brain as described in 
Appendix 3. 
Details of discontinuation due to toxicity are given in Section 5.1. 
Patients who discontinue from study treatment prematurely for any of the above 
reasons will continue to be followed according to Section 4.5.2.4 “Follow-Up 
Assessments”. The primary reason for discontinuation must be recorded on the 
appropriate eCRF page. 
4.6.2 
STUDY DISCONTINUATION 
Sections 3.1.1 and 3.2 describe the EOS definition and discontinuation of study 
treatment. Prior to that, 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 
 
Data recording is inaccurate or incomplete. 
5. 
ASSESSMENT OF SAFETY 
Overall safety will be assessed on an ongoing basis during the conduct of the 
study. 
5.1 
SAFETY PLAN 
The safety plan for patients receiving trastuzumab emtansine is based on the 
toxicities of trastuzumab emtansine observed in nonclinical studies; the toxicities 
related to its components (trastuzumab and maytansine, the parent drug of DM1) 
observed in clinical studies; and the clinical experience with this molecule in 
completed and ongoing studies. Please refer to the trastuzumab emtansine and 
capecitabine (Xeloda®) Investigator’s Brochures for the most recent information. 
All patients will be monitored closely for toxicity. The important safety issues 
anticipated in this trial, as well as measures intended to avoid or minimize such 
toxicities, are outlined in the following sections. 
5.1.1 
RISKS ASSOCIATED WITH TRASTUZUMAB EMTANSINE 
Full details regarding the clinical safety of trastuzumab emtansine are presented 
in Sections 5 and 6 of the Investigator’s Brochure. 
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5.1.1.1 
Cardiotoxicity 
Patients treated with trastuzumab emtansine are at increased risk of developing 
left ventricular dysfunction. LVEF  40% has been observed in patients treated 
with trastuzumab emtansine. Patients without significant cardiac history and with 
an LVEF ≥ 50% determined by ECHO or MUGA scan are eligible for study 
participation. LVEF will be monitored at screening and regularly throughout the 
study until the assessment at the safety follow-up visit. Patients with symptomatic 
cardiac dysfunction will be discontinued from study treatment. Asymptomatic 
LVEF declines will be handled according to the algorithm shown in Figure 6. 
Treatment with trastuzumab emtansine has not been studied in patients with 
LVEF  50%. 
5.1.1.2 
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 
central nervous system 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. 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 
allowed according to and at the discretion of the treating physician. 
5.1.1.3 
Hepatotoxicity 
Hepatotoxicity, predominantly in the form of asymptomatic increases in the 
concentrations of serum transaminases (Grade 14 transaminitis), has been 
observed in patients while on treatment with trastuzumab emtansine in clinical 
trials. Transaminase elevations were generally transient. A cumulative effect of 
trastuzumab emtansine on transaminases has been observed; elevated 
transaminases improved to Grade 1 or normal within 30 days of the last dose of 
trastuzumab emtansine in the majority of the patients. 
Serious hepatobiliary disorders, including nodular regenerative hyperplasia (NRH) 
of the liver and some resulting in fatal liver failure, have been observed in 
patients treated with trastuzumab emtansine in clinical trials. Some of the 
observed cases may have been confounded by comorbidities and/or concomitant 
medications with known hepatotoxic potential. Liver function should be monitored 
before initiation of treatment and each trastuzumab emtansine dose. 
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Trastuzumab emtansine has not been studied in patients with serum 
transaminases  2.5  ULN or total bilirubin  1.5  ULN before initiation of 
treatment. Trastuzumab emtansine treatment in patients with serum 
transaminases  3  ULN and concomitant total bilirubin  2  ULN should be 
permanently discontinued. 
Cases of NRH of the liver have been identified from liver biopsies in patients 
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 hypertension. 
Diagnosis of NRH can only be confirmed by histopathology. 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. 
5.1.1.4 
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. 
5.1.1.5 
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 
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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. Pre-medication 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. 
5.1.1.6 
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. 
5.1.1.7 
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. 
5.1.1.8 
Trastuzumab Emtansine Dose Modification 
Trastuzumab emtansine dose modifications are described in Section 5.1.5.1. 
5.1.2 
RISKS ASSOCIATED WITH CAPECITABINE 
Patients treated with capecitabine should be carefully monitored for toxicity. Most 
AEs are reversible and do not require permanent discontinuation of therapy 
(please refer to the Xeloda® SmPC for more information). 
The spectrum of cardiotoxicity observed with capecitabine is similar to that of 
other fluorinated pyrimidines. This includes myocardial infarction, angina, 
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dysrhythmias, cardiac arrest, cardiac failure and electrocardiographic changes. 
These AEs may be more common in patients with a prior history of coronary 
artery disease. 
Rarely, unexpected, severe toxicity (e.g. stomatitis, diarrhea, mucosal 
inflammation, neutropenia, and neurotoxicity) associated with 5-FU has been 
attributed to deficiency of dihydropyrimidine dehydrogenase (DPD) activity. 
Patients with low or absent DPD activity, an enzyme involved in fluorouracil 
degradation, are at increased risk for severe, life-threatening, or fatal adverse 
reactions caused by fluorouracil.  
 
Although DPD deficiency cannot be precisely defined, it is known that patients 
with certain homozygous or certain compound heterozygous mutations in the 
DPYD gene locus, which can cause complete or near complete absence of DPD 
enzymatic activity (as determined by laboratory assays), have the highest risk of 
life-threatening or fatal toxicity47 and should not be treated with capecitabine. No 
dose has been proven safe for patients with complete absence of DPD activity.  
 
For patients with partial DPD deficiency (such as those with heterozygous 
mutations in the DPYD gene) and where the benefits of capecitabine are 
considered to outweigh the risks (taking into account the suitability of an 
alternative non-fluoropyrimidine chemotherapeutic regimen), these patients must 
be treated with extreme caution and frequent subsequent monitoring and dose 
adjustment according to toxicity. There is insufficient data to recommend a 
specific dose in patients with partial DPD activity as measured by specific test. 
 
In patients with unrecognized DPD deficiency treated with capecitabine, life-
threatening toxicities manifesting as acute overdose may occur. In the event of 
Grade 2–4 acute toxicity, treatment must be discontinued immediately. 
Permanent discontinuation should be considered based on clinical assessment 
of the onset, duration, and severity of the observed toxicities. 
Capecitabine can induce hand-foot syndrome (palmar-plantar erythrodysesthesia 
or chemotherapy-induced acral erythema), which is a cutaneous toxicity. 
Persistent or severe hand-foot syndrome (Grade 2 and above) can eventually 
lead to loss of fingerprints, which could impact patient identification.48 For 
patients receiving capecitabine monotherapy in the metastatic setting, the 
median time to onset was 79 days (range 11–360 days), with a severity range of 
Grades 1 to 3. Grade 1 hand-foot syndrome is defined by numbness, 
dysesthesia/paresthesia, tingling or erythema of the hands and/or feet and/or 
discomfort which does not disrupt normal activities. Grade 2 is defined as painful 
erythema and swelling of the hands and/or feet and/or discomfort affecting the 
patient’s activities of daily living (ADL). Grade 3 is defined as moist 
desquamation, ulceration, blistering or severe pain of the hands and/or feet 
and/or severe discomfort that causes the patient to be unable to work or perform 
ADL. If Grade 2 or 3 hand-foot syndrome occurs, administration of capecitabine 
should be interrupted until the event resolves or decreases in intensity to Grade 1. 
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Following Grade 3 hand-foot syndrome, subsequent doses of capecitabine 
should be decreased. 
Patients should be carefully monitored for ophthalmological complications such 
as keratitis and corneal disorders, especially if they have a prior history of eye 
disorders. Treatment of eye disorders should be initiated as clinically appropriate. 
Capecitabine can induce hyperbilirubinemia. Administration of capecitabine 
should be interrupted if treatment-related elevations in bilirubin of > 3.0 × ULN or 
treatment-related elevations in hepatic aminotransferases (ALT/AST) 
of Grade ≥ 2 occur.  
Dehydration may cause acute renal failure, especially in patients with pre-
existing compromised renal function or when capecitabine is given concomitantly 
with known nephrotoxic agents. Acute renal failure secondary to dehydration 
might be potentially fatal. 
Capecitabine can induce severe skin reactions such as Stevens-Johnson 
syndrome and toxic epidermal necrolysis. Capecitabine should be permanently 
discontinued in patients who experience a severe skin reaction possibly 
attributable to capecitabine treatment. 
Leucovorin affects the pharmacodynamics of capecitabine and may increase the 
toxicity of capecitabine. This may be relevant in patients receiving folic acid 
supplementation for folate deficiency due to the similarity between folinic acid 
and folic acid.  
5.1.3 
RISKS ASSOCIATED WITH TRASTUZUMAB EMTANSINE AND 
CAPECITABINE COMBINATION 
The two DLTs observed in Phase I, Cohort 1 (in mBC) were grade 3 vomiting in 
one patient and grade 3 elevated AST and ALT in one patient (see Section 
3.1.1.2). Both patients were treated at dose level 1 (capecitabine 750 mg/m2 bid, 
days 1–14) in combination with trastuzumab emtansine 3.6 mg/kg q3w). During 
Phase I in LA/mGC, DLTs for the combination of trastuzumab emtansine and 
capecitabine will be observed during Cycle 1 (Days 1–21) of this study. The 
combination treatment must be considered as a new treatment during Cycle 1, 
and no individual dose reduction will be allowed during Cycle 1; the general DLT 
rules will be used instead. Interruptions can be made due to toxicities considered 
by the investigator to be related to capecitabine. Grade 2–4 toxicities should be 
interrupted until resolved to Grade 0–1. For Grade 4 toxicities, consideration to 
discontinue treatment with capecitabine will be made with the adjudication of the 
SC.  
5.1.4 
DEFINITION OF DOSE-LIMITING TOXICITY 
DLTs will be observed during Cycle 1 (Day 1–21). Please refer to the Xeloda® 
SmPC for recommendations on dose reduction in subsequent cycles. 
Definition of DLT: 
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Hematologic 
1. Uncomplicated Grade 4 thrombocytopenia that does not recover 
to ≥ 75,000/Ml before Day 21 
2. Thrombocytopenia (any grade) complicated with clinically significant bleeding 
requiring medical intervention, such as platelet transfusion or cauterization. 
However, patients with Grade 1 or 2 epistaxis may have cauterization and 
this should not be considered as a DLT. 
3. Grade 4 neutropenia lasting > 7 consecutive days 
4. Febrile neutropenia with an ANC of < 1,000 cells/mm3 
Non-hematologic 
5. Grade ≥ 3 diarrhea that does not decrease to Grade ≤ 2 after 24 hours of 
starting recommended anti-diarrheal treatment 
6. Grade 3 hand-foot syndrome (Grade 4 not applicable)  
7. Any other treatment-related toxicity Grade ≥ 3 prohibiting the start of the 
second cycle on Day 22 (3 weeks cycle length plus 1 day) 
NOTE: If a Grade 2 event requires a dose delay, it will not be considered as a 
DLT. However, if the toxicity does not resolve to Grade 1 or baseline by Day 42, 
this requires discontinuation and will be considered as a DLT. 
8. Grade 2 toxicity requiring interruption of treatment for > 14 days 
NOTE: Patients experiencing acute early-onset (within 1 week) or unusually 
severe toxicity of diarrhea, stomatitis, mucosal inflammation, neurotoxicity, 
neutropenia, or febrile neutropenia with ANC < 500 cells/mm3 during Cycle 1 
must be tested for DPD deficiency (a central laboratory will be appointed). The 
SC will adjudicate in cases of DLTs that are not covered by the existing DLT 
criteria. 
9. Having taken < 14 full doses of capecitabine due to toxicity 
10. Patient not able to receive 100% of the dose level going into Cycle 2, Day 1 
5.1.5 
MANAGEMENT OF SPECIFIC ADVERSE EVENTS 
5.1.5.1 
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 those specified below (i.e., 
infusion reactions, thrombocytopenia, hepatotoxicity, neurotoxicity, cardiotoxicity, 
and ILD or pneumonitis) are as follows: 
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 
If significant trastuzumab emtansine-related toxicities (other than infusion 
reactions, thrombocytopenia, hepatotoxicity, neurotoxicity, and cardiotoxicity) 
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 re-
evaluated qw during the delay, whenever possible. If dosing resumes, the 
patient may receive trastuzumab emtansine either at the same dose level as 
before or at one dose level lower (see Table 2 and Table 3), at the discretion 
of the investigator. Subsequent cycles should remain the same (q3w or qw), 
and patients should be assessed for toxicity. 
 
If a patient requires a dose reduction, dosing will be reduced by one dose 
level, per Table 2or Table 3. No dose re-escalation will be allowed. 
 
If 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 PD 
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  
(Patients with mBC) 
 
Dose Level 
q3w Schedule 
0 
3.6 mg/kg 
 - 1 
3.0 mg/kg 
 - 2 
2.4 mg/kg 
Indication for 
further dose 
reduction 
Off study treatment 
q3w = every 3 weeks 
 
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Table 3 Dose Reductions for Trastuzumab Emtansine  
(Patients with mGC) 
 
Dose Level 
qw Schedule 
0 
2.4 mg/kg 
 - 1 
2.0 mg/kg 
 - 2 
Off study 
Indication for 
further dose 
reduction 
Off study 
qw = weekly 
 
In case of toxicities requiring the discontinuation of trastuzumab emtansine, the 
patient will be followed-up until the EOS. 
Protocol requirements for specific toxicities are outlined below. 
5.1.5.1.1 
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 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.  
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5.1.5.1.2 
Trastuzumab Emtansine Dose Modification for Hepatotoxicity 
5.1.5.1.2.1 
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, activated partial 
thromboplastin time [aPTT], INR, and albumin) will be entered into the clinical 
database. 
5.1.5.1.2.2 
Nodular regenerative hyperplasia  
Trastuzumab emtansine must be permanently discontinued in patients who are 
diagnosed with NRH. 
5.1.5.1.2.3 
Transaminase elevations or bilirubin elevation requiring dose 
adjustment 
Patients who experience a Grade 3 elevation of liver function should be checked 
twice weekly for the recovery of transaminases and/or total bilirubin. If a patient’s 
transaminases and/or total bilirubin do not recover according to Table 4 and 
Table 5, 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 4 and Table 5 describe the dose modification guidelines for increases in 
serum bilirubin and transaminases, respectively. 
Table 4 Trastuzumab Emtansine Dose Modification: Total Serum Bilirubin 
 
Grade 2 
(> .5 to ≤ 3 × ULN) 
Grade 3 
(> 3 to ≤ 10 × ULN) 
Grade 4 
(> 10 × ULN) 
Do not administer  
trastuzumab emtansine 
until total bilirubin 
recovers to Grade ≤ 1, 
and then treat at the 
same dose level 
Do not administer  
trastuzumab emtansine 
until total bilirubin 
recovers to Grade ≤  
and then reduce one 
dose level 
Discontinue 
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 5 Trastuzumab Emtansine Dose Modification: Serum ALT or AST 
 
Grade 2 
(> 3 to ≤ 5 × ULN) 
Grade 3 
(> 5 to ≤ 20 × ULN) 
Grade 4 
(> 20 × ULN) 
Treat at the same dose 
level 
 
Do not administer trastuzumab 
emtansine until AST/ALT 
recovers to Grade ≤ 2, and then 
reduce one dose level 
Discontinue 
trastuzumab 
emtansine 
ALT  alanine transaminase; AST  aspartate transaminase; 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. 
5.1.5.1.3 
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. 
5.1.5.1.4 
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. Ejection 
fractions will be monitored during the last week of Cycle 1, Cycle 3 and every 
third cycle thereafter until the assessment at the safety follow-up visit. 
Figure 6 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. 
The decision to stop or continue trastuzumab emtansine should be based on the 
algorithm shown in Figure 6. 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. 
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Figure 6 Algorithm for Continuation and Discontinuation of Trastuzumab 
Emtansine Based on Left Ventricular Ejection Fraction 
Assessments in Patients 
 
 
CHF = congestive heart failure; 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. 
 
5.1.5.1.5 
Trastuzumab Emtansine Dose Modification/Management for 
Infusion-related Reactions, Hypersensitivity Reactions 
Trastuzumab emtansine treatment should be interrupted in patients with severe 
infusion-related reactions. Trastuzumab emtansine treatment should 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 
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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. 
Pre-medication 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. 
In the event of a true hypersensitivity reaction (i.e., if the severity of reaction 
increases with subsequent infusions), trastuzumab emtansine treatment must be 
permanently discontinued. Patients who experience a Grade ≥ 3 hypersensitivity 
reaction or acute respiratory distress syndrome (ARDS) will be discontinued from 
the study. 
Patients who experience a severe delayed infusion reaction will be discontinued 
from study treatment.  
5.1.5.1.6 
Trastuzumab Emtansine Dose Modification for Pulmonary 
Toxicity 
Cases of ILD, including pneumonitis (including severe, life-threatening cases) 
and some leading to ARDS or fatal outcome have been reported with 
trastuzumab emtansine. Treatment with trastuzumab emtansine has to be 
permanently discontinued in patients who are diagnosed with ILD or pneumonitis.  
5.1.5.1.7 
Trastuzumab Emtansine Dose Modification for Extravasation 
During the clinical development of trastuzumab emtansine, reactions secondary 
to extravasation have been observed. These reactions were usually mild and 
consisted of erythema, tenderness, skin irritation, pain or swelling at the infusion 
site. Although trastuzumab emtansine is not considered as a vesicant, close 
monitoring of the infusion site for possible subcutaneous infiltration during drug 
administration is recommended. 
5.1.5.2 
Capecitabine Dosage Modification 
Phase I: Patients with mBC 
The dose of capecitabine can be modified from Cycle 2 onwards if considered 
appropriate by the investigator (please refer to the Xeloda® SmPC for 
recommendations). 
In case of toxicities requiring the discontinuation of capecitabine, single-agent 
trastuzumab emtansine may be continued in patients with mBC. 
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Randomized Phase II: Exploration of Efficacy and Safety in mBC  
During the Randomized Phase II part of the study, the dose of capecitabine will 
be modified according to the Xeloda® SmPC. 
In case of toxicities requiring the discontinuation of capecitabine, single-agent 
trastuzumab emtansine may be continued in patients with mBC. 
Phase I: Patients with mGC 
The dose of capecitabine can be modified from cycle 2 onwards if considered 
appropriate by the investigator (please refer to Xeloda® SmPC for 
recommendations). 
In case of toxicities requiring the discontinuation of capecitabine, single-agent 
trastuzumab emtansine may be continued (see Section 3.1.1).  
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording protocol-defined 
AEs and SAEs; measurement of protocol-specified hematology, clinical 
chemistry, and urinalysis variables; measurement of protocol-specified vital signs; 
and other protocol-specified tests that are deemed critical to the safety evaluation 
of the study drug(s). 
The Sponsor or its designee is responsible for reporting relevant SAEs to the 
Competent Authority, other applicable regulatory authorities, and participating 
investigators, in accordance with International Conference on Harmonisation 
(ICH) guidelines, FDA regulations, European Clinical Trials Directive (Directive 
2001/20/EC), and/or local regulatory requirements. 
The Sponsor or its designee is responsible for reporting unexpected fatal or life-
threatening events associated with the use of the study drug to the regulatory 
agencies and competent authorities by telephone or fax within 7 calendar days 
after being notified of the event. The Sponsor or its designee will report other 
relevant SAEs associated with the use of the study medication to the appropriate 
competent authorities (according to local guidelines), investigators, and central 
Institutional Review Boards/Ethics Committees (IRBs/ECs) by a written safety 
report within 15 calendar days of notification. 
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 
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 
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 it occurred in a more severe form or 
was allowed to continue might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.8) 
 
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) 
 
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). 
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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) regardless of the attribution of causality. AESIs 
for this study include the following: 
 
Potential drug-induced liver injury 
Any case of potential 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 with 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: 
 Defined as any organism, virus, or infectious particle (e.g., prion protein 
transmitting transmissible spongiform encephalopathy), both pathogenic and 
non-pathogenic. A transmission of an infectious agent may be suspected from 
clinical symptoms or laboratory findings indicating an infection in a patient 
exposed to a medicinal product. This term ONLY applies when a 
contamination of the study drug is suspected, NOT for infections supported by 
the mode of action, e.g., immunosuppression. 
5.2.4 
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 7 months following last dose of study drug 
(follow-up period based on PK considerations). 
Trastuzumab, a component of trastuzumab emtansine, can cause fetal harm 
when administered to a pregnant woman; postmarketing 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 
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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 
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  
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≥ 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 or partner of a male 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, including 
the partners of male patients, to the Sponsor within 24 hours. 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. 
Experimental studies have reported that IgGs are present in both the pre-
ejaculate and the seminal plasma.49 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 AE eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4, 5.5, and 
5.6. 
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For each AE recorded on the AE eCRF, the investigator will make an 
assessment of seriousness (see Section 5.2.2, for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
ADVERSE EVENT REPORTING PERIOD 
Investigators will seek information on AEs at each patient contact. All AEs, 
whether reported by the patient or noted by study personnel, will be recorded in 
the patient’s medical record and on the AE eCRF. 
After informed consent has been obtained but prior to initiation of study 
drug, only SAEs caused by a protocol-mandated intervention (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 treatment, all AEs, regardless of relationship to study 
drug, will be reported until 28 days after the last administration of study drug. 
After this period, the investigator is not required to actively monitor for AEs; 
however, the Sponsor should be notified if the investigator becomes aware of 
any poststudy SAEs (see Section 5.6). 
5.3.2 
ELICITING ADVERSE EVENT INFORMATION 
A consistent methodology of non-directive questioning should be adopted for 
eliciting AE information at all patient evaluation time points. Examples of non-
directive questions include the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last 
here?” 
5.3.3 
ASSESSMENT OF SEVERITY OF ADVERSE EVENTS 
The AE grading (severity) scale found in the NCI CTCAE (v. 4.0) will be used for 
assessing AE severity (see Table 6). 
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Table 6 Adverse Event Severity Grading Scale 
 
Grade 
Severity 
Alternate Description a 
1 
Mild (apply event-specific 
NCI CTCAE grading criteria) 
Asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated 
2 
Moderate (apply event-specific  
NCI CTCAE grading criteria) 
Minimal, local or non-invasive intervention 
indicated; limiting age-appropriate instrumental 
ADLb 
3 
Severe (apply event-specific  
NCI CTCAE grading criteria) 
Severe or medically significant but 
not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; 
disabling; limiting self-care ADLc 
4 
Very severe, life-threatening,  
or disabling (apply event-specific 
NCI CTCAE grading criteria) 
Life-threatening consequences; 
urgent intervention indicated 
5 
Death related to AE 
 
ADL = activities of daily living; AE = adverse event; CTCAE = Common Terminology Criteria for 
Adverse Events; NCI = National Cancer Institute. 
The NCI CTCAE v4.0 can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
Note: Regardless of severity, some events may also meet regulatory seriousness criteria. Refer 
to definition of a serious AE (see Section 5.2.2). 
a Use these alternative definitions for Grade 1, 2, 3, and 4 events when the observed or 
reported AE is not in the NCI CTCAE listing. 
b Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
c Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
 
5.3.4 
ASSESSMENT OF CAUSALITY OF ADVERSE EVENTS 
Investigators should use their knowledge of the patient, the circumstances 
surrounding the event, temporal relationship of event onset to the initiation of 
study drug, course of the event considering especially the effects of dose 
reduction or discontinuation of study drug or reintroduction of study drug (as 
applicable), known association of the event with the study drug or with similar 
treatments, known association of the event with the disease under study, 
presence of risk factors in the patient or use of concomitant medications known 
to increase the occurrence of the event, presence of non-treatment-related 
factors that are known to be associated with the occurrence of the event, 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 7. 
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Table 7 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 serious AEs 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. 
5.3.5 
PROCEDURES FOR RECORDING ADVERSE EVENTS 
Investigators should use correct medical terminology/concepts when recording 
AEs on the AE eCRF. Avoid colloquialisms and abbreviations. 
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There is one eCRF page for recording AEs or SAEs. 
Only one AE term should be recorded in the event field on the AE 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-related reaction. However, a diagnosis has to be captured as 
an AE if signs and symptoms constitute a diagnosis of allergic 
reaction/hypersensitivity or infusion-related reaction and are classified as SAEs; 
all such symptoms have to be described in the narrative (e.g., in the Additional 
Case Details field of the eCRF). 
Other Adverse Events 
For AEs other than infusion-related reactions, a diagnosis (if known) should be 
recorded on the AE eCRF rather than individual signs and symptoms (e.g., 
record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of 
reporting, each individual event should be recorded on the AE eCRF. If a 
diagnosis is subsequently established, all previously reported AEs based on 
signs and symptoms should be nullified and replaced by one AE report based on 
the single diagnosis, with a starting date that corresponds to the starting date of 
the first symptom of the eventual diagnosis. 
5.3.5.2 
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. All AEs should be recorded 
separately on the Adverse Event eCRF if it is unclear whether the events are 
associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between 
patient evaluation time points. Such events should only be recorded once on the 
AE eCRF. 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 
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worsens. If the event becomes serious, the AE eCRF should be updated to 
reflect this. 
A recurrent AE is one that resolves between patient evaluation time points and 
subsequently recurs. Each recurrence of an AE should be recorded separately 
on the AE eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
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. 
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 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE. A vital sign result must be 
reported as an AE if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator’s judgment  
It is the investigator’s responsibility to review all vital sign findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated vital sign 
abnormality should be classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be 
recorded on the Adverse Event eCRF. 
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Observations of the same clinically significant vital sign abnormality from visit to 
visit should only be recorded once on the Adverse Event eCRF (see 
Section 5.3.5.3 for details on recording persistent AEs). 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  baseline value) in combination with 
either an elevated total bilirubin ( 2  ULN) or clinical jaundice in the absence of 
cholestasis or other causes of hyperbilirubinemia is considered to be an indicator 
of severe liver injury (as defined by Hy's law). Therefore, investigators must 
report as an AE the occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  baseline value in combination with 
total bilirubin  2  ULN (of which   35% is direct bilirubin) 
 
Treatment-emergent ALT or AST  3  baseline value in combination with 
clinical jaundice 
The most appropriate diagnosis or (if a diagnosis cannot be established) the 
abnormal laboratory values should be recorded on the Adverse Event eCRF 
(see Section 5.3.5.4) and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event), either as an SAE or a non-serious AE of 
special interest (see Section 5.4.2). 
5.3.5.7 
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 mBC or 
mGC 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 AE eCRF and immediately reported to the Sponsor (see 
Section 5.4.2). The IDMC will monitor the frequency of death from all causes. 
Death should be considered an outcome and not a distinct event. The event or 
condition that caused or contributed to the fatal outcome should be recorded as 
the single medical concept on the AE eCRF. Generally, only one such event 
should be reported. If the cause of death is unknown and cannot be ascertained 
at the time of reporting, “unexplained death” should be recorded on the AE 
eCRF. If the cause of death later becomes available (e.g., after autopsy), 
“unexplained death” should be replaced by the established cause of death. The 
term "sudden death" should be used only for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen 
alive and stable. 
During post-study survival follow-up, deaths attributed to progression of mBC or 
LA/mGC should be recorded only on the Survival eCRF. 
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5.3.5.8 
Pre-Existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of this study. 
Such conditions should be recorded on the Medical and Surgical History 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 AE eCRF, it is important to convey the concept that 
the pre-existing condition has changed by including applicable descriptors 
(e.g., “more frequent headaches” or "worsening gastrointestinal reflux disease"). 
5.3.5.9 
Lack of Efficacy or Clinical Worsening 
Events that are clearly consistent with the expected pattern of progression of 
mBC or LA/mGC 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 the RECIST criteria. 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 PD, it should 
be reported as an AE. 
5.3.5.10 
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 planned 
hospitalization or prolonged hospitalization to: 
 
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 
 
5.3.5.11 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher 
than the dose being studied. An overdose or incorrect administration of study 
treatment is not itself an AE, but it may result in an AE. All overdose or incorrect 
administrations of study drug with/without AEs associated should be recorded on 
the AE eCRF. If the associated AE fulfills seriousness criteria, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2). 
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5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO THE 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 (SPONSOR’S 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"). 
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 immediately (i.e., no more than 24 hours) on the AE 
eCRF and submit the report via the electronic data capture (EDC) system. 
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A 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 immediately (i.e., no more than 
24 hours) after learning of the event, using the fax numbers provided to 
investigators (see "Protocol Administrative and Contact Information & List of 
Investigators"). Once the EDC system is available, all information will need to be 
entered and submitted via the EDC system. 
5.4.3 
REPORTING REQUIREMENTS FOR PREGNANCIES 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform 
the investigator if they become pregnant during the study or within 7 months after 
the last dose of study drug. A Pregnancy Report eCRF should be completed by 
the investigator immediately (i.e., no more than 24 hours) after learning of the 
pregnancy and submitted via the EDC system. A Pregnancy Report will 
automatically be generated and sent to the Sponsor Safety Risk Management. 
Pregnancy should not be recorded on the AE eCRF. The investigator should 
have the patient discontinue the study drug and discuss with the patient the risks 
of the pregnancy and the possible effects on the fetus. Monitoring of the patient 
should continue until conclusion of the pregnancy. 
In the event that the EDC system is unavailable, a Pregnancy Report worksheet 
and Pregnancy Fax Coversheet should be completed and faxed to the Sponsor 
Safety Risk Management or its designee immediately (i.e., no more than 24 
hours) after learning of the pregnancy, using the fax numbers provided to 
investigators (see "Protocol Administrative and Contact Information & List of 
Investigators"). 
Additional information on any trastuzumab emtansine-exposed pregnancy and 
infant will be requested by Roche Drug Safety at specific time points (i.e., after 
having received the initial report, at the end of the second trimester, 2 weeks 
after the expected date of delivery, and at 3, 6, and 2 months of the infant’s life).   
Any serious adverse events associated with the pregnancy (e.g., an event in the 
fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the Adverse Event eCRF.  
In addition, the investigator will submit a Clinical Trial Pregnancy Reporting Form 
when updated information on the course and outcome of the pregnancy becomes 
available.   
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 
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study or within 7 months after the last dose of study drug. A Pregnancy Report 
eCRF should be completed by the investigator immediately (i.e., no more than 24 
hours) after learning of the pregnancy and submitted via the EDC system. 
Attempts should be made to collect and report details of the course and outcome 
of any pregnancy in the partner of a male patient exposed to study drug. The 
pregnant partner will need to sign an Authorization for Use and Disclosure of 
Pregnancy Health Information to allow for follow-up on her pregnancy. Once the 
authorization has been signed, the investigator will update the Pregnancy Report 
eCRF with additional information on the course and outcome of the pregnancy. 
An investigator who is contacted by the male patient or his pregnant partner may 
provide information on the risks of the pregnancy and the possible effects on the 
fetus, to support an informed decision in cooperation with the treating physician 
and/or obstetrician. 
In the event that the EDC system is unavailable, follow reporting instructions 
provided in Section 5.4.3.1. 
5.4.3.3 
Abortions 
Any spontaneous abortion should be classified as an SAE (as the Sponsor 
considers spontaneous abortions to be medically significant events), recorded on 
the AE eCRF, and reported to the Sponsor immediately (i.e., no more than 24 
hours) after learning of the event (see Section 5.4.2). 
5.4.3.4 
Congenital Anomalies/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 an SAE, 
recorded on the AE eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours) after learning of the event (see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER 
ADVERSE EVENTS 
5.5.1 
INVESTIGATOR FOLLOW-UP 
The investigator should follow all unresolved AEs and until the events are resolved 
or stabilized, the patient is lost to follow-up, or it has been determined that the study 
treatment or participation is not the cause of the AE/SAE. Resolution of AEs and 
SAEs (with dates) should be documented on the AE eCRF and in the patient’s 
medical record to facilitate source data verification (SDV). 
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 
At the time of study completion or study discontinuation, the investigator should 
instruct each patient to report to the investigator any subsequent AEs that the 
patient’s physician believes could be related to prior study drug treatment or 
study procedures. 
The investigator is not required to actively monitor patients for AEs after the end 
of the AE reporting period (defined as 28 days after the last dose of study drug). 
However, the Sponsor should be notified if the investigator becomes aware of 
any death or other SAE occurring after the end of the AE reporting period, 
regardless of causality.  
The investigator should report these events directly to Roche Safety Risk 
Management via telephone or via facsimile using the Roche Clinical Trial (SAE) 
Reporting Form. 
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 following reference 
documents: 
 
Trastuzumab emtansine and capecitabine Investigator's Brochures 
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 IDMC will closely monitor the incidence of these expected events during the 
study. An aggregate report of any clinically relevant imbalances that do not favor 
the test product will be submitted to health authorities. 
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6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
PLAN 
The design of this study includes: Phase I, Randomized Phase II and different 
cohorts. Corresponding analyses as described in the protocol will be performed 
when all data for a particular cohort and study phase are collected and cleaned. 
Phase I: Patients with mBC: 
Enrollment into Cohort 1, patients with HER2-positive mBC, will open first. 
Enrolled patients will receive study drug until Investigator-assessed PD, 
unacceptable toxicity, withdrawal of consent, death, reasons deemed by the 
treating physician, or study termination by the Sponsor. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
Patients randomized in Phase II will receive study drug until investigator-
assessed PD, unacceptable toxicity, withdrawal of consent, death, reasons 
deemed by the treating physician, or study termination by the Sponsor. 
The primary analysis of BOR will be performed when 70% of the patients have 
experienced a PFS event or at the end of the trial, whichever comes first. It is 
estimated that 70% of patients will have experienced a PFS event approximately 
26 months after the randomization of the first patient.  
The EOS analysis will include an updated analysis of BOR, which will be done in 
a purely exploratory manner.   
Phase I: Patients with mGC: 
Once the MTD is established for Cohort 1, enrollment of patients with HER2-
positive and LA/mGC into Cohort 2 will be opened. 
Enrolled patients will receive study drug until investigator-assessed PD, 
unacceptable toxicity, withdrawal of consent, death, reasons deemed by the 
treating physician, or study termination by the Sponsor. 
6.1 
DETERMINATION OF SAMPLE SIZE 
Sample Size for Phase I: mBC 
This part will be based on a classical 3 plus 3 Phase I design. A minimum of 6 
and up to 18 patients will be enrolled into Cohort 1. There is no formal sample 
size estimation for this part. 
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Sample Size for Randomized Phase II: Exploration of Efficacy and Safety in 
mBC 
The sample size for the primary endpoint BOR is based on a Fisher’s exact test 
with an alpha level of 5% (one-sided),50,51 power of 70% and the clinical 
assumption of a BOR rate of 43% with trastuzumab emtansine alone and 62.5% 
with the combination of trastuzumab emtansine and capecitabine. Approximately 
160 patients (approximately 80 patients in each treatment group), including a 
15% withdrawal rate, will be randomized with a 1:1 ratio to trastuzumab 
emtansine alone or the combination of trastuzumab emtansine and capecitabine. 
An expected BOR rate of 43.6% (95% CI: 38.6%–48.6%) for patients receiving 
trastuzumab emtansine alone was chosen based on previously published data 
for T-DM1 in patients with unresectable, locally advanced or mBC previously 
treated with a taxane and trastuzumab (EMILIA study).27 
The BOR rates for patients treated with the combination of T-DM1 and 
capecitabine were chosen based on recent results from other combination 
studies of T-DM1 plus chemotherapy or trastuzumab plus capecitabine. 
Response rates were based on those observed in patients with HER2-positive 
mBC in a Phase Ib/IIa study (BP22752) that compared the combination of 
trastuzumab emtansine with docetaxel, with or without pertuzumab (ORR: 76% 
[95% CI: 53%–92%]), and also in a Phase II study that compared the 
combination of trastuzumab with docetaxel, with or without capecitabine (ORRs: 
72.7% [95% CI: 63.4%–80.8%] and 70.5% [95% CI: 61.2%–78.8%]).41 
Increased BOR rates for the combination treatment compared with single-agent 
trastuzumab emtansine are in line with previously published results of a 
randomized Phase III study in patients with locally advanced or mBC treated with 
the combination of trastuzumab with capecitabine versus capecitabine alone 
(ORR: 48.1% versus 27.0%, odds ratio = 2.50, p = 0.0115).9 
The estimation of sample size was performed by Nquery® and EAST® programs. 
Stratification Factors 
The following stratification factor will be implemented in the Randomized Phase II 
of the study: 
 
Number of prior lines of treatment for metastatic disease (≤1 or >1; excluding 
single-agent hormones) 
A treatment line is any regimen given to a patient from treatment initiation until 
confirmed PD. 
Sample Size for Phase I: mGC 
This part will be based on a classical 3 plus 3 Phase I design. From 3 to 12 
patients might be enrolled into Cohort 2. There is no formal sample size 
estimation for this part. 
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6.2 
SUMMARIES OF CONDUCT OF STUDY 
Phase I: Patients with mBC 
Due to the small sample size, per-protocol (PP) population will not be defined for 
the Phase I, Cohort 1. 
Major protocol violations will be summarized by treatment dosage. Median follow-
up will be estimated for Phase I, Cohort 1. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
For the Randomized Phase II part of the study, a PP population will be defined 
(Section 6.4).  
Patient enrollment, duration of follow-up, discontinuation from study treatment 
and study, and reasons for study discontinuation will be summarized by 
treatment group for all randomized patients. In addition, major protocol violations 
will be summarized by treatment arm. 
Phase I: Patients with LA/mGC  
Due to the small sample size, a PP population will not be defined for the Phase I, 
Cohort 2. 
Major protocol violations will be summarized by treatment dosage. Median follow-
up will be estimated for Phase I, Cohort 2. 
6.3 
SUMMARIES OF TREATMENT GROUP 
COMPARABILITY 
Phase I: mBC 
As Phase I is the MTD-Finding part of the study, there are no treatment group 
comparisons for this part of the study. 
Demographics, medical history, and baseline characteristics will be summarized. 
Continuous variables will be summarized using median, mean, standard 
deviation, 25th and 75th percentiles and range. Categorical variables will be 
summarized by the number and percentage of patients for each treatment 
dosage. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
The Randomized Phase II part of the study is designed to explore the efficacy 
and safety of the combination of trastuzumab emtansine and capecitabine 
compared with trastuzumab emtansine alone. 
Demographics, medical history, and baseline characteristics will be summarized. 
Continuous variables will be summarized using median, mean, standard 
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deviation, 25th and 75th percentiles and range. Categorical variables will be 
summarized by the number and percentage of patients for each treatment group. 
Phase I: mGC 
As Phase I is the MTD-Finding part of the study, there are no treatment group 
comparisons for this part of the study.  
Demographics, medical history and baseline characteristics will be summarized. 
Continuous variables will be summarized using median, mean, standard 
deviation, 25th and 75th percentiles and range. Categorical variables will be 
summarized by the number and percentage for each treatment dosage. 
6.4 
EFFICACY ANALYSES 
Phase I, Cohort 1: mBC 
The main analysis population will be the DLT-evaluable population as defined in 
Section 6.5. 
Randomized Phase II: Exploration of Efficacy in mBC  
The main analysis population for the efficacy analysis will be the intent-to-treat 
population (ITT), which will include all patients in the Randomized Phase II part 
of the study. The PP population will include all ITT patients who have at least one 
post-baseline tumor assessment during the Phase II part and no major protocol 
violations, which will be defined in the statistical analysis plan (SAP). 
Phase I, Cohort 2: mGC 
The main analysis population will be the DLT-evaluable population as defined in 
Section 6.5. 
6.4.1 
PRIMARY EFFICACY ENDPOINT 
Phase I, Cohort 1: Patients with mBC  
The primary objectives are defining the MTD and establishing the safety profile. 
The number and the proportion of patients with DLTs will be used as the primary 
measure for the MTD determination. 
ORR, as a main efficacy endpoint, will be assessed via BOR rate. The BOR is 
defined as the best response recorded from the date of enrollment until PD, 
death, withdrawal of consent, start of new anticancer treatment, or EOS, 
whichever occurs first. The number of patients is very small in this part of the 
study. Therefore, all analyses will be descriptive. 
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Randomized Phase II: Exploration of Efficacy in mBC  
The primary efficacy endpoint for the Randomized Phase II part of the study is 
the ORR as assessed via BOR. The BOR is defined as the best response 
recorded from the start or randomization into the Phase II part of the study and 
until PD, death, withdrawal of consent, start of new anticancer treatment, or EOS, 
whichever occurs first. 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 28 days after the criteria for 
response are first met, i.e., patients need to have two consecutive assessments 
of PR or CR.  
The primary hypothesis of interest when comparing ORR – as assessed via BOR 
– between the two treatment groups (combination of trastuzumab emtansine and 
capecitabine versus trastuzumab emtansine alone) is:  
 
H0: πTDM1 = πtrastuzumab emtansine + capecitabine where πtrastuzumab emtansine is BOR in 
TDM  and  trastuzumab emtansine + capecitabine is BOR in trastuzumab emtansine + 
capecitabine 
 
H :  trastuzumab emtansine   trastuzumab emtansine + capecitabine  
The number and proportions of responders and non-responders (based on BOR) 
together with 90% Clopper-Pearson CIs will be presented for each treatment 
group.  
The difference in BOR between treatment groups will be displayed with 
associated 90% CIs using the Hauck-Anderson approach and p-values for the 
Fisher’s exact test.  
Logistic analysis will be used to assess the influence of the stratification factor 
and baseline covariates in an exploratory manner. 
The primary analysis of BOR will be performed when 70% of the patients have 
experienced a PFS event or at the end of the trial, whichever comes first. It is 
estimated that 70% of patients will have experienced a PFS event approximately 
26 months after the randomization of the first patient. 
Phase I, Cohort 2: Patients with LA/mGC 
The primary objectives are defining the MTD and establishing the safety profile. 
The number and the proportion of patients with DLTs will be used as the primary 
measure for the MTD determination. 
ORR, as a main efficacy endpoint, will be assessed via BOR rate. The BOR is 
defined as the best response recorded from the date of enrollment until PD, 
death, withdrawal of consent, start of new anticancer treatment, or EOS, 
whichever occurs first. The number of patients is very small in this part of the 
study. Therefore, all analyses will be descriptive. 
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6.4.2 
SECONDARY EFFICACY ENDPOINTS 
Phase I, Cohort 1: mBC 
Due to the small number of patients and the design of this part of the study, no 
secondary efficacy endpoints will be investigated. 
Randomized Phase II: Exploration of Efficacy in mBC  
The secondary efficacy endpoints for the Randomized Phase II will be: 
 
TTR 
 
DoR 
 
TTP 
 
TTF 
 
PFS 
 
CBR 
 
OS 
TTR is defined as the time from randomization to first documentation of 
confirmed PR or CR (whichever occurs first). Patients who do not have a 
confirmed response will be censored at the date of the last tumor assessment. 
DoR is defined as the period from the date of first recorded 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. The method for handling censoring is the same as described 
for PFS below. Only patients with a BOR of CR or PR (i.e., responders) will be 
included in the analysis of DoR. 
For patients with a BOR of CR or PR, TTR is defined as the time from 
randomization to the date of first CR or PR. The censoring rules will be similar to 
those of the PFS. 
TTP is defined as time from randomization to the first occurrence of PD. Patients 
who have not progressed at the time of study completion (including patients who 
have died before PD) or who are lost to follow-up are censored at the date of the 
last tumor assessment. 
TTF is defined as time from randomization until treatment failure, i.e., to PD, 
death, withdrawal due to AE or laboratory abnormality, or refusal of treatment. 
Patients who do not experience any of the above events while on study will be 
censored on the day of their last tumor assessment.  
PFS is defined as the time from randomization 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 
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assessment. Patients with no post-baseline tumor assessment will be censored 
at the time of randomization plus 1 day.  
OS is defined as the time from randomization until the date of death, regardless 
of the cause of death. Patients who are alive at the time of data cut-off will be 
censored at the date of the last follow-up assessment.  
Estimates for the survivor function of both treatment groups for TTR, DoR, TTP, 
TTF, and OS will be obtained by using the Kaplan-Meier method. HRs and 
associated 90% CIs will be estimated from non-stratified and stratified (based on 
the stratification factor) Cox regression models. 
CBR includes patients whose best (confirmed) response was PR, CR or SD that 
lasted at least 6 months. CBR will be summarized in a similar way to the primary 
efficacy endpoint, ORR as assessed by BOR.  
Phase I, Cohort 2: mGC 
Due to the small number of patients and the design of this part of the study, no 
secondary efficacy endpoints will be investigated. 
6.5 
SAFETY ANALYSES 
Safety Population Phase I, Cohort 1: mBC 
The DLT-evaluable population is defined as all enrolled and treated patients who 
have not experienced any major protocol violation (including violation of the 
inclusion and exclusion criteria) and completed Cycle 1.  
The number and the proportion of patients with DLTs will be used as the primary 
measure for the MTD determination. The definition of DLTs is presented in 
Section 5.1.4. DLTs for this part of the study will be summarized by treatment 
dose. 
The safety population (SP) will include all patients who received at least one 
dose of study medication during Phase I. Safety endpoints will be summarized by 
treatment dosage. 
Safety parameters for this part of the study will be summarized by treatment dose. 
The summaries of AEs, SAEs, AEs that caused discontinuation from the study 
treatment and/or study, and AESIs will be analyzed in a similar way to AEs in 
Phase II. 
The incidence of AEs and SAEs will be summarized according to the primary 
SOC and, within each SOC, by MedDRA preferred term. Based on the safety 
profile of trastuzumab emtansine, time to onset of the first episode of any AESI 
described in Section 5 will also be summarized via Kaplan-Meier estimates. 
Additional summaries by frequency tables will also be provided for the AESIs. 
Patients who died will be listed together with the cause of death. 
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Laboratory parameters, hematology and biochemistry will be presented in shift 
tables of NCI-CTC grade at baseline versus worst grade during treatment for 
Phase I, Cohort 2, and overall. 
LVEF will be summarized over time using mean, median and range (minimum 
and maximum) and will be presented graphically.  
Other safety variables, such as exposure to study medication, concomitant 
medications and physical examinations will be analyzed in a similar way. The 
exposure of study medication will be summarized by frequency tables. 
ECOG performance status will be summarized over time and the percentage of 
patients in different categories will be presented by bar charts at different time 
points. 
 
Randomized Phase II: Exploration of Safety in mBC  
The SP will include all patients who received at least one dose of study 
medication during the Randomized Phase II part of the study. Safety endpoints 
will be summarized by treatment group.   
Safety endpoints during Phase II will be assessed via total AEs, Grade ≥3 AEs, 
SAEs, AESIs (as described in Section 5), fatal AEs and their causes, events to 
monitor, premature withdrawal from study medication and/or study, laboratory 
parameters, LVEF, exposure to study medication, concomitant medications, 
ECOG performance status, and physical examination. 
The incidence of AEs and SAEs 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 any AESI described 
in Section 5 will also be summarized via Kaplan-Meier estimates. Additional 
summaries by frequency tables will be provided for the AESIs. Patients who died 
will be listed together with the cause of death. 
Laboratory parameters, hematology, and biochemistry will be presented in shift 
tables of NCI-CTCAE grade at baseline versus worst grade during treatment for 
the Randomized Phase II part of the study. 
LVEF will be summarized over time using mean, median and range (minimum 
and maximum) and will be presented graphically.  
Other safety variables, such as exposure to study medication, concomitant 
medications and physical examinations, will be analyzed in a similar way. The 
exposure to study medication will be summarized by frequency tables. 
ECOG performance status will be summarized over time and the percentage of 
patients in different categories will be presented by bar charts at different time 
points. 
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Safety Population Phase I, Cohort 2: LA/mGC 
The DLT-evaluable population is defined as all enrolled and treated patients who 
have not experienced any major protocol violation (including violation of the 
inclusion and exclusion criteria) and have completed Cycle 1.  
The number and the proportion of patients with DLTs will be used as the primary 
measure for the MTD determination. The definition of DLTs is presented in 
Section 5.1.4. DLTs for this part of the study will be summarized by treatment 
dose. 
The SP will include all patients who received at least one dose of study 
medication during Phase I. Safety endpoints will be summarized by treatment 
dosage. 
Safety parameters will be analyzed in a similar way to safety parameters in 
Phase I, Cohort 1: mBC. 
6.6 
PHARMACODYNAMIC ANALYSES 
No pharmacodynamic analyses are planned for this study. 
6.7 
PHARMACOKINETIC ANALYSES 
For Phase I only (Patients with mBC and LA/mGC): 
The following PK parameters of trastuzumab emtansine, capecitabine and their 
metabolites (including but not limited to those listed below) will be determined 
only in the Phase I part of the study for Cohort 1 and Cohort 2 in all patients who 
receive study treatment using either non-compartmental and/or population 
methods, if data allow: 
 
Serum concentrations of trastuzumab emtansine (conjugate) and total 
trastuzumab 
 
Plasma concentrations of DM1, capecitabine and its active metabolite  
5-FU 
 
Total exposure (e.g., AUC)  
 
Cmax 
 
CL 
 
Vd 
 
T1/2 
The PK of trastuzumab emtansine, total trastuzumab and DM1 will be compared 
with historical single-agent PK data to evaluate the potential effect of 
capecitabine on the PK of trastuzumab emtansine and related analytes. The PK 
of capecitabine and its active metabolite 5-FU in Cycle 1 (in the absence of 
trastuzumab emtansine) will be compared with the PK of Cycle 2 (in the 
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presence of trastuzumab emtansine) to evaluate the potential effect of 
trastuzumab emtansine on the PK of capecitabine and 5-FU. 
All PK parameters will be listed and tabulated by treatment dose and by Cohort. 
Descriptive summary statistics including arithmetic mean, geometric mean (e.g., 
AUC and Cmax), median, range, s.d., and coefficient of variation will be presented 
for each cohort. Nonlinear mixed effects modeling will also be used; details will 
be presented in the SAP. 
PK samples can be obtained ad hoc in case of a SAE or unexpected toxicities 
which may suggest a potential drug-drug interaction. 
6.8 
EXPLORATORY ANALYSES 
For all patients with mBC (Phase I, cohort 1; Phase II Exploration of Efficacy and 
Safety in mBC), a retrospective central confirmation of the HER2 status will be 
done. Further exploratory analysis for HER2-positive patients (based on central 
confirmation) will be done for selected endpoints such as BOR and safety 
endpoints (AEs, SAEs, Grade ≥ 3 AEs, and AESIs). 
For the Randomized Phase II only: Exploration of Efficacy and Safety in 
Patients with mBC: 
Subgroup analysis for BOR, safety endpoints (AEs, SAEs, Grade ≥ 3 AEs, and 
AESIs) in Phase II will be presented for: elderly versus younger patients, patients 
with ECOG 0–1 versus ECOG 2, and patients with ≤ versus >  prior treatment 
regimen for metastatic disease.  
More details about subgroups will be provided in the SAP. 
Pharmacoeconomic Endpoint: 
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 (PD versus AE) will 
also be assessed. 
6.9 
INTERIM ANALYSES 
There is no formal efficacy interim analysis.  
However, an IDMC will recommend whether the Randomized Phase II part of the 
study can commence. The IDMC will also monitor safety outcomes after 25, 75, 
and 150 patients have received at least 3 cycles (Cycle 3 Day 21) of treatment in 
the Randomized Phase II part of the study. Afterwards, the IDMC will monitor 
accumulating patient safety data every 6 months during the course of the 
Randomized Phase II of the study or as requested. 
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Efficacy data will be provided only if required by the IDMC to estimate the risk-
benefit balance for the patients. Further details on the function and logistics of 
the IDMC will be provided in the IDMC Charter. 
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. Central laboratory data and 
other 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 have access to a manual for appropriate eCRF completion. 
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff. eCRFs should 
be reviewed and electronically signed and dated by the investigator or a 
designee. 
At the end of the study, the investigator will receive patient data for his or her site 
in a readable format on a compact disc that must be kept with the study records. 
Acknowledgment of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing SDV to confirm that critical protocol data (i.e., 
source data) entered into the eCRFs by authorized site personnel are accurate, 
complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are 
recorded and documented for the first time. They include, but are not limited to, 
hospital records, clinical and office charts, laboratory notes, memoranda, patient-
reported outcomes, evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies of transcriptions that are 
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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. 
Source documents that are required to verify the validity and completeness of 
data entered into the eCRFs must not be obliterated or destroyed. 
To facilitate SDV, the investigators and institutions must provide the Sponsor with 
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. 
In collaboration with the study monitor, 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 Good Clinical Practice (GCP) (see Section 4.9 of the 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. 
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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 (IND) application, 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 
GCP 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 European Union (EU)/European 
economic area (EEA) will comply with the EU Clinical Trial Directive 
(2001/20/EC). 
8.2 
INFORMED CONSENT 
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 Form or any alternate Consent 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 Form 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. 
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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/IEC 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. 
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 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. 
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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, 
the 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. 
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 investigator 
will permit national and local health authorities, the 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 a SC, IDMC, central laboratory, IxRS, eCRF, and will be 
conducted by a contract research organization (CRO) together with the Sponsor. 
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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 the Sponsor personnel exceeded 
that of conventional monitoring will be considered as a joint publication by the 
investigator and the appropriate the 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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28. Krop IE, Kim SB, González-Martín A, et al. Trastuzumab emtansine versus 
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33. Gupta M, Wang B, Carrothers TJ, et al. Effects of trastuzumab emtansine (T-
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37. Igawa Y, Matsubara M, Matsunaga K, et al. Pharmacokinetic (PK) and 
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first-line trastuzumab plus docetaxel and capecitabine compared with 
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42. Sawaki A, Ohashi Y, Omuro Y, et al. Efficacy of trastuzumab in Japanese 
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testing in large, prospective, randomized clinical trials. Clin Cancer Res 2005; 
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49. 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. 
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the importance of radnomisation. Eur J Cancer 2009;45:275–80. 
 
 
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Appendix 1 
Schedule of Assessments 
Table 1 
Schedule of assessments for mBC patients (Phase I, Cohort 1 and Randomized Phase II) 
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 Onwards 
Safety 
Follow-Up 
Visit 
Follow-Up2 
Day 
-28 to -1 
1 
8 
15 
1 
8 
15 
1 
8 
15 
28-42 days 
after last 
dose 
every 3-6 
months 
Informed Consent 
Xa 
 
 
 
 
 
 
 
 
 
 
 
HER2 Status  
Xb 
 
 
 
 
 
 
 
 
 
 
 
Medical History and Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination  
X 
 
 
 
 
 
 
 
 
 
 
 
Limited Physical Examinationc 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Height and Weightd 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Vital Signse 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
ECOG Performance Status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Concomitant Medication Reporting 
Xf 
X 
Ongoing 
 
AE Reporting 
Xg 
Ongoing 
X 
Xh 
12-lead ECG  
X  
 
 
 
 
 
 
 
 
 
 
 
ECHO/MUGAi 
Xi 
 
 
Xi 
 
 
Xi 
 
 
Xi 
Xi 
 
Tumor Assessmentsj 
X 
At Cycle 3 (9 weeks after randomization), and then every 4th cycle (12 weeks thereafter, 
regardless of dose delay or early discontinuation) until PD or study termination, 
whichever occurs earlier 
X 
X 
Brain CT or MRIk 
X 
At the discretion of the investigator, if clinically indicated, until PD 
Bone Scan/Imagingl 
X 
As clinically indicated 
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Appendix 1 
Schedule of Assessments (cont.) 
Table 1 
Schedule of assessments for mBC patients (Phase I, Cohort 1 and Randomized Phase II) (cont.) 
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 Onwards 
Safety 
Follow-Up 
Visit 
Follow-Up2  
Day 
-28 to -1 
1  
8 
15 
1  
8 
15 
1  
8 
15 
28-42 days 
after last 
dose 
every 3-6 
months 
Hematologym 
X  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
 
 
X 
 
Biochemistryo 
X  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
 
 
X 
 
Urinalysisp 
X  
As clinically indicated 
X 
 
INR/aPTT 
X  
As clinically indicated, e.g. for patients receiving anticoagulation therapy 
X 
 
Pregnancy Testq 
X  
 
 
 
 
 
X q 
 
 
X q 
X  
X 
PK Samples (seeAppendix 2)r 
 
Xr 
 
 
Xr 
 
 
 
 
 
 
 
Assessment of Patient 
Hospitalizations and/or Hospital 
Visits 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Administration of Trastuzumab 
Emtansine 
 
D 2s 
 
 
D 1s 
 
 
D 1s 
 
 
 
 
Administration of Capecitabinet 
 
D 1–14 
 
D 1–14 
 
D 1–14 
 
 
 
Overall Survival 
 
X 
X 
X 
Randomization into the Phase II 
Part of the Study 
Xtu 
 
 
 
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Appendix 1 
Schedule of Assessments (cont.) 
AE = Adverse Event; aPTT = Activated Partial Thromboplastin Time; CT = Computed Tomography; ECHO = Echocardiogram; ECOG = Eastern Cooperative 
Oncology Group; D= Day; 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, INR and aPTT assessments) at Screening: to be performed within 14 days prior to first 
treatment. Screening laboratory assessments may be done on the same day of first study treatment (Cycle1 Day1). 
2.All patients will be followed-up every 6 months (except for pregnancy, which is at 3 and 6 months after safety follow-up visit until disease progresses for 
tumor assessment or study closure, whichever occurs first. Patients who discontinue study treatment for reasons other than PD will continue to undergo 
tumor assessments every 3–6 months. 
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 for patients with mBC.  
c)Limited symptom-directed physical examination. 
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. 
g)During screening, only SAEs considered related to protocol-mandated procedures will be collected. 
h)Patients will be followed for new or worsening AEs for 28 days following the last infusion of study drug or until the early termination visit, until treatment-
related AEs resolve or stabilize, or until the initiation of another anti-cancer therapy, whichever occurs first. After 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, between Days 
15 and 21 in cycles 1 and 3, and between Days 15 and 21 of 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. 
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Appendix 1 
Schedule of Assessments (cont.) 
j)Tumor assessments (± 5 business days), including a CT or MRI with contrast of the chest, abdomen, and pelvis should be performed according to the 
indicated schedule. 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, 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 until PD, withdrawal of consent, or study terminaton (whichever occurs earlier). 
k)Patients with isolated brain metastases may continue study treatment if they demonstrate clinical benefit (CR or PR of any duration or SD ≥ 3 months) as 
detailed in Section 4.5.1.4 of the protocol and in Appendix 3. 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 study treatment, non-isotopic radiographic modalities should be utilized to document the extent of bony 
metastatic disease. Refer to Appendix 4 in the protocol 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)Assessments should be performed at screening, on Day 1, 8 and 15 of Cycles 1–3, on Day 1 of all subsequent cycles, and weekly following any 
hematologic AE. If capecitabine is discontinued due to toxicity, assessments should be performed weekly (minimum) until resolution of the AE (Grade  1/ 
baseline), and on Day 1 of subsequent cycles thereafter. All assessments should 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, blood urea nitrogen (BUN)/urea (mandatory), creatinine, 
uric acid, total protein, albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), G-GT, LDH, total bilirubin (and direct bilirubin where total bilirubin > ULN). 
Fasting is required before biochemistry assessment. 
p)Includes specific gravity, pH, protein, glucose, blood, ketones and bilirubin. 
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Appendix 1 
Schedule of Assessments (cont.) 
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. 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 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. 
r)Pharmacokinetic assessments will be performed during the MTD-Finding part of the study only (see Appendix 2). 
s)Trastuzumab emtansine will be administered on Day 1 of each 3-weekly cycle for all patients with mBC in Cohort 1 and Randomized Phase II period of the 
study except in the first cycle where trastuzumab emtansine will be given on Day 2 (to allow PK sampling). 
t) Capecitabine must be given within 30 minutes after a meal. 
u)Patients will be randomized only in the Randomized Phase II part of the study. No blinding will be used, as this is an open-label study. 
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Appendix 1 
Schedule of Assessments (cont.) 
Table 2 Schedule of assessments for patients with LA/mGC (Phase I, Cohort 2) 
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 Onwards 
Safety 
Follow-Up 
Visit 
Follow-Up2  
Day 
-28 to -1 
1 
8 
15 
1 
8 
15 
1 
8 
15 
28–42 days 
after last 
dose 
every 3–6 
months 
Informed Consent 
Xa 
 
 
 
 
 
 
 
 
 
 
 
HER2 Status  
Xb 
 
 
 
 
 
 
 
 
 
 
 
Medical History and Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination  
X 
 
 
 
 
 
 
 
 
 
 
 
Limited Physical Examinationc 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Height and Weightd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signse 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
ECOG Performance Status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Concomitant Medication Reporting 
Xf 
X 
Ongoing 
 
AE Reporting 
Xg 
Ongoing 
X 
Xh 
12-lead ECG  
X  
 
 
 
 
 
 
 
 
 
 
 
ECHO/MUGAi 
Xi 
 
 
Xi 
 
 
Xi 
 
 
Xi 
Xi 
 
Tumor Assessmentsj 
X 
At 9 weeks after C1D1, and every 12 weeks thereafter, regardless of dose delay or early 
discontinuation, until PD or study termination, whichever occurs earliest 
X 
 
Brain CT or MRIk 
X 
At the discretion of the investigator, if clinically indicated, until PD 
Bone Scan/Imagingl 
X 
As clinically indicated 
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Hematologym 
X  
Xn 
Xn  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
X 
 
Biochemistryo 
X  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
X 
 
Urinalysisp 
X  
As clinically indicated 
X 
 
INR/aPTT 
X  
As clinically indicated, e.g. for patients receiving anticoagulation therapy 
X 
 
Pregnancy Testq 
X  
 
 
 
 
 
Xq 
 
 
Xq 
X 
X 
PK/PD Samples (see Appendix 2 ) 
 
X 
 
 
X 
 
 
 
 
 
 
 
Assessment of Patient 
Hospitalizations and/or Hospital 
Visits 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Administration of Trastuzumab 
Emtansine 
 
D 2r 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Administration of Capecitabines 
 
D 1–14 
 
D 1–14 
 
D 1–14 
 
 
 
Overall Survival 
 
X 
X 
X 
AE = Adverse Event; aPTT = Activated Partial Thromboplastin Time; CT = Computed Tomography; ECHO = Echocardiogram; ECOG = Eastern Cooperative 
Oncology Group; D= Day; 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 
 
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Appendix 1 
Schedule of Assessments (cont.) 
1.NOTE: Local laboratory (hematology, biochemistry, urinalysis, INR and aPTT assessments) at Screening: to be performed within 14 days prior to first study 
treatment. Screening laboratory assessments may be done on the same day of first study treatment (Cycle1 Day1) visit. 
2.All patients will be followed-up every 6 months (except for pregnancy, which is at 3 and 6 months after safety follow-up visit) until disease progresses for 
tumor assessment or study closure, whichever occurs first. Patients who discontinue study treatment for reasons other than PD will continue to undergo 
tumor assessments every 3–6 months. 
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+ alone or IHC 2+ in combination with gene amplification by ISH. For patients with mGC enrolled into Cohort 2, central 
confirmation of HER2 status is required. 
c)Limited symptom-directed physical examination. 
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 fist study treatment. 
g)During screening, only SAEs considered related to protocol-mandated procedures will be collected. 
h)Patients will be followed for new or worsening AEs for 28 days following the last infusion of study drug or until the early termination visit, until treatment-
related AEs resolve or stabilize, or until the initiation of another anti-cancer therapy, whichever occurs first. After 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, between Days 
15 and 21 in cycles 1 and 3, and between Days 15 and 21 of every 3rd 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. 
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Appendix 1 
Schedule of Assessments (cont.) 
j)Tumor assessments (± 5 business days), including a CT or MRI with contrast of the chest, abdomen, and pelvis should be performed according to the 
indicated schedule. 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, e.g. the same contrast protocol for 
CT scans. For patients who discontinue study treatment for reasons other than PD, continue tumor assessments according to the protocol every 3–6 months 
until PD, withdrawal of consent, or study termination (whichever occurs earliest). 
k)Patients with isolated brain metastases may continue study treatment if they demonstrate clinical benefit (CR or PR of any duration or SD ≥ 3 months) as 
detailed in Section 4.5.1.4 of the protocol and in Appendix 3. 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 4 in the protocol for additional details. 
m)Hematologic assessments include Hemoglobin (Hb), hematocrit, red blood cell count, platelet count, and WBC with differential (including neutrophils, 
lymphocytes, monocytes, eosinophils and basophils). 
n)Assessments should be performed at screening, on Day 1, 8 and 15 of all cycles. All assessments should 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/urea (mandatory), creatinine, uric acid, total protein, 
albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), G-GT, LDH, total bilirubin (and direct bilirubin where total bilirubin > ULN). Fasting is required 
before biochemistry assessment. 
p)Includes specific gravity, pH, protein, glucose, blood, ketones and bilirubin. 
q)Serum -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. 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 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. 
r)Trastuzumab emtansine will be administered on Day 1 of each weekly cycle for all patients enrolled in Cohort 2 (A&B) except in the first cycle where 
trastuzumab emtansine will be given on DAY 2 (to allow drug interaction assessment). 
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s)Capecitabine must be given within 30 minutes after a meal. 
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Appendix 3 
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 CT or magnetic resonance imaging (MRI) scan (CT/MRI scan 
slice thickness/interval no greater than 5 mm) 
 
10mm caliper measurement by clinical examination (lesions that cannot 
be accurately measured with calipers should be recorded as non-
measurable) 
 
20 mm by chest X-ray 
Malignant Lymph Nodes. To be considered pathologically enlarged and 
measurable, a lymph node must be  15 mm in the short axis when assessed 
by CT scan (CT scan slice thickness recommended to be no greater than 5 
mm). At baseline and follow-up, only the short axis will be measured and 
followed. See also notes below on “Baseline Documentation of Target and 
Non-Target Lesions” for information on lymph node measurement. 
                                            
 
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228–47. 
2 For consistency within this document, the section numbers and cross-references to other  
sections within the article have been deleted and minor formatting changes have been made. 
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Appendix 3 (cont.) 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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. 
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, 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. 
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Appendix 3 (cont.) 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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 
possible to the treatment start and never more than 28 days 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 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 
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Appendix 3 (cont.) 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
be taken in measurement of target lesions on a different modality and 
interpretation of non-target disease or new lesions, since the same lesion may 
appear to have a different size using a new modality. 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should 
not be used as a method of measurement. 
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology. The 
utilization of these techniques for objective tumor evaluation cannot generally 
be advised. 
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 
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Appendix 3 (cont.) 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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 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 
 
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 
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Appendix 3 (cont.) 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. 
The appearance of one or more new lesions is also considered 
progression. 
 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
on study 
b. Special Notes on the Assessment of Target Lesions 
Lymph Nodes. Lymph nodes identified as target lesions should always have 
the actual short axis measurement recorded (measured in the same 
anatomical plane as the baseline examination), even if the nodes regress 
to < 10 mm on study. This means that when lymph nodes are included as 
target lesions, the sum of lesions may not be zero even if CR criteria are met, 
since a normal lymph node is defined as having a short axis of < 10 mm. 
Target Lesions That Become Too Small to Measure. During the study, all 
lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very 
small (e.g., 2 mm). However, sometimes lesions or lymph nodes that are 
recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may 
report them as being too small to measure. When this occurs, it is important 
that a value be recorded on the CRF, as follows: 
 
If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. 
 
If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned and below 
measurable limit (BML) should be ticked. (Note: It is less likely that this 
rule will be used for lymph nodes since they usually have a definable size 
when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and BML should also be ticked). 
To reiterate, however, if the radiologist is able to provide an actual measure, that 
should be recorded, even if it is below 5 mm, and in that case BML should not be 
ticked. 
Lesions That Split or Coalesce on Treatment. When non-nodal lesions 
fragment, the longest diameters of the fragmented portions should be added  
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Appendix 3 (cont.) 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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. 
 
Complete response (CR): Disappearance of all non-target lesions and 
(if applicable) normalization of tumor marker level 
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
 
Non-CR/Non-PD: Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
 
Progressive disease (PD): Unequivocal progression of existing non-target 
lesions 
The appearance of one or more new lesions is also considered 
progression. 
d. Special Notes on Assessment of Progression of Non-Target Disease 
When the Patient Also Has Measurable Disease. In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be 
an overall level of substantial worsening in non-target disease in a magnitude 
that, even in the presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A 
modest increase in the size of one or more non-target lesions is usually not 
sufficient to qualify for unequivocal progression status. The designation of 
overall progression solely on the basis of change in non-target disease in the 
face of SD or PR of target disease will therefore be extremely rare. 
When the Patient Has Only Non-Measurable Disease. This circumstance 
arises in some Phase III trials when it is not a criterion of study entry to have 
measurable disease. The same general concepts apply here as noted above; 
however, in this instance there is no measurable disease assessment to 
factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by 
definition: if all lesions are truly non-measurable), a useful test that can be  
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Appendix 3 (cont.) 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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 PD; therefore, some 
comments on detection of new lesions are important. There are no specific 
criteria for the identification of new radiographic lesions; however, the finding 
of a new lesion should be unequivocal, that is, not attributable to differences 
in scanning technique, change in imaging modality, or findings thought to 
represent something other than tumor (e.g., some “new” bone lesions may be 
simply healing or flare of pre-existing lesions). This is particularly important 
when the patient’s baseline lesions show partial or CR. For example, necrosis 
of a liver lesion may be reported on a CT scan report as a “new” cystic lesion, 
which it is not. 
A lesion identified during the study in an anatomical location that was not 
scanned at baseline is considered a new lesion and will indicate PD. 
If a new lesion is equivocal, e.g., because of its small size, continued therapy 
and follow-up evaluation will clarify if it represents truly new disease. If repeat 
scans confirm there is definitely a new lesion, then progression should be 
declared using the date of the initial scan. 
Evaluation of Response 
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. 
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Appendix 3 (cont.) 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
When patients have non-measurable (therefore non-target) disease only, 
Table 2 is to be used. 
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. 
 
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Appendix 3 (cont.) 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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 
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. 
c. Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes 
decrease to “normal” size (10 mm), they may still have a measurement 
reported on scans. This measurement should be recorded even though the 
nodes are normal in order not to overstate progression should it be based on 
increase in size of the nodes. As noted earlier, this means that patients with 
CR may not have a total sum of “zero” on the CRF. 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of PD 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, Table 3. 
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Appendix 3 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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. 
 
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Appendix 3 
Response Evaluation Criteria in Solid Tumors (RECIST): 
Modified Excerpt from Original Publication (cont.) 
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 4 
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 5 
New York Heart Association Classification of Functional 
Cardiac Capacity 
 
Class 
 
I 
No limitation: Ordinary physical activity does not cause undue fatigue, 
dyspnea, or palpitation. 
II 
Slight limitation of physical activity: Such patients are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitations, dyspnea, or angina. 
III 
Marked limitation of physical activity: Although patients are comfortable at 
rest, less than ordinary physical activity will lead to symptoms. 
IV 
Inability to carry on physical activity without discomfort: Symptoms of 
congestive heart failure are present even at rest. With any physical activity, 
increased discomfort is experienced. 
From: Criteria Committee, New York Heart Association, Inc. Diseases of the heart 
and blood vessels. Nomenclature and criteria for diagnosis. 6th ed. Boston, Little, 
Brown and Co, 1964:114. 
 
 
 
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Appendix 6 
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 
 
52. http://www.ecog.org/general/perf_stat.html 
 
 
 
 
 
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PROTOCOL AMENDMENT APPROVAL 
 
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 MO28230, Version 2, 03 September 2013 
PROTOCOL 
TITLE: 
PHASE I STUDY OF THE COMBINATION OF 
TRASTUZUMAB EMTANSINE (T-DM1) AND 
CAPECITABINE IN HER2-POSITIVE METASTATIC 
BREAST CANCER AND HER2-POSITIVE LOCALLY 
ADVANCED OR METASTATIC GASTRIC CANCER 
PATIENTS, FOLLOWED BY A RANDOMIZED, 
OPEN-LABEL PHASE II STUDY OF T-DM1 AND 
CAPECITABINE VERSUS T-DM1 ALONE IN HER2-
POSITIVE METASTATIC BREAST CANCER 
PROTOCOL NUMBER: MO28230 
EUDRACT NUMBER: 
2012-001547-46 
TEST PRODUCT: 
Trastuzumab emtansine (RO5304020) 
MEDICAL MONITOR: 
 MD 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version : 21-Aug-2012 
DATE AMENDED: 
Version : 03-Sep-2013 
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PROTOCOL AMENDMENT, VERSION 2 
RATIONALE 
Roche is performing continuous characterization of the trastuzumab 
emtansine (T-DM1) safety profile to ensure patient safety is maintained. 
The recently released Investigator Brochure (IB) version 7.0 includes recent 
safety and clinical data analyses leading to updated guidance on dose 
modification. This dose modification guidance is now reflected in this protocol 
amendment. As stated in the IB v.7.0, these updates have no impact on the 
overall assessment of risk and benefit with T-DM1. 
To date, a total of seven patients have been treated at the dose level 
750 mg/m2 capecitabine. Two dose-limiting toxicities (DLTs), one case of 
nausea and vomiting and one case of a Grade 3 alanine transaminase (ALT) 
elevation, were observed in two patients in this cohort. Both DLTs prevented 
Cycle 2 restarting at 100% of the dose on Cycle 2 Day 1. Another patient in 
this cohort showed ALT and aspartate transaminase (AST) elevation without 
meeting the DLT criteria. A retrospective eligibility review showed that this 
patient had not fulfilled completely the IB requirement of stable liver function 
tests prior to study enrollment. Although the patient did not meet the DLT 
criteria as per protocol, the patient was replaced by a 7th patient, following the 
Steering Committee (SC) recommendation, to ensure that another, more 
informative patient was included to avoid any bias while evaluating the drug 
effect. Following the investigator assessment and the SC recommendation, 
we believe, as a Sponsor, that the available evidence shows an acceptable 
positive risk-benefit in all seven patients treated at Dose Level 1.  
As of 7 August 2013, five patients remain on treatment, with a follow-up 
period of 4 to 8 months. Of the two patients who have discontinued treatment, 
one patient’s disease has progressed, and the other discontinuation was 
based on the investigator’s decision, following the central confirmation, that 
the patient’s disease was HER2-negative. Considering the available safety 
data for all patients (maximum number of cycles is 12), the combination of 
capecitabine and T-DM1 is well tolerated, except for increases in 
transaminases and hand-foot syndrome. Dose modifications of T-DM1 and/or 
capecitabine have allowed those patients to continue on treatment. No 
serious adverse events have been reported and responses have been 
observed in six patients. Latest tumor response data show two patients with 
partial response (PR) and four patients with stable disease (SD). In view of 
the two DLT events in Cohort 1, the SC has recommended the combination of 
T-DM1 and capecitabine to be further explored by introducing a lower-dose 
cohort of capecitabine. 
This protocol amendment aims to further clarify patient retention on 
combination regimen. This will allow an additional safety follow-up and 
collection of tumor response from these patients on combination treatment 
whilst the SC and the Sponsor continually monitor the risk-benefit profile of 
the combination treatment. 
The design of the Phase II part of the study has been changed to the open-
label, randomized Phase II study to explore the efficacy and safety of the 
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combination of T-DM1 with capecitabine compared with T-DM1 alone. A 2:1 
randomization was chosen to allow more patients being exposed to the 
combination of T-DM1 and capecitabine. This will enable a more thorough 
assessment of the corresponding safety profile.  
1. Changes according to IB v.7.0. 
The following sections were updated with the latest clinical information and 
current recommendations: 
 
5.1.1 Risks associated with trastuzumab emtansine (including 
thrombocytopenia, hepatotoxicity, infusion-related 
reactions/hypersensitivity, pulmonary toxicity, neurotoxicity, 
cardiotoxicity, and extravasation) 
 
5.1.2 Risks associated with capecitabine (including cardiotoxicity, 
DPD deficiency, hand-foot syndrome, and hepatotoxicity) 
 
5.1.3 Trastuzumab emtansine and capecitabine combination 
 
5.1.4 Definition of the dose limiting toxicity 
 
5.1.5.1 Trastuzumab emtansine dose modification (including dose 
modification for thrombocytopenia, hepatotoxicity, neurotoxicity, 
cardiotoxicity, infusion-related reactions, hypersensitivity reactions, 
pulmonary toxicity, and extravasation) 
 
5.1.5.2 Capecitabine dosage modification 
2. Changes for introducing lower doses of capecitabine. 
 
Dose Levels -1 (700 mg/m2) and -2 (650 mg/m2) have been added 
 
Rules for escalation and de-escalation of capecitabine doses have 
been amended to allow de-escalation from Dose Level 1 to Dose 
Levels -1 and -2 in case of toxicity. No re-escalation to Dose Level 1 
is allowed 
 
The doses of 750 mg/m2 and higher will not be further explored 
 
The DLT criteria will not be changed, but the SC adjudication will be 
permitted in cases not covered by the criteria 
 
Patients who are currently receiving capecitabine 750 mg/m2 can 
continue with the dose 
3. Changes for introducing the open-label, Randomized Phase II part of the 
study instead of Cohort 1, Phase II 
 
Protocol title has been amended to reflect the change in study design 
 
Objectives of the Phase II part of the study has been amended to 
include new treatment groups 
 
Sample size for Phase II has been recalculated based on estimated 
best overall response (BOR) for the combination treatment and T-
DM1 alone 
 
Number of patients in Phase II and in the whole study has been 
amended according to the new sample size calculation 
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 
A medical justification has been added for the estimation of BOR for 
the combination treatment 
 
Independent Data Monitoring Committee (IDMC) for Phase II has 
been introduced to monitor safety outcomes 
4. Changes for protocol consistency. 
 
The Protocol (Amendment) Acceptance Form has been updated 
according to the latest approved wording 
Additional minor changes have been made to improve clarity and consistency. 
Deleted text appears in red strikethrough. Substantive new information is 
marked with yellow highlighting. This amendment represents cumulative 
changes to the original protocol. 
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PROTOCOL AMENDMENT, VERSION 2 
SUMMARY OF CHANGES 
TITLE PAGE 
TITLE: 
PHASE  I FOLLOWED BY PHASE II STUDY OF THE 
COMBINATION OF TRASTUZUMAB EMTANSINE (T-DM1) AND 
CAPECITABINE IN HER2-POSITIVE METASTATIC BREAST 
CANCER AND HER2-POSITIVE LOCALLY ADVANCED OR 
METASTATIC GASTRIC CANCER PATIENTS, FOLLOWED BY A 
RANDOMIZED, OPEN-LABEL PHASE II STUDY OF T-DM1 AND 
CAPECITABINE VERSUS T-DM1 ALONE IN HER2-POSITIVE 
METASTATIC BREAST CANCER 
SYNOPSIS 
Objectives 
Randomized Phase II: Exploration of Efficacy and Safety in mBC 
Primary Objective: 
 
ORR by investigator assessment  
 
To explore the efficacy of the combination of trastuzumab emtansine and capecitabine 
compared with trastuzumab emtansine in mBC patients, as measured by ORR by 
Response Evaluation Criteria for Solid Tumors (RECIST) v.1.1 per investigator local 
assessment  
Secondary Objectives 
 
Safety profile of the combination of trastuzumab emtansine and capecitabine compared 
with trastuzumab emtansine 
 
To explore the dose established during Phase Iefficacy of the combination of 
trastuzumab emtansine and capecitabine compared with trastuzumab emtansine in 
mBC patients, as measured by: 
Study Design 
Description of Study 
This is an international, multicenter study. 
The study is designed to determine the MTD of capecitabine in combination with 
trastuzumab emtansine in human epidermal growth factor receptor 2 (HER2)-positive mBC 
and locally advanced or mGC patients, using a Phase I design, followed by a randomized, 
open-label Phase II single arm study to explore the efficacy and safety of the combination of 
trastuzumab emtansine and capecitabine compared with trastuzumab emtansine in mBC 
patients. There will be no exploration of efficacy in the mGC cohort. Results from the Phase  
I in mGC will be used as supporting information for future studies in the indication (see 
Figure 4 in the protocol).  
Cohort 1 (mBC) and Cohort 2 (mGC) will open sequentially during Phase I. 
Phase I: MTD Finding, Cohort 1: mBC 
Cohort 1 will open first with a 3 plus 3 classical design. Cohort 1 will enroll patients with 
HER2-positive mBC. The dose tested of trastuzumab emtansine remains fixed at 3.6 mg/kg 
every 3 weeks (q3w) and 3 dose levels of capecitabine administered twice daily (bid) on 
Days 1 to 14 in cycles of 3 weeks will be tested. All patients will be treated until disease 
progression, intolerable toxicity, withdrawn consent, or death. All patients will be followed-up 
intolerable toxicity,until withdrawn consent, death, or up to a maximum of 2 years after the 
last patient was enrolledrandomized in the Phase II part of the study, whichever occurs first. 
Dose Levels Explored in Phase I, Cohort 1 
Dose lLevel 1: 750 mg/m2 capecitabine twice daily (bid) + 3.6 mg/kg every three weeks 
(q3w) trastuzumab emtansine 
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Dose lLevel 2-1: 85700 mg/m2 capecitabine bid + 3.6 mg/kg q3w trastuzumab emtansine 
Dose lLevel 3-2: 100650 mg/m2 capecitabine bid + 3.6 mg/kg q3w trastuzumab emtansine 
The rules for dose escalation determining the MTD are presented below.  
If Dose Level 1 is proved too toxic (dose-limiting toxicity [DLT] > 1/3 or > 1/6), the dose will 
be de-escalated to one dose level below (Dose Level -1)  
If Dose Level -1 is well tolerated (DLT ≤ 1/6), this dose will be considered the MTD and, 
following the independent Data Monitoring Committee (IDMC) agreement, will be further 
explored in the Randomized Phase II part of the study. If Dose Level -1 is too toxic 
(DLT >1/6), the dose will be de-escalated to Dose Level -2. 
If Dose Level -2 is well tolerated (DLT ≤ 1/6), this dose will be considered the MTD and, 
following iDMC approval, will be further explored in the Randomized Phase II part of the 
study. However, if Dose Level -2 is too toxic (DLT > 1/6), the combination may be 
considered unfeasible, recruitment will be closed and no otherneither the Randomized 
Phase II nor mGC cohort will be opened. Patients who, at that point, experience response 
as per RECIST v.1.1 will be offered the possibility to continue on trastuzumab emtansine as 
a single agent, or with the combination, based on risk-benefit balance and agreement with 
the Steering Committee (SC).  
Randomized Phase II: Exploration of Efficacy, Cohort 1:  and Safety in mBC 
Phase II will be conducted in mBC patients only. This part of the study will explore the 
efficacy and safety of the combination treatment of T-DM1 and capecitabine, at the 
established MTD, compared with T-DM1 alone in mBC patients. 
Once the MTD in Cohort  1 is established, recruitment into this cohort will be extended to a 
total of 110additional 117 HER2-positive mBC patients forwill be randomized into the 
Phase II part of the study. Patients, who are on the MTD established in the Phase I part of 
the study, must re consent to be enrolled into Phase II. will not contribute to the Phase II 
part of the study; however, they will be followed-up until end of study (EOS). 
Patients will be treated until disease progression/recurrence, intolerable toxicity, withdrawn 
consent, or death. If capecitabine needs to be discontinued for any reason, trastuzumab 
emtansine may continue, and the patient will remain evaluable in the study.be followed-up 
until EOS. In case of discontinuation of trastuzumab emtansine, patients will be withdrawn 
from the studyfollowed-up until EOS. 
All patients will be followed-up until disease progression, intolerable toxicity, withdrawn 
consent, death, or up to a maximum of 2 years after the last patient was enrolledrandomized 
in the Phase II part of the study, whichever occurs first. Patients who have not progressed at 
that point in time may be enrolled into an extension study. 
Phase I: MTD Finding, Cohort 2: mGC 
Once the capecitabine MTD dose is established in Cohort 1, Cohort 2 will open, with a 3 
plus 3 classical design to enroll HER2-positive mGC patients. Trastuzumab emtansine will 
be administered weekly at the dose of 2.4 mg/kg and capecitabine will start at the MTD 
dose defined in Cohort 1; capecitabine dose level may be de-escalated. 
All patients will be treated until disease progression, intolerable toxicity, withdrawn consent, 
or death. All patients will be followed-up until intolerable toxicity, withdrawn consent, death, 
or up to a maximum of 2 years after the last patient was enrolledrandomized in the Phase II 
part of the study, whichever occurs first. 
The dose levels for capecitabine will be the same as described in Cohort 1, except for Dose 
Level 1, which will not be explored in mGC patients. Guidelines for dose escalation and de-
escalation are as follows: 
If the MTD established in Cohort 1 is defined at Dose Level 1 of 750 mg/m2 bid-1: 
 
EscalationThis will be tothe starting dose in Cohort 2. If Dose Level 2 of 850 mg/m2 bid.-
1 is well tolerated (DLT ≤ 1/6), this dose will be established as the MTD for mGC  
 
De-escalation: if Dose Level -1 is not tolerated (>1/3 or >in Cohort 2 (> 1/6 DLT), de-
escalation will be to Dose Level -2 
If the MTD established in Cohort 1 is defined at Dose Level -2: 
 
This will be the starting dose in Cohort 2. If Dose Level -2 is well tolerated (DLT ≤ 1/6), 
this dose will be established as the MTD for mGC  
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 
De-escalation: if Dose Level -2 is not tolerated in Cohort 2 (> 1/6 DLT), the combination 
will be considered not feasible. for mGC and Cohort 2 will be terminated. Patients who, 
at that point, experience response as per RECIST v.1.1 will be offered the possibility to 
continue on trastuzumab emtansine as a single agent, or with the combination, based 
on risk-benefit balance and agreement with the SC 
If MTD defined at Dose Level 2 of 850 mg/m2 bid: 
 
Escalation will be to Dose Level 3 of 1000 mg/m2 bid 
 
De escalation will be to Dose Level 1 of 750 mg/m2 bid 
If MTD defined at Dose Level 3 of 1000 mg/m2 bid 
 
Escalation: There will be no escalation, MTD will be defined at Dose Level 3 
 
De escalation will be to Dose Level 2 of 850 mg/m2 bid 
Number of Patients 
Phase I, Cohort 1: mBC 
3A minimum of 6 and up to 18 patients maywill be enrolled. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
Cohort 1Exploration of efficacy and safety in mBC will be expanded to enroll 110based on 
117 randomized patients in total. 
Phase I, Cohort 2: mGC 
A total of 3 to 1812 patients maywill be enrolled. 
Target Population 
Phase I, Cohort 1: mBC 
HER2-positive mBC patients will be enrolled. 
The patient’s HER2 status will be considered positive if the local institution or reference lab 
reported Grade 3+ staining intensity (on a scale of 0 to 3) by means of immunohisto-
chemistry (IHC) or fluorescent in situ hybridization (FISH). 
The HER2 status will be retrospectively confirmed by IHC and/or FISH in a central 
laboratory using archival paraffin-embedded tumor tissue. Patients must have received at 
least onemetastatic disease and/or locally recurrent disease not amenable to resection. 
Retrospective central confirmation will not impact the treatment regimendecisions or primary 
endpoint of Phase I and will be used to validate efficacy analyses in Phase I. 
Patients must have received at least one treatment regimen, which includes a 
chemotherapy agent and trastuzumab agent. 
Randomized Phase II, Cohort 1:: Exploration of Efficacy and Safety in mBC  
HER2-positive mBC patients will be enrolledrandomized to one of the treatment groups 
receiving either the combination of trastuzumab emtansine (T-DM1) with capecitabine or T-
DM1 alone. Retrospective central confirmation will be used to censor the efficacy population 
for the Randomized Phase II part of the study. 
Patients must have received at least one treatment regimen, which includes a 
chemotherapy agent and trastuzumab agent. 
Phase I, Cohort 2: mGC 
HER2-positive locally advanced or mGC patients will be enrolled. 
Patients must not have received prior chemotherapy for advanced/metastatic disease. 
Inclusion Criteria: 
For mBC Patients: 
8. Liver function: 
a)  Total bilirubin ≤ 1.5 × the upper limit of normal (ULN). except in patients with 
previously documented Gilbert’s syndrome in which case total bilirubin ≤ 3 mg/dL 
is acceptable 
d)  Evidence of stable liver function during the month prior to enrollment with liver 
function tests’ (LFTs) fluctuations not exceeding 2.5 × ULN (for AST, ALT) and 
1.5 × ULN (for total bilirubin). Patients with bone metastases: AST and ALT ≤ 5.0 x 
ULN. 
14. mBC with at least one measurable lesion according to RECIST v.1.1. 
 
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For mGC Patients: 
8. Liver function: 
a)  Total bilirubin ≤ 1.5 × ULN. except in patients with previously documented 
Gilbert’s syndrome in which case total bilirubin ≤ 3 mg/dL is acceptable 
d)  Evidence of stable liver function during the month prior to enrollment with LFTs 
fluctuations not exceeding 2.5 × ULN (for AST, ALT) and 1.5 × ULN (for total 
bilirubin). Patients with bone metastases: AST and ALT ≤ 5.0 x ULN. 
11. Histologically or cytologically confirmed GCmGC or locally advanced gastric cancer. 
Exclusion Criteria: 
For mBC Patients: 
6. History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity to 
trastuzumab or murine proteins or any component of the product. 
7. History of exposure to the following cumulative doses of anthracyclines: 
a)  Doxorubicin or liposomal doxorubicin > 360500 mg/m2. 
d) If another anthracycline, or more than one anthracycline, has been used, the 
cumulative dose must not exceed the equivalent of 360500 mg/m2 doxorubicin. 
9. Current peripheral neuropathy of Grade ≥ 3 per the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE), v4.0. 
For mGC Patients: 
22. No signs and symptoms suggestive that the patient has DPD deficiency 
23. Lapatinib ≤ 14 days before first study drug administration 
Length of Study 
The duration of the study is estimated to be approximately 4 years. Recruitment is estimated 
to be 2 years for Dose Finding and the Phase II/Exploration of Efficacy and Safety. All 
patients will be followed-up until intolerable toxicity, withdrawn consent, death or up to a 
maximum of 2 years after the last patient was enrolledrandomized in the Phase II part of the 
study, whichever occurs first. In case Dose Level 1-2 is too toxic, the study may be 
terminated prematurely. Patients who, at that point, experience response as per RECIST 
v.1.1 will be offered the possibility to continue on trastuzumab emtansine as a single agent, 
or with the combination, based on risk-benefit balance and agreement with the SC. 
Efficacy Outcome Measures 
Efficacy will be evaluated as per RECIST v.1.1. 
 
Best overall response (BOR) rate  
 
DoR 
 
TTR 
 
TTP 
 
TTF 
 
PFS 
 
CBR 
 
OS 
Safety Outcome Measures 
 
DLT assessment 
 
Incidence and severity by NCI CTCAE version 4.0 of adverse events (AEs) and), 
serious adverse events (SAEs), AEs that cause discontinuation from the study 
treatment, and AEs of special interest (AESIs) 
 
CasesFatal cases and causes of death 
Pharmacokinetic Outcome Measures 
 
PK will be evaluated during Phase I for both trastuzumab emtansine and capecitabine 
(see Appendix 1, Schedule of Assessment in the protocol). In addition, PK samples may 
be taken ad hoc, in case of SAE or unexpected toxicities, which may be suggestive of 
potential drug-drug interaction. 
Investigational Medicinal Products 
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For mBC Patients: 
Capecitabine will be administered twice a day, orally for 14 days followed by a 7-day rest 
period at the Dose Levels 1 3 to -2 described in the ‘Trial Design’ section. 
Capecitabine tablets should be swallowed with water within 30 minutes after a meal. 
Rounding of capecitabine dose, based on 150 mg and 500 mg tablet strength will be 
allowed to the nearest target dose, based on patient body surface area (BSA).  
For mGC Patients: 
Capecitabine will be administered twice a day, orally for 14 days followed by a 7-day rest 
period at the dose levels 1 3Dose Levels -1 to -2 described in the ‘Trial Design’ section. 
Capecitabine tablets should be swallowed with water within 30 minutes after a meal. 
Statistical Analysis 
The study will include 2 phases and 2 cohorts: 
 
Phase I, Cohort 1: mBC Dose Finding Cohort 
 
Randomized Phase II, Cohort 1: mBC : Exploration of Efficacy Cohortand Safety in 
mBC  
 
Phase I, Cohort 2: mGC Dose Finding Cohort 
During Phase I, the primary objective is reaching the MTD and establishing a safety profile. 
There is no formal efficacy interim analysis. However, an independent data monitoring 
committee (IDMC) will advise whether the Randomized Phase II part of the study can 
commence. The IDMC will also monitor safety outcomes after 20 and 60 patients have 
received at least 3 cycles of treatment (Cycle 3 Day 1) in the Randomized Phase II part of 
the study. Afterwards, the IDMC will monitor accumulating patient safety data every 6 
months during the Randomized Phase II of the study or as requested. 
Efficacy data will only be provided if required by the IDMC to estimate the risk-benefit 
balance for the patients. Further details on the function and logistics of the IDMC will be 
provided in the IDMC Charter. 
Corresponding analyses as described in the protocol will be performed when all data for 
both cohorts and study phases are collected and cleaned. 
Analysis of primary and secondary endpoints: 
Analysis Populations: 
Phase  I, Cohort 1: MTD Finding: mBC Patients: 
The main analysis population will befor DLT assessment is the DLT evaluable population, 
which is defined as all enrolled and treated patients who have not experienced any major 
protocol violations (including violations of the inclusion and exclusion criteria) and have 
completed Cycle 1.  
The safety population including(SP) will include all patients in this cohort who received at 
least one dose of study medication (trastuzumab emtansine and capecitabine) during this 
phase. 
Phase I. 
Randomized Phase II: Exploration of Efficacy:  and Safety in mBC Patients 
The main analysis population for the efficacy analysis will be the intent-to-treat (ITT) 
population (ITT) including, which will include all new patients enrolled in Phase II and 
patients from Cohort 1 who achieved the MTD levelrandomized in the Phase II part of the 
study. The per-protocol (PP) population will include all ITT patients who have at least one 
post-baseline tumor assessment during the Phase II II part of the study and no major 
protocol violations, which will be defined in the statistical analysis plan. Safety parameters 
will be summarized for the safety population that includes all patients who received at least 
one dose of study medication in this part of the study. (SAP). 
The SP will include all patients who received at least one dose of study medication during 
the Randomized Phase II part of the study.  
Phase I, Cohort 2: MTD Finding, mGC Patients: 
The main analysis population will befor DLT assessment is the safetyDLT evaluable 
population , which is defined as all enrolled and treated patients who have not experienced 
any major protocol violation (including violation of the inclusion and exclusion criteria) and 
have completed Cycle 1.  
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The SP will include all patients in this cohort who received at least one dose of study 
medication (trastuzumab emtansine and capecitabine) during this phasePhase I. 
Efficacy Endpoints:  
Phase  I, Cohort 1: MTD Finding, mBC 
The primary objectives are reaching the MTD and establishing a safety profile. 
ORR, as a main efficacy endpoint, will be assessed via BORRBOR rate. The BOR is 
defined as the best response recorded from the date when the MTD is achievedof 
enrollment until disease progression/recurrence (or, death)., withdrawal of consent or EOS, 
whichever occurs first. The number of patients is very small in this part of the study. 
Therefore, all analyses will be descriptive. 
Due to the small number of patients and the design of this part of the study, no secondary 
efficacy endpoints will be investigated. 
Randomized Phase  II: Exploration of Efficacy: in mBC  
The primary efficacy endpoint for the Phase  II part of the study is the BORORR, as 
assessed by investigatorsvia BOR. The BOR is defined as the best response recorded from 
the start of thisor randomization into the Phase  II part of the study and until disease 
progression/ or recurrence (or, death) or for patients who were involved in Phase I of the 
study: the best response from the date, withdrawal of the MTD reached until disease 
progression/recurrenceconsent or deathEOS, whichever occurs first. To be assigned a 
status of partial response (PR) or complete response (CR), i.e.., to be a responder, changes 
in tumor measurements must be confirmed by repeatrepeated assessments that should be 
performed no less than 28 days after the response 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). 
The emphasis of the exploratory Randomized Phase II part of the study will not be formal 
statistical hypothesis testing but the estimation of: 
 
The BOR rate with corresponding 95% confidence intervals (CIs) for each treatment 
group. The justification of the sample size is based on considerations regarding the 
width of 95% CIs for each treatment group estimate (precision of the corresponding 
estimate). 
 
The treatment effect (between treatment groups comparison) with corresponding 95% 
CIs.  
The number and proportions of responders and non-responders (based on BOR) together 
with the two-sided, 95% Clopper-Pearson confidence intervals CIs will be presented. CBR 
will be summarized for each treatment group. The difference in a similar way.BOR between 
treatment groups will be displayed with associated 95% CIs using the Hauck-Anderson 
approach.  
The secondary endpoints for the Phase  II part of the study will be: 
 
Time to response (TTR) 
 
Duration of response (DoR) 
 
Time to progression (DoR 
 
TTP) 
 
Time to treatment failure (TTF) 
 
Progression free survival (PFS) 
 
Clinical benefit rate (CBR) 
 
Overall survival (OS) 
 
TTF 
 
PFS 
 
CBR 
 
OS 
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Estimates for the survivor function for the time to event variable such as of both treatment 
groups for TTR, DoR, TTP, TTF, PFS, and OS, will be obtained by using the Kaplan-Meier 
approach. method. Hazard ratios and associated 95% CIs will be estimated from non-
stratified and stratified (based on the stratification factor) Cox regression models. 
Clinical benefit response will include patients whose best (confirmed) response was PR or 
CR, or stable disease (SD) that lasted at least 6 months. CBR will be summarized in a 
similar way to the primary efficacy endpoint, ORR, as assessed by BOR.  
Safety Endpoints: 
Phase  I, Cohort 1: MTD Finding: mBC 
The number and proportion of patients with DLTs will be used as the primary measure for 
the MTD determination. The definition of DLTs is presented in Section 5.1.4. DLTs for this 
part of the study will be summarized by treatment dose. 
Safety parameters for this study part will be summarized by treatment dose. The summaries 
of AEs, SAEs, AEs that cause discontinuation from the study treatment, and AESIs (as 
described in Section 5) will be analyzed in a similar way to AEs in Phase  II. The summaries 
will include all patients who received at least one dose of study medication. 
Randomized Phase II: Exploration of EfficacySafety :in mBC 
Safety endpoints will be summarized by treatment group. 
Safety endpoints during the Randomized Phase II part of the study will be assessed via: 
total AEs, AEs Grade ≥ 3, SAEs, premature withdrawal from study and study medication, 
AESIs, laboratory parameters, LVEF, exposure to study medication, concomitant 
medications, vital signs, ECOG performance status, and physical examination. 
The incidence of AEs and SAEs will be summarized according to the primary system organ 
class (SOC) and within each SOC, by MedDRA preferred term. Time to onset of the first 
episode of AESI will also be summarized via Kaplan-Meier method.Patients who died will be 
listed together with the cause of death. 
Laboratory parameters, hematology and biochemistry, will be presented in shift tables of 
NCI-CTC grade at baseline versus worst grade during treatment for the Randomized Phase 
II of the study, Cohort 1 and overall. 
Phase  I, Cohort 2: MTD Finding: mGC 
The number and the proportion of patients with DLTs will be used as the primary measure 
for the MTD determination. The definition of DLTs is presented in Section 5.1.4. DLTs for 
this part of the study will be summarized by treatment dose. 
Safety parameters will be summarized in a similar way to Phase  I, Cohort 1: mBC. 
Exploratory Analyses 
For all patients a retrospective central confirmation of the HER2 status will be done. Further  
exploratory analysis for HER2-positive patients (based on central confirmation) will be 
done for selected endpoints, e.g. BOR and safety (AEs, SAEs, AEs with Grade ≥ 3, and 
AESIs). 
Subgroup analysis for BOR, safety (AEs, SAEs and AE, AEs with Grade ≥ 3, and AESIs) in 
the Randomized Phase  II part of the study will be presented for both treatment groups: 
elderly versus younger patients, patients with ECOG 0–1 versus ECOG 2. More details will 
be presented in the statistical analysis planSAP. 
Determination of Sample Size 
Sample Size for Phase  I: MTD Finding: mBC 
This part will be based on a classical 3 byplus 3 Phase  I design. From 3A minimum of 6 
and up to 18  patients mightwill be enrolled in Cohort  1. There is no formal sample size 
estimation for this part. 
Sample Size for Randomized Phase  II: Exploration of Efficacy:  and Safety in mBC 
Assuming a preferable BORR of 75% to 80% in Cohort 1 (mBC patients) and aiming for a 
precision of 8 10%, lower limit of 95% confidence interval of at least 65%, a total of 100 
patients would need to be evaluable for Cohort 1. 
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Approximately 117 patients (78 patients in the combination of T-DM1 and capecitabine 
respective 39 patients in T-DM1 treatment group), including a 10% withdrawal rate, will be 
randomized with a 2:1 ratio to the combination of T-DM1 and capecitabine or T-DM1. 
Point estimates and 95% Clopper-Pearson exact CIs are tabulated for a range of possible 
BOR outcomes for both treatment groups: 
Table 1: Sample Size Estimation (2:1 randomization) 
Total number of patients is 100 (Phase II) 
Number of Patients/ 
Response 
95% Clopper Pearson Confidence Intervals 
75 patients (75%) 
65%  83 % 
80 patients (80%) 
71%  87% 
 
 
Total number of patients adjusted for 10% withdrawal rate is 110 patients 
 
Sample size based on BOR  
 
N (T-DM1 and capecitabine)* = 70 patients* 
BOR rate [%] 
95% CI (within treatment group) [%] 
57.5 
(45.1–69.2) 
60.0 
(47.6–71.5) 
62.5 
(50.1–73.8) 
65.0 
(52.7–76.0) 
67.5 
(55.2–78.2) 
 
N (T-DM1) = 35 patients* 
BOR rate [%] 
95% CI (within treatment group) [%] 
37.0 
(21.4–54.9) 
40.0 
(23.9–57.9) 
43.0 
(26.4–60.8) 
46.0 
(29.1–63.6) 
49.0 
(31.8–66.4) 
 
* N = Number of patients without adjustment for withdrawal; CI = confidence interval  
N (T-DM1 and capecitabine) / N (T-DM1) = 2 
 
 BOR of 75% could be estimated to be within 65% and 83% with a probability of 95% 
(Clopper Pearson exact confidence intervals). Adjusting for a withdrawal rate of 
approximately 10%, 110 patients will be enrolled in this phase. 
The BOR rate of 75% is chosen based on the previously published data with trastuzumab 
and capecitabine (see protocol for reference) 
The estimation of Sample Size is performed by Nquery and SAS programs. 
Expected BOR rate for patients who received trastuzumab emtansine of 43.6% (95% CI: 
38.6% – 48.6%) was chosen based on previously published data for trastuzumab emtansine 
(see Section 6.1 of the main body of the protocol for reference). 
The precision for the BOR estimate of the combination of T-DM1 and capecitabine is 
approximately 12%, e.g. BOR of 60%, 95% CI of (47.6%, 71.5%). Due to the lower sample 
size of the treatment group T-DM1, the corresponding precision for the BOR estimate is 
increased to 18%, e.g. BOR of 46%, 95% CI of (29.1%, 63.6%) 
A 2:1 randomization will be applied to allow more patients being exposed to the combination 
of T-DM1 and capecitabine. This will enable a more thorough assessment of the 
corresponding safety profile. 
Stratification Factors 
The following stratification factor will be implemented in the Randomized Phase II part of the 
study: 
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 
Number of prior lines of treatment for metastatic disease (1 or >1; excluding single-
agent hormones). 
A treatment line is defined as any treatment regime given to patient from treatment initiation 
until confirmed disease progression. 
Sample Size for Phase I, Cohort 2: MTD Finding: mGC 
This part will be based on a classical 3 byplus 3 Phase  I design. From 3 to 1812 patients 
might be enrolled in Cohort  2. 
1.   
 
BACKGROUND 
1.2  
 
BACKGROUND ON STUDY DRUGS  
1.2.1   
TRASTUZUMAB EMTANSINE 
1.2.1.6  
Phase  III Study TDM4370g 
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). 
This trial has met its co primary endpoint of improving PFS (by independent 
review committee) compared to those who received the combination of 
lapatinib and capecitabine. 
PFS was 9.6 months Patients in the trastuzumab emtansine arm had a 
median PFS of 9.6 months versus 6.4 months for patients in the control arm 
of lapatinib and  + capecitabine arm. OS has not yet been reached(HR = 0.65; 
95% CI: 0.55–0.77; p < 0.001, log-rank test). Patients in the trastuzumab 
emtansine arm whilehad a median OS of 30.9 months versus 25.1 months for 
patients in the control arm the OS was 23.3 months. The of 
lapatinib + capecitabine (HR for PFS was  = 0.650 (68; 95% CI: 0.55, –
0.7785; p =< 0.0001001, log-rank test). 
It iswas concluded that overall, there is no concern regarding the clinical 
safety of trastuzumab emtansine for the patient population that was studied, 
based on the currently available data. (Verma et al. 2012). 
 
1.3 
 STUDY RATIONALE AND RISK-BENEFIT RISK 
ASSESSMENT 
1.3.1  
FOR MBC 
The Phase  III, TDM4370g trial met its co-primary endpoint of improving PFS 
(by IRC)IRB) and OS compared towith those who received the combination of 
lapatinib and capecitabine (see Section 0).1.2.1.6). 
Approximately 20002,000 patients with breast cancerBC have been treated in 
trastuzumab emtansine clinical trials with an acceptable safety profile and a 
positive risk-benefit ratio. A safety monitoring is in place to avoid potential 
overlapping toxicities. A broad development program is in place to seek 
approval for indications for mBC. Capecitabine in combination with anti-HER2 
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agent is a proven efficacious regimen with a well -established safety profile in 
mBC. Trastuzumab emtansine and capecitabine have no known significant 
overlapping toxicities. As a part of the Phase I conduct, regular teleconference 
calls with the investigators will be held to discuss the study treatment risk-
benefit profile for each patient. An IDMC will be established with the main 
responsibility to assess the risk-benefit for the Phase II part of the study.  
1.3.2  
FOR MGC 
A development program for trastuzumab emtansine is in place to seek 
approval for mGC indications. Capecitabine in combination with anti-HER2 
agent is a proven efficacious regimen with a well -established safety profile in 
mGC. Trastuzumab emtansine and capecitabine might have overlapping 
toxicities and therefore a safety monitoring is in place to avoid exposing 
patients to harm. Therefore, exploring the benefit of combination therapy of 
trastzumabtrastuzumab emtansine and capecitabine in mGC patients with 
mGC seems justified. Results from the Phase I part of the study in mGC will 
be used as supporting information for future studies in the indication. 
2.   
 
OBJECTIVES 
2.2 
 RANDOMIZED PHASE II: EXPLORATION OF 
EFFICACY AND SAFETY IN MBC PATIENTS 
2.2.1   
PRIMARY OBJECTIVE 
To explore the efficacy of the combination of trastuzumab emtansine and 
capecitabine compared with trastuzumab emtansine in patients with mBC, as 
measured by ORR by RECIST v.1.1 per investigator local assessment 
2.2.2  
SECONDARY OBJECTIVES 
Safety profile of the combination atof trastuzumab emtansine and 
capecitabine compared with trastuzumab emtansine 
To explore the dose established during Phase Iefficacy of the combination of 
trastuzumab emtansine and capecitabine compared with trastuzumab 
emtansine in patients with mBC, as measured by: 
 
Time to response (TTR)  
 
Duration of response (DoR) 
 
Time to progression (DoR 
 
TTP) 
 
Time to treatment failure (TTF) 
 
Progression free survival (PFS) 
 
Clinical benefit rate (CBR) 
 
Overall survival (OS) 
 
PFS 
 
CBR 
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 
OS 
3.  
 
STUDY DESIGN 
3.1  
 
DESCRIPTION OF STUDY 
The study is designed to determine the MTD of capecitabine in combination 
with trastuzumab emtansine in a Phase  I study in bothpatients with mBC and 
locally advanced or mGC patients. The MTD efficacy and safety of the 
combination in patients with mBC will also be assessed for anti tumor effects 
(exploration of efficacy)explored in a randomized, open-label Phase  II, single 
arm part of the study in the mBC cohort. There will be no exploration of 
efficacy in the mGC cohort..  
3.1.1  
OVERVIEW OF STUDY DESIGN 
Overview of Study Design 
The study is designed to determine the MTD of capecitabine in combination 
with trastuzumab emtansine, in patients with HER2-positive mBC and locally 
advanced or mGC patients, using a Phase  I design, followed by a 
randomized, open-label Phase  II single armpart of the study to explore the 
efficacy and safety of the combination in mBC patients with mBC. There will 
be no exploration of efficacy in the mGC cohort. Results from the Phase  I in 
mGC will be used as supporting information for future studies in the indication. 
Duration of Treatment and Patient Follow-up 
Length of treatment: All patients will be treated until disease progression, 
intolerable toxicity, withdrawal of consent, or death. 
Patient follow-up: All patients from both cohorts will be followed -up until 
intolerable toxicity, withdrawn consent, death, or up to a maximum of 2 years 
after the last patient was enrolledrandomized in the Randomized Phase  II 
part of the study, whichever occurs first. 
Duration of Study, Data BaseDatabase Closure and Data Reporting 
The duration of the study is estimated to be approximately 4 years. 
Recruitment is estimated to be 2 years for dose findingthe Dose Finding and 
the Phase  II/ Exploration of Efficacy and Safety. The study will end after the 
follow-up period wasis completed, as defined above. Last patient last visit 
(LPLV) is defined as the last data collection point that can be either a clinic 
visit or a lablaboratory sample. At that time point, the database will be closed. 
In the case that in Cohort  1 the dose level 1Dose Level -2 is too toxic (> 1/3 
or >1/6 of dose -limiting toxicity [DLT]), the combination may be considered 
unfeasible. Enrollment, recruitment will be closed and no otherneither the 
Randomized Phase II nor mGC cohort will be opened. Patients, who, at that 
point, experience response as per RECIST v.1.1 will be offered the possibility 
to continue on trastuzumab emtansine as a single agent., or with the 
combination, based on risk-benefit balance and agreement with the Steering 
Committee (SC). 
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Determination of the Maximum Tolerated Dose in mBC Patients with 
mBC  
The trial will first investigate the feasibility of the combination of capecitabine 
and trastuzumab emtansine q3w in one cohort up to 18 patients, by de-
escalating the dose of capecitabine from 750 mg/m2 bid to 1000 650 mg/m2 
bid on daysDays 1 to 14 in cycles of 3 weeks with a 3 byplus 3 classical 
Phase  I design. Cohort  1 will open first and enroll patients with HER2-
positive mBC. 
Enrollment into Cohort 1 
Dose finding in patients with mBC (Phase I) 
If dose level 1Dose Level -2 is found to be too toxic (DLT >1/3 or > 1/6), the 
enrollmentcombination may be considered unfeasible, the recruitment will be 
closed and the study will be terminated. neither the Randomized Phase II nor 
mGC cohort will be opened. Patients who, at that point, experience response 
as per RECIST v.1.1 will be offered the possibility to continue on trastuzumab 
emtansine as a single agent, or with the combination, based on risk-benefit 
balance and agreement with the SC. 
The following escalationMTD determining rules will be applied during the dose 
findingDose Finding treatment phase: 
 
Step 1: Three patients will be enrolled at dose levelDose Level 1 
 
Step 2: The toxicity of dose levelDose Level 1 will be monitored and the 
following actions taken: 
a)  If none of these three3 patients (0/3) experiences a DLT, escalation to 
dose level 2 will occurthe MTD will be established as the current dose 
level and will need to be confirmed in 3 more patients (to achieve ≤ 1/6 
DLT at the current dose level) 
b) If one1 of the initial three3 patients (1/3) experiences a DLT, an 
additional three3 patients should be enrolled and treated at the same 
dose, i.e. dose level., Dose Level 1 
c) If no more patients experience a DLT (1/6), escalation to the nextMTD 
will be established as the current dose level will occur 
d) If one1 or more patients experience a DLT (> 1/6), the MTDdose will be 
established asde-escalated to the immediate inferiornext lower dose 
level or the study may be terminated if it happens at dose level 1. If no 
more than 1 patient experiences a DLT (≤ 1/6) after dose de-escalation, 
the dose will be considered the MTD and, following iDMC agreement, 
will be further explored in the Randomized Phase II part of the study. 
Dose re-escalation will not be allowed. If 2 or more patients experience 
DLT (> 1/6) after dose de-escalation, de-escalation should continue to 
the next lower dose level. Based on the DLT findings, the next dose 
level may be considered the MTD and, following iDMC agreement, be 
further explored in the Randomized Phase II part of the study or the 
study may be terminated if > 1/6 DLTs occur at Dose Level -2 
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 
Step 3: Step 2 should be repeated until the MTD is reached 
 
If the last dose exceeds the MTD, de escalation to the previous dose 
should occur. This dose should be defined as MTD if 6 or more patients 
have been safely treated at this dose level and no more than 1/6 of the 
patients experienced a DLT at that dose level. 
 
If only 3 patients have been treated at this dose level, then 3 more 
patients will be treated and observed at this level in order to achieve at 
least 6 patients treated at the same dose level. 
 
In order to define the dose for the Randomized Phase II/exploration 
Exploration of efficacy Efficacy and Safety part of the study, the Steering 
Committee will evaluate not only the DLTs during Cycle 1 will be 
evaluated but also all available safety information during the subsequent 
cycles. The dose level considered optimal by the Steering Committee will 
be the dose level selected to move forward with in the Phase II and mGC 
parts of the study. 
Once the appropriate dose of study medication is established, the other 
cohortsRandomized Phase II part of the study and Phase I, Cohort 2 will open 
as per Figure 4. 
 
3.1.1.2 
Overview of Phase II: Exploration of Efficacy and Safety in 
Patients with mBC  
This part of the study will explore the efficacy and safety of the combination 
treatment of T-DM1 and capecitabine, at the established MTD, compared with 
T-DM1 alone in mBC patients. 
Once the Steering Committee MTD has been defined the MTD to treat 
patients in Phase  II, approximately 117 additional 90 100 mBC patients will 
be enrolled. 
Only the mBC patients who have received the MTD dose from Phase I with 
mBC will continue with be randomized into the Phase II part of the study. 
Patients in the Phase I part of the study will not contribute to assess efficacy 
and safety of this treatment combination of capecitabine and trastuzumab 
emtansine.the Phase II part of the study; however, they will be followed-up 
until end of study (EOS). 
Patients will be treated until disease progression/recurrence, intolerable 
toxicity, withdrawn consent, or death. If capecitabine needs to be discontinued 
for any reason, trastuzumab emtansine may continue, and the patient will be 
followed-up until EOS. In case of discontinuation of trastuzumab emtansine, 
patients will be followed-up until EOS. 
All patients will be followed-up until withdrawn consent, death, or up to a 
maximum of 2 years after the last patient was randomized in the Phase II part 
of the study, whichever occurs first. 
See Section 3.1.1 for further information. 
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3.1.1.3  
Overview of Phase I Design in mGC Patients 
Enrollment into Cohort 2 
The dose levels for escalation or de-escalation of capecitabine will be the 
same as described for Cohort  1:, except for Dose Level 1, which will not be 
explored in patients with mGC (see also Section 3.3.2.1). 
If the MTD established in Cohort  1 wasis defined at Dose Level -1: 
 
 This will be the starting dose level 1 of 750 mg/m2 bidin Cohort 2.  
If 
Dose Level -1 is well tolerated (DLT ≤ 1/6), this dose will be established 
as the MTD for mGC. 
o 
If dose level 1 is tolerated, doses should be escalated to dose level 2 
of 850 mg/m2 bid 
 
If dose level  
De-escalation: if Dose Level -1 is not tolerated (>1/3 
or >in Cohort 2 (> 1/6 DLT), de-escalation will be to Dose Level -2. 
If the MTD established in Cohort 1 is defined at Dose Level -2: 
 
 
This will be the starting dose in Cohort 2. If Dose Level -2 is well 
tolerated (DLT ≤ 1/6), this dose will be established as the MTD for mGC. 
 
 De-escalation: if Dose Level -2 is not tolerated in Cohort 2 (> 1/6 DLT), 
the combination will  
be considered not feasible in mGC and Cohort  2 
will be terminated. Patients who, at that point, experience response as per 
RECIST v.1.1 will be offered the possibility to continue on trastuzumab 
emtansine as a single agent, or with the combination, based on risk-
benefit balance and agreement with the SC 
e) If the MTD in Cohort 1 was defined at dose level 2 of 850 mg/m2 bid 
o 
If dose level 2 is tolerated, doses should be escalated to dose level 3 
of 1000 mg/m2 bid 
o 
If dose level 2 is not tolerated, doses should be de escalated to dose 
level 1 of 750 mg/m2 bid 
f) 
If the MTD in Cohort 1 was defined at dose level 3 of 1000 mg/m2 bid 
o 
If dose level 3 is tolerated, no escalation will be done and the MTD 
will be defined at dose level 3 
o 
If dose level 3 is not tolerated, doses should be de escalated to dose 
level 2 of 850 mg/m2 bid 
3.1.1.4  
Considerations for all Patients Treated in the Study 
Safety data will be reviewed on an ongoing basis (i.e. real time safety 
monitoring) by the Steering Committee. The preliminary safety review will be 
based on the safety information (DLTs, dose delays, dose reductions and 
Grade 3 5 events) observed during the first cycle in at least 3 patients. 
3.1.1.5  
Number of Patients 
Overall, it is anticipated that the maximum number of patients enrolled into the 
study will be 140approximately 147 patients. 
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Phase  I, Cohort 1: mBC 
From 3 a minimum of 6 to 18 patients will be enrolled into Cohort  1 to 
determine the MTD of capecitabine in combination with trastuzumab 
emtansine in mBC patients with mBC. 
Randomized Phase  II: Exploration of Efficacy and Safety in mBC  
For this part of the study, Cohort 1 a total of approximately 117 patients with 
mBC will be expanded to 110 mBC patientsrandomized. 
Phase  I, Cohort 2: mGC 
After the MTD in Cohort  1 has been established, 3–1812 patients will be 
enrolled into Cohort  2 to determine the MTD of capecitabine in combination 
with trastuzumab emtansine in mGC patients with mGC. 
3.1.2  
STEERING COMMITTEE 
A Steering CommitteeA SC has been established for this study. Initially, it is 
composed of the investigators participating in the Phase  I, Cohort  1 part of 
the study and one medical representative and one statistician of the Sponsor. 
The study design and DLT has been developed by the Steering Committee. 
See Steering CommitteeSC. See SC Charter for further information. 
The SC will collectively review the status of the ongoing patients on a regular 
basis. The SC will also review in due course all available efficacy data and PK 
information to ensure that safety information is in the context of risk-benefit 
and that dosing is also related to exposure to the drug.  
The SC will adjudicate in cases of DLTs that are not covered by the existing 
DLT criteria. 
3.1.3  
INDEPENDENT DATA MONITORING COMMITTEE 
An independent data monitoring committee (IDMC) will be established for the 
Randomized Phase II part of the study. The IDMC will review the safety 
outcomes for patients enrolled in Phase I, Cohort 1 and advise whether the 
Randomized Phase II part of the study can commence. The IDMC will also 
monitor safety outcomes after 20 and 60 patients have received at least 3 
cycles (Cycle 3 Day 1) of treatment in the Phase II part of the study. 
Afterwards, the IDMC will monitor accumulating patient safety data every 6 
months during the Randomized Phase II of the study or as requested. 
3.2  
 
END OF STUDY 
End of study (EOS) is defined as LPLV at the end of the follow-up period, as 
defined in Section 3.1.1. This will be the last data collection point, which can 
be a clinic visit or a laboratory sample. LPLV is expected to occur 
approximately 2 years after the last patient has been enrolled into the trial. 
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3.3  
 
RATIONALE FOR STUDY DESIGN 
3.3.1  
RATIONALE FOR PATIENT GROUP SELECTION 
3.3.1.1  
Rationale for Phase I 
Following review of preliminary data from Cohort 1 of this study by the SC for 
patients enrolled to receive 750 mg/m2 capecitabine, where 2 DLTs were 
observed in 6 evaluable patients, it was decided not to explore dose levels of 
capecitabine higher than 750 mg/m2. According to the investigator 
assessment and the SC recommendation, the available evidence shows an 
acceptable positive risk-benefit in all 7 patients treated at Dose Level 1.  
As of 7 August 2013, five patients remain on treatment, with a follow-up 
period of 4 to 8 months. Of the two patients who have discontinued treatment, 
one patient’s disease has progressed, and the other discontinuation was 
based on the investigator’s decision, following the central confirmation, that 
the patient’s disease was HER2-negative. Considering the available safety 
data for all patients (maximum number of cycles is 12), the combination of 
capecitabine and T-DM1 is well tolerated, except for increases in 
transaminases and hand-foot syndrome. Dose modifications of T-DM1 and/or 
capecitabine have allowed those patients to continue on treatment. Of note, 
no SAE has been reported in 6 patients. Latest tumor response data show 2 
patients with PR and 4 patients with SD. Any required dose modifications 
(dose reductions) are allowed for each individual drug as described in 
Sections 5.1.5.1 and 5.1.5.2 and are in line with the trastuzumab emtansine 
Investigator’s Brochure and Xeloda® Summary of Product Characteristics.  
The combination of T-DM1 and capecitabine will be evaluated with a de-
escalation study design. Patients who are currently receiving the combination 
of T-DM1 and capecitabine 750 mg/m2 can continue to receive the dose as 
per protocol until there is no longer evidence of positive risk-benefit as per 
investigator assessment and SC endorsement. 
3.3.1.2  
Rationale for Randomized Phase II 
Randomized Phase II II part of the study is designed to provide an estimation 
of the treatment effect of the combination, at the selected MTD. , compared 
with T-DM1 alone. 
The patient data will be stratified by previous anti-cancer treatment (excluding 
single-agent hormones) for the treatment of metastatic disease (1 or >1prior 
lines of treatment). The stratified data will be compared with data from 
historical studies of single-agent trastuzumab emtansine in similar patient 
populations. This will allow a more robust evaluation of the added treatment 
effect of Xeloda® within the combination treatment. 
A 2:1 randomization will be applied to allow more patients being exposed to 
the combination of T-DM1 and capecitabine. This will enable a more thorough 
assessment of the corresponding safety profile. 
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3.3.2 
 RATIONALE FOR INVESTIGATIONAL MEDICINAL DOSE 
SELECTION 
3.3.2.1  
In Patients with mBC 
Capecitabine doses have been selected as being in the range of efficacious 
doses for single -agent or combination use. The dosedoses selected are 
within the dosing range included in the Xeloda® Summary of 750 mg/m2 bid 
wasProduct Characteristics (SmPC) and therefore are considered the 
minimumto be efficacious dose. The maximum dose of 1000 mg/m2 bid is the 
currently approved dose of capecitabine (please see the current national 
prescribing information of Xeloda®)..  
3.4  
 
OUTCOME MEASURES 
3.4.1   
PHASE  I: MBC 
3.4.1.3  
Primary Safety Outcome Measure 
The primary safety outcome measure is to establish the MTD. The number 
and the proportion of patients with DLTs will be used as the primary measure 
for the MTD determination and will be summarized for each treatment dosage. 
3.4.1.4  
Secondary Safety Outcome Measures 
Safety endpoints will be summarized for both treatment phases: dose finding 
and exploration of efficacy. Again, the summary of safety endpoints will be 
presented for each cohorteach treatment dosage: 
 
Incidence, nature and severity of AEs, as per National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) v. 4.0 
 
Incidence, nature, and severity of serious SAEs, as per NCI CTCAE v. 4.0 
 
Incidence and nature of AEs equal or higher than Grade 3 
 
Incidence, nature, and severity of AEs of special interest (AESIs), as per 
NCI CTCAE v. 4.0 
 
Premature withdrawal from study and study medication 
 
Abnormal laboratory values 
 
LVEF 
 
Exposure to study medication 
 
Concomitant medications and physical examination 
3.4.2 
 RANDOMIZED PHASE II: EXPLORATION OF EFFICACY AND 
SAFETY IN MBC 
3.4.2.1  
Primary Efficacy Outcome Measure 
The primary outcome measure is ORR by investigator assessment, based on 
best overall response (BOR) (defined as the best response recorded from the 
start of treatment randomization into Phase II part of the study and until 
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disease progression or /recurrence, or death, withdrawal of consent, or EOS, 
whichever occurs first; or for newly enrolled patients the best response from 
the start of Phase II until disease progression or death) by investigator 
assessment; as per RECIST v.1.1 provided in Appendix 3. 
3.4.2.3  
Primary Safety Outcome Measure 
A primary safety outcome is defined only for Phase I, and will be presented for 
both treatment groups. 
3.4.2.4  
Secondary Safety Outcome Measures 
Safety endpoints will be summarized for both treatment phases: dose finding 
and exploration of efficacy. Again, the summary of safety endpoints will be 
presented for each cohort: 
 
Incidence, nature and severity of AEs, as per NCI CTCAE v. 4.0 
 
Incidence, nature, and severity of serious SAEs, as per NCI CTCAE v. 4.0 
 
Incidence and nature of AEs equal or higher than Grade 3 
 
Incidence, nature, and severity of AESIs, as per NCI CTCAE v. 4.0 
 
Premature withdrawal from study and study medication 
 
Abnormal laboratory values 
 
LVEF 
 
Exposure to study medication 
 
Concomitant medications and physical examination 
3.4.3.   
PHASE I: MGC 
3.4.3.3  
Primary Safety Outcome Measure 
The primary outcome measure is to establish MTD. The number and the 
proportion of patients with DLTs will be used as the primary measure for the 
MTD determination and will be summarized for each treatment dosage. 
3.4.3.4  
Secondary Safety Outcome Measures 
Safety endpoints will be summarized for both treatment phases: dose finding 
and exploration of efficacy. Again, the summary of safety endpoints will be 
presented for each cohort: 
 
Incidence, nature and severity of AEs, as per NCI CTCAE v. 4.0 
 
Incidence, nature, and severity of serious SAEs, as per NCI CTCAE v. 4.0 
 
Incidence and nature of AEs equal or higher than Grade 3 
 
Incidence, nature, and severity of AESIs, as per NCI CTCAE v. 4.0 
 
Premature withdrawal from study and study medication 
 
Fatal cases and causes of death 
 
Abnormal lLaboratory values 
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 
LVEF 
 
Treatment Eexposure to study medication 
 
Concomitant medications and physical examination 
 
4.  
 
MATERIALS AND METHODS 
4.1  
 
PATIENTS 
4.1.3  
INCLUSION CRITERIA 
4.1.3.1  
For mBC Patients with mBC 
8.  Liver function: 
a) Total bilirubin ≤ 1.5 × upper limin of normal (ULN) except in patients 
with previously documented Gilbert’s syndrome in which case total 
bilirubin ≤ 3  mg/dL is acceptable 
d)  Evidence of stable liver function during the month prior to enrollment 
with liver function tests’ (LFTs) fluctuations not exceeding 2.5 x ULN (for 
AST, ALT) and 1.5 x ULN (for total bilirubin). Patients with bone 
metastases: AST and ALT ≤ 5.0 x ULN 
4.1.3.2  
For Patients with mGC 
8. Liver function: 
a) Total bilirubin ≤ 1.5 × ULN except in patients with previously 
documented Gilbert’s syndrome in which case total bilirubin ≤ 3 mg/dL is 
acceptable 
d) Evidence of stable liver function in the month prior to enrollment with 
LFTs fluctuations not exceeding 2.5 x ULN (for AST, ALT) and 1.5 x 
ULN (for total bilirubin). Patients with bone metastases: AST and ALT 
≤ 5.0 x ULN 
11. Histologically or cytologically confirmed mGC or locally advanced GC 
4.1.4  
EXCLUSION CRITERIA 
4.1.4.1  
For mBC Patients: with mBC 
6. History of intolerance (including Grade 3 or 4 infusion reaction) or 
hypersensitivity to trastuzumab or murine proteins or any component of 
the product 
7. History of exposure to the following cumulative doses of anthracyclines: 
a) Doxorubicin or liposomal doxorubicin > 360 500 mg/m2 
d) If another anthracycline, or more than one anthracycline, has been 
used, the cumulative dose must not exceed the equivalent of 360 
500 mg/m2 doxorubicin. 
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23. No signs and symptoms suggestive that the patient has 
dihydropyrimidine dehydrogenase (DPD) deficiency 
 
 
4.1.4.2  
For Patients with mGC 
7.  History of exposure to the following cumulative doses of anthracyclines: 
a) Doxorubicin or liposomal doxorubicin > 360 500 mg/m2 
d) If another anthracycline, or more than one anthracycline, has been used, 
the cumulative dose must not exceed the equivalent of 360 500 mg/m2 
doxorubicin. 
22. No signs and symptoms suggestive that the patient has DPD deficiency 
23. Lapatinib ≤ 14 days before first study drug administration 
4.1.5   
PATIENT REPLACEMENT POLICY 
None of the patients in the Phase I part of the study may be replaced unless 
approved by the entire SC. 
4.2  
 
METHOD OF TREATMENT ASSIGNMENT 
In the Randomized Phase II part of the study, patients will be randomized to 
receive either the combination of T-DM1 and capecitabine or T-DM1 alone. 
The 2:1 randomization ratio will be applied to allow more patients being 
exposed to the combination treatment and to enable a more thorough 
assessment of the corresponding safety profile. 
This is an open-label study; therefore, no blinding will be used. 
4.3  
 
STUDY TREATMENT 
4.3.2  
DOSAGE AND ADMINISTRATION 
4.3.2.1  
For Patients with mBC 
Trastuzumab Emtansine 
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 6090 minutes for fever, chills, or other infusion -
associated symptoms. 
Capecitabine 
Capecitabine will be administered twice a day, orally for 14 days followed by a 
7-day rest period at the dose levelsDose Levels 1 3 to -2 described in the 
“study designStudy Design” Section Error! Reference source not 
found..3.1.1. Capecitabine tablets should be swallowed with water within 30 
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minutes after a meal. Capecitabine doses can be delayed for up to 4 hours, 
while keeping the minimal interval of 8 hours between the doses. 
Rounding of the dose, based on 150 and 500 mg strength tablets, will be 
allowed to the nearest dose per patient body surface area (BSA). 
If a dose is missed, the patient should skip that dose. The patient should not 
double the dose during the next administration. 
For Phase II, guidelinesGuidelines for dosage modification and treatment 
interruption or discontinuation are provided in Section Error! Reference 
source not found..5.1. For this part of the study, the MTD fromestablished in 
Phase  I, Cohort 1 will be used as a starting dose. 
4.3.2 2  
For mGC Patients with mGC 
Capecitabine 
Capecitabine will be administered twice a day, orally, for 14 days followed by 
a 7-day rest period at the dose level that was determined during the dose 
findingDose Finding part of the study in mBC patients with mBC as the MTD 
in Cohort  1. Capecitabine tablets should be swallowed with water within 30 
minutes after a meal. Capecitabine doses can be delayed for up to 4 hours, 
while keeping the minimal interval of 8 hours between the doses. 
4.5  
 
STUDY ASSESSMENTS 
4.5.1  
DESCRIPTION OF STUDY ASSESSMENTS 
4.5.1.4  
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 
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 (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 (see Error! Reference source not found.). 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. Please consult the Imaging Manual for guidelines on performing a 
diagnostic quality (optimized) CT exam. For patients who continue study 
treatment after isolated brain progression, the frequency of follow-up scans is 
at the discretion of the investigator. 
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4.5.1.5  
Laboratory Assessments 
Local Laboratory Assessments: 
 
Hematology, biochemistry, coagulation, urinalysis, and pregnancy testing 
 
Prospective or retrospective HER2 status. Patients will be enrolled based 
on local results. 
Central Laboratory Assessments: 
 
Retrospective HER2 status. Retrospective central confirmation will not 
impact the treatment decisions or primary endpoint of Phase I, Cohort 1 
and will be used to validate efficacy analyses in Phase I and to censor the 
efficacy population for the Randomized Phase II part of the study 
4.5.1.7  
ECOG Performance Status 
Performance status will be measured using the ECOG performance status 
scale (see Appendix 6). 
It is recommended, where possible, that a patient’s performance status be 
assessed by the same person throughout the study. 
Performance status will be assessed according to the schedule of 
assessments (see Appendix 1) 
4.5.2  
TIMING OF STUDY ASSESSMENTS 
4.5.2.1  
Screening and Pretreatment Assessments 
Results of standard of care tests or examinations performed prior to obtaining 
informed consent and within 28 days prior to study start may be used; such 
tests do not need to be repeated for screening. Patient must have stable liver 
tests prior to the first dose of study drug. 
Patients who are on the MTD dose established in Cohort 1 will not contribute 
to Phase II; however, they will be followed-up until end of studyEOS. In 
Randomized Phase II, patients will be randomized in a 2:1 ratio to receive  
T-DM1 or the combination of T-DM1 and capecitabine prior to receiving the 
first dose of study medication. 
Patients who are on the MTD dose established in Cohort 1 must re consent to 
be enrolled into Phase II. 
Patients in Cohort 1 will not contribute to Phase II; however, they will be 
followed-up until EOS. In Randomized Phase II, patients will be randomized in 
a 2:1 ratio to receive  
T-DM1 or the combination of T-DM1 and capecitabine prior to receiving the 
first dose of study medication. 
4.5.2.3  
Assessments at Study Completion/Early Termination Visit 
Patients may remain on study treatment until disease progression as 
assessed by the investigator, intolerable toxicity, or until the patient wishes to 
withdraw from study treatment. Patients who discontinue study treatment will 
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be followed-up until EOS and will be asked to return to the clinic 
approximately 28–42 days after the last study treatment administration, for the 
safety follow-up visit. 
 
4.6  
 
PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1  
PATIENT DISCONTINUATION 
Patients must be withdrawn from study treatment if they become pregnant or 
experience any of the following: 
 
Pregnancy 
Diseasedisease progression defined using RECIST v. 1.1 Appendix 3. The 
exception to this is patients who develop isolated progression in the brain as 
described in Appendix 3. 
UnacceptableDetails of discontinuation due to toxicity because of the 
trastuzumab emtansine dose as specifiedare given in Section 5.1. 
 
Unacceptable toxicity because of the capecitabine dose as specified in 
Section Error! Reference source not found. 
Other reasons for patient discontinuation may include, but are not limited to, 
the following: 
 
Noncompliance 
 
Pregnancy 
 
Non-compliance 
 
Investigator decision based on the patient’s best interest 
 
Patient decision 
5.  
ASSESSMENT OF SAFETY 
5.1  
SAFETY PLAN 
All patients will be monitored closely for toxicity. The potentialimportant safety 
issues anticipated in this trial, as well as measures intended to avoid or 
minimize such toxicities, are outlined in the following sections. 
 
5.1.1  
RISKS ASSOCIATED WITH TRASTUZUMAB EMTANSINE 
Trastuzumab emtansine dose modifications are described in Section Error! 
Reference source not found.. 
The following summarizes the experience with trastuzumab emtansine in 
multiple breast cancer studies to date. Trastuzumab emtansine has 
demonstrated a favorable toxicity and tolerability profile to date across 
multiple studies. Please refer to the Investigator’s Brochure for further 
information. 
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Reversible thrombocytopenia has been commonly observed in completed and 
ongoing studies with trastuzumab emtansine. Most events were Grade 1 2; 
Grade 3 4 thrombocytopenia has been observed less commonly. The 
incidence of Grade 1 thrombocytopenia gradually increased over successive 
cycles; however, there was no increase in the proportion of Grade ≥ 3 
abnormalities. The number of patients who experienced platelet count 
recovery to normal levels by Day 1 of the subsequent cycle decreased with 
successive cycles, suggesting a modest cumulative effect of trastuzumab 
emtansine on platelet count. There was no clear association between 
thrombocytopenia and severe hemorrhagic events; however, the use of 
platelet transfusions has been reported. 
Transient and reversible increases in serum AST and ALT have been 
observed across the trastuzumab emtansine studies. Grade 1 2 events have 
been observed frequently; Grade 3 4 events have been observed much less 
commonly. The incidence of increased AST was substantially higher than that 
for ALT. Increases in AST and ALT were commonly observed by Day 8 of 
each cycle and generally returned to baseline by Day 21. The proportion of 
patients with Grade 1 2 increases in transaminases increased with 
successive cycles; however, no increase in the proportion of Grade 3 
abnormalities over time was observed. To date, there have been no cases 
meeting Hy’s Law criteria for drug induced liver injury. Although significant 
hepatotoxicity has rarely been seen in clinical trials with trastuzumab 
emtansine to date, the relationship to trastuzumab emtansine has not been 
established. Nevertheless, severe liver injury remains an important potential 
risk. 
Infusion related reactions are known to occur with the administration of 
monoclonal antibodies and have been reported with trastuzumab emtansine. 
Infusion reaction AEs occurred rarely and were mostly Grade 1 2. Non
specific symptoms that occurred on the first day of trastuzumab emtansine 
infusion that could be associated with an infusion reaction included fatigue, 
nausea, chills, pyrexia, and, less commonly, headache, hypertension, 
vomiting, and cough. 
Pneumonitis has been rarely reported with trastuzumab emtansine. Signs, 
symptoms, and clinical findings include dyspnea, cough, fatigue, and 
pulmonary infiltrates. There were no fatalities among the cases of pneumonitis 
reported with trastuzumab emtansine. 
In clinical trials with trastuzumab emtansine, peripheral neuropathy has been 
reported, mainly as Grade 1 toxicity. Hypokalemia and decreases in serum 
potassium have been reported in completed and ongoing studies with 
trastuzumab emtansine. Most of these AEs were Grade 1 2. 
Although significant cardiac events have been infrequent in clinical trials with 
trastuzumab emtansine to date, severe cardiotoxicity remains an important 
potential risk. Treatment with trastuzumab, a component of trastuzumab 
emtansine, has resulted in subclinical and clinical cardiac failure manifesting 
as CHF, decreased LVEF, and cardiac death. The incidence and severity of 
cardiac dysfunction was highest in patients who received trastuzumab 
concurrently with anthracycline containing chemotherapy regimens. 
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Cardiotoxicity, manifesting as a decline in LVEF or CHF, is being closely 
monitored in the trastuzumab development program. Across studies 
TDM4258g, TDM4374g, and TDM4688g, approximately 273 patients were 
treated, and a total of 8 patients recorded an asymptomatic decrease in 
baseline LVEF of at least 10%, concomitant with an LVEF < 50%. Two 
patients had trastuzumab emtasine treatment withdrawn because of 
decreased LVEF. Rare cases of Grade 3 cardiac dysrhythmias have been 
reported among patients receiving trastuzumab emtansine, although a direct 
relationship to study drug remains unclear. 
Importantly, preliminary evaluations of safety in the randomized study 
TDM4450g suggest that the safety and tolerability of trastuzumab emtansine 
compared favorably with that of trastuzumab plus docetaxel, with the overall 
incidence of Grade ≥ 3 AEs favoring the trastuzumab emtansine arm (46.4% 
vs. 89.4%) (data on file). 
Full details regarding the clinical safety of trastuzumab emtansine are 
presented in Sections 5 and 6 of the Investigator’s Brochure. 
 
5.1.1.1  
Cardiotoxicity 
Patients treated with trastuzumab emtansine are at increased risk of 
developing left ventricular dysfunction. LVEF  40% has been observed in 
patients treated with trastuzumab emtansine. Patients without significant 
cardiac history and with an LVEF ≥ 50% determined by ECHO or MUGA scan 
are eligible for study participation. LVEF will be monitored at screening and 
regularly throughout the study until the assessment at the safety follow-up 
visit. Patients with symptomatic cardiac dysfunction will be discontinued from 
study treatment. Asymptomatic LVEF declines will be handled as per the 
algorithm shown in Figure 6. Treatment with trastuzumab emtansine has not 
been studied in patients with LVEF  50%. 
5.1.1.2  
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 central nervous system 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. 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. 
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Use of erythropoiesis-stimulating agents will be allowed as consistent with 
prescribing guidelines. Transfusion of red blood cells and/or platelets will be 
allowed according to and at the discretion of the treating physician. 
5.1.1.3  
Hepatotoxicity 
Hepatotoxicity, predominantly in the form of asymptomatic increases in the 
concentrations of serum transaminases (Grade 1  4 transaminitis), has been 
observed in patients while on treatment with trastuzumab emtansine in clinical 
trials. Transaminase elevations were generally transient. The incidence of 
increased AST was substantially higher than that for ALT. 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. While there is evidence of 
drug-induced liver toxicity (predominantly in the form of asymptomatic 
increases in the concentrations of serum transaminases) in patients treated 
with trastuzumab emtansine, its potential to cause acute severe liver injury 
with clinically meaningful changes in liver function is unclear as the observed 
cases of acute liver injury were confounded by concomitant medications with 
known hepatotoxic potential and/or underlying conditions. Nevertheless, a 
contributory role of trastuzumab emtansine in these cases cannot be excluded. 
Therefore, acute severe liver injury (Hy’s law) remains an important potential 
risk with trastuzumab emtansine. A Hy’s law case has the following 
components: 
  Aminotransferase enzymes (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.  
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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 
hypertension. Diagnosis of NRH can only be confirmed by histopathology. 
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. 
5.1.1.4  
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. 
5.1.1.5  
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. Pre-medication 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 
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permanently discontinued. Patients who experience a Grade  3 allergic 
reaction or acute respiratory distress syndrome will be discontinued from 
study treatment. 
5.1.1.6  
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. 
5.1.1.7  
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. 
5.1.1.8  
Trastuzumab Emtansine Dose Modification 
Trastuzumab emtansine dose modifications are described in Section 5.1.5.1. 
5.1.2  
RISKS ASSOCIATED WITH CAPECITABINE 
Capecitabine dose modifications will be done according to Section Error! 
Reference source not found., study design. 
Patients treated with capecitabine should be carefully monitored for toxicity. 
Most AEs are reversible and do not require permanent discontinuation of 
therapy (please refer to the Xeloda® Investigator`s Brochure for more 
information). 
The spectrum of cardiotoxicity observed with capecitabine is similar to that of 
other fluorinated pyrimidines. This includes myocardial infarction, angina, 
dysrhythmias, cardiac arrest, cardiac failure and electrocardiographic changes. 
These AEs may be more common in patients with a prior history of coronary 
artery disease. 
DPD deficiency, a rarelyA rare, unexpected, severe toxicity (e.g. stomatitis, 
diarrhea, neutropenia, and neurotoxicity) associated with 5-FU has been 
attributed to a deficiency of dihydropyrimidine dehydrogenase (DPD)DPD 
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activity. Therefore, a link between decreased levels of DPD and increased, 
potentially fatal, toxic effects of 5-FU cannot be excluded. 
Capecitabine can induce hand–-foot syndrome (palmar-plantar 
erythrodysesthesia or chemotherapy-induced acral erythema), which is a 
cutaneous toxicity. For patients receiving capecitabine monotherapy in the 
metastatic setting, the median time to onset was 79 days (range 11 to –360 
days), with a severity range of Grades 1 to 3. Grade 1 hand-foot syndrome is 
defined by numbness, dysesthesia/paresthesia, tingling or erythema of the 
hands and/or feet and/or discomfort which does not disrupt normal activities. 
Grade 2 is defined as painful erythema and swelling of the hands and/or feet 
and/or discomfort affecting the patient’s activities of daily living (ADL). Grade 
3 is defined as moist desquamation, ulceration, blistering or severe pain of the 
hands and/or feet and/or severe discomfort that causes the patient to be 
unable to work or perform ADL. If Grade 2 or 3 hand-foot syndrome occurs, 
administration of capecitabine should be interrupted until the event resolves or 
decreases in intensity to Grade 1. Following Grade 3 hand-foot syndrome, 
subsequent doses of capecitabine should be decreased. 
Capecitabine can induce hyperbilirubinemia. Administration of capecitabine 
should be interrupted if treatment-related elevations in bilirubin of > 3.0 × ULN 
or treatment-related elevations in hepatic aminotransferases (ALT, AST) 
of > 2.5 × ULN occur. Treatment may be resumed when bilirubin decreases 
to ≤ 3.0 × ULN or hepatic aminotransferases decrease to ≤ 2.5 x ULN/AST) 
of Grade ≥ 2 occur.  
5.1.3 
 RISKS ASSOCIATED WITH TRASTUZUMAB EMTANSINE AND 
CAPECITABINE COMBINATION: 
DLTs for the combination of trastuzumab emtansine and capecitabine will be 
observed during Cycle 1 (Day 1–21) of this study. The combination treatment 
must be considered as a new treatment during Cycle 1, and no individual 
dose reduction will be allowed; the general DLT rules will be used instead. 
Interruptions can be made due to toxicities considered by the investigator to 
be related to capecitabine. Grade 2–4 toxicities should be interrupted until 
resolved to Grade 0–1. For Grade 4 toxicities, consideration to discontinue 
treatment with capecitabine will be made with the adjudication of the SC.  
5.1.4  
DEFINITION OF DOSE LIMITING-LIMITING TOXICITY 
DLT toxicities will be observed during Cycle 1 (Day 1–21). Please refer to 
Xeloda® SmPC for recommendations on dose reduction. 
Definition of DLT: 
Hematologic 
1. Uncomplicated thrombocytopenia Grade 4 which does not recover 
to ≥ 75.,000/Ml before Day 21 
2.  
Thrombocytopenia (any grade) complicated with clinically significant 
bleeding requiring medical intervention such as: platelet transfusion, 
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cauterization, patients with epistaxis Grade 1 or 2 may have cauterization 
and this should not be consider as DLT etc. 
3. Neutropenia Grade 4 lasting > 7 consecutive days 
4. Febrile neutropenia with an ANC of < 10001,000 cells/mm3 
Non-hematologic 
5. Diarrhea Grade ≥ 3 which does not decrease to ≤ Grade 2 after 24 hours 
of starting recommended anti-diarrheal treatment in absence of DPD 
deficiency 
6. Hand-foot syndrome Grade ≥ 3 in absence of DPD deficiency 
7.  
Any other treatment-related toxicity ≥ Grade 3 prohibiting the start of 
the 2nd cycle on dayDay 22 (3 weeks cycle length plus 1 day) 
NOTE: If a Grade 2 event requires a dose delay, it will not be considered as 
DLT. However, if the toxicity does not resolve to Grade 1 or baseline by 
Day 42, this requires discontinuation and will be considered as DLT. 
8. Grade 2 toxicity requiring interruption of treatment for > 714 days 
NOTE: Patients experiencing ≥ Grade 3 hand-foot syndrome or diarrhea or 
mucositis or Febrilefebrile neutropenia with ANC < 500 cells/mm3 during 
Cycle 1 must be tested for DPD deficiency (central lablaboratory will be 
appointed). The SC will adjudicate in cases of DLTs that are not covered by 
the existing DLT criteria. 
NOTE TO point 7, if a Grade 2 event requires a dose delay, it will not be 
considered as DLT. 
9. Having taken < 14 full doses of capecitabine due to toxicity 
10. Patient not able to receive 100% of the dose level going into Cycle 2, 
Day 1 
5.1.5  
MANAGEMENT OF SPECIFIC ADVERSE EVENTS 
5.1.5.1  
Trastuzumab Emtansine DosageDose 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 those specified 
below (i.e., infusion reactions, thrombocytopenia, hepatotoxicity, neurotoxicity, 
cardiotoxicity, and ILD or pneumonitis) are as follows: 
Dose delays for trastuzumab emtansine related toxicity other than the ones 
specified below (i.e., infusion reactions, thrombocytopenia, hepatotoxicity, 
neurotoxicity, and cardiotoxicity) are as follows: 
 
If significant trastuzumab emtansine -related toxicities (other than infusion 
reactions, thrombocytopenia, hepatotoxicity, neurotoxicity, and 
cardiotoxicity) have not recovered to Grade 1 or baseline, the next 
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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 
reevaluatedre-evaluated qw during the delay, whenever possible. If 
dosing resumes, the patient may receive trastuzumab emtansine either at 
the same dose level as before or at one dose level lower than the 
previous dose (see Table 2 and Table 3), at the discretion of the 
investigator. Subsequent cycles should remain the same (q3w or qw), 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 or Table 3. No dose re-escalation will be allowed. 
 
If 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 qwweekly 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 ReductionsReduction for Trastuzumab Emtansine (mBC  
(Patients with mBC) 
Dose Level 
q3w Schedule 
0 
3.6 mg/kg 
 - 1 
3.0 mg/kg 
 - 2 
2.4 mg/kg 
Indication for 
further dose 
reduction 
Off study treatment 
q3w = every 3 weeks 
 
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Table 3 Dose Reductions for Trastuzumab Emtansine (mGC  
(Patients with mGC) 
Dose Level 
qw Schedule 
0 
2.4 mg/kg 
 - 1 
2.0 mg/kg 
 - 2 
Off study 
Indication for 
further dose 
reduction 
Off study 
qw = weekly 
 
In case of toxicities requiring the discontinuation of T-DM1, the patient will be 
followed-up until the EOS. 
Protocol requirements for specific toxicities are outlined below. 
5.1.5.1.1 
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 any of the 
following events listed belowa first Grade 4 thrombocytopenia event may, 
after  adequate recovery to a platelet count of Grade ≤  1 ( ≥ 75,000/μL), 
mayor baseline, continue treatment with trastuzumab emtansine at onea dose 
level reductionof 3 mg/kg in subsequent treatment cycles (see Table 2 and 
Table 3). 
Grade 4 Thrombocytopenia: 
Hold study drug until platelet count qualifies for Grade ≤ 1 (≥ 75,000 μL). 
 
Platelets < 10,000 cells/mm3 for any duration 
 
Platelets ≥ 10,000 cells/mm3 but < 25,000 cells/mm3 for more than 7 days 
Grade 3 Thrombocytopenia: 
Hold study drug until platelet count qualifies for Grade ≤ 1 ( ≥ 75,000 μL). 
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 
Trastuzumab emtansine 2.4 mg/mg/week dosing 
 
Platelets must be ≥ 75,000 μL on day of treatment. 
 
Trastuzumab emtansine 3.6 mg/kg/q3w dosing: 
 
Platelets must be ≥ 75,000 μL on day of treatment. 
. Patients on Anticoagulation Therapy: 
Hold study drug until platelet count qualifies for Grade ≤ 1 (≥ 75,000 μL). 
 
For platelet count of Grade ≥ 3 (< 50,000 cells/μL) of any duration 
Patientsat the 3 mg/kg dose level who experience anya 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 a Grade 4 
thrombocytopenia event at the 2.4 mg/kg dose level will be discontinued from 
study treatment. A dose delay of these toxicities should be reassessed at 
least qw for recovery.up to 42 days from the patient’s last dose received is 
permitted.  
5.1.5.1.2 
Trastuzumab Emtansine Dose Modification for Hepatotoxicity 
Table 4 and  
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Up to 
1.5 × ULN 
 > 1.5 3 × ULN 
 ≥ 3 10 × ULN 
 ≥ 10 × ULN 
T-DM1 
action 
Treat without 
dose reduction 
or delay 
Hold a dose; reduce one 
dose level when 
recovered to Grade ≤ 1.  
Discontinue b if 
> 2 × ULN and occurs 
concurrent c with ALT 
and/or AST elevation 
> 3 × ULN 
Hold a dose; reduce 
one dose level when 
recovered to 
Grade ≤ 1.  
Discontinue b if occurs 
concurrent c with ALT 
and/or AST elevation 
> 3 × ULN 
Discontinue. 
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. 
a A dose delay of up to 42 days after the last received dose is permitted for patients on a 
q3w schedule or 28 days for patients on a weekly schedule. 
b Unless a decision is made to hold then continue trastuzumab emtansine treatment based 
on the results of further evaluation of the situation and agreement by the investigator and 
the Sponsor. See also Section 0 
c Within 21 days. 
 
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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. 
 
Table 5 describe the dose modification guidelines for increases in serum 
bilirubin and transaminases, respectively. Patients who develop a Grade 4 
serum total bilirubin increase or a Grade 4  
5.1.5.1.2.1 Concurrent elevations of ALT and/or /AST increase and 
bilirubin meeting Hy’s Law laboratory criteria 
Regardless of dose level, trastuzumab emtansine must discontinue study 
treatment be permanently. Patients should be checked assessed at least qw 
for the recovery of total bilirubin and/or  discontinued in patients with ALT 
and/or AST. If  > 3 × ULN and concurrent increase of total bilirubin 
to > 2 × ULN. All relevant hepatic laboratory tests performed (including AST, 
ALT, total bilirubin, alkaline phosphatase, activated partial thromboplastin time 
[aPTT], INR, and albumin) will be entered into the clinical database. 
5.1.5.1.2.2 Nodular regenerative hyperplasia (NRH) 
Trastuzumab emtansine must be permanently discontinued in patients who 
are diagnosed with NRH. 
5.1.5.1.2.3 Transaminase elevations or bilirubin elevation requiring dose 
adjustment 
Patients who experience a Grade 3 elevation of liver function should be 
checked twice weekly for the recovery of transaminases and/or total bilirubin. 
If a patient’s transaminases and/or ALT and/or ASTtotal bilirubin do not 
recover to baseline or Grade ≤ 1 (total bilirubin) or Grade ≤ 2 (ALT and/or 
AST)as per Table 4 and Table 5, within 42  days afterfrom the patient’s last 
dose received, the patient must discontinue study treatment. Please see 
Section 0 and Table 4 and  
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Up to 
1.5 × ULN 
 > 1.5 3 × ULN 
 ≥ 3 10 × ULN 
 ≥ 10 × ULN 
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T DM1 
action 
Treat without 
dose reduction 
or delay 
Hold a dose; reduce one 
dose level when 
recovered to Grade ≤ 1.  
Discontinue b if 
> 2 × ULN and occurs 
concurrent c with ALT 
and/or AST elevation 
> 3 × ULN 
Hold a dose; reduce 
one dose level when 
recovered to 
Grade ≤ 1.  
Discontinue b if occurs 
concurrent c with ALT 
and/or AST elevation 
> 3 × ULN 
Discontinue. 
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. 
a A dose delay of up to 42 days after the last received dose is permitted for patients on a 
q3w schedule or 28 days for patients on a weekly schedule. 
b Unless a decision is made to hold then continue trastuzumab emtansine treatment based 
on the results of further evaluation of the situation and agreement by the investigator and 
the Sponsor. See also Section 0 
c Within 21 days. 
 
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. 
 
Table 5 for further informationwill be discontinued from study treatment. 
No re-escalation of the trastuzumab emtansine dose is  allowed. 
Table 4 and Table 5 describe the dose modification guidelines for increases in 
serum bilirubin and transaminases, respectively. 
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Table 4 Trastuzumab Emtansine Dose Modification: Total Serum 
Bilirubin 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Up to 
1.5 × ULN 
 > 1.5–3 × ULN 
 ≥ 3–10 × ULN 
 ≥ 10 × ULN 
T DM1 
action 
Treat without 
dose reduction 
or delay 
Hold a dose; reduce one 
dose level when 
recovered to Grade ≤ 1.  
Discontinue b if 
> 2 × ULN and occurs 
concurrent c with ALT 
and/or AST elevation 
> 3 × ULN 
Hold a dose; reduce 
one dose level when 
recovered to 
Grade ≤ 1.  
Discontinue b if occurs 
concurrent c with ALT 
and/or AST elevation 
> 3 × ULN 
Discontinue. 
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. 
a A dose delay of up to 42 days after the last received dose is permitted for patients on a 
q3w schedule or 28 days for patients on a weekly schedule. 
b Unless a decision is made to hold then continue trastuzumab emtansine treatment based 
on the results of further evaluation of the situation and agreement by the investigator and 
the Sponsor. See also Section 0 
c Within 21 days. 
 
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 5 Trastuzumab Emtansine Dose Modification: Serum ALT or AST 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Up to 
3 × ULN 
 > 3–5 × ULN 
 ≥ 5–20 × ULN 
 ≥ 20 × ULN 
T
DM1 
action 
Treat without 
dose 
reduction or 
delay 
Treat without dose 
reduction or delay. 
Discontinue b if 
occurs concurrent c 
with total bilirubin 
> 2 × ULN or clinical 
jaundice 
Hold a dose; reduce one 
dose level when recovered 
to Grade ≤ 2.  Discontinue 
b if occurs concurrent c with 
total bilirubin > 2 × ULN or 
clinical jaundice 
Discontinue 
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. 
a A dose delay of up to 42 days after the last received dose is permitted for patients on a 
q3w schedule or 28 days for patients on a weekly schedule. 
b Unless a decision is made to hold then continue trastuzumab emtansine treatment based 
on the results of further evaluation of the situation and agreement by the investigator and 
the Sponsor.  See also Section 0 
c Within 21 days. 
 
 
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 ≤ 2, 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. 
 
5.1.5.1.3 
Trastuzumab Emtansine Dose Modification for Neurotoxicity 
DM1, an anti microtubule agent, can potentially cause peripheral neuropathy. 
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. 
 
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. 
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5.1.5.1.4 
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. 
Ejection fractions will be monitored according toduring the scheduleslast week 
of Cycle 1, Cycle 3 and every third cycle thereafter until the assessment in 
Appendix 1.at the safety follow-up visit. 
Figure 6 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. 
The decision to stop or continue trastuzumab emtansine should be based on 
the algorithm shown in Figure 6. 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. 
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Figure 6 Algorithm for Continuation and Discontinuation of 
Trastuzumab Emtansine Based on Left Ventricular Ejection 
Fraction Assessments in Patients 
 
CHF = congestive heart failure; 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. 
 
5.1.5.1.5 
Trastuzumab Emtansine Dose Modification/Management for 
Infusion-related Reactions, Hypersensitivity Reactions 
No pre medication for Trastuzumab emtansine treatment should be 
interrupted in patients with severe infusion-related reactions. Trastuzumab 
emtansine treatment should be permanently discontinued in the firstevent of 
life-threatening infusion-related reactions. 
Infusion of trastuzumab emtansine is required; however, pre medication is 
allowed at 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 investigator’s 
discretion. 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. 
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Patients who experience trastuzumab emtansine infusion-related temperature 
elevations ofto > 38.5°C and/or other minor infusion-related symptoms may be 
treated symptomatically with acetaminophen and/or H1 and H2 receptor 
antagonists (e.g., diphenhydramine and ranitidine, respectively).hydrochloride. 
Serious infusion-related events (Grade ≥ 3 allergic reaction or acute 
respiratory distress syndrome [ARDS]) manifested by dyspnea, hypotension, 
wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 
respiratory distress should be managed with supportive therapies as clinically 
indicated according to standard clinical practice. Patients who experience a 
Grade ≥ 3 allergic reaction or ARDS care, such as oxygen, beta agonists, 
antihistamines, antipyretics, or corticosteroids at the investigator's discretion. 
Pre-medication 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. In the event of a true hypersensitivity reaction (i.e., if 
the severity of reaction increases with subsequent infusions), trastuzumab 
emtansine treatment must be permanently discontinued. Patients who 
experience a Grade ≥ 3 hypersensitivity reaction or acute respiratory distress 
syndrome (ARDS) will be discontinued from study treatment. Patients who 
have infusion related symptoms, such as chills or fever, may have the infusion 
rate decreased by 50% or interrupted. When symptoms have resolved, the 
infusion may be restarted at ≤ 50% of the prior rate and increased in 50% 
increments every 30 minutes as tolerated. Pre medication may be used 
before subsequent infusions at the investigator’s discretion. Patients should 
be monitored until complete resolution of symptoms.the study. 
Patients who experience a severe delayed infusion reaction will be 
discontinued from study treatment.  
5.1.5.1.6 
Trastuzumab Emtansine Dose Modification for Pulmonary 
Toxicity 
Cases of ILD, including pneumonitis (including severe, life-threatening cases) 
and some leading to ARDS or fatal outcome have been reported with 
trastuzumab emtansine. Treatment with trastuzumab emtansine has to be 
permanently discontinued in patients who are diagnosed with ILD or 
pneumonitis.  
5.1.5.1.7 
Trastuzumab Emtansine Dose Modification for Extravasation 
During the 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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5.1.5.2  
Capecitabine Dosage Modification 
Phase  I: mBC Patients with mBC 
CapecitabineThe dose modifications during Phase I willof capecitabine can be 
performed accordingmodified if considered appropriate by the investigator 
(please refer to the description in Section Error! Reference source not 
found., study designXeloda® SmPC for mBC recommendations). 
In case of toxicities requiring the discontinuation of capecitabine, single-agent 
trastuzumab emtansine may be continued in patients with mBC. 
Randomized Phase  II: Exploration of Efficacy: and Safety in mBC  
During the Randomized Phase  II, part of the study, the dose of capecitabine 
will be modified as per the Xeloda® Investigator`s Brochure (or SMPC).SmPC. 
In case of toxicities requiring the discontinuation of capecitabine, single-agent 
trastuzumab emtansine may be continued in patients with mBC. 
Phase  I: mGC Patients with mGC 
CapecitabineThe dose modifications during Phase I willof capecitabine can be 
performed accordingmodified if considered appropriate by the investigator 
(please refer to the description in Section Error! Reference source not 
found., study designXeloda® SmPC for mGC recommendations). 
In case of toxicities requiring the discontinuation of capecitabine, single-agent 
trastuzumab emtansine may be continued in patients with mGC. 
5.2  
 
SAFETY PARAMETERS AND DEFINITIONS 
5.2.3 
 PROTOCOL-DEFINED EVENTS OF SPECIAL INTEREST/NON-
SERIOUS EXPEDITED ADVERSE EVENTS 
Non-serious AEs of special interestAESIs are required to be reported by the 
investigator to the Sponsor immediately (i.e., no more than 24 hours) after 
learning of the event (see Section 5.4.2 for reporting instructions). AEs of 
special interest AESIs for this study include the following: 
 
Potential Drugdrug-induced liver injury 
Any potential case of drug-induced liver injury as assessed by laboratory 
criteria for Hy’s Lawlaw 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:  
The following laboratory abnormalities define potential Hy’s law cases: 
AST and/or ALT elevations that are > 3 × the ULN 
 
Concurrent with concurrent elevation (within 21 days of AST and/or ALT 
elevations) of of total bilirubin > 2 × the ULN, except in patients with 
documented GilbertGilbert’s syndrome. For patients with Gilbert’s 
syndrome, elevation of direct bilirubin > 2 × ULN should be used instead 
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Suspected transmission of an infectious agent by the study drug: 
 
Defined as any organism, virus, or infectious particle (e.g., prion protein 
transmitting transmissible spongiform encephalopathy), both pathogenic 
and non-pathogenic. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings indicating an 
infection in a patient exposed to a medicinal product. This term ONLY 
applies when a contamination of the study drug is suspected, NOT for 
infections supported by the mode of action, e.g., immunosuppression. 
5.3 
 METHODS AND TIMING FOR CAPTURING AND 
ASSESSING SAFETY PARAMETERS 
5.3.1  
ADVERSE EVENT REPORTING PERIOD 
Investigators will seek information on AEs at each patient contact. All AEs, 
whether reported by the patient or noted by study personnel, will be recorded 
in the patient’s medical record and on the AE eCRF. 
After informed consent has been obtained but prior to initiation of study drug, 
only SAEs caused by a protocol-mandated intervention should be reported 
(e.g., SAEs related to invasive procedures such as biopsies, medication 
washout, or no treatment run-in). 
After initiation of study treatment, all AEs, regardless of relationship to study 
drug, will be reported until 30 days after the last administration of study drug 
or study discontinuation/termination, whichever is later. After this period, 
investigators should report any deaths,all SAEs, or other AEs and non-serious 
AESIs (regardless of concern that are believedcausality) occurring to be 
related to priora patient after the treatment withof that patient has ended 
should be reported to the Sponsor if the investigator becomes aware of them. 
The investigator is not required to actively monitor patients after the study 
drughas ended (see Section 5.6). 
5.3.5  
PROCEDURES FOR RECORDING ADVERSE EVENTS 
5.3.5.1  
Diagnosis Vversus Signs and Symptoms 
Infusion-Rrelated 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-related reaction. However, a diagnosis has to be captured 
as an AE if signs and symptoms constitute a diagnosis of allergic 
reaction/hypersensitivity or infusion-related reaction and are classified as 
SAEs; all such symptoms have to be described in the narrative (e.g., in the 
Additional Case Details field of the eCRF). 
5.6  
 
POST-STUDY ADVERSE EVENTS 
At the last scheduledstudy completion/early termination visit, the investigator 
should instruct each patient to report to the investigator any subsequent AEs 
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that the patient’s personal physician believes could be related or not related to 
prior studythe drug treatmentunder observation. 
The investigator should notify the Sponsor of any death, SAE or other AE of 
concernAESI occurring at any time after a patient has discontinued study 
participation if the event is believed to be related to prior study drug treatment 
or study procedures. The Sponsor should also be notified if the investigator 
becomes aware of the development of cancer or a congenital anomaly/birth 
defect in a subsequently conceived offspring of a patient that participated in 
this study. 
The investigator does not need to actively monitor patients for AEs once the 
trial has ended. The investigator should report these events to the Sponsor 
Safety Risk Management on the AE eCRF. If the AE eCRF is no longer 
available, the investigator should report the event directly to 
Roche/Genentech Safety Risk Management via telephone or via phone at +1
888 835 2555facsimile using the Roche Clinical Trial (SAE) Reporting Form. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW 
BOARDS, AND ETHICS COMMITTEES 
The Steering CommitteeiDMC will closely monitor the incidence of these 
expected events during the study. An aggregate report of any clinically 
relevant imbalances that do not favor the test product will be submitted to 
health authorities. 
6. 
 STATISTICAL CONSIDERATIONS AND ANALYSIS 
PLAN 
Phase  I: mBC Patients with mBC: 
Enrollment into Cohort  1, patients with HER2-positive mBC patients, will 
open first. 
Enrolled patients will receive study drug until Investigator assessed disease 
progression, unacceptable toxicities, patient consent withdrawal, death, 
reasons deemed by the treating physician or study termination by the Sponsor. 
Phase II: Exploration of Efficacy: mBC Patients 
Phase II will include only Cohort 1, i.e. mBC patients. Patients in Cohort 1, 
who achieved MTD level will continue with the Phase II part to be 
assessed for efficacy and safety. Additional patients will be enrolled in this 
phase in order to achieve the required sample size for this part of the 
study. 
Enrolled patients will receive study drug until Investigator-assessed disease 
progression, unacceptable toxicities, patient consent withdrawal, death, 
reasons deemed by the treating physician, or study termination by the 
Sponsor. 
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Randomized Phase II: Exploration of Efficacy and Safety in mBC Patients 
randomized in Phase II will receive study drug until Investigator-assessed 
disease progression, unacceptable toxicities, patient consent withdrawal, 
death, reasons deemed by the treating physician, or study termination by the 
Sponsor. 
The final analysis of Randomized Phase  II part of this study for ORR will be 
performed at the end of studyEOS (defined in Section 3.2). 
Phase  I: Patients with mGC Patients: 
Once MTD is established for Cohort  1, enrollment of patients with HER2-
positive and locally advanced or mGC patients into Cohort  2 will be opened. 
Enrolled patients will receive study drug until Investigator-assessed disease 
progression, unacceptable toxicities, patient consent withdrawal, death, 
reasons deemed by the treating physician, or study termination by the 
Sponsor. 
6.1  
 
DETERMINATION OF SAMPLE SIZE 
Sample Size for Phase  I: mBC 
This part will be based on a classical 3 byplus 3 Phase  I design. From 3A 
minimum of 6 and up to 18 patients mightwill be enrolled into Cohort  1. 
There is no formal sample size estimation for this part. 
Sample Size for Randomized Phase  II: Exploration of Efficacy:  and 
Safety in mBC 
Assuming a preferable BORR rate of 75% to 80% in Cohort 1 (mBC patients) 
and aiming for a precision of 8 10%, lower limit of 95% confidence interval of 
at least 65%, a total of 100 patients would need to be evaluable for Cohort 1. 
Approximately 117 patients (78 patients in the combination of T-DM1 and 
capecitabine respective 39 patients in TDM1 treatment group), including a 
10% withdrawal rate, will be randomized with a 2:1 ratio to the combination of 
T-DM1 and capecitabine or T-DM1.  
Point estimates and 95% Clopper-Pearson exact CIs are tabulated for a range 
of possible BOR outcomes for both treatment groups in Table 8. 
Table 8 Sample Size Based on BOR  
Total number of patients is 100 (Phase II) 
Number of Patients/ 
Response 
95% Clopper Pearson 
Confidence Intervals 
75 patients (75%) 
65 83% 
80 patients (80%) 
71 87% 
Total number of patients adjusted for 10% withdrawal rate is 
110 patients 
 
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N (T-DM1 and capecitabine)* = 70 patients* 
BOR rate [%] 
95% CI (within the treatment group) [%] 
57.5 
 (45.1–69.2) 
60.0 
 (47.6–71.5) 
62.5 
 (50.1–73.8) 
65.0 
 (52.7–76.0) 
67.5 
 (55.2–78.2) 
 
N (T-DM1) = 35 patients* 
BOR rate [%] 
95% CI (within the treatment group) [%] 
37.0 
 (21.4–54.9) 
40.0 
 (23.9–57.9) 
43.0 
 (26.4–60.8) 
46.0 
 (29.1–63.6) 
49.0 
 (31.8–66.4) 
 
* N = Number of patients without adjustment for withdrawal; CI = confidence 
interval  
N (T-DM1 and capecitabine) / N (T-DM1) = 2 
 
For example, the observed BOR of 75% could be estimated to be within 65% 
and 83% with a probability of 95% (Clopper Pearson exact confidence 
intervals). Adjusting for a withdrawal rate of approximately 10%, 110 patients 
will be enrolled in this phase. Patients from the Phase I (Cohort 1), who 
received the same dose of study medication during Phase I as chosen dose 
during Phase II, will contribute to the sample size of 110 patients. 
The BOR rate of 75% was chosen based on previously published data for 
trastuzumab and capecitabine (Tjulandin et al. 2011). 
Expected BOR rate for patients who received trastuzumab emtansine of 
43.6% (95% CI: 38.6%–48.6%) was chosen based on previously published 
data for T-DM1 in patients with unresectable, locally advanced or mBC 
previously treated with a taxane and trastuzumab (EMILIA study; Verma et al. 
2012). 
The BOR rates for patients treated with the combination of T-DM1 and 
capecitabine were chosen based on recent results from other combination 
studies of T-DM1 plus chemotherapy or trastuzumab plus capecitabine. 
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Response rates were based on those observed in patients with HER2-positive 
mBC in a Phase Ib/IIa study (BP22752) that compared the combination of 
trastuzumab emtansine with docetaxel, with or without pertuzumab (ORR: 
76% [95% CI: 53%–92%]), and also in a Phase II study that compared the 
combination of trastuzumab with docetaxel, with or without capecitabine 
(ORRs: 72.7% [95% CI: 63.4%–80.8%] and 70.5% [95% CI: 61.2%–78.8%]; 
Wardley et al., 2010). 
Increased BOR rates for the combination treatment compared with 
single-agent trastuzumab emtansine are in line with previously published 
results of a randomized Phase III study in patients with locally advanced or 
mBC treated with the combination of trastuzumab with capecitabine versus 
capecitabine alone (ORR: 48.1% versus 27.0%, odds ratio = 2.50, p = 0.0115; 
von Minckwitz et al., 2009). 
The precision for the BOR estimate of the combination of T-DM1 and 
capecitabine is approximately 12%, e.g. BOR of 60%, 95% CI of (47.6%, 
71.5%). Due to the lower sample size of the treatment group T-DM1, the 
corresponding precision for the BOR estimate is increased to 18%, e.g. BOR 
of 46%, 95% CI of (29.1%, 63.6%). 
The 2:1 randomization ratio will be applied to allow more patients being 
exposed to the combination of T-DM1 and capecitabine and to enable a more 
thorough assessment of the corresponding safety profile. 
The estimation of sample size was performed by Nquery® and SAS® 
programs. 
Stratification Factors 
The following stratification factor will be implemented in the Randomized 
Phase II of the trial: 
 
Number of prior lines of treatment for metastatic disease (1 or >1; 
excluding single-agent hormones) 
A treatment line is any regimen given to patient from treatment initiation until 
confirmed disease progression. 
Sample Size for Phase  I: mGC 
This part will be based on a classical 3 byplus 3 Phase  I design. From 3 to 
1812 patients might be enrolled into Cohort  2. There is no formal sample 
size estimation for this part. 
6.2  
 
SUMMARIES OF CONDUCT OF STUDY 
Phase  I: mBC Patients with mBC 
Due to a small sample size, per-protocol (PP) population will not be defined 
for the Phase I, Cohort 1, however major protocol violations will be 
summarized for this phase.  
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Major protocol violations will be summarized by treatment dosage. A median 
follow-up will be estimated for Phase I, Cohort 1. 
Randomized Phase  II: Exploration of Efficacy: and Safety in mBC 
Patients 
For the Randomized Phase  II, Cohort 1, part of the study, a PP population 
will be defined (Section 6.4).  
Patient enrollment, duration of follow-up, discontinuation from study treatment 
and study, and reasons for discontinuation will be summarized by treatment 
group for all randomized patients. In addition, major protocol violations will be 
summarized by treatment arm. 
Phase  I: Patients with mGC Patients 
Due to a small sample size, a PP population will not be defined for the 
Phase  I, Cohort 2, however major protocol violations will be summarized for 
this phase.  
Major protocol violations will be summarized by treatment dosage. A median 
follow-up will be estimated for Phase I, Cohort 2. 
6.3 
 SUMMARIES OF TREATMENT GROUP 
COMPARABILITY 
Phase  I: mBC 
As Phase  I is the Dose Finding part of the study, there are no treatment 
group comparisons for this part of the study. 
Demographics, medical history, and baseline characteristics will be 
summarized. Continuous variablevariables will be summarized by means of 
median, mean, standard deviation, 25th and 75th percentiles and range while 
categorical variables – by the number and percentage of patients infor each 
categorytreatment dosage. 
Randomized Phase  II: Exploration of Efficacy and Safety in mBC  
The Randomized Phase II includes only Cohort 1, hence treatment 
comparability is also not applicable for this part of the study is designed to 
explore the efficacy and safety of the combination of T-DM1 and capecitabine 
compared with T-DM1. 
Demographics, medical history, and baseline characteristics will be 
summarized. Continuous variablevariables will be summarized by means of 
median, mean, standard deviation, 25th and 75th percentiles and range while 
categorical variables – by the number and percentage of patients infor each 
categorytreatment group. 
Phase  I: mGC 
As Phase  I is the Dose Finding part of the study, there are no treatment 
group comparisons for this part of the study.  
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Demographics, medical history and baseline characteristics will be 
summarized. Continuous variablevariables will be summarized by means of 
median, mean, standard deviation, 25th and 75th percentiles and range while 
categorical variables – by the number and percentage of patients infor each 
categorytreatment dosage. 
6.4  
 
EFFICACY ANALYSES 
Phase  I, Cohort 1: mBC 
The main analysis population will be the safety population including all 
patients who received at least one dose of study medication (trastuzumab 
emtansine and capecitabine).DLT evaluable population as defined in Section 
6.5. 
Randomized Phase  II: Exploration of Efficacy: in mBC  
The main analysis population for the efficacy analysis will be the intent-to-treat 
population (ITT) including), which will include all new patients enrolled in the 
Randomized Phase  II and patients from Cohort 1 who achieved the MTD 
levelpart of the study. The PP population will include all ITT patients who have 
at least one post-baseline tumor assessment during the Phase  II and no 
major protocol violations, which will be defined in the statistical analysis plan. 
(SAP). 
Phase  I, Cohort 2: mGC 
The main analysis population will be the safety population including all 
patients who received at least one dose of study medication (trastuzumab 
emtansine and capecitabine).DLT evaluable population as defined in Section 
6.5. 
6.4.1  
PRIMARY EFFICACY ENDPOINT 
Phase  I: mBC, Cohort 1: Patients with mBC  
The primary objectives are reaching the MTD and establishing a safety profile. 
The number and the proportion of patients with DLTs will be used as the 
primary measure for the MTD determination. 
ORR, as a main efficacy endpoint, will be assessed via BORRBOR rate. The 
BOR is defined as the best response recorded from the date when the MTD is 
achievedof enrollment until disease progression/recurrence (or, death)., 
withdrawal of consent or EOS, whichever occurs first. The number of patients 
is very small in this part of the study. Therefore, all analyses will be 
descriptive. 
Randomized Phase  II: Exploration of Efficacy: in mBC Patients 
The primary efficacy endpoint for the Randomized Phase  II part of the study 
is the BORORR as assessed by investigatorsvia BOR. The BOR is defined as 
the best response recorded from the start of this or randomization into the 
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Phase II II part of the study and until disease progression/recurrence (or, 
death) or for patients who were involved in Phase I of the study: the best 
response from the date, withdrawal of the MTD reached until disease 
progression/recurrence or death.consent or EOS, whichever occurs first. 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 28 days 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). 
The emphasis of the exploratory Randomized Phase II part of the study will 
not be formal statistical hypothesis testing but the estimation of: 
 
The BOR rate with corresponding 95% CIs for each treatment group. The 
justification of the sample size is based on considerations regarding the 
width of 95% CIs for each treatment group estimate (precision of the 
corresponding estimate). 
 
The treatment effect (between treatment groups comparison) with 
corresponding 95% CIs.  
The number and proportions of responders and non-responders (based on 
BOR) together with two sided, 95% Clopper-Pearson confidence intervalsCIs 
will be presented. for each treatment group.  
The difference in BOR between treatment groups will be displayed with 
associated 95% CIs using the Hauck-Anderson approach.  
Logistic analysis will be used to assess the influence of the stratification factor 
and baseline covariates in an exploratory manner. 
Phase  I: mGC, Cohort 2: Patients with mGC 
The primary objectives are reaching the MTD and establishing a safety profile. 
The number and the proportion of patients with DLTs will be used as the 
primary measure for the MTD determination. 
ORR, as a main efficacy endpoint, will be assessed via BORRBOR rate. The 
BOR is defined as the best response recorded from the date when the MTD is 
achievedof enrollment until disease progression/recurrence (or, death)., 
withdrawal of consent or EOS, whichever occurs first. The number of patients 
is very small in this part of the study. Therefore, all analyses will be 
descriptive. 
6.4.2  
SECONDARY EFFICACY ENDPOINTS 
Phase  I, Cohort 1: mBC 
Due to the small number of patients and the design of this part of the study, 
no secondary efficacy endpoints will be investigated. 
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Randomized Phase  II: Exploration of Efficacy: in mBC  
The secondary efficacy endpoints for the Randomized Phase  II will be: 
 
Time to response (TTR) 
 
Duration of response (DoR) 
 
Time to progression (TTP) 
 
Time to treatment failure (TTF) 
 
Progression free survival (PFS) 
 
Clinical benefit rate (CBR) 
 
Overall survival (OS) 
 
TTR is defined as the time from enrollmentrandomization to first 
documentation of confirmed PR or CR (whichever occurs first). Patients who 
do not have a confirmed response will be censored at the date of the last 
tumor assessment. 
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 below. Only patients with 
BOR of CR or PR (i.e.., responders) will be included in the analysis of DoR. 
For patients with a BOR of CR or PR, TTR is defined as the time from the 
date of enrollment into Cohort 1randomization to the date of first CR or PR. 
The censoring rules will be similar to those of the PFS. 
TTP is defined as time from enrollment into Cohort 1randomization to the first 
occurrence of PD. Patients who have not progressed at the time of study 
completion (including patients who have died before PD) or who are lost to 
follow-up are censored at the date of the last tumor assessment. 
TTF is defined as time from enrollment into Cohort 1randomization until TTF, 
for example,treatment failure, e.g., to disease progression, death, withdrawal 
due to AE or lablaboratory abnormality, or refusal of treatment. Patients who 
do not experience any of the above events while on study will be censored on 
the day of their last tumor assessment. For patients who were already in 
Phase I, the start date will be date of first study medication that was chosen 
for Phase II.  
PFS is defined as the time from enrolment into Cohort 1randomization until 
the first documented progression of disease or death from any cause, 
whichever occurs first. For patients who were already enrolled in Cohort 1 
during Phase 1, the time to PFS will be defined from the start date of study 
medication that was chosen for Phase II. 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 at the time of Phase  II will be 
censored at the time of enrolmentenrollment plus 1 day. 
Clinical benefit response includes patients whose best (confirmed) response 
was PR or CR or stable disease that lasts at least 6 months. 
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 OS is defined as the time from the date of enrollment into Cohort 
1randomization until the date of death, regardless of the cause of death. For 
patients who were already in Phase I, same rule as for PFS will be applied. 
Patients who were alive at the time of the analysis will be censored at the date 
of the last follow-up assessment.  
Estimates for the survivor function of both treatment groups for the time to
event variable such as TTR, DoR, TTP, TTF, PFS, and OS, will be obtained 
by using the Kaplan-Meier approachmethod. HRs and associated 95% CIs 
will be estimated from non-stratified and stratified (based on the stratification 
factor) Cox regression models. 
Clinical benefit response includes patients whose best (confirmed) response 
was PR, CR or SD that lasted at least 6 months. CBR will be summarized in a 
similar way to the primary efficacy endpoint, ORR as assessed by BOR.  
Phase  I, Cohort 2: mGC 
Due to the small number of patients and the design of this part of the study, 
no secondary efficacy endpoints will be investigated. 
6.5  
 
SAFETY ANALYSES 
Safety Population Phase  I, Cohort 1: mBC 
The DLT evaluable population is defined for all enrolled and treated patients 
who have not experienced any major protocol violation (including violation of 
the inclusion and exclusion criteria) and completed Cycle 1.  
The number and the proportion of patients with DLTs will be used as the 
primary measure for the MTD determination. The definition of DLTs is 
presented in Section 5.1.4. DLTs for this part of the study will be summarized 
by treatment dose. 
The safety population (SP) Phase I, mBC will include all patients who 
received at least one dose of study medication during Phase I. Safety 
endpoints will be summarized for this part of the study and presentedby 
treatment dosage. 
Safety parameters will be analysedanalyzed in a similar way to safety 
parameters in Phase  I, Cohort 2: mGC. 
Randomized Phase  II: Exploration of Efficacy:Safety in mBC  
The SP Phase II, mBC will include all patients who received at least one dose 
of study medication during the Randomized Phase II part of the study. Safety 
endpoints will be summarized for this part of the study and presented.by 
treatment group.   
Safety endpoints during Phase  II will be assessed via: total AEs, AEs 
Grade ≥ 3, SAEs, AESIs (as described in Section 5), premature withdrawal 
from study and study medication, laboratory parameters, LVEF, exposure to 
study medication, concomitant medications, vital signs, ECOG performance 
status, and physical examination. 
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The incidence of AEs and SAEs 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 any AESI 
described in Section 5 will also be summarized via Kaplan-Meier estimates. 
Additional summaries by frequency tables will also be provided for the AESIs. 
Patients who died will be listed together with the cause of death. 
Laboratory parameters, hematology and biochemistry, will be presented in 
shift tables of NCI-CTC grade at baseline versus worst grade during treatment 
for Cohort 1,the Randomized Phase  II and overallpart of the study. 
LVEF will be summarized over time by means of mean, median and range 
(minimum and maximum) and will be presented graphically. Vital signs will be 
analyzed in a similar way. 
Other safety variables, such as exposure to study medication, concomitant 
medications and physical examinations, will be analyzed in a similar way. The 
exposure of study medication will be summarized by frequency tables. 
ECOG performance status will be summarized over time and the percentage 
of patients in different categories will be presented by bar charts at different 
time points. 
Safety Population Phase  I, Cohort 2: mGC 
The DLT evaluable population is defined for all enrolled and treated patients 
who have not experienced any major protocol violation (including violation of 
the inclusion and exclusion criteria) and have completed Cycle 1.  
The number and the proportion of patients with DLTs will be used as the 
primary measure for the MTD determination. The definition of DLTs is 
presented in Section 5.1.4. DLTs for this part of the study will be summarized 
by treatment dose. 
The SP Phase I, mGC will include all patients who received at least one dose 
of study medication during Phase I. Safety endpoints will be summarized for 
this part of the study and presentedby treatment dosage. 
Safety parameters for this part of the study will be summarized by treatment 
dose. The summaries of AEs, SAEs, AEs that causecaused discontinuation 
from the study treatment, and AESIs will be analyzed in a similar way to AEs 
in Phase  II. 
The incidence of AEs and SAEs will be summarized according to the primary 
system organ class (SOC) and, within each SOC, by MedDRA preferred term. 
Based on the safety profile of trastuzumab emtansine time to onset of the first 
episode of any AESI described in Section 5 will also be summarized via 
Kaplan-Meier estimates. Additional summaries by frequency tables will also 
be provided for the AESIs. Patients who died will be listed together with the 
cause of death. 
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Laboratory parameters, hematology and biochemistry, will be presented in 
shift tables of NCI-CTC grade at baseline versus worst grade during treatment 
for Phase I, Cohort  2, Phase I and overall. 
LVEF will be summarized over time by means of mean, median and range 
(minimum and maximum) and will be presented graphically. Vital signs will be 
analyzed in a similar way. 
Other safety variables, such as exposure to study medication, concomitant 
medications and physical examinations will be analyzed in a similar way. The 
exposure of study medication will be summarized by frequency tables. 
ECOG performance status will be summarized over time and the percentage 
of patients in different categories will be presented by bar charts at different 
time points. 
6.6  
 
PHARMACODYNAMIC ANALYSES 
No pharmacodynamic analyses are planned for this study. 
6.7  
 
PHARMACOKINETIC ANALYSES 
For Phase  I only (Patients with mBC and mGC Patients): 
The following PK parameters of trastuzumab emtansine and capecitabine 
(including but not limited to thesethose listed below) will be determined only in 
the Phase  I part of the study for Cohort  1 and Cohort  2 in all patients who 
receive study treatment using either non-compartmental and/or population 
methods, if data allow: 
 
Serum concentrations of trastuzumab emtansine (conjugate) and total 
trastuzumab 
 
Plasma concentrations of DM1, capecitabine and its active metabolite 5
fluorouracil ( 
5-FU) 
 
Total exposure (e.g., AUC)  
 
Cmax 
 
Clearance (CL) 
 
Volume of distribution (Vd) 
 
Terminal half life (Vd 
 
T1/2) 
The pharmacokineticsPK of trastuzumab emtansine, total trastuzumab and 
DM1 will be compared with historical single -agent PK data to evaluate the 
potential effect of capecitabine on the PK of trastuzumab emtansine and 
related analytes. The PK of capecitabine and its active metabolite 5-FU in 
cycleCycle 1 (in the absence of trastuzumab emtansine) will be compared 
with the PK of cycleCycle 2 (in the presence of trastuzumab emtansine) to 
evaluate the potential effect of trastuzumab emtansine on the PK of 
capecitabine and 5-FU. 
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All PK parameters will be listed and tabulated by treatment dose and by 
Cohort. Descriptive summary statistics including arithmetic mean, geometric 
mean (e.g.., AUC and Cmax), median, range, SDs.d., and coefficient of 
variation will be presented for each cohort. Nonlinear mixed effects modeling 
will be also used but details will be presented in the statistical analysis 
planSAP. 
PK samples can be obtained ad hoc in case of SAE or unexpected toxicities 
which may suggest a potential drug-drug interaction. 
6.8  
 
EXPLORATORY ANALYSES 
For all patients a retrospective central confirmation of the HER2 status will be 
done. Further exploratory analysis for HER2-positive patients– (based on 
central confirmation) will be done for selected endpoints such as BOR and 
safety endpoints (AEs, SAEs, AEs with Grade ≥ 3 and AESIs). 
For the Randomized Phase  II: Exploration of Efficacy and Safety in 
mBC Patients with mBC only: 
Subgroup analysis for BOR, safety endpoints (AEs, SAEs and AE, AEs with 
Grade ≥ 3 and AESIs) in Phase II will be presented for: elderly versus 
younger patients, and patients with ECOG 0–1 versus ECOG 2. More details 
about subgroups will be provideded in the statistical analysis plan.  
More details about subgroups will be provided in the SAP. 
Pharmacoeconomic Endpoint: 
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. 
6.9  
 
INTERIM ANALYSES 
There is no formal efficacy interim analysis.  
However, an IDMC will advise whether the Randomized Phase II part of the 
study can commence. The IDMC will also monitor safety outcomes after 20 
and 60 patients have received at least 3 cycles (Cycle 3 Day 1) of treatment in 
the Randomized Phase II part of the study. Afterwards, the IDMC will monitor 
accumulating patient safety data every 6 months during the course of the 
Randomized Phase II of the study or as requested. 
Efficacy data will only be provided if required by the IDMC to estimate the risk-
benefit balance for the patients. Further details on the function and logistics of 
the IDMC will be provided in the IDMC Charter. 
The design of this study includes: Phase  I, Randomized Phase  II and 
different cohorts. Corresponding analyses as described in the protocol will be 
performed when all data for particular cohort and study phase are collected 
and cleaned. 
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9. 
 STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.3  
 
ADMINISTRATIVE STRUCTURE 
The study will have a Steering CommitteeSC, iDMC, central laboratory, IxRS, 
eCRF, and will be conducted by a contract research organization (CRO) 
together with the Sponsor. 
10.  
 
REFERENCES 
31. Sawaki A, Ohashi Y, Omuro Y, et al. Efficacy of trastuzumab in Japanese 
patients with HER2-positive advanced gastric or gastroesophageal 
junction cancer: a subgroup analysis of the Trastuzumab for Gastric 
Cancer (ToGA) study. Gastric Cancer 2011; epub ahead of print. DOI: 
10.1007/s10120 011 0118 12012; 15:313–22. 
{…} 
40. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-
positive advanced breast cancer. N Engl J Med 2012; 367:1783–91. 
{…} 
44. Wardley A, Anton-Torres A, Pivot X, et al. Trastuzumab plus docetaxel 
with or without capecitabine in patients with HER2-positive 
advanced/metastatic breast cancer: first efficacy results from the 
Phase  II MO16419 (CHAT) Study. SABCS 2006; Abstract# 2063. 
45. Wardley A, Pivot X, Morales-Vasquez F, et al. Randomized phase II trial 
of first-line trastuzumab plus docetaxel and capecitabine compared with 
trastuzumab plus docetaxel in HER2-positive metastatic breast cancer. J 
Clin Oncol. 2010; 28:976-83. 
46. World Health Organization, World Health Statistics 2011.; 
http://www.who.int/whosis/whostat/2011/en/  
 
 
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Appendix 1  
Schedule of Assessments 
Table 1 
Schedule of assessments for mBC patients (Phase  I and II, Cohort 1 1 and Randomized Phase II) 
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 
onwardsOnwards 
Safety 
Follow-Up 
Visit 
Safety  
Follow-Up2 
Day 
-28 to -1 
1 
8 
15 
1 
8 
15 
1 
8 
15 
28-42 days 
after last 
dose 
every 3-6 
months 
Informed Consent 
Xa 
 
 
 
 
 
 
 
 
 
 
 
HER2 Status  
Xb 
 
 
 
 
 
 
 
 
 
 
 
Medical History and Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination  
X 
 
 
 
 
 
 
 
 
 
 
 
Limited Physical Examinationc 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Height and Weightd 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Vital Signse 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
ECOG Performance Status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Concomitant Medication Reporting 
Xf 
X 
Ongoing 
 
Adverse EventAE Reporting 
Xg 
Ongoing 
X 
  Xh 
12-lead ECG  
X  
 
 
 
 
 
 
 
 
 
 
 
ECHO/MUGAi 
Xi 
 
 
Xi   
 
 
Xi 
 
 
Xi 
Xi   
 
Tumor Assessmentsj 
X 
At cycleCycle 3 (9 weeks after C1 D1randomization), and then every 4th cycle (12 
weeks there afterthereafter, regardless of dose delay or early discontinuation, until 
disease progression or study termination) 
X 
X 
Brain CT or MRIk 
X 
At the discretion of the investigator, if clinically indicated, until disease progression 
Bone Scan/Imagingl 
X 
As clinically indicated 
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Appendix 1  
Schedule of Assessments (cont.) 
 
Table 1  
Schedule of assessments for mBC patients (Phase I, Cohort 1 and Randomized Phase II) (cont.) 
 
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 
onwardsOnwards 
Safety 
Follow-Up 
Visit 
Safety 
Follow-Up2  
Day 
-28 to -1 
1  
8 
15 
1  
8 
15 
1  
8 
15 
28-42 days 
after last 
dose 
every 3-6 
months 
Hematologym 
X  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
 
 
X 
 
Biochemistryo 
X  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
 
 
X 
 
Urinalysisp 
X  
As clinically indicated 
X 
 
INR/aPTT 
X  
As clinically indicated, e.g. for patients receiving anticoagulation therapy 
X 
 
Pregnancy Testq 
X  
 
 
 
 
 
X q 
 
 
X q 
X  
X 
PK/PD Samples (see Appendix 2)r 
 
Xr 
 
 
Xr 
 
 
 
 
 
 
 
Assessment of Patient 
Hospitalizations and/or Hospital 
Visits 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Administration of trastuzumab 
emtansineTrastuzumab Emtansine 
 
D 2s 
 
 
D 1s 
 
 
D 1s 
 
 
 
 
Administration of 
capecitabineCapecitabine 
 
D 1–14 
 
D 1–14 
 
D 1–14 
 
 
 
Overall survivalSurvival 
X 
X 
X 
X 
Randomization into the Phase II 
Part of the Study 
Xt 
 
 
 
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Appendix 1  
Schedule of Assessments (cont.) 
 
AE = Adverse Event; aPTT = Activated Partial Thromboplastin Time; CT = Computed Tomography; ECHO = Echocardiogram; ECOG = Eastern Cooperative 
Oncology Group; D= Day; 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, INR and aPTT assessments) at Screening: to be performed within 14 days prior to first 
treatment. Screening laboratory assessments may be done on the same day of first study treatment (Cycle1 Day1). 
2. All patients will be followed -up every 6 months (except for pregnancy every, which is at 3 and 6 months) after safety follow-up visit until disease 
progressionprogresses for tumor assessment or study closure, whichever occurs first. Patients who discontinue study treatment for reasons other than 
disease progression will continue to undergo tumor assessments every 3–6 months. 
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. Patients who are on the MTD dose established in Cohort 1 must re consent to 
be enrolled into Phase II.  
b) HER2-positivity is defined as IHC 3+ or gene amplification by ISH. It will be performed locally for mBC patients with mBC.  
c) Limited symptom-directed physical examination. 
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. 
g) During screening, only SAEs considered related to protocol-mandated procedures will be collected. 
h) Patients will be followed for new or worsening AEs for 28 days following the last infusion of study drug or until the early termination visit, until treatment-
related AEs resolve or stabilize, or until the initiation of another anti-cancer therapy, whichever occurs first. After 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 
15-21 of 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. 
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Appendix 1  
Schedule of Assessments (cont.) 
 
j) Tumor assessments (± 5 business days), including a CT or MRI with contrast of the chest, abdomen, and pelvis should be performed according to the 
indicated schedule. 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, e.g. the same contrast protocol for 
CT scans. For patients who discontinue study treatment for reasons other than disease progressionPD, continued tumor assessments according to the 
protocol schedule of assessments is requiredevery 3–6 months. 
a) 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 04.5.1.4 of the protocol and in Error! Reference source not found.. A brain MRI or CT should be performed along with regularly 
scheduled tumor assessments in these instances. 
k) 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. Appendix 3. 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 study treatment, non-isotopic radiographic modalities should be utilized to document the extent of bony 
metastatic disease. Refer to Appendix 4 in the protocol 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) Assessments should be performed at screening, on Day 1, 8 and 15 of Cycles 1–3, on Day 1 of all subsequent cycles, and weekly following any 
hematologic AE. If capecitabine is discontinued due to toxicity, assessments should be performed weekly (minimum) until resolution of the AE (Grade  1/ 
baseline), and on Day 1 of subsequent cycles thereafter. All assessments should 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, blood urea nitrogen (BUN)/urea,), creatinine, uric acid, 
total protein, albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), G-GT, LDH, total bilirubin (and direct bilirubin where total bilirubin > ULN). 
p) Includes specific gravity, pH, protein, glucose, blood, ketones and bilirubin. 
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Appendix 1  
Schedule of Assessments (cont.) 
 
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. 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 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. 
r) Pharmacokinetic assessments will be performed during the dose finding periodDose Finding part of the study only (see Appendix 2). 
s) Trastuzumab emtansine will be administered on Day 1 of each 3 -weekly cycle for all mBC patients with mBC in Cohort  1 and Randomized Phase  II 
period of the study except in the first cycle where trastzumabtrastuzumab emtansine will be given on DAYDay 2 (to allow PK sampling). 
t) Patients will be randomized only in the Randomized Phase II part of the study. No blinding will be used, as this is an open-label study. A 2:1 randomization 
ratio will be applied to allow more patients to be exposed to the combination of T-DM1 and capecitabine, and to enable a more thorough assessment of the 
corresponding safety profile. 
 
 
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Appendix 6  
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 
 
– http://www.ecog.org/general/perf_stat.html 
 
 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
PHASE I STUDY OF THE COMBINATION OF 
TRASTUZUMAB EMTANSINE (T-DM1) AND 
CAPECITABINE FOLLOWED BY A RANDOMIZED, 
OPEN-LABEL PHASE II STUDY OF T-DM1 AND 
CAPECITABINE VERSUS T-DM1 ALONE IN HER2-
POSITIVE METASTATIC BREAST CANCER AND 
HER2-POSITIVE LOCALLY ADVANCED OR 
METASTATIC GASTRIC CANCER PATIENTS 
PROTOCOL NUMBER: MO28230 
EUDRACT NUMBER: 
2012-001547-46 
IND NUMBER 
To be determined 
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 the signed original of this form {as instructed by XX [e.g., your 
local study monitor, the CRO]} [or] {to the contact provided below}. Please retain 
a copy for your study files. 
{Name}  
{Address} 
 
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PROTOCOL AMENDMENT, VERSION 3 
RATIONALE 
At the request of the Independent Data Monitoring Committee (IDMC), the design 
of the trial has been changed to increase the sample size for the randomised 
Part II Exploration of Efficacy and Safety in metastatic breast cancer (mBC) to 
provide a more meaningful estimation of efficacy. Following identification of the 
MTD in Phase I, Cohort 1 in mBC (capecitabine 700 mg/m2 bid days 1–14 every 
3 weeks [q3w]) in combination with trastuzumab emtansine [T-DM1] 3.6 mg/kg 
q3w), and the subsequent IDMC recommendation of this Dose Level, the 
protocol has also been simplified to show this information and remove sections 
describing Phase I dose de-escalation in the mBC part that are no longer 
relevant.  
Additional information relating to weekly dosing of trastuzumab emtansine in 
locally recurrent/metastatic gastric cancer has become available from the 
ongoing adaptive phase II/III GATSBY trial. In October 2013, the IDMC 
recommended the weekly trastuzumab emtansine regimen in preference to the 
q3w regimen for further evaluation in the phase III part of the trial.  
Further minor changes to the protocol have been made according to the latest 
clinical information and current recommendations. Specifically, the advice on 
contraception has been updated in line with the latest Herceptin investigators’ 
brochure. The change in contraception period from 6 to 7 months following the 
last dose of Herceptin treatment was based on a re-assessment of the half-life of 
Herceptin across multiple clinical trials and taking a more conservative estimated 
half-life (up to 38 days). Based on a half-life of up to 38 days, it is expected that 
Herceptin will have cleared from the blood by 7 months. The extension of the 
contraception period from 6 to 7 months following the last dose of Herceptin 
treatment has been implemented in the Herceptin Investigator Brochure, v.14 
and the Herceptin prescribing information. As trastuzumab is a component of 
trastuzumab emtansine, it is now advised that patients of child-bearing potential 
should also use effective contraception for at least 7 months after their last 
trastuzumab emtansine treatment, and that nursing mothers should wait before 
beginning breastfeeding for at least 7 months following treatment. This update is 
not based on any safety findings, and the benefit-risk assessments for both 
trastuzumab and trastuzumab emtansine are unchanged.  
 
Additional minor changes have been made to improve clarity and consistency. 
Deleted text appears in black strikethrough. Substantive new information is 
marked with yellow highlighting. This amendment represents cumulative changes 
to the original protocol. 
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PROTOCOL AMENDMENT, VERSION 3 
SUMMARY OF CHANGES 
STUDY TITLE 
PHASE I STUDY OF THE COMBINATION OF TRASTUZUMAB EMTANSINE 
(T-DM1) AND CAPECITABINE IN HER2-POSITIVE METASTATIC BREAST 
CANCER AND HER2-POSITIVE LOCALLY ADVANCED OR /METASTATIC 
GASTRIC CANCER PATIENTS, FOLLOWED BY A RANDOMIZED, OPEN-
LABEL PHASE II STUDY OF T DM1TRASTUZUMAB EMTANSINE AND 
CAPECITABINE VERSUS T DM1TRASTUZUMAB EMTANSINE ALONE IN 
HER2-POSITIVE METASTATIC BREAST CANCER 
SYNOPSIS 
Study Design 
 
{…} 
 
Phase I: MTD Finding, Cohort 1: mBC 
Cohort 1 used will open first with a 3 plus 3 classical design to determine the MTD of 
capecitabine in combination with trastuzumab emtansine. Initially the study had a dose 
escalation design, but following the occurrence of two DLTs at Dose Level 1 (750 
mg/m2 capecitabine bid + 3.6 mg/kg q3w trastuzumab emtansine, the study design was 
adapted and the dose de-escalated to 700 mg/m2 capecitabine bid + 3.6 mg/kg q3w 
trastuzumab emtansine. At this Dose Level there were no DLTs and following review of 
the safety data, . Cohort 1 will enroll patients with HER2 positive mBC. The dose tested 
of trastuzumab emtansine remains fixed at 3.6 mg/kg every 3 weeks (q3w) and 3 dose 
levels of capecitabine administered twice daily (bid) on Days 1 to 14 in cycles of 3 
weeks will be tested. All patients will be treated until disease progression, intolerable 
toxicity, withdrawn consent, or death. All patients will be followed up until withdrawn 
consent, death, or up to a maximum of 2 years after the last patient was randomized in 
the Phase II part of the study, whichever occurs first. 
Dose Levels Explored in Phase I, Cohort 1  
Dose Level 1: 750 mg/m2 capecitabine bid + 3.6 mg/kg q3w trastuzumab emtansine 
Dose Level 1: 700 mg/m2 capecitabine bid + 3.6 mg/kg q3w trastuzumab emtansine 
Dose Level 2: 650 mg/m2 capecitabine bid + 3.6 mg/kg q3w trastuzumab emtansine 
The rules for determining the MTD are presented below.  
If Dose Level 1 is proved too toxic (dose limiting toxicity [DLT] > 1/3 or > 1/6), the dose 
will be de escalated to one dose level below (Dose Level 1) 
If Dose Level 1 is well tolerated (DLT ≤ 1/6), this dose will be considered the MTD and, 
following the the Independent Data Monitoring Committee (IDMC) 
agreementrecommended that the study should proceed to will be further explore this 
Dose Level further d in the Randomized Phase II part of the study. If Dose Level 1 is 
too toxic (DLT >1/6), the dose will be de escalated to Dose Level 2. 
If Dose Level 2 is well tolerated (DLT ≤ 1/6), this dose will be considered the MTD and, 
following iDMC approval, will be further explored in the Randomized Phase II part of the 
study. However, if Dose Level 2 is too toxic (DLT > 1/6), the combination may be 
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considered unfeasible, recruitment will be closed and neither the Randomized Phase II 
nor mGC cohort will be opened. Patients who, at that point, experience response as per 
RECIST v.1.1 will be offered the possibility to continue on trastuzumab emtansine as a 
single agent, or with the combination, based on risk benefit balance and agreement with 
the Steering Committee (SC).  
Randomized Phase II: Exploration of Efficacy and Safety in mBC 
Phase II will be conducted in mBC patients only. This part of the study will explore the 
efficacy and safety of the combination treatment of trastuzumab emtansine (T -DM1) 
and capecitabine, at 700 mg/m2 bid (the establishedrecommended MTD), compared 
with T DM1trastuzumab emtansine alone in mBC patients with mBC. 
Once the MTD in Cohort 1 is established,Approximately 210 additional 117patients with 
HER2-positive mBC patients will be randomized into the Phase II part of the study. 
Patients in the Phase I part of the study will not contribute to the Phase II part of the 
study; however, they will be followed up until end of study (EOS). 
Patients will be treated until disease progression/recurrence, intolerable toxicity, 
withdrawn consent, or death. If capecitabine needs to be discontinued for any reason, 
trastuzumab emtansine may continue, and the patient will be followed up until EOS. In 
case of discontinuation of trastuzumab emtansine, patients will be followed up until 
EOS. 
All patients will be followed up until withdrawn consent, death, or up to a maximum of 2 
years after the last patient was randomized in the Phase II part of the study, whichever 
occurs first. 
Phase I: MTD Finding, Cohort 2: LA/mGC 
Once the capecitabine MTD dose is established in Cohort 1, Cohort 2 will have open, 
with a 3 plus 3 classical design and to enroll patients with HER2-positive LA/mGC 
patients. Trastuzumab emtansine will be administered weekly at the dose of 2.4 mg/kg 
and capecitabine will start at the MTD dose defined in Cohort 1; capecitabine dose level 
may be de escalated. 
All patients will be treated until disease progression, intolerable toxicity, withdrawn 
consent, or death. All patients will be followed up until withdrawn consent, death, or up 
to a maximum of 2 years after the last patient was randomized in the Phase II part of 
the study, whichever occurs first.The dose levels for capecitabine will be the same as 
described in Cohort 1, except for Dose Level 1, which will not be explored in mGC 
patients. Guidelines for dose escalation and de escalation are as follows: Trastuzumab 
emtansine will be administered weekly at a dose of 2.4 mg/kg and capecitabine will start 
at dose level -1 (700 mg/m2, the MTD defined in Cohort 1), with de-escalation if required 
as follows:  
If the MTD established in Cohort 1 is defined at Dose Level 1: 
 
This will be the starting dose in Cohort 2. If Dose Level -1 is well tolerated (DLT in 
≤ 1/6 patients), this dose will be established as the MTD for LA/mGC  
 
De escalation: If Dose Level -1 is not tolerated in Cohort 2 (>(DLT in > 1/6 
DLTpatients), de-escalation will be to Dose Level -2.  
If the MTD established in Cohort 1 is defined at Dose Level -2: 
 
This will be the starting dose in Cohort 2. If Dose Level 2 is well tolerated 
(DLT ≤ 1/6), this dose will be established as the MTD for mGC  
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 
De escalation: if Dose Level 2 is not tolerated in Cohort 2 (> 1/6 DLT), is too toxic, 
the combination of capecitabine with trastuzumab emtansine 2.4 mg/kg every week 
willmay be considered not feasible for mGC and Cohort 2unfeasible in LA/mGC, 
recruitment will be terminated. Patients who, at that point, experience response as per 
RECIST v.1.1 will be offered the possibility to continue and the LA/mGC part will be 
closed. However, this will have no impact on trastuzumab emtansine as a single agent, 
or with the combination, based on risk benefit balance and agreement with the 
SCcontinuation of the Randomized Phase II mBC part. 
Duration of treatment and follow-up 
All patients will be treated until investigator-assessed disease progression, 
unacceptable toxicity, withdrawal of consent, death, reasons deemed by the treating 
physician, or study termination by the Sponsor. If toxicity is considered by the 
investigator to be related to only one of the two agents, the non-implicated agent can be 
continued as single-agent therapy.  
All patients will be followed up until withdrawal of consent, death, or for up to a 
maximum of 2 years after the last patient was randomized in the Phase II part of the 
study, whichever occurs first. 
 
Number of Patients 
 
{…} 
 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
Exploration of efficacy and safety in mBC will be based on 117approximately 210 
randomized patients in total. 
Phase I, Cohort 2: LA/mGC 
A total of 6 to 12 patients will be enrolled. 
Target Population 
Phase I, Cohort 1: mBC 
 
{…} 
Before entering the study, patients must have received at least one prior treatment 
regimen for early or metastatic disease, which includesd a chemotherapy agent and 
trastuzumab either separately or in combination. 
 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
{…} 
Retrospective central confirmation will be used to censor the efficacy population 
categorize patients for the Randomized Phase II part ofsubgroup analyses according to 
central HER2 testing. 
Before entering the study., patients must have received at least one prior treatment 
regimen, which includesd a chemotherapy agent and trastuzumab either separately or 
in combination. 
{…} 
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Inclusion Criteria: 
For mBC Patients: 
1. Male or female. 
{…} 
 
6. 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 or two effective forms of non-hormonal contraception and to 
continue its use for the duration of study treatment and for 67 months after the last 
dose of study treatment (see Section 5.2.4 in the protocol). 
{…} 
9.  Liver function: 
a)  Total bilirubin ≤ 1.5 × the upper limit of normal (ULN).) or direct bilirubin ≤ 1.5 
× ULN in patients with documented Gilbert’s syndrome.  
b) Serum glutamic oxaloacetic transaminase (SGOT)/aspartate transaminase 
(AST) and serum glutamic pyruvic transaminase (SGPT)/alanine transaminase 
(ALT) ≤ 2.5 × the ULN. 
c)  Alkaline phosphatase ≤ 2.5 × the ULN. In patients with hepatic and/or bone 
metastases: alkaline phosphatase ≤ 5 × the ULN. 
d)  Evidence of stable liver function during the month prior to enrollment with liver 
function tests’ (LFTs) fluctuations not exceeding 2.5 × ULN (for AST, ALT) and 
1.5 × ULN (for total bilirubin). Patients with bone metastases: AST and ALT 
≤ 5.0 x ULN. 
{…} 
12.  Life expectancy ≥12 weeks 
{…} 
15. Tumor block or 158 slides available for retrospective central confirmation of HER2-
positivity (central confirmation not necessary for enrollment).  
 
For LA/mGC Patients: 
1. Male or female 
{…} 
6. 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 or two effective forms of non-hormonal contraception and to 
continue its use for the duration of study treatment and for 67 months after the last 
dose of study treatment (see Section 5.2.4 in the protocol). 
{…} 
9. Liver function: 
a)  Total bilirubin ≤ 1.5 × ULN or direct bilirubin ≤ 1.5 × ULN in patients with 
documented Gilbert’s syndrome.  
b)  SGOT/AST and SGPT/ALT ≤ 2.5 × the ULN. 
c)  Alkaline phosphatase ≤ 2.5 × the ULN. In patients with hepatic and/or bone 
metastases: alkaline phosphatase ≤ 5 × the ULN. 
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d)  Evidence of stable liver function during the month prior to enrollment with LFTs 
fluctuations not exceeding 2.5 × ULN (for AST, ALT) and 1.5 × ULN (for total 
bilirubin). Patients with bone metastases: AST and ALT ≤ 5.0 x ULN. 
{…} 
12.  
Life expectancy ≥12 weeks 
{…} 
 
Exclusion Criteria: 
For mBC Patients: 
 
{…} 
5. Related capecitabine contraindications: 
a)  Treatment with sorivudine or its chemically-related analogues, such as 
brivudine. 
b) Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, 
or glucose-galactose malabsorption. 
c) Signs or symptoms suggesting that the patient has dihydropyrimidine 
dehydrogenase (DPD) deficiency. 
{…} 
23. No signs and symptoms suggestive that the patient has dihydropyrimidine 
dehydrogenase (DPD) deficiency. 
 
For LA/mGC Patients: 
 
{…} 
5. Related capecitabine contraindications: 
a)  Treatment with sorivudine or its chemically-related analogues, such as brivudine. 
b) Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, 
or glucose-galactose malabsorption. 
c) Signs or symptoms suggesting that the patient has dihydropyrimidine 
dehydrogenase (DPD) deficiency. 
{…} 
22. No signs and symptoms suggestive that the patient has dihydropyrimidine 
dehydrogenase (DPD) deficiency. 
 
Length of Study 
The duration of the study is estimated to be approximately 4 years. Recruitment is 
estimated to belast 2 years in total (1 year for DoseMTD Finding and, 1 year for the 
Phase II /Exploration of Efficacy and Safety. All patients in mBC).  
End of Study 
The study will be followed up until withdrawn consent, death or up to a maximum of 2 
yearsend after the follow-up period has been completed as defined above. Last patient 
was randomized in the Phase II part of the study, whichever occurs first. In case Dose 
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Level 2last visit (LPLV) is too toxic, the study may be terminated prematurely. Patients 
who, at thatdefined as the last data collection point, experience response as per 
RECIST v.1.1 will be offered the possibility to continue on trastuzumab emtansine as 
which can be either a clinic visit or a single agent, or with the combination, based on 
risk benefit balance and agreement with the SClaboratory sample. 
End of Study 
Last patient last visit (LPLV) as per definition is the last data collection point that can be 
either a clinic visit or a laboratory sample (see above length of study). 
In case Dose Level -2 is too toxic in LA/mGC, the LA/mGC cohort may be terminated 
prematurely. Patients who, at that point, experience response according to RECIST 
v.1.1 will be offered the possibility to continue on trastuzumab emtansine as a single 
agent or with capecitabine, based on the risk-benefit balance and agreement with the 
SC. 
Randomized Phase II Exploration of Efficacy and Safety in mBC: The primary analysis 
of best overall response (BOR) rate will be performed when 70% of the patients have 
experienced a PFS event or at the end of the trial, whichever occurs first. It is 
estimated that 70% of patients will have experienced a PFS event approximately 26 
months after randomization of the first patient. The EOS analysis (approximately 24 
months after the last patient is randomized) will include an updated analysis of BOR, 
which will be done in a purely exploratory manner.   
 
{…} 
 
Safety Outcome Measures 
 DLT assessment/determination of the MTD of capecitabine when combined with 
trastuzumab emtansine (Phase I only) 
 Incidence, nature, and severity by NCI CTCAE version 4v4.0 of adverse events 
(AEs), serious adverse events (SAEs), AEs that causeleading to discontinuation 
from either component of the study treatment, and AEs of special interest (AESIs) 
 Fatal casesAEs and their causes of death 
 Events to monitor 
 Laboratory parameters 
 LVEF 
 Treatment exposure 
 Physical examinations 
 Vital signs and ECOG performance status 
 Premature withdrawal from study medication and/or study 
 
{…} 
Statistical AnalysisMethods 
{…} 
There is no formal efficacy interim analysis. However, an independent data monitoring 
committee (IDMC) will advise whether the Randomized Phase II part of the study can 
commence. The IDMC will also monitor safety outcomes after 20 and 60 patients have 
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received at least 3 cycles of treatment (Cycle 3 Day 1) in the Randomized Phase II part 
of the study. Afterwards, the IDMC will monitor accumulating patient safety data every 
6 months during the Randomized Phase II of the study or as requested. 
Efficacy data will only be provided if required by the IDMC to estimate the risk benefit 
balance for the patients. Further details on the function and logistics of the IDMC will 
be provided in the IDMC Charter. 
Corresponding analyses as described in the protocol will be performed when all data 
forfrom both study phases are collected and cleaned. 
Randomized Phase II: The primary analysis of BOR will be performed when 70% of the 
patients have experienced a PFS event or at the end of the trial, whichever occurs first. 
It is estimated that 70% of patients will have experienced a PFS event approximately 
26 months after randomization of the first patient. The EOS analysis (approximately 24 
months after the last patient is randomized) will include an updated analysis of BOR, 
which will be done in a purely exploratory manner. 
 
{…} 
 
Randomized Phase II: Exploration of Efficacy in mBC  
The primary efficacy endpoint for the Phase II part of the study is the ORR, as 
assessed via the BOR. The rate. BOR is defined as the best response recorded from 
the start orbetween randomization into the Phase II part of the study and until disease 
progression or recurrence, death, withdrawal of consent, start of new anticancer 
treatment, or EOS, whichever occurs first. To be assigned a status of partial response 
(PR) or complete response (CR), i.e., to be a responder, changes in tumor 
measurements must be confirmed by repeated assessments performed no less than 
28 days after the response criteria are first met, i.e., patients need to have two 
consecutive assessments of PR or CR.  
The emphasis of the exploratory Randomized Phase II part of the study will not be 
formal statisticalprimary hypothesis testing but the estimation of: 
 Theof interest when comparing ORR – as assessed via BOR rate with 
corresponding 95% confidence intervals (CIs) for each treatment group. The 
justification of the sample size is based on considerations regarding the width of 
95% CIs for each treatment group estimate (precision of the corresponding 
estimate). 
The treatment effect (- between the two treatment groups comparison) with 
corresponding 95% CIs., combination of trastuzumab emtansine and capecitabine 
versus trastuzumab emtansine alone:  
   H0: πtrastuzumab emtansine = πtrastuzumab emtansine + capecitabine where πtrastuzumab emtansine is BOR 
in trastuzumab emtansine alone and π trastuzumab emtansine + capecitabine is BOR in 
trastuzumab emtansine + capecitabine 
 H1: π trastuzumab emtansine ≠ π trastuzumab emtansine + capecitabine  
The number and proportions of responders and non-responders (based on BOR) 
together with the two-sided 9095% Clopper-Pearson confidence intervals (CIs) will be 
presented for each treatment group. The difference in BOR between treatment groups 
will be displayed with associated 9095% CIs using the Hauck-Anderson approach and 
p-value for the Fisher’s exact test.  
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{…} 
Estimates for the survivor function of both treatment groups for TTR, DoR, TTP, TTF, PFS and 
OS will be obtained by using the Kaplan-Meier method. Hazard ratios and associated 9095% 
CIs will be estimated from non-stratified and stratified (based on the stratification factor) Cox 
regression models. 
{…} 
Safety Endpoints: 
Phase I, Cohort 1: MTD-Finding: mBC 
 
{…} 
Safety parameters for this study part will also be summarized by treatment dose. The 
summaries of AEs, SAEs, AEs that cause discontinuation from the study treatment, 
and AESIs (as described in Section 5), and events to monitor will be analyzed in a 
similar way to AEs in Phase II. The summaries will include all patients who received at 
least one dose of study medication. 
{…} 
 
Randomized Phase II: Exploration of Safety in mBC  
Safety endpoints will be summarized by treatment group. 
Safety endpoints during the Randomized Phase II part of the study will be assessed via: 
total AEs, AEs Grade ≥ 3 AEs, SAEs, premature withdrawal from study medication, 
AESIs, events to monitor, laboratory parameters, LVEF, exposure to study medication, 
concomitant medications, vital signs, ECOG performance status, and physical 
examination. 
{…} 
 
Exploratory Analyses 
For all patients with mBC (Phase I, cohort 1; Phase II Exploration of Efficacy and 
Safety in mBC), a retrospective central confirmation of the HER2 status will be done. 
Further exploratory analysis foranalyses will be done according to centrally confirmed 
HER2 status positive patients (based on central confirmation) will be done for selected 
endpoints, e.g. BOR and safety (AEs, SAEs, AEs with Grade ≥ 3 AEs, and AESIs). 
Subgroup analysis for BOR, safety (AEs, SAEs, AEs with Grade ≥ 3, and AESIs) in the 
Randomized Phase II part of the study will be presented for both treatment groups with 
respect to: elderly versus younger patients,; patients with ECOG 0–1 versus ECOG 2; 
and patients with ≤1 versus >1 prior treatment line for metastatic disease. More details 
will be presented in the SAP. 
{…} 
 
Sample Size for Randomized Phase II: Exploration of Efficacy and Safety in mBC 
The sample size for the primary endpoint BOR is based on a Fisher’s exact test with an 
alpha level of 5% (one-sided), power of 80% and the clinical assumption of a BOR rate 
of 43% with trastuzumab emtansine alone and 62.5% with the combination of 
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trastuzumab emtansine and capecitabine. Approximately 117210 patients (78105 
patients in the combination of T DM1 and capecitabine respective 39 patients in T
DM1each treatment group), including a 1015% withdrawal rate, will be randomized with 
a 21:1 ratio to either trastuzumab emtansine alone or the combination of T
DM1trastuzumab emtansine and capecitabine or T DM1.  
Point estimates and 95% Clopper Pearson exact CIs are tabulated for a range of possible BOR 
outcomes for both treatment groups: 
Table 1: Sample Size Estimation (2:1 randomization) 
Sample size based on BOR  
 
N (T DM1 and capecitabine)* = 70 patients* 
BOR rate [%] 
95% CI (within treatment group) [%] 
57.5 
(45.1 69.2) 
60.0 
(47.6 71.5) 
62.5 
(50.1 73.8) 
65.0 
(52.7 76.0) 
67.5 
(55.2 78.2) 
 
N (T DM1) = 35 patients* 
BOR rate [%] 
95% CI (within treatment group) [%] 
37.0 
(21.4 54.9) 
40.0 
(23.9 57.9) 
43.0 
(26.4 60.8) 
46.0 
(29.1 63.6) 
49.0 
(31.8 66.4) 
 
 
* N = Number of patients without adjustment for withdrawal; CI = confidence 
interval  
N (T DM1 and capecitabine) / N (T DM1) = 2 
 
Expected BOR rate for patients who received trastuzumab emtansine of 43.6% (95% CI: 38.6% 
 48.6%) was chosen based on previously published data for trastuzumab emtansine (see 
Section 6.1 of the main body of the protocol for reference). 
The precision for the BOR estimate of the combination of T DM1 and capecitabine is 
approximately 12%, e.g. BOR of 60%, 95% CI of (47.6%, 71.5%). Due to the lower sample size 
of the treatment group T DM1, the corresponding precision for the BOR estimate is increased to 
18%, e.g. BOR of 46%, 95% CI of (29.1%, 63.6%) 
A 2:1 randomization will be applied to allow more patients being exposed to the combination of 
T DM1 and capecitabine. This will enable a more thorough assessment of the corresponding 
safety profile. 
 
Stratification Factors 
The following stratification factor will be implemented in the Randomized Phase II part 
of the study: 
 Number of prior lines of treatment for metastatic disease (≤1 or >1; excluding 
single-agent hormones). 
 
A treatment line is defined as any treatment regimen given to a patient from treatment 
initiation until confirmed disease progression. 
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Sample Size for Phase I, Cohort 2: MTD-Finding: LA/mGC 
This part will be based on a classical 3 plus 3 Phase I design. FromBetween 3 toand 
12 patients might be enrolled in Cohort 2. There is no formal sample size estimation for 
this part. 
 
Interim analysis 
There is no formal interim analysis of efficacy.  
An independent data monitoring committee (IDMC) will recommend whether the 
Randomized Phase II part of the study can commence.  
The IDMC will also monitor safety outcomes after 25, 75, and 150 patients have 
received at least 3 cycles of treatment (Cycle 3 Day 21) in the Randomized Phase II 
part of the study. Afterwards, the IDMC will monitor accumulating patient safety data 
every 6 months during the Randomized Phase II part of the study or as requested. 
Efficacy data will be provided only if required by the IDMC to estimate the risk-benefit 
balance for the patients. Further details on the function and logistics of the IDMC will 
be provided in the IDMC Charter. 
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SECTION 1 
1.1.1  
HER2-POSITIVE BREAST CANCER, 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),world1, 
with approximatelyan estimated 1.3867 million new cases diagnosed in 
20082012. It is also the leading cause of cancer death in females in less 
developed regions, accounting for 458,400324,000 deaths (14.3% of all cancer 
deaths) in 2008 (Jemal et al. 2011). Almost 100,000 2012, and the second most 
common cause of these BC relatedcancer death in women in more developed 
regions (198,000 deaths occurred in patients whose tumors overexpressed 
human epidermal growth factor receptor 2 (HER2) receptors., 15.4%) after lung 
cancer.1 Metastatic breast cancer (mBC) is incurable, with the primary goal of 
treatment to extend life and palliate symptoms while preserving quality of life. 
{…} 
However, virtuallydisease progresses in almost all patients with HER2-positive 
mBC develop progressive disease (PD) and these patients require additional 
therapies. Importantly, such tumors continue to express high levels of HER2 
(Spector et al. 2005),7 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.8  
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 aAfter progression, 
the standard strategy is further HER2-directed therapy, either continuing 
trastuzumab with a different chemotherapy agent (eg trastuzumab plus 
capecitabine), or changing to a different HER2-directed regimen (eg lapatinib 
plus capecitabine). In a randomized Phase III trial, GBG26, in patients whose 
disease had progressed on previous trastuzumab-containing therapy, the 
combination of trastuzumab and capecitabine was associated with significantly 
improved time to progression (TTP) (hazard ratio [HR] 0.69, median 8.2 versus 
5.6 months, respectively) and ORR (48% versus 27%) compared with 
capecitabine alone.9 In another 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 rateORR (24% versus 14%) and time to disease progression (TTP 
(median 6.2 months versus 4.3 months) (Geyer et al. 2006).compared with 
capecitabine alone.9   
{…} 
 
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1.1.2  
HER2-POSITIVE LOCALLY ADVANCED OR /METASTATIC 
GASTRIC CANCER 
Gastric cancer (GC) remains one of the most common malignancies in the world 
with an estimated 989,600952,000 new cases in 2008 (Jemal et al. 2011).2012.1 
GC also continues to be a deadly disease; it is the secondthird leading cause of 
cancer-related death, accounting for 738723,000 deaths (9.78.8% of all cancer 
deaths) worldwide in 2008 (Ferlay et al. 2010).2012. The only potentially curative 
treatment for GC is complete resection of localized disease. The overall 5-year 
survival for all cases, regardless of initial stage at diagnosis, is less than 25% 
(Catalano et al. 2005; Faivre et al. 1998; Parkin et al. 2005; Power et al. 
2010).%.11-14 Among patients with localized disease who undergo curative 
surgery, approximately 40–60% will have disease recurrence. Patients with 
unresectable disease due to locally advanced growth or metastatic spread have 
the poorest prognosis, with an overall 5-year survival rate in the range of 3% to 
15% (De Vivo et al. 2000; Ries et al. 2008; Power et al. 2010).%.11,13,14  
1.2.1 
TRASTUZUMAB EMTANSINE 
{…} 
Completed and ongoing Phase I and II single-arm studies were conducted to 
identify the most appropriate dosing regimen for further clinical development, and 
assess the safety of trastuzumab emtansine have shown clinical activity. 
Furthermore,. Low levels of DM1 in systemic circulation supported the stability of 
the linker (Shen et al. ASCPT 2011)..25 The studies also provided an indication of 
clinical activity and led to randomized Phase II study TDM4450g 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. A Phase III study (TDM4370g) is 
underway comparingevaluation of single-agent trastuzumab emtansine 
withversus other HER2-targeted directed therapy in combination therapy 
(capecitabine and lapatinib) for patients with mBC who had received prior with 
chemotherapy. These trials demonstrated significantly superior PFS and OS with 
trastuzumab and taxane therapies.emtansine.26–28 
In this study, anthe ORR ofwas 25.5% (95% CI: 15.2%–38.5%) wasas 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 
Phase III Study TDM4370g 
Roche is conducting A randomized, open-label Phase III trial (TDM4370g) of; 
EMILIA) compared single-agent trastuzumab emtansine versus lapatinib and 
capecitabine in patients with HER2-positive locally advanced unresectable BC or 
mBC who havehad received a prior taxane and trastuzumab therapy and 
havehad documented disease progression. The study is ongoing, enrollment is 
completed, and 991 patients have been enrolled.PD.27  
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Patients arewere randomized in a 1:1 ratio to trastuzumab emtansine or 
capecitabine plus lapatinib. 
Trastuzumab emtansine is administered at 3.6 mg/kg IV q3w. The control arm 
treatment is or the combination of oral capecitabine at 1,000 mg/m2 as oral doses 
twice daily (bid) on Days 1–14 of a q3w cycle plus oral lapatinib 1,250 mg/day 
given as continuous dosing. Study treatment is discontinued based on disease 
progressionTreatment was continued until PD (as assessed by the investigator), 
unmanageable toxicity, or study termination by Roche/Genentech. 
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 are investigated aswere co-primary endpoints in this study, with 
PFS based on modified RECIST (Therasse et al. 2000) and conducted by the 
IRB. An additional tumor assessment of PFS is performed after investigator-
documented disease progression. Furthermore ORR, DoR, and CBR are 
included, on the basis of both investigator and independent review of tumor 
assessments, asRECIST34 and assessed by independent review. Key secondary 
endpoints were ORR, DoR, and CBR, determined both by the investigator and by 
independent review. 
Patients The study demonstrated statistically significant and clinically meaningful 
improvements in both PFS and OS for trastuzumab emtansine compared with 
lapatinib plus capecitabine. Median PFS was 9.6 months in the trastuzumab 
emtansine arm had a median PFS of 9.6 months versus 6.4 months for patients 
in the control arm of lapatinib + capecitabine (HR = 0.65; 95% CI: 0.55–0.77; 
p < 0.001, log-rank test). Patients in the trastuzumab emtansine arm had a 
Median OS ofwas 30.9 months versus 25.1 months for patients in the control arm 
of lapatinib + capecitabine, respectively (HR = 0.68; 95% CI: 0.55–0.85; 
p < 0.001, log-rank test).  
This benefit was supported by consistent improvements in all secondary efficacy 
endpoints, including investigator-assessed PFS, ORR, time to treatment failure 
(TTF), and the patient-reported outcome of time to symptom progression. The 
ORR in the trastuzumab emtansine arm was 43.6% (95% CI: 38.6%–48.6%) 
compared with 30.8% (95% CI: 26.3%–35.7%) in the control arm (based on 786 
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 lapatinib and capecitabine in mBC. The incidence of 
Grade ≥ 3 AEs in the control arm (56.9%; n = 488) was 278; that of trastuzumab 
emtansine (40.8%; n = 490) was 200. The rates of SAEs for both arms were 
similar (control arm 18% versus trastuzumab emtansine 15.5%). 
It was concluded that overall, there is no concern regarding the clinical safety of 
trastuzumab emtansine for the patient population that was studied, based on the 
currently available data (Verma et al. 2012). 
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Based on the results of this phase III trial, both the Food and Drug Administration 
(FDA) in the US and the European Medicines Agency (EMA) in Europe approved 
trastuzumab emtansine for the treatment of HER2-positive mBC previously 
treated with trastuzumab and a taxane.  
1.2.1.7 
Phase III study TDM4997g 
A second open-label randomized Phase III trial (TDM4997g; TH3RESA) 
compared single-agent trastuzumab emtansine versus the investigator’s choice 
of therapy in patients with HER2-positive advanced BC who had previously 
received two or more HER2-directed regimens in the advanced setting, including 
trastuzumab and lapatinib, and previous taxane therapy in any setting.28 A total 
of 602 patients were randomized in a 2:1 ratio (404 to trastuzumab emtansine 
and 198 to physician’s choice).  
After median follow-up of approximately 7 months in both arms, 219 patients 
(54%) in the trastuzumab emtansine group and 129 (65%) in the physician’s 
choice group had experienced PFS events. PFS was significantly improved with 
trastuzumab emtansine compared with physician’s choice (HR 0.528, p<0.0001; 
median PFS 6.2 months with trastuzumab emtansine versus 3.3 months in the 
control arm. The HR for OS at the interim analysis was 0.552 (95% CI 0.369–
0.826) but the stopping boundary was not crossed.  
Grade ≥3 AEs occurred less frequently with trastuzumab emtansine than with 
physician’s choice (32% of patients vs 43%). Grade ≥3 neutropenia, diarrhea, 
and febrile neutropenia were less common with trastuzumab emtansine than 
physician’s choice, whereas grade ≥3 thrombocytopenia (5% vs 2%) was more 
common with trastuzumab emtansine.  
{…} 
1.2.2 
CAPECITABINE 
{…} 
The activity of capecitabine as single-agent chemotherapy was initially 
demonstrated in two multicenter Phase II clinical trials (before testing of HER2 
status was standard) in patients with locally advanced or mBC after failure of a 
taxane and an anthracycline-containing chemotherapy regimen or for whom 
further anthracycline therapy was not indicated.38,39 In these trials, a total of 236 
patients were treated with capecitabine (1,250 mg/m2 bid for 2 weeks followed by 
1-week rest period). The ORRs (investigator assessment) were 20% (first trial) 
and 25% (second trial). The median TTP was 3.1 months and 3.2 months, 
respectively. Median OS was 12.6 months and 12.3 months, respectively. 
The combination of capecitabine and docetaxel was studied as treatment for 
locally advanced or mBC after failure of anthracycline-containing chemotherapy 
in a multicenter randomized controlled Phase III clinical trial (SO14999).40 In this 
trial, 255 patients were randomized to treatment with capecitabine (1,250 mg/m2 
bid for 2 weeks followed by a 1-week rest period) and docetaxel (75 mg/m2 as a 
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1-hour IV infusion q3w) and 256 patients were randomized to treatment with 
docetaxel alone (100 mg/m2 as a 1-hour IV infusion q3w). OS was superior in the 
capecitabine plus docetaxel combination arm (HR 0.775; p = 0.0126). Median 
OS was 14.5 months (capecitabine plus docetaxel) versus 11.5 months 
(docetaxel alone). The ORR in the all-randomized population (investigator 
assessment) was 41.6% (capecitabine plus docetaxel) versus 29.7% (docetaxel 
alone; p = 0.0058). TTP was superior in the capecitabine plus docetaxel 
combination arm (HR 0.652; p < 0.0001). The median TTP was 6.1 months 
(capecitabine plus docetaxel) versus 4.2 months (docetaxel alone).  
This trial led to the randomized Phase II CHAT trial evaluating the addition of 
capecitabine to first-line trastuzumab and docetaxel for locally advanced or 
metastatic HER2-positive mBC.41 PFS was significantly improved with the 
addition of capecitabine (HR 0.72; median 17.9 months versus 12.8 months in 
patients receiving docetaxel and trastuzumab without capecitabine), although 
there was no difference in ORR (71% versus 73%, respectively). 
1.3 
STUDY RATIONALE AND RISK-BENEFIT 
ASSESSMENT 
1.3.2 
FOR MGC 
{…} 
In the ToGA study in LA/mGC, trastuzumab exposure was lower than that 
observed in breast cancer studies. Based on this observation, together with 
pharmacokinetic results and findings from a Phase I study in mBC, it was 
considered that a weekly trastuzumab emtansine regimen may provide higher 
cumulative trastuzumab emtansine exposure than the q3w schedule and was 
therefore chosen for the Phase I, Cohort 2 part of the present study in LA/mGC. 
This approach has subsequently been supported by findings from stage I of the 
adaptive phase II/III BO27952 trial in this setting (see Section Error! Reference 
source not found.). In October 2013, the IDMC for the BO27952 trial 
recommended selection of the weekly 2.4 mg/kg regimen for further evaluation in 
the phase III part of the trial based on pharmacokinetic, safety, and efficacy data 
available at the time. 
{…} 
SECTION 3: STUDY DESIGN 
{…} 
Duration of Treatment and Patient Follow-up 
LengthDuration of treatment: All patients will be treated until disease progression, 
intolerableinvestigator-assessed PD, unacceptable toxicity, (of either or both 
agents), withdrawal of consent, or death, reasons deemed by the treating 
physician, or study termination by the Sponsor. If toxicity is considered by the 
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investigator to be related to only one of the two agents, the non-implicated agent 
can be continued as single-agent therapy. 
If at the time of study closure there are patients whose disease has not 
progressed and who are still receiving study treatment, they will be offered the 
possibility to continue treatment by enrolling in an extension study. 
Patient follow-up: All patients will be followed up until withdrawnwithdrawal of 
consent, death, or for up to a maximum of 2 years after the last patient was 
randomized in the Randomized Phase II part of the study, whichever occurs first. 
Duration of Study, Database Closure and Data Reporting 
The duration of the study is estimated to be approximately 4 years. Recruitment 
is estimated to belast 2 years in total (1 year for the Dose MTD-Finding study in 
mBC and 1 year for the Phase II Exploration of Efficacy and Safety. in mBC). 
See Section 3.2 for further details about EOS. The study will end after the follow
up period is completed, as defined above. Last patient last visit (LPLV) is defined 
as the last data collection point that can be either a clinic visit or a laboratory 
sample. At that time point, the database will be closed. 
In the case that in Cohort 1 the Specifically in Phase I, cohort 2, if dose level -2 is 
too toxic (> 1/6 of dose-limiting toxicity [DLT]), the combination may be 
considered unfeasiblein LA/mGC, recruitment into the LA/mGC cohort will be 
closed and neither the Randomized Phase II nor mGC cohort will be opened. 
See Section 3.1.1.3 for details of treatment continuation if patients who, at that 
point, experience response as per are still responding to treatment at this time. 
RECIST v.1.1 will be offered the possibility to continue on trastuzumab 
emtansine as a single agent, or the combination, based on risk benefit balance 
and agreement with the Steering Committee (SC). 
Data may be reportedpublished/presented publicly at the end of each cohort 
i.e.g., once the MTD for Cohort 1 for mBC has been defined and the dose for 
Phase II /Exploration of Efficacy and Safety has been selected. The latest point 
to write, and after the prespecified analyses for the Randomized Phase II 
exploration of efficacy and safety in mBC. The Clinical Study Report (CSR) will 
be finalized/published within 1 year after database closure. 
Treatment of Patients after Database Closure 
If at the moment of study closure there are patients who have not progressed 
and are still receiving study treatment, they will be offered the possibility to 
continue treatment by enrolling in an extension study. 
Enrollment into Cohort 1 
Dose MTD-finding in patients with mBC (Phase I) 
{…} 
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If Dose Level -2 is found to be too toxic (DLT > 1/6), the combination may be 
considered unfeasible, the recruitment will be closed and neither the 
Randomized Phase II nor mGC cohort will be opened. Patients who, at that point, 
experience response as per RECIST v.1.1 will be offered the possibility to 
continue on trastuzumab emtansine as a single agent, or with the combination, 
based on risk benefit balance and agreement with the SC. 
{…} 
3.1.1.2 
Overview of Phase II: Exploration of Efficacy and Safety in 
Patients with mBC  
After review of safety data from Part 1, cohort 1, the IDMC recommended a 
regimen of capecitabine 700 mg/m2 bid days 1–14 in combination with 
trastuzumab emtansine 3.6 mg/kg q3w for further evaluation. The Phase II This 
part of the study will explore the efficacy and safety of this recommended 
regimen the combination treatment of T-DM1 and capecitabine, at the 
established MTD, compared with T-DM1trastuzumab emtansine alone in mBC 
patients with HER2-positive mBC. See Section 3.1.1 for details of duration of 
treatment. 
Once the MTD has been defined to treat patients in Phase II, approximately 
117Approximately 210 additional patients with HER2-positive mBC will be 
randomized into the Phase II part of the study. Patients in the Phase I part of the 
study will not contribute to the Phase II part of the study; however, they will be 
followed-up until end of study (EOS). 
Patients will be treated until disease progression/recurrence, 
intolerableunacceptable toxicity, withdrawn consent, or death. If capecitabine 
needs to be discontinued for any reason, trastuzumab emtansine may continue, 
and the patient will be followed up until EOS. In case of discontinuation of 
trastuzumab emtansine,at the time of study closure there are will be followed up 
until EOSwhose disease has not progressed and who are still receiving study 
treatment, they will be offered the possibility to continue treatment by enrolling in 
an extension study. 
All patients will be followed up until withdrawnwithdrawal of consent, death, or up 
to a maximum of 2 years after the last patient was randomized in the Phase II 
part of the study, whichever occurs first. 
See Section 3.1.1 for further information. 
 
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3.1.1.3 
Overview of Phase I Design in LA/mGC Patients 
Determination of the MTD in Patients with LA/mGC  
Cohort 2 will open when the capecitabine MTD ishas been established for 
Cohort 1 and Cohort 2 will enroll patients with HER2-positive locally advanced 
and LA/mGC. Trastuzumab emtansine will be administered qw at thea fixed dose 
of 2.4 mg/kg and capecitabine will be started at 700 mg/m2 bid, the MTD defined 
for patients with mBC in Cohort 1. See Section 3.1.1 for further information. 
Enrollment into Cohort 2 
Cohort 2 will open with a 3 plus 3 classical design to investigate the feasibility of 
combination therapy of capecitabine and trastuzumab emtansine in Cohort 2 
(enrolling up to 12 patients with LA/mGC) by de-escalating the dose of . The 
capecitabine dose will be de-escalated from the starting from dose of 700 mg/m2 
bid (the MTD determinedrecommended in Cohort 1. In case the MTD was not 
established or the enrollment was stopped for Cohort 1, enrollment into Cohort 2 
will not take place.).  
The dose levels for de-escalation of capecitabine will be the same as described 
for Cohort 1, except for Dose Level 1, which will not be explored in patients with 
mGC (see also Section 3.3.2.12). 
If Dose Level -1 (700 mg/m2 bid, the MTD establishedrecommended in cohort 1 
is defined at Dose Level -1: 
This will be the starting dose in Cohort 2. If Dose Level -1) is well tolerated (DLT 
in ≤ 1/6), this dose will be established as the MTD for LA/mGC. 
 
De-escalation: If Dose Level -1 is not tolerated in Cohort 2 (>(DLT in>1/3 
patients or  > 1/6 DLTpatients), de-escalation will be to Dose Level -2. 
If the MTD established in Cohort 1 is defined at Dose Level -2: 
 
This will be the starting dose in Cohort 2. If Dose Level -2 is well tolerated 
(DLT ≤ 1/6), this dose will be established as the MTD for mGC. 
 
De-escalation: If Dose Level -2 is not tolerated in Cohort 2 (>(DLT in > 1/6 
DLT), the combination will  be considered not feasible in LA/mGC and 
Cohort 2 will be terminated. Patients who, at that pointtime, experience 
response as peraccording to RECIST v.1.1 will be offered the possibility to 
continue on trastuzumab emtansine as a single agent, or with the 
combination, based on risk-benefit balance and agreement with the SC 
3.1.1.4 
Number of Patients 
Overall, it is anticipated that the maximum number of patients enrolled into the 
study will be approximately 147 patients240. 
 
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{…} 
3.1.2 STEERING COMMITTEE 
A SC has been established for this study. Initially, it is composed of the 
investigators participating in the Phase I, Cohort 1 part of the study and one 
medical representative and one statistician of the Sponsor. The study design and 
DLT hasdefinition have been developed by the SC. See the SC Charter for 
further information. 
The SC will collectively review the status of the ongoing patients in Phase I on a 
regular basis. the SC will also review in due course all available efficacy data and 
PK information to ensure that safety information is in the context of risk benefit 
and that dosing is also related to exposure to the drug.  
The SC will adjudicate in casesthe event of DLTs that are not covered by the 
existing DLT criteria. 
3.1.3 
INDEPENDENT DATA MONITORING COMMITTEE 
An independent data monitoring committee (IDMC) will be established for the 
Randomized Phase II part of the study. TheAn IDMC will review the safety 
outcomes for patients enrolled in Phase I, Cohort 1 and adviserecommend 
whether the Randomized Phase II part of the study can commence. The IDMC 
will also monitor safety outcomes after 2025, 75, and 60 150 patients have 
received at least 3 cycles (Cycle 3 Day 121) of treatment in the Phase II part of 
the study. Afterwards, the IDMC will monitor accumulating patient safety data 
every 6 months during the Randomized Phase II part of the study or as 
requested. 
{…} 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
RATIONALE FOR PATIENT GROUP SELECTION 
{…} 
This study will enroll patients diagnosed with the disease, to which the 
combinationHER2-positive mBC or LA/mGC. Capecitabine is intended.an 
established chemotherapy for both diseases. In patients with HER2-positive mBC 
or LA/mGC, anti-HER2 therapy has demonstrated activity. Furthermore, the 
combination of anti-HER2 agenttherapy and capecitabine has been shown to be 
efficacious in both mBC (von Minckwitz et al. 2011; Geyer et al. 2006)mBC9,10 
and mGC (Bang et al. 2010), and capecitabine is a standard of care treatment for 
both diseases. Both diseasesLA/mGC.18 Eligible patients for this study will have 
been shown to benefit from anti HER2 treatment; therefore, all patients must be 
diagnosed with HER2-positive disease. Patients with incurable mBC and locally 
advanced or mGC, whose tumors are positive for HER2 overexpression, 
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represent the patient population eligible for study enrollmentor LA/mGC 
overexpressing HER2. 
3.3.1.1 
Rationale for Phase I 
The study design of 3 plus 3 Phase Idesign is a well-established and well-known 
method for Phase I studies. PK parameters will be collected and analyzed in 
order to investigate the PK interaction of the drugs under investigation. Since 
both agents are administered at efficacious doses, the risk of enrolling patients at 
the sub-optimal doses is minimal. 
Following review of preliminary data from Cohort 1 of this study by the SC for 
patients enrolled to receive 750 mg/m2 capecitabine, where 2 DLTs were 
observed in 6 evaluable patients, it was decided not to explore dose levels of 
capecitabine higher than 750 mg/m2. According to the investigator assessment 
and the SC recommendation, the available evidence shows an acceptable 
positive risk-benefit in all 7 patients treated at Dose Level 1.  
As of 7 August 2013, five patients remain on treatment, with a follow up period of 
4 to 8 months. Of the two patients who have discontinued treatment, one 
patient’s disease has progressed, and the other discontinuation was based on 
the investigator’s decision, following the central confirmation, that the patient’s 
disease was HER2-negative. Considering the available safety data for all 
patients (maximum number of cycles is 12), the combination of capecitabine and 
T DM1 is well tolerated, except for increases in transaminases and hand foot 
syndrome. Dose modifications of T-DM1 and/or capecitabine have allowed those 
patients to continue on treatment. Of note, no SAE has been reported in 6 
patients. Latest tumor response data show 2 patients with PR and 4 patients with 
SD. Any required dose modifications (dose reductions) are allowed for each 
individual drug as described in Sections 5.1.5.1 and 5.1.5.2 and are in line with 
the trastuzumab emtansine Investigator’s Brochure and Xeloda® Summary of 
Product Characteristics.  
The combination of T DM1 and capecitabine will be evaluated with a de
escalation study design. Patients who are currently receiving the combination of 
T DM1 and capecitabine 750 mg/m2 can continue to receive the dose as per 
protocol until there is no longer evidence of positive risk benefit as per 
investigator assessment and SC endorsement. 
The capecitabine dose evaluated in combination with trastuzumab and docetaxel 
in the CHAT trial was 950 mg/m2 bid. However, retrospective evaluations and 
post hoc analyses of early dose reduction suggest that lower starting doses of 
capecitabine offer similar efficacy with better tolerability. Therefore the 
capecitabine starting dose selected in combination with trastuzumab emtansine 
for the MTD-Finding Phase I part of the present study was 750 mg/m2 bid, taking 
into account the aim of maintaining the good tolerability of trastuzumab 
emtansine while benefitting from synergy observed between the two agents in 
nonclinical studies. 
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The combination of T-DM1 and capecitabine was evaluated with a de-escalation 
study design. Following the emergence of two DLTs (grade 3 vomiting, grade 3 
elevated AST/ALT) at the starting dose of 750 mg/m2 bid (days 1–14 q3w) in 
combination with trastuzumab emtansine 3.6 mg/kg q3w, a de-escalated dose 
cohort was opened to evaluate capecitabine 700 mg/m2 bid combined with the 
same dose of trastuzumab emtansine. At this dose no DLTs were observed in 
the six patients treated, and of note, none of the patients had experienced grade 
≥3 AEs in cycles delivered after the DLT evaluation period.45 Following review of 
safety data from patients treated at these two dose levels, the IDMC 
recommended the regimen of capecitabine 700 mg/m2 bid combined with 
trastuzumab emtansine 3.6 mg/kg q3w for the phase II exploration of efficacy 
and safety.  
In the ToGA study in LA/mGC, trastuzumab exposure was lower than that 
observed in breast cancer studies. A weekly trastuzumab emtansine regimen 
may provide higher cumulative trastuzumab emtansine exposure than the q3w 
schedule and was therefore chosen for the Phase I, Cohort 2 part of the present 
study in LA/mGC. This approach has subsequently been supported by findings 
from stage I of the adaptive phase II/III BO27952 trial in this setting (see Section 
Error! Reference source not found.).  
 
3.3.1.2 
Rationale for Randomized Phase II 
The Randomized Phase II part of the study is designed to explore the efficacy 
and safety of the combination recommended following the Phase I MTD-Finding 
phase (trastuzumab emtansine 3.6 mg/kg in combination with capecitabine 700 
mg/m2) compared with trastuzumab emtansine alone. provide an estimation of 
the treatment effect of the combination, at the selected MTD, compared with 
T-DM1 alone. 
The patient data will be stratified by previous anti-cancer treatment (excluding 
single agent hormones) for the treatment of metastatic disease (1 or >1prior lines 
of treatment). The stratified data will be compared with data from historical 
studies of single agent trastuzumab emtansine in similar patient populations. 
This will allow a more robust evaluation of the added treatment effect of Xeloda® 
within the combination treatment. 
A 2:1 randomization will be applied to allow more patients being exposed to the 
combination of T DM1 and capecitabine. This will enable a more thorough 
assessment of the corresponding safety profile. 
In addition, it will and provide important information on the longer-term safety of 
the combination.information.  
{…} 
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3.3.2.2 
In Patients with mGC 
{…} 
In the ongoing randomized adaptive phase II/III BO27952 trial evaluating 
trastuzumab emtansine versus the investigator’s choice of taxane therapy in 
unrectable LA/mGC, two trastuzumab emtansine regimens were evaluated in 
stage I: 3.6 mg/kg q3w and 2.4 mg/kg qw . In October 2013, the IDMC for the 
BO27952 trial recommended selection of the weekly 2.4 mg/kg regimen for 
further evaluation in the phase III part of the trial based on pharmacokinetic, 
safety, and efficacy data available at the time. This recommendation provides 
further support for using the weekly regimen in Phase I, Cohort 2 of the present 
trial.  
{…} 
3.3.2.3 
Rationale for Duration of Treatment 
Treatment will be given until disease progression or unacceptable 
toxicityinvestigator-assessed PD, unacceptable toxicity, withdrawal of consent, 
death, reasons deemed by the treating physician, or study termination by the 
Sponsor (see Section 3.1.1 for full information). As of 1 January 2010, of 237 
patients enrolled in studies TDM3569g, TDM4258g, and TDM4374g receiving 
trastuzumab emtansine at 3.6 mg/kg, approximately 30% have tolerated more 
than 12 cycles, with 14.8% having received more than 17 cycles. Twenty patients 
(8.4%) have discontinued trastuzumab emtansine due to AEs and 24 patients 
(10.1%) required dose reductions in trastuzumab emtansine because of AEs. In 
the absence of intolerableunacceptable toxicity, patients with mBC are generally 
treated until disease progression.PD. Further support for treatment until PD 
comes from the EMILIA randomized phase III trial.27 Among the 490 patients 
randomized to trastuzumab-emtansine, only 29 (5.9%) discontinued because of 
adverse events. 
{…} 
3.3.3 
PHARMACOKINETIC SAMPLING RATIONALE 
The PK is studied only in the Phase I (MTD-Finding) parts (both cohorts 1 and 2). 
The PK sampling rationale is to characterize the PK of trastuzumab emtansine, 
total trastuzumab, and DM1capecitabine and their metabolites, to assess any 
potential drug-drug interaction when trastuzumab emtansine is given in 
combination with capecitabine, and to explore potential correlations between 
drug exposure and measures of both efficacy (ORR) and toxicity (alanine 
transaminase [ALT]/AST, platelets, etc.), if data allow. 
 
{…} 
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3.4.1.4 
Secondary Safety Outcome Measures 
{…} 
 
Premature withdrawal from study medication 
 
Fatal AEs and their causes  
 
Abnormal lLaboratory parametersvalues 
{…} 
 
Vital signs and ECOG performance status 
 
Premature withdrawal from study medication and/or study 
 
3.4.2 
RANDOMIZED PHASE II: EXPLORATION OF EFFICACY AND 
SAFETY IN MBC 
{…} 
3.4.2.3 
Primary Safety Outcome Measure 
A primary safety outcome is defined only for Phase I, and will be presented for 
both treatment groups.  
3.4.2.4 
Secondary Safety Outcome Measures 
 
Premature withdrawal from study medication 
 
Fatal AEs and their causes  
 
Events to monitor 
 
Laboratory parameters 
 
Abnormal laboratory values 
 
LVEF 
 
Exposure to study medication 
 
Physical examination 
 
Vital signs and ECOG performance status 
 
Premature withdrawal from study medication and/or study 
 
3.4.3 
PHASE I: LA/MGC 
1.1.1.1 
Primary Efficacy Outcome Measure 
The main objective for Phase I is to determine the MTD of capecitabine when 
combined with trastuzumab emtansine. The number and the proportion of 
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patients with DLTs will be used as the primary measure for the MTD 
determination and will be summarized for each treatment dosage. 
1.1.1.2 
Secondary Efficacy Outcome Measure 
The secondary (efficacy) outcome is ORR, based on BOR rate as peraccording 
to RECIST v.1.1; based on according to investigator assessment. 
Primary Safety Outcome Measure 
The primary outcome measure is to establish the MTD. The number and the 
proportion of patients with DLTs will be used as the primary measure for the MTD 
determination and will be summarized for each treatment dosage. 
1.1.1.3 
Secondary Safety Outcome Measures 
Safety endpoints will be summarized for both treatment phases: Dose Finding 
and Exploration of Efficacy. Again, the summary of safety endpoints will be 
presented for each treatment dosage: 
 
Incidence, nature, and severity of AEs, as peraccording to NCI CTCAE v. 4.0 
 
Incidence, nature, and severity of SAEs, as peraccording to NCI CTCAE v. 
4.0 
 
Incidence and nature of AEs equal or higher than Grade ≥3 AEs  
 
Incidence, nature, and severity of AESIs, as peraccording to NCI CTCAE v. 
4.0 
 
Fatal casesAEs and their causes of death 
 
Events to monitor 
 
Laboratory parameters 
 
LVEF 
 
Treatment exposure 
 
Exposure to study medication 
 
Concomitant medications and physical examination 
 
Vital signs and ECOG performance status 
 
Premature withdrawal from study medication and/or study 
 
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SECTION 4: MATERIALS AND METHODS 
4.1.3 
INCLUSION CRITERIA 
4.1.3.1 
For Patients with mBC 
Patients must meet the following criteria for study entry: 
1. Male or female 
{…} 
6. 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 or two effective forms of non-hormonal 
contraception and to continue its use for the duration of study treatment and 
for 67 months after the last dose of study treatment (see Section 5.2.4). 
{…} 
9. Liver function: 
a)  Total bilirubin ≤ 1.5 × upper limit of normal (ULN) or direct bilirubin ≤1.5 
× ULN in patients with documented Gilbert’s syndrome.  
b) Serum glutamic oxaloacetic transaminase (SGOT)/AST and serum 
glutamic pyruvic transaminase (SGPT)/ALT ≤ 2.5 × the ULN 
c) Alkaline phosphatase ≤ 2.5 × the ULN. In patients with hepatic and/or 
bone metastases: alkaline phosphatase ≤ 5 × the ULN 
d) Evidence of stable liver function during the month prior to enrollment with 
liver function tests’ (LFTs) fluctuations not exceeding 2.5 x ULN (for AST, 
ALT) and 1.5 x ULN (for total bilirubin). Patients with bone metastases: 
AST and ALT ≤ 5.0 x ULN 
{…} 
12.  Life expectancy ≥12 weeks 
 
4.1.3.2 
For Patients with LA/mGC 
1.   Male or female 
{…} 
6. 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 or two effective forms of non-hormonal 
contraception and to continue its use for the duration of study treatment and 
for 67 months after the last dose of study treatment (see Section 5.2.4). 
{…} 
9. Liver function: 
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a) Total bilirubin ≤ 1.5 × ULN or direct bilirubin ≤1.5 × ULN in patients with 
documented Gilbert’s syndrome 
b) SGOT/AST and serum glutamic pyruvic transaminase 
(SGPT)//ALT ≤ 2.5 × the ULN 
c) Alkaline phosphatase ≤ 2.5 × the ULN. In patients with hepatic and/or 
bone metastases: alkaline phosphatase ≤ 5 × the ULN 
d) Evidence of stable liver function in the month prior to enrollment with LFTs 
fluctuations not exceeding 2.5 x ULN (for AST, ALT) and 1.5 x ULN (for 
total bilirubin). Patients with bone metastases: AST and ALT ≤ 5.0 x ULN 
 
4.1.4 
EXCLUSION CRITERIA 
4.1.4.1 
For Patients with mBC 
5. Related capecitabine contraindications: 
a) Treatment with sorivudine or its chemically-related analogues, such as 
brivudine 
b)  Rare hereditary problems of galactose intolerance, the Lapp lactase 
deficiency, or glucose-galactose malabsorption 
c) Signs or symptoms suggesting that the patient has DPD deficiency 
{…} 
22. Previous radiotherapy for the treatment of unresectable, locally 
advanced/recurrent or mBC is not allowed if: 
a) The last fraction of radiotherapy has been administered within 14 days 
prior to first study drug administration (28 days for patients with 
radiotherapy to control symptoms of brain metastases, see exclusion 
criterion 8). 
b) More than 25% of marrow-bearing bone has been irradiated. 
c) The patient has not recovered from any resultingAny acute toxicity has not 
resolved to Grade ≤ 1 prior tobefore first study drug administration. 
23. No signs and symptoms suggestive that the patient has dihydropyrimidine 
dehydrogenase (DPD) deficiency 
4.1.4.2 
For Patients with LA/mGC 
{…} 
5. Related capecitabine contraindications: 
a)  Treatment with sorivudine or its chemically-related analogues, such as 
brivudine 
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b)  Rare hereditary problems of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactose malabsorption 
c) Signs or symptoms suggesting that the patient has DPD deficiency 
{…} 
8. Brain metastases that are symptomatic, or require any radiation, surgery, or 
steroid therapy to control their symptoms within 2814 days ofbefore first 
study drug administration 
{…} 
22. No signs and symptoms suggestive that the patient has DPD deficiency 
{…} 
4.2  
METHOD OF TREATMENT ASSIGNMENT 
In the Randomized Phase II part of the study, patients will be randomized to 
receive either the combination of T-DM1 and capecitabine or T-DM1 alone. The 
2:1 randomization ratio will be applied to allow more patients being exposed to 
the combination treatment and to enable a more thorough assessment of the 
corresponding safety profile.trastuzumab emtansine and capecitabine or 
trastuzumab emtansine alone.  
Patients are stratified according to the number of prior lines of treatment for 
metastatic disease (≤1 or >1, excluding single-agent therapy). 
This is an open-label randomized study; therefore, no blinding will be used. 
 
{…} 
4.3.2.2 
For Patients with LA/mGC 
Trastuzumab Emtansine 
{…} 
Capecitabine 
Capecitabine will be administered twiceat a daystarting dose of 700 mg/m2 bid, 
orally, for 14 days followed by a 7-day rest period at (the dose level that was 
determined during the Dose Finding part of the study in patients with mBC as the 
MTD in cohort 1, with de-escalation as described in section 3.1.1.3. Capecitabine 
tablets should be swallowed with water within 30 minutes after a meal. 
Capecitabine doses can be delayed for up to 4 hours, while keeping the minimal 
interval of 8 hours between the doses. 
{…} 
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4.5.1.1 
Medical History and Demographic Data 
Demographic data will include age, sex, and self-reported race/ethnicity (unless 
not allowed per local regulations). 
{…} 
4.5.1.5 
Laboratory Assessments 
For Patients with mBC: 
{…} 
Central Laboratory Assessments: 
 
Retrospective HER2 status. Retrospective central confirmation will not 
impact the treatment decisions or primary endpoint of Phase I, Cohort 1 and 
will be used to validate efficacy analyses in Phase I and to censor thedefine 
subgroups for efficacy population foranalyses in the Randomized Phase II 
part of the study 
{…} 
4.5.2.3 
Assessments at Study Completion/Early Termination Visit 
Patients may remain on study treatment until disease progression as assessed 
by the investigator, intolerable-assessed PD, unacceptable toxicity, (of either or 
until the patient wishes to withdraw fromboth agents), withdrawal of consent, 
death, reasons deemed by the treating physician, or study treatment.termination 
by the Sponsor. Patients who discontinue study treatment will be followed up 
until EOS and will be asked to return to the clinic approximately 28–42 days after 
the last study treatment administration for the safety follow-up visit. 
4.5.2.4 
Follow-up Assessments 
After the Study Treatment Discontinuation Visit, all patients (regardless of reason 
for discontinuation) will have survival status and anti-cancer therapies recorded 
and will be followed for all unresolved study-related AEs and SAEs until their 
resolution or stabilization, the patient is lost to follow-up or dies, 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. 
Patients who discontinue study drugs for any reason other than disease 
progressionPD or withdrawal of consent (e.g., an AE) will continue to be followed 
according to the tumor assessment schedule until the developmentwithdrawal of 
disease progression, consent withdrawal, lost to follow up, death, or beginning of 
another anti cancer therapyEOS, whichever occurs first. 
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After the study treatment completion/early termination visit, AEs should be 
followed as outlined in Section 5.5 and 5.6. 
SECTION 5: ASSESSMENT OF SAFETY 
5.1.1.3 
Hepatotoxicity 
Hepatotoxicity, predominantly in the form of asymptomatic increases in the 
concentrations of serum transaminases (Grade 14 transaminitis), has been 
observed in patients while on treatment with trastuzumab emtansine in clinical 
trials. Transaminase elevations were generally transient. A cumulative effect of 
trastuzumab emtansine on transaminases has been observed; 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. 
Serious hepatobiliary disorders, including nodular regenerative hyperplasia (NRH) 
of the liver and some resulting in fatal liver failure, have been observed in 
patients treated with trastuzumab emtansine in clinical trials. 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. While there is evidence of drug-induced liver toxicity 
(predominantly in the form of asymptomatic increases in the concentrations of 
serum transaminases) in patients treated with trastuzumab emtansine, its 
potential to cause acute severe liver injury with clinically meaningful changes in 
liver function is unclear asSome of the observed cases of acute liver injury were 
may have been confounded by comorbidities and/or concomitant medications 
with known hepatotoxic potential and/or underlying conditions. Liver function 
should be monitored before initiation of treatment and each trastuzumab 
emtansine dose.Nevertheless, a contributory role of trastuzumab emtansine in 
these cases cannot be excluded. Therefore, Acute severe liver injury (Hy’s law) 
remains an important potential risk with trastuzumab emtansine. A Hy’s law case 
has the following components: 
  Aminotransferase enzymes (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) 
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Trastuzumab emtansine has not been studied in patients with serum 
transaminases  2.5  ULN or total bilirubin  1.5  ULN before initiation of 
treatment. 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.  
{…} 
5.1.2 
RISKS ASSOCIATED WITH CAPECITABINE 
{…} 
Capecitabine can induce severe skin reactions such as Stevens-Johnson 
syndrome and toxic epidermal necrolysis. Capecitbaine should be permanently 
discontinued in patients who experience a severe skin reaction during treatment. 
5.1.3 
RISKS ASSOCIATED WITH TRASTUZUMAB EMTANSINE AND 
CAPECITABINE COMBINATION 
The two DLTs observed in Phase I, Cohort 1 (in mBC) were grade 3 vomiting in 
one patient and grade 3 elevated AST and ALT in one patient (see Section Error! 
Reference source not found.). Both patients were treated at dose level 1 
(capecitabine 750 mg/m2 bid, days 1–14) in combination with trastuzumab 
emtansine 3.6 mg/kg q3w). During Phase I in LA/mGC, DLTs for the combination 
of trastuzumab emtansine and capecitabine will be observed during Cycle 1 
(Days 1–21) of this study.  
{…} 
5.1.5.2 
Capecitabine Dosage Modification 
Phase I: Patients with mBC 
The dose of capecitabine can be modified from Cycle 2 onwards if considered 
appropriate by the investigator (please refer to the Xeloda® SmPC for 
recommendations). 
{…} 
Phase I: Patients with mGC 
The dose of capecitabine can be modified from cycle 2 onwards if considered 
appropriate by the investigator (please refer to Xeloda® SmPC for 
recommendations). 
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{…} 
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) regardless of the attribution of causality. AESIs 
for this study include the following: 
 
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 with 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 
{…} 
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 67 months following last dose of study drug 
(follow-up period based on PK considerations). 
{…} 
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 67 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 67 months after the last dose of study treatment. 
A female patient or partner of a male 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, to the Sponsor 
within 24 hours. 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 
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pregnancy. Pregnancies occurring up to 67 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 67 months following the last dose of either study drug. 
{…} 
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 67 months after the last dose of study treatment. 
5.3.1 
ADVERSE EVENT REPORTING PERIOD 
{…} 
After informed consent has been obtained but prior to initiation of study drug, 
only SAEs caused by a protocol-mandated intervention should be reported (e.g., 
SAEs related to invasive procedures such as biopsies, discontinuation of 
medications washout, or no treatment run in) should be reported (see Section 
Error! Reference source not found. for instructions for reporting SAEs). 
After initiation of study treatment, all AEs, regardless of relationship to study drug, 
will be reported until 2830 days after the last administration of study drug or study 
discontinuation/termination, whichever is later. After this period, all SAEs and 
non serious AESIs (regardless of causality) occurring to a patient after the 
treatment of that patient has ended should be reported to the Sponsor if the 
investigator becomes aware of them. After this period, the investigator is not 
required to actively monitor for AEs; however, the Sponsor should be notified if 
the investigator becomes aware of any poststudy SAEs patients after the study 
has ended (see Section 5.6). 
{…} 
5.4.3 
REPORTING REQUIREMENTS FOR PREGNANCIES 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform 
the investigator if they become pregnant during the study or within 67 months 
after the last dose of study drug. A Pregnancy Report eCRF should be completed 
by the investigator immediately (i.e., no more than 24 hours) after learning of the 
pregnancy and submitted via the EDC system. A Pregnancy Report will 
automatically be generated and sent to the Sponsor Safety Risk Management. 
Pregnancy should not be recorded on the AE eCRF. The investigator should 
have the patient discontinue the study drug and discuss with the patient the risks 
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of the pregnancy and the possible effects on the fetus. Monitoring of the patient 
should continue until conclusion of the pregnancy. 
{…} 
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 67 months after the last dose of study drug.  
{…} 
 
5.6 
POST-STUDY ADVERSE EVENTS 
At the time of study completion/early termination visit or study discontinuation, 
the investigator should instruct each patient to report to the investigator any 
subsequent AEs that the patient’s physician believes could be related or not 
related to theprior study drug under observationtreatment or study procedures. 
The investigator should notify the Sponsor of any death, SAE or AESI occurring 
at any time after a patient has discontinued study participation.The investigator is 
not required to actively monitor patients for AEs after the end of the AE reporting 
period (defined as 28 days after the last dose of study drug). However, the 
Sponsor should be notified if the investigator becomes aware of any death or 
other SAE occurring after the end of the AE reporting period, regardless of 
causality. The Sponsor should also be notified if the investigator becomes aware 
of the development of cancer or a congenital anomaly/birth defect in a 
subsequently conceived offspring of a patient that participated in this 
study.female patient exposed to study drug or the female partner of a male 
patient exposed to study drug. 
The investigator does not need to actively monitor patients for AEs once the trial 
has ended. The investigator should report the eventthese events directly to 
Roche Safety Risk Management via telephone or via facsimile using the Roche 
Clinical Trial (SAE) Reporting Form. 
{…} 
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SECTION 6: STATISTICAL CONSIDERATIONS AND ANALYSIS 
PLAN 
The design of this study includes: Phase I, Randomized Phase II and different 
cohorts. Corresponding analyses as described in the protocol will be performed 
when all data for a particular cohort and study phase are collected and cleaned. 
Phase I: Patients with mBC: 
Enrollment into Cohort 1, patients with HER2-positive mBC, will open first. 
Enrolled patients will receive study drug until Investigator-assessed disease 
progressionPD, unacceptable toxicities, patient consenttoxicity, withdrawal of 
consent, death, reasons deemed by the treating physician, or study termination 
by the Sponsor. 
Randomized Phase II: Exploration of Efficacy and Safety in mBC Patients 
randomized in Phase II will receive study drug until Investigator assessed 
disease progression, unacceptable toxicities, patient consent withdrawal, death, 
reasons deemed by the treating physician, or study termination by the Sponsor. 
Patients randomized in Phase II will receive study drug until investigator-
assessed PD, unacceptable toxicity, withdrawal of consent, death, reasons 
deemed by the treating physician, or study termination by the Sponsor. 
The finalprimary analysis of Randomized Phase II part of this study for ORRBOR 
will be performed when 70% of the patients have experienced a PFS event or at 
the end of the trial, whichever comes first. It is estimated that 70% of patients will 
have experienced a PFS event approximately 26 months after the randomization 
of the first patient.  
The EOS (defined in Section 3.2).analysis will include an updated analysis of 
BOR, which will be done in a purely exploratory manner.   
Phase I: Patients with mGC: 
Once the MTD is established for Cohort 1, enrollment of patients with HER2-
positive and locally advanced or LA/mGC into Cohort 2 will be opened. 
Enrolled patients will receive study drug until investigator-assessed disease 
progressionPD, unacceptable toxicities, patient consenttoxicity, withdrawal of 
consent, death, reasons deemed by the treating physician, or study termination 
by the Sponsor. 
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6.1 
DETERMINATION OF SAMPLE SIZE 
Sample Size for Phase I: mBC 
This part will be based on a classical 3 plus 3 Phase I design. A minimum of 6 
and up to 18 patients will be enrolled into Cohort 1. There is no formal sample 
size estimation for this part. 
Sample Size for Randomized Phase II: Exploration of Efficacy and Safety in 
mBC 
The sample size for the primary endpoint BOR is based on a Fisher’s exact test 
with an alpha level of 5% (one-sided),48,49 power of 80% and the clinical 
assumption of a BOR rate of 43% with trastuzumab emtansine alone and 62.5% 
with the combination of trastuzumab emtansine and capecitabine. Approximately 
117210 patients (78105 patients in the combination of T DM1 and capecitabine 
respective 39 patients in TDM1each treatment group), including a 1015% 
withdrawal rate, will be randomized with a 21:1 ratio to trastuzumab emtansine 
alone or the combination of T DM1trastuzumab emtansine and capecitabine or 
T-DM1. . 
Point estimates and 95% Clopper-Pearson exact CIs are tabulated for a range of 
possible BOR outcomes for both treatment groups in Table 8. 
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Table 1  Sample Size Based on BOR 
 
N (T DM1 and capecitabine)* = 70 patients* 
BOR rate [%] 
95% CI (within the treatment group) [%] 
57.5 
 (45.1 69.2) 
60.0 
 (47.6–71.5) 
62.5 
 (50.1 73.8) 
65.0 
 (52.7 76.0) 
67.5 
 (55.2–78.2) 
 
N (T DM1) = 35 patients* 
BOR rate [%] 
95% CI (within the treatment group) [%] 
37.0 
 (21.4 54.9) 
40.0 
 (23.9–57.9) 
43.0 
 (26.4 60.8) 
46.0 
 (29.1 63.6) 
49.0 
 (31.8–66.4) 
 
* N = Number of patients without adjustment for withdrawal; CI = confidence 
interval  
N (T-DM1 and capecitabine) / N (T-DM1) = 2 
 
Expected BOR rate for patients who received trastuzumab emtansine An 
expected BOR rate of 43.6% (95% CI: 38.6%–48.6%) for patients receiving 
trastuzumab emtansine alone was chosen based on previously published data 
for T-DM1 in patients with unresectable, locally advanced or mBC previously 
treated with a taxane and trastuzumab (EMILIA study; Verma et al. 2012).).27 
{…} 
The precision for the BOR estimate of the combination of T DM1 and 
capecitabine is approximately 12%, e.g. BOR of 60%, 95% CI of (47.6%, 71.5%). 
Due to the lower sample size of the treatment group T DM1, the corresponding 
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precision for the BOR estimate is increased to 18%, e.g. BOR of 46%, 95% CI of 
(29.1%, 63.6%). 
The 2:1 randomization ratio will be applied to allow more patients being exposed 
to the combination of T DM1 and capecitabine and to enable a more thorough 
assessment of the corresponding safety profile. 
The estimation of sample size was performed by Nquery® and SASEAST® 
programs. 
Stratification Factors 
The following stratification factor will be implemented in the Randomized Phase II 
of the trialstudy: 
 
Number of prior lines of treatment for metastatic disease (≤1 or >1; excluding 
single-agent hormones) 
A treatment line is any regimen given to a patient from treatment initiation until 
confirmed disease progressionPD. 
{…} 
6.4.1 
PRIMARY EFFICACY ENDPOINT 
{…} 
Randomized Phase II: Exploration of Efficacy in mBC  
The primary efficacy endpoint for the Randomized Phase II part of the study is 
the ORR as assessed via BOR. The BOR is defined as the best response 
recorded from the start or randomization into the Phase II part of the study and 
until disease progression/recurrencePD, death, withdrawal of consent, start of 
new anticancer treatment, or EOS, whichever occurs first. 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 
28 days after the criteria for response are first met, i.e., patients need to have two 
consecutive assessments of PR or CR.  
The emphasis of the exploratory Randomized Phase II part of the study will not 
be formal statisticalprimary hypothesis testing but the estimation of: 
 
Theof interest when comparing ORR – as assessed via BOR rate with 
corresponding 95% CIs for each treatment group. The justification of the 
sample size is based on considerations regarding the width of 95% CIs for 
each treatment group estimate (precision of the corresponding estimate). 
The treatment effect (– between the two treatment groups comparison) with 
corresponding 95% CIs.(combination of trastuzumab emtansine and 
capecitabine versus trastuzumab emtansine alone) is:  
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 
H0: πTDM1 = πtrastuzumab emtansine + capecitabine where πtrastuzumab emtansine is BOR in 
TDM1 and π trastuzumab emtansine + capecitabine is BOR in trastuzumab emtansine + 
capecitabine 
 
H1: π trastuzumab emtansine ≠ π trastuzumab emtansine + capecitabine  
 
The number and proportions of responders and non-responders (based on BOR) 
together with 9095% Clopper-Pearson CIs will be presented for each treatment 
group.  
The difference in BOR between treatment groups will be displayed with 
associated 9095% CIs using the Hauck-Anderson approach and p-values for the 
Fisher’s exact test.  
Logistic analysis will be used to assess the influence of the stratification factor 
and baseline covariates in an exploratory manner. 
The primary analysis of BOR will be performed when 70% of the patients have 
experienced a PFS event or at the end of the trial, whichever comes first. It is 
estimated that 70% of patients will have experienced a PFS event approximately 
26 months after the randomization of the first patient. 
{…} 
6.4.2 
SECONDARY EFFICACY ENDPOINTS 
 
{…} 
Estimates for the survivor function of both treatment groups for TTR, DoR, TTP, 
TTF, and OS will be obtained by using the Kaplan-Meier method. HRs and 
associated 9095% CIs will be estimated from non-stratified and stratified (based 
on the stratification factor) Cox regression models. 
{…} 
6.5 
SAFETY ANALYSES 
{…} 
Randomized Phase II: Exploration of Safety in mBC  
Safety endpoints during Phase II will be assessed via total AEs, AEs Grade ≥3 
AEs, SAEs, AESIs (as described in Section 5), fatal AEs and their causes, 
events to monitor, premature withdrawal from study medication and/or study, 
laboratory parameters, LVEF, exposure to study medication, concomitant 
medications, vital signs, ECOG performance status, and physical examination. 
{…} 
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6.8 
EXPLORATORY ANALYSES 
{…} 
For the Randomized Phase II only: Exploration of Efficacy and Safety in 
Patients with mBC only: 
Subgroup analysis for BOR, safety endpoints (AEs, SAEs, AEs with Grade ≥ 3 
AEs, and AESIs) in Phase II will be presented for: elderly versus younger 
patients, and patients with ECOG 0–1 versus ECOG 2, and patients with ≤ 
versus >1 prior treatment regimen for metastatic disease.  
 
6.9 
INTERIM ANALYSES 
There is no formal efficacy interim analysis.  
However, an IDMC will adviserecommend whether the Randomized Phase II part 
of the study can commence. The IDMC will also monitor safety outcomes after 
2025, 75, and 60 150 patients have received at least 3 cycles (Cycle 3 Day 1) of 
treatment in the Randomized Phase II part of the study. Afterwards, the IDMC 
will monitor accumulating patient safety data every 6 months during the course of 
the Randomized Phase II of the study or as requested. 
 
 
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42 
Appendix 1  
Schedule of Assessments 
Table 1 
  
 
 
 
 
 
 
 
Schedule of assessments for mBC patients (Phase I, Cohort 1 and 
Randomized Phase II) 
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 Onwards 
Safety 
Follow-Up 
Visit 
Follow-
Up2 
Day 
-28 to -1 
1 
8 
15 
1 
8 
15 
1 
8 
15 
28-42 days 
after last 
dose 
every 3-6 
months 
Informed Consent 
Xa 
 
 
 
 
 
 
 
 
 
 
 
HER2 Status  
Xb 
 
 
 
 
 
 
 
 
 
 
 
Medical History and 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination  
X 
 
 
 
 
 
 
 
 
 
 
 
Limited Physical Examinationc 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Height and Weightd 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Vital Signse 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
ECOG Performance Status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Concomitant Medication 
Reporting 
Xf 
X 
Ongoing 
 
AE Reporting 
Xg 
Ongoing 
X 
Xh 
12-lead ECG  
X  
 
 
 
 
 
 
 
 
 
 
 
ECHO/MUGAi 
Xi 
 
 
Xi 
 
 
Xi 
 
 
Xi 
Xi 
 
Tumor Assessmentsj 
X 
At Cycle 3 (9 weeks after randomization), and then every 4th cycle (12 weeks 
thereafter, regardless of dose delay or early discontinuation) until disease 
progressionPD or study termination), whichever occurs earlier 
X 
X 
Brain CT or MRIk 
X 
At the discretion of the investigator, if clinically indicated, until disease progressionPD 
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Bone Scan/Imagingl 
X 
As clinically indicated 
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Appendix 1  
Schedule of Assessments (cont.) 
 
Table 1 
  
 
 
 
 
 
 
 
Schedule of assessments for mBC patients (Phase I, Cohort 1 and 
Randomized Phase II) (cont.)  
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 Onwards 
Safety 
Follow-Up 
Visit 
Follow-
Up2  
Day 
-28 to -1 
1  
8 
15 
1  
8 
15 
1  
8 
15 
28-42 days 
after last 
dose 
every 3-6 
months 
Hematologym 
X  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
 
 
X 
 
Biochemistryo 
X  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
 
 
X 
 
Urinalysisp 
X  
As clinically indicated 
X 
 
INR/aPTT 
X  
As clinically indicated, e.g. for patients receiving anticoagulation therapy 
X 
 
Pregnancy Testq 
X  
 
 
 
 
 
X q 
 
 
X q 
X  
X 
PK/PD Samples (see 
Appendix 2)r 
 
Xr 
 
 
Xr 
 
 
 
 
 
 
 
Assessment of Patient 
Hospitalizations and/or Hospital 
Visits 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Administration of Trastuzumab 
Emtansine 
 
D 2s 
 
 
D 1s 
 
 
D 1s 
 
 
 
 
Administration of Capecitabine 
 
D 1–14 
 
D 1–14 
 
D 1–14 
 
 
 
Overall Survival 
X 
X 
X 
X 
Randomization into the Phase II 
Part of the Study 
Xt 
 
 
 
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Appendix 1  
Schedule of Assessments (cont.) 
 
AE = Adverse Event; aPTT = Activated Partial Thromboplastin Time; CT = Computed Tomography; ECHO = Echocardiogram; ECOG = Eastern 
Cooperative Oncology Group; D= Day; 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, INR and aPTT assessments) at Screening: to be performed within 14 days prior 
to first treatment. Screening laboratory assessments may be done on the same day of first study treatment (Cycle1 Day1). 
2. All patients will be followed-up every 6 months (except for pregnancy, which is at 3 and 6 months after safety follow-up visit until disease 
progresses for tumor assessment or study closure, whichever occurs first. Patients who discontinue study treatment for reasons other than 
disease progressionPD will continue to undergo tumor assessments every 3–6 months. 
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 for patients with mBC.  
c) Limited symptom-directed physical examination. 
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. 
g) During screening, only SAEs considered related to protocol-mandated procedures will be collected. 
h) Patients will be followed for new or worsening AEs for 28 days following the last infusion of study drug or until the early termination visit, until 
treatment-related AEs resolve or stabilize, or until the initiation of another anti-cancer therapy, whichever occurs first. After 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, 
between Days 15 and 21 in cycles 1 and 3, and between Days 15 and 21 and on Days 15 21 of Cycle 1, Cycle 3, 30 42 and on day 21 of 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. 
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Appendix 1  
Schedule of Assessments (cont.) 
 
j) Tumor assessments (± 5 business days), including a CT or MRI with contrast of the chest, abdomen, and pelvis should be performed according 
to the indicated schedule. 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, 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 until PD, withdrawal of consent, or study terminaton (whichever occurs 
earlier). 
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 4.5.1.4 of the protocol and in Appendix 3. 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 study treatment, non-isotopic radiographic modalities should be utilized to 
document the extent of bony metastatic disease. Refer to Appendix 4 in the protocol 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) Assessments should be performed at screening, on Day 1, 8 and 15 of Cycles 1–3, on Day 1 of all subsequent cycles, and weekly following 
any hematologic AE. If capecitabine is discontinued due to toxicity, assessments should be performed weekly (minimum) until resolution of the 
AE (Grade  1/ baseline), and on Day 1 of subsequent cycles thereafter. All assessments should 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, blood urea nitrogen (BUN)/urea (mandatory), 
creatinine, uric acid, total protein, albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), G-GT, LDH, total bilirubin (and direct bilirubin 
where total bilirubin > ULN). 
p) Includes specific gravity, pH, protein, glucose, blood, ketones and bilirubin. 
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Appendix 1  
Schedule of Assessments (cont.) 
 
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. 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 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. 
r) Pharmacokinetic assessments will be performed during the Dose MTD-Finding part of the study only (see Appendix 2). 
s) Trastuzumab emtansine will be administered on Day 1 of each 3-weekly cycle for all patients with mBC in Cohort 1 and Randomized Phase II 
period of the study except in the first cycle where trastuzumab emtansine will be given on Day 2 (to allow PK sampling). 
t) Patients will be randomized only in the Randomized Phase II part of the study. No blinding will be used, as this is an open-label study. A 2:1 
randomization ratio will be applied to allow more patients to be exposed to the combination of T DM1 and capecitabine, and to enable a more 
thorough assessment of the corresponding safety profile. 
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Appendix 1  
Schedule of Assessments (cont.)  
Table 2 Schedule of assessments for patients with LA/mGC (Phase I, Cohort 2) 
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 Onwards 
Safety 
Follow-Up 
Visit 
Follow-
Up2  
Day 
-28 to -1 
1 
8 
15 
1 
8 
15 
1 
8 
15 
28–42 days 
after last 
dose 
every 3–6 
months 
Informed Consent 
Xa 
 
 
 
 
 
 
 
 
 
 
 
HER2 Status  
Xb 
 
 
 
 
 
 
 
 
 
 
 
Medical History and 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical 
Examination  
X 
 
 
 
 
 
 
 
 
 
 
 
Limited Physical Examinationc 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Height and Weightd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signse 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
ECOG Performance Status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Concomitant Medication 
Reporting 
Xf 
X 
Ongoing 
 
AE Reporting 
Xg 
Ongoing 
X 
Xh 
12-lead ECG  
X  
 
 
 
 
 
 
 
 
 
 
 
ECHO/MUGAi 
Xi 
 
 
Xi 
 
 
Xi 
 
 
Xi 
Xi 
 
Tumor Assessmentsj 
X 
At 9 weeks after C1D1, and every 12 weeks thereafter, regardless of dose delay or 
early discontinuation, until PD or study termination, whichever occurs earliest 
X 
 
Brain CT or MRIk 
X 
At the discretion of the investigator, if clinically indicated, until disease progressionPD 
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Hematologym 
X  
Xn 
Xn  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
X 
 
Biochemistryo 
X  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
X 
 
Urinalysisp 
X  
As clinically indicated 
X 
 
INR/aPTT 
X  
As clinically indicated, e.g. for patients receiving anticoagulation therapy 
X 
 
Pregnancy Testq 
X  
 
 
 
 
 
Xq 
 
 
Xq 
X 
X 
PK/PD Samples (see 
Appendix 2) 
 
X 
 
 
X 
 
 
 
 
 
 
 
Assessment of Patient 
Hospitalizations and/or 
Hospital Visits 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Administration of Trastuzumab 
Emtansine 
 
D 2r 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Administration of Capecitabine 
 
D 1–14 
 
D 1–14 
 
D 1–14 
 
 
 
Overall Survival 
X 
X 
X 
X 
AE = Adverse Event; aPTT = Activated Partial Thromboplastin Time; CT = Computed Tomography; ECHO = Echocardiogram; ECOG = Eastern 
Cooperative Oncology Group; D= Day; 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 
 
Bone Scan/Imagingl 
X 
As clinically indicated 
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Appendix 1  
Schedule of Assessments (cont.) 
 
1. NOTE: Local laboratory (hematology, biochemistry, urinalysis, INR and aPTT assessments) at Screening: to be performed within 14 days prior 
to first study treatment. Screening laboratory assessments may be done on the same day of first study treatment (Cycle1 Day1) visit. 
2. All patients will be followed-up every 6 months (except for pregnancy, which is at 3 and 6 months after safety follow-up visit) until disease 
progresses for tumor assessment or study closure, whichever occurs first. Patients who discontinue study treatment for reasons other than 
disease progressionPD will continue to undergo tumor assessments every 3–6 months. 
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+ alone or IHC 2+ in combination with gene amplification by ISH. For patients with mGC enrolled into 
Cohort 2, central confirmation of HER2 status is required. 
c) Limited symptom-directed physical examination. 
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 fist study treatment. 
g) During screening, only SAEs considered related to protocol-mandated procedures will be collected. 
h) Patients will be followed for new or worsening AEs for 28 days following the last infusion of study drug or until the early termination visit, until 
treatment-related AEs resolve or stabilize, or until the initiation of another anti-cancer therapy, whichever occurs first. After 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, 
between Days 15 and 21 in cycles 1 and 3, and between Days 15 and 21 and on Days 15 21, 30 42 and 9 weeks of every 3rd 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. 
j)  
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Appendix 1  
Schedule of Assessments (cont.) 
 
k) Tumor assessments (± 5 business days), including a CT or MRI with contrast of the chest, abdomen, and pelvis should be performed according 
to the indicated schedule. 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, 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 until PD, withdrawal of consent, or study termination (whichever 
occurs earliest). 
l) 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 4.5.1.4 of the protocol and in Appendix 3. A brain MRI or CT should be performed along with regularly scheduled 
tumor assessments in these instances. 
m) 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 4 in the protocol for additional details. 
n) Hematologic assessments include Hemoglobin (Hb), hematocrit, red blood cell count, platelet count, and WBC with differential (including 
neutrophils, lymphocytes, monocytes, eosinophils and basophils). 
o) Assessments should be performed at screening, on Day 1, 8 and 15 of all cycles. All assessments should be performed within 72 hours 
preceding administration of study treatment; results must be reviewed and documented prior to administration of study treatment. 
p) Biochemistry assessments include: sodium, potassium, chloride, calcium, magnesium, glucose, BUN/urea (mandatory), creatinine, uric acid, 
total protein, albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), G-GT, LDH, total bilirubin (and direct bilirubin where total bilirubin > 
ULN). 
q) Includes specific gravity, pH, protein, glucose, blood, ketones and bilirubin. 
r) Serum b-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. 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 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. 
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s) Trastuzumab emtansine will be administered on Day 1 of each weekly cycle for all patients enrolled in Cohort 2 (A&B) except in the first cycle 
where trastuzumab emtansine will be given on DAY 2 (to allow drug interaction assessment). 
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PROTOCOL AMENDMENT APPROVAL 
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 MO282301, Version 4 
 
PROTOCOL 
TITLE: 
PHASE I STUDY OF THE COMBINATION OF 
TRASTUZUMAB EMTANSINE (T-DM1) AND 
CAPECITABINE IN HER2-POSITIVE METASTATIC 
BREAST CANCER AND HER2-POSITIVE LOCALLY 
ADVANCED/METASTATIC GASTRIC CANCER 
PATIENTS, FOLLOWED BY A RANDOMIZED, 
OPEN-LABEL PHASE II STUDY OF 
TRASTUZUMAB EMTANSINE AND CAPECITABINE 
VERSUS TRASTUZUMAB EMTANSINE ALONE IN 
HER2-POSITIVE METASTATIC BREAST CANCER 
PROTOCOL NUMBER: MO28230 
EUDRACT NUMBER: 
2012-001547-46 
TEST PRODUCT: 
Trastuzumab emtansine (RO5304020) 
Capecitabine (RO091978) 
MEDICAL MONITOR: 
 MD 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version: 30-Jun-2014 
DATE AMENDED: 
Version: 23-Mar-2016 
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2 
PROTOCOL AMENDMENT, VERSION 4 
RATIONALE 
Changes to the protocol have been made according to the latest clinical 
information and current recommendations. Specifically, the section on risks 
associated with capecitabine has been updated following the inclusion of the 
contraindication in the capecitabine SmPC for patients with known complete 
absence of dihydropyrimidine dehydrogenase (DPD) activity, and to include 
additional side effects (ophthalmological complications, acute renal failure from 
dehydration) and the risk of leucovorin which may increase the toxicity of 
capecitabine. The safety reporting of pregnancies has also been updated to 
highlight information that will be requested by Roche Drug Safety. 
The sections on Assessment of causality of new adverse events, Adverse events 
occurring secondary to other events, Deaths and Pre-existing medical conditions 
have been updated according to the latest Roche guidance, and new sections 
describing the reporting of Abnormal vital sign values, Abnormal liver function 
tests, and Adverse events associated with an overdose or error in drug 
administration have been added. 
The medical monitor and statistician for the study have been replaced. 
The number of patients in the Randomized Phase II study has been reduced, 
due to slow recruitment and difficulty finding patients. 
Minor changes have been made to inclusion criterion (to improve clarity and to 
align the synopsis and protocol), exclusion criterion (to reflect changes in 
treatment practice following the regulatory approval of trastuzumab emtansine). 
As vital signs are not recorded in the eCRF, there are no data to summarize and 
so this information has been deleted from the statistical analyses. 
Deleted text appears in black strikethrough. New text is marked with yellow 
highlighting. This amendment represents cumulative changes to the original 
protocol. 
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Exclusion Criteria 
For mBC Patients 
2. Prior treatment with trastuzumab emtansine or prior enrollment in a 
trastuzumab emtansine-containing study, regardless of whether the patient 
received trastuzumab emtansine. 
5.  Related capecitabine contraindications: 
a) Treatment with sorivudine or its chemically-related analogues, such as 
brivudine 
b)  Rare hereditary problems of galactose intolerance, Lapp lactase 
deficiency, or glucose-galactose malabsorption 
c) Known complete absence of dihyropyrimidine dehydrogenase (DPD) 
activity. Signs or symptoms suggesting that the patient has 
dihydropyrimidine dehydrogenase (DPD) deficiency 
 
For LA/mGC Patients 
2. Prior treatment with trastuzumab emtansine or prior enrollment in a 
trastuzumab emtansine-containing study, regardless of whether the patient 
received trastuzumab emtansine. 
5.  Related capecitabine contraindications: 
a) Treatment with sorivudine or its chemically-related analogues, such as 
brivudine 
b) Rare hereditary problems of galactose intolerance, Lapp lactase deficiency, 
or glucose-galactose malabsorption 
c) Known complete absence of DPD activity. Signs or symptoms suggesting 
that the patient has DPD deficiency 
Safety Outcome Measures 
 Vital signs and ECOG performance status 
Safety Endpoints: 
Phase I, Cohort 1: MTD-Finding: mBC 
LVEF over time will be summarized as mean, median and range (minimum and 
maximum) and will be presented graphically. Vital signs will be analyzed in a 
similar way. 
Randomized Phase II: Exploration of Safety in mBC  
Safety endpoints during the Randomized Phase II part of the study will be 
assessed via: total AEs, Grade ≥ 3 AEs, SAEs, premature withdrawal from study 
medication, AESIs, events to monitor, laboratory parameters, LVEF, exposure to 
study medication, concomitant medications, vital signs, ECOG performance 
status, and physical examination. 
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LVEF over time will be summarized as mean, median and range (minimum and 
maximum) and will be presented graphically. Vital signs will be analyzed in a 
similar way. 
Determination of Sample Size 
Sample Size for Randomized Phase II: Exploration of Efficacy and Safety in 
mBC 
The sample size for the primary endpoint BOR is based on a Fisher’s exact test 
with an alpha level of 5% (one-sided), power of 70% 80% and the clinical 
assumption of a BOR rate of 43% with trastuzumab emtansine alone and 62.5% 
with the combination of trastuzumab emtansine and capecitabine. Approximately 
160 210 patients (approximately 80 105 patients in each treatment group), 
including a 15% withdrawal rate, will be randomized with a 1:1 ratio to either 
trastuzumab emtansine alone or the combination of trastuzumab emtansine and 
capecitabine.  
SECTION 3: STUDY DESIGN 
3.1.1 
OVERVIEW OF STUDY DESIGN 
{…} 
Duration of Treatment and Patient Follow-up 
Duration of treatment: All patients will be treated until investigator-assessed PD, 
unacceptable toxicity, withdrawal of consent, death, reasons deemed by the 
treating physician, or study termination by the Sponsor. In case of toxicities 
requiring the discontinuation of capecitabine, single agent trastuzumab 
emtansine may be continued. In case of toxicities requiring the discontinuation of 
trastuzumab emtansine, the patient will be followed up until EOS (treatment with 
capecitabine alone is not allowed).If toxicity is considered by the investigator to 
be related to only one of the two agents, the non-implicated agent can be 
continued as single agent therapy.   
{…} 
 
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Duration of Study, Database Closure and Data Reporting 
{…} 
Figure 1 Overview of Study Design 
 
 
 
COHORT 1 mBC 
 
COHORT 2 LA/mGC 
Phase I 
Dose Finding 
 
 
 
n = ~6–18 
3 plus 3 classical design 
Trastuzumab emtansine: 3.6 mg/kg 
q3w 
Capecitabine: Dose Levels 1 to -21 
 
 
 
n = ~3–12 
3 plus 3 classical design 
Trastuzumab emtansine: 2.4 
mg/kg qw 
Capecitabine: Dose Levels -1 to 
-21,3 
 
 
 
Randomized 
Phase II 
Exploration of 
Efficacy and 
Safety 
 
 
n = ~160 210 
Randomized, open-label with two 
treatment groups4 
Trastuzumab emtansine: 3.6 mg/kg 
q3w 
Capecitabine: MTD defined 
 
 
 
1 Capecitabine doses are administered daily on Days 1–14 q3w 
2 The MTD defined in the mBC Phase I study will be implemented in the mBC Randomized 
Phase II and mGC Phase I studies 
3 Cohort 2 will open to recruit patients with LA/mGC using the MTD defined in Phase I for patients 
with mBC. Dose Level 1 will not be explored in Cohort 2 (see also Section 3.3.2.2) 
4 Stratification factor: Number of prior lines of treatment for metastatic disease (≤1 or >1; 
excluding single-agent hormones) 
mBC = metastatic breast cancer; LA/mGC = locally advanced/metastatic gastric cancer; MTD = 
maximum tolerated dose; q3w = every 3 weeks; qw = weekly. 
3.1.1.2 
Overview of Phase II: Exploration of Efficacy and Safety in 
Patients with mBC 
{…} 
Approximately 160 210 additional patients with HER2-positive mBC will be 
randomized into the Phase II part of the study. Patients in the Phase I part of the 
study will not contribute to the Phase II part of the study; however, they will be 
followed-up until end of study (EOS). 
3.1.1.4 
Number of Patients 
Overall, it is anticipated that the maximum number of patients enrolled into the 
study will be approximately 190 240. 
MTD defined2 
MTD defined2 
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{…} 
Randomized Phase II: Exploration of Efficacy and Safety in mBC  
For this part of the study, a total of approximately 160 210 patients with mBC will 
be randomized.  
{…} 
 
3.4.2.4  
Secondary Safety Outcome Measures  
{…} 
 
Vital signs and ECOG performance status 
{…} 
 
3.4.3.3  
Secondary Safety Outcome Measures  
{…} 
 
Vital signs and ECOG performance status 
{…} 
SECTION 4: MATERIALS AND METHODS 
4.1.3 
INCLUSION CRITERIA 
4.1.3.1 
For Patients with mBC 
Patients must meet the following criteria for study entry: 
{…} 
17. Disease progression on at least one prior regimen containing trastuzumab 
and chemotherapy either separately or in combination. Patients may be 
eligible to receive study therapy in the first-line setting if trastuzumab and 
chemotherapy were given in the [neo]adjuvant setting. 
{…} 
4.1.3.2 
For Patients with LA/mGC 
Patients must meet the following criteria for study entry: 
{…} 
12. Life expectancy ≥12 weeks 
{…} 
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4.1.4 
EXCLUSION CRITERIA 
4.1.4.1 For Patients with mBC 
{…} 
2. Prior treatment with trastuzumab emtansine or prior enrollment in a 
trastuzumab emtansine-containing study, regardless of whether the patient 
received trastuzumab emtansine 
{…} 
5.  Related capecitabine contraindications: 
a) Treatment with sorivudine or its chemically-related analogues, such as 
brivudine 
b) Rare hereditary problems of galactose intolerance, Lapp lactase deficiency, 
or glucose-galactose malabsorption 
c) Known complete absence of DPD activity. Signs or symptoms suggesting 
that the patient has DPD deficiency 
{…} 
4.1.4.2 
For Patients with LA/mGC 
{…} 
2. Prior treatment with trastuzumab emtansine or prior enrollment in a 
trastuzumab emtansine-containing study, regardless of whether the patient 
received trastuzumab emtansine 
{…} 
5.  Related capecitabine contraindications: 
a) Treatment with sorivudine or its chemically-related analogues, such as 
brivudine 
b) Rare hereditary problems of galactose intolerance, Lapp lactase deficiency, 
or glucose-galactose malabsorption 
c) Known complete absence of DPD activity. Signs or symptoms suggesting 
that the patient has DPD deficiency 
{…} 
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SECTION 5: ASSESSMENT OF SAFETY 
5.1.2 
RISKS ASSOCIATED WITH CAPECITABINE 
{…} 
RarelyA rare, unexpected, severe toxicity (e.g. stomatitis, diarrhea, mucosal 
inflammation, neutropenia, and neurotoxicity) associated with 5-FU has been 
attributed to deficiency of dihydropyrimidine dehydrogenase (DPD) activity. 
Therefore, a link between decreased levels of DPD and increased, potentially 
fatal, toxic effects of 5-FU cannot be excluded. Patients with low or absent DPD 
activity, an enzyme involved in fluorouracil degradation, are at increased risk for 
severe, life-threatening, or fatal adverse reactions caused by fluorouracil.  
 
Although DPD deficiency cannot be precisely defined, it is known that patients 
with certain homozygous or certain compound heterozygous mutations in the 
DPYD gene locus, which can cause complete or near complete absence of DPD 
enzymatic activity (as determined by laboratory assays), have the highest risk of 
life-threatening or fatal toxicity47 and should not be treated with capecitabine. No 
dose has been proven safe for patients with complete absence of DPD activity.  
 
For patients with partial DPD deficiency (such as those with heterozygous 
mutations in the DPYD gene) and where the benefits of capecitabine are 
considered to outweigh the risks (taking into account the suitability of an 
alternative non-fluoropyrimidine chemotherapeutic regimen), these patients must 
be treated with extreme caution, and frequent subsequent monitoring and dose 
adjustment according to toxicity. There is insufficient data to recommend a 
specific dose in patients with partial DPD activity as measured by specific test. 
 
In patients with unrecognized DPD deficiency treated with capecitabine, life-
threatening toxicities manifesting as acute overdose may occur. In the event of 
Grade 2–4 acute toxicity, treatment must be discontinued immediately. 
Permanent discontinuation should be considered based on clinical assessment 
of the onset, duration, and severity of the observed toxicities. 
Capecitabine can induce hand-foot syndrome (palmar-plantar erythrodysesthesia 
or chemotherapy-induced acral erythema), which is a cutaneous toxicity. 
Persistent or severe hand-foot syndrome (Grade 2 and above) can eventually 
lead to loss of fingerprints, which could impact patient identification.48 For 
patients receiving capecitabine monotherapy in the metastatic setting, the 
median time to onset was 79 days (range 11–360 days), with a severity range of 
Grades 1 to 3. Grade 1 hand-foot syndrome is defined by numbness, 
dysesthesia/paresthesia, tingling or erythema of the hands and/or feet and/or 
discomfort which does not disrupt normal activities. Grade 2 is defined as painful 
erythema and swelling of the hands and/or feet and/or discomfort affecting the 
patient’s activities of daily living (ADL). Grade 3 is defined as moist 
desquamation, ulceration, blistering or severe pain of the hands and/or feet 
and/or severe discomfort that causes the patient to be unable to work or perform 
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ADL. If Grade 2 or 3 hand-foot syndrome occurs, administration of capecitabine 
should be interrupted until the event resolves or decreases in intensity to Grade 1. 
Following Grade 3 hand-foot syndrome, subsequent doses of capecitabine 
should be decreased.  
Patients should be carefully monitored for ophthalmological complications such 
as keratitis and corneal disorders, especially if they have a prior history of eye 
disorders. Treatment of eye disorders should be initiated as clinically appropriate. 
Capecitabine can induce hyperbilirubinemia. Administration of capecitabine 
should be interrupted if treatment-related elevations in bilirubin of > 3.0 × ULN or 
treatment-related elevations in hepatic aminotransferases (ALT/AST) 
of Grade ≥ 2 occur.  
Dehydration may cause acute renal failure, especially in patients with pre-
existing compromised renal function or when capecitabine is given concomitantly 
with known nephrotoxic agents. Acute renal failure secondary to dehydration 
might be potentially fatal. 
Capecitabine can induce severe skin reactions such as Stevens-Johnson 
syndrome and toxic epidermal necrolysis. Capecitabine should be permanently 
discontinued in patients who experience a severe skin reaction possibly 
attributable to capecitabine during treatment. 
Leucovorin affects the pharmacodynamics of capecitabine and may increase the 
toxicity of capecitabine. This may be relevant in patients receiving folic acid 
supplementation for folate deficiency due to the similarity between folinic acid 
and folic acid.  
5.1.4 DEFINITION OF DOSE-LIMITING TOXICITY  
{…} 
Non-hematologic 
{…} 
8. Grade 2 toxicity requiring interruption of treatment for > 14 days 
NOTE: Patients experiencing acute early-onset (within 1 week) or unusually 
severe toxicity of Grade ≥ 3 hand-foot syndrome, diarrhea, mucositisstomatitis, 
mucosal inflammation, neurotoxicity, neutropenia, or febrile neutropenia with 
ANC < 500 cells/mm3 during Cycle 1 must be tested for DPD deficiency (a 
central laboratory will be appointed). The SC will adjudicate in cases of DLTs that 
are not covered by the existing DLT criteria. 
{…} 
 
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5.3.4 
ASSESSMENT OF CAUSALITY OF ADVERSE EVENTS  
Investigators should use their knowledge of the patient, the circumstances 
surrounding the event, temporal relationship of event onset to the initiation of 
study drug, course of the event considering especially the effects of dose 
reduction or discontinuation of study drug or reintroduction of study drug (as 
applicable), known association of the event with the study drug or with similar 
treatments, known association of the event with the disease under study, 
presence of risk factors in the patient or use of concomitant medications known 
to increase the occurrence of the event, presence of non-treatment-related 
factors that are known to be associated with the occurrence of the event, 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.  
{…} 
5.3.5 
PROCEDURES FOR RECORDING ADVERSE EVENTS 
5.3.5.2 
Adverse Events Occurring Secondary to Other Events 
{…} 
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. All AEs should be recorded 
separately on the Adverse Event eCRF if it is unclear whether the events are 
associated. 
5.3.5.5 
Abnormal Vital Sign Values  
Not every vital sign abnormality qualifies as an AE. A vital sign result must be 
reported as an AE if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator’s judgment  
It is the investigator’s responsibility to review all vital sign findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated vital sign 
abnormality should be classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be 
recorded on the Adverse Event eCRF. 
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Observations of the same clinically significant vital sign abnormality from visit to 
visit should only be recorded once on the Adverse Event eCRF (see 
Section 5.3.5.3 for details on recording persistent AEs). 
5.3.5.6 
Abnormal Liver Function Tests  
The finding of an elevated ALT or AST ( 3  baseline value) in combination with 
either an elevated total bilirubin ( 2  ULN) or clinical jaundice in the absence of 
cholestasis or other causes of hyperbilirubinemia is considered to be an indicator 
of severe liver injury (as defined by Hy's law). Therefore, investigators must 
report as an AE the occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  baseline value in combination with 
total bilirubin  2  ULN (of which   35% is direct bilirubin) 
 
Treatment-emergent ALT or AST  3  baseline value in combination with 
clinical jaundice 
The most appropriate diagnosis or (if a diagnosis cannot be established) the 
abnormal laboratory values should be recorded on the Adverse Event eCRF 
(see Section 5.3.5.4) and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event), either as an SAE or a non-serious AE of 
special interest (see Section 5.4.2). 
5.3.5.7 
Deaths 
{…} 
Death should be considered an outcome and not a distinct event. The event or 
condition that caused or contributed to the fatal outcome should be recorded as 
the single medical concept on the AE eCRF. Generally, only one such event 
should be reported. If the cause of death is unknown and cannot be ascertained 
at the time of reporting, “unexplained death” should be recorded on the AE 
eCRF. If the cause of death later becomes available (e.g., after autopsy), 
“unexplained death” should be replaced by the established cause of death. The 
term "sudden death" should be used only for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen 
alive and stable. 
{…} 
5.3.5.8 
Pre-Existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of this study. 
Such conditions should be recorded on the Medical and Surgical History 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 AE eCRF, it is important to convey the concept that 
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the pre-existing condition has changed by including applicable descriptors 
(e.g., “more frequent headaches” or "worsening gastrointestinal reflux disease"). 
5.3.5.11 
Adverse Events Associated with an Overdose or Error in Drug 
Administration  
An overdose is the accidental or intentional use of a drug in an amount higher 
than the dose being studied. An overdose or incorrect administration of study 
treatment is not itself an AE, but it may result in an AE. All overdose or incorrect 
administrations of study drug with/without AEs associated should be recorded on 
the AE eCRF. If the associated AE fulfills seriousness criteria, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2). 
5.4.3 
REPORTING REQUIREMENTS FOR PREGNANCIES 
5.4.3.1 
Pregnancies in Female Patients 
{…} 
Additional information on any trastuzumab emtansine-exposed pregnancy and 
infant will be requested by Roche Drug Safety at specific time points (i.e., after 
having received the initial report, at the end of the second trimester, 2 weeks 
after the expected date of delivery, and at 3, 6, and 12 months of the infant’s life). 
Any serious adverse events associated with the pregnancy (e.g., an event in the 
fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the Adverse Event eCRF.  
In addition, the investigator will submit a Clinical Trial Pregnancy Reporting Form 
when updated information on the course and outcome of the pregnancy becomes 
available.   
6.1 
DETERMINATION OF SAMPLE SIZE 
Sample Size for Randomized Phase II: Exploration of Efficacy and Safety in 
mBC 
The sample size for the primary endpoint BOR is based on a Fisher’s exact test 
with an alpha level of 5% (one-sided),48,4950,51 power of 70% 80% and the clinical 
assumption of a BOR rate of 43% with trastuzumab emtansine alone and 62.5% 
with the combination of trastuzumab emtansine and capecitabine. Approximately 
160 210 patients (approximately 80 105 patients in each treatment group), 
including a 15% withdrawal rate, will be randomized with a 1:1 ratio to 
trastuzumab emtansine alone or the combination of trastuzumab emtansine and 
capecitabine. 
{…} 
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6.5 
SAFETY ANALYSES 
Safety Population Phase I, Cohort 1: mBC 
{…} 
LVEF will be summarized over time using mean, median and range (minimum 
and maximum) and will be presented graphically. Vital signs will be analyzed in a 
similar way. 
{…} 
Randomized Phase II: Exploration of Safety in mBC  
{…} 
Safety endpoints during Phase II will be assessed via total AEs, Grade ≥3 AEs, 
SAEs, AESIs (as described in Section 5), fatal AEs and their causes, events to 
monitor, premature withdrawal from study medication and/or study, laboratory 
parameters, LVEF, exposure to study medication, concomitant medications, vital 
signs, ECOG performance status, and physical examination. 
{…} 
LVEF will be summarized over time using mean, median and range (minimum 
and maximum) and will be presented graphically. Vital signs will be analyzed in a 
similar way. 
{…} 
6.9 
INTERIM ANALYSES 
{…} 
The IDMC will also monitor safety outcomes after 25, 75, and 150 patients have 
received at least 3 cycles (Cycle 3 Day 21) of treatment in the Randomized 
Phase II part of the study.  
{…} 
10.  
REFERENCES 
47. Amstutz U, Froehlich TK, Largiadèr CR. Dihydropyrimidine dehydrogenase 
gene as a major predictor of severe 5-fluorouracil toxicity. 
Pharmacogenomics 2011;12(9):1321–36. 
48. Drug Safety Report – Xeloda and Fingerprint loss, 1067787, January 2016 
 
(CDS Vs 14.0).
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Trastuzumab Emtansine-F. Hoffmann-La Roche Ltd 
Protocol MO282301, Version 4 
 
15 
Appendix 1  
Schedule of Assessments 
Table 1 
Schedule of assessments for mBC patients (Phase I, Cohort 1 and Randomized Phase II)  
 
{…} 
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 Onwards 
Safety 
Follow-Up 
Visit 
Follow-
Up2  
Day 
-28 to -1 
1  
8 
15 
1  
8 
15 
1  
8 
15 
28-42 days 
after last 
dose 
every 3-6 
months 
Administration of Capecitabinet 
 
D 1–14 
 
D 1–14 
 
D 1–14 
 
 
 
Randomization into the Phase II 
Part of the Study 
Xtu 
 
 
 
 
{…} 
 
o) Biochemistry assessments include: sodium, potassium, chloride, calcium, magnesium, glucose, blood urea nitrogen (BUN)/urea (mandatory), 
creatinine, uric acid, total protein, albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), G-GT, LDH, total bilirubin (and direct bilirubin 
where total bilirubin > ULN). Fasting is required before biochemistry assessment. 
t)  Capecitabine must be given within 30 minutes after a meal. 
 
{…} 
 
Trastuzumab Emtansine
RO5304020
762
Study MO28230
                             Research Report 1078906  1849
Kadcyla (RO5304020) Roche Clinical Study Report - Protocol MO28230


Trastuzumab Emtansine-F. Hoffmann-La Roche Ltd 
Protocol MO28230, Version 4 
16 
Appendix 1  
Schedule of Assessments (cont.)  
Table 2 Schedule of assessments for patients with LA/mGC (Phase I, Cohort 2) 
 
{…} 
 
Screening1  
Cycle 1 
Cycle 2–3 
Cycle 4 Onwards 
Safety 
Follow-Up 
Visit 
Follow-
Up2  
Day 
-28 to -1 
1  
8 
15 
1  
8 
15 
1  
8 
15 
28-42 days 
after last 
dose 
every 3-6 
months 
Administration of Capecitabines 
 
D 1–14 
 
D 1–14 
 
D 1–14 
 
 
 
 
{…} 
 
o) Biochemistry assessments include: sodium, potassium, chloride, calcium, magnesium, glucose, blood urea nitrogen (BUN)/urea (mandatory), 
creatinine, uric acid, total protein, albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), G-GT, LDH, total bilirubin (and direct bilirubin 
where total bilirubin > ULN). Fasting is required before biochemistry assessment. 
s)  Capecitabine must be given within 30 minutes after a meal. 
 
Trastuzumab Emtansine
RO5304020
763
Study MO28230
                             Research Report 1078906  1850
Kadcyla (RO5304020) Roche Clinical Study Report - Protocol MO28230

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