Clinical trial NCT02562378
Conditions: Breast Cancer
Sponsor: MedSIR
Start date: 2015-10-01; Completion date: 2018-12-01
Enrollment: 15 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The primary goal is to determine the maximum tolerated dose (MTD) of the combination of T-DM1 and non-pegylated liposomal doxorubicin in metastatic breast cancer (mBC) patients previously treated with taxanes and trastuzumab-based therapy.

In addition, pharmacokinetic data on the combination of T-DM1 and liposomal doxorubicin will be obtained.

Detailed description:
Subjects: Age ≥ 18 years with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer that have relapsed or progressed on or after taxanes and trastuzumab-based therapy. Subjects must have histologic or cytologic confirmation of the HER2-positive metastatic breast cancer. Evidence of measurable or evaluable metastatic disease is required.

Primary objective:

* To determine the maximum tolerated dose (MTD) of the combination of T-DM1 and non-pegylated liposomal doxorubicin in metastatic breast cancer (mBC) patients previously treated with taxanes and trastuzumab-based therapy.

Secondary objectives:

* To determine the efficacy of the combination of T-DM1 and non-pegylated liposomal doxorubicin, defined by the overall response rate (ORR), clinical benefit rate (CBR), number of progressions and number and reasons for deaths.
* To assess the safety profile of the combination of T-DM1 and non-pegylated liposomal doxorubicin, defined by all toxicities reported during the study.
* To evaluate the cardiac safety of the combination of T-DM1 and non-pegylated liposomal doxorubicin measured by left ventricular ejection fraction (LVEF) as assessed by echocardiography, cardiac troponin I and B-type natriuretic peptide (BNP) levels.
* To evaluate the potential role of single nucleotide polymorphisms (SNP) in the predisposition for developing cardiotoxicity.
* To analyze the pharmacokinetics (PK) profile of T-DM1 and its metabolites and non-pegylated liposomal doxorubicin.

Type of study: This is a prospective dose-finding, multicenter and open-label phase I clinical trial.

Treatment: Trastuzumab emtansine (T-DM1) will be administered at a fixed dose of 3.6 mg/kg IV on Day 1 every 3 weeks and three cohorts of patients with three different dose levels of conventional non-pegylated liposomal doxorubicin (45 mg/m2, 50 mg/m2 and 60 mg/m2) IV on Day 1 in cycles of 21 days each are planned.

Arms: arm 1: Trastuzumab emtansine (T-DM1) will be administered at a fixed dose of 3.6 mg/kg IV on Day 1 every 3 weeks and three cohorts of patients with three different dose levels of conventional non-pegylated liposomal doxorubicin (45 mg/m2, 50 mg/m2 and 60 mg/m2) IV
Interventions: intervention 1: Trastuzumab and non-pegylated liposomal doxorubicin
Intervention descriptions: intervention 1: 3 Cohorts (3+3 design):

Cohort 1- Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV

Cohort 2- Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV

Cohort 3- Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV

Protocol documents:
Prot_000.pdf: 
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Protocol Date: 27th June 2017 
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Clinical Trial Protocol 
 
 
 
 
Phase I multicenter clinical trial evaluating the combination of trastuzumab emtansine (T- 
DM1) and non-pegylated liposomal doxorubicin in HER2-positive metastatic breast cancer. 
THELMA Study 
Code: MedOPP038 
 
 
 
 
Study Drug(s): 
T-DM1 (trastuzumab emtansine) 
 
Non-pegylated liposomal doxorubicin 
 
EudraCT#: 
2014-001056-28 
 
Clinical Trials.gov#: 
NCT02562378 
 
Protocol#: 
MedOPP038 
 
 
 
Protocol Date: 
27th June 2017 (updated as per amendment # 10) 
 
 
 
 
 
Protocol Revision History 
 
Initial Approval Version: 
24th October 2014 
 
Amendment #1: 
31st March 2015 
 
Amendment #2: 
17th June 2015 
 
Amendment #3: 
30th June 2015 
 
Amendment #4: 
12th August 2015 
 
Amendment #5: 
16th October 2015 
 
Amendment #6: 
23th November 2015 
 
Amendment #7: 
15st March 2016 (Updated 1st December 2016) 
Amendment #10: 
27th June 2017 


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KEY CONTACTS 
 
 
 
 
Sponsor 
 
Name: 
Medica Scientia Innovation Research (MEDSIR ARO) 
Address: 
Torre Glòries., Av. Diagonal, 211,  
 
Planta 27, 08018, Barcelona. 
Phone: 
+ 34 93 221 41 35 
 
Fax: 
+ 34 93 299 23 82 
 
 
 
Sponsor’s Medical Monitor 
 
Name: 
Address: 
Phone: 
Fax: 
Mobile 
E-mail: 
 
 
 
Sponsor’s Safety Risk Management 
 
Name: 
Address: 
Phone: 
Fax: 
E-mail: 
 
 
 
Sponsor’s Chief Cardiologist Expert 
 
Name: 
Institution: 
 
Phone: 
E-mail: 
 
Sponsor’s Chief Medical Oncologist Expert 
 
Name: 
Institution: 
Phone: 
E-mail: 


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Principal investigators 
 
Name: 
Email: 
Position: 
Institution: 
 
 
 
Name: 
Email: 
Position: 
Institution: 
 
 
Name: 
Email: 
Position: 
Institution: 
 
Name: 
Email: 
Position: 
Institution: 
 
Name: 
Email: 
Position: 
Institution: 
 
 
 
Scientific Global Coordinators 
 
Name: 
Email: 
Position: 
Institution: 
 
 
Name: 
Email: 
Position: 
Institution: 


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Steering Committee 
 
 
 
Molecular study coordinator 
 
Name: 
Email: 
Position: 
Institution: 


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Declaration of Investigators 
 
 
 
Protocol Title: Phase I multicenter clinical trial evaluating the combination of trastuzumab emtansine 
(T-DM1) and non-pegylated liposomal doxorubicin in HER2-positive metastatic breast cancer – 
THELMA Study. 
 
 
Version date: version 9 : 27th June 2017 
 
Protocol number: MedOPP038 
 
I have received, reviewed and understand the following: 
 
a)   Protocol: Phase I multicenter clinical trial evaluating the combination of trastuzumab emtansine (T -DM1) 
and non-pegylated liposomal doxorubicin in HER2-positive metastatic breast cancer, THELMA Study, 
version v9, dated 27th June 2017 
b)   Current Investigator’s Brochure for T-DM1 with details of clinical and nonclinical data on T-DM1 that are 
relevant to the study of the product in human subjects 
c)   Current Summary of Product Characteristics on Non-pegylated liposomal doxorubicin 
 
 
I have been adequately informed about the development of the investigational product to date. I will confirm 
the receipt of updated Investigator’s Brochure. I have read this study protocol and agree that it contains all 
the information required to conduct the study. I agree to conduct the study as set out in this protocol. 
 
 
I fully understand that any changes instituted by the investigator(s) without previous agreement with the 
sponsor would constitute a violation of the protocol, including any ancillary studies or procedures performed 
on study patients (other than those procedures necessary for the well being of the patients). I am aware I 
may only implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to trial 
subjects without prior IRB/IEC approval/favourable opinion and /or before sponsor’s agreement and, in this 
case, and as soon as possible, I will submit in written the implemented deviation or change and the reasons 
for it to the sponsor. 
 
 
I will not enrol the first subject in the study until I have received approval from the appropriate Institutional 
Review Board or Independent Ethics Committee (IRB/IEC) and until all legal and regulatory requirements in 
my country have been fulfilled. 
 
 
The study will be conducted in accordance with the moral, ethical, and scientific principles governing clinical 
research as set out in the Declaration of Helsinki and its amendments, the International Conference on 
Harmonization (ICH) Good Clinical Practice (GCP) guidelines (ICH E6 GCP) and applicable regulations and 
laws. 
 
 
I agree to obtain, in the manner described in this protocol and in ICH E6 GCP, written informed consent by 
the subject or the subject’s legally acceptable representative or witnessed verbal informed consent to 


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participate for all subjects whose participation in this study is proposed to and before any subject’s study 
specific procedure is done. 
 
 
I will ensure that the study drug(s) supplied by the sponsor are being used only as described in this protocol. 
 
 
I  am  aware  of  the  requirements for  the  correct  reporting of  serious  adverse  events,  and  I  commit to 
document and to report such events as required by the sponsor and in accordance with Health Authority 
Regulatory requirements. 
 
 
I agree to supply – upon request – the Sponsor or Sponsor’s representative with evidence of current laboratory 
accreditation, the name and address of the laboratory, and a list of normal values and ranges. 
 
 
I agree with the use of results of the study for the purposes of national and international registration, 
publication, and information for medical and pharmaceutical professionals. 
 
 
I agree to keep all source documents and case report forms as specified in the relevant sections of this 
protocol. 
 
 
I will provide all required Regulatory Authority forms, up-to-date curriculum vitae of myself, sub-investigators 
and of any member of my study team (if requested) before the study starts, which may be submitted to 
regulatory authorities. 
 
 
I am aware of the possibility of being audited by the sponsor or its delegate or inspected by regulatory 
authorities for the performance of this study. I will permit monitoring, auditing and inspection and provide 
direct access to source data/documents and reports for these purposes. 
 
 
Furthermore, I confirm herewith that the sponsor is allowed to enter and utilize my professional contact 
details and function in an electronic database for internal purposes and for submission to Health Authorities 
worldwide. 
 
 
Name:                                                                                                                                                         
 
 
Signature: 
  
 
Date: 


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Protocol synopsis 
 
Product: 
Trastuzumab emtansine (T-DM1) and non-pegylated liposomal doxorubicin 
Protocol 
Number: 
MedOPP038 
EudraCT 
Number: 
2014-001056-28 
Protocol Title: 
Phase I multicenter clinical trial evaluating the combination of trastuzumab 
emtansine (T-DM1)  and non-pegylated  liposomal doxorubicin in HER2- 
positive metastatic breast cancer – THELMA Study 
Target Disease: 
HER2-positive metastatic breast cancer 
Subjects: 
Subjects age ≥ 18 years with HER2-positive metastatic breast cancer that 
have relapsed or progressed on or after taxanes and trastuzumab-based
therapy. Subjects must have histologic or cytologic confirmation of the HER2-
positive metastatic breast cancer. Evidence of measurable or evaluable
metastatic disease is required. There are 3 planned cohorts of patients. 
Number 
of 
subjects: 
A minimum of 12 and up to 24 patients will be enrolled 
Study 
Objectives 
Primary objective: To determine the maximum tolerated dose (MTD) of the 
combination of T-DM1 and non-pegylated liposomal doxorubicin in
metastatic breast cancer (mBC) patients previously treated with taxanes
and trastuzumab-based therapy. 
Secondary objectives: 
- To  determine  the  efficacy  of  the  combination  of  T-DM1  and  non-
pegylated liposomal doxorubicin, defined by the overall response rate
(ORR), clinical benefit rate (CBR), number of progressions and number
and reasons for deaths. 
- To  assess  the  safety  profile  of  the  combination  of T-DM1  and  non-
pegylated liposomal doxorubicin, defined by all toxicities reported during
the study. 
- To evaluate the cardiac safety of the combination of T-DM1 and non-
pegylated liposomal doxorubicin measured by LVEF as assessed by
echocardiography,  cardiac  troponin  I  and  B-type  natriuretic  peptide
(BNP) levels. 
-   To evaluate the potential role of single nucleotide polymorphisms (SNP) 


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in the predisposition for developing cardiotoxicity. 
- To  analyze  the  pharmacokinetics  (PK)  profile  of  T-DM1  and  its 
metabolites and non-pegylated liposomal doxorubicin. 
Type of study 
This  is a prospective  dose-finding,  multicenter  and open-label phase  I 
clinical trial. 
This clinical trial is designed with a dose escalation following a “modified” 3
by  3  design  where  3  patients  will  be  included  at  a  given  cohort  and
followed  to  observe  if  they  experience  any  dose-limiting  toxicity  (DLT)
during   the   first   two   cycles   of   treatment.   If   none   of   the   3   first
patients included in each cohort experience a DLT (0/3), the next patients
will be enrolled in the subsequent cohort. If 1 of these 3 first patients
experience a DLT, 3 more patients will be included at the same cohort to
determine the number patients who experience DLTs in the total group of 6
patients. If 2 or more patients treated at a given cohort of six patients
experience a DLT, the cohort of one dose level below will be established as
the maximum tolerated dose (MTD). No dose escalation between cohorts will
be permitted. Patients assigned on each cohort will remain at their study
cohort during all the study period. Planned number of cohorts is currently 3
(3+3 design), including an expansion cohort of an additional 6 patients at the
maximum tolerated dose (MTD) or recommended phase 2 dose   (RP2D).
The Steering Committee  will review toxicities and may decide to add the
expansion cohort to level -1 in the situation where it is necessary to have a
dose level -1. 
Treatment 
Trastuzumab emtansine (T-DM1) will be administered at a fixed dose of 
3.6 mg/kg IV on Day 1 every 3 weeks and three cohorts of patients with three
different dose levels of conventional non-pegylated liposomal doxorubicin (45
mg/m2, 50 mg/m2  and 60 mg/m2) IV on Day 1 in cycles of 
21 days each are planned. The initial dose of T-DM1 will be administered
over 90 minutes (±10 minutes) and, in the absence of any signs or symptoms
of infusion reactions with the first dose, subsequent doses of T- DM1 may be
administered over 30 minutes (±10 minutes). 
Non-pegylated 
liposomal 
doxorubicin 
will 
be 
administered 
over
approximately 60 minutes starting 60 minutes after the end of T-DM1
infusion. 
After the two first cycles, the combination of study (T-DM1 and non- 
pegylated liposomal doxorubicin) will be administered for up to 6 cycles 


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(including the first two cycles). T-DM1 treatment will continue as a single
agent until disease progression or development of intolerable toxicity,
whichever occurs first. All patients will be followed up until improvement to
grade 1 or complete recovery from all ≥ grade 2 adverse events, or withdrawn
consent, death or up to a maximum of 12 months after the first dose of study
combination whichever occurs first. 
Primary 
endpoint 
The primary endpoint of the study will be to determine the Maximum-
tolerated dose (MTD), defined as the highest dose level at which no more
than one of six patients or 0 of 3 patients experiences dose-limiting toxicity
(DLT) during the first two cycles of study treatment. 
Inclusion criteria 
Patients must meet the following criteria for study entry: 
- 
Signed informed consent prior to any study specific procedure. 
- 
Patient to be able and willing to comply with protocol. 
- 
Patients with cytologically or histologically confirmed carcinoma of the
breast. 
- 
Patients  with  incurable  locally  advanced  or  metastatic  disease  who
have previously received up to two previous chemotherapy regimens in
this setting (patient starting the first, second or third line of treatment
are eligible). Patient must have progressed or relapsed on or after taxane
and trastuzumab-based therapy. 
- 
HER2-positive  disease  immunohistochemistry  (IHC)  3+  or  in  situ
hybridization   (FISH)   positive   assayed   at   local   laboratories   and
according to updated ASCO/CAP criteria. 
- 
At  least  one  measurable  lesion  according  to  Response  Evaluation
Criteria in Solid Tumors (RECIST) version 1.1; or patients with non
measurable lesions could be included with these exceptions: 
o patients with only blastic bone lesions are not eligible 
o patients with only pleural, peritoneal or cardiac effusion, or 
meningeal carcinomatosis are not eligible 
- 
Patient ≥ 18 years of age. 
- 
ECOG performance status of 0 or 1. 
- 
Life expectancy ≥ 3 months. 
- 
Adequate bone marrow function: 
o Hemoglobin ≥ 10 g/dl. 
o Absolute neutrophil count ≥ 1.5 x 109/L. 
o Platelets  ≥  100 x  109/L  without  transfusions  within  21  days 
before 1st study treatment. 


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o International normalized ratio (INR) < 1.5 × the upper limit of 
normal (ULN). 
- 
Adequate hepatic and renal function: 
o Total bilirubin ≤ 1.5 x ULN, except for Gilbert disease patients. 
Gilbert's syndrome is suspected in people who have persistent,
slightly elevated levels of unconjugated bilirubin without any other
apparent cause. A diagnosis of Gilbert’s syndrome will be based
on the exclusion of other diseases based on the following criteria:
unconjugated hyperbilirubinemia noted on several occasions, no
evidence of hemolysis (normal hemoglobin, reticulocyte count,
and LDH), normal liver function tests, and absence of other
diseases associated with unconjugated hyperbilirubinemia. For
patients with Gilbert disease, total bilirubin must be ≤ 3 x ULN 
o Alkaline phosphatase ≤ 2.5 × the ULN (≤ 5 × the ULN if liver 
and/or bone metastases are present). 
o AST (SGOT)/ALT (SGPT)  ≤  1.5  x  ULN (<  3 x  ULN  if  liver 
metastases are present). 
o Creatinine ≤ 1.5 x ULN and calculated creatinine clearance ≥ 50 
mL/min per the Cockcroft and Gault formula. 
- 
Adequate cardiovascular function with LVEF ≥ 55% as assessed by
echocardiography. 
- 
Recovery from all reported toxicities of previous anti-cancer therapies
to baseline or grade ≤ 1 (CTCAE version 4.0), except for alopecia. 
- 
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, and men with partners of childbearing potential,
agreement by the patient and/or partner to use a highly effective, non-
hormonal form of contraception or two effective forms of non-hormonal
contraception and to continue its use for the duration of study treatment
and for 7 months after the last dose administered while being on study.
For all other women, documentation must be present in medical history
confirming that the patient is not of childbearing potential. 
Exclusion 
Patients must not meet the following criteria for study entry: 


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criteria 
- 
Previous  treatment  with  T-DM1  or  anthracyclines,  either  in  the 
 
(neo)adjuvant or in the metastatic setting. 
 
- 
More   than   two   chemotherapeutic   regimens   for   locally   advanced 
incurable disease or metastatic disease. 
- 
Patients   who   have   received   prior   anti-cancer   treatment   with 
chemotherapy,  immunotherapy  or  radiotherapy  within  3  weeks  (6 
weeks for nitrosoureas or mitomycin-C), hormonal therapy or lapatinib 
within 7 days, prior trastuzumab within 21 days (7 days if weekly 
trastuzumab) or any other targeted therapy within the last 21 days prior 
to starting study treatment. 
- 
Previous   radiotherapy   for   the   treatment   of   unresectable,   locally 
advanced/recurrent or mBC is not allowed if: 
o The last fraction of radiotherapy has been administered within 
 
21 days prior to first study drug administration (except for brain 
irradiation; at least 28 days will be required). 
o More than 25% of marrow-bearing bone has been irradiated. 
 
- 
History  of  intolerance  (including  Grade  3  or  4  infusion  reaction)  or 
hypersensitivity to the active substance or to any of the excipients of T- 
DM1 or non-pegylated liposomal doxorubicin. 
- 
Patients with CNS involvement. However, patients with metastatic CNS 
tumors may participate in this trial if the patient is > 4 weeks from 
radiotherapy completion, is clinically stable with respect to CNS tumor 
at the time of study entry and is not receiving steroid therapy for brain 
metastases. 
- 
Severe/uncontrolled  intercurrent  illness  including,  but  not  limited  to, 
ongoing or active infection, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
- 
Cardiopulmonary dysfunction as defined by any of the following: 
 
o History of NCI CTCAE (Version 4.0) Grade ≥ 3 symptomatic 
 
CHF or NYHA criteria Class ≥ II. 
 
o Angina   pectoris   requiring   anti-anginal   medication,   serious 
cardiac arrhythmia not controlled by adequate medication, severe 
conduction abnormality, or clinically significant valvular disease. 
o High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a 
heart rate > 100/min at rest, significant ventricular arrhythmia 
[ventricular tachycardia], or higher-grade atrioventricular [AV]- 


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block  [second  degree  AV-block  Type  2  [Mobitz  2]  or  third 
degree AV-block]). 
o Significant  symptoms (Grade ≥  2)  relating to left  ventricular 
dysfunction, cardiac arrhythmia, or cardiac ischemia. 
o Myocardial infarction within 12 months prior to randomization. 
o Uncontrolled  hypertension  (systolic  blood  pressure  >  180 
mmHg and/or diastolic blood pressure >100 mmHg). 
o Requirement for oxygen therapy. 
- 
Current peripheral neuropathy of Grade ≥ 3 per the NCI CTCAE, v4.0. 
- 
History of a decrease in LVEF to < 40% or symptomatic CHF with
previous trastuzumab treatment. 
- 
Patients who have had a prior malignancy, other than carcinoma in situ
of   the   cervix,   or   non-melanoma   skin   cancer,   unless   the   prior
malignancy was cured ≥ 5 years before first dose of study drug with no
subsequent evidence of recurrence. 
- 
Current known active infection with HIV, hepatitis B, and/or hepatitis C
virus. For patients who are known carriers of hepatitis B virus (HBV),
active hepatitis B infection must be ruled out based on negative serologic
testing and/or determination of HBV DNA viral load per local guidelines. 
- 
Women who are pregnant or breast-feeding. 
Pharmacokinetic 
(PK) 
assessments 
Pharmacokinetic (PK) assessments will be only performed in cycle 1 and 2 
and cycle 4 during the dose-finding period, defined as the period between the
first patient in the study being treated and the MTD definition.
Pharmacokinetic data will be compared with historical data of T-DM1
pharmacokinetics 
and 
non-pegylated 
liposomal 
doxorubicin
pharmacokinetics and will include serum concentrations of T-DM1, total
trastuzumab, free DM1 (maytansinoid, derivative of maytansine) and non-
pegylated liposomal doxorubicin. Approximately 6 ml of whole blood will be
drawn at each time PK point. 
The following PK parameters will be calculated: AUC (main PK data),
clearance  (CL),  distribution  volume  (Vd),  apparent  half-life  (t1/2)  and
maximal serum concentration (Cmax). 
Serum levels of HER2 Extracellular Domain (ECD) will be also measured,
as this biomarker has been shown to be a relevant covariate in the Population
PK model for T-DM1. 
Efficacy 
and The safety and efficacy of combination will be  evaluated in all treated 


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Safety 
assessments 
patients.  However,  a  patient  leaving the  study  for  reasons  other  than 
 
toxicity before the end of first 2 cycles will be replaced by another patient. 
The occurrence and maximal grade of toxicity for the whole duration of 
treatment will be listed and tabulated by type and dose level. Adverse 
events reported as non-drug related by the responsible investigator will be 
reported as well. Toxicity will be evaluated in this study using the Common 
Terminology Criteria for Adverse Events by the NCI (CTCAE version 4.0) 
and the New York Heart Association (NYHA) criteria for cardiotoxicity. 


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Table of abbreviations 
 
 
 
Abbreviation 
Definition 
ACE 
Angiotensin I converting enzyme 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine transaminase 
AML 
Acute myelogenous leukemia 
ANC 
Absolute neutrophil count 
ALP 
Alkaline phosphatase 
aPTT 
Activated partial thromboplastin time 
ARDS 
Acute respiratory distress syndrome 
ARO 
Academic Research Organization 
AST 
Aspartate transaminase 
AT 
Aminotransferase 
AUC 
Area under the serum concentration-time curve 
AV 
Atrioventricular 
BC 
Breast cancer 
BML 
Below measurable limit 
BoR 
Best overall response 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CBR 
Clinical benefit rate 
CDER 
Center for Drug Evaluation and Research 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CL 
Clearance 
Cmax                                   Maximum concentration 
CNS                                    Central Nervous System 
CR                                     Complete response 
CRF 
Case Report Form 
CRO 
Contract research organization 
CSF 
Colony-stimulating factors 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DPD 
Dihydropyrimidine dehydrogenase 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
dV 
Distribution Volume 
DSUR 
EC 
ECD 
ECG 
Development safety update report 
Ethics Committee 
Extracellular domain 
Electrocardiogram 
 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 


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eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
EOS 
End of Study 
ESA 
Erythropoieses stimulating agents 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose-Positron Emission Tomography 
FISH 
Fluorescence in situ hybridization 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B virus 
β-HCG 
Human chorionic gonadotropin 
HER2 
Human epidermal growth factor receptor 2 
HIV 
Human immunodeficiency virus 
HR 
Hazard Ratio 
5-HT 
5-hydroxytryptamine 
ICH 
International Conference on Harmonisation 
IHC 
Immunohistochemistry 
INR 
International normalized ratio 
IRB 
Independent Review Board 
ISH 
In situ hybridation 
ITT 
Intention to Treat 
LDH 
Lactate dehydrogenase 
LC-MS/MS 
Liquid chromatography–mass spectrometry 
LVEF 
Left ventricular ejection fraction 
mBC 
Metastatic Breast Cancer 
MDS 
Myelodysplastic Syndromes 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multi-gated radionuclide angiography 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NRH 
Nodular regenerative hyperplasia 
NYHA 
New York Heart Association 
ORR 
Overall Response Rate 
PCR 
Polymerase chain reaction 
PD 
Progression Disease 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PK 
Pharmacokinetics 
PP 
Protocol compliant population 
PR 
Partial Response 
PVC 
Polyvinyl chloride 
QTcF 
Corrected QT interval using the Fridericia formula 
qw 
Once weekly 
q3w 
Every 3 weeks 
RBC 
Red Blood Cells 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
Ribonucleic acid 


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SADR 
Serious Adverse Drug Reaction 
SAP 
Statistical Analysis Plan 
SC 
Steering Committee 
SD 
Stable Disease 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SmPC 
Summary of Product Characteristics 
SNP 
Single nucleotide polymorphisms 
SOC 
System-organ class 
TBL 
total bilirubin 
T-DM1 
Trastuzumab emtansine 
ULN 
Upper Limit of Normal 
Vss 
Volume of distribution at steady state 
WBC 
White blood cell 


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Table of Contents 
 
KEY CONTACTS.......................................................................................................................................................... 2 
 
Declaration of Investigators ........................................................................................................................................ 5 
 
Protocol synopsis ......................................................................................................................................................... 7 
 
Table of abbreviations ............................................................................................................................................... 14 
 
Table of Contents ....................................................................................................................................................... 17 
 
1. 
BACKGROUND AND RATIONALE ................................................................................................................ 20 
 
1.1. 
HER2-Positive Metastatic Breast Cancer ................................................................................................. 20 
 
1.2. 
Trastuzumab Emtansine (T-DM1) in HER2-Positive Metastatic Breast Cancer ................................. 20 
 
1.3. 
Pharmacokinetics of T-DM1 ........................................................................................................................ 24 
 
1.4. 
Mechanisms of cardiotoxicity of study drugs ............................................................................................ 25 
 
1.5. 
Non-pegylated liposomal doxorubicin ....................................................................................................... 26 
 
1.6. 
Rationale to Study the Combination of T-DM1 and non-pegylated liposomal doxorubicin ............... 26 
 
2. 
OBJECTIVES .................................................................................................................................................... 32 
 
2.1. 
Primary Objective ......................................................................................................................................... 32 
 
2.2. 
Secondary Objectives .................................................................................................................................. 32 
 
3. 
STUDY OVERVIEW ......................................................................................................................................... 33 
 
3.1. 
Study Design ................................................................................................................................................. 33 
 
3.2. 
T-DM1 drug dose schedule ......................................................................................................................... 33 
 
3.3. 
Non-pegylated liposomal doxorubicin drug dose schedule .................................................................... 34 
 
3.4. 
Dose escalation schema: description of cohorts ..................................................................................... 35 
 
3.5. 
Toxicity Criteria.............................................................................................................................................. 37 
 
3.6. 
Definition of Dose-Limiting Toxicities (DLTs)............................................................................................. 39 
 
3.7. 
General Concomitant Medication and Supportive Care Guidelines ..................................................... 41 
 
3.8. 
Women of Childbearing Potential and mandatory use of contraceptive methods .............................. 42 
 
3.9. 
Prohibited therapies ..................................................................................................................................... 43 
 
3.10. 
Duration of study treatment......................................................................................................................... 44 
 
3.11. 
Duration of period of study follow-up ......................................................................................................... 45 
 
3.12. 
End of Study (EoS)....................................................................................................................................... 45 
 
4. 
PATIENT SELECTION ..................................................................................................................................... 45 
 
4.1. 
Target study population................................................................................................................................ 45 
 
4.2. 
Inclusion Criteria ........................................................................................................................................... 45 
 
4.3. 
Exclusion Criteria.......................................................................................................................................... 47 
 
5. 
ASSESS MENTS AND STUDY PROCEDURES .......................................................................................... 48 
 
5.1. 
Registration ................................................................................................................................................... 48 
 
5.2. 
Study assessments ...................................................................................................................................... 49 
 
5.3. 
Schedule of assessments ........................................................................................................................... 51 
 
5.4. 
Polymorphism of HER2 gene (SNP) assessment ................................................................................... 53 


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5.5. 
Pharmacokinetic assessment ..................................................................................................................... 54 
 
5.6. 
Patient, study, and site discontinuation ..................................................................................................... 55 
 
6. 
DOSE DELAYS/DOSE MODIFICATIONS..................................................................................................... 56 
 
6.1. 
Criteria for Recycling and Dose Delays study drugs ............................................................................... 56 
 
6.2. 
Criteria for T-DM1 Dose Modifications in case of specific toxicities...................................................... 58 
 
6.3. 
Study drug dose modification for Cardiotoxicity ....................................................................................... 62 
 
7. 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ..................................................................................... 65 
 
7.1. 
Adverse Events Definitions ......................................................................................................................... 65 
 
7.2. 
Adverse Event Reporting ............................................................................................................................ 68 
 
7.3. 
Safety Reporting Flowcharts ....................................................................................................................... 71 
 
8. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................................................................... 73 
 
8.1. 
Sample size and statistics methods........................................................................................................... 73 
 
8.2. 
Analysis populations .................................................................................................................................... 73 
 
8.3. 
Safety Analyses ............................................................................................................................................ 73 
 
8.4. 
Efficacy Analyses .......................................................................................................................................... 74 
 
8.5. 
Pharmacokinetic Analyses .......................................................................................................................... 75 
 
8.6. 
Steering Committee Review ....................................................................................................................... 76 
 
9. 
PHARMACEUTICAL INFORMATION ............................................................................................................ 76 
 
9.1. 
Trastuzumab emtansine (T-DM1) .............................................................................................................. 76 
 
9.2. 
Non-pegylated liposomal doxorubicin ....................................................................................................... 83 
 
9.3. 
Supplying and Handling Investigational Products ................................................................................... 83 
 
9.4. 
Investigators Responsibilities over the Investigational Products ........................................................... 84 
 
10. 
ETHICAL CONSIDERATIONS ................................................................................................................... 85 
 
10.1. 
Regulatory and Ethics Compliance ............................................................................................................ 85 
 
10.2. 
Institutional Review Board / Independent Ethic Committee: .................................................................. 85 
 
10.3. 
Informed Consent ......................................................................................................................................... 85 
 
10.4. 
Data Protection ............................................................................................................................................. 86 
 
11. 
SOURCE DOCUMENTATION, STUDY MONITORING, AND QUALITY ASSURANCE .................... 87 
 
11.1. 
Source Data Documentation ....................................................................................................................... 87 
 
11.2. 
Study Monitoring and Source Data Verification ....................................................................................... 88 
 
11.3. 
Retention of records ..................................................................................................................................... 88 
 
11.4. 
Data Quality Assurance ............................................................................................................................... 89 
 
12. 
DATA MANAGEMENT ................................................................................................................................. 90 
 
12.1. 
Data Entry and Management ...................................................................................................................... 90 
 
12.2. 
Data Clarification .......................................................................................................................................... 90 
 
12.3. 
Data Coding Procedures ............................................................................................................................. 90 
 
13. 
STUDY MANAGE MENT .............................................................................................................................. 90 
 
13.1. 
Discontinuation of the Study ....................................................................................................................... 90 
 
13.2. 
Changes to the Protocol .............................................................................................................................. 90 


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13.3. 
Publication Policy Protection of Trade Secrets ........................................................................................ 91 
 
Appendix 1: Schedule of assessments and study procedures............................................................................ 92 
 
Appendix 2: Response Evaluation Criteria in Solid Tumors (RECIST criteria) guidelines (version 1.1) ....... 96 
 
Appendix 3: Instructions for Scans in the Event of Isotope Shortage ................................................................ 97 
 
 
Table of Figures 
 
Figure 1. Design of study cohorts ................................................................................................................................ 36 
 
Figure  2 Algorithm  for  continuation and  discontinuation of  combination of  study  drugs  based  on  Left 
 
Ventricular Ejection Fraction assessments ................................................................................................................ 63 
 
 
 
Summary of tables 
 
 
 
Table 1. Scale of ECOG Performance Status ............................................................................................................ 51 
 
Table 2. Dose Reduction for T-DM1 ............................................................................................................................ 58 
 
Table 3. Trastuzumab Emtansine Dose Modification: Total Serum Bilirubin ......................................................... 60 
 
Table 4. Trastuzumab Emtansine Dose Modification: Serum ALT or AST ............................................................. 60 


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1.        BACKGROUND AND RATIONALE 
 
 
1.1. HER2-Positive Metastatic Breast Cancer 
 
Breast cancer is the most common tumor among women. In 2012, around 1.7 million new cases were 
diagnosed with  breast cancer around the  world. Approximately 232,340 new cases of invasive 
breast cancer and 39,620 breast cancer deaths are expected to occur among US women in 2013 
(DeSantis et al. 2014). Approximately 7,900 of these deaths were related to HER2-positive breast 
cancer. Human epidermal growth factor receptor 2 (HER2) is a growth factor receptor gene that  is 
amplified  in  approximately  20%  of  breast  cancers  (Pegram,  Konecny,  and  Slamon 
2000)(Pegram et al. 2000). Studies have shown that women whose tumors exhibit either amplification 
of the HER2 gene or overexpression of its encoded protein have a more aggressive form of cancer 
that is associated with significantly shortened disease-free and overall survival compared with women 
whose tumors do not over express HER2. The incorporation of trastuzumab has significantly altered 
the natural history of HER2-positive breast tumors,  converting them from an aggressive tumor 
subtype to one with improved prognostic outcomes (Dawood et al. 2010; Verma et al. 2013). 
 
 
For patients with HER2-positive mBC, the combination of trastuzumab and a taxane is a globally 
accepted first-line treatment, based on the survival advantage demonstrated in two large pivotal 
trials(Marty et al. 2005; D. Slamon et al. 2011). More recently, the final overall survival analysis of the 
CLEOPATRA study with a dual blockade of the HER2 protein plus docetaxel, made the authorities 
to approve this combination as the first line treatment (Swain et al. 2013). However, virtually all 
patients with HER2-positive mBC develop progressive disease (PD) and require additional therapies. 
Importantly, such tumors continue to express high levels of HER2 (Spector et al. 2005), and neither 
the process of internalization nor the level of surface expression is altered when HER2 is bound by 
trastuzumab (Austin et al. 2004). HER2-directed combination therapy beyond progression for HER2- 
positive mBC is an accepted palliative treatment approach. 
 
 
 
1.2. Trastuzumab Emtansine (T-DM1) in HER2-Positive Metastatic Breast Cancer 
 
A novel approach to HER2-targeted breast cancer therapy is trastuzumab emtansine (T-DM1), an 
antibody-drug conjugate that combines intracellular delivery of the potent cytotoxic agent, DM1 
(maytansinoid, a derivative of maytansine that causes apoptosis through inhibition of microtubule 
assembly, with greater potency than vinka alkaloids and paclitaxel) (Widdison et al. 2006) with the 
antitumor activity of trastuzumab. T-DM1 uses a non reducible thioether linker (MMC) to combine the 
antibody and the cytotoxic (Junttila et al. 2011). The stability of MCC was shown to strongly contribute 
the favorable activity and toxicty profiles of T-DM1, delivering selectively DM1 to HER2- positive cells 
whereas exposure of normal tissue is minimized. Indeed clinical studies have shown 


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that DM1 plasma levels are consistently low (generally <10 ng/ml), transient and with no evidence 
of DM1 accumulation with repeated T-DM1 doses (consistent with a half life of 3.5 days) (I. E. Krop 
et al. 2010; Girish et al. 2012; Hurvitz et al. 2013). However, T-DM1 provides more than just targeted 
delivery of a cytotoxic, since once bound T-DM1 retains the hypothesized mechanisms of action of 
trastuzumab including flagging HER2-positive tumor cells for destruction by antibody- dependent 
cellular toxicity and inhibiting HER2 signalling (Phillips et al. 2014). 
 
 
T-DM1  has  significant  antitumor  potency  in  vitro  and  in  vivo,  which  is  maintained  in  tumors 
resistant to trastuzumab or lapatinib. In Phase I and II trials, T-DM1 provided objective tumor 
responses and was well tolerated across various lines of therapy in patients with HER2-positive 
metastatic breast cancer (I. E. Krop et al. 2010): the study TDM3569g was a Phase I, dose- 
escalation study that evaluated the safety and efficacy of trastuzumab emtansine as a single agent 
in 52 patients with HER2-positive mBC, whose disease progressed on a trastuzumab containing 
chemotherapy regimen. 24 patients received trastuzumab emtansine q3w and 28 patients received 
trastuzumab emtansine on a weekly (qw) schedule. On the q3w dosing schedule, dose-limiting 
toxicities  of  Grade  4  thrombocytopenia  were  seen  in  2  of  3  patients  treated  at  4.8  mg/kg. 
Therefore, 3.6 mg/kg was determined to be the maximum tolerated dose (MTD) of trastuzumab 
emtansine given q3w, and the cohort was expanded to 15 patients. On the basis of these data, the 
recommended dose schedule for the Phase II studies was 3.6 mg/kg q3w. On the qw schedule, 2.4 
mg/kg was identified as the MTD. Treatment with trastuzumab emtansine was well tolerated, and 
toxicity was generally mild, reversible, and non-cumulative. No drug-related cardiac toxicity was 
noted. Trastuzumab emtansine administration demonstrated considerable activity in this PhaseI 
study. The confirmed overall response rate (ORR) in patients with measurable disease at the 3.6 
mg/kg q3w schedule was 44% (4 of 9 patients), as assessed by investigators. The median PFS 
among the 15 patients receiving 3.6 mg/kg q3w was 10.4 months. 
 
 
Clinical efficacy and safety of T-DM1 has been established in several phase II and III trials. T-DM1 
is active in metastatic breast cancer patients with ≥ 1 previous HER2-directed therapy in 2 single- 
arm phase II trials (Study TDM4258g and Study TDM4374g) with an ORRs: 25.9% and 34.5% 
respectively (Burris et al. 2011; I. E. Krop et al. 2012), and prolonged PFS compared with trastuzumab 
plus docetaxel among patients without prior HER2-targeted therapy in a randomized phase II trial 
(Study TDM4450g) (median PFS: 14.2 vs 9.2 months; HR: 0.59; P = 0.035) (Hurvitz et al. 2013). 
 
 
In the Study TDM4258g trastuzumab emtansine was administered at a dose of 3.6 mg/kg (IV) q3w 
in patients with HER2-positive mBC who had progressed on previous HER2-directed therapy and 
conventional chemotherapy. The final analysis of ORR was 37.5% (95% confidence interval [CI]: 


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28.6%–46.6%) by investigator assessment and 25.9% (95% CI: 18.4%–34.4%) by Independent 
 
Review Board (IRB). The clinical benefit rate (CBR) was 46.3% by investigator assessment and 
 
39.3% by independent review. The median PFS was 4.6 months as assessed by both the 
investigators and the IRB. In the subset of patients whose archival primary tumors were 
retrospectively confirmed to be HER2-positive (74 of 95 patients with submitted tumor samples), 
the ORR was 33.8% by independent review and 47.3% based on investigator assessment. The 
most common adverse events (AEs) (occurring in≥ 20% of patients) were fatigue (65.2%), nausea 
(50.9%), headache (40.2%), epistaxis (35.7%), pyrexia (34.8%), constipation (30.4%), cough 
(27.7%), hypokalemia (26.8%), diarrhea (25.9%), vomiting (24.1%), arthralgia (22.3%), pain in 
extremity (22.3%), anemia (20.5%), and dyspnea (20.5%). Most of these AEs were Grade 1–2. 
The three most common Grade 3–4 AEs observed in this trial were hypokalemia (8.9%), 
thrombocytopenia (8.0%), and fatigue (4.5%). There was one reported Grade 5 event in a patient 
who died of respiratory failure attributed by the investigator to underlying disease. No Grade≥ 3 left 
ventricular systolic dysfunction events (symptomatic congestive heart failure [CHF] and/or left 
ventricular ejection fraction [LVEF] of < 40%) were observed (Burris et al. 2011). 
 
 
The other single-arm study of trastuzumab emtansine has been the study TDM4374g where the drug 
was administered at 3.6 mg/kg by IV infusion q3w to patients with HER2 -positive mBC. Patients must 
have received an anthracycline, trastuzumab, a taxane, lapatinib, and capecitabine given in the 
neoadjuvant, adjuvant, or metastatic setting or as treatment for locally advanced disease. Patients 
must have been treated with two HER2-directed therapies in the metastatic or locally  advanced 
setting  and  have  progressed  on  their  most  recent  treatment.  A  total  of  110 patients  were 
enrolled and treated in the study. An efficacy analysis (data cut-off date: 21 June 
2010) with a median follow-up of 17.4 months demonstrated an ORR (complete and PR) of 34.5% 
(95% CI: 26.1%–43.9%; 38 of 110 patients) by independent review and 32.7% (95% CI: 24.1%– 
42.1%; 36 patients) by investigator assessment. The CBR was 48.2% by independent review and 
 
46.4% by investigator assessment. The median duration of response (DoR) and PFS by independent 
review was 7.2 months and 6.9 months, respectively. In the subset of patients whose archival primary 
tumors were retrospectively confirmed to be HER2-positive (80 of 95 patients with submitted tumor 
samples), the ORR was 41.3% by independent review and 40.0% based on investigator assessment. 
The most common AEs (occurring in≥ 20% of patients) were fatigue (61.8%),  thrombocytopenia 
(38.2%), nausea (37.3%), increased aspartate transaminase (AST, 
26.4%), constipation (23.6%), pyrexia (22.7%), epistaxis (22.7%), headache (21.8%), hypokalemia 
(20.9%), decreased appetite (20.9%), dry mouth (20.0%), and anemia (20.0%). Most of these AEs 
were Grade 1–2. Fifty-two patients (47.3%) experienced at least one Grade≥ 3 AE, the most common 
being thrombocytopenia  (9.1%) and fatigue  (4.5%). Serious AEs (SAEs) were recorded by 28 
patients (25.5%), the most common being cellulitis (3.6%), pyrexia (2.7%), and pneumonia 


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(2.7%). One patient recorded a Grade 5 AE of hepatic dysfunction, which was recorded as possibly 
related to trastuzumab emtansine. The patient had pre-existing non-alcoholic fatty liver disease as 
well as multiple other comorbidities, including renal insufficiency (I. E. Krop et al. 2012). 
A randomized  multicenter  phase  II  trial  (Study TDM4450g)  of  trastuzumab  emtansine  versus 
 
trastuzumab plus docetaxel in patients with metastatic HER2-positive BC who had not received 
prior chemotherapy for metastatic disease was conducted. Seventy patients were randomized to 
the control arm and 67 patients to the trastuzumab emtansine arm. The median duration of follow- 
up was 13.5 months for the control arm and 13.8 months for the trastuzumab emtansine arm. As of 
15 November 2010, the PFS was 14.2 months in the trastuzumab emtansine arm versus 9.2 
months in the trastuzumab plus docetaxel arm. The HR for PFS was 0.594 (95% CI: 0.364–0.968; 
p= 0.0353). The ORR in the trastuzumab emtansine arm was 64.2% (95% CI: 51.8%–74.8%) 
compared with 58.0% (95% CI: 45.5%–69.2%) in the control arm (based on 69 evaluable patients). 
The CBR was 74.6% (95% CI: 63.2%–84.2%) in the trastuzumab emtansine arm versus 81.2% 
(95% CI: 70.7%–89.1%) in the trastuzumab plus docetaxel arm (based on 69 evaluable patients). 
Based on safety data analyzed at the data cut-off date, single-agent trastuzumab emtansine appears 
to have a favorable overall safety profile compared with trastuzumab and docetaxel in first-line 
mBC. The incidence of Grade≥ 3 AEs in the control arm (89.4%; n= 66) was nearly twice that of 
trastuzumab emtansine (46.4%; n = 69). The rates of SAEs for both arms were similar (control arm 
25.8% versus trastuzumab emtansine 18.8%). One patient in the trastuzumab emtansine group died 
as a result of an AE (sudden death). This patient was randomized to receive trastuzumab plus 
docetaxel but mistakenly received a single dose of 6 mg/kg trastuzumab emtansine instead of 6 
mg/kg trastuzumab. One patient in the trastuzumab plus docetaxel group died due to 
cardiopulmonary failure. With respect to cardiotoxicity, based on local assessments of LVEF, 
trastuzumab emtansine was not associated with an increase in cardiotoxicity compared with 
trastuzumab plus docetaxel (Hurvitz et al. 2013). 
 
 
The first phase III study to evaluate T-DM1 in HER2-positive metastatic breast cancer (mBC) was 
EMILIA study (Verma et al. 2012). This trial compared T-DM1 with capecitabine plus lapatinib in 
HER2-positive breast cancer treated in first-, second-, or third-line, but previously treated with taxanes 
and trastuzumab. PFS and OS are investigated as co-primary endpoints in this study with PFS based 
on modified RECIST (Therasse et al. 2000) and conducted by the IRB. An additional tumor 
assessment of PFS is performed after investigator documented disease progressionT-DM1. 
Significantly prolonged PFS (median PFS: 9.6 vs 6.4 months; HR: 0.65 (0.55-0.77), p < 0.0001), and 
overall survival (median PFS: 30.9 vs 25.1 months; HR: 0.68 (0.55-0.85), p < 0.001). Based on safety 
data analyzed at the data cut-off date, single-agent trastuzumab emtansine appears to have a 
favorable overall safety profile compared with lapatinib and capecitabine in mBC. The incidence of 
Grade≥ 3 AEs in the control arm (56.9%; n= 488) was 278; that of trastuzumab emtansine 


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(40.8%; n= 490) was 200. The rates of SAEs for both arms were similar (control arm 18% versus 
trastuzumab emtansine 15.5%).It was concluded that overall, there is no concern regarding the 
clinical safety of trastuzumab emtansine for the patient population that was studied, based on the 
currently available data (Verma et al. 2012). 
 
 
T-DM1 has a favorable safety profile as a single agent. There have been no special cardiac safety 
concerns in T-DM1 trials to date. Side effects that would be expected with DM1 such as substantial 
incidence of grade 3-4 peripheral neuropathy, have not been observed in clinical trials with T-DM1 
as single agent, which confirms that there is a low systemic exposure to DM1 (Krop and Winer 
2014). 
 
 
 
 
1.3. Pharmacokinetics of T-DM1 
 
The  PK  of  trastuzumab  emtansine  and  its  analytes  (total  trastuzumab  and  DM1)  were 
characterized in one Phase I study (TDM3569g) and three Phase II studies (TDM4258g, TDM4374g, 
and TDM4688g). 
 
 
For study TDM3569g, the final PK parameter estimates based on noncompartmental PK analysis 
for q3w and qw regimens of trastuzumab emtansine administration are presented in  the table 
below (Cycle 1 mean (s.d) Pharmacokinetic parameters for T-DM1 following T-DM1 administration 
every 3 weeks and weekly in study TDM3569g). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose  intensity,  defined  as percentage of  the planned  trastuzumab emtansine dose that was 
actually received, was higher with the 3.6 mg/kg q3w regimen (median 99.7%, range 88%–106%) 
than with the 2.4 mg/kg qw schedule (median 82%, range 54%–101%). However, since the PK of 
trastuzumab emtansine is linear at doses≥ 2.4 mg/kg, an almost 2-fold higher cumulative dose can 
be administered within a q3w cycle with a 2.4 mg/kg qw regimen compared with 3.6 mg/kg q3w. 
Based on a population PK analysis, trastuzumab emtansine has a consistent PK profile with low 
inter-individual  variability  (21%–48%)  in  PK  parameters  among  patients  with  mBC.  Greater 


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baseline tumor burden and lower serum albumin levels, potential indicators of disease severity, 
resulted in small increases (< 13%) in trastuzumab emtansine clearance (CL). However, trastuzumab 
emtansine PK  was  not  affected by  baseline  residual trastuzumab  (from  prior treatment) or by 
differences in serum concentrations of HER2 extracellular domain (Gupta et al. 
2012). 
 
 
 
An aggregate PK assessment of trastuzumab emtansine was performed with samples from studies 
TDM3569g, TDM4258g, TDM4374g, and TDM4688g (Girish et al. 2012). PK parameters for 
trastuzumab emtansine, total trastuzumab, and DM1 were consistent across the four studies at Cycle 
1 and steady state. Trastuzumab emtansine PK was not affected by residual trastuzumab from prior 
 
therapy or circulating extracellular domain of HER2. No significant correlations were observed 
between trastuzumab emtansine exposure and efficacy, thrombocytopenia, or increased 
concentrations of transaminases. Across the four studies, the incidence of anti-therapeutic 
antibodies to trastuzumab emtansine was low and detected in 4.5% (13/286) of evaluable patients 
receiving trastuzumab emtansine q3w. 
 
 
The PK profile (i.e., maximum concentration [Cmax], area under the serum concentration-time 
curve [AUC], terminal half-life [T½], apparent volume of distribution at steady state[Vss], and CL) of 
single-agent trastuzumab emtansine (3.6 mg/kg q3w) is predictable, well characterized, and 
unaffected   by   circulating   levels   of   HER2   extracellular   domain   or   residual   trastuzumab. 
Trastuzumab emtansine exposure does not correlate with clinical responses or key AEs. Weekly 
administration of trastuzumab emtansine in study TDM3568g at a dose of 2.4 mg/kg showed 
consistent PK data with the q3w dosing schedule. 
 
 
 
1.4.     Mechanisms of cardiotoxicity of study drugs 
 
Cardiac disfunctions are among the most common side effects of anthracyclines. Endomyocardial 
biopsy and troponin I measurements suggest that myocyte injury may occur early after exposure to 
the drug, however clinical manifestation becomes apparent later due to cardiac reserves and 
activation of compensatory mechansims. Clinically, early cardiac events are reversible and include 
arhytmia, repolarization changes, pericarditis and less frequent myocarditis.Late anthracyclcine 
cardiotoxicity includes cardiomyopathy and systolic heart failure. Patients treated with doxorubicin 
are five times more likely to develop chronic heart failure or reduction in LVEF compared to those 
treated with non-antracyclin regimens. Moreover, cardiotoxicity induced by doxorubicin is dose- 
dependent, being 300mg/m*2 the tolerated cumulative dose, although there is substantial 
heterogeneity among patients. The mechanism of doxorubicin-induced cardiotoxicity is not fully 
understood. The drug enters myocits where it causes mitochondrial dysfunction with consecutive 


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changes  in  calcium  and  contractile  function.  Further  increase  in  drug  concentration  causes 
myocyte cell death   (Suter and Ewer 2013).   A strategy to avoid the increased cardiac risk of 
doxorubicin is pharmacokinetic modification by non-pegylated liposomal encapsulation, as discussed 
in section 1.5. 
On   the   other  hand,   trastuzumab   cardiotoxicty  has   been   widely   studied,   specially   when 
administered in combination of anthracyclines. Based on the observations in phase III trials of 
trastuzumab plus anthracyclines (discussed in section 1.6), a correlation between time of 
administration of anthracyclines and trastuzumab was observed, suggesting a high risk of 
cardiotoxicity in the concomitant administration.   From a mechanistic point of view, trastuzumab 
may act as a modulator of anthracyclin toxicity when administered during a period of myocyte 
vulnerability  following  anthracyclin  exposure.  Based  on  these  observations,  the  following  risk 
factors for trastuzumab-associated cardiotoxicity have been identified: prior treatment with 
anthracyclines, borderline limit LVEF, preexisting arterial hypertension and advanced age. 
 
 
 
1.5.     Non-pegylated liposomal doxorubicin 
 
Non-pegylated   liposomal   doxorubicin   is   a   nanotechnology   product   intended   to   passively 
accumulate   into   solid   malignancies   through   gaps   in   the   tumor   microvasculature   while 
circumventing cardiac uptake. In the clinical setting, two randomized clinical trials comparing non- 
pegylated liposomal doxorubicin versus conventional doxorubicin either alone or in combination 
with cyclophosphamide in first line mBC have been shown a statistically significant reduction in 
cardiac toxicity while preserving similar antitumor efficacy (Mayer et al. 1990; Harris et al. 2002; Batist 
et al. 2001). On the other hand, combination therapy with non-pegylated liposomal doxorubicin and 
trastuzumab has been shown to be an active regimen in the clinical setting with no increase in cardiac 
toxicity, as discussed in section 1.6. 
 
 
 
1.6. 
Rationale  to  Study  the  Combination  of  T-DM1  and  non-pegylated  liposomal 
doxorubicin 
Albeit T-DM1 is a major conceptual and clinical advance in the treatment of HER2-positive metastatic 
breast cancer, there are two observations that emphasize the need to explore combination strategies: 
first, the response rate of T-DM1 when given alone in metastatic disease is less than 50%, and 
second, despite the median duration of the response is prolonged, progression inevitably occurs. 
Some of the combinations tested to date include T-DM1 with taxanes +/- pertuzumab, T-DM1 with 
capecitabine or T-DM1 with pertuzumab, that have the potential to result in increased activity with 
an acceptable tolerance to treatment related toxicity. 
 
 
In this context, it is appealing to study T-DM1 and doxorubicin for a number of reasons: 


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Doxorubicin is one of the most active chemotherapeutic agents against breast cancer; 
 
 In preclinical models the combined antitumor activity of trastuzumab plus doxorubicin arm was 
superior than trastuzumab and paclitaxel arm (Baselga et al. 1998). 
  In  the pivotal phase III trial of trastuzumab in first-line HER2-positive metastatic breast 
cancer, the highest antitumor effect was observed in the anthracycline arm compared to the 
taxane arm (D. Slamon et al. 2011; Rayson et al. 2012; Buzdar et al. 2013). In that initial 
phase III randomized registration trial, trastuzumab was combined with an anthracycline 
(doxorubicin or epirubicin) and cyclophosphamide (AC) in patients who had not previously 
received anthracycline therapy, or with paclitaxel (P) in patients who had received adjuvant 
anthracycline (D. J. Slamon et al. 2001; Dawood et al. 2010; Verma et al. 2013). Addition of 
trastuzumab significantly prolonged time to disease progression and overall survival (OS) 
as compared to chemotherapy alone. 
 
 
Cardiotoxicity, however, was significant in the pivotal trial, with 16% New York Heart Association 
(NYHA) Class III-IV heart failure on the trastuzumab/AC arm compared to 3% with AC alone (D. J. 
Slamon et al. 2001). The high cardiotoxicity of the combination of trastuzumab and doxorubicin 
observed in the first pivotal trial has been significantly reduced in subsequent trials with cardiac 
monitoring measures that took advantage of the observations, unexpected at that time, of the 
increased cardiotoxic potential of this combination. Subsequent trials, using careful cardiac 
monitoring, defined safer ways to combine trastuzumab and anthracyclines, but this combination 
has no clear role outside of the context of clinical trials (Romond et al. 2012; Buzdar et al. 2013; 
Baselga et al. 2014).  In this clinical trial and in order to minimize the potential cardiotoxicity of the 
combination of TDM-1 and doxorubicin, the non-pegylated liposomal form of the drug will be 
administered which decreases considerably the risk of cardiotoxicity. The combination of non- 
pegylated liposomal doxorubicin, trastuzumab, and paclitaxel (MTP) was investigated in a phase I– 
II trial, as first-line treatment of patients with HER2-overexpressing locally advanced BC or MBC 
and no prior exposure to anthracyclines, taxanes, or trastuzumab (Cortes et al. 2009). No patient 
developed treatment related symptomatic congestive heart failure (CHF). Asymptomatic protocol- 
defined cardiac dysfunction was found in 11 (17%) of 54 patients at the recommended dose. Left 
ventricular ejection fraction (LVEF) recovered to ≥50% in eight patients and to >45% in the 
 
remaining three patients. Among 26 patients with MBC, 25 responded, median time to progression 
was 22.1 months and median OS was 40.4 months. On the basis of the above results, a prospective, 
randomized phase III study (STM01-102) was designed in patients with HER2- overexpressing MBC 
and no prior chemotherapy for metastatic disease. The phase III trial included 
181 to receive MTP, and 183 to TP, with a median PFS of 16.1 and 14.5 months with MTP and TP, 
respectively [hazard ratio (HR) 0.84; two-sided P = 0.174]. Although the frequency of adverse 


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events was higher with MTP, there was no significant difference in cardiac toxicity between treatment 
arms (Baselga et al. 2014). 
 
 
On the other side, only one study has assessed the effect of trastuzumab emtansine (3.6 mg/kg q3w) 
on the QT interval in patients with HER2-positive recurrent locally advanced BC or mBC was 
evaluated in study TDM4688g, and had no meaningful effect on the corrected QT interval in these 
patients (Gupta et al. 2013). At Cycle 1 Day 1, 15 minutes post-infusion, the baseline-adjusted 
mean heart rate-corrected QT interval using the Fridericia formula (QTcF) increased by 1.2 ms. By 
60 minutes post-infusion, the baseline-adjusted mean QTcF interval decreased by 1.0 ms, and by 
 
Day 8 of Cycle 1, the baseline-adjusted mean QTcF interval decreased by 4.0 ms. By Cycle 3 Day 
 
1, prior to trastuzumab emtansine infusion, the mean QTcF interval had reverted back to baseline. 
Following the third infusion of trastuzumab emtansine, the baseline-adjusted mean QTcF interval at 
both the 15 minute and the 60 minute post-infusion time points was increased by 4.7 ms. No 
patient exhibited a mean change in QTcF interval from baseline exceeding 30 ms at any of the 
protocol-specified time points. 
 
 
The relationship between trastuzumab emtansine pharmacokinetic (PK) and electrocardiogram 
(ECG)  data  was  also  assessed.  While  there  appears  to  be  a  trend  between  trastuzumab 
emtansine drug concentration and its effect on QT interval, at the observed concentration ranges 
of trastuzumab emtansine, DM1, and total trastuzumab, there is reasonable assurance that the 
true increase in mean baseline-adjusted average QTcF does not exceed 5 ms. 
 
 
Moreover, because  trastuzumab  emtansine, total trastuzumab, and  DM1  achieve steady state 
levels  by  Cycle  3,  the  likelihood  of  progressively  longer  QTcF  with  repeated  trastuzumab 
emtansine dosing is low. 
In a pharmacokinetic study in patients treated with doxorubicin and trastuzumab, the exposure to the 
doxorubicin metabolites doxorubicinol and 7-deoxy-13-dihydro-doxorubicinone was increased in the 
presence of trastuzumab (Bianchi et al. 2003) but the clinical significance of this increase was felt 
to be minor, if any. However, pharmacokinetic data on the combination of doxorubicin (Gianni et al. 
1997) and T-DM1 are not available. Another issue of interest is to study genetic factors that may 
predispose to cardiac toxicity. Importantly, polymorphism of HER2 gene coding for the 
transmembrane domain of HER2 [Ile655Val] may predict risk of trastuzumab cardiotoxicity (Roca et 
al. 2013). 
 
 
Since T-DM1 is highly active as single agent due to its dual mechanism of action and being its 
overall safety profile  acceptable,  with an  expected low cardiotoxicity similar to  lapatinib, it is 


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expected that T-DM1 and non-pegylated liposomal doxorubicin may be safely combined together 
and offer the potential of increased antitumor effect compared to each agent given alone. 
 
 
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Toxicity and Efficacy in a Subgroup of Patients from UNICANCER-PACS 04 Trial.” Breast Cancer Research and 
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Romond, Edward H., Jong-Hyeon Jeong, Priya Rastogi, Sandra M. Swain, Charles E. Geyer, Michael S. Ewer, Vikas Rathi, 
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Slamon,  D.  J.,  B.  Leyland-Jones,  S.  Shak,  H.  Fuchs,  V.  Paton,  A.  Bajamonde,  T.  Fleming,  et  al.  2001.  “Use  of 
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2. 
OBJECTIVES 
 
 
2.1. Primary Objective 
 
- 
To determine the maximum tolerated dose (MTD) of the combination of T-DM1 and non- 
pegylated liposomal doxorubicin in HER2-positive metastatic breast cancer (mBC) patients 
previously treated with taxane and trastuzumab-based therapy. 
 
 
  PrimaryEndpoint: Maximum-tolerated dose (MTD) is defined as the highest dose level at 
which no more than one of six patients or 0 of three patients experiences dose-limiting toxicity 
(DLT) during the first two cycles of study treatment. 
 
 
2.2. Secondary Objectives 
 
- 
To explore efficacy of the combination of T-DM1 and non-pegylated liposomal doxorubicin, 
defined by the overall objective response rate (ORR), clinical benefit rate (CBR), number of 
progressions and number and reasons for deaths. 
 
 
SecondaryEndpoints: 
 
   Overall response rate (ORR). Overall response rate (ORR) is defined as the proportion of 
patients  with  best  overall  response  of  confirmed  complete  response  (CR)  or  partial 
response (PR) based on local investigator’s assessment according to RECIST criteria 
guidelines (version 1.1)(Eisenhauer et al. 2009). An objective response needs to be confirmed 
at least 4 weeks after the initial response. 
  Clinical benefit rate (CBR) Clinical benefit rate is defined as the proportion of patients with a 
best overall response of complete response (CR) or partial response (PR) or stable disease 
(SD) lasting more than 24 weeks based on local investigator’s assessment. 
  Number of patients with progressions and number of patients who died. 
 
 
 
- 
To assess the safety profile of the combination of T-DM1 and non-pegylated liposomal 
doxorubicin, defined by all toxicities reported during the study. The NCI CTCAE version 4.0 
and the New York Heart Association (NYHA) criteria (for cardiotoxicity) will be used to 
evaluate the clinical safety of the treatment in this study. Patients will be assessed for adverse 
events at each clinical visit and as necessary throughout the study. 
 
 
- 
To evaluate the cardiac safety of the combination of T-DM1 and non-pegylated liposomal 
doxorubicin measured by LVEF as assessed by echocardiography, cardiac troponin I and 
B-type natriuretic peptide (BNP) levels (if feasible). The number of patients who have 


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defined LVEF decline >10 percentual points or LVEF <50%, develop left ventricular 
dysfunction IV NYHA, discontinue any of the study drugs due to cardiac function or die due 
to  cardiac  cause  will  be  summarized.  Cardiac  troponin  I  elevation  will  be  assessed 
according to CTCAE v4.0 criteria and the segmental wall-motion abnormalities (not described 
in CTCAE v4.0) will be also recorded. 
- 
To explore the potential role of single nucleotide polymorphisms (SNP) in the predisposition 
for developing cardiotoxicity. Polymorphism of HER2 gene coding for the transmembrane 
domain of HER2 [Ile655Val] will be tested at baseline and correlated with LVEF changes 
and overall cardiac toxicity. 
- 
To   analyze   the   pharmacokinetics   (PK)   profile   of   T-DM1,   non-pegylated   liposomal 
doxorubicin and each ones metabolites. The following PK parameters will be calculated: 
AUC, clearance (CL), distribution volume (dV), apparent half life (t1/2) and maximal serum 
concentration (Cmax). Pharmacokinetic data will be compared with historical data of T-DM1 
alone and non-pegylated liposomal doxorubicin alone. 
 
 
 
3.        STUDY OVERVIEW 
 
 
3.1. Study Design 
 
This is a prospective dose finding, multicenter and open-label phase I clinical trial. There are three 
planned cohorts. T-DM1 will be administered at a fixed dose of 3.6 mg/kg IV on Day 1 every 3 
weeks and three cohorts of patients with three different dose levels of non-pegylated liposomal 
doxorubicin (45 mg/m2, 50 mg/m2  and 60 mg/m2) IV on Day 1 in cycles of 21 days each are 
planned. 
 
 
 
Study Cohort 
T-DM1 
Non-pegylated 
liposomal 
doxorubicin 
Cohort 1 (level 1) 
3.6 mg/kg IV D1 
45 mg/m2 IV D1 
Cohort 2 (level 2) 
3.6 mg/kg IV D1 
50 mg/m2 IV D1 
Cohort 3 (level 3) 
3.6 mg/kg IV D1 
60 mg/m2 IV D1 
Note: 
level -1 will be considered with T-DM1 (3.6 mg/kg IV) and weekly non-pegylated liposomal
doxorubicin (15 mg/m2 IV) if more than one of six patients experiences dose-limiting toxicity (DLT)
in the level 1 
 
 
 
 
 
3.2. T-DM1 drug dose schedule 
 
Clinical activity has been observed at a dose of 3.6 mg/kg q3w in two Phase II studies of single- 
agent trastuzumab emtansine in patients with advanced heavily pre-treated HER2-positive mBC 


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(study TDM4258g and study TDM4374g) and in patients who had not received prior chemotherapy 
for metastatic disease (TDM4450g). 
 
 
The initial dose of T-DM1 will be administered over 90 minutes (±10 minutes) and, in the absence 
of any signs or symptoms of infusion reactions with the first dose, subsequent doses of T-DM1 
may be administered over 30 minutes (±10 minutes). T-DM1 will be administered on Day 1 of a 3- 
week cycle at a dose of 3.6 mg/kg IV. If the timing of study drug administration coincides with a 
holiday or any other organizational circumstance that does not allow to administer the study drugs 
on the scheduled date, the treatment should be performed within 3 days of the scheduled date on 
the earliest possible following date. 
 
 
The total dose will be calculated based on the patient’s weight on Day 1 (or up to 3 days before) of 
each cycle. Infusions may be slowed or interrupted for patients experiencing infusion-associated 
symptoms. Any stop and/or change in the infusions rate must be recorded providing data about the 
time the infusion was stopped, restarted, volumes already administered and/or pending to be 
administered and new infusion rate. 
 
 
Vital signs must  be assessed  before and at any time  within 60  min after the end of T -DM1 
administration. Following the initial dose, patients will be observed for at least 60 minutes for fever, 
chills, or any other infusion-associated symptoms. If prior infusions were well tolerated (without any 
signs or symptoms of infusion reactions), subsequent doses of T-DM1 may be administered over 
30 minutes (±10 minutes), with a minimum 60 minutes observation period following the end of the 
 
infusion. Local health authority guidelines must be followed with regard to further observation and 
monitoring, if applicable. 
 
 
No premedication is necessary prior to administration of T-DM1. Pre-medication for nausea and 
infusion reactions (e.g. acetaminophen or other analgesics, antihistamines such as diphenhydramine, 
or corticosteroids) may be given at the investigator’s discretion (see Sections 
3.7, 3.9 and 9.1). 
 
 
 
 
3.3. Non-pegylated liposomal doxorubicin drug dose schedule 
 
Non-pegylated  liposomal  doxorubicin  doses  have  been  selected  as  being  in  the  range  of 
efficacious doses for single-agent or combination use. 
Non-pegylated liposomal doxorubicin will be administered approximately over 60 minutes starting 
 
60 minutes after the end of T-DM1 infusion. Standard antiemetics according to each center’s policy 
will be given for non-pegylated liposomal doxorubicin. 


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3.4. Dose escalation schema: description of cohorts 
 
This clinical trial is designed with a dose escalation following a “modified” 3 by 3 design where 3 
patients will be included at a given cohort and followed to observe if they experience any dose- 
limiting toxicity (DLT) during the first two treatment cycles. If none of the 3 first patients included in 
each cohort experience a DLT (0/3), the next patients will be enrolled in the subsequent cohort. If 1 
of these 3 first patients experience a DLT, 3 more patients will be included at the same cohort to 
determine the number patients who experience DLTs in the total group of 6 patients. If 2 or more of 
the 6 patients at a given cohort experience a DLT, the inferior cohort will be evaluated and established 
as  the  maximum  tolerated  dose  (MTD)  if  correct  (note:  if  2  or  more  of  the  3  first patients 
included at cohort 1 experience a DLT, level -1 will be explored). Once the MTD is established,  6 
additional patients will be enrolled at the  recommended phase 2  dose (RP2D) defined per the 
MTD as the highest dose level at which no more than one of six patients or 0 of three patients 
experiences dose-limiting toxicity (DLT) during the first two cycles of study treatment. The Steering 
Committee will review toxicities and may decide to add the expansion cohort to level - 
1 in the situation where it is necessary to have a dose level -1. 
 
 
 
No dose escalation between  cohorts will  be  permitted.  Patients  assigned on each cohort  will 
remain at their study cohort during all the study period. 
 
 
Dose escalation of non-pegylated liposomal doxorubicin to next level will not occur until all patients 
in a cohort have completed cycle 2 and the Steering Committee and study site Investigator(s) have 
been able to review all toxicities and agreement is reached on the next dose escalation step. 
 
 
After the two first cycles, the study drug combination (T-DM1 and non-pegylated liposomal 
doxorubicin) will be administered for up to 6 cycles (including the first 2 cycles). After that, T-DM1 
treatment may continue as a single agent until disease progression or development of intolerable 
toxicity, whichever occurs first. 
 
 
A simplified overview (not explicity showing the “modified” 3 by 3 design) of the dose escalation 
scheme is shown below. 


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Figure 1. Design of study cohorts 
 
 
Cohort 2 
T-DM1 3.6 mg/kg 
Non-pegylated 
liposomal 
doxorubicin 
50 mg/m
2
 
6 patients (or 3 
if DLT in 0/3) 
 
Cohort 1 
 
T-DM1 3.6 mg/kg 
 
Non-pegylated 
liposomal 
doxorubicin 
45 mg/m
2
 
 
6 patients (or 3 if 
DLT in 0/3) 
 
 
 
DLT 
< 2/6 
 
 
 
DLT 
< 2/6 
Cohort 3 
 
T-DM1 3.6 mg/kg 
 
Non-pegylated 
liposomal 
doxorubicin 
60 mg/m
2
 
 
6 patients (or 3 if 
DLT in 0/3) 
 
 
 
 
DLT 
≥ 2/6 
DLT 
≥ 2/6 
DLT 
≥ 2/6 
DLT 
< 2/6 
 
 
 
 
 
 
Level -1 
 
T-DM1 3.6 mg/kg 
 
Non-pegylated 
liposomal 
doxorubicin weekly 
2 
Expanded 
cohort 1 
 
6 patients 
 
Expanded 
cohort 2 
 
6 patients 
Expanded 
cohort 3 
 
6 patients 
 
15 mg/m 
 
6 patients 
 
 
 
The detailed rules for dose escalation are detailed below: 
 
 
 
Cohort 1: Patients will be treated with a fixed dose of T-DM1 of 3.6 mg/kg IV every 3 weeks. Non- 
pegylated liposomal doxorubicin will be administered at a dose of 45 mg/m2. If none of the 3 first 
patients included experience a  DLT (0/3), the  next  patients will be enrolled  in the  subsequent 
cohort. If 1 of the 3 first included patients experiences a DLT, 3 more patients will be included for a 
maximum of 6. If less than 2 patients in the total group of 6 patients experience any DLT (0/3 or 
1/6), then the following patients will be included in Cohort 2. Otherwise, if 2 or more patients suffer 
 
any DLT (≥ 2/6), then cohort 1 will be declared too toxic and level -1 will be opened. 
 
 
 
Cohort 2: Patients will be treated with a fixed dose of T-DM1 of 3.6 mg/kg IV every 3 weeks. Non- 
pegylated liposomal doxorubicin will be administered at a dose of 50 mg/m2. If none of the 3 first 
patients included experience a  DLT (0/3), the  next  patients will be enrolled  in the  subsequent 
cohort. If 1 of the 3 first included patients experiences a DLT, 3 more patients will be included for a 
maximum of 6. If less than 2 patients in the total group of 6 patients experience any DLT (0/3 or 
1/6), then the next patients will be included in3C6oohf o9r7t 3. Otherwise, if 2 or more patients suffer any 


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DLT (≥ 2/6), then cohort 2 will be declared too toxic, the schedule of cohort 1 will be declared the 
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recommended dose for phase II trials (RP2D) and an expansion cohort of 6 more patients will be 
 
 
added to cohort 1. 
 
 
 
Cohort 3: Patients will be treated with a fixed dose of T-DM1 of 3.6 mg/kg IV every 3 weeks. Non- 
pegylated liposomal doxorubicin will be administered at a dose of 60 mg/m2. If none of the 3 first 
patients included experience a DLT (0/3), then 6 more patients will be included in an expansion 
cohort. If 1 of the 3 first included patients experiences a DLT, 3 more patients will be included for a 
maximum of 6. If less than 2 patients in the total group of 6 patients experience any DLT (0/3 or 
1/6), then 6 more patients will be included in an expansion cohort. Otherwise, if 2 or more patients 
suffer any DLT (≥ 2/6), then cohort 3 will be declared too toxic, and the schedule of cohort 2 will be 
declared the recommended dose for phase II trials (RP2D) and an expansion cohort of 6 more 
patients will be added to cohort 2. If the MTD is not established by the envisaged dose escalation 
for the combination regimen in cohort 3, further escalations may be considered, based on the 
safety profile; alternatively, the established dose in cohort 3 may be declared as the recommended 
phase 2 dose (RP2D). 
 
 
Level -1: Three patients will be treated with a fixed dose of T-DM1 of 3.6 mg/kg IV every 3 weeks. 
Non-pegylated liposomal doxorubicin will be administered at a weekly dose of 15 mg/m2. If 0 or 1 
of the 3 first included patients experiences a DLT, 3 more patients will be included for a maximum 
of 6. If less than 2 patients in the total group of 6 patients experience any DLT (0/6 or 1/6), then this 
schedule will be declared the recommended dose for phase II trials (RP2D). The Steering Committee 
will review toxicities and may decide to add the expansion cohort to level -1 in the situation where it 
is necessary to have a dose level -1. Otherwise, if 2 or more of 6 patients show a DLT (≥ 2/6), then 
level -1 will be declared too toxic and the study will finish. 
 
 
No dose escalation  between  cohorts  will be permitted. Patients assigned on  each cohort  will 
remain at their study cohort during all the study period. The recommended phase II dose (RP2D) 
will not exceed the highest dose level of the combination of T-DM1 and non-pegylated liposomal 
doxorubicin at which < 1 of 6 patients experienced a DLT. In case MTD is exceeded during escalation, 
de-escalation may be not considered. 
 
 
 
3.5. Toxicity Criteria 
 
All patients who receive any study treatment are evaluable for toxicity. Toxicities will be graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4 
(NCI CTCAE v4.0) and the NYHA criteria for cardiotoxicity. 


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Cardiac  segmental  wall-motion  abnormalities (not explicity described in  CTCAE v4.0)  will  be 
 
graded under the category of “investigations – other, specify” with a grading according to: 
 
 
 
Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Investigations 
– other, specify 
Asymptomatic 
or mild 
symptoms; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated 
Moderate; 
minimal, local 
or noninvasive 
intervention 
indicated; 
limiting age- 
appropriate 
instrumental 
ADL 
Severe or 
medically 
significant but 
not 
immediately 
life-threatening; 
hospitalization 
or prolongation 
of existing 
hospitalization 
indicated; 
disabling; 
limiting self 
care ADL 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
 
 
Toxicity of T-DM1 alone and non-pegylated liposomal doxorubicin alone has been well established 
in previous studies. Unexpected adverse reactions will be considered attributable to T-DM1 and 
not to non-pegylated liposomal doxorubicin, unless exacerbation of known adverse reactions is 
observed that could be considered related to the combination. It may only be possible to finally 
attribute an adverse reaction to either T-DM1 or non-pegylated liposomal doxorubicin or their 
combination after discontinuation of one of the drugs and continuation of the therapy with the other 
drug alone. If adverse reactions occur that are considered may be related to the combination of T- 
DM1 with non-pegylated liposomal doxorubicin or to non-pegylated liposomal doxorubicin alone, 
non-pegylated liposomal doxorubicin treatment will be discontinued, and T-DM1 treatment may be 
continued at the discretion of the treating physician who will follow the guidelines for T-DM1 use. 
Patients still not tolerating T-DM1 after discontinuation of non-pegylated liposomal doxorubicin and 
developing unacceptable (Grade 3 or 4) adverse reactions to T-DM1 should be treated using the 
established dose modification scheme for T-DM1 as described in section 6.2 or discontinued from 
T-DM1 treatment at the discretion of the treating physician who must clearly document the reason for 
the discontinuation. 
 
 
Patients are evaluated for safety at the end of cycle 2. After the two first cycles, the study drug 
combination (T-DM1 and non-pegylated liposomal doxorubicin) will be administered for up to 6 cycles 
(including the first 2 cycles). T-DM1 treatment may continue as a single agent until disease 
progression or development of intolerable toxicity, whichever occurs first. Dose of T-DM1 
administered as single agent will be the dose level used at the end of study treatment (combination 
T-DM1+non-pegylated liposomal doxorubicin). 


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3.6. Definition of Dose-Limiting Toxicities (DLTs) 
 
A Dose-Limiting Toxicity (DLT) is defined as any of the drug-related adverse events described in 
the Table 1 occurring during the first two cycles of study treatment. 
Reminder:  Drug-related  is  an  adverse  event  for  which  a  causal  relationship  with  the  study 
treatment (T-DM1 and non-pegylated liposomal doxorubicin combination) cannot be ruled out. 
 
 
If the second dose of study treatment has to be delayed for any reason and the delay has not 
exceeded 42 days from the first dose, the patient is also assessed for DLTs occurrence. 
 
 
When third dose of study treatment is going to be administered, patient will be no longer evaluated 
for DLTs in all subsequent cycles. 
 
 
Any patient who does not complete the DLT assessment (at end of cycle 2 or pre-dose at cycle 3 day 
 
1) will be replaced, except for patients who go end of study due to any DLT that does not allow to 
start cycle 2. 
 
 
For this study, the following toxicities will be defined as DLTs: 
 
 
 
Table 1 Summary of Dose-Limiting Toxicities (DLTs) 
 
Hematological toxicities: 
 
- 
Grade 4 neutropenia (i.e. absolute neutrophil count (ANC) < 0.5 x 109   cells/L for minimal 
duration of 7 days). 
- 
Grades 3 and 4 febrile neutropenia (i.e. ANC < 1.0 x 109  cells/L with a single temperature of 
 
>38.3°C or a sustained temperature of ≥ 38°C for more than one hour). 
 
- 
Uncomplicated Grade 4 thrombocytopenia (< 25.0 x 109  cells/L) which does not recover to ≥ 
 
75.0 x 109 cells/L before next planned dose administration. 
 
- 
Thrombocytopenia (any grade) complicated with clinically significant bleeding requiring medical 
intervention, such as platelet transfusion or cauterization. However, patients with Grade 1 or 2 
epistaxis may have cauterization and this should not be considered as a DLT. 
Cardiac toxicity: 
 
- 
Level I cardiotoxicity defined as: 
 
- 
Sudden death (defined as within 24 hours; unexplained) 
 
- 
Heart failure NYHA criteria class III-IV and LVEF decline defined as an absolute drop ≥10% 
 
resulting in a final LVEF <50% 
Hepatic toxicity: 
- 
Increase in AST (SGOT)/ALT (SGPT) values to >5x ULN 
 
- 
Increase in total bilirubin value to > 3xULN 


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- 
Hy’s Law, defined by The U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation 
and Research (CBER) as the rule of thumb that a drug is at high risk of causing a fatal drug- 
induced liver injury (DILI) when given to a large population, if it caused cases of liver injury that 
satisfied certain criteria when given to a smaller population. Hy’s Law cases have the following 
three components: 
o The drug causes hepatocellular injury, generally shown by more frequent 3-fold or greater 
elevations above the upper limits of normal (ULN) of ALT or AST than the (nonhepatotoxic) 
control agent or placebo. 
o Among  subjects  showing  such  aminotransferase  (AT)  elevations,  often  with ATs  much 
greater than 3xULN, some subjects also show elevation of serum total bilirubin (TBL) to 
>2xULN, without initial findings of cholestasis (serum alkaline phosphatase (ALP) activity 
 
>2xULN). 
 
o No other reason can be found to explain the combination of increased AT and serum TBL, 
such  as viral hepatitis A, B, or C,  pre-existing or acute  liver disease, or another drug 
capable of causing the observed injury. 
OtherGrade≥3non-hematological toxicities with the exception of: 
 
- 
Grade ≥ 3 diarrhea that recovers to Grade ≤ 2 after 24 hours of starting recommended anti- 
diarrheal treatment 
-     Grade 3 nausea, vomiting or diarrhea without appropriate treatment. 
 
-     Grade 3 or 4 nausea or anorexia that resolves to grade 1 prior to the start next cycle. 
 
- 
Infusion-related  reactions  (IRR).  They  are  not  considered  to  be  DLTs  since,  based  on 
experience with monoclonal antibodies, IRRs are not dose-related events. Precautions will be 
taken if IRR grade ≥ 3 occur. If described precautions are not sufficient, other options will be 
discussed between sponsor and investigator. 
-     Laboratory values of ≥ Grade 3 which are judged not clinically significant by the investigator. 
 
The following non-hematological toxicities are considered as DLTs: 
 
- 
Any other treatment-related non-hematological toxicity Grade ≥ 3 preventing the start of the 3rd 
cycle on Day 42 (6 weeks cycle length) 
-     Grade 2 non-hematological toxicity requiring interruption of treatment for > 21 days 
 
-     Patient not able to receive 100% of the dose level going into Cycle 3, Day 1 
 
NOTE: If a Grade 2 event requires a dose delay, it will not be considered as a DLT. However, if the 
toxicity does not resolve to Grade 1 or baseline by Day 42, requiring study treatment discontinuation, 
will be considered as a DLT. The SC will adjudicate in cases of DLTs that are not covered by the 
existing DLT criteria. 


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Finally, failure to recover from any toxicity adequately treated which results in a dose delay of more 
than 21 days will be considered a DLT or any toxicity at cycles 1 and/or 2 that compels to reduce next 
T-DM1 and/or non-pegylated liposomal doxorubicin dose/s or to discontinue the patient’s treatment 
(e.g. Hy’s Law, nodular regenerative hyperplasia, interstitial lung disease (ILD) including 
pneumonitis). 
 
 
In addition, those cases of elevations of Troponin I and BNP values consisting of an increase 
 
>10% from screening values will be considered AESIs and will be reported to Steering Committee for 
being assessed. 
 
 
 
3.7. General Concomitant Medication and Supportive Care Guidelines 
 
Concomitant therapy and pre-medications are defined as non-IMPs. Concomitant therapy includes 
any prescription medication, over-the-counter preparation, or herbal therapy between the 21 days 
preceding first treatment and the safety follow up visit. All concomitant therapies will be registered. 
Afterwards,  only  information  about  further  anti-cancer  therapies  received  by  the  patient  once 
he/she goes off study will be collected. 
 
 
No pre-medication for the first infusion of T-DM1 is required; however, pre-medication is allowed at 
the investigator’s discretion. Additional antiemetics (aprepitant, 5HT3 antagonists) may also be given 
prior to non-pegylated liposomal doxorubicin at investigator’s discretion. 
 
 
Except for cycles 1 and 2, erythropoieses stimulating agents (ESAs) (such as Procrit, Aranesp, 
Epogen) and/or colony-stimulating factors (CSFs) (such as Neupogen, Neulasta, Leukine) may be 
used in accordance with National Comprehensive Cancer Network (NCCN) guidelines. At cycle 3 
and beyond, these agents are allowed if clinically indicated in accordance with local prescribing 
guidelines. 
 
 
Refer to section 9.1 and 9.2 for potential interactions on the use of concomitant medication with T- 
DM1 and non-pegylated liposomal doxorubicin. 
 
 
Once the patient is on study treatment, palliative radiotherapy may be permitted to treat pre- 
existing painful bone metastases or to treat brain metastases (for patients who have disease 
control outside of the brain). The schedule of palliative radiotherapy will start 48 h after last dose of 
non-pegylated liposomal doxorubicin. Please contact the Medical Monitor or Scientific Global 
Coordinator for approval. 


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Other medications considered necessary for the patient’s safety and wellbeing may be given at the 
discretion of the investigator. Use of bisphosphonates or denosumab is permitted for the control of 
bone pain, prevention and/or treatment of bone metastases, and treatment of osteoporosis. If 
bisphosphonates are required for the treatment of symptomatic malignancy-associated 
hypercalcemia, tumor assessments should be performed to assess for potential disease progression. 
 
 
 
3.8. Women of Childbearing Potential and mandatory use of contraceptive methods 
 
Women of childbearing potential (defined as women with regular menses, women with amenorrhea 
for less than 12 months, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to have a 
negative serum pregnancy test within 7 days prior to the first dose of either study medication. 
 
 
All heterosexually active patients are required to use two forms of acceptable contraception, including 
one barrier method, during participation in the study and for 7 months following the last dose of T- 
DM1 and/or non-pegylated liposomal doxorubicin. 
 
 
If a patient is suspected to be pregnant, T-DM1 and non-pegylated liposomal doxorubicin should 
be immediately discontinued. If pregnancy is determined by a positive urine test, the pregnancy 
must be confirmed by a serum pregnancy test. If it is confirmed that the patient is not pregnant, the 
patient may resume dosing. 
 
 
If a patient or a patient’s partner becomes pregnant during study treatment or within 7 months after 
the last dose of T-DM1 and/or non-pegylated liposomal doxorubicin, the Medical Monitor must be 
notified and the pregnant patient will be withdrawn from the study. The Medical Monitor should also 
be notified of any pregnancy occurring during the study but known/confirmed after completion of 
the study. In the event that a patient or a patient’s partner is found to be pregnant during study 
treatment or within 7 months after the last dose of T-DM1 and/or non-pegylated liposomal 
doxorubicin, the pregnancy will be followed and the status of mother and/or child will be reported to 
the sponsor after delivery. A pregnancy notification form will be completed. 
 
 
Fetal harm has been identified as an important potential risk for T-DM1. Pregnant or lactating women 
have been excluded from all trastuzmab emtansine trials, and the use of effective contraception is 
required in the study protocols and the prescribing information. 


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Additional follow up information on any trastuzumab emtansine-exposed pregnancy and infant will be 
requested 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). 
 
 
Follow-up queries may be sent, asking for further information, if required for a comprehensive 
assessment of the case. 
 
 
Please note that a serum β-HCG test must be performed during screening, every 3 cycles and at 3 
and 7 months following the last dose of T-DM1 and/or non-pegylated liposomal doxorubicin for 
women of childbearing potential (including pre-menopausal women who have had a tubal ligation) 
and for women not meeting the definition of postmenopausal. 
 
3.9. Prohibited therapies 
 
Use of the therapies described below is prohibited during the study prior to discontinuation of study 
treatment (collectively, these will be referred to as non-protocol therapy): 
 
 
Erythropoieses stimulating agents (ESAs) (such as Procrit, Aranesp, Epogen), colony-stimulating 
factors  (CSFs)  (such  as  Neupogen,  Neulasta,  Leukine)  and/or  corticosteroids  (except  those 
needed to treat acute hypersensitivity or infusion related reactions or as pre-medication for T-DM1 
and Myocet administration) are prohibited during cycles 1 and 2. 
 
 
Any therapies intended for the treatment of cancer, other than T-DM1 and non-pegylated liposomal 
doxorubicin, whether they are approved by national health authorities or experimental, including 
cytotoxic chemotherapy, immunotherapy, hormonal therapy (other than megestrol acetate), and 
biologic or targeted agents (other than granulocyte colony-stimulating factor and erythropoiesis 
stimulating agents), are prohibited. 
 
 
Radiotherapy for unequivocal disease progression is not permitted while on study treatment, with the 
following exception of new central nervous system (CNS) metastases or isolated progression of 
previously treated CNS lesions. Patients who have disease control outside of the CNS, defined as 
confirmed PR or CR of any duration, or SD for ≥ 3 months, but who have developed CNS metastases 
that are treatable with radiation will be allowed to continue to receive study therapy until they 
either experience systemic progression of their disease outside of the CNS and/or further progression 
in the CNS that cannot be treated with additional radiation. Patients must not miss more than 
one cycle of study treatment for the treatment of their CNS metastases and must have an ECOG 
performance status of 0, 1, or 2 to continue on study treatment. The Medical Monitor 


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should be informed before a decision is made to resume study treatment after radiotherapy for 
 
CNS metastases. 
 
 
 
 
3.10.   Duration of study treatment 
 
The study treatment period is defined as the time between the study entry and the last dose of 
study combination (T-DM1 + non-pegylated liposomal doxorubicin) therapy. T-DM1 administration 
may continue as a single agent until disease progression or development of intolerable toxicity, 
whichever occurs first. 
 
 
If at any time the constraints of this protocol are considered to be detrimental to the patient’s health 
and/or the patient no longer wishes to continue with the protocol therapy, the study treatment 
should be discontinued and the reason(s) for discontinuation documented in the clinical records of 
the patient and corresponding case report form. 
 
 
Study treatment may continue until one of the following criteria applies: 
 
- 
Radiologically confirmed and documented unequivocal disease progression, with the following 
exception of new CNS metastases or isolated progression of previously treated CNS lesions. 
Patients who have disease control outside of the CNS, defined as confirmed PR or CR of any 
duration, or SD for ≥ 3 months, but who have developed CNS metastases that are treatable 
with radiation will be allowed to continue to receive study therapy until they either experience 
systemic progression of their disease outside of the CNS and/or further progression in the CNS 
that cannot be treated with additional radiation 
- 
Adverse event(s) that according to the protocol or in the judgment of the investigator may 
cause severe or permanent harm or which rule out continuation of study drug. Note: see 
detailed criteria for study treatment discontinuation due to toxicity in section 6. 
- 
General or  specific  changes  in the patient’s  condition  render  the patient  unacceptable for 
further treatment in the judgment of the investigator. 
-     Suspected patient’s pregnancy. 
 
-     Serious non-compliance with the study protocol. 
 
-     Investigator removes the patient from study. 
 
-     Death. 
 
-     Lost to follow-up. 
 
-     Patient withdraws consent. 
 
-     The study site or the sponsor decides to close the study. 


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All patients who have not progressed and are still in receipt of T-DM1 therapy at the close of the 
study, as defined here in section 3.12, who are not eligible to receive the T-DM1 treatment in a 
reimbursement setting, will continue to receive the drug per study procedures. 
 
 
 
3.11.   Duration of period of study follow-up 
 
Follow-up period is defined as the time between last dose of study combination (T-DM1 + non- 
pegylated liposomal doxorubicin) up to 12 months after first dose of study treatment. 
 
 
 
3.12.   End of Study (EoS) 
 
EoS is defined as the LPLV at the end of the follow-up period, as defined in previous section. This 
will be the last data collection point, which can be a clinic visit or a laboratory sample. LPLV is 
expected to occur approximately up to one year after the last patient has been enrolled into the study. 
 
 
 
4.        PATIENT SELECTION 
 
 
4.1. Target study population 
 
This study will enroll patients with histologically or cytologically confirmed HER2-positive mBC that 
have relapsed or progressed on or after both taxane and trastuzumab-based therapy Only patients 
whose HER2 tumor status was locally scored as IHC 3+ or ISH positive will be eligible. Evidence of 
measurable or evaluable metastatic disease is required. 
 
4.2. Inclusion Criteria 
 
Patients must meet the following criteria for study entry: 
 
1.  Signed informed consent prior to any study specific procedure. 
 
2.  Patient to be able and willing to comply with protocol. 
 
3.  Patients with cytologically or histologically confirmed carcinoma of the breast. 
 
4.   Patients  with  incurable  locally  advanced  or  metastatic  disease  who  have  previously 
received up to two previous chemotherapy regimens in this setting (patient starting the first, 
second or third line of treatment are eligible). Patient must have progressed or relapsed on or 
after taxane and trastuzumab-based therapy 
5.   HER2-positive  disease  immunohistochemistry  (IHC)  3+  or  in  situ  hybridization  (FISH) 
positive assayed at local laboratories and according to updated ASCO/CAP criteria (Wolff et 
al. 2013). 


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6.   At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1; or patients with non measurable lesions could be included with these 
exceptions: 
- 
patients with only blastic bone lesions are not eligible 
 
- 
patients   with   only   pleural,   peritoneal   or   cardiac   effusion,   or   meningeal 
carcinomatosis are not eligible 
7.  Patient ≥ 18 years of age. 
 
8.  ECOG performance status of 0 or 1. 
 
9.  Life expectancy ≥ 3 months. 
 
10. Adequate bone marrow function: 
 
a.  Hemoglobin ≥ 10 g/dl. 
 
b.  Absolute neutrophil count ≥ 1.5 x 109/L. 
 
c.   Platelets  ≥  100  x  109/L  without  transfusions  within  21  days  before  1st   study 
treatment. 
d.  International normalized ratio (INR) < 1.5 × the upper limit of normal (ULN). 
 
11. Adequate hepatic and renal function: 
 
a.   Total bilirubin ≤ 1.5 x ULN, except for Gilbert disease patients. Gilbert's syndrome is 
suspected in people who have persistent, slightly elevated levels of unconjugated 
bilirubin without any other apparent cause. A diagnosis of Gilbert’s syndrome will be 
based on the exclusion of other diseases based on the following criteria: unconjugated 
hyperbilirubinemia noted on several occasions, no evidence of hemolysis (normal 
hemoglobin, reticulocyte count, and LDH), normal liver function tests, and absence of 
other diseases associated with unconjugated hyperbilirubinemia. For patients with 
Gilbert disease, total bilirubin value must be ≤ 
3 x ULN. 
 
b.   Alkaline  phosphatase  ≤  2.5  ×  the  ULN  (≤  5  ×  the  ULN  if  liver  and/or  bone 
metastases are present). 
c.  AST (SGOT)/ALT (SGPT) ≤ 1.5 x ULN (< 3 x ULN if liver metastases are present). 
 
d.  Creatinine ≤ 1.5 x ULN and calculated creatinine clearance ≥ 50 mL/min per the 
 
Cockcroft and Gault formula. 
 
12. Adequate cardiovascular function with LVEF ≥ 55% as assessed by echocardiography, 
 
13. Recovery from all toxicities  of previous anti-cancer therapies to baseline or grade  ≤ 1 
(CTCAE version 4.0), except for alopecia. 
14. 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,  and  men  with  partners  of  childbearing 


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potential, agreement by the patient and/or partner to use a highly effective, non-hormonal 
form of contraception or two effective forms of non-hormonal contraception and to continue 
its use for the duration of study treatment and for 7 months after the last dose of study. For 
all other women, documentation must be present in medical history confirming that the patient 
is not of childbearing potential. 
 
4.3. Exclusion Criteria 
 
Patients must not meet the following criteria for study entry: 
 
1.  Previous treatment with T-DM1 or anthracyclines, either in the (neo)adjuvant or in the 
metastatic setting. 
2.  More than two chemotherapeutic regimens for locally advanced incurable disease or 
metastatic disease. 
3.   Patients who have received prior anti-cancer treatment with chemotherapy, immunotherapy 
or  radiotherapy  within  3  weeks  (6  weeks  for  nitrosoureas  or  mitomycin-C),  hormonal 
therapy or lapatinib within 7 days, prior trastuzumab within 21 days (7 days if weekly 
trastuzumab) or any other targeted therapy within the last 21 days prior to starting study 
treatment. 
4.  Previous radiotherapy for the treatment of unresectable, locally advanced/recurrent or mBC 
 
is not allowed if: 
 
a.   The last fraction of radiotherapy has been administered within 21 days prior to first 
study drug administration (except for brain irradiation; at least 28 days will be 
required). 
b.  More than 25% of marrow-bearing bone has been irradiated. 
 
5.   History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity to the 
active substance or to any of the excipients of T-DM1 or non-pegylated liposomal doxorubicin. 
6. Patients with CNS involvement. However, patients with metastatic CNS tumors may participate 
 
in this trial if the patient is > 4 weeks from radiotherapy completion, is clinically stable with 
respect to CNS tumor at the time of study entry and is not receiving steroid therapy for brain 
metastases. 
7. Severe/uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
or psychiatric illness/social situations that would limit compliance with study requirements. 
8.  Cardiopulmonary dysfunction as defined by any of the following : 
 
a.  History of NCI CTCAE (Version 4.0) Grade ≥ 3 symptomatic CHF or NYHA criteria 
 
Class ≥ II. 


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b.   Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not 
controlled by adequate medication, severe conduction abnormality, or clinically 
significant valvular disease. 
c.  High-risk  uncontrolled  arrhythmias  (i.e.,  atrial  tachycardia  with  a  heart  rate  > 
 
100/min at rest, significant ventricular arrhythmia [ventricular tachycardia], or higher- 
grade atrioventricular [AV]-block [second degree AV-block Type 2 [Mobitz 2] or third 
degree AV-block]). 
d.  Significant symptoms (Grade ≥ 2) relating to left ventricular dysfunction, cardiac 
arrhythmia, or cardiac ischemia. 
e.  Myocardial infarction within 12 months prior to randomization. 
 
f.   Uncontrolled hypertension (systolic blood pressure > 180 mmHg and/or diastolic 
blood pressure >100 mmHg). 
g.  Requirement for oxygen therapy. 
 
9.  Current peripheral neuropathy of Grade ≥ 3 per the NCI CTCAE, v4.0. 
 
10. History of a decrease in LVEF to < 40% or symptomatic CHF with previous trastuzumab 
treatment. 
11. Patients who have had a prior malignancy, other than carcinoma in situ of the cervix, or 
 
non-melanoma skin cancer, unless the prior malignancy was cured ≥ 5 years before first dose 
of study drug with no subsequent evidence of recurrence. 
12. Current known active infection with HIV, hepatitis B, and/or hepatitis C virus. For patients 
who are known carriers of hepatitis B virus (HBV), active hepatitis B infection must be ruled 
out based on negative serologic testing and/or determination of HBV DNA viral load per 
local guidelines. 
13. Women who are pregnant or breast-feeding. 
 
 
 
 
5.        ASSESSMENTS AND STUDY PROCEDURES 
 
 
5.1. Registration 
 
It should be obtained written patient informed consent prior to undergoing any study related 
procedures. Prior to the first dose of study drugs it is mandatory to register the patient at the Study 
Site. The following steps must be taken before registering patients to this study: 
1.        Completion of patient eligibility checklist 
 
2.        Registration of patient in the sponsor study database 
 
3.        Confirmation of patient allocation by sponsor 


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Completion of patient eligibility checklist and Registration of patient in the sponsor study 
database 
The  investigator’s  team  must  complete  the  patient  eligibility  checklist,  sign  and  date  it.  This 
checklist must be sent to sponsor for the allocation of the patient and his/her registration in the 
study database. 
Confirmation of patient allocation by sponsor 
 
Each patient will be identified with a unique patient number (UPN) for this study by the sponsor. All 
data will be recorded with this identification number on the appropriate CRFs. 
 
 
 
5.2. Study assessments 
 
Medical History and Demographic Data:  Medical  history  includes  clinically  significant  diseases, 
surgeries, cancer history (including prior cancer therapies and procedures), smoking history, use of 
alcohol and drugs of abuse, and all medications (e.g., prescription drugs, over-the-counter drugs, 
herbal/homeopathic remedies, nutritional supplements) used by the patient within 21 days prior to 
the screening visit. Demographic data will include age, sex, and self-reported race/ethnicity. 
 
 
Vital Signs: Vital signs will include measurements of weight, respiratory rate, heart rate, blood 
pressure, and temperature. Abnormal or significant changes to vital signs from baseline should be 
recorded as adverse events, if appropriate. 
 
 
Physical Examinations: A complete physical examination should include the evaluation of head, 
eye, ear, nose, and throat; cardiovascular; dermatological; musculoskeletal; respiratory; 
gastrointestinal; and neurological systems. Changes from baseline abnormalities should be recorded 
at each subsequent physical examination. New or worsened abnormalities should be recorded as 
adverse events if appropriate. 
 
 
As part of tumor assessment, physical examinations should also include the evaluation of the 
presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly. Limited physical 
examinations will be symptom-directed. 
 
 
Tumor and Response Evaluations: All  patients  are  evaluable  for  disease  response  unless  they 
come off study due to treatment related adverse events prior to the completion of cycle 2 and have 
not had any acceptable complete disease assessment. 
 
 
Measurable and unmeasurable disease must be documented at screening and re-assessed at 
each  subsequent  tumor  evaluation.  Tumor  assessments  with  computed  tomography  (CT)  or 


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magnetic resonance imaging (MRI) scans of the chest, abdomen and pelvis are to be performed as 
described in Appendix 1: Schedule of assessments and study procedures. 
 
 
CT or MRI of the brain and bone scan must be obtained at screening. If an isotope-based bone 
scan was performed > 28 days but ≤ 60 days prior to the first study 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. In the event a positron emission tomography (PET)/CT scanner 
is used for tumor assessments, the CT portion of the PET/CT must meet criteria for diagnostic quality. 
Tumor assessments should include an evaluation of all known and/or suspected sites of disease, 
whenever possible. Patients should have lesions selected that can be evaluated at every tumor 
assessment. 
 
 
The same radiographic procedure used at screening must be used throughout the study (e.g., the 
same contrast protocol for CT scans). Initial tumor response assessment will be performed at the end 
of cycle 2. Afterwards, tumor response assessment will be performed at the end of 4thcycle and 
cycles 6. Thereafter, the tumor response assessment will be performed every 9 weeks up to 
progression or up to 12 months after first dose of study treatment. Response assessments will be 
assessed by the investigator, based on physical examinations, CT or MRI scans, and bone scans 
using RECIST v. 1.1 (see Appendix 2: Response Evaluation Criteria in Solid Tumors (RECIST criteria) 
guidelines (version 1.1)). For patients who continue study treatment after isolated brain progression, 
the frequency of follow-up scans is at the discretion of the investigator. At the investigator’s discretion, 
CT scans, MRI scans, and/or bone scans may be obtained at any time when clinically indicated or if 
progressive disease is suspected. 
 
 
If a bone scan cannot be performed during the course of the study because of the unavailability of 
the Tc-99m isotope, the investigator may choose an alternative imaging modality (see SNP). 
 
 
Radiographic imaging should always be performed rather than clinical examination unless the 
lesion(s) being followed cannot be imaged but are assessable by clinical examination. In applying 
RECIST v.1.1, documentation by color photography including a ruler to estimate the size of the 
lesion is recommended. 
 
 
LaboratoryAssessments 
 
Local Laboratory Assessments: Prospective HER2 status Hematology, pregnancy testing, 
biochemistry, coagulation, and cardiac troponin I and B-type natriuretic peptide (BNP) levels (note: 
for those studies where BNP determination is not be feasible this determination will not be done). 
Patients will be enrolled based on local results. 


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Central Laboratory Assessments: Serum T-DM1 and serum non-pegylated liposomal doxorubicin 
concentrations and total trastuzumab metabolite and serum levels of HER2 ECD using a validated 
immunoassay. Plasma concentration of DM1 using a validated liquid chromatography electrospray 
tandem mass spectrometry (LC-MS/MS) method. Polymorphism of HER2 gene coding for the 
transmembrane domain of HER2 [Ile655Val]. The complete description of this procedure will be 
recovered in the “Secondary sub-studies Manual”. 
 
 
Electrocardiograms: A 12-lead ECG should be obtained at baseline and be printed and kept with 
the patient’s record. After the screening visit electrocardiograms will be performed as described in 
Appendix 1: Schedule of assessments and study procedures. 
 
 
Echocardiograms: To be performed as described in Appendix 1: Schedule of assessments and study 
procedures. 
 
 
ECOG Performance Status: Performance status will be measured using the ECOG performance 
status scale (see below). It is recommended, where possible, that a patient’s performance status 
be assessed by the same person throughout the study. 
 
 
Table 1. Scale of ECOG Performance Status 
 
Grade 
Scale 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, i.e., light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
(http://www.ecog.org/general/perf_stat.html) 
 
 
 
 
5.3. Schedule of assessments 
 
Study assessments are outlined in Appendix 1: Schedule of assessments and study procedures. 
Written informed consent for participation in the study must be obtained before performing any 
study specific screening tests or evaluations. Informed Consent Forms for enrolled patients and for 
patients who are not subsequently enrolled will be maintained at the study site. 


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Results of standard of care tests or examinations performed prior to obtaining informed consent 
and within 28 days prior to study start may be used; such tests do not need to be repeated for 
screening. 
 
 
All  screening  evaluations  must  be  completed  and  reviewed  to  confirm  that  patients  meet  all 
eligibility criteria before study start. The investigator will maintain a screening log to record details 
of all patients screened and to confirm eligibility or record reasons for screening failure, as applicable. 
 
 
Visits are based on scheduled 21-day cycles (if no treatment delay due to toxicity occurs). Dose 
delays and dose reductions will be allowed as outlined in Section 6. All visits must occur within ± 3 
business days from the scheduled date, unless otherwise noted in the schedule of assessments. 
All assessments will be  performed on the  day of the  specified  visit unless a time window is 
specified. Assessments scheduled on the day of study treatment administration should be performed 
prior  to  study  treatment  administration  unless  otherwise  noted.  If  the  timing  of  a protocol- 
mandated procedure coincides with a holiday and/or weekend, it should be performed on the nearest 
following date (i.e., within 3 business days). 
 
 
Local laboratory assessments scheduled for Day 1 of all cycles must be performed within 72 hours 
prior to study treatment administration unless otherwise specified. In addition, local laboratory 
assessments scheduled for Days 8 and 15 of cycles 1 and 2 must be performed ± 2 business 
days. Results of local laboratory assessments must be reviewed and the review documented prior 
to study treatment administration. 
 
 
All patients will be closely monitored for safety and tolerability during study treatment and at the follow 
up  period.  Patients  should  be  assessed  for  toxicity  prior  to  any  study  treatment 
administration; dosing will occur only if the clinical assessment and local laboratory test values are 
acceptable. 
 
 
Efficacy follow up:  Initial tumor response  assessment will be performed at the  end of  cycle 2. 
Afterwards, tumor response assessment will be performed at the end of 4thcycle and cycles 6. 
Thereafter, all patients will be followed up for efficacy every 9 weeks for up to 12 months after the 
first dose of study treatment or until progression or the patient withdraws consent or death, whichever 
occurs first. Response and progression will be evaluated in this study using the Response Evaluation 
Criteria in Solid Tumors (RECIST version 1.1). 


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Safetyfollowup: All patients will be followed up for up to 12 months after the first dose of the study 
combination treatment or up to study termination, whichever occurs first. Cardiac safety will be 
included. 
 
 
The first safety follow up visit for the combination treatment will be scheduled for all patients 28 
days (+/- 7 days) after the last study treatment (T-DM1 + non-pegylated liposomal doxorubicin) 
administration in order to follow up toxicities and changes in concomitant medication. Subsequent 
safety visits will be done every 9 weeks. Last safety follow-up visit will be 28(+/- 7 days) after last 
dose of any IMP. 
 
 
Note: for patients that discontinue the study treatment due to the delay of T-DM1 administration for 
 
42 days, the safety follow up visit will be done at 42 days (±5 days) after the last study treatment 
administration. 
 
 
All ≥ grade 2 adverse events will be followed up until improvement to baseline levels, grade 1 or 
complete recovery,  the patient withdraws consent, patient’s death or up to a maximum of  12 
months after the first dose of study combination treatment whichever occurs first. 
 
 
Survivalfollowup: Patients will be followed for survival every 6 months for up to 12 months after 
the first dose of study treatment or the patient withdraws consent or until death, whichever occurs 
first. During survival follow up patients will be assessed at least every six months by means of a 
visit on the site or other means (e.g., phone calls) to assess the current status of patients and the 
possible initiation of other treatments. 
 
 
 
5.4. Polymorphism of HER2 gene (SNP) assessment 
 
Blood samples must be drawn consistently either from any peripheral vein or from the port-a-cath for 
any time point, preferable before the first study treatment will be administered. Details will be provided 
in the Secondary sub-studies Manual. All samples will be labelled with patient study number, date 
and time of collection. 
 
 
Technical properties:  Next-generation  sequencing  technologies  allow  obtaining  sequences  from 
multiple loci in a group of samples at reduced costs. Sequences can be produced for the whole- 
genome or for targeted regions, from one or a few genes or regions to the whole-exome. Briefly, DNA 
is sheared by sonication followed by 5’ ends repair. The resulting fragments are then ligated to 
adaptors and purified size-selected DNA is then amplified by polymerase chain reaction (PCR) and 
hybridized to the capture library containing the targeted sequences. Hybridization is followed 


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by washing and capture of the hybridized DNA through magnetic bead selection, PCR and 
purification. Quantification of the library is assessed using a Bioanalyzer machine and qPCR. 
Sequencing will be performed using Illumina massive parallel sequencing technology (MiSeq or 
NextSeq). 
 
 
Commercially  available  array  include  sets  of  genes  from  pathways  related  to  cancer. As  an 
example, 
the 
GeneRead 
DNAseq 
Breast 
Cancer 
Gene 
Panel 
(Quiagen, 
http://www.sabiosciences.com/NGS_product/HTML/NGHS-001Z.html)   includes   the   coding   and 
UTR regions of the 20 most commonly mutated genes in human breast cancer samples. We will 
produce a high-coverage at the targeted regions for all the individuals in the study. This coverage 
ensures  a  very  low  false  negative  discovery  rate.  Deep-resequencing  will  allow  detecting 
nucleotidic  changes,  short  indels  and  also  structural  mutations.  Using  the  barcoding  system 
several  individuals  are  pooled  to  optimize  the  achieved  coverage.  Thus,  for  a  capture  array 
including 115 Kb of sequences, the expected average coverage is higher to 500X for 12 samples 
included  in  a  MiSeq  run.  Sequence  reads  will  be  aligned  to  the  human  genome  reference 
sequence (hg19, downloaded from http://genome.ucsc.edu). Sequence analysis will result with a 
list of genetic variants for every analyzed individual, including known polymorphisms previously 
related to cancer (e.g. the Ile655Val change at the gene coding for transmembrane domain of HER2) 
as well as new genetic variants not previously described. Newly described genetic variants can be 
ultimately validated by Sanger sequencing. 
 
 
Specific procedures: Purified DNA samples will be shipped on dry ice for analysis to Barcelona 
 
Biomedical Research Park (Spain). Further details are given in the Secondary sub-studies Manual. 
 
 
 
 
5.5. Pharmacokinetic assessment 
 
Rationale and Pharmacokinetic Outcome Measures 
 
The PK sampling rationale is to characterize the PK of T-DM1, total trastuzumab, and DM1, to 
assess potential drug-drug interaction when T-DM1 is given in combination with non-pegylated 
liposomal doxorubicin, and to explore potential correlations between drug exposure and measures of 
both  efficacy  (ORR)  and  toxicity  (troponin  I,  transaminases  (ALT,  AST),  platelets,  etc.),  if 
possible. The following PK parameters of T-DM1 and non-pegylated liposomal doxorubicin (including 
but not limited to those listed below) will be determined for all cohorts in all patients who receive study 
treatment during the dose-finding period, defined as the period between the first patient in the study 
being treated and the MTD definition, using either non-compartmental and/or population methods, if 
possible: 
- 
Serum concentrations of T-DM1 (conjugate) and total trastuzumab 


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- 
Plasma  concentrations  of  DM1,  non-pegylated  liposomal  doxorubicin  and  its  active 
metabolite doxorubicinol 
- 
Total exposure (e.g., AUC) 
 
- 
Cmax 
 
- 
Clearance (CL) 
 
- 
Distribution volume (Vss) 
 
- 
T1/2 
 
 
 
The PK of T-DM1, total trastuzumab and DM1 will be compared with historical T-DM1 single-agent 
PK data to evaluate the potential effect of non-pegylated liposomal doxorubicin on the PK of T- 
DM1 and related analytes. 
 
 
All PK parameters will be listed and tabulated by treatment dose and by cohort. Descriptive summary 
statistics including arithmetic mean, geometric mean (e.g., AUC and Cmax), median, range, and 
coefficient of variation will be presented for each cohort. Nonlinear mixed effects modelling will be 
also used but details will be presented in the statistical analysis plan (SAP). 
 
 
PK samples can be obtained ad hoc in case of SAE or unexpected toxicities which may suggest a 
potential drug-drug interaction. 
 
 
The exact time of PK sampling will be recorded for all samples. Patients will have approximately 6 
ml of peripheral blood collected at each sampling time point. 
 
 
Extracellular domain of HER2 receptor will be also measured, as it has been shown to represent a 
relevant covariate in the population PK modeling for T-DM1. 
 
 
Samples will be shipped to QPS Laboratory (Netherlands) or to PPD Laboratory (USA). Samples 
will be analyzed according to methods previously published. 
 
 
Further details are given in the Secondary sub-studies Manual. 
 
 
 
 
5.6. Patient, study, and site discontinuation 
 
Patient discontinuation: Patients have the right to withdraw from the study at any time for any 
reason. The investigator has the right to discontinue a patient from study treatment or from the 
study for any medical condition that the investigator determines may jeopardize the patient’s safety 


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if he or she continues in the study, for reasons of non-compliance (e.g., missed doses, visits), if the 
patient becomes pregnant, or if the investigator determines it is in the best interest of the patient. 
 
 
Patients must be withdrawn from study treatment if they become pregnant or experience disease 
progression defined using RECIST v. 1.1. The exception to this is patients who develop isolated 
progression in the brain as described in Appendix 2: Response Evaluation Criteria in Solid Tumors 
(RECIST criteria) guidelines (version 1.1). 
 
 
Details of discontinuation due to toxicity are given in section 6. 
 
 
 
Patients who discontinue from study treatment prematurely for any of the above reasons will continue 
to be followed according to section 3.11. The primary reason for discontinuation must be recorded 
on the appropriate CRF page. 
 
 
Study discontinuation: Section 3.12 describes the EOS definition and discontinuation of study. 
Prior to that, the Sponsor has the right to terminate this study at any time. Reasons for terminating 
the study may include, but are not limited to, the following: 
- 
The incidence or severity of AEs in this or other studies indicates a potential health hazard 
to patients 
- 
Patient enrollment is unsatisfactory 
 
- 
Data recording is inaccurate or incomplete 
 
 
 
 
6.        DOSE DELAYS/DOSE MODIFICATIONS 
 
Since the potential adverse events associated to T-DM1 and non-pegylated liposomal doxorubicin 
partly overlap (for instance, cardiac events, liver toxicity, haematological toxicity or mucositis), dose 
delays or modifications will generally apply to both drugs. Exceptions will be discussed with the 
Medical Monitor for special adverse events that can be accurately related only to one of the two 
agents, such as infusion reactions or extravasations. 
 
6.1. Criteria for Recycling and Dose Delays study drugs 
 
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the results of 
clinical assessments and laboratory test values are acceptable. 
 
 
T-DM1 and non-pegylated liposomal doxorubicin will be administered every 21 days only if the 
following criteria are met: 
- 
ANC ≥ 1.5 x 109/L. 
 
- 
Platelets ≥ 75 x 109/L. 


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- 
AST/ALT/bilirubin equal to baseline levels or grade < 1. 
Protocol Date: 27th June 2017 
- 
Recovery or improvement of other treatment related toxicities (except alopecia) equal to 
baseline levels or to grade < 1. 
 
 
Each new cycle may be delayed to a maximum of 3 weeks (maximal duration of cycle of 42 days). 
Dose delays and reductions are designed to maximize treatment for those patients who respond to 
or present clinical benefit from treatment while ensuring patient’s safety. Dose delays due to T- 
DM1 related toxicities and/or non-pegylated liposomal doxorubicin-related toxicities other than 
infusion reactions, thrombocytopenia, hepatotoxicity, neurotoxicity, cardiotoxicity, and ILD or 
pneumonitis are as follows: 
- 
If significant treatment-related toxicities (other than infusion reactions, thrombocytopenia, 
hepatotoxicity, neurotoxicity, and cardiotoxicity) have not recovered to Grade 1 or baseline, 
the next scheduled dose may be delayed for up to 42 days from the last dose received. 
“Significant” and “related” will be based on the judgment of the investigator (in consultation 
with the Sponsor’s Medical Monitor or designee when appropriate). For example, alopecia 
even if considered related would most likely not be considered to be significant. Fatigue 
may or may not be considered either related or significant. 
 
 
- 
In general, when the significant and related toxicity or any other toxicity that the investigator 
chooses  to  delay  dosing  for  (other  than  infusion  reactions,  thrombocytopenia, 
hepatotoxicity, neurotoxicity, and cardiotoxicity) resolves to Grade 1 or baseline, the patient 
may  resume  T-DM1  and  non-pegylated  liposomal  doxorubicin  if  the  delay  has  not 
exceeded 42 days from the last received study treatment. In general, patients should be re- 
evaluated weekly during the delay, whenever possible. In the case of patients who experience 
a Grade 3 or 4 hematologic event, it is mandatory that the re-evaluation is done at least weekly 
until recovery. If dosing resumes, the patient may receive T-DM1 and non- pegylated 
liposomal doxorubicin either at the same dose level as before or at one lower dose level 
(see Table 2 for T-DM1 dose reductions and decrease non-pegylated liposomal doxorubicin 
dose according to national prescribing guidelines). 
 
 
- 
Non-pegylated liposomal doxorubicin should be held for any Grade 3–4 toxicity attributable 
to non-pegylated liposomal doxorubicin until resolution to Grade ≤ 1 or baseline grade 
 
 
- 
 Dose reductions must be discussed previously with the Sponsor’s Medical Monitor 
or designee. 


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- 
If a patient requires a dose reduction, T-DM1 and /or non-pegylated liposomal doxorubicin 
dosing will be reduced by one dose level. No dose re-escalation will be allowed. 
 
 
Table 2. Dose Reduction for T-DM1 
 
Dose Level 
every 3 weeks schedule 
0 
3.6 mg/kg 
-1 
3.0 mg/kg 
-2 
2.4 mg/kg 
Indication for further dose 
reduction 
Off study treatment 
 
 
 
 
The non-pegylated liposomal doxorubicin dose will be reduced to one dose level in the event of grade 
 
3 or 4 mucositis or grade 2 mucositis persisting at day 21; febrile neutropenia or infection of more 
than grade 2 after a 1-week delay, and after an additional 1-week delay. Non-pegylated liposomal 
doxorubicin dose will be also reduced one dose level for any adverse event leading to dose reduction 
of T-DM1, unless the Medical Monitor concludes that non-pegylated liposomal doxorubicin role in 
such adverse event is fully ruled out. 
 
 
Non-pegylated liposomal doxorubicin will be also reduced one dose level for the following: 
 
- 
ANC < 0.500 x 109/L for > 7 days 
 
- 
ANC < 1.0 x 109/L with fever or infection 
 
- 
Platelets < 25 x 109/L 
 
- 
Platelets < 50 x 109/L requiring transfusion 
 
 
If non-pegylated liposomal doxorubicin is delayed, T-DM1 will be also held until both drugs can be 
administered, unless one or both are permanently discontinued. 
- 
If toxicity does not resolve within 42 days from the last study treatment received, the patient 
will discontinue study treatment and will be followed for disease progression and survival 
outcome. 
 
 
 
6.2. Criteria for T-DM1 Dose Modifications in case of specific toxicities 
 
T-DM1DoseModificationforThrombocytopenia 
 
Introduction: 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 x 
109/L), with the nadir occurring by Day 8 and generally improving to Grade 0 or 1 (≥ 75 x 109/L), by 
 
the next scheduled dose. In clinical trials, the incidence and severity of thrombocytopenia were higher 
in Asian patients. Severe cases of both non-fatal and fatal hemorrhagic events including 


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central nervous system hemorrhage have been reported in clinical trials with trastuzumab emtansine; 
these  events  were  independent  of  the  patients’ ethnicity.  In  some  of  the  observed cases the 
patients were also receiving anti-coagulation therapy. The need for platelet transfusions has been 
reported. 
 
 
Patients with  thrombocytopenia and on anti coagulant treatment have to be monitored closely 
during  treatment  with  trastuzumab  emtansine.  Platelet  counts  should  be  obtained  no  less 
frequently than weekly to evaluate recovery whenever any of the events listed below occurs, at 
least prior to each trastuzumab emtansine dose. 
 
 
Monitoring follow up of thrombocytopenia episodes: 
 
- 
If platelet counts do not recover to Grade ≤ 1 within 42 days from the last dose received, 
the patient will be discontinued from study treatment. No re-escalation of the T-DM1 dose is 
allowed. 
Note: although complete blood counts with platelets are required within 72 hours prior to study 
treatment administration at each cycle, the investigator may monitor platelet counts (or any 
other laboratory test) more frequently as clinically indicated. 
-      In the event of decreased platelet count to Grade 3 (< 50 x 109/L), do not administer T-DM1 
 
until platelet counts recover to Grade 1 (≥ 75 x 109/L), then treat at the same dose level. 
 
- 
Patients receiving T-DM1 who experience a first Grade 4 thrombocytopenia event may, 
after adequate recovery to a platelet count of Grade ≤ 1 or baseline, continue treatment 
with T-DM1 at a dose of 3 mg/kg in subsequent treatment cycles. Patients at the 3 mg/kg 
dose  level  who  experience  a  Grade  4  thrombocytopenia  event  may,  after  adequate 
recovery as defined above, continue treatment with T-DM1 at a dose of 2.4 mg/kg in 
subsequent treatment cycles. Patients who experience a Grade 4 thrombocytopenia event 
at the 2.4 mg/kg dose level will be discontinued from study treatment. 
 
 
Use of erythropoiesis stimulating agents will be allowed as consistent with prescribing guidelines. 
Transfusion of red blood cells and/or platelets will be allowed according to and at the discretion of the 
treating physician. 
 
 
T-DM1DoseModificationforHepatotoxicity 
 
Concurrent elevations of ALT/AST and bilirubin meeting Hy’s Law laboratory criteria: Regardless of 
dose level, T-DM1 must be permanently discontinued in patients with ALT and/or AST >3 × ULN 
and concurrent increase of total bilirubin to > 2 × ULN. 


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Nodular regenerative hyperplasia (NRH): T-DM1 must be permanently discontinued in patients 
who are diagnosed with NRH. 
 
 
Transaminase elevations or bilirubin elevation requiring dose adjustment: Patients who experience 
a ≥ Grade 3 elevation of liver function should be checked twice weekly for the recovery of 
transaminases  and/or  total  bilirubin.  If  a  patient’s  transaminases  and/or  total  bilirubin  do  not 
recover as per Table 3 and Table 4, within 42 days from the patient’s last dose of study treatment 
received, the patient will be discontinued from study treatment. 
No re-escalation of the T-DM1 dose is allowed. 
 
 
 
Table 3 and Table 4 describe the dose modification guidelines for increases in serum bilirubin and 
transaminases, respectively. 
 
 
Table 3. Trastuzumab Emtansine Dose Modification: Total Serum Bilirubin 
 
Grade 2 
(> 1.5 to ≤ 3 x ULN) 
Grade 3 
(> 3 to ≤ 10 × ULN) 
Grade 4 
(> 10 × ULN) 
Do not administer T-DM1 until 
total bilirubin recovers to 
Grade ≤ 1, and then treat at 
the same dose level 
Do not administer T-DM1 until 
total bilirubin recovers to 
Grade ≤ 1 and then reduce 
one dose level 
Discontinue T-DM1 
ULN = upper limit of normal. 
 
Note: A maximum of two trastuzumab emtansine dose reductions is allowed. A patient requiring 
more than two dose reductions must discontinue study treatment 
 
 
 
 
Table 4. Trastuzumab Emtansine Dose Modification: Serum ALT or AST 
 
Grade 2 
(> 3 to ≤ 5 × ULN) 
Grade 3 
(> 5 to ≤ 20 × ULN) 
Grade 4 
(> 20 × ULN) 
Treat at the same dose level 
Do not administer trastuzumab 
emtansine until AST/ALT 
recovers to Grade ≤ 2, and then 
reduce one dose level 
Discontinue trastuzumab 
emtansine 
ALT = alanine transaminase; AST = aspartate transaminase; ULN = upper limit of normal. 
Note: A maximum of two trastuzumab emtansine dose reductions is allowed. A patient requiring 
more than two dose reductions must discontinue study treatment. 


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T-DM1DoseModificationforNeurotoxicity: Patients receiving T-DM1 who experience Grade 3 or 4 
peripheral neuropathy that does not resolve to Grade ≤ 2 within  42 days after the last dose 
received will be discontinued from study treatment. 
 
 
T-DM1DoseModification/ManagementforInfusion-relatedReactions,HypersensitivityReactions 
 
T-DM1 treatment should be interrupted in patients with severe infusion-related reactions. T-DM1 
should be permanently discontinued in the event of life-threatening infusion-related reactions. 
Infusion of T-DM1 should be interrupted for patients who develop dyspnea or clinically significant 
hypotension. The infusion should be slowed to ≤ 50% or interrupted for patients who experience 
any other infusion-related symptoms. When the patient’s symptoms have completely resolved, the 
infusion may be continued at ≤ 50% of the rate prior to the reaction and increased in 50% increments 
every 30 minutes as tolerated. Infusions may be restarted at the full rate during the next cycle. 
 
 
Patients who experience T-DM1 infusion-related temperature elevations to > 38.5°C and/or other 
infusion-related symptoms may be treated symptomatically with acetaminophen and/or 
diphenhydramine 
hydrochloride. Serious infusion-related events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory 
distress should be managed with supportive care, such as oxygen, beta agonists, antihistamines, 
or antipyretics, at the investigator's discretion. Antihistamines and antipyretics may be used before 
subsequent infusions of T-DM1 at the investigator’s discretion. Medication with corticosteroids may 
be used after cycle 2. Patients should be monitored until complete resolution of symptoms. In the 
event of a true hypersensitivity reaction (i.e., if the severity of reaction increases with subsequent 
infusions), T-DM1 treatment must be permanently discontinued. Patients who experience a Grade 
≥ 3 hypersensitivity reaction or acute respiratory distress syndrome (ARDS) will be discontinued from 
 
the study. Patients who experience a severe delayed infusion reaction will be discontinued from 
study treatment. 
 
 
T-DM1 Dose Modification for PulmonaryToxicity: Cases of  interstitial lung disease  (ILD), including 
pneumonitis (including severe, life-threatening cases) and some leading to ARDS or fatal outcome 
have been reported with T-DM1. Treatment with T-DM1 has to be permanently discontinued in 
patients who are diagnosed with ILD or pneumonitis. 
 
 
T-DM1 Dose Modification for Extravasation:  During  the  clinical  development  of  T-DM1,  reactions 
secondary to extravasation have been observed. These reactions were usually mild and comprised 
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considered as a vesicant, close monitoring of the infusion site for possible subcutaneous infiltration 
during drug administration is recommended. 
 
 
 
6.3. Study drug dose modification for Cardiotoxicity 
 
Patients without significant cardiac history and with a baseline LVEF ≥ 55% as determined by 
 
ECHO are eligible for study participation. 
 
 
 
LVEF will be monitored during the last week of cycles 1, 2, 3, 4, 5, and 6, and after every 9 weeks 
afterwards. If the LVEF is reported as a range, the median of the range should be taken. 
 
 
 
 
On this protocol cardiotoxicity is defined as follows: 
 
 
 
- 
Cardiotoxicity of Level 1 defined as: 
 
- 
Sudden death (defined as within 24 hours; unexplained) 
- 
Heart failure NYHA criteria class III-IV and LVEF decline defined as an absolute drop ≥ 
 
10% resulting in a final LVEF <50% 
 
 
 
- 
Cardiotoxicity of Level 2 defined as: 
- 
An absolute drop ≥10% resulting in a final LVEF <50% and asymptomatic or heart 
 
failure NYHA criteria class II 
 
 
 
For cardiotoxicity cases, algorithm for continuation and discontinuation of combination of study 
drugs will be as follows: 
- 
For patients with cardiotoxicity of level 1 (as defined as DLT in Table 1) -> Discontinue T- 
DM1 and non-pegylated liposomal doxorubicin according to the algorithm of Figure 2. 
- 
For patients with cardiotoxicity of level 2, defined as asymptomatic or heart failure NYHA 
criteria class II and an absolute drop ≥10% resulting in a final LVEF <50% -> Continue or not 
 
discontinue T-DM1 and non-pegylated liposomal doxorubicin according to the algorithm of 
 
Figure 2. 


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Figure 2 Algorithm for continuation and discontinuation of combination of study drugs 
 
 
 
 
based on Left Ventricular Ejection Fraction assessments 
 
Cardiotoxicity of level 1: 
 
 Sudden   death   (within   24 
hours; unexplained) 
 
 Heart failure (NYHA  criteria 
class    III-IV)    and    LVEF 
decline ≥10% resulting in a 
final LVEF <50% 
 
 
 
Not applicable 
 
 
Discontinue T-DM1 and non- 
pegylated liposomal 
doxorubicin and LVEF 
reassessment a 
 
 
 
 
 
 
Non - level 1 or 2 
cardiotoxicity 
(other cases): 
 
 
 
Cardiotoxicity of level 2: 
 An   absolute   drop   ≥10%   resulting   in   a   final   LVEF   <50%   and 
asymptomatic or heart failure NYHA criteria class II 
 
 
 
LVEF < 40% a asymptomatic or 
heart failure NYHA criteria class II 
40% ≤ LVEF < 50% asymptomatic or 
heart failure NYHA criteria class II 
LVEF ≥ 50% 
asymptomatic 
or heart failure 
NYHA criteria 
Absolut decrease is 
 
≥ 15% points b 
Absolut decrease is 
 
< 15% points b 
 
class II 
 
 
 
 
Discontinue T-DM1 
and non-pegylated 
liposomal doxorubicin 
and LVEF reassessment a 
 
 
If recovery to LVEF >50% and symptoms 
resolve, resume T-DM1 only, never non- 
pegylated liposomal doxorubicin 
Continue T-DM1 
and discontinue 
non-pegylated 
liposomal 
doxorubicin 
(No reintroducible 
even with ulterior 
normalization) 
 
 
Continue T-DM1 
and non-pegylated 
liposomal 
doxorubicin 
and LVEF 
 
reassessment a 
 
 
 
CHF= congestive heart failure; LVEF = left ventricular ejection fraction. 
Note: LVEF assessment results must be reviewed before the next scheduled T-DM1 and non- 
pegylated liposomal doxorubicin infusion. 
a LVEF can be repeated within 21 days. 
b a second LVEF monitoring within 21 days consecutive confirmatory result 
 
 
Previous paragraph and previous figure summarizes the management of the combination of T- 
DM1 and non-pegylated liposomal doxorubicin on the basis of measured LVEF and changes in LVEF 
from baseline in patients, the decision to stop 6o4r ocfo9n7tinue the combination of study should be based 


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on this algorithm. Both, T-DM1 and non-pegylated liposomal doxorubicin, must be withheld 
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in all patients for whom a confirmed drop of LVEF to below 45%. T-DM1 treatment can be resumed 
if LVEF reassessed within 21 days is recovered to values >50%. Non-pegylated liposomal doxorubicin 
should be discontinued permanently. Similar approach should be followed for patients whose LVEF 
drops to values between 45% and 50% with an absolute decrease in LVEF of ≥ 15% points from 
baseline. For these patients, study treatment should be temporarily discontinued, the LVEF should 
be repeated within 21 days, and only T-DM1 should be resumed if the LVEF has recovered to 
within 15% absolute difference below baseline. For patients whose LVEF drops to values between 
45% and 50% with an absolute decrease in LVEF of < 15% points from baseline, non-pegylated 
liposomal doxorubicin should be discontinued permanently but treatment with T- DM1 can continue 
without interruption. If an investigator is concerned that an adverse event may be related to cardiac 
dysfunction, an additional LVEF measurement may be performed. 
 
 
If clinically significant cardiac dysfunction or cardiac failure develops or persists or if significant 
medical management is required to maintain ejection fraction, the patient should be discontinued 
from study treatment. T-DM1 and non-pegylated liposomal doxorubicin will be discontinued as well 
it is summarized in the Figure 2. 
 
 
In addition, those cases of elevations of Troponin I and BNP values consisting of an increase 
 
>10% from screening values will be considered AESIs and will be reported to Steering Committee 
for being assessed and confirmed as DLTs or not, and T-DM1 and non-pegylated liposomal 
doxorubicin will be discontinued and monitored according to decision of the Steering Committee. 


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7.        SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
 
Safety assessments will consist of monitoring and recording protocol-defined AEs, adverse events 
of special interest (AESIs) and SAEs; measurement of protocol-specified hematology, clinical 
chemistry, measurement of protocol-specified vital signs; and other protocol-specified tests that are 
deemed critical to the safety evaluation of the study drug(s). 
 
 
The Sponsor or its designee is responsible for reporting relevant SAEs to the Competent Authority, 
other applicable regulatory authorities, and participating investigators, in accordance with 
International Conference on Harmonisation (ICH) guidelines, European Clinical Trials Directive 
(Directive 2001/20/EC), and/or local regulatory requirements. 
 
 
The Sponsor or its designee is responsible for reporting unexpected fatal or life-threatening events 
associated with the use of the study drug to the regulatory agencies and competent authorities by 
telephone or fax within 7 calendar days after being notified of the event. The Sponsor or its designee 
will report other relevant SAEs associated with the use of the study medication to the appropriate 
competent authorities (according to local guidelines), investigators, and central Institutional Review 
Boards/Ethics Committees (IRBs/ECs) by a written safety report within 15 calendar days of 
notification. 
 
7.1. Adverse Events Definitions 
 
An adverse event is any untoward medical occurrence in a clinical study patient administered a 
pharmaceutical product, which does not necessarily have a causal relationship with this treatment. 
An adverse event can therefore be any unfavorable and/or unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a medicinal 
(investigational) product, regardless of whether it is considered related to the medicinal 
(investigational) product. 
 
 
The causal relationship between an adverse event and the Investigational Medicinal Product (IMP) 
 
will be defined as below: 
 
 
 
Not related: The temporal association between the adverse event and the IMP makes a causal 
relationship unlikely, or the patient’s clinical state or the study procedure/conditions provide a 
sufficient explanation for the adverse event. 


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Related: The temporal association between the adverse event and the IMP makes a causal 
relationship  possible  and  the  patient’s  clinical  state  or  the  study  procedure/conditions  do  not 
provide a sufficient explanation for the adverse event. 
 
 
Each  adverse  event  must  be  assessed  by  the  investigator  as  to  whether  or  not  there  is  a 
reasonable possibility of causal relationship to T-DM1, non-pegylated liposomal doxorubicin and/or 
their combination. 
 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting. A copy of the CTCAE 
version         4.0         can         be         downloaded         from         the         CTEP         website 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf). 
 
 
The intensity (severity) of an adverse event will be recorded as one of the following: 
 
 
 
- 
Mild - Easily tolerated and does not interfere with normal daily activities, CTCAE Grade 1. 
 
- 
Moderate - Causes some interference with daily activities, intervention or treatment may be 
needed. CTCAE Grade 2. 
- 
Severe   -   Normal   daily   activities   are   substantially   impaired,   hospitalization   and/or 
intervention or treatment is required, CTCAE Grade 3 or 4. 
- 
Fatal - Death, CTCAE Grade 5. 
 
- 
Not  applicable  (Clinically  significant  and  asymptomatic  laboratory  test  abnormalities  or 
abnormal assessments, for which no CTCAE grading guidance is applicable but which are 
considered as AEs). 
 
 
A mild, moderate or severe AE may or may not be serious. These terms are used to describe the 
intensity of a specific event. However, a severe event (such as severe headache) may be of relatively 
minor medical significance and is not necessarily serious. For example, nausea lasting several hours 
may be rated as severe, but may not be clinically serious. Fever of 39 °C that is not considered 
severe may become serious if it prolongs hospital discharge by a day. Seriousness rather than 
severity serves as a guide for defining regulatory reporting obligations. 
 
 
Adverse Drug Reactions: All noxious and unintended responses to an IMP (i.e. where a causal 
relationship between an IMP and an adverse event is at least a reasonable possibility), related to any 
dose should be considered adverse drug reactions. For marketed medicinal products, a response to 
a drug which is noxious and unintended and which occurs at doses normally used in 


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man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function, 
is to be considered an adverse drug reaction. 
 
 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. 
 
 
SeriousAdverseEvents 
 
Per definition, a Serious Adverse Event is defined as any adverse event that either: 
 
•          results in death (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 when it occurs), 
•          requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
results in persistent or significant disability/incapacity (disability is defined as a substantial 
disruption of a person ability to conduct normal life functions), 
• 
is a congenital anomaly/birth defect (in a neonate/infant born to a mother exposed to the 
investigational product(s), 
• 
considered a significant medical event by the investigator (e.g., may jeopardize the patient 
or may require medical/surgical intervention to prevent one of the outcomes listed above) (see 
below definition of clinically/medically significant event). 
 
 
Definition ofLifeThreatening: An adverse event is life threatening if the patient was at immediate risk 
of death from the event as it occurred, i.e. does not include a reaction that might have caused death 
if it had occurred in a more serious form. For instance, drug induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life threatening even though drug induced 
hepatitis can be fatal. 
 
 
DefinitionofHospitalization: Adverse events requiring hospitalization should be considered serious. In 
general,  hospitalization  signifies  that  the  patient  has  been  detained  (usually  involving  an 
overnight stay) at the hospital or emergency ward for observation and/or treatment which would not 
have been appropriate at the study site. When in doubt as to whether hospitalization occurred or was 
necessary, the adverse event should be considered as serious. 
 
 
Hospitalization for elective surgery or routine clinical procedures, which are not the result of an 
adverse event, need not to be considered adverse events. If anything untoward is reported during the 
procedure, this must be reported as an adverse event and either ‘serious’ or ‘non-serious’ attributed 
according to the usual criteria. 


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Definitionofclinically/medicallysignificantevent: 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse. 
 
 
Clinically/medically significant events MUST be reported as SAEs 
 
 
 
In this clinical trial and as defined in this protocol, serious adverse events and hospitalizations 
unequivocally and solely related to established tumor disease progression will NOT be treated as 
serious adverse events for reporting obligations. 
 
 
Serious  adverse  events,  if  brought  to  the  attention  of  the  Investigator  at  any  time  after  the 
cessation of the study treatment and considered by the Investigator to be possibly related to the study 
treatment (so, in fact serious adverse reactions), will be reported to the Sponsor. 
 
 
 
7.2. Adverse Event Reporting 
 
Adverse events will be collected from the first study-mandated procedure until the safety follow up 
visit to be done 28 days (+/- 7 days) after the last day of study treatment. All study patients will be 
carefully monitored for the occurrence of adverse events during this period. 
 
 
Clearly related signs, symptoms and abnormal diagnostic procedure results should be grouped 
together and reported as a single diagnosis or syndrome whenever possible. Any additional events 
that fall outside this definition should also be reported separately. 
 
 
All adverse events must be recorded in the CRF. 
 
 
 
Serious Adverse Event Reporting and Timeframe 
 
Europeansites: 
 
Reporting requirements will comply with all EU safety reporting requirements as detailed in “Directive 
 
2001/20/EC of the European Parliament and of the council of 4 April 2001 on the approximation of 
the laws, regulations and administrative provisions of the Member States relating 


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to the implementation of good clinical practice in the conduct of clinical trials on medicinal products 
for human use” and the associated guideline CT-3. 
 
 
All protocol defined SAEs and AESIs will be reported to the Sponsor (MedSIR ARO) within 24 
hours of when the Investigator or anyone of the site study team becomes aware of it as follows: 
•          Report all SAEs and AESIs (as defined in this protocol), irrespective of the study drug 
 
received by the patient, whether or not this event is considered by the Investigator to be related to 
study drug, to MedSIR ARO immediately, but in any event no later than 24 hours of any site study 
team staff becoming aware of the event. 
•          The full details of the SAE and AESI should be collected and fully documented using the 
 
Serious Adverse Event (SAE) form and sent to MedSIR ARO. 
 
•           Follow-up information, copies of the results of any tests, the outcome of the event plus the 
investigator’s opinion of IMP relationship to the SAE(s) and AESI(s), and other document when 
requested and applicable, will accompany the SAE form as available on the day of reporting or 
provided as soon as possible thereafter. 
•          The original SAE Report Form and the fax confirmation sheet from the sponsor must be 
kept with the CRF documentation at the study site(s). 
 
 
All SAE forms will be sent by the investigator or investigator’s team to the Sponsor (MedSIR ARO) 
 
by email and fax as noted below: 
email: pharmacovigilance@medsir.org 
fax: + 34 93 299 23 82 
 
 
SAEs and AESIS will be followed until resolved, a stable outcome is reached, patient is lost to 
follow-up or dies. 
 
 
MedSIR ARO will be responsible for ensuring that events are reported within the mandated 
timeframe to the EMA and other Competent Authorities, IECs/IRBs and investigator(s), as necessary. 
 
 
Adverse Events of Special Interest (AESIs) for T-DM1 
 
AESIs must be reported by the Investigator to the Sponsor expeditiously (see section 7.2), regardless 
of their seriousness (i.e. no more than 24 hours after learning of the event). AESIs for this study 
include: 
o Elevations of Troponin I and BNP values consisting of an increase >10% from screening 
values. 


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o Potential drug-induced  liver  injury as assessed by laboratory criteria  for Hy’s  law. The 
following laboratory abnormalities define potential Hy’s law cases and must be reported as 
an AESI: 
- 
Aspartate 
aminotransferase 
(AST) and/or alanine 
aminotransferase (ALT) 
 
elevations that are >3 × upper limit of normal (ULN) 
 
- 
Concurrent elevation of total bilirubin >2 × ULN (or clinical jaundice if total bilirubin 
measures   are   not   available),   except   in   patients   with   documented   Gilbert’s 
syndrome. For patients with Gilbert’s syndrome, elevation of direct bilirubin >3 × 
ULN should be used instead. 
o Suspected transmission of an infectious agent by a medication, whereby any organism, 
virus or infectious particle (e.g. prion protein transmitting transmissible spongiform 
encephalopathy), pathogenic or non pathogenic, is considered an infectious agent. 
Transmission of an infectious agent may be suspected from clinical symptoms or laboratory 
findings indicating an infection in a patient exposed to a medicinal product. This term ONLY 
applies  when  contamination  of  a  medication  is  suspected  and  DOES  NOT  apply  to 
infections supported by the mode of action, e.g. immunosuppression. 
 
 
Pregnancy Reporting 
 
Irrespective of the treatment received by the patient, any patient’s or patient’s partner pregnancy 
occurring during study treatment or during the 7 months following study drug discontinuation must be 
reported within 24 hours of investigator’s knowledge of the event. 
 
 
Pregnancies will be treated as SAEs and the investigator will complete a pregnancy form, and forward 
it to the sponsor (by e-mail). 
email: pharmacovigilance@medsir.org 
 
fax: + 34 93 299 23 82 
 
 
 
The patient will be asked to provide follow-up information on the outcome of the pregnancy, including 
premature   termination   should   the   case   arise.   Spontaneous   miscarriage   and   congenital 
abnormalities will also be reported as SAEs. 
 
 
The follow-up period will be deemed to have ended when the health status of the child has been 
determined at 12 months of the infant’s life. 
 
 
Additional follow up information on any trastuzumab emtansine-exposed pregnancy and infant will be 
requested at specific time points (i.e., after having received the initial report, at the end of the 


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second trimester, 2 weeks after the expected date of delivery, and at 3, 6, and 12 months of the 
infant’s life). 
 
 
Follow-up queries may be sent, asking for further information, if required for a comprehensive 
assessment of the case. 
 
 
 
Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that govern human 
subjects’ research to follow the determinations of the IRBs/IECs. Non compliance may occur due 
to lack of knowledge or due to deliberate choice to ignore regulations, institutional policies, or 
determinations of the IRB/IECs. 
 
 
Report non-compliance immediately, within 24hours to MedSIR ARO, to the study site Principal 
 
Investigator and, as necessary, to the IRB/IEC. 
 
 
 
Serious Noncompliance 
 
Definition: noncompliance that materially increases risks that result in substantial harm to subjects 
or others, or that materially compromises the rights or welfare of participants. 
 
 
Report serious non-compliance immediately, within 24hours to MedSIR ARO, to the study site 
 
Principal Investigator and, as necessary, to the IRB/IEC. 
 
 
 
Expedited Reporting to Health Authorities, Investigators, Institutional Review Boards, and 
 
Ethics Committees 
 
To  determine  reporting  requirements  for  single  AE  cases,  the  Sponsor  will  assess  the 
expectedness of these events using the following reference documents: 
- 
Trastuzumab emtansine Investigator's Brochures 
 
- 
Current Summary of Product Characteristics on Non-pegylated liposomal doxorubicin 
 
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. 
 
7.3. Safety Reporting Flowcharts 
 
See the following flowcharts for the safety information exchange between MedSIR ARO as sponsor 
of this clinical trial and F. Hoffmann – La Roche as the owner of T-DM1, the investigators, IRB/IEC, 
Competent Authorities and any other applicable regulatory authorities. 


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Non-serious AEs reporting responsibilities: 
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Investigational 
Center (completing 
CRF) 
CRO 
Data 
Management 
& 
MedSIR 
ARO 
(review, 
assessment and processing of 
safety information): 
Quaterly non-serious AE listings 
 
 
Quarterly non-serious AE 
listings to F.Hoffmann – La 
Roche 
 
 
 
Pregnancy cases, AESIs & SAEs (as defined by protocol) reporting responsibilities: 
Investigational 
MedSIR ARO (review, 
Center (SAE, 
assessment and 
pregnancy and 
processing of safety 
AESI report, 24 
information): 
hrs) 
MedWatch/CIOMS 
report
A. F. Hoffmann – La Roche (copy): 
•  SADRs & AESIs requiring expedited 
reporting within 15 days 
•  Unrelated SAEs & other AESIs that 
do not require expedited reporting & 
pregnancy reports within 30 days 
B. FDA, EMA and any regulatory 
authorities, CEIC/IRB, Investigators: 
•  Expedited safety reports & six 
monthly SUSAR reports according 
to regulatory reporting obligations 
(including timelines) 
 
DSUR  for  the  combination  of  T-DM1  plus  non-pegylated  liposomal  doxorubicin  (DSUR 
model: Non-Commercial Sponsor): 
MedSIR ARO (review, assessment and 
processing of safety information): DSUR 
development 
F. Hoffmann – La Roche (copy): asap 
Regulatory authorities, CEIC/IRB according to 
regulatory reporting obligations 
Note: Roche to forward to MedSIR an executive summary of the Roche DSUR upon request from 
MedSIR. MedSIR may cross-reference the executive summary of the Roche DSUR 
 
Investigational Brochure (IB), Medical Alert letters (“Dear Dr.Letters”) & all new information that 
may modify or supplement known data regarding T-DM1,in particular all new AEs and data relating 
to T-DM1 tolerance that is likely to reveal a danger to patients: 
 
F.  Hoffmann  -  La  Roche  (review,  assessment  and  processing  of  safety 
information from any other sources different of this clinical trial): IB latest version 
and IB updates, Medical Alert letters & all new information that may modify or 
supplement known data regarding T-DM1, in particular all new AEs and data 
relating to T-DM1 tolerance that is likely to reveal a danger to patients 
MedSIR 
ARO: 
asap 
 
 
 
Safety Crisis Management & safety queries from regulatory authorities or for publications: 
In case of a safety crisis, e.g. where safety issues have a potential impact on the indication(s), on 
the conduct of the Study, may lead to labeling changes or regulatory actions that limit or restrict the 
way in which T-DM1 is used, or where there is media involvement, the Party (F. Hoffmann – La 
Roche or MedSIR ARO) where the crisis originates will contact the other Party asap. Roche shall 
have the final say and control over safety crisis management issues relating to T-DM1 
MedSIR ARO  shall not answer  any safety query relating to T-DM1 received  from regulatory 
authorities, nor from media and other sources (publications) but shall redirect such queries to 
Roche taking into account and informing about timelines for required answers 


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8.        STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
 
 
8.1. Sample size and statistics methods 
 
The study employed a conventional 3 + 3 dose-escalation design and had no formal sample size 
calculation or hypothesis testing. The total sample size was dependent on the number of dose 
levels required to determine the MTD. A minimum of 12 and up to 24 patients will be enrolled. 
Safety  assessment  was  the  primary  objective  and  efficacy  assessment  was  an  exploratory 
objective. All data will be presented with listings and summarized using descriptive statistics within 
each dose level and/or dosing schedule, and overall in all treated patients. 
 
8.2. Analysis populations 
 
The following populations will be analyzed: 
 
1.  DLT population: all patients who complete the first two cycles of treatment or who stop 
treatment during this time because of DLT. 
2.  The intention to treat (ITT)/safety population: all included patients receiving any dose of 
treatment. 
3.  The protocol compliant population (PP): all patients who receive the protocol required study 
drug exposure and required protocol processing. 
4.  The pharmacokinetic (PK) population: all patients with a complete treatment concentration- 
time profile. 
 
8.3. Safety Analyses 
 
Primaryoutcome: 
 
The number and the proportion of patients with DLTs (with corresponding 95% Clopper Pearson 
confidence intervals) are the primary outcomes. They will be used as the measure for the MTD 
determination. The definition of DLTs has been presented in Section 3.6. DLTs will be summarized 
by treatment dose. Confidence intervals will be calculated, according to Clopper-Pearson (exact 
binomial intervals). The primary outcome will be analysed in DLT population. 
 
 
Safetyoutcomes: 
 
Safety endpoints will be analysed in intention to treat population. Patients who received at least 
one  dose  of  both  study  medications  (T-DM1  plus  non-pegylated  liposomal  doxorubicin)  and 
patients who received one treatment alone (T-DM1 or non-pegylated liposomal doxorubicin), will 
be reported separately. They will be summarized by treatment dosage and will be assessed via 
total AEs, AEs Grade ≥ 3, SAEs (as described in Section 7), premature withdrawal from study 


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medication, laboratory parameters, LVEF, exposure to study medication, concomitant medications, 
vital signs, ECOG performance status, and physical examination. 
 
 
The incidence of AEs and SAEs will be summarized according to the primary system-organ class 
(SOC)  and  within  each  SOC,  by  the  Medical  Dictionary  for  Regulatory  Activities  (MedDRA) 
preferred  term. Additional  summaries  by  frequency  tables  will  also  be  provided  for  the AEs. 
Patients who died will be listed together with the cause of death. 
 
 
Laboratory parameters, hematology and biochemistry will be presented in shift tables of NCI-CTC 
grade at baseline versus worst grade during treatment. LVEF will be summarized over time by means 
of mean, median and  range  (minimum and maximum) and will be presented graphically. Vital 
signs will be analyzed in a similar way. 
 
 
Other safety variables, such as exposure to study medication, concomitant medications and physical 
examinations, will be analyzed in a similar way. Frequency tables will summarize the exposure of 
study medication. 
 
 
ECOG performance status will be summarized over time and the percentage of patients in different 
categories will be presented by bar charts at different time points. 
 
8.4. Efficacy Analyses 
 
Efficacy endpoints will be analysed in ITT and PP populations. 
 
The efficacy analyses are exploratory endpoints and they will be investigated as follow: 
 
   Overall response rate (ORR). Overall response rate (ORR) is defined as the proportion of 
patients  with  best  overall  response  of  confirmed  complete  response  (CR)  or  partial 
response (PR) based on local investigator’s assessment according to RECIST 1.1). An 
objective response needs to be confirmed at least 4 weeks after the initial response. 
  Clinical benefit rate (CBR) Clinical benefit rate is defined as the proportion of patients with a 
best overall response of complete response (CR) or partial response (PR) or stable disease 
(SD) lasting more than 24 weeks based on local investigator’s assessment. 
  Number of patients with progressions and number of patients who died. 
 
 
 
Confidence intervals will be calculated for efficacy data, according to Clopper-Pearson. 
 
Estimates for efficacy data, 95% confidence intervals (CIs) were constructed based on an exact 
binary distribution. 


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For the purposes of this study, patients should be re-evaluated for response at the end of cycle 2, 4 
and cycle 6. After that, the tumor assessment will be performed every 9 weeks. In addition to a 
baseline scan, confirmatory scans should also be obtained 4 weeks following initial documentation of 
objective response. 
 
 
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
 
 
 
8.5. Pharmacokinetic Analyses 
 
Pharmacokinetic Analyses will be analysed in PK population. 
 
The following PK parameters of T-DM1 and non-pegylated liposomal doxorubicin (including but not 
limited to those listed below) will be determined in all patients who receive study treatment using 
either non-compartmental and/or population methods, if data allow: 
- 
Serum concentrations of T-DM1 (conjugate) and total trastuzumab 
 
- 
Plasma  concentrations  of  DM1,  non-pegylated  liposomal  doxorubicin  and  its  active 
metabolite non-pegylated liposomal doxorubicinol 
- 
Total exposure (e.g. AUC) 
 
- 
Cmax 
 
- 
CL 
 
- 
Vd 
 
- 
T1/2 
 
The PK of trastuzumab emtansine, total trastuzumab and DM1 will be compared with historical single- 
agent PK data to evaluate the potential effect of non-pegylated liposomal doxorubicin on the PK of 
T-DM1 and related analytes. All PK parameters will be listed and tabulated by treatment dose. 
Descriptive summary statistics including arithmetic mean, geometric mean (e.g., AUC and Cmax), 
median, range, s.d., and coefficient of variation will be presented for each cohort. Nonlinear mixed 
effects modeling will also be used; details will be presented in the SAP. 
 
 
PK samples can be obtained ad hoc in case of a SAE or unexpected toxicities which may suggest 
a potential drug-drug interaction. 
 
 
Extracellular domain of HER2 receptor will be also measured, as it has been shown to represent a 
relevant covariate in the population PK modeling for T-DM1. 


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8.6. Steering Committee Review 
 
A Steering Committee (SC) has been established for this study. Initially, it is composed of the 
investigators, the study medical monitor, the Scientific Global Coordinator, one physician specialising 
in T-DM1 management and one cardiologist. The study design and DLT definition have been 
developed by the SC. 
 
 
The SC will meet at the end of each treatment cohort to review, discuss and evaluate all of the 
gathered safety data. In case of any arising safety concern, these meetings can also be called at any 
time at request of a participating investigator. At these meetings, MedSIR ARO and the participating 
investigators must reach a consensus on whether to escalate the dose any further, or whether  to 
de-escalate   and/or   expand   recruitment   into   particular   cohorts.  MedSIR  ARO  will prepare 
minutes from these meetings and circulate them to each investigator for comment prior to finalization. 
 
 
The study site Investigators and MedSIR ARO will review all patient data of their site at least monthly 
(or before each dose-escalation if occurring sooner than monthly). Each study site Investigator will 
monitor patients data for serious toxicities on an ongoing basis. 
 
 
In due course, the SC will also review all available efficacy data and PK information to ensure that 
safety information is considered in the context of risk-benefit and that dosing is also related to 
exposure to the drugs. 
 
 
The SC will adjudicate in the event of DLTs that are not covered by the existing DLT criteria. 
 
 
 
 
9.        PHARMACEUTICAL INFORMATION 
 
 
9.1. Trastuzumab emtansine (T-DM1) 
 
Complete description of T-DM1 will be documented in the Investigator Brochure, located in the 
 
Site/Investigator’s file. 
 
Summarized information is reported in this section but the Investigator Brochure is the source 
document for the study drug. 
Chemical name:  The  product  name  and  INN  is  the  following:  Trastuzumab  emtansine.  The 
chemical name is the following: Immunoglobulin G1, anti-(human receptor tyrosine-protein kinase 
erbB-2 (EC 2.7.10.1, p185erbB2, MLN 19 or CD340)); humanized mouse monoclonal rhuMab 
HER2γ1 heavy chain (223-214')-disulfide with humanized mouse monoclonal rhuMab HER2 κlight 
chain, dimer (229-229'':232-232'')-bisdisulfide dimer; conjugated on an average of 3 to 4 lysyl, to 


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maytansinoid DM1 via a succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) 
 
linker. CAS Registry Number: 1018448-65-1. 
 
 
 
Physico-chemical characteristics: Trastuzumab emtansine exhibits potent in vitro cytotoxic activity 
against a number of cultured cell lines that over-express p185HER2. In addition, T-DM1 is effective 
in several murine models of HER2-positive breast cancer, including ones that do not respond to 
unconjugated trastuzumab. Although the primary mechanism of action of T-DM1 is distinct from 
that of unconjugated trastuzumab, the two molecules are similar with respect to a number of biological 
activities  including  binding  to  recombinant  HER2  ECD,  C1q,  and  the  neonatal  Fc receptor 
(FcRn). Trastuzumab emtansine also showed similar binding to FcγRI and moderately increased (2- 
to 3-fold) binding to FcγRIIa and IIb, compared with unconjugated trastuzumab. Additionally, T-DM1 
showed similar FcγRIIIa binding. 
 
 
Structure: Trastuzumab emtansine is an antibody-drug conjugate that contains the humanized anti- 
HER2 IgG1, trastuzumab, linked to the microtubule-inhibitory maytansinoid, DM1, via a thioether 
bond. The drug is linked to antibody lysine residues using the heterobifunctional reagent, SMCC. 
 
 
Clinical Pharmacology:  Clinical  pharmacological  evaluations  of  T-DM1  are  based  on  PK  data 
obtained from 6 clinical studies (TDM3569g, TDM4258g, TDM4374g, TDM4450g, TDM4688g, 
EMILIA and TH3RESA) 
 
 
PharmacokineticsandDrugMetabolism 
 
Patients who received 3.6 mg/kg of T-DM1 intravenously every 3 weeks had a mean maximum 
serum   concentration   (Cmax)   of   T-DM1   of   83.4   (±   16.5)   μg/mL.   Based   on   population 
pharmacokinetic (PK) analysis, following intravenous administration of T-DM1 in patients with HER2- 
positive metastatic breast cancer, the clearance of T-DM1 was 0.68 L/day and the elimination 
half-life (t1/2) was of approximately 4 days. No accumulation of T-DM1 was observed after repeated 
dosing of intravenous infusion every 3 weeks. Trastuzumab emtansine is expected to undergo 
deconjugation and catabolism by means of proteolysis in cellular lysosomes. 
 
 
In vitro metabolism studies in human liver microsomes suggest that DM1 is metabolised mainly by 
CYP3A4 and to a lesser extent by CYP3A5. DM1 did not inhibit major CYP450 enzymes in vitro. In 
human plasma, T-DM1 catabolites MCC-DM1, Lys-MCC-DM1, and DM1 were detected at low levels. 
In vitro, DM1 was a substrate of P-glycoprotein (P-gp). 
 
 
Distribution: Based on population PK analysis, following intravenous administration, the central 
volume of distribution of T-DM1 was (3.13 L) and approximated that of plasma volume. 


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The mean volume of distribution at steady-state (Vss) of T-DM1 observed across the six clinical 
studies in which the drug was administered at 3.6 mg/kg q3w, ranged from 28.4 mL/kg and 58.4 
mL/kg after the first T-DM1 dose (Cycle 1) and from 33.3 mL/kg and 43.6 mL/kg at steady state. 
 
 
Metabolism Half-life:  Mean  clearance  values  ranged  from  7  to  13  mL/day/kg,  the  volume  of 
distribution was limited to the plasma volume, and terminal half-life was approximately 4 days. 
 
 
Excretion: Based on population PK analysis, body weight, albumin, sum of longest diameter of 
target lesions by Response Evaluation Criteria In Solid Tumors (RECIST), HER2 shed extracellular 
domain (ECD), baseline trastuzumab concentrations, and aspartate aminotransferase (AST) were 
identified as statistically significant covariates for T-DM1 PK parameters. However, the magnitude 
of effect of these covariates on T-DM1 exposure, suggests that with the exception of body weight, 
these covariates are unlikely to have any clinically meaningful effect on T-DM1 exposure. In addition, 
exploratory analysis showed that the impact of covariates (i.e., renal function, race and age) on the 
pharmacokinetics of total trastuzumab and DM1 was limited and was not clinically relevant. In 
nonclinical studies, T-DM1 catabolites including DM1, Lys-MCC-DM1, and MCC-DM1 are mainly 
excreted in the bile with minimal elimination in urine. 
 
 
Immunogenicity: Of all patients treated with T-DM1, a total of 836 patients from six studies had at 
least one post-dose ATA timepoint evaluable for ATA response. Overall, confirmed positive ATA 
responses were detected in 44 of 836 (5.3%) patients across the six studies; 28 of these patients 
had negative baseline samples. Positive responses in all 44 patients were confirmed and 
characterized by competitive binding immunodepletion with T-DM1 and trastuzumab. The majority 
(37 of 44) of patients had a positive response immunodepleted by T-DM1 only. The positive response 
from one or more timepoints from 6 patients was immunodepletable by both T-DM1 and trastuzumab, 
and the response from 1 patient was immunodepleted by trastuzumab only. 
The clinical significance of antibody development against T-DM1 is unknown; however, the impact 
of ATA response on pharmacokinetics was assessed. There was no obvious change in the 
pharmacokinetics of patients who tested ATA positive to T-DM1 when compared with data from 
patients who tested ATA negative. 
 
 
Supplier:  Trastuzumab  emtansine  is  provided  as  a  single-use,  lyophilized  formulation  in  a 
colourless 20 mL Type I glass vial containing 160 mg or 100 mg of T-DM1, closed by means of a 
FluroTec coated stopper and an overseal with flip-off cap. Upon receipt of T-DM1, vials should be 
refrigerated at 2–8°C (36–46°F) until use. THE VIAL MUST NOT BE FROZEN OR SHAKEN. 
Trastuzumab emtansine must be stored in the original carton (as the expiry date will only be 


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indicated on the carton) Do not use the product beyond the expiration date provided by the 
manufacturer. The reconstituted product contains no preservative and is intended for single use 
only. Any remaining medication should be discarded. All vials of T-DM1 should be handled by 
appropriately trained site staff wearing gloves and using appropriate procedures in place at the clinical 
site for preparation of chemotherapeutic drugs. Vials should be visually inspected upon receipt to 
ensure that they are intact without exterior contamination. Discard any cracked vials and report vials 
with surface contamination to the clinical site manager for assessment. The lyophilized product 
should be reconstituted using sterile water for injection (SWFI). Using a new syringe, 8 mL SWFI 
should be added to the vial and the vial swirled gently until the product is completely dissolved. The 
vial should not be shaken. The resulting product contains 20 mg/mL T-DM1, 10 mM sodium 
succinate, pH 5.0, 60 mg/mL sucrose, and 0.02% (w/v) polysorbate 20. Each 20 mL vial contains 
enough T-DM1 to allow delivery of 160 mg T-DM1. The reconstituted product contains no 
preservative and is intended for single use only. The vial should be inspected to ensure the 
reconstituted product is a clear colorless solution, and is free of particulates before proceeding. 
Drug from any vial that appears abnormal upon inspection should not be administered to patients. 
 
 
Storage and Stability:  Using a  new syringe, the indicated  volume  of T-DM1 solution should be 
removed from the vial(s) and added to the IV bag containing at least 250 mL of 0.45% sodium 
chloride (preferred) or 0.9% sodium chloride injection and gently inverted to mix the solution. A 
0.22  micron non-protein  adsorptive polyethersulfone  inline filter is  recommended when  using 
 
0.45% sodium chloride and required when using 0.9% sodium chloride injection. The solution of T- 
DM1 should not be shaken. The solution of T-DM1 for infusion should be used immediately. If not 
used immediately, storage times should not be longer than 24 hours at 2–8°C (36–46°F) for solutions 
of T-DM1 diluted in polyvinyl chloride (PVC) or latex free PVC-free polyolefin, polypropylene, or 
polyethylene bags containing 0.45% or 0.9% Sodium Chloride for Injection. For additional details, 
please refer to the current version of the T-DM1 Investigator’s Brochure. 
 
 
SafetyofT-DM1 
 
Full details regarding the clinical safety of T-DM1 are presented in the Investigator’s Brochure. 
 
 
 
Cardiotoxicity: Patients treated with T-DM1 are at increased risk of developing left ventricular 
dysfunction. LVEF < 40% has been observed in patients treated with T-DM1. Patients without 
significant cardiac history and with a LVEF≥ 55% determined by ECHO are eligible for study 
participation. LVEF will be monitored at screening and regularly throughout the study until the 
assessment at the safety follow-up visit. Patients with symptomatic cardiac dysfunction will be 
discontinued from study treatment. 


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Hematologic Toxicity (Thrombocytopenia):  Thrombocytopenia,  or  decreased  platelet  counts,  was 
reported in patients in clinical trials of T-DM1. The majority of these patients had Grade 1 or 2 events 
(≥ 50,000/mm3), with the nadir occurring by Day 8 and generally improving to Grade 0 or 1 (≥ 
75,000/mm3)  by  the  next  scheduled  dose.  In  clinical  trials,  the  incidence  and  severity  of 
 
thrombocytopenia were higher in Asian patients. Severe cases of both non-fatal and fatal 
hemorrhagic events including central nervous system hemorrhage have been reported in clinical trials 
with T-DM1; these events were independent of the patients’ ethnicity. In some of the observed 
cases the patients were also receiving anti-coagulation therapy. The need for platelet transfusions 
has been reported. Patients with thrombocytopenia and on anti-coagulant treatment have to be 
monitored closely during treatment with T-DM1. Platelet counts will be monitored prior to each T- 
DM1 dose. Use of erythropoiesis-stimulating agents will be allowed as consistent with prescribing 
guidelines. Transfusion of red blood cells and/or platelets will be allowed according to and at the 
discretion of the treating physician. 
 
 
Hepatotoxicity: Hepatotoxicity, predominantly in the form of asymptomatic increases in the 
concentrations of serum transaminases (Grade 1 − 4 transaminitis), has been observed in patients 
while on treatment with T-DM1 in clinical trials. Transaminase elevations were generally transient. 
The incidence of increased AST was substantially higher than that for ALT. The proportion of patients 
with  Grade  1  or  2  increases  in  transaminases  increased  with  successive  cycles, suggesting 
a modest cumulative effect of trastuzumab emtansine on transaminases; however, no increase over 
time in the proportion of Grade 3 abnormalities was observed. Patients with elevated transaminases 
improved to Grade 1 or normal within 30 days of the last dose of T-DM1 in the majority of the 
patients. Rare cases of severe hepatotoxicity, including death due to drug-induced liver injury and 
associated hepatic encephalopathy, have been observed in patients treated with T- DM1. Some of 
the observed cases of acute liver injury may be confounded by concomitant medications with known 
hepatotoxic  potential  and/or  underlying  conditions.  Acute  severe  liver injury (potential Hy’s law 
case) has the following laboratory components: 
• Aminotransferase enzymes (ALT/AST) greater than 3× ULN with concurrent elevation of 
serum total bilirubin to> 2 × ULN, 
 
 
Patients must have adequate and stable liver function: hepatic transaminases (AST/ALT) and total 
bilirubin must be within acceptable range, as defined in the protocol, within 4 weeks prior to the first 
dose of T-DM1. Liver function will be monitored prior to each T-DM1 dose. 
 
 
Cases  of  nodular  regenerative  hyperplasia  (NRH)  of  the  liver  have  been  identified  from  liver 
biopsies in patients treated with T-DM1 and presenting with signs and symptoms of portal 
hypertension. NRH was also observed in one fatal case of hepatic failure. NRH is a rare liver 


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condition characterized by widespread benign transformation of hepatic parenchyma into small 
regenerative nodules; NRH may lead to non-cirrhotic portal hypertension. Diagnosis of NRH can only 
be confirmed by histopathology. NRH should be considered in patients who develop clinical 
symptoms of portal hypertension and/or a cirrhosis-like pattern seen on CT scan of the liver but 
with normal transaminases and no other manifestations of cirrhosis or liver failure following long- term 
treatment with T-DM1. Upon diagnosis of NRH, T-DM1 treatment must be permanently discontinued. 
 
 
PulmonaryToxicity: Cases of interstitial lung disease (ILD), including pneumonitis, some leading to 
acute respiratory distress syndrome or fatal outcome, have been reported in clinical trials with T- 
DM1.  Signs  and  symptoms  include dyspnea,  cough,  fatigue,  and pulmonary  infiltrates. These 
events may or may not occur as sequelae of infusion reactions. Treatment has included 
administration of steroids and oxygen, and study drug discontinuation. Patients with dyspnea at 
rest due to complications of advanced malignancy and comorbidities may be at increased risk of 
pulmonary events. Treatment with T-DM1 has to be permanently discontinued in patients who are 
diagnosed with ILD or pneumonitis. 
 
 
Infusion-related Reactions/Hypersensitivity:  Infusion-related  reactions  characterized  by  one  or 
more of the following symptoms, flushing, chills, pyrexia, dyspnea, hypotension, wheezing, 
bronchospasm, and tachycardia may occur with the administration of monoclonal antibodies and 
have been reported with T-DM1. In general, these symptoms were not severe. In most patients, these 
reactions resolved over the course of several hours to a day after the infusion was terminated. 
Patients should be observed closely for infusion-related reactions, especially during the first infusion. 
Patients   should   be   observed   closely   for   hypersensitivity.   Serious, allergic/anaphylactic-like 
reactions have been observed in clinical trials with treatment of T-DM1. Administration of trastuzumab 
emtansine will be performed in a setting with access to emergency facilities and staff who are trained 
to monitor and respond to medical emergencies. Patients will be observed  closely  for  infusion- 
related/hypersensitivity during and after each T-DM1 infusion for a minimum of 90 minutes after 
the first infusion and for a minimum of 30 minutes after subsequent infusions in the absence of 
infusion-related AEs. Pre-medication is allowed according to standard practice guidelines. In the 
event of a true hypersensitivity reaction (in which severity of reaction increases  with  subsequent 
infusions), T-DM1 treatment must be permanently discontinued. Patients who experience a Grade 
≥ 3 allergic reaction or acute respiratory distress syndrome will be discontinued from study treatment. 
 
 
 
Neurotoxicity: DM1, an anti-microtubule agent, can potentially cause peripheral neuropathy. 
Peripheral neuropathy, mainly Grade 1 and predominantly sensory, has been reported in clinical 


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trials of T-DM1. Treatment with T-DM1 should be temporarily discontinued in patients experiencing 
Grade 3 or 4 peripheral neuropathy until symptoms resolve or improve to≤ Grade 2. Patients 
should be examined for signs of peripheral neuropathy prior to each dose of T-DM1. Patients who 
experience Grade≥ 3 neurotoxicity in the form of peripheral neuropathy that does not resolve to 
Grade≤ 2 within 42 days after last dose received will be discontinued from study treatment. 
 
 
Extravasation:  In  T-DM1  clinical  studies,  reactions  secondary  to  extravasation  have  been 
observed. These reactions were usually mild and comprised erythema, tenderness, skin irritation, 
pain, or swelling at the infusion site. Rare reports of more severe events such as cellulitis, pain 
(tenderness and burning sensation), and skin irritation have been received as part of the continuing 
surveillance of T-DM1 safety. These reactions have been observed more frequently within 24 hours 
of infusion. 
 
 
Specific treatment for T-DM1 extravasation is unknown at this time. The infusion site should be 
closely monitored for possible subcutaneous infiltration during drug administration. 
 
 
Precautions and warnings 
 
A Population PK analysis was performed, which identified several covariates with a significant 
effect on Population PK parameters. Yet, with the exception of body weight. The impact of these 
identified covariate on exposure was low. Body weight based dose of 3.6 mg/kg every 3 week without 
correction for other covariates is considered appropriate. 
 
 
Elderlypatients: A population pharmacokinetic analysis indicates that age does not have a clinically 
meaningful effect on the pharmacokinetics of T-DM1. There are insufficient data to provide dosing 
recommendations in patients≥ 75 years due to limited data in this subgroup, therefore no dose 
adjustment is proposed. 
 
 
Renal impairment: T-DM1 derived DM1 and metabolites MCC-DM1 and lys-MCC-DM1 has only 
been partially characterised in humans. However, the concentration of DM1 were always low, often 
lower than the LLOQ, which precluded a formal PK analysis. The impact of renal impairment on the 
PK of T-DM1 was investigated through a Population PK analysis. The results showed a lack of 
effect of renal impairment on the exposure to T-DM1, which is consistent with the protein moiety of 
drug being eliminated by ubiquitary proteolysis. The nonclinical data, a mass balance study in rats, 
and exploratory PK analyses in patients with and without renal impairment in Study TDM4688g that 
renal impairment has a minimal effect on the exposure to the DM1-containing catabolites, namely 
MCC-DM1 and Lys-MCC-DM1. 


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No adjustment to the starting dose is needed in patients with mild or moderate renal impairment. The 
potential need for dose adjustment in patients with severe renal impairment cannot be determined 
due to insufficient data and therefore patients with severe renal impairment should be monitored 
carefully. 
 
 
A dedicated study of the PK of T-DM1 and relevant catabolites in metastatic breast cancer (mBC) 
patients with mild to moderate hepatic impairment is ongoing (see Risk-management plan in the 
Investigator Brochure). 
 
 
Hepatic impairment: Liver function should be monitored prior to initiation of treatment and each 
dose. Patients with baseline elevation of ALT (e.g due to liver metastases) may be predisposed to 
liver injury with a higher risk of a Grade 3-5 hepatic event or liver function test increase. 
 
 
Interactions: The potential for interaction has been sufficiently investigated. In vitro metabolism 
studies in human liver microsomes suggest that DM1 is metabolised mainly by CYP3A4 and, to a 
lesser extent, by CYP3A5. Concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, 
itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, and voriconazole) with T-DM1 should be avoided due to the potential for an increase 
in DM1 exposure and toxicity. Consider an alternate medicinal product with no or minimal potential to 
inhibit  CYP3A4.  If  concomitant  use  of  strong  CYP3A4  inhibitors  is  unavoidable,  consider 
delaying T-DM1 treatment until the strong CYP3A4 inhibitors have cleared from the circulation 
(approximately 3 elimination half-lives of the inhibitors) when possible. If a strong CYP3A4 inhibitor 
is coadministered and T-DM1 treatment cannot be delayed, patients should be closely monitored 
for adverse reactions. 
 
 
 
9.2. Non-pegylated liposomal doxorubicin 
 
Complete description of non-pegylated liposomal doxorubicin will be documented in the Summary 
of Product Characteristics (SmPC), located in the Site/Investigator’s file. 
 
 
 
9.3. Supplying and Handling Investigational Products 
 
All investigational medicinal products (IMPs) required for the conduct of this study (T-DM1 or non- 
pegylated liposomal doxorubicin) will be provided by the MedSIR ARO/Roche. 
 
 
T-DM1 will be released and distributed to study centres by Roche, while non-pegylated liposomal 
doxorubicin will be released and distributed by sponsor’s designee. 


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The sponsor will ensure supply of the study IMP and appropriate labeling of study IMP provided 
that it complies with the legal requirements of each country where the study is to be performed. 
 
 
9.4. Investigators Responsibilities over the Investigational Products 
 
The Investigator must ensure the following: 
 
 
acknowledgement of receipt of the study IMP by a designated staff member at the site, 
including confirmation that IMP was received in good condition. Any damaged shipments 
will be replaced. 
 
proper storage of study IMP, including storage in a secure, locked, temperature-controlled 
location and  according to the instructions specified on the labels. IMP that have  been 
stored differently from the manufacturer’s indications must not be used unless the sponsor 
provides written authorization for use 
 
appropriate record keeping and inventory of the study IMP, including regular documentation 
of adequate storage temperature. 
 
appropriate  use  of the study IMP, including use only in accordance with the approved 
protocol 
 
proper handling, including confirmation that IMP has not expired prior to administration 
 
 
appropriate documentation of IMP administration to study patients including: 
 
 
date, dosage, batch/serial numbers, expiration dates, unique identifying numbers assigned 
to patients and study IMP, and time of administration. This information will be maintained in 
an accountability log that will be reviewed by the site monitor. 
 
proper reconciliation of all study IMP received from the sponsor. Reconciliation is defined 
as maintaining records of which and how many IMP was received, administered and 
destroyed at site and returned, as applicable. 
 
IMPs will be either disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate documentation. 
The site's method of IMP destruction must be agreed upon by the Sponsor. The site must 
obtain written authorization from the Sponsor before any IMP is destroyed, and IMP 
destruction must be documented on the appropriate form 
 
proper  adherence  to  the  local  institutional  policy  with  respect  to  destruction  of  study 
including documentation. 


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10.      ETHICAL CONSIDERATIONS 
 
 
10.1.   Regulatory and Ethics Compliance 
 
The study will be performed and reported in accordance with the guidelines of the International 
Conference on Harmonization (ICH), and the ethical principles laid down in the Declaration of 
Helsinki.  The  study  will  be  also  compliance  with  European  Directive  2001/20/EC  and  any 
applicable local regulations. 
 
 
 
10.2.   Institutional Review Board / Independent Ethic Committee: 
 
Conduct of the study must be approved by an appropriately constituted IRB/IEC. Approval is 
required for the study protocol, protocol amendments, informed consent forms, study subject 
information sheets, and advertising materials. The IRB/IEC must also be contacted in the event of 
any major protocol violation or any SAE. 
 
 
It is the Investigator’s responsibility to communicate with their local IRB/IEC to ensure accurate and 
timely information is provided at all phases during the study. 
 
The Principal Investigator is responsible for providing written summaries of the status of the study 
to the IRB/EC annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC. Investigators are also responsible for promptly informing 
the IRB/EC of any protocol amendments. 
 
In addition to the requirements to report protocol-defined AEs to the Sponsor, investigators are 
required to promptly report to their respective IRB/EC all unanticipated problems involving risk to 
human patients. Some IRBs/ECs may want prompt notification of all SAEs, whereas others require 
notification only about events that are serious, assessed to be related to study treatment, and are 
unexpected.  Investigators  may  receive  written  safety  reports  or  other  safety  related 
communications from the Sponsor. Investigators are responsible for ensuring that such reports are 
reviewed and processed in accordance with regulatory requirements and with the policies and 
procedures established by their IRB/EC and archived in the site’s study file. 
 
 
 
10.3.   Informed Consent 
 
For each study subject, written informed consent will be obtained prior to any protocol related 
activities. As part of this procedure, the study site Investigator or designee must explain orally and 
in writing the nature, duration, and purpose of the study, and the action of the drugs in such a manner 
that the study subject is aware of the potential risks, inconveniences, or adverse effects that may 
occur. The study subject should be informed that he/she is free to withdraw from the 


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study at any time. The subject will receive all information that is required by local regulations and 
 
ICH guidelines. 
 
 
 
The Consent Form must be signed and dated by the patient or the patient’s legally authorized 
representative before her participation in the study. The case history or clinical records for each 
patient shall document the informed consent process and that written informed consent was obtained 
prior to participation in the study. 
 
A copy of each signed Consent Form must be provided to the patient or the patient’s legally 
authorized representative, if applicable. 
 
All signed and dated Consent Forms must remain in each patient’s study file and must be available 
for verification by study monitors at any time. 
 
The Informed Consent Form should be revised whenever there are changes to procedures outlined 
in the informed consent or when new information becomes available that may affect the willingness 
of the patient to participate. 
 
For any updated or revised Consent Forms, the case history for each patient shall document the 
informed consent process and that written informed consent was obtained for the updated/revised 
Consent Form for continued participation in the study. The final revised IRB/EC-approved Informed 
Consent Form must be provided to the Sponsor for regulatory purposes. 
 
 
 
 
10.4.   Data Protection 
 
The sponsor will ensure the confidentiality of patient’s medical information in accordance with all 
applicable laws and regulations. 
 
 
The  sponsor  as  Data  Controller  according  to  the  European  Directive  on  the  protection  of 
individuals with regard to the processing of personal data and on the free movement of such data 
[95/46/EC] confirms herewith compliance to Directive 95/46/EC in all stages of Data Management. 
 
 
Data generated by this study must be available for inspection upon request by representatives of 
national and local health authorities, the Sponsor monitors, representatives, and collaborators, and 
the IRB/EC for each study site, as appropriate. 


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11.      SOURCE DOCUMENTATION, STUDY MONITORING, AND QUALITY ASSURANCE 
 
 
11.1.   Source Data Documentation 
 
Source data refers to all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in source documents (original records or certified 
copies). 
 
 
 
Source documents are original documents, data, and records (e.g., hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified 
after verification as being accurate and complete, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial). 
 
 
 
Sponsor’s Quality Assurance group may assist in assessing whether electronic records generated 
from computerized medical record systems used at investigational sites can serve as source 
documents for the purposes of this protocol. 
 
If a site’s computerized medical record system is not adequately validated for the purposes of clinical 
research (as opposed to general clinical practice), applicable hardcopy source documents must be 
maintained to ensure that critical protocol data entered into the eCRFs can be verified. 
 
At a minimum, source documentation must be available to substantiate subject identification, 
eligibility, and participation; proper informed consent procedures; dates of visits; adherence to 
protocol procedures; adequate reporting and follow-up of AEs; administration of concomitant 
medication; study receipt/dispensing/return records; study administration information; and date of 
completion and reason. 
 
 
Data recorded on the CRF will be verified by checking the CRF entries against source documents 
(i.e., all original records, laboratory reports, medical records) in order to ensure data completeness 
and accuracy as required by study protocol. The Investigator and/or site staff must make CRFs 
and source documents of subjects enrolled in this study available for inspection by MedSIR or its 
representative at the time of each monitoring visit. 
 
 
The source documents must also be available for inspection, verification, and copying, as required 
by regulations, officials of the regulatory health authorities (e.g., FDA, EMEA, and others), and/or 
ECs/IRBs.  The  Investigator  and  study  site  staff  must  comply  with  applicable  privacy,  data 


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protection, and medical confidentiality laws for use and disclosure of information related to the 
study and enrolled subjects. 
 
 
The patient must also allow access to the patients’ medical records. Each patient should be informed 
of this prior to the start of the study. 
 
 
 
11.2.   Study Monitoring and Source Data Verification 
 
Study progress will be monitored by MedSIR ARO or its representative (e.g., a CRO) as frequently 
as necessary to ensure: 
That the rights and well-being of human subjects are protected; 
 
- 
the reported trial data are accurate, complete, and verifiable from the source documents; 
 
and 
 
- 
the conduct of the trial is in compliance with the current approved protocol/amendment(s), 
GCP, and applicable regulatory requirements. 
Contact details for the team involved in study monitoring will be identified in a handout located in 
 
the Investigator Site File. 
 
 
 
Data recorded on the CRF will be verified by checking the CRF entries against source documents 
(i.e., all original records, laboratory reports, medical records, subject diaries) in order to ensure 
data completeness and accuracy as required by study protocol. The Investigator and/or site staff 
must make CRFs and source documents of subjects enrolled in this study available for inspection 
by the sponsor or its representative at the time of each monitoring visit. 
 
 
 
11.3.   Retention of records 
 
Investigators must retain all study records required by the applicable regulations in a secure and safe 
facility. The Investigator must consult a sponsor representative before disposal of any study records 
and must notify the sponsor of any change in the location, disposition, or custody of the study files. 
 
 
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. “Essential documents” are defined as documents that 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced. These documents should be retained for a longer period, however, if required by the 
applicable e regulatory requirements or by an agreement with the sponsor. The CHMP requires 


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retention for the maximum period of time permitted by the institution, but not less than 15 years 
(ICH E6, 4.9.5). It is the responsibility of the sponsor to inform the Investigator/institution as to 
when these documents no longer need to be retained (ICH E6, 5.5.12). 
 
 
The study site Investigator must not dispose of any records relevant to this study without either (1) 
written permission from the Sponsor or (2) providing an opportunity for the Sponsor to collect such 
records. The study site Investigator shall take responsibility for maintaining adequate and accurate 
electronic or hard copy source documents of all observations and data generated during this study. 
Such  documentation  is  subject  to  inspection  by  the  Sponsor  and  the  FDA  and/or  EMA  (or 
respective individual EU country regulatory authorities). 
 
 
These principles of record retention will also be applied to the storage of laboratory samples, provided 
that the integrity of the stored sample permits testing. 
 
 
 
11.4.   Data Quality Assurance 
 
During and/or after completion of the study, quality assurance auditor (s) named by the MedSIR ARO 
or the regulatory authorities may wish to perform on-site audits. The Investigators will be expected 
to cooperate with any audit and provide assistance and documentation (including source data) as 
requested. 
 
 
The Sponsor’s representatives are responsible for contacting and visiting the Investigator for the 
purpose of inspecting the facilities and, upon request, inspecting the various records of the clinical 
study (e.g., CRFs and other pertinent data) provided that patient confidentiality is respected. 
 
 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing CRFs, are resolved. 
 
 
In accordance with ICH E6 Good Clinical Practice (GCP) and the Sponsor’s audit plans, this study 
may be selected for audit by representatives from the Sponsor’s (or designee’s) Quality Assurance 
Department. Inspection of site facilities (e.g., pharmacy, drug storage areas, laboratories) and review 
of study-related records will occur to evaluate the study conduct and compliance with the protocol, 
ICH GCP (ICH E6), and applicable country regulatory requirements. 


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12.      DATA MANAGEMENT 
 
 
12.1.   Data Entry and Management 
 
In this study, all data will be entered onto CRFs in a timely fashion by the Investigator and/or the 
 
Investigator’s dedicated site staff. 
 
 
 
The Investigator must review data recorded in the CRF to verify their accuracy. 
 
 
 
Reconciliation of the data will be performed by the designated CRO. At the conclusion of the study, 
the occurrence of any protocol violations will be identified and recorded as part of the clinical 
database. After these actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and will become available for statistical data analysis. 
 
 
 
12.2.   Data Clarification 
 
As part of the conduct of the trial, MedSIR ARO may have questions about the data entered by the 
site, referred to as queries. The monitors and the sponsor are the only parties that can generate a 
query. 
 
 
12.3.   Data Coding Procedures 
 
Coding of AEs, medical history, and prior and concomitant medications will be performed using 
standard dictionaries as described in the Data Management Plan. 
 
 
 
13.      STUDY MANAGEMENT 
 
 
13.1.   Discontinuation of the Study 
 
MedSIR ARO reserves the right to discontinue the study for safety or administrative reasons at any 
time. Should the study be terminated and/or the site closed for whatever reason, all investigational 
drugs pertaining to the study must be returned to MedSIR ARO. Any actions required to assess or 
maintain study subject safety will continue as required, in spite of termination of the study. 
 
 
 
13.2.   Changes to the Protocol 
 
Any change or addition to this protocol requires a written protocol amendment or administrative 
letter that must be approved by MedSIR ARO, the Scientific Global Coordinator, the study site 
Investigator and the IRB/IEC before implementation. This requirement for approval should in no 
way prevent any immediate action from being taken by the study site Investigator or MedSIR ARO 


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in the interests of preserving the safety of all subjects included in the trial. If an immediate change 
to the protocol is felt to be necessary by the study site Investigator and is implemented for safety 
reasons, MedSIR ARO should be notified as soon as possible (within 24 hours if possible) and the 
IRB/IEC should be informed as necessary. 
 
 
 
13.3.   Publication Policy Protection of Trade Secrets 
 
All information generated in this study must be considered highly confidential and must not be 
disclosed to any persons not directly concerned with the study without prior written permission from 
the Scientific Global Coordinator and MedSIR ARO However, authorized regulatory officials, the 
Scientific Global Coordinator or the study site Investigator, and MedSIR ARO personnel (or their 
representatives) will be allowed full access to inspect and copy the records. All clinical investigational 
drug, patient bodily fluids, and/or other materials collected shall be used solely in accordance  with 
this  protocol,  unless  otherwise  agreed  to  in  writing  by  Scientific  Global Coordinator or the 
study site Investigator and MedSIR ARO. 
 
The sponsor will ensure that as far as possible results of this study will be published as 
scientific/clinical papers in high-quality peer-reviewed journals. Preparation of such manuscripts 
will be made with full collaboration of principal Investigators and in accordance with the current 
guidelines of Good Publication Practice. 
 
 
The sponsor must be notified of any intent to publish data collected from the study and prior approval 
from sponsor must be obtained prior to publication 


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Appendix 1: Schedule of assessments and study procedures 
 
Study Period 
Screening 
Study Treatment (T-DM1 + non- 
pegylated liposomal 
doxorubicin) 
End of Study 
Treatment 
Follow-up 
Cycles 1-2 
Cycles 3-6 
While on T-DM1 
treatment 
28 (-42) days after 
last T-DM1 dosea 
End of 
Study visit 
Day 
-28 to -1 
1 
21 
1 
21 
28±7 last dose 
TMD1 + Non- 
pegylated 
liposomal 
doxorubicin 
Every 3 weeks 
Informed Consent 
X 
HER2 status 
X 
Medical History 
X 
Physical Examination and 
X 
X 
X 
X 
X 
X 
ECOG status 
Weight 
X 
X 
X 
X 
Vital signsb 
Concomitant
Medication 
X 
X 
X 
X 
X 
X 
Reporting 
------------------------------------------------------------------------------------------------------------------------------------------------------------- 
AE reporting 
----------------------------------------------- ------------------------------------------------------------------------------------- ------------------------- 
ECHO 
X 
X 
X 
Xc 
Xc 
12-lead ECG 
X 
X 
X 
Xc 
Xc 
DLT assessment 
X 
Tumor Assessments 
X 
Xd 
Xd 
Xdo 
Xd 
Xd 


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Overall survival 
---------------------------------------------------------------------------------------------------------------------------------------------------------------- 


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X
 
 
 
Study Period 
Screening 
Study Treatment (T-DM1 + non- 
pegylated liposomal 
doxorubicin) 
 
Cycles 1-2 
Cycles 3-6 
 
End of Study 
 
Treatment 
 
 
 
28±7 last dose 
 
TMD1 + Non- 
 
 
 
 
While on T -DM1 
treatment 
 
Follow-up 
 
 
 
 
 
28 (-42) days after 
last T-DM1 dosea 
 
 
 
 
End of 
 
Study visit 
Day 
-28 to -1 
1 
21 
1 
21 
 
 
 
 
Standard Laboratory Procedures: 
pegylated 
 
liposomal 
doxorubicin 
Every 3 weeks 
 
Pregnancy teste 
X 
Xe 
Xe 
 
Xg 
Hematologyf 
X 
 
 
Biochemistryh 
X 
(Days 8 and 15) 
Xg 
Xg
 
 
Xg 
(Days 8 and 15) 
Xg 
Xg
 
 
INR/aPTT 
X 
As clinically indicated 
As clinically 
indicated 
Troponin I determination 
Xij (Days 8 and 
X 
 
ij 
Xij 
 
 
B-type natriuretic peptide 
X 
(BNP) 
15) 
X 
 
Xkl (Days 8 and 
kl 
Xkl 
15) 
 
Experimental laboratory (to be performed in a central lab) 
 
PK samplesm 
X 
X 
Single 
Nucleotide 
X 
Polymorphisms (SNP) 
 
Drug Administrations 
 
Trastuzumab Emtansine 
X 
X 
Xno 


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Study Period 
Screening 
Study Treatment (T-DM1 + non- 
pegylated liposomal 
doxorubicin) 
End of Study 
Follow-up 
Treatment 
Cycles 1-2 
Cycles 3-6 
While on T -DM1 
treatment 
28 (-42) days after 
last T-DM1 dosea 
End of 
Study visit 
Day 
-28 to -1 
1 
21 
1 
21 
28±7 last dose 
TMD1 + Non- 
pegylated 
liposomal 
doxorubicin 
Every 3 weeks 
(T-DM1) 
Non-pegylated   liposomal 
doxorubicin 
Xp 
Xp 
AE = Adverse Event; aPTT = Activated Partial Thromboplastin Time; ECG = Electrocardiogram; ECHO = Echocardiogram; ECOG = Eastern Cooperative Oncology Group; INR = International 
Normalized Ratio 
a Patients will be followed for new or worsening adverse events for 28 (+/- 7 days) days following the last dose of any study IMP. All ≥ grade 2 adverse events will be followed up until improvement to 
baseline levels, grade 1 or complete recovery, initiation of another anti-cancer therapy, the patient withdraws consent, patient’s death or up to a maximum of 24 months after the first dose of study 
combination treatment whichever occurs first. Additionally, patients will be contacted regarding the occurrence of any new SAE considered to be treatment-related at 60 and 90 days following the last 
study treatment administration or until initiation of another anti-cancer therapy, whichever occurs first. 
b Vital signs will include measurements of respiratory rate, heart rate, blood pressure, and temperature. Abnormal or significant changes to vital signs from baseline should be recorded as adverse 
events, if appropriate. 
c ECHO and ECG will be performed every 1 cycle (cycles 1-6) during treatment with T-DM1 + non-pegylated liposomal doxorubicin. Thereafter, ECHO and ECG will be performed every 9 weeks 
until 12 months since last dose of study treatment (T-DM1+ non-pegylated liposomal doxorubicin) 
d During study treatment (T-DM1+ non-pegylated liposomal doxorubicin) tumor assessment wil be performed at the end of cycle 2, cycle 4, and cycle 6. Thereafter, the tumor response assessment 
will be performed every 9 weeks up to progression or up to 12 months after the first dose of the study combinated treatment for patients who discontinue all study IMP for reasons other than PD. 
Response assessments will be assessed by the investigator, based on physical examinations, CT or MRI scans, and bone scans using RECIST v. 1.1 
e Serum β-HCG test must be performed during screening, every 3 cycles and at 3 and 7 months following the last dose of T-DM1 and/or non-pegylated liposomal doxorubicin for women of 
childbearing potential (including pre-menopausal women who have had a tubal ligation) and for women not meeting the definition of postmenopausal. Testing should be performed at a local 
laboratory within 7 days prior to the first administration of study treatment. For all other women, documentation must be present in medical history confirming that the patient is not of childbearing 
potential. 


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f Hematologic assessments include hemoglobin (Hb), hematocrit, red blood cell count, platelet count, and white blood cells (WBC) with differential (including neutrophils, lymphocytes, monocytes, 
eosinophils and basophils) 
g Assessments should be performed at screening, within 72 hours prior to any IMP administration, at days 8 and 15 after any IMP administration during the first 2 cycles, weekly following any 
hematologic adverse event. If non-pegylated liposomal doxorubicin is discontinued due to toxicity, assessments should be performed weekly (minimum) until resolution of the adverse event (Grade 
≤ 1 or baseline levels), and on Day 1 of subsequent cycles thereafter. All assessments at Day 1 should be performed within 72 hours preceding administration of any study IMP; results must be 
reviewed and documented prior to administration of study treatment. Assessments at days 8 and 15 should be performed 7 (±2) and 14 (±2) days after any IMP administration 
h  Biochemistry assessments include: sodium, potassium, chloride, calcium, magnesium, glucose, urea or blood urea nitrogen (BUN) , creatinine, uric acid, total protein, albumin, alkaline 
phosphatase, ALT (SGPT), AST (SGOT), G-GT, LDH, total bilirubin (and direct bilirubin where total bilirubin > ULN). 
i TPN I determination will be performed 7 days (with a window of ± 2 days) after every infusion of every cycle and also 14 days (with a window of ± 2 days) after infusion of cycles 1 and 2. 
j TPN I determination will be performed every 1 cycle (cycles 1-6) during treatment with T-DM1 + non-pegylated liposomal doxorubicin. Thereafter, TPN I will be performed every 9 weeks until 12 
months since first dose of study treatment (T-DM1+ non-pegylated liposomal doxorubicin). 
k BNP determination will be performed 7 days (with a window of ± 2 days) after every infusion of every cycle and also 14 days (with a window of ± 2 days) after infusion of cycles 1 and 2. 
l BNP determination will be performed every 1 cycle (cycles 1-6) during treatment with T-DM1 + non-pegylated liposomal doxorubicin. Thereafter, BNP will be performed every 9 weeks up to 12 
months since first dose of study treatment (T-DM1+ non-pegylated liposomal doxorubicin) 
m Pharmacokinetic assessments will be performed during the Dose Finding part of the study on Cycles 1 and 2 and also on cycle 4. 
n: Every 3 weeks from last dose of study treatment (combination T-DM1+ Non-pegylated liposomal doxorubicin) until disease progression or development of intolerable toxicity, whichever occurs 
first. 
o Optional as per investigator’s criteria 
p At the Level -1, non-pegylated liposomal doxorubicin will be administered in a weekly schedule. 


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Appendix 2:  Response  Evaluation Criteria in Solid Tumors (RECIST criteria) guidelines 
 
(version 1.1) 
 
European Journal of Cancer 45 (2009) 228 – 247 


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

SAP_001.pdf: 
CONFIDENTIAL INFORMATION 
 
Statistical Analysis Plan (SAP) 
 
Final Version v1 
13th February 2019 
 
NCT Number 
NCT02562378 
EudraCT Number 
2014-001056-28 
Protocol Number 
MedOPP038 (THELMA study) 
Protocol Version Date 
23th November 2015 
Title 
Phase I multicenter clinical trial evaluating the 
combination of trastuzumab emtansine (T-DM1) 
and non-pegylated liposomal doxorubicin in 
HER2-positive metastatic breast cancer. 
Sponsor 
 
Medica Scientia Innovation Research 
MEDSIR ARO 
Rambla Cataluña, 2-4, 2D 
08007 Barcelona (Spain) 
 
 
 
 
 
 
 
 
 
 
 
Performed by: 
 
Avenida Meridiana 350, 9 D 
08027 Barcelona (Spain) 
STATISTICAL ANALYSIS PLAN (SAP) 


www.sail-biometria.com 
 


Study Code: 2014-001056-28 (MedOPP038)                                                               Statistical Analysis Plan 
 
 February 13, 2019                                                  3                                                                 Final v1 
 
 
Signature Page 
 
 
EudraCT Number: 
2014-001056-28 
Protocol Number: 
MedOPP038 
 
 
Written by:  
Signature:  
                            ___________________________ 
Date:  
                            ___________________________ 
Xavier Masramon 
Biostatistician  
SAIL S.L. 
Barcelona, Spain 
 
 
Sponsor Signature: 
The undersigned hereby declare that they have examined the Statistical Analysis Plan 
document and agree to its form and content.  
Represented by: 
 
Signature: 
__________________________ 
Date: 
__________________________ 
Name: 
__________________________ 
Title: 
__________________________ 
Signature: 
__________________________ 
Date: 
__________________________ 
Name: 
__________________________ 
Title: 
__________________________ 
 
 
 


Study Code: 2014-001056-28 (MedOPP038)                                                               Statistical Analysis Plan 
 
 February 13, 2019                                                  4                                                                 Final v1 
 
 
SAP Revision History: 
 
Version 
Number 
Date 
Changes 
v1 
13th February 2019 
Initial version 
 
 
 
 
 
 
 
 
 
 
 
 


Study Code: 2014-001056-28 (MedOPP038)                                                               Statistical Analysis Plan 
 
 February 13, 2019                                                  5                                                                 Final v1 
 
 
LIST OF ABBREVIATIONS 
 
Abbreviation Definition 
AE Adverse event 
AESI Adverse Event of Special Interest 
ARO Academic Research Organization  
ATC Anatomical Therapeutic Chemical 
AUC Area Under Curve 
BLQ Below the Limit of Quantification 
BNP B-type Natriuretic Peptide 
CBR Clinical Benefit Rate 
CI Confidence Interval 
CL Clearance 
CMAX Maximal Serum Concentration 
CR Complete Response 
CTCAE Common Terminology Criteria for Adverse Events 
DLT Dose-Limiting Toxicity 
DV distribution volume 
ER Estrogen Receptor 
HER2 Human Epidermal Growth Factor Receptor 2 
ICH International Conference on Harmonization 
IHC Immunohistochemistry 
IQR Interquartile Range 
ISH In Situ Hybridization 
ITT Intention-To-Treat 
IV Intravenous 
LVEF Left Ventricular Ejection Fraction 
M2 square meter 
MBC Metastatic Breast Cancer 
MEDDRA Medical Dictionary for Regulatory Activities 
MG Milligrams 
MTD Maximum Tolerated Dose 
NYHA New York Heart Association 
ORR Objective Response Rate 
PD Progressive Disease 
PGR Progesterone Receptor 
PK Pharmacokinetics 
PP Protocol Population 
PR Partial Response 
PT Preferred Term 
RDI Relative Dose Intensity 
RP2D Recommended Phase 2 Dose 
SAE Serious Adverse Event 
SAP Statistical Analysis Plan 
SD Stable Disease 
SD Standard Deviation 
SI International System of Units 
SOC System Organ Class 


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Abbreviation Definition 
T1/2 half-life 
T-DM1 Trastuzumab emtansine 
TEAE Treatment Emergent Adverse Event 
TLF Tables, Listings, Figures 
 
 
 


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TABLE OF CONTENTS 
1 
INTRODUCTION _____________________________________________ 9 
1.1 
General ____________________________________________________________ 9 
1.2 
Type of Study _______________________________________________________ 9 
1.3 
Study Population _____________________________________________________ 9 
1.4 
Study Design ________________________________________________________ 9 
1.5 
Study Schedule _____________________________________________________ 10 
1.6 
Sample Size ________________________________________________________ 11 
2 
STUDY OBJECTIVES __________________________________________ 11 
2.1 
Primary objective ___________________________________________________ 11 
2.2 
Secondary Objectives ________________________________________________ 11 
3 
ANALYSIS POPULATIONS _____________________________________ 12 
4 
DEFINITION OF ENDPOINTS ___________________________________ 12 
4.1 
Primary Endpoint ___________________________________________________ 12 
4.2 
Secondary Endpoints ________________________________________________ 12 
5 
STATISTICAL METHODS ______________________________________ 13 
5.1 
General Methodology ________________________________________________ 13 
5.2 
Subject Disposition __________________________________________________ 14 
5.3 
Baseline Characteristics ______________________________________________ 14 
5.4 
Efficacy ___________________________________________________________ 15 
5.4.1 
Secondary Efficacy Analysis _________________________________________ 15 
5.4.2 
Handling of Missing Data ___________________________________________ 16 
5.5 
Safety ____________________________________________________________ 17 
5.5.1 
Primary Safety Analysis _____________________________________________ 17 
5.5.2 
Duration and Extent of Exposure _____________________________________ 17 
5.5.3 
Adverse Events ___________________________________________________ 19 
5.5.4 
Cardiac Safety ____________________________________________________ 20 
5.5.5 
Concomitant Medications ___________________________________________ 20 
5.5.6 
Clinical Laboratory Parameters _______________________________________ 21 
5.5.7 
Vital Signs _______________________________________________________ 21 
5.5.8 
Physical Examination _______________________________________________ 21 


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5.6 
Pharmacokinetic ____________________________________________________ 22 
5.7 
Deviations from SAP _________________________________________________ 22 
6 
APPENDICES _______________________________________________ 23 
6.1 
List of Tables, Listings, Figures ________________________________________ 23 
 
 
 


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1 
INTRODUCTION 
1.1 General 
The purpose of this statistical analysis plan (SAP) is to provide a protocol specific description of the 
statistical analysis that will be performed to produce an integrated clinical/statistical report. 
This SAP is based upon the following study documents: 
- 
Protocol version dated: 27th June 2017 
- 
electronic Case Report Form: 27th July 2016 
1.2 Type of Study 
This is a prospective dose-finding, multicenter and open-label phase I clinical trial. 
1.3 Study Population 
This study will enroll patients with histologically or cytologically confirmed HER2-positive metastatic 
breast cancer (mBC) that have relapsed or progressed on or after both taxane and trastuzumab-
based therapy. Only patients whose human epidermal growth factor receptor 2 (HER2) tumor status 
was locally scored as Immunohistochemistry (IHC) 3+ or In Situ Hybridization (ISH) positive will be 
eligible. Evidence of measurable or evaluable metastatic disease is required. 
1.4 Study Design 
This is a prospective dose finding, multicenter and open-label phase I clinical trial. There are three 
planned cohorts. Trastuzumab emtansine (T-DM1) will be administered at a fixed dose of 3.6 mg/kg 
IV on Day 1 every 3 weeks and three cohorts of patients with three different dose levels of non-
pegylated liposomal doxorubicin (45 mg/m2, 50 mg/m2 and 60 mg/m2) IV on Day 1 in cycles of 21 
days each are planned. 
Study Cohort 
T-DM1 
Non-pegylated liposomal doxorubicin 
Cohort 1 (level 1) 3.6 mg/kg IV D1 
45 mg/m2 IV D1 
Cohort 2 (level 2) 3.6 mg/kg IV D1 
50 mg/m2 IV D1 
Cohort 3 (level 3) 3.6 mg/kg IV D1 
60 mg/m2 IV D1 
No dose escalation between cohorts will be permitted. Patients assigned on each cohort will remain at 
their study cohort during all the study period. 
Planned number of cohorts is currently 3 (3+3 design), including an expansion cohort of an additional 
6 patients at the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). 
The Steering Committee will review toxicities and may decide to add the expansion cohort to level -1 
in the situation where it is necessary to have a dose level -1. 
The detailed rules for dose escalation are detailed at figure 1 of the protocol. 


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1.5 Study Schedule 
Summary of study assessments is reported in Appendix 1 of the protocol: Schedule of assessments 
and study procedures. 
 
AE = Adverse Event; aPTT = Activated Partial Thromboplastin Time; ECG = Electrocardiogram; ECHO = Echocardiogram; ECOG = Eastern 
Cooperative Oncology Group; INR = International Normalized Ratio 
a Patients will be followed for new or worsening adverse events for 28 (+/- 7 days) days following the last dose of any study IMP. All ≥ 
grade 2 adverse events will be followed up until improvement to baseline levels, grade 1 or complete recovery, initiation of another anti-
cancer therapy, the patient withdraws consent, patient’s death or up to a maximum of 24 months after the first dose of study combination 
treatment whichever occurs first. Additionally, patients will be contacted regarding the occurrence of any new SAE considered to be 
treatment-related at 60 and 90 days following the last study treatment administration or until initiation of another anti-cancer therapy, 
whichever occurs first. 
b Vital signs will include measurements of respiratory rate, heart rate, blood pressure, and temperature. Abnormal or significant changes to 
vital signs from baseline should be recorded as adverse events, if appropriate. 
c ECHO and ECG will be performed every 1 cycle (cycles 1-6) during treatment with T-DM1 + non-pegylated liposomal doxorubicin. 
Thereafter, ECHO and ECG will be performed every 9 weeks until 12 months since last dose of study treatment (T-DM1+ non-pegylated 
liposomal doxorubicin)  
d During study treatment (T-DM1+ non-pegylated liposomal doxorubicin) tumor assessment wil be performed at the end of cycle 2, cycle 4, 
and cycle 6. Thereafter, the tumor response assessment will be performed every 9 weeks up to progression or up to 24 months for patients 


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who discontinue all study IMP for reasons other than PD. Response assessments will be assessed by the investigator, based on physical 
examinations, CT or MRI scans, and bone scans using RECIST v. 1.1 
e Serum β-HCG test must be performed during screening, every 3 cycles and at 3 and 7 months following the last dose of T-DM1 and/or 
non-pegylated liposomal doxorubicin for women of childbearing potential (including pre-menopausal women who have had a tubal ligation) 
and for women not meeting the definition of postmenopausal. Testing should be performed at a local laboratory within 7 days prior to the 
first administration of study treatment. For all other women, documentation must be present in medical history confirming that the patient 
is not of childbearing potential. 
f Hematologic assessments include hemoglobin (Hb), hematocrit, red blood cell count, platelet count, and white blood cells (WBC) with 
differential (including neutrophils, lymphocytes, monocytes, eosinophils and basophils) 
g Assessments should be performed at screening, within 72 hours prior to any IMP administration, at days 8 and 15 after any IMP 
administration during the first 2 cycles, weekly following any hematologic adverse event. If non-pegylated liposomal doxorubicin is 
discontinued due to toxicity, assessments should be performed weekly (minimum) until resolution of the adverse event (Grade ≤ 1 or 
baseline levels), and on Day 1 of subsequent cycles thereafter. All assessments at Day 1 should be performed within 72 hours preceding 
administration of any study IMP; results must be reviewed and documented prior to administration of study treatment. Assessments at days 
8 and 15 should be performed 7 (±2) and 14 (±2) days after any IMP administration 
h Biochemistry assessments include: sodium, potassium, chloride, calcium, magnesium, glucose, urea or blood urea nitrogen (BUN), 
creatinine, uric acid, total protein, albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), G-GT, LDH, total bilirubin (and direct bilirubin 
where total bilirubin > ULN). 
i TPN I determination will be performed 7 days (with a window of ± 2 days) after every infusion of every cycle. 
j TPN I determination will be performed every 1 cycle (cycles 1-6) during treatment with T-DM1 + non-pegylated liposomal doxorubicin. 
Thereafter, TPN I will be performed every 9 weeks until 12 months since last dose of study treatment (T-DM1+ non-pegylated liposomal 
doxorubicin). 
k BNP determination will be performed 7 days (with a window of ± 2 days) after every infusion of every cycle. 
l BNP determination will be performed every 1 cycle (cycles 1-6) during treatment with T-DM1 + non-pegylated liposomal doxorubicin. 
Thereafter, BNP will be performed every 9 weeks until 12 months since last dose of study treatment (T-DM1+ non-pegylated liposomal 
doxorubicin)  
m Pharmacokinetic assessments will be performed during the Dose Finding part of the study on Cycles 1 and 2 and also on cycle 4. 
n: Every 3 weeks from last dose of study treatment (combination T-DM1+ Non-pegylated liposomal doxorubicin) until disease progression or 
development of intolerable toxicity, whichever occurs first. 
o Optional as per investigator’s criteria 
p At the Level -1, non-pegylated liposomal doxorubicin will be administered in a weekly schedule. 
 
1.6 Sample Size 
The total sample size was dependent on the number of dose levels required to determine the 
maximum tolerated dose (MTD). A minimum of 12 and up to 24 patients was planned. 
The inclusion of patients has already been completed. The total number of patients is 15. 
Study Cohort 
N 
Cohort 1 
3 
Cohort 2 
3 
Cohort 3 
9 
 
2 
STUDY OBJECTIVES 
2.1 Primary objective 
To determine the MTD of the combination of T-DM1 and non-pegylated liposomal doxorubicin. 
2.2 Secondary Objectives 
• 
To assess the overall objective response rate (ORR). 
• 
To assess the clinical benefit rate (CBR) 
• 
To assess the number of progressions. 
• 
To assess the number of deaths and reasons. 


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• 
To assess the safety profile of the combination of T-DM1 and non-pegylated liposomal 
doxorubicin. 
• 
To assess the cardiac safety of the combination of T-DM1 and non-pegylated liposomal 
doxorubicin.  
• 
To explore the potential role of single nucleotide polymorphisms (SNP) in the predisposition for 
developing cardiotoxicity. 
• 
To analyze the pharmacokinetics (PK) profile of T-DM1 and non-pegylated liposomal doxorubicin.  
3 
ANALYSIS POPULATIONS 
The following populations will be analyzed: 
• 
Screening Population: All patients who were present at the screening visit will be included in the 
screening population.  
• 
DLT population: all patients who complete the first two cycles of treatment or who stop treatment 
during this time because of dose-limiting toxicity (DLT).  
• 
The Safety / Intention-To-Treat (ITT) population: all included patients receiving any dose of study 
treatment.  
• 
Per protocol population (PP): all patients who receive the protocol required study drug exposure 
and required protocol processing. 
To determine the Per Protocol Population, all protocol deviations will be reviewed prior to 
database lock to determine which ones should be classified as major deviations. 
4 
DEFINITION OF ENDPOINTS 
4.1 Primary Endpoint 
• 
MTD is defined as the highest dose level at which no more than one of six patients (i.e. less or 
equal than 16,7%) experience DLT during the first two cycles of study treatment. 
4.2 Secondary Endpoints  
• 
ORR, according RECIST v1.1 
• 
CBR according RECIST v1.1 
• 
Number and Rate of patients with progression 
• 
Number and Rate of patients who died 
• 
The extent of exposure 
• 
Grade 3 and 4 AEs, SAEs, AESIs, deaths, and study discontinuations for each study group will be 
described and assessed. 
• 
Number and Rate of patients with left ventricular dysfunction IV NYHA, defined as LVEF decline 
>10 percentual points or LVEF <50% 


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• 
Number and Rate of patients who discontinue any of the study drugs due to cardiac function or 
die due to cardiac cause. 
• 
Number and Rate of patients with cardiac troponin I elevation, according to CTCAE v4.0 criteria. 
• 
Number and Rate of patients with B-type Natriuretic Peptide (BNP) levels, according to CTCAE 
v4.0 criteria. 
• 
Number and Rate of patients with segmental wall-motion abnormalities. 
• 
Association between HER2 Ile655Val single nucleotide polymorphism and LVEF changes. 
• 
Association between HER2 Ile655Val single nucleotide polymorphism and prevalence of a cardiac 
toxicity. 
• 
PK profile: AUC, clearance (CL), distribution volume (dV), apparent half-life (t1/2) and maximal 
serum concentration (Cmax).  
• 
Clinically relevant tests, concomitant medications, and reported AEs will be described in every 
study subgroup. For AEs, severity, expectedness, causality, relationship, body system, action 
taken, and outcome will be reported. 
5 
STATISTICAL METHODS 
5.1 General Methodology 
Definition of baseline: For each safety or efficacy parameter, the last valid assessment made before 
first study drug administration will be used as the baseline for all analyses of that safety or efficacy 
parameter unless otherwise specified. 
Continuous data will be summarized in terms of the number of observations, mean, standard 
deviation (SD), median, minimum, maximum, and first and third quartiles, unless otherwise stated. 
Where data are collected over time, both the observed data and change from baseline will be 
summarized at each time point. 
The minimum and maximum will be reported to the same number of decimal places as the raw data 
recorded in the database. The mean, median, and first and third quartiles will be reported to one 
more decimal place than the raw data recorded in the database. The SD will be reported to two more 
decimal places than the raw data recorded in the database. In general, the maximum number of 
decimal places reported shall be four for any summary statistic. 
Categorical data will be summarized in terms of the number of subjects providing data at the relevant 
time point (n), frequency counts and percentages. Changes from baseline in categorical data will be 
summarized using shift tables where appropriate. 
Percentages will be presented to one decimal place. A percentage of 100% will be reported as 100%. 
Percentages will not be presented for zero counts. Unless otherwise stated, percentages will be 
calculated using n as the denominator, for frequency tables not assessed by time point the population 
will be used as denominator. If sample sizes are small, the data displays will show the percentages, 
but any textual report (e.g. clinical study report) will describe frequencies only. 


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P-values greater than or equal to 0.001, in general, will be presented to three decimal places. 
However, if a p-value is only presented to four decimal places (by SAS) it will not be rounded again 
but will be presented to four decimal places. P-values less than 0.0001 will be presented as 
“<0.0001”. 
Confidence intervals will be presented to one more decimal place than the raw data. A two-sided 
significance level of 5% will be used for confidence intervals. 
All report outputs will be produced using SAS® version 9.4 version in a secure and validated 
environment. All report outputs will be provided to the Sponsor in a single Microsoft Word document. 
5.2 Subject Disposition 
Descriptive statistics will be provided for the following: 
- 
Overall number of subjects in the screening population, the number of patients eligible to 
participate in the study, and number of screen failures. 
- 
Number and percent of subjects in each of the analysis populations (DLT, Safety/ITT, PP). 
- 
Number and percent of subjects excluded from each of the analysis populations along with reason 
for exclusion. 
- 
Listing of subjects excluded from each of the analysis populations along with reason for exclusion. 
- 
Listing of protocol deviations. 
- 
Study termination: 
o Number and percent of subjects who completed the study. 
o Frequency of premature termination reasons. 
o Listing of all dropouts along with reason for termination, treatment group and time of 
termination. 
No statistical tests are planned for these data. 
5.3 Baseline Characteristics 
Baseline characteristics will be provided overall for the Safety/ITT. 
Descriptive statistics, including number of subjects, mean, standard deviation (SD), median and range 
for continuous variables and frequency and percent for categorical variables will be provided. 
Baseline Characteristics: 
o Demographic characteristics 
o Physical examination 
o Medical history 
o Prior concomitant medication 
o Estrogen receptor (ER) 
o Progesterone receptor (PgR) 


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o Human epidermal growth factor receptor 2 (HER2) 
o Previous treatment for local breast cancer 
o Previous surgeries for breast cancer 
o ECOG performance status 
o TNM staging 
o Tumor physical exam 
o Metastases sites 
o Vital signs 
o Electrocardiogram 
o Left Ventricular Ejection Fraction (LVEF) 
No statistical tests are planned for these data. 
A by-subject listing of all demographic and other baseline characteristics will be provided. 
5.4 Efficacy 
5.4.1 Secondary Efficacy Analysis 
All secondary efficacy analysis will be based on the Safety/ITT and PP population. 
Confidence intervals will be calculated for efficacy data, according to Clopper-Pearson. 
Estimates for efficacy data, 95% confidence intervals (CIs) were constructed based on an exact 
binary distribution. 
- 
Tumor response rate by MRI, according to the RECIST criteria version 1.1, is defined as best 
overall response in terms of: 
o Complete response (CR) 
o Partial response (PR) 
o Stable disease (SD) 
o Progressive disease (PD) 
Best overall response is obtained, from target lesion response, non-target lesion response and 
new lesions, as follows: 


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For each response category, the number and proportion of patients, with its 95% Pearson-
Clopper confidence intervals, will be calculated. 
- 
Overall Response Rate (ORR), based on local investigator’s assessment according to RECIST 1.1, 
is defined as the proportion of patients with best overall response of CR or PR. The ORR with its 
95% Pearson-Clopper confidence interval, will be calculated. 
- 
Clinical Benefit Rate (CBR), based on local investigator’s assessment according to RECIST 1.1, is 
defined as those patients who experience a complete response, partial response or stable disease 
(for at least 24 weeks). The CBR with its 95% Pearson-Clopper confidence interval, will be 
calculated. 
- 
The number and proportion of patients with progression disease (PD) with its 95% Pearson-
Clopper confidence intervals will be calculated. 
- 
The number and proportion of deaths with its 95% Pearson-Clopper confidence intervals will be 
calculated. 
- 
The number and proportion for each reason of death with its 95% Pearson-Clopper confidence 
intervals will be calculated. 
5.4.2 Handling of Missing Data 
Study variables could be missing for patients who withdrawn from the trial or for specific visits. We 
will report reasons for withdrawal. Patient with missing in response outcomes (ORR and CBR) will 
considered as no responders in intention to treat set. The other variables will be managed with simple 
imputations methods (last observation carried forward). The effect that any missing data might have 
on results will be assessed via sensitivity analysis of study sets. 
 
 


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5.5 Safety 
All safety tables will list or summarize subjects on the entire Safety/ITT Population and by each 
cohort, except for the primary safety analysis. 
5.5.1 Primary Safety Analysis 
The primary outcome will be analyzed in DLT population. 
For each cohort (treatment dose), see section 1.4, the number and the proportion of patients with 
DLT with its 95% Pearson-Clopper confidence intervals will be calculated. 
A DLT is defined as any of the drug-related adverse events, described in the Table 1 of the protocol, 
occurring during the first two cycles of study treatment. It will be used as the measure for the MTD 
determination. 
5.5.2 Duration and Extent of Exposure 
The study treatment period is defined as the time between the study entry and the last dose of study 
combination (T-DM1 + non-pegylated liposomal doxorubicin) therapy. T-DM1 administration may 
continue as a single agent until disease progression or development of intolerable toxicity, whichever 
occurs first. 
For T-DM1 and non-pegylated liposomal doxorubicin the following parameters will be calculated: 
• 
b: “Actual Cycle Duration” is the treatment duration for a cycle per CRF. It is the length of time 
(days) between actual and next cycle start date dose. At the last cycle is the difference between 
start and stop date dose.  
• 
c: “Actual Cycle Dose Days” is the number of days with dose administration in the cycle, 
considering the interruptions. 
• 
d: “Actual Total Dose per Cycle” is the total dose a patient took in a cycle, considering 
interruptions and reductions. 
• 
e: “Intended Daily Dose per Cycle”. 
• 
f: “Intended Cycle Duration”. 
• 
g: “Intended Cycle Dose Days”. 
• 
A: “Total number of cycles”. 
• 
B: “Treatment Duration” = Sum over all cycles of (b). 
• 
C: “Days on drug” = Sum over all cycles of (c). 
• 
D: “Total Actual Total Dose” = Sum over all cycles of (d). 
• 
E: “Mean Intended Daily Dose” = Mean over all cycles of (e). 
• 
F: “Total Intended Duration” = Sum over all cycles of (f). 
• 
G: “Total Intended Dose Days” = Sum over all cycles of (g). 


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• 
H: “Intended Total Dose” = G*E  
• 
I: “Actual Average Daily Dose on Dose Days” = D/C 
• 
J: “Ratio for Dose Interruption” = C/G 
• 
K: “Ratio for Cycle Duration” = F/B 
• 
L: “Actual Average Daily Dose Intensity” = I*J*K 
• 
M: “Relative Dose Intensity (RDI)” = L/E*100 
The treatment duration (days), days on Drug and Treatment compliance (%) will be summarized in 
terms of the number of observations, mean, standard deviation (STD), median, minimum and 
maximum, to each treatment cohort. 
Extent of exposure measured as RDI by cohort will be described with median, interquartile range 
(IQR) and range. The RDI will be dichotomized in different cutoffs (≥50%, ≥70%, ≥80%, ≥90%, 
≥100%) and described with frequencies and percentages.  


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5.5.3 Adverse Events 
All AEs will be recorded on the eCRF “Adverse Events” page and will be coded using the current 
version of MedDRA® to give a system organ class (SOC) and preferred term (PT) for each event. All 
adverse event safety data will be updated to the version of MedDRA that is current at the time of the 
database lock and statistical analyses. Adverse events will be coded with grades defined according to 
CTCAE V4.0 criteria. 
Treatment-emergent AEs (i.e. those events occur after the first study medication administration and 
were not present at baseline or worsened in severity following the start of treatment) will be 
tabulated. The TEAE will be tabulated according to intensity and causality. If intensity of an AE or 
causality of an AE to the study medication is missing, a worst-case scenario will prevail (severe in 
intensity or probably related will be assumed). In the summary tables the number of subjects with 
events and the number of events will be presented. 
The onset date of an AE will be compared to the date of first dose of study drug to determine 
whether or not the AE is treatment-emergent. Adverse events with an onset date on or after the date 
of first dose of study drug will be classified as treatment-emergent. 
All deaths and SAEs, regardless of cause, from treatment start until 28 days after final dose of 
treatment.  Non-fatal AEs occurring after treatment start regardless of cause, up until 28 days after 
final dose of treatment or until start of new anti-cancer treatment, whichever is first.  Disease 
progression is not considered a treatment emergent adverse event unless the patient dies of disease 
prior to 28 days after discontinuation of treatment.  Events that are continuations of baseline 
abnormalities are considered treatment emergent adverse events only if there is an increase in grade 
over baseline, or if there is an increase following a decrease during the study. 
Treatment emergent adverse events with cause possibly, probably or definitely related to treatment 
as judged by the investigator.  Events that are continuation of baseline abnormalities are not 
considered treatment related unless there is an increase in grade, or if there is an increase following 
a decrease, and the increase is judged by the investigator to be due to treatment. 
The following summaries will be provided: 
- 
An overview of adverse events (number of subjects with at least one AEs, number of subjects 
with at least one TEAE, number of subjects with grade 3 and 4 TEAE, number of subjects with 
related study drug TEAE, number of subjects with serious TEAE, number of subjects with non-
serious TEAE, number of subjects with AESI, number of deaths, number of subjects with TEAE 
leading to discontinuation of study treatment, number of subjects dropped out due to AE). 
- 
A summary of the number and percentage of subjects reporting a treatment-emergent adverse 
event by SOC, and PT. 
- 
A summary of the number and percentage of subjects reporting a treatment-emergent adverse 
event related to study drug by SOC, and PT. 
- 
A summary of the number and percentage of subjects reporting a grade 3 and 4 treatment-
emergent adverse event by SOC, and PT. 
- 
A summary of the number and percentage of subjects reporting a treatment-emergent adverse 
event by maximum intensity, SOC and PT. 


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- 
A summary of the number and percentage of subjects reporting a serious treatment-emergent 
adverse event, by SOC and PT. 
- 
A summary of the number and percentage of subjects reporting a treatment-emergent adverse 
event resulting in death during the study, by SOC and PT. 
- 
A summary of the number and percentage of subjects with adverse events leading to 
discontinuation of study drug, by SOC and PT. 
For adverse events, we will report intensity, casualty, relation, body system, action taken, and 
outcome. 
Serious adverse events, deaths and study discontinuations will be described and examined in each 
study group. 
5.5.4 Cardiac Safety 
- 
Number and proportion (95% Pearson-Clopper confidence interval) of patients with left 
ventricular dysfunction IV NYHA, defined as LVEF decline >10 percentual points or LVEF <50%. 
- 
Number and proportion (95% Pearson-Clopper confidence interval) of patients who discontinue 
any of the study drugs due to cardiac function or die due to cardiac cause.  
- 
Number and proportion (95% Pearson-Clopper confidence interval) of patients with cardiac 
troponin I elevation, according to CTCAE v4.0 criteria. 
- 
Number and proportion (95% Pearson-Clopper confidence interval) of patients with BNP 
elevation, according to CTCAE v4.0 criteria. 
- 
Association between HER2 Ile655Val single nucleotide polymorphism and LVEF changes will be 
analyzed by Spearman's rank correlation. 
- 
Association between HER2 Ile655Val single nucleotide polymorphism and prevalence of a cardiac 
toxicity (binary outcome) will be analyzed by U Mann-Whitney Test. 
5.5.5 Concomitant Medications 
The number and percent of unique patients taking concomitant medications will be summarized by 
therapeutic classification, coded term and cohort group. Elective surgeries/procedures performed 
during the study will be presented in a listing. 
The following are conventions that will be used to classify individual medications as prior and/or 
concomitant: 
- 
Medications with stop dates prior to screening visit date will be considered prior. 
- 
Medications with missing stop dates or stop dates the day of or after screening visit date will be 
considered concomitant, regardless of start date.  Additionally, if the start date is prior to 
screening visit date or missing, the medication will also be considered prior. 
Frequencies and by-subject listing of all prior and concomitant medications will be provided, 
containing variables listed on Prior/Concomitant Assessment eCRF, their corresponding categories 
(Prior or Concomitant), and WHO Anatomical Therapeutic Chemical (ATC) level 2 and ATC Name. 


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5.5.6 Clinical Laboratory Parameters 
All hematology and biochemistry parameters will be presented by descriptive statistics in a tabulated 
summary by time point of assessment per treatment group together with the respective changes 
from baseline. In addition, a frequency table for clinically significant values will be presented by time 
point of assessment.  
A by-subject listing for hematology and clinical chemistry will be provided. These listings will be 
presented by treatment group and time point and will include: center, subject identifier, laboratory 
parameter, parameter values (in SI units), SI unit, normal range and a flag with respect to normal 
range (below, within and above normal range). 
5.5.7 Vital Signs 
Weight, systolic and diastolic blood pressure, heart rate and respiratory rate will be presented by 
descriptive statistics in a tabulated summary by time point of assessment per treatment group 
together with the respective changes from baseline. In addition, frequency tables for the number of 
patients with increases or decreases from baseline in systolic/diastolic blood pressure of >20 mmHg 
and pulse rate of >15 bpm will be provided by time point of assessment and overall. A by-subject 
listing for all vital signs per treatment group and time point will be provided. 
5.5.8 Physical Examination 
A frequency table per treatment group, time point, and body system will be provided for assessment 
results of normal, abnormal and not done. 
A by-subject listing for all body systems per treatment group and time point will be provided. Only 
subjects with at least one abnormal finding will be included in this listing. 
 
 


Study Code: 2014-001056-28 (MedOPP038)                                                               Statistical Analysis Plan 
 
 February 13, 2019                                                  22                                                                 Final v1 
 
5.6  Pharmacokinetic 
The Pharmacokinetic Analyses will be performed by PPD. 
5.7 Deviations from SAP 
Any deviations from the original statistical plan will be described and justified in the final clinical study 
report. 
 
 


Study Code: 2014-001056-28 (MedOPP038)                                                               Statistical Analysis Plan 
 
 February 13, 2019                                                  23                                                                 Final v1 
 
6 
APPENDICES 
6.1 List of Tables, Listings, Figures 
A complete list of tables, listings and figures (TLFs) will be given in a separate document which can 
be updated without updating the SAP. The list will serve as a reference for both the Sponsor, the trial 
statistician and the statistical programmer and includes the totality of statistical output to be 
produced. 
All output will be headed with an appropriate heading specifying the study ID and abbreviated study 
title. 
All output will be dated and have page numbers in the form 'Page [x / y]' where x denotes the 
current page within an output and y the total number of pages of that output. 
All statistical output will identify the underlying analysis populations and indicate the number of 
patients/events in this population (N) and the number of patient/events actual contributing to the 
output (n). All statistical output will be presented per treatment (if applicable). 
All patient listings will contain additionally to the patient identification the analysis population and the 
treatment.