Phase II Study of Trastuzumab-Deruxtecan (T-DX; DS-8201a) in HER2-positive Breast Cancer Patients With Newly Diagnosed or Progressing Brain Metastases
Phase: PHASE2
Conditions: Breast Cancer Stage IV
Sponsor: Medical University of Vienna

Clinical Study Protocol 
Phase II Study of Trastuzumab-Deruxtecan (T-DX; DS-8201a) in HER2-
positive Breast Cancer Patients with newly diagnosed or progressing 
Brain Metastases 
TUXEDO-1  
Version 2.0/05.05.2020 
EudraCT 2020-000981-41 
Confidentiality Statement 
 The information contained in this document is the property of the sponsor of this trial and therefore is 
provided to you in confidence for review by you, your staff, an applicable Ethics Committee/Institutional 
Review Board and regulatory authorities. It is understood that the information will not be disclosed to 
others without prior written approval from the sponsor, except to the extent necessary to obtain 
informed consent from those persons to whom the medication may be administered. 

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Test drug (IMP)  
Trastuzumab-Deruxtecan (T-DXd; DS-8201a) 
Protocol authors 
Assoc.-Prof. PD Dr. Rupert Bartsch, Ass.-Prof. PD Dr. Anna Sophie 
Berghoff, Dr. Elisabeth Sophie Bergen, Mag. Ortrun Neuper,  
o.Univ. Prof. Matthias Preusser 
Principal investigator 
Assoc.-Prof. PD Dr. Rupert Bartsch,   
Deptartment of Medicine I, Division of Oncology, Medical University 
of Vienna, Vienna General Hospital 
Waehringer-Gürtel 18-20 
1090 Vienna 
email: rupert.bartsch@meduniwien.ac.at 
Document type 
Clinical Study Protocol 
Study phase 
Phase II 
Version/Date 
2.0/05.05.2020 
Number of Pages 
73 

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SPONSOR, INVESTIGATOR AND SIGNATURES 
TUXEDO-1, Version 2.0/05.05.2020/Amendment 0 
Sponsor/OEL   
 
 
 
_________________ 
 
___________ 
Signature 
 
 
Date 
 
o. Univ. Prof. Dr. Herbert Watzke                                                       
Department of Medicine I, Medical University of Vienna, Austria,       
                                                 
Investigator 
 
I have thoroughly read and reviewed the study protocol “Phase II Study of 
Trastuzumab-Dexruxtecan (T-DXd; DS-8201a) in HER2-positive Breast 
Cancer Patients with newly diagnosed or progressing Brain Metastases” 
Version 2.0_05.05.2020/Amendment 0. Having read and understood the 
requirements and conditions of the study protocol, I agree to perform the 
clinical study according to the international good clinical practice 
principles and regulatory authority requirements.  
I understand that changes to the protocol must be made in form of an 
official amendment.  
I agree to report all serious adverse events, whether considered 
treatment-related or not within one working day. 
 
 
_________________ 
 
___________ 
Signature 
 
 
Date 
 
Assoc.-Prof. PD Dr. Rupert Bartsch, Department of Medicine I,       
Division of Oncology, Medical University of Vienna, Austria 
 
 
 
 
 
 

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PROTOCOL SYNOPSIS 
 
TITLE 
Phase II Study of Trastuzumab-Deruxtecan (T-DXd; DS-8201a) in HER2-positive 
Breast Cancer Patients with newly diagnosed or progressing Brain Metastases 
ACRONYM 
TUXEDO-1 
INDICATION 
Patients with histologically proven HER2-positive metastatic breast cancer and 
newly diagnosed or progressing brain metastases eligible for systemic treatment  
SCIENTIFIC 
RATIONAL 
Brain metastases (BM) are a common and devastating complication of HER2-positive 
breast cancer. For decades, local therapy such as whole brain radiotherapy (WBRT), 
radiosurgery and/or neurosurgical resection has been the mainstay of treatment. 
While WBRT usually yield response rates of around 50% and may alleviate 
neurological symptom, severe neurological late toxicity must be expected. This 
problem became evident with BM patients surviving for more than two years since 
the introduction of highly active systemic treatment. 
In order to delay the need for WBRT, activity of upfront systemic treatment was 
evaluated within the LANDSCAPE trial of lapatinib plus capecitabine defining a 
potential novel treatment standard in patients with multiple oligo- or asymptomatic 
BM. More recently, promising data were published with the second- and third-
generation tyrosine-kinase inhibitors neratinib and tucatinib and the antibody-drug 
conjugate T-DM1. As T-DM1 is increasingly used in the early-stage disease setting, 
further options for the treatment of metastatic disease are urgently required. 
Trastuzumab-deruxtecan (DS-8201a) is a novel HER2-directed antibody-drug 
conjugate with high clinical activity in HER2-positive MBC and other HER2-
overexpressing solid cancers. In addition, responses were also noted in patients with 
HER2-low expressing tumours. Of note, treatment was generally well tolerated with 
rare cases of pneumonitis observed. Thus, the promising clinical activity in 
conjunction with the safety profile renders this drug attractive for the treatment of 
patients with BM. 
In this phase II study, activity and safety of trastuzumab-deruxtecan in patients with 
BM from HER2-positive breast cancer will be evaluated. 
DESIGN / PHASE 
Prospective, single centre, open label, non-comparative, phase II 
STUDY DURATION 
3 years 

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CENTER 
/ COUNTRY 
Medical University of Vienna, Department of Medicine I, Division of Oncology, 
Vienna, Austria 
PATIENTS / GROUPS 15 evaluable patients overall; in stage 1, 6 patients will be initially accrued, with 
accrual of additional 9 patients up to 15 maximum patient population in stage 2 
according to the number of responses seen in stage 1 

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INCLUSION 
CRITERIA 
• Histologically confirmed breast cancer 
• Radiologically documented metastatic disease 
• HER2-positive as defined by IHC 3+ and/or HER2/neu gene amplification 
• Newly diagnosed brain metastases or brain metastases progressing after prior 
local therapy 
• Measurable disease (RANO-BM criteria) 
• No indication for immediate local treatment 
• No indication of leptomeningeal disease 
• KPS >70%, ECOG <2 
• Indication for systemic anti-HER2 treatment 
• Prior exposure to trastuzumab and pertuzumab 
• Prior exposure to T-DM1 allowed 
• Life expectancy of at least 3 months 
• Age ≥18 years  
• Patient must be able to tolerate therapy, and have adequate cardiac function 
(defined by baseline left ventricular ejection fraction ≥50%) 
• Adequate bone-marrow, liver and kidney function  
• Adequate treatment washout period before enrolment, defined as: 
• Major Surgery: ≥4 weeks 
• Radiation therapy: ≥4 weeks 
• Chemotherapy, small-molecule targeted agents, anticancer hormonal 
therapy: ≥3 weeks 
• Antibody-based treatment: ≥4 weeks 
• Patient must be capable of understanding the purpose of the study and have 
given written informed consent 

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EXCLUSION 
CRITERIA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Metastatic breast cancer other than HER2-positve disease 
• Use of any investigational agent within 28 days prior to initiation of treatment 
• History of malignancy other than squamous cell carcinoma, basal cell carcinoma 
of the skin or carcinoma in situ of the cervix within the last 3 years including 
contralateral breast cancer 
• Major surgery, other than diagnostic surgery, within the last 4 weeks 
• Indication for immediate local therapy as defined by local standard 
• Leptomeningeal involvement 
• Other anticancer therapy, including cytotoxic, targeted agents, immunotherapy, 
antibody, retinoid, or anti-cancer hormonal treatment 
• Concomitant radiotherapy 
• Prior radiotherapy to the thorax other than breast irradiation or irradiation of 
bone metastases 
• A history of uncontrolled seizures, central nervous system disorders or 
psychiatric disability judged by the investigator to be clinically significant and 
adversely affecting compliance to study drugs 
• Clinically significant cardiac disease including unstable angina, acute myocardial 
infarction within six months prior to randomization, congestive heart failure 
(NYHA III-IV), left ventricular ejection fraction <50%, arrhythmia unless controlled 
by therapy, with the exception of extra systoles or minor conduction 
abnormalities, and long QT syndrome (QTc interval >450 ms) 
• Subjects who have current active hepatic or biliary disease (with exception of 
patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or 
stable chronic liver disease per investigator assessment) including acute and 
chronic infections with hepatitis B and C 
• Inadequate haematological status at baseline prior to study entry: Dependency 
on red blood cell and/or platelet transfusions, ANC (absolute neutrophil count 
(segmented + bands) <1.0 x 109/L; platelets <100 x 109/L 
• Inadequate kidney function: serum-creatinine >1.5 times upper normal limit  
• Hepatic dysfunction: total bilirubin >1.5 times upper normal limit (>3 in patients 
with liver metastases or known history of Gilbert’s disease); ALT, AST >3 times 

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upper normal limit (>5 in patients with liver metastases); serum albumin <2.5 
g/dL; INR ≥1.5 
• Clinically severe pulmonary compromise resulting from intercurrent pulmonary 
illnesses including, but not limited to, any underlying pulmonary disorder (i.e. 
pulmonary emboli within three months of the study enrolment, severe asthma, 
severe COPD, restrictive lung disease, pleural effusion etc.), and any 
autoimmune, connective tissue or inflammatory disorders with pulmonary 
involvement (i.e. rheumatoid arthritis, Sjogren's syndrome, sarcoidosis etc.), or 
prior pneumonectomy. 
• Subjects with bronchopulmonary disorders who require intermittent use of 
bronchodilators (such as albuterol) will not be excluded from this study 
• Patients with active opportunistic infections 
• Known HIV infection 
• Concomitant treatment with chloroquine or hydroxychloroquine 
• Pregnant or lactating women. Women with childbearing potential must have a 
negative pregnancy test at screening 
• Women with childbearing potential, including women whose last menstrual 
period was less than one year prior to screening, unable or unwilling to use 
adequate contraception from study start to one year after the last dose of 
protocol therapy. Acceptable contraception methods included the application of 
an intrauterine device, barrier method or total abstinence 
• Patients with known hypersensitivity to trastuzumab 
• Patients not able to provide written informed consent 
• Patients with known substance abuse or any other medical conditions such as 
clinically significant cardiac or psychological conditions, that may, in the opinion 
of the investigator, interfere with the subject’s participation in the clinical study 
or evaluation of the clinical study results 
• Patients requiring concomitant use of chronic systemic (IV or oral) corticosteroids 
at doses higher than 4 mg dexamethasone per day or other immunosuppressive 
medications except for managing adverse events (inhaled steroids or intra 
articular steroid injections are permitted in this study) 

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PLANNED STUDY 
DURATION 
Stage 1: Enrolment period 8 months 
Stage 2: Enrolment period 12 months 
FPFV: July 2020, LPLV August 2022 
TEST DRUG (IMP) 
Trastuzumab-deruxtecan 5.4 mg/kg body weight i.v. on day 1 once every three 
weeks 
CONCOMITANT 
MEDICATION 
Supportive concomitant medication is allowed according to local treatment 
standard. A detailed list of forbidden concomitant medication is provided in section 
8.5.2 
  
EFFICACY 
ENDPOINTS 
• Primary endpoint: Response rate (CNS) at any timepoint as judged by best 
response during the study period (clinical response measured according to 
RANO-BM criteria) 
• Secondary endpoints: Clinical benefit rate (CNS defined by RANO-BM; CR+PR+SD 
≥6 months), extracranial response rate and clinical benefit rate (RECIST 1.1), 
progression-free survival, time-to-WBRT, overall survival 
TOLERABILITY / 
SAFETY ENDPOINTS 
• 
Endpoint:  Safety & tolerability of trastuzumab-deruxtecan in terms of 
haematologic and non-haematologic side effects as assessed by the 
investigators 
• 
Assessment of clinical adverse events & laboratory parameters 
QUALITY OF LIFE 
ENDPOINTS 
• 
Endpoint: Evaluation of Quality-of-Life (QoL) in patients receiving trastuzumab-
deruxtecan for HER2-positive breast cancer brain metastases 
• 
Assessment of QoL with EORTC QLQ-c30, the brain specific tool (BN20), 
and the breast specific tool BR45 
EXPLORATORY 
ENDPOINTS 
• 
Endpoint: Evaluation of biomarkers potentially predicting for response to 
trastuzumab-deruxtecan 
• 
Assessment of HER2 gene copy numbers and the rate of tumour-
infiltrating lymphocytes in primary tumour or (preferentially) from a 
metastatic biopsy 
• 
Blood samples for ancillary studies at baseline, before cycle 4 and at EOT 
STATISTICAL 
CONSIDERATIONS 
Efficacy: Primary endpoint is the rate of objective responses at any timepoint as 
judged by best response during therapy, i.e. complete remission (CR), partial 
remission (PR), stable disease (SD) / no change and progressive disease as defined 
by RANO response criteria  

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This is a single-arm non-comparative phase II study evaluating the rate of objective 
CNS responses to trastuzumab-deruxtecan in HER2-positive metastatic breast 
cancer patients with brain metastases. 
A Simon’s two-stage phase II design will be applied. A response rate of 61% would 
be considered as indicating clinically relevant activity in this patient population. A 
response rate of <26%, on the other hand, must be considered clinically 
unmeaningful (null hypothesis).  
In the first stage, 6 patients will initially be accrued. If there are two or fewer 
responses in these 6 patients, the study will be stopped. Otherwise, 9 additional 
patients will be accrued for a total number of 15 patients. The null hypothesis will 
be rejected if 7 or more responses are observed in these 15 patients. This design 
yields a type I error rate of 5% and a power of 80% to reject the null-hypothesis. 
P0=0.250, P1=0.610, Alpha=0.050, Beta=0.200 
N1 
R1 
N 
R 
Alpha Beta 
6 
2 
15 
6 
0.050 0.200 
 
N1 is the sample size in the first stage. 
R1 is the drug rejection number in the first stage. 
N is the combined sample size of both stages. 
R is the combined drug rejection number after both stages. 
Alpha is the probability of rejecting that P<=P0 when this is true. 
Beta is the probability of rejecting that P>=P1 when this is true. 
P0 is the response proportion of a poor drug. 
P1 is the response proportion of a good drug. 
Tolerability and Safety:            
Endpoints are safety & tolerance of treatment in terms of haematologic and non-
haematologic side effects as assessed by the investigators. Adverse events will also 
be summarised using frequency counts and percentages.  
All patients who are eligible for the study and receive at least one dose of study drug 
l be will be included in the safety analysis. 

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Patients who drop out or die prior to the first response assessment will be included 
in the denominator when calculating the response rate. Any patients who enrol into 
the study but who receive no study medication will be excluded, but a sensitivity 
analysis will be conducted which will include all enrolled patients. An analysis of all 
patients undergoing treatment per protocol excluding drop out will also be 
performed. 

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LIST OF ABBREVATIONS 
 
ADC 
Antibody-Drug Conjugate 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event  
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BC 
Breast Caner 
BM 
Brain Metastases 
CBR 
Clinical Benefit Rate 
CR 
Complete Remission 
CRF 
Case Report Form 
CRO 
Clinical Research Organization  
CSR 
Clinical Study Report 
CT 
Computed Tomography 
DOH 
Declaration of Helsinki 
DSUR 
Development Safety Update Report  
ECG 
Electrocardiography 
ECOG 
Eastern Cooperative Oncology Group 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOS 
End of Study 
EU 
European Union 
FPFV 
First Patient First Visit 
GCP 
Good Clinical Practice  
GGT 
Gamma-Glutamyltransferase  
HBsAg 
Hepatitis B Surface Antigen 

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HBV 
Hepatitis B Virus 
HCG 
Human Corionic Gonadotropin 
HER2 
Human Epidermal Growth Factor Receptor 2 
HVC 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
ISF 
Investigator Site File 
ILD 
Interstitial Lung Disease 
ISO 
International Standardisation Organization 
KKS 
Koordinationszentrum für Klinische Studien 
LPLV 
Last Patient Last Visit 
LVEF 
Left Ventricular Ejection Fraction 
mL 
Milliliter 
mm 
Millimeter 
MRI 
Magnetic Resonance Imaging 
MUGA scan 
Multigated Acquisition Scan 
MUW 
Medical University of Vienna 
NCI CTCAE 
 National Cancer Institute Common Terminology Criteria for Adverse 
Events 
OS 
Overall Survival 
PARP 
Poly (ADP-ribose) Polymerase 
PFS 
Progression-free Survival 
PD-L1 
Programmed cell Death Ligand 1 
PK 
Pharmacokinetics 
PR 
Partial Remission 
PD 
Progressive Disease 

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QoL 
Quality-of-Life 
RANO 
Response Assessment in Neuro-Oncology 
RBC 
Red Blood Cells 
RR 
response Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan  
SAR 
Serious Adverse Reaction 
SD 
Stable Disease 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
STX 
Stereotactic Radiotherapy  
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T-DM1 
Trastuzumab-DM1 
T-DXd 
Trastuzumab-Deruxtecan 
TEAE 
Treatment-emerging adverse event 
TILs 
Tumour-Infiltrating Lymphocytes 
TMF 
Trial Master File 
TKI 
Tyrosine-Kinase Inhibitor 
WBC 
White Blood Cells 
WBRT 
Whole Brain Radiotherapy 
WHO 
World Health Organization 
 
 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ............................................................................................................. 4 
1. 
BACKGROUND ............................................................................................................. 22 
1.1 
BREAST CANCER BRAIN METASTASES................................................................................ 22 
1.2 
TRASTUZUMAB-DERUXTECAN BACKGROUND AND RATIONAL ......................................... 25 
2. 
STUDY DESIGN ............................................................................................................. 30 
2.1 
STUDY OBJECTIVES ............................................................................................................ 30 
3. 
STUDY DURATION ........................................................................................................ 31 
4. 
NUMBER OF CENTRES .................................................................................................. 31 
5. 
SELECTION CRITERIA .................................................................................................... 32 
5.1. 
TOTAL NUMBER OF PATIENTS ........................................................................................... 32 
5.2. 
INCLUSION CRITERIA ......................................................................................................... 32 
5.3. 
EXCLUSION CRITERIA ......................................................................................................... 33 
6. 
DISEASE EVALUATION .................................................................................................. 35 
6.1 
PRIMARY ACTIVITY PARAMETERS ...................................................................................... 35 
7. 
STUDY MEDICATION .................................................................................................... 38 
7.1 
TRASTUZUMAB-DERUXTECAN........................................................................................... 38 
8. 
SCREENING, ELIGIBILITY & TREATMENT ........................................................................ 40 
8.1 
STUDY TREATMENT ........................................................................................................... 40 
8.2 
STUDY PROCEDURES.......................................................................................................... 40 
8.3 
DOSE CONTINUATION, MODIFICATION & INTERRUPTION ................................................ 40 
8.4 
TREATMENT COMPLIANCE ................................................................................................ 51 
8.5 
CONCOMITANT THERAPY .................................................................................................. 51 
9. 
PREMATURE WITHDRAWAL ......................................................................................... 52 
9.1 
PREMATURE TRIAL TERMINATION .................................................................................... 52 
9.2 
REPLACEMENT POLICY ....................................................................................................... 52 
10. 
STATISTICAL CONSIDERATIONS................................................................................. 52 
10.1 
SAMPLE SIZE CALCULATION ............................................................................................... 52 
10.2 
EFFICACY ............................................................................................................................ 54 
10.3 
TOLERABILITY & SAFETY .................................................................................................... 54 
10.4 
QUALITY-OF-LIFE ............................................................................................................... 55 
10.5 
EXPLORATORY ENDPOINTS ................................................................................................ 55 
10.6 
ANALYSIS PLAN .................................................................................................................. 55 
10.7 
RELEVANT PROTOCOL DEVIATIONS ................................................................................... 55 
10.8 
MISSING, UNUSED AND SPURIOUS DATA .......................................................................... 55 
11. 
SAFETY .................................................................................................................... 55 

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11.1 
ADVERSE EVENTS ............................................................................................................... 55 
11.2 
SERIOUS ADVERSE EVENTS ................................................................................................ 56 
11.3 
ADVERSE EVENT OF SPECIAL INTEREST .............................................................................. 57 
11.4 
CLASSIFICATION OF SEVERITY ............................................................................................ 58 
11.5 
CLASSIFICATION OF RELATIONSHIP/CAUSALITY OF ADVERSE EVENTS (AE/SAE) TO IMP .. 59 
11.6 
SAE AND SUSAR REPORTING.............................................................................................. 59 
11.7 
PREGNANCIES .................................................................................................................... 60 
12. 
QUALITY CONTROL & QUALITY ASSURANCE .............................................................. 61 
12.1 
PERIODIC MONITORING .................................................................................................... 61 
12.2 
AUDITS & INSPECTIONS ..................................................................................................... 62 
12.3 
PUBLICATION OF STUDY RESULTS ..................................................................................... 62 
13. 
ETHICAL & LEGAL ASPECT ......................................................................................... 62 
13.1 
INFORMED CONSENT OF SUBJECTS ................................................................................... 62 
13.2 
ACKNOWLEDGEMENT/APPROVAL OF THE STUDY ............................................................ 62 
13.3 
PROTOCOL AMENDMENTS ................................................................................................ 63 
13.4 
STUDY TERMINATION ........................................................................................................ 63 
13.5 
CLINICAL STUDY REPORT (CSR) .......................................................................................... 63 
13.6 
FINANCE & INSURANCE ..................................................................................................... 63 
13.7 
ETHICS AND GOOD CLINICAL PRACTICE (GCP) ................................................................... 64 
14. 
APPENDICES ............................................................................................................ 65 

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FIGURE 1 STUDY FLOW 
 
 
 

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TABLE 1 VISIT AND ASSESSMENT SCHEDULE 
 
 
 
SCR 
Cycle 1 
Cycle 2  
Cycle 3  
Cycle 4 and 
subsequent 
cycles Day 1 
EOT  
Safety 
F/U (4 
weeks 
after 
EOT)  
OS  
F/U 
at 3, 
9, 18 
and 
30 m 
Day  
1 
Day  
8 
Day 
 15 
Day  
1 
Day  
1 
-21 days  
BI(a) 
EOI 
(±1 day) 
(±1 day) 
BI(a) 
EOI 
BI(a) 
EOI 
BI(a) 
E
OI 
 
 
 
Medical history  
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Antibody Test 
(b) 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B/C 
serology (b)  
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (c)  
 
● 
 
 
 
 
 
 
 
 
 
 
● 
 
 
Vital Signs 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
● 
● 
 
Physical 
Examination 
● 
● 
 
 
 
● 
 
● 
 
● 
 
● 
● 
 
SpO2 
● 
● 
 
 
 
● 
 
● 
 
● 
 
● 
● 
 
Height 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, ECOG PS 
● 
● 
 
 
 
● 
 
● 
 
● 
 
● 
● 
 
Hematology 
& 
Blood 
Chemistry 
Tests (d) 
● 
● 
 
● 
● 
● 
 
●  
 
● 
 
● 
● 
 

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SCR 
Cycle 1 
Cycle 2  
Cycle 3  
Cycle 4 and 
subsequent 
cycles Day 1 
EOT  
Safety 
F/U (4 
weeks 
after 
EOT)  
OS  
F/U 
at 3, 
9, 18 
and 
30 m 
Day  
1 
Day  
8 
Day 
 15 
Day  
1 
Day  
1 
-21 days  
BI(a) 
EOI 
(±1 day) 
(±1 day) 
BI(a) 
EOI 
BI(a) 
EOI 
BI(a) 
E
OI 
 
 
 
Troponin (ed) 
● 
 
 
 
 
 
 
 
 
 
 
● 
 
 
ECHO or MUGA 
(LVEF) (fe) 
●(bf) 
 
 
 
 
 
 
 
 
● 
 
● 
 
 
12-lead ECG in 
triplicate (g) 
● 
● 
 
 
 
 
 
 
 
 
 
●  
 
 
CT-chest/abdomen 
(h) 
● 
 
 
 
 
 
 
●(i) 
 
Before 
cycle 5 and 
every 9 
weeks 
thereafter 
(i,j) 
 
 
 
 
Cranial MRI 
● 
 
 
 
 
 
 
● (i) 
 
Before 
cycle 5 and 
every 9 
weeks 
thereafter 
(i,j) 
 
 
 
 
Quality-of-Life 
 
● 
 
 
 
 
 
● 
 
Before 
cycle 5 and 
every 9 
weeks 
thereafter  
 
● 
 
Final 
QoL 
analy
sis at 
3 
mont
hs 
Bone Scan (h) 
● 
 
 
 
 
 
 
 
 
Whenever 
clinically 
indicated 
 
 
 
 

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SCR 
Cycle 1 
Cycle 2  
Cycle 3  
Cycle 4 and 
subsequent 
cycles Day 1 
EOT  
Safety 
F/U (4 
weeks 
after 
EOT)  
OS  
F/U 
at 3, 
9, 18 
and 
30 m 
Day  
1 
Day  
8 
Day 
 15 
Day  
1 
Day  
1 
-21 days  
BI(a) 
EOI 
(±1 day) 
(±1 day) 
BI(a) 
EOI 
BI(a) 
EOI 
BI(a) 
E
OI 
 
 
 
Ophthalmologic 
Assessments (k) 
●(b) 
 
 
 
 
 
 
 
 
 
 
● 
 
 
Urinalysis 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue Sample for 
Biomarker Studies 
(l) 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Samples for 
Ancillary Studies 
 
● 
 
 
 
 
 
 
 
● 
 
● 
 
 
Concomitant 
Medications  
● 
 
AEs 
● 
 
Survival F/U 
 
● 
 
a Within 3 days before administration 
b Within 28 days before randomization/enrollment 
c Within 72 hours before enrollment for all female subjects of childbearing potential; a positive urine pregnancy test result must immediately be confirmed using a serum test. Perform repeat pregnancy tests (urine or serum test per 
institutional guideline) 72 hours before infusion of each cycle and at end of treatment.   
 
d Laboratory tests include: Hematology - red blood cell count, hemoglobin, hematocrit, platelet count, white blood cell count, differential white blood cell count (neutrophils,  
lymphocytes, monocytes, eosinophils, basophils) and Chemistry - total protein, albumin, ALP, ALT, AST, total bilirubin, BUN, Ca, Cl, serum creatinine, LDH, K, Na and magnesium 
e Collect blood samples for troponin (preferably high-sensitivity troponin-T) at screening, EOT, and if at any time a subject reports signs or symptoms suggesting congestive heart failure, myocardial infarction, or other causes of 
myocyte necrosis.  
f ECHO or MUGA scan assessments (note: the same test must be used for the subject throughout the study) will be performed at Screening and BI on Day 1 of Cycle 5 and then every 4 cycles (±7 days) (e.g. Cycle 5, 9, 13…) 
g ECGs will be taken in close succession, while in a supine/semi-recumbent position 
h With further workup as indicated  
i Within 10 days before the next treatment cycle 
j Staging investigations should be conducted whenever disease progression is suspected 
k Ophthalmologic assessments including visual acuity testing, slit lamp examination and fundoscopy will be performed at screening and EOT 
l Tissue should be collected from the primary tumour or (preferentially)from a metastatic biopsy  
 

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For suspected ILD/pneumonitis, study drug should be interrupted pending evaluation, which should include: 
• 
high resolution CT  
• 
pulmonary consultation (Infectious Disease consultation as clinically indicated)  
• 
Blood culture and CBC. Other BLOOD tests could be considered as needed 
• 
Consider bronchoscopy and bronchoalveolar lavage if clinically indicated and feasible 
• 
pulmonary function tests and pulse oximetry (SpO2) 
• 
arterial blood gases if clinically indicated  
• 
one blood sample collection for PK analysis as soon as ILD/pneumonitis is suspected, if feasible 
Other tests could be considered as needed. 
 
 
 
 

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1. BACKGROUND 
1.1 
BREAST CANCER BRAIN METASTASES 
Up to 15% of all patients with metastatic breast cancer (MBC) will develop brain metastases (BM) 
during their course of disease, making MBC after lung cancer the second most common cause of 
BM among solid malignancies [1]. Incidence of MBC BM has been rising over the last years 
commonly attributed to the tremendous progress of systemic therapy resulting in prolonged 
overall survival (OS) of MBC patients with human epidermal growth factor receptor 2 (HER2) 
positive disease [2] and a hypothetical shift to more aggressive courses of MBC in patients 
recurring after optimal adjuvant treatment [3]. Screening of asymptomatic patients and in 
consequence the more frequent diagnosis of a- to oligosymptomatic patients might be further 
attributing to the increasing incidence of breast cancer (BC) BM patients.  Prognosis of patients 
with BM remains poor with median OS times ranging from 2 to 16 months and differs greatly 
depending on the BC subtype [1]. 
In daily clinical practice, BC subtypes are classified as luminal, triple-negative, and HER2-positive 
as defined by the expression of the oestrogen- (ER) and/or progesterone-receptor (PR) and HER2 
overexpression as defined by immunohistochemistry and/or HER2/neu gene amplification [4 ,5]. 
Treatment of different BC subtypes differs substantially since endocrine therapy (ET) is the 
standard-of-care for luminal disease and HER2-targeted treatment plays a pivotal role in HER2-
positive BC. Chemotherapy remains the backbone of treatment for triple-negative breast cancer 
(TNBC) patients with inhibitors of PARP and PD-L1 just recently introduced. Patients with triple-
negative tumours are at greatest risk for being diagnosed with BM followed by patients with 
HER2-positive disease [6]. In addition to BM incidence, brain metastases free survival (BMFS) was 
shown to differ between subtypes as well [7]. 
Treatment decisions in BM patients should be based on clinical characteristics such as Karnofsky 
performance score, age, number of BM and the status of extracranial disease [8]. Local therapy 
(surgical resection, stereotactic radiosurgery (SRS) und whole brain radiotherapy (WBRT)) remains 
the mainstay of treatment, especially for symptomatic patients with a need for rapid symptom 
relief [8,9]. By contrast, about 20% of BC patients are diagnosed with asymptomatic BM which 
may have a better prognosis [10]. For these patients, systemic treatment has become an 
attractive alternative approach since long-term toxicity of WBRT can be postponed. In certain 

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areas of BM, the blood-brain barrier (BBB) is disrupted and replaced by a blood-tumour barrier 
with higher fenestration of the endothelium allowing bigger molecules to penetrate the brain 
parenchyma [11,12]. 
1.1.1. Lapatinib as upfront systemic therapy for BM 
The prospective non-comparative single-arm phase II LANDSCAPE trial accrued 45 patients with 
HER2-positive BC and newly diagnosed BM; more than 40% of all patients had no neurological 
symptoms at diagnosis, therefore representing an asymptomatic screening population [13]. CNS 
response rate was specified as the primary study endpoint and defined as a 50% or greater 
volumetric reduction of CNS lesions in the absence of increased steroid use, progressive 
neurological symptoms, or progressive extra-cranial disease. At a median follow-up of 21.2 
months, CNS response rate in this selected population was 65.9% (95% CI 50.1-79.5) and PFS 5.5 
months (95% CI 4,3-6). Other relevant secondary endpoints included time-to-WBRT (8.3 months; 
95% CI 5.4-9.1) and OS (17.0 month; 95%CI 13.7-24.9). On the downside, 49% of all study subjects 
experienced grade 3/4 adverse events indicative of relevant toxicity while no quality-of-life data 
are available. Despite this, LANDSCAPE defined a potential new treatment standard for patients 
with multiple BM without severe neurological symptoms. 
1.1.2. Neratinib and Tucatinib in BM 
Neratinib is a second generation (irreversible) TKI of HER2 and EGFR. The direct activity of 
neratinib in HER2-positive BC BM was evaluated in a multicohort prospective phase II trial 
(TBCRC022) including forty patients whose BM had progressed on prior local therapy (78% WBRT) 
[14]. In this study, however, activity of single agent neratinib was disappointing with a CNS 
response rate of 8%; median PFS was 1.9 months. Another cohort of this phase II study evaluated 
the combination of neratinib and capecitabine (with upfront loperamide prophylaxis) [15]. Thirty-
seven patients with progressive BM were included. A CNS response rate of 49% (95% CI 32-66%) 
was reported; PFS and OS were 5.5 and 13.5 months, respectively, indicating relevant clinical 
activity. On the downside, grade 3 diarrhoea was observed in 32% of patients despite prophylaxis. 
Tucatinib (ONT-380) is a third generation HER2 TKI. In contrast to lapatinib and neratinib, this drug 
has only minor inhibitory activity against EGFR resulting in a lower diarrhoea-rate [16]. In a joint 
analysis of two phase Ib studies investigating different tucatinib-based combinations, the rate of 
patients with prolonged PFS (defined as PFS ≥16 months) was evaluated [17]. Overall, 22% of this 

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heavily pretreated population achieved prolonged disease control. Of note, 50% of these patients 
had BM at baseline indicating a promising activity of tucatinib in this patient subset. 
The prospective randomized phase II HER2CLIMB randomized 612 HER2-positive MBC patients to 
the triple combination of trastuzumab, capecitabine and tucatinib or trastuzumab, capecitabine 
and placebo [18]. Nearly half of these patients had a known history of brain metastases at 
baseline; importantly, approximately 40% of these had active (i.e. previously untreated or 
progressing) BM. In this heavily pretreated population (prior treatment with trastuzumab, 
pertuzumab and T-DM1 was required), a significant prolongation of progression-free survival (HR 
0.54; 95% CI 0.42-0.71; p=0.00001) and overall survival ()HR 0.66; 95% CI 0.5-0.88; p=0.0048) was 
observed in favour of the tucatinib group. In the subset of BM patients, a similar benefit in terms 
of PFS was reported (HR 0.48; 95% CI 0.34-069; p<0.00001) with 25% of patients free of 
progression at one year versus 0%. CNS response rates in patients with active BM, however, are 
still awaited.  
1.1.3. Trastuzumab-DM1 in BM 
Trastuzumab passes an impaired BBB at the site of BM while similar to lapatinib, no significant 
uptake of radioactively tagged trastuzumab in healthy brain tissue was observed [19]. In addition, 
there is currently no prove of direct activity of trastuzumab monotherapy in newly diagnosed or 
progressing BM. This led to growing interest regarding the potential activity of trastuzumab-DM1 
(T-DM1), an antibody-drug-conjugate linking the anti-microtubule-agent DM1 to trastuzumab.  
The phase III EMILIA trial compared T-DM1 with lapatinib plus capecitabine in the second-line 
setting and in first-line patients progressing on adjuvant trastuzumab or within six months since 
the end of adjuvant immunotherapy; inclusion of patients with stable BM after local therapy was 
allowed [20]. In the overall population, T-DM1 was associated with a significant and clinically 
relevant advantage over lapatinib plus capecitabine in terms of PFS (9.6 vs. 6.4 months; HR 0.65; 
95% CI 0.55-0.77; p<0.001) and OS (30.9 vs. 25.1 months; HR 0.68; 95% CI 0.55-0.85; p<0.001). In 
patients with stable BM at baseline (n=95), superiority of T-DM1 was maintained although not 
surprisingly, OS in absolute numbers was shorter in both arms (26.8 vs. 12.0 months; HR 0.38; 
p=0.008) [21]. 
Meanwhile, several reports and case series suggested clinically relevant activity of T-DM1 in newly 
diagnosed or progressive BM. In a population of ten patients with HER2-positive BM, T-DM1 was 

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administered as upfront therapy for newly diagnosed BM (n=2) or upon progression of BM after 
prior local therapy (n=8) [22]. Thus, this analysis allowed for an appraisal of the direct activity of 
T-DM1 in BM. A partial remission as defined by RANO BM response criteria (decrease in the sum 
of longest diameters of CNS target lesions of at least 30% sustained for at least 4 weeks in the 
absence of new lesions, increased corticosteroid dose and/or clinical deterioration [23]) was 
observed in three patients (PR, 30%), while disease stabilization of ≥6 months was reported in 
two additional subjects, resulting in a clinical benefit rate (CR, PR, SD ≥6 months) of 50%. In 
addition, two further patients experienced stable disease ≥3 months but <6 months. Of note, 
activity was not restricted to patients with newly diagnosed BM as one of the two responders and 
both patients with SD ≥6 months had progressive BM at baseline. At a median follow-up of 8.5 
months, intracranial PFS was 5 months (95% CI 3.69-6.32), and median OS from initiation of T-
DM1 based treatment had not been reached. Another retrospective study included thirty-nine 
patients from five French centres [24]. Patients had received a median of two prior HER2-directed 
treatment lines for metastatic disease and 36 patients had received prior local therapy as well, 
consisting mostly of WBRT (72%). In this pretreated population, a response rate of 44 % was 
reported; median PFS was 6.1 months (95 %CI 5.2–18.3). These clinical data are supported by a 
preclinical model of trastuzumab or T-DM1 at equivalent doses in female nude mice with BM [25]. 
Median survival in mice bearing BM generated with the luminal B/HER2-positive BT474 cell line 
was 28 days for trastuzumab and 112 days for T-DM1 (HR 6.2; 95% 6.1-85.84; p<0.001). In 
addition, a significantly higher rate of tumour cell apoptosis was observed in the T-DM1 group. 
In summary, these clinical and preclinical data suggest that T-DM1 harbours clinically relevant 
activity in MBC BM; the prospective phase II KIARA (Kadcyla In pAtients With bRAin Metastasis) 
trial (NCT03203616) intended as prospective verification of this concept, however, was recently 
stopped due to poor accrual. Concurrent administration of T-DM1 and radiosurgery, on the other 
hand, may not be advisable as a rate of irradiation necrosis of 50% was observed in another small 
retrospective case series [26].  
1.2 
TRASTUZUMAB-DERUXTECAN BACKGROUND AND RATIONAL 
1.2.1. Trastuzumab-Deruxtecan 
Trastuzumab-deruxtecan (T-DXd) is a antibody-drug conjugate consisting of a humanized HER2-
directed monoclonal antibody (MAAL-9001) with the same amino acid sequence as trastuzumab 

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and the cytotxocic agent deruxtecan (MAAA-1181a), a potent inhibitor of topoisomerase I with a 
drug to antibody ratio of 8 [27]. 
- Preclinical Data 
Results of in vitro cell growth inhibition studies conducted using several cancer cell lines have 
shown that T-DXd has a more potent growth inhibitory effect against HER2-positive cells than 
MAAL-9001 does, suggesting that the conjugation of MAAA-1181a enhances the growth inhibition 
of T-DXd. Moreover, no growth inhibition was observed in HER2-negative cells, confirming the 
HER2 specificity of T-DXd. Similarly, when the in vivo antitumor activity of T-DXd in a tumour-
bearing mouse model of a HER2-positive gastric cancer cell line (NCI-N87) was studied, it was 
confirmed that the drug exhibited potent, dose-dependent antitumor activity with tumour 
regression and that this activity was even stronger than that of MAAL-9001. T-DXd also exhibited 
antitumor activity in a tumour-bearing mouse model of human breast cancer cell line (KPL-4). Of 
note, T-DXd demonstrated more potent antitumor activity than T-DM1 in several mouse 
xenograft models of breast and gastric cancer. 
Information regarding safety pharmacology, pharmacokinetics and toxicology are provided in the 
IB [27]. 
- Clinical Data: Clinical Pharmacology 
Preliminary PK data from the Dose Escalation part of the DS8201-A-J101 study showed that the 
Cmax of T-DXd was dose proportional across the dose range of 0.8 mg/kg to 8.0 mg/kg. The area 
under the serum concentration-time curve up to the last quantifiable time (AUClast) increased 
greater than dose proportionally from 0.8 mg/kg to 3.2 mg/kg and then increased dose 
proportionally from 3.2 mg/kg and above. On a molar basis, T-DXd exposures at the 5.4-mg/kg 
dose were approximately 39-fold to 44-fold higher than those for MAAA-1181a. Preliminary PK 
data from the Dose Expansion part showed that the T-DXd, total anti-HER2 antibody, and MAAA-
1181a exposures were similar between HER2-positive and HER2-low breast cancer. The T-DXd and 
total anti-HER2 antibody exposures appeared to be numerically lower in HER2-positive 
gastric/gastroesophageal junction (GEJ) cancer than in breast cancer. MAAA-1181a exposures 
were consistent across all tumour types evaluated. 
Preliminary PK data of the DS8201-A-U201 study showed that the ratio of T-DXd and total anti-
HER2 antibody was approximately 1 for Cmax and approximately 0.8 for AUC and trough 

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concentrations. The serum concentrations of MAAA-1181a gradually increased and reached peak 
concentrations, with longer median Tmax (approximately 7 hours) than those for T-DXd 
(approximately 4 hours). On a molar basis, the T-DXd Cmax and trough concentrations were 
approximately 54-fold and 74-fold higher, respectively, than those for MAAA-1181a. These results 
demonstrate the in vivo stability of the ADC. 
In the DS8201-A-J102 study, the concentration profile of total anti-HER2 antibody was similar to 
that of T-DXd. The exposure of MAAA-1181a was low compared with those of T-DXd and total 
anti-HER2 antibody. The mean accumulation ratio (AR) for area under the plasma concentration-
time curve during dosing interval (AUCtau) at Cycle 3 was 1.35 for T-DXd, 1.36 for total anti-HER2 
antibody, and 1.09 for MAAA-1181a. 
The concentration profile of total anti-HER2 antibody was similar to that of T-DXd in study 
DS8201-A-A103. Some accumulation (approximately 57%) of T-DXd was observed at Cycle 3. The 
systemic exposure to MAAA-1181a was lower than that of T-DXd, but t1/2 values were similar 
across the 3 analytes. 
Final PK data from DS8201-A-A104 showed that concomitant use of ritonavir or itraconazole 
resulted in minimal increases in exposure of MAAA-1181a, with increases in area under the 
concentration-time curve up to 17 days (AUC17d) of 22% and 18%, respectively. Concomitant use 
of ritonavir or itraconazole resulted in minimal increases in exposure of T-DXd, with increases in 
AUC17d of 19% and 11%, respectively. The results indicate that concomitant use of ritonavir (dual 
inhibitor of OATP1B/CYP3A) or itraconazole (strong CYP3A inhibitor) would not result in clinically 
meaningful increases in exposures of T-DXd or MAAA-1181a. 
- Clinical Data: Efficacy 
DS8201-A-J101 
Preliminary efficacy results of this phase I trial showed confirmed objective RR (ORR) by 
independent central review (ICR) of 52.5% (95% confidence interval [CI]: 43.1, 62.0) among the 
118 subjects with HER2-positive breast cancer. RR was 51.0% (95% CI 36.6-65.2) in the 5.4-mg/kg 
dose group and 53.7% (95% CI 41.1-66.0) in the 6.4-mg/kg dose group, respectively. The median 
confirmed duration of response was 13.3 months and median PFS 13.7 months; median OS was 
not reached as of the data cut-off. 

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Among the 54 subjects with HER2-low breast cancer, confirmed objective RR was 37.0% (95% CI 
24.3-51.3). A median PFS of 11.1 months (95% CI 7.6-not estimable) and median OS was 29.4 
months (95% CI 12.9-29.4) war reported. Among the 44 subjects with HER2-positive gastric/GEJ 
cancer, confirmed objective RR was 29.5% (95% CI 16.8-45.2); median PFS was 5.4 months (95% 
CI 4.1-8.5) and median OS 20.2 months (95% CI 10.0-not estimable), respectively. Finally, in the 
group of 61 patients with other cancers, confirmed RR was 29.5% (95% CI 18.5-42.6). Median PFS 
was 7.2 months (95% CI 4.8-11.1) and median OS was 23.4 months (95% CI 15.6-not estimable). 
DESTINY-Breast01 
In the single-arm phase II trial DESTINY-Breast01, 253 pretreated HER2-positive MBC patients 
received T-DXd at different doses [28]. After PK and dose-finding stage, 5.4 mg/kg body once 
every three weeks weight was defined as the recommended dose for further development. All 
patients had received prior treatment with trastuzumab and T-DM1. In addition, two thirds had 
received prior pertuzumab and 54% other HER2-targeted agents as well; the median number of 
prior treatment lines was 6 (range 2-27). Efficacy analysis included 184 patients treated with 5.4 
mg/kg.  In this heavily pretreated population, a clinically relevant response rate of 60.9% was 
observed; median PFS was 16.4 months (95% CI 12.7-NE) and median OS not yet reached. In 24 
patients with stable brain metastases at baseline, activity was comparable (median PFS 18,1 
months; 95% CI 6.7-18.1 months). Based upon these results, no final conclusion regarding the 
activity T-DXd in active BM can be drawn; however, these data indicate that further investigation 
of this drug in breast cancer brain metastases is warranted.  
- Clinical Data: Safety 
As of June 8th 2019, based on the cumulative review of the safety data, including available 
nonclinical, clinical, and epidemiologic information and scientific literature (published and 
unpublished) and taking into consideration biological plausibility, interstitial lung disease (ILD), 
anaemia, neutrophil count decrease including febrile neutropenia, and platelet count decrease 
are classified as important identified risks. Left ventricular ejection fraction (LVEF) decrease is 
classified as an important potential risk. Infusion-related reactions, which were previously 
classified as an important potential risk, are reclassified as an identified risk. QT prolongation is 
no longer considered an important potential risk and has been removed from the list of safety 

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concerns for T-DXd. Both QT prolongation and infusion-related reactions are no longer considered 
adverse events of special interest (AESIs). 
In the T-DXd clinical program, the inclusion/exclusion criteria and monitoring/management 
guidelines are currently in place in all protocols to mitigate the important identified risks of ILD, 
anaemia, neutrophil count decrease including febrile neutropenia, and platelet count decrease, 
and important potential risk of LVEF decrease. 
Interstitial lung disease is a known serious risk of T-DXd, and cases with fatal outcomes have been 
reported. Most events were grade 1 or grade 2 and were manageable by dose modification and 
following clinical treatment guidelines for drug-induced ILD, with specific recommendations 
including close monitoring of signs/symptoms of ILD (e.g. cough, fever, and dyspnoea) to identify 
potential ILD and proactively managing ILD with dose modification, treatment interruption and 
application of immunosuppressive drugs 
Other identified risks of trastuzumab deruxtecan in order of descending frequencies are nausea, 
decreased appetite, alopecia, vomiting, fatigue, constipation, diarrhoea, white blood cell (WBC) 
count decrease, stomatitis, aspartate aminotransferase increased, cough, headache, abdominal 
pain, alanine aminotransferase increased, hypokalaemia, epistaxis, dyspnoea, dyspepsia, 
dizziness, dry eye, upper respiratory tract infection, asthenia, and infusion-related reactions. 
These identified risks were generally manageable through dose modification and routine clinical 
practice. 
1.2.2. Rationale for Performing the Study 
The conventional standard treatment of multiple BM is WBRT. With highly active HER2-directed 
drugs available today, prolonged survival >24 months despite the presence of BM is possible; such 
patients are therefore at risk of experiencing WBRT-associated neurological decline. TKIs such as 
lapatinib and neratinib and the ADC T-DM1 were shown to exert clinically relevant activity in both 
newly diagnosed BM and patients with BM progressing after prior local treatment. The 
combination of lapatinib or neratinib with capecitabine, however, is associated with a high rate 
of severe diarrhoea, thereby hampering the broad clinical use of these combination. In addition, 
T-DM1 is currently the standard-of-care in the second-line setting and also used as first-line 
therapy in patients with early progression on adjuvant trastuzumab when BM may not yet be 
present; increasingly T-DM1 is also being used in the postneoadjuvant setting based upon the 

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KATHERINE trial [29]. These facts render the development of novel active and well-tolerated drugs 
in the setting of HER2-positive BC patients with BM necessary. 
As outlined above, T-DXd is a highly active HER2-directed ADC showing relevant clinical activity 
even after progression on T-DM1 with a favourable safety profile. As the rate of patients with 
early T-DM1 exposure is expected to increase further in the future, T-DXd appears to be an 
attractive candidate for the evaluation in pretreated patients with brain metastases. Of note, 
results of the phase II DESTINY-Breast01 trial suggested that patients with stable brain metastases 
at the time of inclusion derived relevant clinical benefit from T-DXd. This single-arm phase II study 
was developed to evaluate the direct activity of trastuzumab-deruxtecan on HER2-positive 
multiple BM. 
 
2. STUDY DESIGN 
This is an open label, non-comparative, single-centre, phase II study to evaluate the efficacy and 
safety of trastuzumab-deruxtecan (T-DXd; DS-8201a) in HER2-positive breast cancer patients with 
newly diagnosed or progressing brain metastases who are deemed candidates for systemic 
therapy. In this trial, trastuzumab-deruxtecan will be administered at a dose of 5.4 mg/kg 
bodyweight on day one of each cycle once every three weeks until progression, inacceptable 
toxicity or withdrawal (Figure 1). Before the first administration of the IMP, a cranial MRI and a 
CT scan of chest and abdomen will be conducted with further workup if indicated. Staging 
investigations will be repeated before the third and fifth treatment cycle and every nine weeks 
thereafter or whenever symptoms of disease progression occur. 
2.1 
STUDY OBJECTIVES         
2.1.1. Primary Objective  
To evaluate the ability of trastuzumab-deruxtecan to induce CNS responses in patients with HER2-
positive breast cancer and newly diagnosed or progressive brain metastases. 
2.1.2. Secondary Objectives 
To evaluate the activity of trastuzumab-deruxtecan on extracranial disease, safety and tolerability 
of trastuzumab-deruxtecan in the patient population and QoL of study participants. 

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2.1.3. Exploratory Objectives 
To evaluate biomarkers associated with response to trastuzumab-deruxtecan. 
2.2. 
STUDY ENDPOINTS 
2.2.1. Primary Endpoints 
The primary endpoint of this study is the rate of best responses of BM at any assessment after 
the administration of at least one cycle of the IMP defined as CR, PR, SD and PD according to the 
RANO-BM criteria and as determined by the local investigator. 
2.2.2. Secondary Endpoints 
The secondary endpoints of this study consist of Clinical Benefit Rate CNS (CBR CNS as defined by 
RANO-BM; CR+PR+SD ≥6 months), extracranial response rate defines as CR, PR, SD and PD 
according to RECIST 1.1 criteria, progression-free survival defined as the interval from study 
inclusion until progression or death, time-to-WBRT defined as the interval from study inclusion 
until WBRT, overall survival defined as the interval from study inclusion until death, safety and 
QoL.  
2.2.3. Exploratory Endpoints 
Exploratory endpoints of this study include the number of HER/neu gene copies and the rate of 
TILs. For ancillary biomarker studies, blood samples (3 ml EDTA, 3 ml serum) will be drawn before 
administration of the IMP at cycles 1 and 4 and at EOT. 
 
3. STUDY DURATION 
• 
Duration of the study: 3 years 
• 
Recruitment period: 30 months 
• 
This study is expected to start in Q3 2020; last patient last visit (LPLV) is expected in Q3 2022. 
 
4. NUMBER OF CENTRES 
This is a single centre study conducted at the Medical University of Vienna/Vienna General 
Hospital, Department of Internal Medicine I, Division of Oncology. 

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5. SELECTION CRITERIA 
5.1. 
TOTAL NUMBER OF PATIENTS  
A maximum number of 15 evaluable patients will be enrolled based upon a Simon’s optimal two-
stage design; in stage 1, 6 patients will be accrued, with accrual of additional 9 patients up in stage 
2 according to the number of responses seen in stage 1. 
5.2. 
INCLUSION CRITERIA 
To be eligible for inclusion, each patient must fulfil all of the following criteria: 
• Histologically confirmed breast cancer 
• Radiologically documented metastatic disease 
• HER2-positive as defined by IHC 3+ and/or HER2/neu gene amplification 
• Newly diagnosed brain metastases or brain metastases progressing after prior local therapy 
• Measurable disease (RANO-BM criteria) 
• No indication for immediate local treatment 
• No indication of leptomeningeal disease 
• KPS >70%, ECOG <2 
• Indication for systemic anti-HER2 treatment 
• Prior exposure to trastuzumab and pertuzumab 
• Prior exposure to T-DM1 allowed 
• Life expectancy of at least 3 months 
• Age ≥18 years  
• Patient must be able to tolerate therapy, and have adequate cardiac function (defined by 
baseline left ventricular ejection fraction ≥50%)  

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• Adequate bone-marrow, liver and kidney function 
• Adequate treatment washout period before enrolment, defined as: 
• Major Surgery: ≥4 weeks 
• Radiation therapy: ≥4 weeks 
• Chemotherapy, small-molecule targeted agents, anticancer hormonal therapy: ≥3 weeks 
• Antibody-based treatment: ≥4 weeks 
• Patient must be capable of understanding the purpose of the study and have given written 
informed consent 
5.3. 
EXCLUSION CRITERIA 
Patients who fulfil any of the following criteria will be excluded: 
• Metastatic breast cancer other than HER2-positve disease 
• Use of any investigational agent within 28 days prior to initiation of treatment 
• History of malignancy other than squamous cell carcinoma, basal cell carcinoma of the skin or 
carcinoma in situ of the cervix within the last 3 years including contralateral breast cancer 
• Major surgery, other than diagnostic surgery, within the last 4 weeks 
• Indication for immediate local therapy by local standard 
• Leptomeningeal involvement 
• Other anticancer therapy, including cytotoxic, targeted agents, immunotherapy, antibody, 
retinoid, or anti-cancer hormonal treatment 
• Concomitant radiotherapy 
• Prior radiotherapy to the thorax other than breast irradiation or irradiation of bone metastases 
• A history of uncontrolled seizures, central nervous system disorders or psychiatric disability 
judged by the investigator to be clinically significant and adversely affecting compliance to 
study drugs 
• Clinically significant cardiac disease including unstable angina, acute myocardial infarction 
within six months prior to randomization, congestive heart failure (NYHA III-IV), left ventricular 

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ejection fraction <50%, arrhythmia unless controlled by therapy, with the exception of extra 
systoles or minor conduction abnormalities, and long QT syndrome (QTc interval >450 ms) 
• Subjects who have current active hepatic or biliary disease (with exception of patients with 
Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease 
per investigator assessment) including acute and chronic infections with hepatitis B and C 
• Inadequate haematological status at baseline prior to study entry: Dependency on red blood 
cell and/or platelet transfusions, ANC (absolute neutrophil count (segmented + bands) <1.0 x 
109/L; platelets <100 x 109/L 
• Inadequate kidney function: serum-creatinine >1.5 times upper normal limit  
• Hepatic dysfunction: total bilirubin >1.5 times upper normal limit (>3 in patients with liver 
metastases or known history of Gilbert’s disease); ALT, AST >3 times upper normal limit (>5 in 
patients with liver metastases); serum albumin <2.5 g/dL; INR ≥1.5 
• Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses 
including, but not limited to, any underlying pulmonary disorder (i.e. pulmonary emboli 
within three months of the study enrolment, severe asthma, severe COPD, restrictive lung 
disease, pleural effusion etc.), and any autoimmune, connective tissue or inflammatory 
disorders with pulmonary involvement (i.e. rheumatoid arthritis, Sjogren's syndrome, 
sarcoidosis etc.), or prior pneumonectomy 
• Subjects with bronchopulmonary disorders who require intermittent use of bronchodilators 
(such as albuterol) will not be excluded from this study 
• Patients with active opportunistic infections 
• Known HIV infection 
• Concomitant treatment with chloroquine or hydroxychloroquine 
• Pregnant or lactating women. Women with childbearing potential must have a negative 
pregnancy test at screening 
• Women with childbearing potential, including women whose last menstrual period was less 
than one year prior to screening, unable or unwilling to use adequate contraception from study 

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start to one year after the last dose of protocol therapy. Acceptable contraception methods 
included the application of an intrauterine device, barrier method or total abstinence 
• Patients with known hypersensitivity to trastuzumab 
• Patients not able to provide written informed consent 
• Patients with known substance abuse or any other medical conditions such as clinically 
significant cardiac or psychological conditions, that may, in the opinion of the investigator, 
interfere with the subject’s participation in the clinical study or evaluation of the clinical study 
results 
• Patients requiring concomitant use of chronic systemic (IV or oral) corticosteroids at doses 
higher than 4 mg dexamethasone per day or other immunosuppressive medications except for 
managing adverse events; (inhaled steroids or intra articular steroid injections are permitted 
in this study) 
 
6. DISEASE EVALUATION  
6.1 
PRIMARY ACTIVITY PARAMETERS 
Response to treatment will be assessed for the first time within ten days before the third 
administration of trastuzumab-deruxtecan. At this assessment, a cranial MRI and a CT-scan of the 
chest and abdomen/pelvis will be performed with further workup if indicated. Any other 
instrumental investigations found to be abnormal at baseline evaluation prior to study entry will 
be repeated.                 
Patients with complete remission, partial response or stable disease will continue treatment per 
protocol, while patients progressing will be taken off study (at the assessment time points during 
the treatment period of the study).  
2nd assessment: The second response assessment will be conducted within ten days before the 
fifth administration of trastuzumab-deruxtecan 
Further assessment: Further response assessments will be conducted every nine weeks (e.g. 
before the eight, eleventh, fourteenth cycle) 

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In addition, reassessment should always be performed in case of symptoms indicating disease 
progression. 
6.1.1 
Response criteria (BM) 
The rate of objective responses of BM will be assess using objective radiological criteria 
(Response Assessment in Neuro-Oncology; RANO) [23] according to the definitions of CR, PR, SD 
and PD. 
Target lesions 
• 
Complete remission (CR): Disappearance of all CNS target lesions sustained for at least 4 
weeks; with no new lesions, no use of corticosteroids, and patient is stable or improved 
clinically. 
• 
Partial remission (PR): At least a 30% decrease in the sum longest diameter of CNS target 
lesions, taking as reference the baseline sum longest diameter sustained for at least 4 
weeks; no new lesions; stable to decreased corticosteroid dose; stable or improved 
clinically. 
• 
Stable disease (SD): Neither sufficient shrinkage to qualify for partial response nor sufficient 
increase to qualify for progressive disease, taking as reference the smallest sum longest 
diameter while on study. 
• 
Progressive disease (PD): At least a 20% increase in the sum longest diameter of CNS target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative increase of 20%, at least one lesion must 
increase by an absolute value of 5 mm or more to be considered progression. 
Non-target lesions 
• 
Complete remission (CR): Requires all of the following: disappearance of all enhancing CNS 
non-target lesions, no new CNS lesions. 
• 
Non-CR/Non-PD: Persistence of one or more non-target CNS lesion or lesions. 
• 
Progressive disease (PD): Any of the following: unequivocal progression of existing enhancing 
non-target CNS lesions, new lesion(s) (except while on immunotherapy-based treatment), or 
unequivocal progression of existing tumour-related non-enhancing (T2/FLAIR) CNS lesions. In 
the case of immunotherapy-based treatment, new lesions alone may not constitute 
progressive disease. 

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6.1.2 
Response criteria (extracranial disease) 
The rate of objective extracranial responses will be assessed using objective radiological criteria 
(Response Evaluation Criteria In Solid Tumors; RECIST 1.1) [30] in patients with measurable 
disease according to the definitions of CR, PR, SD and PD. 
Target lesions: 
• 
Complete remission (CR):  Disappearance of all target lesions. Any pathological lymph node 
(whether target or non-target) must have reduction in short axis to <10 mm. 
• 
Partial remission (PR): At least a 30% decrease in the sum of diameter of target lesions, taking 
as reference the baseline sum diameters. 
• 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameter while on study. 
• 
Progressive disease (PD): At least 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest sum on study) In addition of to the relative increase of 20 percent, the sum must also 
demonstrate an absolute increase  of at least 5 mm. The appearance of 1 or more new lesions 
is also considered progression.  
Non-target lesions: 
• 
Complete remission (CR): Disappearance of all non-target lesions and normalisation of 
tumour marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). 
• 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumour marker level above normal limits. 
• 
Progressive disease (PD):  Unequivocal progression of existing non-target lesions. The 
appearance of one or more new lesions is also considered progression. 
Patients progressing during treatment will be taken off study and treated at the judgement of the 
clinician. Patients progressing in the brain may continue on trastuzumab-deruxtecan after local 
therapy in the absence of extracranial disease progression. 
 

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7. STUDY MEDICATION   
7.1 
TRASTUZUMAB-DERUXTECAN 
See also 1.2 “Trastuzumab-Deruxtecan Background and Rationale” 
7.1.1 
Formulation 
Trastuzumab deruxtecan drug product is supplied in a single-use vial as 100 mg of DS-8201a in a 
sterile lyophilized powder dosage form (Lyo-DP) to be reconstituted with 5 mL of water for 
injection to 20 mg/mL, manufactured using DS2. Lyo-DP is a sterile lyophilized powder in an amber 
glass vial for intravenous infusion. Prior to use, Lyo-DP is reconstituted with 5 mL of water for 
injection to provide a solution with the concentration of 20 mg/mL DS-8201a in a buffer 
containing L-histidine, L-histidine hydrochloride monohydrate, sucrose, and polysorbate 80. Each 
vial contains 100 mg of DS-8201a. 
7.1.2 
Preparation 
The instructions for the preparation of the trastuzumab-deruxtecan solution are found in the 
pharmacy instructions or in the IB. 
7.1.3. Therapeutic regimen and dose 
Trastuzumab-deruxtecan is administered at a dose of 5.4 mg/kg bodyweight as an intravenous 
infusion every 3 weeks (21-day cycle). First administration should occur a maximum of 7 days after 
enrolment. 
The initial dose should be administered as a 90 minutes intravenous infusion. Patients should be 
observed during the infusion and for at least 90 minutes following the initial infusion for fever, 
chills, or other infusion-related reactions. The infusion site should be closely monitored for 
possible subcutaneous infiltration during administration. If the prior infusion was well tolerated, 
subsequent doses of T-DXd may be administered as 30 minutes infusions. 
Patients should be observed during the infusion and for at least 30 minutes after infusion. The 
infusion rate of T-DXd should be slowed or interrupted if the patient develops infusion-related 
symptoms. T-DXd should be discontinued in case of life-threatening infusion reactions. Medicinal 
products to treat allergic/anaphylactic infusion reactions, as well as emergency equipment should 
be available for immediate use at site. 

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T-DXd is administered until disease progression (either in the brain or systemic), intolerable 
toxicity or subject withdrawal. Patients that progress in the brain but still have controlled systemic 
disease, and who receive local brain treatment, can continue to receive trastuzumab-deruxtecan 
off study until systemic progression after receiving local treatment. 
7.1.4. Packaging & Labelling 
The sponsor is responsible for providing the shipping orders. T-DXd will be provided by the 
manufacturer and labelled by the sponsor of this trial. 
The IMP will be provided free of charge to the sponsor in individual pharmaceutical packings. Each 
pharmaceutical packing will identify the contents as study medication and bear protocol number.  
In addition, the label will bear the sponsors name, quantity contained, a package number and the 
standard caution statement as follows: Caution: New drug - Limited by Federal law to 
investigational use.  The study drug label must be clearly visible. 
7.1.5. Receipt of study drug 
The hospital pharamcist is responsible for taking an inventory of each shipment of study drug 
received and for comparing it with the accompanying study drug accountability form.  The 
pharmacist will verify the accuracy of the information on the form, sign, and date it, retain a copy 
in the study file.  The numbers of pharmaceutical packings must be recorded when drug is 
received and dispensed. 
7.1.6. Storage 
Trastuzumab-deruxtecan will be stored at the hospital pharmacy in a secure area in accordance 
with Good Clinical Practice (GCP) and Good Manufacturing Practice (GMP) requirements and must 
be accessible to authorised personnel only. The storage condition for Lyo-DP is 2°C to 8°C 
(protected from light). 
7.1.7. Unused study drug supplies 
Unused study drug will be destroyed due to local SOPs.  If any study drug is lost or damaged, its 
disposition should be documented in the source documents and Drug Dispensing Log.   
 

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8. SCREENING, ELIGIBILITY & TREATMENT 
The Investigator is responsible for keeping a record of all subjects who sign an Informed Consent 
Form for entry into the study. All participants will be screened for eligibility. Investigations at 
baseline and during the study are outlined in Table 1. Study Assessments, unless otherwise 
specified, must take place within 21 days prior to initiation of therapy. Screening pregnancy tests 
for women of child-bearing potential must occur within three days before first application of IMP.  
8.1 
STUDY TREATMENT 
In this trial, T-DXd will be administered at a dose of 5.4 mg/kg bodyweight once every three weeks 
by intravenous infusion until disease progression, inacceptable toxicity or withdrawal. A detailed 
summary of assessment schedules is provided in Table 1 and section 6.1. 
8.2 
STUDY PROCEDURES 
Table 1 provides a detailed overview of study procedures at baseline (within 21 days of the first 
administration of the study drug) and the required investigations during the study. cMRI and CT 
of chest and abdomen required for study inclusion need not to be repeated if the interval from 
the investigation to the first administration of the study drug is ≤21 days. In women of 
childbearing potential, a pregnancy test not older than 72 hours is required before the first 
administration of the study drug. 
8.3 
DOSE CONTINUATION, MODIFICATION & INTERRUPTION    
Subjects will be evaluated for AEs at each visit with the NCI CTCAE version 5.0 used as a guide for 
the grading of severity. 
All dose modifications (interruption, reduction and/or discontinuation) should be based on the 
worst preceding toxicity (NCI CTCAE version 5.0). Specific criteria for interruption, re-initiation, 
dose reduction and/or discontinuation of trastuzumab deruxtecan are listed in table below, which 
is applicable only to TEAEs that are assessed as related to use of T-DXd by the investigator(s). For 
non-drug related TEAEs, standard clinical practice should be followed. In addition, appropriate 
clinical experts should be consulted as deemed necessary.    
8.3.1. Dose Reduction Levels of Trastuzumab-deruxtecan 
 

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Starting Dose 
Dose Level -1 
Dose Level -2 
5.4 mg/kg bodyweight 
 
4.4 mg/kg bodyweight 
 
3.2 mg/kg bodyweight 
 
 
Once the dose of T-DXd has been reduced because of toxicity, all subsequent cycles should be 
administered at that lower dose level unless further dose reduction is required.  More than 2 dose 
reductions are not allowed, and the subject will be withdrawn from the study treatment if further 
toxicity meeting the requirement for dose reduction occurs. T-DXd dose increases are not allowed 
in the study. 
8.3.2. Dose Interruption and Modification /Toxicity Management Guidelines 
A dose can be delayed for up to 28 days (Cycle Day 50) from the planned date of administration.  
If a subject is assessed as requiring a dose delay of longer than 28 days, the subject will be 
withdrawn from the study. 
Treatment cycles for a subject for whom T-DXd dosing is temporarily withheld for any reason may 
have future cycles scheduled based on the date of the last T-DXd dose. All confirmed infections 
with SARS-CoV2 must be recorded in the study clinical database. 
 
Worst toxicity CTCAE v5.0 Grade  
(unless otherwise specified) 
Dose or schedule modification for DS-8201a 
No toxicity 
Maintain dose and schedule 
Infusion-Related Reaction 
Grade 1  
(Mild transient reaction; infusion 
interruption not indicated; intervention 
not indicated) 
If infusion related reaction (such as fever and chills, with 
and without nausea/vomiting, pain, headache, dizziness, 
dyspnea, hypotension) is observed during administration, 
the infusion rate should be reduced by 50% and subjects 
should be closely monitored.  
If no other reactions appear, the subsequent infusion rate 
could be resumed at the initial planned rate.  
Grade 2  
(Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, nonsteroidal anti-
inflammatory drugs (NSAIDs), narcotics, 
Administration of DS-8201a should be interrupted and 
symptomatic treatment started (e.g. antihistamines, 
NSAIDs, narcotics, IV fluids). 
If the event resolves or improves to grade 1, infusion can be 
re-started at a 50% reduced infusion rate. 

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Worst toxicity CTCAE v5.0 Grade  
(unless otherwise specified) 
Dose or schedule modification for DS-8201a 
IV fluids); prophylactic medications 
indicated for ≤ 24 hrs) 
Subsequent administrations should be conducted at the 
reduced rate. 
Grade 3 or 4  
(Prolonged or life-threatening 
consequences, urgent intervention 
indicated) 
Administration of DS-8201a should be discontinued 
immediately and permanently. 
Urgent intervention indicated.  Antihistamines, steroids, 
epinephrine, bronchodilators, vasopressors, intravenous 
fluid therapy, oxygen inhalation etc., should be 
administered. 
Hematologic Toxicity 
Neutrophil Count Decrease and/or White Blood Cell Count Decrease 
Grade 3  
Delay dose until resolved to ≤ Grade 2, then maintain dose 
Grade 4 
Delay dose until resolved to ≤ Grade 2,  
Reduce dose 1 level 
Febrile Neutropenia  
(absolute neutrophil count < 1 x 109/L, 
fever > 38.3°C or a sustained 
temperature of ≥ 38 °C for more than 
one hour) 
Delay dose until resolved,  
Reduce dose by 1 level 
Lymphocyte Count Decreased 
Grade 1 to Grade 3  
Lymphopenia 
No dose modification 
Grade 4  
(< 0.2 x 109/L) 
Delay dose until resolved to ≤ Grade 2: 
- 
If resolved in ≤ 14 days from day of onset, maintain 
dose 
- 
If resolved in > 14 days from day of onset, reduce dose 
1 level 
Anemia 
Grade 3  
(Hemoglobin (Hb) <8.0 g/dL); transfusion 
indicated 
Delay dose until resolved to ≤ Grade 2, then maintain dose 
Grade 4  
Delay dose until resolved to ≤ Grade 2, then reduce dose 1 
level 

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Worst toxicity CTCAE v5.0 Grade  
(unless otherwise specified) 
Dose or schedule modification for DS-8201a 
Life threatening consequences; urgent 
intervention indicated 
Platelet Count Decreased 
Grade 3  
(platelets <50 – 25 x 109/L) 
Delay dose until resolved to ≤ Grade 1: 
- 
If resolved in ≤ 7 days from day of onset, maintain dose 
- 
If resolved in > 7 days from day of onset, reduce dose 1 
level 
Grade 4  
(platelets < 25 x 109/L) 
Delay dose until resolved to ≤ Grade 1, then reduce dose 1 
level 
Cardiac Toxicity 
Symptomatic congestive heart failure 
(CHF) 
Discontinue subject from study treatment 
Decrease in Left ventricle ejection 
fraction (LVEF) 10-20% (absolute value), 
but LVEF > 45% 
Continue treatment with DS-8201a 
LVEF 40% to ≤ 45% and decrease is < 
10% (absolute value) from baseline 
Continue treatment with DS-8201a 
Repeat LVEF assessment within 3 weeks 
LVEF 40% to ≤ 45% and decrease is ≥ 
10% (absolute value) from baseline 
Interrupt DS-8201a dosing 
Repeat LVEF assessment within 3 weeks. 
If LVEF has not recovered to within 10% from baseline 
absolute value, discontinue subject from study treatment 
If LVEF recovers to within 10% from baseline, resume study 
drug treatment 
LVEF < 40% or > 20% (absolute value) 
drop from baseline 
Interrupt trastuzumab deruxtecan dosing 
Repeat LVEF assessment within 3 weeks. 
If LVEF < 40% or > 20% drop from baseline is confirmed, 
discontinue subject from study treatment 
ECG QTc Prolongation 
Grade 3  
(Average QTc> 500 ms or >60 ms change 
from baseline) 
Delay dose until resolved to ≤ Grade 1 (QTc ≤480 ms), 
determine if another medication the subject was taking 
may be responsible and can be adjusted or if there are any 
changes in serum electrolytes that can be corrected, then if 
attributed to trastuzumab deruxtecan, reduce dose 1 level 

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Worst toxicity CTCAE v5.0 Grade  
(unless otherwise specified) 
Dose or schedule modification for DS-8201a 
Grade 4  
(Torsade de pointes or polymorphic 
ventricular tachycardia or 
signs/symptoms of serious arrhythmia) 
Discontinue subject from study treatment 

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Worst toxicity CTCAE v5.0 Grade  
(unless otherwise specified) 
Dose or schedule modification for DS-8201a 
Pulmonary Toxicity  
If a subject develops radiographic changes potentially 
consistent with ILD/pneumonitis or develops an acute onset 
of new or worsening pulmonary or other related 
signs/symptoms such as dyspnea, cough or fever, rule out 
ILD/pneumonitis.  
If the AE is confirmed to have an aetiology other than 
ILD/pneumonitis, follow the management guidance 
outlined in the “Other Non-Laboratory Adverse Events” 
dose modification section below. 
If the AE is suspected to be ILD/pneumonitis, treatment 
with study drug should be interrupted pending further 
evaluations.  
Evaluations should include: 
• 
High resolution CT  
• 
Pulmonologist consultation (Infectious Disease 
consultation as clinically indicated) 
• 
Blood culture and CBC. Other BLOOD tests could be 
considered as needed 
• 
Consider bronchoscopy and bronchoalveolar 
lavage if clinically indicated and feasible 
• 
Pulmonary function tests and pulse oximetry 
(SpO2)  
• 
Arterial blood gases if clinically indicated  
• 
One blood sample collection for PK analysis as 
soon as ILD is suspected, if feasible. 
 
Other tests could be considered, as needed.If the AE is 
confirmed to be ILD/pneumonitis, follow the management 
guidance as outlined below. 
All events of ILD/pneumonitis regardless of severity or 
seriousness will be followed until resolution including after 
drug discontinuation. 
Grade 1 
The administration of trastuzumab-deruxtecan must be 
interrupted for any ILD/pneumonitis events regardless of 
grade.  
• 
Monitor and closely follow-up in 2 to 7 days for 
onset of clinical symptoms and pulse oximetry 
 

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Worst toxicity CTCAE v5.0 Grade  
(unless otherwise specified) 
Dose or schedule modification for DS-8201a 
• 
Consider follow-up imaging in 1-2 weeks (or as 
clinically indicated). 
 
• 
Consider starting systemic steroids (e.g. at least 
0.5 mg/kg/day prednisone or equivalent) until 
improvement, followed by gradual taper over at 
least 4 weeks. 
 
• 
If worsening of diagnostic observations despite 
initiation of corticosteroids, then follow Grade 2 
guidelines.* 
 
For Grade 1 events, trastuzumab deruxtecan can be 
restarted only if the event is fully resolved to Grade 0: 
• 
If resolved in ≤ 28 days from day of onset, maintain 
dose 
• 
If resolved in > 28 days  from day of onset, reduce dose 
1 level  
 
However, if the event grade 1 ILD/pneumonitis occurs 
beyond cycle day 22 and has not resolved within 49 days 
from the last infusion, the drug should be discontinued. 
 
* If participant is asymptomatic, then patient should still be 
considered as Grade 1 even if steroid treatment is given  
 
Grade 2 
Permanently discontinue subject from study treatment. 
 
Promptly start and treat with systemic steroids (e.g., at least 
1mg/kg/day prednisone or equivalent) for at least 14 days or 
until complete resolution of clinical and chest CT findings, 
then followed by a gradual taper over at least 4 weeks. 
• 
Monitor symptoms closely. 
• 
Re-image as clinically indicated. 
• 
If worsening or no improvement in clinical or 
diagnostic observations in 5 days 

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Worst toxicity CTCAE v5.0 Grade  
(unless otherwise specified) 
Dose or schedule modification for DS-8201a 
• 
Consider increasing dose of steroids (e.g., 
2 mg/kg/day prednisone or equivalent) 
and administration may be switched to 
intravenous (e.g. methylprednisolone). 
• 
Re-consider 
additional 
work-up 
for 
alternative aetiologies as described above. 
• 
Escalate care as clinically indicated.  
  
Grade 3 and 4 
Permanently discontinue subject from study treatment. 
 
• 
Hospitalization required. 
• 
Promptly initiate empiric high-dose 
methylprednisolone IV treatment (e.g., 500-1000 
mg/day for 3 days), followed by at least 1.0 
mg/kg/day of prednisone (or equivalent) until 
clinical improvement, or at least 14 days or until 
complete resolution of clinical and chest CT 
findings, then followed by a gradual taper over at 
least 4 weeks. 
• 
. 
• 
Re-image as clinically indicated. 
• 
If still no improvement within 3 to 5 days,  
• 
Re-consider additional work-up for 
alternative etiologies as described above. 
Consider other immuno-suppressants and/or treat per local 
practice.  
Ocular 
Grade 3 
Delay dose until resolved to ≤ Grade 1: 
If resolved in ≤ 7 days from day of onset, maintain dose 
If resolved in > 7 days from day of onset, reduce dose 1 
level 
Grade 4 
Discontinue subject from study treatment 
Blood creatinine increase 

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Worst toxicity CTCAE v5.0 Grade  
(unless otherwise specified) 
Dose or schedule modification for DS-8201a 
Grade 3 (> 3.0 to 6.0 x upper limit of 
normal [ULN]) 
Delay dose until resolved to ≤ Grade 2 or baseline, then 
reduce dose 1 level 
Grade 4 (> 6.0 x ULN) 
Discontinue subject from study treatment 
Hepatic Toxicity 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) with simultaneous Total 
bilirubin increase (TBL) 
AST/ALT > 3.0 x ULN with simultaneous 
TBL > 2.0 x ULN 
Delay study medication until drug-induced liver injury can 
be ruled out.  
If drug-induced liver injury is ruled out, the subject should 
be treated accordingly, and resumption of study drug may 
occur after discussion between the Investigator and 
Sponsor.  
If drug-induced liver injury cannot be ruled out from 
diagnostic workup, permanently discontinue study 
treatment. 
Monitor AST/ALT and TBL twice weekly until resolution or 
return to baseline. 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
Grade 2 (>3.0 - 5.0 x ULN if baseline was 
normal; >3.0 - 5.0 x baseline if baseline 
was abnormal) 
No action for Grade 2 AST/ALT  
Grade 3 (>5.0 - 20.0 x ULN if baseline 
was normal; >5.0 - 20.0 x baseline if 
baseline was abnormal) 
In subjects without liver metastases and 
subjects with liver metastases and 
baseline level ≤ 3 x ULN 
Repeat testing within 3 days. Delay dose until resolved to ≤ 
Grade 1 if baseline ≤ 3 x ULN, otherwise delay dose until 
resolved to ≤ baseline, then: 
If resolved in ≤ 7 days from day of onset, maintain dose 
If resolved in > 7 days from day of onset, reduce dose 1 
level 
Grade 3:  (>8.0 - 20.0 x ULN if baseline 
was normal; >8.0 - 20.0 x baseline if 
baseline was abnormal) 
In subjects with liver metastases, if the 
baseline level was > 3 x ULN 
Repeat testing within 3 days. Delay dose until resolved to ≤ 
baseline level, then: 
If resolved in ≤ 7 days from day of onset, maintain dose 
If resolved in > 7 days from day of onset, reduce dose 1 
level 
Grade 4  (>20.0 x ULN if baseline was 
normal; >20.0 x baseline if baseline was 
abnormal) 
Discontinue subject from study treatment 

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Worst toxicity CTCAE v5.0 Grade  
(unless otherwise specified) 
Dose or schedule modification for DS-8201a 
Blood bilirubin increase 
Grade 2  (>1.5 - 3.0 x ULN if baseline was 
normal; >1.5 - 3.0 x baseline if baseline 
was abnormal) 
If no documented Gilbert’s syndrome or liver metastases at 
baseline, delay dose until resolved to ≤ Grade 1: 
- 
If resolved in ≤ 7 days from day of onset, maintain 
dose 
- 
If resolved in > 7 days from day of onset, reduce 
dose 1 level    
 
If documented Gilbert’s syndrome or liver metastases at 
baseline, continue study treatment 
Grade 3  (>3.0 - 10.0 x ULN if baseline 
was normal; >3.0 - 10.0 x baseline if 
baseline was abnormal) 
If no documented Gilbert’s syndrome or liver metastases at 
baseline, repeat testing within 3 days.  Delay dose until 
resolved to ≤ Grade 1: 
- 
If resolved in ≤ 7 days from day of onset, reduce 
dose 1 level 
- 
If resolved in > 7 days from day of onset, 
discontinue DS-8201a   
 
If documented Gilbert’s syndrome or liver metastases at 
baseline, repeat testing within 3 days. Delay dose until 
resolved to < Grade 2: 
- 
If resolved in ≤ 7 days from day of onset,  reduce 
dose 1 level 
- 
If resolved in > 7 days from day of onset, 
discontinue DS-8201a 
Grade 4  (>10.0 x ULN if baseline was 
normal; >10.0 x baseline if baseline was 
abnormal) 
Discontinue subject from study treatment 
Blood alkaline phosphatase Increase 
Grade 3 (>5.0 - 20.0 x ULN if baseline 
was normal; >5.0 - 20.0 x baseline if 
baseline was abnormal) 
or  
Grade 4 (>20.0 x ULN if baseline was 
normal; >20.0 x baseline if baseline was 
abnormal) 
No modification unless determined by the Investigator to be 
clinically significant or life-threatening. 
Gastrointestinal 
Nausea 
Grade 3  
Delay dose until resolved to ≤ Grade 1  
If resolved in ≤ 7 days from day of onset, maintain dose 

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Worst toxicity CTCAE v5.0 Grade  
(unless otherwise specified) 
Dose or schedule modification for DS-8201a 
If resolved in > 7 days from day of onset, reduce dose 1 
level 
Diarrhoea/Colitis 
Grade 3 
Delay dose until resolved to ≤ Grade 1 
If resolved in ≤ 3 days from day of onset, maintain dose 
If resolved in > 3 days from day of onset, reduce dose 1 
level 
Grade 4 
Discontinue subject from study treatment 
Other Laboratory Adverse Events 
Grade 3 
Delay dose until resolved to ≤ Grade 1 or baseline level:  
If resolved in ≤ 7 days from day of onset, maintain dose 
If resolved in > 7 days from day of onset, reduce dose 1 
level 
Grade 4 
Discontinue subject from study treatment 
Other Non-Laboratory Adverse Events 
Grade 3 
Delay dose until resolved to ≤ Grade 1 or baseline:  
If resolved in ≤ 7 days from day of onset, maintain dose 
If resolved in > 7 days from day of onset, reduce dose 1 
level  
Grade 4 
Discontinue subject from study treatment 
All dose modifications should be based on the worst preceding toxicity. 
CTCAE: Common Terminology Criteria for Adverse Events. 
 
In addition, Investigators may consider dose reductions or discontinuations of the study drug 
according to the subject’s condition and after discussion with the Principal Investigator, Daiichi 
Sankyo’s Medical Monitor or designee. 

 
 
8.4 
TREATMENT COMPLIANCE 
At all times, study drug will be prepared and administered by study site personnel. Quantity and Lot-
numbers of used vials/pharmaceutical packings must be recorded on “Drug Dispensing Logs” and in 
the source documents. 
8.5 
CONCOMITANT THERAPY 
8.5.1 
Recommended Concomitant Therapy 
Subjects should receive full supportive care, including transfusions of blood and blood products when 
appropriate. 
Hematopoietic growth factors may be used for prophylaxis or treatment based upon the investigator’s 
judgment.  Prophylactic or supportive treatment of study-drug induced AEs (e.g. nausea) will be 
performed as per institutional guidelines. Concomitant use of dietary supplements, medications not 
prescribed by the investigator, and alternative/complementary treatments is discouraged, but not 
prohibited.   
8.5.2 
Prohibited Concomitant Therapy 
• Concomitant use of other anti-cancer therapies, including radiation, chemotherapy or any other 
investigational agents is not permitted while subjects are receiving study drug during the 
treatment phase of the study. 
• CYP3A4 strong inhibitors (include but are not limited to: boceprevir, clarithromycin, conivaptan, 
indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, saquinavir, 
telaprevir, telithromycin, voriconazole). Consult with your local resources as needed to evaluate 
potential CYP3A4 inhibitors 
• If concomitant use of strong CYP3A4 inhibitors is unavoidable, consider delaying DS-8201a 
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 co-
administered and DS-8201a treatment cannot be delayed, patients should be closely monitored for 
adverse reactions 
• Organic anion transporting polypeptide (OATP) 1B inhibitors (include but are not limited to: 
atazanavir, clarithromycin, cyclosporine, erythromycin, gemfibrozil, lopinavir, rifampin, ritonavir, 
simeprevir). Consult with your local resources as needed to evaluate potential OATP1B inhibitors 
• If concomitant use of OATP1B inhibitors is unavoidable, consider delaying DS-8201a treatment until 
the OATP1B inhibitors have cleared from the circulation (approximately 3 x the elimination half-life 
of the inhibitors) as far as possible 
• If an OATP1B inhibitor is co-administered and DS-8201a treatment cannot be delayed, patients 
should be closely monitored for adverse reactions 

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• Concomitant use of foods or beverages containing grapefruit 
 
9. PREMATURE WITHDRAWAL 
Any patients who experience a serious adverse event may be withdrawn at any time from the study at 
the discretion of the investigator. If trastuzumab-deruxtecan is stopped for any reason other than 
progression (either toxicity or voluntary withdrawal from study treatment) patients will have the 
planned safety follow-up visit and enter in efficacy follow-up with cranial MRI and CT scans of chest 
and abdomen as well as other investigations according to the same timetable as if the treatment 
interruption had not occurred. This follow-up is to continue until disease progression or until voluntary 
withdrawal of the patient from the study. In case the follow-up is impossible (due to patient refusing 
to perform assessments or other reasons), survival data can be collected at the defined timepoints via 
chart review or telephone. 
9.1 
PREMATURE TRIAL TERMINATION  
If any serious disadvantage of the treatment becomes evident during the clinical trial, therapy will be 
terminated. In this case the necessary procedures will be arranged to ensure protection of the subjects’ 
interests. 
9.2 
REPLACEMENT POLICY 
A total of 15 patients will be enrolled into the study; 6 evaluable patients (stage 1), with accrual of 
additional 9 patients (stage 2) according to the number of responses seen in stage 1. If patients are 
withdrawn within the first 9 weeks of the study (i.e. before the first response evaluation) for reasons 
other than progression or death, they will be replaced. 
 
10. STATISTICAL CONSIDERATIONS 
10.1 SAMPLE SIZE CALCULATION 
This is a phase II study for proof of principle on the activity of trasuzumab-deruxtecan to induce 
objective responses in patients with HER2-positive metastatic breast cancer with newly diagnosed or 
progressing brain metastases based upon a Simon's two-stage design [31]. 
A response rate of 61% would be considered as indicating clinically relevant activity in this patient 
population. A response rate of <26%, on the other hand, must be considered clinically unmeaningful 
(null hypothesis). These assumptions are based on previous studies conducted in HER2-positive breast 

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cancer patients with brain metastases. In the LANDSCAPE trial evaluating lapatinib plus capecitabine 
as upfront systemic therapy in patients with newly diagnosed BM, a response rate of 66% was 
observed; in contrast, the same regimen yielded a response rate of 20% in progressive BM after prior 
local therapy [32]. In a mixed population of patients with newly-diagnosed or progressive BM treated 
with T-DM1, a response rate of 30% was reported [22]; this study, however, included only two patients 
with newly diagnosed BM. Therefore, any response rate below 26% was considered to indicate little 
benefit of T-DXd over the currently available drugs in this specific population. In the phase II DESTINY-
Breast01 study [28], T-DXd yielded an extracranial response rate of 60.9% in an extremely heavily 
pretreated population of HER2-positive MBC patients with virtually all patients showing some degree 
of tumour shrinkage. As the participants of TUXEDO-1 are expected to be similarly heavily pretreated, 
a response rate >60% is believed to indicate relevant clinical activity of T-DXd also in brain metastases 
of HER2-positive breast cancer.   
In the first stage, 6 patients will initially be accrued. If there are two or fewer responses in these 6 
patients, the study will be stopped. Otherwise, 9 additional patients will be accrued for a total number 
of 15 patients. The null hypothesis will be rejected if 7 or more responses are observed in these 15 
patients. This design yields a type I error rate of 5% and a power of 80% to reject the null-hypothesis. 
P0=0.250, P1=0.610, Alpha=0.050, Beta=0.200 
N1 
R1 
N 
R 
Alpha Beta 
6 
2 
15 
6 
0.050 0.200 
N1 is the sample size in the first stage. 
R1 is the drug rejection number in the first stage. 
N is the combined sample size of both stages. 
R is the combined drug rejection number after both stages. 
Alpha is the probability of rejecting that P<=P0 when this is true. 
Beta is the probability of rejecting that P>=P1 when this is true. 
P0 is the response proportion of a poor drug. 
P1 is the response proportion of a good drug. 
 
Tolerability and Safety:            

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Endpoints are safety & tolerance of treatment in terms of haematologic and non-haematologic side 
effects as assessed by the investigators. Adverse events will also be summarised using frequency 
counts and percentages.   
All patients who are eligible for the study and receive at least one dose of study drug l be will be 
included in the safety analysis.  
Patients who drop out or die prior to the first response assessment will be included in the denominator 
when calculating the response rate. Any patients who enrol into the study but who receive no study 
medication will be excluded, but a sensitivity analysis will be conducted which will include all enrolled 
patients.An analysis of all patients undergoing treatment per protocol excluding drop out will also be 
performed 
10.2 EFFICACY 
10.2.1. Primary Endpoint 
Rate of objective responses of BM as judged by best response during therapy i.e. complete remission 
(CR), partial remission (PR), stable disease (SD)/no change and progressive disease as defined by RANO 
criteria. 
Response categories according to RANO-BM criteria will be summarised using frequency counts and 
percentages. Exact 95% two-sided confidence intervals will also be provided for the response rate. 
10.2.2. Secondary Endpoints 
Rate of objective responses of extracranial metastases as judged by best response during therapy i.e. 
complete remission (CR), partial remission (PR), stable disease (SD)/no change and progressive disease 
as defined by RECIST 1.1 criteria. 
Response categories according to RECIST 1.1 criteria will be summarised using frequency counts and 
percentages. Exact 95% two-sided confidence intervals will also be provided for the response rate. 
Progression-free survival and overall survival will be assessed using the Kaplan-Maier product-limit 
method. Differences in PFS and OS curves in subgroups will be analysed by the log-rank test. A 
competing-risk model including death or study withdrawal will be calculated to assess time-to-WBRT 
and differences in the respective curves will be analysed by the Gray’s test. 
10.3 TOLERABILITY & SAFETY 
10.3.1. Endpoint 

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Safety and tolerance of treatment in terms of haematologic and non-haematologic side effects as 
assessed by the investigators. Adverse events will also be summarised using frequency counts and 
percentages. MedDRA terminology will be used and grading of AEs will be performed according to NCI 
CTCAE v5.0. 
10.4 QUALITY-OF-LIFE 
10.4.1. Endpoint 
Quality-of-Life (QoL) in patients receiving trastuzumab-deruxtecan for HER2-positive breast cancer 
brain metastases will be assessed with the EORTC QLQ-c30 questionnaire, the brain specific tool 
(BN20), and the breast specific tool (BR45) at baseline, before cycle 3 and 5 and every 9 weeks 
thereafter and at EOT. 
10.5 EXPLORATORY ENDPOINTS 
10.5.1. Endpoint 
Analysis of biomarkers potentially associated with response to trastuzumab-deruxtecan. 
10.6 ANALYSIS PLAN 
All patients who are eligible for the study and receive at least one dose of study drug will be included 
in the analysis. Any patients who enrol into the study but who receive no study medication will be 
excluded, but a sensitivity analysis will be conducted which will include all enrolled patients. An 
analysis of all patients undergoing treatment per protocol excluding drop out will also be performed. 
10.7 RELEVANT PROTOCOL DEVIATIONS  
Major deviations regarding to patients’ safety will lead to subject withdrawal. 
All protocol deviations will be listed in the clinical study report (CSR). 
10.8 MISSING, UNUSED AND SPURIOUS DATA 
Missing values will not be imputed. 
 
11. SAFETY 
11.1 ADVERSE EVENTS 
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence occurring at any 
dose that may appear or worsen in a subject during a study. It may be a new intercurrent illness, a 
worsening concomitant illness, an injury, or any concomitant impairment of the subject’s health, 
including laboratory test values (as specified by the criteria below), regardless of etiology. Any medical 

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condition that was present prior to study treatment and that remains unchanged or improved should 
not be recorded as an AE. If there is a worsening of that medical condition this should be considered 
an AE. A diagnosis or syndrome should be recorded on the AE page of the Case Report Form rather 
than the individual signs or symptoms of the diagnosis or syndrome. All AEs will be recorded by the 
investigator from the time of signing the informed consent through to the end of the designated 
follow-up period. 
A Treatment-emergent adverse event  (TEAE) is defined as an AE that occurs, having been absent 
before the first dose of study drug, or has worsened in severity or seriousness after the initiating the 
study drug until 47 days after last dose of the study drug.  SAEs with an onset or worsening 48 days or 
more after the last dose of study drug, if considered related to the study treatment, are also TEAEs. 
11.2 SERIOUS ADVERSE EVENTS 
A serious adverse event (SAE) is any AE which: 
• 
Results in death 
• 
Is life-threatening (i.e., in the opinion of the Investigator(s) the subject is at immediate 
risk of death from the AE) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions) 
• 
Is a congenital anomaly/birth defect 
• 
Constitutes an important medical event 
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or require 
medical or surgical intervention to prevent one of the other outcomes listed above.  Medical and 
scientific judgment should be exercised in deciding whether such an AE should be considered serious. 
Events not considered to be SAEs are hospitalizations which: were planned before entry into the 
clinical study; are for elective treatment of a condition unrelated to the studied indication or its 
treatment; occur on an emergency outpatient basis and do not result in admission (unless fulfilling 
other criteria above); are part of the normal treatment or monitoring of the studied indication and are 
not associated with any deterioration in condition. 

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If an AE is considered serious, both the AE pages of the CRF and the SAE Report Form must be 
completed. 
For each SAE, the Investigator will provide information on severity, start and stop dates, relationship 
to study drug, action taken regarding study drug, and outcome. 
11.3 ADVERSE EVENT OF SPECIAL INTEREST 
For the DS-8201a clinical program, based on the available pre-clinical data, review of the cumulative 
literature, reported toxicities for the same class of agents and biological plausibility, the following 
events are considered to be adverse events of special interest (AESI): Interstitial lung 
disease/pneumonitis, and LVEF decrease. 
11.3.1. Interstitial Lung Disease/Pneumonitis  
Clinical Summary:  
Interstitial lung disease/pneumonitis is considered an important identified risk based on a 
comprehensive cumulative review of the available safety data from the clinical development program. 
Refer to the current IB for a summary of preliminary clinical study data. 
Management Guidance:  
ILD should be ruled out if a subject develops radiographic changes potentially consistent with ILD or 
develops an acute onset of new or worsening pulmonary or other related signs/symptoms such as 
dyspnoea, cough or fever. If the AE is confirmed to have an aetiology other than ILD, follow the 
management guidance outlined in the designated “Other Non-Laboratory Adverse Events” dose 
modification section of the study protocol.  
If the AE is suspected to be ILD, treatment with study drug should be interrupted pending further 
diagnostic evaluations. Evalations, should include high resolution CT, pulmonologist consultation 
(infectious disease consultation as clinically indicated), blood culture and CBC (other blood tests could 
be considered as needed), bronchoscopy and bronchoalveolar lavage if clinically indicated and feasible 
should be considered, pulmonary function tests and pulse oximetry (SpO2), arterial blood gases if 
clinically indicated, One blood sample collection for PK analysis as soon as ILD  is suspected, if feasible.  

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If the AE is confirmed to be ILD, follow the management guidance outlined in the designated 
“Pulmonary Toxicity” dose modification section of the study protocol. All events of ILD regardless of 
severity or seriousness will be followed until resolution including after drug discontinuation. 
11.3.2. LVEF decrease 
Clinical Summary:  
LVEF decrease in association with DS-8201a treatment is considered to be an important potential risk 
based on the available pre-clinical data, literature and available safety information for drugs of a similar 
class. Refer to the current IB for a summary of preliminary clinical trial data. 
Management Guidance:  
LVEF will be measured by either ECHO or MUGA scan.  All ECHOs/MUGAs will be evaluated by the 
Investigator or delegated physician for monitoring cardiac function.  
 Troponin will be measured at screening and EOT, and as needed based on subject reported cardiac 
signs or symptoms suggesting congestive heart failure, myocardial infarction, or other causes of 
cardiac myocyte necrosis.   
Triplicate ECGs will be performed and standard ECG parameters will be measured, including RR, PR, 
QT intervals, and QRS duration.  All ECGs must be evaluated by Investigator or delegated physician for 
the presence of abnormalities.  Whether or not measurement is performed, date performed, results, 
and findings for each parameter is to be recorded in the CRF.  
 
11.4 CLASSIFICATION OF SEVERITY 
For both AEs and SAEs, the investigator must assess the severity of the event. The severity of adverse 
events (AEs) will be graded on a scale of 1 to 5 according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE). The NCI CTCAE V5.0 can be viewed 
on-line at the following NCI: web site:  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50. 
 
If a specific event is not included in the NCI CTCAE toxicity scale, the following scale should be used to 
grade the event  

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Grade  Definition  
1  
Mild Awareness of sign, symptom, or event, usually transient, requiring no special 
treatment and generally not interfering with usual daily activities  
2  
Moderate Discomfort that causes interference with usual activities; usually 
ameliorated by basic therapeutic manoeuvres  
3  
Severe Incapacitating with inability to do usual activities or significantly affects clinical 
status and warrants intervention. Hospitalization may or may not be required  
4 
Life-threatening Immediate risk of death; requires hospitalization and clinical 
intervention 
5  
Death  
11.5 CLASSIFICATION OF RELATIONSHIP/CAUSALITY OF ADVERSE EVENTS (AE/SAE) TO IMP 
The Investigator must determine the relationship between the administration of study drug and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below: 
Not suspected: 
The temporal relationship of the adverse event to study drug administration makes a causal 
relationship unlikely or remote, or other medications, therapeutic interventions, or underlying 
conditions provide a sufficient explanation for the observed event. 
Suspected: 
The temporal relationship of the adverse event to study drug administration makes a causal 
relationship possible, and other medications, therapeutic interventions, or underlying conditions do 
not provide a sufficient explanation for the observed event. 
11.6 SAE AND SUSAR REPORTING 
11.6.1. Reporting to the Regulatory Authority and the Ethics Committee 
The sponsor will inform relevant Regulatory Authority and the Ethics Committee: 
• 
Of all relevant information about suspected unexpected serious adverse reactions related 
to the study medication (SUSARs) that are fatal or life threatening as soon as possible, and 
in any case no later than seven days after knowledge of such a case. Relevant follow-up 
information for these cases will subsequently be submitted within an additional eight days. 

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• 
Of all other SUSARs as soon as possible, but within a maximum of fifteen days of first 
knowledge by the investigator. 
11.6.2. Reporting to Daiichi Sankyo 
The investigator will inform Daiichi Sankyo (email address: cspv-clinical@dsi.com) within 24 hours of 
the following types of events: 
• 
All SAEs 
• 
All potential ILD/pneumonitis cases should be reported within 24 hours including both 
serious and non-serious potential ILD/pneumonitis cases (potential ILD/pneumonitis is 
defined by the Event Adjudication Site Manual List of PTs). 
• 
Pregnancies 
• 
Hepatic events (both serious and non-serious) which meet the potential Hy’s Law criteria 
defined as an elevated (ALT or AST) ≥ 3 x ULN and an elevated TBL > 2 x ULN that may 
occur either at different time points or simultaneously during the study. Overdose, defined 
as the accidental or intentional administration of any dose of a product that is considered 
both excessive and medically important. An “excessive and medically important” overdose 
includes any overdose in which either a serious adverse event, a non-serious adverse 
event, or no adverse event occurs and is considered by the Investigator as clinically 
relevant, i.e. poses an actual or potential risk to the subject.  
• 
Overdose is always serious. By definition, an overdose is medically important, which meets 
the seriousness criterion of important medical event. An overdose can occur with or 
without an AE. AEs can either be serious or non-serious. Details of the overdose including 
DS-8201a dosage, clinical course, associated AEs, and outcome must be captured in the 
Narrative form of the CRF.  
11.6.3. Immediate Reporting  
The investigator will inform the pharmacovigilance officer for this study of all SAEs within 24 hours 
after knowledge of such a case in order that the sponsor can fulfil his regulatory reporting obligations 
within the required timeframes. 
The IB will be provided by Daiichi-Sankyo in the currently available form. 
11.7 PREGNANCIES 
Female of Childbearing Potential: 

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Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on study drug, or within 28 days of the 
subject’s last dose of study drug, are considered events to be reported immediately to Sponsor. If the 
subject is on study drug, the study drug is to be discontinued immediately and the subject instructed 
to return any unused portion of the study drug to the Investigator. The pregnancy, suspected 
pregnancy, or positive pregnancy test must be reported to Sponsor.  
The female should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for 
further evaluation and counseling. 
The investigator will follow the female subject until completion of the pregnancy, and must notify the 
Sponsor of the outcome of the pregnancy within 5 days or as specified below.  The Investigator will 
provide this information as a follow-up to the initial pregnancy report. 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE (i.e., 
spontaneous or therapeutic abortion [any congenital anomaly detected in an aborted fetus is to be 
documented], stillbirth, neonatal death, or congenital anomaly [including that in an aborted fetus]), 
the Investigator should follow the procedures for reporting SAEs. 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to causality, 
as SAEs.  In addition, any infant death after 28 days that the Investigator suspects is related to the in 
utero exposure to the study drug should also be reported. 
 
12. QUALITY CONTROL & QUALITY ASSURANCE 
12.1 PERIODIC MONITORING 
The designated monitor will contact and visit the investigator regularly and will be allowed to have 
access to all source documents needed to verify the entries in the CRFs and other protocol-related 
documents provided that subject confidentiality is maintained in agreement with local regulations. It 
will be the monitor's responsibility to inspect the CRFs at regular intervals throughout the study, to 
verify the adherence to the protocol and the completeness, consistency and accuracy of the data being 
entered on them. The monitoring standards require full verification for the presence of informed 
consent, adherence to the inclusion/exclusion criteria, documentation of SAEs and the recording of 
the main efficacy & safety endpoints. 

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To be GCP compliant at least 3 monitoring visits are scheduled. An initiation visit, one routine visit and 
a final visit after the last patient has finished the study. The monitor will provide a GCP-compliant 
monitoring report after each visit for the sponsor. The investigator will cooperate with the CRA to 
ensure that any identified discrepancies are resolved. 
12.2 AUDITS & INSPECTIONS 
The main purpose of an audit or inspection is to confirm that the rights and welfare of the subjects 
have been adequately protected, and that all data relevant for assessment of safety and efficacy of 
the investigational product have appropriately been reported. 
The sponsor/investigator will permit trial related monitoring, audit, IRB/IEC review & regulatory 
inspections and provide direct access to study related-source data and source documents. 
12.3 PUBLICATION OF STUDY RESULTS 
The findings of this study will be published by the Principal Investigator in a scientific journal and 
presented at scientific meetings. 
  
13. ETHICAL & LEGAL ASPECT 
13.1 INFORMED CONSENT OF SUBJECTS 
Following comprehensive instruction regarding the nature, significance, impact and risks of this clinical 
trial, the patient must give written consent to participation in the study. 
• 
The patients are made aware of the fact that they can with-draw their consent – without 
giving reasons – at any time without their further medical care being influenced in any way 
and they also receive a written patient information sheet in comprehensible language, 
explaining the nature and purpose of the study and its progress. 
• 
The patients also must agree to the possibility of study-related data being passed on to 
relevant authorities. 
• 
The patients will be informed in detail of their obligations in relation to the insurance in 
order not to jeopardize insurance cover. 
13.2 ACKNOWLEDGEMENT/APPROVAL OF THE STUDY 
The investigator submits this protocol and any related document provided to the subject (such as 
subject information used to obtain informed consent) to an Ethics Committee (EC) or Institutional 

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Review Board (IRB). Approval from the committee must be obtained before starting the study, and 
should be documented in a dated letter to the investigator.  
Adverse events - whether serious and/or unexpected, and possibly endangering the safety of the study 
participants - are likewise to be reported to the ethics committee. 
The clinical trial will be performed in full compliance with the valid legal regulations according to the 
Drug Law (AMG - Arzneimittelgesetz) of the Republic of Austria. 
The study will be notified to the Austrian Agency for Health and Food Safety (AGES) and registered to 
the European Clinical Trial Database (EudraCT) using the required forms. 
13.3 PROTOCOL AMENDMENTS 
 
Proposed amendments will be submitted to the appropriate CA and ECs. Substantial amendments may 
be implemented only after CA/EC approval has been obtained. Amendments that are intended to 
eliminate an apparent immediate hazard to subjects will be implemented prior to receiving CA/EC 
approval. However, in this case, approval must be obtained as soon as possible after implementation. 
13.4 STUDY TERMINATION 
If the investigator/sponsor decides to terminate the study before it is completed, he will ensure that 
adequate consideration is given to the protection of the subject interests. The investigator/ sponsor 
will notify the relevant CA and EC. Documentation will be filed in the TMF and the ISF.     
13.5  CLINICAL STUDY REPORT (CSR) 
Within one year after the final completion of the study, a full CSR will be written by the investigator or 
designee and submitted to the EC and the competent authority. The Principal Investigator will review 
and sign the final study report. 
13.6 FINANCE & INSURANCE 
13.6.1 Finance 
Investigator Initiated trial; study drug  is made available by the aponsor. 
13.6.2 Insurance 
During their participation in the clinical trial the patients will be insured as defined by legal 
requirements.  The sponsor is providing insurance in order to indemnify (legal and financial coverage) 
the investigator/centre against claims arising from the study, except for claims that arise from 
malpractice and/or negligence. The compensation of the subject in the event of study-related injuries 
will comply with the applicable regulations. 
Details on the existing patients’ insurance: 

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Zürich Versicherungs-AG, Schwarzenbergplatz 15, 1010 Vienna; Policy: 07229622-2 
These details are also provided in the patient information sheet. 
13.7 ETHICS AND GOOD CLINICAL PRACTICE (GCP) 
The investigator ensures that this study is conducted in full conformance with the principles of the 
current version from "Declaration of Helsinki", the ICH GCP Guidelines and the laws and regulations of 
Austria. 
 
 

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14. APPENDICES 
14.1 APPENDIX I 
 
ECOG Performance Status Scale [33] 
 
 
ECOG Scale 
Performance Status 
 
0 
Fully active, able to carry out all pre-disease performance without 
restriction. 
 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry 
out work of a light or sedentary nature, e.g. light housework, office work. 
 
2 
Ambulatory and capable of all selfcare, but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
 
4 
Completed disabled. Cannot carry out any selfcare. Totally confined to bed 
or chair. 
 
5 
Dead 
 
 
ECOG and Karnofsky Performance Status: 
ECOG 0 corresponds to Karnofsky Performance Status of 
100-90 
ECOG 1 corresponds to Karnofsky Performance Status of  
80-70 
ECOG 2 corresponds to Karnofsky Performance Status of  
  60-50 
ECOG 3 corresponds to Karnfosky Performance Status of  
  40-30 
ECOG 4 corresponds to Karnofsky Performance Status of  
  20-10 
ECOG 5 corresponds to Karnofsky Performance Status of  
0 
 
14.2 APPENDIX II 
 Laboratory Parameter 
Haematology: 
Haemoglobin, Leucocytes, Neutrophiles abs., Lymphocytes abs., Monocytes abs., Eosinophiles abs., 
Basophiles abs., Platelets 

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Biochemistry: 
Total protein, Albumin, CRP, IgG, IgA, IgM,  ß2-Microglobulin, Glucose, Serum Creatinine, BUN, Uric 
acid, total bilirubin, ASAT (SGOT), ALAT (SGPT), γGT, Alkaline phosphatase, LDH, Cholesterol, 
Triglycerides, Sodium, Phosphat, Potassium, Calcium, Magnesium, Normotest, Fibrinogen. 
13.3. 
APPENDIX III 
DECLARATION OF HELSINKI 
Amended at the 64th WMA General Assembly, Fortaleza, Brazil, October 2013 [34]. 
Preamble 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical 
principles for medical research involving human subjects, including research on identifiable human material and 
data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be applied with 
consideration of all other relevant paragraphs. 
 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The WMA 
encourages others who are involved in medical research involving human subjects to adopt these principles. 
 
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient will be 
my first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act in the 
patient’s best interest when providing medical care.” 
 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, including 
those who are involved in medical research. The physician’s knowledge and conscience are dedicated to the 
fulfilment of this duty. 
 
5. Medical progress is based on research that ultimately must include studies involving human subjects. 
 
6. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best proven interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and quality. 
 
7. Medical research is subject to ethical standards that promote and ensure respect for all human subjects and 
protect their health and rights. 
 

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8. While the primary purpose of medical research is to generate new knowledge, this goal can never take 
precedence over the rights and interests of individual research subjects. 
 
9. It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and condentiality of personal information of research subjects. 
The responsibility for the protection of research subjects must always rest with the physician or other health care 
professionals and never with the research subjects, even though they have given consent. 
 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research involving human 
subjects in their own countries as well as applicable international norms and standards. No national or 
international ethical, legal or regulatory requirement should reduce or eliminate any of the protections for 
research subjects set forth in this Declaration. 
 
11. Medical research should be conducted in a manner that minimises possible harm to the environment. 
 
12. Medical research involving human subjects must be conducted only by individuals with the appropriate ethics 
and scientific education, training and qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other health care professional. 
 
13. Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
 
14. Physicians who combine medical research with medical care should involve their patients in research only to 
the extent that this is justified by its potential preventive, diagnostic or therapeutic value and if the physician has 
good reason to believe that participation in the research study will not adversely affect the health of the patients 
who serve as research subjects. 
 
15. Appropriate compensation and treatment for subjects who are harmed as a result of participating in research 
must be ensured. 
 
Risks, Burdens and Benefits 
16. In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of the objective outweighs 
the risks and burdens to the research subjects. 
 
17. All medical research involving human subjects must be preceded by careful assessment of predictable risks 
and burdens to the individuals and groups involved in the research in comparison with foreseeable benefits to 
them and to other individuals or groups affected by the condition under investigation. Measures to minimise the 

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risks must be implemented. The risks must be continuously monitored, assessed and documented by the 
researcher. 
 
18. Physicians may not be involved in a research study involving human subjects unless they are confident that 
the risks have been adequately assessed and can be satisfactorily managed. When the risks are found to 
outweigh the potential benets or when there is conclusive proof of definitive 
outcomes, physicians must assess whether to continue, modify or immediately stop the study. 
 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of being 
wronged or of incurring additional harm. All vulnerable groups and individuals should receive specifically 
considered protection. 
 
20. Medical research with a vulnerable group is only justified if the research is responsive to the health needs or 
priorities of this group and the research cannot be carried out in a non-vulnerable group. In addition, this group 
should stand to benet from the knowledge, practices or interventions that result from the research. 
 
Scientific Requirements and Research Protocols 
21. Medical research involving human subjects must conform to generally accepted scientific principles, be based 
on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate 
laboratory and, as appropriate, animal experimentation. The welfare of animals used for research must be 
respected. 
 
22. The design and performance of each research study involving human subjects must be clearly described and 
justified in a research protocol. The protocol should contain a statement of the ethical considerations involved 
and should indicate how the principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for 
subjects and information regarding provisions for treating and/or compensating subjects who are harmed as a 
consequence of 
participation in the research study. In clinical trials, the protocol must also describe appropriate arrangements 
for post-trial provisions. 
 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the study begins. This committee must be transparent in its 
functioning, must be independent of the researcher, the sponsor and any other undue influence and must be 
duly qualified. It must take into consideration the laws and regulations of the country or countries in which the 
research is to be performed as well as applicable international norms and standards but these must not be 
allowed to reduce or eliminate any of the protections for research subjects set forth in this Declaration. The 
committee must have the right to monitor ongoing studies. The researcher must provide monitoring information 
to the committee, especially information about any serious adverse events. No amendment to the 

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protocol may be made without consideration and approval by the committee. After the end of the study, the 
researchers must submit a nal report to the committee containing a summary of the study’s findings and 
conclusions. 
 
Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their 
personal information. 
 
Informed Consent 
25. Participation by individuals capable of giving informed consent as subjects in medical research must be 
voluntary. Although it may be appropriate to consult family members or community leaders, no individual 
capable of giving informed consent may be enrolled in a research study unless he or she freely agrees. 
 
26. In medical research involving human subjects capable of giving informed consent, each potential subject must 
be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may 
entail, post-study provisions and any other relevant aspects of the study. The potential subject must be informed 
of the right to refuse to participate in the study or to withdraw consent to participate at any time without reprisal. 
Special attention should be given to the specific information needs of individual potential subjects as well as to 
the methods used to deliver the information. 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed consent, 
preferably in writing. If the consent cannot be expressed in writing, the non-written consent must be formally 
documented and witnessed. 
All medical research subjects should be given the option of being informed about the general outcome and 
results of the study. 
 
27. When seeking informed consent for participation in a research study the physician must be particularly 
cautious if the potential subject is in a dependent relationship with the physician or may consent under duress. 
In such situations the informed consent must be sought by an appropriately qualified individual who is 
completely independent of this relationship. 
 
28. For a potential research subject who is incapable of giving informed consent, the physician must seek 
informed consent from the legally authorised representative. These individuals must not be included in a 
research study that has no likelihood of benet for them unless it is intended to promote the health of the group 
represented by the potential subject, the research cannot instead be performed with persons capable of 
providing informed consent, and the research entails only minimal risk and minimal burden. 
 
29. When a potential research subject who is deemed incapable of giving informed consent is able to give assent 
to decisions about participation in research, the physician must seek that assent in addition to the consent of the 
legally authorised representative. The potential subject’s dissent should be respected. 
 

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30. Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving informed consent 
is a necessary characteristic of the research group. In such circumstances the physician must seek informed 
consent from the legally authorised representative. If no such representative is available and if the research 
cannot be delayed, the study may proceed without informed consent provided that the specific reasons for 
involving subjects with a condition that renders them unable to give informed consent have been stated in the 
research protocol and the study has been approved by a research ethics committee. Consent to remain in the 
research must be obtained as soon as possible from the subject or a legally authorised representative. 
 
31. The physician must fully inform the patient which aspects of their care are related to the research. The refusal 
of a patient to participate in a study or the patient’s decision to withdraw from the study must never adversely 
affect the patient-physician relationship. 
 
32. For medical research using identifiable human material or data, such as research on material or data 
contained in biobanks or similar repositories, physicians must seek informed consent for its collection, storage 
and/or reuse. There may be exceptional situations where consent would be impossible or impracticable to obtain 
for such research. In such situations the research may be done only after consideration and approval of a research 
ethics committee. 
 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best 
proven intervention(s), except in the following circumstances: Where no proven intervention exists, the use of 
placebo, or no intervention, is acceptable; or where for compelling and scientifically sound methodological 
reasons the use of any intervention less effective than the best proven one, the use of placebo, or no intervention 
is necessary to determine the efficacy or safety 
of an intervention and the patients who receive any intervention less effective than the best proven one, placebo, 
or no intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving 
the best proven intervention. Extreme care must be taken to avoid abuse of this option. 
 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as beneficial in the 
trial. This information must also be disclosed to participants during the informed consent process. 
 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly accessible database before 
recruitment of the first subject. 
 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the 
publication and dissemination of the results of research. Researchers have a duty to make publicly available the 
results of their research on human subjects and are accountable for the completeness and accuracy of their 
reports. All parties should adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well 

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as positive results must be published or otherwise made publicly available. Sources of funding, institutional 
affiliations and conflicts of interest must be declared in the publication. Reports of research not in accordance 
with the principles of this Declaration should not be accepted for publication. 
 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent from the 
patient or a legally authorised representative, may use an unproven intervention if in the physician’s judgement 
it offers hope of saving life, re-establishing health or alleviating suffering. This intervention should subsequently 
be made the object of research, designed to evaluate its safety and efficacy. In all cases, new information must 
be recorded and, where appropriate, made publicly available. 
 

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