Clinical trial NCT02999672
Conditions: Bladder Cancer Pancreas Cancer Cholangiocellular Carcinoma
Sponsor: Hoffmann-La Roche
Start date: 2016-12-23; Completion date: 2018-04-10
Enrollment: 20 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This multicenter, non-randomized, Phase II study will assess the efficacy, safety, and pharmacokinetics of trastuzumab emtansine in participants with HER2 overexpressing locally advanced (unresectable and not treatable with curative intent) or metastatic urothelial bladder cancer (UBC), locally advanced (unresectable and not treatable with curative intent) or metastatic pancreatic cancer/cholangiocarcinoma with advanced disease where cure is no longer possible and where no other treatment options are available anymore. Participants will receive intravenous (IV) infusion of trastuzumab emtansine as Regimen A (2.4 milligrams per kilogram \[mg/kg\], weekly \[qw\]) or Regimen B (3.6 mg/kg, every 3 weeks \[q3w\]) until unacceptable toxicity, withdrawal of consent, disease progression (PD), or death, whichever occurs first. Based on tolerability and safety aspects, steering committee and Independent Data Monitoring Committee (iDMC) will decide on expansion of the study to include more participants with other carcinoma types.

Detailed description:

Arms: arm 1: First six participants with locally advanced (unresectable and not treatable with curative intent) or metastatic UBC will initially receive Regimen A (trastuzumab emtansine at a dose of 2.4 mg/kg qw). An iDMC will assess the safety among the first six participants and decide whether dose will be switched to Regimen B (trastuzumab emtansine at a dose of 3.6 mg/kg q3w). arm 2: First six participants with metastatic pancreatic cancer/cholangiocarcinoma will receive Regimen A (trastuzumab emtansine at a dose of 2.4 mg/kg qw). An iDMC will assess the safety among the first six participants and decide whether dose will be switched to Regimen B (trastuzumab emtansine at a dose of 3.6 mg/kg q3w).
Interventions: intervention 1: Trastuzumab Emtansine
Intervention descriptions: intervention 1: Trastuzumab emtansine will be administered as Regimen A (2.4 mg/kg qw via IV infusion) or Regimen B (3.6 mg/kg q3w via IV infusion) until unacceptable toxicity, withdrawal of consent, disease progression, or death, whichever occurs first.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
 
PHASE II, EXPLORATORY, MULTICENTER, NON 
RANDOMIZED, SINGLE AGENT COHORT STUDY TO 
DETERMINE BEST TUMOR RESPONSE WITH 
TRASTUZUMAB EMTANSINE IN HER2 OVEREXPRESSING 
SOLID TUMORS 
NCT Number: 
NCT02999672 
Document Dates: 
Protocol Version 2: 09 Feb 2017 
Statistical Analysis Plan (SAP) Version 2: 05 Jun 2018 
 
 
 


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Title
09-Feb-2017 09:50:30
Date and Time (UTC)
Company Signatory
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, Switzerland. 
However, it may be implemented in individual countries by Roche’s local affiliates, including Genentech, 
Inc. in the United States. The information contained in this document, especially any unpublished data, 
is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in 
confidence as an investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Ethics Committee or Institutional Review Board. It is understood that this information will not 
be disclosed to others without written authorization from Roche except to the extent necessary to obtain 
informed consent from persons to whom the drug may be administered. 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Protocol MO29694, Version 2 
PROTOCOL 
TITLE: 
PHASE II, EXPLORATORY, MULTICENTER, NON 
RANDOMIZED, SINGLE AGENT COHORT STUDY 
TO DETERMINE BEST TUMOR RESPONSE WITH 
TRASTUZUMAB EMTANSINE IN HER2 
OVEREXPRESSING SOLID TUMORS 
PROTOCOL NUMBER: MO29694/NCT02999672 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2015-001377-40 
IND NUMBER: 
N/A 
TEST PRODUCT: 
Trastuzumab Emtansine (RO5304020) 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd
DATE FINAL: 
Version 1:  27 June 2016
DATE AMENDED 
Version 2:  See electronic date stamp below


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PROTOCOL AMENDMENT, VERSION 2 
RATIONALE 
Changes to the protocol have been made to address the following: 
 
Modifications in study screening and assessments, and to include separate 
‘Schedule of Activities’ for the weekly (Regimen A) and 3-weekly (Regimen B) 
dosing of trastuzumab emtansine treatment. 
 
The addition of pharmacokinetic objective and endpoints. 
 
The medical monitor for the study has been replaced. 
 
Clarification and correction to some minor errors/inconsistencies in the text have 
been made. 
 
Deleted text appears in black strikethrough. New text is marked in italics. This 
amendment represents changes to the original protocol. 


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PROTOCOL AMENDMENT, VERSION 2 
SUMMARY OF CHANGES 
GLOBAL CHANGES 
The Medical Monitor has been changed to 
.  
 
The protocol title has been amended throughout the protocol, for consistency, to: 
‘PHASE II, EXPLORATORY, MULTICENTER, NON RANDOMIZED, SINGLE AGENT 
COHORT STUDY TO DETERMINE BEST TUMOR RESPONSE WITH 
TRASTUZUMAB EMTANSINE IN HER2 OVEREXPRESSING SOLID TUMORS’  
 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
1.1 
BACKGROUND ON HUMAN EPIDERMAL GROWTH FACTOR 
RECEPTOR HER2 
{…} 
HER2 aberrations (gene amplification, gene mutations and protein overexpression) are 
reported in diverse other malignancies for instance esophagus, colorectal, pancreatic, 
bladder and prostate cancer (Yan et al 2014, Yoon et al 2014, Sato-Kuwabara et al 2009, 
Seo et al 2014, Stoecklein et al 2004, Minner et al 2010, Carneiro et al 2015, Hansel et 
al 2008). Urothelial bladder cancer (UBC) and pancreatic 
cancers/cholangiocarcinomaare are is an areas of high unmet medical need, and a more 
efficacious and less toxic therapy is desired. It For UBC, it is currently estimated that the 
incidence of HER2 overexpression (immunohistochemistry [IHC]3+ and IHC2+/in situ 
hybridization [ISH]+) in UBC ranges from 22-37% (Internal Data, Dendreon DN24-02, 
Hayashi et al 2014). In pancreatic ductal adenocarcinoma (PDAC), the HER2 gene locus 
was frequently (24%) amplified and the rate of overexpression (2+ and 3+) was 10%, but 
no prognostic significance was found (Stoecklein et al 2004). In addition, Safran et al 
(2004) have reported 30 patients (88%) with IHC2+ and 4 patients (12%) with IHC3+ 
HER2 status in a Phase II study of trastuzumab in HER2-positive metastatic pancreatic 
adenocarcinoma. In another Phase II study it has been shown that in contrary to breast 
and gastric cancer, where HER2 protein and HER2 gene amplification normally match, 
only 7 out of 11 (64%) patients with IHC3+ and 1 out of 22 (5%) with IHC2+ HER2 
expression showed gene amplification (Harder et al 2012). Maybe HER2 overexpression 
in pancreatic cancer is regulated by other mechanisms on the transcriptional or 
translational level rather than gene amplification as postulated by Ukita et al (2002) for 
intrahepatic biliary tract cancer. The role of HER2 targeting therapy in this these and 
potentially other indications is still unclear and needs to be further explored. 
1.2.2.5 
Nonclinical Development of Trastuzumab Emtansine in 
Pancreatic Cancers/Cholangiocarcinoma Cancer 
In a study by Buechler et al (2005) the effect of a combination therapy consisting of 
Herceptin, gemcitabine and docetaxel on anchorage-independent growth of different 
human pancreatic cancer cell lines was tested. Monotherapy with Herceptin had shown 


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some tumor suppressive activity particularly in those cell lines, which overexpress the 
HER2 receptor (Buechler et al 2001) and gemcitabine is the current standard 
chemotherapeutic agent for therapy of pancreatic cancer (Slamon 2000). Because of the 
promising results in BC where the combination therapy of Herceptin plus taxanes has 
been clinically effective, the combination of Herceptin with docetaxel and gemcitabine 
was tested (Slamon et al 2001; Pegram et al 2004, Kimura et al 2006). In order to test 
whether this therapeutic regimen was also effective in vivo, a murine model for 
pancreatic cancer in which tumor xenografts were grown in an orthotopic location within 
the pancreatic parenchyma was used. Two different human pancreatic cancer cell lines 
with different characteristics of HER2 expression were tested induced. According to the 
clinical scoring scheme grading of HER2 expression, the MIA PaCa-2 cell line would be 
scored graded as HER2 3+ whereas the HPAF-II cell line would be scored graded as 
HER2 (+/-). Monotherapy with individual substances improved the survival benefit 
moderately. In contrast, there was a dramatic survival improvement upon combination 
therapy of gemcitabine and docetaxel or both substances plus Herceptin compared to 
monotherapy alone. More importantly, the metastatic score was reduced when Herceptin 
was added to gemcitabine and docetaxel in the high HER2-expressing cell line, MIA 
PaCa-2. 
1.2.2.10 
Pharmacokinetic Properties of Trastuzumab Emtansine in 
Pancreatic Cancers/Cholangiocarcinoma Cancer 
Currently, there are no PK data available for trastuzumab emtansine in pancreatic 
cancers/cholangiocarcinoma cancer. 
1.3  
 
STUDY RATIONALE AND BENEFIT RISK RATIO 
A number of anti-HER2 therapies have proven efficacy, are approved and part of the 
SOC for HER2-positive BC and GC (see Sections 1.1 and 1.2). However, this is not yet 
the case for trastuzumab emtansine which currently is only available for BC. HER2 
overexpression has been identified in some other tumors as described in Section 1.1. 
These findings pose the intriguing question if trastuzumab emtansine could improve 
patient outcomes in those tumor types and beyond BC and GC. There is currently no 
clinical data on the potential therapeutic effect of trastuzumab emtansine treatment in 
HER2-positive tumors such as esophageal-, colorectal-, pancreatics/cholangio-, prostate 
and bladder carcinoma. 
{…} 
1.3.1 
Rationale for Patient Selection 
{…} 
Pancreatic cancers/cholangiocarcinoma cancer: Pancreatic adenocarcinoma is the 
5th most frequent cause of cancer related deaths (Hartwig et al 2013). Survival rates 
remain disappointing (median OS with palliative chemotherapy 11.1 months) and many 
patients will develop distant metastases (Conroy et al 2011). The HER2 overexpression 
rate is as high as 11% (and varies widely between patients). Interestingly, 
overexpression of the HER2 protein does not correlate well to amplification of the HER2 


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locus; especially it was shown, that HER2 IHC3+ protein expression did not correlate 
with gene amplification (Harder et al 2012). HER2 overexpression in pancreatic cancer 
may be due to gene deregulation rather than gene amplification as postulated by Ukita 
et al (2002) for intrahepatic biliary tract cancer (Harder et al 2012). Nevertheless an 
approach with an ADC such as trastuzumab emtansine may be considered a potential 
treatment option. 
Cholangiocarcinomas may be considered related tumors and these patients can be 
included in later stages of this study. The incidence and mortality rates of 
cholangiocarcinoma, especially those of intrahepatic cholangiocarcinoma IHC, are 
increasing worldwide (Khan et al 2005). Complete resection is the only way to cure the 
disease at present. However, because cholangiocarcinoma are difficult to diagnose at an 
early stage and extend diffusely, most patients have unresectable disease at clinical 
presentation, and prognosis is very poor (5-year survival is 0–40% even in resected 
cases) (Yoshikawa et al 2008). Approximately 8% of patients have HER2 
overexpression (Yan et al 2015 2014) and may therefore benefit from a HER2-targeted 
therapeutic approach. 
Patients diagnosed with locally advanced (unresectable and not treatable with curative 
intent) or metastatic UBC (MUBC) or locally advanced (unresectable and not treatable 
with curative intent) or metastatic pancreatic cancer/cholangiocarcinoma cancer have 
very limited treatment options to date, especially if they present in an advanced stage of 
their cancer, with a high mortality and low long-time survival rates. New therapeutic 
approaches are therefore needed for these patients with a high unmet medical need and 
limited other treatment options, especially in late stage. 
1.3.2 
Rationale for Study Design 
KAMELEON is a Phase II, proof of concept, single arm study, designed to estimate the 
efficacy of trastuzumab emtansine in HER2 overexpressing locally advanced 
(unresectable and not treatable with curative intent) or metastatic MUBC, locally 
advanced (unresectable and not treatable with curative intent) or metastatic and 
metastatic pancreatic cancers/cholangiocarcinoma cancer in patients with advanced 
disease where cure is no longer possible and where no other treatment options are 
available anymore. This The trial might be opened up to a diverse range of other HER2 
overexpressing tumors as described further above. Trastuzumab emtansine has proven 
efficacious in HER2-positive BC and has a tolerable safety profile (see Section 1.2.2.10). 
Therefore, the risk benefit in this study is deemed positive.  
The study design will allow for the examination of locally advanced (unresectable and 
not treatable with curative intent) or metastatic MUBC and metastatic pancreatic 
cancers/cholangiocarcinoma cancer with enough statistical power to determine whether 
further examination may be warranted in these indications or potential additional 
indications. To investigate a potential difference in treatment efficacy for MUBC and 
metastatic pancreatic cancers/cholangiocarcinoma cancer with homogeneous HER2 
expression and the carcinoma with a more focal HER2 expression, patients will be 
stratified according to the HER2 IHC pattern in their baseline tissue biopsy (e.g., 30-70% 


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vs 71-100% of tumor cells expressing HER2). Patients with very focal HER2 IHC pattern 
(e.g., < 30%) will be excluded from this study. The open-label, uncontrolled design is 
appropriate since the trial will only enroll patients with HER2-positive cancers and who in 
the opinion of the investigator have trastuzumab emtansine as their best treatment 
option. The study is intended as a proof of concept.  
{…} 
1.3.4 
Rationale for Translational Research Program 
This study will generate a unique data set of patients with HER2 expressing locally 
advanced (unresectable and not treatable with curative intent) or metastatic MUBC or 
locally advanced (unresectable and not treatable with curative intent) or metastatic 
pancreatic cancers/cholangiocarcinoma cancer treated with trastuzumab emtansine. It 
will create a comprehensive data set of markers that will be informative about 
differences and similarities between tissues, treatment outcome in these patients. 
Therefore, the mandatory archival tumor biopsies from all patients included in this study 
and the optional biopsy collected at disease progression may be used for exploratory 
protein, deoxyribonucleic acid (DNA)-based analyses and ribonucleic acid (RNA)-based 
expression analyses. In addition, mandatory plasma samples at baseline and at various 
timepoints during treatment will be collected (see Schedule of Activities, Appendix 1). 
These plasma samples will be used for exploratory biomarker assays which may include 
but are not limited to analysis of circulating protein and circulating tumor DNA. All 
exploratory biomarker analyses will be performed retrospectively and are clearly defined 
in the patient’s informed consent.  


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1.3.5 
Benefit Risk Assessment 
{…} 
HER2 overexpression has been shown in a number of other tumor types. The tumor 
types investigated in this study have poor prognosis in the advanced setting. Despite 
some recent progresses in the treatment of these cancers, the current standard of care 
still results in modest prolongation of survival in the advanced setting. Therefore the 
prognosis for this advanced-staged cancer types is still poor. Targeted therapies for 
locally advanced (unresectable and not treatable with curative intent) or metastatic 
MUBC or locally advanced (unresectable and not treatable with curative intent) or 
metastatic pancreatic cancers/cholangiocarcinoma cancer must not only demonstrate 
anti-tumor activity but should also minimize the toxicities commonly associated with 
currently available treatment options. Based on the clinical experience in MBC to date, 
trastuzumab emtansine has the potential to fulfill this need as therapy for advanced 
HER2 IHC-positive urothelial and/or pancreatic cancers/cholangiocarcinoma, with the 
option to subsequently include other tumor types as well. A safety plan for this study, 
including appropriate eligibility criteria, dose modification and/or discontinuation 
guidelines for each identified and potential risk (see Section 5.1), monitoring of patients 
at risk as well as regular monitoring of patient safety data by an iDMC, has been put into 
place to minimize any potential risk in the study patient population. 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics of trastuzumab 
emtansine in patients with locally advanced (unresectable and not treatable with curative 
intent) or metastatic MUBC or locally advanced (unresectable and not treatable with 
curative intent) or metastatic pancreatic cancers/cholangiocarcinomancer. Specific 
objectives and corresponding endpoints for the study are outlined in Table 1 below. 
Table 1  
Objectives and Corresponding Endpoints 
{…} 
Pharmacokinetic Objective: 
 To characterize the 
pharmacokinetics of trastuzumab 
emtansine 
 Concentrations of trastuzumab emtansine in 
plasma/serum to determine exposure. 
(Exploratory) Immunogenicity Objective: 
 To evaluate the immune response to 
trastuzumab emtansine 
 Incidence of anti-therapeutic antibodies (ATAs) 
during the study relative to the prevalence of ATAs 
at baseline. 
 Exploratory assessment of immune checkpoints e.g. 
inhibitors infiltrating lymphocyctes in the tumor 
before and after treatment by the assessment of 
immune-related biomarkers such as PDL1 and CD8. 
Exploratory Biomarker Objective: 
 To identify biomarkers that are 
predictive of response, can provide 
 To evaluate the HER2 status by IHC and ISH of all 


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evidence of trastuzumab emtansine 
activity, or can increase the 
knowledge and understanding of 
disease biology 
consenting screened patients. 
 To further evaluate the HER2 status by other 
exploratory testing methods such as a novel 
gene-protein assay (GPA), e.g. IHC and ISH 
combined in one assay, on samples of all 
consenting screened patients. 
 Correlate levels of HER2 protein expression, HER2 
gene amplification and circulating HER2 
extracellular domain (HER2 ECD) to trastuzumab 
emtansine efficacy. 
 To evaluate biomarkers that may be associated with 
response and/or safety on the protein, RNA and 
DNA level (e.g. by molecular subtyping and gene 
mutation analysis). 
 
3.1 
DESCRIPTION OF THE STUDY 
This is an exploratory, multicenter, non-randomized, Phase II, single agent cohort study 
designed to evaluate the efficacy of trastuzumab emtansine in patients with locally 
advanced (unresectable and not treatable with curative intent) or metastatic MUBC or 
locally advanced (unresectable and not treatable with curative intent) or metastatic 
pancreatic cancers/cholangiocarcinoma cancer, with other tumor types being potentially 
explored at a later point in time. 
{…} 
Figure 1 
Schematic illustration of the KAMELEON study with trastuzumab 
emtansine treatment in HER2 IHC3+ locally advanced (unresectable 
and not treatable with curative intent) or metastatic urothelial bladder 
cancer and pancreatic cancers/cholangiocarcinoma cancer 
Figure 1 has been updated to include the pharmacokinetic assessments 
{…} 
The percentage of HER2 positive UBC differs in the literature and ranges between 
22 and 37%, (see Section 1.1). For HER2 IHC3+ with expression equal to 30% and 
above, the prevalence is between 7 and 18%, for pancreas cancer it is 11% and 8% for 
cholangiocarcinoma cancer (see Section 1.3.1), depending on the tumor sample, pre-
study biopsy or archived tissue. Best tumor response on trastuzumab emtansine 
treatment will be evaluated; also PFS and OS will be studied as secondary endpoints.  
{…} 
 
Figure 2 
Schematic illustration of the KAMELEON study with trastuzumab 
emtansine treatment in HER2 IHC3+ locally advanced (unresectable 
and not treatable with curative intent) or metastatic urothelial bladder 
cancer and pancreatic cancers/cholangiocarcinoma cancer 


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Figure 2 has been updated to amend the target population to include IHC3+, non-focal 
(≥ 30% stained cells) from (> 30% stained cells). 
Figure 4  
Study scheme of 2.4 mg/kg weekly trastuzumab emtansine 
administration (Regimen A) 
Figure 4 has been updated to include ‘Regimen A’ in the title. The blood sample has 
been corrected to ‘blood sample for HER2 ECD). An extra footnote has been added to 
confirm that the figure refers to Cycles 1 to 5 and for Cycle 6 onwards to refer to the 
Schedule of Assessments (Appendix 1.1).  
Figure 5 
Study scheme of 3.6 mg/kg 3-weekly trastuzumab emtansine 
administration (Regimen B) 
Figure 5 has been updated to include ‘Regimen B’ in the title. The blood sample has 
been corrected to ‘blood sample for HER2 ECD). An extra footnote has been added to 
confirm that the figure refers to Cycles 1 to 5 and for Cycle 6 onwards to refer to the 
Schedule of Assessments (Appendix 1.2). 
3.2 END OF STUDY AND LENGTH OF STUDY 
{…} 
Patients will receive study medication until unacceptable toxicity, withdrawal of consent, 
disease progression, or death, whichever occurs first. After completion of treatment, 
patients will be followed up in a 3 monthly schedule until study close (18 months after 
last patient in in each cohort). The treatment period is expected to be 6 months. 
The data cutoff for the primary analysis of BOR will take place 12 10 weeks after the last 
patient of an individual cohort has been recruited (following a tumor assessment after 6 
weeks [2 cycles] with a confirmation of BOR performed no less than 4 weeks after the 
criteria for response are first met). of BOR within 4 weeks). 
{…} 
3.3 
RATIONALE FOR STUDY DESIGN 
{…} 
3.3.2 
Rationale for Patient Population 
{…} 
There is currently no clinical data on the potential therapeutic effect of trastuzumab 
emtansine treatment in other HER2 positive tumors such as locally advanced 
(unresectable and not treatable with curative intent) or metastatic MUBC or locally 
advanced (unresectable and not treatable with curative intent) or metastatic pancreatic 
cancers/cholangiocarcinoma cancer. Further information on this disease is presented in 
Section 1.3.1. 


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4 
MATERIALS AND METHODS 
4.1 
PATIENTS 
Up to 38 patients per cancer type, i.e. locally advanced (unresectable and not treatable 
with curative intent) or metastatic MUBC and locally advanced (unresectable and not 
treatable with curative intent) or metastatic pancreatic cancers/cholangiocarcinoma 
cancer, will be enrolled in this study. 
4.1.1 
Inclusion Criteria 
1. 
Histologically centrally confirmed HER2-positive (IHC3+ in ≥ 30% of tumor cells): 
locally advanced (unresectable and not treatable with curative intent) or metastatic 
or unresectable (not treatable with curative intent) UBC or locally advanced 
(unresectable and not treatable with curative intent) or metastatic pancreatic 
cancers/cholangiocarcinoma cancer. 
HER2 status may be pre-screened at the participating site. However, HER2 
determination at the referral center is not accepted to determine study eligibility. 
HER2 positivity needs to be prospectively confirmed with central laboratory HER2 
testing before patient enrollment. 
2. 
There must be no standard treatment options available for patients with the above 
HER2 overexpressing tumors and they must have undergone at least one prior 
platinum-based treatment for locally advanced (unresectable and not treatable with 
curative intent) inoperable, locally advanced or metastatic tumor. (Note: for 
pancreatic cancers/cholangiocarcinoma cancer, prior treatments are NOT required 
to be platinum-based.) 
{…} 
6. 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-21. 
{…} 
4.1.2 
Exclusion Criteria 
{…} 
3 
Patients with bone metastases are not eligible.  
3 4. Patients with brain metastasis as the sole site of metastatic disease and/or are 
symptomatic or require therapy to control symptoms. 
NB: Brain metastases are allowed provided they are asymptomatic and controlled 
by previous radiotherapy. 
4 5. Current uncontrolled hypertension (systolic > 150 mmHg and/or 
diastolic > 100 mmHg). 
5 6. Current unstable angina pectoris. 
6 7. History of symptomatic CHF of any New York Heart Association (NYHA) criteria or 
ventricular arrhythmia that requires treatment. 


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7 8. History of myocardial infarction within the last 6 months. 
8 9. Peripheral neuropathy, Grade ≥ 3. 
9 10.Current dyspnea at rest due to complications of advanced malignancy, or other 
diseases that require continuous oxygen therapy. 
1011.Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers; 
or bone fractures). 
1112.History of other malignancy within the last 5 years, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, stage I uterine 
cancer, or other cancers with a similar outcome as those previously mentioned. 
1213.For female patients, current pregnancy and lactation. 
1314.Concurrent, serious, uncontrolled infections or current known infection with human 
immunodeficiency virus (HIV), active hepatitis B and/or hepatitis C. 
1415.Known prior severe hypersensitivity to trastuzumab and trastuzumab emtansine or 
the excipients of the investigational medicinal product (IMP). 
1516.Clinically significant bleeding within 30 days before enrollment 
1617.Major surgical procedure or significant traumatic injury within 28 days prior to 
randomization or anticipation of the need for major surgery during the course of 
study treatment 
1718.Concurrent participation in any other therapeutic clinical trial. 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Trastuzumab Emtansine 
Trastuzumab emtansine treatment only starts after a successfully completed screening 
period. There are two treatment regimens: 
 
Regimen A: trastuzumab emtansine 2.4 mg/kg weekly, IV or 
 
Regimen B: trastuzumab emtansine 3.6 mg/kg every 3 weeks, IV. 
{…} 
Regimen A: Trastuzumab emtansine 2.4 mg/kg, weekly dosing in a 3-weekly cycle  
{…} 
The only available route of administration for trastuzumab emtansine is IV infusion. 
Trastuzumab emtansine infusion time may be decreased, depending on the patient’s 
tolerability of the infusion. For the first cycle, trastuzumab emtansine should be 
administered as a 90 (+/- 10) minutes IV infusion. Following the initial dose, patients will 
be observed for at least 90 60 minutes for fever, chills, or other infusion-associated 
symptoms. If the 90 minutes infusion is well tolerated, subsequent infusions may be 
delivered over 30 (+/- 10) minutes with a minimum 30 minute observation period after 


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the infusion. The volume contained in the administration tubing should be completely 
flushed with saline after administration of trastuzumab emtansine. The line should not be 
used for any other drug administration, but it can be used to administer IV fluids. A filter 
should be used in conjunction with the infusion set when using 0.9% sodium chloride for 
dilution. 
{…} 
Regimen B: Trastuzumab emtansine 3.6 mg/kg, 3-weekly cycle of dosing 
{…} 
The only available route of administration for trastuzumab emtansine is IV infusion. 
Trastuzumab emtansine infusion time may be decreased, depending on the patient’s 
tolerability of the infusion. For the first cycle, trastuzumab emtansine should be 
administered as a 90 (+/- 10) minutes IV infusion. Following the initial dose, patients will 
be observed for at least 90 60 minutes for fever, chills, or other infusion-associated 
symptoms. If the 90 minutes infusion is well tolerated, subsequent infusions may be 
delivered over 30 (+/- 10) minutes with a minimum 30 minute observation period after 
the infusion. The volume contained in the administration tubing should be completely 
flushed with saline after administration of trastuzumab emtansine. The line should not be 
used for any other drug administration, but it can be used to administer IV fluids. A filter 
should be used in conjunction with the infusion set when using 0.9% sodium chloride for 
dilution. 
{…} 
4.3.4 
Post-Trial Access to Trastuzumab Emtansine 
{…} 
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 locally advanced (unresectable and not treatable 
with curative intent) or metastatic MUBC or metastatic pancreatic 
cancers/cholangiocarcinoma cancer 
 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for locally advanced (unresectable and not treatable with curative intent) or 
metastatic MUBC or metastatic pancreatic cancers/cholangiocarcinoma cancer 
 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 


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The study will be concluded 18 months after the last patient has been enrolled in the last 
cohort after the last patient has been followed up for 18 months after last patient has 
been enrolled. Patients who have not progressed at the end of the trial and who are still 
on treatment will be offered the possibility to continue treatment in an extension study. 
{…} 
4.5.1 
Informed Consent Forms and Screening Log 
{…} 
Screening is to be and HER2 testing should ideally be completed within 28 14 days prior 
to baseline, however HER2 testing can be performed up to a maximum of 2 years prior 
to baseline (see Appendices 1.1 and 1.2 for Regimen A and B, respectively). 28 days is 
accepted unless otherwise stated (see Appendix 1). 
A separate ICF can be used for HER2 testing. The HER2 screening test (determined by 
the central laboratory) may be performed as soon as a potential patient is identified, at 
any time prior to enrollment, as long as provided that the HER2 Screening Informed 
Consent is signed. 
4.5.6 
LVEF Evaluation 
{…} 
ECHO/MUGA will be performed at screening and between Days 15 and 21 in Cycles 1 
and 3, and of at every third cycle thereafter (Cycles 6, 9 etc), and at the study drug 
completion visit. and at survival follow up visits, i.e., patients are followed for 18 months 
after last patient in; during the treatment they will be followed as per treatment schedule 
and at treatment discontinuation, every 3 months. The same method used at screening 
should be used throughout the study. 
{…} 
4.5.8 
Laboratory, Biomarker, and Other Biological Samples 
{…} 
4.5.8.2 
Blood Samples for Pharmacokinetic Assessments 
Samples for evaluation of trastuzumab emtansine, DM1, and total trastuzumab will be 
collected as shown in Figure 4 (Regimen A) and Figure 5 (Regimen B).  
Limited PK assessments will be made:  
 
Regimen A: with six sampling timepoints in Cycle 1 (Day 1, Day 8, and Day 15, 
each predose and 15-30 minutes postdose), one sampling timepoint in Cycle 2 
(Day 1, predose), and two sampling timepoints in Cycle 4 (Day 1, predose and 
15-30 minutes postdose), 


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 
Regimen B: with two sampling timepoints in Cycle 1 (Day 1 predose and 
15-30 minutes postdose), one sampling timepoint in Cycle 2 (Day 1, predose), and 
two sampling timepoints in Cycle 4 (Day 1, predose and 15-30 minutes postdose). 
with six sampling timepoints in Cycle 1 (Day 1, Day 8, and Day 15, each predose and 
15-30 minutes postdose), and one sampling timepoint in Cycle 2 (Day 1, predose), and 
two sampling timepoints in Cycle 4 (Day 1, predose and 15-30 minutes postdose), as 
shown in Figure 4 and Figure 5, will be made. 
5.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint. Deaths that occur during the protocol-
specified AE reporting period (see Section 5.3.1) that are attributed by the investigator 
solely to progression of locally advanced (unresectable and not treatable with curative 
intent) or metastatic MUBC or pancreatic cancers/cholangiocarcinoma cancer should be 
recorded on the Death Attributed to Progressive Disease eCRF. All other on-study 
deaths, regardless of relationship to study drug, must be recorded on the Adverse Event 
eCRF and immediately reported to the Sponsor (see Section 5.4.2). An independent 
monitoring committee will monitor the frequency of deaths from all causes. 
Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the 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. The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
{…} 
5.3.5.11 
Hospitalization or Prolonged HospitalizATION 
{…} 
The following hospitalization scenarios are not considered to be AEs: An event that 
leads to hospitalization under the following circumstances should not be reported as an 
adverse event or a serious adverse event: 
 
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) 


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 
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: An event that leads to hospitalization under the following 
circumstances is not considered to be a SAE, but should be reported as an AE instead: 
 
Hospitalization for an AE that would ordinarily have been treated in an outpatient 
setting 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
6.4 
EFFICACY ANALYSES 
{…} 
The primary efficacy analysis will determine the BOR for all patients of a cohort who 
received a dose of study medication in the selected treatment regimen and will take 
place 12 10 weeks after the last patient of an individual cohort has been recruited 
(following a tumor assessment after 6 weeks [2 cycles] with a confirmation of BOR 
performed no less than 4 weeks after the criteria for response are first met). confirmation 
of BOR within 4 weeks). 
6.6 
IMMUNOGENICITY ANALYSES 
{…} 
Corresponding analyses will be performed for immune checkpointsinhibitors and e.g. 
infiltrating lymphocyctes in the tumor before and after treatment by the assessment of 
immune-related biomarkers such as PDL1 and CD8. 
8.2 
INFORMED CONSENT 
The Sponsor’s sample ICF, including the sample ICF for the HER2 screening test, will 
be provided to each site and ancillary sample ICFs such as a Child’s Informed Assent 
Form or Mobile Nursing ICF, if applicable) will be provided to each site. If applicable, the 
ICFs 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 
ICFs 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 


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provided to the Sponsor for health authority submission purposes according to local 
requirements. 
{…} 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.5 
PUBLICATION OF DATA AND PROTOECTION 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 
{…} 
10. 
REFERENCES 
Kimura K, et al. Antitumor effect of trastuzumab for pancreatic cancer with high HER-2 
expression and enhancement of effect by combined theray with gemcitabine. Clin 
Cancer Res. 2006;12(16):4925-32. 
Safran H, Iannitti D, Ramanathan R, et al. Herceptin and gemcitabine for metastatic 
pancreatic cancers that overexpress HER-2/neu. Cancer Invest. 
2004;22(5):706-12  
 
Schedule of Activities: The Schedule of Activities has been revised for Regimen A 
and B separately, to reflect the changes to the protocol. 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 24 
PROTOCOL SYNOPSIS .................................................................................... 25 
1. 
BACKGROUND .......................................................................................... 34 
1.1 
Background on Human Epidermal Growth Factor 
Receptor HER2 ..................................................................... 34 
1.2 
Background on Study Drug .................................................... 35 
1.2.1 
Background on Trastuzumab ................................................. 35 
1.2.2 
Background on Trastuzumab Emtansine ............................... 36 
1.2.2.1 Nonclinical and Clinical Development of 
Trastuzumab Emtansine in Breast Cancer ......................................... 37 
1.2.2.2 Nonclinical and Clinical Development of 
Trastuzumab Emtansine in Gastric Cancer ........................................ 37 
1.2.2.3 Nonclinical and Clinical Development of 
Trastuzumab Emtansine in Lung Cancer ........................................... 38 
1.2.2.4 Nonclinical Development of Trastuzumab 
Emtansine in Bladder Cancer ............................................................. 38 
1.2.2.5 Nonclinical Development of Trastuzumab 
Emtansine in Pancreatic Cancer/Cholangiocarcinoma ....................... 38 
1.2.2.6 Pharmacokinetic Properties of Trastuzumab 
Emtansine in Breast Cancer ............................................................... 39 
1.2.2.7 Pharmacokinetic Properties of Trastuzumab 
Emtansine in Gastric Cancer .............................................................. 40 
1.2.2.8 Pharmacokinetic Properties of Trastuzumab 
Emtansine in Lung Cancer ................................................................. 40 
1.2.2.9 Pharmacokinetic Properties of Trastuzumab 
Emtansine in Urothelial Bladder Cancer ............................................. 40 
1.2.2.10 Pharmacokinetic Properties of Trastuzumab 
Emtansine in Pancreatic Cancer/Cholangiocarcinoma ....................... 41 
1.2.2.11 Clinical Safety with Trastuzumab Emtansine ..................... 41 
1.3 
Study Rationale and Benefit-Risk Assessment ...................... 43 
1.3.1 
Rationale for Patient Selection .............................................. 44 
1.3.2 
Rationale for Study Design .................................................... 46 
1.3.3 
Rationale for Dose Selection ................................................. 46 
1.3.4 
Rationale for Translational Research Program ...................... 47 


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1.3.5 
Benefit Risk Assessment ....................................................... 47 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 48 
3. 
STUDY DESIGN ......................................................................................... 50 
3.1 
Description of the Study ......................................................... 50 
3.2 
End of Study and Length of Study ......................................... 59 
3.3 
Rationale for Study Design .................................................... 59 
3.3.1 
Rationale for Trastuzumab Emtansine Dose and 
Schedule 59 
3.3.2 
Rationale for Patient Population ............................................ 59 
4. 
MATERIALS AND METHODS .................................................................... 60 
4.1 
Patients .................................................................................. 60 
4.1.1 
Inclusion Criteria .................................................................... 60 
4.1.2 
Exclusion Criteria ................................................................... 62 
4.2 
Method of Treatment Assignment and Blinding ..................... 63 
4.3 
Study Treatment .................................................................... 63 
4.3.1 
Formulation, Packaging, and Handling .................................. 63 
4.3.1.1 Trastuzumab Emtansine ...................................................... 63 
4.3.2 
Dosage, Administration, and Compliance .............................. 64 
4.3.2.1 Trastuzumab Emtansine ...................................................... 64 
4.3.3 
Investigational Medicinal Product Accountability ................... 69 
4.3.4 
Post-Trial Access to Trastuzumab Emtansine ....................... 69 
4.4 
Concomitant Therapy ............................................................ 70 
4.4.1 
Permitted Therapy ................................................................. 70 
4.4.2 
Prohibited Therapy ................................................................ 71 
4.5 
Study Assessments ............................................................... 72 
4.5.1 
Informed Consent Forms and Screening Log ........................ 72 
4.5.2 
Medical History and Demographic Data ................................ 72 
4.5.3 
Physical Examinations ........................................................... 72 
4.5.4 
Vital Signs .............................................................................. 73 
4.5.5 
Tumor and Response Evaluations ......................................... 73 
4.5.6 
LVEF Evaluation .................................................................... 74 
4.5.7 
ECOG Performance Status ................................................... 74 


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4.5.8 
Laboratory, Biomarker, and Other Biological 
Samples 
74 
4.5.8.1 Samples for General Assessments ...................................... 74 
4.5.8.2 Blood Samples for Pharmacokinetic 
Assessments ...................................................................................... 75 
4.5.8.3 Blood Samples for HER2 ECD Assessments ....................... 75 
4.5.8.4 Blood Samples for Evaluation of Antitherapeutic 
Antibodies ........................................................................................... 75 
4.5.8.5 Samples for Research Purposes .......................................... 76 
4.5.8.6 Translational Research Program .......................................... 76 
4.5.9 
Electrocardiograms ................................................................ 76 
4.5.10 
Samples for Research Biosample Repository ....................... 77 
4.5.10.1 Overview of the Research Biosample 
Repository .......................................................................................... 77 
4.5.10.2 Approval by the Institutional Review Board or 
Ethics Committee ............................................................................... 77 
4.5.10.3 Sample Collection .............................................................. 77 
4.5.10.4 Confidentiality ..................................................................... 78 
4.5.10.5 Consent to Participate in the Research 
Biosample Repository ......................................................................... 79 
4.5.10.6 Withdrawal from the Research Biosample 
Repository .......................................................................................... 79 
4.5.10.7 Monitoring and Oversight ................................................... 79 
4.5.11 
Follow-Up Assessments ........................................................ 80 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation ...................................................................... 80 
4.6.1 
Patient Discontinuation .......................................................... 80 
4.6.2 
Study Treatment Discontinuation ........................................... 80 
4.6.3 
Study and Site Discontinuation .............................................. 81 
5. 
ASSESSMENT OF SAFETY ....................................................................... 82 
5.1 
Safety Plan ............................................................................ 82 
5.1.1 
Risks Associated with Trastuzumab Emtansine .................... 82 
5.1.1.1 Pulmonary Toxicity ............................................................... 82 
5.1.1.2 Hepatotoxicity ....................................................................... 82 
5.1.1.3 Left Ventricular Dysfunction ................................................. 83 


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5.1.1.4 Infusion-Related Reactions and Hypersensitivity 
Reactions ........................................................................................... 84 
5.1.1.5 Hematologic Toxicity ............................................................ 84 
5.1.1.6 Neurotoxicity ........................................................................ 85 
5.1.1.7 Extravasation ....................................................................... 85 
5.1.2 
Management of Patients Who Experience 
Specific Adverse Events .......................................................................... 86 
5.2 
Safety Parameters and Definitions ........................................ 90 
5.2.1 
Adverse Events ..................................................................... 90 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ........................................................................................ 90 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................................... 91 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 91 
5.3.1 
Adverse Event Reporting Period ........................................... 92 
5.3.2 
Eliciting Adverse Event Information ....................................... 92 
5.3.3 
Assessment of Severity of Adverse Events ........................... 92 
5.3.4 
Assessment of Causality of Adverse Events ......................... 93 
5.3.5 
Procedures for Recording Adverse Events ............................ 94 
5.3.5.1 Infusion-Related Reactions .................................................. 94 
5.3.5.2 Diagnosis versus Signs and Symptoms ............................... 94 
5.3.5.3 Adverse Events That Are Secondary to Other 
Events 94 
5.3.5.4 Persistent or Recurrent Adverse Events .............................. 95 
5.3.5.5 Abnormal Laboratory Values ................................................ 95 
5.3.5.6 Abnormal Vital Sign Values .................................................. 96 
5.3.5.7 Hepatic Events ..................................................................... 96 
5.3.5.8 Deaths .................................................................................. 97 
5.3.5.9 Preexisting Medical Conditions ............................................ 97 
5.3.5.10 Lack of Efficacy or Worsening of Urothelial 
Bladder Cancer .................................................................................. 98 
5.3.5.11 Hospitalization or Prolonged Hospitalization ...................... 98 
5.3.5.12 Adverse Events Associated with an Overdose 
or Error in Drug Administration ........................................................... 98 


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5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 99 
5.4.1 
Emergency Medical Contacts ................................................ 99 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ..................................... 100 
5.4.2.1 Events That Occur prior to Study Drug Initiation ................ 100 
5.4.2.2 Events That Occur after Study Drug Initiation .................... 100 
5.4.3 
Reporting Requirements for Pregnancies ............................ 100 
5.4.3.1 Pregnancies in Female Patients ......................................... 100 
5.4.3.2 Pregnancies in Female Partners of Male 
Patients 101 
5.4.3.3 Abortions ............................................................................ 101 
5.4.3.4 Congenital Anomalies/Birth Defects ................................... 101 
5.5 
Follow-Up of Patients after Adverse Events ........................ 101 
5.5.1 
Investigator Follow-Up ......................................................... 101 
5.5.2 
Sponsor Follow-Up .............................................................. 102 
5.6 
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 102 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ............................................................... 102 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ..................... 102 
6.1 
Determination of Sample Size ............................................. 103 
6.2 
Summaries of Conduct of Study .......................................... 104 
6.3 
Summaries of Demographic and Baseline 
Characteristics ..................................................................... 104 
6.4 
Efficacy Analyses ................................................................ 104 
6.4.1 
Primary Efficacy Endpoint .................................................... 105 
6.4.2 
Secondary Efficacy Endpoints ............................................. 106 
6.5 
Safety Analyses ................................................................... 106 
6.6 
Immunogenicity Analyses .................................................... 107 
6.7 
Biomarker Analyses ............................................................. 108 
6.8 
Interim Analysis ................................................................... 108 
6.8.1 
Optional Interim Analysis ..................................................... 108 


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7. 
DATA COLLECTION AND MANAGEMENT ............................................. 108 
7.1 
Data Quality Assurance ....................................................... 108 
7.2 
Electronic Case Report Forms ............................................. 109 
7.3 
Source Data Documentation ................................................ 109 
7.4 
Use of Computerized Systems ............................................ 110 
7.5 
Retention of Records ........................................................... 110 
8. 
ETHICAL CONSIDERATIONS .................................................................. 110 
8.1 
Compliance with Laws and Regulations .............................. 110 
8.2 
Informed Consent ................................................................ 110 
8.3 
Institutional Review Board or Ethics Committee .................. 111 
8.4 
Confidentiality ...................................................................... 112 
8.5 
Financial Disclosure ............................................................ 112 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 113 
9.1 
Study Documentation .......................................................... 113 
9.2 
Protocol Deviations .............................................................. 113 
9.3 
Site Inspections ................................................................... 113 
9.4 
Administrative Structure ....................................................... 113 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 113 
9.6 
Protocol Amendments ......................................................... 114 
10. REFERENCES ......................................................................................... 115 
 
LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ................................... 49 
Table 2 
Guidelines for Trastuzumab Emtansine Dose Reductions .......... 86 
Table 3 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events ............................................................. 87 
Table 4 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 93 
Table 5 
Estimation of Confidence Intervals for a Sample Size N = 27 
(per cohort) ............................................................................... 104 
 


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LIST OF FIGURES 
Figure 1 
Schematic illustration of the KAMELEON study with 
trastuzumab emtansine treatment in HER2 IHC3+ locally 
advanced (unresectable and not treatable with curative intent) 
or metastatic urothelial bladder cancer and pancreatic 
cancer/cholangiocarcinoma ........................................................ 51 
Figure 2 
Schematic illustration of the KAMELEON study with 
trastuzumab emtansine treatment in locally advanced 
(unresectable and not treatable with curative intent) or 
metastatic urothelial bladder cancer and pancreatic 
cancer/cholangiocarcinoma ........................................................ 53 
Figure 3 
Extensive flow-chart regarding study design and decision 
points .......................................................................................... 54 
Figure 4 
Study scheme of 2.4 mg/kg weekly trastuzumab emtansine 
administration (Regimen A)......................................................... 57 
Figure 5 
Study scheme of 3.6 mg/kg 3-weekly trastuzumab emtansine 
administration (Regimen B)......................................................... 58 
Figure 6 
Cycles and missed dosing .......................................................... 66 
 
LIST OF APPENDICES 
Appendix 1.1 Schedule of Activities: Regimen A (Trastuzumab emtansine, 
2.4 mg/kg weekly) ..................................................................... 121 
Appendix 1.2 Schedule of Activities: Regimen B (Trastuzumab emtansine 
3.6 mg/kg 3-weekly) .................................................................. 124 
Appendix 2    Revised RECIST Guideline (version 1.1) .................................... 127 
 
 
 


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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
PHASE II, EXPLORATORY, MULTICENTER, NON 
RANDOMIZED, SINGLE AGENT COHORT STUDY 
TO DETERMINE BEST TUMOR RESPONSE WITH 
TRASTUZUMAB EMTANSINE IN HER2 
OVEREXPRESSING SOLID TUMORS 
PROTOCOL NUMBER: MO29694 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2015-001377-40 
IND NUMBER: 
N/A 
TEST PRODUCT: 
Trastuzumab Emtansine (RO5304020)  
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files. Please return a copy as 
instructed by your local study monitor. 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL SYNOPSIS 
TITLE: 
PHASE II, EXPLORATORY, MULTICENTER, NON RANDOMIZED, 
SINGLE AGENT COHORT STUDY TO DETERMINE BEST TUMOR 
RESPONSE WITH TRASTUZUMAB EMTANSINE IN HER2 
OVEREXPRESSING SOLID TUMORS 
PROTOCOL NUMBER: 
MO29694 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2015-001377-40 
IND NUMBER: 
N/A 
TEST PRODUCT: 
Trastuzumab Emtansine (RO5304020)  
PHASE: 
Phase II 
INDICATION: 
HER2 overexpressing solid tumors 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives and Endpoints 
This study will evaluate the efficacy, safety and pharmacokinetics of trastuzumab emtansine in 
patients with locally advanced (unresectable and not treatable with curative intent) or metastatic 
urothelial bladder cancer (UBC) or locally advanced (unresectable and not treatable with 
curative intent) or metastatic pancreatic cancer/cholangiocarcinoma. Specific objectives and 
corresponding endpoints for the study are outlined below. 
 
Objectives 
Corresponding Endpoints 
Primary Efficacy Objective: 
 To evaluate the efficacy of 
trastuzumab emtansine 
 Best overall response rate (BOR) as determined by 
the investigator (using RECIST 1.1). BOR is defined 
as the best response recorded from the first day of 
study treatment until disease progression/recurrence 
or death. Responders, as assessed every 6 weeks, 
will be defined based on tumor assessment status as 
partial responder (PR) or complete responder (CR) at 
these time points. To be assigned a status of PR or 
CR (i.e., a responder), changes in tumor 
measurements must be confirmed by repeat 
assessments that should be performed no less than 
4 weeks after the criteria for response are first met, 
i.e., patients need to have two consecutive 
assessments of PR or CR to be a responder. 


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Secondary Efficacy Objective: 
 To evaluate the efficacy of 
trastuzumab emtansine 
 Progression-free survival (PFS), defined as the time 
from beginning of treatment to the first occurrence of 
disease progression, as determined by the 
investigator (using RECIST 1.1), or death from any 
cause, whichever occurs first. 
 Overall survival (OS), defined as the time from 
beginning of treatment to death from any cause. 
Safety Objective: 
 To evaluate the safety of  
trastuzumab emtansine 
 Incidence, type and severity of all adverse events 
(AEs) and serious adverse events (SAEs) based on 
National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE v4.03).  
 Incidence and type of AEs leading to 
discontinuation, modification, or delay of 
trastuzumab emtansine dose. 
 Changes in vital signs, physical examination 
findings, and clinical laboratory results during and 
following trastuzumab emtansine administration. 
 Death and cause of death. 
 Cases of drug-induced liver injury meeting Hy’s Law 
criteria. 
 Pneumonitis of all grades.  
 Change in left ventricular ejection fraction (LVEF) 
over the course of the study as measured by 
echocardiogram (ECHO) or multiple-gated 
acquisition scan (MUGA). 
 Incidence of congestive heart failure (CHF). 
Pharmacokinetic Objective: 
 To characterize the 
pharmacokinetics of trastuzumab 
emtansine 
 Concentrations of trastuzumab emtansine in 
plasma/serum to determine exposure. 


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(Exploratory) Immunogenicity Objective: 
 To evaluate the immune response to 
trastuzumab emtansine 
 Incidence of anti-therapeutic antibodies (ATAs) 
during the study relative to the prevalence of ATAs 
at baseline. 
 Exploratory assessment of immune checkpoints and 
infiltrating lymphocyctes in the tumor before and 
after treatment by the assessment of immune-
related biomarkers such as PDL1 and CD8. 
Exploratory Biomarker Objective: 
 To identify biomarkers that are 
predictive of response, can provide 
evidence of trastuzumab emtansine 
activity, or can increase the 
knowledge and understanding of 
disease biology 
 To further evaluate the HER2 status by other 
exploratory testing methods such as a novel 
gene-protein assay (GPA), e.g. 
immunohistochemistry (IHC) and in situ hybridization 
(ISH) combined in one assay on samples of all 
consenting screened patients. 
 Correlate levels of HER2 protein expression, HER2 
gene amplification and circulating HER2 
extracellular domain (HER2 ECD) to trastuzumab 
emtansine efficacy. 
 To evaluate biomarkers that may be associated with 
response and/or safety on the protein, RNA and 
DNA level (e.g. by molecular subtyping and gene 
mutation analysis). 
 
Study Design 
Description of Study 
This is an exploratory, multicenter, non-randomized, Phase II, single agent cohort study 
designed to evaluate the efficacy of trastuzumab emtansine in patients with locally advanced 
(unresectable and not treatable with curative intent) or metastatic urothelial bladder cancer 
(UBC) or locally advanced (unresectable and not treatable with curative intent) or metastatic 
pancreatic cancer/cholangiocarcinoma. 
Number of Patients 
In total, 32-38 patients will be enrolled per cohort; 64-76 patients in total. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Histologically centrally confirmed HER2-positive (IHC3+ in ≥ 30% of tumor cells): locally 
advanced (unresectable and not treatable with curative intent) or metastatic urothelial 
bladder cancer or locally advanced (unresectable and not treatable with curative intent) or 
metastatic pancreatic cancer/cholangiocarcinoma. 
HER2 status may be pre-screened at the participating site. However, HER2 determination 
at the referral center is not accepted to determine study eligibility. HER2 positivity needs to 
be prospectively confirmed with central laboratory HER2 testing before patient enrollment. 
 
There must be no standard treatment options available for patients with the above HER2 
overexpressing tumors and they must have undergone at least one prior platinum-based 
treatment for locally advanced (unresectable and not treatable with curative intent) or 
metastatic tumor. (Note: for pancreatic cancer/cholangiocarcinoma, prior treatments are 
NOT required to be platinum-based.) 
 
The patient must have evaluable disease fulfilling all of the following imaging criteria: 


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a. On diagnostic computed tomography scan/magnetic resonance imaging: lesion should 
be measurable according to RECIST 1.1. 
b. Target lesion(s) should not have been previously irradiated. 
 
At least one formalin-fixed paraffin-embedded biopsy of the primary tumor and/or from a 
metastatic site is required.  
 
Age ≥ 18 years. 
 
Eastern Cooperative Oncology Group performance status of 0-2. 
 
No significant cardiac history and a current LVEF ≥ 50%. LVEF should be determined within 
28 days before the start of trastuzumab emtansine treatment. 
 
Adequate organ function, evidenced by the following laboratory results (performed within 
7 days prior to commencement of dosing): 
a. Absolute neutrophil count > 1,500 cells/mm3. 
b. Platelet count > 100,000 cells/mm3. 
c. Hemoglobin > 9 g/dL. 
d. Aspartate aminotransferase and alanine aminotransferase < 2.5 x upper limit of normal 
(ULN). 
e. Total bilirubin ≤ 1.5 x ULN unless the patient has documented Gilbert’s syndrome, in 
which case direct (conjugated) bilirubin level needs to be within normal limits. 
f. 
Serum alkaline phosphatase ≤ 2.5 x ULN. Patients with bone metastases: alkaline 
phosphatase ≤ 5 x ULN. 
g. Serum creatinine < 2.0 mg/dL or < 177 µmol/L. 
h. International normalized ratio and activated partial thromboplastin time or partial 
thromboplastin time < 1.5 ULN. 
 
Absence of any psychological, familial, sociological or geographical condition potentially 
hampering compliance with the study protocol and follow-up schedule; those conditions 
should be discussed with the patient before registration in the study. 
 
Negative serum pregnancy test for women of childbearing potential (including pre-
menopausal women who have had a tubal ligation) and for all women not meeting the 
definition of postmenopausal (≥ 12 months of amenorrhea), and who have not undergone 
surgical sterilization with a hysterectomy and/or bilateral oophorectomy. For all other 
women, documentation must be present in medical history confirming that the patient is not 
of childbearing potential. 
For women of childbearing potential and men with partners of childbearing potential, 
agreement by the patient and/or partner to use a highly effective non-hormonal form of 
contraception such as surgical sterilization or two effective forms of non-hormonal 
contraception until 7 months after the last dose of trastuzumab emtansine. 
Methods of birth control are considered highly effective forms of contraception in case they 
result in a low failure rate (i.e., < 1% per year) when used consistently and correctly. The 
use of the following non-hormonal methods of contraception is acceptable: 
a. True abstinence, when this is the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, and symptothermal post ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
b. Male sterilization (with appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate). For female patients, the vasectomized male partner should be 
the sole partner. 
Alternatively, use of two of the following effective forms of contraception is acceptable: 
a. Placement of intrauterine device or intrauterine system. Consideration should be given 
to the type of device being used, as there are higher failure rates for certain types (e.g., 
steel or copper wire). 
b. Condom with spermicidal foam/gel/film/cream/suppository. 


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c. Occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository. 
The use of barrier contraceptives should always be supplemented with the use of a 
spermicide. The following should be noted: Failure rates indicate that, when used alone, the 
diaphragm and condom are not highly effective forms of contraception. Therefore, the use 
of additional spermicides does confer additional theoretical contraceptive protection. 
However, spermicides alone are ineffective at preventing pregnancy when the whole 
ejaculate is spilled. Therefore, spermicides are not a barrier method of contraception and 
should not be used alone. 
 
Signed written informed consent approved by Ethics Committee and obtained prior to any 
study procedure. 
 
Life expectancy of at least 12 weeks. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Patients with previous exposure to HER2-targeted therapies in any setting. 
 
Patients showing histologically confirmed focal HER2-expression, i.e., < 30% of positively 
stained tumor cells.  
 
Patients with brain metastasis as the sole site of metastatic disease and are symptomatic or 
require therapy to control symptoms. 
NB: Brain metastases are allowed provided they are asymptomatic and/or controlled by 
previous radiotherapy. 
 
Current uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg). 
 
Current unstable angina pectoris. 
 
History of symptomatic CHF of any New York Heart Association criteria or ventricular 
arrhythmia that requires treatment. 
 
History of myocardial infarction within the last 6 months. 
 
Peripheral neuropathy, Grade ≥ 3. 
 
Current dyspnea at rest due to complications of advanced malignancy, or other diseases 
that require continuous oxygen therapy. 
 
Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary, or metabolic disease; wound healing disorders; ulcers; or bone fractures). 
 
History of other malignancy within the last 5 years, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, stage I uterine cancer, or 
other cancers with a similar outcome as those previously mentioned. 
 
For female patients, current pregnancy and lactation. 
 
Concurrent, serious, uncontrolled infections or current known infection with human 
immunodeficiency virus, active hepatitis B and/or hepatitis C. 
 
Known prior severe hypersensitivity to trastuzumab and trastuzumab emtansine or the 
excipients of the investigational medicinal product (IMP). 
 
Clinically significant bleeding within 30 days before enrollment 
 
Major surgical procedure or significant traumatic injury within 28 days prior to randomization 
or anticipation of the need for major surgery during the course of study treatment 
 
Concurrent participation in any other therapeutic clinical trial. 
End of Study 
Each cohort will close 18 months after the last patient was recruited or once all patients have 
died or withdrawn from study, whatever happens first.  
End of study for a cohort will be declared at the last patient last visit (LPLV) as per definition is 
the last data collection point, which can be a clinic visit or a laboratory sample. 


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Length of Study 
The total length of the study for an individual cohort, from screening of the first patient to the 
end of the study, is expected to be approximately 3 years (18 months of recruitment, an 
expected 6 months of treatment and a further 12 months of follow-up). 
Patients will receive study medication until unacceptable toxicity, withdrawal of consent, disease 
progression, or death, whichever occurs first.  
The data cutoff for the primary analysis of BOR will take place 12 weeks after the last patient of 
an individual cohort has been recruited (following a tumor assessment after 6 weeks [2 cycles] 
with a confirmation of BOR performed no less than 4 weeks after the criteria for response are 
first met.  
The data cutoff for the final analysis for each cohort of all primary and secondary efficacy 
measures will take place 18 months after the last patient of a cohort was recruited, or once all 
patients have reported a progression event, whichever occurs earlier.  
Investigational Medicinal Products 
Test Product (Investigational Drug) 
The IMP for this study is trastuzumab emtansine (Kadcyla). 
Trastuzumab emtansine will be administered by intravenous infusion  
 
Regimen A: trastuzumab emtansine 2.4 mg/kg, weekly 
 
Regimen B: trastuzumab emtansine 3.6 mg/kg every 3 weeks. 
In a safety run-in, the first 6 patients of each cohort will enter Regimen A and receive 2.4 mg/kg 
weekly trastuzumab emtansine. These first 6 patients will be assessed on an ongoing and 
patient per patient basis – i.e. based on the tolerability criteria (as defined in the Independent 
Data Monitoring Committee [iDMC] charter) and in consultation with the Steering Committee 
(SC) and iDMC if needed. Recruitment for the respective cohort will be suspended until all 6 of 
these patients have completed the 2nd cycle (6 weeks) and the ‘regimen decision point’ has 
been reached. Based on tolerability and safety aspects, the iDMC will decide for each cohort if 
the study is to continue on Regimen A (2.4 mg/kg qw), extending recruitment to a total of 32 
patients (additional 26 patients) per cohort, or if the dose switches to Regimen B (3.6 mg/kg 
q3w). If the regimen is changed to Regimen B, 32 additional patients will be included per cohort; 
if the regimen remains unchanged (i.e., Regimen A), only 26 additional patients will be recruited. 
Statistical Methods 
The first 6 patients of each cohort will be analyzed on an ongoing and patient per patient basis – 
i.e. based on the tolerability criteria (as defined in the iDMC charter) and in consultation with the 
SC and iDMC if needed. 
Primary Analysis 
The primary efficacy endpoint BOR will be analyzed as follows:  
Responders as assessed every 6 weeks will be defined based on tumor assessment status of 
PR or CR at these time points. Only patients with measurable disease at baseline will be 
included in the analysis of the response rate. Patients without a post-baseline tumor 
assessment will be considered to be non-responders. BOR is defined as the best response 
recorded from the first day of study treatment until disease progression/recurrence or death. To 
be assigned a status of PR or CR (i.e., a responder), changes in tumor measurements must be 
confirmed by repeat assessments that should be performed no less than 4 weeks after the 
criteria for response are first met, i.e., patients need to have two consecutive assessments of 
PR or CR to be a responder. The primary analysis will be based on the BOR result after 
12 weeks (an assessment after 6 weeks [2 cycles] with a confirmation of BOR performed no 
less than 4 weeks after the criteria for response are first met). 
The null hypothesis (H0) is that the best response rate is 5% or less, which would yield a low 
activity profile. The alternative hypothesis (H1) is that the best response rate is greater than or 
equal to 20%, which would yield an encouraging activity profile: 
H0: best response rate ≤ 5% vs 
H1: best response rate ≥ 20% 
A Simon's two-stage design (Simon 1989) will be used to allow the study to stop early if there is 
no evidence of efficacy. The null hypothesis that the true response rate (BOR) is ≤ 5% will be 


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tested against a one-sided alternative. In the first stage, 13 patients in each cohort will be 
accrued. If there are 0 responses (CR or PR) in these 13 patients, the study will be stopped for 
the respective cohort. Otherwise, 14 additional patients will be accrued per cohort for a total of 
27. Recruitment may be suspended after the 13th patient in a cohort has been enrolled in the 
selected treatment regimen. This suspension will occur if there are no responses observed in 
the previous 12 patients (since the decision will be made to stop the study only if there are no 
responses in the first 13 patients). 
In the primary analysis of efficacy the null hypothesis will be rejected if 4 or more responses are 
observed in 27 patients. This design yields a type I error rate of 0.05 and power of 80% when 
the true response rate is ≥ 20%. 
It is planned to recruit more than the required 27 patients per cohort to allow for drop-outs. If 
there are no drop-outs amongst the 32 enrolled patients in a certain cohort then the decision 
rule will be revised as necessary to retain the same alpha and power. For example, if 32 
patients have evaluable efficacy data, then if 5 or more responders are observed then we will 
reject H0 and accept H1 – i.e., accept that the best response rate ≥ 20%. If 4 or fewer 
responders are observed then we will accept H0. 
A response rate of less than 5% will be considered of no clinical interest. A response rate of 
more than 20% will be considered of interest to potentially start a further study, which will not be 
part of this protocol. 
Determination of Sample Size 
The sample size estimation is based on the method of A'Hern (2001) and Simon (1989) and 
corresponding Statistical Analysis System programs. 
To test the null hypothesis (H0) that the best BOR is 5% or less (which would yield a low activity 
profile) against the alternative hypothesis (H1) that the BOR is greater than or equal to 20% 
(which would yield an encouraging activity profile), 27 patients per cohort would be required to 
perform the test with 80% power, at the one-sided alpha=0.05 level. To allow for drop-outs 
(10-15%) and to ensure that at least 27 patients will have efficacy data available, 32 patients will 
be recruited per cohort on the respective treatment regimen. 
Assuming a preferable BOR of 20% is observed, then with 27 patients, the 95% confidence 
limits would range from 7.2% to 39.8% (Clopper-Pearson exact confidence intervals).  
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ADC 
antibody-drug conjugate 
AGC 
advanced gastric cancer 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
ATA 
anti-therapeutic antibody 
BC 
breast cancer 
BOR 
best overall response rate 
CHF 
congestive heart failure 
CI 
confidence interval 
CNS 
central nervous system 
CR 
complete responder 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
deoxyribonucleic acid  
EBC 
early breast cancer 
EC 
Ethics Committee 
ECD 
extracellular domain 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
EU 
European Union 
FDA 
Food and Drug Administration 
GC 
gastric cancer 
GGT 
gamma-glutamyl-transferase 
HER2 
human epidermal growth factor receptor 2 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 


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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 
ISH 
in-situ hybridization 
ITT 
intent-to-treat 
IV 
intravenous 
IxRS 
interactive voice/web recognition system 
KM 
Kaplan-Meier 
LABC 
locally advanced breast cancer 
LDH 
lactate dehydrogenase 
LPI 
last patient in 
LPLV 
last patient last visit 
LVEF 
left ventricular ejection fraction 
MBC 
metastatic breast cancer 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerable dose  
MUGA 
multiple-gated acquisition scan 
NCI 
National Cancer Institute 
NGS 
next-generation sequencing 
NRH 
nodular regenerative hyperplasia 
NYHA 
New York Heart Association 
PD 
pharmacodynamics / progressive disease 
PDAC 
pancreatic ductal adenocarcinoma 
PET 
positron emission tomography 
PFS 
progression free survival 
PK 
pharmacokinetic 
PR 
partial responder 
PS 
performance status 
PT 
preferred term 
PTT 
partial thromboplastin time  
PVC 
polyvinylchloride 
RBC 
red blood cells 
RBR 
Research Biosample Repository 
RECIST 
Response Evaluation Criteria In Solid Tumors 


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RNA 
ribonucleic acid 
RNA-seq 
RNA sequencing 
SAE 
serious adverse event 
SC 
steering committee 
SmPC 
Summary of medicinal Product Characteristics 
SOC 
system organ class/standard of care 
SOP 
standard operating procedure 
SP 
safety population 
SWFI 
sterile water for injection 
TPC 
treatment of physician’s choice 
UBC 
urothelial bladder cancer 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cells 
WGS 
whole genome sequencing  
 
 
1. 
BACKGROUND 
1.1 
BACKGROUND ON HUMAN EPIDERMAL GROWTH FACTOR 
RECEPTOR HER2 
The human epidermal growth factor receptor 2 (HER2) gene is a proto-oncogene, which 
is located on chromosome 17q11.2-12 and encodes a transmembrane tyrosine kinase 
receptor, which is responsible for cell growth, differentiation, migration and apoptosis 
(Normanno et al 2005).  
Amplification of the HER2 gene occurs in approximately 20% to 25% of primary human 
breast cancers (BC) and typically results in overexpression of the HER2 protein 
at > 1 million copies per cell (Slamon et al 1987, Slamon et al 1989, Pegram et al 2000). 
Such tumors are considered “HER2-positive” and are associated with aggressive growth 
and poor clinical outcome (Slamon et al 1987, Slamon et al 1989). 
Recently, new results on the role of HER2-targeted therapies in antitumor therapy for BC 
were published (refer to the Investigator’s Brochure [IB] for further information). In other 
tumors like gastric cancer (GC) trastuzumab is approved as well, which is not the case 
for trastuzumab emtansine (e.g., Lewis et al 2013).  
HER2 aberrations (gene amplification, gene mutations and protein overexpression) are 
reported in diverse other malignancies for instance esophagus, colorectal, pancreatic, 
bladder and prostate cancer (Yan et al 2014, Yoon et al 2014, Sato-Kuwabara et al 2009, 


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Seo et al 2014, Stoecklein et al 2004, Minner et al 2010, Carneiro et al 2015, Hansel et 
al 2008). Urothelial bladder cancer (UBC) and pancreatic cancer/cholangiocarcinoma 
are areas of high unmet medical need, and a more efficacious and less toxic therapy is 
desired. For UBC, it is currently estimated that the incidence of HER2 overexpression 
(immunohistochemistry [IHC]3+ and IHC2+/in situ hybridization [ISH]+) ranges from 
22-37% (Internal Data, Dendreon DN24-02, Hayashi et al 2014). In pancreatic ductal 
adenocarcinoma (PDAC), the HER2 gene locus was frequently (24%) amplified and the 
rate of overexpression (2+ and 3+) was 10%, but no prognostic significance was found 
(Stoecklein et al 2004). In addition, Safran et al (2004) have reported 30 patients (88%) 
with IHC2+ and 4 patients (12%) with IHC3+ HER2 status in a Phase II study of 
trastuzumab in HER2-positive metastatic pancreatic adenocarcinoma. In another 
Phase II study it has been shown that in contrary to breast and gastric cancer, where 
HER2 protein overexpression and HER2 gene amplification are highly concordant, only 
7 out of 11 (64%) patients with IHC3+ and 1 out of 22 (5%) with IHC2+ HER2 expression 
showed gene amplification (Harder et al 2012). Maybe HER2 overexpression in 
pancreatic cancer is regulated by other mechanisms on the transcriptional or 
translational level rather than gene amplification as postulated by Ukita et al (2002) for 
intrahepatic biliary tract cancer. The role of HER2 targeting therapy in these and 
potentially other indications is still unclear and needs to be further explored. 
1.2 
BACKGROUND ON STUDY DRUG  
Four HER2-targeted therapies have been approved for HER2-positive BC: Two 
monoclonal antibodies (trastuzumab and pertuzumab), an antibody-drug conjugate 
(trastuzumab emtansine/ado trastuzumab emtansine), and a small molecule kinase 
inhibitor (lapatinib) (Giordano et al 2014). 
1.2.1 
Background on Trastuzumab 
Trastuzumab is a humanized monoclonal antibody directed against the extracellular 
domain of HER2. Trastuzumab mediates antibody-dependent cellular cytotoxicity, 
inhibits HER2 extracellular domain shedding, and inhibits the phosphatidylinositol 3 
kinase signaling pathway. 
Trastuzumab is currently approved and it is part of the current standard of care (SOC) in 
HER2-positive BC for both the early breast cancer (EBC) and the metastatic breast 
cancer (MBC) setting, as shown in the pivotal randomized phase III study (Slamon et al 
2001). The American Society of Clinical Oncology (ASCO) guidelines 2014 recommend 
HER2 targeted therapy for all patients with advanced HER2-positive BC, except for 
those with clinical congestive heart failure or significantly compromised left ventricular 
ejection fraction (LVEF, Giordano et al 2014). 
Trastuzumab is also currently approved for the treatment of first-line HER2 
overexpressing GC (including gastroesophageal [GE] junction adenocarcinoma), the 
second most common cause of cancer related deaths worldwide (Kamangar et al 2006). 


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One study (Peyromaure et al 2005) explored the activity of trastuzumab in six patients 
with metastatic urothelial tract carcinoma. All of these patients had a positive 
immunohistochemistry for HER2. Four cases were treated with trastuzumab, paclitaxel, 
and carboplatin; one case with trastuzumab and paclitaxel; and the other case with 
trastuzumab monotherapy. The six patients achieved a partial response, ranging from 30 
to 80% reduction in the size of the metastatic lesions. Interval between trastuzumab 
initiation and death varied from 8 to 22 months. This study showed a potential role for 
anti-HER2 strategies in metastatic bladder carcinoma with HER2 overexpression. In 
2007, a phase II trial conducted by Hussain et al (2007) tested the combination of 
carboplatin, paclitaxel, gemcitabine, and trastuzumab in advanced urothelial carcinoma. 
A total number of 44 patients with HER2-positive tumors were treated with this 
combination. Five of these patients (11%) achieved a complete response, 26 (59%) a 
partial response, 5 (11%) had stable disease, and 5 (11%) had no response assessment, 
with an overall response rate of 70%. Median time to progression was 9.3 months, and 
median survival was 14.1 months. (Marin et al 2010) 
1.2.2 
Background on Trastuzumab Emtansine 
Trastuzumab emtansine (Kadcyla, also known as T-DM1, trastuzumab emtansine/ado-
trastuzumab emtansine) is a novel antibody-drug conjugate (ADC) that is specifically 
designed for the treatment of HER2-positive malignancies. Trastuzumab emtansine is 
composed of trastuzumab; an average of 3.5 molecules of DM1, an anti-microtubule 
agent derived from maytansine; and MCC, a linker that conjugates each molecule of 
DM1 to trastuzumab. Trastuzumab emtansine recognizes an epitope on the extracellular 
domain (ECD) of HER2 and binds to HER2 with an affinity similar to that of trastuzumab. 
It is hypothesized that after binding to HER2, trastuzumab emtansine undergoes 
receptor-mediated internalization. Following internalization, the endosome is fused with 
the lysosomal compartment, the ADC undergoes lysosomal degradation and the active 
metabolites lys-MCC-DM1 and DM1 are released (Erickson et al 2006, Erickson et al 
2012). DM1 is a highly potent thiol-containing derivative of maytansine and is 
synthesized from ansamitocin P3. It is an inhibitor of tubulin polymerization; it binds to 
tubulin competitively with vinca alkaloids but is 20-100 times more potent than vincristine 
in its cytotoxic effect against tumor cell lines. Its parent molecule, maytansine, was 
studied in approximately 800 patients, with responses seen in patients with BC and lung 
cancer (Issell et al 1978); however, because of its narrow therapeutic index, clinical 
development was not continued (Cassady et al 2004). 
In vitro studies of trastuzumab emtansine demonstrate enhanced cytotoxicity in 
HER2-overexpressing BC cell lines compared to BC cell lines with low HER2 expression. 
The requirement for receptor binding for trastuzumab emtansine activity has been 
demonstrated in vivo where a non-HER2-binding isotype-matched ADC served as a 
control. In these experiments, the control antibody-MCC-DM1 had no anti-tumor activity 
in the HER2-positive for BC model whereas trastuzumab emtansine exhibited significant 
anti-tumor activity. 


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Trastuzumab emtansine has been approved globally as a single agent and is indicated 
for the treatment of adult patients with HER2-positive, unresectable locally advanced 
breast cancer (LABC) or MBC who previously received trastuzumab and a taxane. 
1.2.2.1 
Nonclinical and Clinical Development of Trastuzumab 
Emtansine in Breast Cancer 
The nonclinical development of trastuzumab emtansine was designed to provide proof of 
concept for the mechanism of action of trastuzumab emtansine as a single agent and in 
combination with other therapies. Detailed summaries of nonclinical data for BC are 
provided in the IB. 
Data are available from six completed clinical studies assessing the safety and/or 
efficacy of single-agent trastuzumab emtansine: in MBC the dose-finding Phase I study 
TDM3569g (Krop et al 2010), two single-arm Phase II studies TDM4258g (Burris et al 
2010) and TDM4374g (Krop et al 2012), the single-arm Phase II study TDM4688g, 
which evaluated effects of trastuzumab emtansine on cardiac safety, the randomized 
Phase II study TDM4450g/BO21976, comparing single-agent trastuzumab emtansine 
with trastuzumab plus docetaxel and the expanded access, open-label study TDM4884g.  
Efficacy and safety data are also available from three Phase III studies evaluating single-
agent trastuzumab emtansine in MBC. Study TDM4370g/BO21977 (EMILIA) compared 
trastuzumab emtansine with lapatinib plus capecitabine (Verma et al 2012), and study 
TDM4997g/BO25734 (TH3RESA) evaluated trastuzumab emtansine versus treatment of 
physician’s choice (TPC): standard treatment with chemotherapy, hormone therapy 
and/or biologic agents (Krop et al 2014). A Phase IIIb safety study (MO28231; KAMILLA) 
is also ongoing.  
Trastuzumab emtansine treatment, with or without pertuzumab, is being compared with 
trastuzumab plus taxane (docetaxel or paclitaxel) in an ongoing Phase III study 
(TDM4788g/BO22589; MARIANNE). The primary results were presented at a recent 
medical congress and demonstrated non-inferiority of trastuzumab emtansine containing 
arms in progression free survival (PFS) compared to control. Trastuzumab emtansine 
was better tolerated than trastuzumab plus taxane, and no new safety issues were 
identified. 
1.2.2.2 
Nonclinical and Clinical Development of Trastuzumab 
Emtansine in Gastric Cancer 
Detailed summaries of nonclinical data for GC are provided in the IB. 
In terms of clinical studies in GC, one Phase II/III study evaluating trastuzumab 
emtansine versus taxane in patients with HER2-positive locally advanced or metastatic 
GC (BO27952; GATSBY) was published recently. While trastuzumab emtansine 
2.4 mg/kg qw did not show an efficacy benefit (with no improvement in overall survival 
[OS], PFS, overall response rate, or duration of response with trastuzumab emtansine in 


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the primary analysis population or subgroups), it was well tolerated and the safety 
profiles were comparable. The lack in efficacy benefit was even more accentuated in the 
non-IHC3+ population as per subgroup analyses (Kang et al 2016). 
1.2.2.3 
Nonclinical and Clinical Development of Trastuzumab 
Emtansine in Lung Cancer 
Detailed summaries of nonclinical data for lung cancer are provided in the IB. 
In two models of HER2-overexpressing (HER2 IHC3+) lung cancer, Calu-3 and 
NCIH2170, a single 7 mg/kg dose of trastuzumab emtansine resulted in tumor stasis. An 
additional lung cancer model, with HER2 expressed at the 1+ level, was tested for 
response to trastuzumab emtansine. In this model, 10 mg/kg trastuzumab emtansine 
administered every three weeks resulted in tumor stasis. In the Calu-3 HER2-positive 
lung cancer model, the combination of trastuzumab emtansine with pertuzumab was 
more efficacious than treatment with either single-agent trastuzumab emtansine or 
pertuzumab (Lewis et al 2013). 
HER2Lung (BO29389) is an ongoing Phase II study of trastuzumab emtansine in 
patients with HER2-positive advanced non-small cell lung cancer who have received at 
least one prior chemotherapy regimen. 
1.2.2.4 
Nonclinical Development of Trastuzumab Emtansine in Bladder 
Cancer 
Trastuzumab emtansine showed promising antitumor effects in preclinical models of 
HER2-overexpressing UBC. The bladder cell line with the highest HER2-expression 
(RT4V6), showed modest sensitivity to trastuzumab emtansine at concentrations less 
than 1 µ/mL but 24% higher growth inhibition compared to trastuzumab at a 
concentration of 1 µ/mL (Hayashi et al 2014). In an orthotopic bladder cancer xenograft 
model tumor growth of cisplatin resistant RT112 was significantly inhibited by 
trastuzumab emtansine via the induction of apoptosis compared to treatment with control 
IgG or trastuzumab. 
1.2.2.5 
Nonclinical Development of Trastuzumab Emtansine in 
Pancreatic Cancer/Cholangiocarcinoma 
In a study by Buechler et al (2005) the effect of a combination therapy consisting of 
Herceptin, gemcitabine and docetaxel on anchorage-independent growth of different 
human pancreatic cancer cell lines was tested. Monotherapy with Herceptin had shown 
some tumor suppressive activity particularly in those cell lines, which overexpress the 
HER2 receptor (Buechler et al 2001) and gemcitabine is the current standard 
chemotherapeutic agent for therapy of pancreatic cancer (Slamon 2000). Because of the 
promising results in BC where the combination therapy of Herceptin plus taxanes has 
been clinically effective, the combination of Herceptin with docetaxel and gemcitabine 
was tested (Slamon et al 2001; Pegram et al 2004, Kimura et al 2006). In order to test 
whether this therapeutic regimen was also effective in vivo, a murine model for 


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pancreatic cancer in which tumor xenografts were grown in an orthotopic location within 
the pancreatic parenchyma was used. Two different human pancreatic cancer cell lines 
with different characteristics of HER2 expression were tested. According to the clinical 
grading of HER2 expression, the MIA PaCa-2 cell line would be graded as HER2 3+ 
whereas the HPAF-II cell line would be graded as HER2 (+/-). Monotherapy with 
individual substances improved the survival benefit moderately. In contrast, there was a 
dramatic survival improvement upon combination therapy of gemcitabine and docetaxel 
or both substances plus Herceptin compared to monotherapy alone. More importantly, 
the metastatic score was reduced when Herceptin was added to gemcitabine and 
docetaxel in the high HER2-expressing cell line, MIA PaCa-2. 
1.2.2.6 
Pharmacokinetic Properties of Trastuzumab Emtansine in 
Breast Cancer 
The PK of trastuzumab emtansine and its analytes (i.e., the trastuzumab emtansine 
conjugate [hereafter referred to as trastuzumab emtansine], total trastuzumab and DM1) 
have been evaluated in a Phase I study (TDM3569g), four Phase II studies (Studies 
TDM4258g, TDM4374g, TDM4688g, TDM4450g/BO21976), and two Phase III studies 
(Study TDM4370g/BO21977 and TDM4997g/BO25734). 
The recommended dose of trastuzumab emtansine for BC is 3.6 mg/kg given as an IV 
infusion q3w. The PK analysis from the Phase I study (TDM3569g) following 
administration of 0.3 mg/kg to 4.8 mg/kg trastuzumab emtansine q3w showed that at the 
dose of 3.6 mg/kg q3w, the systemic clearance was approximately 12.7 mL/day/kg and 
the elimination half-life was approximately 3.1 days. The clearance of trastuzumab 
emtansine was nonlinear at doses less than or equal to 1.2 mg/kg. At doses ranging 
from 2.4 to 4.8 mg/kg q3w, trastuzumab emtansine exhibited linear PK. 
A qw dosing regimen was also evaluated in Study TDM3569g, and 2.4 mg/kg qw was 
identified as the maximum tolerable dose (MTD). Key trastuzumab emtansine PK 
parameters (i.e., CL, Vss and t1/2) at 2.4 mg/kg qw were similar to those observed at 
3.6 mg/kg q3w dosing. Measurable levels of free DM1 are found, but are approximately 
10,000 fold (by mass ratio) and approximately 50 fold (by molar ratio) lower than 
trastuzumab emtansine levels. 
In the Phase II and III studies in MBC patients (TDM4258g, TDM4374g, TDM4688g, 
TDM4450g/BO21976, and TDM4370g/BO21977 and TDM4997g/BO25734), PK 
parameter values for trastuzumab emtansine after a 3.6 mg/kg dose given q3w were 
similar to those observed for the q3w dosing regimen in the Phase I study regardless of 
lines of therapy. 
A robust population PK (popPK) model has been developed based on single-agent 
trastuzumab emtansine PK data from 671 HER2-positive MBC patients in five Phase I, II, 
and III studies (TDM3569g, TDM4258g, TDM4374g, TDM4450g/BO21976, and 
TDM4370g/BO21977). The estimated total body clearance, central volume of distribution, 


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and elimination half-life for trastuzumab emtansine was 0.676 L/day, 3.127 L, and 3.94 
days, respectively. Among ~30 covariates tested in the model, body weight, sum of 
longest dimension of target lesions, serum HER2 ECD concentration, baseline serum 
aspartate aminotransferase (AST), serum albumin, and baseline trastuzumab 
concentrations were identified as statistically significant covariates for trastuzumab 
emtansine PK but, with the exception of body weight, none had any clinically meaningful 
effect on trastuzumab emtansine exposure. Therefore, the weight-based dose of 
3.6 mg/kg q3w is considered appropriate in BC patients. 
1.2.2.7 
Pharmacokinetic Properties of Trastuzumab Emtansine in 
Gastric Cancer 
An important observation from the ToGA study (described in the IB) was the difference 
in the PK of trastuzumab in patients with advanced GC (AGC) compared with the PK of 
trastuzumab in patients with BC (Cosson et al 2014).  
Two regimens of trastuzumab emtansine were evaluated in the GATSBY trial (BO27952). 
The 3.6-mg/kg every-3-weeks regimen (MTD in Phase I studies) has been tested in 
several Phase II studies in MBC and is the regimen being studied in several Phase III 
BC studies and the approved regimen for MBC. The 3.6 mg/kg dose has a reasonable 
amount of clinical safety and efficacy data that can be found in greater detail in the IB. 
GATSBY used the 3.6-mg/kg every-3-weeks regimen as one of the trastuzumab 
emtansine doses in the study. However, because of the lower exposure of trastuzumab 
in gastric cancer patients in the ToGA study (BO18255) versus the exposure observed in 
BC studies (Bang et al 2010), the trial was also exploring an alternative regimen of 
trastuzumab emtansine (2.4 mg/kg weekly), which may provide a higher cumulative 
exposure of trastuzumab emtansine than the every-3-weeks schedule. 
The dosing of trastuzumab emtansine has been established in BC and recently in GC. It 
was demonstrated that 2.4 mg/kg dosing was well tolerated by patients and that event 
rates were comparable to taxane. This suggests 2.4 mg/kg to be the preferred dose as 
benefit-risk appears acceptable. However, as an additional safety measure and following 
the same process as GATSBY, an Independent Data Monitoring Committee (iDMC) will 
be used during this study that will provide additional safety monitoring. 
1.2.2.8 
Pharmacokinetic Properties of Trastuzumab Emtansine in 
Lung Cancer 
Currently, there are no PK data available for trastuzumab emtansine in lung cancer. 
1.2.2.9 
Pharmacokinetic Properties of Trastuzumab Emtansine in 
Urothelial Bladder Cancer 
Currently, there are no PK data available for trastuzumab emtansine in UBC. 


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1.2.2.10 
Pharmacokinetic Properties of Trastuzumab Emtansine in 
Pancreatic Cancer/Cholangiocarcinoma 
Currently, there are no PK data available for trastuzumab emtansine in pancreatic 
cancer/cholangiocarcinoma. 
1.2.2.11 
Clinical Safety with Trastuzumab Emtansine 
The following section summarizes the experience with trastuzumab emtansine in several 
BC studies to date (described in the trastuzumab emtansine IB). Trastuzumab 
emtansine has demonstrated a favorable toxicity and tolerability profile to date across 
several studies. This safety profile of trastuzumab emtansine in MBC is based on data 
from 1871 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 (Studies TDM4373g/BO22495 and TDM4688g), with a clinical 
cut-off date of 31 July 2012. (Dieras et al 2014). 
Thrombocytopenia: Thrombocytopenia, or decreased platelet counts, was reported in 
patients in clinical trials of trastuzumab emtansine. The majority of these patients had 
Grade 1 or 2 events (≥ 50,000/mm3), with the nadir occurring by Day 8 and generally 
improving to Grade 0 or 1 (≥ 75,000/mm3) by the next scheduled dose. In clinical trials, 
the incidence and severity of thrombocytopenia were higher in Asian patients. Cases of 
bleeding events with a fatal outcome have been observed. Severe cases of hemorrhagic 
events, including central nervous system (CNS) 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. 
Hepatotoxicity: Hepatotoxicity, predominantly in the form of asymptomatic increases in 
the concentrations of serum transaminases, has been observed while on treatment with 
trastuzumab emtansine in clinical trials. Grade 1−2 events have been observed 
frequently; Grade 3−4 events have been observed less commonly. 
Transaminase elevations were generally transient. A cumulative effect of trastuzumab 
emtansine on transaminases has been observed; elevated transaminases improved to 
Grade 1 or normal within 30 days of the last dose of trastuzumab emtansine in the 
majority of the patients. Serious hepatobiliary disorders, including nodular regenerative 
hyperplasia (NRH) of the liver and some resulting in fatal liver failure, have been 
observed in patients treated with trastuzumab emtansine in clinical trials. Some of the 
observed cases may have been confounded by comorbidities and/or concomitant 
medications with known hepatotoxic potential. 
Cases of NRH of the liver have been identified from liver biopsies in patients presenting 
with signs and symptoms of portal hypertension. NRH was also observed in one fatal 
case of hepatic failure. NRH is a rare liver condition characterized by widespread benign 
transformation of hepatic parenchyma into small regenerative nodules; NRH may lead to 


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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 computed tomography (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.  
Infusion-Related Reactions and Hypersensitivity Reactions: Infusion-related 
reactions, 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. Hypersensitivity reactions, including serious 
anaphylactic-like reactions, have been observed in clinical trials with treatment of 
trastuzumab emtansine. 
Pulmonary Toxicity: Severe cases of interstitial lung disease (ILD), including 
pneumonitis, some leading to acute respiratory distress syndrome or a fatal outcome, 
have been reported in clinical trials with trastuzumab emtansine. Signs and symptoms 
include dyspnea, cough, fatigue, and pulmonary infiltrates. These events may or may not 
occur as sequelae of infusion reactions. Treatment has included administration of 
steroids, oxygen, and study drug discontinuation. In some patients with multiple lung 
metastases, ventilatory support (mechanical ventilation) was required. Patients with 
dyspnea at rest due to complications of advanced malignancy and comorbidities may be 
at increased risk of pulmonary events. 
Neurotoxicity: Peripheral neuropathy, mainly Grade 1 and predominantly sensory, has 
been reported in clinical trials of trastuzumab emtansine. 
Left Ventricular Dysfunction: Patients treated with trastuzumab emtansine are at 
increased risk of developing left ventricular dysfunction. LVEF < 40% has been observed 
in patients treated with trastuzumab emtansine, and therefore symptomatic congestive 
heart failure (CHF) is a potential risk. Treatment with trastuzumab emtansine has not 
been studied in patients with LVEF <50% prior to initiation of treatment. 
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.  
Full details regarding the clinical safety of trastuzumab emtansine are presented in the 
IB and in the Summary of Medicinal Product Characteristics (SmPC)/US data sheet for 
trastuzumab emtansine. 


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1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
A number of anti-HER2 therapies have proven efficacy, are approved and part of the 
SOC for HER2-positive BC and GC (see Sections 1.1 and 1.2). However, this is not yet 
the case for trastuzumab emtansine which currently is only available for BC. HER2 
overexpression has been identified in some other tumors as described in Section 1.1. 
These findings pose the intriguing question if trastuzumab emtansine could improve 
patient outcomes in those tumor types and beyond BC and GC. There is currently no 
clinical data on the potential therapeutic effect of trastuzumab emtansine treatment in 
HER2-positive tumors such as esophageal-, colorectal-, pancreatic/cholangio-, prostate 
and bladder carcinoma. 
UBC seems to be an interesting target that shows a similar HER2 overexpression rate 
as in breast cancer, although the IHC staining pattern is expected to be more 
heterogeneous. HER2 expression in UBC is associated with high-grade tumors and 
advanced local disease (Hussain et al 2007, Simon et al 2003, Gehani et al 2012, Chen 
et al 2013), more metastatic sites and visceral metastases (Hussain et al 2007), higher 
recurrence risk (Chen et al 2013) and shorter OS and disease specific survival (Krueger 
et al 2002, Simon et al 2003). 
Trastuzumab and lapatinib in combination with chemotherapeutic agents showed activity 
in bladder cancer cell lines (Pegram et al 1999, McHugh et al 2007, McHugh et al 2009) 
and trastuzumab emtansine showed growth inhibition in cisplatin-resistant, HER2 
overexpressing bladder cell lines and orthotopic xenograft models (Hayashi et al 2015). 
This proof of effectiveness of HER2-targeted therapies in bladder cell lines as well as 
some activity of trastuzumab in combination with chemotherapeutic agents in metastatic 
bladder cancer (Hussain et al 2007) – although in small non-controlled studies - 
suggests further clinical assessment in a clearly defined UBC population.  
Harder et al (2012) conducted a study to investigate the efficacy and safety of 
trastuzumab and capecitabine as first-line treatment in patients with IHC3+ HER2 
expressing advanced pancreatic cancer or cancer with HER2 gene amplification of stage 
IVB (T1-4N0-1M1). The objective was to show activity of the combination of trastuzumab 
and capecitabine in these patients. Median PFS was 65 days, with an estimated PFS 
rate after 6 months of 11.8% (95% CI: 0-27.1) and of 0% after 12 months. Median OS 
was 6.9 months, with an estimated OS probability after 6 months of 52.9% (95% CI: 
29.2-76.7), and after 12 months of 29.4% (95% CI: 7.8-51.1). Even though these were 
promising results, capecitabine in combination with trastuzumab anti-HER2 therapy did 
not seem to significantly improve treatment effects in comparison with historical 
capecitabine monotherapy (mean OS 6.0 months; Cartwright et al 2002). However, as 
found in a post-hoc analysis, one-third of IHC3+ HER2-positive tumors did not show 
HER2 amplification and thus may be an explanation for the findings in patients with 
treated with trastuzumab plus capecitabine.  


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Therefore, focusing on non-focal expressers in the current study may eliminate some of 
these limitations and lead to better results. 
At a later point in time additional HER2 positive tumors might be evaluated and further 
assessed as well. 
1.3.1 
Rationale for Patient Selection 
Trastuzumab emtansine is proven to be efficacious in HER2 positive BC tumors.  
In patients with HER2-positive LABC or MBC who had received prior taxane and 
trastuzumab-based therapy (TDM4370g/BO21977), statistically significant and clinically 
meaningful improvements in PFS and OS were observed in patients receiving 
trastuzumab emtansine compared with patients receiving lapatinib plus capecitabine. 
This benefit was supported by improvements in all secondary efficacy endpoints, 
including overall response rate, time to treatment failure, and in the patient-reported 
outcome of time to symptom progression.  
Consistent with these results, in patients with HER2-positive MBC (see Section 1.2.2) 
who had received at least two HER2-directed regimens in the metastatic setting 
(TDM4997g/BO25734), trastuzumab emtansine gave a significant improvement in PFS 
compared with TPC, and a strong positive trend at the first interim analysis of OS. At the 
second interim analysis of OS, treatment with trastuzumab emtansine resulted in a 
statistically significant and clinically meaningful improvement in OS compared with TPC. 
Since the related p-value crossed the OS efficacy stopping boundary, the results were 
considered final. Patients receiving trastuzumab emtansine also showed a consistent 
treatment benefit compared with the subgroup of patients receiving a trastuzumab-
containing TPC. 
The comparison of trastuzumab emtansine treatment, with or without pertuzumab with 
trastuzumab plus taxane (docetaxel or paclitaxel) in HER2-positive, progressive or 
recurrent LABC or MBC (TDM4788g/BO22589) demonstrated PFS non-inferiority for 
both trastuzumab emtansine-containing regimens compared with trastuzumab plus 
taxane: The addition of pertuzumab to trastuzumab emtansine did not result in a 
statistically significant increase in PFS. 
The indication of trastuzumab emtansine in BC is limited to patients with HER2-positive, 
unresectable LABC or MBC who have received prior treatment with trastuzumab and a 
taxane. 
UBC: UBC is a major global health challenge with an estimated 429,000 new cases 
resulting in 165,000 deaths annually (Ferlay et al 2013). In males, UBC represents the 
fourth most frequent diagnoses of new cancer yearly. Over the past two decades, there 
has been no significant improvement in survival of UBC with 5-year relative survival 
rates for locally advanced and metastatic disease of 33% and 5%, respectively (Siegel et 


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al 2014). Around 5% of the patients have metastases at diagnosis. 75% are non-muscle 
invasive (whereas around 20-30% progress) and 20% are muscle-invasive (of these 
around 50% progress to the metastatic stage) at diagnosis. In urothelial carcinoma of the 
bladder, different levels of HER2 expression have been reported, between 22% and 
37% (Internal Data; Dendreon DN24-02; Hayashi et al 2013) and there is a high 
concordance between overexpression (IHC) and amplification (ISH). This makes them 
an interesting potential group for trastuzumab emtansine treatment. However, UBC has 
a more heterogeneous HER2-expression than for example BC and GC (Internal Data; 
Sauter et al 1993, Lae et al 2010). It was therefore decided to only include non-focal 
expressers with ≥30% of HER2 IHC3+ positively stained cells as efficacy of trastuzumab 
emtansine in more heterogeneous cancers is currently unknown. 
Pancreatic cancer/cholangiocarcinoma: Pancreatic adenocarcinoma is the 5th most 
frequent cause of cancer related deaths (Hartwig et al 2013). Survival rates remain 
disappointing (median OS with palliative chemotherapy 11.1 months) and many patients 
will develop distant metastases (Conroy et al 2011). The HER2 overexpression rate is as 
high as 11% (and varies widely between patients). Interestingly, overexpression of the 
HER2 protein does not correlate well to amplification of the HER2 locus; especially it 
was shown, that HER2 IHC3+ protein expression did not correlate with gene 
amplification (Harder et al 2012). HER2 overexpression in pancreatic cancer may be due 
to gene deregulation rather than gene amplification as postulated by Ukita et al (2002) 
for intrahepatic biliary tract cancer (Harder et al 2012). Nevertheless an approach with 
an ADC such as trastuzumab emtansine may be considered a potential treatment option. 
Cholangiocarcinomas may be considered related tumors and these patients can be 
included in later stages of this study. The incidence and mortality rates of 
cholangiocarcinoma, especially those of intrahepatic cholangiocarcinoma, are increasing 
worldwide (Khan et al 2005). Complete resection is the only way to cure the disease at 
present. However, because cholangiocarcinoma are difficult to diagnose at an early 
stage and extend diffusely, most patients have unresectable disease at clinical 
presentation, and prognosis is very poor (5-year survival is 0–40% even in resected 
cases) (Yoshikawa et al 2008). Approximately 8% of patients have HER2 
overexpression (Yan et al 2015) and may therefore benefit from a HER2-targeted 
therapeutic approach. 
Patients diagnosed with locally advanced (unresectable and not treatable with curative 
intent) or metastatic UBC or locally advanced (unresectable and not treatable with 
curative intent) or metastatic pancreatic cancer/cholangiocarcinoma have very limited 
treatment options to date, especially if they present in an advanced stage of their cancer, 
with a high mortality and low long-time survival rates. New therapeutic approaches are 
therefore needed for these patients with a high unmet medical need and limited other 
treatment options, especially in late stage. 


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1.3.2 
Rationale for Study Design 
KAMELEON is a Phase II, proof of concept, single arm study, designed to estimate the 
efficacy of trastuzumab emtansine in HER2 overexpressing locally advanced 
(unresectable and not treatable with curative intent) or metastatic UBC, locally advanced 
(unresectable and not treatable with curative intent) or metastatic pancreatic 
cancer/cholangiocarcinoma in patients with advanced disease where cure is no longer 
possible and where no other treatment options are available anymore. The trial might be 
opened up to a diverse range of other HER2 overexpressing tumors as described further 
above. Trastuzumab emtansine has proven efficacious in HER2-positive BC and has a 
tolerable safety profile (see Section 1.2.2.10). Therefore, the risk benefit in this study is 
deemed positive.  
The study design will allow for the examination of locally advanced (unresectable and 
not treatable with curative intent) or metastatic UBC and pancreatic 
cancer/cholangiocarcinoma with enough statistical power to determine whether further 
examination may be warranted in these indications or potential additional indications. To 
investigate a potential difference in treatment efficacy for UBC and pancreatic 
cancer/cholangiocarcinoma with homogeneous HER2 expression and the carcinoma 
with a more focal HER2 expression, patients will be stratified according to the HER2 IHC 
pattern in their baseline tissue biopsy (e.g., 30-70% vs 71-100% of tumor cells 
expressing HER2). Patients with very focal HER2 IHC pattern (e.g., < 30%) will be 
excluded from this study. The open-label, uncontrolled design is appropriate since the 
trial will only enroll patients with HER2-positive cancers and who in the opinion of the 
investigator have trastuzumab emtansine as their best treatment option. The study is 
intended as a proof of concept.  
Recruitment might be expanded to combination treatments and a broader range of 
patients if a response rate has been demonstrated in Phase II as defined in the protocol 
and/or a clear clinical benefit for patients is observed based on RECIST 1.1. The 
sponsor in discussion with the study steering committee (SC) and the iDMC will decide 
on the expansion. The data from these additional patients will help further characterize 
the safety and efficacy of trastuzumab emtansine in the specific indication and 
potentially in combination with other agents. 
1.3.3 
Rationale for Dose Selection 
A 2.4 mg/kg qw dose has been chosen as the starting dose for this study as it has 
already been explored in BC and GC patients and it is considered that it will provide the 
highest exposure with an acceptable safety profile in UBC patients. If tolerability is poor, 
the dose will be changed to 3.6 mg/kg q3w dose.  
The weight-based dose of 3.6 mg/kg q3w for trastuzumab emtansine in BC was 
considered appropriate based on the Phase I dose-finding study and established by 
Phase II/III trials as shown in Section 1.2.2.6 in BC patients.  


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However, the dose chosen for the current study was explored in a Phase I dosing study 
in MBC (Beeram et al 2012), which determined the MTD to be 2.4 mg/kg qw. There are 
currently no data on alternative dosing such as a lower dose weekly or a higher dose 
every 2 weeks.  
In a trastuzumab PK analysis (Cosson et al 2014), it was shown that the PK profiles for 
trastuzumab in the GC population are lower than what was observed in the BC 
population (see Sections 1.2.2.6 and 1.2.2.7) and patients with the lowest Cmin had a 
shorter OS and the highest progressive disease (PD) rate.  
1.3.4 
Rationale for Translational Research Program 
This study will generate a unique data set of patients with HER2 expressing locally 
advanced (unresectable and not treatable with curative intent) or metastatic UBC or 
locally advanced (unresectable and not treatable with curative intent) or metastatic 
pancreatic cancer/cholangiocarcinoma treated with trastuzumab emtansine. It will create 
a comprehensive data set of markers that will be informative about differences and 
similarities between tissues, treatment outcome in these patients. Therefore, the 
mandatory archival tumor biopsies from all patients included in this study and the 
optional biopsy collected at disease progression may be used for exploratory protein, 
deoxyribonucleic acid (DNA)-based analyses and ribonucleic acid (RNA)-based 
expression analyses. In addition, mandatory plasma samples at baseline and at various 
timepoints during treatment will be collected (see Schedule of Activities, Appendix 1). 
These plasma samples will be used for exploratory biomarker assays which may include 
but are not limited to analysis of circulating protein and circulating tumor DNA. All 
exploratory biomarker analyses will be performed retrospectively and are clearly defined 
in the patient’s informed consent.  
1.3.5 
Benefit Risk Assessment 
Anti HER2-therapies have shown clinical utility and are approved in both BC and GC 
(trastuzumab) or BC (trastuzumab emtansine, see Section 1.2.2). Trastuzumab 
emtansine has demonstrated a favorable toxicity and tolerability profile to date across 
several phase I-III studies in BC patients (see Section 1.2.2.11). 
HER2 overexpression has been shown in a number of other tumor types. The tumor 
types investigated in this study have poor prognosis in the advanced setting. Despite 
some recent progresses in the treatment of these cancers, the current standard of care 
still results in modest prolongation of survival in the advanced setting. Therefore the 
prognosis for this advanced-staged cancer types is still poor. Targeted therapies for 
locally advanced (unresectable and not treatable with curative intent) or metastatic UBC 
or locally advanced (unresectable and not treatable with curative intent) or metastatic 
pancreatic cancer/cholangiocarcinoma must not only demonstrate anti-tumor activity but 
should also minimize the toxicities commonly associated with currently available 
treatment options. Based on the clinical experience in MBC to date, trastuzumab 


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emtansine has the potential to fulfill this need as therapy for advanced HER2 IHC-
positive urothelial and/or pancreatic cancer/cholangiocarcinoma, with the option to 
subsequently include other tumor types as well. A safety plan for this study, including 
appropriate eligibility criteria, dose modification and/or discontinuation guidelines for 
each identified and potential risk (see Section 5.1), monitoring of patients at risk as well 
as regular monitoring of patient safety data by an iDMC, has been put into place to 
minimize any potential risk in the study patient population. 
Based on all of the above it is considered that the benefit risk for patients participating in 
this study is positive. 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics of trastuzumab 
emtansine in patients with locally advanced (unresectable and not treatable with curative 
intent) or metastatic UBC or locally advanced (unresectable and not treatable with 
curative intent) or metastatic pancreatic cancer/cholangiocarcinoma. Specific objectives 
and corresponding endpoints for the study are outlined in Table 1 below. 


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Table 1 
Objectives and Corresponding Endpoints 
Objectives 
Corresponding Endpoints 
Primary Efficacy Objective: 
 To evaluate the efficacy of 
trastuzumab emtansine 
 Best overall response rate (BOR) as determined by 
the investigator (using RECIST 1.1). BOR is defined 
as the best response recorded from the first day of 
study treatment until disease progression/recurrence 
or death. Responders, as assessed every 6 weeks, 
will be defined based on tumor assessment status as 
partial responder (PR) or complete responder (CR) at 
these time points. To be assigned a status of PR or 
CR (i.e., a responder), changes in tumor 
measurements must be confirmed by repeat 
assessments that should be performed no less than 
4 weeks after the criteria for response are first met, 
i.e., patients need to have two consecutive 
assessments of PR or CR to be a responder. 
Secondary Efficacy Objective: 
 To evaluate the efficacy of 
trastuzumab emtansine 
 PFS, defined as the time from beginning of treatment 
to the first occurrence of disease progression, as 
determined by the investigator (using RECIST 1.1), or 
death from any cause, whichever occurs first. 
 OS, defined as the time from beginning of treatment 
to death from any cause. 
Safety Objective: 
 To evaluate the safety of trastuzumab 
emtansine 
 Incidence, type and severity of all adverse events 
(AEs) and serious adverse events (SAEs) based on 
National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE v4.03).  
 Incidence and type of AEs leading to discontinuation, 
modification, or delay of trastuzumab emtansine dose. 
 Changes in vital signs, physical examination findings, 
and clinical laboratory results during and following 
trastuzumab emtansine administration. 
 Death and cause of death. 
 Cases of drug-induced liver injury meeting Hy’s Law 
criteria. 
 Pneumonitis of all grades.  
 Change in LVEF over the course of the study as 
measured by echocardiogram (ECHO) or multiple-
gated acquisition scan (MUGA). 
 Incidence of CHF. 
 


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Table 1 
Objectives and Corresponding Endpoints (cont.) 
Pharmacokinetic Objective: 
 To characterize the 
pharmacokinetics of trastuzumab 
emtansine 
 Concentrations of trastuzumab emtansine in 
plasma/serum to determine exposure. 
(Exploratory) Immunogenicity Objective: 
 To evaluate the immune response to 
trastuzumab emtansine 
 Incidence of anti-therapeutic antibodies (ATAs) 
during the study relative to the prevalence of ATAs 
at baseline. 
 Exploratory assessment of immune checkpoints e.g. 
infiltrating lymphocyctes in the tumor before and 
after treatment by the assessment of immune-
related biomarkers such as PDL1 and CD8. 
Exploratory Biomarker Objective: 
 To identify biomarkers that are 
predictive of response, can provide 
evidence of trastuzumab emtansine 
activity, or can increase the 
knowledge and understanding of 
disease biology 
 To further evaluate the HER2 status by other 
exploratory testing methods such as a novel Gene-
Protein-Assay (GPA), e.g. IHC and ISH combined in 
one assay on samples of all consenting screened 
patients 
 Correlate levels of HER2 protein expression, HER2 
gene amplification and circulating HER2 
extracellular domain (HER2 ECD) to trastuzumab 
emtansine efficacy. 
 To evaluate biomarkers that may be associated with 
response and/or safety on the protein, RNA and 
DNA level (e.g. by molecular subtyping and gene 
mutation analysis). 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is an exploratory, multicenter, non-randomized, Phase II, single agent cohort study 
designed to evaluate the efficacy of trastuzumab emtansine in patients with locally 
advanced (unresectable and not treatable with curative intent) or metastatic UBC or 
locally advanced (unresectable and not treatable with curative intent) or metastatic 
pancreatic cancer/cholangiocarcinoma, with other tumor types being potentially explored 
at a later point in time. 
If no patients are enrolled in an individual cohort one year after enrolment started, then 
enrolment for that cohort will be stopped.  
The accrual inclusion time for this study is expected to be 18 months per cohort. 


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Patients who fulfill the inclusion/exclusion criteria will be screened for HER2 status and 
enrolled in the study; a total of 32-38 patients per cohort will be enrolled; 64-76 patients 
in total.  
In a safety run-in, the first 6 patients of each cohort will enter Regimen A and receive 
2.4 mg/kg weekly trastuzumab emtansine. These first 6 patients will be assessed on an 
ongoing and patient per patient basis – i.e. based on the tolerability criteria (as defined in 
the iDMC charter) and in consultation with the SC and iDMC if needed. Recruitment for 
the respective cohort will be suspended until all 6 of these patients have completed the 
2nd cycle (6 weeks) and the ‘regimen decision point’ has been reached. Based on 
tolerability and safety aspects (see Figure 2 and Figure 3), such as lack of unacceptable 
toxicities (e.g., drug-related fatal case(s), severe drug-induced liver injury [confirmed 
Hy’s Law cases], Grade ≥ 3 pneumonitis, or other relevant severe toxicities determined 
by the iDMC) a decision will be made by the iDMC if the cohort is to continue on 
Regimen A (2.4 mg/kg qw), extending recruitment to a total of 32 patients (additional 26 
patients) per cohort, or if the dose switches to Regimen B (3.6 mg/kg q3w). If the 
regimen is changed to Regimen B in an individual cohort, 32 additional patients will be 
included in this cohort; if the regimen remains unchanged (i.e., Regimen A), only 26 
additional patients will be recruited.  
If treatment in a cohort is switched to Regimen B, the 6 patients that were initially started 
on Regimen A will be allowed to switch if an additional benefit can be expected. 
However, for patients of a cohort who showed initial response on Regimen A, it is 
recommended to keep them on Regimen A. If any of these patients experiences PD, no 
switch is allowed and the patient will be discontinued from the study. Irrespective of 
these potential changes, these patients will not be included in the primary efficacy 
analysis.  
The primary (and final) analysis for efficacy would be based only on those patients of a 
cohort who started on the selected treatment regimen. If the decision is made to switch 
to Regimen B then those patients who started on Regimen A would not be included in 
the primary or final efficacy analyses (whether they stay on Regimen A or switched to 
Regimen B) but their results would be included in a supplementary descriptive analysis. 
An extensive flow chart is given below and in Figure 3. Decision on expansion of the 
study to include other carcinoma types will be made via collaboration of the SC and 
iDMC. The iDMC has to look at the initial tolerability data before the decision to include 
more carcinoma types is being made. Efficacy data will not be considered for this 
decision. 


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Figure 3 Extensive flow-chart regarding study design and decision points 


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Study Procedures 
General screening assessment will be performed as per the Schedule of Activities 
(Appendix 1). Mandatory pre-treatment tumor samples for HER2 status assessment and 
biomarkers will be taken. Exploratory biomarker analysis will be performed at the end of 
the study. Optional informed consent will be asked as well for the collection of a second 
biopsy at PD and long-term storage for further exploratory research under Research 
Biosample Repository (RBR) guidelines. 
Tumor Assessments 
Tumor responses will be measured according to RECIST 1.1 as per the Schedule of 
Activities (Appendix 1). Objective response (complete, partial) and progression will be 
assessed by CT and, in case of brain metastases, also by magnetic resonance imaging 
(MRI).  
Tumor Sampling 
Mandatory Tumor Samples 
Pre-treatment formalin-fixed tumor tissue embedded in paraffin blocks (or parts of tumor 
blocks) or alternatively 20 freshly cut slides will be taken for the assessment of HER2 
positivity and e.g. for DNA/RNA extraction and/or assessment of biomarkers by protein 
expression. These procedures are necessary to obtain reliable biomarker and 
translational research information. For further exploratory assessment of HER2 positivity 
of consenting patients, additional HER2 testing methods assessing the HER2 protein 
expression and the gene amplification with tests that are new and under development 
will be applied. However, these additional assessments will not be relevant for patient 
screening and selection. All tissue samples will be stored in the central laboratory where 
HER2 positivity for patient inclusion is assessed for up to 5 years after the date of final 
closure of the associated clinical database.  
Optional Tumor Samples 
Besides the mandatory baseline biopsy, patients will also be asked to undergo optional 
post-treatment biopsies. Post-treatment biopsies will take place at discontinuation of 
trastuzumab emtansine, either due to PD, unacceptable toxicity of systemic treatment or 
any other reason. This allows to determine long-term effects of the systemic therapy on 
the mutational profile (in case of discontinuation of treatment due to disease control) and 
to observe new mutations that cause insensitivity to systemic treatment (PD after 
multiple cycles). 
Standardized collection of adequate tissue samples is important in performing biomarker 
research and will be defined in a Sampling Manual. 


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After the protocol-defined biomarker analysis will be completed, residual tissue and 
extracted DNA and RNA samples may be transferred to the RBR if the patient signs the 
optional informed consent for RBR. These samples can be used for further exploratory 
research and for long-term storage. All RBR specimen(s) will be destroyed no later than 
15 years after the final freeze of the respective clinical database unless regulatory 
authorities require that specimens be maintained for a longer period. 
Blood Sampling 
Mandatory plasma samples for general assessments will be collected at baseline 
(Cycle 1, Day 1), every study visit and at PD for all patients. Further samples at baseline 
will be collected for biomarkers, PK, HER2 ECD, ATAs and genotyping, for PK at each 
subsequent visit during Cycle 1 and at Cycle 4, Day 1, for HER2 ECD at Cycle 2 and 
Cycle 4, Day 1 and for ATAs at Cycle 4, Day 1, drug completion and every 3 months 
thereafter. These specimens will be used for research purposes to identify biomarkers 
that correlate to response to trastuzumab emtansine treatment (in terms of dose, safety 
and tolerability) and will help to better understand the pathogenesis, course, and 
outcome of the carcinomas under investigation and related diseases. Serial serum and 
plasma samples will be used for example to evaluate changes in circulating protein 
markers or circulating tumor DNA during course of treatment until progression to better 
understand (duration of) response to treatment. In addition, one 6 mL blood sample for 
retrospective genotyping of inherited genes will be collected at baseline from all patients 
(see Appendix 1, Schedule of Activities). 
Administration of Study Drug and Selected Study Assessments 
Trastuzumab emtansine will be administered weekly at the dose of 2.4 mg/kg 
(Regimen A, see Figure 4) or every 3 weeks at the dose of 3.6 mg/kg (Regimen B, see 
Figure 5). Patients will be treated until PD, intolerable toxicity, death, and patient or 
investigator decision to discontinue treatment. 
 


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3.2 
END OF STUDY AND LENGTH OF STUDY 
The total length of the study for an individual cohort, from screening of the first patient to 
the end of the study, is expected to be approximately 3 years (18 months of recruitment, 
6 months of treatment and 12 months of follow-up). 
Each cohort will close 18 months after the last patient was recruited or once all patients 
have died or withdrawn from the study, whichever happens first. End of study in a cohort 
will be declared at the last patient last visit (LPLV) as per definition is the last data 
collection point, which can be a clinic visit or a laboratory sample. 
Patients will receive study medication until unacceptable toxicity, withdrawal of consent, 
disease progression, or death, whichever occurs first. After completion of treatment, 
patients will be followed up in a 3 monthly schedule until study close (18 months after 
last patient in in each cohort). The treatment period is expected to be 6 months. 
The data cutoff for the primary analysis of BOR will take place 12 weeks after the last 
patient of an individual cohort has been recruited (following a tumor assessment after 6 
weeks [2 cycles] with a confirmation of BOR performed no less than 4 weeks after the 
criteria for response are first met). 
The data cutoff for the final analysis for each cohort of all primary and secondary efficacy 
measures will take place 18 months after the last patient was recruited, or once all 
patients have reported a progression event, whichever occurs earlier.  
Interim analyses will take place as described in Section 6.8. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Trastuzumab Emtansine Dose and Schedule 
In this study, patients will be treated with trastuzumab emtansine. No comparator or 
placebo will be used. Trastuzumab emtansine is considered the investigational medicinal 
product (IMP) in this study. 
The weight-based doses of 2.4 mg/kg qw and 3.6 mg/kg q3w for trastuzumab emtansine 
are considered appropriate based on the Phase I dose-finding study and established by 
Phase II/III trials. PK characteristics of trastuzumab (backbone antibody of trastuzumab 
emtansine) differ between different tumor types (Cosson et al 2014). Current knowledge 
of trastuzumab emtansine PK derives mostly from BC. For further information see 
Sections 1.2.2.5 and 1.3.3. 
3.3.2 
Rationale for Patient Population 
Trastuzumab emtansine is proven to be efficacious in HER2 positive BC. Recently 
published results in locally advanced or metastatic GC (BO27952; GATSBY) showed 
that, though not demonstrating a direct efficacy benefit over taxane, trastuzumab 


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emtansine was well tolerated and the safety profile was acceptable. It is currently being 
under evaluation for the treatment of HER2 lung cancer (Lewis et al 2013).  
There is currently no clinical data on the potential therapeutic effect of trastuzumab 
emtansine treatment in other HER2 positive tumors such as locally advanced 
(unresectable and not treatable with curative intent) or metastatic UBC or locally 
advanced (unresectable and not treatable with curative intent) or metastatic pancreatic 
cancer/cholangiocarcinoma. Further information on this disease is presented in 
Section 1.3.1. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Up to 38 patients per cancer type, i.e. locally advanced (unresectable and not treatable 
with curative intent) or metastatic UBC and locally advanced (unresectable and not 
treatable with curative intent) or metastatic pancreatic cancer/cholangiocarcinoma, will 
be enrolled in this study. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. 
Histologically centrally confirmed HER2-positive (IHC3+ in ≥ 30% of tumor cells): 
locally advanced (unresectable and not treatable with curative intent) or metastatic 
UBC or locally advanced (unresectable and not treatable with curative intent) or 
metastatic pancreatic cancer/cholangiocarcinoma. 
HER2 status may be pre-screened at the participating site. However, HER2 
determination at the referral center is not accepted to determine study eligibility. 
HER2 positivity needs to be prospectively confirmed with central laboratory HER2 
testing before patient enrollment. 
2. 
There must be no standard treatment options available for patients with the above 
HER2 overexpressing tumors and they must have undergone at least one prior 
platinum-based treatment for locally advanced (unresectable and not treatable with 
curative intent) or metastatic tumor. (Note: for pancreatic 
cancer/cholangiocarcinoma, prior treatments are NOT required to be platinum-
based.) 
3. 
The patient must have evaluable disease fulfilling all of the following imaging criteria: 
a. On diagnostic CT scan/MRI: lesion should be measurable according to 
RECIST 1.1. 
b. Target lesion(s) should not have been previously irradiated. 
4. 
At least one formalin-fixed paraffin-embedded (FFPE) biopsy of the primary tumor 
and/or from a metastatic site is required.  
5. 
Age  18 years. 
6. 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2. 


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7. 
No significant cardiac history and a current LVEF ≥ 50%. LVEF should be 
determined within 28 days before the start of trastuzumab emtansine treatment. 
8. 
Adequate organ function, evidenced by the following laboratory results (performed 
within 7 days prior to commencement of dosing): 
a. Absolute neutrophil count > 1,500 cells/mm3. 
b. Platelet count > 100,000 cells/mm3. 
c. Hemoglobin > 9 g/dL. 
d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
< 2.5 x upper limit of normal (ULN). 
e. Total bilirubin ≤ 1.5 x ULN unless the patient has documented Gilbert’s 
syndrome, in which case direct (conjugated) bilirubin level needs to be 
within normal limits. 
f. Serum alkaline phosphatase ≤ 2.5 x ULN. Patients with bone metastases: 
alkaline phosphatase ≤ 5 x ULN. 
g. Serum creatinine < 2.0 mg/dL or < 177 µmol/L. 
h. International normalized ratio (INR) and activated partial thromboplastin 
time or partial thromboplastin time (aPTT or PTT) < 1.5 ULN. 
9. 
Absence of any psychological, familial, sociological or geographical condition 
potentially hampering compliance with the study protocol and follow-up schedule; 
those conditions should be discussed with the patient before registration in the 
study. 
10. Negative serum pregnancy test for women of childbearing potential (including pre-
menopausal women who have had a tubal ligation) and for all women not meeting 
the definition of postmenopausal ( 12 months of amenorrhea), and who have not 
undergone surgical sterilization with a hysterectomy and/or bilateral oophorectomy. 
For all other women, documentation must be present in medical history confirming 
that the patient is not of childbearing potential (see Section 5.4.3). 
11. For women of childbearing potential and men with partners of childbearing potential, 
agreement by the patient and/or partner to use a highly effective non-hormonal form 
of contraception such as surgical sterilization or two effective forms of non-
hormonal contraception until 7 months after the last dose of trastuzumab emtansine.  
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). 
Methods of birth control are considered highly effective forms of contraception in 
case they result in a low failure rate (i.e., < 1% per year) when used consistently 
and correctly. The use of the following non-hormonal methods of contraception is 
acceptable: 
a. True abstinence, when this is the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, and symptothermal post 


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ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
b. Male sterilization (with appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate). For female patients, the 
vasectomized male partner should be the sole partner. 
Alternatively, use of two of the following effective forms of contraception is 
acceptable: 
a. Placement of intrauterine device or intrauterine system. Consideration 
should be given to the type of device being used, as there are higher 
failure rates for certain types (e.g., steel or copper wire). 
b. Condom with spermicidal foam/gel/film/cream/suppository. 
c. Occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository. 
The use of barrier contraceptives should always be supplemented with the use of a 
spermicide. The following should be noted: Failure rates indicate that, when used 
alone, the diaphragm and condom are not highly effective forms of contraception. 
Therefore, the use of additional spermicides does confer additional theoretical 
contraceptive protection. However, spermicides alone are ineffective at preventing 
pregnancy when the whole ejaculate is spilled. Therefore, spermicides are not a 
barrier method of contraception and should not be used alone. 
12. Signed written informed consent approved by Ethics Committee (EC) and obtained 
prior to any study procedure. 
13. Life expectancy of at least 12 weeks. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. 
Patients with previous exposure to HER2-targeted therapies in any setting. 
2. 
Patients showing histologically confirmed focal HER2-expression, i.e., < 30% of 
positively stained tumor cells.  
3. 
Patients with brain metastasis as the sole site of metastatic disease and/or are 
symptomatic or require therapy to control symptoms. 
NB: Brain metastases are allowed provided they are asymptomatic and controlled 
by previous radiotherapy. 
4. 
Current uncontrolled hypertension (systolic > 150 mmHg and/or 
diastolic > 100 mmHg). 
5. 
Current unstable angina pectoris. 
6. 
History of symptomatic CHF of any New York Heart Association (NYHA) criteria or 
ventricular arrhythmia that requires treatment. 
7. 
History of myocardial infarction within the last 6 months. 
8. 
Peripheral neuropathy, Grade ≥ 3. 


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9. 
Current dyspnea at rest due to complications of advanced malignancy, or other 
diseases that require continuous oxygen therapy. 
10. Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers; 
or bone fractures). 
11. History of other malignancy within the last 5 years, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, stage I uterine 
cancer, or other cancers with a similar outcome as those previously mentioned. 
12. For female patients, current pregnancy and lactation. 
13. Concurrent, serious, uncontrolled infections or current known infection with human 
immunodeficiency virus (HIV), active hepatitis B and/or hepatitis C. 
14. Known prior severe hypersensitivity to trastuzumab and trastuzumab emtansine or 
the excipients of the investigational medicinal product (IMP). 
15. Clinically significant bleeding within 30 days before enrollment 
16. Major surgical procedure or significant traumatic injury within 28 days prior to 
randomization or anticipation of the need for major surgery during the course of 
study treatment 
17. Concurrent participation in any other therapeutic clinical trial. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
This is a single arm open label study. All patients will be treated with trastuzumab 
emtansine single agent.  
4.3 
STUDY TREATMENT  
The IMP for this study is trastuzumab emtansine (Kadcyla). 
 
Trastuzumab emtansine will be administered by intravenous (IV) infusion  
o Regimen A: trastuzumab emtansine 2.4 mg/kg, weekly or 
o Regimen B: trastuzumab emtansine 3.6 mg/kg every 3 weeks. 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Trastuzumab Emtansine 
Trastuzumab emtansine is provided as a single-use, lyophilized formulation in a 
colorless 20 mL Type I glass vial containing 160 mg of trastuzumab emtansine closed by 
means of a FluroTec coated stopper and an overseal with flip-off cap. Upon receipt of 
trastuzumab emtansine, vials should be refrigerated at 2–8°C (36–46°F) until use. Do 
not use the product beyond the expiration date provided by the manufacturer.  
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 


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to ensure that they are intact without exterior contamination. Discard any cracked vials 
and report vials with surface contamination to the clinical site manager for assessment. 
The lyophilized product should be reconstituted using sterile water for injection (SWFI). 
Using a new syringe, 8 mL SWFI should be added to the vial and the vial swirled gently 
until the product is completely dissolved. THE VIAL SHOULD NOT BE SHAKEN. The 
resulting product contains 20 mg/mL trastuzumab emtansine, 10 mM sodium succinate, 
pH 5.0, 60 mg/mL sucrose, and 0.02% (w/v) polysorbate 20. Each 20 mL vial contains 
enough trastuzumab emtansine to allow delivery of 160 mg trastuzumab emtansine. The 
reconstituted product contains no preservative and is intended for single use only. The 
reconstituted lyophilized vials should be used within one hour of reconstitution with SWFI. 
If not used within this time frame, the reconstituted vials can be stored for up to 24 hours 
in a refrigerator at 2°C-8°C. Vials stored beyond this time period should be discarded. 
The vial should be inspected to ensure the reconstituted product is a clear colorless 
solution, and is free of particulates before proceeding. Drug from any vial that appears 
abnormal upon inspection should not be administered to patients. Using a new syringe, 
the indicated volume of trastuzumab emtansine solution should be removed from the 
vial(s) and added to the IV bag containing at least 250 mL of 0.45% sodium chloride 
(preferred) or 0.9% sodium chloride injection and gently inverted to mix the solution. A 
0.2 or 0.22 micron non-protein adsorptive polyethersulfone in-line filter is recommended 
when using 0.45% sodium chloride and required when using 0.9% sodium chloride 
injection. The solution of trastuzumab emtansine should not be shaken. 
Once reconstituted, trastuzumab emtansine solution is diluted into polyvinylchloride 
(PVC), latex-free PVC-free, polyolefin, polypropylene or polyethylene bags containing 
0.45% or 0.9% NaCl. From a microbiological point of view, the diluted trastuzumab 
emtansine in infusion bags should be used immediately. If not used immediately, in-use 
storage times and conditions are the responsibility of the user and should not be longer 
than 24 hours at 2°C-8°C. For additional information, refer to the IB. 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Trastuzumab Emtansine 
Trastuzumab emtansine treatment only starts after a successfully completed screening 
period. There are two treatment regimens: 
 
Regimen A: trastuzumab emtansine 2.4 mg/kg weekly, IV or 
 
Regimen B: trastuzumab emtansine 3.6 mg/kg every 3 weeks, IV. 
The iDMC will recommend a trastuzumab emtansine regimen based on tolerability data 
available at the time of the regimen-selection analysis. 
If the timing of a protocol mandated procedure (e.g., infusion of study drug) coincides 
with a holiday and/or weekend that preclude the procedure, the procedure should be 


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performed on the nearest following date, with subsequent protocol-specified procedures 
rescheduled accordingly. 
Each treatment cycle is 21 days in length. 
Patients on a weekly regimen (Regimen A) will receive three weekly doses of study 
therapy every 21 days (on Days 1, 8, and 15 of a 21-day cycle).  
Patients on the every 3-week regimen will receive one dose of study therapy every 
21 days (on Day 1 of a 21-day cycle).  
If a patient is not dosed on a cycle day because of toxicity, the dose will be held on that 
cycle dosing day, and dosing will resume on the next appropriate cycle dosing day when 
the toxicity has resolved. For example, if the patient received study treatment at Cycle X, 
Day 1, but is not dosed on Day 8 because of toxicity and she or he can be dosed again 
on Day 15, then for that cycle the patient will have received dosing on Days 1 and 15, 
with Day 8 held because of such an event. Similarly, if a patient received dosing on Days 
1 and 8 but Day 15 was held because of toxicity and he or she is able to start dosing 
again the next week, then next week begins a new cycle (see Figure 6). Every effort 
should be made to keep to the 21-day cycle for weekly dosing. 


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Please refer to Figure 2 for a general overview of the study and Figure 3 for a more 
detailed description of decision points. 
Regimen A: Trastuzumab emtansine 2.4 mg/kg, weekly dosing in a 3-weekly cycle  
The regimen selection will be performed for each cohort individually after 6 patients have 
been enrolled under Regimen A and followed for at least 6 weeks. If – based on 
tolerability data – the dosing regimen of 2.4 mg/kg every week is considered unfavorable 
then future patients of the respective cohort will be switched to the Regimen B with 
3-weekly dosing of trastuzumab emtansine 3.6 mg/kg.  
The administered dose will depend on the patient’s weight on Day 1 (or up to 3 days 
before) of each trastuzumab emtansine cycle. The actual dose administered should be 
+/-10% of the dose calculated for the patient. Trastuzumab emtansine will be 
administered on Days 1, 8 and 15 of a 21 day cycle. 
If the timing of a protocol-mandated procedure such as administration of trastuzumab 
emtansine coincides with a holiday that precludes the procedure, the procedure should 
be performed on the earliest following date, with subsequent protocol-specified 
procedures rescheduled accordingly. The weekly schedule allows for -1/+3 days. The 
interval between trastuzumab emtansine weekly dosing is 7 days, and should not be 
< 6 days. 
Treatment continues until disease progression, unacceptable toxicity or request of the 
patient to withdraw of the study. Also in the event of an intercurrent illness – which would 
in the judgment of the investigator affect patient safety – treatment will be discontinued. 
The only available route of administration for trastuzumab emtansine is IV infusion. 
Trastuzumab emtansine infusion time may be decreased, depending on the patient’s 
tolerability of the infusion. For the first cycle, trastuzumab emtansine should be 
administered as a 90 (+/- 10) minutes IV infusion. Following the initial dose, patients will 
be observed for at least 90 minutes for fever, chills, or other infusion-associated 
symptoms. If the 90 minutes infusion is well tolerated, subsequent infusions may be 
delivered over 30 (+/- 10) minutes with a minimum 30 minute observation period after 
the infusion. The volume contained in the administration tubing should be completely 
flushed with saline after administration of trastuzumab emtansine. The line should not be 
used for any other drug administration, but it can be used to administer IV fluids. A filter 
should be used in conjunction with the infusion set when using 0.9% sodium chloride for 
dilution. 
Premedication for nausea and infusion reactions (e.g., acetaminophen or other 
analgesics, antihistamines or corticosteroids) may be given at the investigator’s 
discretion. 


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If infiltration of the trastuzumab emtansine infusion site occurs, the following steps 
should be taken: 
 
Discontinue the IV infusion. 
 
If a significant volume of the trastuzumab emtansine infusion remains, re-start the IV 
infusion elsewhere. 
 
Treat the infiltration according to institutional guidelines for infiltration of a non 
caustic agent. 
Patients will be carefully monitored during study drug infusion. 
Regimen B: Trastuzumab emtansine 3.6 mg/kg, 3-weekly cycle of dosing 
Trastuzumab emtansine will be given at a dose of 3.6 mg/kg every 3 weeks (21 days 
+/- 3 days) until disease progression, unacceptable toxicity or request of the patient to 
withdraw from the study. Also in the event of an intercurrent illness – which would in the 
judgment of the investigator affect patient safety – treatment will be discontinued.  
The total dose will depend on the patient’s weight on Day 1 (or up to 3 days before) of 
each trastuzumab emtansine cycle. The actual dose administered should be +/-10% of 
the dose calculated for the patient. 
The only available route of administration for trastuzumab emtansine is IV infusion. 
Trastuzumab emtansine infusion time may be decreased, depending on the patient’s 
tolerability of the infusion. For the first cycle, trastuzumab emtansine should be 
administered as a 90 (+/- 10) minutes IV infusion. Following the initial dose, patients will 
be observed for at least 90 minutes for fever, chills, or other infusion-associated 
symptoms. If the 90 minutes infusion is well tolerated, subsequent infusions may be 
delivered over 30 (+/- 10) minutes with a minimum 30 minute observation period after 
the infusion. The volume contained in the administration tubing should be completely 
flushed with saline after administration of trastuzumab emtansine. The line should not be 
used for any other drug administration, but it can be used to administer IV fluids. A filter 
should be used in conjunction with the infusion set when using 0.9% sodium chloride for 
dilution. 
Premedication for nausea and infusion related reactions (e.g., acetaminophen or other 
analgesics, antihistamines or corticosteroids) may be given at the investigator’s 
discretion. 
If infiltration of the trastuzumab emtansine infusion site occurs, the following steps 
should be taken: 
 
Discontinue the IV infusion. 
 
If a significant volume of the trastuzumab emtansine infusion remains, re-start the IV 
infusion elsewhere. 


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 
Treat the infiltration according to institutional guidelines for infiltration of a non-
caustic agent. 
Patients will be carefully monitored during study drug infusion. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF). AEs associated with an 
overdose or incorrect administration of study drug should be recorded on the 
Adverse Event eCRF.  
4.3.3 
Investigational Medicinal Product Accountability 
The IMP required for completion of this study (trastuzumab emtansine) will be provided 
by the Sponsor. The investigational site will acknowledge receipt of IMPs, using the 
interactive voice/web recognition system (IxRS) to confirm the shipment condition and 
content. Any damaged shipments will be replaced. 
The IMP either will be disposed of at the study site according to the study site’s 
institutional standard operating procedure or will be 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. 
4.3.4 
Post-Trial Access to Trastuzumab Emtansine 
Currently, the Sponsor does not have any plans to provide trastuzumab emtansine or 
any other study treatments or interventions to patients who have completed the study. 
The Sponsor may evaluate whether to continue providing trastuzumab emtansine in 
accordance with the Roche Global Policy on Continued Access to Investigational 
Medicinal Product, available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
The Sponsor will offer post-trial access to the study drug (trastuzumab emtansine) free 
of charge to eligible patients in accordance with the Roche Global Policy on Continued 
Access to IMP, 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  


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 
There are no appropriate alternative treatments available to the patient 
 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
A patient will not be eligible to receive study drug after completing the study if any of the 
following conditions are met: 
 
The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient) 
 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for locally advanced (unresectable and not treatable 
with curative intent) or metastatic UBC or pancreatic cancer/cholangiocarcinoma 
 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for locally advanced (unresectable and not treatable with curative intent) or 
metastatic UBC or pancreatic cancer/cholangiocarcinoma 
 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
The study will be concluded 18 months after the last patient has been enrolled in the last 
cohort. Patients who have not progressed at the end of the trial and who are still on 
treatment will be offered the possibility to continue treatment in an extension study. 
In case a patient decides to withdraw from the study, no post-trial access will be granted. 
Currently, the Sponsor does not have any plans to provide other study interventions to 
patients after conclusion of the study or any earlier patient withdrawal. 
4.4 
CONCOMITANT THERAPY 
All concomitant medications and premedication therapies are considered non-IMPs. 
Concomitant therapy (non-investigational products) includes any prescription medication, 
over-the-counter preparation, herbal therapy, or radiotherapy used by a patient between 
the 28 days preceding study enrollment and the study follow-up or study drug completion 
visit. All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF. 
4.4.1 
Permitted Therapy  
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use. 
Permitted concomitant therapy: 
 
Bisphosphonates and other bone supportive agents are allowed if the dose and 
renal function have been stable for at least 12 weeks before the enrollment and no 
related side effects of ≥ CTCAE Grade 2 are present for at least 4 weeks prior to 
study drug treatment. 


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 
Premedication is allowed according to standard practice guidelines. 
 
No pre-medication for the first infusion of trastuzumab emtansine with steroids is 
specified or expected; any planned pre-medication for the first infusion with steroids 
should be discussed with the oncologist prior to administration.  
 
Premedication for nausea and infusion related reactions (e.g., acetaminophen) may 
be given at the investigator’s discretion. Anti-emetics are allowed. 
 
Patients who experience nausea and trastuzumab emtansine infusion-related 
temperature elevations of 38.5°C or other minor infusion related symptoms may be 
treated symptomatically with acetaminophen or other analgesics, antihistamines or 
corticosteroids. Serious infusion-related events manifested by dyspnea, hypotension, 
wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory 
distress should be managed with supportive therapies clinically indicated according 
to standard clinical practice (e.g., supplemental oxygen, β2 agonists, and 
corticosteroids). 
 
Palliative radiotherapy is allowed to treat painful bone metastases. 
Brain stereotactic radiosurgery is allowed if metastatic brain lesions become 
symptomatic during trastuzumab emtansine treatment. (Of note, patients with brain 
metastases are allowed to enter the study provided they are asymptomatic and 
controlled at beginning of the study, see exclusion criteria in Section 4.1.2). Please 
contact the Medical Monitor for approval. 
4.4.2 
Prohibited Therapy 
Use of the following therapies is prohibited during the study treatment prior to 
documented disease progression and for at least 28 days prior to initiation of study 
treatment: 
 
Investigational therapy other than study drug. 
 
Cytotoxic chemotherapy. 
 
Biologic agents, e.g., trastuzumab. 
 
Any therapies intended for the treatment of the tumor type whether they are 
approved by national health authorities or experimental. 
 
Erythropoiesis stimulating agents. 
 
G-CSF. 
 
Strong CYP3A4 inhibitors including but not limited to ketoconazole, itraconazole, 
clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, voriconazole. 
 
Therapeutic agents that have a high risk of bleeding or might increase the risk of 
bleeding (e.g., clopidogrel, ASS, diclofenac), except therapeutic anticoagulation if 
absolutely needed by the patient. 
Other medications considered necessary for the patient’s safety and well-being may be 
given at the discretion of the investigator. 


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4.5 
STUDY ASSESSMENTS  
Please see Appendix 1 for the Schedule of Activities to be performed during the study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study related procedures unless the assessments were performed as 
standard of care prior to obtaining informed consent and within 2 weeks prior to study 
entry. Informed Consent Forms (ICFs) 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. 
Screening is to be completed within 28 days prior to baseline, however HER2 testing 
can be performed up to a maximum of 2 years prior to baseline (see Appendices 1.1 and 
1.2 for Regimen A and B, respectively). 
A separate ICF can be used for HER2 testing. The HER2 screening test (determined by 
the central laboratory) may be performed as soon as a potential patient is identified, 
provided the HER2 Screening Informed Consent is signed. 
4.5.2 
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; in addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal/homeopathic remedies, nutritional supplements) 
used by the patient within 28 days prior to the screening visit. 
Demographic data will include age, sex, and self-reported ethnicity. 
4.5.3 
Physical Examinations 
A complete physical examination should be performed at screening and 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. Height and weight should also 
be recorded in the eCRF. 
At subsequent visits (as shown in Appendix 1), a limited, symptom-directed physical 
examination should be performed. Changes from baseline abnormalities should be 


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recorded in patient notes. New or worsened abnormalities should be recorded as AEs on 
the Adverse Event eCRF. Weight should also be recorded in the eCRF. 
As part of tumor assessment, physical examinations should also include the evaluation 
of the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly. 
Any new or worsened abnormalities should be recorded as AEs on the Adverse Event 
eCRF. 
4.5.4 
Vital Signs 
Vital signs (including systolic and diastolic blood pressure, pulse rate, oxygen saturation, 
respiratory rate, temperature) should be collected at screening, pre-dose, every 15 (+/- 5) 
minutes during the first trastuzumab emtansine infusion, and 60 (+/- 10) minutes after 
the infusion. In subsequent cycles, vital signs should be recorded within 60 minutes pre- 
and post-infusion (see Appendix 1). Measurements should be taken with the patient in a 
supine position. 
Vital signs will be measured at every visit in the first 3 cycles and at Day 1 of all 
subsequent cycles. 
Abnormal or significant changes to vital signs from baseline should be recorded as AEs, 
if appropriate. 
4.5.5 
Tumor and Response Evaluations 
All known sites of disease (measurable and immeasurable) 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, CT or MRI scans, 
and bone scans using RECIST v1.1, see Appendix 2. 
Assessments will be done every 6 weeks from the start date of the study drug, 
regardless of dose delay or early discontinuation, until disease progression or study 
termination. Tumor assessments obtained within 30 days of Cycle 1, Day 1 may be used 
for screening purposes. Response must be assessed through physical examination and 
imaged-based evaluation, using RECIST 1.1. The same radiographic procedure used to 
define measurable disease sites at baseline must be used throughout the study. 
CT scans should include chest, abdomen, and pelvic scans; CT scans of the neck 
should be included if clinically indicated. At the investigator’s discretion, CT scans may 
be repeated at any time if PD is suspected. 
CT or MRI of the brain and baseline radioisotope bone scan must be obtained at 
screening. If an isotope-based scan was performed ≥ 28 days but ≤ 60 days prior to first 
treatment the bone scan does not need to be repeated and non-isotopic radiographic 
modalities should be utilized to document the extent of bony metastatic disease. Tumor 
assessments should include an evaluation of all known and/or suspected sites of 


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disease, whenever possible. Patients should have lesions selected that can be 
evaluated at every tumor assessment. The same radiographic procedure used at 
screening must be used throughout the study for the same patient (e.g., the same 
contrast protocol for CT scans). 
4.5.6 
LVEF Evaluation 
LVEF assessments will be performed, according to the Schedule of Activities (see 
Appendix 1), by either ECHO or MUGA scan. ECHO is the preferred method. 
ECHO/MUGA will be performed at screening and between Days 15 and 21 in Cycles 1 
and 3 at every third cycle thereafter (Cycles 6, 9 etc) and at the study drug completion 
visit. The same method used at screening should be used throughout the study. 
Patients will be reassessed with the same technique used for baseline cardiac 
evaluation throughout the study and, to the extent possible, will be obtained at the same 
institution for an individual patient. If treatment is delayed for any reason, LVEF 
assessments can be postponed to allow them to be performed within 7 days prior to the 
next treatment administration. 
For extensive follow-up instructions, see ‘cardiotoxicity’ in Section 5.1.1.3. 
4.5.7 
ECOG Performance Status 
Performance status will be measured using the ECOG performance status scale, 
according to the Schedule of Activities (see Appendix 1). 
It is recommended, where possible, that a patient’s performance status will be assessed 
by the same person throughout the study. 
4.5.8 
Laboratory, Biomarker, and Other Biological Samples 
4.5.8.1 
Samples for General Assessments 
Blood samples for hematology, biochemistry, coagulation, urinalysis, serology, and 
pregnancy testing will be collected as per the Schedule of Activities (see Appendix 1) 
and will be analyzed at the study site’s local laboratory: 
 
Hematology (hemoglobin, hematocrit, red blood cells [RBC], platelet count, white 
blood cells [WBC] with differential [including neutrophils, lymphocytes, monocytes, 
eosinophils and basophils]) 
 
Serum chemistry (glucose, blood urea nitrogen [BUN], creatinine, sodium, 
potassium, bicarbonate, phosphorus, chloride, calcium, uric acid, total protein, 
albumin, total bilirubin, direct bilirubin, alkaline phosphatase, lactate dehydrogenase 
[LDH], AST, ALT, gamma-glutamyl-transferase [GGT]) 
 
Coagulation (INR and aPTT)  


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 
Urinalysis (dipstick including pH, specific gravity, glucose, protein, ketones, blood, 
bilirubin and microscopic examination including sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, bacteria) 
 
Viral serology, performed at screening only (HIV, hepatitis B surface antigen 
[HBsAg], total hepatitis B core antibody [HBcAb], and hepatitis C virus [HCV] 
antibody) 
 
Pregnancy test: All women of childbearing potential will have a serum pregnancy 
test within 7 days prior to the first administration of study drug (Day 1, Cycle 1). 
Urine pregnancy tests will be performed at specified subsequent visits. If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
During the study, blood samples will be taken before each trastuzumab emtansine 
administration to secure adequate organ function and safety (see Appendix 1, Schedule 
of Activities). 
4.5.8.2 
Blood Samples for Pharmacokinetic Assessments 
Samples for evaluation of trastuzumab emtansine, DM1, and total trastuzumab will be 
collected as shown in Figure 4 (Regimen A) and Figure 5 (Regimen B).  
Limited PK assessments will be made:  
 
Regimen A: with 6 sampling timepoints in Cycle 1 (Day 1, Day 8, and Day 15, each 
predose and 15-30 minutes postdose), 1 sampling timepoint in Cycle 2 (Day 1, 
predose), and 2 sampling timepoints in Cycle 4 (Day 1, predose and 15-30 minutes 
postdose). 
 
Regimen B: with 2 sampling timepoints in Cycle 1 (Day 1 predose and 
15-30 minutes postdose), 1 sampling timepoint in Cycle 2 (Day 1, predose), and two 
sampling timepoints in Cycle 4 (Day 1, predose and 15-30 minutes postdose). 
 
4.5.8.3 
Blood Samples for HER2 ECD Assessments 
HER2 ECD serum samples will be obtained predose at baseline (Cycle 1, Day 1), at 
Cycle 2, Day 1 and at Cycle 4, Day 1; see Appendix 1. 
4.5.8.4 
Blood Samples for Evaluation of Antitherapeutic Antibodies 
Serum samples for assessing trastuzumab emtansine ATAs will be collected for all 
patients dosed with trastuzumab emtansine. Samples for ATA assessment will be 
collected before dosing in Cycles 1 and 4, at the study drug completion visit, and 
3 months after the last trastuzumab emtansine dose (see Figure 4 and Figure 5). ATA 
samples will be aliquoted into 2 tubes: one to measure ATA levels, and one to measure 
trastuzumab emtansine concentrations if necessary in the case of interference in the 
ATA assay. 


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4.5.8.5 
Samples for Research Purposes 
A tumor tissue sample will be submitted at screening (see Appendix 1). Tissue samples 
for HER2 testing will be sent to a central laboratory (Targos, Kassel, Germany). In 
addition, an optional tissue biopsy is taken at discontinuation of trastuzumab emtansine, 
either due to PD, unacceptable toxicity of systemic treatment or any other reason. DNA 
and RNA will be extracted for exploratory research from these samples, protein 
expression may be assessed as well. 
4.5.8.6 
Translational Research Program 
Biomarkers that may be associated with response and/or safety will retrospectively be 
evaluated on the protein, RNA and DNA level. Pathological scoring of HER2 and 
heterogeneity of the HER2 expression in the tumor will be evaluated. 
Isolation of RNA and DNA will be performed in the central study laboratory. Gene 
expression analysis of tumors from all patients included in this study will be performed. 
In addition, tumor DNA mutation analysis may be performed using the most up to date 
technology. Depending on the technology used, the 6 mL blood sample collected at 
baseline may then be genotyped simultaneously as intrapatient reference of inherited 
genes. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.10) biological samples will be destroyed 
no later than 5 years after the date of final closure of the clinical database. 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples. 
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
4.5.9 
Electrocardiograms 
A 12-lead electrocardiogram (ECG) recording will be obtained at screening and as 
clinically indicated during the study, as outlined in the Schedule of Activities (see 
Appendix 1).  
ECG recordings must be performed using a standard high quality, high fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements. 
ECGs for each patient should be obtained from the same machine whenever possible. 
Lead placement should be as consistent as possible. ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes. 
ECGs are to be obtained prior to other procedures scheduled at that same time (e.g., 


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vital sign measurements, blood draws) and should not be obtained within 3 hours after 
any meal. Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre ECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings. Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site. 
4.5.10 
Samples for Research Biosample Repository 
4.5.10.1 
Overview of the Research Biosample Repository 
The RBR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides). The collection, storage, and analysis of RBR 
specimens will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future. 
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research. RBR specimens will be used to achieve the 
following objectives: 
 
To study the association of biomarkers with efficacy, AEs, or disease progression 
 
To increase knowledge and understanding of disease biology 
 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.10.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the ICF by each 
site's Institutional Review Board (IRB) or EC and, if applicable, an appropriate regulatory 
body. If a site has not been granted approval for RBR sampling, this section of the 
protocol (Section 4.5.10) will not be applicable at that site. 
4.5.10.3 
Sample Collection 
Patients who have been enrolled in the study will be asked to consent to the optional 
RBR program to allow residuals of the collected tissue, blood and plasma samples as 
described above in Section 3.1 to be stored for 15 years and also to be used for further, 
exploratory biomarker research. 


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For all samples, dates of consent should be recorded on the associated RBR page of 
the eCRF.  
RBR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database. The RBR storage period will be in accordance with the 
IRB/EC approved ICF and applicable laws (e.g., health authority requirements). 
The above samples may be sent to one or more laboratories for DNA extraction to 
enable analysis of germline mutations, somatic mutations via whole genome sequencing 
(WGS), next-generation sequencing based analyses (NGS), or other genomic analysis 
methods.  
Genomics is increasingly informing researcher's understanding of disease pathobiology. 
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches. Data will be analyzed in the context of this study but will also be explored in 
aggregate with data from other studies. The availability of a larger dataset will assist in 
identification of important pathways, guiding the development of new targeted agents. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted. However, the RBR storage period will be in accordance with the 
IRB/EC-approved ICF and applicable laws (e.g., health authority requirements). 
4.5.10.4 
Confidentiality 
Specimens and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the ICF (or separate authorization for use 
and disclosure of personal health information) signed by the patient, unless permitted or 
required by law. 
Given the complexity and exploratory nature of the analyses, data derived from RBR 
specimens will generally not be provided to study investigators or patients unless 
required by law. The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication. 
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 


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Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.10.5 
Consent to Participate in the Research Biosample Repository 
The ICF will contain a separate section that addresses participation in the RBR. The 
investigator or authorized designee will explain to each patient the objectives, methods, 
and potential hazards of participation in the RBR. Patients will be told that they are free 
to refuse to participate and may withdraw their specimens at any time and for any 
reason during the storage period. A separate, specific signature will be required to 
document a patient's agreement to provide optional RBR specimens. Patients who 
decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research. 
4.5.10.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR specimens have the right to withdraw their 
specimens from the RBR at any time for any reason. If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and, if the trial is ongoing, must enter the date of withdrawal on the 
RBR Research Sample Withdrawal of Informed Consent eCRF. The patient will be 
provided with instructions on how to withdraw consent after the trial is closed. A patient's 
withdrawal from Study MO29694 does not, by itself, constitute withdrawal of specimens 
from the RBR. Likewise, a patient's withdrawal from the RBR does not constitute 
withdrawal from Study MO29694. 
4.5.10.7 
Monitoring and Oversight 
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the ICF. 
Sponsor monitors and auditors will have direct access to appropriate parts of records 
relating to patient participation in the RBR for the purposes of verifying the data provided 
to the Sponsor. The site will permit monitoring, audits, IRB/EC review, and health 
authority inspections by providing direct access to source data and documents related to 
the RBR samples. 


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4.5.11 
Follow-Up Assessments 
After the safety follow-up visit, AEs should be followed as outlined in Sections 5.5 and 
5.6. 
After completion of treatment, patients will be followed up for survival in a 3 monthly 
schedule (± 7 working days) until 18 months after LPI. Patients who discontinue study 
treatment for reasons other than disease progression will continue to undergo tumor 
assessments every 6 weeks until disease progression, withdrawal of consent, loss to 
follow-up, death or study termination. If assessments cannot be done at survival visits, 
the study site is permitted to collect survival information by phone call. After disease 
progression, patients will be followed up for survival every 3 months (± 7 working days) 
until study closure (at 18 months after LPI) after completion of treatment or until death, 
loss to follow-up, withdrawal of consent or study discontinuation by the Sponsor 
(whichever occurs first).  
Assessments are no longer required to evaluate new lesions, non-target lesions, and 
target lesions. However a visit to collect survival information is still required. If a visit 
cannot be done, the study site is permitted to collect survival information by phone call. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
Patients must return for a follow-up visit within 30 days after the last dose of study drug; 
however, the visit at which a tumor assessment shows disease progression may be 
used as the early termination visit if it is within 30 days of the last administration of study 
drug. Every effort should be made to have patients return for this visit. 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason. 
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for withdrawal from the study may include, but are not limited to, the following: 
 
Patient withdrawal of consent at any time 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
 
Investigator or Sponsor determines it is in the best interest of the patient 
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. In case of premature withdrawal of non-evaluable patients, these 
patients will not be replaced. Follow-up of withdrawn subjects will be done by the 
referring physician/oncologist. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 


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 
Pregnancy 
 
Disease progression 
 
Toxicities requiring permanent discontinuation as outlined in Section 5.1.2 
 
Sponsor’s decision to stop study 
 
Commencement of another anticancer therapy before documented disease 
progression 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. Patients who discontinue study treatment prematurely will not be 
replaced. 
Patients who discontinue study treatment for any of the above reasons will continue to 
be followed for their survival status for 12 months after discontinuation of study treatment 
according to protocol or until one of the following outcomes occurs: 
 
Death 
 
Loss to follow-up 
 
Withdrawal from the study 
 
Study termination by the Sponsor 
Patients who discontinue trastuzumab emtansine for reasons other than disease 
progression (e.g., toxicity) will continue scheduled tumor assessments every 6 weeks 
(± 7 days) for 12 months after discontinuation or until disease progression, withdrawal of 
consent, loss to follow-up, death, or study termination. 
4.6.3 
Study and Site Discontinuation 
In case the study does not recruit at least 4 patients in the first year the Sponsor might 
decide to either amend the protocol for inclusion/exclusion, open more sites or stop the 
study. 
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 


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 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
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 of trastuzumab emtansine are outlined below. 
Please refer to the trastuzumab emtansine IB 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 (see 
Section 4.1). In addition, patients will undergo safety monitoring during the study 
including assessment of the nature, frequency, and severity of AEs (see Section 4.5). 
The first 6 patients of a cohort (i.e. during the safety run-in) will be assessed on an 
ongoing and patient per patient basis – i.e. based on the tolerability criteria (as defined in 
the iDMC charter) and in consultation with the SC and iDMC if needed.  
Finally, guidelines for managing AEs, including criteria for dosage modification and 
treatment interruption or discontinuation, have been provided (see Section 5.1.2). 
5.1.1 
Risks Associated with Trastuzumab Emtansine 
5.1.1.1 
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 4.1.2).  
Guidelines for management of patients who develop ILD or pneumonitis are provided in 
Table 3.  
5.1.1.2 
Hepatotoxicity 
The following events have been reported with administration of trastuzumab emtansine: 
 
Severe hepatotoxicity 


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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 may have been 
confounded by concomitant medications with known hepatotoxic potential. 
 
Increased serum transaminases 
Increases in serum AST and ALT have been observed in all trastuzumab emtansine 
studies. Grade 1 and 2 events have been observed frequently; Grade 3 and 4 
events have been observed less commonly. Increases in AST and ALT were 
commonly observed by Day 8 of each cycle and generally recovered to ≤ 2.5 x ULN 
by Day 21. A cumulative effect of trastuzumab emtansine, that is, an increase in the 
proportion of patients with Grade 1 or 2 elevations in transaminases with successive 
cycles has been observed. 
 
NRH 
Cases of NRH have been identified from liver biopsies in patients treated with 
trastuzumab emtansine who presented with signs and symptoms of portal 
hypertension. NRH is a rare liver condition characterized by widespread benign 
transformation of hepatic parenchyma into small regenerative nodules. NRH may 
lead to non-cirrhotic portal hypertension. Diagnosis of NRH can only be confirmed 
by histopathology. Biopsy-confirmed NRH leading to fatal hepatic failure has been 
reported. 
NRH should be considered in all patients with clinical symptoms of portal hypertension, 
even with normal transaminases, and no other manifestations of cirrhosis; in patients 
with a cirrhosis-like pattern seen on a CT scan of the liver; and/or in patients with liver 
failure following long-term treatment with trastuzumab emtansine.  
Patients must meet specified hepatic laboratory test requirements to be included in this 
study (see Section 4.1).  
Hepatic laboratory parameters will be monitored as described in Section 4.5 and the 
Schedule of Activities (see Appendix 1). 
Guidelines for management of trastuzumab emtansine in patients who develop 
increased serum transaminases, increased serum bilirubin, or NRH are provided in 
Table 3.  
5.1.1.3 
Left Ventricular Dysfunction 
Patients treated with trastuzumab emtansine are at risk of developing left ventricular 
dysfunction. To date, significant cardiac events, including LVEF of   40%, have been 
observed infrequently in clinical trials of trastuzumab emtansine. 


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Patients must meet specified LVEF requirements to be included in this study (see 
Section 4.1).  
Left ventricular function will be monitored by measurement of ejection fraction using 
ECHO or MUGA scans as described in Section 4.5 and the Schedule of Activities (see 
Appendix 1). 
Guidelines for management of patients who develop left ventricular dysfunction are 
provided in Table 3.  
5.1.1.4 
Infusion-Related Reactions and Hypersensitivity Reactions 
Infusion-related reactions (IRRs) and hypersensitivity reactions have been reported with 
administration of trastuzumab emtansine. Despite the different pathophysiology of IRRs 
(reactions involving cytokine release) and hypersensitivity (allergic) reactions, the clinical 
manifestations are the same. In general, IRRs are expected to be more frequent and 
severe with the first infusion and to decrease in number and severity over time. The 
severity of true hypersensitivity reactions would be expected to increase with 
subsequent infusions. 
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. 
Hypersensitivity reactions, including serious anaphylactic-like reactions, have been 
observed in clinical trials of trastuzumab emtansine. 
Patients with a history of intolerance to trastuzumab or trastuzumab emtansine will be 
excluded from this study (see Section 4.1).  
Administration of trastuzumab emtansine will be performed in a setting with access to 
emergency facilities and staff who are trained to monitor and respond to medical 
emergencies. Patients should be closely monitored for infusion-related reactions during 
and after each infusion of trastuzumab emtansine, as described in Section 4.3.2.1.  
Guidelines for management of patients who experience IRRs or hypersensitivity 
reactions are provided in Table 3.  
5.1.1.5 
Hematologic Toxicity 
Thrombocytopenia has been reported in patients in clinical trials of trastuzumab 
emtansine. The majority of these patients had Grade 1 or 2 events (platelet count 
 50,000/µL), with the nadir occurring by Day 8 and generally improving to Grade 0 or 1 
(platelet count  75,000/µL) by the next scheduled dose (i.e., within 3 weeks). In clinical 
trials, the incidence and severity of thrombocytopenia were higher in Asian patients.  


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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 of trastuzumab emtansine; these events were independent of ethnicity. In 
some of the observed cases, the patients were also receiving anti-coagulation therapy. 
In addition, severe hemorrhagic events have been reported in the absence of 
thrombocytopenia.  
Declines in other hematopoietic lineages, for example, leukopenia, neutropenia, and 
anemia, were less frequent than that observed for platelets. 
Patients must meet specified hematologic laboratory test requirements to be included in 
this study (see Section 4.1).  
Hematologic laboratory parameters will be monitored as described in Section 4.5 and 
the Schedule of Activities (see Appendix 1). Patients on anticoagulant or antiplatelet 
treatment should be monitored closely.  
Guidelines for management of trastuzumab emtansine in patients who develop 
hematologic toxicity are provided in Table 3. 
5.1.1.6 
Neurotoxicity 
Peripheral neuropathy, mainly Grade 1 and predominantly sensory, has been reported in 
clinical trials of trastuzumab emtansine.  
Patients with Grade  3 peripheral neuropathy must be excluded]} peripheral neuropathy 
will be excluded from this study (see Section 4.1). 
Patients will be clinically monitored on an ongoing basis for signs or symptoms of 
peripheral neuropathy as described in Section 4.5 and the Schedule of Activities (see 
Appendix 1). 
Guidelines for management of trastuzumab emtansine in patients who develop 
peripheral neuropathy are provided in Table 3. 
5.1.1.7 
Extravasation 
In trastuzumab emtansine clinical studies, reactions secondary to extravasation have 
been observed. These reactions were usually mild and consisted of erythema, 
tenderness, skin irritation, pain, or swelling at the infusion site. These reactions have 
been observed more frequently within 24 hours of infusion. Rare reports of more severe 
events, such as cellulitis, pain (tenderness and burning sensation), and skin irritation, 
have been received.  
The infusion site will be closely monitored for possible subcutaneous infiltration during 
drug administration, as described in Section 4.3.2.1. Specific treatment for trastuzumab 


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emtansine extravasation is unknown at this time. Patients should be managed 
symptomatically per local institutional guidelines. 
5.1.2 
Management of Patients Who Experience Specific Adverse 
Events 
Guidelines for trastuzumab emtansine dose reductions are provided in Table 2. 
Table 2 
Guidelines for Trastuzumab Emtansine Dose Reductions 
 
Regimen A 
Regimen B 
Dose Level 
Dose 
0 (starting dose) 
2.4 mg/kg 
3.6 mg/kg 
1 (first reduction) 
2 mg/kg 
3.0 mg/kg 
2 (second reduction) 
1.6 mg/kg 
2.4 mg/kg 
Note: The dose of trastuzumab emtansine, once reduced, may not be re-escalated. A maximum 
of two dose reductions is allowed; patients with any further requirement for dose reduction will 
discontinue treatment with trastuzumab emtansine. 
 
Guidelines for management of patients who experience specific AEs are provided in 
Table 3. Guidelines for managing trastuzumab emtansine-related toxicities other than 
the ones specified in Table 3 are as follows: 
 
If significant trastuzumab emtansine-related toxicities have not recovered to Grade 1 
or baseline, the study drug may be delayed for 42 days from the last dose for the 
every 3 weeks regimen and 28 days from the last dose for the weekly regimen to 
assess or treat AEs. “Significant” and “related” will be based on the judgment of the 
investigator (in consultation with the Medical Monitor or designee when appropriate). 
For example, alopecia, even if considered related to trastuzumab emtansine, would 
most likely not be considered significant. Fatigue may or may not be considered 
either related or significant. Patients should be re-evaluated weekly during the delay, 
whenever possible. 
 
In general, when a toxicity resolves to Grade 1 or baseline, the patient may resume 
trastuzumab emtansine if the delay has not exceeded 42 days (Regimen B) or 
28 days (Regimen A) after the date of the last dose received. If dosing resumes, the 
patient may receive trastuzumab emtansine either at the same dose level as before 
or at one dose level lower (see Table 2Table 2), at the discretion of the investigator. 
The dose of trastuzumab emtansine, once reduced, may not be re escalated. If 
possible, subsequent cycles should continue at 21 day intervals. 
 
Trastuzumab emtansine must be discontinued for patients who experience an AE 
requiring a dose delay of > 28 days (Regimen A) or > 42 days (Regimen B) after the 
last dose received and for patients who experience an AE requiring dose reduction 
while being treated at the 2.4 mg/kg dose.  
 


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Table 3 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events 
Event 
Action to Be Taken 
Pulmonary toxicity 
 
ILD  
Discontinue trastuzumab emtansine.  
Pneumonitis 
Discontinue trastuzumab emtansine. 
Hepatotoxicity 
 
ALT or AST increase that meets Hy's 
law criteria: ALT or AST   3  ULN in 
combination with TBILI   2  ULN or 
clinical jaundice 
Discontinue trastuzumab emtansine. 
ALT or AST increase that does not 
meet Hy's law criteria: 
 
> 1  ULN to   5  ULN 
Continue trastuzumab emtansine at the same dose level. 
 5  ULN to   20  ULN 
Withhold trastuzumab emtansine until recovery 
to   5  ULN. Following recovery, resume trastuzumab 
emtansine with one dose level reduction. Discontinue 
trastuzumab emtansine if the event has not resolved 
to   5  ULN within 42 days after the last dose received. 
 20  ULN 
Discontinue trastuzumab emtansine. Laboratory tests 
may be repeated (within 24 hours) to exclude laboratory 
error prior to discontinuing trastuzumab emtansine. 
TBILI increase that does not meet Hy's 
law criteria 
 
 1.5  ULN to   3  ULN 
Withhold trastuzumab emtansine until recovery 
to   1.5  ULN. Following recovery, resume trastuzumab 
emtansine at the same dose level. Discontinue 
trastuzumab emtansine if the event has not resolved 
to   1.5  ULN within 42 days after the last dose received.  
 3  ULN to   10  ULN 
Withhold trastuzumab emtansine until recovery 
to   1.5  ULN. Following recovery, resume trastuzumab 
emtansine with one dose level reduction. Discontinue 
trastuzumab emtansine if the event has not resolved 
to   1.5  ULN within 42 days after the last dose received. 
 10  ULN 
Discontinue trastuzumab emtansine. 
NRH 
Discontinue trastuzumab emtansine. 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ILD = interstitial lung disease; 
LVEF  left ventricular ejection fraction; NRH = nodular regenerative hyperplasia; TBILI  total bilirubin; 
ULN  upper limit of normal. 
 
 


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Table 3 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.) 
Event 
Action to Be Taken 
Left ventricular dysfunction 
 
Symptomatic CHF 
Discontinue trastuzumab emtansine. 
Asymptomatic LVEF decrease 
 
LVEF   45% 
Continue trastuzumab emtansine at the same dose level. 
LVEF 40% to   45% and 
decrease from baseline 
of   10% points 
Withhold trastuzumab emtansine. Repeat LVEF 
assessment within 3 weeks. If LVEF decrease from 
baseline of   10% points is confirmed, discontinue 
trastuzumab emtansine. 
LVEF 40% to   45% and 
decrease from baseline 
of   10% points 
Continue trastuzumab emtansine at the same dose level. 
Repeat LVEF assessment within 3 weeks. 
LVEF   40% 
Withhold trastuzumab emtansine. Repeat LVEF 
assessment within 3 weeks. If LVEF  40% is confirmed, 
discontinue trastuzumab emtansine. 
Infusion-related reaction (caused by cytokine release) or hypersensitivity (allergic) reaction 
Grade 2 reaction  
Decrease trastuzumab emtansine infusion rate or interrupt 
infusion. Administer supportive care with oxygen, -
agonists, antihistamines, antipyretics, or corticosteroids, 
as appropriate, at the investigator’s discretion. Monitor 
patient until complete resolution of symptoms.  
May continue trastuzumab emtansine at the same dose 
level at the investigator’s discretion. In the event of a true 
hypersensitivity reaction (in which severity of reaction 
increases with subsequent infusions), discontinue 
trastuzumab emtansine.  
Premedication for infusion reactions (e.g., antihistamines 
such as diphenhydramine or corticosteroids) may be given 
at the investigator’s discretion. 
Grade 3 reaction  
Stop trastuzumab emtansine infusion. Administer 
supportive care with oxygen, -agonists, antihistamines, 
antipyretics, or corticosteroids, as appropriate, at the 
investigator’s discretion. Monitor patient until complete 
resolution of symptoms.  
May continue trastuzumab emtansine at the same dose 
level at the investigator’s discretion. In the event of a true 
hypersensitivity reaction (in which severity of reaction 
increases with subsequent infusions), discontinue 
trastuzumab emtansine.  
Premedication for infusion reactions (e.g., antihistamines 
such as diphenhydramine or corticosteroids) may be 
given at the investigator’s discretion. 
CHF = congestive heart failure; LVEF  left ventricular ejection fraction; TBILI  total bilirubin; ULN  upper limit 
of normal. 
 


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Table 3 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.) 
Event 
Action to Be Taken 
Infusion-related reaction (caused by cytokine release) or hypersensitivity (allergic) reaction 
(cont.) 
Grade 4 reaction  
Stop trastuzumab emtansine infusion. Administer supportive 
care with oxygen, -agonists, antihistamines, antipyretics, 
or corticosteroids, as appropriate, at the investigator’s 
discretion. Monitor patient until complete resolution of 
symptoms. Discontinue trastuzumab emtansine. 
Hematologic toxicity 
 
Grade 3 thrombocytopenia 
(25,000 to   50,000/L) 
Withhold trastuzumab emtansine until recovery to Grade   1 
(75,000/L). Following recovery, resume trastuzumab 
emtansine at the same dose level. Discontinue trastuzumab 
emtansine if the event has not resolved to Grade   1 within 
42 days after the last dose received. 
Grade 4 thrombocytopenia 
( 25,000/L) at any time 
Withhold trastuzumab emtansine until recovery to Grade   1 
( 75,000/L). Following recovery, resume trastuzumab 
emtansine with one dose level reduction. Discontinue 
trastuzumab emtansine if the event has not resolved to 
Grade   1 within 42 days after the last dose received. 
For all patients on anticoagulation 
therapy:  
Withhold study drug until platelet count is Grade  1 
(>75,000/mm3) – irrespective of the grade of 
thrombocytopenia 
Grade  3 hematologic toxicity 
other than thrombocytopenia 
Withhold trastuzumab emtansine until recovery to Grade   2. 
Following recovery, resume trastuzumab emtansine at the 
same dose level. Discontinue trastuzumab emtansine if the 
event has not resolved to Grade   2 within 42 days after the 
last dose received. 
Grade 2 Neutropenia:  
Withhold study drug until neutrophil count ≥ 1500 cells/mm3 
(Grade ≤ 1). No dose reduction is required. 
Grade 3 Neutropenia:  
Withhold study drug until neutrophil count ≥ 1500 cells/mm3 
(Grade ≤ 1). No dose reduction required. 
Grade 4 Neutropenia:  
Withhold study drug until neutrophil count ≥ 1500 cells/mm3 
(Grade ≤ 1). If the duration of Grade 4 neutropenia is 
>7 days, then either reduce one dose level for subsequent 
doses. No dose modification is required for a Grade 4 
neutropenia lasting 7 or fewer days. 
Patients who experience any of these toxicities should be reassessed at least weekly for recovery. 
Neurotoxicity 
 
Grade   3 peripheral neuropathy 
Withhold trastuzumab emtansine until recovery to Grade   2. 
Following recovery, resume trastuzumab emtansine at the 
same dose level or with one dose level reduction, at the 
investigator's discretion. Discontinue trastuzumab emtansine 
if the event has not resolved to Grade   2 within 42 days after 
the last dose received. 
LVEF  left ventricular ejection fraction; TBILI  total bilirubin; ULN  upper limit of normal. 


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5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, including SAEs and 
AEs of special interest, performing protocol-specified safety laboratory 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 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an AE is any untoward 
medical occurrence in a clinical investigation subject administered a pharmaceutical 
product, regardless of causal attribution. An AE can therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
 
AEs that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., screening invasive procedures such as 
biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
An SAE is any AE that meets any of the following criteria: 
 
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 5.3.5.11) 
 
Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
 
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]; see Section 5.3.3); the 
event itself may be of relatively minor medical significance (such as severe headache 
without any further findings). 
Severity and seriousness need to be independently assessed for each AE recorded on 
the eCRF. 
SAEs are required to be reported by the investigator to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2 for reporting 
instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
AEs of special interest are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). AEs of special interest for this study include the following: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.7) 
 
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. 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all AEs (see Section 5.2.1 for definition) 
are recorded on the Adverse Event eCRF and reported to the Sponsor in accordance 
with instructions provided in this section and in Sections 5.45.6. 
For each AE recorded on the Adverse Event eCRF, the investigator will make an 
assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  


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5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on AEs at each patient contact. All AEs, whether 
reported by the patient or noted by study personnel, will be recorded in the patient’s 
medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
SAEs caused by a protocol-mandated intervention (e.g., invasive procedures such as 
biopsies, discontinuation of medications) should be reported (see Section 5.4.2 for 
instructions for reporting SAEs). 
After initiation of study drug, all AEs will be reported until 28 days after the last dose 
of study drug.  
Instructions for reporting AEs that occur after the AE reporting period are provided in 
Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all patient evaluation timepoints. Examples of non-directive questions 
include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The AE severity grading scale for the NCI CTCAE (v4.03) will be used for assessing AE 
severity. Table 4 will be used for assessing severity for AEs that are not specifically 
listed in the NCI CTCAE. 


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Table 4 
Adverse Event Severity Grading Scale 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 (v4.03), 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 an SAE (see 
Section 5.4.2 for reporting instructions), per the definition of SAE in Section 5.2.2. 
d Grade 4 and 5 events must be reported as SAEs (see Section 5.4.2 for reporting 
instructions), per the definition of SAE in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether 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, with special consideration of 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 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 


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5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording AEs on 
the Adverse Event eCRF. Avoid colloquialisms and abbreviations. 
Only one AE term should be recorded in the event field on the Adverse Event eCRF. 
5.3.5.1 
Infusion-Related Reactions 
AEs 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. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
For AEs other than infusion-related reactions (see Section 5.3.5.1), a diagnosis (if known) 
should be recorded on the Adverse Event eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases). However, if a constellation of signs and/or symptoms cannot 
be medically characterized as a single diagnosis or syndrome at the time of reporting, 
each individual event should be recorded on the Adverse Event eCRF. If a diagnosis is 
subsequently established, all previously reported AEs based on signs and symptoms 
should be nullified and replaced by one AE report based on the single diagnosis, with a 
starting date that corresponds to the starting date of the first symptom of the eventual 
diagnosis. 
5.3.5.3 
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. 
 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 


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 
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. 
5.3.5.4 
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. Details regarding any 
increases or decreases in severity will be captured on the Adverse Event Intensity or 
Grade Changes eCRF. If the event becomes serious, it should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning that the event became 
serious; see Section 5.4.2 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 SAE. 
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. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE. 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 whether 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 5.3.5.4 for 
details on recording persistent AEs). 
5.3.5.6 
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 5.3.5.4 for 
details on recording persistent AEs). 
5.3.5.7 
Hepatic Events 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  ULN) 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  ULN in combination with total bilirubin 
 2  ULN 


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 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as an SAE or an AE of special interest (see Section 5.4.2). 
Nodular Regenerative Hyperplasia 
NRH, whether or not accompanied by abnormal liver function tests, should be reported 
to the Sponsor as a SAE. 
5.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint. Deaths that occur during the protocol-
specified AE reporting period (see Section 5.3.1) that are attributed by the investigator 
solely to progression of locally advanced (unresectable and not treatable with curative 
intent) or metastatic UBC or pancreatic cancer/cholangiocarcinoma should be recorded 
on the Death Attributed to Progressive Disease eCRF. All other on-study deaths, 
regardless of relationship to study drug, must be recorded on the Adverse Event eCRF 
and immediately reported to the Sponsor (see Section 5.4.2). An independent monitoring 
committee will monitor the frequency of deaths from all causes. 
Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only one such event should be reported. 
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the 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. The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the AE reporting period should be reported as described in 
Section 5.6. 
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such 
events on the Adverse Event eCRF, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., "more 
frequent headaches"). 


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5.3.5.10 
Lack of Efficacy or Worsening of Urothelial Bladder 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 v1.1. 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. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any AE that results in hospitalization (i.e., inpatient admission to a hospital) or prolonged 
hospitalization should be documented and reported as an SAE (per the definition of SAE 
in Section 5.2.2), except as outlined below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
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 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a SAE, but should be reported as an AE instead: 
 
Hospitalization for an AE that would ordinarily have been treated in an outpatient 
setting 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.12 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied. An overdose or incorrect administration of study treatment is not 
itself an 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 
associated AE fulfills seriousness criteria, the event should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 


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AEs associated with an overdose of trastuzumab emtansine in previous clinical studies 
include thrombocytopenia and increased ALT. There was one case of overdose in which 
the patient died. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event. The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
 
SAEs (see Section 5.4.2 for further details) 
 
AEs of special interest (see Section 5.4.2 for further details) 
 
Pregnancies (see Section 5.4.3 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. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information  
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 
Responsible (listed on the Roche Medical Emergency List), 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 and Medical 
Responsible contact information, will be distributed to all investigators. 


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5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention should be reported. The Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, SAEs and AEs of special interest will be reported until 
28 days after the last dose of study drug. Investigators should record all case details that 
can be gathered immediately (i.e., within 24 hours after learning of the event) on the 
Adverse Event eCRF and submit the report via the electronic data capture (EDC) system. 
A report will be generated and sent to Roche Safety Risk Management by the EDC 
system. 
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators. Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.  
Instructions for reporting SAEs that occur  28 days after the last dose of study treatment 
are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 7 months after the last 
dose of study drug. A Clinical Trial Pregnancy Reporting Form 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. Pregnancy should not be 
recorded on the Adverse Event eCRF. The investigator should counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus. Monitoring of 
the patient should continue until conclusion of the pregnancy. Additional information on 
any trastuzumab emtansine-exposed pregnancy and infant will be requested by Roche 
Drug Safety at specific time points (i.e., after having received the initial report, at the end 
of the second trimester, 2 weeks after the expected date of delivery, and at 3, 6, and 
12 months of the infant’s life). 


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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 addition, the investigator will submit 
a Clinical Trial Pregnancy Reporting Form when updated information on the course and 
outcome of the pregnancy becomes available.  
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the ICF to immediately inform the investigator if 
their partner becomes pregnant during the study or within 7 months after the last dose of 
study drug. A Clinical Trial Pregnancy Reporting Form 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. 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. After the authorization has been signed, the investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available. 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. 
5.4.3.3 
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 reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).  
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient 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 reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow 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. 


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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. 
5.5.2 
Sponsor Follow-Up 
For SAEs, AEs of special interest, and pregnancies, the Sponsor or a designee may 
follow up by telephone, fax, electronic mail, and/or a monitoring visit to obtain additional 
case details and outcome information (e.g., from hospital discharge summaries, 
consultant reports, autopsy reports) in order to perform an independent medical 
assessment of the reported case. Pathology materials (e.g., pathology specimens and 
reports), if already obtained to evaluate the event, may be requested for review. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
After the end of the AE reporting period (defined as 28 days after the last dose of study 
drug), all deaths, regardless of cause, should be reported through use of the Long-Term 
Survival Follow-Up eCRF. In addition, if the investigator becomes aware of an SAE that 
is believed to be related to prior study drug treatment, the event should be reported 
through use of the Adverse Event eCRF. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all SAEs and 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 following reference document: 
 
Trastuzumab emtansine IB 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The primary efficacy objective of this study is to determine the best tumor response 
(BOR). 


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Based on the results of the tolerability analysis, a decision will be made for each 
individual cohort as to whether to continue with the trastuzumab emtansine regimen of 
2.4 mg/kg every week (Regimen A) or switch to the trastuzumab emtansine regimen of 
3.6 mg/kg every 3 weeks (Regimen B). Once the preferred trastuzumab emtansine 
dosing regimen has been determined for a cohort, the primary efficacy objective is to 
determine BOR. 
The main analysis population for the analysis of safety will be the safety population (SP), 
which will include all patients who received at least one dose of the study drug (Regimen 
A and/or B). The main analysis population for the analysis of efficacy will be the intent-
to-treat (ITT) population and will include all patients enrolled who started on the selected 
treatment regimen. If the decision is made to switch to Regimen B then those patients 
who started on Regimen A would not be included in the primary or final efficacy analyses 
(whether they stay on Regimen A or switched to Regimen B) but their results would be 
included in a supplementary descriptive analysis. 
Biomarker analyses will be of exploratory nature.  
6.1 
DETERMINATION OF SAMPLE SIZE 
The sample size estimation is based on the method of A'Hern (2001) and Simon (1989) 
and corresponding SAS programs. 
To test the null hypothesis (H0) that the best BOR is 5% or less (which would yield a low 
activity profile) against the alternative hypothesis (H1) that the BOR is greater than or 
equal to 20% (which would yield an encouraging activity profile):  
 
H0: BOR  5% 
vs. H1: BOR ≥ 20%. 
27 patients per cohort would be required to perform the test with 80% power, at the 
one-sided alpha=0.05 level. To allow for drop-outs (10-15%) and to ensure that at least 
27 patients will have efficacy data available, 32 patients will be recruited per cohort on 
the respective treatment regimen. 
Assuming a preferable BOR of 20% is observed, then with 27 patients in a cohort, the 
95% confidence limits would range from 7.2% to 39.8% (Clopper-Pearson exact 
confidence intervals). 
The 95% confidence intervals for different BOR rates, and with 27 patients per cohort, 
were determined using SAS (Version 9.2) and the results are presented in Table 5 below. 


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Table 5 
Estimation of Confidence Intervals for a Sample Size N = 27 (per 
cohort) 
Sample Size 
BOR 
95% Clopper Pearson Exact 
Confidence Intervals 
27 patients 
15%  
4.4% – 34.2% 
 
20%  
7.2% – 39.8% 
 
25%  
10.6% – 45.5% 
 
30%  
35%  
14.0% – 50.6%  
17.9% - 55.8% 
 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of patients who enroll, discontinue, or complete the study will be 
summarized. Reasons for premature study withdrawal will be listed and summarized. 
Enrollment and major protocol deviations will be listed and evaluated for their potential 
effects on the interpretation of study results. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, race, cancer 
characteristics, medical history and prior cancer treatment) will be summarized using 
means, standard deviations, medians, and ranges for continuous variables and 
proportions for categorical variables, as appropriate.  
Concomitant therapy will be summarized by frequency tables and percentages. 
Medical history will be summarized. 
6.4 
EFFICACY ANALYSES 
The primary and secondary efficacy analyses will include all enrolled and treated 
patients in the selected treatment regimen.  
There are two efficacy analyses – a primary and a final analysis. 
The primary efficacy analysis will determine the BOR for all patients of a cohort who 
received a dose of study medication in the selected treatment regimen and will take 
place 12 weeks after the last patient of an individual cohort has been recruited (following 
a tumor assessment after 6 weeks [2 cycles] with a confirmation of BOR performed no 
less than 4 weeks after the criteria for response are first met). 
The final efficacy analysis will include all primary (BOR) and secondary efficacy 
measures.  


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Results may also be presented according to cell heterogeneity, i.e., by percentage of 
positively stained tumor cells: 30-70% and ≥ 71%.  
Number and percentage of responders with corresponding Clopper-Pearson 95% 
confidence intervals will be provided. Estimates for the survivor function for the time-to-
event variables, such as PFS and OS will be obtained by using the Kaplan-Meier (KM) 
approach together with associated 95% CI. 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is: 
 
BOR 
Responders as assessed every 6 weeks will be defined based on tumor assessment 
status of PR or CR at these time points. Only patients with measurable disease at 
baseline will be included in the analysis of the response rate. Patients without a post-
baseline tumor assessment will be considered to be non-responders. BOR is defined as 
the best response recorded from the first day of study treatment until disease 
progression/recurrence or death. To be assigned a status of PR or CR (i.e., a responder), 
changes in tumor measurements must be confirmed by repeat assessments that should 
be performed no less than 4 weeks after the criteria for response are first met, i.e., 
patients need to have two consecutive assessments of PR or CR to be a responder.  
The null hypothesis (H0) is that the best response rate is 5% or less, which would yield a 
low activity profile. The alternative hypothesis (H1) is that the best response rate is 
greater than or equal to 20%, which would yield an encouraging activity profile.  
H0: best response rate  5% 
vs H1: best response rate ≥ 20% 
A Simon's two-stage design (Simon 1989) will be used to allow the study to stop early if 
there is no evidence of efficacy. The null hypothesis that the true response rate (BOR) is 
≤ 5% will be tested against a one-sided alternative. In the first stage, 13 patients in each 
cohort will be accrued and their BOR results will be evaluated 12 weeks after the 13th 
patient was enrolled. If there are 0 responses (CR or PR) in these 13 patients, the study 
will be stopped for the respective cohort. Otherwise, 14 additional patients will be 
accrued per cohort for a total of 27. Recruitment may be suspended after the 13th patient 
in a cohort has been enrolled in the selected treatment regimen. This suspension will 
occur if there are no responses observed in the previous 12 patients (since the decision 
will be made to stop the study for a cohort only if there are no responses in the first 13 
patients). 
Of the 27 patients with evaluable efficacy data, if 4 or more responders are observed 
then we will reject H0 and accept H1 – i.e., accept that the best response rate ≥ 20%. If 3 
or fewer responders are observed then we will accept H0 – i.e., accept that the best 
response rate  5%. If there are no drop-outs amongst the 32 enrolled patients in a 


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certain cohort then the decision rule will be revised as necessary to retain the same 
alpha and power. For example, if 32 patients in a cohort have evaluable efficacy data, 
then if 5 or more responders are observed then we will reject H0 and accept H1 – i.e., 
accept that the best response rate ≥ 20%. If 4 or fewer responders are observed then we 
will accept H0. 
A response rate of less than 5% will be considered of no clinical interest. A response 
rate of more than 20% will be considered of interest to potentially start a further study, 
which will not be part of this protocol. 
This is an early phase II study, hence there will be no adjustment for multiplicity. 
6.4.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints will include: 
 
PFS 
 
OS 
PFS is defined as the time from the first day of study treatment, until the first 
documented progression of disease (as determined by the investigator using RECIST 
1.1), or death from any cause, whichever occurs first. Patients with no PFS events will 
be censored at the time of the last evaluable tumor assessment. Patients with no tumor 
assessment after the baseline visit will be censored at the time of the first day of study 
treatment plus 1 day. 
OS (time to death) is defined as time between the first day of study treatment and date 
of death of any cause. Patients for whom no death is captured on the clinical database 
are censored at the most recent date they were known to be alive. 
6.5 
SAFETY ANALYSES 
The safety variables will be summarized for the safety population at the same time as 
the final efficacy analysis. All safety variables will be summarized. 
The analysis of AEs will focus on treatment-emergent AEs, i.e., AEs occurring on the 
day of or after first administration of study drug. Non-treatment emergent AEs (i.e., those 
occurring before commencement of study drug) will only be listed. 
All AEs will be assessed according to the NCI CTCAE, v4.03, grading system. The 
incidence, type, and severity of AEs will be summarized according to the primary system 
organ class (SOC) and within each SOC, by MedDRA preferred term. 
AEs Grade 3 or higher for hepatic events, allergic reactions, thrombocytopenia, 
hemorrhage events, and also all other AEs Grade 3 or higher related to trastuzumab 
emtansine will be summarized. 


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Pneumonitis of all grades and the incidence of CHF will also be summarized. 
AEs leading to treatment interruption and discontinuation and SAEs will be analyzed in a 
similar way to all AEs. Cause of death will also be summarized and listed. 
The number of patients prematurely discontinued from the treatment with corresponding 
reason for discontinuation will be summarized and listed. The discontinuation from study 
will be also summarized and listed. 
Descriptive statistics will be presented for cumulative trastuzumab emtansine doses and 
duration of exposure. 
Laboratory parameters, hematology, and serum biochemistry will be presented in shift 
tables of NCI-CTCAE grade at baseline versus worst grade during the Treatment Period. 
The summary of laboratory parameters presented by means, standard deviation, 
minimum, and maximum will be also presented.  
Vital signs (blood pressure, temperature, heart rate, and respiratory rate, oxygen 
saturation) and ECG findings will be also presented by frequency tables over time. 
Change in LVEF over the course of the study as measured by ECHO or MUGA will be 
summarized. 
Cases of drug-induced liver injury meeting Hy’s Law criteria will be summarized. 
The ECOG PS will be summarized by frequency tables over time and percentage of 
patients in different categories will be presented by bar charts at different time points. 
Physical examination variables collected only at baseline (e.g., height) will be 
summarized for baseline only while other physical examination variables will be 
summarized over time by visits and reported in patients’ listings. 
6.6 
IMMUNOGENICITY ANALYSES 
The immunogenicity analyses will include patients with at least one pre-dose (baseline) 
and one post-dose ATA assessment. 
The numbers and proportions of ATA-positive patients and ATA-negative patients during 
both the treatment and follow-up periods will be summarized by treatment group. 
Patients are considered to be ATA positive if they are ATA negative at baseline but 
develop an ATA response following study drug administration (treatment-induced ATA 
response), or if they are ATA positive at baseline and the titer of one or more post-
baseline samples is at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the 
baseline sample (treatment-enhanced ATA response). Patients are considered to be 
ATA negative if they are ATA negative at baseline and all post-baseline samples are 
negative, or if they are ATA positive at baseline but do not have any post-baseline 


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samples with a titer that is at least 4 fold greater than the titer of the baseline sample 
(treatment unaffected). 
The relationship between ATA status, and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported descriptively via subgroup analyses. 
Corresponding analyses will be performed for immune checkpoints e.g. infiltrating 
lymphocyctes in the tumor before and after treatment by the assessment of immune-
related biomarkers such as PDL1 and CD8. 
6.7 
BIOMARKER ANALYSES 
Biomarkers that may be associated with response will be evaluated. These may include 
but are not limited to HER2 positivity analyses by IHC and ISH of all consenting 
screened patients, as well as circulating HER2 ECD and molecular subtyping by RNA 
expression, DNA analysis and/or protein analyses 
6.8 
INTERIM ANALYSIS 
The first 6 patients of each cohort will be analyzed on an ongoing and patient per patient 
basis – i.e. based on the tolerability criteria (as defined in the iDMC charter) and in 
consultation with the SC and iDMC if needed. Further, there will be an analysis of the 
safety data after the first 6 patients of a cohort have completed 2 cycles of Regimen A. 
The results will be made available to the IDMC in order for them to make the decision as 
to whether to continue with Regimen A or to switch to Regimen B. 
There will be analysis of the BOR results for the first 13 patients of a cohort (12 weeks 
after the 13th patient has been enrolled) in the selected treatment regimen. This will be 
done in order to decide whether to stop the study or not (as outlined in Section 6.4.1).  
6.8.1 
Optional Interim Analysis 
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct additional interim efficacy analyses. The decision to conduct an optional interim 
analysis and the timing of the analysis will be documented in the Sponsor’s trial master 
file prior to the conduct of the interim analysis. The interim analysis will be performed 
and interpreted by Sponsor study team personnel, who will have full access to the data. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
A contract research organization (CRO) will be responsible for the data management of 
this study, including quality checking of the data. Data entered manually will be collected 
via EDC through use of eCRFs. Sites will be responsible for data entry into the EDC 
system. In the event of discrepant data, the CRO will request data clarification from the 
sites, which the sites will resolve electronically in the EDC system.  


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The Sponsor will perform oversight of the data management of this study. Central 
laboratory data will be sent directly to the Sponsor, using the Sponsor’s standard 
procedures to handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail. 
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system. Sites will 
receive training and have access to a manual for appropriate eCRF completion. eCRFs 
will be submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff. eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records. 
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan. This includes any protocol data to be entered 
directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 


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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. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research. An 
acceptable computerized data collection system allows preservation of the original entry 
of data. If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO data (if applicable), ICFs, laboratory test results, 
and medication inventory records, must be retained by the Principal Investigator for at 
least 15 years after completion or discontinuation of the study or for the length of time 
required by relevant national or local health authorities, whichever is longer. After that 
period of time, the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor. Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws. Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample ICF, including the sample ICF for the HER2 screening test, will 
be provided to each site. If applicable, the ICFs will be provided in a certified translation 
of the local language. The Sponsor or its designee must review and approve any 


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proposed deviations from the Sponsor's sample ICFs 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. 
If applicable, the ICF will contain separate sections for any optional procedures. The 
investigator or authorized designee will explain to each patient the objectives, methods, 
and potential risks associated with each optional procedure. Patients will be told that 
they are free to refuse to participate and may withdraw their consent at any time for any 
reason. A separate, specific signature will be required to document a patient's 
agreement to participate in optional procedures. Patients who decline to participate will 
not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study. The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate. The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative. All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the ICFs, 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, 


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policies, and procedures established by the IRB/EC. Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
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 
reports are reviewed and processed in accordance with health authority requirements 
and the policies and procedures established by their IRB/EC, and archived in the site’s 
study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number. This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the ICF (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. 
Given the complexity and exploratory nature of the analyses, data derived from 
exploratory biomarker specimens will generally not be provided to study investigators or 
patients unless required by law. The aggregate results of any conducted research will be 
available in accordance with the effective Roche policy on study data publication (see 
Section 9.5). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV). 


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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, ICFs, and documentation of IRB/EC and governmental approval. In 
addition, at the end of the study, the investigator will receive the patient data, including 
an audit trail containing a complete record of all changes to data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects’ medical records, and eCRFs. The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
The study will have an iDMC, an SC, and a Pathology Panel to make crucial decisions at 
the above defined timepoints and to ensure patient safety. The study will be conducted 
with an IxRS and all study-related information and procedures documented in an eCRF. 
It will be run by a contract research organization (CRO) together with the Sponsor. 
Assessment of laboratory test results will be performed locally and confirmed centrally 
(HER2). 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results. For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data. 
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 


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


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10. 
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immunohistochemistry. BMC Cancer. 2009 Jan 7;9:6. doi: 10.1186/1471-2407-9-6. 
Sauter G, Moch H, Moore D. Heterogeneity of erbB-2 gene amplification in bladder 
cancer. Cancer Res 1993;53(Suppl. 10):2199–203. 
Scaltriti M, Chandarlapaty S, Prudkin L, et al. Clinical benefit of lapatinib-based therapy 
in patients with human epidermal growth factor receptor 2-positive breast tumors 
coexpressing the truncated p95HER2 receptor. Clin Cancer Res 2010;16:2688-95. 
Seo AN, Kwak Y, Kim DW, et al. HER2 status in colorectal cancer: its clinical 
significance and the relationship between HER2 gene amplification and expression. 
PLoS One 2014;9:e98528. 
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9-29. 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 
1989;10(1):1-10. 
Simon R, Atefy R, Wagner U, et al. HER-2 and TOP2A coamplification in urinary bladder 
cancer. Int J Cancer. 2003;107(5):764-72. 
Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and 
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Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER2/neu proto oncogene in 
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Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal 
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Engl J Med 2001;344(11):783-92.  


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Stoecklein NH, Luebke AM, Erbersdobler A, et al. Copy number of chromosome 17 but 
not HER2 amplification predicts clinical outcome of patients with pancreatic ductal 
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Ukita Y, Kato M, Terada T. Gene amplification and mRNA and protein overexpression of 
c-erbB-2 (HER-2/neu) in human intrahepatic cholangiocarcinoma as detected by 
fluorescence in situ hybridization, in situ hybridization, and immunohistochemistry. 
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Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced 
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therapy. Cancer Treat Rev 2014;40:770-80. 
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expression of HER2 and HER3 proteins in patients with esophageal 
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29;98(2):418-25. 
 
 


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Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
121/Protocol MO29694, Version 2 
Appendix 1.1 Schedule of Activities: Regimen A (Trastuzumab emtansine, 2.4 mg/kg weekly) 
Screening
Study Drug Completion Visit d Survival Follow-Up e
-28 to 0
1
8
15
1
8
15
1
8
15
1
8
15
(-1,+3) (-1,+3) (-1,+3) (-1,+3) (-1,+3) (-1,+3) (-1,+3) (-1,+3) (-1,+3) (-1,+3) (-1,+3)
Informed Consent a
x
Assignment of patient numbers through the IwRS
x
Tumor tissue for HER2 status testing b
x
Medical history and demographics
x
AEs
x c
x c
x c
Concomitant medications f
x f
x f
x f
Complete physical examination
x
Limited physical examination g
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Height
x
Weight
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signs h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECOG PS
x
x
x
x
x
x
Hematology i, j, k
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum chemistry j, k, m
x m
x m
x n
x n
x m
x n
x n
x m
x n
x n
x m
x n
x n
x m
INR and aPTT
x
x
Pregnancy test l
x l
x l
x l
x l
Laboratory urinalysis o
x
Blood sample for exploratory biomarker research
x
x
x
every 3 months
Blood sample for PK p
x
x
x
x
x
Blood sample HER2 ECD
x
x
x
Blood sample for retrospective genotyping q
x
ATA r
x
x
x
x
Hepatitis B/C serology, HIV
x
12-lead ECG s
x
LVEF by ECHO (or MUGA) t
xt
x t
xt
xt
Tumor tissue for exploratory biomarker research1
x
x 1
Tumor assessment 2, 3, 5
x 2, 3, 5
x 2, 3, 5
x 2, 3, 5
Bone scan 4, 5
x 4, 6
Trastuzumab emtansine administration/distribution6
x (A)
x (A)
x (A)
x (A)
x (A)
x (A)
x (A)
x (A)
x (A)
x (A)
x (A)
x (A)
                                                               every 6 weeks 2, 3, 5
As clinically indicated 
As clinically indicated (e.g. for patients on anticoagulation therapy)
As clinically indicated 
Cycle 1 (day)
Cycle 2 (day)
Cycle 3 (day)
Cycle 4+ (day)
As clinically indicated
ongoing c
ongoing f
every 3rd cycle 
 
a Informed Consent must be obtained prior to performance of any study related procedure unless the assessments were performed as standard of care 
prior to obtaining informed consent and within 2 weeks prior to study entry. 
b HER2 status (IHC3+) should be completed within 28 days prior to baseline, however a maximum of 2 years is accepted unless otherwise stated. 
c After informed consent has been obtained but prior to initiation of study drug, only SAEs caused by a protocol-mandated intervention should be reported. 
After initiation of study drug, all AEs will be reported until 28 days after the last dose of study drug. After this period, the Sponsor should be notified in the 
investigator becomes aware of any SAE that is believed to be related to prior study drug treatment (see Section 5.6)  
d Performed 30 days (+/- 7 days) after the last dose of study treatment. Patients who discontinue study treatment will be asked to return to the clinic 
4-6 weeks after the last dose of study drug for study drug completion visit. If the reason for study drug discontinuation is other than PD, tumor 


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Protocol MO29694     Report Number 1089629
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Appendix 1.1 
Schedule of Activities: Regimen A (Trastuzumab emtansine, 2.4 mg/kg weekly) (cont.) 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
122/Protocol MO29694, Version 2 
assessments should be continued to be performed every 6 weeks from the first dose of study drug until PD or death 
e After completion of treatment, patients will be followed up for survival in a 3-monthly schedule until 18 months after LPI. 
f Record all concomitant therapy (non-investigational products), which includes prescription medication, over-the-counter preparation, herbal therapy, or 
radiotherapy used by a patient between the 28 days preceding date of first dose of study drug and the study drug completion/early termination visit. 
g Limited symptom-directed physical examination focusing on organ systems related to potential AEs based on patient's interim medical history and/or 
existing AE profiles of the study drug. 
h Systolic and diastolic blood pressure, pulse rate, oxygen saturation, respiratory rate, temperature should all be collected at screening, pre-dose, every 
15 (+/- 5) minutes during the first trastuzumab emtansine infusion and 60 (+/-10) minutes after the infusion. In subsequent cycles, vital signs should be 
recorded within 60 minutes pre- and post-infusion. Abnormal or significant changes to vital signs from baseline should be recorded as an AE.  
i Includes hemoglobin, hematocrit, platelet count, RBCs, WBCs; differentials including neutrophils, lymphocytes, monocytes, eosinophils and basophils. 
j Assessments should be performed at screening, on Day 1 of all cycles, and weekly following any hematologic AE. Local laboratory assessments should 
be performed within 72 hours preceding trastuzumab emtansine administration unless otherwise specified. Results of these local laboratory assessments 
must be reviewed and the review documented prior to trastuzumab emtansine administration.  
k For AEs associated with abnormal laboratory values, assessments should be performed at a minimum weekly until recovery to Grade ≤ 2. Additional 
assessments may be done as clinically indicated. 
l For women of childbearing potential (including premenopausal women who have had a tubal ligation) and for women not considered post-menopausal, a 
serum b-HCG pregnancy test must be performed at a local laboratory within  7 days prior to the first administration of study drug (Day 1, Cycle 1). Urine 
pregnancy tests will be performed at specified subsequent visits (every 3 cycles, study completion visit, at 3 and 6 months (+/- 2 weeks) after last dose of 
study drug) within 7 days prior to receiving further study drug. All positive urine pregnancy tests must be confirmed by a serum b-HCG test. 
m Glucose, blood urea nitrogen (BUN)/urea , creatinine, sodium, potassium, bicarbonate, phosphorus, chloride, calcium, uric acid, total protein, albumin, 
total and direct bilirubin, alkaline phosphatase, LDH, ALT, AST, and GGT. 
n AST, ALT, GGT, and total bilirubin only. 
o includes specific gravity, pH, protein, glucose, blood, ketones, bilirubin and microscopic examination including sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, bacteria. 
p Six sampling timepoints in Cycle 1 (Day 1, Day 8, and Day 15, each predose and 15-30 minutes postdose), one sampling timepoint in Cycle 2 (Day 1, 
predose), and two sampling timepoints in Cycle 4 (Day 1, predose and 15 30 minutes postdose). . 
q To be taken at baseline (Cycle 1, Day 1) 
r Samples for ATA assessment will be collected before dosing in Cycles 1 and 4, at the study drug completion visit, and 3 months after the last 
trastuzumab emtansine dose.  
s ECGs for each patient should be obtained from the same machine whenever possible. One set of all ECG tracings should be printed and kept with the 
patient's record.  
t Cardiac monitoring (ECHO/MUGA) will be performed in all patients enrolled in the study. Assessments will occur during the screening period, between 
Days 15 and 21 in Cycles 1 and 3, and between Days 15 and 21 of every 3rd cycle thereafter (Cycle 6, 9 etc). ECHO or MUGA will be performed following 
study treatment discontinuation only if the most recent follow-up ECHO/MUGA was performed ≥ 28 days after last study treatment administration or if no 
post-treatment evaluation was performed. The LVEF follows the actual treatment cycle. Dose modification of study drug will follow the algorithm/process 
described in Table 2. 
1 An optional tissue biopsy is taken at discontinuation of trastuzumab emtansine, either due to PD, unacceptable toxicity of systemic treatment or any other 
reason. 
2 Every 6 weeks from the start date of the study drug, regardless of dose delay or early discontinuation, until PD or study termination. Tumor assessments 
obtained within 28 days of Cycle 1, Day 1 may be used for screening purposes. Tumor assessments with CT or MRI scans of the chest, abdomen, and 
pelvis are to be performed every 6 weeks (+/- 3 business days). Response must be assessed through physical examination and imaged-based evaluation, 


Clinical Study Report: trastuzumab emtansine - F. Hoffmann-La Roche Ltd
Protocol MO29694     Report Number 1089629
341
Appendix 1.1 
Schedule of Activities: Regimen A (Trastuzumab emtansine, 2.4 mg/kg weekly) (cont.) 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
123/Protocol MO29694, Version 2 
using RECIST 1.1. Assessments should include an evaluation of all known or suspected sites of disease whenever possible. The same radiographic 
procedure used to define measurable disease sites at baseline must be used throughout the study. 
3 If a patient inadvertently misses a prescribed tumor evaluation or a technical error prevents the evaluation, the patient may continue treatment until the 
next scheduled assessments, unless signs of clinical progression are present. In cases where there is suspicion of clinical progression before the next 
scheduled assessment, an unscheduled assessment should be performed. 
4 A CT or MRI of the brain and an isotope bone scan will be performed at screening. The bone scan and/or X-ray should be repeated in the event of 
clinical suspicion of progression of existing bone lesions and/or the development of new bone lesions. 
5 At the investigator's discretion, CT scans, MRI scans, and/or bone scans may be obtained at any time when clinically indicated or if PD is suspected. 
6 A = Regimen A (trastuzumab emtansine weekly, 2.4 mg/kg). Trastuzumab emtansine should be given over 90 minutes for the first dose and, in the 
absence of infusion-related AEs, over 30 minutes in subsequent doses. Vital signs should be taken before and after the trastuzumab emtansine infusion. 
Patients will be monitored for any untoward effects for at least 90 minutes after completion of the first trastuzumab emtansine infusion and, in the absence 
of infusion-related events, for a minimum of 30 minutes at subsequent infusions. 
 


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Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
124/Protocol MO29694, Version 2 
Appendix 1.2 
Schedule of Activities: Regimen B (Trastuzumab emtansine 3.6 mg/kg 3-weekly) 
Screening
Study Drug Completion Visit d Survival Follow-Up e
-28 to 0
1
8
15
1
8
15
1
8
15
1
8
15
(-3,+3)
(-3,+3)
(-3,+3)
Informed Consent a
x
Assignment of patient numbers through the IwRS
x
Tumor tissue for HER2 status testing b
x
Medical history and demographics
x
AEs
x c
x c
x c
Concomitant medications f
x f
x f
x f
Complete physical examination
x
Limited physical examination g
x
x
x
x
x
x
Height
x
Weight
x
x
x
x
x
x
Vital signs h
x
x
x
x
x
x
x
ECOG PS
x
x
x
x
x
x
Hematology i, j, k
x
x
x
x
x
x
Serum chemistry j, k, m
x m
x m
x m
x m
x m
x m
INR and aPTT
x
x
Pregnancy test l
x l
x l
x l
x l
Laboratory urinalysis n
x
Blood sample for exploratory biomarker research
x
x
x
every 3 months
Blood sample for PK o
x
x
x
Blood sample HER2 ECD
x
x
x
Blood sample for retrospective genotyping p
x
ATA q
x
x
x
x
Hepatitis B/C serology, HIV
x
12-lead ECG r
x
LVEF by ECHO (or MUGA) s
xs
x s
xs
xs
Tumor tissue for exploratory biomarker research1
x
x 1
Tumor assessment 2, 3, 5
x 2, 3, 5
x 2, 3, 5
x 2, 3, 5
Bone scan 4, 5
x 4, 6
Trastuzumab emtansine administration/distribution6
x (B)
x (B)
x (B)
x (B)
                                                               every 6 weeks 2, 3, 5
As clinically indicated 
As clinically indicated (e.g. for patients on anticoagulation therapy)
As clinically indicated 
Cycle 1 (day)
Cycle 2 (day)
Cycle 3 (day)
Cycle 4+ (day)
As clinically indicated
ongoing c
ongoing f
 
a Informed Consent must be obtained prior to performance of any study related procedure unless the assessments were performed as standard of care prior to 
obtaining informed consent and within 2 weeks prior to study entry. 
b HER2 status (IHC3+) should be completed within 28 days prior to baseline, however a maximum of 2 years is accepted unless otherwise stated. 
c After informed consent has been obtained but prior to initiation of study drug, only SAEs caused by a protocol-mandated intervention should be reported. After 
initiation of study drug, all AEs will be reported until 28 days after the last dose of study drug. After this period, the Sponsor should be notified if the investigator 
becomes aware of any SAE that is believed to be related to prior study drug treatment (see Section 5.6).  The investigator should follow each AE until the event has 


Clinical Study Report: trastuzumab emtansine - F. Hoffmann-La Roche Ltd
Protocol MO29694     Report Number 1089629
343
Appendix 1.2 
Schedule of Activities: Regimen B (Trastuzumab emtansine 3-weekly, 3.6 mg/kg) (cont.) 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
125/Protocol MO29694, Version 2 
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. 
d Performed 30 days (+/- 7 days) after the last dose of study treatment. Patients who discontinue study treatment will be asked to return to the clinic 4-6 weeks after 
the last dose of study drug for study drug completion visit. If the reason for study drug discontinuation is other than PD, tumor assessments should be continued to 
be performed every 6 weeks from the first dose of study drug until PD or death. 
e After completion of treatment, patients will be followed up for survival in a 3-monthly schedule until 18 months after LPI. 
f Record all concomitant therapy (non-investigational products), which includes prescription medication, over-the-counter preparation, herbal therapy, or 
radiotherapy used by a patient between the 28 days preceding date of first dose of study drug and the study drug completion/early termination visit. 
g Limited symptom-directed physical examination focusing on organ systems related to potential AEs based on patient's interim medical history and/or existing AE 
profiles of the study drug. 
h Systolic and diastolic blood pressure, pulse rate, oxygen saturation, respiratory rate, temperature should all be collected at screening, pre-dose, every 15 (+/- 5) 
minutes during the first trastuzumab emtansine infusion and 60 (+/-10) minutes after the infusion. In subsequent cycles, vital signs should be recorded within 
60 minutes pre- and post-infusion. Abnormal or significant changes to vital signs from baseline should be recorded as an AE. 
i Includes hemoglobin, hematocrit, platelet count, RBCs, WBCs; differentials including neutrophils, lymphocytes, monocytes, eosinophils and basophils. For 
Regimen B, laboratory assessments need only be performed in conjunction with a clinical visit, i.e. every 3 weeks on Day 1 of each cycle. 
j Assessments should be performed at screening, on Day 1 of all cycles, and weekly following any hematologic AE. Local laboratory assessments should be 
performed within 72 hours preceding trastuzumab emtansine administration unless otherwise specified. Results of these local laboratory assessments must be 
reviewed and the review documented prior to trastuzumab emtansine administration. 
k For AEs associated with abnormal laboratory values, assessments should be performed at a minimum weekly until recovery to Grade ≤ 2. Additional assessments 
may be done as clinically indicated. 
l For women of childbearing potential (including premenopausal women who have had a tubal ligation) and for women not considered post-menopausal, a serum 
b-HCG pregnancy test must be performed at a local laboratory within 7 days prior to the first administration of study drug (Day 1, Cycle 1). Urine pregnancy tests 
will be performed at specified subsequent visits (every 3 cycles, study completion visit, at 3 and 6 months (+/- 2 weeks) after last dose of study drug) within 7 days 
prior to receiving further study drug. All positive urine pregnancy tests must be confirmed by a serum b-HCG test. 
m Glucose, blood urea nitrogen (BUN)/urea , creatinine, sodium, potassium, bicarbonate, phosphorus, chloride, calcium, uric acid, total protein, albumin, total and 
direct bilirubin,  alkaline phosphatase, LDH, ALT, AST, and GGT. 
n Includes specific gravity, pH, protein, glucose, blood, ketones, bilirubin and microscopic examination including sediment, RBCs, WBCs, casts, crystals, epithelial 
cells, bacteria. 
oTwo sampling timepoints in Cycle 1 (Day 1 predose and 15-30 minutes postdose), one sampling timepoint in Cycle 2 (Day 1, predose), and two sampling 
timepoints in Cycle 4 (Day 1, predose and 15-30 minutes postdose). . 
p To be taken at baseline (Cycle 1, Day 1). 
q Samples for ATA assessment will be collected before dosing in Cycles 1 and 4, at the study drug completion visit, and 3 months after the last trastuzumab 
emtansine dose. 
r ECGs for each patient should be obtained from the same machine whenever possible. One set of all ECG tracings should be printed and kept with the patient's 
record. 
s Cardiac monitoring (ECHO/MUGA) will be performed in all patients enrolled in the study. Assessments will occur during the screening period, between Days 15 
and 21 in Cycles 1 and 3, and between Days 15 and 21 of every 3rd cycle thereafter (Cycle 6. 9 etc). ECHO or MUGA will be performed following study treatment 
discontinuation only if the most recent follow-up ECHO/MUGA was performed ≥ 28 days after last study treatment administration or if no post-treatment evaluation 
was performed. The LVEF follows the actual treatment cycle. Dose modification of study drug will follow the algorithm/process described in Table 2. 
1 An optional tissue biopsy is taken at discontinuation of trastuzumab emtansine, either due to PD, unacceptable toxicity of systemic treatment or any other reason. 


Clinical Study Report: trastuzumab emtansine - F. Hoffmann-La Roche Ltd
Protocol MO29694     Report Number 1089629
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Appendix 1.2 
Schedule of Activities: Regimen B (Trastuzumab emtansine 3-weekly, 3.6 mg/kg) (cont.) 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
126/Protocol MO29694, Version 2 
2 Every 6 weeks from the start date of the study drug, regardless of dose delay or early discontinuation, until PD or study termination. Tumor assessments obtained 
within 30 days of Cycle 1, Day 1 may be used for screening purposes. Tumor assessments with CT or MRI scans of the chest, abdomen, and pelvis are to be 
performed every 6 weeks (+/- 3 business days). Response must be assessed through physical examination and imaged-based evaluation, using RECIST 1.1. 
Assessments should include an evaluation of all known or suspected sites of disease whenever possible. The same radiographic procedure used to define 
measurable disease sites at baseline must be used throughout the study. 
3 If a patient inadvertently misses a prescribed tumor evaluation or a technical error prevents the evaluation, the patient may continue treatment until the next 
scheduled assessments, unless signs of clinical progression are present. In cases where there is suspicion of clinical progression before the next scheduled 
assessment, an unscheduled assessment should be performed. 
4 A CT or MRI of the brain and an isotope bone scan will be performed at screening. The bone scan and/or X-ray should be repeated in the event of clinical 
suspicion of progression of existing bone lesions and/or the development of new bone lesions. 
5 At the investigator's discretion, CT scans, MRI scans, and/or bone scans may be obtained at any time when clinically indicated or if PD is suspected. 
6 B = Regimen B (trastuzumab emtansine 3-weekly, 3.6 mg/kg). Trastuzumab emtansine should be given over 90 minutes for the first dose and, in the absence of 
infusion-related AEs, over 30 minutes in subsequent doses. Vital signs should be taken before and after the trastuzumab emtansine infusion. Patients will be 
monitored for any untoward effects for at least 90 minutes after completion of the first trastuzumab emtansine infusion and, in the absence of infusion-related 
events, for a minimum of 30 minutes at subsequent infusions. 
 


Clinical Study Report: trastuzumab emtansine - F. Hoffmann-La Roche Ltd
Protocol MO29694     Report Number 1089629
598
CONFIDENTIAL 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  
Nothing herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MO29694, Version 2.0 
STATISTICAL ANALYSIS PLAN 
TITLE: 
PHASE II, EXPLORATORY, MULTICENTER, NON 
RANDOMIZED, SINGLE AGENT COHORT STUDY TO 
DETERMINE BEST TUMOR RESPONSE WITH 
TRASTUZUMAB EMTANSINE IN HER2 OVEREXPRESSING 
SOLID TUMORS  
PROTOCOL NUMBER: 
STUDY DRUG: 
VERSION NUMBER: 
IND NUMBER: 
EUDRACT NUMBER: 
SPONS31OR: 
PLAN PREPARED BY: 
DATE FINAL: 
MO29694/NCT02999672
Trastuzumab Emtansine (RO5304020) 
2.0 
N/A 
2015-001377-40 
F. Hoffmann-La Roche Ltd
, France 
05-JUN-2018


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Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29694, Version 2.0 
2 
STATISTICAL ANALYSIS PLAN HISTORY 
SAP Version / Date 
Description 
Version 1.0 / 23 March 2017 
Initial version. 
Version 2.0 / 5 June 2018 
The Sponsor decided to prematurely terminate the 
study and to produce an abbreviated clinical study 
report (CSR). As a consequence, some of the 
analyses planned in the version 1.0 won’t be 
performed and have been removed in this version. 
  
 


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Statistical Analysis Plan MO29694, Version 2.0 
3 
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN HISTORY ............................................ 2 
1. 
LIST OF ABBREVIATIONS .............................................................. 6 
2. 
BACKGROUND ............................................................................... 8 
3. 
STUDY DESIGN .............................................................................. 9 
3.1 
Protocol Synopsis ..................................................... 11 
3.2 
Outcome Measures .................................................. 11 
3.2.1 
Primary Efficacy Outcome Measures ....................... 11 
3.2.1.1 Best Overall Response ............................................ 11 
3.2.1.2 Overall Response Rate ........................................... 13 
3.2.2 
Secondary Efficacy Outcome Measures ................... 13 
3.2.2.1 Progression-Free Survival ....................................... 13 
3.2.2.2 Overall Survival ....................................................... 13 
3.2.3 
Safety Outcome Measures ....................................... 13 
3.2.4 
Pharmacokinetic Outcome Measures ....................... 13 
3.3 
Determination of Sample Size .................................. 13 
3.4 
Analysis Timing ........................................................ 14 
4. 
STUDY CONDUCT ........................................................................ 15 
4.1 
Data Monitoring ........................................................ 15 
5. 
STATISTICAL METHODS ............................................................. 15 
5.1 
Definitions of Cohort and Regimens ......................... 15 
5.2 
General Descriptive methods ................................... 15 
5.3 
Definition of Treatment Period .................................. 16 
5.4 
Data Convention ....................................................... 16 
5.5 
Computing Environment ........................................... 17 
5.6 
Grading and Coding of Adverse Events, Laboratory 
Parameters and Medications .................................... 17 
5.7 
Adjustments for Covariates ....................................... 17 
5.8 
Subgroup Analysis .................................................... 17 
5.9 
Analysis Populations ................................................ 17 
5.9.1 
Safety Population ..................................................... 17 
5.9.2 
Screened Population ................................................ 18 
5.9.3 
Efficacy Population ................................................... 18 
5.9.4 
Per Protocol Population ............................................ 18 


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Statistical Analysis Plan MO29694, Version 2.0 
4 
5.10 
Analysis of Study Conduct ........................................ 18 
5.10.1 
Patient Disposition .................................................... 18 
5.10.2 
Protocol Deviations ................................................... 19 
5.11 
Analysis of Treatment Group .................................... 20 
5.11.1 
Demographics and Baseline Disease 
Characteristics ............................................................................ 20 
5.11.2 
Prior and Concomitant Treatments ........................... 21 
5.11.2.1 Prior Anti-Cancer Treatment/Procedure ................ 21 
5.11.2.2 Non Anti-Cancer Treatment/Procedure ................. 21 
5.11.2.3 On-Study Anti-Cancer Treatment/Procedure ........ 22 
5.11.3 
Subsequent Anti-Cancer Therapy ............................ 22 
5.12 
Efficacy Analysis ....................................................... 22 
5.12.1 
Primary Efficacy Endpoint ......................................... 22 
5.12.2 
Secondary Efficacy Endpoints .................................. 23 
5.12.2.1 Progression-Free Survival ..................................... 23 
5.12.2.2 Overall Survival ..................................................... 23 
5.12.2.3 Duration of response ............................................. 23 
5.12.3 
Sensitivity Analyses .................................................. 24 
5.13 
Pharmacokinetic and Pharmacodynamic Analyses .. 24 
5.14 
Safety Analyses ........................................................ 24 
5.14.1 
Exposure of Study Medication .................................. 24 
5.14.1.1 Treatment Duration and Dose Exposure ............... 24 
5.14.1.2 Infusion Interrupted or Delayed ............................. 25 
5.14.1.3 Infusion Rate Reduction ........................................ 25 
5.14.2 
Adverse Events ........................................................ 25 
5.14.3 
Infusions-Related Reactions (IRR) ........................... 28 
5.14.4 
Death ........................................................................ 28 
5.14.5 
Laboratory Data ........................................................ 28 
5.14.6 
Vital Signs ................................................................. 29 
5.14.7 
ECOG PS ................................................................. 29 
5.14.8 
Left Ventricular Ejection Fraction (LVEF).................. 29 
5.14.9 
Electrocardiogram .................................................... 29 
5.15 
Biomarker Analysis ................................................... 29 
5.16 
Missing Data ............................................................. 30 
5.17 
Interim Analyses ....................................................... 31 
5.17.1 
Optional Interim Analysis .......................................... 31 


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6. 
REFERENCES .............................................................................. 32 
 
LIST OF TABLES 
Table 1: Estimation of Confidence Intervals for a Sample Size N = 27 
(per cohort) .................................................................... 14 
Table 2: Exposure Definitions ................................................................ 24 
Table 3 : Adverse Events Definitions ..................................................... 25 
 
 
LIST OF APPENDICES 
Appendix 1 
 Protocol Synopsis ......................................................... 33 
Appendix 2 
 Schedule of Assessments ............................................. 40 
Appendix 3 
 List of Outputs  .............................................................. 46 
 
 
 


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1. 
 LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
AE 
adverse events 
AESI 
ALK 
ALT 
ANC 
aPTT 
AST 
adverse events of special interest 
anaplastic lymphoma kinase 
alanine aminotransferase 
absolute neutrophil count 
activated partial thromboplastin time 
aspartate aminotransferase 
BOR 
CI 
best overall response 
confidence interval 
CR 
complete response 
CSR 
clinical study report 
ECG 
electrocardiogram 
ECOG 
eCRF 
EORTC 
 
FDA 
GGT 
IC 
Eastern Cooperative Oncology Group 
electronic Case Report Form 
European Organization for the Research and 
Treatment of Cancer 
Food and Drug Administration 
gamma glutamyl transferase 
Informed Consent 
ICH 
International Conference on Harmonization 
iDMC 
IV 
INR 
Independent Data Monitoring Committee 
Intra-Venous 
international normalized ratio 
ITT 
Intent-to-treat 
KM 
Kaplan Meier 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI CTCAE 
National Cancer Institute Common Terminology 
Criteria for Adverse Events 
NE 
not evaluable 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression free survival 
PK 
pharmacokinetic 
PR 
partial response 
PS 
performance status 
PT 
preferred term 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 


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Abbreviation 
Definition 
SAE 
serious adverse event 
SAF 
safety population 
SAP 
SC 
statistical analysis plan 
Steering Committee 
SD 
stable disease 
SI 
System International 
SOC 
System Organ Class 
TEAE 
MUBC 
treatment emergent adverse event 
Metastatic Urothelial bladder cancer 
WBC 
white blood cell 
 
 
 


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2. 
BACKGROUND 
The human epidermal growth factor receptor 2 (HER2) gene is a proto-oncogene, 
which is located on chromosome 17q11.2-12 and encodes a transmembrane tyrosine 
kinase receptor, which is responsible for cell growth, differentiation, migration and 
apoptosis (Normanno et al 2005). Amplification of the HER2 gene occurs in 
approximately 20% to 25% of primary human breast cancers (BC) and typically results 
in overexpression of the HER2 protein at > 1 million copies per cell (Slamon et al 1987, 
Slamon et al 1989, Pegram et al 2000). Such tumors are considered “HER2-positive” 
and are associated with aggressive growth and poor clinical outcome (Slamon et al 
1987, Slamon et al 1989).  
 
A number of anti-HER2 therapies have proven efficacy, are approved and part of the 
SOC for HER2-positive Breast Cancer (BC) and Gastric Cancer GC. However, this is 
not yet the case for trastuzumab emtansine which currently is only available for BC. 
HER2 overexpression has been identified in some other tumors as esophagus, 
colorectal, pancreatic, bladder and prostate cancer (Yan et al 2014, Yoon et al 2014, 
Sato-Kuwabara et al 2009, Seo et al 2014, Stoecklein et al 2004, Minner et al 2010, 
Carneiro et al 2015, Hansel et al 2008). These findings pose the intriguing question if 
trastuzumab emtansine could improve patient outcomes in those tumor types and 
beyond BC and GC. There is currently no clinical data on the potential therapeutic 
effect of trastuzumab emtansine treatment in HER2-positive tumors such as 
esophageal-, colorectal-, pancreas/cholangio-, prostate and bladder carcinoma.  
 
Urothelial bladder cancer (UBC) is an area of high unmet medical need. UBC seems 
to be an interesting target that shows a similar HER2 overexpression rate as in breast 
cancer, although the IHC staining pattern is expected to be more heterogeneous. 
HER2 expression in UBC is associated with high-grade tumors and advanced local 
disease (Hussain et al 2007, Simon et al 2003, Gehani et al 2012, Chen et al 2013), 
more metastatic sites and visceral metastases (Hussain et al 2007), higher recurrence 
risk (Chen et al 2013) and shorter OS and disease specific survival (Krueger et al 2002, 
Simon et al 2003). 
 
Pancreatic adenocarcinoma is also an area of high unmet medical need with survival 
rates, which remain disappointing (median OS with palliative chemotherapy 11.1 
months). The HER2 overexpression rate is as high as 11% (and varies widely between 
patients). Interestingly, overexpression of the HER2 protein does not correlate well to 
amplification of the HER2 locus. HER2 overexpression in pancreatic cancer may be 
due to gene deregulation rather than gene amplification as postulated by Ukita et al 
(2002) for intrahepatic biliary tract cancer (Harder et al 2012). Nevertheless an 
approach with an ADC such as trastuzumab emtansine may be considered a potential 
treatment option.  
 
Cholangiocarcinomas may be considered related tumors and these patients can be 
included in later stages of this study. The incidence and mortality rates of 
cholangiocarcinoma, especially those of IHC, are increasing worldwide (Khan et al 
2005). Complete resection is the only way to cure the disease at present. However, 
because cholangiocarcinoma are difficult to diagnose at an early stage and extend 
diffusely, most patients have unresectable disease at clinical presentation, and 
prognosis is very poor (5-year survival is 0–40% even in resected cases) (Yoshikawa 
et al 2008). Approximately 8% of patients have HER2 overexpression (Yan et al 2014) 
and may therefore benefit from a HER2-targeted therapeutic approach.  
 
Patients diagnosed with metastatic UBC (MUBC) or metastatic pancreatic/cholangio 
cancer have very limited treatment options to date, especially if they present in an 


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advanced stage of their cancer, with a high mortality and low long-time survival rates. 
New therapeutic approaches are therefore needed for these patients with a high unmet 
medical need and limited other treatment options, especially in late stage. 
 
This trial is a Phase II, proof of concept, single arm study, designed to estimate the 
efficacy of trastuzumab emtansine in HER2 overexpressing MUBC and metastatic 
pancreas/cholangio cancer in patients with advanced disease where cure is no longer 
possible and where no other treatment options are available anymore. This might be 
opened up to a diverse range of other HER2 overexpressing tumors as described 
further above. Trastuzumab emtansine has proven efficacious in HER2-positive BC 
and has a tolerable safety profile. Therefore, the risk benefit in this study is deemed 
positive.  
 
The study design will allow for the examination of MUBC and metastatic 
pancreas/cholangio cancer with enough statistical power to determine whether further 
examination may be warranted in these indications or potential additional indications. 
To investigate a potential difference in treatment efficacy for MUBC and metastatic 
pancreas/cholangio cancer with homogeneous HER2 expression and the carcinoma 
with a more focal HER2 expression, patients will be stratified according to the HER2 
IHC pattern in their baseline tissue biopsy (e.g., 30-70% vs 71-100% of tumor cells 
expressing HER2). Patients with very focal HER2 IHC pattern (e.g., < 30%) will be 
excluded from this study. The open-label, uncontrolled design is appropriate since the 
trial will only enroll patients with HER2-positive cancers and who in the opinion of the 
investigator have trastuzumab emtansine as their best treatment option. The study is 
intended as a proof of concept. 
 
3. 
STUDY DESIGN 
This trial is an exploratory, multicenter, non-randomized, Phase II, single agent study 
designed to evaluate the efficacy and safety of trastuzumab emtansine in two cohorts: 
 
patients with MUBC  
 
patients with metastatic pancreas/cholangio cancer. 
Other tumor types may be potentially explored at a later point in time.  
 
If no patients are enrolled in an individual cohort one year after enrolment started, then 
enrolment for that cohort will be stopped. A total of 32-38 patients per cohort will be 
enrolled i.e. 64-76 patients in total. 
The accrual inclusion time for this study is expected to be 18 months per cohort. 
 
In a safety run-in, the first 6 patients of each cohort will enter Regimen A and receive  
2.4 mg/kg weekly trastuzumab emtansine intravenously (iv). Recruitment for the 
respective cohort will be suspended until all 6 of these patients have completed the 
2nd cycle (6 weeks) and the ‘regimen decision point’ has been reached. Based on 
tolerability and safety aspects, a decision will be made by the iDMC if the cohort is to 
continue on Regimen A (2.4 mg/kg qw), extending recruitment to a total of 32 patients 
(additional 26 patients) per cohort, or if the dose switches to Regimen B (3.6 mg/kg 
q3w). If the regimen is changed to Regimen B in an individual cohort, 32 additional 
patients will be included in this cohort; if the regimen remains unchanged (i.e., 
Regimen A), only 26 additional patients will be recruited.  
If treatment in a cohort is switched to Regimen B, the 6 patients that were initially 
started on Regimen A will be allowed to switch if an additional benefit can be expected. 
However, for patients of a cohort who showed initial response on Regimen A, it is 
recommended to keep them on Regimen A. If any of these patients experiences PD, 
no switch is allowed and the patient will be discontinued from the study. Irrespective of 


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these potential changes, these patients will not be included in the primary efficacy 
analysis. 
 
A Simon's two-stage design (Simon 1989) will be used to allow the study to stop early 
if there is no evidence of efficacy. In the first stage, 13 patients in each cohort will be 
accrued and their BOR results will be evaluated 12 weeks after the 13th patient was 
enrolled. If there are 0 objective responses (CR or PR) in these 13 patients, the study 
will be stopped for the respective cohort. Otherwise, 14 additional patients will be 
accrued per cohort for a total of 27. 
 
The data cutoff for the primary analysis will take place 12 weeks after the last patient 
of an individual cohort has been recruited (following a tumor assessment after 6 weeks 
[2 cycles] with a confirmation of BOR within 4 weeks).  
 
The data cutoff for the final analysis for each cohort of all primary and secondary 
efficacy measures will take place 18 months after the last patient of a cohort was 
recruited, or once all patients have reported a progression event, whichever occurs 
earlier. 
 
The primary (and final) analysis for efficacy would be based only on those patients of 
a cohort who started on the selected treatment regimen. If the decision is made to 
switch to Regimen B then those patients who started on Regimen A would not be 
included in the primary or final efficacy analyses (whether they stay on Regimen A or 
switched to Regimen B) but their results would be included in a supplementary 
descriptive analysis.  
 
Decision on expansion of the study to include other carcinoma types will be made via 
collaboration of the SC and iDMC. The iDMC has to look at the initial tolerability data 
before the decision to include more carcinoma types is being made. Efficacy data will 
not be considered for this decision. 
 
Figure 1 Trial design 
 
ECOG PS = Eastern Cooperative Oncology Group Performance Status; PD = progressive 
disease;  
 
Objectives of the study covered in the present statistical analysis plan: 
The primary efficacy objective for this study is to evaluate the efficacy of trastuzumab 
emtansine in term of best tumor response. 
 
The secondary efficacy objective for this study is to evaluate the efficacy of 
trastuzumab emtansine in term of progression-free survival, overall survival. 
 
Tareet population: 
HER2+ 2L+ without 
treatment options 
Locally 
advanced/metastatic 
IHC3+, non-focal (>30% 
stained cells) 
ECOG PS: 0-1 
Stratific.ation by tumor 
cell heterogeneity: 
30·70% and 2 71% of 
HER2 IHC3+ stained 
tumorc~lls 
Dose dedslon 
Ctolenbi 
I 
I 
I 
I 
I 
stoppins Rule: 
checll of response 
alter 13 patients 
enrolled In• cohort 
L-----
Repmen B 
__ .J 


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The safety objective is to evaluate the safety of trastuzumab emtansine in term of 
adverse events, vital signs and clinical laboratory results. An independent data 
monitoring committee (IDMC) will be responsible for reviewing periodically safety data. 
 
 
Objectives of the study that will be covered in separate documents: 
The pharmacokinetic objective is to characterize the pharmacokinetics of trastuzumab 
emtasine concentration in plasma and/or serum. This analysis will be handled by 
Clinical Pharmacology department at Roche. 
 
The immunogenicity objective is to evaluate the immune response to trastuzumab 
emtansine. Endpoints for this objective will be the incidence of anti-therapeutic 
antibodies (ATAs) during the study relative to the prevalence of ATAs at baseline, and 
immune-related biomarkers such PDL1 and CD8. 
 
The biomarker objective is to identify biomarkers that are predictive of response, can 
provide evidence of trastuzumab emtansine activity, or can increase the knowledge 
and understanding of disease biology. 
 
3.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2. 
3.2 
OUTCOME MEASURES 
3.2.1 
Primary Efficacy Outcome Measures 
3.2.1.1 
Best Overall Response 
The best overall response will be assessed by investigator using the following definition. 
 
The best overall response for a subject is defined as the most favorable outcome, 
according to RECIST v1.1 criteria, at any visit after first day of study treatment and up 
to the analysis data cut-off or the first disease progression, whichever occurs first.  
 
The outcomes are ordered below from most to least favorable: 
 
Complete Response (CR) 
 
Partial Response (PR) 
 
Stable Disease (SD) 
 
Progressive Disease (PD) 
 
Non-Evaluable (NE) 
Responses of Non CR/Non PD are treated as SD.  
 
For investigator assessments, the best overall response will be derived 
programmatically, according to RECIST v1.1, based on the investigator overall subject 
response per visit collected on the eCRF. The investigator overall subject response 
per timepoint will not be re-derived programmatically. Best overall response is the first 
occurrence of the most favorable outcome, as detailed above. A best response of CR 
or PR cannot be assessed unless it is confirmed, no earlier than four (4) weeks (28 
days) from the time a response of CR or PR is first suspected. Refer to the below table 
if the patient experienced at least one overall response of Complete Response (CR), 
Partial Response (PR) or Not Evaluable (NE) at any time on-treatment, the following 
conventions will be used to derive the confirmed best overall response: 


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Overall Response at First 
Timepoint 
Overall Response at 
Subsequent Timepoint 
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. 
a  If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, 
even disease meeting PR criteria relative to baseline, qualifies as PD at that point 
(since disease must have reappeared after CR).  Best response would depend on 
whether the minimum duration for SD was met.  However, sometimes CR may be 
claimed when subsequent scans suggest small lesions were likely still present and in 
fact the patient had PR, not CR, at the first timepoint.  Under these circumstances, the 
original CR should be changed to PR and the best response is PR. 
If a subject experienced only CR - NE - CR, BOR will be CR. 
If a subject experienced only PR - NE - PR, BOR will be PR. 
If a subject experienced only PR - SD - PR, BOR will be SD. 
If a subject had only one tumor assessment post baseline with an overall response of 
NE, then the overall response will be set to NE. 
 
A minimum interval of 5 weeks (35 days) will be considered for Stable Disease (SD) to 
be assigned as best overall response, i.e. in the case the single response is SD, PR 
or CR, this single response must have been assessed no less than 5 weeks (at least 
35 days) after treatment start.  
 
If the subject has a missing baseline tumor assessment, he/she will be excluded from 
the BOR calculation. 
It the subject has no post-baseline tumor assessment, his/her best overall response 
will be Non-Evaluable (NE) and will be regarded as no responder. 
 


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3.2.1.2 
Overall Response Rate 
Overall response rate (ORR) as per investigator is defined as the percentage of 
patients who attain complete response (CR) or partial response (PR), as per RECIST 
v1.1. Only patients with measurable disease and with tumor assessment at baseline 
will be included in the denominator of the response rate. Patients without any post-
baseline assessments will be assigned to the Non-Evaluable (NE) category and 
regarded as non-responders.  
3.2.2 
Secondary Efficacy Outcome Measures 
3.2.2.1 
Progression-Free Survival 
Progression-free survival (PFS) as per investigator is defined as the time from start of 
treatment to the first documented disease progression, as determined using RECIST 
v1.1 from tumor assessments or reported in the eCRF follow-up pages, or death from 
any cause, whichever occurs first. Patients without an event will be censored at latest 
date between the last tumor assessment and the date of treatment start.. 
3.2.2.2 
Overall Survival 
Overall survival (OS) is defined as the time from start of treatment to death from any 
cause. Patients without an event will be censored at the last date known to be alive. 
Patients without any post-baseline information will be censored at the date of treatment 
start plus one day. 
3.2.3 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
 
Incidence, type and severity of all adverse events (AEs) and serious adverse 
events (SAEs) based on National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE v4.03).  
 
Incidence and type of AEs leading to discontinuation, modification, or delay of 
trastuzumab emtansine dose.  
 
Changes in vital signs and clinical laboratory results during and following 
trastuzumab emtansine administration.  
 
Death and cause of death.  
 
Cases of drug-induced liver injury meeting Hy’s Law criteria.  
 
Pneumonitis of all grades.  
 
Change in LVEF over the course of the study as measured by echocardiogram 
(ECHO) or multiple- gated acquisition scan (MUGA).  
 
Incidence of congestive heart failure (CHF).  
3.2.4 
Pharmacokinetic Outcome Measures 
Analysis of PK/PD will be handled by Clinical Pharmacology department at Roche. 
Details of statistical methods used for PK/PD exploratory analyses will be provided in 
a separate document. 
3.3 
DETERMINATION OF SAMPLE SIZE 
The sample size estimation is based on the method of A'Hern (2001) and Simon (1989) 
and corresponding SAS programs. 
 


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To test the null hypothesis (H0) that the best BOR is 5% or less (which would yield a 
low activity profile) against the alternative hypothesis (H1) that the BOR is greater 
than or equal to 20% (which would yield an encouraging activity profile):  
 
H0: BOR  5% 
vs. H1: BOR ≥ 20%. 
27 patients per cohort would be required to perform the test with 80% power, at the 
one-sided alpha=0.05 level. To allow for drop-outs (10-15%) and to ensure that at least 
27 patients will have efficacy data available, 32 patients will be recruited per cohort on 
the respective treatment regimen. 
 
Assuming a preferable BOR of 20% is observed, then with 27 patients in a cohort, the 
95% confidence limits would range from 7.2% to 39.8% (Clopper-Pearson exact 
confidence intervals). 
 
The 95% confidence intervals for different BOR rates, and with 27 patients per cohort, 
were determined using SAS (Version 9.2) and the results are presented in Table 1: 
Estimation of Confidence Intervals for a Sample Size N = 27 (per cohort) below. 
Table 1: Estimation of Confidence Intervals for a Sample Size N = 27 (per 
cohort) 
Sample Size 
BOR 
95% Clopper Pearson Exact 
Confidence Intervals 
27 patients 
15%  
4.4% – 34.2% 
 
20%  
7.2% – 39.8% 
 
25%  
10.6% – 45.5% 
 
30%  
35%  
14.0% – 50.6%  
17.9% - 55.8% 
 
3.4 
ANALYSIS TIMING 
The following analyses are scheduled for each cohort (of note: timing of each analysis 
might differ for each cohort): 
 
 
Safety analysis for the review by iDMC of the accrued safety data of the first 
6 patients treated for at least 6 weeks. This safety review will be based on 
individual patient listings provided by the data management vendor and is not 
covered by the present SAP. 
 
Interim analysis after Stage 1 for the review by iDMC of the BOR results of 
the first 13 patients treated at least 12 weeks  
 
Primary analysis with a data cutoff 12 weeks after the last patient of the cohort 
has been recruited.  
 
Final analysis with a data cutoff 18 months after the last patient of a cohort 
has been recruited, or once all patients have reported a progression event, 
whichever occurs earlier. 
 
All data after cut-off date will be excluded from the analyses. Details of outputs to be 
produced for each analysis will be provided in Appendix 3.  
 


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The interim, primary and final analyses for efficacy will be based only on those patients 
of a cohort who started on the selected treatment regimen. If the decision is made to 
switch to Regimen B then those patients who started on Regimen A will not be included 
in the primary or final efficacy tables (whether they stay on Regimen A or switched to 
Regimen B) but their results will be included in listings.  
 
4. 
STUDY CONDUCT 
4.1 
DATA MONITORING 
An independent data monitoring committee (iDMC) will be established to monitor the 
progress of the study, ensure that the safety of patients enrolled in the study is not 
compromised, make recommendation based on safety data whether each cohort can 
be continue with Regimen A or should switch to Regimen B and make recommendation 
at end of Stage 1 based on BOR results whether the cohort should be continued or 
not. Details of the composition, roles, responsibilities and processes of the iDMC are 
documented in a separate iDMC charter.  
5. 
STATISTICAL METHODS 
The analysis specifications described in this SAP supersede the specifications 
available in the protocol. 
5.1 
DEFINITIONS OF COHORT AND REGIMENS 
Patients can enter into the study via two cohorts: 
 
Metastatic urothelial bladder cancer: This cohort consists of patients with 
locally advanced/ metastatic urothelial bladder cancer  
 
Pancreas/cholangio cancer: This cohort consists of patients with locally 
advanced/ metastatic pancreas/cholangio cancer  
Cohort as recorded on the ‘Cohort Assessment’ eCRF page will be used for the 
analysis. 
 
Patients may receive trastuzumab emtansine in two different regimens depending on 
the decision at end of safety run-in and when patients are enrolled: 
 
Regimen A: trastuzumab emtansine 2.4 mg/kg, weekly. This regimen will 
be administered to at least the first six patients in each cohort. 
 
Regimen B: trastuzumab emtansine 3.6 mg/kg every 3 weeks. This 
regimen will only be administered if decision at end of safety run-in is to 
switch to this regimen B. 
Of note: For sake of completeness, the SAP and shells have been developed in case 
both regimens are used in the study. In case, only regimen A will be used then only 
one column will have to be displayed in the outputs. 
The first received regimen (as entered in eCRF at the first treatment visit) will be used 
to classify each patient into one of the two possible regimens. 
5.2 
GENERAL DESCRIPTIVE METHODS 
Descriptive statistics will be provided for each cohort separately and by first regimen 
received and overall (i.e. if patients starting on Regimen A switch to Regimen B then 
their data will still be displayed in Regimen A column). For safety data, all data will be 
included in tables and listings, including data reported when receiving non-selected 
regimen as well as data reported after potential switch of regimen. For efficacy data, 


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only data from patients who started on the selected regimen will be included in 
summary tables and figures, but all data will be included in listings.  
For categorical variables, summary tabulations of the number and percentage within 
each category (with a category for missing data) of the parameter will be presented.  
Percentage will be calculated by using as denominators the ‘N’ in column header and 
will be rounded to one decimal place, unless specified otherwise. Therefore, there may 
be cases where for instance the total of the percentages does not exactly equal 100%. 
If number of patients is ‘0’ then 0 will be reported instead of ‘0 (0.0%)’. 
 
For continuous variables, N, mean, median, standard deviation, 25th and 75th 
percentile, minimum and maximum values will be presented. The number of missing 
is displayed between brackets next to ‘N’. Mean, standard deviation, and median will 
be presented with one more decimal place compared to the raw data, minimum and 
maximum will be presented with same number of decimal places as the raw data. 
5.3 
DEFINITION OF TREATMENT PERIOD 
The first day of treatment is defined as the earliest day of non-null trastuzumab 
emtansine administration of the first regimen received. 
 
The last day of treatment is defined as the latest day of non-null trastuzumab 
emtansine administration of any regimen received. 
 
Baseline assessments are defined as the latest assessment performed prior to the 
first day of treatment, unless otherwise stated. For vital signs, ECG, laboratory 
examinations and ECOG PS the latest available assessment within 28 days prior to or 
on the first day of treatment (this latest assessment will be assumed to have been 
performed before drug was given) will be considered as baseline evaluation.  
 
On-treatment evaluations will be evaluations performed on or after the first day of 
treatment and until 28 days from last day of treatment. 
 
On-treatment laboratory, ECOG PS, vital signs and ECG will be all values collected 
after the first day of treatment and until 28 days from last day of treatment otherwise. 
5.4 
DATA CONVENTION 
All data will be listed (e.g. pre-treatment serious adverse events), whereas only 
baseline and on-treatment evaluations will be considered for summary tables, except 
for Progression-Free and Overall Survival which will be summarized using data 
recorded during the follow-up period.    
The following conversion factors will be used to convert days to months or years, where 
applicable:  
 
1 week = 7 days 
 
1 month = 30.4375 days  
 
1 year = 365.25 days 
 
Age at informed consent (yrs) = (date of informed consent – date of birth) / 365.25. 
 
To calculate duration / time between two dates, the following convention will be used: 
[Later date] – [earlier date] + 1 day. 
 


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Durations and times between two dates will be calculated only when both start and 
end dates are available (imputed dates cannot be used for computation, apart for 
overall survival when date of death has only day as missing). 
 
The last known date to be alive will be the latest date among all dates specified in the 
eCRF except the following: 
 
Survival Follow-up date when status is either death or lost to follow-up 
 
Study Completion/Early Discontinuation Date when reason is either death or 
lost to follow-up 
 
A sample / record with test ‘Not Done’. 
 
Imputation of partial and missing dates is described in section 5.16. 
5.5 
COMPUTING ENVIRONMENT 
All descriptive statistical analyses will be performed using SAS statistical software 
(Version 9.2 or newer version), unless otherwise noted.   
5.6 
GRADING AND CODING OF ADVERSE EVENTS, 
LABORATORY PARAMETERS AND MEDICATIONS 
Laboratory results, adverse events, and other symptoms will be graded using the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event 
(CTCAE), version 4.03, except where CTC grades are not available. 
 
Adverse events and relevant Medical History data fields (i.e. prior symptoms / AEs) 
will be coded using the most recent version of MedDRA dictionary available at the time 
of analysis.  
 
Prior and concomitant anti-cancer therapy / other medications will be coded using the 
most up-to-date version of the in house Roche Drug Thesaurus dictionary. 
 
Dictionary versions used will be displayed in analysis outputs. 
5.7 
ADJUSTMENTS FOR COVARIATES 
No adjustment will be performed.  
5.8 
SUBGROUP ANALYSIS 
Analysis of primary endpoint (BOR) will be performed according to cell heterogeneity 
(percentage of HER2 positively stained tumor cells: 30-70% versus ≥ 71%). 
5.9 
ANALYSIS POPULATIONS 
5.9.1 
Safety Population 
Safety (SAF) Population: all patients who received at least one non-null dose of 
trastuzumab emtansine. The SAF population is the primary population for the analysis 
of safety parameters.  


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5.9.2 
Screened Population 
Screened (SCR) Population: all screened subjects who signed the optional informed 
consent for the additional gene protein assessment. The SCR population will be used 
for the analysis of biomarkers. 
 
5.9.3 
Efficacy Population 
The analyses of efficacy parameter will be done on the SAF population as defined in 
section 5.9.1. 
5.9.4 
Per Protocol Population 
Not applicable. 
5.10 
ANALYSIS OF STUDY CONDUCT 
5.10.1 
Patient Disposition 
The overall subject disposition table will be based on the SAF population and will 
display the following information by first regimen received and overall:    
 
Number of subjects who signed informed consent 
 
Number of subjects who met all eligibility criteria: Yes/No 
 
Number of treated subjects with any regimen (SAF): Yes/No 
 
Number of treated subjects who switch from Regimen A to Regimen B (if 
applicable): Yes/No 
 
Number of patients in ITT: Yes/No 
 
Summary of patient discontinuation and early termination will be tabulated on SAF 
population and will display the following information by first regimen received and 
overall: 
 
Number of subjects who discontinued from treatment phase and the reason 
 
Number of subjects who discontinued survival follow-up and the reason 
 
The number of patients in SAF population by country and site will be summarized by 
first regimen started and overall. 
 
Follow-up duration, defined as the time from start of treatment to the last date known 
to be alive, for patients who are still alive at the end of the study, will be estimated 
using Kaplan Meier product-method estimates. Patients who died during the study will 
be censored at the date of death. Follow-up duration will be summarized by displaying 
the following information: 
 
Number of patients with event (absence of death),  
 
Number of patients censored,  
 
Median and two-sided 95% CI computed according to Brookmeyer and 
Crowley method, 
 
25th and 75th quantile, and the corresponding two-sided 95% CI computed 
according to Brookmeyer and Crowley method, 
 
Minimum and maximum for event time. 
 
By-patient listing will be provided using SAF population for the following information: 
 
Date of start of treatment 


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 
Date of completion/discontinuation and reason for completion/discontinuation 
for the treatment phase 
 
Date of completion/discontinuation and reason for completion/discontinuation 
for the follow-up phase 
 
Primary cause of death 
 
5.10.2 
Protocol Deviations 
The protocol deviations as reported in the Protocol Deviation Management System 
(PDMS) will be considered. In PDMS, major protocol deviation is defined as any 
deviation impacting:  
 
Subject’s rights, safety or well-being 
 
Study efficacy and/or safety results 
 
The following major protocol deviations will be considered:    
 
Unfilled inclusion and/or exclusion criteria 
 
IMP dosing error 
 
Trastuzumab Emtansine dose not given according to weight assessed at D1 of 
each cycle 
 
Scheduling errors 
 
Failure to conduct Safety Follow-up visit 28 days (+-3 days) after end of study 
 
Failure to conduct Post-Treatment Follow-Up Visit, every 3 months 
 
Failure to provide full supportive care including transfusion of blood, blood 
products and antibiotics, according to standard of care 
 
Use of prohibited concomitant medication and/or procedures during course of 
treatment period including treatment with other systemic anticancer agents, 
concurrent investigational agents of any type, therapeutic agents that have a 
high risk of bleeding or might increase the risk of bleeding, and strong CYP3A4 
inhibitors 
 
Failure to follow the Toxicity Management Guidelines 
 
Failure to perform baseline total tumor burden within 30 days before the first 
dose of study drug treatment, and post-baseline assessments every 6 weeks 
(+- 3 business days) 
 
Change in tumour assessment methods without medical rationale 
 
Treatment not discontinued after withdrawal criteria are met 
 
Failure to obtain informed consent at next scheduled protocol visit if protocol 
amendment or EC/IRB requires changes to ICF 
 
Failure to report a Serious Adverse Event in accordance with timelines 
 
Any screening assessment not done or not done within timelines without 
retrospective confirmation that the missed assessment was with normal range 
 
Protocol deviations (as reported in PDMS) will be summarized by first regimen 
received and overall on SAF population: 
 
Number of patients having at least one major protocol deviations 
 
Number of subjects by major protocol deviations category as mentioned above. 
 
Number of patients having at least one non-major protocol deviations 


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 
Number of subjects by non-major protocol deviations category as defined in 
PDMS 
5.11 
ANALYSIS OF TREATMENT GROUP 
5.11.1 
Demographics and Baseline Disease Characteristics 
The following information will be summarized by first regimen received and overall on 
SAF population: 
 
Patient Demographics 
o Age 
o Age (categories: <18, 18-64, 65-84, >=85, missing) 
o Sex 
o Ethnicity 
o Race (if Asian, region will be specified) 
o ECOG Performance Status at baseline ( 0, 1, 2, 3, 4, 5) 
o HER2 positively stained tumor cells: <30%, 30-70%, > 70%. 
o Tobacco use history: Never, Current, Previous 
o Alcohol use history: Never, Current, Previous 
o Substance use: Yes, No 
o Female reproductive status (for female participants only. Percentage 
will be based on the total number of female patients) 
o Baseline weight (kg) 
o Baseline height (cm) 
 
 
Metastatic urothelial bladder cancer history (for the cohort of patients with 
metastatic urothelial bladder cancer) 
o Diagnosis confirmed histologically/ cytologically: Yes/No 
o Primary tumor site: Bladder/Ureter/Urethra/Renal Pelvis/Other 
o Intravesical therapy administered: Yes/No 
o Histology at time of enrollment: Transitional (urothelial) cell carcinoma/  
Transitional (urothelial) cell carcinoma with mixed histology 
o Time from initial diagnosis to start of treatment date (weeks) 
o Staging at initial diagnosis: Pathological/ Clinical 
o Classification of primary tumor at initial diagnosis: (TX, T0,Ta etc…)   
o Classification of regional lymph nodes at initial diagnosis (NX, N0, N1 
etc…) 
o Classification of distant metastasis at initial diagnosis (Mx, M0, M1 
etc…) 
o Status of disease at time of enrollment: locally advanced disease/ 
metastatic disease 
o Staging at time of enrollment: Pathological/ Clinical 
o Classification of primary tumor at enrollment: (TX, T0,Ta etc…)   
o Classification of regional lymph nodes at enrollement (NX, N0, N1 
etc…) 
o Classification of distant metastasis at enrollment (Mx, M0, M1 etc…) 
o Sites of metastatic disease 
o Time from first diagnosis of metastatic disease to start of treatment date 
(weeks) 
 
 
Pancreas/Cholangio cancer history (for the cohort of patients with 
pancreas/cholangio cancer) 
o Primary tumor site: Gallbladder/Intrahepatic/Vater Ampulla/Other 
o Histology: Adenocarcinoma, Squamous cell carcinoma/Small cell/ 
Undifferentiated carcinomas/Other 


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o Time from initial diagnosis to start of treatment date (weeks) 
o Stage at primary diagnosis: Stage 0, Stage1 etc… 
o Classification of primary tumor at primary diagnosis: (TX, T0,Ta etc…)   
o Classification of regional lymph nodes at primary diagnosis (NX, N0, N1 
etc…) 
o Classification of distant metastasis at primary diagnosis (Mx, M0, M1 
etc…) 
o Stage at enrollment: Stage 0, Stage1 etc… 
o Classification of primary tumor at enrollment: (TX, T0,Ta etc…)   
o Classification of regional lymph nodes at enrollment (NX, N0, N1 etc…) 
o Classification of distant metastasis at enrollment (Mx, M0, M1 etc…) 
o Location of metastases 
o Time from first metastasis to start of treatment date (weeks) 
 
 
5.11.2 
Prior and Concomitant Treatments 
5.11.2.1 
Prior Anti-Cancer Treatment/Procedure 
Prior anti-cancer treatments/procedures summary on SAF population will present the 
following information by first regimen received and overall: 
 
Number of subjects with prior tumor surgery for the cancer of interest: Yes, No 
 
Number of patient by site of prior surgery for the cancer of interest 
 
Number of patients with prior radiotherapy: Yes, No 
 
Number of patients with prior systemic cancer therapy: Yes, No 
 
Number of lines of therapy by patient: 1 prior line, 2 prior lines, etc… 
 
Number of patients by type of prior therapy: chemotherapy, immunotherapy 
etc… 
 
In addition, prior anti-cancer therapies will be tabulated on SAF by Drug/Medication 
Class and generic name/Standardized Medication Name using the in house Roche 
Drug Thesaurus dictionary. Drug Thesaurus Class will be sorted in a descending order 
of the total frequency count and the generic names with the highest frequency will be 
displayed first within each Drug Thesaurus class, unless otherwise indicated.  
 
By-patient listing will be provided using SAF population for the following information: 
 
Prior tumor surgery other than  cancer of interest  
 
Prior tumor surgery for cancer of interest  
 
Prior systemic cancer therapy 
 
Prior cancer radiotherapy 
5.11.2.2 
Non Anti-Cancer Treatment/Procedure 
Prior medication is defined as any medication with end date prior to the start of the first 
day of treatment. Methods for handling partial or complete missing medication date are 
detailed in section 5.17. 
 
Concomitant medication is defined as any medication/therapy with: 
 
start date until 28 days from last day of treatment  
 
end-date on or after first day of treatment or missing (ongoing). 
 
Prior and concomitant therapies will be listed. 
 


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5.11.2.3 
On-Study Anti-Cancer Treatment/Procedure 
By-patient listing will be provided using SAF population for the following information 
coming from eCRF dedicated pages: 
 
On-study cancer radiotherapy (Brain Therapy)  
 
On-study cancer surgery 
5.11.3 
Subsequent Anti-Cancer Therapy 
Subsequent anti-cancer therapies (as reported on the ‘Subsequent anti-cancer 
therapies’ CRF page) will be listed. 
5.12 
EFFICACY ANALYSIS 
Efficacy analysis will be conducted on SAF population.    
5.12.1 
Primary Efficacy Endpoint 
The primary efficacy objective of this study is to determine the best overall tumor 
response (BOR) as per RECIST 1.1 for all treated patients. 
 
To answer the primary objective, the following hypotheses will be tested: 
 
H0: the best response rate is 5% or less, which would yield a low activity profile 
 
H1: the best response rate is greater than or equal to 20%, which would yield 
an encouraging activity profile 
H0: best response rate ≤ 5% vs H1: best response rate ≥ 20% 
 
A Simon's two-stage design (Simon 1989) will be used to allow the study to stop early 
if there is no evidence of efficacy. The null hypothesis that the true response rate (BOR) 
is ≤ 5% will be tested against a one-sided alternative.  
 
 
In the first stage, 13 patients in each cohort will be accrued and their BOR 
results will be evaluated 12 weeks after the 13th patient was enrolled. If there 
are 0 responses (CR or PR) in these 13 patients, the study will be stopped for 
the respective cohort. Otherwise, 14 additional patients will be accrued per 
cohort for a total of 27.  
 
 
In the second and last stage, H0 will be rejected if the lower bound of the 90% 
confidence interval is greater than 5%. The minimum number of responders 
that will permit to reject H0 will depend of the final number of patients with 
evaluable response data. For example, 4 or more responders will permit to 
reject H0 if the number of patients is 27 or 28, where 5 or more responders will 
be needed if the number of patients between 29 and 32. 
 
This is an early phase II study, hence there will be no adjustment for multiplicity. 
 
Number and percentage of responders (i.e. subjects with objective response (CR or 
PR) as best overall response) with corresponding Clopper-Pearson 90% confidence 
interval will be provided. (Note: 90% CI (instead of 95% CI) will be used to be aligned 
with the testing at one-sided alpha level = 5%) 
 
The following SAS code will be used: 
PROC FREQ DATA= dataset; 
TABLE response/ binomial (clopperpearson level='1') alpha=0.1;run; 
* response represents the response variable; 


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Further options to control the output may be added. 
 
The number and percentage of each response category will also be presented. 
 
Analysis will be repeated by subgroups of cell heterogeneity. 
 
By-patient listing will be provided using SAF population for the following information:  
 
Tumor assessment and overall response per timepoint as per investigator 
 
Best overall response as per investigator  
5.12.2 
Secondary Efficacy Endpoints 
5.12.2.1 
Progression-Free Survival 
PFS will be estimated using Kaplan Meier product-method estimates. PFS will be 
summarized by displaying the following information: 
 
Number of patients in the population (N),  
 
Number of patients with PFS event,  
 
Number of patients censored,  
 
Median and two-sided 95% CI computed according to Brookmeyer and 
Crowley method, 
 
25th and 75th quantile, and the corresponding two-sided 95% CI computed 
according to Brookmeyer and Crowley method, 
 
Minimum and maximum for event time 
 
Minimum and maximum for censored time 
 
The event rates at certain time points (e.g. 3, 6, 9 and higher (every 3 months) 
if appropriate) with the relevant two-sided 95% CIs. 
 
Kaplan-Meier estimates and median survival times are calculated with the PROC 
LIFETEST procedure in SAS. The CIs of the event rates will be calculated via log-log 
transformation method (default option CONFTYPE=LOGLOG in SAS) based on 
standard errors computed using the Greenwood’s formula.  
 
The following SAS code will be used: 
PROC LIFETEST data=dataset METHOD=KM CONFTYPE=LOGLOG; 
TIME survtime*censor(1); 
RUN; 
* survtime represents variable containing event/censor times; 
* censor represents censoring variable (1=censored, 0=event); 
Further options to control the output may be added. 
 
Kaplan Meier (KM) plot of PFS will be generated. 
 
PFS time will be listed on SAF population. 
5.12.2.2 
Overall Survival 
The same analysis as for PFS will be repeated for OS.  
5.12.2.3 
Duration of response 
Duration of response (DOR) is defined as the time from the first occurrence of 
response (complete response [CR] or partial response [PR], whichever is first reported) 
to disease progression, as determined by the investigator according to RECIST v1.1, 


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or death from any cause, whichever occurs first, among patients with a best overall 
response as CR or PR.  
Patients who are alive and have not experienced disease progression will be censored 
at the time of the last tumor assessment date. If no tumor assessments were performed 
after the date of the first occurrence of a CR or PR, DOR will be censored at the date 
of the first occurrence of a CR or PR plus 1 day. 
If there is a sufficient amount of responders (patients with a best overall response as 
CR or PR), DOR will be estimated using Kaplan Meier product-method estimates. DOR 
will be summarized by displaying the following information: 
 
Median and two-sided 95% CI computed according to Brookmeyer and 
Crowley method. 
DOR time will be listed on SAF population. 
5.12.3 
Sensitivity Analyses 
No sensitivity analysis are planned. 
5.13 
PHARMACOKINETIC AND PHARMACODYNAMIC 
ANALYSES 
Analysis of PK/PD will be handled by Clinical Pharmacology department at Roche. 
Details of statistical methods used for PK/PD exploratory analyses will be provided in 
a separate document.  
5.14 
SAFETY ANALYSES 
Safety summaries will be produced by first regimen received and overall on the SAF 
population.  
5.14.1 
Exposure of Study Medication 
5.14.1.1 
Treatment Duration and Dose Exposure 
Definition of treatment duration, cycle initiated and dose exposure variables are in 
Table 2. 
 
Table 2: Exposure Definitions  
 
Regimen A  
(2.4 mg/kg weekly) 
Regimen B  
(3.6 mg/kg every 3 weeks) 
Time on 
Treatment (in 
weeks) 
[min (last treatment day+7, death 
date, discontinuation date of 
treatment) – (first treatment day) +1] 
/ 7. 
Note: Subjects still on treatment will 
be censored at minimum date 
between (cut-off date, last known 
drug administration date) 
 
[min (last treatment day+21, 
death date, discontinuation date 
of treatment) – (first treatment 
day) +1] / 7. 
  
Note: Subjects still on treatment 
will be censored at minimum date 
between (cut-off date, last known 
drug administration date) 
Number of cycles 
initiated 
The number of cycle initiated will 
correspond to the number of non-
null treatment dose administered at 
a “Day 1” visit in the eCRF. 
 
The number of cycle initiated will 
correspond to the number of non-
null treatment dose administered 
at a “Day 1” visit in the eCRF. 


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Regimen A  
(2.4 mg/kg weekly) 
Regimen B  
(3.6 mg/kg every 3 weeks) 
Cumulative dose 
(in mg) 
Sum of all dose administered (in mg) as reported on ‘Trastuzumab 
emtasine administration eCRF page’ . 
 
Note: If patients switch from regimen A to regimen B, the different period of treatment 
will be summed for the time on treatment, number of cycles initiated and cumulative 
dose 
Time on treatment (in weeks) and cumulative dose (in mg) will be summarized using 
descriptive statistics, by first regimen received and overall. 
 
In addition, number of cycles initiated by patient considered as both continuous and 
categorical variables will also be summarized using descriptive statistics.  
5.14.1.2 
Infusion Interrupted or Delayed 
Infusion interruption/ delayed as reported on the ‘Traztuzumab Emtansine 
Administration’ eCRF page will be summarized by first regimen received and overall. 
The following will be displayed: 
 
Number of patients with at least one infusion interrupted/delayed 
 
Infusion interrupted/delayed per patient: as continuous and as categorical (1, 
2, 3, or ≥3). 
 
Reason for interrupted/delayed infusion 
5.14.1.3 
Infusion Rate Reduction 
Infusion rate reduction as reported on the ‘Traztuzumab Emtansine Administration’ 
eCRF page will be summarized by first regimen received and overall. The following 
will be displayed: 
 
Number of patients with at least one infusion rate reduced 
 
Number of infusion rate reductions per patient: (1, 2). 
 
Reason for first infusion rate reduction 
 
Reason for second infusion rate reduction. 
 
By patients listings will be provided for the following information. 
 
Drug administration. 
 
Drug exposure,  
 
Infusion rate interrupted delayed, 
 
Infusion rate reduction and reason. 
5.14.2 
Adverse Events 
Adverse events variables are defined in Table 3. Adverse events outputs will include 
all adverse events including those reported as infusion-related reactions. 
Tables outputs will include only the Treatment Emergent Adverse Events. All events 
recorded in eCRF will be presented in listings, with a flag for emergence from the first 
day of treatment until last day of administration + 28 days. 
 
Table 3 : Adverse Events Definitions 
Variable 
Definition 
Treatment 
Emergent 
Adverse 
Events 
(TEAEs)(1)  
Any adverse events (serious and non-serious) with an onset 
date on (only if the “Event occurred prior to first Trastuzumab 
Emtansine administration” from the AE eCRF page is not 


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Variable 
Definition 
checked) or after the first day of treatment and until  last day 
of administration +28  days  
Adverse Events NCI 
CTCAE grade 
The adverse events grade displayed in the AE summary 
table will be the one with tick box checked for "AE most 
extreme NCI CTCAE grade". Any AEs with a missing CTC 
grade will be reported in the “missing” category grade.  
Serious 
Adverse 
Events (SAEs) 
Any adverse events with “Serious” box checked for “Is this 
AE non-serious or serious?”. In case of missing seriousness, 
TEAE will be considered serious.  
Adverse events related 
to 
Trastuzumab 
Emtansine 
Any adverse events with ‘Yes’ for “AE suspected to be 
caused by Trastuzumab Emtansine” 
Adverse Events with 
fatal outcome 
Any adverse events with tick box checked for “It resulted in 
death” or with a most extrement NCI CTCAE grade equal to 
5 
Adverse events leading 
to 
Trastuzumab 
Emtansine 
discontinuation 
Any adverse events with an “Action taken with Trastuzumab 
Emtansine due to SAE/AE” of “drug withdrawn” 
Adverse events leading 
to 
Trastuzumab 
Emtansine modification 
Any adverse events with an “Action taken with Trastuzumab 
Emtansine due to SAE/AE” of “drug interrupted”, “dose 
reduced”, “drug withdrawn” or “dose delayed” 
Adverse 
events 
of 
Special Interest (AESI) 
based 
on 
eCRF 
categories 
Any adverse events with “Yes” box checked for “Is this an 
adverse event of special interest?” in the eCRF  AESIs will 
be summarized based on the tick box from the eCRF. The 
categories from the AE eCRF page will be considered. 
Selected 
Adverse 
events  
Selected adverse events will be defined by Roche Safety 
group in Excel file. 
It will include (drug-induced liver injury meeting Hy’s Law 
criteria., pneumonitis, congestive heart failure, hepatic 
events, allergic reactions, thrombocytopenia, hemorrhage 
events) 
 
An overview table will be provided by first regimen received and overall, and will display 
number and percentage of patients with at least one: 
 
TEAE 
 
TEAE by CTC most extreme grade: 1, 2, 3, 4, 5, >=3,missing 
 
TEAE  related to Trastuzumab Emtansine 
 
Serious TEAE 
 
Serious TEAE (SAE) related to Trastuzumab Emtansine 
 
TEAE with fatal outcome 
 
TEAEs leading to discontinuation of Trastuzumab Emtansine 
 
TEAEs leading to modification of Trastuzumab Emtansine 
 
TEAE of special interest  


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 
Serious TEAE of special interest  
 
The incidence of TEAEs will be summarized by worst intensity (grade 1 - grade 5, 
missing, overall) and will display number of patients with at least one TEAE, for the 
following AEs: 
 
TEAE  
 
TEAE related to Trastuzumab Emtansine 
 
Selected TEAEs  
 
The TEAE tables will include the number and percentage of patients with at least one 
TEAE, by MedDRA primary System Organ Classes (SOC) (sorted in descending order 
of the total frequency count) and MedDRA Preferred Terms (PT) (sorted in descending 
order of the total frequency count within each SOC) unless otherwise indicated. A 
patient with more than one occurrence of the same adverse event in a particular 
system organ class/preferred term will be counted only once in the total of those 
experiencing adverse events in that particular system organ class/preferred term. 
 
The above summary tables will be repeated for the following categories of TEAEs; 
however the following tables will not be split by intensity. 
 
TEAE with NCI CTCAE grade >=3 
 
TEAE of special interest based on the eCRF categories 
 
Serious TEAE  
 
Serious TEAE related to Trastuzumab Emtansine 
 
Serious TEAE of special interest  
 
TEAEs leading to discontinuation of Trastuzumab Emtansine 
 
TEAEs leading to modification of Trastuzumab Emtansine 
 
TEAE with fatal outcome 
 
 
 
To address EudraCT requirements, the following tables by first regimen received and 
overall will be produced: 
 
Summary of serious treatment emergent adverse events, presenting number 
of subjects with event, number of events, number of treatment related events, 
number of events resulting in death, number of treatment related events 
resulting in death 
 
Summary of non-serious treatment emergent adverse events reported in at 
least 5% of subjects in any regimen, presenting number and percentage of 
subjects with event, number of events 
For these specific EUdraCT tables, the SOC/PT categories will be sorted by 
alphabetical order. 
 
In addition, by-patients listing will be provided. All AEs regardless of emergent status 
will be listed with the following items: 
 
All adverse events 
 
All adverse events with Missing or Partial Start Date 
 
All adverse events of grade 3 or more 
 
All serious adverse events 
 
All adverse events leading to treatment discontinuation 
 
All AESI based on the eCRF categories 
 
All selected adverse events 


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5.14.3 
Infusions-Related Reactions (IRR) 
Infusion-related reaction will also be described separately on SAF by first regimen 
received and overall. 
Infusion-related reaction is defined as any adverse events with “Infusion Related 
Reaction” box checked in the eCRF. 
An overview table will be provided by first regimen received and overall, and will display 
number and percentage of patients with at least one: 
 
IRR 
 
IRR by CTC most extreme grade: 1, 2, 3, 4, 5, >=3,missing 
 
IRR related to Trastuzumab Emtansine 
 
Serious IRR related to Trastuzumab Emtansine 
 
IRR with fatal outcome 
 
IRR leading to treatment discontinuation of Trastuzumab Emtansine 
 
IRR leading to treatment modification of Trastuzumab Emtansine 
 
The summary tables by SOC and PT will be provided for: 
 
IRR by worst NCI CTCAE grade 
 
IRR related to Trastuzumab Emtansine by worst NCI CTCAE grade 
 
IRR with NCI CTCAE grade >=3 
 
Serious IRR 
 
Serious IRR related to Trastuzumab Emtansine 
5.14.4 
Death 
A summary table will be provided on SAF by first regimen received and overall, and 
will present: 
 
Number of patients who died with the corresponding cause of death 
 
Number of patients who died within 28 days from last day of study drug 
administration and the corresponding cause of death. 
 
Listing of deaths, dates and cause of deaths will be provided.  
5.14.5 
Laboratory Data 
Laboratory parameters include: 
 
Hematology: hemoglobin, hematocrit, red blood cells [RBC], platelet count, 
white blood cells [WBC] with differential [including neutrophils, lymphocytes, 
monocytes, eosinophils and basophils] 
 
Biochemistry: glucose, blood urea nitrogen [BUN], creatinine, sodium, 
potassium, bicarbonate, phosphorus, chloride, calcium, uric acid, total protein, 
albumin, total bilirubin, direct bilirubin, alkaline phosphatase, lactate 
dehydrogenase [LDH], AST, ALT, gamma-glutamyl-transferase [GGT]. 
 
Coagulation (as clinically indicated): INR and aPTT. 
 
Urinalysis: pH, specific gravity, glucose, protein, ketones, blood, bilirubin and 
microscopic examination including sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, bacteria 
 
Clinical laboratory values will be expressed using conventional SI units. 
 
 


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All laboratory values will be listed. Separate listings will be generated to include all 
abnormal laboratory values, urinalysis and serology. 
 
5.14.6 
Vital Signs 
Vital sign parameters include: 
 
Temperature (C) 
 
Pulse rate (beats/min) 
 
Respiratory rate (breaths/min) 
 
Systolic blood pressure (mmHg) 
 
Diastolic blood pressure (mmHg) 
 
Weight (kg) 
 
Oxygen saturation (%) 
 
 
All vital signs data will be listed. 
5.14.7 
ECOG PS 
 
All ECOG PS will be listed. 
5.14.8 
Left Ventricular Ejection Fraction (LVEF) 
Actual value (as continuous and categorical variable) and change from baseline for 
LVEF (%) will be summarized by first regimen received and overall, for each visit using 
descriptive statistics.  
 
Worst on treatment value (as categorical variable with categories >45%,40-45% and 
<10% drop from baseline, 40-45% and >=10% drop from baseline, <40%) will also be 
described by first regimen received and overall. 
 
All LVEF data will be listed. 
 
A boxplot figure describing the LVEF percentage over time will be provided. The figure 
will present boxplots of LVEF values at each visit from screening to the last visit with 
at least 5 non missing LVEF values. 
5.14.9 
Electrocardiogram 
All ECG data will be listed. 
5.15 
BIOMARKER ANALYSIS 
A descriptive analysis of HER2 status will be performed. 
HER2 status and proportion of positively stained tumor cells, in categories, by 
immunohistochemistry (IHC), will be summarized overall, by cohort and for both 
cohorts combined. This analysis will be performed on the SAF population. 
HER2 IHC status and proportion of positively stained tumor cells will also be 
summarized, in correlation with the presence of gene amplification (gene protein 
assay). This analysis will be performed on the SCR population. 


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In addition, all data related to HER2 biomarker will be listed. 
5.16 
MISSING DATA  
 
Imputation of partial/missing death date will be done as follows:  
 
If the date is completely missing, then the day of “Last known to be alive” +1 
will be used  
 
If only day is missing and year and month are same as “Last known to be alive”, 
then the day of “Last known to be alive”+1 will be used otherwise the 1st day of 
the month will be used 
 
If day and month are missing and year is same as “Last known to be alive”, 
then the “Last known to be alive”+1 will be used, otherwise 1st of January will 
be used 
 
Partially missing dates for adverse events (AEs) will be imputed as follows. Of note, 
imputation of missing/partial AE date will be done only to identify treatment emergent 
AEs. 
 
AE onset dates 
 
Partially missing onset dates will be imputed as follows 
o When only Day is missing :  
 
If Month & Year of the onset date are the same as Month & Year 
of first day of treatment, the imputed onset date will be imputed 
as the minimum of first day of treatment and the AE resolution 
date (imputed if needed). 
 
Otherwise, the missing day will be replaced by “1”. 
o When Day & Month are missing:  
 
If Year of the onset date is the same as Year of first day of 
treatment, the imputed onset date will be imputed as the 
minimum of first day of treatment and the AE resolution date 
(imputed if needed). 
 
Otherwise, the missing Day & Month will be replaced by 
“01JAN”. 
 
 
Complete missing onset dates for AEs will be imputed by first day of treatment 
and the AE will be considered as treatment emergent, unless the end date of 
the AE (imputed if needed) or the end year of the AE (if day and month are 
missing) is entered and is before the year of the first day of treatment. 
 
AE resolution dates 
 
Incomplete resolution dates will be replaced by the last day of the month (if day 
is missing only), if not resulting in a date later than the date of patient's death. 
In the latter case the date of death will be used to impute the incomplete 
resolution date. 
 
In all other cases the incomplete resolution date will not be imputed. 
 
Partially missing dates for medications and procedures will be imputed as follows. Of 
note, imputation of missing/partial medications/procedures date will be done only to 
identify concomitant medications/procedures. 
 
If the start date of the medication/procedure is unknown (i.e. complete missing 
date) and there is no end date, the worst-case scenario will be assumed. The 
medication/procedure will be considered as both a prior medication/procedure 
and a concomitant medication/procedure for both treatment periods. In case 
there is an unknown start date but the end date is known and is prior to the first 


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day of treatment, then the medication/procedure will not be considered as 
concomitant for the first treatment period/post-progression treatment period.  
 
If the month and the day of the start date of the medication/procedure are 
missing and there is no end date, the month and the day will be imputed to 
January, 1st of the year specified. In case the month and the day of the start 
date are unknown but the end date is known and is prior to the first day of 
treatment, then the medication/procedure will not be considered as 
concomitant for the first treatment period /post-progression treatment period.  
 
If the day of the start date of the medication/procedure is missing and there is 
no end date, the day will be imputed to the first day of the month specified. In 
case the day of the start date is unknown but the end date is known and is prior 
to the first day of treatment, then the medication/procedure will not be 
considered as concomitant for the first treatment period/post-progression 
treatment period.  
 
If the end date is unknown (i.e. missing), the date will be kept as missing 
however the medication/procedure will be considered concomitant. 
 
If the month and the day of the end date of the medication/procedure are 
missing, the month and the day will be imputed to December, 31st of the year 
specified. 
 
If the day of the end date of the medication/procedure is missing, the day will 
be imputed to the last day of the month specified.  
 
No other dates will be imputed, unless otherwise specified. The original incomplete or 
missing dates will be presented in the listings, not the imputed dates. 
5.17 
INTERIM ANALYSES 
The first 6 patients of each cohort will be analyzed on an ongoing and per patient basis 
– i.e. based on the tolerability criteria (as defined in the iDMC charter) and in 
consultation with the SC and iDMC if needed. Further, there will be an analysis of the 
safety data after the first 6 patients of a cohort have completed 2 cycles of Regimen A. 
The results will be made available to the IDMC in order for them to make the decision 
as to whether to continue with Regimen A or to switch to Regimen B.  
 
There will be analysis of the ORR results for the first 13 patients of each cohort (12 
weeks after the 13th patient has been enrolled) in the selected treatment regimen. This 
will be done in order to decide whether to stop the study or not (as outlined in Section 
3).  
5.17.1 
Optional Interim Analysis  
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct additional interim efficacy analyses. The decision to conduct an optional 
interim analysis and the timing of the analysis will be documented in the Sponsor’s trial 
master file prior to the conduct of the interim analysis. The interim analysis will be 
performed and interpreted by Sponsor study team personnel, who will have full access 
to the data. 


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6. 
REFERENCES 
A'Hern, RP (2001). Sample size tables for exact single-stage phase II designs. 
Statistics in Medicine ; 20(6):859-866. 
Simon R. (1989) Optimal two-stage designs for phase II clinical trials. Control Clin 
Trials. 10(1):1-10. 
Clopper, C.; Pearson, E. S. (1934). "The use of confidence or fiducial limits illustrated 
in the case of the binomial". Biometrika. 26: 404–413. 
Kaplan, E. L.; Meier, P. (1958): Nonparametric estimation from incomplete 
observations. J. Amer. Statist. Assn. 53:457–481. 
 
 


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Appendix 1  
Protocol Synopsis 
 
 
 
 
 
 
Objectives and Endpoints 
This study will evaluate the efficacy, safety and pharmacokinetics of trastuzumab emtansine in 
patients with locally advanced (unresectable and not treatable with curative intent) or metastatic 
urothelial bladder cancer (UBC) or locally advanced (unresectable and not treatable with 
curative intent) or metastatic pancreatic cancerlcholangiocarcinoma. Specific objectives and 
corresponding endpoints for the study are outlined below. 
Objectives 
Corresponding Endpoints 
Primary Efficacy Objective: 
• To evaluate the efficacy of 
• Best overall response rate (BOR) as determined by 
trastuzumab emtansine 
the investigator (using RECIST 1.1 ). BOR is defined 
as the best response recorded from the first day of 
study treatment until disease progression/recurrence 
or death. Responders, as assessed every 6 weeks, 
will be defined based on tumor assessment status as 
partial responder (PR) or complete responder (CR) at 
these time points. To be assigned a status of PR or 
CR (i.e., a responder), changes in tumor 
measurements must be confirmed by repeat 
assessments that should be performed no less than 
4 weeks after the criteria for response are first met, 
i.e., patients need to have two consecutive 
assessments of PR or CR to be a responder. 


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Secondary Efficacy Objective: 
• To evaluate the efficacy of 
• Progression-free survival (PFS), defined as the time 
trastuzumab emtansine 
from beginning of treatment to the first occurrence of 
disease progression, as determined by the 
investigator (using RECIST 1.1 ), or death from any 
cause, whichever occurs first. 
• Overall survival (OS), defined as the time from 
beginning of treatment to death from any cause. 
Safety Objective: 
• To evaluate the safety of 
• Incidence, type and severity of all adverse events 
trastuzumab emtansine 
(AEs) and serious adverse events (SAEs) based on 
National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE v4.03). 
• Incidence and type of AEs leading to 
discontinuation, modification, or delay of 
trastuzumab emtansine dose. 
• Changes in vital signs, physical examination 
findings, and clinical laboratory results during and 
following trastuzumab emtansine administration. 
• Death and cause of death. 
• Cases of drug-induced liver injury meeting Hy's Law 
criteria. 
• Pneumonitis of all grades. 
• Change in left ventricular ejection fraction (L VEF) 
over the course of the study as measured by 
echocardiogram (ECHO) or multiple-gated 
acquisition scan (MUGA). 
• Incidence of congestive heart failure (CHF). 
Pharmacokinetic Objective: 
• To characterize the 
• Concentrations of trastuzumab emtansine in 
pharmacokinetics of trastuzumab 
plasma/serum to determine exposure. 
emtansine 


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(Exploratory) lmmunogenicity Objective: 
• To evaluate the immune response to 
trastuzumab emtansine 
Exploratory Biomarker Objective: 
• To identify biomarkers that are 
predictive of response, can provide 
evidence of trastuzumab emtansine 
activity, or can increase the 
knowledge and understanding of 
disease biology 
Study Design 
Description of Study 
• Incidence of anti-therapeutic antibodies (ATAs) 
during the study relative to the prevalence of AT As 
at baseline. 
• Exploratory assessment of immune checkpoints and 
infiltrating lymphocyctes in the tumor before and 
after treatment by the assessment of immune-
related biomarkers such as POL 1 and CDS. 
• To further evaluate the HER2 status by other 
exploratory testing methods such as a novel 
gene-protein assay (GPA), e.g. 
immunohistochemistry {IHC) and in situ hybridization 
(/SH) combined in one assay on samples of all 
consenting screened patients. 
• Correlate levels of HER2 protein expression, HER2 
gene amplification and circulating HER2 
extracellular domain (HER2 ECO) to trastuzumab 
emtansine efficacy. 
• To evaluate biornarkers that may be associated with 
response and/or safety on the protein, RNA and 
DNA level (e.g. by molecular subtyping and gene 
mutation analysis). 
This is an exploratory, multicenter. non-randomized, Phase 11, single agent cohort study 
designed to evaluate the efficacy of trastuzumab emtansine in patients with locally advanced 
(unresectable and not treatable with curative intent) or metastatic urothelia/ bladder cancer 
(I.JBCJ or locally advanced (unresectable and not treatable with curative intent) or metastatic 
pancreatic cancerlcholangiocarcinoma. 
Numbe< of Patients 
In total, 32-38 patients will be enrolled per cohort; 64-76 patients in total. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Histologically centrally confirmed HER2-positive (IHC3+ in a: 30% of tumor cells}: locally 
advanced (unresectab/e and not treatable with curative intent) or metastatic urothelial 
bladder cancer or locally advanced (unresectable and not treatable with curative intent) or 
metastatic pancreatic cancerlcholangiocarcinoma. 
HER2 status may be pre-screened at the participating site. However, HER2 determination 
at the referral center is not accepted to determine study eligibility. HER2 positivity needs to 
be prospectively oonfirmed with central laboratory HER2 testing before patient enrollment. 
• 
There must be no standard treatment options available for patients with the above HER2 
overexpressing tumors and they must have undergone at least one prior platinum-based 
treatment for locally advanced (unresectable and not treatable with curative intent) or 
metastatic tumor. (Note: for pancreatic cancerlcholangiocarcinoma, prior treatments are 
NOT required to be platinum-based.) 
• 
The patient must have evaluable disease fulfilling all of the following imaging criteria: 


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a. On diagnostic computed tomography scan/magnetic resonance imaging: lesion should 
be measurable according to RECIST 1.1. 
b. Target lesion(s) should not have been previously irradiated. 
• 
At least one formalin-fixed paraffin-embedded biopsy of the primary tumor and/or from a 
metastatic site is required. 
• 
Age ;, 18 years. 
• 
Eastern Cooperative Onoology Group performance status of 0-2. 
• 
No significant cardiac history and a current LVEF ;, 50%. LVEF should be determined withn 
28 days before the start of trastuzumab emtansine treatmenl 
• 
Adequate organ function, evidenced by the following laboratO<)' results (performed within 
7 days poor to commencement of dosing): 
a. Absolute neutrophil count > 1,500 cells/mm•. 
b. Platelet count> 100,000 cells/mm'. 
c. 
Hemoglobin > 9 g/dl. 
d. Aspartate aminotransferase and alanine aminotransferase < 2.5 x upper limit of normal 
(ULN). 
e. Total bilirubin :s: 1.5 x ULN unless the patient has documented Gilbert' s syndrome, in 
which case direct (conjugated) bilirubin level needs to be within normal limits. 
f. 
Serum alkaline phosphatase :s: 2.5 x ULN. Patients with bone metastases: alkaline 
phosphatase :s: 5 x ULN. 
g. Serum creatinine < 2.0 mg/dl or < 177 µmoli\.. 
h. International normalized ratio and activated partial thromboplastin time or partial 
thromboplastin time < 1.5 ULN. 
• 
Absence of any psychological, familial, sociological or geographical condition potentially 
hampering compliance with the study protocol and follow-up schedule; those conditions 
should be discussed with the patient before registration in the study. 
• 
Negative serum pregnancy test for women of childbearing potential (including pre-
menopausal women who have had a tubal ligation) and for an women not meeting the 
definition of postmenopausat (l< 12 months of amenorrhea), and who have not undergone 
surgical sterilization with a hysterectomy and/or bilateral oophorectomy. For all other 
women, documentation must be present In medical history confirming that the patient is not 
of childbearing potential. 
For women of childbearing potential and men with partners of childbearing potential, 
agreement by the patient and/or partner to use a highly effective non-hormonal form of 
contraception such as surgical sterilization or two effective forms of non-hormonal 
contraception until 7 months after the last dose of trastuzumab emtansine. 
Methods of birth control are considered highly effective forms of oontraception in case they 
result in a low failure rate (i.e.,< 1% per year) when used consistently and correctly. The 
use of the following non-honnonal methods of contraception is acceptable: 
a. True abstinence, when this is the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, and symptothermat post ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
b. Male sterilization (with appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate). For female patients, the vasectomized male partner should be 
the sole partner. 
Alternatively, use of two of the following effective forms of contraception is acceptable: 
a. Placement of intrauterine device or intrauterine system. Consideration should be given 
to the type of device being used, as there are higher failure rates for certain types (e.g., 
steel or copper wire). 
b. Condom with spermicidal foam/geVfilm/cream/suppository. 


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c. Occlusive cap (diaphragm or cervicaVvault caps) with spermicidal 
foam/gel/film/cream/suppository. 
The use of barrier contraceptives should always be supplemented with the use of a 
spenmicide. The following should be noted: Failure rates indicate that, when used alone, the 
diaphragm and condom are not highly effective forms of contraception. Therefore, the use 
of additional spermicides does confer additional theoretical contraceptive protection. 
However, spenmicides alone are ineffective at preventing pregnancy when the whole 
ejaculate is spilled. Therefore, spermicides are not a barrier method of contraception and 
should not be used alone. 
• 
Signed written informed consent approved by Ethics Committee and obtained prior to any 
study procedure. 
• 
Life expectancy of at least 12 weeks. 
Exclus;oo Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Patients with previous exposure to HER2-targeted therapies in any setting. 
• 
Patients showing histologically confinmed focal HER2-expression, i.e., < 30% of positively 
stained tumor cells. 
• 
Patients with brain metastasis as the sole site of metastatic disease and are symptomatic or 
require therapy to control symptoms. 
NB: Brain metastases are allowed provided they are asymptomatic and/or controlled by 
previous radiotherapy. 
• 
Current uncontrolled hypertension (systolic> 150 mmHg and/or diastolic> 100 mm Hg). 
• 
Current unstable angina pectoris. 
• 
History of symptomatic CHF of any New York Heart Association aiteria or ventricular 
arrhythmia that requires treatment. 
• 
History of myocardial infarction within the last 6 months. 
• 
Peripheral neuropathy, Grade.? 3. 
• 
Current dyspnea at rest due to complications of advanced malignancy, or other diseases 
that require continuous oxygen therapy. 
• 
Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary, or metabolic disease; wound healing disorders; ulcers; or bone fractures). 
• 
History of other malignancy within the last 5 years, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, stage I uterine cancer, or 
other cancers with a similar outcome as those previously mentioned. 
• 
For female patients, current pregnancy and lactation. 
• 
Concurrent, serious. uncontrolled infections or current known infection with human 
immunodeficiency virus, active hepatitis B and/or hepatitis C. 
• 
Known prior severe hypersensitivity to trastuzumab and trastuzumab emtansine or the 
excipients of the investigational medicinal product (IMP). 
• 
Clinically significant bleeding within 30 days before enrollment 
• 
Major surgical procedure or significant traumatic injury within 28 days prior to randomization 
or anticipation of the need for major surgery during the course of study treatment 
• 
Concurrent participation in any other therapeutic clinical trial. 
End of Study 
Each oohort will close 18 months alter the last patient was recruited or once all patients have 
died or withdrawn from study, whatever happens first 
End of study for a cohort will be declared at the last patient last visit (LPL V) as per definition is 
the last data collection point, which can be a clinic visit or a laboratory sample. 


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Length of Study 
The total length of the study for an individual cohort, from screening of the first patient to the 
end of the study. is expected to be approximately 3 years (18 months of recruitment, an 
expected 6 months of treatment and a further 12 months of follow-up). 
Patients will receive study medication until unacceptable toxicity, withdrawal of consent, disease 
progression, or death, whichever occurs first. 
The data cutoff for the primary analysis of BOR will take place 12 weeks after the last patient of 
an individual cohort has been recruited (following a tumor assessment after 6 weeks [2 cycles] 
with a confirmation of BOR performed no less than 4 weeks after the criteria for response are 
first met. 
The data cutoff for the final analysis for each cohort of all primary and secondary efficacy 
measures will take place 18 months after the last patient of a cohort was recruited, or once all 
patients have reported a progression event, whichever occurs earlier. 
lnvestigational Medicinal Products 
Test Product (lnvestigational Drug) 
The IMP for this study is trastuzumab emtansine (Kadcyla). 
Trastuzumab emtansine will be administered by intravenous infusion 
• 
Regimen A: trastuzumab emtansine 2.4 mg,1<g, weekly 
• 
Regimen B: trastuzumab emtansine 3.6 mg,1<g every 3 weeks. 
In a safety run-in, the first 6 patients of each cohort wil enter Regimen A and receive 2.4 mg/kg 
weekly trastuzumab emtansine. These first 6 patients will be assessed on an ongoing and 
patient per patient basis - i.e. based on the tolerability criteria (as defined in the Independent 
Data Monitoring Committee (iDMC] charter) and in consultation with the Steering Committee 
(SC) and iDMC if needed. Recruitment for the respective cohort will be suspended until all 6 of 
these patients have completed the 2nd cycle (6 weeks) and the 'regimen decision point' has 
been reached. Based on tolerability and safety aspects, the iDMC will decide for each cohort if 
the study is to continue on Regimen A (2.4 mg/kg qw), extending recruitment to a total of 32 
patients {additional 26 patients) per cohort, or if the dose switches to Regimen B (3.6 mg/kg 
q3w). If the regimen is changed to Regimen B, 32 additional patients will be included per cohort; 
if the regimen remains unchanged (i.e., Regimen A), only 26 additional patients will be recruited. 
Statistical Methods 
The first 6 patients of each cohort will be analyzed on an ongoing and patient per patient basis -
i.e. based on the tolerability criteria (as defined in the iDMC charter) and in consultation with the 
SC and iDMC if needed. 
Primary Analysis 
The primary efficacy endpoint BOR will be analyzed as follows: 
Responders as assessed every 6 weeks will be defined based on tumor assessment status of 
PR or CR at these time points. Only patients with measurable disease at baseline will be 
included in the analysis of the response rate. Patients without a post-baseline tumor 
assessment will be considered to be non-responders. BOR is defined as the best response 
recorded from the first day of study treatment until disease progression/recurrence or death. To 
be assigned a status of PR or CR (i.e., a responder), changes in tumor measurements must be 
confirmed by repeat assessments that should be performed no less than 4 weeks after the 
criteria for response are first met, i.e., patients need to have two consecutive assessments of 
PR or CR to be a responder. The primary analysis will be based on the BOR result after 
12 weeks (an assessment after 6 weeks [2 cycles) with a confirmation of BOR performed no 
less than 4 weeks after the criteria for response are rust met). 
The null hypothesis (Ho) is that the best response rate is 5% or less, which would yield a low 
activity profile. The allernative hypothesis (H,) is that the best response rate is greater than or 
equal to 20%, which would yield an encouraging activity profile: 
Ho: best response rate s 5% vs 
H,: best response rate a 20% 
A Simon's two-stage design (Simon 1989) will be used to allow the study to stop early if there is 
no evidence of efficacy. The null hypothesis that the true response rate (BOR) is s 5% will be 


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Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29694, Version 2.0 
39 
 
 
 
 
 
tested against a one-sided alternative. In the first stage, 13 patients in each cohort will be 
accrued. If there are O responses (CR or PR) in these 13 patients, the study will be stopped for 
the respective cohort. Otherwise, 14 additional patients will be accrued per cohort for a total of 
27. Recruitment may be suspended after the 131h patient n a cohort has been enrolled in the 
selected treatment regimen. This suspension will occur if there are no responses observed in 
the previous 12 patients (since the decision will be made to stop the study only if there are no 
responses in the first 13 patients). 
In the primary analysis of efficacy the null hypothesis will be rejected if 4 or more responses are 
obS9fVed in 27 patients. Ttis design yields a type I error rate of 0.05 and power of 80% when 
the true response rate is ;, 20%. 
It is planned to recruit more than the required 27 patients per cohort to allow for drop-outs. If 
there are no drop-outs amoogst the 32 enrolled patients in a certain cohort then the decision 
rule will be revised as necessary to retain the same alpha and power. For example, if 32 
patients have evaluable efficacy data, then if 5 or more responders are observed then we will 
reject Ho and accept H1 - i.e., accept that the best response rate;, 20%. If 4 or fewer 
responaers are ooservea men we will accept Ho. 
A response rate of less than 5% will be considered of no dinical interest. A response rate of 
more than 20% will be considered of interest to potentially start a further study, which will not be 
part of this protocol. 
Determination of Sample Size 
The sample size estimation is based on the method of A'Hern (2001) and Simon (1989) and 
corresponding Statistical Analysis System programs. 
To test the null hypothesis (Ho) that the best BOR is 5% or less (which would yield a low activity 
profile) against the alternative hypothesis (H,) that the BOR is greater than or equal to 20% 
(which would yield an encouraging activity profile), 27 patients per cohort would be required to 
perform the test with 80% power, at the one-sided alpha=0.05 level. To allow for drop-outs 
(10-15%) and to ensure that at least 27 patients will have efficacy data available, 32 patients will 
be recruited per cohort on the respective treatment regimen. 
Assuming a preferable BOR of 20% is observed, then with 27 patients, the 95% confidence 
limits would range from 7.2% to 39.8% (Clopper-Pearson exact confidence intervals). 


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Statistical Analysis Plan MO29694, Version 2.0 
40 
Appendix 2  
Schedule of Assessments 
 
 
Schedule of Activities: Regimen A (Trastuzumab emtansine, 2.4 mg/kg weekly) 
Scr.enlng ; 
Cyc:19 1 (day) 
Cyclo 2 (day) 
Cyc:19 3 (day) 
Cyclo.,. (day) 
Studv Drua ComDletlon Visit"' SUMYalF--Uo• 
·28to0 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1(·1.+3) 1(-1.+3) 1(-1.+3) 1(-1.+3) 1(-1.+3) 1(-1.+3) 1(-1.+3) 1(-1,+3) 1(-1,+3) 1(-1,+3) (-1,+3) 
~fonnad Consent • 
X 
Assklnment of oatient numbers throuah the lwRS 
X 
Tumor tissue for HE.R2 status teslina b 
X 
Medical history and demoaraphb 
X 
AEs 
.. 
~-· 
.. 
.. 
Concomitant medk:ations' 
•' 
f'VY11oina 1 
•' 
•' 
Com,nletie phvsleal examination 
X 
Limited nhvsk:al examination 9 
. 
X . 
X . 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hek:lht 
X 
Welaht 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs h 
X 
. 
X 
X 
X 
X 
X 
X 
X . . 
X 
X 
X 
X 
ECOGPS 
X 
X 
X 
X 
X 
X 
Hematoloay 1. '-11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemlstrv '- 111..,. 
Xm 
X m 
x " 
X n 
X m 
X . 
X n 
X m 
X n 
. 
X 
X m 
x " .. 
Xm 
INRandaPTT 
X 
As ctini~ lv indicated (e.Q. for patients on articoaQ~ation lheranv \ 
X 
Prao.nancv test 1 
x ' 
x ' 
x ' 
x ' 
Laboratory urinalysis 
0 
X 
As cliriicaly in:licated 
Blood sa, .... .,,le fol" eJCDloratorv bk,rnarker research 
X 
X 
X 
_,. rv 3 mor'lhs 
Blood sample fOI' PK P 
X 
X 
X 
X 
X 
Blood sa.mple HER2 ECO 
. 
X 
. 
Blood sa.--le to, retrosr,eettve aen......,-lna q 
X 
ATA' 
X 
X 
X 
X 
Hepatitis BJC seroannv, Hrv 
X 
12-lead ECG., 
X 
As cliriicalyiOOicated 
LVEF by ECHO (or MUGAl • 
-,! 
x' 
-,! 
ew rv :fdr'6'1A 
x' 
Tumor tiss ue for exploratory bk>marker research 
1 
X 
X ' 
Tumior U AH&fflAl'\t Z. l, 5 
x2. l. S 
SUAN6 we4lks 2, l, S 
xZ.3.5 
xZ.3r..5 
Bone scan'-• 
)(4 , 8 
As clinicalyin:licated 
Trastuzumab emtanslne admln .. tnllonldia1rtbutlon• 
x (A ) 
x (AJ 
x (A ) 
x (A) 
x (A) 
x (A) 
x (A J 
x (A) 
x(A) 
x (A) 
x(A ) 
x (A) 
• Informed Consent must be obtained prior to performance of any study related procedure unless the assessments were performed as standard of care 
prior to obtaining informed consent and within 2 weeks prior to study entry. 
• HER2 status (IHC3+) should be completed within 28 days prior to baseline, however a maximum of 2 years is accepted unless otherwise stated. 
cAfter informed consent has been obtained but prior to initiation of study drug, only SA Es caused by a protocol-mandated intervention should be reported. 
After initiation of study drug, all A Es will be reported until 28 days after the last dose of study drug. After this period, the Sponsor should be notified in the 
investigator becomes aware of any SAE that is believed to be related to prior study drug treatment (see Section 5.6) 
a Performed 30 days (+/. 7 days) after the last dose of study treatment. Patients who discontinue study treatment w ill be asked to return to the clinic 
4-6 weeks after the last dose of study drug for study drug completion visit. If the reason for study drug discontinuation is other than PD , tumor 


Clinical Study Report: trastuzumab emtansine - F. Hoffmann-La Roche Ltd
Protocol MO29694     Report Number 1089629
638
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29694, Version 2.0 
41 
 
 
assessments should be continued to be performed every 6 weeks from the first dose of study drug until PD or death 
• After completion of treatment, patients will be followed up for survival in a 3-monthly schedule until 18 months after LPL 
1 Record all concomitant therapy (non-investigational products), which includes prescription medication, over-the-counter preparation, herbal therapy, or 
radiotherapy used by a patient between the 28 days preceding date of first dose of study drug and the study drug completion/early termination visit. 
g Limited symptom-directed physical examination focusing on organ systems related to potential AEs based on patient's interim medical history and/or 
existing AE profiles of the study drug. 
h Systolic and diastolic blood pressure, pulse rate, oxygen saturation, respiratory rate, temperature should all be collected at screening, pre-dose, every 
15 (+/- 5) minutes during the first trastuzumab emtansine infusion and 60 (+/-10) minutes after the infusion. In subsequent cycles, vital signs should be 
recorded within 60 minutes pre- and post-infusion. Abnormal or significant changes to vital signs from baseline should be recorded as an AE. 
; Includes hemoglobin, hematocrit, platelet count, RBCs, WBCs; differentials including neutrophils, lymphocytes, monocytes, eosinophils and basophils. 
i Assessments should be performed at screening, on Day 1 of all cycles, and weekly following any hematologic AE. Local laboratory assessments should 
be performed within 72 hours preceding trastuz umab emtansine administration unless otherwise specified. Results of these local laboratory assessments 
must be reviewed and the review documented prior to trastuzumab emtansine administration. 
k For AEs associated with abnormal laboratory values, assessments should be performed at a minimum weekly until recovery to Grade :s 2. Additional 
assessments may be done as clinically indicated. 
1 For women of childbearing potential (including premenopausal women who have had a tubal ligation) and for women not considered post-menopausal, a 
serum b-HCG pregnancy test must be performed at a local laboratory within 7 days prior to the first administration of study drug (Day 1, Cycle 1 ). Urine 
pregnancy tests will be performed at specified subsequent visits (every 3 cycles, study completion visit, at 3 and 6 months(+/- 2 weeks) after last dose of 
study drug) within 7 days prior to receiving further study drug. All positive urine pregnancy tests must be confirmed by a serum b-HCG test. 
m Glucose, blood urea nitrogen (BUN)/urea , creatinine, sodium, potassium, bicarbonate, phosphorus, chloride, calcium, uric acid, total protein, albumin, 
total and direct bilirubin, alkaline phosphatase, LOH, ALT, AST, and GGT. 
• AST, ALT, GGT, and total bilirubin only. 
0 includes specific gravity, pH, protein, glucose, blood, ketones, bilirubin and microscopic examination including sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, bacteria. 
P Six sampling timepoints in Cycle 1 (Day 1, Day 8, and Day 15, each predose and 15-30 minutes postdose), one sampling timepoint in Cycle 2 (Day 1, 
predose), and two sampling timepoints in Cycle 4 (Day 1, predose and 15 30 minutes postdose) . . 
• To be taken at baseline (Cycle 1, Day 1) 
' Samples for ATA assessment will be collected before dosing in Cycles 1 and 4, at the study drug completion visit, and 3 months after the last 
trastuzumab emtansine dose. 
• EC Gs for each patient should be obtained from the same machine whenever possible. One set of all ECG tracings should be printed and kept with the 
patient's record. 
1 Cardiac monitoring (ECHO/MU GA) will be performed in all patients enrolled in the study. Assessments will occur during the screening period, between 
Days 15 and 21 in Cycles 1 and 3, and between Days 15 and 21 of every 3rd cycle thereafter (Cycle 6, 9 etc). ECHO or MUGA will be performed following 
study treatment discontinuation only if the most recent follow-up ECHO/MUGA was performed ~ 28 days after last study treatment administration or if no 
post-treatment evaluation was performed. The LVEF follows the actual treatment cycle. Dose modification of study drug will follow the algorithm/process 
described in Table 2. 
1 An optional tissue biopsy is taken at discontin uation of trastuzumab emtansine, either due to PD, unacceptable toxicity of systemic treatment or any other 
reason. 
2 Every 6 weeks from the start date of the study drug, regardless of dose delay or early discontinuation, until PD or study termination. Tumor assessments 
obtained within 28 days of Cycle 1, Day 1 may be used for screening purposes. Tumor assessments with CT or MRI scans of the chest, abdomen, and 
pelvis are to be performed every 6 weeks(+/- 3 business days). Response must be assessed through physical examination and imaged-based evaluation, 


Clinical Study Report: trastuzumab emtansine - F. Hoffmann-La Roche Ltd
Protocol MO29694     Report Number 1089629
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Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29694, Version 2.0 
42 
 
 
 
 
using RECIST 1.1. Assessments should include an evaluation of all known or suspected sites of disease whenever possible. The same radiographic 
procedure used to define measurable disease sites at baseline must be used throughout the study· 
3 If a patient inadvertently misses a prescribed tumor evaluation or a technical error prevents the evaluation, the patient may continue treatment until the 
next scheduled assessments, unless signs of clinical progression are present. In cases where there is suspicion of clinical progression before the next 
scheduled assessment, an unscheduled assessment should be performed. 
4 A CT or MRI of the brain and an isotope bone scan will be performed at screening. The bone scan and/or X-ray should be repeated in the event of 
clinical suspicion of progression of existing bone lesions and/or the development of new bone lesions. 
5 At the investigator's discretion, CT scans, MRI scans, and/or bone scans may be obtained at any time when clinically indicated or if PD is suspected· 
6 A = Regimen A (trastuzumab emtansine weekly, 2.4 mg/kg). Trastuzumab emtansine should be given over 90 minutes for the first dose and, in the 
absence of infusion-related AEs, over 30 minutes in subsequent doses. Vital signs should be taken before and after the trastuzumab emtansine infusion. 
Patients will be monitored for any untoward effects for ai least 90 minutes after completion of the first trastuzumab emtansine infusion and, in the absence 
of infusion-related events, for a minimum of 30 minutes at subsequent infusions. 


Clinical Study Report: trastuzumab emtansine - F. Hoffmann-La Roche Ltd
Protocol MO29694     Report Number 1089629
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Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29694, Version 2.0 
43 
 
 
 
 
Regimen B (Trastuzumab emtansine 3.6 mg/kg 3-weekly) 
lnfornwd Con1wit • 
AaslgnMOnt of poii.,,1 n umbe,. through tho lwRS 
Tumor dsaue for HER2 1tatu1 t.adna • 
Medical hlstorv and domoaraohlca 
AEs 
Concomllant medlc.ation1 ' 
ComDlele 0hv1k:.al exemlnadon 
Limit.cl ohvslcol examination • 
Holaht 
Woloht 
Vltaltlnn1 l'I 
ECOG PS 
Hemato1,v,., '-J. • 
Swum chemlatnr ._ •· m 
N R and a PTT 
Prwa nancv tall 1 
L.aboratorv ur1natval9 " 
Blood 1amn1a for exoloratorv blomar1'er reaearch 
Blood ■am.....&.. for PK 0 
Blood ■am- HER2 ECD 
Blood aamnla few r9t,ospectlve genotvnlng P 
ATA 41 
He0atiU1 BJC ■ero-u Hrv 
12-load ECG ' 
LVEF by ECHO (or MUGA) • 
Tumor tiss ue for e.xolom orv biomarker resnrch 1 
Tumor ua .. sment 2. 1. 1 
Boneacan ._• 
Trastuzumab emtanelne ac1m1n•n11onldlatrlbutlon1 
-28to0 
x' 
•' 
. -
•' 
,t 
x'·• 
Cycle 1 (dayl 
Cyclo 2 (dayl 
Cydel (dayl 
... 
x(B) 
15 
8 
15 
8 
15 
.J,•31 
-3.•31 
-3.•31 
,,,., <nn I 
As c:iricallt lndlc.w.d le.a. ror oa1oent1 on ar6~<Aalion 1toetao1 
•' 
• 
.. 
•(BJ 
As clirkalylndkalld 
As c:iricalyindkalld 
e•_,6weeks 2, 3,s 
As cliricalyindkal9d 
x(B) 
• • 
• 
,t 
x(B) 
8 
15 
""'<V3rnorl!'l0 
•' •' 
•' 
X 1 
•' •' 
X 
•' 
• 
• Informed Consent must be obtained prior to performance of any study related procedure unless the assessments were performed as standard of care prior to 
obtaining informed consent and within 2 weeks prior to study entry. 
• HER2 status (IHC3+) should be completed within 28 days prior to baseline, however a maximum of 2 years is accepted unless otherwise stated. 
c After informed consent has been obtained but prior to initiation of study drug, only SAEs caused by a protocol-mandated intervention should be reported. After 
initiation of study drug, all AEs will be reported until 28 days after the last dose of study drug. After this period, the Sponsor should be notified if the investigator 
becomes aware of any SAE that is believed to be related to prior study drug treatment (see Section 5.6). The investigator should follow each AE until the event has 


Clinical Study Report: trastuzumab emtansine - F. Hoffmann-La Roche Ltd
Protocol MO29694     Report Number 1089629
641
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29694, Version 2.0 
44 
 
 
 
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. 
d Performed 30 days (+/- 7 days) after the last dose of study treatment. Patients who discontinue study treatment will be asked to return to the clinic 4-6 weeks after 
the last dose of study drug for study drug completion visit. If the reason for study drug discontinuation is other than PD, tumor assessments should be continued to 
be performed every 6 weeks from the first dose of study drug until PD or death. 
• After completion of treatment, patients will be followed up for survival in a 3-monthly schedule until 18 months after LPI. 
' Record all concomitant therapy (non-investigational products), which includes prescription medication, over-the-counter preparation, herbal therapy, or 
radiotherapy used by a patient between the 28 days preceding date of first dose of study drug and the study drug completion/early termination visit. 
g Limited symptom-directed physical examination focusing on organ systems related to potential AEs based on patient's interim medical history and/or existing AE 
profiles of the study drug. 
h Systolic and diastolic blood pressure, pulse rate, oxygen saturation, respiratory rate, temperature should all be collected at screening, pre-dose, every 15 (+/- 5) 
minutes during the first trastuzumab emtansine infusion and 60 (+/-10) minutes after the infusion. In subsequent cycles, vital signs should be recorded within 
60 minutes pre- and post-infusion. Abnormal or significant changes to vital signs from baseline should be recorded as an AE. 
; Includes hemoglobin, hematocrit, platelet count, RBCs, WBCs; differentials including neutrophils, lymphocytes, monocytes, eosinophils and basophils. For 
Regimen B, laboratory assessments need only be performed in conjunction with a clinical visit, i.e. every 3 weeks on Day 1 of each cycle. 
i Assessments should be performed at screening, on Day 1 of all cycles, and weekly following any hematologic AE. Local laboratory assessments should be 
performed within 72 hours preceding trastuzumab emtansine administration unless otherwise specified. Results of these local laboratory assessments must be 
reviewed and the review documented prior to trastuzumab emtansine administration. 
k For AEs associated with abnormal laboratory values, assessments should be performed at a minimum weekly until recovery to Grade :s 2. Additional assessments 
may be done as clinically indicated. 
1 For women of childbearing potential (including premenopausal women who have had a tubal ligation) and for women not considered post-menopausal, a serum 
b-HCG pregnancy test must be performed at a local laboratory within 7 days prior to the first administration of study drug (Day 1, Cycle 1 ). Urine pregnancy tests 
will be performed at specified subsequent visits (every 3 cycles, study com;pletion visit, at 3 and 6 months (+/- 2 weeks) after last dose of study drug) within 7 days 
prior to receiving further study drug. All positive urine pregnancy tests must be confirmed by a serum b-HCG test. 
m Glucose, blood urea nitrogen (BUN)/urea , creatinine, sodium, potassium , bicarbonate, phosphorus, chloride, calcium, uric acid, total protein, albumin, total and 
direct bilirubin, alkaline phosphatase, LDH, ALT, AST, and GGT. 
• Includes specific gravity, pH, protein, glucose, blood, ketones, bilirubin and microscopic examination including sediment, RBCs, WBCs, casts, crystals, epithelial 
cells, bacteria. 
0 Two sampling timepoints in Cycle 1 (Day 1 predose and 15-30 minutes postdose), one sampling timepoint in Cycle 2 (Day 1, predose), and two sampling 
timepoints in Cycle 4 (Day 1, predose and 15-30 minutes postdose) . . 
P To be taken at baseline (Cycle 1, Day 1 ). 
• Samples for ATA assessment will be collected before dosing in Cycles 1 and 4, at the study drug completion visit, and 3 months after the last trastuzumab 
emtansine dose. 
'ECGs for each patient should be obtained from the same machine whenever possible. One set of all ECG tracings should be printed and kept with the patient's 
record. 
• Cardiac monitoring (ECHO/MUGA) will be performed in all patients enrolled in the study. Assessments will occur during the screening period, between Days 15 
and 21 in Cycles 1 and 3, and between Days 15 and 21 of every 3rd cycle tlhereafter (Cycle 6. 9 etc). ECHO or MUGA will be performed following study treatment 
discontinuation only if the most recent follow-up ECHO/MUGA was performed ;;, 28 days after last study treatment administration or if no post-treatment evaluation 
was performed. The LVEF follows the actual treatment cycle. Dose modification of study drug will follow the algorithm/process described in Table 2. 
1 An optional tissue biopsy is taken at discontinuation of trastuzumab emtansine, either due to PD, unacceptable toxicity of systemic treatment or any other reason. 


Clinical Study Report: trastuzumab emtansine - F. Hoffmann-La Roche Ltd
Protocol MO29694     Report Number 1089629
642
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29694, Version 2.0 
45 
 
 
 
 
2 Every 6 weeks from the start date of the study drug, regardless of dose delay or early discontinuation, until PD or study termination. Tumor assessments obtained 
within 30 days of Cycle 1, Day 1 may be used for screening purposes. Tumor assessments with CT or MRI scans of the chest, abdomen, and pelvis are to be 
performed every 6 weeks (+/- 3 business days). Response must be assessed through physical examination and imaged-based evaluation, using RECIST 1.1. 
Assessments should include an evaluation of all known or suspected sites of disease whenever possible. The same radiographic procedure used to define 
measurable disease sites at baseline must be used throughout the study. 
3 If a patient inadvertently misses a prescribed tumor evaluation or a technical error prevents the evaluation, the patient may continue treatment until the next 
scheduled assessments, unless signs of clinical progression are present. In cases where there is suspicion of clinical progression before the next scheduled 
assessment, an unscheduled assessment should be performed. 
• A CT or MRI of the brain and an isotope bone scan will be performed at screening. The bone scan and/or X-ray should be repeated in the event of clinical 
suspicion of progression of existing bone lesions and/or the development of new bone lesions. 
5 At the investigato~s discretion, CT scans, MRI scans, and/or bone scans may be obtained at any time when clinically indicated or if PD is suspected. 
6 8 = Regimen 8 (trastuzumab emtansine 3-weekly, 3.6 mg/kg). Trastuzumab emtansine should be given over 90 minutes for the first dose and, in the absence of 
infusion-related AEs, over 30 minutes in subsequent doses. Vital signs should be taken before and after the trastuzumab emtansine infusion. Patients will be 
monitored for any untoward effects for at least 90 minutes after completion of the first trastuzumab emtansine infusion and, in the absence of infusion-related 
events, for a minimum of 30 minutes at subsequent infusions. 


Clinical Study Report: trastuzumab emtansine - F. Hoffmann-La Roche Ltd
Protocol MO29694     Report Number 1089629
643
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29694, Version 2.0 
46 
Appendix 3  
List of Outputs  
Outputs Number 
Output Title 
Population 
Topline 
outputs for 
SREP 
  
TABLES 
  
 
14.1.1.1.x 
Patient Disposition 
SAF 
X 
14.1.1.2.x 
Patient Discontinuation and Early Termination 
SAF 
X 
14.1.2.x 
Enrolment by Country and Site  
SAF 
 
14.1.3.x 
Median Follow-up Duration 
SAF 
 
14.1.4.x 
Protocol Deviations 
SAF 
X 
  
Demographics and Baseline Characteristics 
  
 
14.1.5.x 
Summary of Baseline and Demographic Characteristics 
SAF 
X 
14.1.6.a 
Summary of Metastatic Urothelial Bladder Cancer History  
SAF 
X 
14.1.6.b 
Summary of Pancreas/Cholangio Cancer History  
SAF 
X 
14.1.7.x 
Summary of Prior Anti-Cancer Treatment/Procedures 
SAF 
X 
14.1.8.x 
Prior Anti-Cancer Therapies 
SAF 
 
 
Exposure 
 
 
14.1.9.x 
Summary of Drug Exposure  
SAF 
X 
14.1.10.x 
Summary of Infusion Interrupted or Delayed  
SAF 
 
14.1.11.x 
Summary of Infusion Rate Reduction 
SAF 
 
  
Efficacy 
 
 
  
Overall Response Rate 
 
 
14.2.1.1.x 
Summary of Overall Response Rate and Duration of Response as per Investigator 
SAF 
X 
14.2.1.2.x 
Summary of Overall Response Rate as per Investigator, by Cell Heterogeneity 
SAF 
X 
  
Progression Free Survival 
 
 
14.2.2.x 
Summary of Progression Free Survival as per Investigator 
SAF 
X 
  
Overall Survival 
  
 
14.2.3.x 
Summary of Overall Survival 
SAF 
X 
  
Safety 
  
 


Clinical Study Report: trastuzumab emtansine - F. Hoffmann-La Roche Ltd
Protocol MO29694     Report Number 1089629
644
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29694, Version 2.0 
47 
Outputs Number 
Output Title 
Population 
Topline 
outputs for 
SREP 
  
AEs 
  
 
14.3.1.1.x 
Overview of Treatment Emergent Adverse Events  
SAF 
X 
14.3.1.2.x 
Treatment-Emergent Adverse Events by SOC and PT and by Worst Intensity  
SAF 
 
14.3.1.3.x 
Treatment-Emergent Adverse Events Related to Trastuzumab Emtansine by SOC and PT 
and by Worst Intensity  
SAF 
 
 
14.3.1.4.x 
Selected Treatment-Emergent Adverse Events by Grouped Term and by Worst Intensity 
SAF 
X 
14.3.1.5.x 
Treatment Emergent Adverse Events of Grade 3 or More by SOC and PT  
SAF 
X 
14.3.1.6.x 
Serious Treatment Emergent Adverse Events by SOC and PT  
SAF 
X 
14.3.1.7.x 
Serious Treatment Emergent Adverse Events Related to Trastuzumab Emtansine by SOC 
and PT  
SAF 
 
14.3.1.8.x 
Treatment Emergent Adverse Events Leading to Discontinuation of Trastuzumab 
Emtansine by SOC and PT 
SAF 
X 
14.3.1.9.x 
Treatment Emergent Adverse Events Leading to Modification of Trastuzumab 
Emtansine by SOC and PT 
SAF 
 
14.3.1.10.x 
Treatment Emergent Adverse Events with Fatal Outcome by SOC and PT  
SAF 
X 
14.3.1.11.x 
Treatment-Emergent Adverse Event of Special Interest (AESI) Based on the eCRF 
Categories by SOC and PT  
SAF 
X 
14.3.1.12.x 
Serious Treatment-Emergent Adverse Event of Special Interest (AESI) Based on the 
eCRF Categories by SOC and PT  
SAF 
 
14.3.1.13.x 
Serious Treatment-Emergent Adverse Events – EudraCT Disclosure Requirements Data  
SAF 
 
14.3.1.14.x 
Non-Serious Treatment-Emergent Adverse Events Reported in >=5% of Subjects – 
EudraCT Disclosure Requirements Data  
SAF 
 
14.3.1.15.x 
Overview of Infusion-Related Reactions   
SAF 
 
14.3.1.16.x 
Infusion-Related Reactions by SOC and PT and by Worst Intensity  
SAF 
 
14.3.1.17.x 
Infusion-Related Reactions Related to Trastuzumab Emtansine by SOC and PT and by 
Worst Intensity  
SAF 
 
 
14.3.1.18.x 
Infusion-Related Reactions of Grade 3 or More by SOC and PT  
SAF 
 
14.3.1.19.x 
Serious Infusion-Related Reactions by SOC and PT  
SAF 
 
14.3.1.20.x 
Serious Infusion-Related Reactions Related to Trastuzumab Emtansine by SOC and PT  
SAF 
 
14.3.1.21.x 
Deaths and Reason for Death 
SAF 
X 


Clinical Study Report: trastuzumab emtansine - F. Hoffmann-La Roche Ltd
Protocol MO29694     Report Number 1089629
645
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29694, Version 2.0 
48 
Outputs Number 
Output Title 
Population 
Topline 
outputs for 
SREP 
 
Other Safety Assessments 
 
 
14.3.7.1.x 
Left Ventricular Ejection Fraction Over Time  
SAF 
 
14.3.7.2.x 
Left Ventricular Ejection Fraction Worst on Treatment Value  
SAF 
 
 
Biomarkers 
 
 
14.3.8.1 
Summary of HER2 Status – Immunohistochemistry (IHC) 
SAF 
 
14.3.8.2 
Summary of HER2 Status – Gene Protein Assay by Immunohistochemistry (IHC) 
SCR 
 
  
Figures 
  
 
  
Efficacy 
  
 
14.2.2.x 
Kaplan Meier Plot for Progression Free Survival as per Investigator 
SAF 
 
14.2.3.x 
Kaplan Meier Plot for Overall Survival 
SAF 
 
  
Safety 
  
 
14.3.7.1.x 
Boxplot of LVEF Over Time  
SAF 
 
  
LISTINGS 
  
 
  
Patient Disposition 
 
 
16.2.1.x 
Subject Disposition and Study Termination Information 
SAF 
 
16.2.2.x 
Protocol Deviations 
SAF 
 
16.2.3.x 
Analysis Populations 
SAF 
 
  
Demographics and Baseline Characteristics 
  
 
16.2.4.1.x 
Demographics and Baseline Characteristics 
SAF 
 
16.2.4.2.a 
Metastatic Urothelial Bladder Cancer History 
SAF 
 
16.2.4.2.b 
Pancreas/Cholangio Cancer History 
SAF 
 
16.2.4.3.x 
Medical History 
SAF 
 
16.2.4.4.a 
Prior Surgery other than for Metastatic Urothelial Bladder Cancer 
SAF 
 
16.2.4.4.b 
Prior Surgery History other than for Pancreas/Cholangio Cancer 
SAF 
 
16.2.4.5.a 
Prior Metastatic Urothelial Bladder Cancer Surgery 
SAF 
 
16.2.4.5.b 
Prior Pancreas/Cholangio Cancer Surgery 
SAF 
 
16.2.4.6.x 
Prior Systemic Cancer Therapy  
SAF 
 
16.2.4.7.x 
Prior Cancer Radiotherapy 
SAF 
 
16.2.4.8.x 
On-Study Cancer Surgery 
SAF 
 


Clinical Study Report: trastuzumab emtansine - F. Hoffmann-La Roche Ltd
Protocol MO29694     Report Number 1089629
646
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29694, Version 2.0 
49 
Outputs Number 
Output Title 
Population 
Topline 
outputs for 
SREP 
16.2.4.9.x 
On-Study Cancer Radiotherapy 
SAF 
 
16.2.4.10.x 
Prior and Concomitant Medications 
SAF 
 
16.2.4.11.x 
Subsequent Anti-Cancer Therapy 
SAF 
 
  
Drug Administration 
  
 
16.2.5.1.x 
Trastuzumab Emtansine Administration  
SAF 
 
16.2.5.2.x 
Drug Exposure  
SAF 
 
  
Efficacy 
  
 
16.2.6.1.x 
Individual Tumor Assessment and Overall Response as per Investigator 
SAF 
 
16.2.6.2.x 
Best Overall Response and duration of response 
SAF 
 
16.2.6.3.x 
Progression-Free Survival as per Investigator 
SAF 
 
16.2.6.4.x 
Overall Survival 
SAF 
 
 
Safety 
  
 
16.2.7.1.x 
Adverse Events 
SAF 
 
16.2.7.1.1.x 
Adverse Events with Missing or Partial Start Date 
SAF 
 
16.2.7.2.x 
Adverse Events of Grade 3 or More 
SAF 
 
16.2.7.3.x 
Serious Adverse Events 
SAF 
 
16.2.7.4.x 
Adverse Events Leading to Treatment Discontinuation 
SAF 
 
16.2.7.5.x 
Adverse Events of Special Interest 
SAF 
 
16.2.7.6.x 
Selected Adverse Events 
SAF 
 
16.2.7.7.x 
Infusion Related Reactions 
SAF 
 
16.2.7.8.x 
Deaths  
SAF 
 
16.2.8.1.x 
Laboratory Values: Hematology 
SAF 
 
16.2.8.2.x 
Laboratory Values: Biochemistry 
SAF 
 
16.2.8.3.x 
Laboratory Values: Coagulation 
SAF 
 
16.2.8.4.x 
Laboratory Abnormalities: Hematology 
SAF 
 
16.2.8.5.x 
Laboratory Abnormalities: Biochemistry 
SAF 
 
16.2.8.6.x 
Laboratory Abnormalities: Coagulation 
SAF 
 
16.2.8.7.x 
Laboratory Values: Urinalysis 
SAF 
 
16.2.8.8.x 
Serology 
SAF 
 
16.2.8.9.x 
Pregnancy Test 
SAF 
 
16.2.9.1.x 
Vital Signs 
SAF 
 
16.2.9.2.x 
ECOG Performance Status 
SAF 
 


Clinical Study Report: trastuzumab emtansine - F. Hoffmann-La Roche Ltd
Protocol MO29694     Report Number 1089629
647
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29694, Version 2.0 
50 
Outputs Number 
Output Title 
Population 
Topline 
outputs for 
SREP 
16.2.9.3.x 
Left Ventricular Ejection Fraction 
SAF 
 
16.2.9.4.x 
Electrocardiograms 
SAF 
 
 
Biomarker 
 
 
16.2.10.1.x 
Biomarker: HER2 IHC 
SAF 
 
16.2.10.2 
Biomarker: HER2 IHC and Gene Protein Assay 
SCR