Conditions: HER2 Positive Breast Cancer, Metastatic Breast Cancer, Locally Advanced Breast Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 70
Healthy volunteers: no

Brief summary:
This is a Phase IV, single-arm, multicenter, open-label clinical trial designed to assess the safety of trastuzumab emtansine in Indian patients with HER2-positive unresectable locally advanced breast cancer (LABC) or metastatic breast cancer (mBC) who have received prior treatment with trastuzumab and a taxane.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Trastuzumab emtansine
Intervention descriptions: intervention 1: 3.6 mg/kg intravenously (IV) over 30-90 minutes on day 1 of 21 day cycle, repeated every 3 weeks

Protocol document:
Prot_000.pdf: 
 
Official Title: 
 
A Multicenter, Open-Label, Single-Arm, Phase IV Study of Trastuzumab 
Emtansine in Indian Patients With HER2-Positive Unresectable Locally 
Advanced or Metastatic Breast Cancer Who Have Received Prior 
Treatment With Trastuzumab and a Taxane 
NCT Number: 
NCT02658734 
Document Date: 
Protocol Version 2: 12-February-2018 
 
 
 






 
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PROTOCOL AMENDMENT, VERSION 2.0 
RATIONALE 
Changes to the protocol, along with a rationale for each change, are summarized below: 
 
Pharmacokinetic (PK) objective and endpoint has been removed due to logistic 
problems in transportation of samples to the central laboratory outside of India. 
Moreover, the T-DM1 assays are not available in the local laboratories. Therefore, all 
text pertaining to PK sampling and analysis have been removed. 
 
It has been clarified that patients who have had HER2 testing done by the same local 
laboratory for their prior treatment need not undergo re-testing. 
 
CNS only disease will not be eligible for participation in the study. 
 
Safety update on hemorrhagic events has been added in the section on Risks 
Associated with trastuzumab emtansine 
 
Audio-video consenting is no longer required for this study population as per the 
communication received from the Health Authority in India. 
 
The steps to be followed in case of any temperature excursion either during shipment 
from depot to site or at the site, have been included as an appendix to the protocol. 
 
Contact details of product complaint have been provided. 
 
It has been specified that all deaths that occur either during the study period, 
regardless of relationship to study drug, must be reported to the Sponsor and Health 
Authorities within 24 hours of the occurrence of the event. 
 
It has been specified that the investigator must report events that require immediate 
reporting (e.g. deaths, AESIs, abortions, 9.4.3.4 congenital anomalies etc.) to the 
Sponsor not more than 24 hours after the occurrence of the event and not more than 
24 hours after the Investigator learns of the event as mentioned in the previous 
version of the protocol.  
 
The name and contact information of the Medical Monitor and Alternate Medical 
Monitor has been updated. 
 
Reference to Appendix 3 RECIST criteria has been added. 
 
Errors in referencing the safety section have been corrected in the text, wherever 
applicable. 
Recent updates on clinical trial data of trastuzumab emtansine have been added 


 
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PROTOCOL AMENDMENT, VERSION 2.0 
SUMMARY OF CHANGES 
GLOBAL CHANGES  
Text and sections on Pharmacokinetic objectives or analysis have been removed 
throughout the document.  
It has been clarified throughout the Safety sections of the document that Serious 
Adverse Events and Adverse Events of Special Interest should be reported no more 
than 24 hours of occurrence of the event instead of no more than 24 hours after 
occurrence/learning of the event.  
Name of the Medical Monitor was updated. 
PROTOCOL SYNOPSIS  
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 2.1:  DESCRIPTION OF THE STUDY 
Revised text: The estimated duration of enrollment is 12 months or till achievement of 
enrolment target. 
SECTION 2.3.1 and SECTION 8.1.1 Inclusion Criteria 
2. Prospectively confirmed HER2-positive (i.e., IHC 3+ or IHC 2+ and gene-
amplified by fluorescence in situ hybridization [FISH] positive) as assessed on 
primary tumor and/or metastatic site if primary tumor not available (ISH positivity 
is defined as a ratio of 2.0 or greater for the number of HER2 gene copies to the 
number of signals for CEP17, or for single probe tests, a HER2 gene count greater 
than 4) as determined in a local laboratory that is experienced/certified in HER2-
expression testing using an accurate and validated assay (*Except for those 
patients who had HER2 testing done by the same local laboratory for their 
prior treatment) 
 
12. An audio visual recording of the informed consent process and a signed written 
informed consent approved by the relevant IRB/EC. 
SECTION 2.3.2 and SECTION 8.1.2 Exclusion Criteria 
9. 
CNS only disease 
SECTION 7.4.1 PRIMARY ANALYSIS 
The primary efficacy analyses will be conducted on the safety population that will 
include all enrolled patients who receive at least one dose of study medication.  
 
SECTION 5.2 BACKGROUND ON TRASTUZUMAB EMTANSINE 
The patient-reported outcome of time to symptom progression demonstrated an 
improvement with trastuzumab emtansine (7.1 months) as compared to (4.6 months) 


 
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Protocol ML29662, Version 2.0 
treatment with lapatinib plus capecitabine (Verma S et al, 2012). The descriptive 
analysis of the final overall survival data from this trial reported median overall 
survival of 29.9 months [95% CI 26·3–34·1] with trastuzumab emtansine vs 25.9 
months [95% CI 22·7–28·3] with control (Dieras et al, 2017). 
 
SECTION 8.3.1.1. Trastuzumab emtansine 
In case of any temperature excursion either during shipment from depot to site or 
at the site, the steps outlined in Appendix 5 should be followed. Any damage or 
product complaints should be reported as follows and as per details in Appendix 5: 
Contact details for Product Complaint: 
During Office Hours: 
 
Mobile [24 x7]: 
 
Fax: +91-22-33941054 
Product Complaint Mailbox: india.productcomplaints@roche.com  
Adverse Event Mailbox: india.drugsafety@roche.com 
Reporting Timelines: within ONE business day. 
 
SECTION 8.5.1 Informed Consent Forms and Screening Log 
Audio visual recordings of wWritten informed consent for participation in the study 
must be obtained before performing any study-specific screening tests or 
evaluations. 
 
SECTION 8.5.4 Vital Signs  
Vital signs will include measurements of respiratory rate, pulse rate, and systolic 
and diastolic blood pressures while the patient is in a seated position, and 
temperature. Vital signs will be assessed before treatment on Day 1 of every 
treatment cycle, recorded again after infusion during the observation period. 
 
SECTION 8.5.6.2 Performance Status 
Performance status will be measured using the ECOG performance status scale (see 
Appendix 32). It is recommended, where possible, that a patient’s performance status will 
be assessed by the same person throughout the study. Performance status will be 
assessed at baseline, after every three cycles of treatment, and at the 28-days post-
treatment safety follow-up visit.  
SECTION 9.5.7 Laboratory Assessments 
HER2 testing: HER2-positive status on fixed tissue blocks from the primary tumor (and/or 
metastatic site) to be assessed by IHC and/or ISH at a local laboratory that is 
experienced/certified in HER2- expression testing. Patients who have had HER2 testing 
done at the same local laboratory for their prior treatment will not require re-testing. 


 
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For sampling procedures, storage conditions, and shipment instructions, please refer to 
the Sample Handling and Logistics Manual which will be provided separately. 
 
For sampling procedures, storage conditions, and shipment instructions, please refer to 
the laboratory manual, which will be provided separately.  
SECTION 9.1 
SAFETY PLAN 
The safety plan for patients in this study is based on clinical experience with trastuzumab 
emtansine in completed and ongoing studies.and knowledge of toxicities related to 
trastuzumab and maytansine (a parent compound of emtansine and DM1). The 
anticipated important safety risks for trastuzumab emtansine are outlined below. Please 
refer to the Ttrastuzumab emtansine Investigator's Brochure for a complete summary of 
safety information. 
Dose delays and dose reductions will be allowed for trastuzumab emtansine please refer 
the tables below (Prescribing Information Trastuzumab emtansine, February 20175) 
SECTION 9.1.1 Risks Associated with Trastuzumab Emtansine 
Hemorrhage  
Cases of hemorrhagic events, including central nervous system, respiratory, and 
gastrointestinal hemorrhage, have been reported with trastuzumab emtansine. Some of 
these bleeding events resulted in fatal outcomes. In some of the observed cases, the 
patients were also receiving anti-coagulation therapy, antiplatelet therapy, or had 
thrombocytopenia, in others there were no known additional risk factors.  Additional 
monitoring should be considered when concomitant use is medically necessary. 
SECTION 9.1.3 Hepatotoxicity 
 
Transaminase elevations were generally transient with peak elevation at day 8 after 
therapy and subsequent recovery to Grade 1 or less prior to the next cycle. 
 
SECTION 9.3.1 Adverse Event Reporting Period 
All AEs, whether reported by the patient or noted by study personnel, will be recorded in 
the patient’s medical record and on the Adverse Event eCRF. and All SAEs will be 
notified as per local regulations in the Appendix XI Form. 
 
SECTION 9.3.5.8 Deaths 
All deaths that occur during the protocol-specified AE reporting study period (see Section 
59.3.1),) regardless of relationship to study drug, must be recorded on the Adverse Event 
eCRF and, the Appendix XI Form and immediately reported to the Sponsor and Health 
Authorities (see Section 59.4.2).) within 24 hours of occurrence of the event. This 


 
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includes death attributed to progression of HER2-positive unresectable, locally advanced 
or mBC. 
During survival follow-up, all deaths should be recorded  only on in the Survival eCRF 
and the Appendix XI Form and reported to the Sponsor and Health Authorities (see 
Section 9.4.2) within 24 hours of occurrence of the event. 
SECTION 9.4 IMMEDIATE REPORTING REQUIREMENTS FROM INVESTIGATOR TO 
SPONSOR 
The investigator must report such events to the Sponsor immediately; under no 
circumstances should reporting take place more than 24 hours after of the investigator 
learns occurrence of the event. The following is a list of events that the investigator must 
report to the Sponsor within 24 hours after of occurrence or learning of the event, 
regardless of relationship to study drug: 
 
Serious adverse events (see Section 5.49.2.2 for further details) 
 
Non-serious adverse events of special interest (see Section 5.49.2.3 for further 
details) 
 
Pregnancies (see Section 59.4.3 for further details) 
 
SECTION 9.4.1 Emergency Medical Contacts  
Medical Monitor contact information for all sites  
Medical Monitor: 
Dr. 
 
 
Telephone No.: 
 
Mobile Telephone No.: 
 
 
Alternate Medical Monitor contact information for all sites: 
Medical Monitor: 
Dr. 
 
 
Telephone No.: 
 
Mobile Telephone No.: 
 
 
SECTION 10.5.1 
Secondary Efficacy Endpoints 
To be assigned a status of PR or CR (i.e., a responder), changes) determined by the 
investigator using Response Evaluation Criteria in Solid Tumors (RECIST) criteria 
version 1.1 (Appendix 3). 
 
SECTION 13.2 
INFORMED CONSENT 
The Informed Consent Form will contain separate sections for any optional procedures 
such as PK sampling. 


 
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An audio visual recording taken with the patient’s consent will document the informed 
consent process and that written informed consent was obtained prior to participation in 
the study. 
 
 




 
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drug 
conjugate 
PK sampling11 
 
Pre dose and 
15 min post
infusion 
 
 
 
Adverse event 
reporting121 
X 
X 
X 
X 
X 
Administration 
of trastuzumab 
emtansine12 
 
X 
 
 
 
Pregnancy test13 
Within 7 
days prior to 
1st dosing 
Every 3 
cycles of 
antibody 
drug 
conjugate 
X 
At 4 and 7 
months after 
the last dose 
of antibody 
drug 
conjugate 
 
 
Survival15 
X 
X 
X 
X 
X 
 
Notes: 
1. Signed and dated informed consent in language comprehended by the potential clinical trial 
subject/Legally acceptable representative 
2. Complete medical history and demographics (i.e. age, sex, race, and ethnicity, if applicable) 
and all medications taken during the last 28 days prior to screening visit will be collected 
3. Physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, 
and neurological systems. Record abnormalities observed at baseline on the General Medical 
History and Baseline Conditions eCRF. Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF 
4. Vital signs will be assessed before treatment on Day 1 of every treatment cycle, recorded 
again after infusion during the observation period. Vital signs include respiratory rate, pulse 
rate, and systolic, and diastolic blood pressure while the patient is in a seated position, and 
oral or axillary temperature 
5. Current concomitant medication will be recorded at screening and on an ongoing basis 
6. HER2-positive status on fixed tissue blocks from the primary tumor (and/or metastatic site, if 
primary tumor not available) to be assessed by IHC and/or FISH at a local laboratory 
7. On treatment days, all assessments should be performed prior to dosing, unless otherwise 
specified. A CT or MRI and (if indicated) isotope bone scan (evaluation according to RECIST 
criteria) should be performed at screening and as clinically indicated. Scans at screening 
should not be older than 28 days prior to first study medication administration. NB: Bone scan, 
PET scan or plain films are not considered adequate imaging techniques to measure bone 
lesions. Tumor assessment ± 3 days of planned scheduled visit. At the end of study visit, if a 
patient does not fit into the end of study definition, then tumor assessment to be done as per 
institutional criteria and routine clinical practice.  
8. Laboratory assessment as per routine standard of care must be performed within 3 days (with 
results available) prior to the administration of study medication. Hematology, as per routine 


 
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standard of care, may include hemoglobin, hematocrit, platelet count, RBC, WBC with 
differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils, other cells). Serum 
chemistry, as per routine standard of care, may include sodium, potassium, calcium, chloride, 
magnesium, BUN (urea), uric acid, total protein, albumin, alkaline phosphatase, ALT, AST, 
lactate dehydrogenase (LDH), total bilirubin, creatinine, and blood glucose and calculated 
creatinine clearance at baseline. Coagulation tests will consist of international normalized ratio 
(INR) and aPTT or PTT. 
9. ECOG performance status to be recorded after every 3 cycles until disease progression. 
10. LVEF ≥ 50% at screening period to be determined by ECHO. To the extent possible, 
assessment to be obtained at the same institution. 
11. Blood and serum samples will be collected pre dose on Cycle 1, 2, and 3 and post infusion 
on Cycle 1 and 3 only from patients that have signed the PK substudy informed consent form 
12. After informed consent and prior to dosing, SAEs considered related to a study mandated 
procedure are reportable. As of cycle 1 all AEs and SAEs considered will be collected. AEs 
and SAEs to be monitored and continuously collected till end of study visit and to be recorded 
with grading according to NCI-CTCAE version 4.03. 
13. The initial dose of trastuzumab emtansine will be administered over 90 minutes and if well 
tolerated subsequent infusions may be administered over 30 min (±10 min). 
14. For women of childbearing potential, serum β-HCG test must be performed within 7 days prior 
to the first dose of study treatment with the result available prior to first dosing. Urine β-HCG 
test must be performed within 7 days prior to every 3rd cycle (with results available prior to 
treatment), at the safety follow up visit, and at 4 and 7 months after the last dose of study 
treatment. All positive urine pregnancy tests must be confirmed by a serum β HCG test. 
15. Patients who complete the study or discontinue from the study early will be asked to return 
to the hospital within 28 days after the last dose of study drug for the end of the study visit. 
16. Survival status will be recorded during the treatment period and every 3 months after the one 
month post-treatment safety follow up visit until 12 months after the last patient enrolled in 
study or lost to follow up, withdrawn consent, or died, or if the study is prematurely 
terminated by Roche, whichever occurs first. Patients who are alive at the time of the 
analysis will be censored at the date of the last follow up assessment 
 


 
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TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................. 17 
PROTOCOL SYNOPSIS .................................................................................... 18 
1. 
OBJECTIVES AND ENDPOINTS ............................................................... 19 
1.1 
Safety Objectives ................................................................... 19 
1.1.1 
Primary Safety Objective ....................................................... 19 
1.1.2 
Secondary Safety Objectives ................................................. 19 
1.2 
Efficacy Objectives ................................................................ 19 
1.2.1 
Secondary Efficacy Objectives .............................................. 19 
2. 
STUDY DESIGN ......................................................................................... 20 
2.1 
Description of the Study......................................................... 20 
2.2 
Number of Patients ................................................................ 21 
2.3 
Target Population .................................................................. 21 
2.3.1 
Inclusion Criteria .................................................................... 21 
2.3.2 
Exclusion Criteria ................................................................... 23 
2.4 
End of Study and Length of Study ......................................... 25 
3. 
INVESTIGATIONAL MEDICINAL PRODUCTS .......................................... 25 
4. 
STATISTICAL METHODS .......................................................................... 26 
4.1 
Primary Analysis .................................................................... 26 
4.2 
Determination of Sample Size ............................................... 26 
4.3 
Interim Analysis ..................................................................... 27 
5. 
BACKGROUND .......................................................................................... 30 
5.1 
Background on Breast Cancer ............................................... 30 
5.2 
Background on Trastuzumab emtansine ............................... 31 
5.3 
Study Rationale and Benefit-Risk Assessment ...................... 32 
6. 
OBJECTIVES AND ENDPOINTS ............................................................... 33 
6.1 
Safety Objectives ................................................................... 33 
6.1.1 
Primary Safety Objective ....................................................... 33 
6.1.2 
Secondary Safety Objectives ................................................. 33 
6.2 
Efficacy Objectives ................................................................ 34 


 
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6.2.1 
Secondary Efficacy Objectives .............................................. 34 
7. 
STUDY DESIGN ......................................................................................... 34 
7.1 
Description of the Study......................................................... 34 
7.2 
End of Study and Length of Study ......................................... 35 
7.3 
Rationale for Study Design .................................................... 36 
7.3.1 
Rationale for Trastuzumab Emtansine Dose and 
Schedule 36 
7.3.2 
Rationale for Patient Population ............................................ 36 
8. 
MATERIALS AND METHODS .................................................................... 36 
8.1 
Patients .................................................................................. 36 
8.1.1 
Inclusion Criteria .................................................................... 37 
8.1.2 
Exclusion Criteria ................................................................... 39 
8.2 
Method of Treatment Assignment and Blinding ..................... 40 
8.3 
Study Treatment .................................................................... 41 
8.3.1 
Formulation, Packaging, and Handling .................................. 41 
8.3.1.1 Trastuzumab emtansine ....................................................... 41 
8.3.2 
Dosage, Administration, and Compliance .............................. 42 
8.3.2.1 Trastuzumab emtansine ....................................................... 42 
8.3.3 
Investigational Medicinal Product Accountability ................... 43 
8.3.4 
Post-Trial Access to Trastuzumab Emtansine ....................... 43 
8.4 
Concomitant Therapy ............................................................ 44 
8.4.1 
Permitted Therapy ................................................................. 44 
8.4.2 
Prohibited Therapy ................................................................ 45 
8.5 
Study Assessments ............................................................... 46 
8.5.1 
Informed Consent Forms and Screening Log ........................ 46 
8.5.2 
Medical History and Demographic Data ................................ 46 
8.5.3 
Physical Examinations ........................................................... 46 
8.5.4 
Vital Signs .............................................................................. 47 
8.5.5 
Tumor and Response Evaluations ......................................... 47 
8.5.6 
Other Disease-Specific Assessments .................................... 47 
8.5.6.1 LVEF assessments .............................................................. 47 
8.5.6.2 Performance Status .............................................................. 47 


 
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8.5.7 
Laboratory Assessments ....................................................... 47 
8.6 
Patient, Treatment, Study, and Site 
Discontinuation ...................................................................... 48 
8.6.1 
Patient Discontinuation .......................................................... 48 
8.6.2 
Study Treatment Discontinuation ........................................... 49 
8.6.3 
Study and Site Discontinuation .............................................. 49 
9. 
ASSESSMENT OF SAFETY ....................................................................... 50 
9.1 
Safety Plan ............................................................................ 50 
9.1.1 
Cardiotoxicity ......................................................................... 51 
9.1.2 
Hematologic Toxicity (Thrombocytopenia)............................. 51 
9.1.3 
Hepatotoxicity ........................................................................ 52 
9.1.4 
Pulmonary Toxicity ................................................................ 54 
9.1.5 
Infusion-Related Reactions, Hypersensitivity 
Reactions 54 
9.1.6 
Neurotoxicity .......................................................................... 55 
9.1.7 
Extravasation ......................................................................... 55 
9.1.8 
Management of Specific Adverse Events .............................. 55 
9.2 
Safety Parameters and Definitions ........................................ 55 
9.2.1 
Adverse Events ..................................................................... 56 
9.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ........................................................................................ 56 
9.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) ................................................ 57 
9.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 58 
9.3.1 
Adverse Event Reporting Period ........................................... 58 
9.3.2 
Eliciting Adverse Event Information ....................................... 58 
9.3.3 
Assessment of Severity of Adverse Events ........................... 58 
9.3.4 
Assessment of Causality of Adverse Events ......................... 59 
9.3.5 
Procedures for Recording Adverse Events ............................ 60 
9.3.5.1 Infusion-Related Reactions .................................................. 60 
9.3.5.2 Diagnosis versus Signs and Symptoms ............................... 60 
9.3.5.3 Adverse Events That Are Secondary to Other 
Events 60 


 
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9.3.5.4 Persistent or Recurrent Adverse Events .............................. 61 
9.3.5.5 Abnormal Laboratory Values ................................................ 61 
9.3.5.6 Abnormal Vital Sign Values .................................................. 62 
9.3.5.7 Abnormal Liver Function Tests ............................................. 62 
9.3.5.8 Deaths .................................................................................. 63 
9.3.5.9 Preexisting Medical Conditions ............................................ 63 
9.3.5.10 Lack of Efficacy or Worsening of Breast 
Cancer 
64 
9.3.5.11 Hospitalization or Prolonged Hospitalization ...................... 64 
9.3.5.12 Adverse Events Associated with an Overdose 
or Error in Drug Administration ........................................................... 64 
9.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 65 
9.4.1 
Emergency Medical Contacts ................................................ 65 
9.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of Special Interest .................. 66 
9.4.2.1 Events That Occur prior to Study Drug Initiation .................. 66 
9.4.2.2 Events That Occur after Study Drug Initiation ...................... 66 
9.4.3 
Reporting Requirements for Pregnancies .............................. 67 
9.4.3.1 Pregnancies in Female Patients ........................................... 67 
9.4.3.2 Pregnancies in Female Partners of Male 
Patients 67 
9.4.3.3 Abortions .............................................................................. 68 
9.4.3.4 Congenital Anomalies/Birth Defects ..................................... 68 
9.5 
Follow-Up of Patients after Adverse Events .......................... 68 
9.5.1 
Investigator Follow-Up ........................................................... 68 
9.5.2 
Sponsor Follow-Up ................................................................ 69 
9.6 
Post-Study Adverse Events ................................................... 69 
9.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ................................................................. 69 
10. STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 69 
10.1 
Determination of Sample Size ............................................... 69 
10.2 
Summaries of Conduct of Study ............................................ 70 


 
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10.3 
Summaries of Demographic and Baseline 
Characteristics ....................................................................... 71 
10.4 
Safety Analyses ..................................................................... 71 
10.4.1 
Primary Safety Endpoint ........................................................ 71 
10.4.2 
Secondary Safety Endpoints ................................................. 71 
10.5 
Efficacy Analyses .................................................................. 72 
10.5.1 
Secondary Efficacy Endpoints ............................................... 72 
10.6 
Interim Analysis ..................................................................... 73 
10.6.1 
Planned Interim Analysis ....................................................... 73 
11. DATA COLLECTION AND MANAGEMENT ............................................... 73 
11.1 
Data Quality Assurance ......................................................... 73 
11.2 
Electronic Case Report Forms ............................................... 74 
11.3 
Source Data Documentation .................................................. 74 
11.4 
Use of Computerized Systems .............................................. 75 
11.5 
Retention of Records ............................................................. 75 
12. ETHICAL CONSIDERATIONS .................................................................... 75 
12.1 
Compliance with Laws and Regulations ................................ 75 
12.2 
Informed Consent .................................................................. 75 
12.3 
Institutional Review Board or Ethics Committee .................... 76 
12.4 
Confidentiality ........................................................................ 77 
12.5 
Financial Disclosure .............................................................. 77 
13. STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 77 
13.1 
Study Documentation ............................................................ 77 
13.2 
Protocol Deviations ................................................................ 77 
13.3 
Site Inspections ..................................................................... 78 
13.4 
Administrative Structure......................................................... 78 
13.5 
Publication of Data and Protection of Trade 
Secrets .................................................................................. 78 
13.6 
Protocol Amendments ........................................................... 79 
14. REFERENCES ........................................................................................... 79 
 


 
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LIST OF TABLES 
Table 1 Administration of First and Subsequent Infusions of Trastuzumab 
emtansine ................................................................................... 42 
Table 2 Dose Reduction Schedule ..................................................................... 50 
Table 3 Dose Modifications for Left Ventricular Dysfunction .............................. 51 
Table 4 Dose Modification Guidelines for Thrombocytopenia ............................ 52 
Table 6 Dose Modification Guidelines for Increased Transaminases 
(AST/ALT) ................................................................................... 53 
Table 7 Dose Modification Guidelines for Hyperbilirubinemia ............................ 53 
Table 8 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE .................................................................. 59 
 
 
LIST OF FIGURES 
 
Figure 1 
Study Schema ............................................................................. 35 
 
35 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments ........................................................... 81 
Appendix 2  
Eastern Cooperative Oncology Group (ECOG) Performance 
Status .......................................................................................... 84 
Appendix 3  
RECIST Criteria Version 1.1 ....................................................... 85 
Appendix 4 
Algorithm for Continuation and Discontinuation of 
Trastuzumab emtansine Based on Left Ventricular Fraction 
Assessments in Patients   ........................................................... 96 


 
CONFIDENTIAL 
This clinical study is being sponsored in India by Roche Products (India) Pvt. Ltd. An affiliate of F. Hoffmann-La Roche Ltd 
of Basel, Switzerland. The information contained in this document, especially any unpublished data, is the property of 
Roche (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 ML29662, Version 2.0 
17 
PROTOCOL ACCEPTANCE FORM 
 
TITLE: 
A MULTICENTER, OPEN-LABEL, SINGLE-ARM, 
PHASE IV STUDY OF TRASTUZUMAB EMTANSINE 
IN 
INDIAN 
PATIENTS 
WITH 
HER2-POSITIVE 
UNRESECTABLE 
LOCALLY 
ADVANCED 
OR 
METASTATIC BREAST CANCER WHO HAVE 
RECEIVED 
PRIOR 
TREATMENT 
WITH 
TRASTUZUMAB AND A TAXANE  
PROTOCOL NUMBER: ML29662 
VERSION NUMBER: 
2.0 
EUDRACT NUMBER: 
2008-005 713-22 
IND NUMBER: 
71072 
TEST PRODUCT: 
Trastuzumab emtansine (T-DM1) 
MEDICAL MONITOR: 
Dr. 
 
SPONSOR: 
Roche Products (India) Pvt.Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files. Please return a copy as 
instructed by the local study monitor at Roche Products (India) Pvt. Ltd. 
 


 
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PROTOCOL SYNOPSIS 
 
TITLE: 
A MULTICENTER, OPEN-LABEL, SINGLE-ARM, PHASE IV 
STUDY OF TRASTUZUMAB EMTANSINE IN INDIAN 
PATIENTS 
WITH 
HER2-POSITIVE 
UNRESECTABLE 
LOCALLY ADVANCED OR METASTATIC BREAST CANCER 
WHO 
HAVE 
RECEIVED 
PRIOR 
TREATMENT 
WITH 
TRASTUZUMAB AND A TAXANE 
PROTOCOL 
NUMBER: 
ML29662 
VERSION NUMBER: 
2.0 
EUDRACT NUMBER: 
2008-005 713-22 
IND NUMBER: 
71072 
TEST PRODUCT: 
Trastuzumab emtansine (T-DM1) 
PHASE: 
IV 
INDICATION: 
HER2-positive unresectable locally advanced or metastatic 
breast cancer 
SPONSOR: 
Roche Products (India) Pvt.Ltd 
 
 
 
 
 


 
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Protocol ML29662 Version 2.0 
1. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the safety, efficacy of trastuzumab emtansine in Indian patients 
with HER2-positive unresectable locally advanced or metastatic breast cancer (mBC) who 
have received prior treatment with trastuzumab and a taxane. Specific objectives and 
corresponding endpoints for the study are outlined below. 
1.1 
SAFETY OBJECTIVES 
1.1.1 
Primary Safety Objective 
The primary safety objective for this study is to evaluate the safety of trastuzumab 
emtansine in Indian patients on the basis of the following endpoint: 
 
Incidence and severity of AEs as per National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) (version 4.03) 
1.1.2 
Secondary Safety Objectives 
The secondary safety objectives for this study are to evaluate the safety of trastuzumab 
emtansine on the basis of the following endpoints: 
 
Incidence and severity of SAEs as per NCI-CTCAE (version 4.03) 
 
Incidence of non-serious AEs of special interest 
 
Cases of drug-induced liver injury meeting Hy’s law criteria 
 
Incidence of CHF 
 
Left Ventricular ejection fraction (LVEF) decrease over the course of the study as 
measured by echocardiogram (ECHO) 
 
Laboratory results abnormalities  
 
Incidence of AEs leading to discontinuation, modification, or interruption of study 
medication 
 
Exposure to study medication 
1.2 
EFFICACY OBJECTIVES 
1.2.1 
Secondary Efficacy Objectives 
 
The secondary efficacy objectives of this study are to evaluate the efficacy of trastuzumab 
emtansine in Indian patients with respect to:- 
 
Progression-free survival (PFS)  
 
Overall survival (OS)  
 
Overall response rate (ORR) 
 


 
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2. 
STUDY DESIGN 
2.1 
DESCRIPTION OF THE STUDY 
This is a Phase IV, single-arm, multicenter, open-label clinical trial designed to assess the 
safety of trastuzumab emtansine in Indian patients with HER2-positive unresectable LABC 
or mBC who have received prior treatment with trastuzumab and a taxane.  
The estimated duration of enrollment is 12 months or till achievement of enrolment target. 
All patients fulfilling the eligibility criteria and willing to provide informed consent will 
receive intravenous (IV) trastuzumab emtansine 3.6 mg/kg over 30−90 minutes on Day 1 
of a 21-day cycle. Patients will receive treatment until disease progression, unacceptable 
toxicity, withdrawal of consent, or death. 
The study will include a screening phase, treatment phase and post-treatment safety 
follow-up phase for each patient as described in the Study Schema (Figure 1).  
All patients will be followed-up for at least 12 months after the last patient is enrolled; 
unless they have been lost to follow up, withdrawn consent, or died, or the study is 
prematurely terminated by the Sponsor.  
Patients will receive study medication until unacceptable toxicity, withdrawal of consent, 
disease progression, death, or up to a maximum of 12 months after last patient first visit, 
whichever occurs first. Patients who have not progressed at the end of the trial will be 
offered options to continue with trastuzumab emtansine treatment, see Section 8.3.4 
An independent data monitoring committee (iDMC) will be formed for this study and will 
comprise of three members including a statistician. The iDMC will review the safety data 
for interim analysis after approximately 50% patients complete 6 months investigational 
medicinal product therapy. See the iDMC charter for further information. 
A schedule of assessments is provided in Appendix 1. 
 
 
 
 




 
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ii. Trastuzumab, alone or in combination with another agent in the adjuvant, 
unresectable, locally advanced, or metastatic setting 
5. Documented progression of unresectable, locally advanced, or mBC, 
determined by the investigator; progression must occur during or after most 
recent treatment for LABC/mBC or within 6 months after completing adjuvant 
therapy 
6. Measurable and/or non-measurable disease 
7. LVEF ≥ 50% by echocardiogram (ECHO)  
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
9. Adequate organ function, evidenced by the following laboratory results within 
30 days of enrollment: 
i. 
Absolute neutrophil count > 1,500 cells/mm3 
ii. Platelet count > 100,000 cells/mm3 
iii. Hemoglobin > 9.0 g/dL. Patients will be allowed to be transfused red blood 
cells to this level 
iv. Albumin ≥ 2.5 g/dL 
v. Total bilirubin ≤ 1.5 upper limit of normal (ULN)  
vi. Serum glutamic oxaloacetic transaminase (SGOT) or aspartate 
aminotransferase (AST), serum glutamic pyruvic transaminase (SGPT) or 
alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 2.5 × 
ULN with the following exception: Patients with bone metastases: ALP ≤ 5 
× ULN 
vii. Creatinine clearance > 50 mL/min based on Cockroft-Gault glomerular 
filtration rate estimation: (140 − Age) × (weight in kg) × (0.85 if female)/(72 
× serum creatinine) 
viii. International normalized ratio (INR) and activated partial thromboplastin 
time (aPTT) < 1.5 × ULN (unless on therapeutic coagulation) 
10. A negative serum β-Human Chorinic Gonadotropin (β-HCG) test for women 
of childbearing potential (premenopausal or not meeting the definition of 
postmenopausal i.e. ≥ 12 months of amenorrhea), and women who have not 
undergone surgical sterilization (i.e., absence of ovaries and/or uterus) within 
7 days prior to the first dose of study treatment with the result available prior 
to first dosing 
11. For women of childbearing potential: agreement to remain abstinent (refrain 
from heterosexual intercourse) or use two adequate non-hormonal methods of 
contraception, including at least one method with a failure rate of  1% per 


 
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year, during the treatment period and for at least 7 months after the last dose of 
study drug 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state ( 12 continuous months of amenorrhea 
with no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus). 
Examples of non-hormonal contraceptive methods with a failure rate of  1% per 
year include bilateral tubal ligation, male sterilization, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception. 
Barrier methods must always be supplemented with the use of a spermicide. 
For men: agreement to remain abstinent (refrain from heterosexual intercourse) 
or use contraceptive measures and agreement to refrain from donating sperm, 
as defined below: 
With female partners of childbearing potential, men must remain abstinent or 
use a condom plus an additional contraceptive method that together result in a 
failure rate of 1% per year during the treatment period and for at least 7 months 
plus 90 days (a spermatogenesis cycle) after the last dose of study drug. Men 
must refrain from donating sperm during this same period. 
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for at least 7 months after the last dose of study 
drug. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
12. A signed written informed consent approved by the relevant IRB/EC.  
2.3.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Prior treatment with trastuzumab emtansine 
2. Prior treatment with lapatinib or lapatinib with capecitabine or non-comparable 
biologic or biosimilar of trastuzumab  
3. Peripheral neuropathy of Grade ≥ 3 per NCI CTCAE (version 4.03) 


 
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4. History of other malignancy within the previous 5 years, except for appropriately 
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage 1 
uterine cancer, synchronous or previously diagnosed HER2-positive breast 
cancer, or cancers with a similar curative outcome as those mentioned above 
5. History of receiving any anti-cancer drug/biologic or investigational treatment 
within 21 days prior to enrollment except hormone therapy, which can be given 
up to 7 days prior to enrollment; recovery of treatment-related toxicity consistent 
with other eligibility criteria 
6. History of exposure to the following cumulative doses of anthracyclines: 
i. 
Doxorubicin or liposomal doxorubicin > 500 mg/m2 
ii. Epirubicin > 900 mg/m2 
iii. Mitoxantrone > 120 mg/m2 
iv. If another anthracycline, or more than one anthracycline, has been used, 
the cumulative dose must not exceed the equivalent of 500 mg/m2 
doxorubicin 
7. History of radiation therapy within 14 days of enrollment. The patient must have 
recovered from any resulting acute toxicity (to Grade ≤ 1) prior to enrollment. 
8. Brain metastases that are untreated, symptomatic, or require therapy to control 
symptoms, as well as a history of radiation, surgery, or other therapy, including 
steroids, to control symptoms from brain metastases within 2 months (60 days) 
before enrollment 
9. CNS only disease 
10. History of a decrease in LVEF to < 40% or symptomatic congestive heart failure 
(CHF) with previous trastuzumab treatment 
11. History of symptomatic chronic heart failure (New York Heart Association [NYHA] 
Classes II−IV) or serious cardiac arrhythmia requiring treatment 
12. History of myocardial infarction or unstable angina within 6 months of enrollment 
13. Current dyspnea at rest due to complications of advanced malignancy or 
requirement for continuous oxygen therapy 
14. Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, or metabolic disease) 
15. Pregnancy or lactation 
16. Concurrent, serious, uncontrolled infections or current known infection with human 
immunodeficiency virus (HIV) or active hepatitis B and/or hepatitis C. For patients 
who are known carriers of hepatitis B virus (HBV), active hepatitis B infection must 


 
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Protocol ML29662 Version 2.0 
be ruled out based on negative serologic testing and/or determination of HBV DNA 
viral load per local guidelines 
17. Presence 
of 
conditions 
that 
could 
affect 
gastrointestinal 
absorption: 
malabsorption syndrome, resection of the small bowel or stomach, and ulcerative 
colitis 
18. History of intolerance (such as Grade 3-4 infusion reaction) or known 
hypersensitivity to trastuzumab or murine proteins or any component of the 
product 
19. Assessed by the investigator to be unable or unwilling to comply with the 
requirements of the protocol  
2.4 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs 
or the date at which the safety follow-up is received from the last patient, whichever occurs 
later. The LPLV is to occur 12 months after the last patient is enrolled; unless they have 
been lost to follow-up, withdrawn consent, or died, or if the study is prematurely terminated 
by the Sponsor, whichever occurs first.  
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 2 to 3 years. 
Following the completion of the study, Roche will continue to provide study medication 
to all the patients:-  
 
who are still receiving the study medication and have not progressed on study 
medication at the end of the study 
 
and who are willing to continue study medication 
 
and are considered suitable by the investigator to continue receiving study 
medication till progression of the disease 
and signed written post trial access consent form, approved by the relevant 
Institutional Review Board (IRB)/Ethics Committee (EC) 
3. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
All investigational medicinal products (IMPs) required for completion of this study 
(trastuzumab emtansine) will be provided by the Sponsor where required by local health 
authority regulations. The study site will acknowledge receipt of IMPs by returning the 
appropriate documentation form 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 




 
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Protocol ML29662 Version 2.0 
 
09 % 
19 
22 
24 
 
10 % 
16 
18 
20 
 
4.3 
INTERIM ANALYSIS 
In addition to the final analysis, there will be interim analysis for safety once approximately 
50% patients complete 6 months investigational medicinal product therapy.  
An independent Data Monitoring Committee (iDMC) will be formed which will include a 
statistician. An iDMC will perform the review of this interim analysis of efficacy and safety 
and subsequent safety reviews as described in the iDMC Charter. 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADC 
Antibody-drug Conjugate 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
aPTT 
activated Partial Thromboplastin Time 
BOR 
Best Overall Response 
BUN 
Blood Urea Nitrogen 
β-HCG 
Beta Human Chorionic Gonadotropin 
CHF 
Congestive Heart Failure 
CR 
Complete Response 
CRO 
Contract Research Organization 
CT 
Computed Tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
DIBD 
Developmental International Birth Date  
DLP 
Data Lock Point 
EC 
Ethics Committee 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FISH 
Fluorescence In Situ Hybridization 
HER2 
Human Epidermal Growth Factor Receptor 2 
ICH 
International Conference on Harmonization 
iDMC 
Independent Data Monitoring Committee 
IHC 
Immunohistochemistry 
ILD 
Interstitial Lung Disease 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug (application) 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRR 
Infusion Related Reaction 
IV 
Intravenous 
LABC 
Locally Advanced Breast Cancer 


 
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LDH 
Lactate Dehydrogenase 
LPLV 
Last Patient, Last Visit 
LVEF 
Left Ventricular Ejection Fraction 
mBC 
Metastatic Breast Cancer 
NCI 
National Cancer Institute 
NRH 
Nodular Regenerative Hyperplasia  
NYHA 
New York Heart Association 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PR 
Partial Response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
T-DM1 
Trastuzumab Emtansine 
ULN 
Upper Limit Of Normal 
 
 
 


 
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5. 
BACKGROUND 
5.1 
BACKGROUND ON BREAST CANCER  
Breast cancer accounts for nearly one in three cancers diagnosed among women in the 
United States, and the second leading cause of cancer death around the world (Ferlay et 
al. 2010; DeSantis et al. 2011 ). Approximately 20% of breast cancers are characterized 
by amplification of the human epidermal growth factor receptor 2 (HER2) gene and 
overexpression of HER2, which functions as a driver oncogene for such tumors (Slamon 
et al. 1989 and Wolff et al. 2013).  
HER2-positive breast cancers have historically been associated with decreased relapse 
free survival, decreased overall survival (OS) and poorer prognosis (Slamon et al. 1987, 
1989; Perou et al. 2000; Sørlie et al. 2001). In contrast to normal cells which express 
approximately 20,000 HER2 receptors on the cell membrane, each HER2-positive breast 
cancer cell expresses approximately one to two million HER2 receptors, making HER2 an 
attractive candidate for targeted therapy (Venter et al., 1987). 
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. 
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. 


 
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5.2 
BACKGROUND ON TRASTUZUMAB EMTANSINE 
Trastuzumab emtansine (also known as T-DM1) the investigational product is a novel 
antibody-drug conjugate (ADC) that is specifically designed for the treatment of HER2-
positive malignancies. Trastuzumab emtansine is composed of trastuzumab (Herceptin®), 
a humanized monoclonal antibody directed against the extracellular region of HER2 and 
of DM1 (maytansinoid), an anti-microtubule agent derived from maytansine; and the 
thioether linker maleimidylmethyl cylcohexane-1-carboxylate (MCC), which is used to 
conjugate each molecule of DM1 to trastuzumab. DM1 is a highly potent drug synthesized 
from maytansinol that binds β–tubulin to inhibit tubulin polymerization. It binds to tubulin 
competitively with vinca alkaloids, but is 20–100 times more potent than vincristine in its 
cytotoxic effect against tumor cell lines. Its parent molecule, maytansine, has been studied 
in approximately 800 cancer patients in the 1970s and 1980s, with responses seen in 
patients with breast and lung cancer (Junttila et al. 2011; Issell and Crooke 1978). 
However, because of its narrow therapeutic index and the observed gastrointestinal 
toxicity of the free drug, it was not developed further as a therapeutic option (Cassady et 
al. 2004; Cabanillas et al. 1979). 
Trastuzumab emtansine and trastuzumab recognize the same epitope on HER2 and are 
binding with a similar affinity. Following antigen specific binding of trastuzumab emtansine 
to HER2, it is hypothesized that the complex of receptor and ADC is internalized, where 
upon DM1-containing catabolites are released into the cytosol following proteolytic 
cleavage of the antibody in lysosomes (Erickson et al. 2006). Binding of these DM1-
containing species to β-tubulin inhibits tubulin polymerization resulting in cell death 
(Cassady et al.2004). 
In addition to targeting delivery of DM1 to HER2-overexpressing tumor cells, trastuzumab 
emtansine retains the anti-tumor activities of trastuzumab, including suppression of HER2 
signaling pathways that confer a proliferative and survival advantage to cells, and the 
flagging of cells for destruction through antibody-dependent cell cytotoxicity (Junttila et al. 
2011). 
Completed and ongoing Phase I and II single arm studies of trastuzumab emtansine have 
demonstrated clinical activity. The randomized Phase II study BO21976 which compared 
single-agent trastuzumab emtansine with trastuzumab plus docetaxel showed a 
significant improvement in PFS with a HR 0.59 p=0.0353 and a favorable safety profile. A 
Phase III study BO21977 compared trastuzumab emtansine to standard of care HER2-
targeted combination therapy (capecitabine and lapatinib) for patients with mBC who had 
received prior trastuzumab and taxane therapies. The study demonstrated a statistically 
significant and clinically meaningful improvement in both PFS (9.6 months with 
trastuzumab emtansine vs 6.4 months with lapatinib plus capecitabine) and OS. (29·9 
30.9 months with trastuzumab emtansine vs 25.1 9 months with lapatinib plus 
capecitabine). The patient-reported outcome of time to symptom progression 


 
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demonstrated an improvement with trastuzumab emtansine (7.1 months) as compared to 
(4.6 months) treatment with lapatinib plus capecitabine (Verma S et al, 2012). The 
descriptive analysis of the final overall survival data from this trial reported median overall 
survival of 29.9 months [95% CI 26·3–34·1] with trastuzumab emtansine vs 25.9 months 
[95% CI 22·7–28·3] with control (Dieras et al, 2017). 
Based on the data from these trials trastuzumab emtansine has been approved as a single 
agent, for the treatment of patients with HER2-positive, unresectable locally advanced or 
metastatic breast cancer who have received prior treatment with trastuzumab and a 
taxane in over 70 countries including India. 
 
See the trastuzumab emtansine Investigator’s Brochure and local prescribing information 
for trastuzumab emtansine for additional details on nonclinical and clinical studies. 
5.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Trastuzumab emtansine is a novel agent that has demonstrated efficacy in the treatment 
of HER2-positive mBC who progressed on trastuzumab and taxane based treatment. 
Registration Study TDM4370g/BO21977 met its co-primary endpoints of improving PFS 
in patients who received trastuzumab emtansine (by Independent Review Committee) and 
OS compared with those who received the combination of lapatinib and capecitabine as 
described in section  5.2. The safety profile of trastuzumab emtansine was consistent with 
that seen in previous studies. 
The safety profile of trastuzumab emtansine in mBC is based on data from 884 patients 
receiving single-agent trastuzumab emtansine treatment at 3.6mg/kg q3w (Studies 
TDM3569g, 
TDM4258g, 
TDM4374g, 
TDM4688g, 
TDM4450g/BO21976, 
TDM4370g/BO21977 and TDM4529g/BO25430) and combined treatment with 
pertuzumab in 87 patients (from Studies TDM4373g/BO22495 and TDM4688g). The most 
common adverse events (AEs) for trastuzumab emtansine (AEs, in ≥ 25% of patients) 
were fatigue, nausea, thrombocytopenia, headache, constipation, and epistaxis. 
(Investigator’s Brochure Trastuzumab emtansine, 2014). 
According to Periodic Benefit-Risk Evaluation Report, the estimated overall cumulative 
exposure to trastuzumab emtansine (i.e., from Roche − and Chugai − sponsored clinical 
trials and from marketing experience) since the Developmental International Birth Date 
(DIBD) (19 January 2006) until the data lock point (DLP) (21 February 2015) is 28,366 
worldwide. 


 
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 
From the DIBD (19 January 2006), to the DLP (21 February 2015) of this PBRER, 
an estimated total of 7,157 patients have received trastuzumab emtansine via 
Roche − and Chugai − sponsored interventional clinical trials participation. 
 
From the international birth date (February 2013) to January 2015, an estimated 
cumulative total of 21,209 patients have received trastuzumab emtansine from 
marketing experience; of which 7,527 patients were estimated to have received 
trastuzumab emtansine during the reporting interval. Based on the evaluation of 
these data, the clinical trial results are consistent with the safety profile observed 
in the postmarketing setting. Thus, the benefit−risk profile of trastuzumab 
emtansine remains favorable. 
This current Phase IV, single-arm, open-label, multicenter study is planned to be 
conducted to fulfil a post-marketing regulatory requirement. It is aimed to gain more 
insights into the safety and efficacy of trastuzumab emtansine for the treatment of Indian 
patients with HER2-positive advanced (metastatic or locally recurrent) breast cancer.  
6. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the safety, efficacy of trastuzumab emtansine in Indian patients 
with HER2-positive unresectable locally advanced or metastatic breast cancer (mBC) who 
have received prior treatment with trastuzumab and a taxane. Specific objectives and 
corresponding endpoints for the study are outlined below. 
6.1 
SAFETY OBJECTIVES 
6.1.1 
Primary Safety Objective 
The primary safety objective for this study is to evaluate the safety of trastuzumab 
emtansine in Indian patients on the basis of the following endpoint: 
 
Incidence and severity of AEs as per National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) (version 4.03) 
6.1.2 
Secondary Safety Objectives 
The secondary safety objectives for this study are to evaluate the safety of trastuzumab 
emtansine on the basis of the following endpoints: 
 
Incidence and severity of SAEs as per NCI-CTCAE (version 4.03) 
 
Incidence of non-serious AEs of special interest 
 
Cases of drug-induced liver injury meeting Hy’s law criteria 
 
Incidence of CHF 
 
Left Ventricular ejection fraction (LVEF) decrease over the course of the study as 
measured by ECHO  
 
Laboratory results abnormalities  


 
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 
Incidence of AEs leading to discontinuation, modification, or interruption of study 
medication 
 
Exposure to study medication 
6.2 
EFFICACY OBJECTIVES 
6.2.1 
Secondary Efficacy Objectives 
 
The secondary efficacy objectives of this study are to evaluate the efficacy of trastuzumab 
emtansine in Indian patients with respect to: 
 
Progression-free survival (PFS)  
 
Overall survival (OS)  
 
Overall response rate (ORR) 
  
7. 
STUDY DESIGN 
7.1 
DESCRIPTION OF THE STUDY 
This is a Phase IV, single-arm, multicenter, open-label clinical trial designed to assess the 
safety of trastuzumab emtansine in Indian patients with HER2-positive unresectable LABC 
or mBC who have received prior treatment with trastuzumab and a taxane.  
This study is planned to be conducted in 70 patients across 12-15 centers in India. 
Enrollment is estimated to take 12 months. All patients fulfilling the eligibility criteria and 
willing to provide informed consent will receive intravenous (IV) trastuzumab emtansine 
3.6 mg/kg over 30−90 minutes on Day 1 of a 21-day cycle. Patients will receive treatment 
until disease progression, unacceptable toxicity, withdrawal of consent, or death. 
The study will include a screening phase, treatment phase and post-treatment safety 
follow-up phase for each patient as described in the Study Schema (Figure 1).  
All patients will be followed-up for at least 12 months after the last patient is enrolled; 
unless they have been lost to follow up, withdrawn consent, or died, or the study is 
prematurely terminated by the Sponsor.  
Patients will receive study medication until unacceptable toxicity, withdrawal of consent, 
disease progression, death, or up to a maximum of 12 months after last patient first visit, 
whichever occurs first. Patients who have not progressed at the end of the trial will be 
offered options to continue with trastuzumab emtansine treatment, see Section 8.3.4 
An independent data monitoring committee (iDMC) will be formed for this study and will 
comprise of three members including a statistician. The iDMC will review the safety data 




 
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7.3 
RATIONALE FOR STUDY DESIGN 
In this open-label, multicenter study, the safety of trastuzumab emtansine will be evaluated 
to gain a better insight into its safety profile in the Indian population to fulfill post-marketing 
regulatory requirements.  
The study design employs standard methods for Phase IV safety studies in patients with 
cancer. 
The primary objective is to assess the safety of trastuzumab emtansine in patients with 
HER2-positive LABC or mBC. Additionally, the efficacy of trastuzumab emtansine in this 
patient population will also be determined in this study.  
As this is a predominantly safety study, the type of data collected and the frequency with 
which patients are monitored will ensure the safety of the patients at all times as well as 
fulfilling local regulatory requirements. 
7.3.1 
Rationale for Trastuzumab Emtansine Dose and Schedule 
Trastuzumab emtansine will be administered intravenously q3w at a dose of 3.6 mg/kg 
over approximately 90 minutes for the first dose and 30 (±10) minutes for subsequent 
doses as in the Phase III registration trial (BO21977) (Verma S et al., 2012). The total 
trastuzumab emtansine dose will be calculated based on the patient’s weight on Day 1 (or 
up to 28 days before) of each cycle with no upper limit. 
7.3.2 
Rationale for Patient Population  
The patient population for this study comprises of patients with HER2-positive advanced 
breast cancer (metastatic or locally recurrent) which is not amenable to curative resection 
and has already undergone treatment with trastuzumab and a taxane alone or in 
combination. Measurement of HER2 gene amplification has traditionally been performed 
using immunohistochemistry (IHC) and determination by in situ hybridization (ISH) has 
also proven to be a reliable method for demonstrating HER2-positive status (Press et al. 
2005). Therefore, patients’ eligibility will be determined at a local laboratory that is 
experienced/certified in HER2-expression testing using an accurate and validated assay. 
Good efficacy and a manageable safety profile have been demonstrated in clinical trials 
of trastuzumab emtansine in this patient population globally.  
 
8. 
MATERIALS AND METHODS  
8.1 
PATIENTS 
Approximately 70 patients with HER2-positive, unresectable, LABC or mBC who have 
received prior chemotherapy treatment with a taxane, alone or in combination with another 
agent and anti-HER2 treatment with trastuzumab, alone or in combination with another 


 
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agent. These patients would have progressed on or after the most recent treatment of 
LABC or mBC, or within 6 months of completing adjuvant trastuzumab and taxane therapy.  
8.1.1 
Inclusion Criteria 
Patients must meet the following criteria to be eligible for study entry: 
1. Male or female of age ≥ 18 years 
2. Prospectively confirmed HER2-positive (i.e., IHC 3+ or IHC 2+ and gene-
amplified by fluorescence in situ hybridization [FISH] positive) as assessed on 
primary tumor and/or metastatic site if primary tumor not available (ISH positivity 
is defined as a ratio of 2.0 or greater for the number of HER2 gene copies to the 
number of signals for CEP17, or for single probe tests, a HER2 gene count 
greater than 4) as determined in a local laboratory that is experienced/certified in 
HER2-expression testing using an accurate and validated assay (*Except for 
those patients who had HER2 testing done by the same local laboratory for their 
prior treatment). 
3. Histologically or cytologically documented invasive breast cancer: unresectable, 
LABC or mBC 
4. Prior treatment for breast cancer in the adjuvant, unresectable, locally advanced, 
or metastatic setting must include:- 
i. 
A taxane, alone or in combination with another agent, AND 
ii. Trastuzumab, alone or in combination with another agent in the adjuvant, 
unresectable, locally advanced, or metastatic setting 
5. Documented progression of unresectable, locally advanced, or mBC, determined 
by the investigator; progression must occur during or after most recent treatment 
for LABC/mBC or within 6 months after completing adjuvant therapy 
6. Measurable and/or non-measurable disease 
7. LVEF ≥ 50% by echocardiogram (ECHO)  
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
9. Adequate organ function, evidenced by the following laboratory results within 30 
days of enrollment: 
ix. Absolute neutrophil count > 1,500 cells/mm3 
x. Platelet count > 100,000 cells/mm3 
xi. Hemoglobin > 9.0 g/dL. Patients will be allowed to be transfused red blood 
cells to this level 
xii. Albumin ≥ 2.5 g/dL 
xiii. Total bilirubin ≤ 1.5 upper limit of normal (ULN)  


 
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xiv. Serum glutamic oxaloacetic transaminase (SGOT) or aspartate 
aminotransferase (AST), serum glutamic pyruvic transaminase (SGPT) or 
alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 2.5 × 
ULN with the following exception: Patients with bone metastases: ALP ≤ 5 
× ULN 
xv. Creatinine clearance > 50 mL/min based on Cockroft-Gault glomerular 
filtration rate estimation: (140 − Age) × (weight in kg) × (0.85 if female)/(72 
× serum creatinine) 
xvi. International normalized ratio (INR) and activated partial thromboplastin 
time (aPTT) < 1.5 × ULN (unless on therapeutic coagulation) 
10. A negative serum β-Human Chorinic Gonadotropin (β-HCG) test for women of 
childbearing potential (premenopausal or not meeting the definition of 
postmenopausal i.e. ≥ 12 months of amenorrhea), and women who have not 
undergone surgical sterilization (i.e., absence of ovaries and/or uterus) within 7 
days prior to the first dose of study treatment with the result available prior to first 
dosing 
11. For women of childbearing potential: agreement to remain abstinent (refrain 
from heterosexual intercourse) or use two adequate non-hormonal methods of 
contraception, including at least one method with a failure rate of  1% per year, 
during the treatment period and for at least 7 months after the last dose of study 
drug 
A woman is considered to be of childbearing potential if she is 
postmenarcheal, has not reached a postmenopausal state ( 12 continuous 
months of amenorrhea with no identified cause other than menopause), and 
has not undergone surgical sterilization (removal of ovaries and/or uterus). 
Examples of non-hormonal contraceptive methods with a failure rate of  1% 
per year include bilateral tubal ligation, male sterilization, and copper 
intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
Periodic 
abstinence 
(e.g., 
calendar, 
ovulation, 
symptothermal, 
or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Barrier methods must always be supplemented with the use of a spermicide. 
For men: agreement to remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive measures and agreement to refrain from 
donating sperm, as defined below: 


 
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With female partners of childbearing potential, men must remain abstinent 
or use a condom plus an additional contraceptive method that together result 
in a failure rate of 1% per year during the treatment period and for at least 
7 months plus 90 days (a spermatogenesis cycle) after the last dose of study 
drug. Men must refrain from donating sperm during this same period. 
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for at least 7 months after the last dose of 
study drug. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
12. A signed written informed consent approved by the relevant IRB/EC  
8.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Prior treatment with trastuzumab emtansine 
2. Prior treatment with lapatinib or lapatinib with capecitabine or non-comparable 
biologic or biosimilar of trastuzumab 
3. Peripheral neuropathy of Grade ≥ 3 per NCI CTCAE (version 4.03) 
4. History of other malignancy within the previous 5 years, except for appropriately 
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage 1 
uterine cancer, synchronous or previously diagnosed HER2-positive breast 
cancer, or cancers with a similar curative outcome as those mentioned above 
5. History of receiving any anti-cancer drug/biologic or investigational treatment 
within 21 days prior to enrollment except hormone therapy, which can be given 
up to 7 days prior to enrollment; recovery of treatment-related toxicity consistent 
with other eligibility criteria 
6. History of exposure to the following cumulative doses of anthracyclines: 
v. Doxorubicin or liposomal doxorubicin > 500 mg/m2 
vi. Epirubicin > 900 mg/m2 
vii. Mitoxantrone > 120 mg/m2 
viii. 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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7. History of radiation therapy within 14 days of enrollment. The patient must have 
recovered from any resulting acute toxicity (to Grade ≤ 1) prior to enrollment. 
8. Brain metastases that are untreated, symptomatic, or require therapy to control 
symptoms, as well as a history of radiation, surgery, or other therapy, including 
steroids, to control symptoms from brain metastases within 2 months (60 days) 
before enrollment 
9. CNS only disease 
10. History of a decrease in LVEF to < 40% or symptomatic congestive heart failure 
(CHF) with previous trastuzumab treatment 
11. History of symptomatic chronic heart failure (New York Heart Association [NYHA] 
Classes II−IV) or serious cardiac arrhythmia requiring treatment 
12. History of myocardial infarction or unstable angina within 6 months of enrollment 
13. Current dyspnea at rest due to complications of advanced malignancy or 
requirement for continuous oxygen therapy 
14. Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, or metabolic disease) 
15. Pregnancy or lactation 
16. Concurrent, serious, uncontrolled infections or current known infection with human 
immunodeficiency virus (HIV) or active hepatitis B and/or hepatitis C. 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 
17. Presence 
of 
conditions 
that 
could 
affect 
gastrointestinal 
absorption: 
malabsorption syndrome, resection of the small bowel or stomach, and ulcerative 
colitis 
18. History of intolerance (such as Grade 3-4 infusion reaction) or known 
hypersensitivity to trastuzumab or murine proteins or any component of the 
product 
19. Assessed by the investigator to be unable or unwilling to comply with the 
requirements of the protocol  
 
8.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
This is an open-label, single arm study. Therefore, all the enrolled patients fulfilling the 
eligibility criteria will receive trastuzumab emtansine.  


 
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8.3 
STUDY TREATMENT 
The investigational medicinal product (IMP) for this study is trastuzumab emtansine. 
8.3.1 
Formulation, Packaging, and Handling 
8.3.1.1 
Trastuzumab emtansine 
Trastuzumab emtansine will be provided by the Sponsor as a lyophilized product in either 
15 mL or 20 mL single-use vials, which contain enough products to deliver 100 mg or 160 
mg, respectively, of trastuzumab emtansine. The lyophilized form of the product is 
provided for reconstitution to a liquid concentrate using sterile water for injection.  
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 drug product, after reconstitution, contains 20 mg/mL trastuzumab 
emtansine. The reconstituted product will contain no preservative and should be intended 
for single use only. Using a new syringe, add 8.0 mL of sterile water for injection to the 20 
mL (160 mg) trastuzumab emtansine vial configuration, or 5.0 mL of sterile water for 
injection to the 15 mL (100 mg) trastuzumab emtansine vial configuration. Swirl gently 
until completely dissolved (do not shake vigorously). Reconstituted trastuzumab 
emtansine should be diluted into polyvinyl chloride (PVC), latex-free PVC-free polyolefin 
bags (PO), polypropylene (PP) or polyethylene (PE) bags containing 0.45% or 0.9% 
sodium chloride injection (minimum volume of 250 mL). Sodium chloride 0.45% may be 
used without a 0.2 or 0.22 micron in-line polyethersulfone (PES) filter. If 0.9% sodium 
chloride is used for infusion, a 0.2 or 0.22 micron in-line PES filter is required. 
The stopper of lyophilized product vials should be punctured once to introduce the sterile 
water for injection and once to remove the constituted product. Vials that have been used 
for one patient should not be used for any other patient. 
For information on the formulation and handling of trastuzumab emtansine see the the 
current version of the Investigator's Brochure or local prescribing information of 
trastuzumab emtansine. 
In case of any temperature excursion either during shipment from depot to site or at the 
site, the steps outlined in Appendix 5 should be followed. Any damage or product 
complaints should be reported as follows and as per details in Appendix 5: 
Contact details for Product Complaint: 
During Office Hours: 
 


 
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Mobile [24 x7]: 
 
Fax: +91-22-33941054 
Product Complaint Mailbox: india.productcomplaints@roche.com  
Adverse Event Mailbox: india.drugsafety@roche.com 
Reporting Timelines: within ONE business day. 
8.3.2 
Dosage, Administration, and Compliance 
8.3.2.1 
Trastuzumab emtansine 
Trastuzumab emtansine will be administered on Day 1 of a 3-week cycle at a dose of 3.6 
mg/kg IV unless dose reductions or dose delays are required. The total dose will be 
calculated based on the patient’s weight up to 28 days before each cycle with no upper 
limit. If within these 28 days the patient experiences a severe weight loss, the dose should 
be recalculated accordingly. 
If the timing of trastuzumab emtansine coincides with a holiday that precludes the 
procedure, the procedure should be performed within 3 working days of the scheduled 
date and, when possible, on the earliest following date, with subsequent protocol-specified 
procedures rescheduled accordingly. 
Trastuzumab emtansine infusions will be administered per the instructions outlined in 
Table 1. 
Table 1 Administration of First and Subsequent Infusions of Trastuzumab 
emtansine 
First Infusion 
Subsequent Infusions 
 Trastuzumab emtansine will be administered 
on Day 1 of a 3-week cycle at a dose of 3.6 
mg/kg IV 
 The initial dose will be delivered over 90  10 
minutes. Vital signs will 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 the first infusion is tolerated without 
infusion-associated AEs (fever or chills), the 
subsequent infusions may be delivered 
over 30  10 minutes. 
 Patients who experience an infusion–
associated AE may be premedicated for the 
next infusion, but the infusion time may not 
be decreased for that infusion.  
 In the case of infusion-related reactions, 
consideration for re-treatment should be 
based on clinical assessment of the severity 
and 
pathophysiology 
of 
the 
reaction 
(specific guidance is provided in study 
protocols). 
In 
the 
event 
of 
a 
true 
hypersensitivity reaction (in which severity 
of reaction increases with subsequent 
infusions), 
trastuzumab 
emtansine 
treatment 
must 
be 
permanently 
discontinued.  
 


 
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Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 8.6. 
Any overdose or incorrect administration of study drug should be noted on the Study Drug 
Administration electronic Case Report Form (eCRF). Adverse events associated with an 
overdose or incorrect administration of study drug should be recorded on the 
Adverse Event eCRF. Section 9.3.5.12 summarizes available safety data related to 
overdosing of trastuzumab emtansine. 
8.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(trastuzumab emtansine) will be provided by the Sponsor where required by local health 
authority regulations. The study site will acknowledge receipt of IMPs by returning the 
appropriate documentation form 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 to 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. 
8.3.4 
Post-Trial Access to Trastuzumab Emtansine 
The Sponsor will offer post-trial access to trastuzumab emtansine free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product as outlined below. 
A patient will be eligible to receive study drug after completing the study if all of the 
following conditions are met: 
 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being  
 
There are no appropriate alternative treatments available to the patient 
 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 


 
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A patient will not be eligible to receive study drug after completing the study if any of the 
following conditions are met: 
 
The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient) 
 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for HER2-positive unresectable, LABC or mBC 
 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for HER2-positive unresectable, LABC or mBC 
 
Provision of study drug is not permitted under the laws and regulations of the patient's 
country 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
 
http://www.roche.com/policy continued access to investigational medicines.pdf 
 
8.4 
CONCOMITANT THERAPY 
Concomitant therapy and premedication are defined as non-IMP. No formal drug-drug 
interaction studies with trastuzumab emtansine in humans have been conducted. 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal/homeopathic remedies, nutritional supplements) used by a patient between 
the 14 days preceding first treatment and the safety follow-up visit.  
8.4.1 
Permitted Therapy  
Premedication is allowed according to standard practice guidelines. 
No premedication for the first infusion of trastuzumab emtansine is required; however, 
premedication is allowed at the investigator’s discretion.  
Concomitant use of erythropoiesis-stimulating agents is allowed if clinically indicated in 
accordance with local prescribing guidelines. 
Palliative radiotherapy may be permitted to treat pre-existing bone metastases or to treat 
brain metastases (for patients who have disease control outside of the brain). Please 
contact the Medical Monitor for approval. If the Medical Monitor cannot be reached, 
radiotherapy may be administered, but the Medical Monitor should still be informed. 


 
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Other medications considered necessary for the patient’s safety and wellbeing may be 
given at the discretion of the investigator. Use of bisphosphonates or denosumab is 
permitted for the control of bone pain, prevention and/or treatment of bony metastases, 
and treatment of osteoporosis. If bisphosphonates are required for the treatment of 
symptomatic malignancy associated hypercalcemia, tumor assessments should be 
performed to assess for potential disease progression. Premedication for nausea and 
infusion reactions (e.g., paracetamol or other analgesics, antihistamines such as 
diphenhydramine, or corticosteroids) may also be given at the investigator’s discretion. 
8.4.2 
Prohibited Therapy 
Use of the following therapies is prohibited: 
 
Any other systemic anticancer agent or other treatments not part of protocol-
specified anticancer therapy 
 
Any oral, injected, or implanted hormonal methods of contraception 
 
Any other investigational agent 
 
Initiation of herbal remedies for cancer treatment. Herbal remedies initiated prior to 
study entry and continuing during the study are permitted and must be reported on 
the appropriate eCRF. 
The following treatments should be avoided because of the risk of immunosuppression: 
 
Chronic or high-dose oral corticosteroid therapy 
 
Tumor necrosis factor (TNF)-α inhibitors 
 
Anti-T cell antibodies 
Radiotherapy for unequivocal disease progression is not permitted while on study 
treatment, with the exception of new brain metastases or isolated progression of 
previously treated brain lesions. Patients who have disease control outside of the brain, 
defined as continued PR or CR of any duration, or stable disease for ≥ 4 months, but who 
have developed brain metastases that are treatable with radiation will be allowed to 
continue to receive study therapy until they either experience systemic progression of their 
disease and/or further progression in the brain that cannot be treated with additional 
radiation. 
Radiotherapy should be finished at least 7 days before resuming administration of 
trastuzumab emtansine and all toxicities need to have resolved. The Medical Monitor 
should be informed before a decision is made to resume study treatment after 
radiotherapy for brain metastases. 
Patients with thrombocytopenia and on anti-coagulant treatment must be monitored 
closely during treatment with trastuzumab emtansine. Platelet counts will be monitored 
prior to each trastuzumab emtansine dose.  


 
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The above list of medications are not necessarily comprehensive. Thus, the investigator 
should consult the prescribing information for any concomitant medication. In addition, the 
investigator should contact the Medical Monitor if questions arise regarding medications 
not listed above. 
  
8.5 
STUDY ASSESSMENTS  
Please see Appendix 1 for the schedule of assessments performed during the study. 
8.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before performing 
any study-specific screening tests or evaluations. Informed Consent Forms for enrolled 
patients and for patients who are not subsequently enrolled will be maintained at the study 
site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment. 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. 
8.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, cancer history (including 
prior cancer therapies and procedures), reproductive status, smoking history, use of 
alcohol and drugs of abuse,and all medications (e.g., prescription drugs, over-the-counter 
drugs, herbal or 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. 
8.5.3 
Physical Examinations 
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems. Any abnormality identified at 
baseline should be recorded on the General Medical History and Baseline Conditions 
eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline abnormalities should be 
recorded in patient notes. New or worsened clinically significant abnormalities should be 
recorded as AEs on the Adverse Event eCRF. 


 
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8.5.4 
Vital Signs  
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressures while the patient is in a seated position, and temperature. Vital 
signs will be assessed before treatment on Day 1 of every treatment cycle, recorded again 
after infusion during the observation period. 
8.5.5 
Tumor and Response Evaluations  
All known sites of disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation. Response will be assessed by the investigator on the basis 
of physical examinations, computed tomography (CT) scans, and other modalities (e.g., 
MRI, brain scans, bone marrow examinations), using the RECIST criteria 1.1. An 
objective response should be confirmed by repeat assessments  4 weeks after initial 
documentation. The same radiographic procedure used to assess disease sites at 
screening should be used throughout the study (e.g., the same contrast protocol for CT 
scans). Assessments should be performed by the same evaluator as far as possible to 
ensure internal consistency across visits. 
8.5.6 
Other Disease-Specific Assessments  
8.5.6.1 
LVEF assessments 
LVEF assessments will be performed within 42 days of enrollment and after every 3 
treatment cycles by either ECHO scan. For being eligible for this study, LVEF ≥ 50% is 
required at screening. ECHO should be the method of choice for these assessments. The 
same method of LVEF assessment must be used for the same patient throughout the 
study, and to the extent possible, be obtained at the same institution. All pre-study LVEF 
values during and following trastuzumab adjuvant treatment for all patients will be 
collected. 
8.5.6.2 
Performance Status 
Performance status will be measured using the ECOG performance status scale (see 
Appendix 2). It is recommended, where possible, that a patient’s performance status will 
be assessed by the same person throughout the study. Performance status will be 
assessed at baseline, after every three cycles of treatment, and at the 28-days post-
treatment safety follow-up visit.  
8.5.7 
Laboratory Assessments 
Samples for the following laboratory tests will be sent to the study site’s accredited local 
laboratory for analysis: 
 
HER2 testing: HER2-positive status on fixed tissue blocks from the primary tumor 
(and/or metastatic site) to be assessed by IHC and/or ISH at a local laboratory that 
is experienced/certified in HER2- expression testing. Patients who have had HER2 
testing done at the same local laboratory for their prior treatment will not require re-
testing. 


 
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 
Hematology (WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count [neutrophils, eosinophils, basophils, monocytes, lymphocytes, other 
cells]) 
 
Serum chemistry (sodium, potassium, chloride, bicarbonate, magnesium, blood 
glucose, blood urea nitrogen [BUN] or urea, creatinine, total protein, albumin, calcium, 
total and direct bilirubin, ALP, ALT, AST, uric acid, lactate dehydrogenase [LDH]) 
 
Coagulation (INR, aPTT, and partial thromboplastin time (PTT) 
Hematology, biochemistry, and coagulation tests will be done as part of regular safety 
assessments: at screening/baseline, every treatment cycle, and at the 1-month post-
treatment safety follow-up. Assessments must be performed at each cycle within 3 days 
(with results available) prior to the administration of study medication. 
 
Viral serology at screening (HIV, hepatitis B surface antigen  
 
Hepatitis B surface antigen, total Hepatitis B core antibody, Hepatitis C virus 
antibody) 
 
Pregnancy test 
For women of childbearing potential, serum β-HCG test must be performed within 7 days 
prior to the first dose of study treatment with the result available prior to first dosing. Urine 
β-HCG test must be performed within 7 days prior to every 3rd cycles (with results 
available prior to treatment), at the safety follow-up visit, and at 4 and 7 months after the 
last dose of study treatment. All positive urine pregnancy tests must be confirmed by a 
serum β-HCG test.  
8.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
8.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason. 
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for withdrawal from the study may include, but are not limited to, the following: 
 
Patient withdrawal of consent at any time 
 
Any medical condition that the investigator or Sponsor determines may jeopardize the 
patient’s safety if he or she continues in the study 
 
Investigator or Sponsor determines it is in the best interest of the patient 
 
Patient non-compliance, defined as as non-compliance with the study procedures, 
the schedule of protocol-defined assessments 
Every effort should be made to obtain information on patients who withdraw from the study. 
The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF. However, patients will not be followed for any reason after consent has 
been withdrawn. Patients who withdraw from the study will not be replaced. 


 
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8.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
 
Pregnancy 
 
Serious hypersensitivity reaction/anaphylaxis 
 
Clinical signs and symptoms suggesting CHF 
 
Changes in LVEF (see Appendix 4)  
 
Dyspnea or clinically significant hypotension (defined per investigator discretion) 
 
Details of discontinuation due to toxicity are given in Section  9.1. 
The investigator has the right to discontinue a patient from study drug or withdraw a patient 
from the study at any time due to any of the following reasons: 
 
Patient withdrawal of consent at any time 
 
Any medical condition that the investigator or Sponsor determines may jeopardize the 
patient’s safety if he or she continues in the study 
 
Investigator or Sponsor determines it is in the best interest of the patient 
 
Patient non-compliance, specifically defined as non-compliance with the study 
procedures, the schedule of assessments, or the protocol defined timelines  
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. Patients who discontinue study treatment prematurely will not be 
replaced. 
8.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time. Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients. 
 
Patient enrollment is unsatisfactory. 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
The Sponsor has the right to close a site at any time. Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
 
No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 


 
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9. 
ASSESSMENT OF SAFETY  
9.1 
SAFETY PLAN 
Trastuzumab emtansine is approved in India for treatment of patients with HER2-positive, 
unresectable, LABC or mBC who have received prior treatment with trastuzumab and a 
taxane. The safety plan for patients in this study is based on clinical experience with 
trastuzumab emtansine in completed and ongoing studies and knowledge of toxicities 
related to trastuzumab and maytansine (a parent compound of emtansine and DM1). The 
anticipated important safety risks for trastuzumab emtansine are outlined below. Please 
refer to the trastuzumab emtansine Investigator's Brochure for a complete summary of 
safety information.  
Several measures will be taken to ensure the safety of patients participating in this study. 
Eligibility criteria have been designed to exclude patients at higher risk for toxicities. 
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of AEs. In addition, guidelines for managing AEs, including 
criteria for dosage modification and treatment interruption or discontinuation, are provided 
below. 
An iDMC will review the safety data for interim analysis after approximately 50% patients 
complete 6 months investigational medicinal product therapy. 
The NCI-CTCAE version 4.03 will be used to grade toxicity. Trastuzumab emtansine will 
be administered as specified in Section  8.3.2. 
Before starting a new treatment cycle, toxicity must have resolved as specified in the 
following sections. Trastuzumab emtansine administration may be delayed to assess or 
treat AEs such as cardiac AEs, myelosuppression, or other events. Dose delays and dose 
reductions will be allowed for trastuzumab emtansine please refer the tables below 
(Prescribing Information Trastuzumab emtansine, April 2017).  
Table 2 Dose Reduction Schedule  
Dose Reduction Schedule 
Dose Level 
Starting Dose 
3.6 mg/kg 
First dose reduction 
3 mg/kg 
Second dose reduction 
2.4 mg/kg 
Requirement for further dose reduction 
Discontinue treatment 


 
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9.1.1 
Risks Associated with Trastuzumab Emtansine 
9.1.1.1 
Cardiotoxicity 
Patients treated with trastuzumab emtansine are at risk of developing left ventricular 
dysfunction. To date, significant cardiac events, including left ventricular ejection fraction 
(LVEF) of <40%, have been observed infrequently in clinical trials of trastuzumab 
emtansine. 
Patients must meet specified LVEF requirements to be included in this study (see Section  
8.1.  
Left ventricular function will be monitored by measurement of ejection fraction using 
echocardiogram (ECHO) as described in Section 8.5 and the schedule of assessments 
(see Appendix 1). 
Guidelines for management of patients who develop left ventricular dysfunction are 
provided in Table 3.  
Table 3 Dose Modifications for Left Ventricular Dysfunction 
 
Symptomatic 
CHF 
LVEF <40% 
LVEF 40% to ≤45% 
and decrease is 
≥10% points from 
baseline 
LVEF 40% to 
≤45% and 
decrease is 
<10% points 
from baseline 
LVEF >45% 
Discontinue 
trastuzumab 
emtansine 
Do not administer 
trastuzumab 
emtansine. 
Repeat LVEF 
assessment 
within 3 weeks. If 
LVEF <40% is 
confirmed, 
discontinue 
trastuzumab 
emtansine 
 
Do not administer 
trastuzumab 
emtansine. 
Repeat LVEF 
assessment within 
3 weeks. If the 
LVEF has not 
recovered to within 
10% points from 
baseline , 
discontinue 
trastuzumab 
emtansine 
Continue 
treatment with 
trastuzumab 
emtansine. 
Repeat LVEF 
assessment 
within 3 weeks. 
Continue 
treatment with 
trastuzumab 
emtansine 
9.1.2 
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 


 
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1 (≥75,000/mm3) by the next scheduled dose. In clinical trials, the incidence and severity 
of thrombocytopenia were higher in Asian patients. 
Cases of bleeding events with a fatal outcome have been observed. Severe cases of 
hemorrhagic events, including central nervous system hemorrhage, have been reported 
in clinical trials with trastuzumab emtansine; these events were independent of ethnicity. 
In some of the observed cases the patients were also receiving anti-coagulation therapy. 
Patients with thrombocytopenia (<100,000/mm3) and patients on anti-coagulant treatment 
should be monitored closely while on trastuzumab emtansine treatment. It is 
recommended that platelet counts are monitored prior to each trastuzumab emtansine 
dose. Trastuzumab emtansine has not been studied in patients with platelet counts 
<100,000/mm3 prior to initiation of treatment. In the event of decreased platelet count to 
Grade 3 or greater (<50,000/mm3), do not administer trastuzumab emtansine until platelet 
counts recover to Grade 1 (≥75,000/mm3). 
Table 4 Dose Modification Guidelines for Thrombocytopenia 
 
Grade 3 
Grade 4 
25,000 to < 50,000/mm3 
< 25,000/mm3 
Do not administer trastuzumab emtansine 
until platelet count recovers to ≤ Grade 1 (≥ 
75,000/mm3), and then treat at the same dose 
level. 
Do not administer trastuzumab emtansine 
until platelet count recovers to ≤ Grade 1 (≥ 
75,000/mm3), and then reduce one dose 
level. 
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. 
Hemorrhage 
Cases of hemorrhagic events, including central nervous system, respiratory, and 
gastrointestinal hemorrhage, have been reported with trastuzumab emtansine. Some of 
these bleeding events resulted in fatal outcomes. In some of the observed cases, the 
patients were also receiving anti-coagulation therapy, antiplatelet therapy, or had 
thrombocytopenia, in others there were no known additional risk factors.  Additional 
monitoring should be considered when concomitant use is medically necessary. 
9.1.3 
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 with peak elevation at day 8 after therapy and subsequent recovery to 


 
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Grade 1 or less prior to the next cycle. The incidence of increased AST was substantially 
higher than that for ALT.  
Trastuzumab emtansine has not been studied in patients with serum transaminases >2.5× 
ULN or total bilirubin >1.5x ULN prior to initiation of treatment. Trastuzumab emtansine 
treatment in patients with serum transaminases >3x ULN and concomitant total 
bilirubin >2x ULN should be permanently discontinued.  
Dose adjustments for increased transaminases should be done as follows: 
Table 5 Dose Modification Guidelines for Increased Transaminases (AST/ALT) 
Grade 2  
(>2.5 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 
trastuzumab emtansine until 
AST/ALT recovers to Grade ≤ 
2, and then reduce one dose 
level 
Discontinue trastuzumab 
emtansine 
Rare cases of severe hepatotoxicity, including death due to drug-induced liver injury and 
associated hepatic encephalopathy, have been observed in patients treated with 
trastuzumab emtansine. Some of the observed cases of acute liver injury may have been 
confounded by concomitant medications with known hepatotoxic potential and/or 
underlying conditions. An acute severe liver injury (Hy’s law) case has the following 
components:  
 
Aminotransferase enzymes (ALT/AST) greater than 3’× ULN with concurrent 
elevation of serum total bilirubin to >2 × ULN, without initial findings of cholestasis 
(elevated serum alkaline phosphatase) 
 
No other reason can be found to explain the combination of increased 
aminotransferases and serum total bilirubin, such as viral Hepatitis A, B, or C, pre-
existing or acute liver disease, or another drug capable of causing the observed 
injury. 
 
The finding should be serious as shown by gross jaundice, clinical disability, need 
for hospital care, and be at least probably drug-induced (by trastuzumab 
emtansine) 
The following are the guidelines for dose modification for hyperbilirubinemia: 
Table 6 Dose Modification Guidelines for Hyperbilirubinemia 
Grade 2  
(>1.5 to ≤3 × the ULN) 
Grade 3  
(> 3 to ≤10 × the ULN) 
Grade 4  
(>10 × the ULN) 
Do not administer 
trastuzumab emtansine until 
total bilirubin recovers to 
Do not administer 
trastuzumab emtansine until 
total bilirubin recovers to 
Discontinue trastuzumab 
emtansine 


 
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Grade ≤1, and then treat at 
the same dose level. 
Grade ≤1 and then reduce 
one dose level. 
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. 
9.1.4 
Pulmonary Toxicity 
Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute 
respiratory distress syndrome or death, have been reported in patients receiving 
trastuzumab emtansine. Signs and symptoms may include dyspnea, cough, fatigue, and 
pulmonary infiltrates. Patients with dyspnea at rest due to complications of advanced 
malignancy and comorbidities may be at risk of pulmonary events. 
Patients with clinically significant pulmonary symptoms or disease will be excluded from 
this study (see Section 8.1.2).  
Treatment with trastuzumab emtansine has to be permanently discontinued in patients 
who are diagnosed with ILD or pneumonitis. 
9.1.5 
Infusion-Related Reactions, Hypersensitivity Reactions 
Treatment with trastuzumab emtansine has not been studied in patients who had 
trastuzumab 
permanently 
discontinued 
due 
to 
infusion 
related 
reactions 
(IRR)/hypersensitivity; treatment with trastuzumab emtansine is not recommended for 
these patients. 
Infusion related reactions (IRR): IRRs, characterized by one or more of the following 
symptoms - flushing, chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm, and 
tachycardia-have been reported in clinical trials of trastuzumab emtansine. In general, 
these symptoms were not severe. In most patients, these reactions resolved over the 
course of several hours to a day after the infusion was terminated. Trastuzumab 
emtansine treatment should be interrupted in patients with severe IRR. Trastuzumab 
emtansine treatment should be permanently discontinued in the event of a life threatening 
IRR. 


 
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Hypersensitivity Reactions: Hypersensitivity reactions, including serious, anaphylactic 
like reactions have been observed in clinical trials with treatment of trastuzumab 
emtansine. Patients who develop a severe IRR/hypersensitivity, including anaphylaxis, 
angioedema, or acute respiratory distress syndrome, during an infusion of trastuzumab 
emtansine should discontinue treatment. 
Patients should be observed closely for IRR/hypersensitivity reactions for a minimum of 
90 minutes after the first infusion and for a minimum of 30 minutes after subsequent 
infusions. Medications to treat such reactions, as well as emergency equipment, should 
be available for immediate use. In the case of infusion-related reactions, consideration for 
re-treatment should be based on clinical assessment of the severity and pathophysiology 
of the reaction. In the event of a true hypersensitivity reaction (in which severity of reaction 
increases with subsequent infusions), trastuzumab emtansine treatment must be 
permanently discontinued. 
9.1.6 
Neurotoxicity 
Peripheral neuropathy, mainly Grade 1 and predominantly sensory, has been reported in 
clinical trials of trastuzumab emtansine. Treatment with trastuzumab emtansine should be 
temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until 
symptoms resolve or improve to ≤Grade 2. Patients should be clinically monitored on an 
ongoing basis for signs/symptoms of neurotoxicity.  
9.1.7 
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. 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. 
9.1.8 
Management of Specific Adverse Events 
Adverse events of particular relevance include thrombocytopenia and hemorrhage, 
hepatotoxicity (increases in serum transaminases and nodular regenerative hyperplasia 
[NRH] of liver), IRR/hypersensitivity, cardiac dysfunction (left ventricular dysfunction), 
peripheral neuropathy and pulmonary toxicity (ILD). 
Please refer to the local prescribing information and section 9.1 for the management of 
specific AEs are provided. 
9.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, including SAEs and non-
serious AEs of special interest, performing protocol-specified safety laboratory 


 
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assessments, measuring protocol-specified vital signs, and conducting other protocol-
specified tests that are deemed critical to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in Section 
9.4. 
9.2.1 
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 9.3.5.10 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive procedures 
such as biopsies) 
 
9.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
An SAE is any AE that meets any of the following criteria: 
 
Is fatal (i.e., the AE actually causes or leads to death) 
 
Is 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 9.3.5.11) 
 
Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 


 
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 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of 
an AE (e.g., rated as mild, moderate, or severe, or according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) criteria; see Section 
9.3.3); 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 occurrence of the event; see Section 9.4.2 for reporting 
instructions). 
9.2.3 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious AEs of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after occurrence of the event; see 
Section 9.4.2 for reporting instructions). Adverse events of special interest for this study 
include the following: 
 
Cases of severe drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 9.3.5.7). The following laboratory abnormalities define potential Hy’s 
law cases:  
o AST and/or ALT elevations that are >3 × ULN 
o 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, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection 
in a patient exposed to a medicinal product. This term applies only when a 
contamination of the study drug is suspected. 
  


 
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9.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all AEs (see Section 9.2.1 for definition) 
are recorded on the Adverse Event eCRF and Appendix XI Form and reported to the 
Sponsor in accordance with instructions provided in this section and in Sections 9.49.6. 
For each AE recorded on the Adverse Event eCRF, the investigator will make an 
assessment of seriousness (see Section 9.2.2 for seriousness criteria), severity (see 
Section 9.3.3), and causality (see Section 9.3.4).  
9.3.1 
Adverse Event Reporting Period 
Investigators will seek information on AEs at each patient contact. All AEs, whether 
reported by the patient or noted by study personnel, will be recorded in the patient’s 
medical record and on the Adverse Event eCRF. All SAEs will be notified as per local 
regulations in the Appendix XI Form. 
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 9.4.2 for 
instructions for reporting SAEs). 
After initiation of study drug, all AEs will be reported until the end of the study (as 
defined in Section 7.1). After this period, the investigator should report SAEs that are 
believed to be related to prior study drug treatment (see Section 9.6). 
9.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all patient evaluation timepoints. Examples of non-directive questions 
include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
9.3.3 
Assessment of Severity of Adverse Events 
The AE severity grading scale for the NCI CTCAE (version 4.03) will be used for assessing 
AE severity. Table 8 will be used for assessing severity for AE that are not specifically 
listed in the NCI CTCAE. 


 
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Table 7 Adverse Event Severity Grading Scale for Events Not Specifically Listed in 
NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to AE d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note: Based on the most recent version of NCI CTCAE (v 4.03), which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a SAE (see 
Section 9.4.2 for reporting instructions), per the definition of SAE in Section 9.2.2. 
d Grade 4 and 5 events must be reported as SAEs (see Section 9.4.2 for reporting 
instructions), per the definition of SAE in Section 9.2.2. 
9.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an AE is considered to be related to the study drug, indicating "yes" or "no" accordingly. 
The following guidance should be taken into consideration: 
 
Temporal relationship of event onset to the initiation of study drug 
 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
 
Known association of the event with the study drug or with similar treatments 
 
Known association of the event with the disease under study 
 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 


 
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9.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF. Avoid colloquialisms and abbreviations. 
Only one AE term should be recorded in the event field on the Adverse Event eCRF and 
Appendix XI Form. 
9.3.5.1 
Infusion-Related Reactions  
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis (e.g., 
"infusion-related reaction") on the Adverse Event eCRF. If possible, avoid ambiguous 
terms such as "systemic reaction." Associated signs and symptoms should be recorded 
on the dedicated Infusion-Related Reaction eCRF. If a patient experiences both a local 
and systemic reaction to the same dose of study drug, each reaction should be recorded 
separately on the Adverse Event eCRF, with signs and symptoms also recorded 
separately on the dedicated Infusion-Related Reaction eCRF. 
9.3.5.2 
Diagnosis versus Signs and Symptoms 
For AEs other than infusion-related (see Section 9.3.5.1), a diagnosis (if known) should 
be recorded on the Adverse Event eCRF and the Appendix XI Form rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, 
asterixis, and elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or syndrome at the 
time of reporting, each individual event should be recorded on the Adverse Event eCRF. 
If a diagnosis is subsequently established, all previously reported AEs based on signs and 
symptoms should be nullified and replaced by one AE report based on the single diagnosis, 
with a starting date that corresponds to the starting date of the first symptom of the 
eventual diagnosis. 
9.3.5.3 
Adverse Events That are Secondary to Other Events 
In general, AEs that are secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events. A medically significant secondary AE that is separated in time 
from the initiating event should be recorded as an independent event on the Adverse 
Event eCRF. For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 


 
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 
If dizziness leads to a fall and consequent fracture, all three events should be reported 
separately on the eCRF. 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to 
whether the events are associated. 
9.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation timepoints. Such events should only be recorded once on the Adverse Event 
eCRF. The initial severity (intensity or grade) of the event will be recorded at the time the 
event is first reported. If a persistent AE becomes more severe, the most extreme severity 
should also be recorded on the Adverse Event eCRF. If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after learning 
that the event became serious; see Section 9.4.2 for reporting instructions). The Adverse 
Event eCRF should be updated by changing the event from "non-serious" to "serious," 
providing the date that the event became serious, and completing all data fields related to 
SAEs. 
A recurrent AE is one that resolves between patient evaluation timepoints and 
subsequently recurs.  Each recurrence of an AE should be recorded as a separate event 
on the Adverse Event eCRF. 
9.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event. A laboratory test 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 (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
Is clinically significant in the investigator’s judgment  
Note: For oncology trials, certain abnormal values may not qualify as AEs. 
 
It is the investigator’s responsibility to review all laboratory findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality 
should be classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5  ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 


 
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If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the Adverse Event eCRF, along with a descriptor 
indicating if the test result is above or below the normal range (e.g., "elevated potassium," 
as opposed to "abnormal potassium"). If the laboratory abnormality can be characterized 
by a precise clinical term per standard definitions, the clinical term should be recorded as 
the AE. For example, an elevated serum potassium level of 7.0 mEq/L should be recorded 
as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 9.3.5.4 for details 
on recording persistent AEs). 
9.3.5.6 
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. 
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 9.3.5.4 for details 
on recording persistent AEs). 
9.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  baseline value) in combination with either an 
elevated total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's law). Therefore, investigators must report as an 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) 


 
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 
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 9.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours of occurrence of the 
event), either as a SAE or a non-serious adverse event of special interest (see 
Section 9.4.2). 
9.3.5.8 
Deaths 
All deaths that occur during the study period (see Section 9.3.1) regardless of relationship 
to study drug, must be recorded on the Adverse Event eCRF, the Appendix XI Form and 
reported to the Sponsor and Health Authorities (see Section 9.4.2) within 24 hours of  
occurrence of the event. This includes death attributed to progression of HER2-positive 
unresectable, locally advanced or mBC. 
Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only one such event should be reported. 
The term "sudden death" should be used only for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without preexisting 
heart disease, within 1 hour after the onset of acute symptoms or, in the case of an 
unwitnessed death, within 24 hours after the patient was last seen alive and stable. If the 
cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF. If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be 
replaced by the established cause of death. 
If the death is attributed to progression of HER2-positive unresectable, locally advanced 
or mBC, "breast cancer progression" should be recorded in the Adverse Event eCRF.  
During survival follow-up, all deaths should be recorded in the Survival eCRF and the 
Appendix XI Form and reported to the Sponsor and Health Authorities (see Section 9.4.2) 
within 24 hours of occurrence of the event. 
9.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an AE only if the frequency, severity, 
or character of the condition worsens during the study. When recording such events on 
the Adverse Event eCRF, it is important to convey the concept that the preexisting 


 
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condition has changed by including applicable descriptors (e.g., "more frequent 
headaches"). 
9.3.5.10 
Lack of Efficacy or Worsening of Breast Cancer  
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as AEs. These data will be captured as efficacy 
assessment data only. In most cases, the expected pattern of progression will be based 
on RECIST criteria 1.1. In rare cases, the determination of clinical progression will be 
based on symptomatic deterioration. However, every effort should be made to document 
progression through use of objective criteria. If there is any uncertainty as to whether an 
event is due to disease progression, it should be reported as an AE. 
9.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any AE that results in hospitalization (i.e., in-patient admission to a hospital) or prolonged 
hospitalization should be documented and reported as a SAE (per the definition of SAE in 
Section 9.2.2), except as outlined below.  
The following hospitalization scenarios are not considered to be AE: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration) 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected normal 
progression of the disease 
The patient has not experienced an AE 
 
Hospitalization due solely to progression of the underlying cancer 
 
The following hospitalization scenarios are not considered to be SAEs, but should be 
reported as AEs instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
9.3.5.12 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied. An overdose or incorrect administration of study treatment is not itself 
an AE, but it may result in an AE. All AEs associated with an overdose or incorrect 
administration of study drug should be recorded on the Adverse Event eCRF. If the 


 
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associated AE fulfills seriousness criteria, the event should be reported to the Sponsor 
immediately (i.e., no more than 24 hours of occurrence of the event; see Section 9.4.2). 
Adverse events associated with an overdose of trastuzumab emtansine in previous clinical 
studies include thrombocytopenia or increased ALT. In the few cases of medication error 
due to confusion between two products and consequent overdose with trastuzumab 
emtansine to date, events of either thrombocytopenia without hemorrhage or 
asymptomatic increases in transaminases have been observed. A single case of sudden 
death after medication error has been reported to date; however, after analysis of this 
case by the Applicant, a causal relationship to the medication error was considered 
unlikely. Please refer to Investigator’s Brochure for more information on the cases. 
9.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours of the occurrence of the event. The following is a list of events 
that the investigator must report to the Sponsor within 24 hours of occurrence of the event, 
regardless of relationship to study drug: 
 
Serious adverse events (see Section 9.2.2 for further details) 
 
Non-serious adverse events of special interest (see Section 9.2.3 for further details) 
 
Pregnancies (see Section 9.4.3 for further details) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
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 IRB/EC. 
9.4.1 
Emergency Medical Contacts 
Medical Monitor contact information for all sites  
Medical Monitor: 
Dr. 
 
Telephone No.: 
 


 
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Mobile Telephone No.: 
 
 
Alternate Medical Monitor contact information for all sites: 
Medical Monitor: 
Dr. 
 
Telephone No.: 
 
Mobile Telephone No.: 
 
 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls. The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week. Toll-free numbers for the Help Desk, as well 
as Medical Monitor contact information, will be distributed to all investigators.  
Drug Safety: Contact Information 
 
To ensure the safety reporting, following contact information will be available to all 
investigators. 
Telephone No.: 
 
Direct: 
 
Fax: +91-22-33941054 
E-mail: india.drugsafety@roche.com 
 
9.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
9.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention should be reported. The Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form and the Appendix XI Form as per 
local regulations provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e, no more than 24 hours of occurrence of the 
event), either by faxing or by scanning and emailing the Appendix XI Form using the fax 
number or email address provided to investigators. 
9.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, SAEs and non-serious AEs of special interest will be reported 
until 12 months after last patient enrolled in the study. Investigators should record all case 
details that can be gathered immediately (i.e., within 24 hours of occurrence of the event) 
on the Adverse Event eCRF and submit the report via the electronic data capture (EDC) 
system. A report will be generated and sent to Roche Safety Risk Management by the 
EDC system. 


 
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In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours of 
the occurrence of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators. Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.  
Instructions for reporting post-study AEs are provided in Section 9.6. 
9.4.3 
Reporting Requirements for Pregnancies 
9.4.3.1 
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 Roche Safety Risk 
Management. Pregnancy should not be recorded on the Adverse Event eCRF. The 
investigator should discontinue study drug and counsel the patient, discussing the risks of 
the pregnancy and the possible effects on the fetus. Monitoring of the patient should 
continue until conclusion of the pregnancy. Any SAEs associated with the pregnancy (e.g., 
an event in the fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the Adverse Event eCRF. 
In the event that the EDC system is unavailable, the Clinical Trial Pregnancy Reporting 
Form provided to investigators should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), either 
by faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators. Once the EDC system is available, all information will need to 
be entered and submitted via the EDC system. 
In order to learn more about the effects of trastuzumab emtansine on pregnancy, Roche 
Safety will request detailed follow-up information during the pregnancy and during the 
baby’s first year of life, even if the patient has left the study. 
9.4.3.2 
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 and 
additional 90 days (a spermatogenesis cycle) 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. 


 
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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 9.4.3.1. 
In order to learn more about the effects of trastuzumab emtansine on pregnancy, Roche 
Safety will request detailed follow-up information during the patient’s partner’s pregnancy 
and during the baby’s first year of life, even if the patient has left the study. 
9.4.3.3 
Abortions 
Any abortion should be classified as an SAE (as the Sponsor considers abortions to be 
medically significant), recorded on the Adverse Event eCRF and the Appendix XI Form, 
and reported to the Sponsor immediately (i.e., no more than 24 hours of occurrence of the 
event; see Section 9.4.2).  
9.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified as 
an SAE, recorded on the Adverse Event eCRF and the Appendix XI Form and reported to 
the Sponsor immediately (i.e., no more than 24 hours of occurrence of the event; see 
Section 9.4.2). 
9.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
9.5.1 
Investigator Follow-Up 
The investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or 
the patient withdraws consent. Every effort should be made to follow all SAEs considered to 
be related to study drug or trial-related procedures until a final outcome can be reported. 
During the study period, resolution of AEs (with dates) should be documented on the Adverse 
Event eCRF and in the patient’s medical record to facilitate source data verification. 
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 9.4.3.1. 


 
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9.5.2 
Sponsor Follow-Up 
For SAEs, non-serious adverse events of special interest, and pregnancies, the Sponsor 
or a designee may follow up by telephone, fax, electronic mail, and/or a monitoring visit to 
obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
9.6 
POST-STUDY ADVERSE EVENTS 
The Sponsor should be notified if the investigator becomes aware of any SAE that occurs 
after the end of the adverse event reporting period (defined as section 9.3.1 after the last 
dose of study drug), if the event is believed to be related to prior study drug treatment.  
The investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form and the Appendix XI form as per local requirements using 
the fax number or email address provided to investigators. 
9.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all SAEs and non-serious AEs of special interest 
against cumulative product experience to identify and expeditiously communicate possible 
new safety findings to investigators, IRBs, ECs, and applicable health authorities based 
on applicable legislation. 
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the local prescribing information and Investigator’s 
Brochure for trastuzumab emtansine  
 
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. 
10. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
A total of approximately 70 patients will be enrolled in this study.  
10.1 
DETERMINATION OF SAMPLE SIZE 
For the purpose of the estimation of sample size, the incidence of all grade AEs was 
chosen as a safety endpoint of primary interest. If the observed incidence of all grade AEs 




 
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 
Intent-to-treat (ITT) population: The ITT population will be defined as all enrolled 
patients. All baseline summaries and efficacy analyses will be based on the ITT 
population.  
 
Safety population: The safety population is defined as all enrolled patients who 
receive at least one dose of study medication.  
10.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Baseline and disease characteristics such as demographics, medical history, etc. will be 
summarized by descriptive statistics (frequency tables for categorical variables and mean, 
median, range, standard deviation [SD], and 25th-75th quartiles for the continuous 
variables. 
10.4 
SAFETY ANALYSES 
All safety variables will be analyzed for the safety population that will include all patients 
who receive at least one dose of study medication.  
10.4.1 
Primary Safety Endpoint 
The primary safety endpoint for this study is as follows: 
 
Incidence and severity of AEs as per National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) (version 4.03) 
10.4.2 
Secondary Safety Endpoints 
The following variables will be measured as secondary safety endpoints:- 
 
Incidence and severity of SAEs as per NCI-CTCAE (version 4.03) 
 
Incidence of non-serious AEs of special interest 
 
Cases of drug-induced liver injury meeting Hy’s law criteria 
 
Incidence of CHF 
 
LVEF decrease over the course of the study as measured by ECHO  
 
Laboratory results abnormalities  
 
Incidence of AEs leading to discontinuation, modification, or interruption of study 
medication 
 
Exposure to study medication 
 
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 


 
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Activities (MedDRA) preferred term. Summaries will include: the incidence of AEs and 
SAEs (overall, by severity using NCI CTCAE version 4.03, by action taken with study drug). 
Incidence of CHF and/or significant decline in LVEF: The incidence of CHF and/or 
significant decline in LVEF will be summarized using number (n) and percentage. LVEF 
over time will be analyzed using descriptive statistics for continuous variable and 
presented graphically over time. 
The number of patients prematurely discontinued from the treatment and the 
corresponding reasons for discontinuation will be summarized and listed. Laboratory 
parameters (hematology, serum biochemistry, and coagulation) will be presented by 
means, standard deviation, minimum, and maximum. 
10.5 
EFFICACY ANALYSES 
Efficacy variables (PFS, ORR, and OS) will be summarized for the intent-to-treat (ITT) 
population defined as a population that includes all patients enrolled in the study. 
10.5.1 
Secondary Efficacy Endpoints 
The following variables will be measured as secondary efficacy endpoints:- 
 
Overall response rate (ORR) 
 
Progression free survival (PFS) 
 
Overall survival (OS) 
PFS is defined as the time from the date of enrollment until the first documented 
progression of disease or death from any cause, whichever occurs first. PFS will be 
obtained by the Kaplan-Meier approach. Patients with no PFS events will be censored at 
the time of the last evaluable tumor assessment. Patients with no tumor assessment after 
the baseline visit will be censored at the time of enrollment plus one day.  
OS is defined as the time from the date of enrollment until the date of death, regardless of 
the cause of death. Patients who are alive at the time of the final analysis will be censored 
at the date of the last follow-up assessment. OS analysis will be done at 12 months from 
the last patient enrolled in the study using the Kaplan-Meier estimate. 
The analysis of ORR will be based on the best (confirmed) overall response (BOR). Best 
(confirmed) overall response (BOR) is defined as the best response recorded from the 
start of trial treatment until disease progression/recurrence or death. To be assigned a 
status of PR or CR (i.e., a responder) determined by the investigator using Response 
Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 (Appendix 3). Changes 
in tumor measurements must be confirmed by repeat assessments that should be 
performed no less than 4 weeks after the criteria for response are first met, i.e., patients 
need to have two consecutive assessments of PR or CR to be a responder. 


 
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Patients without a post-baseline tumor assessment will be considered to be non-
responders. Ninety five percent confidence intervals (calculated using Clopper-Pearson 
methodology) for this will be provided. 
10.6 
INTERIM ANALYSIS 
10.6.1 
Planned Interim Analysis 
In addition to the final analysis, there will be interim analysis for safety [refer to safety 
outcome measures] once approximately 50% patients complete 6 months investigational 
medicinal product therapy.  
An independent Data Monitoring Committee (iDMC) will be formed which will include a 
statistician. An iDMC will perform the review of this interim analysis of efficacy and safety 
and subsequent safety reviews as described in the iDMC Charter. 
11. 
DATA COLLECTION AND MANAGEMENT 
11.1 
DATA QUALITY ASSURANCE 
The Sponsor will supply eCRF specifications for this study. A contract research 
organization (CRO) will be responsible for data management of this study, including 
quality checking of the data. Data entered manually will be collected via EDC using eCRFs. 
Sites will be responsible for data entry into the EDC system. In the event of discrepant 
data, the CRO will request data clarification from the sites, which the sites will resolve 
electronically in the EDC system. 
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data. Laboratory data will be sent directly to the CRO, using the CRO's 
standard procedures to handle and process the electronic transfer of these data. 
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO’s data management plans and specifications. Data will be periodically 
transferred electronically from the CRO to the Sponsor, and the Sponsor’s standard 
procedures will be used to handle and process the electronic transfer of these data.  
eCRFs and correction documentation will be maintained in the EDC system’s audit trail. 
System backups for data stored at the CRO and records retention for the study data will 
be consistent with the CRO’s standard procedures.  


 
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11.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system. Sites will 
receive training and have access to a manual for appropriate eCRF completion. eCRFs 
will be submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff. Electronic CRFs 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. 
11.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical protocol 
data (i.e., source data) entered into the eCRFs by authorized site personnel are accurate, 
complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded and 
documented for the first time. They include, but are not limited to, hospital records, clinical 
and office charts, laboratory notes, memoranda, patient-reported outcomes, evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies of transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, and 
records kept at pharmacies, laboratories, and medico-technical departments involved in a 
clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan. This includes any protocol data to be entered 
directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data entered 
into the eCRFs must not be obliterated or destroyed and must be retained per the policy 
for retention of records described in Section 11.5. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review. The study site must also allow inspection 
by applicable health authorities. 


 
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11.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research. An 
acceptable computerized data collection system allows preservation of the original entry 
of data. If original data are modified, the system should maintain a viewable audit trail that 
shows the original data as well as the reason for the change, name of the person making 
the change, and date of the change. 
11.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of IMP, 
including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years after 
completion or discontinuation of the study, or for the length of time required by relevant 
national or local health authorities, whichever is longer. After that period of time, the 
documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor. Written 
notification should be provided to the Sponsor prior to transferring any records to another 
party or moving them to another location. 
12. 
ETHICAL CONSIDERATIONS 
12.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the ICH 
E2A guideline (Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting).  
12.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form will be provided to each site. As applicable, 
it will be provided in a certified translation of the local language. The Sponsor or its 
designee must review and approve any proposed deviations from the Sponsor's sample 
Informed Consent Forms or any alternate consent forms proposed by the site (collectively, 
the "Consent Forms") before IRB/EC submission. The final IRB/ECapproved Consent 
Forms must be provided to the Sponsor for health authority submission purposes 
according to local requirements. 


 
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The investigator or authorized designee will explain to each patient the objectives, 
methods, and potential risks associated with each optional procedure. Patients will be told 
that they are free to refuse to participate and may withdraw their consent at any time for 
any reason. A separate, specific signature will be required to document a patient's 
agreement to participate in optional procedures. Patients who decline to participate will 
not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate. The final revised IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative. All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
12.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, and 
relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated. 
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC. Investigators are also 
responsible for promptly informing the IRB/EC of any protocol amendments (see Section 
13.6). 
In addition to the requirements for reporting all AEs to the Sponsor, investigators must 
comply with requirements for reporting SAEs to the local health authority and IRB/EC. 
Investigators may receive written IND safety reports or other safety-related 
communications from the Sponsor. Investigators are responsible for ensuring that such 


 
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reports are reviewed and processed in accordance with health authority requirements and 
the policies and procedures established by their IRB/EC, and archived in the site’s study 
file.  
12.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number. This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed to 
third parties only as permitted by the Informed Consent Form (or separate authorization 
for use and disclosure of personal health information) signed by the patient, unless 
permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
12.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV). 
13. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
13.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and governmental 
approval. In addition, at the end of the study, the investigator will receive the patient data, 
including an audit trail containing a complete record of all changes to data. 
13.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 


 
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data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. 
13.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for inspection 
of study data, patients’ medical records, and eCRFs. The investigator will permit national 
and local health authorities, Sponsor monitors, representatives, and collaborators, and the 
IRBs/ECs to inspect facilities and records relevant to this study. 
13.4 
ADMINISTRATIVE STRUCTURE 
The study will have an iDMC and an eCRF. It will be conducted by a CRO together with 
the Sponsor. Assessment of laboratory test results will be performed locally. 
13.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all requirements 
for publication of study results. For more information, refer to the Roche Global Policy on 
Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
The results of this study may be published or presented at scientific congresses. For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal manuscript 
reporting primary clinical trial results within 6 months after the availability of the respective 
clinical study report. In addition, for all clinical trials in patients involving an IMP for which 
a marketing authorization application has been filed or approved in any country, the 
Sponsor aims to publish results from analyses of additional endpoints and exploratory 
data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior to 
submission for publication or presentation. This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that may 
not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. Any formal publication of 


 
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the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the appropriate 
Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
13.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor. Protocol amendments will be 
submitted to the IRB/EC and to regulatory authorities in accordance with local regulatory 
requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally required) 
before implementation of any changes, except for changes necessary to eliminate an 
immediate hazard to patients or changes that involve logistical or administrative aspects 
only (e.g., change in Medical Monitor or contact information). 
14. 
REFERENCES 
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. 
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. 
Cassady JM, Chan KK, Floss HG, et al. Recent developments in the maytansinoid 
antitumor agents. Chem Pharm Bull (Tokyo) 2004; 52:1–26. 
Diéras V, Miles D, Verma S, Pegram M, Welslau M et al. Trastuzumab emtansine versus 
capecitabine plus lapatinib in patients with previously treated HER2-positive advanced 
breast cancer (EMILIA): a descriptive analysis of final overall survival results from a 
randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18:732-742. 
DeSantis C, Siegel R, Bandi P, et al. Breast cancer statistics, 2011. CA Cancer J Clin 
2011;61:409-18.  
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; 66:4426–4433. 
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. 
Investigator’s Brochure Kadcyla® (Trastuzumab emtansine) Version 9, December 2014 
Issell BF, Crooke ST. Maytansine. Cancer Treat Rev. 1978; 5:199–207. 


 
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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. 
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. 
Perou CM1, Sørlie T, Eisen MB Molecular portraits of human breast tumours. Nature. 
2000;406:747-52 
Prescribing Information Kadcyla® (Trastuzumab emtansine) revised on April 2017, F. 
Hoffmann-La Roche Ltd, Basel, Switzerland 
Periodic Benefit-Risk Evaluation Report/ Periodic Safety Update Report 1063701 for 
Trastuzumab emtansine. Interval Covered 22 August 2014 to 21 February 2015 (inclusive), 
released on 22 April 2015 
Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in 
human breast and ovarian cancer. Science 1989;244: 707-12. 
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. 
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. 
Sundaresan S, Penuel E, Sliwkowski MX. The biology of human epidermal growth factor 
receptor 2. Curr Oncol Rep. 1999; 1:16–22. 
Sørlie T1, Perou CM, Tibshirani R et al. Gene expression patterns of breast carcinomas 
distinguish tumor subclasses with clinical implications Proc Natl Acad Sci. 2001;98:10869-
74. 
Venter DJ, Tuzi NL, Kumar S, et al. Overexpression of the c-erbB-2 oncoprotein in human 
breast carcinomas: immunohistological assessment correlates with gene amplification. 
Lancet 1987;2:69–72. 
Verma S, Miles D, Gianni L et al. Trastuzumab emtansine for HER2-positive advanced 
breast cancer. N Engl J Med. 2012:367:1783-91. 
Wolff AC, Hammond ME, Hicks DG et al. Recommendations for human epidermal growth 
factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College 
of American Pathologists clinical practice guideline update. J Clin Oncol. 2013:31:3997–
4013. 
 
 
 




 
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Laboratory Investigations 
(Hematology, serology 
and serum chemistry)8 
X 
X 
X 
 
 
ECOG performance 
status9 
X 
Every 3 cycles of 
antibody drug 
conjugate 
X 
 
X 
LVEF10 
X 
Every 3 cycles of 
antibody drug 
conjugate 
X 
X 
 
Adverse event reporting11 
X 
X 
X 
X 
X 
Administration of 
trastuzumab emtansine12 
 
X 
 
 
 
Pregnancy test13 
Within 7 days prior 
to 1st dosing 
Every 3 cycles of 
antibody drug 
conjugate 
X 
At 4 and 7 months 
after the last dose of 
antibody drug 
conjugate
 
Survival15 
X 
X 
X 
X 
X 
 
Notes: 
17. Signed and dated informed consent in language comprehended by the potential clinical trial subject/Legally acceptable representative 
18. Complete medical history and demographics (i.e. age, sex, race, and ethnicity, if applicable) and all medications taken during the last 28 days 
prior to screening visit will be collected 
19. Physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurological systems. Record abnormalities observed at baseline on the General Medical History 
and Baseline Conditions eCRF. Record new or worsened clinically significant abnormalities on the Adverse Event eCRF 
20. Vital signs will be assessed before treatment on Day 1 of every treatment cycle, recorded again after infusion during the observation period. Vital 
signs include respiratory rate, pulse rate, and systolic, and diastolic blood pressure while the patient is in a seated position, and oral or axillary 
temperature 


 
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21. Current concomitant medication will be recorded at screening and on an ongoing basis 
22. HER2-positive status on fixed tissue blocks from the primary tumor (and/or metastatic site, if primary tumor not available) to be assessed by IHC 
and/or FISH at a local laboratory 
23. On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. A CT or MRI and (if indicated) isotope bone 
scan (evaluation according to RECIST criteria) should be performed at screening and as clinically indicated. Scans at screening should not be 
older than 28 days prior to first study medication administration. NB: Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions. Tumor assessment ± 3 days of planned scheduled visit. At the end of study visit, if a patient does not fit 
into the end of study definition, then tumor assessment to be done as per institutional criteria and routine clinical practice.  
24. Laboratory assessment as per routine standard of care must be performed within 3 days (with results available) prior to the administration of 
study medication. Hematology, as per routine standard of care, may include hemoglobin, hematocrit, platelet count, RBC, WBC with differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils, other cells). Serum chemistry, as per routine standard of care, may include 
sodium, potassium, calcium, chloride, magnesium, BUN (urea), uric acid, total protein, albumin, alkaline phosphatase, ALT, AST, lactate 
dehydrogenase (LDH), total bilirubin, creatinine, and blood glucose and calculated creatinine clearance at baseline. Coagulation tests will consist 
of international normalized ratio (INR) and aPTT or PTT. 
25. ECOG performance status to be recorded after every 3 cycles until disease progression. 
26. LVEF ≥ 50% at screening period to be determined by ECHO. To the extent possible, assessment to be obtained at the same institution. 
27. After informed consent and prior to dosing, SAEs considered related to a study mandated procedure are reportable. As of cycle 1 all AEs and 
SAEs considered will be collected. AEs and SAEs to be monitored and continuously collected till end of study visit and to be recorded with 
grading according to NCI-CTCAE version 4.03. 
28. The initial dose of trastuzumab emtansine will be administered over 90 minutes and if well tolerated subsequent infusions may be administered 
over 30 min (±10 min). 
29. For women of childbearing potential, serum β-HCG test must be performed within 7 days prior to the first dose of study treatment with the result 
available prior to first dosing. Urine β-HCG test must be performed within 7 days prior to every 3rd cycle (with results available prior to treatment), 
at the safety follow up visit, and at 4 and 7 months after the last dose of study treatment. All positive urine pregnancy tests must be confirmed 
by a serum β HCG test. 
30. Patients who complete the study or discontinue from the study early will be asked to return to the hospital within 28 days after the last dose of 
study drug for the end of the study visit. 
31. Survival status will be recorded during the treatment period and every 3 months after the one month post-treatment safety follow up visit until 
12 months after the last patient enrolled in study or lost to follow up, withdrawn consent, or died, or if the study is prematurely terminated by 
Roche, whichever occurs first. Patients who are alive at the time of the analysis will be censored at the date of the last follow up assessment 


Trastuzumab emtansine—Roche Products (India) Pvt. Ltd 
Protocol ML29662 Version 1  
 
 
 
84 
Appendix 2 Eastern Cooperative Oncology Group (ECOG) 
Performance Status 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g. light house work, 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 
 
As published in: 
Oken, MM, Creech, RH, Tormey, DC, Horton, J, Davis, TE, McFadden, ET, Carbone, PP. Toxicity 
and Response Criteria of The Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-
55.


 
85 
Appendix 3 RECIST Criteria Version 1.1 
 
Response Evaluation Criteria in Solid Tumors (RECIST): An Excerpt from 
Original Publication 
 
 
 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1,1 are presented below, with the addition of explanatory text as needed for 
clarity.2 
1. 
Measurability of Tumor at Baseline 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as discussed below. 
i. 
Measurable  
Tumor Lesions  
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows:  
 10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) 
scan (CT/MRI scan slice thickness/interval no greater than 5 mm) 
 10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 20 mm by chest X-ray 
Malignant Lymph Nodes 
 To be considered pathologically enlarged and measurable, a lymph node must be  15 
mm in the short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and follow-up, only the short axis will be 
measured and followed. See also notes below on “Baseline Documentation of Target and 
Non-Target Lesions” for information on lymph node measurement. 
ii. 
Non-Measurable Tumor Lesions 
Non-measurable tumor lesions include small lesions (longest diameter  10 mm or 
pathological lymph nodes with short axis  10 but  15 mm) as well as truly 
                                            
 
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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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. 
iii. 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as given below. 
Bone Lesions 
 Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques for measuring bone lesions. 
However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
 Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such 
as CT or MRI can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability described above. 
 Blastic bone lesions are non-measurable. 
Cystic Lesions 
 Lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions. 
Lesions with Prior Local Treatment 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there 
has been demonstrated progression in the lesion. Study protocols should detail 
the conditions under which such lesions would be considered measurable. 


 
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iv. 
 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 4 weeks before the beginning of the treatment. 
b. Method of Assessment 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during the follow-up visits. Imaging-
based evaluation should always be preferred over clinical examination. 
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 in certain situations (e.g. for body 
scans).  
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 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. 


 
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Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. 
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology: The utilization of 
these techniques for objective tumor evaluation cannot generally be advised. However, 
these techniques can be used to confirm the complete pathological response.  
2.  
Tumor Response Evaluation 
i. 
 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 
described above. 
ii. 
 Baseline Documentation of Target and Non-Target Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative of 
all involved organs should be identified as target lesions and will be recorded and 
measured at baseline. This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two sites), 
respectively, will be recorded. Other lesions (albeit measurable) in those organs will be 
recorded as non-measurable lesions (even if the size is  10 mm by CT scan).  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, 
the largest lesion does not lend itself to reproducible measurement, in which circumstance 
the next largest lesion that can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures that may 
be visible by imaging even if not involved by tumor. As noted above, pathological nodes 
that are defined as measurable and may be identified as target lesions must meet the 
criterion of a short axis of ≥ 15 mm by CT scan. Only the short axis of these nodes will 
contribute to the baseline sum. The short axis of the node is the diameter normally used 
by radiologists to judge if a node is involved by solid tumor. Nodal size is normally reported 
as two dimensions in the plane in which the image is obtained (for CT this is almost always 
the axial plane; for MRI the plane of acquisition may be axial, sagittal, or coronal). The 
smaller of these measures is the short axis. For example, an abdominal node that is 
reported as being 20 mm × 30 mm has a short axis of 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 


 
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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”). 
iii. 
Response Criteria 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
a. 
Evaluation of 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%, the sum must also demonstrate an 
absolute increase of at least 5mm. 
 
The appearance of one or more new lesions is also considered progression. 
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. 


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


 
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no measurable disease assessment to factor into the interpretation of an increase in non-
measurable disease burden. Because worsening in non-target disease cannot be easily 
quantified (by definition: if all lesions are truly non-measurable), a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if the increase 
in overall disease burden based on the change in non-measurable disease is comparable 
in magnitude to the increase that would be required to declare PD for measurable disease, 
that is, an increase in tumor burden representing an additional 73% increase in volume 
(which is equivalent to a 20% increase in diameter in a measurable lesion). Examples 
include an increase in a pleural effusion from “trace” to “large” or an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols as 
“sufficient to require a change in therapy.” If unequivocal progression is seen, the patient 
should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease 
makes it impossible to do so; therefore, the increase must be substantial. 
e. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal, that is, not attributable to differences in scanning technique, change in 
imaging modality, or findings thought to represent something other than tumor (for 
example, some “new” bone lesions may be simply healing or flare of preexisting lesions). 
This is particularly important when the patient’s baseline lesions show PR or CR. For 
example, necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic 
lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify 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. 
iv. 
Evaluation of Response 
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment taking into account any requirement for confirmation. 
On occasion a response may not be documented until after the end of therapy so protocols 
should be clear if post-treatment assessments are to be considered in determination of 
best overall response. Protocols must specify how any new therapy introduced before 
progression will affect best response designation. The patient’s best overall response 
assignment will depend on the findings of both target and non-target disease and will also 
take into consideration the appearance of new lesions. Specifically, in non-randomized 
trials where response is the primary endpoint, confirmation of PR or CR is needed to deem 
either one the ‘best overall response’.  


 
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a. 
Time point Response  
It is assumed that at each protocol-specified time point, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each time point 
for patients who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be 
used. 
 
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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b. 
Missing Assessments and Inevaluable 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. 
Best Overall Response: All Time Points  
The best overall response is determined once all the data for the patient is known. 
Best response determination in trials where confirmation of complete or partial 
response IS NOT required: Best response in these trials is defined as the best response 
across all time points (for example, a patient who has SD at first assessment, PR at 
second assessment, and PD on last assessment has a best overall response of PR). 
When SD is believed to be best response, it must also meet the protocol specified 
minimum time from baseline. If the minimum time is not met when SD is otherwise the 
best time point response, the patient’s best response depends on the subsequent 
assessments. For example, a patient who has SD at first assessment, PD at second and 
does not meet minimum duration for SD, will have a best response of PD. The same 
patient lost to follow-up after the first SD assessment would be considered inevaluable. 
Best response determination in trials where confirmation of complete or partial 
response IS required: Complete or partial responses may be claimed only if the criteria 
for each are met at a subsequent time point as specified in the protocol (generally 4 weeks 
later). In this circumstance, the best overall response can be interpreted as in Table 3. 
 


 
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Table 3 Best Overall Response When Confirmation Is Required 
Overall Response at First 
Time point 
Overall Response at 
Subsequent Time point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
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. 
aIf 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. 
d. 
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 


 
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response status of such patients is to be determined by evaluation of target and non-target 
disease as shown in Table 1, 2 and 3. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate. This is to avoid an incorrect assessment of CR if the primary tumor 
is still present but not evaluated as a target or non-target lesion. 
v. 
Frequency of tumor re-evaluation 
Frequency of tumor re-evaluation while on treatment should be protocol specific and 
adapted to the type and schedule of treatment. After the end of the treatment, the need 
for repetitive tumor evaluations depends on whether the trial has as a goal the response 
rate or the time to an event (progression/death). If ‘time to an event’ (e.g. time to 
progression, disease-free survival, progression-free survival) is the main endpoint of the 
study, then routine scheduled re-evaluation of protocol specified sites of disease is 
warranted. In randomized comparative trials in particular, the scheduled assessments 
should be performed as identified on a calendar schedule (for example: every 6–8 weeks 
on treatment or every 3–4 months after treatment) and should not be affected by delays 
in therapy, drug holidays or any other events that might lead to imbalance in a treatment 
arm in the timing of disease assessment. 


 
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Appendix 4 
Algorithm for Continuation and Discontinuation of Trastuzumab emtansine 
Based on Left Ventricular Fraction Assessments in Patients 
 
 
 
 
 
 
Reference: Prescribing information Kadcyla® (Trastuzumab emtansine) Feb 2015 
 
 


 
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Appendix 5 
Guidance on Temperature Excursion and Product Complaint 
In case of a temperature excursion and/or any product complaint noted at the site, the following 
steps should be followed. The excursion aspect includes shipment excursion from IMP depot to 
site and excursion noted during IMP storage at site. 
TEMPERATURE EXCURSION 
Excursion noted during shipment from 
depot to site: 
 
Once the temperature excursion is 
noted upon receipt of the study drug, 
temperature 
recording 
of 
the 
temperature logger should be stopped.  
 
The temperature on the IMP receipt 
form should be recorded. 
 
The affected IMP should be kept in 
allocated bags and a ‘QUARANTINE’ 
label affixed on the bags and stored in 
the 
study 
refrigerator 
isolated/ 
separated from the usable stock under 
protocol 
mandated 
temperature 
conditions and the temperature on the 
study temperature log should be 
noted. 
 
The site monitor should be informed of 
the excursion with details through e-
mail communication. 
 
The PD103 form (IMP Deviation Form) 
should be completed by the Monitor 
based on information provided by site 
and the site should be consulted for 
additional information, if required. 
 
The affected IMP should not be 
dispensed to any subject till a decision 
is received in writing from Sponsor. 
 
If approved by Sponsor in writing, the 
‘QUARANTINE’ 
label 
should 
be 
removed from the affected IMP and 
released. 
 
If rejected by Sponsor, a “DO NOT 
USE” label should be affixed on the 
bags with the affected IMP and not 
dispensed to any of the subjects and 
proceeded for destruction of the 
affected IMP after the approval from 
Sponsor 
 
The completed PD103 form shared by 
Monitor, temperature recording logs 
and 
related 
communication 
from 
Excursion noted at site: 
 
The deviated temperature (higher/lower) 
and duration of excursion when the site 
staff noticed the excursion on the study 
temperature log should be noted. 
 
The affected IMP should be transferred to 
another secured, temperature controlled 
refrigerator under protocol mandated 
temperature 
conditions 
and 
the 
temperature and time should be recorded 
on the study temperature log. 
 
The affected IMP should be kept in 
allocated 
bags 
and 
affixed 
a 
‘QUARANTINE’ label on the bags and 
stored in the study refrigerator isolated/ 
separated from the usable stock under 
protocol 
mandated 
temperature 
conditions and the temperature on the 
study temperature log should be noted. 
 
The site monitor should be informed of the 
excursion with details through e-mail 
communication 
along 
with 
relevant 
temperature recording logs. 
 
The Monitor should complete PD103 form 
(IMP 
Deviation 
Form) 
based 
on 
information provided by site and consult 
site for additional information, if required 
 
The 
affected 
IMP 
should 
not 
be 
dispensed to any subject till a decision is 
received in writing from Sponsor. 
 
If approved by Sponsor in writing, the 
‘QUARANTINE’ label from the affected 
IMP and it may be dispensed to subjects. 
 
If rejected by Sponsor, a “DO NOT USE” 
label should be affixed on the bags with 
the 
affected 
IMP 
and 
should 
not 
dispensed it to any of the subjects. 
 
The completed PD103 form shared by 
Monitor, temperature recording logs and 
related communication from Sponsor on 
approval/ rejection, destruction record 
(where applicable) should be filed in 


 
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Sponsor 
on 
approval/ 
rejection, 
destruction record (where applicable) 
should be filed in appropriate section 
of the investigator site file. 
 
The Sponsor has a timeline of 3 
working days to provide approval/ 
rejection decision on the impacted 
batch of IMP. 
appropriate section of the investigator site 
file. 
 
The reason for temperature excursion 
should 
be 
identified 
and 
required 
assessments and corrections should be 
performed to avoid recurrence of the 
same and the details shared with 
sponsor. 
 
The Sponsor has a timeline of 3 working 
days to provide approval/ rejection 
decision on the impacted batch of IMP. 
In case of temperature excursions, below are the minimum details of affected IMP to be reported 
by site: 
 
Name and number of affected IMP 
 
Dosage Form (e.g. tablet, syringe, vial) 
 
Batch number and Expiry Date 
 
Strength 
 
Shipment ID (If related to shipment) 
 
Minimum temperature 
 
Duration below lower limit 
 
Maximum temperature 
 
Duration above upper limit 
 
Did the concerned IMP have a temperature deviation before? 
In case of a product complaint, the following details should be provided: 
 
Product Name and number of affected IMP 
 
Dosage Form (e.g. tablet, syringe, vial) 
 
Batch number and Expiry Date 
Examples of Product Complaints include the following, but not limited to:- 
 Broken Solvent Vials 
 Missing Component 
 Unusual Appearance 
 Smudging of Batch Number 
 Defective Component/Packaging 
 Reconstitution Problems 
 Discoloration 
 Bacterial/microbial contamination 
 Size/Shape Variation 
 Foreign Matter  
 
Contact details for Product Complaint: 
 During Office Hours: 
 
 Mobile [24 x7]: 
 
 Fax: +91-22-33941054 


 
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 Product Complaint Mailbox: india.productcomplaints@roche.com  
Adverse Event Mailbox: india.drugsafety@roche.com 
 Reporting Timelines: within ONE business day. 
The site monitor should be copied on all e-mail communications. In case of any issues or 
clarification, please feel free to contact your site monitor. 
 
 
 

SAP_001.pdf: 
 
Official Title: 
 
A Multicenter, Open-Label, Single-Arm, Phase IV Study of Trastuzumab 
Emtansine in Indian Patients With HER2-Positive Unresectable Locally 
Advanced or Metastatic Breast Cancer Who Have Received Prior 
Treatment With Trastuzumab and a Taxane 
NCT Number: 
NCT02658734 
Document Date: 
SAP Version 1: 16-May-2018 
 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL 
[Change to STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL for SAP  
Hand written signatures are allowed only with external partners and affiliates that are not 
fully integrated into RAPID.  The approver manually signs a separate signature page 
which is incorporated into the pdf file and published and signed in PDR. 
The Study Biostatistician must determine whether formal review and approval is needed 
for this ISAP per current departmental process. 
CONFIDENTIAL 
 
This is a Roche Products (India) Pvt. Ltd. document that contains confidential information.  
Nothing herein is to be disclosed without written consent from Roche Products (India) Pvt. Ltd. 
 
Trastuzumab emtansine—Roche Products (India) Pvt. Ltd 
Statistical Analysis Plan ML29662 Version 0.2 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A MULTICENTER, OPEN-LABEL, SINGLE-ARM, PHASE IV 
STUDY OF TRASTUZUMAB EMTANSINE IN INDIAN 
PATIENTS WITH HER2-POSITIVE UNRESECTABLE 
LOCALLY ADVANCED OR METASTATIC BREAST CANCER 
WHO HAVE RECEIVED PRIOR TREATMENT WITH 
TRASTUZUMAB AND A TAXANE 
PROTOCOL NUMBER: 
ML29662 
STUDY DRUG: 
Trastuzumab emtansine (T-DM1) 
VERSION NUMBER: 
1.0 
IND NUMBER: 
71072 
EUDRACT NUMBER: 
2008-005 713-22 
SPONSOR: 
Roche Products (India) Pvt. Ltd. 
PLAN PREPARED BY: 
 
 
DATE FINAL: 
16-MAY-2018 


Trastuzumab emtansine—Roche Products (India) Pvt. Ltd 
Statistical Analysis Plan ML29662 Version Draft 0.2 
 
TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 5 
2. 
STUDY DESIGN ........................................................................................... 6 
2.1 
Protocol Synopsis .................................................................... 7 
2.2 
Objectives and endpoints ........................................................ 7 
2.2.1 
Safety Objectives ..................................................................... 7 
2.2.1.1 Primary Safety Objective ........................................................ 7 
2.2.1.2 Secondary Safety Objective ................................................... 8 
2.2.2 
Efficacy Objective .................................................................... 8 
2.2.2.1 Secondary Efficacy Objective ................................................. 8 
2.3 
Determination of Sample Size ................................................. 8 
2.4 
Analysis Timing ....................................................................... 9 
3. 
STUDY CONDUCT ....................................................................................... 9 
3.1 
Randomization Issues ........................................................... 10 
3.2 
Data Monitoring ..................................................................... 10 
3.3 
ASSESSMENT of RECIST visit responses ........................... 10 
4. 
STATISTICAL METHODS .......................................................................... 16 
4.1 
GENERAL PRINCIPLES ....................................................... 16 
4.2 
Analysis Populations ............................................................. 18 
4.2.1 
Intent-to-treat Population ....................................................... 18 
4.2.2 
Safety Population .................................................................. 18 
4.3 
Analysis of Study Conduct ..................................................... 18 
4.4 
Demographic and baseline characteristics and 
subject disposition ................................................................. 19 
4.5 
Safety Analysis ...................................................................... 19 
4.5.1 
Primary and Secondary Safety Endpoints ............................. 19 
4.5.1.1 Adverse events..................................................................... 19 
4.5.1.2 Exposure: ............................................................................. 22 
4.5.1.3 Laboratory Data.................................................................... 22 
4.5.1.4 Vital Signs ............................................................................ 24 
4.5.1.5 LVEF Assessments .............................................................. 24 


Trastuzumab emtansine—Roche Products (India) Pvt. Ltd 
Statistical Analysis Plan ML29662 Version Draft 0.2 
4.5.1.6 Performance Status .............................................................. 24 
4.6 
Efficacy Analysis .................................................................... 25 
4.6.1 
Secondary Efficacy Endpoints ............................................... 25 
4.6.1.1 Progression-free Survival (PFS) ........................................... 25 
4.6.1.2 Objective Response Rate (ORR) ......................................... 26 
4.6.1.3 Overall survival ..................................................................... 27 
4.6.1.4 Duration of Response ........................................................... 27 
4.7 
Interim Analyses .................................................................... 28 
5. 
REFERENCES ........................................................................................... 29 
5.1 
OBJECTIVES AND ENDPOINTS .......................................... 31 
5.1.1 
SAFETY OBJECTIVES ......................................................... 31 
5.1.1.1 Primary Safety Objective ...................................................... 31 
5.1.1.2 Secondary Safety Objectives ............................................... 31 
5.1.2 
EFFICACY OBJECTIVES ...................................................... 31 
5.1.2.1 Secondary Efficacy Objectives ............................................. 31 
6. 
STUDY DESIGN ......................................................................................... 32 
6.1 
DESCRIPTION OF THE STUDY ........................................... 32 
6.2 
NUMBER OF PATIENTS ....................................................... 33 
6.3 
TARGET POPULATION ........................................................ 33 
6.3.1 
Inclusion Criteria .................................................................... 33 
6.3.2 
Exclusion Criteria ................................................................... 36 
6.4 
END OF STUDY AND LENGTH OF STUDY ......................... 37 
7. 
INVESTIGATIONAL MEDICINAL PRODUCTS .......................................... 38 
8. 
STATISTICAL METHODS .......................................................................... 38 
8.1 
PRIMARY ANALYSIS ............................................................ 38 
8.2 
DETERMINATION OF SAMPLE SIZE................................... 39 
8.3 
INTERIM ANALYSIS ............................................................. 40 
 
 
LIST OF APPENDICES 
Appendix 1 
 Protocol Synopsis ...................................................................... 30 
Appendix 2 
 Schedule of Assessments .......................................................... 41 


Trastuzumab emtansine—Roche Products (India) Pvt. Ltd 
Statistical Analysis Plan ML29662 Version Draft 0.2 
Appendix 3 
 Eastern Cooperative Oncology Group (ECOG) Performance 
Status .......................................................................................... 46 
Appendix 4 
 Data Display for Interim Analysis ............................................... 47 
 
 
 
 
 
 
 
 
 
 
 


Trastuzumab emtansine—Roche Products (India) Pvt. Ltd 
Statistical Analysis Plan ML29662 Version Draft 0.2 
1. 
BACKGROUND 
Trastuzumab emtansine is a novel agent that has demonstrated efficacy in the treatment 
of HER2-positive mBC who progressed on trastuzumab and taxane based treatment. 
Registration Study TDM4370g/BO21977 met its co-primary endpoints of improving PFS 
in patients who received trastuzumab emtansine (by Independent Review Committee) and 
OS compared with those who received the combination of lapatinib and capecitabine. The 
safety profile of trastuzumab emtansine was consistent with that seen in previous studies. 
The safety profile of trastuzumab emtansine in mBC is based on data from 884 patients 
receiving single-agent trastuzumab emtansine treatment at 3.6mg/kg q3w (Studies 
TDM3569g, 
TDM4258g, 
TDM4374g, 
TDM4688g, 
TDM4450g/BO21976, 
TDM4370g/BO21977 and TDM4529g/BO25430) and combined treatment with 
pertuzumab in 87 patients (from Studies TDM4373g/BO22495 and TDM4688g). The most 
common adverse events (AEs) for trastuzumab emtansine (AEs, in ≥ 25% of patients) 
were fatigue, nausea, thrombocytopenia, headache, constipation, and epistaxis. 
Phase I and II single arm studies of trastuzumab emtansine have demonstrated profound 
clinical activity. A Phase III study BO21977 compared trastuzumab emtansine to standard 
of care HER2-targeted combination therapy (capecitabine and lapatinib) for patients with 
mBC who had received prior trastuzumab and taxane therapies. The study demonstrated 
a statistically significant and clinically meaningful improvement in both PFS (9.6 months 
with trastuzumab emtansine vs 6.4 months with lapatinib plus capecitabine) and OS. (30.9 
months with trastuzumab emtansine vs 25.1 months with lapatinib plus capecitabine). The 
patient-reported outcome of time to symptom progression demonstrated an improvement 
with trastuzumab emtansine (7.1 months) as compared to (4.6 months) treatment with 
lapatinib plus capecitabine (Verma S et al, 2012). 
Based on the data from the above said trials trastuzumab emtansine has been approved 
as a single agent, for the treatment of patients with HER2-positive, unresectable locally 
advanced or metastatic breast cancer who have received prior treatment with trastuzumab 
and a taxane in over 70 countries including India. 
From the international birth date (February 2013) to January 2015, an estimated 
cumulative total of 21,209 patients have received trastuzumab emtansine from marketing 
experience; of which 7,527 patients were estimated to have received trastuzumab 


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emtansine during the reporting interval. Based on the evaluation of these data, the clinical 
trial results are consistent with the safety profile observed in the postmarketing setting. 
Thus, the benefit−risk profile of trastuzumab emtansine remains favorable. 
This current Phase IV, single-arm, open-label, multicenter study is planned to be 
conducted to fulfil a post-marketing regulatory requirement. It is aimed to gain more 
insights into the safety and efficacy of trastuzumab emtansine for the treatment of Indian 
patients with HER2-positive advanced (metastatic or locally recurrent) breast cancer. 
2. 
STUDY DESIGN 
This is a Phase IV, single-arm, multicenter, open-label clinical trial designed to assess the 
safety of trastuzumab emtansine in Indian patients with HER2-positive unresectable LABC 
or mBC who have received prior treatment with trastuzumab and a taxane. 
All patients fulfilling the eligibility criteria and willing to provide informed consent will 
receive intravenous (IV) trastuzumab emtansine 3.6 mg/kg over 30−90 minutes on Day 1 
of a 21-day cycle. Patients will receive treatment until disease progression, unacceptable 
toxicity, withdrawal of consent, or death. 
The study will include a screening phase, treatment phase and post-treatment safety 
follow-up phase for each patient as described in the Study Schema (Figure 1). 
All patients will be followed-up for at least 12 months after the last patient is enrolled; 
unless they have been lost to follow up, withdrawn consent, or died, or the study is 
prematurely terminated by the Sponsor. 
Patients will receive study medication until unacceptable toxicity, withdrawal of consent, 
disease progression, death, or up to a maximum of 12 months after last patient first visit, 
whichever occurs first. Patients who have not progressed at the end of the trial will be 
offered options to continue with trastuzumab emtansine treatment, see Section 4.2.4. An 
independent data monitoring committee (iDMC) will be formed for this study and will 
comprise of three members including a statistician. The iDMC will review the safety data 
for interim analysis after approximately 50% patients complete 6 months investigational 
medicinal product therapy. See the iDMC charter for further information. 
. A schedule of assessments is provided in Appendix 1. 


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Figure 1. Study Schema 
 
 
 
 
 
 
 
 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 2. 
2.2 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the safety, efficacy of trastuzumab emtansine in Indian patients 
with HER2-positive unresectable locally advanced or metastatic breast cancer (mBC) who 
have received prior treatment with trastuzumab and a taxane. Specific objectives and 
corresponding endpoints for the study are outlined below. 
2.2.1 
Safety Objectives 
2.2.1.1 Primary Safety Objective 
The primary safety objective for this study is to evaluate the safety of trastuzumab 
emtansine in Indian patients on the basis of the following endpoint: 
 
Incidence and severity of AEs as per National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) (version 4.03) 
HER2 positive 
Unresectable 
LABC or mBC 
patients with prior 
treatment with 
i). A Taxane 
alone or in 
combination 
with another 
agent 
And 
ii). Trastuzumab 
alone or in 
combination 
with another 
agent 
Treatment with 
Trastuzumab 
emtansine 
3.6 mg/kg IV 
every 
3 weeks 
(Until disease 
Progression, 
unacceptable 
toxicity, 
Withdrawal or 
death) 
Post-treatment 
Safety 
Follow-up 
(Till 12 months 
from LPI) 
Enrollment


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2.2.1.2 Secondary Safety Objective 
The secondary safety objectives for this study are to evaluate the safety of trastuzumab 
emtansine on the basis of the following endpoints: 
 
Incidence and severity of SAEs as per NCI-CTCAE (version 4.03) 
 
Incidence of non-serious AEs of special interest 
 
Cases of drug-induced liver injury meeting Hy’s law criteria 
 
Incidence of CHF 
 
Left Ventricular ejection fraction (LVEF) decrease over the course of the study as 
measured by ECHO 
 
Laboratory results abnormalities  
 
Incidence of AEs leading to discontinuation, modification, or interruption of study 
medication  
 
Exposure to study medication 
2.2.2 
Efficacy Objective 
2.2.2.1 Secondary Efficacy Objective 
The secondary efficacy objectives of this study are to evaluate the efficacy of trastuzumab 
emtansine in Indian patients with respect to: 
 
Progression-free survival (PFS) 
 
Overall survival (OS) 
 
Overall response rate (ORR) 
2.3 
DETERMINATION OF SAMPLE SIZE 
For the purpose of the estimation of sample size, the incidence of all grade AEs was 
chosen as a safety endpoint of primary interest. If the observed incidence of all grade AEs 
is 95.9% according to the EMILIA study and assuming level of significance 5% (i.e. 95% 
CI) and precision 5% with drop out of 10%, approximately 70 patients are planned for 
enrollment this study. 
Sample size formula used for estimating proportion is, 
n =
Zα/2
2
 p ∗ (1 −p)
d2
 




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3.1 
RANDOMIZATION ISSUES 
This is an open-label non randomized study. 
3.2 
DATA MONITORING 
An independent data monitoring committee (iDMC) will be formed for this study and will 
comprise of three members including a statistician. The iDMC will review the safety data 
for interim analysis after approximately 50% patients complete 6 months investigational 
medicinal product therapy. Details of the iDMC roles and process will be in separate 
charter. 
3.3 
ASSESSMENT OF RECIST VISIT RESPONSES  
For all subjects, the RECIST tumour response data will be used to determine each 
subject’s visit response according to RECIST version 1.1.  It will also be used to determine 
if and when a subject has progressed in accordance with RECIST and also their best 
overall response.  
Baseline radiological tumour assessments are to be performed no more than 28 days 
before the start of study medication. Tumour assessments are then performed every 3 
cycles following study medication administration until disease progression.  
Response will be assessed by the investigator on the basis of physical examinations, 
computed tomography (CT) scans, and other modalities (e.g., MRI, brain scans, bone 
marrow examinations), using the RECIST criteria 1.1. An objective response should be 
confirmed by repeat assessments ≥ 4 weeks after initial documentation. The same 
radiographic procedure used to assess disease sites at screening should be used 
throughout the study (e.g., the same contrast protocol for CT scans). Assessments should 
be performed by the same evaluator as far as possible to ensure internal consistency 
across visits. 
Measurable disease: 
A lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 
mm in the longest diameter (except lymph nodes which must have short axis ≥15 mm) 
with CT or MRI and which is suitable for accurate repeated measurements. 


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Non-measurable disease: 
 
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 to <15 mm short axis at baseline). 
 
Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical examination that is not measurable by CT or 
MRI. 
 
Previously irradiated lesions 
 
Skin lesions assessed by clinical examination 
 
Brain metastasis 
Special cases: 
 
Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques for measuring bone lesions. However, 
these techniques can be used to confirm the presence or disappearance of bone 
lesions. 
 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets 
the definition of measurability.  
 
Blastic lesions are considered non-measurable. 
 
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. 
 
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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Target lesions  
A subject can have a maximum of 5 measurable lesions recorded at baseline and these 
are referred to as the target lesions. If more than one baseline scan is recorded, then 
measurements from the one that is closest to start of study medication will be used to 
define the baseline sum of TLs. 
The baseline assessment is the assessment recorded before, or on the day of study 
medication and is that which is closest to the day of study medication will be used as long 
as it is not after the date of first dose. 
Note: For patients who do not have measurable disease at entry (i.e. no TLs), evaluation 
of overall visit responses will be based on the overall non-target lesion (NTL) assessment 
and the absence/presence of new lesions. Note that if a patient does not have measurable 
disease at baseline then the TL visit response will be not applicable (NA). 
Table 1 
TL visit responses 
Visit Responses 
Description 
Complete Response (CR) 
Disappearance of all target lesions.  Any pathological lymph nodes 
selected as target lesions must have a reduction in short axis to 
<10mm. 
Partial response (PR) 
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum of diameters as long as criteria 
for PD are not met. 
Progressive disease (PD) 
A ≥ 20% increase in the sum of diameters of target lesions and an 
absolute increase of ≥ 5mm, taking as reference the smallest sum of 
diameters since treatment started including the baseline sum of 
diameters. 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD 
Not Evaluable (NE) 
All target lesion measurements are missing and sum of diameters of 
non-missing target lesions does not qualify for PD. 
Not applicable (NA) 
No target lesions are recorded at baseline 
Lymph nodes 
For lymph nodes, if the size reduces to < 10mm then these are considered non-
pathological. However a size will still be given and this size should still be used to 
determine the TL visit response as normal.  In the special case where all lymph nodes are 


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< 10mm and all other TLs are 0mm then although the sum may be >0mm the calculation 
of TL response should be over-written as a CR. 
TL too small to measure: 
If a target lesion becomes too small to measure a value of 5mm will be entered into the 
database and used in TL calculations, unless the radiologist has indicated and entered a 
smaller value that can be reliably measured.  If it is the opinion of the radiologist that the 
lesion has likely disappeared, the measurement should be recorded as 0 mm. 
Missing Assessments and Inevaluable 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. 
Any TL (including lymph nodes), which has had intervention during the study (for example, 
irradiation / palliative surgery / embolisation/ curative surgery), should be treated as 
missing and should be handled as specified as above. in the following way and once a 
lesion has had intervention then it should be treated as having intervention for the 
remainder of the study noting that an intervention will most likely shrink the size of tumours. 
Lesions That Split or Coalesce on Treatment 


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When non-nodal lesions fragment, the longest diameters of the fragmented portions 
should be added together to calculate the target lesion sum. Similarly, as lesions coalesce, 
a plane between them may be maintained that would aid in obtaining maximal diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the vector of the longest diameter in this instance should be the 
maximum longest diameter for the coalesced lesion. 
Change in method of assessment of target lesions: 
If a change in method of assessment occurs between CT and MRI this will be considered 
acceptable and no adjustment is required while response derivation. 
If a change in method involves clinical examination (e.g. CT changes to clinical 
examination or vice versa), any affected lesions should be treated as missing.   
Non-Target Lesions and new lesions 
Non-target lesion response will be derived based on the Investigator’s overall 
assessment of NTLs as follows: 
Progressive disease: Unequivocal progression of existing NTLs, which may be due to 
an important progression in one lesion only or in several lesions. 
Complete response:  Disappearance of all NTLs present at baseline with all lymph 
nodes non-pathological in size (<10mm short axis). 
Non-CR/Non-PD:  
Persistence of one or more NTLs with no evidence of progression. 
Not evaluable:  
Only relevant when one or some of the NTLs have not been 
assessed and in the Investigator’s opinion they are not able to 
provide an evaluable overall NTL assessment. 
Not applicable: 
Only relevant if there are no NTLs at baseline. 
New lesions will be identified via a Yes/No tick box. A new lesion indicates progression so 
the overall visit response will be PD irrespective of the TL and NTL response. 
If the question ‘Were there any new lesions (since baseline) at this timepoint?’ has not 
been answered with Yes or No and the new lesion details are blank this is not evidence 
that no new lesions are present and should be treated as NE in the derivation of overall 
visit response. 


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Overall visit response 
Table 3 defines how the previously defined TL and NTL visit responses will be combined 
with new lesion information to give an overall visit response. 
Table 2 
Overall visit responses 
TARGET 
NON-TARGET 
NEW LESIONS 
OVERALL VISIT 
RESPONSE 
CR 
CR (or NA) 
No 
CR 
CR 
Non-CR/Non-PD or 
NE 
No (or NE) 
PR 
PR 
 Non-PD or NE 
No (or NE) 
PR 
SD 
 Non-PD or NE 
No (or NE) 
SD 
PD 
Any 
Any 
PD 
Any 
PD 
Any 
PD 
Any 
Any 
Yes 
PD 
NE 
Non-PD 
No 
NE 
NA 
CR 
No 
CR 
NA 
Non-CR/Non-PD 
No 
Non-CR/non-PD a 
NA 
NE 
No (or NE) 
NE 
NA 
Non-PD 
NE 
SD 
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. 
 
Best Overall Response When Confirmation Is Required 
Best (confirmed) overall response (BOR) is defined as the best response recorded from 
the start of trial treatment until disease progression/recurrence or death. The best overall 
response can be interpreted as in Table 4. Complete or partial responses may be claimed 
as Best Overall Response only if the following criteria met. 
CR:    Overall visit response of CR confirmed at least 4 weeks (28 days) later by another 
overall visit response of CR (intervening responses of NE are possible and are acceptable 
but PD is not)  
PR:    Overall visit response of PR confirmed at least 4 weeks (28 days) later by an overall 
visit response of at least PR (i.e CR/PR) (with no intervening response of PD)  


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SD>= 54 days: Stable disease recorded at least 54 days after start of treatment 
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, 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. 
4. 
STATISTICAL METHODS 
4.1 
GENERAL PRINCIPLES 
The below mentioned general principles will be followed throughout the study: 


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 
All summaries (safety) will be presented at each schedule time point, wherever 
applicable. 
 
The change from baseline is defined as the post-baseline value minus the baseline 
value.  
 
Study day: Study day for given reference point (such as AE start date, visit date or 
ECG date) will be calculated as number of days from date of first administration of 
study medication, i.e., 
 Study day = Reference date – study medication administration start date, if visit 
date is before the study medication administration date. OR 
 Study day = Reference date – study medication administration start date + 1, 
if visit date is on or after the study medication administration date.  
If the study medication administration start date or reference date is missing 
then study day will be set as missing. 
 
Descriptive statistics will include number of non-missing subject (n), mean, 
standard deviation (SD), 25th quartile, median,75th quartile, minimum and 
maximum values for continuous variables, and for categorical variables the 
frequencies and percentages of subjects will be presented. For baseline and 
demographic characteristic data in addition to above statistics range will also be 
presented. 
 
For continuous safety data, mean, median and quartiles will be rounded to 1 
additional decimal place, standard deviation (SD) will be rounded to 2 additional 
decimal places compared to the original data and minimum and maximum will be 
displayed with the same precision as the original data. 
 
For categorical data, percentages will be rounded to 1 decimal place. 
 
For laboratory values below or above the limit of quantification (e.g., value reported 
by the laboratory as ‘<0.10’or ‘>2.90’), a numeric value (i.e. 0.10 or 2.90) equal to 
the reported quantification limit will be imputed in a manner consistent with the 
corresponding laboratory flags and limits, and the imputed values will be utilized in 
data summaries and the imputed values along with corresponding symbol (‘<’ or 
‘>’) will be listed. 


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 
All study data will be included in study data listings. In general, all data will be listed 
by time point within subject. 
 
SAS® version 9.2 or higher will be used for all analyses. 
4.2 
ANALYSIS POPULATIONS 
4.2.1 
Intent-to-treat Population 
The Intent-to-treat (ITT) population is defined as all enrolled patients regardless of whether 
or not study medication was administered. All baseline summaries and efficacy analysis 
will be based on ITT population. 
4.2.2 
Safety Population 
The safety population is defined as all enrolled patients who have received at least one 
dose of study medication. All safety endpoints will be analyzed based on safety population. 
4.3 
ANALYSIS OF STUDY CONDUCT 
The number of patients who enroll, discontinue, or complete the study will be summarized. 
Reasons for premature study withdrawal will be listed and summarized. 
Screened patients are defined as any patient who signed the informed consent. 
Enrolled patients are defined as any patient who met all eligibility criteria. 
For patient study status, the total number of patients in each of the following categories 
will be presented in summary table: 
 
Screened patients 
 
Enrolled patients 
 
Enrolled and treated patients  
 
Patients who completed the treatment  
 
Patients who discontinued the treatment 
 
Reasons for premature treatment withdrawal 
 
Patients who completed the study 
 
Patients who discontinued the study 
 
Reasons for premature study withdrawal 


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Screen failed patients and screen failure reasons will be summarized separately. 
Major protocol deviations will be listed and summarized for their potential effects on the 
interpretation of study results. 
4.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS AND 
SUBJECT DISPOSITION 
Characteristics of the patients, including inclusion in analysis populations, age, sex, self-
reported race/ethnicity, ECOG performance status, Breast cancer history, previous cancer 
therapy, radiotherapy, medical history, surgical history and concomitant medications will 
be listed for each patient and summarized. 
Previous anti-cancer treatments at baseline and concomitant medication will be 
summarized and listed as appropriate. Disallowed concomitant medications, post-study 
medication will also be listed. Systemic anti-cancer treatments received prior/post to 
progression by line may be summarized. Height, weight and BMI will be listed for each 
patient and summarized. 
4.5 
SAFETY ANALYSIS 
Safety data will be summarized and listed only, as appropriate. No formal statistical 
analyses will be performed on the safety data. All safety data will be summarized including 
patients who have dose reduction. However, some listings such as AEs listings will display 
the actual dose the patient received at onset of an AE. Data from all cycles of initial 
treatment will be combined in the presentation of safety data. 
The following sections describe the planned safety summaries. However, additional safety 
tables may need to be produced to aid interpretation of the safety data. 
4.5.1 
Primary and Secondary Safety Endpoints 
4.5.1.1 Adverse events 
Data from all cycles of initial treatment will be combined in the presentation of safety data.  
All adverse events will be listed individually for each patient and summarized according to 
the system organ class (SOC) and preferred term (PT) assigned to the event using the 
MedDRA. AEs will be graded according to the NCI CTCAE version 4.03 for AEs. The 


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CTCAE grade will be assigned by the investigator. MedDRA version 18.0 or higher will be 
used for coding. 
Any AEs occurring after the first dose of study treatment and within 35 days of the last 
dose of study treatment will be included in the AE summaries. AEs occurring before the 
first dose of study treatment or more than 35 days after the last dose of study treatment 
will not be included in AE summaries but will be included and presented in the patient 
listings. 
AEs will be categorized into one or more of the following categories depending on the type 
of events reported: 
 
All AEs 
 
All AEs (by episode) 
 
All AEs by severity (CTCAE grade) 
 
All AEs with by relationship to the study medication 
 
All AEs related to study medication by severity 
 
All serious adverse events (SAEs) 
 
All SAEs by severity (CTCAE grade) 
 
All SAEs with by relationship to the study medication 
 
All SAEs related to study medication by severity 
 
AE leading to interruption of study medication 
 
AE leading to dose reduction of study medication 
 
AEs leading to discontinuation of study medication 
 
AEs leading to discontinuation of study medication, causally related to study 
medication 
 
AEs with an outcome of death 
 
AEs with an outcome of death, causally related to study medication 
 
AEs with CTCAE grade 3 or higher 
 
AEs with CTCAE grade 3 or higher, causally related to study medication 
 
Summary of cause of Serious Adverse Events 
 
Summary of Outcome of Adverse Events 
 
Summary of Outcome of study medication related Adverse Events 
 
Summary of Outcome of Serious Adverse Events 


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 
Summary of Outcome of study medication related Serious Adverse Events 
An overall summary of the number and percentage of patients in each category will be 
presented, as well an overall summary of the number of events in each category. 
The number and percentage of patients reporting adverse events in each category above 
will be summarized by MedDRA system organ class and preferred term. 
AEs will be assigned a CTCAE version 4.03 grade and summaries of the number and 
percentage of patients will be provided by worst CTCAE grade, preferred term  
All adverse event data will be listed for all patients. Investigator terms with their MedDRA 
preferred terms will be listed for each patient. Listings will include the last dose for the 
patient along with the number of days since last dose. In addition, serious adverse events, 
other significant adverse events, adverse events that led to withdrawal, adverse events 
with causality trastuzumab emtansine and adverse events of special interest will be listed. 
Adverse events that occur after the last trastuzumab emtansine dose and within 30 days 
of the last trastuzumab emtansine dose will be attributed to the visit in which the last dose 
was given. 
The summary of death will be categorized as follows, 
 
 AEs  with outcome= death by system organ class (SOC) and preferred term (PT) 
 
AEs  with outcome= death, causally related to study medication, system organ 
class (SOC) and preferred term (PT) 
 
Number (%) of patients who died by the end of study period (on-study, post-study) 
and reasons for death 
On-study period is from first dose of study treatment and till 35 days of the last dose of 
study treatmentAdverse events of special interest  
AESI will be identified using CRF  
Grouped summary tables of certain preferred terms will be produced. For each ‘grouped’ 
term, the number (%) of patients experiencing any of the specified terms will be presented 
by maximum CTCAE grade. A listing of the preferred terms in each grouping will be 
provided. Changes observed in CTCAE grade during study will be listed only. 


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 Additional summaries of the above-mentioned grouped AE categories will include number 
(%) of patients who have: 
 
At least adverse event of special interest presented by outcome 
 
At least one adverse event of special interest by CTCAE grade 
 
At least one adverse event of special interest causally related to study medication 
 
At least one adverse event of special interest leading to discontinuation of study 
medication. 
4.5.1.2 Exposure: 
Total duration of exposure of study medication in weeks will be calculated as: 
(minimum of date of progression or date of discontinuation - Date of first dose of study 
medication + 1)/7 
Exposure to investigational product i.e., total amount of study medication received will be 
listed for all patients and summarized. 
Total exposure, total time on study and total number of cycles administered per patient 
will be summarized by mean, standard deviation, minimum, maximum, median and 
number of observations. In addition, the number and percentage of patients with at least 
one dose interruption and at least one dose reduction will be presented separately, if 
appropriate.  
4.5.1.3 Laboratory Data 
Blood sample for the determination of Hematology, biochemistry, and coagulation tests 
will be done as part of regular safety assessments: at screening/baseline, every treatment 
cycle, and at the 28 days (±7 days) from last treatment cycle/dose. Assessments must be 
performed at each cycle within ±3 days (with results available) prior to the administration 
of study medication. 
The baseline value is the last value observed prior to first administration of study 
medication on cycle 1 and any information taken after first administration of study 
medication is regarded as post baseline information. When there are multiple observations 
within a nominal visit, most extreme value will be taken for continuous variables and worse 
value will be taken for categorical variables.  


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All laboratory data is to be collected and reported in SI units 
All laboratory data (result) and change from baseline values will be summarized using 
descriptive statistics at each scheduled assessment time. For categorical data, shift from 
baseline will be summarised using frequency and proportion at each assessment time. 
Numerical summaries should provide the mean, median and lower and upper quartile 
(25th and 75th), in addition to other statistics, for visit based tabular summaries. 
Shift tables for laboratory values by worst Common toxicity criteria (CTC) grade will be 
produced, and for specific parameters separate shift tables indicating hyper- and hypo- 
directionality of change will be produced. For parameters with no CTCAE grading, shift 
tables from baseline to worst value on-treatment will be provided (i.e. on-treatment is 
defined as data collected up until the last dose of study medication). 
Results along with reference ranges will be listed. All laboratory summaries and listings 
will be presented by parameter. 
Other summaries will include number (%) of patients who have: 
 
Elevated Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) and 
elevated bilirubin during the study 
 
ALT  <= 1x ,  > 1x – 3x, > 3x – 5x, > 5x – 10x, > 10x – 20x and > 
20x ULN during the study 
 
AST  <= 1x,  > 1x – 3x, > 3x – 5x, > 5x – 10x, > 10x – 20x and > 20x 
ULN during the study 
 
Total bilirubin <= 1x, > 1x - 1.5x, > 1.5x – 2x, > 2x ULN during the 
study 
Individual patient data where ALT or AST plus bilirubin are elevated at any time will be 
listed. 
Box-plots of absolute values and change from baseline in Hemoglobin, Neutrophils, 
Potassium, AST, ALT and Total bilirubin will be presented. Shift plots comparing baseline 
to minimum value for hemoglobin, neutrophils and potassium while shift plots comparing 
baseline to maximum value for potassium, AST, ALT and total bilirubin will be provided. 


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4.5.1.4 Vital Signs 
Vital signs will be assessed before treatment on Day 1 of every treatment cycle, recorded 
again after infusion during the observation period. Vital signs will include respiratory rate, 
pulse rate, and systolic and diastolic blood pressure while the patient is in a seated 
position, and oral or axillary temperature. 
The baseline value is the last value observed prior to first administration of study 
medication on cycle 1. The change from baseline is defined as the post-baseline value 
minus the baseline value. There will not be any imputation for missing values. 
Vital signs (SBP, DBP respiratory rate, and pulse rate) will be summarized over time in 
terms of absolute values and changes from baseline at each scheduled measurement Box 
plots of change from baseline in SBP, DBP, respiratory rate, and pulse will be presented. 
All data will be listed individually  
4.5.1.5 LVEF Assessments 
Echocardiogram (ECHO) will be performed to assess left ventricular ejection fraction 
(LVEF) at screening (baseline), every three cycles of treatment, and at the 28-days post-
treatment safety follow-up visit. 
The incidence of CHF and/or significant decline in LVEF will be summarized using number 
(n) and percentage. LVEF over time will be analyzed using descriptive statistics for 
continuous variable and presented graphically over time. 
4.5.1.6 Performance Status 
Performance status will be measured using the ECOG performance status scale (see 
Appendix 3). Performance status will be assessed at baseline, every three cycles of 
treatment, and at the 28-days post-treatment safety follow-up visit. 
ECOG performance status at will be summarized by frequency counts and percentage at 
each scheduled visit and listed individually. Also a change from Baseline in ECOG 
performance status at last available visit will be summarized using shift table. 


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4.6 
EFFICACY ANALYSIS 
The primary objective for this study is to assess the safety of trastuzumab emtansine and 
efficacy is being the secondary objective. There will be no formal statistical hypothesis 
testing performed for secondary efficacy endpoints. All the secondary efficacy endpoint 
(PFS, ORR, and OS) data will be summarized and listed based on ITT population. 
4.6.1 
Secondary Efficacy Endpoints 
The following variables will be measured as secondary efficacy endpoints:- 
 
Progression free survival (PFS) 
 
Overall response rate (ORR) 
 
Overall survival (OS) 
4.6.1.1 Progression-free Survival (PFS) 
PFS is defined as the time from the date of enrollment until the date of first documented 
progression of disease or the date of death (by any cause in the absence of progression) 
whichever happens first regardless of whether the subject withdraws from study 
medication or receives another anti-cancer therapy prior to progression. Patients who 
have not progressed or died at the time of analysis will be censored at the last evaluable 
tumour assessment. However, if the subject progresses or dies after two or more missed 
visits (18 weeks), the subject will be censored at the time of the latest evaluable RECIST 
assessment.If the subject has no evaluable post-baseline visits or does not have baseline 
data they will be censored at 01 days. The number of subjects who were censored at time 
01 day will be reported. 
PFS will be calculated using the objective tumour assessment collected on CRF form 
RECIST 1.1 - Response Assessment 
The PFS time will always be derived based on scan/assessment dates not visit dates. 
RECIST assessments/scans contributing towards a particular visit may be performed on 
different dates. The following rules will be applied: 
The progression status of patients at the time of analysis will be summarized. This will 
include the number (%) of patients who have a progression event along with the type of 
progression event (i.e. RECIST progression or death). The reasons that patients were 


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censored at the time of analysis will also be presented with appropriate reasons listed as 
Alive at time of analysis in the absence of RECIST progression, no baseline RECIST 
assessment, no evaluable post-baseline assessment. 
The treatment status at progression of patients at the time of analysis will also be 
summarized. This will include the number (%) of patients who were on study treatment at 
the time of progression, the number (%) of patients who discontinued study treatment prior 
to progression, the number (%) of patients who have not progressed and were on 
treatment or discontinued treatment. Number of days prior to progression for the patients 
who have discontinued treatment will be presented descriptively. 
Point estimates of median PFS (in months), 25th and 75th percentile will be presented 
and PFS will be displayed graphically using Kaplan-Meier plots. Kaplan-Meier estimates 
of survival at 3 months, 6 months and 12 months, as appropriate, will be tabulated. 
4.6.1.2 Objective Response Rate (ORR)  
The analysis of ORR will be based on the best (confirmed) overall response (BOR). ORR 
is defined as the number (%) of subjects with confirmed complete response (CR) or partial 
response (PR) where the confirmation should be performed no less than 4 weeks after the 
criteria for response are first me. Data obtained up until progression or death, or last 
evaluable assessment in the absence of progression, will be included in the assessment 
of ORR. This will be irrespective of whether or not subjects discontinued treatment or 
received a subsequent therapy prior to progression. The denominator for ORR will be the 
ITT population. Patients without a post-baseline tumor assessment will be considered to 
be non-responders. 
A summary of best response (CR, PR, SD, PD, NE) will be reported at the time of the 
tumour size analysis and a summary of best overall response will be produced at the time 
of the PFS analysis. These summaries will be presented in terms of the number and 
percentage of patients for each category. In addition, ninety five percent confidence 
intervals (95% CI) for the responder patients will be calculated by using Clopper- Pearson 
methodology, where the confidence interval for the Clopper-Pearson method can be 
written as 
{θ|P[Bin(n, θ) ≤X] > α
2]} ∩ {θ|P[Bin(n, θ) ≥X] > α
2]}   


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Where X is the number of responders and the Bin (n, θ) represents a binomial variable 
with n being the number of subjects and θ being the probability of success. 
The following SAS code may be used to calculate the Clopper-Pearson CI for responders: 
proc freq data=<<data>>; 
tables CPCI/ nocum norow binomial; 
exact binomial; 
run; 
4.6.1.3 Overall survival  
Overall survival is defined as the time from the date of enrollment until the date of death 
due to any cause. Any patient not known to have died at the time of final analysis will be 
censored based on the last recorded date on which the subject was known to be alive. 
Overall survival will be summarized and graphically displayed at the time of final analysis 
(12 months from the last patient enrolled in the study). Overall survival will be displayed 
graphically using a Kaplan-Meier plot. Kaplan-Meier estimates of survival at 3 months, 6 
months and 12 months, as appropriate, will be tabulated. 
A summary of survival status at the time of final analysis will be produced. This will 
summarize the number of patients who have died, still in survival follow-up, are lost to 
follow-up (LTFU) and have withdrawn consent. 
Survival data will be listed for all enrolled patients. 
4.6.1.4 Duration of Response 
Duration of response will be defined as the time from the date of first documented 
response until date of documented progression or death in the absence of disease 
progression, the end of response should coincide with the date of progression or death 
from any cause used for the PFS endpoint.  The time of the initial response will be defined 
as the latest of the dates contributing towards the first visit response of PR or CR. 
If a subject does not progress following a response, then their duration of response will 
use the PFS censoring time. 


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Duration of response will be summarized for responder patients using the Kaplan-Meier 
method. 
4.7 
INTERIM ANALYSES 
In addition to the final analysis, there will be interim analysis for safety once approximately 
50% patients complete 6 months investigational medicinal product therapy. 
An independent Data Monitoring Committee (iDMC) will be formed which will include a 
statistician. An iDMC will perform the review of this interim analysis of efficacy and safety 
and subsequent safety reviews as described in the iDMC Charter. The list of Tables, 
Listings and figures for interim analysis is given in Appendix 4. 


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5. 
REFERENCES 
Not Applicable. 
 


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Appendix 1  
Protocol Synopsis 
TITLE 
: 
A MULTICENTER, OPEN-LABEL, SINGLE-ARM, PHASE IV 
STUDY OF TRASTUZUMAB EMTANSINE IN 
INDIANPATIENTS WITH HER2-POSITIVE 
UNRESECTABLE LOCALLY ADVANCED OR 
METASTATIC BREAST CANCER WHO HAVE RECEIVED 
PRIOR TREATMENT WITH TRASTUZUMAB AND A 
TAXANE 
PROTOCOL 
NUMBER 
: ML29662 
VERSION 
NUMBER 
: 1 
EUDRACT 
NUMBER 
: 2008-005 713-22 
IND NUMBER 
: 71072 
TEST PRODUCT 
: Trastuzumab emtansine (T-DM1) 
PHASE 
: IV 
INDICATION 
: 
HER2-positive unresectable locally advanced or metastatic 
breast cancer 
SPONSOR 
: Roche Products (India) Pvt.Ltd 
 
 
 


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5.1 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the safety, efficacy, of trastuzumab 
emtansine in Indian patients with HER2-positive unresectable locally advanced or 
metastatic breast cancer (mBC) who have received prior treatment with trastuzumab and 
a taxane. Specific objectives and corresponding endpoints for the study are outlined 
below. 
5.1.1 
SAFETY OBJECTIVES 
5.1.1.1 Primary Safety Objective 
The primary safety objective for this study is to evaluate the safety of trastuzumab 
emtansine in Indian patients on the basis of the following endpoint: 
 
Incidence and severity of AEs as per National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) (version 4.03) 
5.1.1.2 Secondary Safety Objectives 
The secondary safety objectives for this study are to evaluate the safety of trastuzumab 
emtansine on the basis of the following endpoints: 
 
Incidence and severity of SAEs as per NCI-CTCAE (version 4.03) 
 
Incidence of non-serious AEs of special interest 
 
Cases of drug-induced liver injury meeting Hy’s law criteria 
 
Incidence of CHF 
 
Left Ventricular ejection fraction (LVEF) decrease over the course of the study 
as measured by ECHO 
 
Laboratory results abnormalities 
 
Incidence of AEs leading to discontinuation, modification, or interruption of 
study medication 
 
Exposure to study medication 
5.1.2 
EFFICACY OBJECTIVES 
5.1.2.1 Secondary Efficacy Objectives 
The secondary efficacy objectives of this study are to evaluate the efficacy of 
trastuzumab emtansine in Indian patients with respect to:- 
 
Progression-free survival (PFS) 
 
Overall survival (OS) 
 
Overall response rate (ORR) 


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6. 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
This is a Phase IV, single-arm, multicenter, open-label clinical trial designed to assess the 
safety of trastuzumab emtansine in Indian patients with HER2-positive unresectable LABC 
or mBC who have received prior treatment with trastuzumab and a taxane. 
The estimated duration of enrollment is 12 months. All patients fulfilling the eligibility 
criteria and willing to provide informed consent will receive intravenous (IV) trastuzumab 
emtansine 3.6 mg/kg over 30−90 minutes on Day 1 of a 21-day cycle. Patients will receive 
treatment until disease progression, unacceptable toxicity, withdrawal of consent, or 
death. 
The study will include a screening phase, treatment phase and post-treatment safety 
follow-up phase for each patient as described in the Study Schema (Figure 1). 
All patients will be followed-up for at least 12 months after the last patient is enrolled; 
unless they have been lost to follow up, withdrawn consent, or died, or the study is 
prematurely terminated by the Sponsor. 
Patients will receive study medication until unacceptable toxicity, withdrawal of consent, 
disease progression, death, or up to a maximum of 12 months after last patient first visit, 
whichever occurs first. Patients who have not progressed at the end of the trial will be 
offered options to continue with trastuzumab emtansine treatment, see Section 4.2.4 
An independent data monitoring committee (iDMC) will be formed for this study and will 
comprise of three members including a statistician. The iDMC will review the safety data 
for interim analysis after approximately 50% patients complete 6 months investigational 
medicinal product therapy. See the iDMC charter for further information. 
A schedule of assessments is provided in Appendix 1. 


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6.2 
NUMBER OF PATIENTS 
This study is planned to be conducted in 70 patients across 12-15 centers in India. 
6.3 
TARGET POPULATION 
6.3.1 
Inclusion Criteria 
Patients must meet the following criteria to be eligible for study entry:- 
1. 
Male or female of age ≥ 18 years 
2. 
Prospectively confirmed HER2-positive (i.e., IHC 3+ or IHC 2+ and gene-amplified 
by fluorescence in situ hybridization [FISH] positive) as assessed on primary tumor 
and/or metastatic site if primary tumor not available (ISH positivity is defined as a ratio of 
2.0 or greater for the number of HER2 gene copies to the number of signals for CEP17, 
or for single probe tests, a HER2 gene count greater than 4) as determined in a local 


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laboratory that is experienced/certified in HER2-expression testing using an accurate 
and validated assay 
3. 
Histologically or cytologically documented invasive breast cancer: unresectable, 
LABC or mBC 
4. 
Prior treatment for breast cancer in the adjuvant, unresectable, locally advanced, or 
metastatic setting must include:- 
i. 
A taxane, alone or in combination with another agent, AND  
ii. 
Trastuzumab, alone or in combination with another agent in the adjuvant, 
unresectable, locally advanced, or metastatic setting 
5. 
Documented progression of unresectable, locally advanced, or mBC, determined by 
the investigator; progression must occur during or after most recent treatment for 
LABC/mBC or within 6 months after completing adjuvant therapy  
6. 
Measurable and/or non-measurable disease 
7. 
LVEF ≥ 50% by echocardiogram (ECHO) 
8. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
9. 
Adequate organ function, evidenced by the following laboratory results within 30 
days of enrollment: 
i. 
Absolute neutrophil count > 1,500 cells/mm3 
ii. 
Platelet count > 100,000 cells/mm3 
iii. 
Hemoglobin > 9.0 g/dL. Patients will be allowed to be transfused red blood 
cells to this level 
iv. 
 Albumin ≥ 2.5 g/dL  
v. 
Total bilirubin ≤ 1.5 upper limit of normal (ULN) 
vi. 
Serum glutamic oxaloacetic transaminase (SGOT) or aspartate 
aminotransferase (AST), serum glutamic pyruvic transaminase (SGPT) 
or alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤2.5 
× ULN with the following exception: Patients with bone metastases: ALP 
≤ 5 × ULN 
vii. 
Creatinine clearance > 50 mL/min based on Cockroft-Gault glomerular 
filtration rate estimation: (140 − Age) × (weight in kg) × (0.85 if female)/(72 
× serum creatinine)  


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viii. 
International normalized ratio (INR) and activated partial thromboplastin 
time (aPTT) < 1.5 × ULN (unless on therapeutic coagulation) 
10. A negative serum β-Human Chorinic Gonadotropin (β-HCG) test for women of 
childbearing potential (premenopausal or not meeting the definition of postmenopausal 
i.e. ≥ 12 months of amenorrhea), and women who have not undergone surgical 
sterilization (i.e., absence of ovaries and/or uterus) within 7 days prior to the first dose of 
study treatment with the result available prior to first dosing 
11. For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use two adequate non-hormonal methods of contraception, including at least one method with a failure rate of 1% per year,
 during the treatment 
period and for at least 7 months after the last dose of study drug 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 
Examples of non-hormonal contraceptive methods with a failure rate of 1% per 
year include bilateral tubal ligation, male sterilization, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception. 
Barrier methods must always be supplemented with the use of a spermicide. 
For men: agreement to remain abstinent (refrain from heterosexual intercourse) 
or use contraceptive measures and agreement to refrain from donating sperm, 
as defined below: 
With female partners of childbearing potential, men must remain abstinent or use 
a condom plus an additional contraceptive method that together result in a failure 
rate of 1% per year during the treatment period and for at least 7 months plus 
90 days (a spermatogenesis cycle) after the last dose of study drug. Men must 
refrain from donating sperm during this same period. 


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With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for at least 7 months after the last dose of study 
drug. 
The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception. 
12. An audio-visual recording of the informed consent process and a signed written 
informed consent approved by the relevant IRB/EC 
6.3.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. 
Prior treatment with trastuzumab emtansine 
2. 
Prior treatment with lapatinib or lapatinib with capecitabine or non-comparable 
biologic or biosimilar of trastuzumab  
3. 
Peripheral neuropathy of Grade ≥ 3 per NCI CTCAE (version 4.03) 
4. 
History of other malignancy within the previous 5 years, except for appropriately 
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage 1 uterine 
cancer, synchronous or previously diagnosed HER2-positive breast cancer, or cancers 
with a similar curative outcome as those mentioned above  
5. 
History of receiving any anti-cancer drug/biologic or investigational treatment within 
21 days prior to enrollment except hormone therapy, which can be given up to 7 days 
prior to enrollment; recovery of treatment-related toxicity consistent with other eligibility 
criteria  
6. 
History of exposure to the following cumulative doses of anthracyclines: 
i. 
Doxorubicin or liposomal doxorubicin > 500 mg/m2  
ii. 
Epirubicin > 900 mg/m2  
iii. 
Mitoxantrone > 120 mg/m2 
iv. 
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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7. 
History of radiation therapy within 14 days of enrollment. The patient must have 
recovered from any resulting acute toxicity (to Grade ≤ 1) prior to enrollment. 
8. 
Brain metastases that are untreated, symptomatic, or require therapy to control 
symptoms, as well as a history of radiation, surgery, or other therapy, including steroids, 
to control symptoms from brain metastases within 2 months (60 days) before enrollment  
9. 
History of a decrease in LVEF to < 40% or symptomatic congestive heart failure 
(CHF) with previous trastuzumab treatment  
10. History of symptomatic chronic heart failure (New York Heart Association [NYHA] 
Classes II−IV) or serious cardiac arrhythmia requiring treatment  
11. History of myocardial infarction or unstable angina within 6 months of enrollment  
12. Current dyspnea at rest due to complications of advanced malignancy or 
requirement for continuous oxygen therapy  
13. Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, or metabolic disease)  
14. Pregnancy or lactation  
15. Concurrent, serious, uncontrolled infections or current known infection with human 
immunodeficiency virus (HIV) or active hepatitis B and/or hepatitis C. 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 5viral load per 
local guidelines  
16. Presence of conditions that could affect gastrointestinal absorption: malabsorption 
syndrome, resection of the small bowel or stomach, and ulcerative colitis  
17. History of intolerance (such as Grade 3-4 infusion reaction) or known 
hypersensitivity to trastuzumab or murine proteins or any component of the product  
18. Assessed by the investigator to be unable or unwilling to comply with the 
requirements of the protocol 
6.4 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs 
or the date at which the safety follow-up is received from the last patient, whichever occurs 
later. The LPLV is to occur 12 months after the last patient is enrolled; unless they have 


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been lost to follow-up, withdrawn consent, or died, or if the study is prematurely terminated 
by the Sponsor, whichever occurs first. 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 2 to 3 years. 
Following the completion of the study, Roche will continue to provide study medication to 
all the patients:- 
 
who are still receiving the study medication and have not progressed on study 
medication at the end of the study 
 
and who are willing to continue study medication  
 
and are considered suitable by the investigator to continue receiving study 
medication till progression of the disease and signed written post trial access 
consent form, approved by the relevant Institutional Review Board (IRB)/Ethics 
Committee (EC) 
7. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
All investigational medicinal products (IMPs) required for completion of this study 
(trastuzumab emtansine) will be provided by the Sponsor where required by local health 
authority regulations. The study site will acknowledge receipt of IMPs by returning the 
appropriate documentation form 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 sites institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation. The site's method of IMP destruction must be agreed to by the Sponsor. 
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
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. 
8. 
STATISTICAL METHODS 
8.1 
PRIMARY ANALYSIS 
The primary safety objective for this study is to evaluate the safety of trastuzumab 
emtansine in Indian patients on the basis of the following endpoint: 




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8.3 
INTERIM ANALYSIS 
In addition to the final analysis, there will be interim analysis for safety once approximately 
50% patients complete 6 months investigational medicinal product therapy. 
An independent Data Monitoring Committee (iDMC) will be formed which will include a 
statistician. An iDMC will perform the review of this interim analysis of efficacy and safety 
and subsequent safety reviews as described in the iDMC Charter. The list of Tables, 
Listings and figures for interim analysis is given in Appendix 4. 
 




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HER2 reports review for 
eligibility6 
X 
 
 
 
 
Tumor evaluation7 
X 
Every 3 cycles of 
antibody drug 
conjugate 
If disease 
progression not 
yet established 
If disease progression 
not yet established 
 
Laboratory Investigations 
(Hematology and serum 
chemistry)8 
X 
X 
X 
 
 
ECOG performance status9 
X 
Every 3 cycles of 
antibody drug 
conjugate 
X 
 
X 
LVEF10 
X 
Every 3 cycles of 
antibody drug 
conjugate 
X 
X 
 
PK sampling11 
X 
Pre-dose and 15 min 
post-infusion 
 
 
 
Adverse event reporting12 
X 
X 
X 
X 
X 
Administration of 
trastuzumab emtansine13 
 
X 
 
 
 


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Pregnancy test14 
Within 7 days 
prior to 1st dosing 
 
 
 
 
Survival16 
X 
X 
X 
X 
X 
1. Signed and dated informed consent in language comprehended by the potential clinical trial subject/Legally acceptable representative 
2.  Complete medical history and demographics (i.e. age, sex, race, and ethnicity, if applicable) and all medications taken during the last 28 
days prior to screening visit will be collected  
3. Physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems. Record abnormalities observed at baseline on the 
General Medical History and Baseline Conditions eCRF. Record new or worsened clinically significant abnormalities on the Adverse Event 
eCRF  
4. Vital signs will be assessed before treatment on Day 1 of every treatment cycle, recorded again after infusion during the observation period. 
Vital signs include respiratory rate, pulse rate, and systolic, and diastolic blood pressure while the patient is in a seated position, and oral or 
axillary temperature  
5. Current concomitant medication will be recorded at screening and on an ongoing basis 
6. HER2-positive status on fixed tissue blocks from the primary tumor (and/or metastatic site, if primary tumor not available) to be assessed by 
IHC and/or FISH at a local laboratory  
7. On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. A CT or MRI and (if indicated) isotope 
bone scan (evaluation according to RECIST criteria) should be performed at screening and as clinically indicated. Scans at screening 
should not be older than 28 days prior to first study medication administration. NB: Bone scan, PET scan or plain films are not considered 
adequate imaging techniques to measure bone lesions. Tumor assessment ± 3 days of planned scheduled visit. At the end of study visit, if 
a patient does not fit into the end of study definition, then tumor assessment to be done as per institutional criteria and routine clinical 
practice. 
8. Laboratory assessment as per routine standard of care must be performed within 3 days (with results available) prior to the administration 
of study medication. Hematology, as per routine standard of care, may include hemoglobin, hematocrit, platelet count, RBC, WBC with 


Trastuzumab emtansine—Roche Products (India) Pvt. Ltd 
Statistical Analysis Plan ML29662 Version Draft 0.2 
differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils, other cells). Serum chemistry, as per routine standard of care, 
may include sodium, potassium, calcium, chloride, magnesium, BUN (urea), uric acid, total protein, albumin, alkaline phosphatase, ALT, 
AST, lactate dehydrogenase (LDH), total bilirubin, creatinine, and blood glucose and calculated creatinine clearance at baseline. 
Coagulation tests will consist of international normalized ratio (INR) and aPTT or PTT. 
9. ECOG performance status to be recorded every 3 cycles until disease progression. 
10. LVEF ≥ 50% at screening period to be determined by ECHO. To the extent possible, assessment to be obtained at the same institution 
11. Blood and serum samples will be collected pre-dose on Cycle 1, 2, and 3 and post-infusion on Cycle 1 and 3 only from patients that have 
signed the PK substudy informed consent form  
12. After informed consent and prior to dosing, SAEs considered related to a study mandated procedure are reportable. As of cycle 1 all AEs 
and SAEs considered will be collected. AEs and SAEs to be monitored and continuously collected till end of study visit and to be recorded 
with grading according to NCI-CTCAE version 4.03 
13. The initial dose of trastuzumab emtansine will be administered over 90 minutes and if well tolerated subsequent infusions may be 
administered over 30 min (±10 min)  
14. For women of childbearing potential, serum β-HCG test must be performed within 7 days prior to the first dose of study treatment with the 
result available prior to first dosing. Urine β-HCG test must be performed within 7 days prior to every 3rd cycle (with results available prior to 
treatment), at the safety follow up visit, and at 4 and 7 months after the last dose of study treatment. All positive urine pregnancy tests must 
be confirmed by a serum β HCG test 
15. Patients who complete the study or discontinue from the study early will be asked to return to the hospital within 28 days after the last dose 
of study drug for the end of the study visit  
16. Survival status will be recorded during the treatment period and every 3 months after the one month post-treatment safety follow up visit 
until 12 months after the last patient enrolled in study or lost to follow up, withdrawn consent, or died, or if the study is prematurely 
terminated by Roche, whichever occurs first. Patients who are alive at the time of the analysis will be censored at the date of the last follow 
up assessment


Trastuzumab emtansine—Roche Products (India) Pvt. Ltd 
Statistical Analysis Plan ML29662 Version Draft 0.2 
 
 




Trastuzumab emtansine—Roche Products (India) Pvt. Ltd 
Statistical Analysis Plan ML29662 Version Draft 0.2 
Appendix 4  
Data Display for Interim Analysis 
The following data but not limiting to will be reviewed and discussed by IDMC at interim analysis. 
Baseline Tables 
 
Subject Disposition 
 
Subject Disposition by Visit 
 
Summary of Demographics and Baseline characteristics  
 
Summary of significant medical history 
 
Summary of Prior Systemic Cancer Therapy 
 
Summary of Prior Systemic Cancer Therapy by different factors 
 
Summary of Prior Radiotherapy  
 
Summary of Prior Radiotherapy by different factors 
 
Summary of Prior Concomitant Medications  
 
Summary of Concomitant Medications  
 
Summary of Dose of Trastuzumab emtansine by Visit 
Efficacy Tables 
 
Summary of Progression free survival (PFS) using Kaplan Meier estimates  
 
Kaplan Meier graph for progression free survival – Total 
 
Summary of Overall survival using Kaplan Meier estimates  


Trastuzumab emtansine—Roche Products (India) Pvt. Ltd 
Statistical Analysis Plan ML29662 Version Draft 0.2 
 
Kaplan Meier graph for Overall survival – Total 
 
Analysis of Duration of Response  
 
Analysis of Overall Response  
 
Summary of Progression free survival (PFS) using Kaplan Meier estimates by disease status 
 
Kaplan Meier graph for progression free survival by disease status 
 
Summary of Overall survival using Kaplan Meier estimates by disease status 
 
Kaplan Meier graph for Overall survival by disease status 
 
Summary of Progression free survival (PFS) using Kaplan Meier estimates by disease location 
 
Kaplan Meier graph for progression free survival by disease location 
 
Summary of Overall survival using Kaplan Meier estimates by disease location 
 
Kaplan Meier graph for Overall survival by disease location 
 
Summary of Progression free survival (PFS) using Kaplan Meier estimates by disease evaluation 
 
Kaplan Meier graph for progression free survival by disease evaluation 
 
Summary of Overall survival using Kaplan Meier estimates by disease evaluation 
 
Kaplan Meier graph for Overall survival by disease evaluation 
 
Distribution of site and location of Target Lesions 
 
Summary of target lesions 
 
Analysis of Target Lesions-Diameter 
Safety Tables 
 
Summary of Adverse Events 


Trastuzumab emtansine—Roche Products (India) Pvt. Ltd 
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 
 Summary of Adverse Events by severity (CTCAE grade) 
 
Summary of Adverse Events by Relationship to the study medication 
 
Summary of Adverse Events related to study medication by severity 
 
Summary of Serious Adverse Events 
 
Summary of Serious Adverse Events by severity  
 
Summary of Serious Adverse Events by Relationship to the study medication 
 
Summary of study medication related Serious Adverse Events by severity  
 
Summary of Outcome of Adverse Events 
 
Summary of Outcome of study medication related Adverse Events 
 
Summary of Outcome of Serious Adverse Events 
 
Summary of Outcome of study medication related Serious Adverse Events 
 
Summary of cause of Serious Adverse Events 
 
Summary of number of cycles and duration of treatment  
 
Summary of Deaths 
 
Summary of LVEF change in Baseline  
 
Summary of Physical Examination  
 
Summary of Vital Signs Measurements  
 
Summary of Other Lab tests  
 
Summary of ECOG performance status  
 
Analysis of ECOG performance status –Change from Baseline